A novel tandem Michael addition/Meerwein-Ponndorf-Verley reduction: Asymmetric reduction of acyclic α,β-unsaturated ketones using a chiral mercapto alcohol

Article abstract of DOI:10.1021/ja993546y

The introduction of a thiol group into a chiral alcohol reagent for asymmetric Meerwein-Ponndorf-Verley (MPV) reductions allows asymmetric reduction of α,β-unsaturated ketones to secondary alcohols and allylic alcohols via a novel tandem Michael addition/MPV reduction. The reaction of acyclic α,β-unsaturated ketones 1 and an optically active 1,3-mercapto alcohol (-)-2 using dimethylaluminum chloride afforded the MPV reduction products 3 diastereoselectively in very high yields (up to 96%). Mechanistic studies elucidated (1) the structure of the chelation complex D with (-)-2 and Me₂AlCl, (2) an asymmetric 1,7-hydride shift (intramolecular MPV reduction), and (3) dynamic kinetic resolution via reversible Michael addition. Subsequent reductive desulfurization of the MPV products 3 with a modified Raney nickel system led to the highly enantioselective reduction of α,β-unsaturated ketones to saturated secondary alcohols in 96-98% ee. β-Elimination of the corresponding sulfoxides gave the allylic alcohols in 86-98% ee. Applications to the asymmetric reduction of a synthetic intermediate 1m of prostaglandins and to a new asymmetric synthesis of the (+)-Rove beetle pheromone 11 are described.

Full text of DOI:10.1021/ja993546y

J. Am. Chem. Soc. 2000, 122, 1927-1936
1927
A Novel Tandem Michael Addition/Meerwein-Ponndorf-Verley
Reduction: Asymmetric Reduction of Acyclic R,â-Unsaturated
Ketones Using A Chiral Mercapto Alcohol
Manabu Node,* Kiyoharu Nishide, Yukihiro Shigeta, Hiroaki Shiraki, and Kenichi Obata
Contribution from the Department of Pharmaceutical Manufacturing Chemistry,
Kyoto Pharmaceutical UniVersity, Misasagi, Yamashina, Kyoto 607-8414, Japan
ReceiVed October 4, 1999
Abstract: The introduction of a thiol group into a chiral alcohol reagent for asymmetric Meerwein-Ponndorf-
Verley (MPV) reductions allows asymmetric reduction of R,â-unsaturated ketones to secondary alcohols and
allylic alcohols via a novel tandem Michael addition/MPV reduction. The reaction of acyclic R,â-unsaturated
ketones 1 and an optically active 1,3-mercapto alcohol (-)-2 using dimethylaluminum chloride afforded the
MPV reduction products 3 diastereoselectively in very high yields (up to 96%). Mechanistic studies elucidated
(1) the structure of the chelation complex D with (-)-2 and Me2AlCl, (2) an asymmetric 1,7-hydride shift
(intramolecular MPV reduction), and (3) dynamic kinetic resolution via reversible Michael addition. Subsequent
reductive desulfurization of the MPV products 3 with a modified Raney nickel system led to the highly
enantioselective reduction of R,â-unsaturated ketones to saturated secondary alcohols in 96-98% ee.
â-Elimination of the corresponding sulfoxides gave the allylic alcohols in 86-98% ee. Applications to the
asymmetric reduction of a synthetic intermediate 1m of prostaglandins and to a new asymmetric synthesis of
the (+)-Rove beetle pheromone 11 are described.
Introduction
enantioselectivity was realized by this methodology.8 Con-
versely, it was shown that intramolecular MPV reduction (1,5-
hydride shift) proceeds with extremely high stereoselectivity,9
though this method is not applicable to asymmetric reduction
of the usual ketones without a chiral alcohol moiety. Evans and
co-workers devised a catalytic highly enantioselective MPV
reduction using a chiral samarium catalyst.10 Noyori and co-
workers also exploited an excellent asymmetric transfer hydro-
genation of aromatic ketones using a late transition metal chiral
ruthenium or iridium catalyst. The reaction is similar to the MPV
The Meerwein-Ponndorf-Verley (MPV) reduction, discov-
ered in the 1920s, still is a useful method for the reduction of
carbonyl compounds because of its chemoselectivity.1 Various
alkoxides of Li,2 Mg,3 and early transition metals (Sc,4 Y,4
lanthanide,5 Zr,6 Hf,6 Ta7), variants of the original aluminum
isopropoxide, have been used in this reaction. In the 1950s and
1960s, asymmetric versions of the intermolecular MPV reduc-
tion of ketones employing optically active alcohols as chiral
sources were widely studied. However, only low or moderate
* Address correspondence to this author.
(5) (a) Lanthanide alkoxide: Lebrun, A.; Namy, J. L.; Kagan, H. B.
Tetrahedron Lett. 1991, 32, 2355-2358. (b) Okano, T.; Matsuoka, M.;
Konishi, H.; Kiji, J. Chem. Lett. 1987, 181-184. (c) Namy, J. L.; Souppe,
J.; Collin, J.; Kagan, H. B. J. Org. Chem. 1984, 49, 2045-2049. (d)
Intramolecular Tishchenko reduction (SmI2): Evans, D. A.; Hoveyda, A.
H. J. Am. Chem. Soc. 1990, 112, 6447-6449.
(1) Review: (a) Wilds, A. L. Org. React. 1944, 2, 178-223. (b) de
Graauw, C. F.; Peters, J. A.; van Bekkum, H.; Huskens, J. Synthesis 1994,
1007-1017. (c) Takahashi, K.; Shibagaki, M.; Kuno, H.; Matsushita, H.
Shokubai 1995, 37, 23-27 and references therein. Also see: (d) Knauer,
B.; Krohn, K. Liebigs Ann. 1995, 677-683. (e) Krohn, K.; Knauer, B.
