Fused-ring structure of decahydroisoquinolin as a novel scaffold for SARS 3CL protease inhibitors
Identifieur interne : 000E49 ( Pmc/Corpus ); précédent : 000E48; suivant : 000E50Fused-ring structure of decahydroisoquinolin as a novel scaffold for SARS 3CL protease inhibitors
Auteurs : Yasuhiro Shimamoto ; Yasunao Hattori ; Kazuya Kobayashi ; Kenta Teruya ; Akira Sanjoh ; Atsushi Nakagawa ; Eiki Yamashita ; Kenichi AkajiSource :
- Bioorganic & Medicinal Chemistry [ 0968-0896 ] ; 2014.
Abstract
Url:
DOI: 10.1016/j.bmc.2014.12.028
PubMed: 25614110
PubMed Central: 7111320
Links to Exploration step
PMC:7111320Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Fused-ring structure of decahydroisoquinolin as a novel scaffold for SARS 3CL protease inhibitors</title><author><name sortKey="Shimamoto, Yasuhiro" sort="Shimamoto, Yasuhiro" uniqKey="Shimamoto Y" first="Yasuhiro" last="Shimamoto">Yasuhiro Shimamoto</name><affiliation><nlm:aff id="af005">Department of Medicinal Chemistry, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan</nlm:aff></affiliation></author><author><name sortKey="Hattori, Yasunao" sort="Hattori, Yasunao" uniqKey="Hattori Y" first="Yasunao" last="Hattori">Yasunao Hattori</name><affiliation><nlm:aff id="af005">Department of Medicinal Chemistry, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan</nlm:aff></affiliation></author><author><name sortKey="Kobayashi, Kazuya" sort="Kobayashi, Kazuya" uniqKey="Kobayashi K" first="Kazuya" last="Kobayashi">Kazuya Kobayashi</name><affiliation><nlm:aff id="af005">Department of Medicinal Chemistry, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan</nlm:aff></affiliation></author><author><name sortKey="Teruya, Kenta" sort="Teruya, Kenta" uniqKey="Teruya K" first="Kenta" last="Teruya">Kenta Teruya</name><affiliation><nlm:aff id="af010">Department of Chemistry, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Sakyo-ku, Kyoto 606-0823, Japan</nlm:aff></affiliation></author><author><name sortKey="Sanjoh, Akira" sort="Sanjoh, Akira" uniqKey="Sanjoh A" first="Akira" last="Sanjoh">Akira Sanjoh</name><affiliation><nlm:aff id="af015">R&D Center, Protein Wave Co., Nara 631-0006, Japan</nlm:aff></affiliation></author><author><name sortKey="Nakagawa, Atsushi" sort="Nakagawa, Atsushi" uniqKey="Nakagawa A" first="Atsushi" last="Nakagawa">Atsushi Nakagawa</name><affiliation><nlm:aff id="af020">Institute for Protein Research, Osaka University, Suita, Osaka 565-0871, Japan</nlm:aff></affiliation></author><author><name sortKey="Yamashita, Eiki" sort="Yamashita, Eiki" uniqKey="Yamashita E" first="Eiki" last="Yamashita">Eiki Yamashita</name><affiliation><nlm:aff id="af020">Institute for Protein Research, Osaka University, Suita, Osaka 565-0871, Japan</nlm:aff></affiliation></author><author><name sortKey="Akaji, Kenichi" sort="Akaji, Kenichi" uniqKey="Akaji K" first="Kenichi" last="Akaji">Kenichi Akaji</name><affiliation><nlm:aff id="af005">Department of Medicinal Chemistry, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">25614110</idno><idno type="pmc">7111320</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7111320</idno><idno type="RBID">PMC:7111320</idno><idno type="doi">10.1016/j.bmc.2014.12.028</idno><date when="2014">2014</date><idno type="wicri:Area/Pmc/Corpus">000E49</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000E49</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Fused-ring structure of decahydroisoquinolin as a novel scaffold for SARS 3CL protease inhibitors</title><author><name sortKey="Shimamoto, Yasuhiro" sort="Shimamoto, Yasuhiro" uniqKey="Shimamoto Y" first="Yasuhiro" last="Shimamoto">Yasuhiro Shimamoto</name><affiliation><nlm:aff id="af005">Department of Medicinal Chemistry, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan</nlm:aff></affiliation></author><author><name sortKey="Hattori, Yasunao" sort="Hattori, Yasunao" uniqKey="Hattori Y" first="Yasunao" last="Hattori">Yasunao Hattori</name><affiliation><nlm:aff id="af005">Department of Medicinal Chemistry, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan</nlm:aff></affiliation></author><author><name sortKey="Kobayashi, Kazuya" sort="Kobayashi, Kazuya" uniqKey="Kobayashi K" first="Kazuya" last="Kobayashi">Kazuya Kobayashi</name><affiliation><nlm:aff id="af005">Department of Medicinal Chemistry, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan</nlm:aff></affiliation></author><author><name sortKey="Teruya, Kenta" sort="Teruya, Kenta" uniqKey="Teruya K" first="Kenta" last="Teruya">Kenta Teruya</name><affiliation><nlm:aff id="af010">Department of Chemistry, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Sakyo-ku, Kyoto 606-0823, Japan</nlm:aff></affiliation></author><author><name sortKey="Sanjoh, Akira" sort="Sanjoh, Akira" uniqKey="Sanjoh A" first="Akira" last="Sanjoh">Akira Sanjoh</name><affiliation><nlm:aff id="af015">R&D Center, Protein Wave Co., Nara 631-0006, Japan</nlm:aff></affiliation></author><author><name sortKey="Nakagawa, Atsushi" sort="Nakagawa, Atsushi" uniqKey="Nakagawa A" first="Atsushi" last="Nakagawa">Atsushi Nakagawa</name><affiliation><nlm:aff id="af020">Institute for Protein Research, Osaka University, Suita, Osaka 565-0871, Japan</nlm:aff></affiliation></author><author><name sortKey="Yamashita, Eiki" sort="Yamashita, Eiki" uniqKey="Yamashita E" first="Eiki" last="Yamashita">Eiki Yamashita</name><affiliation><nlm:aff id="af020">Institute for Protein Research, Osaka University, Suita, Osaka 565-0871, Japan</nlm:aff></affiliation></author><author><name sortKey="Akaji, Kenichi" sort="Akaji, Kenichi" uniqKey="Akaji K" first="Kenichi" last="Akaji">Kenichi Akaji</name><affiliation><nlm:aff id="af005">Department of Medicinal Chemistry, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan</nlm:aff></affiliation></author></analytic><series><title level="j">Bioorganic & Medicinal Chemistry</title><idno type="ISSN">0968-0896</idno><idno type="eISSN">1464-3391</idno><imprint><date when="2014">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><title>Graphical abstract</title><fig 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Bioorg Med Chem</journal-id><journal-id journal-id-type="iso-abbrev">Bioorg. Med. Chem</journal-id><journal-title-group><journal-title>Bioorganic & Medicinal Chemistry</journal-title></journal-title-group><issn pub-type="ppub">0968-0896</issn><issn pub-type="epub">1464-3391</issn><publisher><publisher-name>Elsevier Ltd.</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">25614110</article-id><article-id pub-id-type="pmc">7111320</article-id><article-id pub-id-type="publisher-id">S0968-0896(14)00876-1</article-id><article-id pub-id-type="doi">10.1016/j.bmc.2014.12.028</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Fused-ring structure of decahydroisoquinolin as a novel scaffold for SARS 3CL protease inhibitors</article-title></title-group><contrib-group><contrib contrib-type="author" id="au005"><name><surname>Shimamoto</surname><given-names>Yasuhiro</given-names></name><xref rid="af005" ref-type="aff">a</xref></contrib><contrib contrib-type="author" id="au010"><name><surname>Hattori</surname><given-names>Yasunao</given-names></name><xref rid="af005" ref-type="aff">a</xref></contrib><contrib contrib-type="author" id="au015"><name><surname>Kobayashi</surname><given-names>Kazuya</given-names></name><xref rid="af005" ref-type="aff">a</xref></contrib><contrib contrib-type="author" id="au020"><name><surname>Teruya</surname><given-names>Kenta</given-names></name><xref rid="af010" ref-type="aff">b</xref></contrib><contrib contrib-type="author" id="au025"><name><surname>Sanjoh</surname><given-names>Akira</given-names></name><xref rid="af015" ref-type="aff">c</xref></contrib><contrib contrib-type="author" id="au030"><name><surname>Nakagawa</surname><given-names>Atsushi</given-names></name><xref rid="af020" ref-type="aff">d</xref></contrib><contrib contrib-type="author" id="au035"><name><surname>Yamashita</surname><given-names>Eiki</given-names></name><xref rid="af020" ref-type="aff">d</xref></contrib><contrib contrib-type="author" id="au040"><name><surname>Akaji</surname><given-names>Kenichi</given-names></name><email>akaji@mb.kyoto-phu.ac.jp</email><xref rid="af005" ref-type="aff">a</xref><xref rid="cor1" ref-type="corresp">⁎</xref></contrib></contrib-group><aff id="af005"><label>a</label>Department of Medicinal Chemistry, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan</aff><aff id="af010"><label>b</label>Department of Chemistry, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Sakyo-ku, Kyoto 606-0823, Japan</aff><aff id="af015"><label>c</label>R&D Center, Protein Wave Co., Nara 631-0006, Japan</aff><aff id="af020"><label>d</label>Institute for Protein Research, Osaka University, Suita, Osaka 565-0871, Japan</aff><author-notes><corresp id="cor1"><label>⁎</label>Corresponding author. Tel./fax: +81 75 595 4635. <email>akaji@mb.kyoto-phu.ac.jp</email></corresp></author-notes><pub-date pub-type="pmc-release"><day>20</day><month>12</month><year>2014</year></pub-date><pmc-comment> PMC Release delay is 0 months and 0 days and was based on .</pmc-comment>
<pub-date pub-type="ppub"><day>15</day><month>2</month><year>2015</year></pub-date><pub-date pub-type="epub"><day>20</day><month>12</month><year>2014</year></pub-date><volume>23</volume><issue>4</issue><fpage>876</fpage><lpage>890</lpage><history><date date-type="received"><day>8</day><month>11</month><year>2014</year></date><date date-type="rev-recd"><day>3</day><month>12</month><year>2014</year></date><date date-type="accepted"><day>5</day><month>12</month><year>2014</year></date></history><permissions><copyright-statement>Copyright © 2014 Elsevier Ltd. All rights reserved.</copyright-statement><copyright-year>2014</copyright-year><copyright-holder>Elsevier Ltd</copyright-holder><license><license-p>Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.</license-p></license></permissions><abstract abstract-type="graphical" id="ab005"><title>Graphical abstract</title><fig id="f0055" position="anchor"><graphic xlink:href="fx1"></graphic></fig></abstract><abstract id="ab010"><p>The design and evaluation of a novel decahydroisoquinolin scaffold as an inhibitor for severe acute respiratory syndrome (SARS) chymotrypsin-like protease (3CL<sup>pro</sup>) are described. Focusing on hydrophobic interactions at the S<sub>2</sub> site, the decahydroisoquinolin scaffold was designed by connecting the P<sub>2</sub> site cyclohexyl group of the substrate-based inhibitor to the main-chain at the α-nitrogen atom of the P<sub>2</sub> position via a methylene linker. Starting from a cyclohexene enantiomer obtained by salt resolution, <italic>trans</italic>-decahydroisoquinolin derivatives were synthesized. All decahydroisoquinolin inhibitors synthesized showed moderate but clear inhibitory activities for SARS 3CL<sup>pro</sup>, which confirmed the fused ring structure of the decahydroisoquinolin functions as a novel scaffold for SARS 3CL<sup>pro</sup> inhibitor. X-ray crystallographic analyses of the SARS 3CL<sup>pro</sup> in a complex with the decahydroisoquinolin inhibitor revealed the expected interactions at the S<sub>1</sub> and S<sub>2</sub> sites, as well as additional interactions at the <italic>N</italic>-substituent of the inhibitor.</p></abstract><kwd-group id="kg005"><title>Keywords</title><kwd>SARS 3CL protease</kwd><kwd>Inhibitor</kwd><kwd>Decahydroisoquinolin</kwd><kwd>Hydrophobic interaction</kwd></kwd-group></article-meta></front><body><sec id="s0005"><label>1</label><title>Introduction</title><p id="p0005">Although the primary epidemic of SARS (Severe Acute Respiratory Syndrome)<xref rid="b0005" ref-type="bibr">1</xref>, <xref rid="b0010" ref-type="bibr">2</xref>, <xref rid="b0015" ref-type="bibr">3</xref> affecting about 8500 patients and 800 dead was eventually brought under control, the recent identification of a SARS CoV (coronavirus)-like virus in Chinese bats<xref rid="b0020" ref-type="bibr">4</xref>, <xref rid="b0025" ref-type="bibr">5</xref> and of a novel coronavirus MERS-CoV (Middle East Respiratory Syndrome Corona Virus, previously known as human CoV-EMC) raise the possibility of a reemergence of SARS or related diseases.<xref rid="b0030" ref-type="bibr">6</xref>, <xref rid="b0035" ref-type="bibr">7</xref> Since no effective therapy exists for these viral infections, developing anti-SARS agents against future outbreaks remains a formidable challenge.</p><p id="p0010">SARS is a positive-sense, single-stranded RNA virus featuring the largest known viral RNA which produces two large proteins with overlapping sequences, polyproteins 1a (∼450 kDa) and 1ab (∼750 kDa).<xref rid="b0040" ref-type="bibr">8</xref>, <xref rid="b0045" ref-type="bibr">9</xref>, <xref rid="b0050" ref-type="bibr">10</xref> SARS 3CL (chymotrypsin like) protease (3CL<sup>pro</sup>) is a key enzyme to cleave the polyproteins to yield functional polypeptides.<xref rid="b0055" ref-type="bibr">11</xref>, <xref rid="b0060" ref-type="bibr">12</xref> The 3CL<sup>pro</sup> is a cysteine protease containing a Cys-His catalytic dyad and it exists as a homodimer; each monomer contains the catalytic dyad at each active site. Due to its functional importance in the viral life cycle, 3CL<sup>pro</sup> is considered an attractive target for the structure-based design of drugs against SARS. Thus, numerous inhibitors of 3CL<sup>pro</sup> have been reported including peptide-mimics<xref rid="b0065" ref-type="bibr">13</xref>, <xref rid="b0070" ref-type="bibr">14</xref>, <xref rid="b0075" ref-type="bibr">15</xref>, <xref rid="b0080" ref-type="bibr">16</xref>, <xref rid="b0085" ref-type="bibr">17</xref> and small molecules derived from natural products,<xref rid="b0090" ref-type="bibr">18</xref>, <xref rid="b0095" ref-type="bibr">19</xref>, <xref rid="b0100" ref-type="bibr">20</xref> anti-viral agents,<xref rid="b0105" ref-type="bibr">21</xref>, <xref rid="b0110" ref-type="bibr">22</xref> anti-malaria agents,<xref rid="b0115" ref-type="bibr"><sup>23</sup></xref> or high throughput screening.