Bisphosphine-catalyzed mixed double-Michael reactions: Asymmetric synthesis of oxazolidines, thiazolidines, and pyrrolidines

Article abstract of DOI:10.1021/ja073754n

Bisphosphine-catalyzed mixed double-Michael reactions have been developed to afford β-amino carbonyl derivatives of oxazolidines, thiozolidines, and pyrrolidines in excellent yields and with high diastereoselectivities. Efficient reactions between amino-a

Full text of DOI:10.1021/ja073754n

Published on Web 10/09/2007
Bisphosphine-Catalyzed Mixed Double-Michael Reactions: Asymmetric
Synthesis of Oxazolidines, Thiazolidines, and Pyrrolidines
Vardhineedi Sriramurthy, Gregg A. Barcan, and Ohyun Kwon*
Department of Chemistry and Biochemistry, UniVersity of California, Los Angeles, California 90095-1569
Received May 24, 2007; E-mail: ohyun@chem.ucla.edu
Table 1. Evaluation of Catalysts for Double-Michael Additionsa
Five-membered nitrogen-atom-containing heterocycles are struc-
tural components of many natural products and pharmaceuticals;1
in addition, many of themsfor example, enantiopure azolidine
derivativesshave been employed as synthetic intermediates, aux-
iliaries, ligands, and catalysts for asymmetric synthesis.2 Conse-
quently, there is a high demand for new methods for the efficient
construction of optically active azolidine derivatives.3 As part of a
program aimed at developing phosphine-mediated annulation reac-
tions,4 we sought a novel route toward highly substituted and
functionalized five-membered-ring nitrogen-atom-containing het-
erocycles. In light of recent reports on the phosphine-catalyzed
conjugate additions of electron-deficient olefins and acetylenes with
alcohols,5 herein we report a bisphosphine-catalyzed mixed double-
Michael process6 that generates azolidines (2; eq 1). Use of amino-
acid-derived pronucleophiles (1) as Michael donors and electron-
deficient acetylenes as Michael acceptors provides efficient access
to azolidines containing both diversity and asymmetry.
isolated yields (%)
entry
catalyst
solvent
2a
3a
1b
2b
3b
4b
5
6
7
8
9
Ph3P
Ph2PEt
Me3P
toluene
toluene
toluene
toluene
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
35
42
0
71
92
37
84
82
79
40
30
22
12
0
42
0
0
DPPP
DPPPc
DPPMc
DPPEc
DPPBc
DPPPentc
6
a All reactions were performed using 1 mmol of 1a, 1.1 mmol of
methylpropiolate, and 10 mol % of the catalyst. b These reactions were run
for 48 h. c DPPM, DPPE, DPPP, DPPB, and DPPPent are acronyms for
diphenylphosphinomethane, -ethane, -propane, -butane, and -pentane,
respectively.
as in DPPP, provides additional stabilization to the intermediate
phosphonium ions 6 and 7. The latter undergoes SN2 displacement
to produce the cyclized product 2.11 In the absence of anchimeric
assistance, as in the case of the monodentate phosphines, the
decreased stability of the phosphonium ion led to an unfavorable
equilibrium for the formation of 6 from 3.12 The relatively short
tether of DPPM prohibits the orbital overlap required for anchimeric
assistance because of geometrical constraints. The other phosphines
for which intramolecular stabilization was possible, namely, DPPE,
DPPB, and DPPPent, gave results similar to those obtained using
DPPP. Note that intramolecular stabilization of phosphonium ions
by nitrogen atoms has precedent in the literature.13
With the optimal reaction conditions in hand, that is, DPPP as
catalyst and CH3CN as solvent, we next explored the scope of the
double-Michael reaction using a variety of amino-acid-derived
pronucleophiles and electron-deficient acetylenes (Table 2). The
formation of oxazolidines from â-amino alcohols and methyl
propiolate proceeded smoothly, with high yields and diastereose-
lectivities (entries 1 and 4). The Michael acceptors acetylacetylene
and tosylacetylene also gave good results (entries 2 and 3). This
methodology works well for the syntheses of thiazolidines from
â-amino thiols (entries 5-7).14 All of the substrates provided
similarly high yields and diastereoselectivities for the formation of
thiazolidines.15
Our initial evaluation of the proposed double-Michael addition
