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. Author manuscript; available in PMC: 2015 Oct 14.
Published in final edited form as: J Am Chem Soc. 2006 Apr 12;128(14):4568–4569. doi: 10.1021/ja061082f

New Chiral Synthons for Efficient Preparation of Bispropionates via Stereospecific Oxonia-Cope Rearrangements

Yi-Hung Chen 1, Frank E McDonald 1,*
PMCID: PMC4604445  NIHMSID: NIHMS63670  PMID: 16594682

The synthesis of polypropionates, a common structural motif in many biologically active natural products, provides inspiration and impetus for exploring new carbon-carbon bond-forming reactions. Iterative aldol1 or crotylation transformations2 build polypropionate structures by forming every other carbon-carbon bond of a carbon chain, but more efficient processes use larger building blocks.3 In this communication, we report a novel approach to the stereospecific introduction of bispropionate synthons in a non-aldol fashion, which utilizes Lewis acid catalysis rather than base-promoted conditions.

The design for this synthon is based on allylic rearrangements pioneered by the Nokami laboratory,4 in which a chiral non-racemic homoallylic alcohol is condensed with aldehydes to accomplish transfer of crotyl and other allylic units, with chirality transfer and regioselectivity consistent with a 2-oxonia-[3,3]-sigmatropic rearrangement mechanism. We envisioned extension to a more highly functionalized bispropionate synthon I (Figure 1), so that rearrangement of III might be favored to IV by concomitant reaction of tethered alcohol. 5

Figure 1.

Figure 1

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Design of bispropionate transfer synthon

Several compounds corresponding to synthon I were evaluated for this transformation, including isomeric compounds 3 and 4 (Scheme 1). Reductive coupling of allylic benzoate 2 6 with ortho-silyloxymethylbenzaldehyde 1,7 using Tamaru's conditions8 of palladium/phosphine catalyst and diethylzinc, provided racemic diastereomers 3 and 4 as a 1 : 2.7 separable mixture, which in turn underwent kinetic resolution9 catalyzed by Fu's planar-chiral modified DMAP catalyst10 to provide the alcohols (R,S)-3 and (R,R)-4 and acetates (S,R)-5 and (S,S)-6 in excellent enantiomeric purity from each racemate. The acetate esters 5 and 6 were converted into (S,R)-3 and (S,S)-4, respectively.11,12

Scheme 1.

Scheme 1

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Preparation and resolution of bispropionate synthons a

Reactions of (S,R)-3 with acetaldehyde or isobutyraldehyde were promoted by Sn(OTf)213 to give initial formation of cyclic acetals 8a-b rather than direct bispropionate transfer, but treatment of 8a-b with SnCl4 and Ag2CO3 provided products 7a-b (Scheme 2). The E-alkene and anti-relationship of the two chiral centers corresponds to a chair-like transition state 9. The diastereomer (S,S)-4 produced the lactones 10a-b under identical conditions, with in situ intramolecular cyclization enforced by the Z-alkene. Rearrangement of acetals 8 arising from diastereomer 3 occurs observably faster than the corresponding process from diastereomer 4, but isolated yields of the acyclic alcohols 7 are consistently lower than for the production of lactones 10, as the product alcohols 7 decompose upon prolonged contact with the Lewis acids that promote this transformation.

Scheme 2.

Scheme 2

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Initial results with simple aldehydes a

This methodology was then evaluated with (R)-2-methylpentanal (11)14 and (2R,3S)-3-acetoxy-2,4-dimethylpentanal (12)15 (Table 1). In these cases catalytic TMSOTf was used in the first step (procedure A), to minimize epimerization of the chiral aldehydes. From aldehyde 12, the initial products from 3 were observed to undergo partial migration of the acetate protective group,16 thus acetylation of the product mixture was employed to produce 17 and 18 (procedure B). The bispropionate transfer reaction occurs without observable double diastereoselection from α-chiral aldehyde 11, but some diminuation in yield and stereoselectivity is observed for Felkin model “mismatched” cases with aldehyde 12 (i.e. from (S,R)-3 and (S,S)-4). To validate the structural assignment for product 15, we prepared (−)-invictolide 2117 by Pd-C catalyzed hydrogenation of 15 (Scheme 3).17b

Table 1.

Synthesis of bispropionates from synthons 3 and 4

synthon aldehyde procedurea product (isolated yield, dr)
(R,S)-3 (87% ee) graphic file with name nihms-63670-t0005.jpg A graphic file with name nihms-63670-t0006.jpg
(S,R)-3 (85% ee) graphic file with name nihms-63670-t0007.jpg A graphic file with name nihms-63670-t0008.jpg
(R,R)-4 (89% ee) graphic file with name nihms-63670-t0009.jpg A graphic file with name nihms-63670-t0010.jpg
(S,S)-4 (90% ee) graphic file with name nihms-63670-t0011.jpg A graphic file with name nihms-63670-t0012.jpg
(R,S)-3 (87% ee) graphic file with name nihms-63670-t0013.jpg B graphic file with name nihms-63670-t0014.jpg
(S,R)-3 (85% ee) graphic file with name nihms-63670-t0015.jpg B graphic file with name nihms-63670-t0016.jpg
(R,R)-4 (89% ee) graphic file with name nihms-63670-t0017.jpg A graphic file with name nihms-63670-t0018.jpg
(S,S)-4 (90% ee) graphic file with name nihms-63670-t0019.jpg A graphic file with name nihms-63670-t0020.jpg
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a

Procedure A: TMSOTf (10 mol %), CH2Cl2, −78 °C, 4 h, pyridine quench; then SnCl4 (0.6 equiv), Ag2CO3 (2 equiv), MeNO2 / CH2Cl2, 20 °C, Procedure B: same as procedure A, except followed by Ac2O, pyridine.

Scheme 3.

Scheme 3

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A short synthesis of invictolide

In summary, the new bispropionate synthons 3 and 4 are easily prepared in stereochemically pure form, and undergo stereospecific transfer to a variety of aldehydes to provide rapid access to highly functionalized polypropionate products. Current research activities include the application of this synthetic methodology to more complex natural product structures.

Supplementary Material

1si20060313_03
2si20060313_03

Acknowledgement

This research was supported by the National Institutes of Health (CA-59703).

Footnotes

Supporting Information Available: Procedures and characterization data for all new compounds. This material is available free of charge via the Internet at http://pubs.acs.org.

References

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Associated Data

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Supplementary Materials

1si20060313_03
NIHMS63670-supplement-1si20060313_03.pdf (849.2KB, pdf)
2si20060313_03
NIHMS63670-supplement-2si20060313_03.pdf (14.2MB, pdf)

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