Rational Synthesis of Contra-Thermodynamic Spiroacetals by Reductive Cyclizations

Abstract

A synthesis of spiroacetals was developed using a reductive cyclization strategy that leads stereoselectively to spiroacetals with a single anomeric stabilization. The method begins with the synthesis of spiro ortho esters. The ortho ester is converted to a cyano acetal. Reductive lithiation of the cyano acetal generates an axial dialkoxylithium reagent, and intramolecular cyclization produces a new ring with retention of configuration. The strategy is convergent and produces complex spiro acetals in only a few steps. The method will be useful in the synthesis of natural products and will facilitate the synthesis of previously inaccessible contra-thermodynamic acetals.

A Reductive Cyclization Approach to Attenol A

“…31 The [5.5]-spiro orthoester 8 was opened with BF 3 ·OEt 2 and TMSCN with excellent regio-and chemoselectivity to give alcohol 44 (Scheme 9) in 71% yield as a single diastereomer. 5 The reaction proceeded to completion faster than the analogous reaction of a [5.4]-spiro orthoester. In our previous synthetic endeavors the electrophile, a primary alkyl chloride, was installed prior to cyanoacetal synthesis.…”

“…5 An example of this cyclization reaction is illustrated in Scheme 1. In contrast to traditional spiroacetal syntheses, this strategy is convergent and gives rise to a non-anomeric stabilized [5.4]-spiroacetal as a single stereoisomer.…”

Development of a General, Sequential, Ring-Closing Metathesis/Intramolecular Cross-Coupling Reaction for the Synthesis of Polyunsaturated Macrolactones

“…The assembly began with the conversion of acid 2 to the acid chloride that was then added dropwise to cooled solutions of known diols 3b-f 52 in collidine to provide esters 4b-f in 72-79% yields (Table 3). The esters were converted to their respective silyl ethers 5b-f and then were subjected to ring closing metathesis with catalyst 6 as before to afford siloxanes 7b-f .…”

Asymmetric Synthesis of Naturally Occuring Spiroketals

“…have reported the total synthesis of attenol A using a reductive cyclisation approach [ 146 ]. This reductive cyclisation strategy facilitates the stereoselective assembly of nonanomeric spiroacetals [ 147 ]. The advantage of this strategy over the traditional spiroacetal syntheses is that it gives rise to a single nonanomeric stabilized [5.4]-spiroacetal, which equilibrates under acidic conditions to the more stable anomeric epimer [ 147 ].…”