Synthetic Study of Azaspiracid-1:  Synthesis of the EFGHI-Ring Fragment

Abstract

Here, we report a synthesis of the lower half C 21 −C 40 fragment of the shellfish toxin, azaspiracid-1. The C 28 −C 40 fragment was synthesized by a coupling between the C 28 −C 35 epoxide and the C 36 −C 40 dithioacetal anion, followed by the HI-ring spiroaminal formation. An aldehyde corresponding to the C 28 −C 40 fragment was then coupled with the C 21 −C 27 allylic stannane by using InCl 3 . Finally, the FG-ring was constructed by HF‚pyridine to accomplish the synthesis of the suitably protected C 21 −C 40 fragment.

Synthesis of the Southern FGHI Ring System of Azaspiracid‐1 and Investigation into the Controlling Elements of C28‐ and C36‐Ketalization

“…The outlined approach represents the shortest route to the FGHI ring system reported to date 2e. 3e,g,p In addition, we have demonstrated that careful selection of conditions for the ketalization steps allows control over the stereochemical outcome of the reaction. Completion of the total synthesis of azaspiracid‐1 ( 1 ) will be reported in due course.…”

“…CSA, MeOH) led to extensive decomposition. Interestingly, treatment of 46 with Yb(OTf) 3 2e, 3e,g,p in PhMe led to rapid formation (30 min, room temperature) of a single new product 47 . Careful analysis by 2D NMR spectroscopy revealed that 47 possessed the undesired stereochemistry at C36.…”

Synthesis of Open-Chain C21-C40 Fragment of Azaspiracid-1

“…In contrast, longer steps are generally required in a diverted synthesis, where fragment assembly is performed at an earlier stage in synthesis. The current diverted strategy, however, is expected to require 39 steps for the longest linear route which is only 2 steps longer than our previous convergent synthesis (37 steps), 9 as shown below. Preparation of C21-C27 allylic stannane 4, 12 corresponding to the E-ring moiety, is shown in Scheme 2.…”

“…A new method for construction of the E-ring moiety has been also developed. In combination with the FGHI-ring formation method, 9,13 the complete ring system is expected to be constructed from 3 in 15 steps which is only 2 steps longer (in total) than our previous route as shown in Scheme 6 9. Studies are currently underway to synthesize the EFGHI-ring domain 2 and the structural analogues from 3, and the result will be reported as a full account in due course.…”

Synthetic Approaches to Spiroaminals

“…In the same way, spiroaminal 46a , a precursor of azaspiracid‐1, has been stereoselectively prepared from 45a through the use of a propyl carbamate protecting group and Yb(OTf) 3 as acid catalyst (78 % yield); the unnatural isomer 46b was prepared from the (2‐nitrophenyl)sulfonylamine 45b in 89 % yield with BF 3 · OEt 2 at lower temperature (Scheme ) 21b…”