LrgpV1, Istex, Corpus, bibRecord, 000647

Synthetic studies towards garsubellin A: synthesis of model systems and potential mimics by regioselective lithiation of bicyclo[3.3.1]nonane-2,4,9-trione derivatives from catechinic acid

Identifieur interne : 000647 ( Istex/Corpus ); précédent : 000646; suivant : 000648

Synthetic studies towards garsubellin A: synthesis of model systems and potential mimics by regioselective lithiation of bicyclo[3.3.1]nonane-2,4,9-trione derivatives from catechinic acid

Auteurs : Nadia M. Ahmad ; Vincent Rodeschini ; Nigel S. Simpkins ; Simon E. Ward ; Claire Wilson

Source :

Organic & Biomolecular Chemistry [ 1477-0520 ] ; 2007.

RBID : ISTEX:B7DF17E00AEC85F9B1966633ABA866EAB6A765A7

English descriptors

KwdEn :
- Allyl, Aqueous nacl, Aroch, Aromatic moiety, Biomol, Bridged, Bridged ketone, Bridgehead, Bridgehead position, Bridgehead substitution, Bromide, Carboxylic acid, Catechinic, Catechinic acid, Catechol, Cdcl3, Chcl3, Chcl3 mmax, Chem, Column chromatography, Deep solution, Derivative, Electrophiles, Garsubellin, Hrms, Ketal, Ketone, Lett, Lithiation, Ltmp, Mgso4, Mmax, Mmol, Nacl, Natural products, Organic extracts, Organic layers, Oxidative, Oxidative degradation, Petroleum, Prenyl, Prenyl bromide, Quenched, Reaction mixture, Regioselective lithiation, Royal society, Substituents, Substitution, Tetrahedron lett, Title compound, Total synthesis, Vacuo, Various electrophiles.
Teeft :
- Allyl, Aqueous nacl, Aroch, Aromatic moiety, Biomol, Bridged, Bridged ketone, Bridgehead, Bridgehead position, Bridgehead substitution, Bromide, Carboxylic acid, Catechinic, Catechinic acid, Catechol, Cdcl3, Chcl3, Chcl3 mmax, Chem, Column chromatography, Deep solution, Derivative, Electrophiles, Garsubellin, Hrms, Ketal, Ketone, Lett, Lithiation, Ltmp, Mgso4, Mmax, Mmol, Nacl, Natural products, Organic extracts, Organic layers, Oxidative, Oxidative degradation, Petroleum, Prenyl, Prenyl bromide, Quenched, Reaction mixture, Regioselective lithiation, Royal society, Substituents, Substitution, Tetrahedron lett, Title compound, Total synthesis, Vacuo, Various electrophiles.

Abstract

Bridgehead lithiations have successfully been carried out on substrates derived from catechinic acid, which possess the core bicyclo[3.3.1]nonane-1,3,5-trione structure present in garsubellin A. Using an external quench method, various electrophiles have been incorporated at the C-5 bridgehead position in a one-step process that appears to be sensitive to the substitution pattern on the bicyclic system. Regioselective lithiation at the C-3 sp2 centre was achieved by changing the base used from LDA to LTMP. Following the introduction of a prenyl substituent by bridgehead substitution, annulation of a THF ring, analogous to that in garsubellin A, was possible via an epoxidation–ring opening sequence. Oxidative modification of the catechol substituent of the catechinic acid core was possible to give systems with muconic acid, ortho-quinone or furan 2-carboxylic acid side chains.

Url:

https://api.istex.fr/document/B7DF17E00AEC85F9B1966633ABA866EAB6A765A7/fulltext/pdf