<xref rid="b0120" ref-type="bibr">24</xref>, <xref rid="b0125" ref-type="bibr">25</xref>, <xref rid="b0130" ref-type="bibr">26</xref>, <xref rid="b0135" ref-type="bibr">27</xref></p><p id="p0015">In the course of our own studies on the SARS 3CL<sup>pro</sup> and its inhibitors,<xref rid="b0140" ref-type="bibr"><sup>28</sup></xref> we found that the addition of an extra sequence to the N- or C-terminus of the mature SARS 3CL<sup>pro</sup> lowered the catalytic activity and that the mature SARS 3CL<sup>pro</sup> is sensitive to degradation at the 188Arg/189Gln site, which causes a loss of catalytic activity. The stability of 3CL<sup>pro</sup> is dramatically increased by mutating the Arg at the 188 position to Ile. The enzymatic efficiency of the R188I mutant was increased by a factor of more than 1 × 10<sup>6</sup>. The potency of the mutant protease makes it possible to quantitatively evaluate substrate-based peptide-mimetic inhibitors easily by conventional HPLC using a substrate peptide containing no fluorescence derivatives. The evaluations revealed that a peptide aldehyde covering the P-site sequence of substrate, Ac-Ser-Ala-Val-Leu-NHCH(CH<sub>2</sub>CH<sub>2</sub>CON(CH<sub>3</sub>)<sub>2</sub>)–CHO, inhibits the SARS 3CL<sup>pro</sup> with an IC<sub>50</sub> value of 37 μM. Systematic modification guided by the X-ray crystal structure of a series of peptide-mimics in a complex with R188I SARS 3CL<sup>pro</sup> resulted in <bold>1</bold> with an IC<sub>50</sub> value of 98 nM (<xref rid="f0005" ref-type="fig">Fig. 1</xref>).<xref rid="b0065" ref-type="bibr"><sup>13</sup></xref> All of the side-chain structures of <bold>1</bold> differed from the substrate sequence except at the P<sub>3</sub> site, where the side-chain was directed outward. Kinetic inhibition data for <bold>1</bold> obtained from Lineweaver–Burk plots suggested that inhibitors containing an aldehyde at the C-terminus can be expected to function as competitive inhibitors.<fig id="f0005"><label>Figure 1</label><caption><p>Design of a decahydroisoquinolin scaffold.</p></caption><graphic xlink:href="gr1"></graphic></fig></p><p id="p0020">In the present study, we designed a novel non-peptide inhibitor focusing on the interactions at the S<sub>1</sub> and S<sub>2</sub> sites of the 3CL<sup>pro</sup> Confirmed to be critical to make the <bold>1</bold> potent competitive inhibitor. Among the key interactions clarified by X-ray crystallographic study, we focused on hydrophobic interactions at the cyclohexyl side-chain to design a novel inhibitor scaffold. Thus, the cyclohexyl ring is connected to the main-chain at an α-nitrogen atom of the P<sub>2</sub> position Cha (cyclohexylalanine) via a methylene linker to yield compound <bold>2</bold> (<xref rid="f0005" ref-type="fig">Fig. 1</xref>). The resulting decahydroisoquinolin scaffold of <bold>2</bold> is expected to keep the hydrophobic interactions at the cyclohexyl ring of the substrate-based inhibitor at the S<sub>2</sub> pocket. In addition, the resulting decahydroisoquinolin scaffold arranges the P<sub>1</sub> site imidazole and active site functional aldehyde at each required position, giving the fused-ring structure of decahydroisoquinolin as a scaffold for a novel inhibitor. The acyl substituent on the nitrogen in the decahydroisoquinolin scaffold may add an extra position for the interactions with the 3CL<sup>pro</sup>.</p></sec><sec id="s0010"><label>2</label><title>Results and discussion</title><sec id="s0015"><label>2.1</label><title>Chemistry</title><p id="p0025">The retro synthetic route for the desired decahydroisoquinolin derivative <bold>2</bold> is shown in <xref rid="f0025" ref-type="fig">Scheme 1</xref>. The P<sub>1</sub> site His derivative could be introduced by a reductive amination reaction using an aldehyde derivative prepared by oxidative cleavage of the olefin bond of <bold>3</bold>. The <italic>trans</italic>-decahydroisoquinolin scaffold of <bold>3</bold> could be constructed via Pd-mediated stereoselective intra-molecular cyclization<xref rid="b0145" ref-type="bibr"><sup>29</sup></xref> by nucleophilic attack of a nitrogen atom to the Pd-activated olefin moiety of an allyl alcohol of <bold>4</bold>. The olefin structure of <bold>4</bold> could be constructed by a Horner–Emmons reaction utilizing an aldehyde of precursor <bold>5</bold>, and the amino group of <bold>4</bold> could be introduced by a Mitsunobu reaction to the alcohol of <bold>5</bold>. The six-membered ring structure of <bold>5</bold> could be constructed by a Diels–Alder reaction of known ester <bold>6</bold><xref rid="b0150" ref-type="bibr"><sup>30</sup></xref> with butadiene.<fig id="f0025"><label>Scheme 1</label><caption><p>Retro synthetic route for the decahydroisoquinolin derivative.</p></caption><graphic xlink:href="gr5"></graphic></fig></p><p id="p0030">Thus, the key intermediates <bold>12</bold> and <bold>13</bold>, a precursor of the Pd-mediated cyclization, were prepared according to the route shown in <xref rid="f0030" ref-type="fig">Scheme 2</xref>. The known ester <bold>6</bold> was first reacted with butadiene to construct the six-membered ring structure to yield <bold>7</bold> as an enantiomer mixture of 1,6<italic>-trans</italic>-substituted cyclohexene. The product was reduced with LAH and the resulting alcohol was then protected as <italic>tert</italic>-butyldiphenylsilyl ether to give <bold>8</bold>. The benzyl group was removed by catalytic hydrogenation, which reduced the cyclohexene to cyclohexane at the same time. The resulting hydroxyl group was then oxidized with PCC and the resulting aldehyde was then reacted with (EtO)<sub>2</sub>P(O)CH<sub>2</sub>COOEt to yield <bold>9</bold>. The ethyl ester of <bold>9</bold> was reduced with DIBALH and the resulting alcohol was protected as acetyl ester to give <bold>10</bold>. After treatment with TBAF, the resulting alcohol was converted to the azide derivative <bold>11</bold> by a Mitsunobu reaction. Since the product <bold>11</bold> was rather unstable, <bold>11</bold> was immediately reduced to the corresponding amine. Without further purification, the amine derivative was coupled with <italic>p</italic>-phenylbenzoic acid using HBTU to yield <bold>12</bold> as an enantiomer mixture. Coupling with <italic>p</italic>-bromobenzoic acid was similarly conducted to yield a related derivative <bold>13</bold>.<fig id="f0030"><label>Scheme 2</label><caption><p>Synthesis of intermediate <bold>12</bold> or <bold>13</bold>. Configurations in the racemic compounds <bold>7</bold>–<bold>13</bold> indicate the relative 1,6-<italic>trans</italic> configurations. Reagents: (a) 1,3-butadiene; (b) (1) LAH, (2) TBDPS-Cl/imidazole; (c) (1) H<sub>2</sub>/Pd(OH)<sub>2</sub>-C (2) PCC (3) (EtO)<sub>2</sub>P(O)CH<sub>2</sub>COOEt/NaH; (d) (1) DIBALH (2) Ac<sub>2</sub>O/pyridine/DMAP; (e) (1) TBAF, (2) (EtO)<sub>2</sub>P(O)N<sub>3</sub>/DIAD/PPh<sub>3</sub>; (f) (1) LAH, (2) 4-phenylbenzoic acid or 4-bromobenzoic acid/HBTU/DIPEA.</p></caption><graphic xlink:href="gr6"></graphic></fig></p><p id="p0035">Construction of the decahydroisoquinolin scaffold was achieved as shown in <xref rid="f0035" ref-type="fig">Scheme 3</xref>. (CH<sub>3</sub>CN)<sub>2</sub>PdCl<sub>2</sub>-mediated cyclization of <bold>12/13</bold> gave the desired <italic>trans</italic>-decahydroisoquinolin derivative <bold>14/15</bold> as a major product. The product was an enantiomer mixture which was thought to have the relative configuration of <bold>14/15</bold> due to the cyclization through a less hindered Pd-chelated intermediate. Thus, the vinyl substituent of the product <bold>14/15</bold> was thought to be axial, which was clearly confirmed by X-ray crystallographic studies of the inhibitor in a complex with the R188I mutant SARS 3CL<sup>pro</sup> as discussed below. The olefin bond of <bold>14/15</bold> was oxidatively cleaved by the treatment with K<sub>2</sub>O<sub>s</sub>O<sub>2</sub>(OH)<sub>4</sub> followed by NaIO<sub>4</sub> to yield aldehyde <bold>16/17</bold>. Reductive amination by H-His(Trt)-N(OCH<sub>3</sub>)CH<sub>3</sub> gave the coupling products <bold>18</bold> and <bold>20</bold> or <bold>19</bold> and <bold>21</bold> as a 1:1 diastereomer mixture which was separable on a reversed-phase column (YMC Pack ODS) by analytical HPLC (<xref rid="s0245" ref-type="sec">Fig. S1</xref>). The diastereomers could also be separated by conventional silica-gel column chromatography to yield diastereomers <bold>18</bold> and <bold>20</bold> or <bold>19</bold> and <bold>21</bold>, each having single peak on the above reversed-phase column. Each separated diastereomer was then treated with TFA to cleave the Trt group at the imidazole ring, and the product was reduced with DIBALH to yield the desired aldehyde <bold>22/23</bold> or <bold>24/25</bold>. Although the absolute configuration of each product was not determined at this stage, the purity of each product was confirmed by analytical HPLC. Since moderate but clear inhibitory activities were observed in a preliminary evaluation on the inhibitory potency of <bold>22</bold> and <bold>24</bold>, the identification of the stereo-structure was then conducted.<fig id="f0035"><label>Scheme 3</label><caption><p>Construction of the decahydroisoquinolin scaffold. Reagents: (a) (CH<sub>3</sub>CN)<sub>2</sub>PdCl<sub>2</sub>; (b) K<sub>2</sub>OsO<sub>2</sub>(OH)<sub>4</sub>/NaIO<sub>4</sub>; (c) (1) H-His(Trt)-N(OCH<sub>3</sub>)CH<sub>3</sub>/NaBH<sub>3</sub>CN; (d) (1) TFA, (2) DIBALH.</p></caption><graphic xlink:href="gr7"></graphic></fig></p><p id="p0040">To separately prepare the above diastereomers and estimate the absolute configurations, cyclohexene carboxylic acid obtained by a Diels–Alder reaction was converted to a salt with (<italic>R</italic>)- or (<italic>S</italic>)-α-methylbenzylamine and resolved according to the literature procedure for (1<italic>R</italic>/6<italic>S</italic>,1<italic>S</italic>/6<italic>R</italic>)-6-(2-bromophenyl)cyclohex-3-ene-1-carboxylic acid <bold>26</bold><xref rid="b0155" ref-type="bibr"><sup>31</sup></xref> (<xref rid="f0040" ref-type="fig">Scheme 4</xref>). Resolution of a carboxylic acid derived from compound <bold>7</bold> and compound <bold>29</bold> having the corresponding <italic>p</italic>-bromobenzyl group gave compounds showing the same polarimetric characters as the literature compounds.<xref rid="b0155" ref-type="bibr"><sup>31</sup></xref> (−) Carboxylic acid <bold>27</bold> or <bold>30</bold> was obtained by salt formation with (<italic>R</italic>)-α-methylbenzylamine and following salt-liberation with HCl, whereas the salt with (<italic>S</italic>)-α-methylbenzylamine gave (+) carboxylic acid <bold>28</bold> or <bold>31</bold>. Compared with the literature values, these results strongly suggest that <bold>27</bold> and <bold>30</bold> would have (1<italic>R</italic>,6<italic>S</italic>) and <bold>28</bold> and <bold>31</bold> would have (1<italic>S</italic>,6<italic>R</italic>) absolute configurations. Optical purity of each enantiomer was further confirmed using a chiral column (YMC CHIRAL Amylose-C) by HPLC (<xref rid="s0245" ref-type="sec">Fig. S2</xref>). Since the chemical yield from the <italic>p</italic>-bromobenzyl derivative <bold>29</bold> was superior to the benzyl derivative <bold>7</bold>, enantiomer <bold>30</bold> or <bold>31</bold> was used as the starting compound for the separate synthesis of decahydroisoquinolin diastereomers.<fig id="f0040"><label>Scheme 4</label><caption><p>Resolution by salt formation.</p></caption><graphic xlink:href="gr8"></graphic></fig></p><p id="p0045">The separated (1<italic>S</italic>,6<italic>R</italic>) enantiomer <bold>31</bold> was then used to synthesize the corresponding decahydroisoquinolin diastereomer <bold>40</bold> or <bold>41</bold> using basically the same route as above (<xref rid="f0045" ref-type="fig">Scheme 5</xref>i). (1<italic>R</italic>,6<italic>S</italic>) Enantiomer <bold>30</bold> was also employed for the syntheses of diastereomer <bold>44</bold> or <bold>45</bold> (<xref rid="f0045" ref-type="fig">Scheme 5</xref>ii). The protected intermediate <bold>38</bold> (R =
<italic>p</italic>-phenylphenyl) from <bold>31</bold> and the diastereomer <bold>42</bold> (R =