Liebigs Ann. 1995, 1347-1351. (f) Castellani, C. B.; Carugo, O.; Perotti,
A.; Sacchi, D.; Invernizzi, A. G.; Vidari, G. J. Mol. Catal. 1993, 85, 65-
74. (g) Strickler, J. R.; Bruck, M. A.; Wexler, P. A.; Wigley, D. E.
Organometallics 1990, 9, 266-273. (h) Ramig, K.; Kuzemko, M. A.;
Parrish, D.; Carpenter, B. K. Tetrahedron Lett. 1992, 33, 6279-6282. (i)
Kaspar, J.; Trovarelli, A.; Lenarda, M.; Graziani, M. Tetrahedron Lett. 1989,
30, 2705-2706. (j) Hutton, J. Synth. Commun. 1979, 9, 483-486. (k)
Kowalski, C.; Creary, X.; Rollin, A. J.; Burke, M. C. J. Org. Chem. 1978,
43, 2601-2608. (l) Takezawa, N.; Kobayashi, H. Chem. Lett. 1977, 123-
126. (m) Doering, W. von E.; Aschner, T. C. J. Am. Chem. Soc. 1953, 75,
393-397. (n) Ooi, T.; Miura, T.; Maruoka, K. Angew. Chem., Int. Ed. 1998,
37, 2347-2349.
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P.; Thebtaranonth, C.; Thebtaranonth, Y. J. Chem. Soc., Chem. Commun.
1991, 1016-1017. (b) i-Pr2OLi SET mechanism: Ashby, E. C.; Argy-
ropoulos, J. N. J. Org. Chem. 1986, 51, 3593-3597. (c) Ashby, E. C. Acc.
Chem. Res. 1988, 21, 414-421.
(3) (a) MgO: Kaspar, J.; Trovarelli, A.; Lenarda, M.; Graziani, M.
Tetrahedron Lett. 1989, 20, 2705-2706. (b) MgO mechanism: Takezawa,
N.; Kobayashi, H. Chem. Lett. 1977, 123-126. (c) Equilibrium: Doering,
W. von E.; Aschner, T. C. J. Am. Chem. Soc. 1953, 75, 393-397.
(4) Castellani, C. B.; Carugo, O.; Perotti, A.; Sacchi, D.; Invernizzi, A.
G.; Vidari, G. J. Mol. Catal. 1993, 85, 65-74.
(6) (a) Zirconium or Hafnium hydride i-PrOH: Nakano, T.; Umano, S.;
Kino, Y.; Ishii, Y.; Ogawa, M. J. Org. Chem. 1988, 53, 3752-3757. (b)
Cp2ZrH2: Ishii, Y.; Nakano, T.; Inada, A.; Kishigami, Y.; Sakurai, K.;
Ogawa, M. J. Org. Chem. 1986, 51, 240-242. (c) (i-PrO)4Zr (pyrimidone
3,4-reduction): Hfseggen, T.; Rise, F.; Undheim, K. J. Chem. Soc., Perkin
Trans. 1 1986, 849-850. (d) Zr(t-OBu)4-1-(4-dimethylaminophenyl)-
ethanol: Knauer, B.; Krohn, K. Liebigs Ann. 1995, 677-683.
(7) Tantalum(V): Strickler, J. R.; Bruck, M. A.; Wexler, P. A.; Wigley,
D. E. Organometallics 1990, 9, 266-273.
(8) Chiral Grignard reagent: (a) Streitweiser, A., Jr.; Wolfe, J. R.;
Schaeffer, W. D. Tetrahedron 1959, 6, 338-344. (b) Foley, W. M.; Welch,
F. J.; La Combe, E. M.; Mosher, H. S. J. Am. Chem. Soc. 1959, 81, 2779-
2784. (c) MacLeod, R.; Welch, F. J.; Mosher, H. S. J. Am. Chem. Soc.
1960, 82, 876-880. (d) Burrows, E. P.; Welch, F. J.; Mosher, H. S. J. Am.
Chem. Soc. 1960, 82, 880-885. (e) Birtwistle, J. S.; Lee, K.; Morrison, J.
D.; Sanderson, W. A.; Mosher, H. S. J. Org. Chem. 1964, 29, 37-40. Chiral
aluminum alkoxide: (f) Doering, W. von E.; Young, R. W. J. Am. Chem.
Soc. 1950, 72, 631. (g) Jackman, L. M.; Mills, J. A.; Shannon, J. S. J. Am.
Chem. Soc. 1950, 72, 4814-4815. (h) Newman, P.; Rutkin, P.; Mislow, K.
J. Am. Chem. Soc. 1958, 80, 465-473. (i) Nasipuri, D.; Sarker, G. J. Indian
Chem. Soc. 1967, 44, 165-166. (j) Nasipuri, D.; Sarker, G.; Ghosh C. K.
Tetrahedron Lett. 1967, 5189-5192. (k) Fles, D.; Majhofer, B.; Kovac,
M. Tetrahedron 1968, 24, 3053-3057.
10.1021/ja993546y CCC: $19.00 © 2000 American Chemical Society
Published on Web 02/23/2000

1928 J. Am. Chem. Soc., Vol. 122, No. 9, 2000
Node et al.
Scheme 1. Inter- and Intramolecular Meerwein-Ponndorf-Verley Reductions
reduction but has a different mechanism.11 These reactions are
limited in that only aryl methyl ketones give products in
excellent enantiomeric excesses. Therefore, we decided to
investigate a new type of asymmetric MPV reduction that would
have few substrate limitations. We report herein the full account
of the asymmetric reduction12 of R,â-unsaturated ketones to
saturated secondary alcohols or allylic alcohols, using an
optically active mercapto alcohol as a chiral reagent via a noVel
tandem Michael addition/MPV reduction and subsequent des-
ulfurization.
reductions (eqs 1 and 2, Scheme 1). The low enantioselectivity
in eq 18 can be attributed to a relatively small energy difference
between the two possible six-membered monocyclic transition
states, in which the controlling factor of the enantiofacial
selectivity of the carbonyl group is the bulkiness of the four
substituents. In eq 2,9a the high enantioselectivity presumably
is due to the formation of the single bicyclic transition state by
steric restriction of the chiral alcohol moiety on the eight-
membered chelated structure. Although intramolecular MPV
reduction is superior to intermolecular reduction in terms of
stereoselectivity, the former has two serious drawbacks: (1)
another asymmetric synthesis is required in the substrate
preparation and (2) the ketone moiety remains in the product,
making its removal difficult.