DOI: 10.1039/b704311b

Links to Exploration step

ISTEX:B7DF17E00AEC85F9B1966633ABA866EAB6A765A7

Le document en format XML

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<front><div type="abstract">Bridgehead lithiations have successfully been carried out on substrates derived from catechinic acid, which possess the core bicyclo[3.3.1]nonane-1,3,5-trione structure present in garsubellin A. Using an external quench method, various electrophiles have been incorporated at the C-5 bridgehead position in a one-step process that appears to be sensitive to the substitution pattern on the bicyclic system. Regioselective lithiation at the C-3 sp2 centre was achieved by changing the base used from LDA to LTMP. Following the introduction of a prenyl substituent by bridgehead substitution, annulation of a THF ring, analogous to that in garsubellin A, was possible via an epoxidation–ring opening sequence. Oxidative modification of the catechol substituent of the catechinic acid core was possible to give systems with muconic acid, ortho-quinone or furan 2-carboxylic acid side chains.</div>
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<note>Electronic supplementary information (ESI) available: Experimental procedures and/or full spectroscopic data for compounds 19–26, 32–42, 44, 46–50. See DOI: 10.1039/b704311b</note>
<note>Transformations of catechinic acid, including protection, bridgehead substitution, and catechol oxidation were explored as a possible approach to garsubellin A [b704311b-ga.tif]</note>
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<monogr><title level="j">Organic & Biomolecular Chemistry</title>
<title level="j" type="abbrev">Org. Biomol. Chem.</title>
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<abstract><p>Bridgehead lithiations have successfully been carried out on substrates derived from catechinic acid, which possess the core bicyclo[3.3.1]nonane-1,3,5-trione structure present in garsubellin A. Using an external quench method, various electrophiles have been incorporated at the C-5 bridgehead position in a one-step process that appears to be sensitive to the substitution pattern on the bicyclic system. Regioselective lithiation at the C-3 sp2 centre was achieved by changing the base used from LDA to LTMP. Following the introduction of a prenyl substituent by bridgehead substitution, annulation of a THF ring, analogous to that in garsubellin A, was possible via an epoxidation–ring opening sequence. Oxidative modification of the catechol substituent of the catechinic acid core was possible to give systems with muconic acid, ortho-quinone or furan 2-carboxylic acid side chains.</p>
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<doi>10.1039/b704311b</doi>
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<day>21</day>
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<date role="accepted"><year>2007</year>
<month>April</month>
<day>25</day>
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<date><year>2007</year>
<month>May</month>
<day>15</day>
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<published type="print"><journalref><link>OB</link>
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<published type="subsyear"><journalref><title type="abbreviated">Org. Biomol. Chem.</title>
<title type="full">Organic & Biomolecular Chemistry</title>
<title type="journal">Organic & Biomolecular Chemistry</title>
<title type="display">Organic & Biomol. Chem + Perkin Trans. + Contemp. Org Synth.</title>
<title type="pubmed">Org Biomol Chem</title>
<sercode>OB</sercode>
<publisher><orgname><nameelt>The Royal Society of Chemistry</nameelt>
</orgname>
</publisher>
<issn type="print">1477-0520</issn>
<issn type="online">1477-0539</issn>
<coden>OBCRAK</coden>
<cpyrt>This journal is © The Royal Society of Chemistry</cpyrt>
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<issueref><link>12</link>
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</published>
<art-links><suppinf><link>INFO</link>
</suppinf>
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<art-front><titlegrp><title>Synthetic studies towards garsubellin A: synthesis of model systems and potential mimics by regioselective lithiation of bicyclo[3.3.1]nonane-2,4,9-trione derivatives from catechinic acid<fnoteref idrefs="fn1"></fnoteref>
<footnote id="fn1"><p>Electronic supplementary information (ESI) available: Experimental procedures and/or full spectroscopic data for compounds <compoundref idrefs="chem19">19–26</compoundref>
, <compoundref idrefs="chem32">32–42</compoundref>
, <compoundref idrefs="chem44">44</compoundref>
, <compoundref idrefs="chem46">46–50</compoundref>
. See DOI: <url>10.1039/b704311b</url>
</p>
</footnote>
</title>
</titlegrp>
<authgrp><author aff="affa"><person><persname><fname>Nadia M.</fname>
<surname>Ahmad</surname>
</persname>
</person>
</author>
<author aff="affa"><person><persname><fname>Vincent</fname>
<surname>Rodeschini</surname>
</persname>
</person>
</author>
<author aff="affa" role="corres"><person><persname><fname>Nigel S.</fname>
<surname>Simpkins</surname>
</persname>
</person>
</author>
<author aff="affb"><person><persname><fname>Simon E.</fname>
<surname>Ward</surname>
</persname>
</person>
</author>
<author aff="affa"><person><persname><fname>Claire</fname>
<surname>Wilson</surname>
</persname>
</person>
</author>
<aff id="affa"><org><orgname><nameelt>School of Chemistry</nameelt>
<nameelt>The University of Nottingham</nameelt>
</orgname>
</org>
<address><addrelt>University Park</addrelt>
<city>Nottingham</city>
<postcode>NG7 2RD</postcode>
<country>UK</country>
</address>
<email>nigel.simpkins@nottingham.ac.uk</email>
</aff>
<aff id="affb"><org><orgname><nameelt>Medicinal Chemistry</nameelt>
<nameelt>Psychiatry Centre of Excellence for Drug Discovery</nameelt>
<nameelt>GlaxoSmithKline</nameelt>
</orgname>
</org>
<address><addrelt>New Frontiers Science Park</addrelt>
<addrelt>Third Avenue</addrelt>
<city>Harlow, Essex</city>
<postcode>CM19 5AW</postcode>
<country>UK</country>
</address>
</aff>
</authgrp>
<art-toc-entry><ictext>Transformations of catechinic acid, including protection, bridgehead substitution, and catechol oxidation were explored as a possible approach to garsubellin A</ictext>
<icgraphic xsrc="b704311b-ga.tif" id="ga"></icgraphic>
</art-toc-entry>
<abstract><p>Bridgehead lithiations have successfully been carried out on substrates derived from catechinic acid, which possess the core bicyclo[3.3.1]nonane-1,3,5-trione structure present in garsubellin A. Using an external quench method, various electrophiles have been incorporated at the C-5 bridgehead position in a one-step process that appears to be sensitive to the substitution pattern on the bicyclic system. Regioselective lithiation at the C-3 sp<sup>2</sup>
 centre was achieved by changing the base used from LDA to LTMP. Following the introduction of a prenyl substituent by bridgehead substitution, annulation of a THF ring, analogous to that in garsubellin A, was possible <it>via</it>
 an epoxidation–ring opening sequence. Oxidative modification of the catechol substituent of the catechinic acid core was possible to give systems with muconic acid, <it>ortho</it>
-quinone or furan 2-carboxylic acid side chains.</p>
</abstract>
</art-front>
<art-body><section><title>Introduction</title>
<p>The natural products known as polyprenylated acylphloroglucinols (PPAPs) have emerged as an important class of compounds due to their broad range of biological activities.<citref idrefs="cit1">1</citref>
 These compounds, isolated from various plants and trees from the family Clusiaceae, are characterised by the presence of a common bicyclo[3.3.1]nonane-1,3,5-trione core, decorated with prenyl (or geranyl) and acyl groups. Important examples include garsubellin A, hyperforin and clusianone, <figref idrefs="fig1">Fig. 1</figref>
.</p>
<figure xsrc="b704311b-f1.tif" id="fig1"><title>Representative PPAP natural products.</title>
</figure>
<p>These challenging structures, together with promising therapeutic potential have made these molecules attractive targets for total synthesis.<citref idrefs="cit2">2</citref>
 As a result, a number of research groups have described synthetic approaches to these compounds, and recently garsubellin A (<compoundref idrefs="chem1">1</compoundref>
) has succumbed to total synthesis by the groups of Shibasaki, and Danishefsky.<citref idrefs="cit3 cit4">3,4</citref>
</p>
<p>We recently described the first total synthesis of clusianone (<compoundref idrefs="chem3">3</compoundref>
),<citref idrefs="cit5">5</citref>
 and also a formal synthesis of garsubellin A.<citref idrefs="cit6">6</citref>
 This work, inspired by a previous approach of Spessard and Stoltz,<citref idrefs="cit7">7</citref>
 employed a malonyl dichloride (<compoundref idrefs="chem5">5</compoundref>
) annulation (Effenberger cyclisation)<citref idrefs="cit8">8</citref>
 of a cyclohexanone-derived enol ether <compoundref idrefs="chem4">4</compoundref>
 to set up the [3.3.1] trione core structure <compoundref idrefs="chem6">6</compoundref>
, <schemref idrefs="sch1">Scheme 1</schemref>
. Subsequent elaboration to the target natural product was then possible by regioselective metallation–substitution reactions at both the bridgehead C-5 and C-3 sp<sup>2</sup>
 hybridised positions.</p>
<scheme xsrc="b704311b-s1.tif" id="sch1"><title>Access to the [3.3.1] core <it>via</it>
 Effenberger annulation.</title>
</scheme>
<p>Although this approach enabled a rapid access to clusianone, and has the potential to deliver other PPAPs, it has a number of deficiencies. First and foremost is the consistently modest efficiency of the type of annulation shown in <schemref idrefs="sch1">Scheme 1</schemref>
 which, at least in our hands, rarely provides more than 25–30% yields.<citref idrefs="cit9">9</citref>
 Secondly, and in line with most other synthetic work in this area, the method has provided only racemic intermediates to date.<citref idrefs="cit10">10</citref>
</p>
<p>In parallel with our synthetic investigations summarised above, we also surveyed the literature for alternative promising entries to enantiopure starting materials for PPAP synthesis. We identified a little-known, and remarkable, rearrangement of the naturally occurring, readily available, flavanoid (+)-catechin (<compoundref idrefs="chem7">7</compoundref>
) into the bicyclo[3.3.1]nonane-1,3,5-trione derivative catechinic acid (<compoundref idrefs="chem8">8</compoundref>
) under alkaline conditions (<schemref idrefs="sch2">Scheme 2</schemref>
).<citref idrefs="cit11">11</citref>
</p>
<scheme xsrc="b704311b-s2.tif" id="sch2"><title>Preparation and protection of catechinic acid.</title>
</scheme>
<p>Reported over thirty years ago by Sears <it>et al.</it>
 this highly stereoselective transformation has not attracted much interest since. For our purpose, catechinic acid (<compoundref idrefs="chem8">8</compoundref>
) constituted a promising, enantiopure entry into the bicyclic core of PPAP type structures, and might even constitute a chiral pool starting material for natural products such as garsubellin A.</p>
<p>As a prerequisite to a synthetic study towards <compoundref idrefs="chem1">1</compoundref>
 using <compoundref idrefs="chem8">8</compoundref>
 as a template, two key issues needed to be addressed: (i) the introduction of appropriate substituents at both bridgehead positions C-1 and C-5, as well as at position C-3; (ii) the conversion of the catechol ring at position C-8 of <compoundref idrefs="chem8">8</compoundref>
 into the <it>gem</it>
-dimethyl group present in <compoundref idrefs="chem1">1</compoundref>
.</p>
<p>The solution to the substitution problems at C-1, C-3 and C-5 were explored in parallel to our studies using the Effenberger derived materials (<schemref idrefs="sch1">Scheme 1</schemref>
). In this regard the catechinic acid derived bicyclic systems could function as useful, and readily available, model systems to probe the scope and regiocontrol of substitution chemistry. Clearly, if the catechinic acid system was to provide access to the natural products themselves then degradation of the C-8 catechol unit was a key issue. In this regard the oxidative degradation of an aromatic ring into a carboxylic acid derivative is a well known transformation.<citref idrefs="cit12">12</citref>
