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Highly Stereoselective Synthesis of Cyclopentanes Bearing Four Stereocentres by a Rhodium Carbene-Initiated Domino Sequence

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Highly Stereoselective Synthesis of Cyclopentanes Bearing Four Stereocentres by a Rhodium Carbene-Initiated Domino Sequence ARTICLE Received 21 Oct 2013 | Accepted 19 Jun 2014 | Published 1 Aug 2014 DOI: 10.1038/ncomms5455 Highly stereoselective synthesis of cyclopentanes bearing four stereocentres by a rhodium carbene-initiated domino sequence Brendan T. Parr1 & Huw M.L. Davies1 Stereoselective synthesis of a cyclopentane nucleus by convergent annulation constitutes a significant challenge for synthetic chemists. Although a number of biologically relevant cyclopentane natural products are known, more often than not, the cyclopentane core is assembled in a stepwise manner because of the lack of efficient annulation strategies. Here we report the rhodium-catalysed reactions of vinyldiazoacetates with (E)-1,3-disubstituted 2-butenols generate cyclopentanes, containing four new stereogenic centres with very high levels of stereoselectivity (99% ee, 497: 3 dr). The reaction proceeds by a carbene-initiated domino sequence consisting of five distinct steps: rhodium-bound oxonium ylide formation, [2,3]-sigmatropic rearrangement, oxy-Cope rearrangement, enol—keto tautomerization and finally an intramolecular carbonyl ene reaction. A systematic study is presented detailing how to control chirality transfer in each of the four stereo-defining steps of the cascade, consummating in the development of a highly stereoselective process. 1 Department of Chemistry, Emory University, 1515 Dickey Drive, Atlanta, Georgia 30322, USA. Correspondence and requests for materials should be addressed to H.M.L.D. (email: [email protected]). NATURE COMMUNICATIONS | 5:4455 | DOI: 10.1038/ncomms5455 | www.nature.com/naturecommunications 1 & 2014 Macmillan Publishers Limited. All rights reserved. ARTICLE NATURE COMMUNICATIONS | DOI: 10.1038/ncomms5455 onstruction of cyclopentanes constitutes an area of One of the classic strategies for chiral cyclopentene synthesis significant interest in the organic community1–3,as involves stereoselective cyclopropanation of a 1,3-diene, followed Cevidenced by numerous campaigns towards land- by vinylcyclopropane rearrangement33–36. Contemporary efforts mark natural products, including the prostaglandins4–16, have involved the coupling of a suitably activated olefinic motif jatrophanes17–25 and pactamycin26,27. Synthetic cyclopentanes with an all carbon (1,3) dipole bound to a chiral metal centre via a are a central motif common to prostaglandin antagonist formal [3 þ 2]-cycloaddition37–40. A significant advancement antiglaucoma agents28–32. Indeed, the convergent, asymmetric has been the enantioselective cycloaddition of palladated synthesis of a cyclopentane nucleus bearing multiple chiral trimethylenemethane with electron-deficient alkenes developed centres presents a distinct challenge for modern synthetic by Trost et al.41–43 Alternatively, Fu et al.44,45 and chemists. A general difficulty for a [3 þ 2]-cycloaddition Zhang et al.46 have disclosed enantioselective variants of the Lu approach is developing a mild protocol to render a transient cycloaddition47–53 implementing