Results and Discussion
A. Design of a Novel Asymmetric Tandem Michael
Addition/MPV Reduction. We began by analyzing the transi-
tion states of various inter- and intramolecular asymmetric MPV
To overcome these disadvantages, we designed a tandem
Michael addition/MPV reduction of an R,â-unsaturated ketone
1 using Lewis acid and a chiral 1,3-mercapto alcohol 2 (Scheme
2). Michael addition of 2 to 1 using Lewis acid proceeded easily
to give the sulfide A containing ketone and chiral alcohol
moieties, which then underwent intramolecular MPV reduction
(1,7-hydride shift) to give the MPV product B with high
stereoselectivity. Removal of the ketone moiety from 3 by
desulfurization afforded the optically active saturated alcohol
4 or the allylic alcohol 5.
(9) (a) Zhou, W. S.; Zhou, X. M.; Ni, Y. Acta Chim. Sin. 1984, 42,
706-709. (b) Zhou, W. S.; Wang, Z. Q.; Zhang, H.; Fei, R. Y.; Zhuang, Z.
P. Acta Chim. Sin. 1985, 43, 168-173. (c) Ishihara, K.; Hanaki, N.;
Yamamoto, H. J. Am. Chem. Soc. 1991, 113, 7074-7075. (d) Ishihara, K.;
Hanaki, N.; Yamamoto, H. Synlett 1993, 127-129. (e) Molander, G. A.;
McKie, J. A. J. Am. Chem. Soc. 1993, 115, 5821-5822. (f) Baramee, A.;
Chaichit, N.; Intawee, P.; Thebtaranonth, C.; Thebtaranonth, Y. J. Chem.
Soc., Chem. Commun. 1991, 1016-1017. (g) Fujita, M.; Takarada, Y.;
Sugimura, T.; Tai, A. J. Chem. Soc., Chem. Commun. 1997, 1631-1632.
Also see intramolecular Tishchenko reduction: (h) Evans, D. A.; Hoveyda,
A. H. J. Am. Chem. Soc. 1990, 112, 6447-6449. Also see hydride shift in
a rigid cyclic system: (i) Sherrod, M. J.; Menger, F. M. Tetrahedron Lett.
1990, 31, 459-462. (j) Mills, O. S.; Watt, C. I. F.; Whitworth, S. M. J.
Chem. Soc., Perkin Trans. 2 1990, 487-497. (k) Denmark, S. E.; Henke,
B. R. J. Am. Chem. Soc. 1991, 113, 2177-2194.
Since the intramolecular MPV conversion of A to B is
reversible, a large energy difference favoring B over A is needed
to provide the driving force for the reaction. Generally, a large
energy change is not expected in an intramolecular MPV
reduction because the substrate and the product usually have
the same kind of functional groups. The contribution of the
structural change of the reagent (mercapto alcohol) to the driving
force of the reaction biased A into B also must be considered.
The torsional strain of a cyclopentanol system, including its
eclipsing interactions, is partially released by conversion to the
ketone. The strain energy difference in a five-membered ring
would be greater than that in a six-membered ring or an acyclic
system.
(10) Evans, D. A.; Nelson, S. G.; Gagne´, M. R.; Muci, A. R. J. Am.
Chem. Soc. 1993, 115, 9800-9801.
(11) (a) Hashiguchi, S.; Fujii, A.; Takehara, J.; Ikariya, T.; Noyori, R.
J. Am. Chem. Soc. 1995, 117, 7562-7563. (b) Fujii, A.; Hashiguchi, S.;
Uematsu, N.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1996, 118, 2521-
2522. (c) Gao, J.-X.; Ikariya, T.; Noyori, R. Organometallics 1996, 15,
1087-1089. (d) Inoue, S.; Nomura, K.; Hashiguchi, S.; Noyori, R.; Izawa,
Y. Chem. Lett. 1997, 957-958. (e) Matsumura, K.; Hashiguchi, S.; Ikariya,
T.; Noyori, R. J. Am. Chem. Soc. 1997, 119, 8738-8739. (f) Also see
BINAP-diamine-ruthenium catalyst: Ohkuma, T.; Ooka, H.; Hashiguchi,
S.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1995, 117, 2675-2676.
(12) For a preliminary communication see: Nishide, K.; Shigeta, Y.;
Obata, K.; Node, M. J. Am. Chem. Soc. 1996, 118, 13103-13104.

Asymmetric Reduction of Acyclic R,â-Unsaturated Ketones
J. Am. Chem. Soc., Vol. 122, No. 9, 2000 1929
Scheme 2. Asymmetric Reduction of R,â-Unsaturated Ketones via Tandem Michael Addition-MPV Reduction
Scheme 3. Aluminum Complexes of Michael Adduct and MPV Product of (-)-2a
Scheme 4. Comparison of Chiral Mercapto Alcohols 2a,b for Tandem Michael-MPV Reduction
Using the above criteria, we chose 10-mercaptoisoborneol
[(+)- or (-)-2a]13 as a chiral reagent and an acyclic R,â-
unsaturated ketone as the substrate for this asymmetric reduction.