 In turn, a C-8 carboxylic function would allow introduction of the desired <it>gem</it>
-dimethyl through a methylation–reduction sequence. In order to address these issues, a systematic study was initiated on suitably protected derivatives of <compoundref idrefs="chem8">8</compoundref>
.</p>
<p>In this paper we describe in full detail our results concerning the bridgehead substitution of catechinic acid derivatives through the selective formation of bridgehead enolates. Also reported is the selective introduction of various substituents at the C-3 sp<sup>2</sup>
 position of <compoundref idrefs="chem8">8</compoundref>
. Additionally, the formation of the THF ring present in <compoundref idrefs="chem1">1</compoundref>
 is reported starting with a prenylated derivative, involving an epoxidation–ring opening sequence. Finally, some interesting results obtained by the oxidative degradation of the aromatic moiety of intermediates derived from <compoundref idrefs="chem8">8</compoundref>
 are described.</p>
</section>
<section><title>Results and discussion</title>
<subsect1><no>(i)</no>
<title>Regioselective bridgehead substitution</title>
<p>Our study began with the protection of the acidic residues present in catechinic acid (<compoundref idrefs="chem8">8</compoundref>
). Following literature precedent, methylation under basic conditions afforded regioisomers <compoundref idrefs="chem9">9</compoundref>
 and <compoundref idrefs="chem10">10</compoundref>
 in 58% overall yield from <compoundref idrefs="chem7">7</compoundref>
 (<schemref idrefs="sch2">Scheme 2</schemref>
). The mixture of secondary alcohols was then treated with TIPSOTf and lutidine to afford the corresponding silylated vinylogous ester derivatives <compoundref idrefs="chem11">11</compoundref>
 and <compoundref idrefs="chem12">12</compoundref>
 in 75% yield (3 : 1 ratio), which were separated by column chromatography.</p>
<p>With suitable substrates in hand, initial studies of bridgehead substitution reactions were undertaken. Initial attempts to deprotonate major regioisomer <compoundref idrefs="chem11">11</compoundref>
 using excess LDA or LTMP (1 to 5 eq.) in THF at −78 °C in the presence of Me<inf>3</inf>
SiCl (<it>in situ</it>
 quench) failed to give any silylated product and starting material was recovered, <schemref idrefs="sch3">Scheme 3</schemref>
.</p>
<scheme xsrc="b704311b-s3.tif" id="sch3"><title>Initial metallation attempts.</title>
</scheme>
<p>Although previously this <it>in situ</it>
 quench technique had proved highly effective for bridgehead silylation of various substrates,<citref idrefs="cit13">13</citref>
 it proved singularly unsuccessful in this case, starting with either regioisomer <compoundref idrefs="chem11">11</compoundref>
 or <compoundref idrefs="chem12">12</compoundref>
. Similar lack of product formation was also observed when more conventional external quenching reactions were attempted, using similar excess of base at low temperature for up to 3 hours, followed by addition of D<inf>2</inf>
O, or reactive alkyl halides. After some experimentation under these external quench conditions, we found that increasing the amount of LDA to 10 equivalents allowed the bridgehead deprotonation of <compoundref idrefs="chem11">11</compoundref>
 to occur, and after a quench with prenyl bromide, derivative <compoundref idrefs="chem13">13</compoundref>
 was isolated in 42% yield, <schemref idrefs="sch3">Scheme 3</schemref>
.</p>
<p>Despite this preliminary success, the modest yield of <compoundref idrefs="chem13">13</compoundref>
 obtained, together with the fact that the reaction was less effective with a number of other electrophiles, prompted us to modify the structures of our substrates in order to make bridgehead lithiation more facile. We were interested to probe the effect of modifying the bridging ketone, especially since reduction or protection could generate slightly less rigid structures that might better accommodate the ‘bridgehead enolate’ character of the reactive intermediate. The first modification tested was to convert the bridgehead ketone into the corresponding dimethylketal. Thus, under acidic conditions, ketones <compoundref idrefs="chem9">9</compoundref>
 and <compoundref idrefs="chem10">10</compoundref>
 were converted into intermediate ketals, and the secondary alcohols were then directly silylated as previously described to afford the regioisomeric ketals <compoundref idrefs="chem16">16</compoundref>
 and <compoundref idrefs="chem17">17</compoundref>
 (<schemref idrefs="sch4">Scheme 4</schemref>
).</p>
<scheme xsrc="b704311b-s4.tif" id="sch4"><title>Synthesis of [3.3.1] systems with bridging ketal functions.</title>
</scheme>
<p>We were able to clarify any regiochemical ambiguity as X-ray crystallography confirmed the structure of the major isomer <compoundref idrefs="chem16">16</compoundref>
 (<figref idrefs="fig2">Fig. 2</figref>
).</p>
<figure xsrc="b704311b-f2.tif" id="fig2"><title>X-Ray structure of <compoundref idrefs="chem16">16</compoundref>
 (ellipsoids are shown at 50% probability).</title>
</figure>
<p>Further studies focused on the lithiation of the major regioisomeric ketal <compoundref idrefs="chem16">16</compoundref>
. As observed with ketone <compoundref idrefs="chem11">11</compoundref>
, the use of an excess of LDA or LTMP under <it>in situ</it>
 quench conditions with various electrophiles failed to give any bridgehead substituted products when using ketal <compoundref idrefs="chem16">16</compoundref>
. In contrast, the use of 5 equivalents of LDA–LiCl under external quench conditions (<schemref idrefs="sch3">Scheme 3</schemref>
), enabled efficient bridgehead deprotonation–substitution of <compoundref idrefs="chem16">16</compoundref>
 to afford prenylated product <compoundref idrefs="chem18">18</compoundref>
 in a very acceptable 75% yield. The use of external quench conditions opened up the opportunity to use various electrophiles, and pleasingly, under our optimised conditions, various C-5 derivatives <compoundref idrefs="chem18">18</compoundref>
–<compoundref idrefs="chem26">26</compoundref>
 were furnished in moderate to good yield (<tableref idrefs="tab1">Table 1</tableref>
).</p>
<table-entry id="tab1"><title>Bridgehead alkylation of ketal <compoundref idrefs="chem16">16</compoundref>
<ugraphic xsrc="b704311b-u1.tif" id="ugr1"></ugraphic>
</title>
<table><tgroup cols="4"><colspec colname="1" colwidth="0.81*"></colspec>
<colspec colname="2" colwidth="0.74*"></colspec>
<colspec colname="3" colwidth="1.61*"></colspec>
<colspec colname="4" colwidth="0.84*"></colspec>
<thead><row><entry>Electrophile</entry>
<entry>R</entry>
<entry>Yield</entry>
<entry>Compound</entry>
</row>
</thead>
<tfoot><row><entry namest="1" nameend="4"><footnote id="tab1fna">Yield in parentheses is based on recovered starting material.</footnote>
<footnote id="tab1fnb">Diastereomeric ratio.</footnote>
</entry>
</row>
</tfoot>
<tbody><row><entry>Prenyl bromide</entry>
<entry>Prenyl</entry>
<entry>75 (89)<fnoteref idrefs="tab1fna"></fnoteref>
</entry>
<entry><compoundref idrefs="chem18">18</compoundref>
</entry>
</row>
<row><entry>Me<inf>3</inf>
SiCl</entry>
<entry>Me<inf>3</inf>
Si</entry>
<entry>46 (59)<fnoteref idrefs="tab1fna"></fnoteref>
</entry>
<entry><compoundref idrefs="chem19">19</compoundref>
</entry>
</row>
<row><entry>Allyl Br</entry>
<entry>Allyl</entry>
<entry>46</entry>
<entry><compoundref idrefs="chem20">20</compoundref>
</entry>
</row>
<row><entry>BnBr</entry>
<entry>Bn</entry>
<entry>56</entry>
<entry><compoundref idrefs="chem21">21</compoundref>
</entry>
</row>
<row><entry>MeI</entry>
<entry>Me</entry>
<entry>48 (55)<fnoteref idrefs="tab1fna"></fnoteref>
</entry>
<entry><compoundref idrefs="chem22">22</compoundref>
</entry>
</row>
<row><entry>PhCHO</entry>
<entry>PhCH(OH)</entry>
<entry>51 (1 : 1)<fnoteref idrefs="tab1fnb"></fnoteref>
</entry>
<entry><compoundref idrefs="chem23">23</compoundref>
</entry>
</row>
<row><entry><sup>i</sup>
PrCHO</entry>
<entry><sup>i</sup>
PrCH(OH)</entry>
<entry>31 (42)<fnoteref idrefs="tab1fna"></fnoteref>
</entry>
<entry><compoundref idrefs="chem24">24</compoundref>
</entry>
</row>
<row><entry>Ph<inf>2</inf>
S<inf>2</inf>
</entry>
<entry>PhS</entry>
<entry>67</entry>
<entry><compoundref idrefs="chem25">25</compoundref>
</entry>
</row>
<row><entry><sup><it>n</it>
</sup>
Bu<inf>3</inf>
SnCl</entry>
<entry>Bu<inf>3</inf>
Sn</entry>
<entry>63</entry>
<entry><compoundref idrefs="chem26">26</compoundref>
</entry>
</row>
</tbody>
</tgroup>
</table>
</table-entry>
<p>The origin of the requirement for a large excess of base is unclear but lower yields of the products were obtained when fewer equivalents of base were employed. We saw no evidence for substitution at the alternative C-1 bridgehead position, and fortuitously for our planned natural product work quenching with prenyl bromide proved to be most effective. Heteroatom substituents such as Si, Sn or S groups could also be efficiently introduced at the bridgehead position, although attempted iodine quenching led to intractable mixtures, probably involving C-3 substitution. When benzaldehyde was used as electrophile, the aldol product <compoundref idrefs="chem23">23</compoundref>
 was isolated as an equimolar mixture of diastereoisomers, whereas the use of isobutyraldehyde resulted in a single isomer <compoundref idrefs="chem24">24</compoundref>
, albeit in modest yield.</p>
<p>Surprisingly, reaction of <compoundref idrefs="chem16">16</compoundref>
 with the acylating agent EtOCOCN gave product <compoundref idrefs="chem27">27</compoundref>
, in which substitution had occurred at both the C-3 and C-5 positions, <schemref idrefs="sch5">Scheme 5</schemref>
. This behaviour appears unlikely to be due to dianion formation (little or no disubstituted product was observed in most other cases) and could be the result of activation of the system at C-3 following initial acylation at the bridgehead.</p>
<scheme xsrc="b704311b-s5.tif" id="sch5"><title>Double acylation of <compoundref idrefs="chem16">16</compoundref>
.</title>
</scheme>
<p>In order to further probe the metallation chemistry of these systems we also prepared a catechinic acid derivative in which the bridging ketone was converted into a protected alcohol. Thus, diastereoselective reduction of ketone <compoundref idrefs="chem11">11</compoundref>
, using NaBH<inf>4</inf>
, provided alcohol <compoundref idrefs="chem28">28</compoundref>
, which was then protected as the corresponding TES ether (<schemref idrefs="sch6">Scheme 6</schemref>
).</p>
<scheme xsrc="b704311b-s6.tif" id="sch6"><title>Synthesis and lithiation of reduced derivative <compoundref idrefs="chem29">29</compoundref>
.</title>
</scheme>
<p>In this case, our standard metallation–quenching conditions furnished the prenylated product <compoundref idrefs="chem30">30</compoundref>
 in a very modest 26% yield. This result contradicts our early hypothesis that an sp<sup>3</sup>
-hybridised bridging atom might prove superior to a more rigid bridging ketone. The bridgehead substitution is clearly viable in each of <compoundref idrefs="chem11">11</compoundref>
, <compoundref idrefs="chem16">16</compoundref>
 and <compoundref idrefs="chem29">29</compoundref>
, but the overall efficiency of the process is difficult to predict. It is possible that chelation with the ketal oxygen atoms plays a part in facilitating lithiation in the case of ketal derivative <compoundref idrefs="chem16">16</compoundref>
, whereas steric effects may have the opposite effect in the bulky OTES compound <compoundref idrefs="chem29">29</compoundref>
.</p>
</subsect1>
<subsect1><no>(ii)</no>
<title>Regioselective sp<sup>2</sup>
 substitution</title>
<p>So far, our successful results relied on the use of LDA, and only bridgehead substitution was observed, with no isolable quantities of side products from substitution at either C-1 or C-3. It was interesting to study whether the nature of the base could allow us to modify this selectivity, and based on literature precedent it appeared that substitution of the vinylogous ester at C-3 should be possible.<citref idrefs="cit14">14</citref>
 When changing LDA for the more sterically encumbered LTMP, ketal <compoundref idrefs="chem16">16</compoundref>
 failed to give any bridgehead substitution product when the lithiated intermediate was quenched with prenyl (or allyl) bromide. In contrast, the use of Me<inf>3</inf>