<italic>p</italic>-phenylphenyl) from (1<italic>R</italic>,6<italic>S</italic>) enantiomer <bold>30</bold> were co-eluted with a previously synthesized diastereomixture of <bold>18</bold> and <bold>20</bold> on a reversed-phase column (YMC Pack ODS). Intermediate <bold>38</bold> had the same retention time as <bold>18</bold>, whereas intermediate <bold>42</bold> had the same retention time as <bold>20</bold> (<xref rid="s0245" ref-type="sec">Fig. S3</xref>). The comparison was also conducted on <bold>39</bold> and <bold>43</bold> having a <italic>p</italic>-bromophenyl <italic>N</italic>-substituent with the corresponding diastereomers <bold>19</bold> and <bold>21</bold>, and the same results as above were obtained (<xref rid="s0245" ref-type="sec">Fig. S4</xref>). These results clearly demonstrated that the two diastereomers <bold>18</bold> and <bold>20</bold> were derived from the <italic>trans</italic>-decahydroisoquinolin structure constructed from enantiomer <bold>7</bold>. Each protected diastereomer <bold>38</bold>/<bold>39</bold> and <bold>42</bold>/<bold>43</bold> thus synthesized was converted to the desired derivatives <bold>40/41</bold> and <bold>44/45</bold> without difficulty. Several analogs shown in <xref rid="t0005" ref-type="table">Table 1</xref>containing different <italic>N</italic>-acyl substituents of the decahydroisoquinolin scaffold were also prepared using the same synthetic route (<xref rid="s0245" ref-type="sec">Fig. S5</xref>).<fig id="f0045"><label>Scheme 5</label><caption><p>Construction of the decahydroisoquinolin scaffold starting from the separated enantiomer. Reagents: (a) (1) IBCF/NaBH<sub>4</sub>, (2) TBDPS-Cl/imidazole, (3) H<sub>2</sub>/Pd-C/sat. NaHCO<sub>3</sub> aq.; (b) (1) PCC, (2) (EtO)<sub>2</sub>P(O)CH<sub>2</sub>COOEt/NaH, (3) DIBALH, (4) Ac<sub>2</sub>O/pyridine/DMAP; (c) (1) TBAF, (2) (EtO)<sub>2</sub>P(O)N<sub>3</sub>/DIAD/PPh<sub>3</sub>, (3) LAH, (4) 4-phenylbenzoic acid or 4-bromobenzoic acid/HBTU/DIPEA; (d) (CH<sub>3</sub>CN)<sub>2</sub>PdCl<sub>2</sub>; (e) (1) K<sub>2</sub>OsO<sub>2</sub>(OH)<sub>4</sub>/NaIO<sub>4</sub>, (2) H-His(Trt)-N(OCH<sub>3</sub>)CH<sub>3</sub>/NaBH<sub>3</sub>CN; (f) (1) TFA, (2) DIBALH.</p></caption><graphic xlink:href="gr9"></graphic></fig><table-wrap position="float" id="t0005"><label>Table 1</label><caption><p>Inhibitory activities of the decahydroisoquinolin derivatives<fig id="f0050"><graphic xlink:href="fx2"></graphic></fig></p></caption><table frame="hsides" rules="groups"><thead><tr><th rowspan="2">R</th><th colspan="2" align="center">IC<sub>50</sub><hr></hr></th></tr><tr><th>(3<italic>S</italic>,4a<italic>R</italic>,8a<italic>S</italic>)</th><th>(3<italic>R</italic>,4a<italic>S</italic>,8a<italic>R</italic>)</th></tr></thead><tbody><tr><td rowspan="2"><inline-graphic xlink:href="fx3.gif"></inline-graphic></td><td><bold>40</bold></td><td><bold>44</bold></td></tr><tr><td>108 μM</td><td>240 μM</td></tr><tr><td rowspan="2"><inline-graphic xlink:href="fx4.gif"></inline-graphic></td><td><bold>46</bold></td><td></td></tr><tr><td>135 μM</td><td></td></tr><tr><td rowspan="2"><inline-graphic xlink:href="fx5.gif"></inline-graphic></td><td><bold>47</bold></td><td></td></tr><tr><td>135 μM</td><td></td></tr><tr><td rowspan="2"><inline-graphic xlink:href="fx6.gif"></inline-graphic></td><td><bold>48</bold></td><td></td></tr><tr><td>68 μM</td><td></td></tr><tr><td rowspan="2"><inline-graphic xlink:href="fx7.gif"></inline-graphic></td><td><bold>41</bold></td><td>45</td></tr><tr><td>63 μM</td><td>175 μM</td></tr><tr><td rowspan="2"><inline-graphic xlink:href="fx8.gif"></inline-graphic></td><td><bold>49</bold></td><td></td></tr><tr><td>57 μM</td><td></td></tr></tbody></table></table-wrap></p></sec><sec id="s0020"><label>2.2</label><title>Inhibitory activity</title><p id="p0050">Digestion of the substrate peptide with R188I SARS 3CL<sup>pro</sup> in the presence of decahydroisoquinolin derivatives of different concentrations was conducted according to the published procedure.<xref rid="b0065" ref-type="bibr"><sup>13</sup></xref> The inhibitory activities were evaluated based on IC<sub>50</sub> values calculated from the decrease in the substrate digested by R188I SARS 3CL<sup>pro</sup>; a typical sigmoidal curve used for estimation of the IC<sub>50</sub> value is shown in <xref rid="s0245" ref-type="sec">Figure S6</xref>. As summarized in <xref rid="t0005" ref-type="table">Table 1</xref>, synthesized decahydroisoquinolin derivatives all showed inhibitory activities for the mutant 3CL<sup>pro</sup>. The results strongly suggest that the decahydroisoquinolin fused-ring can function as an inhibitor scaffold. Comparison of IC<sub>50</sub> values of <italic>trans</italic>-decahydroisoquinolin diastereomers in <italic>N</italic>-4-phenylbenzoyl derivatives (<bold>40</bold> vs <bold>44</bold>) or <italic>N</italic>-4-bromobenzoyl derivative (<bold>41</bold> vs <bold>45</bold>) clearly showed that the (4a<italic>R</italic>,8a<italic>S</italic>) isomer is more potent than (4a<italic>S</italic>,8a<italic>R</italic>) isomer. The results suggest the importance of the interaction at the S<sub>2</sub> pocket of the mutant 3CL<sup>pro</sup>. It was also demonstrated that a series of the <italic>N</italic>-benzoyl derivative was more potent than <italic>N</italic>-4-phenylbenzoyl derivatives. Substitution at the 4-position of the benzoyl substituent in <bold>48</bold> with halogen showed no significant effect on the inhibitory activity (<bold>41</bold> and <bold>49</bold>), whereas substitution at the 4-position of the phenyl group in the <italic>N</italic>-biphenylacyl derivative <bold>40</bold> gave a slightly more potent inhibitor than 2- or 3-substituted biphenyl derivatives (<bold>46</bold> and <bold>47</bold>). The results suggest that the substituent on the nitrogen atom of the decahydroisoquinolin scaffold may have some interactions with R188I SARS 3CL<sup>pro</sup>.</p></sec><sec id="s0025"><label>2.3</label><title>Evaluation of the interactions</title><p id="p0055">To clarify the interactions of a newly synthesized decahydroisoquinolin inhibitor with R188I SARS 3CL<sup>pro</sup>, the structure of the protease in a complex with the inhibitor was revealed by X-ray crystallography. Subsequently, a co-crystal of the inhibitor with 3CL<sup>pro</sup> was prepared and analyzed. Structures of the 3CL<sup>pro</sup> in a complex with inhibitors <bold>40</bold>, <bold>41</bold>, and <bold>44</bold> were refined to resolutions of 1.60 Å, 2.42 Å, and 1.89 Å, respectively (PDB code 4TWY, 4TWW, and 4WY3). The data obtained are summarized in <xref rid="t0010" ref-type="table">Table 2</xref>.<table-wrap position="float" id="t0010"><label>Table 2</label><caption><p>Data collection and refinement statistics for the R188I SARS 3CL protease in complexes with compounds <bold>40</bold>, <bold>41</bold>, and <bold>44</bold></p></caption><table frame="hsides" rules="groups"><thead><tr><th rowspan="2">PDB ID</th><th>4TWY</th><th>4TWW</th><th>4WY3</th></tr><tr><th>In complex with <bold>40</bold></th><th>In complex with <bold>41</bold></th><th>In complex with <bold>44</bold></th></tr></thead><tbody><tr><td>Space group</td><td><italic>C</italic>121</td><td><italic>P</italic>1</td><td><italic>C</italic>121</td></tr><tr><td colspan="4"><italic>Unit cell parameters</italic></td></tr><tr><td>Length <italic>a</italic></td><td>107.83</td><td>54.89</td><td>108.11</td></tr><tr><td>Length <italic>b</italic></td><td>82.128</td><td>59.52</td><td>81.82</td></tr><tr><td>Length <italic>c</italic></td><td>53.271</td><td>68.40</td><td>53.24</td></tr><tr><td>Angle <italic>α</italic></td><td>90</td><td>93.11</td><td>90</td></tr><tr><td>Angle <italic>β</italic></td><td>104.98</td><td>102.82</td><td>104.69</td></tr><tr><td>Angle <italic>γ</italic></td><td>90</td><td>107.30</td><td>90</td></tr><tr><td>Resolution</td><td>1.60</td><td>2.42</td><td>1.89</td></tr><tr><td colspan="4">
</td></tr><tr><td colspan="4"><italic>Observations</italic></td></tr><tr><td>Unique observations</td><td>57,490</td><td>31,213</td><td>49,270</td></tr><tr><td>Redundancy</td><td>4.2</td><td>1.75</td><td>4.1</td></tr><tr><td>Completeness</td><td>88.6</td><td>94.3</td><td>93.2</td></tr><tr><td>Mean <italic>I</italic>/<italic>σ</italic> (<italic>I</italic>)</td><td>2.18 (at 1.60 Å)</td><td>9.96 (at 2.42 Å)</td><td>2.49 (at 1.89 Å)</td></tr><tr><td><italic>R</italic> merge</td><td>0.08</td><td>0.05</td><td>0.07</td></tr><tr><td colspan="4">
</td></tr><tr><td colspan="4"><italic>Refinement</italic></td></tr><tr><td>Resolution range</td><td>25.3–1.60</td><td>66.1–2.42</td><td>30.6–1.89</td></tr><tr><td><italic>R</italic><sub>cryst</sub></td><td>0.29</td><td>0.23</td><td>0.27</td></tr><tr><td><italic>R</italic><sub>free</sub></td><td>0.32</td><td>0.26</td><td>0.30</td></tr><tr><td colspan="4">
</td></tr><tr><td colspan="4"><italic>RMSZ from ideal</italic></td></tr><tr><td>Bond length (Å)</td><td>0.93</td><td>0.73</td><td>0.86</td></tr><tr><td>Bond angle (°)</td><td>0.96</td><td>0.86</td><td>0.90</td></tr></tbody></table></table-wrap></p><p id="p0060">The overall structure of the 3CL<sup>pro</sup> in complex with inhibitor <bold>41</bold> (IC<sub>50</sub> = 63 μM) was first compared with the substrate-based inhibitor <bold>1</bold> (PDB code 3ATW) (<xref rid="f0010" ref-type="fig">Fig. 2</xref>). Basically, the decahydroisoquinolin inhibitor <bold>41</bold> was at the active site cleft of the 3CL<sup>pro</sup> as observed in the highly potent inhibitor <bold>1</bold>. The aldehyde group and imidazole ring of His-al, as well as the decahydroisoquinolin structure of <bold>41</bold>, had an almost identical conformation with <bold>1</bold> and similarly interacted with 3CL<sup>pro</sup>. In contrast, the direction of the <italic>p</italic>-bromobenzoyl group was outward from 3CL<sup>pro</sup> and opposite to the P<sub>3</sub> to P<sub>4</sub> sites of <bold>1</bold>. The <italic>N</italic>-<italic>p</italic>-bromobenzoyl group, however, was at the surface of 3CL<sup>pro</sup>, where additional hydrophobic interaction with Met of the 3CL<sup>pro</sup> may be possible (<xref rid="s0245" ref-type="sec">Fig. S7</xref>).<fig id="f0010"><label>Figure 2</label><caption><p>(i) X-ray structure of the inhibitor <bold>41</bold> in complex with R188I SARS 3CL<sup>pro</sup> (PDB code 4TWW) and molecular graphics image around the P<sub>1</sub> and P<sub>2</sub> sites. (ii) X-ray structure of the inhibitor <bold>1</bold> in complex with R188I SARS 3CL<sup>pro</sup> (Ref. <xref rid="b0065" ref-type="bibr">13</xref>; PDB code 4ATW) and molecular graphics image around the P<sub>1</sub> and P<sub>2</sub> sites.</p></caption><graphic xlink:href="gr2"></graphic></fig></p><p id="p0065">The carbonyl carbon of the aldehyde group in <bold>41</bold> was detected at a distance of 2.43 Å from the active center thiol of Cys-145, and its electron density could be fitted to an sp<sup>2</sup> carbonyl carbon as in <bold>1</bold> (<xref rid="f0015" ref-type="fig">Fig. 3</xref>i). The results suggest that the decahydroisoquinolin inhibitor would function as a competitive inhibitor as do the peptide-aldehyde inhibitor <bold>1</bold>.<xref rid="b0065" ref-type="bibr"><sup>13</sup></xref> It was clearly confirmed that the decahydroisoquinolin scaffold of <bold>41</bold> took a <italic>trans</italic>-fused (4a<italic>R</italic>,8a<italic>S</italic>) configuration, as expected from the salt-resolution of enantiomixture <bold>29</bold>. It was also confirmed that the P<sub>1</sub> His-al substituent on the decahydroisoquinolin scaffold took an axial-configuration, as expected from the Pd(II)-mediated cyclization. The decahydroisoquinolin scaffold of <bold>41</bold> was inserted into a large S<sub>2</sub> pocket created by His-41, Met-49, Met-165, and Asp-187, as in the case of a parent peptide aldehyde inhibitor, and most of the S<sub>2</sub> pocket was occupied by the fused-ring structure of decahydroisoquinolin (<xref rid="f0015" ref-type="fig">Fig. 3</xref>i). The nitrogen atom of the P<sub>1</sub> site imidazole of <bold>41</bold> formed a hydrogen bond with the imidazole nitrogen of His-163, resulting in close fitting at the other side of the S<sub>1</sub> pocket formed from the Phe-140, Leu-141, and Glu-166 side chains of the protease (<xref rid="f0015" ref-type="fig">Fig. 3</xref>ii). These interactions, especially of the decahydroisoquinolin scaffold in the S<sub>2</sub> pocket, function to hold the P<sub>1</sub> site imidazole and terminal aldehyde tightly inside the active site cleft, which resulted in the compact fitting of the novel scaffold to the 3CL<sup>pro</sup>.<fig id="f0015"><label>Figure 3</label><caption><p>(i) Interactions of the inhibitor <bold>41</bold> with R188I SARS 3CL<sup>pro</sup> at the active center and P<sub>2</sub> site. (ii) Interactions at the P<sub>1</sub>site.</p></caption><graphic xlink:href="gr3"></graphic></fig></p><p id="p0070">To evaluate the effects of absolute configuration of the decahydroisoquinolin scaffold, structures of the 3CL<sup>pro</sup> in complex with (4a<italic>R</italic>,8a<italic>S</italic>)-<italic>N</italic>-4-phenylbenzoyl decahydroisoquinolin inhibitor <bold>40</bold> and (4a<italic>S</italic>,8a<italic>R</italic>)-<italic>N</italic>-4-phenylbenzoyl decahydroisoquinolin inhibitor <bold>44</bold> were compared (<xref rid="f0020" ref-type="fig">Fig. 4</xref>i). In both inhibitors, the P<sub>1</sub> site imidazole ring and the terminal aldehyde group had nearly the same interactions as in the (4a<italic>R</italic>,8a<italic>S</italic>)-<italic>N</italic>-bromobenzoyl decahydroisoquinolin inhibitor <bold>41</bold> described above. Due to the configuration change at the decahydroisoquinolin moiety, however, the (4a<italic>S</italic>,8a<italic>R</italic>) decahydroisoquinolin scaffold was clearly twisted compared to the (4a<italic>R</italic>,8a<italic>S</italic>) decahydroisoquinolin in the S<sub>2</sub> pocket (<xref rid="f0020" ref-type="fig">Fig. 4</xref>ii). This conformation change of the decahydroisoquinolin scaffold transferred to the direction of the <italic>N</italic>-substituent. Thus, the substituent of (4a<italic>R</italic>,8a<italic>S</italic>) decahydroisoquinolin <bold>40</bold> took nearly the same conformation as the <italic>N</italic>-<italic>p</italic>-bromobenzoyl inhibitor <bold>41</bold> located on the surface of the 3CL<sup>pro</sup>, whereas the substituent of (4a<italic>S</italic>,8a<italic>R</italic>) decahydroisoquinolin directed outside from the protease surface. These conformational differences at the <italic>N</italic>-substituent, as well as the interactions at the S<sub>2</sub> pocket, explain the discrepancy in the inhibitory activity between (4a<italic>R</italic>,8a<italic>S</italic>) and (4a<italic>S</italic>,8a<italic>R</italic>) decahydroisoquinolin inhibitors (<bold>41</bold> vs <bold>44</bold>).