In the MPV reduction of the Michael adduct from (-)-2a and
an R,â-unsaturated ketone, a single bicyclic transition state is
expected due to the five fixed atoms of the 10-mercap-
toisoborneol (2a) moiety in the normally flexible 10-membered-
ring chelated structure (Scheme 3), thus making possible a high
yield and high diastereoselectivity.
To confirm the above hypothesis, we compared the reactions
of methyl vinyl ketone (1j) with mercapto alcohols 2a13 and
2b14 using Me2AlCl in toluene at room temperature for 3 h
(Scheme 4). The reaction of 2a afforded only the MPV product
3j. On the other hand, 2b gave both the Michael adduct 6j (36%)
and the MPV product 3′j (30%). Benzoylation of 3j and 3′j
and desulfurization with Raney nickel gave the corresponding
benzoate 4j in >98% ee and 90% ee, respectively (determination
of optical purity will be described later). As expected, the five-
membered-ring alcohol 2a was notably superior to the six-
membered-ring alcohol 2b. The intermolecular MPV reduction
of ketones 7 and 8 with borneol (2c) and isoborneol (2d) (same
method) gave the secondary alcohols 4a (6% ee) and 4f (47%
ee), respectively (Scheme 5), thus confirming the superiority
of the intramolecular process.
B. Optimization of Reaction Conditions (Solvents, Lewis
Acids, Temperatures, Times). Reaction conditions were
optimized using benzalacetone (1a) and (-)-2a (98% ee). The
optical purity of 4-phenyl-2-butanol (4a) obtained by reductive
desulfurization15 of 3a was determined by chiral HPLC analysis
(Daicel CHIRALCEL OD). Assignment of the stereochemistry
on the chiral carbon attached to a sulfur atom in 3a will be
discussed later. Dichloromethane was the solvent providing 4a
with the highest (97%) ee. Other solvents giving 4a in >90%
(13) Eliel, E. L.; Frazee, W. J. J. Org. Chem. 1979, 44, 3598-3599.
(14) (a) Eliel, E. L.; Lynch, J. E. Tetrahedron Lett. 1981, 22, 2855-
2858. (b) Lynch, J. E.; Eliel, E. L. J. Am. Chem. Soc. 1984, 106, 2943-
2948. (c) Eliel, E. L.; Lynch, J. E.; Kume, F.; Frye, S. V. Org. Synth. 1987,
65, 214-223.
(15) (a) Nishide, K.; Shigeta, Y.; Obata, K.; Inoue, T.; Node, M.
Tetrahedron Lett. 1996, 37, 2271-2274. (b) Node, M.; Nishide, K.; Shigeta,
Y.; Obata, K.; Shiraki, H.; Kunishige, H. Tetrahedron 1997, 53, 12883-
12894.

1930 J. Am. Chem. Soc., Vol. 122, No. 9, 2000
Node et al.
Table 2. Relationship of Reaction Time and Optical Purity
Scheme 5. Intermolecular MPV Reduction Using Borneol
and Isoborneol
reaction time (h)
6fb:3f
yield (%) of 3f
ee (%) of 4f
1.5
3
6
12
24
48
1:2.1
1:2.3
1:3.6
1:13.1
1:>20
1:>20
96
96
96
96
96
96
59
85
a Reductive desulfurization with Raney Ni-NaPH2O2. b Diastereo-
meric mixture (ca. 1:1).
Table 1. Reaction Data
Figure 1. Aluminum complexes of Michael adduct and MPV product.
entry
Lewis acid
yield (%) of 3a
% eeb of 4a
1
2
3
4
5
Me2AlCl
Et2AlCl
Pr2AlCl
EtAlCl2
AlCl3
61
66
97
95
90
suggests that the MPV reduction proceeds via an asymmetric
intramolecular 1,7-hydride shift in which a rigid bicyclic
transition state is involved.
35
n.r.c
n.r.c
C. MOPAC PM3 Calculations. PM3 calculations (MOPAC
version 6) were performed to clarify the energy difference
between the Michael adduct and the MPV product. To simplify
calculations, we used Michael adduct Aj and MPV product Bj
of 2a with methyl vinyl ketone (1a). The calculated heats of
formation were -172.14 kcal/mol for Aj and -173.96 kcal/
mol for Bj, indicating the latter to be 1.82 kcal/mol more stable
than the former.
a Reductive desulfurization with Raney Ni-NaPH2O2. b Determined
by HPLC Chiralcel OD. c Chiral mercapto alcohol 2a was decomposed.
ee were benzene, toluene, and Et2O. The yield of 3a was highest
in hexane, but the product ee was somewhat lower than that in
dichloromethane. The reaction did not occur in THF presumably
due to its high coordinating ability to the aluminum Lewis acid.
Dialkylaluminum chlorides proved to be the most successful
Lewis acid for this reaction (Table 1). Among the organoalu-
minums tested, Me2AlCl clearly was the best with regard to
the ee of the MPV product. Higher alkyl substituents than methyl
on aluminum decreased ee. EtAlCl2 and AlCl3 caused decom-
position of 2a due to their stronger Lewis acidity.
The temperature effect was next studied. The MPV reduction
did not occur at -78 °C, it proceeded at 0 °C, but the yield
was higher at room temperature (ca. 20 °C). Higher temperatures
(ca. 35 °C) caused the decomposition of 2a with Me2AlCl. The
ee values of 4a at 0 °C and at room temperature were equal
and very high (97%), indicating that stereoselectivity of the
attack on the carbonyl group is independent of temperature,
probably due to the rigid bicyclic transition state (Scheme 3).
