First Model Reactions towards the Synthesis of Sarain A Core Skeleton Based upon a Biogenetic Scenario

Abstract

Sarain A is a complex macrocyclic marine alkaloid extracted from sponges of the order Haplosclerida. It is likely that this alkaloid shares a common origin with manzamine alkaloids, also extracted from sponges of the same order. In this paper, new concepts concerning this origin are presented and conSarain A is a complex alkaloid isolated from the sponge Reniera Sarai.[1] Despite its unique skeleton, it is believed to have the same biogenetic origin as other macrocyclic alkaloids extracted from sponges of the same order (Haplosclerida) such as, inter alia, manzamine A, halicyclamine A, keramaphidin B.[2] The basis for an understanding of this origin were initially formulated by Baldwin and Whitehead who proposed an original pathway for explaining the origin of keramaphidin B and manzamine A. This pathway involved formation of dihydropyridine intermediates from long-chain aminoaldehydes and acrolein, followed by intra- [a]

A Biogenetically Based Strategy Towards the Polycyclic Core Skeleton of Sarain A

“…The best alternative was the reduction of enaminal 14 in order to introduce the third stereocenter (Scheme 4) by using sodium borohydride in acetic acid which fully reduced the enaminal function but stereospecifically delivered the undesired alcohol isomer 15. We had shown in our previous paper [7] that such a configuration is the thermodynamic one, as was further confirmed when alcohol 16 was oxidized to the corresponding aldehyde. Under enolization conditions, this aldehyde was completely epimerized at C-3 (results not shown).…”

“…[6] We have suggested [7] that the biogenetic origin of sarain A (1) could Scheme 1. Proposed biogenetic pathway.…”

2.14 Other Condensation Reactions (Knoevenagel, Perkin, Darzens)

“…The Knoevenagel condensation of ethylmalonate with butyraldehyde was used to synthesize highly functionalized fivemembered nitrogen heterocycles (94-96) (Scheme 30). 71 Use of chlorotrimethylsilane, (CH 3 ) 3 SiCl, as a promoter and water scavenger enables the Knoevenagel condensation of aromatic aldehydes with various methylene compounds. Intermediate 96 can be viewed as a possible synthon for further work that involves the synthesis of sarin A because it possesses the same ring junction as the natural alkaloid.…”

Biomimetic Synthesis of Manzamine Alkaloids

“…Inspection of this alkaloid reveals a polyenic 1,2,3-aminodiol, sphingolipid-like moiety, suggesting a distinct biogenetic origin relative to the manzamines previously described in this chapter. Indeed, retro-biosynthetic analysis of sarain A type alkaloids 10) using iminium-based disconnections provides with key amino-aldehyde 15 and two C 3 synthons [postulated as malondialdehyde (17) according to Marazano's model], along with cyclic amino acid 144 (that may result from the catabolism of sphingolipid 143) (Scheme 6.38) [61]. From these biogenetic elements, but with a philosophy identical to what we have seen up to now, it thus appears that sarain A type alkaloids are not directly connected to the elaborated manzamines presented before, with which they only share simple amino-aldehyde precursors 15.…”

“…Biosynthetic proposal for xestospongin A and related structures.synthesis of ent-xestospongins A (ent-57) and C (ent-58) and ent-araguspongin B (ent-59) from ent-60 and ent-62 as depicted in Scheme 6.12 probably proceeds via this pathway, and implicates intermediate ent-61. Two distinct reaction conditions permitting a reduction of the unsaturated piperidine without reduction of the masked iminium were studied (i.e., hydrogenation with catalytic rhodium or Raney nickel), and gave different ratios of the three natural substances ent-57 and ent-58 Selected synthetic approaches to upenamide.…”