SiCl as electrophile gave a new product in a modest yield, which proved to be the vinyl silane <compoundref idrefs="chem31">31</compoundref>
. Thus by using a bulkier lithium amide, the site of deprotonation on ketal <compoundref idrefs="chem16">16</compoundref>
 could be altered. This trend was further exemplified by reaction of the lithiated species with different electrophiles (<tableref idrefs="tab2">Table 2</tableref>
).</p>
<table-entry id="tab2"><title>C-3 substitution of ketal <compoundref idrefs="chem16">16</compoundref>
<ugraphic xsrc="b704311b-u2.tif" id="ugr2"></ugraphic>
</title>
<table><tgroup cols="4"><colspec colname="1" colwidth="0.94*"></colspec>
<colspec colname="2" colwidth="0.59*"></colspec>
<colspec colname="3" colwidth="1.46*"></colspec>
<colspec colname="4" colwidth="1.01*"></colspec>
<thead><row><entry>Electrophile</entry>
<entry>R</entry>
<entry>Yield</entry>
<entry>Compound</entry>
</row>
</thead>
<tfoot><row><entry namest="1" nameend="4"><footnote id="tab2fna">No reaction, starting material was recovered.</footnote>
</entry>
</row>
</tfoot>
<tbody><row><entry>Me<inf>3</inf>
SiCl</entry>
<entry>Me<inf>3</inf>
Si</entry>
<entry>45</entry>
<entry><compoundref idrefs="chem31">31</compoundref>
</entry>
</row>
<row><entry>MeI</entry>
<entry>Me</entry>
<entry>36</entry>
<entry><compoundref idrefs="chem32">32</compoundref>
</entry>
</row>
<row><entry>PhCOCl</entry>
<entry>PhCO</entry>
<entry>50</entry>
<entry><compoundref idrefs="chem33">33</compoundref>
</entry>
</row>
<row><entry><sup><it>n</it>
</sup>
Bu<inf>3</inf>
SnCl</entry>
<entry>Bu<inf>3</inf>
Sn</entry>
<entry>61</entry>
<entry><compoundref idrefs="chem34">34</compoundref>
</entry>
</row>
<row><entry>Allyl bromide</entry>
<entry>Allyl</entry>
<entry>—<fnoteref idrefs="tab2fna"></fnoteref>
</entry>
<entry>—</entry>
</row>
<row><entry>Prenyl bromide</entry>
<entry>Prenyl</entry>
<entry>—<fnoteref idrefs="tab2fna"></fnoteref>
</entry>
<entry>—</entry>
</row>
</tbody>
</tgroup>
</table>
</table-entry>
<p>Disappointingly, allyl or prenyl substituents could not be introduced at this position by this method (we later developed the use of cuprates to effect this type of substitution<citref idrefs="cit6">6</citref>
). The use of iodine or diphenyl disulfide as the electrophile led to complex mixtures. In the case of benzoyl chloride, the benzoylated derivative <compoundref idrefs="chem33">33</compoundref>
 was isolated in 50% yield. Increasing the amount of LTMP to 10 equivalents resulted in the isolation of the di-substituted product <compoundref idrefs="chem35">35</compoundref>
 in 55% yield. As with the previously described acylation leading to <compoundref idrefs="chem27">27</compoundref>
 this last result could be due to sequential substitution or may indicate the intermediacy of a dianion. However, we were unable to provide further evidence that the reactive species may be a dianion in this system (for example quenching with D<inf>2</inf>
O did <it>not</it>
 give double incorporation).<ugraphic xsrc="b704311b-u3.tif" id="ugr3"></ugraphic>
</p>
<p>Thus far, various substituents had been selectively introduced at positions C-3 and C-5 by altering the base employed. However, it was also of interest to introduce substituents at bridgehead position C-1, as most natural PPAPs have substituents at both their bridgehead positions. We thought that using the minor regioisomeric ketal <compoundref idrefs="chem17">17</compoundref>
 might allow lithiation to occur at position C-1 by analogy with previous results. Thus, isomer <compoundref idrefs="chem17">17</compoundref>
 was subjected to our optimised conditions. In this case, bridgehead substitution was not observed, only vinylic substitution (<tableref idrefs="tab3">Table 3</tableref>
).</p>
<table-entry id="tab3"><title>Lithiation-substitution of regioisomeric ketal <compoundref idrefs="chem17">17</compoundref>
<ugraphic xsrc="b704311b-u4.tif" id="ugr4"></ugraphic>
</title>
<table><tgroup cols="5"><colspec colname="1" colwidth="0.92*"></colspec>
<colspec colname="2" colwidth="0.67*"></colspec>
<colspec colname="3" colwidth="0.86*"></colspec>
<colspec colname="4" colwidth="1.54*"></colspec>
<colspec colname="5" colwidth="1.02*"></colspec>
<thead><row><entry>Electrophile</entry>
<entry>R</entry>
<entry>Base</entry>
<entry>Yield</entry>
<entry>Compound</entry>
</row>
</thead>
<tfoot><row><entry namest="1" nameend="5"><footnote id="tab3fna">Yields in parentheses based on recovered starting material.</footnote>
</entry>
</row>
</tfoot>
<tbody><row><entry>Me<inf>3</inf>
SiCl</entry>
<entry>Me<inf>3</inf>
Si</entry>
<entry>LDA–LiCl</entry>
<entry>31 (34)<fnoteref idrefs="tab3fna"></fnoteref>
</entry>
<entry><compoundref idrefs="chem36">36</compoundref>
</entry>
</row>
<row><entry>MeI</entry>
<entry>Me</entry>
<entry>LDA–LiCl</entry>
<entry>60</entry>
<entry><compoundref idrefs="chem37">37</compoundref>
</entry>
</row>
<row><entry>Prenyl bromide</entry>
<entry>Prenyl</entry>
<entry>LDA–LiCl</entry>
<entry>25 (33)<fnoteref idrefs="tab3fna"></fnoteref>
</entry>
<entry><compoundref idrefs="chem38">38</compoundref>
</entry>
</row>
<row><entry>Prenyl bromide</entry>
<entry>Prenyl</entry>
<entry>LTMP</entry>
<entry>51</entry>
<entry><compoundref idrefs="chem38">38</compoundref>
</entry>
</row>
</tbody>
</tgroup>
</table>
</table-entry>
<p>It is likely that the steric bulk of the aromatic residue at C-8 hinders deprotonation at C-1 in this case, although it should be noted that Danishefsky accomplished metallation at this position during the aforementioned garsubellin A synthesis.<citref idrefs="cit4">4</citref>
 Using TMSCl, MeI or prenyl bromide as electrophiles, derivatives <compoundref idrefs="chem36">36</compoundref>
–<compoundref idrefs="chem38">38</compoundref>
 were isolated in moderate to good yields. It is worth noting that changing the base to LTMP did not change the selectivity, but allowed us to improve the yield of prenylation at the vinylic position. Having established that the selective introduction of substituents at the C-5 bridgehead and C-3 sp<sup>2</sup>
 positions was possible through the use of an appropriate base, we decided to further advance key intermediates by constructing the five-membered THF ring present in <compoundref idrefs="chem1">1</compoundref>
.</p>
</subsect1>
<subsect1><no>(iii)</no>
<title>Synthesis of the THF ring</title>
<p>In contrast with the methodologies used previously by the groups of Danishefsky and Shibasaki during their total synthesis of <compoundref idrefs="chem1">1</compoundref>
, we wanted to form the THF ring through the epoxidation of the C-5 bridgehead prenyl residue, followed by a <it>5</it>
-<it>exo</it>
-<it>tet</it>
 cyclisation involving the C-4 oxygen atom. This cyclisation would be accompanied by the cleavage of the vinylogous ester. Our first attempts to form the epoxide of <compoundref idrefs="chem18">18</compoundref>
 using <it>m</it>
CPBA resulted in very low mass recovery. In contrast, the use of freshly prepared dimethyldioxirane (DMDO) allowed the epoxidation to proceed smoothly, affording a diastereomeric mixture of two epoxides. Due to instability of the epoxides on silica, we explored methods to directly cyclise the crude diastereomeric mixture, and we established that reaction with TMSCl effected their conversion into the separable THF derivatives <compoundref idrefs="chem39">39</compoundref>
 and <compoundref idrefs="chem40">40</compoundref>
 (<schemref idrefs="sch7">Scheme 7</schemref>
).<citref idrefs="cit15">15</citref>
</p>
<scheme xsrc="b704311b-s7.tif" id="sch7"><title>Side chain epoxidation and cyclisation.</title>
</scheme>
<p>Trimethylsilyl chloride was found to be much more effective than the corresponding iodide for this cyclisation, which we assume proceeds <it>via</it>
 silicon-mediated activation of the epoxide. Surprisingly, however, we have not been able to directly isolate the silicon protected alcohol derivatives from this reaction.</p>
<p>The relative stereochemistry of the major diastereoisomer <compoundref idrefs="chem40">40</compoundref>
 was determined through NOE studies and proved to have the unnatural side chain configuration. The alcohols <compoundref idrefs="chem39">39</compoundref>
 and <compoundref idrefs="chem40">40</compoundref>
 were readily converted into the corresponding silyl ethers <compoundref idrefs="chem41">41</compoundref>
 and <compoundref idrefs="chem42">42</compoundref>
. We decided to use the major silyl ether <compoundref idrefs="chem42">42</compoundref>
 to probe the feasibility of the direct installation of a prenyl residue at the C-3 sp<sup>2</sup>
 position, a result that had eluded us with compound <compoundref idrefs="chem16">16</compoundref>
. Once again we were unable to effect C-3 allylation or prenylation using either LDA or LTMP under the conditions described previously, <schemref idrefs="sch8">Scheme 8</schemref>
.</p>
<scheme xsrc="b704311b-s8.tif" id="sch8"><title>Attempted C-3 prenylation of <compoundref idrefs="chem42">42</compoundref>
.</title>
</scheme>
<p>The facile synthesis of vinyl bromide <compoundref idrefs="chem44">44</compoundref>
 enabled us to try the same type of substitution, originating with a halogen–metal transfer process, but again no product was obtained. The problem here is certainly one of poor reactivity of the intermediate organolithium and, as mentioned earlier, we eventually solved this problem by allylation of a mixed cuprate generated using thienyl copper cyanide.<citref idrefs="cit6">6</citref>
 This chemistry was not explored on the catechinic acid systems.</p>
</subsect1>
<subsect1><no>(iv)</no>
<title>Oxidative degradation of the catechol ring</title>
<p>As shown before, in order to set up a synthesis of <compoundref idrefs="chem1">1</compoundref>
, the aromatic moiety at position C-8 needed to be converted into the <it>gem</it>
-dimethyl group present in <compoundref idrefs="chem1">1</compoundref>
. The use of a ruthenium based oxidation on a suitably protected derivative of catechinic acid <compoundref idrefs="chem8">8</compoundref>
 was attempted to degrade the aromatic ring to a carboxylic acid (<compoundref idrefs="chem11">11</compoundref>
					→
					<compoundref idrefs="chem45">45</compoundref>
, <schemref idrefs="sch9">Scheme 9</schemref>
).</p>
<scheme xsrc="b704311b-s9.tif" id="sch9"><title>Attempted oxidative cleavage of <compoundref idrefs="chem11">11</compoundref>
.</title>
</scheme>
<p>In our case, however, a variety of conditions failed to provide any quantities of acid <compoundref idrefs="chem45">45</compoundref>
. Use of Sharpless conditions rapidly led to decomposition of the starting material.<citref idrefs="cit16">16</citref>
 Alternative conditions for the <it>in situ</it>
 formation of the active species RuO<inf>4</inf>
 were tried, including the use of RuO<inf>2</inf>
 or the complex <it>cis</it>
[Ru(bpy)]<inf>2</inf>
Cl<inf>2</inf>
 with NaIO<inf>4</inf>
 but in each case only decomposition was observed.<citref idrefs="cit17 cit18">17,18</citref>
 Ozonolysis of <compoundref idrefs="chem11">11</compoundref>
 followed by an acidic work up also failed to provide derivative <compoundref idrefs="chem45">45</compoundref>
.<citref idrefs="cit19">19</citref>
</p>
<p>At this stage, a system bearing a free catechol unit was prepared as a means to make the aromatic moiety more easily oxidisable. Catechol derivatives <compoundref idrefs="chem46">46</compoundref>
 and <compoundref idrefs="chem47">47</compoundref>
 were prepared from <compoundref idrefs="chem8">8</compoundref>
 as depicted in <schemref idrefs="sch10">Scheme 10</schemref>
.</p>
<scheme xsrc="b704311b-s10.tif" id="sch10"><title>Synthesis of systems with a free catechol unit.</title>
</scheme>
<p>Initial silylation of the secondary alcohol as well as the two phenolic positions of <compoundref idrefs="chem8">8</compoundref>
 led, after methylation of the 1,3 diketone moiety to an inseparable mixture of tris-silylated derivatives. Selective deprotection of the phenolic hydroxyls was easily performed under acidic conditions to provide catechols <compoundref idrefs="chem46">46</compoundref>
 and <compoundref idrefs="chem47">47</compoundref>
 which were then separated by chromatography.</p>
<p>As seen for <compoundref idrefs="chem11">11</compoundref>
, the use of RuO<inf>4</inf>
