Sporolides

Buchanan GO, Williams PG, Feling RH, Kauffman CA, Jensen PR, Fenical W (2005) Sporolides A and B Structurally Unprecedented Halogenated Macrolides from the Marine Actinomycete Salinispora tropica. Org Lett 7 2731... 

A biradical mechanism is also proposed for the formation of certain biomolecules found in marine sporolides that have a chlorobenzene unit as part of their structure. In this mechanism a halide salt provides the halogen. A model reaction with the... 

Sporolides A and B were isolated in 2005 from a fermentation broth of a strain of the marine actinomycete Salinispora tropica. The structures 377 and 378 and the absolute stereochemistries for sporolide A and sporolide B were elucidated using a combination of NMR spectroscopy and X-ray crystallography. Unformnately, the sporolides, tested for antitumor and antibacterial activity, were inactive (Figure 3.130) [470]. 

In the attempt to unravel the biosynthetic origin of sporolides, and considering that these compounds are composed of a chlorinated cyclopenta[a]indene ring and a cyclohexenone moiety, it was hypothesized that the former fragment could be nonenzymatically derived from an unstable nine-membered enediyne precursor by the nucleophilic addition of chloride. Support to this suggestion came from sequence analysis of S. tropica CNB-440 genome, which led to the identification of two biosynthetic loci encoding enediyne PKSs. Analysis of the respective... 

Subsequently, the organization of the 60-kb biosynthetic gene cluster of sporolides was reported. Putative assignments include spoE, E2-E11, and spoF in the biosynthesis of the enediyne core, spoTl-TlO in the construction and attachment of the cyclohexenone precursor, 6 genes involved in regulation, transport, and resistance, and 19 of unknown or unassigned function [472]. 

Figure 3.131 Proposed biosynthesis of the precursor of the cyclohexenone moiety of sporolides A and B.

The ruthenium-catalyzed [2+2+2] cycloaddition of a functionalized chloro-diyne with a functionalized propargylic alcohol furnished the corresponding chlorinated indene derivative as a single regioisomer. This product was successfully transformed into the natural product, sporolide B (Scheme 21.9) [12],... 

SCHEME 21.9 Ru-catalyzed [2-i-2-1-2] cycloaddition of chloro-diyne with monoyne for synthesis of sporolide B. 

Figure 1. Naturally occurring enediynes and natural products for which enediynes have been proposed as biosynthetic intermediates, (a) The 10-memberedfamily includes calicheamicin, dynemicin, esperamicin, shishijimicin, namenamicin, and uncialamycin. (b) The 9-membered enediynes include neocarzinostatin (NCS), C-1027, maduropeptin, kedarcidin, andN1999A2. (c) Sporolides A and B and cyanosporasides A and B are all hypothesized to originate from enediyne precursors (bracketed) based on the presence of the enediyne polyketide synthase (PKSE) in the Salinaspora genome of each producing organism.

Recent application of PKSE data sets and the noted PCR-based strategy has revealed that the biosynthetic gene cluster for sporolides A and B contains two loci encoding PKSEs 13). Produced by Salinispora tropica, sporolides A and B do not contain enediynes per se (Figure Ic). Rather, each substance contains a tricyclic motif that is proposed to originate biosynthetically from a transient... 

Remarkably, this complete regiocontrol was due to the sterical hindrance imposed by the chlorine substituent on the diyne 88 building block—and therefore the use of alkynyl chloride 88 turned out to be ideal for the regioselective assembly of the chlorobenzene moiety of sporolide B (94). The [2 + 2 + 2] cycloaddition product 91 was then transformed into the o-quinone 92 to prepare the second key step of this total synthesis, the thermally induced intramolecular Diels-Alder macrocyclization reaction (Scheme 7.20). 

Notably, the indene moiety of the [2 + 2 + 2] cycloaddition product 91 now served as the dienophile, and the o-quinone moiety of 92 provided the heterodiene unit in this brilliant example of an intramolecular hetero-Diels-Alder reaction. Nine more steps were then required to transform the polycycle 93 into sporolide B (94). 

Salinispora tropica (N PI-0052) Sediment (-1 m) Bahamas Sporolides Salinosporamides A-C Salinosporamides D-j Anti proteal ide Cytotoxics, inhibitors of proteasome Buchanan et al., 2005 Williams et al., 2005 Beer eto/., 2007 Reed et al., 2007 Udwaryeto/., 2007 Manam et al., 2009... 

Buchanan, G,0 Williams, P,G Feling, R.H., Kauffman, C.A, Jensen, P.R., and Fenical, W, (2005) Sporolides A and B Structurally unprecedented halogenated macrolides from the marine actinomycete Salinispora tropica. Org. Lett., 7, 2731-2734. 

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