We initially assumed that prolonged reaction time decreased
product ee, because the MPV reduction is known to be
reversible. Therefore, the above reactions were quenched at
relatively short times (3 h). The moderate yields of the products
3 and isolation of the adducts 6 prompted us to examine the
relationship of reaction times and yields as well as ee values of
4. Results using trans-chalcone (1f) are summarized in Table
2. The ratio of the Michael adduct 6f to the MPV product 3f
decreased as reaction time was prolonged. After 24 h, the ratio
reached a plateau (1:>20) with corresponding enhancement of
the yield to 85%, in contrast to 59% after 3 h. The most
important observation was that the ee of 4f derived from 3f
remained constant irrespective of reaction time. This strongly
The ratio of the two components in equilibrium is related to
their free energy difference. If the MPV reduction is an intra-
molecular reaction (proved later), Figure 1, the entropy can be
neglected in the free energy equation. The free energy then
can be approximated by the enthalpy. The equilibrium constant
(K ) k1/k2) can be calculated to be 22.8. This constant is
close to the experimental value (>20) for 24 and 48 h. Thus, it
may be concluded that the reaction reaches equilibrium after
24 h.
D. Asymmetric Reduction of r,â-Unsaturated Ketones to
Secondary Alcohols. Using the above optimization results, we
set about generalizing the reaction. Reductions of various R,â-
unsaturated ketones 1a-h, bearing an aromatic group as R1,
are summarized in Table 3. Reaction products 3a-h were
reductively desulfurized using the Raney nickel-NaPH2O2
combination system15 to give the corresponding products 4a-h
in high yields. No racemization of the optically active secondary
alcohol was observed.16 Reaction of benzalacetone (1a) with
2a (1.2 equiv, 98% ee) and Me2AlCl (1.2 equiv) (room
temperature, 12 h) in CH2Cl2 under N2 gave 3a in 83% yield.
Reductive desulfurization of 3a resulted in (S)-4-phenyl-2-
butanol (4a) with 97% ee in 89% yield (entry 1, Table 3). The
yield of 3a was improved to 94% by using benzene instead of
(16) (a) Butlin, R. J.; Linney, I. D.; Mahon, M. F.; Tye, H.; Wills, M. J.
Chem. Soc., Perkin Trans. 1 1996, 95-105. (b) Garc´ıa, M. M. C.; Rauno,
J. L. G.; Castro, A. M. M.; Ramos, J. H. R.; Ferna´ndez, I. Tetrahedron:
Asymmetry 1998, 9, 859-864.

Asymmetric Reduction of Acyclic R,â-Unsaturated Ketones
J. Am. Chem. Soc., Vol. 122, No. 9, 2000 1931
Table 3. Tandem Michale-MPV Reaction and Subsequent Reductive Desulfurization
tandem Michael-MPV reaction
reductive desulfurization
entry
compd
R1
R2
solv.
time (h)
yield (%)a of 3
time (min)
yield (%)a of 4
% eeb of 4
config.
1
2
3
4
5
6
7
8
9
1a
1a
1b
1c
1d
1e
1f
Ph
Me
CH2Cl2
benzene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
benzene
CH2Cl2
benzene
CH2Cl2
12
12
13
16
12
12
25
24
33
38
16
83
94
90
81
83
90
89
94
75
88
73
40
40
20
20
40
40
20
20
20
20
20
89
88
91
95
89
99
96
99
97
85
90
97
89
98
98
97
98
96
95
96d
92d
98
Sc
S
S
S
S
Ph
Ph
Ph
Ph
Ph
Et
Pr
Bu
Oct
Ph
S
R
R
Re
R
Re
1f
1g
1g
1h
p-MeOPh
Ph
10
11
p-Tolyl
Ph
a Isolated yield. b HPLC analysis using a Daicel Chiralcel OD column unless otherwise noted. c Determined by X-ray crystallographic analysis
of the corresponding sulfone 10 of 3a. d Daicel Chiralpak AS. e Determined by the CD spectrum comparison with 4f.
Table 4. Tandem Michael-MPV Reaction and Subsequent Reductive Desulfurization
tandem Michael-MPV reaction
reductive desulfurization
entry
compd
R1
R2
R3
solv.
time (h)
yield (%)a of 3
time (h)
yield (%)b of 4
% eec of 4
config.
1
2
3
4
5
1i
1i
1j
1k
1l
Me
Me
Me
CH2Cl2
benzene
CH2Cl2
CH2Cl2
CH2Cl2
16
15
12
15
24
90
96
82
82
95
1.5
4
75
73
73
77
86g
98
98
98
97f
93
Sd
Sd
Sd
R
H
H
Me
H
H
H
Me
Pent
Ph
2e
31
24
R
a Isolated yield. b Overall yield of protection and desulfurization. c HPLC analysis using a Daicel Chiralcel OB column unless otherwise noted.
d Determined by modified Mosher’s method: see ref 17. e Reflux 2 h. f Daicel Chiralcel OF. g The MOM group was removed during isolation by
SiO2 chromatography.
CH2Cl2 as a solvent, but the ee of 4a dropped to 89% (entry 2,
Table 3). We observed the same phenomenon in the reactions
of 1g and 1f (entries 7-10, Table 3). Reductions of other R,â-
unsaturated ketones, with either an aromatic or an aliphatic
substituent as R2, afforded fairly high yields (73-94%). The
ee values of the resulting secondary alcohols were also excellent
(96-98%), except for the reaction in benzene (entries 3-11,
Table 3).
The reaction of R,â-unsaturated ketones 1i-l bearing an
aliphatic group as R1 and R2, under conditions similar to those
in Table 3, proceeded smoothly to give the products 3i-l in
high yields (82-96%) (Table 4). With aliphatic R,â-unsaturated
ketones, the reductive desulfurization with the Raney nickel
combination system15 did not take place. Therefore, Raney
nickel (W-2) was used, after benzoylation of 3 to prevent
racemization.15 In the reductive desulfurization with Raney
nickel, the benzoates of 3i-k afforded the corresponding
benzoates 4i-k in excellent ee values (97-98%), although the
yield was moderate (73-77%). In the reaction of mesityl oxide
1i, benzene produces a higher yield than in CH2Cl2, without
lowering the ee (entry 2, Table 4). Since the benzoylation of 3l
bearing a phenyl group as R3 did not proceed cleanly, the
reductive desulfurization of 3l with Raney nickel was conducted
after methoxymethylation of the alcohol.