<fig id="f0020"><label>Figure 4</label><caption><p>(i) X-ray structures of R188I SARS 3CL<sup>pro</sup> in complex with (4a<italic>R</italic>/8a<italic>S</italic>)-<italic>N</italic>-4-phenylbenzoyl decahydroisoquinolin inhibitor <bold>40</bold> (PDB code 4TWY) and (4a<italic>S</italic>/8a<italic>R</italic>)-<italic>N</italic>-4-phenylbenzoyl decahydroisoquinolin inhibitor <bold>44</bold> (PDB code 4WY3). (ii) Interactions of <bold>40</bold> and <bold>44</bold> at the P<sub>2</sub> site.</p></caption><graphic xlink:href="gr4"></graphic></fig></p></sec></sec><sec id="s0030"><label>3</label><title>Conclusion</title><p id="p0075">A novel non-peptide inhibitor based on the interactions at the S<sub>1</sub> and S<sub>2</sub> sites of SARS 3CL<sup>pro</sup> was designed and synthesized. Focusing on cleavage site interaction at the S<sub>1</sub> site and hydrophobic interaction at the S<sub>2</sub> site, a decahydroisoquinolin scaffold was designed. Using a cyclohexene enantiomer obtained by salt resolution using chiral amine, the <italic>trans</italic>-decahydroisoquinolin derivative was synthesized as an enantiomer. Several analogs containing different <italic>N</italic>-substituents were also prepared similarly. All decahydroisoquinolin inhibitors showed moderate but clear inhibitory activities for SARS 3CL<sup>pro</sup>, which confirmed that the fused ring structure of the decahydroisoquinolin scaffold functions as an inhibitor for SARS 3CL<sup>pro</sup>. By X-ray crystallographic studies, it was confirmed that the decahydroisoquinolin inhibitors were at the active site cleft of 3CL<sup>pro</sup>, as observed in the highly potent peptide–aldehyde inhibitor. The decahydroisoquinolin scaffold was inserted into a large S<sub>2</sub> pocket and occupied most of the pocket. The P<sub>1</sub> site imidazole was inserted into the S<sub>1</sub> pocket as expected. These interactions were effective to hold the terminal aldehyde tightly inside the active site cleft, which resulted in the compact fitting of the novel scaffold to 3CL<sup>pro</sup>. The acyl substituent on the nitrogen in the decahydroisoquinolin scaffold was at the surface of the 3CL<sup>pro</sup>, where additional interactions with the 3CL<sup>pro</sup> may be possible. Evaluations on the analogs focusing on the interactions at the <italic>N</italic>-substituent are now underway.</p></sec><sec id="s0035"><label>4</label><title>Experimental</title><sec id="s0040"><label>4.1</label><title>General</title><p id="p0080">All solvents were of reagent grade. THF was distilled from sodium and benzophenone ketyl. CH<sub>2</sub>Cl<sub>2</sub> was distilled from CaH<sub>2</sub>. All commercial reagents were of the highest purity available. Analytical TLC was performed on silica gel (60 F-254, 0.25 mm Plates). Column chromatography was carried out on Wakogel C-200E (particle size, 75–150 μm) or Wakogel FC-40 (particle size, 20–40 μm). <sup>1</sup>H NMR spectra were recorded in CDCl<sub>3</sub> (unless otherwise stated) on agilent UNITY INOVA 400 NB, JEOL JNM-ECS 400, Bruker AM-300, or JEOL JNM-LA 500 spectrometers. Chemical shifts are expressed in ppm relative to tetramethylsilane (0 ppm) or CHCl<sub>3</sub> (7.28 ppm). The coupling constants are given in Hz. <sup>13</sup>C NMR spectra were recorded on the same spectrometers at 100 or 125 MHz, using the central resonance of CDCl<sub>3</sub> (<italic>δ</italic><sub>C</sub> 77.0 ppm) as the internal reference unless otherwise stated. High-resolution mass spectra (HRMS) were obtained on a JMS-HX-110A (FAB), and Shimadzu LCMS-IT-TOF (ESI). Low-resolution mass spectra (LRMS) were obtained on a Shimadzu LCMS-2010EV (ESI). Optical rotations were determined with a HORIBA SEPA-300 polarimeter. Preparative HPLC was performed using a COSMOSIL 5C18-ARII column (20 × 250 mm) with a linear gradient of CH<sub>3</sub>CN in 0.1% aqueous TFA at a flow rate of 5.0 mL/min on a HITACHI LaChrom system (OD, 254 nm). For analytical HPLC, unless otherwise noted, a COSMOSIL 5C18-ARII column (4.6 × 150 mm) was employed with a linear gradient of CH<sub>3</sub>CN in 0.1% aqueous TFA at a flow rate of 0.9 mL/min on a HITACHI LaChrom system (OD, 254 nm). The purity of the test compounds was determined by analytical HPLC. All test compounds showed ⩾95% purity.</p><sec id="s0045"><label>4.1.1</label><title>(1<italic>S</italic>/<italic>R</italic>,6<italic>R</italic>/<italic>S</italic>)-Ethyl 6-[2-(benzyloxy)ethyl]cyclohex-3-enecarboxylate <bold>7</bold></title><p id="p0085">To a solution of 1,3-butadiene (20 wt% solution in hexane, 17 mL, 40 mmol) was added ester <bold>6</bold> (2.34 g, 10.0 mmol), heated at 250 °C for 60 h. After the reaction mixture was cooled to room temperature, water was added and the whole was extracted with AcOEt. The organic layer was washed with 1 M HCl and brine, dried over MgSO<sub>4</sub>, filtered, and concentrated. The residue was purified by silica gel column chromatography (hexane/AcOEt = 30:1) to give <bold>7</bold> (1.87 g, 65%) as a yellow pale oil. <sup>1</sup>H NMR (400 MHz): <italic>δ</italic> = 7.36–7.31 (m, 4H), 7.29–7.26 (m, 1H), 5.64 (m, 2H), 4.51 (d, <italic>J</italic> = 11.6 Hz, 1H), 4.46 (d, <italic>J</italic> = 12.0 Hz, 1H), 4.14 (q, <italic>J</italic> = 7.2 Hz, 2H), 3.54–3.50 (m, 2H), 2.41–2.35 (m, 1H), 2.31–2.20 (m, 3H), 2.09–2.04 (m, 1H), 1.84–1.73 (m, 2H), 1.54–1.45 (m, 1H), 1.25 (t, <italic>J</italic> = 7.2 Hz, 3H); <sup>13</sup>C NMR (100 MHz): <italic>δ</italic> = 175.8, 138.5, 128.3, 127.6, 127.5, 125.7, 124.7, 72.8, 67.9, 60.2, 45.3, 33.7, 32.4, 29.9, 28.0, 14.2; HRMS (EI) calcd for C<sub>18</sub>H<sub>24</sub>O<sub>3</sub> [M]<sup>+</sup>: 288.1725. Found: 288.1722.</p></sec><sec id="s0050"><label>4.1.2</label><title>{(1<italic>S</italic>/<italic>R</italic>,6<italic>R</italic>/<italic>S</italic>)-6-[2-(Benzyloxy)ethyl]cyclohex-3-en-1-yl}methanol</title><p id="p0090">To a suspension of LiAlH<sub>4</sub> (387 mg, 10.2 mmol) in ether (30 mL) was added <bold>7</bold> (1.47 g, 5.12 mmol) at 0 °C. After being stirred for 15 min at 0 °C, the reaction was quenched with H<sub>2</sub>O. The mixture was warmed to room temperature and filtered through Celite and a silica gel layer, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane/AcOEt = 1:1) to give a title alcohol (1.25 g, quant.) as a colorless oil. <sup>1</sup>H NMR (400 MHz): <italic>δ</italic> = 7.37–7.32 (m, 4H), 7.30–7.26 (m, 1H), 5.65–5.57 (m, 2H), 4.51 (s, 2H), 3.66 (dd, <italic>J</italic> = 10.8, 6.0 Hz, 1H), 3.62–3.48 (m, 3H), 2.14–2.09 (m, 2H), 2.01–1.75 (m, 5H), 1.66–1.59 (m, 1H), 1.55–1.48 (m, 1H); <sup>13</sup>C NMR (100 MHz): <italic>δ</italic> = 138.3, 128.4, 127.7, 127.6, 125.8, 125.5, 73.1, 68.5, 65.0, 39.7, 32.9, 31.0, 29.5, 26.7; HRMS (EI) calcd for C<sub>16</sub>H<sub>22</sub>O<sub>2</sub> [M]<sup>+</sup>: 246.1620. Found: 246.1618.</p></sec><sec id="s0055"><label>4.1.3</label><title>({(1<italic>S</italic>/<italic>R</italic>,6<italic>R</italic>/<italic>S</italic>)-6-[2-(Benzyloxy)ethyl]cyclohex-3-en-1-yl}methoxy)(<italic>tert</italic>-butyl)diphenylsilane <bold>8</bold></title><p id="p0095">TBDPS-Cl (3.6 mL, 13.1 mmol) was added to a solution of the above alcohol (2.92 g, 11.9 mmol) and imidazole (1.21 g, 17.8 mmol) in CH<sub>2</sub>Cl<sub>2</sub> (30 mL) and the mixture was stirred for 16 h. The reaction was quenched with saturated aqueous NH<sub>4</sub>Cl, and the whole was extracted with AcOEt. The organic layer was washed with brine, dried over Na<sub>2</sub>SO<sub>4</sub>, filtered, and concentrated. The residue was purified by silica gel column chromatography (hexane/AcOEt = 20:1) to give 8 (5.76 g, quant.) as a colorless oil. <sup>1</sup>H NMR (400 MHz): <italic>δ</italic> = 7.67–7.65 (m, 4H), 7.43–7.30 (m, 10H), 7.28 (m, 1H), 5.63–5.54 (m, 2H), 4.49 (d, <italic>J</italic> = 12.0 Hz, 1H), 4.45 (d, <italic>J</italic> = 12.0 Hz, 1H), 3.68 (dd, <italic>J</italic> = 10.0, 5.2 Hz, 1H), 3.62 (dd, <italic>J</italic> = 9.8, 7.0 Hz, 1H,), 3.54–3.45 (m, 2H), 2.17–2.06 (m, 2H), 2.02–1.95, (m, 1H), 1.87–1.80 (m, 2H), 1.73–1.67 (m, 2H), 1.51–1.42 (m, 1H), 1.05 (s, 9H); <sup>13</sup>C NMR (100 MHz): <italic>δ</italic> = 138.6, 135.62, 135.61, 133.98, 133.95, 129.5, 128.3, 127.58, 127.56, 127.4, 125.8, 125.4, 72.9, 68.6, 65.9, 39.6, 32.9, 30.9, 29.1, 26.9, 26.7, 19.3; HRMS (FAB) calcd for C<sub>32</sub>H<sub>41</sub>O<sub>2</sub>Si [M+H]<sup>+</sup>: 485.2876. Found: 485.2870.</p></sec><sec id="s0060"><label>4.1.4</label><title>2-[(1<italic>R</italic>/<italic>S</italic>,6<italic>S</italic>/<italic>R</italic>)-6-{[(<italic>tert</italic>-Butyldiphenylsilyl)oxy]methyl}cyclohexyl]ethanol</title><p id="p0100">To a solution of <bold>8</bold> (3.40 g, 7.01 mmol) in CH<sub>3</sub>OH/AcOEt/CH<sub>2</sub>Cl<sub>2</sub> (10:10:1, 21 mL) Pd(OH)<sub>2</sub>–C (610 mg) was added and stirred under a hydrogen gas atmosphere at room temperature for 12 h. The mixture was filtered through Celite and a silica gel layer, and the filtrate was dried over Na<sub>2</sub>SO<sub>4</sub>, filtered, and concentrated. The residue was purified by silica gel column chromatography (hexane/AcOEt = 3:1) to give a title alcohol (2.78 g, quant.) as a colorless oil. <sup>1</sup>H NMR (400 MHz): <italic>δ</italic> = 7.68–7.65 (m, 4H), 7.45–7.36 (m, 6H), 3.68–3.54 (m, 4H), 1.78–1.66 (m, 5H), 1.37–1.18 (m, 7H), 1.06 (s, 9H), 1.01–0.96 (m, 1H); <sup>13</sup>C NMR (100 MHz): <italic>δ</italic> = 135.69, 135.66, 133.92, 133.90, 129.55, 129.54, 127.60, 127.57, 66.6, 61.1, 44.5, 36.5, 35.5, 31.9, 30.0, 26.9, 26.1, 26.0, 19.3; HRMS (FAB) calcd for C<sub>25</sub>H<sub>37</sub>O<sub>2</sub>Si [M+H]<sup>+</sup>: 397.2563. Found: 397.2569.</p></sec><sec id="s0065"><label>4.1.5</label><title>(<italic>E</italic>)-Ethyl 4-[(1<italic>R</italic>/<italic>S</italic>,2<italic>S</italic>/<italic>R</italic>)-2-{[(<italic>tert</italic>-butyldiphenylsilyl)oxy]methyl}cyclohex-1-yl]but-2-enoate <bold>9</bold></title><p id="p0105">To a solution of PCC (3.45 g, 16.0 mmol) and Celite (3.5 g) in CH<sub>2</sub>Cl<sub>2</sub> (20 mL), above alcohol (2.50 g, 6.30 mmol) was added at 0 °C. The temperature was gradually raised to room temperature. After being stirred for 6 h, the reaction mixture was filtered through a silica gel layer and the filtrate was concentrated. This compound was immediately used for the next step without purification. Triethylphosphonoacetate (1.5 mL, 7.7 mmol) was added to a suspension of NaH [60% in mineral oil (308 mg, 7.70 mmol)] in THF (10 mL) at −20 °C under an argon gas atmosphere and the mixture was stirred for 0.5 h. The oxidized product was added drop-wise to the reaction mixture and stirred for 1.5 h at −20 °C. The reaction was quenched with saturated aqueous NH<sub>4</sub>Cl, and the whole was extracted with AcOEt. The organic layer was washed with brine, dried over Na<sub>2</sub>SO<sub>4</sub>, filtered, and concentrated. The residue was purified by silica gel column chromatography (hexane/AcOEt = 20:1) to give <bold>9</bold> (2.70 g, 92%, 2 steps) as a colorless oil. <sup>1</sup>H NMR (400 MHz): <italic>δ</italic> = 7.67–7.64 (m, 4H) 7.45–7.36 (m, 6H), 6.91 (ddd, <italic>J</italic> = 15.4, 8.8, 6.4 Hz, 1H), 5.72 (d, <italic>J</italic> = 15.6 Hz, 1H), 4.18 (q, <italic>J</italic> = 7.1 Hz, 2H), 3.63–3.57 (m, 2H), 2.38–2.32 (m, 1H), 1.97 (td, <italic>J</italic> = 14.8, 8.1 Hz, 1H), 1.79–1.76 (m, 1H), 1.71–1.69 (m, 4H), 1.54–1.49 (m, 1H), 1.32–1.18 (m, 4H), 1.29 (t, <italic>J</italic> = 7.2 Hz, 3H), 1.05 (s, 9H), 1.03–0.97 (m, 1H); <sup>13</sup>C NMR (100 MHz): <italic>δ</italic> = 166.6, 148.2, 135.62, 135.61, 133.82, 133.80, 129.59, 129.55, 127.62, 127.59, 122.4, 66.2, 60.1, 43.9, 37.8, 36.4, 31.9, 30.0, 26.9, 26.1, 26.0, 19.3, 14.3; HRMS (FAB) calcd for C<sub>29</sub>H<sub>40</sub>NaO<sub>3</sub>Si [M+Na]<sup>+</sup>: 487.2644. Found: 487.2651.</p></sec><sec id="s0070"><label>4.1.6</label><title>(<italic>E</italic>)-4-[(1<italic>R</italic>/<italic>S</italic>,2<italic>S</italic>/<italic>R</italic>)-2-{[(<italic>tert</italic>-Butyldiphenylsilyl)oxy]methyl}cyclohexyl]but-2-en-1-ol</title><p id="p0110">To a solution of <bold>9</bold> (1.92 g, 4.13 mmol) in CH<sub>2</sub>Cl<sub>2</sub> (20 mL), DIBALH (1.0 mol/L solution in hexane, 12.4 mL, 12.4 mmol) was added at −78 °C. After being stirred for 15 min at the same temperature, the reaction was quenched with CH<sub>3</sub>OH (5.0 mL). The mixture was warmed to room temperature, and filtered through Celite and a silica gel layer. The filtrate was dried over Na<sub>2</sub>SO<sub>4</sub>, filtered, and concentrated. The residue was purified by silica gel column chromatography (hexane/AcOEt = 1:1) to give a title alcohol (1.74 g, quant.) as a colorless oil. <sup>1</sup>H NMR (400 MHz): <italic>δ</italic> = 7.68–7.65 (m, 4H), 7.44–7.36 (m, 6H), 5.64–5.48 (m, 2H), 4.04 (d, <italic>J</italic> = 6.0 Hz, 2H), 3.66 (dd, <italic>J</italic> = 10.0, 2.8 Hz, 1H), 3.58 (dd, <italic>J</italic> = 9.8, 5.4 Hz, 1H), 2.23–2.17 (m, 1H), 1.87–1.79 (m, 2H), 1.72–1.69 (m, 3H), 1.43–1.32 (m, 1H), 1.30–1.18 (m, 4H), 1.05 (s, 9H), 1.01–0.94 (m, 1H); <sup>13</sup>C NMR (100 MHz): <italic>δ</italic> = 135.64, 135.63, 134.0, 131.6, 130.2, 129.52, 129.50, 127.58, 127.55, 66.3, 63.8, 43.9, 38.1, 36.2, 31.7, 30.0, 26.9, 26.2, 26.1, 19.4; HRMS (FAB) calcd for C<sub>27</sub>h<sub>38</sub>nao<sub>2</sub>si [M+Na]<sup>+</sup>: 445.2539. Found: 445.2541.