Catalytic asymmetric reductive coupling of alkynes and aldehydes: Enantioselective synthesis of allylic alcohols and α-hydroxy ketones

Article abstract of DOI:10.1021/ja034366y

A highly enantioselective method for catalytic reductive coupling of alkynes and aldehydes is described. Allylic alcohols are afforded with complete E/Z selectivity, generally >95:5 regioselectivity, and in up to 96% ee. In conjunction with ozonolysis, th

Full text of DOI:10.1021/ja034366y

Published on Web 03/04/2003
Catalytic Asymmetric Reductive Coupling of Alkynes and Aldehydes:
Enantioselective Synthesis of Allylic Alcohols and r-Hydroxy Ketones
Karen M. Miller, Wei-Sheng Huang, and Timothy F. Jamison*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
Received January 27, 2003; E-mail: tfj@mit.edu
Catalytic asymmetric carbonyl addition reactions are among the
Table 1. Ca atalytic Asymmetric Reductive Alkyne/Aldehyde
Couplings
most studied and useful methods of enantioselective carbon-carbon
1
bond formation, but very few are catalyzed by complexes of group
entry/
product
yield (%),
regioselectivity
ee
(%)
R1
R2
R3
i-Pr
2
1
0 metals. Examples include Pd(II)- and Pt(II)-catalyzed aldol and
3
ene processes, as well as Ni(II)-catalyzed Nozaki-Hiyama-Kishi
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Me
Me
Me
Me
Me
Me
Me
Et
95 (>95:5)
97 (>95:5)
79 (91:9)
82 (>95:5)
80 (>95:5)
75 (>95:5)
93 (>95:5)
81 (>95:5)
78 (>95:5)
74 (>95:5)
90
90
73
65
88
83
90
93
89
92
92
85
96
92
42
4
5,6
c-C H
reactions and Ni(0)-catalyzed 1,3-dien-ω-al cyclizations. Herein
we describe a new member of this unusual class of reactions, the
first highly enantioselective method for catalytic reductive coupling
of alkynes and aldehydes (eq 1).
6
11
Ph
n-Pr
i-Pr
i-Pr
i-Pr
i-Pr
(p-MeO)Ph
(p-Cl)Ph
1-naphthyl
Ph
Ph
Ph
Ph
Ph
Ph
Ph
n-Pr
b
9
Et
n-Pr
i-Pr
CH2OTBS
CH2NHBoc
SiMe3
c-C6H11
i-Pr
i-Pr
i-Pr
i-Pr
1
1
1
1
1
1
0
1
2
3
4
5
c
58 (>95:5)
59 (>95:5)
60 (>95:5)
c
n-Pr
i-Pr
43 (>95:5)
c
n-Pr
35 (-)
a
See eq 1. Experimental procedure (see Supporting Information): A
7
solution of Ni(cod)2 (0.05 mmol), (+)-NMDPP (0.10 mmol), and Et3B (1.0
mmol) in EtOAc/DMI (1:1, total volume 0.50 mL) was cooled to -25 °C.
An alkyne (0.50 mmol) was added via syringe, and then an aldehyde (1.0
mmol) was added via syringe over 8 h. The solution was allowed to stir 36
h, and silica gel chromatography afforded allylic alcohols 1-15. Regiose-
Allylic alcohols are useful starting materials and are prevalent
8
in complex natural products. Enantioselective methods for their
preparation from alkynes and aldehydes that use stoichiometric
amounts of transition metals include those of Oppolzer and Wipf,
which are particularly effective for preparing (E)-disubstituted allylic
alcohols from terminal alkynes, and that of Sato, which utilizes a
chiral titanium-alkyne complex. Nickel-catalyzed intramolecular
9
10
1
lectivity was determined by H NMR; enantioselectivity was determined
by chiral GC or HPLC analysis. b Performed on 5.0 mmol scale. c Some
alkylative coupling was observed (transfer of Et group (instead of H) from
Et B).
3
11
12
and intermolecular13 reductive coupling of alkynes and aldehydes
has been reported, yet asymmetric catalysis has been limited to
only a few cases, all of which utilize “alkyl-alkyl” alkynes (alkyl-
contrast to our recent studies with chiral ferrocenyl monophos-
phines, enantioselectivities are significantly lower using NMDPP
in couplings involving alkyl-CtC-alkyl alkynes (entry 15).