The conversion of 3 to allylic alcohol 5 is summarized in
Table 5. The oxidation of sulfides 3a,d,e,f with sodium periodate
afforded the corresponding sulfoxides in almost quantitative
yields. The subsequent â-elimination (toluene reflux) of the
sulfoxide of 3a furnished 5a quantitatively, but the ee of 5a
was 5% lower than that in the reductive desulfurization (entry
1, Table 5). With a butyl or octyl substituent as R, the allylic
alcohols 5d,e showed excellent ee values (entries 2 and 3, Table
5). However, in the â-elimination of the sulfoxide of 3f, the ee
of 5f was 86% (entry 4, Table 5). When the â-elimination was
conducted at benzene reflux to give 5f in 72% yield, the ee
improved to 91% despite the longer reaction time (entry 5, Table
5). A similar decrease in ee values of optically active alcohols
has been reported.18
(17) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem.
Soc. 1991, 113, 4092-4096.
(18) Barrett, A. G. M.; Kamimura, A. J. Chem. Soc., Chem. Commun.
1995, 1754-1755.

1932 J. Am. Chem. Soc., Vol. 122, No. 9, 2000
Table 5. Asymmetric Synthesis of Allylic Alcohols
Node et al.
substrate
R
oxidation to sulfoxide
oxidative desulfurization
entry
compd
o.p.b (%)
time (h)
yieldc (%)
conditions
time (h)
yieldc (%)
% eed
config.
1
2
3
4
5
3a
3d
3e
3f
Me
Bu
Oct
Ph
96
98
96
96
22
24
16
20
98
98
100
95
A
A
A
A
B
4
2
4
4
72
100
93
95
87
72
92
98
95
86
91
S
S
S
R
R
3f
a Method A: CaCO3, 130 °C in toluene.; Method B: CaCO3, 100 °C in benzene. b Optical purity of the side chain of 3 which was observed by
the reductive desulfurization. c Isolated yield. d HPLC analysis. See Experimental Section (Supporting Information).
Scheme 6. Asymmetric Reduction of a Synthetic Intermediate of Prostaglandins
Since the substituent on the carbon attached to the sulfur atom
in the above substrates 3 is limited to a phenyl group, the
elimination of the sulfoxides gives the E-allylic alcohol
selectively. However, substrates bearing an alkyl group instead
of a phenyl group could give both allylic and homoallylic
alcohols. To study the reactivity of such a substrate, we tried
the asymmetric reduction of the key intermediate in a synthesis
of prostaglandins (Scheme 6). Reaction of the optically active
1m and (-)-2a (2 equiv) with Me2AlCl (2 equiv) after 21 h
afforded the sulfide 3m as a single diastereomer in 89% yield.
Oxidation of 3m and subsequent â-elimination resulted in a 59%
yield of allylic alcohol 5m (97% de) and a 31% yield of
homoallylic alcohol 9. Thus the regioselectivity of the â-elim-
ination appears to be directly proportional to the number of
hydrogen atoms on the â- and â′-carbon atoms.
E. Mechanistic Aspects. 1. Structure of the Aluminum
Complex of the Chiral Reagent (-)-2a. Two possible struc-
tures C and D were considered for the complex of (-)-2a and
Me2AlCl (Scheme 7). Structure C was eliminated because the
formation of methane gas19 was observed in the following
reactions: (1) the addition of Me2AlCl into the CH2Cl2 solution
of (-)-2a and (2) the addition of s-BuOH into the CH2Cl2
solution of Me2AlCl at room temperature, but not in the reaction
of EtSH with Me2AlCl. Furthermore, methane gas was released
from the reaction mixture when 1 equiv of s-BuOH was added
to the aluminum complex generated from (-)-2a and Me2AlCl.
If the aluminum complex of (-)-2a had been structure C, the
tandem reaction of 1f would have given the deuterated Michael
product and/or the deuterated MPV product by quenching the
aluminum enolate E with 20% DCl. But no deuterium was
incorporated into the R position in the products 3f and 6f; the
structure of the chiral aluminum Lewis acid therefore should
be D.
The thiol proton in structure D could play an important role
in promoting the subsequent MPV reduction. Intermediate A,
which becomes a substrate for the subsequent MPV reduction,
could be produced by proton migration in the aluminum enolate
F formed by the Michael addition of the complex D.
2. Asymmetric Intramolecular 1,7-Hydride Shift.20
A
crossover experiment using Michael adducts revealed this MPV
reaction to be completely an intramolecular hydride shift
(Scheme 8). Thus, a mixture of equimolar amounts of deuterium-
labeled Michael adduct 6j(D) (≈98% D) and the unlabeled
Michael adduct 6n was treated with Me2AlCl (2.0 equiv) in
CH2Cl2 at room temperature for 22 h to give the MPV products,
labeled 3j(D) (92%) and unlabeled 3n (91%), respectively. The
deuterium content of all products was measured by integration
1
of their H NMR spectra. The possibility of an intermolecular
MPV reaction between the Michael adduct and (-)-2a was ruled
out by another crossover experiment in which a mixture of
equimolar amounts of the deuterium-labeled adduct 6j(D)
(≈98% D) and unlabeled (-)-2a was treated with Me2AlCl (2.0
(19) (a) Starowieyski, K. B.; Pasynkiewicz, S.; Skowron˜ska-Ptasin˜ska,
M. J. Organomet. Chem. 1975, 90, C43-C44. (b) Maruoka, K.; Itoh, T.;
Yamamoto, H. J. Am. Chem. Soc. 1985, 107, 4573-4576. (c) Ooi, T.;
Maruoka, K. J. Synth. Org. Chem. Jpn. 1996, 54, 200-211.