</p></sec><sec id="s0075"><label>4.1.7</label><title>(<italic>E</italic>)-4-[(1<italic>R</italic>/<italic>S</italic>,2<italic>S</italic>/<italic>R</italic>)-2-{[(<italic>tert</italic>-Butyldiphenylsilyl)oxy]methyl}cyclohexyl]but-2-en-1-yl acetate <bold>10</bold></title><p id="p0115">To a solution of above alcohol (1.74 g, 4.11 mmol) in CH<sub>2</sub>Cl<sub>2</sub> (20 mL), pyridine (0.50 mL, 6.2 mmol), acetic anhydride (0.59 mL, 6.19 mmol), and DMAP (50 mg, 0.41 mmol) were added at 0 °C. The mixture was stirred at room temperature for 1 h. The reaction was quenched with saturated aqueous NH<sub>4</sub>Cl. The mixture was extracted with AcOEt. The organic layer was washed with brine, dried over Na<sub>2</sub>SO<sub>4</sub>, filtered, and concentrated. The residue was purified by silica gel column chromatography (hexane/AcOEt = 30:1) to give <bold>10</bold> (1.81 g, 95%) as a colorless oil. <sup>1</sup>H NMR (400 MHz): <italic>δ</italic> = 7.67–7.64 (m, 4H), 7.44–7.36 (m, 6H), 5.71–5.64 (m, 1H), 5.49–5.42 (m, 1H), 4.47 (d, <italic>J</italic> = 6.4 Hz, 2H), 3.65 (dd, <italic>J</italic> = 9.8, 3.0 Hz, 1H), 3.57 (dd, <italic>J</italic> = 10.0, 4.8 Hz, 1H), 2.23–2.18 (m, 1H), 2.05 (s, 3H), 1.87–1.79 (m, 2H), 1.71–1.68 (m, 3H), 1.43–1.35 (m, 1H), 1.30–1.18 (m, 4H), 1.05 (s, 9H), 1.00–0.94 (m, 1H); <sup>13</sup>C NMR (100 MHz): <italic>δ</italic> = 170.9, 135.6, 134.8, 133.94, 133.93, 129.5, 127.6, 125.0, 66.3, 65.3, 43.8, 38.0, 36.3, 31.7, 30.0, 26.9, 26.2, 26.1, 21.0, 19.3; HRMS (FAB) calcd for C<sub>29</sub>H<sub>40</sub>NaO<sub>3</sub>Si [M+Na]<sup>+</sup>: 487.2644. Found: 487.2642.</p></sec><sec id="s0080"><label>4.1.8</label><title>(<italic>E</italic>)-4-[(1<italic>R</italic>/<italic>S</italic>,2<italic>S</italic>/<italic>R</italic>)-2-(Hydroxymethyl)cyclohexyl]but-2-en-1-yl acetate</title><p id="p0120">To a solution of <bold>10</bold> (1.81 g, 3.89 mmol) in THF (20 mL), TBAF [1.0 M solution in THF (7.8 mL, 7.8 mmol)] was added at room temperature. After the mixture was stirred for 12 h, the reaction was quenched with saturated aqueous NH<sub>4</sub>Cl and the whole was extracted with AcOEt. The organic layer was washed with brine, dried over Na<sub>2</sub>SO<sub>4</sub>, filtered, and concentrated. The residue was purified by silica gel column chromatography (hexane/AcOEt = 6:1) to give a title alcohol (1.03 g, quant.) as a colorless oil. <sup>1</sup>H NMR (400 MHz): <italic>δ</italic> = 5.80–5.72 (m, 1H), 5.60–5.53 (m, 1H), 4.51 (d, <italic>J</italic> = 6.4 Hz, 2H), 3.69 (dd, <italic>J</italic> = 10.8, 3.2 Hz, 1H), 3.59 (dd, <italic>J</italic> = 10.8, 5.6 Hz, 1H), 2.33–2.27 (m, 1H), 2.06 (s, 3H), 2.02–1.90 (m, 1H), 1.81–1.79 (m, 1H), 1.74–1.67 (m, 3H), 1.37–1.11 (m, 5H), 1.05–0.95 (m, 1H); <sup>13</sup>C NMR (100 MHz): <italic>δ</italic> = 170.9, 134.5, 125.3, 65.7, 65.2, 43.8, 38.0, 36.4, 31.7, 29.5, 26.0, 25.8, 21.0; HRMS (FAB) calcd for C<sub>13</sub>H<sub>22</sub>NaO<sub>3</sub> [M+Na]<sup>+</sup>: 249.1467. Found: 249.1460.</p></sec><sec id="s0085"><label>4.1.9</label><title><italic>N</italic>-({(1<italic>S</italic>/<italic>R</italic>,2<italic>R</italic>/<italic>S</italic>)-2-[(<italic>E</italic>)-4-Hydroxybut-2-en-1-yl]cyclohexyl}methyl)-[1,1′-biphenyl]-4-carboxamide <bold>12</bold></title><p id="p0125">DPPA (2.4 mL, 11 mmol) was added drop-wise to a solution of above alcohol (1.03 g, 4.56 mmol), triphenylphosphine (2.80 g, 10.8 mmol), and DEAD (40% solution in toluene, 4.2 mL, 10.8 mmol) in THF (10 mL) at 0 °C. The mixture was stirred for 16 h at the same temperature, and then the reaction mixture was concentrated. The residue was roughly purified by silica gel column chromatography (hexane/AcOEt = 30:1) to give <bold>11</bold>. <sup>1</sup>H NMR (400 MHz): <italic>δ</italic> = 5.77–5.69 (m, 1H), 5.62–5.54 (m, 1H), 4.52 (d, <italic>J</italic> = 6.0 Hz, 2H), 3.40 (dd, <italic>J</italic> = 12.0, 3.2 Hz, 1H), 3.25 (dd, <italic>J</italic> = 12.2, 6.2 Hz, 1H), 2.29–2.24 (m, 1H), 2.06 (s, 3H), 2.00–1.91 (m, 1H), 1.80–1.65 (m, 4H), 1.34–1.29 (m, 2H), 1.27–1.11 (m, 3H), 1.05–0.95 (m, 1H).</p><p id="p0130">The crude <bold>11</bold> was dissolved in ether (10 mL) and added to a suspension of LiAlH<sub>4</sub> (1.04 g, 27.4 mmol) in ether (10 mL) at 0 °C. The reaction was quenched with CH<sub>3</sub>OH and concentrated. The mixture was stirred for 6 h under reflux. The reaction mixture cooled to room temperature and then quenched with CH<sub>3</sub>OH and concentrated to give a corresponding amine derivative. <sup>1</sup>H NMR (400 MHz): <italic>δ</italic> = 5.63–5.48 (m, 2H), 3.94–3.92 (m, 2H), 2.81 (dd, <italic>J</italic> = 12.6, 3.0 Hz, 1H), 2.43 (dd, <italic>J</italic> = 12.8, 7.6 Hz, 1H), 2.20–2.15 (m, 1H), 1.97–1.86 (m, 1H), 1.79–1.75 (m, 1H), 1.69–1.60 (m, 3H), 1.24–1.09 (m, 5H), 1.05–0.96 (m, 1H).</p><p id="p0135">The residue was used in the next step without purification. The crude product in CH<sub>2</sub>Cl<sub>2</sub> (10 mL) was added to a solution of HBTU (4.32 g, 11.4 mmol), DIPEA (2.4 mL, 14 mmol), and 4-biphenyl carboxylic acid (903 mg, 4.56 mmol) in CH<sub>2</sub>Cl<sub>2</sub> (10 mL) at 0 °C. The mixture was stirred for 3 h at room temperature. The reaction was quenched with saturated aqueous NH<sub>4</sub>Cl and extracted with CH<sub>2</sub>Cl<sub>2</sub>. The organic layer was washed with brine and dried over Na<sub>2</sub>SO<sub>4</sub>, filtered, and concentrated. The residue was purified by silica gel column chromatography (hexane/AcOEt = 1:1) to afford <bold>12</bold> (1.04 g, 63%, 3 steps) as a colorless oil. <sup>1</sup>H NMR (400 MHz): <italic>δ</italic> = 7.84–7.82 (m, 2H), 7.67–7.59 (m, 4H), 7.48–7.44 (m, 2H), 7.41–7.37 (m, 1H), 6.28 (br s, 1H), 5.79–5.67 (m, 2H), 4.10 (d, <italic>J</italic> = 4.4 Hz, 2H), 3.78 (ddd, <italic>J</italic> = 13.6, 6.0, 3.6 Hz, 1H), 3.20 (ddd, <italic>J</italic> = 13.7, 8.1, 5.9 Hz, 1H), 2.32–2.27 (m, 1H), 2.21–2.12 (m, 1H), 1.87–1.84 (m, 1H), 1.74–1.72 (m, 3H), 1.52–1.41 (m, 1H), 1.32–1.04 (m, 5H); <sup>13</sup>C NMR (100 MHz): <italic>δ</italic> = 167.2, 144.2, 140.0, 133.3, 131.2, 130.5, 128.9, 128.0, 127.3, 127.23, 127.17, 63.8, 43.3, 41.1, 39.6, 36.5, 31.9, 30.6, 26.0, 25.7; HRMS (EI) calcd for C<sub>24</sub>H<sub>29</sub>NO<sub>2</sub> [M]<sup>+</sup>:363.2198. Found: 363.2207.</p></sec><sec id="s0090"><label>4.1.10</label><title>4-Bromo-<italic>N</italic>-({(1<italic>S</italic>/<italic>R</italic>,2<italic>R</italic>/<italic>S</italic>)-2-[(<italic>E</italic>)-4-hydroxybut-2-en-1-yl]cyclohexyl}methyl)benzamide <bold>13</bold></title><p id="p0140">A title compound was similarly prepared from <bold>10</bold> as above. Colorless oil; yield 50% (3 steps): <sup>1</sup>H NMR (400 MHz): <italic>δ</italic> = 7.64–7.61 (m, 2H), 7.58–7.56 (m, 2H), 6.16 (m, 1H), 5.78–5.66 (m, 2H), 4.10 (d, <italic>J</italic> = 4.8 Hz, 2H), 3.76 (ddd, <italic>J</italic> = 13.4, 5.8, 3.8 Hz, 1H), 3.16 (ddd, <italic>J</italic> = 13.7, 8.1, 5.9 Hz, 1H), 2.29–2.25 (m, 1H), 2.18–2.11 (m, 1H), 1.84–1.80 (m, 1H), 1.73–1.71 (m, 3H), 1.50–1.41 (m, 1H), 1.28–0.96 (m, 5H); <sup>13</sup>C NMR (100 MHz): <italic>δ</italic> = 166.5, 133.5, 131.8, 131.2, 130.4, 128.5, 126.0, 63.7, 43.3, 41.0, 39.6, 36.4, 31.9, 30.5, 26.0, 25.7; HRMS (EI) calcd for C<sub>18</sub>H<sub>24</sub>BrNO<sub>2</sub> [M]<sup>+</sup> 365.0990. Found 365.0996.</p></sec><sec id="s0095"><label>4.1.11</label><title>(1,1′-Biphenyl)-4-yl{(3<italic>S</italic>/<italic>R</italic>,4a<italic>R/S</italic>,8a<italic>S/R</italic>)-3-vinyloctahydroisoquinolin-2(1<italic>H</italic>)-yl}methanone <bold>14</bold></title><p id="p0145">To a solution of <bold>12</bold> (120 mg, 0.331 mmol) in dry CH<sub>2</sub>Cl<sub>2</sub> (1 mL), (CH<sub>3</sub>CN)<sub>2</sub>PdCl<sub>2</sub> (15 mg, 0.056 mmol) was added at 0 °C under an argon gas atmosphere, and the mixture was stirred at the same temperature for 4 h. The reaction mixture was filtered and concentrated. The residue was purified by silica gel column chromatography (hexane/AcOEt = 10:1) to give <bold>14</bold> (100 mg, 88%) as a colorless oil. <sup>1</sup>H NMR (400 MHz): <italic>δ</italic> = 7.64–7.58 (m, 4H), 7.49–7.43 (m, 4H), 7.38–7.35 (m, 1H), 5.87 (ddd, <italic>J</italic> = 17.5, 10.7, 3.7 Hz, 0.4H), 5.78 (ddd, <italic>J</italic> = 17.5, 10.7, 3.5 Hz, 0.6H), 5.55 (br s, 0.4H), 5.31–5.28 (m, 1H), 5.23–5.16 (m, 1H), 4.54 (br s, 0.6H), 4.49 (dd, <italic>J</italic> = 13.2, 4.0 Hz, 0.6H), 3.49 (dd, <italic>J</italic> = 13.0, 3.8 Hz, 0.4H), 2.86 (dd, <italic>J</italic> = 13.2, 11.6 Hz, 0.4H), 2.61 (dd, <italic>J</italic> = 12.8, 11.6 Hz, 0.6H), 1.84–1.52 (m, 5H), 1.47–1.18 (m, 5H), 1.15–1.13 (m, 0.4H), 1.03–0.98 (m, 1H), 0.90–0.84 (m, 0.6H); <sup>13</sup>C NMR (100 MHz): <italic>δ</italic> = 171.1, 170.4, 142.3, 142.2, 140.3, 137.1, 136.7, 135.4, 128.8, 127.69, 127.66, 127.4, 127.1, 126.8, 116.6, 116.1, 57.2, 50.8, 49.7, 43.5, 42.8, 41.9, 37.5, 36.8, 35.9, 32.9, 29.9, 29.7, 26.2, 26.1, 25.8, 25.7; HRMS (EI) calcd for C<sub>24</sub>H<sub>27</sub>NO [M]<sup>+</sup>: 345.2093. Found: 345.2090.</p></sec><sec id="s0100"><label>4.1.12</label><title>(4-Bromophenyl)((3<italic>S</italic>,4a<italic>R/S</italic>,8a<italic>S/R</italic>)-3-vinyloctahydroisoquinolin-2(1<italic>H</italic>)-yl)methanone <bold>15</bold></title><p id="p0150">A title compound was similarly prepared as above. Colorless oil; yield 57%: <sup>1</sup>H NMR (400 MHz): <italic>δ</italic> = 7.56–7.50 (m, 2H), 7.29–7.27 (m, 2H), 5.84 (ddd, <italic>J</italic> = 17.4, 10.6, 3.8 Hz, 0.4H), 5.74 (ddd, <italic>J</italic> = 17.5, 10.7, 3.5 Hz, 0.6H), 5.49 (br s, 0.4H), 5.29–5.26 (m, 1H), 5.19–5.10 (m, 1H), 4.44 (dd, <italic>J</italic> = 13.4, 3.8 Hz, 0.6H), 4.39 (s, 0.6H), 3.33 (dd, <italic>J</italic> = 13.2, 3.6 Hz, 0.4H), 2.82 (dd, <italic>J</italic> = 13.0, 11.8 Hz, 0.4H), 2.57 (dd, <italic>J</italic> = 13.0, 11.4 Hz, 0.6H), 1.83–1.49 (m, 5H), 1.43–1.19 (m, 5H), 1.13–1.04 (m, 0.4H), 0.99–0.96 (m, 1H), 0.88–0.83 (m, 0.6H); <sup>13</sup>C NMR (100 MHz): <italic>δ</italic> = 170.2, 169.6, 136.9, 136.5, 135.4, 131.7, 131.6, 128.6, 128.0, 123.7, 123.6, 116.7, 116.2, 57.2, 50.8, 49.6, 43.5, 42.8, 41.8, 37.5, 36.7, 35.9, 32.8, 29.9, 29.6, 26.1, 26.0, 25.7, 25.6; HRMS (EI) Calcd for C<sub>18</sub>H<sub>22</sub>BrNO [M]<sup>+</sup>: 347.0885. Found: 347.0879.</p></sec><sec id="s0105"><label>4.1.13</label><title>(<italic>S</italic>)-2-({[(3<italic>S</italic>,4a<italic>R</italic>,8a<italic>S</italic>)-2-[(1,1′-Biphenyl)-4-carbonyl]decahydroisoquinolin-3-yl]methyl}amino)-<italic>N</italic>-methoxy-<italic>N</italic>-methyl-3-(1-trityl-1<italic>H</italic>-imidazol-4-yl)propanamide <bold>18</bold></title><p id="p0155">To a solution of K<sub>2</sub>OsO<sub>2</sub>(OH)<sub>4</sub> (3.1 mg, 0.0083 mmol) and <italic>N</italic>-methylmorpholine <italic>N</italic>-oxide (389 mg, 3.32 mmol), <bold>14</bold> (286 mg, 0.829 mmol) was added in THF/H<sub>2</sub>O (3:1, 10 mL). After being stirred for 12 h, NaIO<sub>4</sub> (710 mg, 3.32 mmol) was added to the mixture. The resultant mixture was stirred for 30 min. The reaction was quenched with H<sub>2</sub>O, and the whole was extracted with AcOEt. The organic layer was washed with brine, dried over MgSO<sub>4</sub>, filtered, and concentrated. The residue was roughly purified by silica gel column chromatography (hexane/AcOEt = 3:1) to give <bold>16</bold>. <sup>1</sup>H NMR (400 MHz): <italic>δ</italic> = 9.69 (s, 0.75H), 9.65 (s, 0.25H), 7.69–7.54 (m, 5H), 7.49–7.37 (m, 4H), 5.50 (d, <italic>J</italic> = 6.4 Hz, 0.75H), 4.62–4.59 (m, 0.25H), 4.44 (d, <italic>J</italic> = 5.6 Hz, 0.25H), 3.69–3.65 (m, 0.75H), 2.81 (dd, <italic>J</italic> = 13.2, 11.6 Hz, 0.75H), 2.40 (t, <italic>J</italic> = 12.6 Hz, 0.25H), 2.33 (d, <italic>J</italic> = 13.6 Hz, 0.75H), 2.15 (dd, <italic>J</italic> = 13.6 Hz, 0.25H), 1.74–1.69 (m, 3H), 1.59–1.50 (m, 1H), 1.44–1.41 (m, 1H), 1.25–1.11 (m, 3H), 1.08–0.96 (m, 2H), 0.92–0.76 (m, 1H).</p><p id="p0160">The product was used without further purification. To a solution of <bold>16</bold> and H-His(Trt)-N(OCH<sub>3</sub>)CH<sub>3</sub> (410 mg, 0.930 mmol) in CH<sub>2</sub>Cl<sub>2</sub> (1 mL), AcOH (0.05 mL, 0.8 mmol) was added. The mixture was stirred at room temperature for 2 h and then NaBH<sub>3</sub>CN (181 mg, 2.88 mmol) was added. The resultant mixture was stirred for 30 min. The reaction was quenched with 1 M HCl and the whole was extracted with AcOEt. The organic layer was washed with saturated aqueous NaHCO<sub>3</sub> and brine, dried over Na<sub>2</sub>SO<sub>4</sub>, filtered, and concentrated. The residue was purified by flash column chromatography (CHCl<sub>3</sub>/CH<sub>3</sub>OH = 25:1) to give <bold>18</bold> and <bold>20</bold>.</p><p id="p0165"><italic>Compound <bold>18</bold>:</italic> [80 mg, 13% (50% max.), 3 steps] as a colorless oil. [<italic>α</italic>]<sup>28</sup><sub>D</sub> −20 (<italic>c</italic> 0.48, CHCl<sub>3</sub>); <sup>1</sup>H NMR (400 MHz): <italic>δ</italic> = 7.59–7.53 (m, 4H), 7.47–7.41 (m, 4H), 7.37–7.29 (m, 11H), 7.13–7.09 (m, 6H), 6.62 (m, 0.6H), 6.56 (m, 0.4H), 4.94 (br s, 0.6H), 4.41 (dd, <italic>J</italic> = 13.0, 3.0 Hz, 0.4H), 4.12–4.11 (m, 0.4H), 3.93 (m, 1H), 3.69 (s, 1.8H), 3.50 (s, 1.2H), 3.44–3.41 (m, 0.6H), 3.14 (s, 1.8H), 3.08 (s, 1.2H), 2.93–2.84 (m, 2.4H), 2.76–2.66 (m, 2H), 2.46 (t, <italic>J</italic> = 12.2 Hz, 0.6H), 1.80–1.70 (m, 3H), 1.61–1.54 (m, 1H), 1.43–1.17 (m, 6H), 1.08–0.85 (m, 2H); <sup>13</sup>C NMR (100 MHz): <italic>δ</italic> = 175.4, 175.2, 171.3, 170.5, 142.44, 142.38, 141.88, 141.86, 140.42, 140.35, 138.2, 138.1, 137.6, 137.2, 135.9, 135.7, 129.72, 129.66, 129.3, 128.8, 128.7, 127.91, 127.87, 127.54, 127.46, 127.4, 127.2, 127.1, 127.04, 126.99, 119.3, 115.6, 77.2, 75.03, 75.02, 61.6, 61.5, 57.8, 57.4, 55.5, 49.5, 48.3, 47.1, 46.6, 43.1, 42.6, 42.1, 36.4, 36.2, 34.4, 33.0, 32.9, 32.6, 32.2, 32.0, 29.9, 29.7, 26.14, 26.05, 25.8, 25.7; HRMS (EI) calcd for C<sub>50</sub>H<sub>53</sub>N<sub>5</sub>O<sub>3</sub> [M]<sup>+</sup>: 771.4148. Found: 771.4141.