A summary
of the investigation and applications of the inverse
electron demand Diels–Alder reaction is provided that have
been conducted in our laboratory over a period that now spans more
than 35 years. The work, which continues to provide solutions to complex
synthetic challenges, is presented in the context of more than 70
natural product total syntheses in which the reactions served as a
key strategic step in the approach. The studies include the development
and use of the cycloaddition reactions of heterocyclic azadienes (1,2,4,5-tetrazines;
1,2,4-, 1,3,5-, and 1,2,3-triazines; 1,2-diazines; and 1,3,4-oxadiazoles),
1-aza-1,3-butadienes, α-pyrones, and cyclopropenone ketals.
Their applications illustrate the power of the methodology, often
provided concise and nonobvious total syntheses of the targeted natural
products, typically were extended to the synthesis of analogues that
contain deep-seated structural changes in more comprehensive studies
to explore or optimize their biological properties, and highlight
a wealth of opportunities not yet tapped.
A series of 180 vinblastine 20’ amides were prepared in three steps from commercially available starting materials, systematically exploring a typically inaccessible site in the molecule enlisting a powerful functionalization strategy. Clear structure–activity relationships and a structural model were developed in the studies which provided many such 20’ amides that exhibit substantial and some even remarkable enhancements in potency, many that exhibit further improvements in activity against a Pgp overexpressing resistant cancer cell line, and an important subset of the vinblastine analogs that display little or no differential in activity against a matched pair of vinblastine sensitive and resistant (Pgp overexpressing) cell lines. The improvements in potency directly correlated with target tubulin binding affinity and the reduction in differential functional activity against the sensitive and Pgp overexpressing resistant cell lines was found to correlate directly with an impact on Pgp-derived efflux.
Herein,
the first total syntheses of (−)-pseudocopsinine
(1) and (−)-minovincine (3) from
a common intermediate 8 are detailed, enlisting late-stage,
hydrogen atom transfer (HAT)-mediated free radical bond formations
(C20–C2 and C20–OH, respectively) that are unique to
their core or structure. The approach to 1 features an
Fe-mediated HAT reaction of the intermediate olefin 2, effecting a transannular C20–C2 free radical cyclization
of a challenging substrate with formation of a strained [2.2.1] ring
system and reaction of a poor acceptor tetrasubstituted alkene with
a hindered secondary free radical to form a bond and quaternary center
adjacent to another quaternary center. Central to the assemblage of
their underlying Aspidosperma skeleton is a powerful
[4 + 2]/[3 + 2] cycloaddition cascade of 1,3,4-oxadiazole 9, which affords the stereochemically rich and highly functionalized
pentacyclic intermediate 8 as a single diastereomer in
one step. The work extends the divergent total synthesis of four to
now six different natural product alkaloid classes by distinguishing
late stage key strategic bond formations within the underlying Aspidosperma core from the common intermediate 8. Together, the work represents use of strategic bond analysis combined
with the strategy of divergent synthesis to access six different natural
product classes from a single intermediate.
The design, synthesis, and evaluation of methyl 1,2,8,8a-tetrahydrocyclopropa[c]imidazolo[4,5-e]indol-4-one-6-carboxylate (CImI) derivatives are detailed representing analogs of duocarmycin SA and yatakemycin containing an imidazole replacement for the fused pyrrole found in the DNA alkylation subunit.
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