1
4
CtC-alkyl′) and are of low to moderate regioselectivity and
enantioselectivity.14
To illustrate the utility of this method further, allylic alcohols 9
and 13 were converted to R-hydroxy ketones via ozonolysis.
Enantiomeric purity was preserved in both cases, giving 16 (89%
ee), whose TBS ether was developed by Masamune for asymmetric
aldol reactions,18 and 17 (96% ee), whose R-amino-R′-hydroxy
pattern is found in molecules targeted against trypanosomes,
parasites that cause African sleeping sickness upon transmission
from tsetse flies,19 and in aerothionin natural products with anti-
tuberculosis activity.20 Common methods of R-hydroxy ketone
Although (+)-(neomenthyl)diphenylphosphine (NMDPP) was
first prepared by Morrison over 30 years ago and is commercially
available, this chiral monophosphine has thus far found only limited
utility in asymmetric catalysis.15 Nevertheless, in extensive evalu-
ations of chiral ligands, transition metals, and reducing agents,
2 3
NMDPP, Ni(cod) , and triethylborane (Et B) consistently provided
superior results.16 Yield and enantioselectivity were improved
further by using a solvent composed of equal volumes of ethyl
acetate and 1,3-dimethylimidazolidinone (DMI) in conjunction with
slow addition of the aldehyde (see Supporting Information). All
other solvents and additives reduced efficacy and/or selectivity, as
did varying the mode of addition of other components.
This catalytic system affords trisubstituted allylic alcohols
corresponding to exclusive cis addition to the alkyne in excellent
regioselectivity and in up to 96% ee (Table 1). Branched aldehydes
provide high enantioselectivities in reductive couplings with
1
-phenyl-1-propyne, and variation of the alkyne aromatic group
synthesis via asymmetric catalysis involve dihydroxylation or
epoxidation of ketone enolate derivatives. The reductive coupling/
ozonolysis approach obviates a regioselective ketone enolization
1
21
(R ) is tolerated, with 1-naphthyl-1-propyne being particularly
2
effective (entries 5-7). The other alkyne substituent (R ) can also
be varied considerably (entries 8-14), and protected alcohols,
protected amines, and SiMe
that would be required (and difficult) for cases represented by 16
groups are accommodated.17 In
and 17 and is therefore complementary.
22
3
3442
9
J. AM. CHEM. SOC. 2003, 125, 3442-3443
10.1021/ja034366y CCC: $25.00 © 2003 American Chemical Society

C O MMU N I C A T I O N S
Scheme 1. Proposed Steric and Electronic Control in Catalytic
Asymmetric Reductive Couplings
(2) (a) Gorla, F.; Togni, A.; Venanzi, L. M.; Abinati, A.; Lianza, F.
Organometallics 1994, 13, 1607-1616. (b) Sodeoka, M.; Ohrai, K.;
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Am. Chem. Soc. 1998, 120, 10032-10039. (d) Motoyama, Y.; Kawakami,
H.; Shimozono, K.; Aoki, K.; Nishiyama, H. Organometallics 2002, 21,
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(
3) (a) Hao, J.; Hatano, M.; Mikami, K. Org. Lett. 2000, 2, 4059-4062. (b)
Koh, J. H.; Larsen, A. O.; Gagn e´ , M. R. Org. Lett. 2001, 3, 1233-1236.
4) Choi, H. W.; Nakajima, K.; Demeke, D.; Kang, F. A.; Jun, H. S.; Wan,
Z. K.; Kishi, Y. Org. Lett. 2002, 4, 4435-4438.
(
(
(
(
5) Sato, Y.; Saito, N.; Mori, M. J. Am. Chem. Soc. 2000, 122, 2371-2372.
6) Bercot, E. A.; Rovis, T. J. Am. Chem. Soc. 2002, 124, 174-175.
7) (a) Br u¨ ckner, R. In ComprehensiVe Organic Synthesis; Trost, B. M., Ed.;
Pergamon: New York, 1991; Vol. 6, Chapter 4.6, pp 873-908. (b) Hill,
R. K. In ComprehensiVe Organic Synthesis; Trost, B. M., Ed.; Perga-
mon: New York, 1991; Vol. 5, Chapter 7.1, pp 785-826. (c) Wipf, P. In
ComprehensiVe Organic Synthesis; Trost, B. M., Ed.; Pergamon: New
York, 1991; Vol. 5, Chapter 7.2, pp 827-873. (d) Hoveyda, A. H.; Evans,
D. A.; Fu, G. C. Chem. ReV. 1993, 93, 1307-1370.
(8) (a) Barchi, J. J., Jr.; Moore, R. E.; Patterson, G. M. L. J. Am. Chem. Soc.