 based oxidation led to the rapid decomposition of the starting material. However, the presence of a free catechol function opened up the possibility of a more step-wise strategy, for example <it>via</it>
 muconic acid or quinone intermediates. To explore the first of these we followed the procedure of Gilheany,<citref idrefs="cit20">20</citref>
 which involved reaction of catechol <compoundref idrefs="chem46">46</compoundref>
 with Pb(OAc)<inf>4</inf>
 in MeOH, and were pleased to isolate the muconic acid diester derivative <compoundref idrefs="chem48">48</compoundref>
 in very high yield (<schemref idrefs="sch11">Scheme 11</schemref>
).</p>
<scheme xsrc="b704311b-s11.tif" id="sch11"><title>Oxidative cleavage of <compoundref idrefs="chem46">46</compoundref>
.</title>
</scheme>
<p>With this new intermediate, we were hoping to be able to reach an acid derivative similar to <compoundref idrefs="chem45">45</compoundref>
 by the simultaneous oxidative cleavage of the two conjugated olefins in <compoundref idrefs="chem48">48</compoundref>
. However, <compoundref idrefs="chem48">48</compoundref>
 proved to be completely inert towards dihydroxylation. In the case of ozonolysis, the substrate reacted with the initial cleavage of the disubstituted olefin but no products resulting from the cleavage of both C–C double bonds of the muconic acid moiety could be isolated.</p>
<p>Another potential route for the degradation of the aromatic part was explored using the minor regioisomer <compoundref idrefs="chem47">47</compoundref>
, as depicted in <schemref idrefs="sch12">Scheme 12</schemref>
.</p>
<scheme xsrc="b704311b-s12.tif" id="sch12"><title>Formation of side chain quinone <compoundref idrefs="chem49">49</compoundref>
 and furan <compoundref idrefs="chem50">50</compoundref>
.</title>
</scheme>
<p>Oxidation of <compoundref idrefs="chem47">47</compoundref>
 using Ag<inf>2</inf>
CO<inf>3</inf>
 on Celite (Fetizon's reagent)<citref idrefs="cit21">21</citref>
 resulted in an extremely clean conversion to the corresponding <it>ortho</it>
-quinone <compoundref idrefs="chem49">49</compoundref>
. Then, a one pot dihydroxylation–diol cleavage sequence was attempted, using a mixture of OsO<inf>4</inf>
 and NaIO<inf>4</inf>
.<citref idrefs="cit22">22</citref>
 To our surprise, under these conditions, <compoundref idrefs="chem49">49</compoundref>
 was converted into a furan carboxylic acid derivative, which was isolated as the corresponding methyl ester <compoundref idrefs="chem50">50</compoundref>
 after methylation under basic conditions. On further checking the literature we established a reasonable precedent for this transformation in the work of Gierer and Imsgard.<citref idrefs="cit23">23</citref>
</p>
<p>Further attempts to cleave the furan ring using ozonolysis failed to give any usable products.<citref idrefs="cit24">24</citref>
</p>
</subsect1>
</section>
<section><title>Conclusions</title>
<p>In conclusion, the regioselective lithiation of derivatives of catechinic acid (<compoundref idrefs="chem8">8</compoundref>
), possessing the bicyclo[3.3.1]nonane-1,3,5-trione core has been achieved. In the case of bridging ketal <compoundref idrefs="chem16">16</compoundref>
, the use of LDA promoted selective bridgehead substitution, whilst LTMP enabled metallation–substitution at the C-3 sp<sup>2</sup>
 centre. With reactive electrophiles, such as acylating agents, we observed a tendency towards double substitution at both the C-3 and C-5 positions.</p>
<p>With regioisomer <compoundref idrefs="chem17">17</compoundref>
, the use of either LDA or LTMP led to lithiation at the sp<sup>2</sup>
 center. These lithiations have been shown to be dependent on the nature of substitution at the bridging atom with the bridging dimethylketal proving superior to either a bridging ketone or a reduced and silicon protected variant.</p>
<p>A THF ring, resembling that present in garsubellin A, was appended to the catechinic acid system through an epoxidation–ring opening sequence. Oxidative degradation of the aryl group of our catechinic acid derivatives to give a carboxylic acid derivative did not succeed as predicted, although an interesting transformation of an <it>ortho</it>
-quinone intermediate into a furan derivative was achieved. Although we have not yet been able to use catechinic acid to achieve an asymmetric synthesis of <compoundref idrefs="chem1">1</compoundref>
, this template has provided us with a very rapid access to a wide range of enantiomerically pure bicyclo[3.3.1]nonane derivatives. Some of these new compounds have been tested for their biological properties; results will be reported in due course.</p>
</section>
<section><title>Experimental</title>
<subsect1><title>General methods</title>
<p>All reactions were performed under an atmosphere of nitrogen in flame dried glassware unless otherwise stated. Organic solvents and reagents were dried by distillation from the following as required: THF (sodium–benzophenone), DCM, TMSCl (CaH<inf>2</inf>
). Allyl bromide, prenyl bromide, benzaldehyde, benzyl bromide, ethyl cyanoformate, iodomethane, and triethylamine were all distilled before use. Lead tetraacetate was freshly recrystallised before use from AcOH–Ac<inf>2</inf>
O. All other solvents and reagents were used as received from commercial suppliers unless otherwise stated. RT relates to the temperature range 20–25 °C. Reaction progress was monitored by thin layer chromatography (TLC) performed on Merck aluminium plates coated with kieselgel F<inf>254</inf>
. Visualisation was achieved by a combination of ultraviolet light (254 nm) and anisaldehyde or acidic potassium permanganate. Flash chromatography was performed using silica gel (Merck 7734 grade), eluted with the indicated solvent. Melting points were recorded on a Stuart Scientific SMP3 apparatus and are uncorrected. Infrared spectra were recorded on a Perkin-Elmer 1600 FT-IR spectrometer as dilute solutions in spectroscopic grade chloroform within a NaCl cell. NMR spectra were recorded on a Bruker AV400 or DRX500 machine, using CDCl<inf>3</inf>
 as solvent at 298 K. Chemical shifts are given in ppm downfield from tetramethylsilane, using residual protic solvent as an internal standard. <it>J</it>
 values are reported in Hz and rounded to the nearest 0.1 Hz. Where required, assignments were confirmed by two-dimensional homonuclear (<sup>1</sup>
H–<sup>1</sup>
H) and heteronuclear (<sup>1</sup>
H–<sup>13</sup>
C) correlation spectroscopy on a Brucker AV400 spectrometer. Mass spectra were obtained using a VG Micromass 70E spectrometer, using electron impact (EI) at 70 eV or chemical ionisation (CI) or electrospray ionisation (ESI). Optical rotations were recorded as dilute solutions in the indicated solvent in a 100 mm cell using a JASCO DIP370 digital polarimeter at a wavelength of 598 nm.</p>
</subsect1>
<subsect1><title>(1<it>S</it>
,5<it>R</it>
,7<it>S</it>
,8<it>R</it>
)-(+)-8-(3,4-Dimethoxyphenyl)-7-hydroxy-2-methoxybicyclo[3.3.1]non-2-ene-4,9-one <compoundref idrefs="chem9">9</compoundref>
 and (1<it>S</it>
,5<it>R</it>
,7<it>S</it>
,8<it>R</it>
)-(+)-8-(3,4-dimethoxyphenyl)-7-hydroxy-4-methoxy-bicyclo[3.3.1]non-3-ene-2,9-one <compoundref idrefs="chem10">10</compoundref>
</title>
<p>Solid KOH (600 mg, 6.90 mmol) was added to a solution of (+)-catechin (<compoundref idrefs="chem7">7</compoundref>
) (2.00 g, 25.0 mmol) in water (80 ml) and the reaction mixture was then heated under reflux for 105 min. The reaction mixture was allowed to cool, filtered through a pad of Amberlite IR-120 and concentrated <it>in vacuo</it>
 to give a dark red solid (2.0 g, quantitative). Crude catechinic acid (<compoundref idrefs="chem8">8</compoundref>
) was used without purification. Dimethyl sulfate (25.0 mL, 36.9 mmol, 7.7 eq.) and K<inf>2</inf>
CO<inf>3</inf>
 (15.7 g, 15.8 mmol, 3.3 eq.) were added to crude <compoundref idrefs="chem8">8</compoundref>
 (10.0 g, 4.8 mmol) in acetone (500 mL), and the solution was heated under reflux for 18 h. The reaction mixture was allowed to cool, diluted with H<inf>2</inf>
O (200 mL), and extracted with EtOAc (4 × 100 mL). The organic extract was dried (MgSO<inf>4</inf>
) and concentrated <it>in vacuo</it>
 to give the crude product as a fluffy orange solid. Purification by column chromatography (petroleum ether–EtOAc 3 : 7) gave regioisomers <compoundref idrefs="chem9">9</compoundref>
 and <compoundref idrefs="chem10">10</compoundref>
 in a 3 : 1 ratio (6.4 g, 58% over two steps) data for <compoundref idrefs="chem9">9</compoundref>
; [<it>α</it>
]<stack><above>27</above>
<below>D</below>
</stack>
 +147 (<it>c</it>
 1.0 in CHCl<inf>3</inf>
); <it>ν</it>
<inf>max</inf>
 (CHCl<inf>3</inf>
) 3463 (br), 2906, 1652, 1603, 1516, 1452, 1379, 1230, 1105, 1068 cm<sup>−1</sup>
; <sup>1</sup>
H NMR (400 MHz, CDCl<inf>3</inf>
) <it>δ</it>
 1.89–1.97 (m, 1H, CH<it>H</it>
), 2.23 (br s, 1H, O<it>H</it>
), 2.57 (ddd, <it>J</it>
 13.0, 8.8, 5.3, 1H, C<it>H</it>
H), 3.08 (dd, <it>J</it>
 11.0, 3.9, 1H, ArC<it>H</it>
), 3.29 (m, 2H, 1-C<it>H</it>
, 5-C<it>H</it>
), 3.57 (s, 3H, OC<it>H</it>
<inf>3</inf>
), 3.85 (s, 3H, OC<it>H</it>
<inf>3</inf>
), 3.86 (s, 3H, OC<it>H</it>
<inf>3</inf>
), 4.40 (ddd, <it>J</it>
 11.0, 11.0, 5.3, 1H, C<it>H</it>
OH), 5.70 (s, 1H, CC<it>H</it>
), 6.66 (d, <it>J</it>
 2.0, 1H, Ar<it>H</it>
), 6.69 (dd, <it>J</it>
 8.2, 2.0, 1H, Ar<it>H</it>
), 6.84 (d, <it>J</it>
 8.2, 1H, Ar<it>H</it>
); <sup>13</sup>
C NMR (100 MHz, CDCl<inf>3</inf>
) <it>δ</it>
 37.2 (CH<inf>2</inf>
), 53.2 (CH), 56.5 (CH<inf>3</inf>
), 56.5 (CH<inf>3</inf>
), 57.1 (CH<inf>3</inf>
), 58.9 (CH), 59.4 (CH), 66.1 (CH), 105.1 (CH), 111.0 (CH), 111.3 (CH), 119.8 (CH), 129.7 (C), 148.7 (C), 149.2 (C), 174.5 (C), 194.9 (C), 203.9 (C); HRMS (EI) <it>m</it>
/<it>z</it>
 333.1362 [M + H]<sup>+</sup>
, [C<inf>18</inf>
H<inf>21</inf>
O<inf>6</inf>
]<sup>+</sup>
 requires 333.1338; <compoundref idrefs="chem10">10</compoundref>
: [<it>α</it>
]<stack><above>20</above>
<below>D</below>
</stack>
 +67 (<it>c</it>
 0.5 in CHCl<inf>3</inf>
); <it>ν</it>
<inf>max</inf>
 (CHCl<inf>3</inf>
) 2936, 1736, 1657, 1602, 1462, 1365, 1142, 908, cm<sup>−1</sup>
; <sup>1</sup>
H NMR (400 MHz, CDCl<inf>3</inf>
) <it>δ</it>
 1.96–2.05 (m, 1H, C<it>H</it>
H), 2.63 (ddd, <it>J</it>
 13.4, 8.6, 5.3, 1H, CH<it>H</it>
), 3.09 (dd, <it>J</it>
 10.8, 4.0, 1H, ArC<it>H</it>
), 3.33–3.40 (m, 2H, 1-C<it>H</it>
, 5-C<it>H</it>
), 3.86–3.89 (m, 9H, OC<it>H</it>
<inf>3</inf>
, 2 × ArOC<it>H</it>
<inf>3</inf>
), 4.46 (ddd, <it>J</it>
 10.8, 10.8, 5.3, 1H, C<it>H</it>
OH), 5.79 (s, 1H, CC<it>H</it>
), 6.67–6.72 (m, 2H, 2 × Ar<it>H</it>
), 6.84–6.87 (m, 1H, Ar<it>H</it>
); <sup>13</sup>
C NMR (100 MHz, CDCl<inf>3</inf>
) <it>δ</it>
 35.3 (CH<inf>2</inf>
), 51.6 (CH), 53.3 (CH), 55.8 (CH<inf>3</inf>
), 55.9 (CH<inf>3</inf>
), 56.5 (CH<inf>3</inf>
), 57.1 (CH<inf>3</inf>
), 66.5 (CH), 66.8 (CH), 105.3 (CH), 111.3 (CH), 112.1 (CH), 120.1 (CH), 128.4 (C), 149.0 (C), 149.3 (C), 175.5 (C), 191.9 (C), 203.8 (C); HRMS (ESI) <it>m</it>
/<it>z</it>
 333.1316 [M + H]<sup>+</sup>
, [C<inf>18</inf>
H<inf>21</inf>
O<inf>6</inf>
]<sup>+</sup>
 requires 333.1338.</p>
</subsect1>
<subsect1><title>(1<it>S</it>
,5<it>R</it>
,7<it>S</it>
,8<it>R</it>
)-(+)-8-(3,4-Dimethoxyphenyl)-2-methoxy-7-triisopropylsilanyloxy-bicyclo[3.3.1]non-2-ene-4,9-dione <compoundref idrefs="chem11">11</compoundref>
 and (1<it>S</it>
,5<it>R</it>
,7<it>S</it>
,8<it>R</it>
)-(+)-8-(3,4-dimethoxyphenyl)-4-methoxy-7-triisopropylsilanyloxy-bicyclo[3.3.1]non-3-ene-2,9-dione <compoundref idrefs="chem12">12</compoundref>
</title>
<p>Triisopropylsilyl trifluoromethanesulfonate (2.06 mL, 7.68 mmol, 1.5 eq.) was added to a solution of bridged ketones <compoundref idrefs="chem9">9</compoundref>
 and <compoundref idrefs="chem10">10</compoundref>
 (1.70 g, 5.10 mmol) and 2,6-lutidine (1.79 mL, 15,4 mmol, 3 eq.) in dry CH<inf>2</inf>
Cl<inf>2</inf>
 (10.0 mL) at 0 °C. The mixture was allowed to warm to RT over 3 h, then stirred at RT for 16 h. After this period, the crude reaction mixture was washed with 2 M HCl (2 × 5 mL) and extracted with CH<inf>2</inf>
Cl<inf>2</inf>
 (2 × 10 mL). The organic extracts were combined and dried (Na<inf>2</inf>
CO<inf>3</inf>
), then concentrated <it>in vacuo</it>
. Purification by column chromatography (petroleum ether–EtOAc 4 : 1) gave firstly <compoundref idrefs="chem11">11</compoundref>
 as a pale yellow solid (1.4 g, 56%); mp 128 °C; [<it>α</it>