began with the reaction between amino alcohol 1a and methyl
propiolate (Table 1). Employing PPh3 as the catalyst gave the
desired double-Michael adduct 2a in 35% yield in addition to a
40% yield of the mono-Michael adduct 3a (entry 1).7 Use of Ph2-
PEt led to a moderate improvement in the yield of the oxazolidine
product 2a (entry 2), but none was formed from the reaction
catalyzed by Me3P (entry 3).8 In contrast, diphenylphosphinopro-
pane (DPPP) catalysis increased the yield of the desired double-
Michael adduct 2a to 71% (entry 4).9 Further increases in the yield
and reaction rate were achieved when performing the reaction in a
more polar solvent, CH3CN (entry 5). On the basis of the
encouraging results we obtained with DPPP as the catalyst, we also
tested the applicability of the homologous bisphosphines diphe-
nylphosphinomethane (DPPM), diphenylphosphinoethane (DPPE),
diphenylphosphinobutane (DPPB), and diphenylphosphinopentane
(DPPPent). The appreciably poorer yield (37%) of the DPPM-
mediated reaction, relative to those of the other bisphosphines
(entries 6-9), provides a critical clue regarding the reaction
mechanism (vide infra).
Scheme 1 presents a plausible mechanism for the dependence
of the reaction on both the bidentate nature of the phosphine catalyst
and the tether length between the two phosphine moieties. The
reaction is triggered by the conjugate addition of the phosphine to
the electron-deficient acetylene. The resulting vinyl anion 4
deprotonates the pronucleophile 1, which facilitates the first
conjugate addition to form intermediate 6.5b,10 Upon â-elimination
of the phosphine, the mono-Michael product 3 is formed. The
presence of an additional phosphine moiety at the optimal distance,
We further tested the generality of our reaction by using
carbonucleophiles (entries 8-10) for the preparation of pyrrolidine
derivatives, which are ubiquitous in natural products of pharma-
cological interest.16 Under the optimized conditions, we generated
the pyrrolidines 2h and 2i from the valine-derived γ-amino malonate
1h (entries 8 and 9, respectively).17 Employing the cyclic γ-amino
diester 1j furnished the octahydroindole derivative 2j as a single
diastereoisomer in good yield (entry 10). Octahydroindoles, which
9
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J. AM. CHEM. SOC. 2007, 129, 12928-12929
10.1021/ja073754n CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Scheme 1. Proposed Mechanism for the Formation of 2
crystallographic analyses. O.K. thanks Dr. Patrick J. Walsh, Richard
P. Hsung, and Chulbom Lee for helpful discussions.
Supporting Information Available: Representative experimental
procedures and spectral data for all new compounds (PDF). Crystal-
lographic data for 2a and 3a (CIF). This material is available free of
charge via the Internet at http://pubs.acs.org.
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a All reactions were performed using 1 mmol of the substrate, 1.1 equiv
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1
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are present in a large number of natural products, are often
challenging synthetic targets.18
In summary, we have developed a remarkably simple protocol
for the synthesis of oxazolidines, thiozolidines, pyrrolidines, and
octahydroindoles. This mixed double-Michael process operates best
under bisphosphine catalysis to provide â-amino carbonyl deriva-
tives of azolidines19 in excellent yields and with high diastereose-
lectivities. Presumably, the use of bis(diphenylphosphine) deriva-
tives allows intramolecular stabilization of the phosphonium ion
intermediates. We are currently exploring the development of an
enantioselective version of this ring-forming process from achiral
starting materials and its application to the synthesis of selected
drug candidates.
(19) Fustero, S.; Jimenez, D.; Sanchez-Rosello, M.; del Pozo, C. J. Am. Chem.
Soc. 2007, 129, 6700.
Acknowledgment. This study was funded by the NIH
(R01GM071779). We thank Dr. Saeed Khan for performing the
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