1984, 106, 8193-8197. (b) Bollag, D. M.; McQueney, P. A.; Zhu, J.;
Hensens, O.; Koupal, L.; Liesch, J.; Goetz, M.; Lazarides, E.; Woods, C.
M. Cancer Res. 1995, 55, 2325-2333. (c) Oka, M.; Iimura, S.; Tenmyo,
O.; Sawada, Y.; Sugawara, M.; Ohkusa, N.; Yamamoto, H.; Kawano, K.;
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9) Oppolzer, W.; Radinov, R. N. HelV. Chim. Acta 1992, 75, 170-173.
The sense of asymmetric induction in these couplings is
consistent with the model in Scheme 1. Several lines of evidence
point to an oxametallocyclopentene intermediate, arising from
complexes such as A-D.23 Both the axial placement and the
(
(10) Wipf, P.; Ribe, S. J. Org. Chem. 1998, 63, 6454-6455.
(11) Takayanagi, Y.; Yamashita, K.; Yoshida, Y.; Sato, F. Chem. Commun.
1996, 1725-1726.
orientation of a metal-PPh
2
group over the cyclohexyl ring of
(12) (a) Oblinger, E.; Montgomery, J. J. Am. Chem. Soc. 1997, 119, 9065-
NMDPP have been observed in the solid state.24 Rotation of one
9066. (b) See also: Crowe, W. E.; Rachita, M. J. J. Am. Chem. Soc. 1995,
117, 6787-6788.
of the phenyl groups to avoid interaction with the isopropyl group
places a C-H bond in the ligand plane on one side, disfavoring
aldehyde complexation (A and B). Coordination of the aldehyde
to the less encumbered side (C or D) by way of the electron pair
cis to the aldehyde H and placement of the aldehyde R group away
from the metal center appear to minimize steric interactions.
The high enantioselectivity uniquely provided by NMDPP in
these couplings can thus be explained by a cooperative effect
between steric properties of the ligand and electronic differences
of the alkyne substituents. Two of four modes of aldehyde
coordination (A and C) are inconsistent with the sense and degree
of regioselectivity, and one of the remaining two is more accessible
(13) Huang, W.-S.; Chan, J.; Jamison, T. F. Org. Lett. 2000, 2, 4221-4223.
(
(
14) Colby, E. A.; Jamison, T. F. J. Org. Chem. 2003, 68, 156-166.
15) (a) Morrison, J. D.; Burnett, R. E.; Aguiar, A. M.; Morrow, C. J.; Philips,
C. J. Am. Chem. Soc. 1971, 93, 1301-1303. (b) Blum, J.; Eisen, M.;
Schumann, H.; Gorella, B. J. Mol. Catal. 1989, 56, 329-337. (c) Lee,
S.; Hartwig, J. F. J. Org. Chem. 2001, 66, 3402-3415. (d) Recent chiral
monophosphine review: Komarov, I. V.; B o¨ rner, A. Angew. Chem., Int.
Ed. 2001, 40, 1197-1200.
(
16) Most monophosphines formed catalytically active complexes, but all ee’s
1
2
3
were lower than 25% (R ) Ph, R ) Me, R ) n-Pr). For example:
1
4
(S)-ferrocenylmethylphenylphosphine (15% ee); [(S)-(R)-PPF-OMe]
5% ee); (R,R)-2,5-dimethyl-1-phenylphospholane (0% ee). Nickel com-
(
plexes incorporating diphosphines (e.g., BINAP, BPE, DuPHOS) did not
catalyze the reaction. Couplings utilizing 200 mol % aldehyde were of
much higher yield than those with 100 mol %; reactions employing an
NMDPP/Ni ratio of 2:1 gave slightly higher yields than those with a 1:1
ratio. Kimura and Tamaru have also observed that a combination of a
3
nickel catalyst and Et B effects reductive carbonyl additions; see, for
(D) and leads to the major enantiomer observed. This framework
example: Kimura, M.; Ezoe, A.; Shibata, K.; Tamaru, Y. J. Am. Chem.