]<stack><above>22</above>
<below>D</below>
</stack>
 +109 (<it>c</it>
 1.0 in CHCl<inf>3</inf>
); <it>ν</it>
<inf>max</inf>
 (CHCl<inf>3</inf>
) 2939, 1736, 1657, 1604, 1374, 1118, 907 cm<sup>−1</sup>
; <sup>1</sup>
H NMR (500 MHz, CDCl<inf>3</inf>
) <it>δ</it>
 0.63–0.75 (m, 21H, OSi(C<it>H</it>
(C<it>H</it>
<inf>3</inf>
)<inf>2</inf>
)<inf>3</inf>
), 1.83–1.91 (m, 1H, CH<it>H</it>
), 2.48–2.52 (m, 1H, C<it>H</it>
H), 3.00 (dd, <it>J</it>
 10.3, 3.8, 1H, ArC<it>H</it>
), 3.17–3.22 (m, 2H, 1-C<it>H</it>
, 5-C<it>H</it>
), 3.54 (s, 3H, OC<it>H</it>
<inf>3</inf>
), 3.73 (s, 3H, ArOC<it>H</it>
<inf>3</inf>
), 3.75 (s, 3H, ArOC<it>H</it>
<inf>3</inf>
), 4.40 (ddd, <it>J</it>
 10.3, 10.3, 5.2, 1H, C<it>H</it>
OSi(CH(CH<inf>3</inf>
)<inf>2</inf>
)<inf>3</inf>
), 5.67 (s, 1H, CC<it>H</it>
), 6.52–6.53 (m, 1H, Ar<it>H</it>
), 6.55 (dd, <it>J</it>
 8.2, 1.9, 1H, Ar<it>H</it>
), 6.70 (d, <it>J</it>
 8.2, 1H, Ar<it>H</it>
); <sup>13</sup>
C NMR (125 MHz, CDCl<inf>3</inf>
) <it>δ</it>
 12.8 (CH), 17.5 (CH<inf>3</inf>
), 39.0 (CH<inf>2</inf>
), 54.6 (CH), 55.8 (CH<inf>3</inf>
), 55.9 (CH<inf>3</inf>
), 56.4 (CH<inf>3</inf>
), 59.1 (CH), 59.4 (CH), 67.6 (CH), 105.1 (CH), 111.0 (CH), 111.6 (CH), 120.4 (CH), 131.5 (C), 148.5 (C), 148.7 (C), 174.9 (C), 194.8 (C), 204.1 (C); HRMS (CI, NH<inf>3</inf>
) <it>m</it>
/<it>z</it>
 489.2633 [M + H]<sup>+</sup>
, [C<inf>27</inf>
H<inf>41</inf>
O<inf>6</inf>
Si]<sup>+</sup>
 requires 489.2671 and secondly <compoundref idrefs="chem12">12</compoundref>
 as a yellow oil (0.42 g, 19%); [<it>α</it>
]<stack><above>27</above>
<below>D</below>
</stack>
 +6.0 (<it>c</it>
 1.0 in CHCl<inf>3</inf>
); <it>ν</it>
<inf>max</inf>
 (CHCl<inf>3</inf>
) 2942, 1743, 1650, 1594, 1462, 1373, 1123 cm<sup>−1</sup>
; <sup>1</sup>
H NMR (500 MHz, CDCl<inf>3</inf>
) <it>δ</it>
 0.75–0.90 (m, 21H, OSi(C<it>H</it>
(C<it>H</it>
<inf>3</inf>
)<inf>2</inf>
)<inf>3</inf>
), 1.96–2.04 (m, 1H, CH<it>H</it>
), 2.53–2.59 (m, 1H, C<it>H</it>
H), 3.06 (dd, <it>J</it>
 10.5, 4.1, 1H, ArC<it>H</it>
), 3.24–3.26 (m, 1H, 5-C<it>H</it>
), 3.34–3.37 (m, 1H, 1-C<it>H</it>
), 3.83 (s, 9H, OC<it>H</it>
<inf>3</inf>
, 2 × ArOC<it>H</it>
<inf>3</inf>
), 4.54 (ddd, <it>J</it>
 10.5, 10.5, 5.2, 1H, C<it>H</it>
OSi(CH(CH<inf>3</inf>
)<inf>2</inf>
)<inf>3</inf>
), 5.80 (s, 1H, CC<it>H</it>
), 6.60–6.65 (m, 2H, 2 × Ar<it>H</it>
), 6.78 (d, <it>J</it>
 8.0, 1H, Ar<it>H</it>
); <sup>13</sup>
C NMR (125 MHz, CDCl<inf>3</inf>
) <it>δ</it>
 12.5 (CH), 17.5 (CH<inf>3</inf>
), 37.1 (CH<inf>2</inf>
), 51.6 (CH), 55.8 (CH<inf>3</inf>
), 55.9 (CH<inf>3</inf>
), 56.2 (CH<inf>3</inf>
), 57.0 (CH) 67.8 (CH), 68.3 (CH), 105.1 (CH), 110.9 (CH), 112.5 (CH), 120.9 (CH), 130.5 (C), 148.5 (C), 148.6 (C), 175.4 (C), 192.5 (C), 204.0 (C); HRMS (CI, NH<inf>3</inf>
) <it>m</it>
/<it>z</it>
 488.2585 [M]<sup>+</sup>
, [C<inf>27</inf>
H<inf>40</inf>
O<inf>6</inf>
Si]<sup>+</sup>
 requires 488.2594.</p>
</subsect1>
<subsect1><title>(1<it>S</it>
,5<it>R</it>
,7<it>S</it>
,8<it>R</it>
)-(+)-8-(3,4-Dimethoxyphenyl)-2-methoxy-1-(prenyl)-7-triisopropylsilanyloxy-bicyclo[3.3.1]non-2-ene-4,9-dione <compoundref idrefs="chem13">13</compoundref>
</title>
<p>A solution of LDA·LiCl was prepared by treatment of a suspension of DIPA·HCl (256 mg, 2.04 mmol) in THF (4 mL) at −78 °C with <sup><it>n</it>
</sup>
BuLi (1.6 M solution in hexanes; 2.56 mL, 4.08 mmol). The solution was allowed to warm to RT and after 10 min re-cooled to −78 °C. This LDA·LiCl solution was added dropwise <it>via</it>
 syringe to a solution of bridged ketone <compoundref idrefs="chem11">11</compoundref>
 (100 mg, 0.20 mmol) in THF (1 mL) at −78 °C resulting in a deep yellow-coloured solution. The solution was stirred at −78 °C for 3 h, followed by addition of prenyl bromide (0.25 mL, 2.04 mmol, 10 eq.) and stirring for a further 3 h at −78 °C. The reaction mixture was quenched after this period with H<inf>2</inf>
O (5 mL) followed by extraction with EtOAc (3 × 5 mL). The organic layers were combined and washed with saturated aqueous NaCl (5 mL), dried (MgSO<inf>4</inf>
), and concentrated <it>in vacuo</it>
. Purification by column chromatography (petroleum ether–EtOAc 4 : 1) gave the title compound <compoundref idrefs="chem13">13</compoundref>
 as a yellow oil (47 mg, 42%); [<it>α</it>
]<stack><above>20</above>
<below>D</below>
</stack>
 +82 (<it>c</it>
 1.0 in CHCl<inf>3</inf>
); <it>ν</it>
<inf>max</inf>
 (CHCl<inf>3</inf>
) 2940, 2258, 1736, 1650, 1095 cm<sup>−1</sup>
; <sup>1</sup>
H NMR (400 MHz, CDCl<inf>3</inf>
) <it>δ</it>
 0.82 (m, 21H, OSi(C<it>H</it>
(C<it>H</it>
<inf>3</inf>
)<inf>2</inf>
)<inf>3</inf>
), 1.64 (s, 3H, C<it>H</it>
<inf>3</inf>
), 1.69 (s, 3H, OC<it>H</it>
<inf>3</inf>
), 1.74–1.78 (m, 1H, 8-CH<it>H</it>
), 2.32 (dd, <it>J</it>
 12.7, 5.3, 1H, 8-C<it>H</it>
H), 2.52 (dd, <it>J</it>
 15.0, 7.0, 1H, CH<it>H</it>
CHC), 2.56 (dd, <it>J</it>
 15.0, 7.0, 1H, C<it>H</it>
HCHC), 3.07 (dd, <it>J</it>
 10.3, 4.3, 1H, ArC<it>H</it>
), 3.33 (dd, <it>J</it>
 4.3, 1H, 5-C<it>H</it>
), 3.61 (s, 3H, OC<it>H</it>
<inf>3</inf>
), 3.84 (s, 3H, OC<it>H</it>
<inf>3</inf>
), 3.86 (s, 3H, OC<it>H</it>
<inf>3</inf>
), 4.46 (ddd, <it>J</it>
 10.3, 10.3, 5.3, 1H, C<it>H</it>
OSi(CH(CH<inf>3</inf>
)<inf>2</inf>
)<inf>3</inf>
), 4.95–5.01 (m, 1H, C<it>H</it>
C(CH<inf>3</inf>
)<inf>2</inf>
), 5.75 (s, 1H, CC<it>H</it>
), 6.63 (d, <it>J</it>
 2.0, 1H, Ar<it>H</it>
), 6.66 (dd, <it>J</it>
 8.2, 2.0, 1H, Ar<it>H</it>
), 6.80 (d, <it>J</it>
 8.2, 1H, Ar<it>H</it>
); <sup>13</sup>
C NMR (100 MHz, CDCl<inf>3</inf>
) <it>δ</it>
 12.5 (CH), 17.8 (CH<inf>3</inf>
), 18.0 (CH<inf>3</inf>
), 25.9 (CH<inf>3</inf>
), 29.4 (CH<inf>2</inf>
), 45.8 (CH<inf>2</inf>
), 54.9 (CH<inf>3</inf>
), 55.8 (CH<inf>3</inf>
), 56.0 (CH), 56.2, (CH<inf>3</inf>
), 59.3 (CH<inf>3</inf>
), 62.6 (C), 68.2 (CH), 105.2 (CH), 110.0 (CH), 117.0 (CH), 119.1 (CH), 120.5 (CH), 122.2 (CH), 131.6 (C), 134.5 (C), 148.5 (C), 148.7 (C), 173.8 (C), 196.8 (C), 205.9 (C); HRMS (EI) <it>m</it>
/<it>z</it>
 557.3293 [M + H]<sup>+</sup>
, [C<inf>32</inf>
H<inf>49</inf>
O<inf>6</inf>
Si]<sup>+</sup>
 requires 557.3298.</p>
</subsect1>
<subsect1><title>(1<it>S</it>
,5<it>S</it>
,7<it>S</it>
,8<it>R</it>
)-(+)-8-(3,4-Dimethoxyphenyl)-7-hydroxy-2,9,9-trimethoxy-bicyclo[3.3.1]non-2-en-4-one <compoundref idrefs="chem14">14</compoundref>
 and (1<it>R</it>
,5<it>R</it>
,7<it>S</it>
,8<it>R</it>
)-(−)-8-(3,4-dimethoxyphenyl)-7-hydroxy-4,9,9-trimethoxy-bicyclo[3.3.1]non-3-en-2-one <compoundref idrefs="chem15">15</compoundref>
</title>
<p>Trimethyl orthoformate (0.50 mL, 4.50 mmol, 1.5 eq.) and <it>p</it>
TsOH (57 mg, 0.30 mol, 0.1 eq.), were added to a solution of bridged ketones <compoundref idrefs="chem9">9</compoundref>
 and <compoundref idrefs="chem10">10</compoundref>
 (1.00 g, 3.0 mmol) in MeOH (20 mL), and the mixture was heated under reflux for 24 h. After this period, the solution was allowed to cool then concentrated <it>in vacuo</it>
. Purification by column chromatography (EtOAc–petroleum ether 7 : 3) gave a mixture of ketals <compoundref idrefs="chem14">14</compoundref>
 and <compoundref idrefs="chem15">15</compoundref>
 in a 3 : 1 ratio (898 mg, 79%); data for <compoundref idrefs="chem14">14</compoundref>
: [<it>α</it>
]<stack><above>30</above>
<below>D</below>
</stack>
 +169 (<it>c</it>
 0.9 in CHCl<inf>3</inf>
); <it>ν</it>
<inf>max</inf>
 (CHCl<inf>3</inf>
) 3463, 2906, 1652, 1603, 1516, 1230, 1105, 1068, cm<sup>−1</sup>
; <sup>1</sup>
H NMR (400 MHz, CDCl<inf>3</inf>
) <it>δ</it>
 1.84–1.92 (m, 1H, CH<it>H</it>
), 2.17 (ddd, <it>J</it>
 12.8, 8.8, 5.6, 1H, C<it>H</it>
H), 2.92 (m, 2H, 1-C<it>H</it>
, 5-C<it>H</it>
), 3.13 (s, 3H, OC<it>H</it>
<inf>3</inf>
), 3.21 (dd, <it>J</it>
 10.4, 3.6, 1H, ArC<it>H</it>
), 3.31 (s, 3H, OC<it>H</it>
<inf>3</inf>
), 3.50 (s, 3H, OC<it>H</it>
<inf>3</inf>
), 3.86 (s, 3H, ArOC<it>H</it>
<inf>3</inf>
), 3.87 (s, 3H, ArOC<it>H</it>
<inf>3</inf>
), 4.17–4.29 (m, 1H, C<it>H</it>
OH), 5.51 (s, IH, CC<it>H</it>
), 6.67 (d, <it>J</it>
 2.0, 1H, Ar<it>H</it>
), 6.70 (dd, <it>J</it>
 8.0, 2.0, 1H, Ar<it>H</it>
), 6.84 (d, <it>J</it>
 8.0, 1H, Ar<it>H</it>
); <sup>13</sup>
C NMR (100 MHz, CDCl<inf>3</inf>
) <it>δ</it>
 32.0 (CH<inf>2</inf>
), 47.4 (CH), 48.7 (CH<inf>3</inf>
), 48.8 (CH<inf>3</inf>
), 49.3 (CH), 49.8 (CH), 55.7 (CH<inf>3</inf>
), 55.8 (CH<inf>3</inf>
), 55.9 (CH<inf>3</inf>
), 66.4 (CH), 101.3 (C), 103.4 (CH), 111.3 (CH), 111.6 (CH), 120.0 (CH), 131.4 (C), 148.4 (C), 149.2 (C), 175.7 (C), 190.0 (C); HRMS (ES) <it>m</it>
/<it>z</it>
 379.1768 [M + H]<sup>+</sup>
, [C<inf>20</inf>
H<inf>27</inf>
O<inf>7</inf>
]<sup>+</sup>
 requires 379.1757; data for <compoundref idrefs="chem15">15</compoundref>
: [<it>α</it>
]<stack><above>20</above>
<below>D</below>
</stack>
					−5 (<it>c</it>
 0.5 in CHCl<inf>3</inf>
); <it>ν</it>
<inf>max</inf>
 (CHCl<inf>3</inf>
) 2939, 1650, 1611, 1462, 1375, 1108, 1068, 1027, cm<sup>−1</sup>
; <sup>1</sup>
H NMR (400 MHz, CDCl<inf>3</inf>
) <it>δ</it>
 1.94–2.00 (m, 1H, CH<it>H</it>
), 2.21 (ddd, <it>J</it>
 12.9, 8.8, 5.5, 1H, C<it>H</it>
H), 2.94–2.99 (m, 2H, 1-C<it>H</it>
, 5-C<it>H</it>
), 3.12 (dd, <it>J</it>
 10.9, 4.0, 1H, ArC<it>H</it>
), 3.15 (s, 3H, OC<it>H</it>
<inf>3</inf>
), 3.33 (s, 3H, OC<it>H</it>
<inf>3</inf>
), 3.78 (s, 3H, OC<it>H</it>
<inf>3</inf>
), 3.85 (s, 3H, ArOC<it>H</it>
<inf>3</inf>
), 3.87 (s, 3H, ArOC<it>H</it>
<inf>3</inf>
), 4.24 (ddd, <it>J</it>
 10.9, 10.9, 5.5, 1H, C<it>H</it>
OH), 5.55 (s, 1H, CC<it>H</it>
), 6.65–6.67 (m, 2H, 2 × Ar<it>H</it>
), 6.81–6.83 (m, 1H, Ar<it>H</it>
); <sup>13</sup>
C NMR (100 MHz, CDCl<inf>3</inf>
) <it>δ</it>
 30.4 (CH<inf>2</inf>
), 42.4 (CH), 47.2 (CH<inf>3</inf>
), 48.7 (CH<inf>3</inf>
), 48.7 (CH), 55.8 (CH<inf>3</inf>
), 55.8 (CH<inf>3</inf>
), 56.4 (CH<inf>3</inf>
), 56.5 (CH), 67.2 (CH), 101.0 (C), 103.1 (CH), 111.3 (CH), 112.5 (CH), 120.2 (CH), 130.3 (C), 148.4 (C), 149.1 (C), 176.9 (C), 196.5 (C); HRMS (ESI) <it>m</it>
/<it>z</it>
 379.1756 [M + H]<sup>+</sup>
, [C<inf>20</inf>
H<inf>27</inf>
O<inf>7</inf>
]<sup>+</sup>
 requires 379.1757.</p>
</subsect1>
<subsect1><title>(1<it>S</it>
,5<it>S</it>
,7<it>S</it>
,8<it>R</it>
)-(+)-8-(3,4-Dimethoxyphenyl)-2,9,9-trimethoxy-7-triisopropylsilanyloxy-bicyclo[3.3.1]non-2-en-4-one <compoundref idrefs="chem16">16</compoundref>
 and (1<it>R</it>
, 5<it>R</it>
, 7<it>S</it>
, 8<it>R</it>
)-(+)-8-(3,4-dimethoxyphenyl)-4,9,9-trimethoxy-7-triisopropylsilanyloxy-bicyclo[3.3.1]non-3-en-2-one <compoundref idrefs="chem17">17</compoundref>
</title>
<p>2,6-Lutidine (0.64 mL, 5.55 mmol, 3 eq.) and triisopropylsilyl trifluoromethanesulfonate (0.75 mL, 3.70 mmol, 1.5 eq.) were added to a solution of <compoundref idrefs="chem14">14</compoundref>
 and <compoundref idrefs="chem15">15</compoundref>
 (0.7 g, 1.85 mmol) in dry CH<inf>2</inf>
Cl<inf>2</inf>
 (10 mL) at 0 °C. The reaction mixture was allowed to warm to RT over 1 h then stirred at RT overnight. The reaction mixture was washed with 2 M HCl (3 × 7 mL) and saturated aqueous NaCl (1 × 10 mL), extracted with CH<inf>2</inf>
Cl<inf>2</inf>
 (2 × 10 mL), dried (MgSO<inf>4</inf>
), then concentrated <it>in vacuo</it>
. Purification by column chromatography (petroleum ether–EtOAc 85 : 15) gave firstly bridged ketal <compoundref idrefs="chem16">16</compoundref>
 as a white solid (480 mg, 56%); [<it>α</it>
]<stack><above>26</above>
<below>D</below>
</stack>
 +154 (<it>c</it>
 1.0 in CHCl<inf>3</inf>
); <it>ν</it>
<inf>max</inf>
 (CHCl<inf>3</inf>
) 2941, 2865, 1650, 1604, 1462, 1379, 1106 cm<sup>−1</sup>
; <sup>1</sup>
H NMR (500 MHz, CDCl<inf>3</inf>
) <it>δ</it>
 0.83–0.93 (m, 21H, OSi(C<it>H</it>
(C<it>H</it>
<inf>3</inf>
)<inf>2</inf>
)<inf>3</inf>
), 1.90–1.97 (m, 1H, CH<it>H</it>
), 2.19 (ddd, <it>J</it>
 12.8, 5.6, 3.7, 1H, C<it>H</it>
H), 2.93–2.94 (m, 2H, 1-C<it>H</it>
, 5-C<it>H</it>
), 3.15 (s, 3H, OC<it>H</it>
<inf>3</inf>
), 3.19 (dd, <it>J</it>
 10.6, 3.7, 1H, ArC<it>H</it>
), 3.35 (s, 3H, OC<it>H</it>
<inf>3</inf>
), 3.60 (s, 3H, OC<it>H</it>
<inf>3</inf>
), 3.87 (s, 3H, ArOC<it>H</it>
<inf>3</inf>
), 3.39 (s, 3H, ArOC<it>H</it>
<inf>3</inf>
), 4.33 (ddd, <it>J</it>
 10.7, 10.7, 5.6, 1H, C<it>H</it>
OSi(CH(CH<inf>3</inf>
)<inf>2</inf>
)<inf>3</inf>
), 5.58 (s, 1H, CC<it>H</it>
), 6.66 (d, <it>J</it>
 1.8, 1H, Ar<it>H</it>
), 6.68 (dd, <it>J</it>
 8.2, 1.8, 1H, Ar<it>H</it>
), 6.82 (d, <it>J</it>
 8.2, 1H, Ar<it>H</it>
); <sup>13</sup>
C NMR (125 MHz, CDCl<inf>3</inf>