(20) [1,7] sigmatropic rearrangement of conjugated trienes: for ex-
ample: (a) Baldwin, J. E.; Reddy, V. P. J. Am. Chem. Soc. 1988, 110,
8223-8228. (b) Baldwin, J. E.; Reddy, V. P. J. Am. Chem. Soc. 1987,
109, 8051-8056.

Asymmetric Reduction of Acyclic R,â-Unsaturated Ketones
J. Am. Chem. Soc., Vol. 122, No. 9, 2000 1933
Scheme 7. Plausible Structures of the Complex from Me2AlCl and (-)-10-Mercaptoisoborneol (-)-2a]
Scheme 8. Crossover Experiments for Intramolecular MPV Reduction (Asymmetric 1,7-Hydride Shift)
Scheme 9
equiv) to give the MPV products 3j(D) (59%) and recoveries
of 6j(D) (41%) and (-)-2a (100%). Although some deuterium
dispersion (less than 2%) was observed among the experiments
that were repeated several times, almost all the deuterium of
6j(D) had been retained in the product 3j(D). We will discuss
this deuterium dispersion below. The crossover experiments
showed that this novel MPV reduction indeed proceeded via
an intramolecular 1,7-hydride shift.
3. Equilibration in the Tandem Michael/MPV Reaction.
As shown in Scheme 9, the oily 3a obtained by the tandem
reaction of benzalacetone (1a) with (-)-2a was converted into
crystalline sulfone 10 (97%) by oxidation with OXONE. The
chiral carbon attached to the sulfur atom in 3a was revealed to
have the R-configuration by X-ray crystallographic analysis of
10. The reaction of 1a and (-)-2a with Me2AlCl at 0 °C gave
adduct 6a (78%) as a 1:1 diastereomeric mixture. Subsequent
MPV reduction of this 1:1 mixture furnished a single diaste-
reomer of 3a in which the configuration of both chiral centers
was highly controlled.
These facts suggested that this tandem Michael addition/MPV
reduction involves a dynamic kinetic resolution21 when the
reversibly formed Michael adduct bears a â-substituent. To
confirm the involvement of this equilibrium/resolution, the 1:1
mixture of 6a diastereomers was subjected to MPV reduction
with Me2AlCl (1.2 equiv, in CH2Cl2, 20 °C, 13 h; Scheme 10).
Single diastereomer 3a (86%) was obtained along with the

1934 J. Am. Chem. Soc., Vol. 122, No. 9, 2000
Node et al.
Scheme 10. Equilibrium in a Tandem Michael Addition-MPV Reduction
Scheme 11. Crossover Experiments between Michael Adducts 6a and 6f(D)
recovered ketone adduct (8%, 1:1 diastereomers), benzalacetone
(1a) (5%), and (-)-2a (5%). The MPV product 3a was subjected
to similar reaction conditions. Only a trace of the Michael adduct
(0.7%) and benzalacetone (1a) (2.4%) was produced; 97% of
the starting material was recovered. Since these reactions
afforded both the retro-Michael and the retro-MPV products,
the two reactions were confirmed to be reversible (equilibrium).
Appreciable formation of 1a and 6a in the reaction of 3a
suggests that the reversible MPV reaction step might be
kinetically controlled to a considerable extent at about 20 °C.
Consequently, crossover experiments were conducted to
verify the equilibrium between the Michael adduct and the R,â-
unsaturated ketone (Scheme 11). A mixture (1:1) of deuterated
6f(D) and unlabeled 6a was subjected to MPV reduction with
Me2AlCl at 20 °C for 24 h to give partially deuterated 3f (64%
incorporation of D) and 3a (21% incorporation of D). The
reaction using deuterated 6f(D) and unlabeled alcohol 2a gave
partially deuterated 3f (70% D) and 2a (21% D). This MPV
reduction is not an intermolecular reaction but an intramolecular
reaction, according to the experiments in Scheme 8. The above
results indicate that during the MPV reduction, the Michael
adducts exist in equilibrium between the retro-Michael reaction
and the Michael addition. The observed deuterium dispersion
could be explained by the partial formation of deuterium-labeled
6a and unlabeled 6f via this equilibrium. Although the experi-
ments in Schemes 8 and 11 seem to be in conflict with the
deuterium dispersion, it is believed that these experiments are
fundamentally consistent with the observation of trace amounts
of deuterium dispersion in Scheme 8, i.e., the retro-Michael
reactions of 6j and 6n in Scheme 8 are retarded by kinetic
control near room temperature. The difference in the above
crossover experiments is whether the R,â-unsaturated ketone
generated from a Michael adduct has a substituent (phenyl
group) at the â-position and whether these structural changes
cause significant differences in the rate of the retro-Michael
reaction.
A summary of a plausible mechanism for the tandem Michael
addition/MPV reduction is illustrated by eqs A and B in Scheme
12. The â-substituted R,â-unsaturated ketone 1a reacts reversibly
with the chiral aluminum complex D derived from (-)-2 and
Me2AlCl to give two diastereomeric chelated adducts. The
R-diastereomer (at the carbon attached to the sulfur atom) is
subjected to the reversible intramolecular MPV reduction, even
though the reduction does not proceed by complete thermody-
namic control. Based on PM3 calculations, the distance from
the migrating hydrogen to the carbonyl carbon in the chelated
R-diastereomer is about 3.1-3.4 Å. Therefore, the R-diastere-
omer of the 10-membered ring could easily proceed to the rigid
bicyclic transition state. On the other hand, the phenyl ring in
the S-diastereomer lies on the â-face of the 10-membered chelate
ring, which places it very near a C-10 hydrogen of the isoborneol
skeleton. Therefore, MPV reduction in the S-diastereomer is
greatly retarded by its high transition state energy. Consequently,
the production of a single isomer 3a is attributable to dynamic
kinetic resolution21 via reversible Michael addition and kineti-
cally controlled intramolecular MPV reduction of one of the
two Michael adducts (eq A). The tandem reaction of the
nonsubstituted R,â-unsaturated ketone 1j consists of the nearly
irreversible Michael addition by kinetic control and the revers-
ible intramolecular MPV reduction by thermodynamic control
(eq B).