chiral phosphine catalysts. carbon dipole. Although a number of methods are available, the development a Known MeO C 2 Me OH Rh2(R-DOSP)4 MeO2C Me N 2 then Sc(OTf)3/D + Me high dr, moderate ee HO R1 R RR1 1 2 3 b This work MeO C OH 2 1 MeO C R1 R Rh2(R-DOSP)4 then D 2 N 2 No Sc(OTf)3 + Me high dr, high ee 2 R HO R RR2 14 5 Figure 1 | Evolution of a Convergent Cyclopentane Synthesis. (a) One-pot synthesis of a cyclopentane (3) from a vinyldiazoacetate (1) and racemic allyl alcohol (2) in modest enantioselectivity via a rhodium-initiated cascade. (b) A second-generation cyclopentane (5) synthesis from analogous starting materials in high stereoselectivity. MeO2C Rh Rh-bound N Ph CO2Me 2 oxonium ylide + HO H O Me Ph Me 6 7 I [2,3] 98% ee O MeO2C [3,3]/ MeO C CO2Me enol-keto 2 Ph OH 82% ee Ph >30:1 dr Me OH Me Ph Me 9 II 8 OH H MeO C CH 2 O 2 Carbonyl ene Me Ph Me 82% ee CO Me >30:1 dr 2 Ph Me Me III 10 Figure 2 | Mechanism of cyclopentane synthesis. Mechanism of the one-pot domino sequence for the synthesis of a cyclopentane (10)froma diazoacetate (6) and a racemic allyl alcohol (7). 2 NATURE COMMUNICATIONS | 5:4455 | DOI: 10.1038/ncomms5455 | www.nature.com/naturecommunications & 2014 Macmillan Publishers Limited. All rights reserved. NATURE COMMUNICATIONS | DOI: 10.1038/ncomms5455 ARTICLE a b CO2Me MeO2C HO OH ΔG = 1.25 kcal mol–1 ΔG = 0.55 kcal mol–1 c OH MeO2C MeO2C Ph MeO2C Ph 91% OH O Ph IV 9′ 10 CO Me HO 2 MeO2C MeO2C HO O 9% Ph Ph Ph IV′ ent-9′ ent-10 Favorable configuration Unfavorable configuration Figure 3 | Stereoelectronic considerations for an oxy-Cope rearrangement. Cyclohexane A values for carbomethoxy- (a) and hydroxy (b) -substituted cyclohexanes. (c) Manifestation of stereoelectronic effects in the competition between two chair-like transition states (IV and IV0). a CO2Me CO Me 2 R 2 OH R Rh2(DOSP)4 OH + 2 R N 3 1 All stereoisomers R 2 R R R3 prepared R1 1 11 12 – >20:1 dr, 12 >99% ee b CO Me 2 R2 CO Me 2 R MeO C 2 OH R Rh2(R-DOSP)4 OH 2 + R1 R2 R RN2 R3 R1 3 R 3 OH R1 R 1(S)-11 (S,R )-12 (S,R )-12′ Catalyst controlled stereocenter Favorable configuration Alcohol controlled stereocenter Figure 4 | Rationale for improved chirality transfer during an oxy-Cope rearrangement. (a) The tandem-ylide formation/[2,3]-sigmatropic rearrangement between a diazoacetate (1) and allyl alcohol (S)-11 (2) to generate a 3-hydroxy-1,5-hexadiene (12) bearing vicinal stereocentres and (b) application toward stabilization of a chair-like transition state. of complementary strategies for the rapid construction of in the presence of the dual-catalyst system, Rh2(DOSP)4 and complex cyclopentanes is nonetheless desirable. Sc(OTf)3, shown in Fig. 1a. Implementing 1 Mol % of chiral Rh In this article, we describe a convergent, stereoselective catalyst enabled a high-yielding preparation of a range of synthesis of cyclopentanes with four stereogenic centres from cyclopentanes 3, containing four stereogenic centres, as single an annulation cascade involving vinyldiazoacetates and chiral diastereomers. Although we were pleased with the general allyl alcohols. Moreover, a detailed analysis to account for efficacy with which a high degree of structural complexity correlations between starting material architecture and reaction was introduced from readily available building blocks, the efficacy is described. reaction was characterized