</p><p id="p0170"><italic>Compound <bold>20</bold>:</italic> [75 mg, 12% (50% max.), 3 steps] as a colorless oil. [<italic>α</italic>]<sub>D</sub><sup>28</sup> +32 (<italic>c</italic> 2.3, CHCl<sub>3</sub>); <sup>1</sup>H NMR (400 MHz): <italic>δ</italic> = 7.58–7.24 (m, 19H), 7.13–7.07 (m, 6H), 6.58 (m, 0.4H), 6.55 (m, 0.6H), 5.02–4.97 (m, 0.4H), 4.46 (dd, <italic>J</italic> = 13.2, 3.6 Hz, 0.6H), 4.13 (br s, 0.4H), 3.95 (m, 1H), 3.65 (s, 1.2H), 3.62–3.58 (m, 0.6H), 3.50 (s, 1.8H), 3.44 (dd, <italic>J</italic> = 13.4, 3.4 Hz, 0.4H), 3.14 (s, 1.2H), 3.11 (s, 1.8H), 3.01–2.94 (m, 1H), 2.89–2.81 (m, 2H), 2.65 (dd, <italic>J</italic> = 11.8, 6.6 Hz, 0.4H), 2.52 (dd, <italic>J</italic> = 12.0, 6.8 Hz, 0.6H), 2.50–2.44 (m, 0.6H), 2.26–2.24 (br s, 1H), 1.71–1.69 (m, 3H), 1.60–1.52 (m, 2H), 1.45–1.16 (m, 5H), 1.07–0.83 (m, 2H); <sup>13</sup>C NMR (100 MHz): <italic>δ</italic> = 175.6, 175.3, 171.1, 170.8, 142.44, 142.37, 141.9, 141.8, 140.41, 140.39, 138.12, 138.08, 137.5, 137.3, 135.7, 129.72, 129.66, 128.73, 128.68, 127.9, 127.5, 127.4, 127.1, 127.05, 127.03, 126.95, 119.5, 119.3, 77.2, 75.0, 61.6, 61.5, 57.7, 57.5, 55.4, 49.3, 48.4, 47.4, 47.2, 43.0, 42.8, 42.0, 36.7, 36.5, 34.6, 33.5, 33.00, 32.96, 32.3, 32.1, 29.9, 29.7, 29.6, 26.2, 26.0, 25.8, 25.7; HRMS (EI) calcd for C<sub>50</sub>H<sub>53</sub>N<sub>5</sub>O<sub>3</sub> [M]<sup>+</sup>: 771.4148. Found: 771.4154.</p></sec><sec id="s0110"><label>4.1.14</label><title>(<italic>S</italic>)-2-({[(3<italic>S</italic>,4a<italic>R</italic>,8a<italic>S</italic>)-2-(4-Bromobenzoyl)decahydroisoquinolin-3-yl]methyl}amino)-<italic>N</italic>-methoxy-<italic>N</italic>-methyl-3-(1-trityl-1<italic>H</italic>-imidazol-4-yl)propanamide <bold>19</bold></title><p id="p0175">Compound <bold>19</bold> was similarly synthesized as <bold>18</bold>. Colorless oil; yield 11% (50% max., 3 steps): [<italic>α</italic>]<sub>D</sub><sup>28</sup> −31 (<italic>c</italic> 0.83, CHCl<sub>3</sub>); <sup>1</sup>H NMR (400 MHz): <italic>δ</italic> = 7.47 (d, <italic>J</italic> = 8.4 Hz, 1.2H), 7.44 (d, <italic>J</italic> = 8.4 Hz, 0.8H), 7.34–7.31 (m, 10.8H), 7.22 (d, <italic>J</italic> = 8.4 Hz, 1.2H), 7.12–7.11 (m, 6H), 6.60 (br s, 0.6H), 6.55 (br s, 0.4H), 4.87 (m, 0.6H), 4.37 (dd, <italic>J</italic> = 13.2, 3.6 Hz, 0.4H), 4.10 (br s, 0.6H), 3.89 (br s, 0.4H), 3.78 (m, 0.6H), 3.64 (s, 1.8H), 3.51 (s, 1.2H), 3.24 (dd, <italic>J</italic> = 13.2, 3.6 Hz, 0.6H), 3.13 (s, 1.8H), 3.11 (s, 1.2H), 2.91–2.80 (m, 2.4H), 2.73–2.62 (m, 2H), 2.47–2.41 (m, 0.4H), 1.76–1.65 (m, 3.4H), 1.60–1.54 (m, 1.6H), 1.36–1.25 (m, 5H), 1.00–0.82 (m, 2H); <sup>13</sup>C NMR (100 MHz): <italic>δ</italic> = 175.5, 175.1, 170.4, 169.7, 142.5, 142.4, 138.3, 138.1, 137.7, 137.2, 135.9, 135.8, 131.52, 131.49, 129.75, 129.72, 128.7, 128.4, 127.94, 127.91, 123.24, 123.21, 119.26, 119.25, 77.2, 75.1, 61.6, 61.5, 57.8, 57.5, 55.6, 49.3, 48.4, 47.1, 46.6, 43.1, 42.6, 42.0, 36.4, 36.2, 34.5, 33.0, 32.9, 32.7, 32.3, 32.0, 29.9, 29.7, 26.1, 26.0, 25.8, 25.7; HRMS (EI) calcd for C<sub>44</sub>H<sub>48</sub>BrN<sub>5</sub>O<sub>3</sub> [M]<sup>+</sup>: 773.2941. Found: 773.2948.</p></sec><sec id="s0115"><label>4.1.15</label><title>(<italic>S</italic>)-2-({[(3<italic>R</italic>,4a<italic>S</italic>,8a<italic>R</italic>)-2-(4-Bromobenzoyl)decahydroisoquinolin-3-yl]methyl}amino)-<italic>N</italic>-methoxy-<italic>N</italic>-methyl-3-(1-trityl-1<italic>H</italic>-imidazol-4-yl)propanamide <bold>21</bold></title><p id="p0180">Compound <bold>21</bold> was similarly synthesized as <bold>20</bold>. Colorless oil; yield 11% (50% max., 3 steps): [<italic>α</italic>]<sub>D</sub><sup>28</sup> +4.5 (<italic>c</italic> 0.42, CHCl<sub>3</sub>); <sup>1</sup>H NMR (400 MHz): <italic>δ</italic> = 7.47–7.43 (m, 2H), 7.37–7.29 (m, 12H), 7.12–7.10 (m, 6H), 6.55 (m, 1H), 4.98–4.95 (m, 0.4H), 4.40 (dd, <italic>J</italic> = 13.2, 3.6 Hz, 0.6H), 4.10 (br s, 0.4H), 3.90 (br s, 0.6H), 3.84–3.81 (m, 0.6H), 3.64–3.58 (m, 0.4H), 3.63 (s, 1.8H), 3.54 (s, 1.2H), 3.28 (dd, <italic>J</italic> = 13.2, 3.6 Hz, 0.4H), 3.13 (s, 1.8H), 3.11 (s, 1.2H), 2.98–2.91 (m, 1H), 2.86–2.74 (m, 2.6H), 2.60 (dd, <italic>J</italic> = 11.6, 6.0 Hz, 0.6H), 2.47–2.41 (m, 1.4H), 1.72–1.65 (m, 3H), 1.59–1.47 (m, 2H), 1.43–1.12 (m, 5H), 1.04–0.79 (m, 2H); <sup>13</sup>C NMR (100 MHz): <italic>δ</italic> = 175.6, 175.2, 170.3, 170.0, 142.42, 142.37, 138.2, 138.1, 137.35, 137.25, 135.70, 135.66, 131.47, 131.45, 129.73, 129.70, 128.9, 128.7, 127.93, 127.91, 123.32, 123.26, 119.5, 119.3, 77.2, 75.1, 75.0, 61.5, 57.5, 57.4, 55.5, 49.2, 48.4, 47.4, 47.2, 42.9, 42.8, 42.0, 36.6, 36.5, 34.7, 33.6, 33.0, 32.9, 32.3, 32.0, 29.8, 29.6, 26.1, 26.0, 25.8, 25.6; HRMS (EI) calcd for C<sub>44</sub>H<sub>48</sub>BrN<sub>5</sub>O<sub>3</sub> [M]<sup>+</sup>: 773.2941. Found: 773.2944.</p></sec><sec id="s0120"><label>4.1.16</label><title>(<italic>S</italic>)-2-[({(3<italic>S</italic>,4a<italic>R</italic>,8a<italic>S</italic>)-2-[(1,1′-Biphenyl)-4-carbonyl]decahydroisoquinolin-3-yl}methyl)amino]-3-(1<italic>H</italic>-imidazol-4-yl)-<italic>N</italic>-methoxy-<italic>N</italic>-methylpropanamide</title><p id="p0185">TFA/CH<sub>2</sub>Cl<sub>2</sub>/TIS/H<sub>2</sub>O (10:10:1.0:1.0, 5.5 mL) was added to <bold>18</bold> (40 mg, 0.052 mmol). The mixture was stirred at room temperature for 4 h. The mixture was concentrated under reduced pressure. The residue was diluted with AcOEt and basified by saturated aqueous NaHCO<sub>3</sub>. The whole was extracted with AcOEt and the organic layer was washed with brine, dried over Na<sub>2</sub>SO<sub>4</sub>, filtered, and concentrated. The residue was purified by silica gel column chromatography (CHCl<sub>3</sub>/CH<sub>3</sub>OH = 10:1) to give the de-tritylated product (25 mg, 90%) as a yellowish oil. [<italic>α</italic>]<sub>D</sub><sup>28</sup> −33 (<italic>c</italic> 0.51, CHCl<sub>3</sub>); <sup>1</sup>H NMR (400 MHz): <italic>δ</italic> = 7.68–7.36 (m, 10H), 6.84 (s, 0.6H), 6.82 (s, 0.4H), 5.03–5.01 (m, 0.4H), 4.31–4.27 (m, 0.6H), 4.15 (br s, 0.6H), 3.86 (br s, 0.4H), 3.73 (s, 1.2H), 3.66 (s, 1.8H), 3.54–3.51 (m, 1H), 3.25 (s, 1.2H), 3.19 (s, 1.8H), 3.00–2.86 (m, 1H), 2.75–2.62 (m, 2H), 2.52–2.44 (m, 2H), 1.77–1.68 (m, 3.4H), 1.62–1.59 (m, 1.6H), 1.49–1.23 (m, 5H), 1.17–1.11 (m, 0.4H), 1.07–0.99 (m, 1H), 0.89–0.85 (m, 0.6H); <sup>13</sup>C NMR (100 MHz): <italic>δ</italic> = 174.4, 171.0, 143.1, 142.4, 140.2, 140.1, 135.8, 135.3, 135.2, 134.8, 128.84, 128.83, 128.2, 127.8, 127.7, 127.5, 127.20, 127.18, 127.14, 127.08, 77.2, 61.7, 59.8, 58.4, 55.7, 49.5, 49.4, 48.6, 48.1, 43.5, 42.6, 42.0, 36.7, 34.3, 34.1, 33.0, 32.9, 32.2, 30.0, 29.6, 26.2, 26.0, 25.8, 25.6; HRMS (EI) calcd for C<sub>31</sub>H<sub>39</sub>N<sub>5</sub>O<sub>3</sub> [M]<sup>+</sup>: 529.3053. Found: 529.3057.</p><p id="p0190">Compounds <bold>19</bold>, <bold>20</bold>, and <bold>21</bold> were similarly treated with TFA/CH<sub>2</sub>Cl<sub>2</sub>/TIS/H<sub>2</sub>O (10:10:1.0:1.0, 5.5 mL) as above to yield the corresponding de-tritylated products.</p></sec><sec id="s0125"><label>4.1.17</label><title>From <bold>19</bold>: (<italic>S</italic>)-2-({[(3<italic>S</italic>,4a<italic>R</italic>,8a<italic>S</italic>)-2-(4-bromobenzoyl)decahydroisoquinolin-3-yl]methyl}amino)-3-(1<italic>H</italic>-imidazol-4-yl)-<italic>N</italic>-methoxy-<italic>N</italic>-methylpropanamide</title><p id="p0195">Yellowish oil; yield, 70%: [<italic>α</italic>]<sub>D</sub><sup>28</sup> −33.9 (<italic>c</italic> 0.415, CHCl<sub>3</sub>); <sup>1</sup>H NMR (400 MHz): <italic>δ</italic> = 7.66 (s, 0.6H), 7.56–7.53 (m, 2H), 7.38 (s, 0.4H), 7.32 (d, <italic>J</italic> = 8.4 Hz, 1.2H), 7.19 (d, <italic>J</italic> = 8.4 Hz, 0.8H), 6.83 (s, 0.6H), 6.81 (s, 0.4H), 4.97–4.95 (m, 0.4H), 4.26–4.22 (m, 0.6H), 4.00–3.98 (m, 0.6H), 3.85–3.84 (m, 0.4H), 3.72 (s, 1.2H), 3.66 (s, 1.8H), 3.56–3.53 (m, 0.6H), 3.35 (dd, <italic>J</italic> = 13.4, 3.8 Hz, 0.4H), 3.24 (s, 1.2H), 3.20 (s, 1.8H), 2.99–2.83 (m, 2H), 2.71–2.60 (m, 2H), 2.54–2.41 (m, 2H), 1.77–1.58 (m, 4H), 1.51–1.33 (m, 1H), 1.30–1.17 (m, 5H), 1.05–0.80 (m, 2H); <sup>13</sup>C NMR (100 MHz): <italic>δ</italic> = 174.3, 173.1, 170.2, 135.8, 135.4, 135.3, 134.7, 131.9, 131.7, 129.3, 128.3, 124.2, 123.7, 77.2, 61.7, 59.7, 58.4, 55.8, 49.6, 49.4, 48.5, 48.0, 43.5, 42.6, 42.0, 36.6, 34.2, 34.0, 33.0, 32.8, 32.6, 29.9, 29.6, 26.1, 26.0, 25.8, 25.6; HRMS (EI) calcd for C<sub>25</sub>H<sub>34</sub>BrN<sub>5</sub>O<sub>3</sub> [M]<sup>+</sup>: 531.1845. Found: 531.1839.</p></sec><sec id="s0130"><label>4.1.18</label><title>From <bold>20</bold>: (<italic>S</italic>)-2-[({(3<italic>R</italic>,4a<italic>S</italic>,8a<italic>R</italic>)-2-[(1,1′-biphenyl)-4-carbonyl]decahydroisoquinolin-3-yl}methyl)amino]-<italic>N</italic>-methoxy-<italic>N</italic>-methyl-3-(1<italic>H</italic>-imidazol-4-yl)propanamide</title><p id="p0200">Yellowish oil; yield, quantitative: [<italic>α</italic>]<sub>D</sub><sup>28</sup> −41 (<italic>c</italic> 0.45, CHCl<sub>3</sub>); <sup>1</sup>H NMR (400 MHz): <italic>δ</italic> = 7.65–7.59 (m, 4H), 7.54 (s, 1H), 7.49–7.44 (m, 4H), 7.39–7.36 (m, 1H), 6.78 (m, 1H), 5.21–5.20 (m, 0.75H), 4.52–4.49 (m, 0.25H), 4.12 (m, 0.25H), 3.90–3.88 (m, 0.75H), 3.67 (s, 2.25H), 3.67–3.65 (m, 0.75H), 3.56 (s, 0.75H), 3.56–3.49 (m, 0.75H), 3.25 (s, 2.25H), 3.25–3.21 (m, 0.25H), 3.21 (s, 0.75H), 3.11–3.05 (m, 0.25H), 2.98–2.95 (m, 0.75H), 2.89–2.83 (m, 0.75H), 2.63–2.52 (m, 1.5H), 2.37 (dd, <italic>J</italic> = 12.0, 4.4 Hz, 1H), 2.29 (m, 1H), 1.72 (br s, 2H), 1.62–1.41 (m, 4H), 1.30–1.22 (m, 4H), 1.19–1.06 (m, 0.75H), 1.00–0.85 (m, 1.25H); <sup>13</sup>C NMR (100 MHz): <italic>δ</italic> = 174.9, 171.6, 171.0, 142.4, 140.2, 135.6, 135.4, 135.2, 134.4, 128.9, 128.8, 127.7, 127.4, 127.23, 127.16, 127.1, 127.0, 77.2, 61.7, 58.5, 55.5, 49.4, 49.1, 47.5, 42.8, 42.3, 36.9, 36.8, 35.2, 34.3, 33.1, 32.9, 32.3, 29.9, 29.65, 29.56, 29.2, 26.2, 26.0, 25.8, 25.6; HRMS (EI) calcd for C<sub>31</sub>H<sub>39</sub>N<sub>5</sub>O<sub>3</sub> [M]<sup>+</sup>: 529.3053. Found: 529.3060.</p></sec><sec id="s0135"><label>4.1.19</label><title>From <bold>21</bold>: (<italic>S</italic>)-2-({[(3<italic>R</italic>,4a<italic>S</italic>,8a<italic>R</italic>)-2-(4-bromobenzoyl)decahydroisoquinolin-3-yl]methyl}amino)-<italic>N</italic>-methoxy-<italic>N</italic>-methyl-3-(1<italic>H</italic>-imidazol-4-yl)propanamide</title><p id="p0205">Yellowish oil; yield, 65%: [<italic>α</italic>]<sub>D</sub><sup>28</sup> −27.7 (<italic>c</italic> 0.96, CHCl<sub>3</sub>); <sup>1</sup>H NMR (400 MHz): <italic>δ</italic> = 7.57–7.47 (m, 3H), 7.30–7.27 (m, 2H), 6.79 (s, 0.25H), 6.78 (s, 0.75H), 5.17–5.14 (m, 0.75H), 4.45 (dd, <italic>J</italic> = 13.4, 3.4 Hz, 0.25H), 3.94 (br s, 0.25H), 3.87–3.86 (m, 0.75H), 3.67 (s, 2.25H), 3.59 (s, 0.75H), 3.39 (dd, <italic>J</italic> = 13.6, 3.2 Hz, 0.75H), 3.25 (s, 2.25H), 3.21 (s, 0.75H), 3.19–3.16 (m, 0.75H), 3.07–3.01 (m, 0.25H), 2.98–2.89 (m, 1H), 2.82 (dd, <italic>J</italic> = 13.4, 11.8 Hz, 0.75H), 2.70–2.48 (m, 1.5H), 2.36 (dd, <italic>J</italic> = 12.2, 4.6 Hz, 0.75H), 2.30 (dd, <italic>J</italic> = 11.8, 5.8 Hz, 0.25H), 1.82–1.61 (m, 5H), 1.48–1.28 (m, 5H), 1.09–1.04 (m, 0.75H), 0.98–0.87 (m, 1.25H); <sup>13</sup>C NMR (100 MHz): <italic>δ</italic> = 174.9, 170.7, 170.2, 135.6, 135.31, 135.26, 134.5, 131.8, 131.6, 128.7, 128.4, 123.8, 123.5, 77.2, 61.7, 58.4, 58.0, 55.4, 49.5, 49.1, 47.5, 47.4, 42.8, 42.7, 42.2, 36.8, 36.7, 35.1, 34.2, 33.0, 32.9, 32.3, 29.8, 29.5, 29.2, 26.1, 26.0, 25.8, 25.6; HRMS (EI) Calcd. For C<sub>25</sub>H<sub>34</sub>BrN<sub>5</sub>O<sub>3</sub> [M]<sup>+</sup>: 531.1845. Found: 531.1839.</p></sec><sec id="s0140"><label>4.1.20</label><title>(<italic>S</italic>)-2-[({(3<italic>S</italic>,4a<italic>R</italic>,8a<italic>S</italic>)-2-[(1,1′-Biphenyl)-4-carbonyl]decahydroisoquinolin-3-yl}methyl)amino]-3-(1<italic>H</italic>-imidazol-4-yl)propanal <bold>22</bold></title><p id="p0210">To a solution of above de-tritylated product of <bold>18</bold> (33 mg, 0.61 mmol) in CH<sub>2</sub>Cl<sub>2</sub> (1 mL), DIBALH (1.0 mol/L solution in hexane, 1.2 mL, 1.2 mmol) was added drop-wise at −78 °C. The reaction mixture was stirred for 5 min. The reaction was quenched with CH<sub>3</sub>OH and concentrated. The residue was dissolved in CH<sub>3</sub>OH and filtered through a silica gel layer. The filtrate was concentrated. The residue was purified by HPLC to give <bold>22</bold> (10.5 mg, 28%) as a colorless oil. [<italic>α</italic>]<sub>D</sub><sup>28</sup> −3.2 (<italic>c</italic> 0.48, CH<sub>3</sub>OH); <sup>1</sup>H NMR (500 MHz, CD<sub>3</sub>OD, referenced to residual CH<sub>3</sub>OH): <italic>δ</italic> = 8.80 (br s, 1H), 7.75–7.73 (m, 2H), 7.67–7.65 (m, 2H), 7.58 (d, <italic>J</italic> = 8.4 Hz, 2H), 7.50 (br s, 1H), 7.48–7.45 (m, 2.5H), 7.40–7.36 (m, 1.5H), 5.13 (m, 1H), 4.82 (dd, <italic>J</italic> = 8.4, 3.2 Hz, 1H), 3.88–3.79 (m, 2H), 3.63–3.59 (m, 1H), 3.43–3.40 (m, 1H), 3.34 (s, 1H), 2.97 (t, <italic>J</italic> = 12.6 Hz, 1H), 1.77–1.68 (m, 5H), 1.45–1.34 (m, 5H), 1.06–0.98 (m, 2H); <sup>13</sup>C NMR (125 MHz, CD<sub>3</sub>OD, referenced to CD<sub>3</sub>OD): <italic>δ</italic> = 175.1, 175.0, 163.0, 162.7, 144.70, 144.66, 141.1, 141.04, 135.5, 134.86, 134.80, 129.87, 129.86, 129.00, 128.97, 128.92, 128.0, 127.9, 118.6, 95.0, 94.9, 61.3, 61.0, 50.7, 50.5, 49.6, 47.2, 47.1, 43.2, 43.1, 37.59, 37.56, 35.2, 33.5, 30.2, 26.9, 26.5, 23.1, 22.9; HRMS (ESI) calcd for C<sub>29</sub>H<sub>35</sub>N<sub>4</sub>O<sub>2</sub> [M+H]<sup>+</sup>: 471.2760. Found: 471.2760.</p></sec><sec id="s0145"><label>4.1.21</label><title>(<italic>S</italic>)-2-((((3<italic>S</italic>,4a<italic>R</italic>,8a<italic>S</italic>)-2-(4-Bromobenzoyl)decahydroisoquinolin-3-yl)methyl)amino)-3-(1<italic>H</italic>-imidazol-4-yl)propanal <bold>23</bold></title><p id="p0215">A title compound <bold>23</bold> was synthesized from the de-tritylated product of <bold>19</bold> as above. Colorless oil; yield, 36%: [<italic>α</italic>]<sub>D</sub><sup>28</sup> −1.1 (<italic>c</italic> 0.40, CH<sub>3</sub>OH); <sup>1</sup>H NMR (400 MHz, CD<sub>3</sub>OD, referenced to residual CH<sub>3</sub>OH): <italic>δ</italic> = 8.72 (br s, 1H), 7.66–7.64 (m, 2H), 7.46 (br s, 1H), 7.41 (d, <italic>J</italic> = 8.4 Hz, 2H), 5.11–5.03 (m, 1H), 4.78 (dd, <italic>J</italic> = 11.0, 3.0 Hz, 1H), 3.85–3.75 (m, 2H), 3.47–3.39 (m, 2H), 3.26–3.24 (m, 1H), 2.96–2.84 (m, 1H), 1.78–1.54 (m, 5H), 1.43–1.22 (m, 5H), 1.07–0.93 (m, 2H); <sup>13</sup>C NMR (100 MHz, CD<sub>3</sub>OD, referenced to CD<sub>3</sub>OD): <italic>δ</italic> =
