Chemoenzymatic Approaches to the Montanine Alkaloids:  A Total Synthesis of (+)-Brunsvigine

Abstract

The readily available and enzymatically derived cis-1,2-dihydrocatechols 3a and 3b have been elaborated over 17 steps, including a novel radical addition/elimination sequence, into the enantiomer, (+)-1, of the montanine alkaloid brunsvigine [(-)-1].

The Exploitation of Enzymatically‐Derived cis‐1,2‐Dihydrocatechols and Related Compounds in the Synthesis of Biologically Active Natural Products

“…Another very useful feature associated with derivatives of the chlorinated and brominated cis ‐1,2‐dihydrocatechols 1 (X=Cl and Br, respectively) is the capacity to engage them in intramolecular, radical addition/elimination reactions. So, for example, when the α‐thiophenylated amide 189 (Scheme ) derived from compound 1 (X=Cl) is treated under radical generating conditions it is converted into the lactam 190 (94 %) that can be elaborated, using Pictet‐Spengler chemistry, to compound 191 , the enantiomer of the montanine alkaloid (−)‐brunsvigine . Interestingly, the equivalent radical cyclisation of the bromo‐analogue of compound 189 is a much less efficient process (29 % of compound 190 was obtained).…”

Bioinspired Total Synthesis of Montanine‐Type Amaryllidaceae Alkaloids

“…In various approaches to the assembly of the 5,11‐methanomorphanthridine skeleton, the five types of advanced synthons I – V (Scheme ) have been strategically involved,6–10 and the closure of ring C, D, C/D, or E has constituted the final step in the construction of the polycyclic system. Significantly, the synthetic elaboration of these synthons I – V has involved the elegant development and application of many novel methodologies (e.g., an aza‐Cope rearrangement/Mannich cyclization,5a, 6a an allenylsilane imino ene reaction,9b,c a [3+2] cycloaddition,6b,g, 10 and a chemoenzymatic approach6i,k,l). Despite the substantial progress made in the racemic5, 6c–e,o, 7, 8, 9a, 10 and asymmetric6a,b,f–n, 9b,c synthesis of the montanine‐type alkaloids, a general strategy for the effective bioinspired total synthesis of these architecturally unique molecules has not previously been explored.…”

Radical Reactions in Alkaloid Synthesis: A Perspective from Carbon Radical Precursors

“…In a synthesis of the montanine alkaloid (+)‐brunsvigine (Scheme ), the hexahydroindole moiety was assembled by a radical addition/elimination process from 134 , which embodies a sulfide as the radical precursor and a vinylhalide as the radical acceptor. After the formation of the C–C bond via a 5‐ exo ‐ trig process, the resulting cyclohexyl radical underwent a fragmentation with the adjacent chlorine atom to diastereoselectively give 135 .…”