Catalytic asymmetric assembly of stereodefined propionate units: An enantioselective total synthesis of (-)-pironetin

Article abstract of DOI:10.1021/ja061938g

Double diastereoselection in alkaloid-catalyzed acyl halide-aldehyde cyclocondensation (AAC) reactions provides a strategy for realizing syn- or anti-selective propionate aldol additions from a common reaction manifold. Matched AAC homologation of enantio

Full text of DOI:10.1021/ja061938g

Published on Web 05/19/2006
Catalytic Asymmetric Assembly of Stereodefined Propionate Units: An
Enantioselective Total Synthesis of (-)-Pironetin
Xiaoqiang Shen, Andrew S. Wasmuth, Junping Zhao, Cheng Zhu, and Scott G. Nelson*
Department of Chemistry, UniVersity of Pittsburgh, Pittsburgh, PennsylVania 15260
Received March 21, 2006; E-mail: sgnelson@pitt.edu
The importance of aldol-based bond constructions in modern
asymmetric synthesis has generated considerable interest in devel-
oping catalytic asymmetric reaction variants. Catalyzed aldol addi-
tions eliminate the requirement for installing and recycling, or
destroying, a chiral auxiliary used to affect asymmetric bond con-
structions. A number of highly successful catalytic asymmetric aldol
addition reactions have been developed involving both direct aldol
processes and additions of pregenerated latent enolates.1 How-
ever, examples of these catalytic asymmetric aldol reactions being
used in an iterative fashion to assemble repeating propionate or
acetate networks are rare.2 Herein, we describe the utility of alka-
loid-catalyzed acyl halide-aldehyde cyclocondensation (AAC) reac-
Figure 1. Iterative application of asymmetric catalytic AAC reactions.
tions for the catalytic asymmetric synthesis of extended propionate
networks (Figure 1).3 The utility of this reaction technology in
synthesis activities is exemplified in a catalytic asymmetric total
synthesis of (-)-pironetin.
Scheme 1 a
As one solution to catalytic asymmetric aldol additions, we de-
veloped acyl halide-aldehyde cyclocondensations that provide
enantioenriched â-lactones 1 as syn propionate aldol equivalents.4
Extending these reactions to AAC-based strategies for assembling
repeating propionate units was predicated on engaging the enan-
tioenriched â-lactone-derived syn aldehyde 2 in further AAC
homologation (Figure 1). Ensuing AAC reactions of 2 with correct
selection of alkaloid catalyst (3 or 4) would then deliver the
stereochemically complementary propionate dimers 5 or 6. A central
issue to be addressed in this context would be the catalyst’s ability
to reliably and predictably complement or override the intrinsic
facial bias expressed by the chiral aldehyde substrates.5
a Conditions: (a) 10 mol % of 4a, LiClO4, iPr2NEt, -78 °C (74%); (b)
(i) (MeO)MeNH2Cl, Me2AlCl (80%); (ii) TMSOTf, 2,6-lutidine (86%); (iii)
iBu2AlH, THF (80%); (c) 10 mol % of 3a, LiI, iPr2NEt (84%); (d) 10 mol
i
Iterative AAC homologation of R-substituted aldehyde 7 pro-
vided a representative test sequence for evaluating this polypropi-
onate synthesis design (Scheme 1). Reacting (S) aldehyde 7 with
propionyl chloride using 10 mol % of 4a as catalyst (2 equiv of
% of 4b, LiI, Pr2NEt (72%).
delivered the anticipated syn,anti,syn â-lactones 13a/b with com-
plete stereocontrol (Table 1, entries a and b). The mismatched
quinine-catalyzed AAC homologations of syn aldehydes 12a/c
faithfully produced the anti,anti,syn â-lactones 14a/c with high
diastereoselectivity (g90% de) (entries c and d). Matched AAC
homologation (quinine catalyst) of anti aldehyde 15 afforded the
syn,anti,anti â-lactone 16 with equally high diastereoselection (entry
e).8 However, in contrast to the syn aldehyde electrophiles, the anti
aldehyde 15 does not undergo the mismatched AAC reaction. To
