Synthesis of (±)-Serralongamine A and the Revised Structure of Huperzine N

Abstract

A revised structure for the Lycopodium alkaloid huperzine N is proposed and confirmed by synthesis. The key synthetic steps involve an epimerization of a cis-5-oxodecahydroquinoline to the corresponding trans isomer and a coupling, followed by a diastereoselective hydrogenation using Wilkinson's catalyst to incorporate the pyridylmethyl moiety. This route allowed the alkaloid serralongamine A to be synthesized for the first time, and two additional steps led to the revised structure of huperzine N, both products bearing an unusual decahydroquinoline stereostructure.

Decahydroquinoline Ring 13C NMR Spectroscopic Patterns for the Stereochemical Elucidation of Phlegmarine-Type Lycopodium Alkaloids: Synthesis of (−)-Serralongamine A and Structural Reassignment and Synthesis of (−)-Huperzine K and (−)-Huperzine M (Lycoposerramine Y)

“…Structural Reassignment of Huperzine K and Huperzine M (Lycoposerramine Y). After the total synthesis of huperzine N (16) 6 it was evident that huperzine M (15) should have a trans-configuration in the DHQ ring fusion (type D), considering the close correlation with its Noxide analogue (i.e., 16), rather than the cis ring fusion reported after its isolation. 5 Moreover, it became clear that the proposed trans-decahydroquinoline structure for lycoposerramine Y 11 (Figure 5) was also misassigned, as its NMR spectroscopic data are identical to those reported for huperzine M, and both isolated alkaloids should therefore have the same structure.…”

“…24 The latter was transformed into the key advanced synthetic intermediate trans-decahydroquinoline (−)-28, using the methodology reported for our synthesis of racemic serralongamine. 6 Thus, protection of ketone (+)-22, removal of the tosyl group in (+)-23, and promotion of an epimerization process by treatment of (+)-24 in acid medium led to a transdecahydroquinoline, which after N-tosylation 42 furnished ketone (+)-25. A Wittig−Horner reaction gave diastereoselective access 6 to vinylpyridine (+)-26, which upon hydrogenation using Wilkinson's catalyst under optimized reaction conditions (only 2.5% of catalyst loading) furnished (+)-27 in 95% yield, with the same stereochemical arrangement of the four stereogenic carbons as the targeted alkaloids.…”

“…Figure 1 depicts the main differences in NMR spectroscopic data between the putative structure of the initially synthesized huperzine N and the reassigned structure of the isolated alkaloid. After confirming the real structure of huperzine N by total synthesis, 6 we were interested in identifying 13 C NMR spectroscopic patterns associated with the relative configurations of the decahydroquinoline core in phlegmarine alkaloids. 7 This would help to identify other misassigned phlegmarine alkaloids in the literature and also assist in the structural assignments of new alkaloids of this family.…”

Synthesis of cis-hydrindan-2,4-diones bearing an all-carbon quaternary center by a Danheiser annulation

“…This strategy is based on the disconnection across the C1–C7a and C3–C3a bonds, which according to the Danheiser annulation logic would reveal the cyclohexenone intermediate I and a silylallene such as II . The former, in turn, would disconnect back to β-keto ester 1 ( Scheme 1 ), which we have employed in the synthesis of phlegmarine-type Lycopodium alkaloids [ 23 – 26 ].…”

“…As a continuation of our work on the synthesis of Lycopodium alkaloids [ 23 – 26 ], we hypothesized that decahydroquinoline 1 , a versatile building block for the synthesis of phlegmarine-type alkaloids, available in both enantiomeric forms, could also serve as an intermediate toward other Lycopodium alkaloids (e.g., fawcettimine). Thus, we surmised that building block 1 could be a new precursor of 3a-substituted hydrindan-2,4-diones ( Scheme 1 ).…”