<italic>δ</italic> = 174.1, 173.5, 163.1, 162.6, 135.7, 135.45, 135.39, 133.0, 130.39, 130.35, 130.2, 125.84, 125.78, 118.8, 118.7, 95.1, 94.9, 61.3, 61.0, 50.64, 50.58, 43.3, 43.2, 37.71, 37.70, 37.68, 35.25, 35.22, 33.7, 30.4, 30.3, 27.0, 26.6, 23.2, 23.0; HRMS (ESI) calcd for C<sub>23</sub>H<sub>30</sub>BrN<sub>4</sub>O<sub>2</sub> [M+H]<sup>+</sup>: 473.1552. Found: 473.1543.</p></sec><sec id="s0150"><label>4.1.22</label><title>(<italic>S</italic>)-2-[({(3<italic>R</italic>,4a<italic>S</italic>,8a<italic>R</italic>)-2-[(1,1′-Biphenyl)-4-carbonyl]decahydroisoquinolin-3-yl}methyl)amino]-3-(1<italic>H</italic>-imidazol-4-yl)propanal <bold>24</bold></title><p id="p0220">A title compound <bold>24</bold> was synthesized from the de-tritylated product of <bold>20</bold> as above. Colorless oil; yield, 30%: [<italic>α</italic>]<sub>D</sub><sup>29</sup> −2.3 (<italic>c</italic> 0.61, CH<sub>3</sub>OH); <sup>1</sup>H NMR (500 MHz, CD<sub>3</sub>OD, referenced to residual CH<sub>3</sub>OH): <italic>δ</italic> = 8.76 (s, 1H), 7.74 (d, <italic>J</italic> = 6.4 Hz, 2H), 7.66 (d, <italic>J</italic> = 6.0 Hz, 2H), 7.56 (d, <italic>J</italic> = 6.4 Hz, 2H), 7.48–7.45 (m, 3.5H), 7.40–7.37 (m, 1.5H), 5.09 (br s, 1H), 3.86–3.75 (m, 2H), 3.64–3.59 (m, 1H), 3.55–3.48 (m, 1H), 3.35–3.32 (m, 1H), 3.28–3.26 (m, 1H), 2.93–2.91 (m, 1H), 1.79–1.66 (m, 5H), 1.47–1.28 (m. 5H), 1.07–0.97 (m, 2H); <sup>13</sup>C NMR (125 MHz, CD<sub>3</sub>OD, referenced to CD<sub>3</sub>OD): <italic>δ</italic> = 175.5, 175.4, 163.1, 162.8, 145.0, 141.2, 135.7, 135.6, 134.9, 130.1, 129.2, 129.1, 128.2, 128.1, 119.0, 95.4, 95.1, 62.1, 61.6, 50.8, 43.2, 43.1, 37.7, 35.5, 35.4, 33.8, 33.7, 30.4, 27.0, 26.6, 24.5, 24.1; LRMS (ESI) calcd for C<sub>29</sub>H<sub>35</sub>N<sub>4</sub>O<sub>2</sub> [M+H]<sup>+</sup>: 471.28. Found: 471.30.</p></sec><sec id="s0155"><label>4.1.23</label><title>(<italic>S</italic>)-2-({[(3<italic>R</italic>,4a<italic>S</italic>,8a<italic>R</italic>)-2-(4-Bromobenzoyl)decahydroisoquinolin-3-yl]methyl}amino)-3-(1<italic>H</italic>-imidazol-4-yl)propanal <bold>25</bold></title><p id="p0225">A title compound <bold>25</bold> was synthesized from the de-tritylated product of <bold>21</bold> as above. Colorless oil; yield, 28%: [<italic>α</italic>]<sub>D</sub><sup>29</sup> −7.8 (<italic>c</italic> 0.36, CH<sub>3</sub>OH); <sup>1</sup>H NMR (500 MHz, CD<sub>3</sub>OD, referenced to residual CH<sub>3</sub>OH): <italic>δ</italic> = 8.72 (br s, 1H), 7.66–7.62 (m, 2H), 7.45 (s, 1H), 7.43–7.36 (m, 2H), 5.06 (m, 1H), 3.83–3.75 (m, 2H), 3.49–3.46 (m, 2H), 3.34–3.33 (m, 1H), 3.28–3.23 (m, 1H), 2.92–2.85 (m, 1H), 1.76–1.58 (m, 5H), 1.44–1.26 (m, 5H), 1.06–0.93 (m, 2H); <sup>13</sup>C NMR (125 MHz, CD<sub>3</sub>OD, referenced to CD<sub>3</sub>OD): <italic>δ</italic> = 174.43, 174.35, 163.1, 162.8, 135.7, 135.6, 135.3, 133.0, 130.3, 125.9, 118.8, 95.4, 95.1, 62.1, 61.6, 50.7, 43.1, 43.0, 37.7, 37.6, 35.4, 35.3, 33.7, 30.3, 27.0, 26.6, 24.6, 24.1; LRMS (ESI) calcd for C<sub>23</sub>H<sub>30</sub>BrN<sub>4</sub>O<sub>2</sub> [M+H]<sup>+</sup>: 473.16. Found: 473.25.</p></sec><sec id="s0160"><label>4.1.24</label><title>(1<italic>S</italic>,6<italic>R</italic>)-6-{2-[(4-Bromobenzyl)oxy]ethyl}cyclohex-3-enecarboxylic acid <bold>31</bold></title><p id="p0230">To a solution of 1,3-butadiene (20 wt% solution in toluene, 108 mL, 255 mmol) was added (<italic>E</italic>)-ethyl 5-[(4-bromobenzyl)oxy]pent-2-enoate<xref rid="b0160" ref-type="bibr"><sup>32</sup></xref> (20.0 g, 63.9 mmol), and the mixture was heated at 225 °C for 60 h. After the reaction mixture was cooled to room temperature, water was added and the whole was extracted with AcOEt. The organic layer was washed with 1 M HCl and brine, dried over Na<sub>2</sub>SO<sub>4</sub>, filtered, and concentrated. The residue was purified by silica gel column chromatography (hexane/AcOEt = 35:1) to give an ethyl ester of <bold>29</bold>, (1<italic>S</italic>/<italic>R</italic>, 6<italic>R</italic>/<italic>S</italic>)-ethyl 6-{2-[(4-bromobenzyl)oxy]ethyl)}cyclohex-3-enecarboxylate, (11.7 g, 50%) as a yellow pale oil. <sup>1</sup>H NMR (400 MHz): <italic>δ</italic> = 7.47–7.45 (m, 2H), 7.22 (d, <italic>J</italic> = 8.4 Hz, 2H), 5.65 (m, 2H), 4.43 (dd, <italic>J</italic> = 18.8, 12.0 Hz, 2H) 4.14 (q, <italic>J</italic> = 7.2 Hz, 2H), 3.52–3.49 (m, 2H), 2.41–2.20 (m, 4H), 2.08–2.03 (m, 1H), 1.81–1.72 (m, 2H), 1.53–1.46 (m, 1H), 1.26 (t, <italic>J</italic> = 7.2 Hz, 3H); <sup>13</sup>C NMR (100 MHz): <italic>δ</italic> = 175.8, 137.5, 131.4, 129.2, 125.7, 124.8, 121.3, 72.1, 68.1, 60.3, 45.3, 33.7, 32.4, 29.9, 28.1, 14.3; HRMS (EI) Calcd for C<sub>18</sub>H<sub>23</sub>BrO<sub>3</sub> [M]<sup>+</sup>: 366.0831. Found: 366.0826.</p><p id="p0235">The above ester (31.8 g, 86.6 mmol) was dissolved in 2 M NaOH/THF (1:1, 100 mL). After being stirred for 15 h under reflux, the reaction mixture was cooled to room temperature. The mixture was acidified with 2 M HCl, and the whole was extracted with AcOEt. The organic layer was washed with brine, dried over Na<sub>2</sub>SO<sub>4</sub>, filtered, and concentrated. The residue purified by silica gel column chromatography (hexane/AcOEt = 3:1). The product was dissolved in AcOEt (300 mL) and then (<italic>S</italic>)-(−)-phenylethylamine (11 mL, 87 mmol) was added. After 12 h, the solid was collected by suction filtration. The free acid was liberated from the salt by treatment with 2 M HCl and extraction with AcOEt. The organic layer was washed with brine, dried over Na<sub>2</sub>SO<sub>4</sub>, filtered and concentrated. The residue was purified by silica gel column chromatography (hexane/AcOEt = 3:1) to give <bold>31</bold> [7.63 g, 26% (50% max.)] as a colorless oil. [<italic>α</italic>]<sub>D</sub><sup>28</sup> +22 (<italic>c</italic> 0.78, CHCl<sub>3</sub>); <sup>1</sup>H NMR (400 MHz): <italic>δ</italic> = 7.47–7.45 (m, 2H), 7.20 (d, <italic>J</italic> = 8.0 Hz, 2H), 5.69–5.66 (m, 2H), 4.44 (dd, <italic>J</italic> = 17.0, 12.2 Hz, 2H) 3.56–3.49 (m, 2H), 2.47–2.20 (m, 4H), 2.12–2.07 (m, 1H), 1.91–1.75 (m, 2H), 1.60–1.51 (m, 1H); <sup>13</sup>C NMR (100 MHz): <italic>δ</italic> = 181.1, 137.3, 131.5, 129.3, 125.7, 124.5, 121.4, 72.2, 68.0, 44.9, 33.6, 32.1, 29.5, 27.7; HRMS (EI) calcd for C<sub>16</sub>H<sub>19</sub>BrO<sub>3</sub> [M]<sup>+</sup>: 338.0518. Found: 338.0520.</p></sec><sec id="s0165"><label>4.1.25</label><title>[(1<italic>S</italic>,6<italic>R</italic>)-6-{2-[(4-Bromobenzyl)oxy]ethyl}cyclohex-3-en-1-yl]methanol</title><p id="p0240">To a solution of <bold>31</bold> (7.70 g, 22.7 mmol) in THF (80 mL), Et<sub>3</sub>N (6.4 mL, 46 mmol) and IBCF (4.5 mL, 34 mmol) were added at −20 °C. After being stirred for 15 min at the same temperature, NaBH<sub>4</sub> (3.47 g, 91.2 mmol) and H<sub>2</sub>O (10 drops from a pipette) was added. The mixture was warmed up to room temperature and then the reaction was quenched with saturated aqueous NH<sub>4</sub>Cl. The whole was extracted with AcOEt and the organic layer was washed with brine and dried over Na<sub>2</sub>SO<sub>4</sub>, filtered, and concentrated. The residue was purified by silica gel column chromatography (hexane/AcOEt = 3:1) to give a title alcohol (5.68 g, 77%) as a colorless oil. [<italic>α</italic>]<sub>D</sub><sup>29</sup> +22 (<italic>c</italic> 0.65, CHCl<sub>3</sub>); <sup>1</sup>H NMR (400 MHz): <italic>δ</italic> = 7.48–7.46 (m, 2H), 7.20 (d, <italic>J</italic> = 8.4 Hz, 2H), 5.65–5.58 (m, 2H), 4.45 (s, 2H), 3.68 (dd, <italic>J</italic> = 10.8, 6.4 Hz, 1H), 3.62 (dd, <italic>J</italic> = 10.8, 5.2 Hz, 1H), 3.58–3.47 (m, 2H), 2.15–2.09 (m, 2H), 2.00–1.76 (m, 4H), 1.66–1.49 (m, 3H); <sup>13</sup>C NMR (100 MHz): <italic>δ</italic> = 137.4, 131.5, 129.3, 125.8, 125.5, 121.4, 72.3, 68.7, 65.0, 39.7, 32.9, 31.1, 29.5, 26.6; HRMS (EI) calcd for C<sub>16</sub>H<sub>21</sub>BrO<sub>2</sub> [M]<sup>+</sup>: 324.0725. Found: 324.0732.</p></sec><sec id="s0170"><label>4.1.26</label><title>{[(1<italic>S</italic>,6<italic>R</italic>)-6-{2-[(4-Bromobenzyl)oxy]ethyl}cyclohex-3-en-1-yl]methoxy}(<italic>tert</italic>-butyl)diphenylsilane</title><p id="p0245">TBDPS-Cl (5.0 mL, 19 mmol) was added to a solution of above alcohol (5.66 g, 17.4 mmol) and imidazole (1.43 g, 21.0 mmol) in CH<sub>2</sub>Cl<sub>2</sub> (50 mL), and the mixture was stirred for 8 h at room temperature. The reaction was quenched with saturated aqueous NH<sub>4</sub>Cl, and the whole was extracted with AcOEt. The organic layer was washed with brine, dried over Na<sub>2</sub>SO<sub>4</sub>, filtered, and concentrated. The residue was purified by silica gel column chromatography (hexane/AcOEt = 30:1) to give a di-protected alcohol compound (9.81 g, quant.) as a colorless oil. [<italic>α</italic>]<sub>D</sub><sup>28</sup> +18.6 (<italic>c</italic> 1.74, CHCl<sub>3</sub>); <sup>1</sup>H NMR (400 MHz): <italic>δ</italic> = 7.67–7.64 (m, 4H), 7.44–7.34 (m, 8H), 7.17 (d, <italic>J</italic> = 8.4 Hz, 2H), 5.63–5.54 (m, 2H), 4.41 (dd, <italic>J</italic> = 15.2, 12.0 Hz, 2H), 3.68 (dd, <italic>J</italic> = 9.8, 5.4 Hz, 1H), 3.62 (dd, <italic>J</italic> = 10.0, 6.8 Hz, 1H), 3.50–3.46 (m, 2H), 2.16–1.96 (m, 3H), 1.87–1.81 (m, 2H), 1.71–1.68 (m, 2H), 1.48–1.44 (m, 1H), 1.05 (s, 9H); <sup>13</sup>C NMR (100 MHz): <italic>δ</italic> = 137.7, 135.61, 135.60, 133.94, 133.92, 131.4, 129.5, 129.1, 127.6, 125.8, 125.3, 121.2, 72.1, 68.7, 65.9, 39.6, 32.9, 30.8, 29.0, 26.9, 26.7, 19.3; HRMS (FAB) Calcd. For C<sub>32</sub>H<sub>40</sub>BrO<sub>5</sub> [M+H]<sup>+</sup>: 563.1981. Found: 563.1988.</p></sec><sec id="s0175"><label>4.1.27</label><title>2-[(1<italic>R</italic>,2<italic>S</italic>)-2-{[(<italic>tert</italic>-Butyldiphenylsilyl)oxy]methyl}cyclohexyl]ethanol 32</title><p id="p0250">To a solution of above di-protected alcohol (9.81 g, 17.4 mmol) in CH<sub>3</sub>OH/EtOAc/saturated aqueous NaHCO<sub>3</sub> (5:5:1, 110 mL), Pd-C (3.8 g) was added, and the mixture was stirred under a hydrogen gas atmosphere at room temperature for 6 h. The mixture was filtered through Celite and a silica gel layer, and the filtrate was dried over Na<sub>2</sub>SO<sub>4</sub>, filtered, and concentrated. The residue was purified by silica gel column chromatography (hexane/AcOEt = 6:1) to give <bold>32</bold> (6.90 g, quant.) as a colorless oil. [<italic>α</italic>]<sub>D</sub><sup>28</sup> +12 (<italic>c</italic> 0.65, CHCl<sub>3</sub>); <sup>1</sup>H NMR (400 MHz): <italic>δ</italic> = 7.68–7.65 (m, 4H), 7.43–7.36 (m, 6H), 3.67–3.56 (m, 4H), 1.78–1.70 (m, 5H), 1.37–1.21 (m, 6H), 1.06 (s, 9H), 1.02–0.96 (m, 1H); <sup>13</sup>C NMR (100 MHz): <italic>δ</italic> = 135.69, 135.66, 133.91, 133.89, 129.55, 129.54, 127.60, 127.57, 66.5, 61.0, 44.5, 36.5, 35.5, 31.9, 30.0, 26.9, 26.1, 26.0, 19.3; HRMS (FAB) calcd for C<sub>25</sub>H<sub>37</sub>O<sub>2</sub>Si [M+H]<sup>+</sup>: 397.2563. Found: 397.2558.</p></sec><sec id="s0180"><label>4.1.28</label><title>(<italic>S</italic>)-2-[({(3<italic>S</italic>,4a<italic>R</italic>,8a<italic>S</italic>)-2-[(1,1′-Biphenyl)-4-carbonyl]decahydroisoquinolin-3-yl}methyl)amino]-3-(1<italic>H</italic>-imidazol-4-yl)propanal <bold>40</bold></title><p id="p0255">Title compound was prepared from <bold>32</bold> according to the same procedure<xref rid="b0165" ref-type="bibr"><sup>33</sup></xref> employed for the synthesis of <bold>22</bold> starting from enantiomer mixture <bold>7</bold>. Colorless solid; yield, 30%: [<italic>α</italic>]<sub>D</sub><sup>28</sup> −4.3 (<italic>c</italic> 0.83, CH<sub>3</sub>OH); <sup>1</sup>H NMR (500 MHz, CD<sub>3</sub>OD, referenced to residual CH<sub>3</sub>OH): <italic>δ</italic> = 8.81 (br s, 1H), 7.75–7.73 (m, 2H), 7.67–7.65 (m, 2H), 7.58 (d, <italic>J</italic> = 8.0 Hz, 2H), 7.51 (br s, 1H), 7.48–7.45 (m, 2.5H), 7.40–7.36 (m, 1.5H), 5.14–5.13 (m, 1H), 4.81 (dd, <italic>J</italic> = 9.8, 2.6 Hz, 1H), 3.89–3.80 (m, 2H), 3.63–3.59 (m, 1H), 3.44–3.39 (m, 1H), 3.34 (s, 1H), 2.97 (t, <italic>J</italic> =12.6 Hz, 1H), 1.82–1.62 (m, 5H), 1.45–1.28 (m, 5H), 1.09–0.89 (m, 2H); <sup>13</sup>C NMR (125 MHz, CD<sub>3</sub>OD, referenced to CD<sub>3</sub>OD): <italic>δ</italic> = 175.24, 175.17, 163.2, 162.8, 144.9, 144.8, 141.21, 141.20, 135.6, 135.03, 134.97, 130.1, 129.22, 129.18, 129.12, 128.2, 128.1, 118.98, 118.95, 95.0, 94.9, 61.3, 60.9, 50.73, 50.69, 49.8, 47.1, 47.0, 43.33, 43.30, 37.8, 37.7, 35.4, 33.7, 30.4, 27.0, 26.6, 23.1, 22.9; HRMS (ESI) Calcd. For C<sub>29</sub>H<sub>35</sub>N<sub>4</sub>O<sub>2</sub> [M+H]<sup>+</sup>: 471.2760. Found: 471.2765.</p><p id="p0260">Compounds <bold>41</bold>, <bold>44</bold>, and <bold>45</bold>–<bold>49</bold> listed in <xref rid="t0005" ref-type="table">Table 1</xref> were similarly prepared as above.