) <it>δ</it>
 12.8 (CH), 17.9 (CH<inf>3</inf>
), 34.0 (CH<inf>2</inf>
), 47.3 (CH<inf>3</inf>
), 48.3 (CH), 48.6 (CH<inf>3</inf>
), 49.5 (CH), 49.9 (CH), 55.6 (CH<inf>3</inf>
), 55.7 (CH<inf>3</inf>
), 55.9 (CH<inf>3</inf>
), 68.2 (CH), 101.3 (C), 103.12 (CH), 110.8 (CH), 111.9 (CH) 120.8 (CH), 133.2 (C), 147.9 (C), 148.5 (C), 176.6 (C), 198.9 (C); HRMS (ES) <it>m</it>
/<it>z</it>
 535.3069 [M + H]<sup>+</sup>
, [C<inf>29</inf>
H<inf>47</inf>
O<inf>7</inf>
Si]<sup>+</sup>
 requires 535.3091; and secondly bridged ketal <compoundref idrefs="chem17">17</compoundref>
 as a yellow oil (250 mg, 22%); [<it>α</it>
]<stack><above>30</above>
<below>D</below>
</stack>
 +81 (<it>c</it>
 0.9 in CHCl<inf>3</inf>
); <it>ν</it>
<inf>max</inf>
 (CHCl<inf>3</inf>
) 2941, 2865, 1650, 1604, 1462, 1379, 1106 cm<sup>−1</sup>
; <sup>1</sup>
H NMR (500 MHz, CDCl<inf>3</inf>
) <it>δ</it>
 0.77–0.87 (m, 21H, CHOSi(C<it>H</it>
(C<it>H</it>
<inf>3</inf>
)<inf>2</inf>
)<inf>3</inf>
), 1.93–1.99 (m, 1H, CH<it>H</it>
), 2.13 (ddd, <it>J</it>
 12.8, 5.4, 3.7, 1H, C<it>H</it>
H), 2.89–2.92 (m, 2H, C<it>H</it>
, C<it>H</it>
), 3.06 (dd, <it>J</it>
 10.7, 3.7, 1H, ArC<it>H</it>
), 3.12 (s, 3H, OCH<inf>3</inf>
), 3.21 (s, 3H, OC<it>H</it>
<inf>3</inf>
), 3.75 (s, 3H, OC<it>H</it>
<inf>3</inf>
), 3.81 (s, 3H, ArOC<it>H</it>
<inf>3</inf>
), 3.82 (s, 3H, ArOC<it>H</it>
<inf>3</inf>
), 4.31 (ddd, <it>J</it>
 10.7, 10.7, 5.4, 1H, C<it>H</it>
OSi(CH(CH<inf>3</inf>
)<inf>2</inf>
)<inf>3</inf>
), 5.56 (s, 1H, CC<it>H</it>
), 6.57–6.60 (m, 2H, 2 × Ar<it>H</it>
), 6.75 (d, <it>J</it>
 7.9, Ar<it>H</it>
); <sup>13</sup>
C NMR (125 MHz, CDCl<inf>3</inf>
) <it>δ</it>
 12.6 (CH), 17.9 (CH<inf>3</inf>
), 32.4 (CH<inf>2</inf>
), 42.5 (CH), 47.2 (CH<inf>3</inf>
), 48.6 (CH<inf>3</inf>
), 49.3 (CH), 55.7 (CH<inf>3</inf>
), 55.9 (CH<inf>3</inf>
), 56.4 (CH<inf>3</inf>
), 57.0 (CH), 68.9 (CH), 100.9 (C), 103.0, (CH), 110.8 (CH), 112.9 (CH), 121.0 (CH), 132.3 (C), 147.9 (C), 148.4 (C), 176.6 (C), 197.4 (C); HRMS (ES) <it>m</it>
/<it>z</it>
 535.3086 [M + H]<sup>+</sup>
, [C<inf>29</inf>
H<inf>47</inf>
O<inf>7</inf>
Si]<sup>+</sup>
 requires 535.3091.</p>
<subsect2><title>Crystal data for <compoundref idrefs="chem16">16</compoundref>
</title>
<p>C<inf>29</inf>
H<inf>46</inf>
O<inf>7</inf>
Si, <it>M</it>
 = 534.75, monoclinic, <it>a</it>
 = 8.2824(6), <it>b</it>
 = 13.7389(10), <it>c</it>
 = 12.7110(10) Å, <it>β</it>
 = 91.2840(10)°, <it>U</it>
 = 1446.04(19) Å<sup>3</sup>
, <it>T</it>
 = 150 K, space group <it>P</it>
2<inf>1</inf>
 (no. 4), <it>Z</it>
 = 2, <it>µ</it>
(Mo-Kα) = 0.124 mm<sup>−1</sup>
, 12515 reflections measured, 6307 unique (<it>R</it>
<inf>int</inf>
 = 0.031) which were used in all calculations. The final <it>wR</it>
(<it>F</it>
<sup><it>2</it>
</sup>
) was 0.100 (all data) and the Flack parameter refined to 0.09(9) confirming the determination of the absolute configuration.<fnoteref idrefs="fn2"></fnoteref>
<footnote id="fn2">CCDC reference number 641180. For crystallographic data in CIF or other electronic format see DOI: <url>10.1039/b704311b</url>
</footnote>
</p>
</subsect2>
</subsect1>
<subsect1><title>Typical procedure A for lithiation substitution using LDA (<tableref idrefs="tab1 tab3">Table 1 and Table 3</tableref>
): (1<it>S</it>
,5<it>S</it>
,7<it>S</it>
,8<it>R</it>
)-(+)-8-(3,4-dimethoxyphenyl)-2,9,9-trimethoxy-5-(prenyl)-7-triisopropylsilanyloxy-bicyclo[3.3.1]non-2-en-4-one <compoundref idrefs="chem18">18</compoundref>
</title>
<p>A solution of LDA·LiCl was prepared by treatment of a suspension of DIPA·HCl (180 mg, 1.31 mmol) in THF (2.5 mL) at −78 °C with <sup><it>n</it>
</sup>
BuLi (1.64 mL, 2.62 mmol, 1.6 M solution in hexanes). The solution was allowed to warm to RT and after 10 min re-cooled to −78 °C. This LDA·LiCl solution was added dropwise <it>via</it>
 syringe to a solution of bridged ketone <compoundref idrefs="chem16">16</compoundref>
 (140 mg, 0.26 mmol) in THF (1.4 mL) at −78 °C resulting in a deep yellow-coloured solution. The solution was stirred at −78 °C for 3 h, followed by addition of prenyl bromide (0.30 mL, 2.62 mmol, 10 eq.) and stirring for a further 3 h at −78 °C. The reaction mixture was quenched after this period with H<inf>2</inf>
O (5 mL) followed by extraction with EtOAc (3 × 5 mL). The organic layers were combined and washed with saturated aqueous NaCl (5 mL), dried (MgSO<inf>4</inf>
), and concentrated <it>in vacuo</it>
. Purification by column chromatography (petroleum ether–EtOAc 4 : 1) gave the title compound <compoundref idrefs="chem18">18</compoundref>
 as a light brown oil (118 mg, 75%); [<it>α</it>
]<stack><above>23</above>
<below>D</below>
</stack>
 +150 (<it>c</it>
 0.9 in CHCl<inf>3</inf>
); <it>ν</it>
<inf>max</inf>
 (CHCl<inf>3</inf>
) 2940, 2865, 1649, 1615, 1462, 1381, 1132, 1055 cm<sup>−1</sup>
; <sup>1</sup>
H NMR (500 MHz, CDCl<inf>3</inf>
) <it>δ</it>
 0.77–0.88 (m, 21H, OSi(C<it>H</it>
(C<it>H</it>
<inf>3</inf>
)<inf>2</inf>
)<inf>3</inf>
), 1.62 (s, 3H, C<it>H</it>
<inf>3</inf>
), 1.67 (s, 3H, C<it>H</it>
<inf>3</inf>
), 1.82–1.84 (m, 2H, 8-C<it>H</it>
<inf>2</inf>
), 2.47 (dd, <it>J</it>
 15.0, 7.0, 1H, CH<it>H</it>
CHC(CH<inf>3</inf>
)<inf>2</inf>
), 2.60 (dd, <it>J</it>
 15.0, 7.0, 1H, C<it>H</it>
HCHC(CH<inf>3</inf>
)<inf>2</inf>
), 2.92 (d, <it>J</it>
 4.0, 1H, 5-C<it>H</it>
), 3.07 (dd, <it>J</it>
 10.4, 4.0, 1H, ArC<it>H</it>
), 3.22 (s, 3H, OC<it>H</it>
<inf>3</inf>
), 3.47 (s, 3H, OC<it>H</it>
<inf>3</inf>
), 3.54 (s, 3H, OC<it>H</it>
<inf>3</inf>
), 3.82 (s, 3H, ArOC<it>H</it>
<inf>3</inf>
), 3.84 (s, 3H, ArOC<it>H</it>
<inf>3</inf>
), 4.22 (ddd, <it>J</it>
 10.4, 10.4, 7.0, 1H, C<it>H</it>
OSi(CH(CH<inf>3</inf>
)<inf>2</inf>
)<inf>3</inf>
), 5.47–5.52 (m, 1H, (CH<inf>3</inf>
)<inf>2</inf>
CC<it>H</it>
), 5.53 (s, 1H, CC<it>H</it>
), 6.60 (d, <it>J</it>
 1.9, 1H, Ar<it>H</it>
), 6.64 (dd, <it>J</it>
 8.2, 1.9, 1H, Ar<it>H</it>
), 6.77 (d, <it>J</it>
 8.2, 1H, Ar<it>H</it>
); <sup>13</sup>
C NMR (125 MHz, CDCl<inf>3</inf>
) <it>δ</it>
 12.6 (CH), 17.9 (CH<inf>3</inf>
), 25.9 (CH<inf>3</inf>
), 30.2 (CH<inf>2</inf>
), 41.1 (CH<inf>2</inf>
), 48.2 (CH), 49.7 (CH<inf>3</inf>
), 50.6 (CH), 51.1 (CH<inf>3</inf>
), 55.5 (CH<inf>3</inf>
), 55.7 (CH<inf>3</inf>
), 55.9 (CH<inf>3</inf>
), 57.1 (C), 68.7 (CH), 103.6 (CH), 103.9 (C), 110.8 (CH), 111.9 (CH), 121.0 (CH), 122.3 (CH), 131.5 (C), 133.2 (C), 147.9 (C), 148.4 (C), 174.7 (C), 201.2 (C); HRMS (EI) <it>m</it>
/<it>z</it>
 603.3712 [M + H]<sup>+</sup>
, [C<inf>34</inf>
H<inf>55</inf>
O<inf>7</inf>
Si]<sup>+</sup>
 requires 603.3717.</p>
<subsect2><title>(1<it>S</it>
,5<it>R</it>
,7<it>S</it>
,8<it>R</it>
)-(+)-8-(3,4-Dimethoxyphenyl)-4-oxo-2,9,9-trimethoxy-7-triisopropylsilanyloxy-bicyclo[3.3.1]non-2-ene-3,5-dicarboxylic acid diethyl ester <compoundref idrefs="chem27">27</compoundref>
</title>
<p>Isolated as an amorphous yellow solid (55 mg, 45%); [<it>α</it>
]<stack><above>30</above>
<below>D</below>
</stack>
 +173 (<it>c</it>
 0.5 in CHCl<inf>3</inf>
); <sup>1</sup>
H NMR (500 MHz, CDCl<inf>3</inf>
) <it>δ</it>
 0.75–0.90 (m, 21H, OSi(C<it>H</it>
(C<it>H</it>
<inf>3</inf>
)<inf>2</inf>
)<inf>3</inf>
), 1.29 (t, <it>J</it>
 7.1, 3H, C<it>H</it>
<inf>3</inf>
), 1.33 (t, <it>J</it>
 7.1, 3H, C<it>H</it>
<inf>3</inf>
), 2.26 (t, <it>J</it>
 12.9, 1H, CH<it>H</it>
), 2.39 (dd, <it>J</it>
 12.9, 5.3, 1H, C<it>H</it>
H), 3.15 (d, <it>J</it>
 4.5, 1H, C<it>H</it>
), 3.22 (s, 3H, OC<it>H</it>
<inf>3</inf>
), 3.28 (dd, <it>J</it>
 10.6, 4.5, 1H ArC<it>H</it>
), 3.3 (s, 3H, OC<it>H</it>
<inf>3</inf>
), 3.37 (s, 3H, OC<it>H</it>
<inf>3</inf>
), 3.86 (s, 3H, ArOC<it>H</it>
<inf>3</inf>
), 3.89 (s, 3H, ArOC<it>H</it>
<inf>3</inf>
), 4.21–4.38 (m, 5H, C<it>H</it>
OSi(CH(CH<inf>3</inf>
)<inf>2</inf>
)<inf>3</inf>
), OC<it>H</it>
<inf>2</inf>
CH<inf>3</inf>
, OC<it>H</it>
<inf>2</inf>
CH<inf>3</inf>
), 6.77–6.83 (m, 3H, Ar<it>H</it>
, Ar<it>H</it>
, Ar<it>H</it>
); <sup>13</sup>
C NMR (125 MHz, CDCl<inf>3</inf>
) <it>δ</it>
 13.9 (CH<inf>3</inf>
), 14.2 (CH<inf>3</inf>
), 12.5 (CH), 18.0 (CH<inf>3</inf>
), 38.9 (CH<inf>2</inf>
), 48.8 (CH), 49.0 (CH<inf>3</inf>
), 49.3 (CH<inf>3</inf>
), 49.4 (CH), 55.8 (CH<inf>3</inf>
), 56.0 (CH<inf>3</inf>
), 56.8 (CH<inf>3</inf>
), 61.6 (CH<inf>2</inf>
), 61.7 (CH<inf>2</inf>
), 62.9 (C), 68.0 (CH), 101.8 (C), 111.0 (CH), 111.1 (CH), 115.1 (C), 121.6 (CH), 132.2 (C), 148.2 (C), 148.8 (C), 165.4 (C), 170.3 (C), 171.9 (C), 192.7 (C). IR <it>ν</it>
<inf>max</inf>
 2913, 2847, 1729, 1614, 1463, 1373, 1249, 1089, 1051 cm<sup>−1</sup>
; HRMS (ES) <it>m</it>
/<it>z</it>
 679.3508 [M + H]<sup>+</sup>
, [C<inf>35</inf>
H<inf>55</inf>
O<inf>11</inf>
Si]<sup>+</sup>
 requires 679.3513.</p>
</subsect2>
</subsect1>
<subsect1><title>(1<it>R</it>
,5<it>S</it>
,7<it>S</it>
,8<it>R</it>
,9<it>R</it>
)-(+)-8-(3,4-Dimethoxyphenyl)-9-hydroxy-2-methoxy-7-triisopropylsilanyloxy-bicyclo[3.3.1]non-2-en-4-one <compoundref idrefs="chem28">28</compoundref>
</title>
<p>Sodium borohydride (60.0 mg, 1.54 mmol, 1.5 eq.) in CH<inf>3</inf>
OH (4 mL) was added to a solution of <compoundref idrefs="chem9">9</compoundref>
 (500 mg, 1.02 mmol) in 2 : 1 CH<inf>3</inf>
OH : CH<inf>2</inf>
Cl<inf>2</inf>
 (15 mL) at −78 °C. The reaction mixture was stirred at −78 °C for 1 h. After this period the reaction was quenched with aqueous NaOH (2 mL, 2 M), extracted with EtOAc (3 × 5 mL). The organic extracts were combined and washed with saturated aqueous NaCl (aq.) (1 × 10 mL), dried (MgSO<inf>4</inf>
), then concentrated <it>in vacuo</it>
. Purification by column chromatography (petroleum ether–EtOAc 3 : 7) gave the title compound <compoundref idrefs="chem28">28</compoundref>
 as a fluffy white solid (470 mg, 94%); mp 178–180 °C; [<it>α</it>
]<stack><above>24</above>
<below>D</below>
</stack>
 +163 (<it>c</it>
 0.5 in CHCl<inf>3</inf>
); <it>ν</it>
<inf>max</inf>
 (CHCl<inf>3</inf>
) 3606, 2940, 1646, 1597, 1463, 1378, 1116, 1026, 882 cm<sup>−1</sup>
; <sup>1</sup>
H NMR (400 MHz, CDCl<inf>3</inf>
) <it>δ</it>
 0.79–0.88 (m, 21H, OSi(C<it>H</it>
(C<it>H</it>
<inf>3</inf>
)<inf>2</inf>
)<inf>3</inf>
), 1.99–2.20 (m, 2H, 8-C<it>H</it>
<inf>2</inf>
), 2.32 (d, <it>J</it>
 3.5, 1H, O<it>H</it>
), 2.78 (m, 2H, 1-C<it>H</it>
, 5-C<it>H</it>
), 3.29 (dd, <it>J</it>
 10.2, 4.1, 1H, ArC<it>H</it>
), 3.56 (s, 3H, OC<it>H</it>
<inf>3</inf>
), 3.83 (s, 3H, ArOC<it>H</it>
<inf>3</inf>
), 3.86 (s, 3H, ArOC<it>H</it>
<inf>3</inf>
), 4.20–4.27 (m, 2H, C<it>H</it>
OSi(CH(CH<inf>3</inf>
)<inf>2</inf>
)<inf>3</inf>
, C<it>H</it>
OH), 5.55 (s, 1H, CC<it>H</it>
), 6.62–6.65 (m, 2H, 2 × Ar<it>H</it>
), 6.78 (d, <it>J</it>
 8.7, 1H, Ar<it>H</it>
); <sup>13</sup>
C NMR (100 MHz, CDCl<inf>3</inf>
) <it>δ</it>
 12.6 (CH), 17.9 (CH<inf>3</inf>
), 18.1 (CH<inf>3</inf>
), 31.7 (CH<inf>2</inf>
), 45.7 (CH), 49.9 (CH), 50.4 (CH), 55.6 (CH<inf>3</inf>
), 55.7 (CH<inf>3</inf>
), 56.0 (CH<inf>3</inf>
), 68.3 (CH), 68.3 (CH), 104.0 (CH), 110.9 (CH), 112.2 (CH), 120.8 (CH), 133.6 (C), 147.8 (C), 148.5 (C), 178.7 (C), 200.2 (C); HRMS (ESI) <it>m</it>
/<it>z</it>
 491.2811 [M + H]<sup>+</sup>
, [C<inf>27</inf>
H<inf>43</inf>
O<inf>6</inf>
Si]<sup>+</sup>
 requires 491.2828.</p>
</subsect1>
<subsect1><title>(1<it>R</it>
,5<it>S</it>
,7<it>S</it>
,8<it>R</it>
,9<it>R</it>
)-(−)-8-(3,4-Dimethoxyphenyl)-2-methoxy-9-triethylsilanyloxy-7-triisopropylsilanyloxy-bicyclo[3.3.1]non-2-en-4-one <compoundref idrefs="chem29">29</compoundref>
</title>
<p>Triethylsilyl triflate (0.33 mL, 1.3 mmol, 1.5 eq.) was added to a solution of <compoundref idrefs="chem28">28</compoundref>
 (470 mg, 9.56 mmol) and 2,6-lutidine (0.33 mL, 2.6 mmol, 3 eq.) in dry CH<inf>2</inf>
Cl<inf>2</inf>
 (10 mL) at −78 °C and the solution stirred at −78 °C for 1 h. The reaction was quenched with aqueous HCl (10 mL, 2 M) and extracted with CH<inf>2</inf>
Cl<inf>2</inf>
 (3 × 8 mL). The organic extracts were combined and washed with saturated aqueous NaCl (10 mL), dried (MgSO<inf>4</inf>
), then concentrated <it>in vacuo</it>
. Purification by column chromatography (petroleum ether–EtOAc 8 : 2) gave the title compound <compoundref idrefs="chem29">29</compoundref>
 as a pale yellow oil (500 mg, 86%); [<it>α</it>
]<stack><above>30</above>
<below>D</below>
</stack>
					−50 (<it>c</it>
 1.0 in CHCl<inf>3</inf>
); <it>ν</it>
<inf>max</inf>
 (CHCl<inf>3</inf>
) 2918, 1660, 1612, 1462, 1107, 831 cm<sup>−1</sup>
; <sup>1</sup>
H NMR (400 MHz, CDCl<inf>3</inf>
) <it>δ</it>
 0.64 (q, <it>J</it>
