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Published in final edited form as: J Am Chem Soc. 2007 Jul 14;129(31):9534–9535. doi: 10.1021/ja073547n

Enantioselective Route to Platensimycin: An Intramolecular Robinson Annulation Approach

Pingfan Li 1, Joshua N Payette 1, Hisashi Yamamoto 1,*
PMCID: PMC2553032  NIHMSID: NIHMS62591  PMID: 17630748

Platensimycin (1) (Scheme 1) is a novel antibiotic lead compound recently discovered by Merck scientists from a strain of Streptomyces platensis.1a,b The potential medicinal applications1c,d and challenging structure motif, especially the cage-like tetracyclic core with several stereogenic centers, made this compound very attractive as a target for chemical synthesis. To this end, total synthesis of its racemic form was first reported by Nicolaou and co-workers,2a and later they also reported corresponding asymmetric versions.2b More recently, two other routes to the tetracyclic core structure (±)-92c,d and synthesis of a related structure2e have been reported. Whereas these reported routes all utilized intramolecular etherification reactions2a between the alcohol motifs and the alkene parts as key steps, an alternative intramolecular Robinson annulation approach seems to be more straightforward. Herein, we describe our efforts in the enantioselective synthesis of the key cage-like tetracyclic core structure of platensimycin.

Scheme 1.

Scheme 1

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Retrosynthetic analysis.

The retrosynthetic analysis presented in Scheme 1 envisions a Robinson annulation event3 of bicyclic compound 8 to give the tetracyclic core structure 9.2a Specifically, we expect that by using proline-type catalysts, high diastereoselectivity will be obtained.4 Compound 8 could be constructed from bicyclic lactone 4 by adding two appendages in an appropriate manner. Lactone 4 has turned out to be a known compound, which was encountered in the total synthesis of a series of natural products in the hirsutene family.5 In contrast to the methods in the literature, we believe the potential precursor of lactone 4 could be ketone 3, through a Baeyer-Villiger oxidation/rearrangement sequence.6 And by utilizing our recently developed Brønsted acid-assisted chiral Lewis acid (BLA)7 catalyzed highly enantio- and regioselective Diels-Alder reaction,8 and subsequent N-nitroso aldol addition/decarboxylation sequence,9 enantiomerically pure ketone 3 could be easily prepared from inexpensive, commercially available starting materials.

The implementation of the above mentioned approach is outlined in Scheme 2. BLA catalyst (2 mol%) prepared in situ from oxazaborolidine10 10 and carbon-based Brønsted acid11 11 promoted the Diels-Alder reaction between methyl acrylate and methyl cyclopentadiene to give adduct 2 in 92% yield with essentially complete regio-, diastereo- and enantiocontrol. The Diels-Alder adduct 2 was transformed to the desired ketone 3 in a one-pot procedure: nitroso aldol reaction of lithium enolate of 2 gave the N-nitroso adduct exclusively, which upon treatment with lithium hydroxide in dioxane/H2O underwent oxidative decarboxylation to give 3 in 75% yield after hydrolysis during work-up.12 Baeyer-Villiger oxidation of ketone 3 under basic hydrogen peroxide conditions13 gave lactone 4 in 68% yield, presumably through hydrolysis of the initially formed Baeyer-Villiger product followed by dehydrative lactonization.6

Scheme 2.

Scheme 2

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Synthetic route toward tetracyclic compound 9.

Addition of vinyl cuprate reagent14 to lactone 4 led to the corresponding carboxylic acid, which underwent an acid catalyzed lactonization with a catalytic amount of trifluoromethanesulfonimide15 to give vinyl lactone 5 as an inconsequential diastereomeric mixture (ca. 10:1 d.r.) in 81% yield over two steps.16 DIBAL-H reduction of 5 was followed by Lewis acid mediated cyanation in one pot, giving desired cyanide 6 and undesired cyanide 6′ as a separable diastereomeric mixture in 1:1 ratio with 85~95% yield. This one-pot sequence eliminated the need to go through corresponding acetate intermediates as is often seen in the literature.17 The undesired cyanide 6′ can be converted back to a 2:3 mixture of 6 and 6′ by deprotonation with LiHMDS followed by aqueous work-up. Cyanide 6 was reduced by DIBAL-H/n-BuLi to the corresponding aldehyde,18 which was immediately subjected to Wadsworth-Emmons conditions19 to give enone 7 in 65% yield over two steps. The protocol of ruthenium catalyzed oxidative cleavage of terminal olefins20 chemoselectively gave aldehyde 8 in 59% yield (86% based on recovered 7).

Gratifyingly, the key Robinson annulation event was accomplished in one pot by using L-proline as the chiral control element to mediate the initial intramolecular Michael addition, followed by sodium hydroxide treatment to finish the aldol dehydration. The tetracyclic core structure 9 and its C-9 epimer (platensimycin numbering1b) 9′ was obtained with 5:1 d.r. favoring the desired isomer. The observed preference for the enone’s si face being attacked (Figure 1) can be understood by the stereoelectronic reasons previously proposed.21 With L-proline as the matched chiral control element, such intrinsic preference is reinforced to give higher diastereoselectivity than the mismatched D-proline (3:1 d.r., favoring 9).22,23 The 1H and 13C NMR spectra of 9 are identical to those previously reported2a,c,d. Thus, our formal synthesis of platensimycin is finished.

Figure 1.

Figure 1

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Facial selectivity for the intramolecular Michael addition.

In conclusion, an enantioselective route to the tetracyclic core structure of platensimycin is accomplished in ten steps from simple commercially available starting materials. A number of the steps in this synthesis are noteworthy or novel: (1) the regio- and enantioselective Diels-Alder reaction between methyl acrylate and methyl cyclopentadiene with only 2 mol% catalyst loading; (2) the one-pot conversion from ester 2 to ketone 3 using nitrosobenzene under mild conditions; (3) the one-pot reductive cyanation of lactone 4; (4) the stereoselective intramolecular Michael addition24 between the α-branched aldehyde moiety and the β-substituted enone part of bicyclic compound 8.

Supplementary Material

1si20070627_03. Supporting Information Available.

Experiment procedures and spectral data for compounds, complete author list of reference 1a. This material is available free of charge via the Internet at http://pubs.acs.org.

Acknowledgments

This paper is dedicated to the memory of the late Professor Yoshihiko Ito. Partial financial support from the National Institute of Health (NIH, GM5-20121) is acknowledged. Special thanks to Ian Steele for X-ray analysis.

References

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

1si20070627_03. Supporting Information Available.

Experiment procedures and spectral data for compounds, complete author list of reference 1a. This material is available free of charge via the Internet at http://pubs.acs.org.

NIHMS62591-supplement-1si20070627_03.pdf (790.5KB, pdf)

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