Phosphine-catalyzed enantioselective synthesis of oxygen heterocycles

Article abstract of DOI:10.1002/anie.200805377

(Chemical Equation Presented) Chiral phosphepine 1 catalyzes the transformation of an array of hydroxy-2-alkynoates into saturated oxygen heterocycles with good enantioselectivity. Phenols are also shown to participate in such phosphine-catalyzed cyclizat

Full text of DOI:10.1002/anie.200805377

Angewandte
Chemie
DOI: 10.1002/anie.200805377
Asymmetric Catalysis
Phosphine-Catalyzed Enantioselective Synthesis of Oxygen
Heterocycles**
Ying Kit Chung and Gregory C. Fu*
Although phosphines serve as nucleophilic catalysts for an
array of useful transformations, comparatively few highly
enantioselective variants in the presence of chiral phosphines
have been described.[1,2] In 1994, Trost discovered a novel
dppp-catalyzed (dppp = 1,3-bis(diphenylphosphino)propane)
cyclization of hydroxy-2-alkynoates that generates saturated
oxygen heterocycles.[3] Despite the importance of such
structures, owing to their presence in a wide range of
bioactive molecules,[4] there has been no progress toward
the development of an asymmetric version of the Trost
cyclization. Herein, we establish that chiral spiro phosphepine
1 can achieve this objective with a variety of hydroxy-2-
alkynoates with good enantiomeric excess [Eq. (1)].
Scheme 1. Outline of a possible pathway for the phosphine-catalyzed
synthesis of oxygen heterocycles from hydroxy-2-alkynoates. For the
sake of simplicity, all elementary steps are drawn as irreversible and all
olefins are depicted as single isomers.
promising catalysts,[5,6] with the spiro phosphepine 1[7] accom-
plishing the desired cyclization with particularly good ee value
and yield (Table 1, entry 9).[8]
A plausible pathway for the phosphine-catalyzed cycliza-
tion of hydroxy-2-alkynoates has been suggested by Trost and
Li (Scheme 1).[3] On the basis of this mechanism, it seemed
reasonable to anticipate that the catalytic asymmetric syn-
thesis of oxygen heterocycles might be achieved through the
use of an appropriate chiral phosphine. In our initial studies,
we investigated the cyclization of hydroxy-2-alkynoate 2 to
form tetrahydrofuran 3 in the presence of an array of chiral
bisphosphines (Table 1, entries 1–4), since Trost had reported
that dppp is significantly more effective than PPh3 for non-
asymmetric processes.[3] Because the results were not espe-
cially promising, we turned our attention to monophosphines
(Table 1, entries 5–9). Phosphepines emerged as the most
The conditions that we developed for the cyclization of
hydroxy-2-alkynoate 2 can be applied to a variety of
substrates (Table 2), providing not only tetrahydrofurans
(Table 2, entries 1–3), but also tetrahydropyrans (Table 2,
entries 4–8), with high ee values and generally good yields.
Substituents could be tolerated a, b, or g to the hydroxy
group.
To date, phenols have not been utilized as nucleophiles in
phosphine-catalyzed syntheses of oxygen heterocycles from 2-
alkynoates. We have determined that, under similar condi-
tions as for aliphatic alcohols,[9] spiro phosphepine 1 catalyzes
the cyclization of 2-alkynoates that bear pendant phenols,
thereby providing access to enantioenriched dihydrobenzo-
pyrans[10] (Table 3). Phenols with ortho substituents or those
fused to nitrogen heterocycles are suitable substrates.
We have not yet pursued extensive mechanistic studies of
this phosphine-catalyzed method for the enantioselective
synthesis of oxygen heterocycles. According to 31P NMR
spectroscopy, when benzoic acid is added to a solution of spiro
phosphepine 1 in THF, proton transfer to form an ion pair
does not occur. Furthermore, the resting state of the
phosphepine during the catalytic cycle is free phosphepine 1
(rather than, for example, a phosphonium salt, as illustrated in
Scheme 1). Spiro phosphepine 1 is reasonably air-stable.