 7.9, 6H, OSi(C<it>H</it>
<inf>2</inf>
(CH<inf>3</inf>
)<inf>2</inf>
)<inf>3</inf>
), 0.77–0.89 (m, 21H, OSi(C<it>H</it>
(C<it>H</it>
<inf>3</inf>
)<inf>2</inf>
)<inf>3</inf>
), 1.01 (t, <it>J</it>
 7.9, 9H, OSi(CH<inf>2</inf>
(C<it>H</it>
<inf>3</inf>
)<inf>2</inf>
)<inf>3</inf>
), 2.04 (ddd, <it>J</it>
 12.4, 8.6, 5.2, 1H, CH<it>H</it>
), 2.14–2.18 (m, 1H, C<it>H</it>
H), 2.61–2.67 (m, 2H, 1-C<it>H</it>
, 5-C<it>H</it>
), 3.28 (dd, <it>J</it>
 10.5, 3.8, 1H, ArC<it>H</it>
), 3.55 (s, 3H, OC<it>H</it>
<inf>3</inf>
), 3.82 (s, 3H, ArOC<it>H</it>
<inf>3</inf>
), 3.85 (s, 3H, ArOC<it>H</it>
<inf>3</inf>
), 4.09 (t, <it>J</it>
 3.6, 1H, C<it>H</it>
OSi(CH<inf>2</inf>
CH<inf>3</inf>
)<inf>3</inf>
), 4.21 (ddd, <it>J</it>
 10.5, 10.5, 5.2, 1H, C<it>H</it>
OSi(CH(CH<inf>3</inf>
)<inf>2</inf>
)<inf>3</inf>
), 5.53 (s, 1H, CC<it>H</it>
), 6.59 (d, <it>J</it>
 1.9, 1H, Ar<it>H</it>
), 6.63 (dd, <it>J</it>
 8.2, 1.9, 1H, Ar<it>H</it>
), 6.78 (d, <it>J</it>
 8.2, 1H, Ar<it>H</it>
); <sup>13</sup>
C NMR (125 MHz, CDCl<inf>3</inf>
) <it>δ</it>
 4.8 (CH<inf>2</inf>
), 6.9 (CH<inf>3</inf>
), 12.7 (CH), 18.0 (CH<inf>3</inf>
), 18.1 (CH<inf>3</inf>
), 31.8 (CH<inf>2</inf>
), 45.7 (CH), 50.8 (CH), 51.3 (CH), 55.6 (CH<inf>3</inf>
), 55.7 (CH<inf>3</inf>
), 55.9 (CH<inf>3</inf>
), 68.2 (CH), 68.7 (CH), 104.1 (CH), 110.8 (CH), 111.9 (CH), 121.0 (CH), 134.0 (C), 147.7 (C), 148.4 (C), 178.8 (C), 200.7 (C); HRMS (ESI) <it>m</it>
/<it>z</it>
 605.3724 [M + H]<sup>+</sup>
, [C<inf>33</inf>
H<inf>57</inf>
O<inf>6</inf>
Si<inf>2</inf>
]<sup>+</sup>
 requires 605.3694.</p>
</subsect1>
<subsect1><title>(1<it>R</it>
,5<it>S</it>
,7<it>S</it>
,8<it>R</it>
,9<it>R</it>
)-(+)-8-(3,4-Dimethoxyphenyl)-2-methoxy-5-(prenyl)-9-triethylsilanyloxy-7-triisopropylsilanyloxy-bicyclo[3.3.1]non-2-en-4-one <compoundref idrefs="chem30">30</compoundref>
</title>
<p>A solution of LDA·LiCl was prepared by treatment of a suspension of DIPA·HCl (141 mg, 1.03 mmol) in THF (2.5 mL) at −78 °C with <sup><it>n</it>
</sup>
BuLi (1.28 mL, 2.05 mmol, 1.6 M solution in hexanes). The solution was allowed to warm to RT and after 10 min re-cooled to −78 °C. The LDA·LiCl solution was added dropwise <it>via</it>
 syringe to a solution of bicyclic compound <compoundref idrefs="chem29">29</compoundref>
 (124 mg, 0.20 mmol) in THF (2 mL) at −78 °C resulting in a yellow-coloured solution. The solution was stirred at −78 °C for 3 h, followed by addition of prenyl bromide (0.25 mL, 2.05 mmol, 10 eq.) and stirring for a further 4 h at −78 °C. The reaction mixture was quenched after this period with H<inf>2</inf>
O (5 mL) followed by extraction with EtOAc (3 × 5 mL). The organic layers were combined and washed with saturated aqueous NaCl (15 mL), dried (MgSO<inf>4</inf>
), and concentrated <it>in vacuo</it>
. Purification by column chromatography (petroleum ether–EtOAc 4 : 1) gave the title compound <compoundref idrefs="chem30">30</compoundref>
 as a pale yellow oil (35 mg, 26%); [<it>α</it>
]<stack><above>22</above>
<below>D</below>
</stack>
 +73 (<it>c</it>
 0.15 in CHCl<inf>3</inf>
); <it>ν</it>
<inf>max</inf>
 (CHCl<inf>3</inf>
) 2256, 1816, 1793, 1380, 1095, 947, 888, 641 cm<sup>−1</sup>
; <sup>1</sup>
H NMR (400 MHz, CDCl<inf>3</inf>
) <it>δ</it>
 0.66–0.74 (m, 6H, OSi(C<it>H</it>
<inf>2</inf>
CH<inf>3</inf>
)<inf>3</inf>
), 0.78–0.88 (m, 21H, OSi(C<it>H</it>
(C<it>H</it>
<inf>3</inf>
)<inf>2</inf>
)<inf>3</inf>
), 1.06 (t, <it>J</it>
 8.0, 9H, OSi(CH<inf>2</inf>
C<it>H</it>
<inf>3</inf>
)<inf>3</inf>
), 1.64 (s, 3H, CC(C<it>H</it>
<inf>3</inf>
)<inf>2</inf>
), 1.65 (s, 3H, CC(C<it>H</it>
<inf>3</inf>
)<inf>2</inf>
), 1.74 (dd, <it>J</it>
 12.0, 5.2, 1H, CH<it>H</it>
), 1.93 (t, <it>J</it>
 12.0, 10.3, 1H, C<it>H</it>
H), 2.20 (dd, <it>J</it>
 15.0, 7.0, 1H, CH<it>H</it>
CHC(CH<inf>3</inf>
)<inf>2</inf>
), 2.56 (dd, <it>J</it>
 15.0, 7.0, 1H, C<it>H</it>
HCHC(CH<inf>3</inf>
)<inf>2</inf>
), 2.69 (dd, <it>J</it>
 4.0, 4.0, 1H, 5-C<it>H</it>
), 3.20 (dd, <it>J</it>
 10.3, 4.0, 1H, ArC<it>H</it>
), 3.54 (s, 3H, OC<it>H</it>
<inf>3</inf>
), 3.81 (s, 3H, ArOC<it>H</it>
<inf>3</inf>
), 3.85 (s, 3H, ArOC<it>H</it>
<inf>3</inf>
), 4.07 (d, <it>J</it>
 4.0, 1H, C<it>H</it>
OSi(CH<inf>2</inf>
CH<inf>3</inf>
)<inf>3</inf>
), 4.16 (ddd, <it>J</it>
 10.3, 10.3, 5.2, 1H, C<it>H</it>
OSi(CH(CH<inf>3</inf>
)<inf>2</inf>
)<inf>3</inf>
), 4.91 (t, <it>J</it>
 7.0, 1H, C<it>H</it>
C(CH<inf>3</inf>
)<inf>2</inf>
), 5.54 (s, 1H, CC<it>H</it>
), 6.60 (d, <it>J</it>
 1.9, 1H, Ar<it>H</it>
), 6.63 (dd, <it>J</it>
 8.2, 1.9, 1H, Ar<it>H</it>
), 6.78 (d, <it>J</it>
 8.2, 1H, Ar<it>H</it>
); <sup>13</sup>
C NMR (100 MHz, CDCl<inf>3</inf>
) <it>δ</it>
 5.1 (CH<inf>2</inf>
), 7.0 (CH<inf>3</inf>
), 12.7 (CH), 18.0 (CH<inf>3</inf>
), 18.2 (CH<inf>3</inf>
), 25.8 (CH<inf>3</inf>
), 26.9 (CH<inf>3</inf>
), 31.3 (CH<inf>2</inf>
), 39.4 (CH<inf>2</inf>
), 45.8 (CH), 51.2 (CH), 53.4 (CH), 55.4 (CH<inf>3</inf>
), 55.6 (CH<inf>3</inf>
), 55.9 (CH<inf>3</inf>
), 68.8 (CH), 70.0 (CH), 104.5 (CH), 110.9 (CH), 111.9 (CH), 119.7 (CH), 121.0 (CH), 133.5 (C), 147.7 (C), 148.4 (C), 177.0 (C), 201.4 (C); HRMS (ESI) <it>m</it>
/<it>z</it>
 557.3293 [M − OSi(CH<inf>2</inf>
CH<inf>3</inf>
)<inf>3</inf>
]<sup>+</sup>
, [C<inf>32</inf>
H<inf>49</inf>
O<inf>6</inf>
Si]<sup>+</sup>
 requires 557.3298.</p>
</subsect1>
<subsect1><title>Typical procedure B for lithiation substitution using LTMP (<tableref idrefs="tab2">Table 2</tableref>
): (1<it>S</it>
,5<it>S</it>
,7<it>S</it>
,8<it>R</it>
)-(+)-8-(3,4-dimethoxyphenyl)-2,9,9-trimethoxy-7-triisopropylsilanyloxy-3-trimethylsilanyl-bicyclo[3.3.1]non-2-en-4-one <compoundref idrefs="chem31">31</compoundref>
</title>
<p>A solution of LTMP was prepared by adding <sup><it>n</it>
</sup>
BuLi (0.59 mL, 0.93 mmol, 1.6 M solution in hexanes) to tetramethylpiperidine (0.19 mL, 0.93 mmol, 5 eq.) in THF (1 mL) at −78 °C. The solution was allowed to warm to RT and after 10 min re-cooled to −78 °C. This LTMP–THF solution was added dropwise <it>via</it>
 syringe to a solution of bridged ketone <compoundref idrefs="chem16">16</compoundref>
 (100 mg, 0.19 mmol) in THF (1 mL) at −78 °C resulting in a deep yellow-coloured solution. The solution was stirred at −78 °C for 3 h, followed by addition of trimethylsilyl chloride (0.24 mL, mmol, 10 eq.) and stirring for a further 3 h at −78 °C. The reaction mixture was quenched after this period with H<inf>2</inf>
O (5 mL) followed by extraction with EtOAc (3 × 5 mL). The organic layers were combined and washed with saturated aqueous NaCl (5 mL), dried (MgSO<inf>4</inf>
), and concentrated <it>in vacuo</it>
. Purification by column chromatography (petroleum ether–EtOAc 4 : 1) gave the title compound <compoundref idrefs="chem31">31</compoundref>
 as a clear viscous oil (53 mg, 45%); [<it>α</it>
]<stack><above>22</above>
<below>D</below>
</stack>
 +169 (<it>c</it>
 1.0 in CHCl<inf>3</inf>
); <it>ν</it>
<inf>max</inf>
 (CHCl<inf>3</inf>
) 2941, 2866, 1634, 1565, 1462, 1366, 1141, 1108, 1027, 881 cm<sup>−1</sup>
; <sup>1</sup>
H NMR (500 MHz, CDCl<inf>3</inf>
) <it>δ</it>
 0.22 (s, 9H, Si(C<it>H</it>
<inf>3</inf>
)<inf>3</inf>
), 0.72–0.89 (m, 21H, OSi(C<it>H</it>
(C<it>H</it>
<inf>3</inf>
)<inf>2</inf>
)<inf>3</inf>
), 1.81–1.87 (m, 1H, CH<it>H</it>
), 2.13 (ddd, <it>J</it>
 12.5, 9.2, 5.3, 1H, C<it>H</it>
H), 2.80–2.82 (m, 1H, 1-C<it>H</it>
), 2.86 (s, 3H, OC<it>H</it>
<inf>3</inf>
), 3.11 (s, 3H, OC<it>H</it>
<inf>3</inf>
), 3.16 (dd, <it>J</it>
 10.9, 3.0, 1H, ArC<it>H</it>
), 3.22–3.24 (m, 1H, 5-C<it>H</it>
), 3.31 (s, 3H, OC<it>H</it>
<inf>3</inf>
), 3.83 (s, 3H, ArOC<it>H</it>
<inf>3</inf>
), 3.86 (s, 3H, ArOC<it>H</it>
<inf>3</inf>
), 4.25 (ddd, <it>J</it>
 10.9, 10.9, 5.3, 1H, C<it>H</it>
OSi(CH(CH<inf>3</inf>
)<inf>2</inf>
)<inf>3</inf>
), 6.76–6.81 (m, 3H, 3 × Ar<it>H</it>
); <sup>13</sup>
C NMR (125 MHz, CDCl<inf>3</inf>
) <it>δ</it>
 0.82 (CH<inf>3</inf>
), 12.6 (CH), 17.9 (CH<inf>3</inf>
), 18.1 (CH<inf>3</inf>
), 34.4 (CH<inf>2</inf>
), 44.3 (CH), 47.3 (CH<inf>3</inf>
), 48.5 (CH<inf>3</inf>
), 48.7 (CH), 49.7 (CH<inf>3</inf>
), 54.4 (CH<inf>3</inf>
), 55.7 (CH<inf>3</inf>
), 56.0 (CH<inf>3</inf>
), 56.1 (CH<inf>3</inf>
), 68.1 (CH), 101.2 (C), 111.1 (CH), 116.8 (C), 132.9 (C), 148.2 (CH), 148.7 (C), 180.9 (C), 201.9 (C); HRMS (ES) <it>m</it>
/<it>z</it>
 607.3461 [M + H]<sup>+</sup>
, [C<inf>32</inf>
H<inf>55</inf>
O<inf>7</inf>
Si<inf>2</inf>
]<sup>+</sup>
 requires 607.3486.</p>
</subsect1>
</section>
</art-body>
<art-back><ack><p>We acknowledge DEFRA and a Marie-Curie Fellowship for support of VR, and GSK, Harlow, UK and the University of Nottingham for support of NMA.</p>
</ack>
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<titleInfo type="alternative" contentType="CDATA"><title>Synthetic studies towards garsubellin A: synthesis of model systems and potential mimics by regioselective lithiation of bicyclo[3.3.1]nonane-2,4,9-trione derivatives from catechinic acid</title>
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<name type="personal"><namePart type="given">Nadia M.</namePart>
<namePart type="family">Ahmad</namePart>
<affiliation>School of Chemistry, The University of Nottingham, NG7 2RD, University Park, Nottingham, UK</affiliation>
<affiliation>E-mail: nigel.simpkins@nottingham.ac.uk</affiliation>
</name>
<name type="personal"><namePart type="given">Vincent</namePart>
<namePart type="family">Rodeschini</namePart>
<affiliation>School of Chemistry, The University of Nottingham, NG7 2RD, University Park, Nottingham, UK</affiliation>
<affiliation>E-mail: nigel.simpkins@nottingham.ac.uk</affiliation>
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<name type="personal"><namePart type="given">Nigel S.</namePart>
<namePart type="family">Simpkins</namePart>
<affiliation>School of Chemistry, The University of Nottingham, NG7 2RD, University Park, Nottingham, UK</affiliation>
<affiliation>E-mail: nigel.simpkins@nottingham.ac.uk</affiliation>
</name>
<name type="personal"><namePart type="given">Simon E.</namePart>
<namePart type="family">Ward</namePart>
<affiliation>Medicinal Chemistry, Psychiatry Centre of Excellence for Drug Discovery, GlaxoSmithKline, CM19 5AW, New Frontiers Science Park, Third Avenue, Harlow, Essex, UK</affiliation>
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<name type="personal"><namePart type="given">Claire</namePart>
<namePart type="family">Wilson</namePart>
<affiliation>School of Chemistry, The University of Nottingham, NG7 2RD, University Park, Nottingham, UK</affiliation>
<affiliation>E-mail: nigel.simpkins@nottingham.ac.uk</affiliation>
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<abstract>Bridgehead lithiations have successfully been carried out on substrates derived from catechinic acid, which possess the core bicyclo[3.3.1]nonane-1,3,5-trione structure present in garsubellin A. Using an external quench method, various electrophiles have been incorporated at the C-5 bridgehead position in a one-step process that appears to be sensitive to the substitution pattern on the bicyclic system. Regioselective lithiation at the C-3 sp2 centre was achieved by changing the base used from LDA to LTMP. Following the introduction of a prenyl substituent by bridgehead substitution, annulation of a THF ring, analogous to that in garsubellin A, was possible via an epoxidation–ring opening sequence. Oxidative modification of the catechol substituent of the catechinic acid core was possible to give systems with muconic acid, ortho-quinone or furan 2-carboxylic acid side chains.</abstract>
<note type="footnote" displayLabel="fn1">Electronic supplementary information (ESI) available: Experimental procedures and/or full spectroscopic data for compounds 19–26, 32–42, 44, 46–50. See DOI: 10.1039/b704311b</note>
<note>Transformations of catechinic acid, including protection, bridgehead substitution, and catechol oxidation were explored as a possible approach to garsubellin A [b704311b-ga.tif]</note>
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Synthetic studies towards garsubellin A: synthesis of model systems and potential mimics by regioselective lithiation of bicyclo[3.3.1]nonane-2,4,9-trione derivatives from catechinic acid

Synthetic studies towards garsubellin A: synthesis of model systems and potential mimics by regioselective lithiation of bicyclo[3.3.1]nonane-2,4,9-trione derivatives from catechinic acid

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