</p></sec><sec id="s0185"><label>4.1.29</label><title>Compound <bold>41</bold></title><sec id="s0190"><label>4.1.29.1</label><title>(S)-2-({[(3S,4aR,8aS)-2-(4-Bromobenzoyl)decahydroisoquinolin-3-yl]methyl}amino)-3-(1H-imidazol-4-yl)propanal <bold>41</bold></title><p id="p0265">Colorless solid; yield, 23%: [<italic>α</italic>]<sub>D</sub><sup>28</sup> −0.64 (<italic>c</italic> 0.88, CH<sub>3</sub>OH); <sup>1</sup>H NMR (400 MHz, CD<sub>3</sub>OD, referenced to residual CH<sub>3</sub>OH): <italic>δ</italic> = 8.80 (br s, 1H), 7.65–7.63 (m, 2H), 7.49 (br s, 1H), 7.42 (d, <italic>J</italic> = 8.4 Hz, 2H), 5.11 (m, 1H), 4.81–4.78 (m, 1H), 3.86–3.78 (m, 2H), 3.47–3.34 (m, 2H), 2.97–2.91 (m, 1H), 1.75–1.60 (m, 5H), 1.42–1.24 (m, 5H), 1.04–0.96 (m, 2H); <sup>13</sup>C NMR (100 MHz, CD<sub>3</sub>OD, referenced to CD<sub>3</sub>OD): <italic>δ</italic> = 174.2, 174.1, 163.2, 162.8, 135.6, 135.44, 135.39, 132.9, 130.40, 130.36, 130.0, 125.8, 125.7, 119.0, 118.9, 95.0, 94.9, 61.2, 60.8, 50.64, 50.60, 43.24, 43.22, 37.69, 37.66, 35.25, 35.23, 33.7, 30.4, 30.3, 27.0, 26.6, 23.1, 22.9; HRMS (ESI) calcd for C<sub>23</sub>H<sub>30</sub>BrN<sub>4</sub>O<sub>2</sub> [M+H]<sup>+</sup>: 473.1552. Found: 473.1546.</p></sec></sec><sec id="s0195"><label>4.1.30</label><title>Compound <bold>44</bold></title><p id="p0270">Colorless solid; yield, 31%: [<italic>α</italic>]<sub>D</sub><sup>28</sup> −1.62 (<italic>c</italic> 1.23, CH<sub>3</sub>OH); <sup>1</sup>H NMR (500 MHz, CD<sub>3</sub>OD, referenced to residual CH<sub>3</sub>OH): <italic>δ</italic> = 8.75 (s, 1H), 7.75 (d, <italic>J</italic> = 8.0 Hz, 2H), 7.66 (d, <italic>J</italic> = 7.2 Hz, 2H), 7.57 (d, <italic>J</italic> = 8.0 Hz, 2H), 7.47–7.45 (m, 3.5H), 7.40–7.37 (m, 1.5H), 5.09 (br s, 1H), 3.80 (m, 2H), 3.66–3.63 (m, 1H), 3.51 (m, 1H), 3.26 (m, 1H), 2.93–2.91 (m, 1H), 1.77–1.68 (m, 5H), 1.45–1.35 (m, 5H), 1.07–0.97 (m, 2H); <sup>13</sup>C NMR (125 MHz, CD<sub>3</sub>OD, referenced to CD<sub>3</sub>OD): <italic>δ</italic> = 175.5, 175.4, 163.2, 162.8, 144.9, 141.2, 135.6, 135.5, 134.9, 130.1, 129.2, 129.1, 128.2, 128.1, 119.1, 95.2, 95.0, 62.0, 61.4, 50.8, 43.12, 43.10, 37.73, 37.69, 35.5, 35.4, 33.7, 30.4, 27.0, 26.6, 24.4, 23.9; HRMS (ESI) calcd for C<sub>29</sub>H<sub>35</sub>N<sub>4</sub>O<sub>2</sub> [M+H]<sup>+</sup>: 471.2760. Found: 471.2756.</p></sec><sec id="s0200"><label>4.1.31</label><title>Compound <bold>45</bold></title><p id="p0275">Colorless solid; yield, 30%: [<italic>α</italic>]<sub>D</sub><sup>28</sup> −6.1 (<italic>c</italic> 1.0, CH<sub>3</sub>OH); <sup>1</sup>H NMR (500 MHz, CD<sub>3</sub>OD, referenced to residual CH<sub>3</sub>OH): <italic>δ</italic> = 8.82 (br s, 1H), 7.65 (d, <italic>J</italic> = 8.4 Hz, 2H), 7.49 (s, 1H), 7.40 (d, <italic>J</italic> = 8.0 Hz, 2H), 5.06 (m, 1H), 4.83 (m, 1H), 3.86–3.76 (m, 2H), 3.51–3.43 (m, 2H), 3.27–3.25 (m, 1H), 2.93–2.90 (m, 1H), 1.76–1.66 (m, 5H), 1.44–1.30 (m, 5H), 1.04–0.96 (m, 2H); <sup>13</sup>C NMR (125 MHz, CD<sub>3</sub>OD, referenced to CD<sub>3</sub>OD): <italic>δ</italic> = 174.43, 174.35, 163.1, 162.8, 135.6, 135.5, 135.3, 133.0, 130.4, 125.9, 119.1, 95.3, 95.0, 61.8, 61.3, 50.7, 43.03, 43.01, 37.7, 37.6, 35.4, 35.3, 33.7, 30.33, 30.31, 27.0, 26.6, 24.4, 23.9; HRMS (ESI) calcd for C<sub>23</sub>H<sub>30</sub>BrN<sub>4</sub>O<sub>2</sub> [M+H]<sup>+</sup>: 473.1552. Found: 4731537. Found: 4731537.</p></sec><sec id="s0205"><label>4.1.32</label><title>Compound <bold>46</bold></title><p id="p0280">Colorless solid; yield, 31%: [<italic>α</italic>]<sub>D</sub><sup>29</sup> −6.7 (<italic>c</italic> 0.10, CH<sub>3</sub>OH); <sup>1</sup>H NMR (400 MHz, CD<sub>3</sub>OD, referenced to residual CH<sub>3</sub>OH): <italic>δ</italic> = 8.66 (br s, 1H), 7.79–7.73 (m, 2H), 7.64–7.55 (m, 4H), 7.48–7.45 (m, 3.5H), 7.41–7.37 (m, 1.5H), 5.19–5.18 (m, 1H), 4.77 (dd, <italic>J</italic> = 12.6, 3.2 Hz, 1H), 3.87–3.79 (m, 2H), 3.63–3.58 (m, 1H), 3.46–3.40 (m, 1H), 3.36–3.34 (m, 0.5H), 3.25–3.23 (m, 1.5H), 2.99–2.93 (m, 1H), 1.79–1.62 (m, 5H), 1.42–1.21 (m, 5H), 1.10–0.89 (m, 2H); LRMS (ESI) calcd for C<sub>29</sub>H<sub>35</sub>N<sub>4</sub>O<sub>2</sub> [M+H]<sup>+</sup>: 471.28. Found: 471.35.</p></sec><sec id="s0210"><label>4.1.33</label><title>Compound <bold>47</bold></title><p id="p0285">Colorless solid; yield, 27% (obtained as the mixture of a diastereomer derived from Pd-mediated cyclization): <sup>1</sup>H NMR (400 MHz, CD<sub>3</sub>OD, referenced to residual CH<sub>3</sub>OH): <italic>δ</italic> = 8.84 (br s, 1H), 7.59–7.38 (m, 11H), 5.03 (m, 1H), 4.81 (dd, <italic>J</italic> = 10.0, 2.8 Hz, 1H), 3.90 (m, 1H), 3.69–3.59 (m, 1H), 3.41 (m, 1H), 3.34 (s, 1H), 3.27–3.24 (m, 1H), 2.93–2.87 (m, 1H), 2.61–2.54 (m, 1H), 1.59–1.56 (m, 2H), 1.50 (d, <italic>J</italic> = 10.4 Hz, 1H), 1.42 (d, <italic>J</italic> = 12.4 Hz, 1H), 1.18–1.08 (m, 2H), 0.99–0.88 (m, 3H), 0.70–0.61 (m, 1H), 0.46–0.44 (m, 1H); LRMS (ESI) calcd for C<sub>29</sub>H<sub>35</sub>N<sub>4</sub>O<sub>2</sub> [M+H]<sup>+</sup>: 471.28. Found: 471.35.</p></sec><sec id="s0215"><label>4.1.34</label><title>Compound <bold>48</bold></title><p id="p0290">Colorless solid; yield, 25%: [<italic>α</italic>]<sub>D</sub><sup>29</sup> −3.7 (<italic>c</italic> 0.15, CH<sub>3</sub>OH); <sup>1</sup>H NMR (400 MHz, CD<sub>3</sub>OD, referenced to residual CH<sub>3</sub>OH): <italic>δ</italic> = 8.61 (br s, 1H), 7.52–7.46 (m, 6H), 7.45–7.41 (m, 1H), 5.13–5.11 (m, 2H), 4.77 (dd, <italic>J</italic> = 11.8, 3.4 Hz, 1H), 3.79–3.66 (m, 1H), 3.56–3.50 (m, 1H), 3.42–3.32 (m, 1H), 3.26–3.20 (m, 1H), 2.97–2.91 (m, 1H), 1.78–1.59 (m, 5H), 1.40–1.20 (m, 5H), 1.08–0.86 (m, 2H); LRMS (ESI) calcd for C<sub>23</sub>H<sub>31</sub>N<sub>4</sub>O<sub>2</sub> [M+H]<sup>+</sup>: 395.24. Found: 395.30.</p></sec><sec id="s0220"><label>4.1.35</label><title>Compound <bold>49</bold></title><p id="p0295">Colorless solid; yield, 18%: [<italic>α</italic>]<sub>D</sub><sup>29</sup> −3.6 (<italic>c</italic> 0.18, CH<sub>3</sub>OH); <sup>1</sup>H NMR (400 MHz, CD<sub>3</sub>OD, referenced to residual CH<sub>3</sub>OH): <italic>δ</italic> = 8.68 (br s, 1H), 7.56–7.53 (m, 2H), 7.44 (br s, 1H), 7.25–7.19 (m, 3H), 5.10 (m, 1H), 4.77 (dd, <italic>J</italic> = 11.4, 3.2 Hz, 1H), 3.84–3.75 (m, 2H), 3.52–3.47 (m, 1H), 3.40–3.34 (m, 1H), 3.25–3.23 (m, 1H), 2.96–2.89 (m, 1H), 1.78–1.65 (m, 5H), 1.43–1.23 (m, 5H), 1.05–0.93 (m, 2H); LRMS (ESI) calcd for C<sub>23</sub>H<sub>30</sub>FN<sub>4</sub>O<sub>2</sub> [M+H]<sup>+</sup>: 413.24. Found: 413.35.</p></sec></sec><sec id="s0225"><label>4.2</label><title>Estimation of IC<sub>50</sub> values</title><p id="p0300">Peptide substrate [H-Thr-Ser-Ala-Val-Leu-Gln-Ser-Gly-Phe-Arg-Lys-NH<sub>2</sub>]<xref rid="b0140" ref-type="bibr"><sup>28</sup></xref> (111 μM) in a reaction solution (25 μL of 20 mM Tris–HCl buffer pH 7.5 containing 7 mM DTT) was incubated with the R188I SARS 3CL<sup>pro</sup><xref rid="b0140" ref-type="bibr"><sup>28</sup></xref> (56 nM) at 37 °C for 60 min in the presence of various inhibitor concentrations at 37 °C for 60 min. The cleavage reaction was monitored by analytical HPLC [Cosmosil 5C18 column (4.6 × 150 mm), a linear gradient of CH<sub>3</sub>CN (10–20%) in an aq0.1% TFA over 30 min], and the cleavage rates were calculated from the reduction in the substrate peak area. Each IC<sub>50</sub> value was obtained from the sigmoidal dose-response curve (see <xref rid="s0245" ref-type="sec">Fig. S1</xref> for a typical sigmoidal curve). Each experiment was repeated 3 times and the results were averaged.</p></sec><sec id="s0230"><label>4.3</label><title>X-ray crystallography</title><p id="p0305">The purified SARS 3CL<sup>pro</sup> in 20 mM Bis–Tris pH 5.5, 10 mM NaCl, and 1 mM DTT was concentrated to 8 mg/mL.<xref rid="b0065" ref-type="bibr"><sup>13</sup></xref> Crystals of SARS 3CL<sup>pro</sup> were grown at 4 °C using a sitting-drop vapor diffusion method by mixing it with an equal volume of reservoir solution containing 100 mM MES pH 6.2, 5–10% PEG20000, and 5 mM DTT. Cubic-shaped crystals with dimensions of 0.3 mm × 0.3 mm × 0.3 mm grew within 3 days. The crystals were then soaked for 24 h with reservoir-based solution of 100 mM MES pH 6.2, 5–8% PEG20000, and 5 mM DTT containing 3 mM of <bold>40</bold> or <bold>44</bold>. Crystals were then transferred into a cryobuffer of 100 mM MES pH 6.2, 10% PEG20000, 5 mM DTT, 15% ethylene glycol containing 3 mM of <bold>40</bold> or <bold>44</bold>, and flash-frozen in a nitrogen stream at 100 K. X-ray diffraction data of SARS 3CL<sup>pro</sup> in complexes with inhibitor <bold>40</bold> or <bold>44</bold> were collected at the SPring-8, beamline BL44XU with a Rayonix MX300HE CCD detector at a wavelength of 0.900 Å.</p><p id="p0310">Crystals of SARS 3CL<sup>pro</sup> in a complex with <bold>41</bold> were obtained by co-crystallization using sitting-drop vapor diffusion at 4 °C and mixing an equal volume of protein-inhibitor complex (final inhibitor concentration of 3 mM) and a reservoir solution containing 100 mM MES pH 6.0, 5–6% PEG20000, and 5 mM DTT. Cubic-shaped crystals with dimensions of 0.2 mm × 0.2 mm × 0.2 mm were obtained within 3 days. Crystals were transferred into cryobuffer with 100 mM MES pH 6.0, 6% PEG20000, 5 mM DTT, 15% ethylene glycol, and 3 mM of <bold>41</bold> and then flash-frozen in a nitrogen stream at 100 K. X-ray diffraction data were collected on a Rigaku RAXIS VII imaging-plate detector at a wavelength of 1.5418 Å equipped with an in-house rotating anode FR-E/Super Bright X-ray generator and Confocal VariMax (VariMax HF) optics system.</p><p id="p0315">The structures of SARS 3CL<sup>pro</sup> in a complex with inhibitors were determined by molecular replacement using the Molrep<xref rid="b0170" ref-type="bibr"><sup>34</sup></xref> program with a R188I SARS 3CL<sup>pro</sup> structure (PDB code 3AW1<xref rid="b0065" ref-type="bibr"><sup>13</sup></xref>) as the search model. Rigid body refinement and subsequent restrained refinement protocols were performed with the program Refmac 5<xref rid="b0175" ref-type="bibr"><sup>35</sup></xref> of the CCP package.<xref rid="b0180" ref-type="bibr"><sup>36</sup></xref> The Coot program<xref rid="b0185" ref-type="bibr"><sup>37</sup></xref> was used for manual model rebuilding. Water molecules were added using Coot only after the refinement of protein structures had converged. Ligands generated on JLigand<xref rid="b0190" ref-type="bibr"><sup>38</sup></xref> software were directly built into the corresponding difference in electron density, and the model was then subjected to an additional round of refinement. The figures for structural representation were generated on Pymol<xref rid="b0195" ref-type="bibr"><sup>39</sup></xref> or chimera<xref rid="b0200" ref-type="bibr"><sup>40</sup></xref> software.</p></sec></sec><sec id="s0235"><label>5</label><title>PDB ID codes</title><p id="p0320">4TWY, 4TWW, and 4WY3.</p></sec></body><back><ref-list id="bi005"><title>References and notes</title><ref id="b0005"><label>1</label><element-citation publication-type="journal" id="h0005"><person-group person-group-type="author"><name><surname>Lee</surname><given-names>N.</given-names></name><name><surname>Hui</surname><given-names>D.</given-names></name><name><surname>Wu</surname><given-names>A.</given-names></name><name><surname>Chan</surname><given-names>P.</given-names></name><name><surname>Cameron</surname><given-names>P.</given-names></name><name><surname>Joynt</surname><given-names>F.M.</given-names></name><name><surname>Ahuja</surname><given-names>A.</given-names></name><name><surname>Yung</surname><given-names>M.Y.</given-names></name><name><surname>Leung</surname><given-names>C.B.</given-names></name><name><surname>To</surname><given-names>K.F.</given-names></name><name><surname>Leu</surname><given-names>M.D.</given-names></name><name><surname>Szeto</surname><given-names>C.C.</given-names></name><name><surname>Chung</surname><given-names>S.</given-names></name><name><surname>Sung</surname><given-names>J.J.Y.</given-names></name></person-group><source>N. 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Chem.</source><volume>25</volume><year>2004</year><fpage>1605</fpage><pub-id pub-id-type="pmid">15264254</pub-id></element-citation></ref></ref-list><sec id="s0245" sec-type="supplementary-material"><title>Supplementary data</title><p id="p0335"><supplementary-material content-type="local-data" id="m0005"><caption><title>Supplementary data</title><p>The HPLC data for the evaluation of purities using a reversed-phase or chiral column, typical sigmoidal curves used to obtain IC<sub>50</sub> values, and NMR data of synthesized compounds.</p></caption><media xlink:href="mmc1.pdf"></media></supplementary-material></p></sec><ack id="ak005"><title>Acknowledgments</title><p>This work was supported, in part, by a Grant-in-aid for Scientific Research 25460160 to K.A. from the <funding-source id="gp005">Japan Society for the Promotion of Science</funding-source> and by a grant for Adaptable and Seamless Technology Transfer Program through Target-driven R&D AS251Z01976Q to Y.H. from <funding-source id="gp010">Japan Science and Technology Agency</funding-source>. We thank Shimadzu Co. for the measurements of mass spectra using LCMS-IT-TOF MS.</p></ack><fn-group><fn id="s0240" fn-type="supplementary-material"><p id="p0330">Supplementary data (the HPLC data for the evaluation of purities using a reversed-phase or chiral column, typical sigmoidal curves used to obtain IC<sub>50</sub> values, and NMR data of synthesized compounds) associated with this article can be found, in the online version, at <ext-link ext-link-type="doi" xlink:href="10.1016/j.bmc.2014.12.028" id="ir005">http://dx.doi.org/10.1016/j.bmc.2014.12.028</ext-link>.</p></fn></fn-group></back></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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