After exposure of the solid to air for three days at room
[*] Y. K. Chung, Prof. Dr. G. C. Fu
Department of Chemistry, Massachusetts Institute of Technology
Cambridge, MA 02139 (USA)
Fax: (+1)617-324-3611
E-mail: gcf@mit.edu
[**] We thank Prof. Qi-Lin Zhou, Kodak, and Degussa for generous gifts
of catalysts and catalyst precursors. Support has been provided by
the National Institutes of Health (National Institute of General
Medical Sciences, grant R01-GM57034), the Croucher Foundation
(postdoctoral fellowship for Y.K.C.), Merck Research Laboratories,
and Novartis.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200805377.
1
temperature, no phosphine oxide was detected by H NMR
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Table 1: Catalytic enantioselective synthesis of oxygen heterocycles by
chiral bidentate and monodentate phosphines.
Table 2: Catalytic enantioselective synthesis of tetrahydrofurans and
tetrahydropyrans.
Entry
Catalyst
ee [%][a]
Yield [%][b]
Entry
Substrate
ee [%]
87
Yield [%][a]
1
2
3
4
5
6
7
8
9
(S,S)-chiraphos
(R,R)-dipamp
(R,R)-Me-duphos
(R,R)-binaphane
(R)-mop
(S)-monophos
(S)-4
(S)-5
–
22
–
17
–
<2
70
<2
9
<2
<2
72
1
2
78
90
94
–
3
4
87
92
63
90
À66
À45
87
65
80
(S)-1
All data are the average of two experiments. [a] A negative value for the ee
signifies that the enantiomer of 3 is formed preferentially. [b] The yield
was determined by GC analysis with the aid of a calibrated internal
standard. Chiraphos=2,3-bis(diphenylphosphano)butane; dipamp=
1,2-ethanediylbis[(2-methoxyphenyl)phenylphosphane]; Me-duphos=
5
6
94
92
85
72
1,2-bis(2,5-dimethylphospholanyl)benzene;
mop=2-(diphenylphos-
phanyl)-2’-methoxy-1,1’-binaphthyl.
7
8
94
91
82
80
All data are the average of two experiments. [a] Yield of purified product.
spectroscopy. In addition, the phosphine oxide does not serve
as a catalyst for the cyclization.
Table 3: Catalytic enantioselective synthesis of dihydrobenzopyrans.
Prior to this study, three types of phosphine-catalyzed
processes had been described that furnish very good enantio-
selectivity with some generality: acylations of alcohols,
Morita–Baylis–Hillman reactions, and couplings of allenes
with an unsaturated partner, such as an alkene or imine.[2] The
current process, adding to some promising earlier results with
carbon nucleophiles,[11] represents a fourth class of asymmet-
ric transformations that can be effectively catalyzed by chiral
phosphines, g additions of nucleophiles to unsaturated
carbonyl compounds.
In summary, we have established that a chiral phosphine
can catalyze the transformation of an array of hydroxy-2-
alkynoates into saturated oxygen heterocycles with good
enantioselectivity. In particular, we have demonstrated that
spiro phosphepine 1, which had previously proved effective as
a chiral ligand in transition-metal chemistry, catalyzes the
synthesis of tetrahydrofurans, tetrahydropyrans, and dihydro-
benzopyrans with high efficiency. Additional studies are
Entry
1
Substrate
ee [%]
Yield [%][a]
86
88
2
3
4
63
84
84
82
89
79
All data are the average of two experiments. [a] Yield of purified product.
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palytoxin. For some leading references to the synthesis of
saturated oxygen heterocycles, see: M. C. Elliott, J. Chem. Soc.
Perkin Trans. 1 2002, 2301 – 2323.
underway that exploit the rich potential of chiral phosphines
as asymmetric nucleophilic catalysts.
[5] For pioneering studies of phosphepines 4 and 5, see: a) S.
Gladiali, A. Dore, D. Fabbri, O. De Lucchi, M. Manassero,
Tetrahedron: Asymmetry 1994, 5, 511 – 514; b) K. Junge, B.
Hagemann, S. Enthaler, G. Oehme, M. Michalik, A. Monsees, T.