F. Application to Asymmetric Synthesis of the Rove Beetle
Pheromone. The Rove beetle pheromone (+)-12 is an optically
active γ-lactone, the synthesis of which would demonstrate this
tandem Michael addition/MPV reduction. Representative asym-
metric syntheses22 of the Rove beetle pheromone include
asymmetric reduction of R,â-alkynyl ketones with BINAL-H,22a
asymmetric reduction of γ-keto esters with BINAP-Ru(II)
catalysts,22b and asymmetric ene reaction of aldehydes.22c Our
(21) (a) Noyori, R.; Tokunaga, M.; Kitamura, M. Bull. Chem. Soc. Jpn.
1995, 68, 36-56. (b) Ward, R. S. Tetrahedron: Asymmetry 1995, 6, 1475-
1490,and references therein.

Asymmetric Reduction of Acyclic R,â-Unsaturated Ketones
J. Am. Chem. Soc., Vol. 122, No. 9, 2000 1935
Scheme 12. A Plausible Mechanism for a Novel Tandem Michale Addition-MPV Reduction
Scheme 13. Asymmetric Synthesis of the (+)-Rove Beetle Pheromone
synthetic route to the (+)-Rove beetle pheromone is illustrated
in Scheme 13. The tandem Michael addition/MPV reduction
of (E)-1-phenyl-1-undecen-3-one (1e) with (+)-2a (97% ee)
gave the MPV product in 90% yield. Subsequent reductive
desulfurization with Raney Ni-NaPH2O2 afforded (R)-(-)-1-
phenylundecan-3-ol (4e) in 99% yield and 97% ee. Ruthenium
oxide oxidation23 of (-)-4e after acetylation gave (R)-4-
acetoxydodecanoic acid (11), which was hydrolyzed with 1 N
sodium hydroxide and acidified with 10% hydrochloric acid to
afford the (R)-(+)-Rove beetle pheromone 12 in 75% yield from
type of MPV reduction, i.e., a tandem Michael addition/MPV
reduction, making it possible to circumvent the low enantiose-
lectivity of the classical asymmetric intermolecular MPV
reduction.
In this novel MPV reduction, we observed for the first
time both an asymmetric 1,7-hydride shift and a dynamic
kinetic resolution Via a reVersible Michael addition. High
diastereoselectivity was achieved at the two newly generated
chiral carbons bearing the alcohol and the sulfide. The facial
selectivity of the oxycarbenium ion on the 10-membered ring
chelated structure A reached 98-100% in dichloromethane,
based on the optical purity (98% ee) of the chiral alcohol
used. The high facial selectivity at the carbonyl carbon atom
is due to the formation of a rigid bicyclic transition state
(because of the five fixed atoms in the bornane skeleton) even
though the usual 10-membered ring is supposed to be con-
formationally flexible. Highly enantioselective reduction of
acyclic R,â-unsaturated ketones to saturated secondary alcohols
or to their benzoates (96-98% ee) and allylic alcohols (91-
98% ee) was achieved by subsequent reductive or oxidative
desulfurization. Because of its effectiveness in reducing
both aromatic and aliphatic R,â-unsaturated ketones, this
reaction should be eminently suitable for a wide range of
substrates.
(R)-1-phenylundecan-3-ol (1e). The specific rotation {[R]18
D
+37.3 (0.82, MeOH), lit.22c [R]26D +36.6 (0.29, MeOH) (>98%
ee)} and spectroscopic data of the synthetic 12 were identical
with those reported in the literature. The overall yield of this
synthesis was 67% (5 steps).
Conclusion
Introduction of a thiol group as a tether to connect a secondary
alcohol with acyclic R,â-unsaturated ketones allows for a new
(22) (a) Noyori, R.; Tomino, M.; Yamada, M.; Nishizawa, M. J. Am.
Chem. Soc. 1984, 106, 6717-6725. (b) Ohkuma, T.; Kitamura, M.; Noyori,
R. Tetrahedron Lett. 1990, 31, 5509-5512. (c) Masuya, K.; Tanino, K.;
Kuwajima, I. Tetrahedron Lett. 1994, 35, 7965-7968. (d) Pirkle, W. H.;
Adams, P. E. J. Org. Chem. 1979, 44, 2169. (e) Vigneron, J. P.; Bloy, V.
Tetrahedron Lett. 1980, 21, 1735. (f) Sugai, T.; Mori, K. Agric. Biol. Chem.
1984, 48, 2497-2500.
We have also synthesized the (+)-Rove beetle pheromone
in high enantiomeric purity and high overall yield in only a
few synthetic steps.
(23) Carlsen, P. H. J.; Katuki, T.; Martin, V. S.; Sharpless, K. B. J. Org.
Chem. 1981, 46, 3936-3938.

1936 J. Am. Chem. Soc., Vol. 122, No. 9, 2000
Node et al.
Acknowledgment. We are grateful for a Grant-in-Aid (No.
09470489 to M.N.) from the Ministry of Education, Science,
Sports and Culture of Japan, in partial financial support of this
research. We thank the Nippon Aluminum Alkyls, Ltd. and Fuji
Chemical Industries, Ltd. for their generous gift of several
alkylaluminum reagents and the compounds related to prostag-
landins, respectively.
Supporting Information Available: Experimental details
and table of results, including crystallographic data, atomic
coordinates, anisotropic displacement parameters, bond lengths
and angles, torsion angles, and nonbonded contacts (PDF). This
material is available free of charge via the Internet at
http://pubs.acs.org.
JA993546Y