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. 2009 Feb 18;131(6):2113-5.
doi: 10.1021/ja8077945.

Cascade reactions during coronafacic acid biosynthesis: elongation, cyclization, and functionalization during Cfa7-catalyzed condensation

Eric R Strieter  1 , Alexander Koglin, Zachary D Aron, Christopher T Walsh
Affiliations

Cascade reactions during coronafacic acid biosynthesis: elongation, cyclization, and functionalization during Cfa7-catalyzed condensation

Eric R Strieter et al. J Am Chem Soc. .

Abstract

Herein, the biogenesis of the hydrindane ring system within coronafacic acid (CFA) has been investigated. These studies reveal that in addition to the canonical polyketide chain elongation and functionalization encoded by type I polyketide synthase (PKSs), cascade reactions can take place during assembly line-like biosynthesis. Indeed, upon Cfa7-catalyzed Claisen condensation between enzyme-bound malonate and an N-acetylcysteamine (SNAC) thioester, latent reactivity within the elongated enzyme-bound intermediate is unveiled. This reactivity translates into an intramolecular cyclization, which can proceed in a facile manner as observed by the enzyme-independent cyclization of a linear beta-ketothioester intermediate.

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Figures

Figure 1
Figure 1
Coronatine and its two components, coronafacic acid (CFA) and coronamic acid (CMA).
Figure 2
Figure 2
HPLC (a) and radio-HPLC (b) analysis of the Cfa7-catalyzed condensation between 1 and malonate: (i) Cfa7, 1, and NADPH present in the reaction; (ii) Cfa7 is absent from the reaction; (iii) 1 is absent; and (iv) NADPH is absent.
Figure 3
Figure 3
(a) Hydrolysis of 8-9 to afford 10 at pH 9.5 and co-elution with the 14C-radolabelled product from Figure 2b-iv. (b) radio-HPLC analysis of the Cfa7-catalyzed reduction of the β-keto thioester 8-9 using [3H]-NADPH.
Scheme 1
Scheme 1
Proposed biosynthetic pathway for CFA.
Scheme 2
Scheme 2
Synthesis of β-keto thioester 2.
Scheme 3
Scheme 3
6-endo-trig cyclization of 2.
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