Background: The oxo polyene macrolide antibiotics are a class of large-ring compounds that bear an extended conjugated polyene fragment and a polyol fragment which consists predominantly of 1,3,5...-hydroxyl groups. There has been significant interest in these compounds due to their biological activity and structural complexity, and our approach to two of these compounds, RK-397 and dermostatin A, is summarized below. The construction of such skipped polyols can be accomplished asymmetric acetate aldol reactions, and during the course of this research, we devised a new reagent for accomplishing this transformation.

Graph 1Synthesis of RK-397:Our synthesis of RK-397 is summarized in the scheme below. We adopted a two-directional chain synthesis strategy starting with siloxy-gluteradehyde derivative 1, which was subjected to allylation with the carene derived allylation reagent developed by Brown. This reaction provided the pseudo-C2 symmetric product 2 which was subjected to a diastereotopic group selective desymmetrization and further functionalization to provide the right hand polyol fragment 3. The synthesis of the left hand fragment (5) proceeded via compound 4, which was prepared using a Sharpless asymmetric epoxidation reaction to set the stereochemistry. Selective elimination of the OMOM group in preference to the OH group in staled the alkene, and was followed by anti-reduction and protecting group manipulations to provide 5. Fragment 3 and 5 were coupled using the Paterson / Evans methylketone aldol reaction which proceeds with 1,5-asymmetric induction to provide the full polyol fragment. Finally, installation of the polyene was accomplished using an unprecedented cross metathesis reaction of trienal 6. Completion of the synthesis proceeded using standard methods (vinylogous Horner-Emmons reaction and Yamaguchi macrocyclization).


Mitton-Fry, M. J.; Cullen, A. J.; Sammakia, T. "The Total Synthesis of the Oxopolyene Macrolide RK-397" Angew. Chem., Int. Ed. 2007,46, 1066 – 1070.

Graph 2Methods for the Synthesis of Polyacetate Fragments:

The crossed aldol reaction has emerged as one of the most powerful and general C-C bond forming reactions. The first asymmetric variant of this reaction that was reliable across a broad range of substrates was that of Evans using the chiral acyl oxazolidinone reagents he developed. While this reaction is truly remarkable in its selectivity, it is, unfortunately, limited to propionate enolates as the seemingly simpler and less complicated acetate derived enolates provide low levels of asymmetric induction. We have devised a variation of the Evans aldol reaction that uses the L-tert-leucine-derived thiazolidine thione reagent shown in the scheme below, and enolization with the hindered base sparteine and PhBCl2 to provide high yields and levels of asymmetric induction.

Graph 3The enantiomeric reagent would be derived from D-tert-leucine; however, this is a prohibitively expensive starting material, and as such, we sought an alternative. We developed the pseudo-enantiomeric reagent derived from the inexpensive L-cysteine as shown below. The behavior of this system is remarkably similar to that of the tert-leucine-derived reagent; apparently the substitution of one of the tert-butyl methyl groups for an OTES has little effect on the reactivity of the reagent.


Zhang, Y.; Sammakia, T. "Synthesis of a New N-Acetyl Thiazolidinethione Reagent and Its Application to a Highly Selective Asymmetric Acetate Aldol Reaction" Org Lett. 20046,3139 – 3141.

Graph 4We also studied the use these reagents with chiral aldehydes to see if the reagent can over come the intrinsic stereochemical preference of the aldehyde. We found that in cases where the stereochemical preference of the aldehyde matches that of the reagent, very high levels of asymmetric induction are observed. In cases where the stereochemical preferences are mismatched, the outcome is dictated by the reagent in somewhat diminished selectivity.


Sammakia, T.; Zhang, Y. "Double Diastereoselective Acetate Aldol Reactionswith Chiral N-Acetyl Thiazolidinethione Reagents" J. Org. Chem. 2006,71, 6262 – 6265.

Application of the Asymmetric Acetate Aldol Reaction to Natural Products Synthesis

Graph 5In order to benchmark the utility of our acetate aldol method, we wished to compared it to the Brown allylation. We therefore subjected the same substrate, siloxy gluteraldehyde derivative 6, to both the Brown allylation and the asymmetric acetate aldol, and measured the yield, diastereoselectivity and enantioselectivity. This is a challenging substrate for the aldol reaction, yet our method performs comparably to the Brown method and provides good yields and excellent selectivities. The product of this reaction was then taken on to the oxopolyene dermostatin A.


Oxocarbenium Ions in Organic Synthesis

Selective Catalysis

Complex Natural Product Synthesis