by a significant shortcoming: the enantioselectivity for the synthesis of 3 was variable (68–92% ee). In this paper we describe our diagnosis of the stereochemical Results limitations in our initial study, and the logical design of a First-generation synthesis. In a 2011 report, we described our stereo-controlled cyclopentane 5 synthesis, as illustrated in initial attempts to synthesize complex cyclopentanes 3 by means Fig. 1b. of a cascade sequence54. The strategy involved the coupling of Our previous synthesis of cyclopentane 3 involved four racemic 3,3-dimethyl allyl alcohols (2) and donor/acceptor- discrete, stereo-defining reactions, as illustrated for the specific substituted Rh(II) carbenes55,56 derived from vinyldiazoacetates 1 example in Fig. 2 (ref. 52). The steps include: Rh-bound NATURE COMMUNICATIONS | 5:4455 | DOI: 10.1038/ncomms5455 | www.nature.com/naturecommunications 3 & 2014 Macmillan Publishers Limited. All rights reserved. ARTICLE NATURE COMMUNICATIONS | DOI: 10.1038/ncomms5455 a Control - Match O CO2Me MeO C Me Ph 2 OH Heptanes, Δ H 31% yield Me >30:1 dr, >99% ee Me Ph Me 13 14 b Control - Match MeO C OH CO2Me 2 Ph Δ OH Heptanes, * H 99% yield Me 88:12 dr, >99% ee Me Ph Me 13 15 c Control - Mismatch OH MeO2C OH Ph Heptanes, Δ CO2Me H 82% yield Me 88:12 dr, 39% ee Me Ph Me epi-13 15 d One-Pot - Match MeO2C MeO C OH Me Rh2(R-DOSP)4 2 N2 heptanes, 0-120 °C + 71% yield 88:12 dr, 91% ee Ph HO Me Ph Me 6 16 15 e One-Pot - Mismatch MeO2C MeO C OH Me Rh2(S-DOSP)4 2 N2 heptanes, 0-120 °C + 52% yield 88:12 dr, 40% ee Ph HO Me Ph Me 61615 f Rh Ph CO2Me CO Me Ph 2 [2,3] OH Ph CO2Me H O 91% H Me Me H N2 Me H Me 13 6 V Rh2(R-DOSP)4 + si approach OH Rh CO Me CO2Me Me Me 2 [2,3] Ph Ph H OH 16 O H 9% Me Me Me H Me H epi-13 VI Figure 5 | Control studies relevant to the synthesis of cyclopentane 15. (a) Chirality transfer control for the oxy-Cope rearrangement. Matched (b) and mismatched (c) tandem oxy-Cope rearrangement hetero-ene reactions of stereoisomerically pure 3-hydroxy-1,3-hexadienes (13 and epi-13, respectively). Matched (d) and mismatched (e) one-pot cyclopentane (15) syntheses. (f) Justification for high, but imperfect, diastereocontrol during the rhodium-catalysed ylide formation/[2,3]-sigmatropic rearrangement. oxonium ylide formation (6 and 7-I), [2,3]-sigmatropic re- in the tandem reaction, its intermediacy is well precedented in the arrangement (I-8)55 oxy-Cope rearrangement (8-II-9) and literature54–60. From previous studies on the tandem ylide intramolecular carbonyl ene reaction (9-III-10). Although the formation/[2,3]-sigmatropic rearrangement61 as well as control metal-bound ylide intermediate I is neither isolated nor observed studies52 we have analysed the stereochemically relevant steps in 4 NATURE COMMUNICATIONS | 5:4455 | DOI: 10.1038/ncomms5455 | www.nature.com/naturecommunications & 2014 Macmillan Publishers Limited. All rights reserved. NATURE COMMUNICATIONS | DOI: 10.1038/ncomms5455 ARTICLE a H MeO2C OH O H ene CH2 Ph 88% CO Me Me 2 VII Ph Me CO2Me 15 Ph O HO CO Me Me CO2Me 2 ene Me O H 14 12% Ph CH2 Me H Ph Me epi-15 VIII R b H R MeO2C OH O ene Ph H Me H O MeO Ph Me CO Me 2 IX 20 Ph O R Me H H O MeO2C OH R ene R 21 Ph Me H MeO O Ph Me X (Z )-20 Figure 6 | Rationale for diastereoselectivities in the hetero-ene reaction.
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