Whole-cell biooxidation of bromobenzene with Pseudomonas
putida 39D or the recombinant
Escherichia
coli JM109 (pDTG601) yields
(1S,2S)-3-bromocyclohexa-3,5-diene-1,2-diol
(9a), which is protected as the acetonide
and converted to vinylaziridines 7, 15a,
63, and 64. Our route to
(+)-pancratistatin features the coupling of a higher
order cyanocuprate (derived by ortho-metalation from
N,N-dimethyl-2-[(tert-butyldimethylsilyl)oxy]-3,4-(methylenedioxy)benzamide) with aziridine 7 to generate
28, which contains the carbon framework of the title
alkaloid.
Functional group manipulations resulted in the preparation of
epoxydiol 50, which was transformed in a unique
fashion and under mild conditions
(H2O/PhCO2Na) to (+)-pancratistatin,
thus completing a concise synthesis of
(+)-pancratistatin in 14 steps from bromobenzene (2% overall yield).
To improve this first generation attempt, a
new route was devised utilizing carbomethoxyaziridine 64 and
its coupling to the cuprate of 3,4-(methylenedioxy)bromobenzene. The adduct was converted to
(+)-7-deoxypancratistatin in a total of 11 steps from
bromobenzene
(3% overall yield), and the basis for further improvement toward a
practical synthesis of pancratistatin-type alkaloids
was formulated.
The finale of the large-scale preparation of 60 g of the highly complex marine natural product, (+)-discodermolide (1), using a hybridized Novartis-Smith-Paterson synthetic route is presented. This contribution, which is the concluding part of a five-part series, highlights a reagent-controlled stereoselective boron enolate aldol reaction between 2 and 3 forming the C7 hydroxyl-bearing stereocenter, selective reduction of 4a to generate the 1,3-anti-diol 5, and a global deprotection and concomitant lactonization leading to (+)-discodermolide (1). A novel procedure for converting the minor epimeric aldol adduct 4b into discodermolide using a five-step sequence is also described. This large-scale synthesis of discodermolide involved 39 steps (26 steps in the longest linear sequence) and several chromatographic purifications and delivered sufficient material for early-stage human clinical trials.
IntroductionAfter 36 chemical steps and a gallant effort by many dedicated scientists, we now describe the finale that resulted in the delivery of 60 g of (+)-discodermolide (1), attesting to the power of contemporary organic synthesis in making available sufficient quantities of a highly complex organic molecule, sourced from nature in submilligram quantities, for a thorough evaluation of its therapeutic potential.
A concise large-scale synthesis of 1, a new antimitotic agent is described. The key step was a one-pot Sonogashira crosscoupling of an aryl halide with a heteroaryl halide through an acetylene using the readily available 2-methyl-3-butyn-2-ol ( 7). An innovative approach for palladium removal was designed and successfully scaled-up on a multikilogram scale. The product was crystallized from the crude reaction mixture while keeping the residual palladium in the mother liquor by using Pd-scavenging agents such as N-acetylcysteine or thiourea.
Coupling of C9
-
14 (4) and C15
-
21 (5a) fragments to produce the
cis-trisubstituted olefin was achieved using Suzuki-type coupling
conditions employed by Marshall (5a/tert-BuLi/B-OMe-9-BBN
added to 4/Cs2CO3/Pd(dppf)2). The terminal (Z)-diene moiety
was attached to aldehyde 10 by using a sequential Nozaki−Hiyama allylation and Peterson olefination sequence; careful
monitoring of the disappearance of both diastereomeric β-hydroxysilanes was found to be essential for achieving a high yield.
In the oxidation of alcohols 12 and 16 to 13 and 7, respectively,
using iodobenzene diacetate and TEMPO, addition of a trace
of water was found to be crucial for complete conversion. The
C8
-
9 (Z)-olefin functionality was introduced on to aldehyde 13
using a Still−Gennari HWE reaction. Subsequent carbamate
installation at C-19 followed by a reduction/oxidation sequence
gave the title fragment C7
-
24 (7) ready to be coupled with the
C1
-
6 fragment, which is described in Part 2 of this series.
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