Polyketides asymmetric aldol reactions

Paterson, I., Doughty, V. A., Florence, G., Gerlach, K., McLeod, M. D., Scott, J. P., Trieselmann, T. Asymmetric aldol reactions using boron enolates applications to polyketide synthesis. ACS Symp. Ser. 2001, 783, 195-206. 

Evans synthesis of bryostatin 2 (113) also relied upon asymmetric aldol reactions for the introduction of most of the 11 stereocenters [58], At different points, the synthesis used control from an auxiliary, a chiral Lewis acid, chiral ligands on the enolate metal and substrate control from a chiral aldehyde. Indeed, this represents the current state of the art in the aldol construction of complex polyketide natural products. 

Compound 34 was transformed to fragment C15-C21 in six steps. The polyketide structural motif of this fragment suggested a second asymmetric aldol reaction. Compound 34 was transformed to the... 

A number of combinatorial-based syntheses have been reported. Andrus et al. prepared a solution-phase indexed combinatorial library of nonnatural polyenes such as 291 for multidrug resistance reversal.298 This library was formed by modification of R and R. Ellman and co-workers reported a combinatorial library of synthetic receptors targeting vancomycin-resistant bacteria,209 and Paterson et al. prepared polyketide-type libraries by iterative asymmetric aldol reactions on solid support.2l0 Rieser et al. used combinatorial liquid-phase synthesis to prepare [1,4]-oxazepine-7-ones by the Baylis-Hillman reaction (see sec. 9.7.B).2H Schreiber and co-workers reported the synthesis and evaluation of a library of polycyclic small molecules for use in chemical genetic assays.2 2 Bauer et al. reported a library of N-substituted 2-pyrazoline compounds... 

You saw in Chapter 33 that it is possible to use aldol reactions to create two new chiral centres in a single step, and that the relative stereochemistry of the two chiral centres depends in many cases on the geometry of the enolate used to do the aldol reaction. The power of an asymmetric aldol reaction is easy to see it creates two new chiral centres with control over their absolute stereochemistry, and also constructs a new C—C bond. What is more, the products of aldol reactions are very common features in a huge number of natural products known as polyketides—as you will see in the next chapter, polyketides are made by living things using a series of successive enzyme-controlled aldol reactions. 

Paterson, 1. and Temal-Laib, T., Toward the combinatorial synthesis of polyketide hbraries asymmetric aldol reactions with a-chiral aldehydes on sohd-support, Org. Lett., 4, 2473, 2002. 

Paterson, L, Donghi, M., and Gerlach, K., A combinatorial approach to polyketide-type hbraries by iterative asymmetric aldol reactions performed on sohd-support, Angew. Chem. Int. Ed. Engl., 39, 3315, 2000. 

Asymmetric Aldol Reactions Using Boron Enolates Applications to Polyketide Synthesis... 

Reggl996 Reggelin, M. and Brenig, V, Towards Polyketide Libraries Iterative, Asymmetric Aldol Reactions on a Solid Support, Tetrahedron Lett., 37 (1996) 6851-6852. 

Woerpel has recently reported a tandem double asymmetric aldol/C=0 reduction sequence that diastereoselectively affords propionate stereo-triads and -pentads commonly found in polyketide-derived natural products (Scheme 8-2) [14], When the lithium enolate of propiophenone is treated with excess aldehyde, the expected aldolates 30/31 are formed however, following warming to ambient temperature a mono-protected diol 34 can be isolated. In a powerful demonstration of the method, treatment of 3-pentanone with 1.3 equiv of LDA and excess benzaldehyde yielded product in corporating five new stereocenters in 81% as an 86 5 5 3 mixture of diastereomers (Eq. (8.8)). A series of elegant experiments have shown that under the condition that the reaction is conducted, the aldol addition reaction is rapidly reversible with an irreversible intramolecular Tischenko reduction serving as the stereochemically determining step (32 34, Scheme 8-2). 

As an application of the stereoselective synthesis of anti-aldol adducts, the asymmetric total synthesis of octalactins, peculiar eight-membered polyketides, was accomplished starting from these chiral templates generated by enantioselective aldol reaction using Sn(II) catalysts (Scheme 10.44) [68]. Details of the asymmetric... 

Because the products of 1,7- and 1,6,7-asymmetric induction reactions have structures frequently found in polyketide compounds and multifunctional groups to be manipulated, these reactions have been applied to synthesize polyketide in short steps. For example, the saii-Helicobacter pylori agent actinopyrone A 313 was synthesized in nine steps from ent -305 (Scheme 8.52). The total synthesis started from the vinylogous Mukaiyama aldol reaction to give the C11-C18 moiety 311 as a single isomer. Protection of the secondary alcohol was followed by DIBAL reduction to give aldehyde 312. As mentioned, the methodology makes it possible to synthesize polyketide compounds in short steps. 

The first catalytic asymmetric Michael addition of an mygen-centred addition of salicylaldoxime to a,p-unsaturated imides was achieved by the Jacobsen group in 2004 (Scheme 19.34). With p-oxo dimer catalyst [r,R)-[(salan)Al]20 5 as the catalyst, a series of a,p-unsaturated imides worked well. It should be noted that this method could tolerate ester, acetal, and silyl ether functionality, allowing its potential application as an acetate aldol alternative in polyketide natural product synthesis. When combined with efficient N-O bond hydrogenolysis, this (salen)aluminium-catalysed reaction enables the net enantioselective hydration of electron-deficient olefins with no need for purification of the intermediate oxime ethers. 

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