Soc. 1998, 120, 4033-4034.
suggests that increased steric differentiation of the two aldehyde
coordination sites might further enhance enantioselectivity. Finally,
the general strategy of tandem electronic and steric control of
enantioselectivity presented here may be applicable to related
reactions involving alkynes, such as those described by our group
and others.4
(
17) The allylic alcohol derived from phenylacetylene and isobutyraldehyde
1
2
3
(
R ) Ph, R ) H, R ) i-Pr) was afforded in 75% ee, >95:5
regioselectivity, and 15% yield. Alkyne cyclotrimerization is competitive
with reductive coupling under these conditions.
(
18) (a) Masamune, S.; Choy, W.; Kerdesky, F. A. J.; Imperiali, B. J. Am.
Chem. Soc. 1981, 103, 1566-1568. (b) Masamune, S.; Hirama, M.; Mori,
S.; Ali, S. A.; Garvey, D. S. J. Am. Chem. Soc. 1981, 103, 1568-1571.
19) (a) Eisenthal, R.; Game, S.; Holman, G. D. Biochim. Biophys. Acta 1989,
-6,12a,23,25
(
9
85, 81-89. (b) Az e´ ma, L.; Bringaud, F.; Blonski, C.; P e´ ri e´ , J. Bioorg.
Acknowledgment. We thank the National Institute of General
Medical Sciences (GM-063755), the NSF (CAREER CHE-
Med. Chem. 2000, 8, 717-722.
(
20) Ciminiello, P.; Costantino, V.; Fattorusso, Magno, S.; Mangioni, A.;
Pansini, M. J. Nat. Prod. 1994, 57, 705-712.
21) (a) Hashiyama, T.; Morikawa, K.; Sharpless, K. B. J. Org. Chem. 1992,
0134704), Merck Research Laboratories, Pfizer, Boehringer-Ingel-
(
heim, Bristol-Myers Squibb, 3M, Johnson & Johnson, the donors
of the Petroleum Research Fund, and MIT for financial support.
We are grateful to Robert D. Jackson, Chudi O. Ndubaku, Justin
P. Cohen, and Elizabeth A. Colby for experimental assistance. The
NSF (CHE-9809061 and DBI-9729592) and NIH (1S10RR13886-
5
7, 5067-5068. (b) Zhu, Y.; Tu, Y.; Yu, H.; Shi, Y. Tetrahedron Lett.
1998, 39, 7819-7822. (c) Davis, F. A.; Chen, B. C. Chem. ReV. 1992,
2, 919-934.
9
(
22) See also: (a) Trost, B. M.; Pinkerton, A. B. J. Am. Chem. Soc. 2002,
124, 7376-7389. (b) D u¨ nkelmann, P.; Kolter-Jung, D.; Nitsche, A.; Demir,
A. S.; Siegert, P.; Lingen, B.; Baumann, M.; Pohl, M.; M u¨ ller, M. J. Am.
Chem. Soc. 2002, 124, 12084-12085.
01) provide partial support for the MIT Department of Chemistry
(23) Patel, S. J.; Jamison, T. F. Angew. Chem., Int. Ed. 2003, 42, in press, and
references therein.
Instrumentation Facility.
(
24) Whittall, I. R.; Humphrey, M. G.; Samoc, M.; Luther-Davies, B.; Hockless,
D. C. R. J. Organomet. Chem. 1997, 544, 189-196.
Supporting Information Available: Experimental procedures and
data for compounds 1-17 (PDF). This material is available free of
charge via the Internet at http://pubs.acs.org.
(
25) Reviews: (a) Tamaru, Y. J. Organomet. Chem. 1999, 576, 215-231. (b)
Montgomery, J. Acc. Chem. Res. 2000, 33, 467-473. (c) Ikeda, S.-i. Acc.
Chem. Res. 2000, 33, 511-519. (d) Houpis, I. N.; Lee, J. Tetrahedron
2
000, 56, 817-846. Recent examples involving alkynes: (e) Ni, Y.;
Amarasinghe, K. D.; Montgomery, J. Org. Lett. 2002, 4, 1743-1745. (f)
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J. AM. CHEM. SOC.
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