Polyketide synthesis

Donadio, S., McAlpine, J.B., Sheldon, P.J. et al. (1993) An erythromycin analog produced by reprogramming of polyketide synthesis. Proceedings of the National Academy of Sciences of the United States of America, 90,7119. 

FERRER, J.-L., JEZ, J.M., BOWMAN, M.E., DIXON, R.A., NOEL, J.P., Structure of chalcone synthase and the molecular basis of plant polyketide synthesis, Nature Struct. Biol., 1999,6, 775-784. 

The addition of allenyl metal reagents to aldehydes affords homopropargylic alcohols with contiguous OH- and Me-substituted stereocenters, which serves as a complementary approach to the aldol condensation for polyketide synthesis. Marshall has developed this method extensively and this work is the subject of a more detailed review (cf. Chapter 9) [50]. The applications of this method to the synthesis of naturally occurring compounds have also been wide-ranging and a few are highlighted below. 

The approach to polyketide synthesis described in Scheme 5.2 requires the relatively nontrivial synthesis of acid-sensitive enol acetals 1. An alternative can be envisioned wherein hemiacetals derived from homoallylic alcohols and aldehydes undergo dia-stereoselective oxymercuration. Transmetallation to rhodium could then intercept the hydroformylation pathway and lead to formylation to produce aldehydes 2. This proposal has been reduced to practice as shown in Scheme 5.6. For example, Yb(OTf)3-cata-lyzed oxymercuration of the illustrated homoallyhc alcohol provided organomercurial 14 [6]. Rhodium(l)-catalyzed hydroformylation of 14 proved successful, giving aldehyde 15, but was highly dependent on the use of exactly 0.5 equiv of DABCO as an additive [7]. Several other amines and diamines were examined with variation of the stoichiometry and none proved nearly as effective in promoting the reaction. This remarkable effect has been ascribed to the facilitation of transmetallation by formation of a 2 1 R-HgCl DABCO complex and the unique properties of DABCO when both amines are complexed/protonated. 

Facciotti, D. Metz, J.G. Lassner, M. (1998) Polyketide synthesis graes of marine microbe and production of polyunsaturated fatty acids and PUFA-containing plant oils with transgenic plants. PCT Int. Appl. 10 Dec. to Calgene LLC Co) Chem. Abstr., 1999,130, 62050. 

Polyketide synthesis. Polyketides (2) are obtained on reaction of the sodium lithium dianion (1) of methyl acetoacetate with dimethyl glutarates. When refluxed with Ca(OAc)2 in CH3OH, 2 cyclizes to l-oxo-l,2,3,4-tetrahydronaphthalenes in 30-75% yield.1... 

Funa N, Ohnishi Y, Fujii I, Shibuya M, Ebizuka Y, Horinouchi S (1999) A new pathway for polyketide synthesis in microorganisms. Nature 400 897-899... 

Ziermann R, Betlach MC (1999) Recombinant polyketide synthesis in Streptomyces. engineering of improved host strains. Biotechniques 26 106-110... 

KEH Wiesmann, J Cortes, MJB Brown, AL Cutter, J Staunton, PF Leadlay. Polyketide synthesis in vitro on a modular polyketide synthase. Chem Biol 2 583-589, 1995. 

L Katz, S Donadio. Polyketide synthesis prospects for hybrid antibiotics. Annu Rev Microbiol 875-912, 1993. 

A-L Matharu, RJ Cox, J Crosby, KJ Byrom, TJ Simpson. MCAT is not required for in vitro polyketide synthesis in a minimal actinorhodin polyketide synthase from Streptomyces coelicolor. Chem Biol 5 699-712, 1998. 

In a more complex scenario, the /J-substituents were also found to participate in partially matched or mismatched reactions577. Examples of double induction pave the route of polypropionate and polyketide synthesis and it was emphasized that the relative influence of the enolate or aldehyde component may be enhanced, depending on the coordinating metal employed in the double stereodifferentiating aldol reaction. Thus, it was found that, in spite of their modest synlanti selectivity, lithium enolates are effective in double stereodifferentiating aldol reaction578. In the matched and partially matched cases, lithium enolate face selectivity is opposite to that which is found for their boron or titanium counterparts. This is perfectly illustrated in a recent work by Roush and coworkers reporting a partial synthesis of Bafilomycin Aj (Scheme 122)579. 

The modular design of PKS and NRPS renders them convenient for protein engineering to generate hybrid enzymes that can synthesize a range of natural and unnatural metabolites. By independently manipulating what Cane et al. [143] call the four degrees of freedom in polyketide synthesis variation of chain length, choice of ACP... 

Figure 2 (A) Decarboxylative condensation during polyketide synthesis. (B) Reductive steps in type 1PKS...

Polyketide synthesis by a Type III PKS involves three steps. First, an appropriate primer unit in the form of acyl-CoA is recraited. The acyl group is transferred to the... 

In addition to demonstrating the first cell-free PKS activity, early studies of the tcm PKS provided information concerning the properties of isolated aromatic PKSs. The first suggestion that a PKS is capable of decarboxylating malonyl CoA to acetyl CoA for use as a starter unit came from studies which used extracts containing the tcm PKS. These extracts catalyzed polyketide synthesis in the absence of acetyl CoA with [ Cjmalonyl CoA as the sole substrate. Although it remains possible that an additional enzyme present in the extract is responsible for this activity, decarboxylation of malonyl CoA for use as a starter unit has previously been demonstrated in purified FAS systems, as indicated above, and this result is the first indication that PKSs may also have this capability. 

Gonzalez-Lergier J, Broadbelt LJ, Hatzimanikatis V. Theoretical considerations and computational analysis of the complexity in polyketide synthesis pathways. J. Am. Chem. Soc. 2005 127 9930-9938. 

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