Riermeier, U. Dingerdissen, M. Beller, Angew. Chem. 2004, 116,
5176 – 5179; Angew. Chem. Int. Ed. 2004, 43, 5066 – 5069.
[6] For our efforts to employ phosphepine 4 as a chiral nucleophilic
catalyst, see Reference [2c].
Received: November 3, 2008
Published online: February 11, 2009
Keywords: asymmetric catalysis · cyclization · isomerization ·
.
oxygen heterocycles · phosphanes
[1] For reviews of phosphine-catalyzed reactions, see: a) J. L.
Methot, W. R. Roush, Adv. Synth. Catal. 2004, 346, 1035 –
1050; b) L.-W. Ye, J. Zhou, Y. Tang, Chem. Soc. Rev. 2008, 37,
1140 – 1152.
[7] a) S.-F. Zhu, Y. Yang, L.-X. Wang, B. Liu, Q.-L. Zhou, Org. Lett.
2005, 7, 2333 – 2335; b) J.-H. Xie, Q.-L. Zhou, Acc. Chem. Res.
2008, 41, 581 – 593. To our knowledge, until now, spiro phosphe-
pine 1 had been used exclusively as a ligand for transition-metal
catalyzed asymmetric processes, not as an enantioselective
nucleophilic catalyst.
[8] Notes: a) In the absence of benzoic acid, under otherwise
identical conditions, spiro phosphepine 1 generates the tetrahy-
drofuran with 80% ee and 13% yield. An array of other acids,
including chiral acids, furnish lower ee values and/or yields;
b) With catalyst 1 (5 mol%) and benzoic acid (25 mol%), the
reaction proceeded more slowly (e.g., for the substrate illus-
trated in entry 1 of Table 2, the product was generated in 86% ee
and 58% yield after four days).
[2] For some key studies of asymmetric catalysis, see: a) kinetic
resolutions of alcohols: E. Vedejs, O. Daugulis, S. T. Diver, J.
Org. Chem. 1996, 61, 430 – 431; E. Vedejs, O. Daugulis, J. Am.
Chem. Soc. 1999, 121, 5813– 5814; b) Morita–Baylis–Hillman
reactions: T. Hayase, T. Shibata, K. Soai, Y. Wakatsuki, Chem.
Commun. 1998, 1271 – 1272; M. Shi, L.-H. Chen, C.-Q. Li, J. Am.
Chem. Soc. 2005, 127, 3790 – 3800; c) couplings of allenes with an
unsaturated partner: G. Zhu, Z. Chen, Q. Jiang, D. Xiao, P. Cao,
X. Zhang, J. Am. Chem. Soc. 1997, 119, 3836 – 3837; R. P. Wurz,
G. C. Fu, J. Am. Chem. Soc. 2005, 127, 12234 – 12235; J. E.
Wilson, G. C. Fu, Angew. Chem. 2006, 118, 1454 – 1457; Angew.
Chem. Int. Ed. 2006, 45, 1426 – 1429; B. J. Cowen, S. J. Miller, J.
Am. Chem. Soc. 2007, 129, 10988 – 10989; Y.-Q. Fang, E. N.
Jacobsen, J. Am. Chem. Soc. 2008, 130, 5660 – 5661; A. Voituriez,
A. Panossian, N. Fleury-Bregeot, P. Retailleau, A. Marinetti, J.
Am. Chem. Soc. 2008, 130, 14030 – 14031.
[9] For the substrate illustrated in entry 1 of Table 3, we obtained
65% ee and 86% yield under the conditions employed in
Table 2.
[10] An array of natural products, including vitamin E, siccanin, and
tazettine, bear a dihydrobenzopyran subunit.
[11] Z. Chen, G. Zhu, Q. Jiang, D. Xiao, P. Cao, X. Zhang, J. Org.
Chem. 1998, 63, 5631 – 5635.
[3] B. M. Trost, C.-J. Li, J. Am. Chem. Soc. 1994, 116, 10819 – 10820.
[4] For example, saturated five- and six-membered oxygen hetero-
cycles are found in gingkolide B, monensin, morphine, and
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