evaluate these reactions as potential conduits to extended propionate
networks, the syn,anti,syn aldehyde 17, obtained from â-lactone
13a, was engaged in TMSQn (O-trimethylsilylquinine; 4a)-
catalyzed (matched) cyclocondensation with propionyl chloride to
afford the propionate trimer equivalent 18 as a single diastereomer
(entry f, 79% yield).
A catalytic asymmetric total synthesis of (-)-pironetin (19)
highlights this reaction technology’s utility in the context of a
representative polyketide-derived target.9,10 The AAC-derived â-lac-
tone 20 (99% ee, 89:11 syn:anti) was subjected to the three-step
lactone-to-aldehyde conversion to afford syn aldehyde 21 (Scheme
2).11 TMSQn-catalyzed (matched) homologation of 21 then provided
the syn,anti,syn â-lactone 22 (g95% de). Lactone reduction to the
corresponding diol preceded selective primary alcohol tosylation
and installation of the C9 methyl ether to afford the protected tetraol
23. Tosylate substitution by Cu(I)-mediated allyl Grignard addition
i
LiI, Pr2NEt) afforded the anticipated syn,anti â-lactone 8 in 78%
yield (syn,anti:Σothers ) 92:8).6 Reformatting lactone 8 as the
corresponding syn aldehyde 9 proceeded by amine-mediated lactone
ring opening, alcohol silylation, and Weinreb amide reduction (55%
yield for three steps). Ensuing TMSQd (O-trimethylsilylquinidine;
3a)-catalyzed AAC homologation of 9 afforded â-lactone 10 (94%
de, 84%) as a surrogate for the corresponding syn,anti,syn propi-
onate trimer.7 The magnitude of double diastereoselection operative
in these reactions became apparent upon AAC homologation of 9
employing the pseudoenantiomeric quinine-derived catalyst 4b (10
i
mol %, EtCOCl, Pr2NEt, 3 equiv of LiI) that afforded lactone 11
with excellent diastereoselection albeit with the unanticipated C2-
C3/C3-C4 anti,anti stereochemistry. Our failure to isolate the all-
syn lactone expected from catalyst-dominated stereocontrol sug-
gested that mismatched substrate/catalyst chirality was responsible
for the anti diastereoselection across the â-lactone, an observation
previously unprecedented for the AAC reactions. Nevertheless, this
observation suggested a strategy for realizing syn- or anti-selective-
catalyzed aldol additions via the AAC reaction design.
Examining the generality of the AAC-based propionate synthesis
revealed the conditions under which matched and mismatched
diastereoselection was manifested. Under the ostensibly matched
AAC reaction conditions, the â-lactone-derived syn aldehydes 12a/b
9
7438
J. AM. CHEM. SOC. 2006, 128, 7438-7439
10.1021/ja061938g CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Matched and Mismatched AAC Reactions
Scheme 3 a
a Conditions: (a) (i) DDQ, aq. CH2Cl2 (81%); (ii) Swern (88%); (b)
i
nPrCOBr, Pr2NEt, 50 mol % of 27, BTF, -25 °C (65%); (c) t-BuOAc,
KHMDS then MgBr2 (66%); (d) (i) NaBH4, EtOH; (ii) TsOH, toluene, 110
°C (56% for two steps).
utility in synthesis efforts directed toward polyketide-derived
materials.
Acknowledgment. Support from the National Institutes of
Health (R01 GM63151), the Bristol-Myers Squibb Foundation, Eli
Lilly & Co., and the Merck Research Laboratories is gratefully
acknowledged.
a Catalyst (10 mol %) 3a, entries a, b; 4a, entries c-f. b Stereochemical
assignments based on X-ray structure determinations of derivatives of 14c
and 16 and comparison of 1H coupling constants. c Diastereomeric ratios
1
determined by HPLC or H NMR analysis of crude reaction mixtures.
Scheme 2 a
Supporting Information Available: Experimental procedures,
stereochemical proofs, and representative 1H and 13C spectra. This
material is available free of charge via the Internet at http://pubs.acs.org.
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