Catalytic enantioselective conjugate reduction of lactones and lactams

Article abstract of DOI:10.1021/ja0351692

A dramatic acceleration of the enantioselective copper-catalyzed conjugate reduction of α,β-unsaturated lactones, lactams, and esters is reported upon addition of alcohol additives. Good to excellent yields and enantioselectivities were realized using a catalyst generated in situ from CuCl₂·H₂O, t-BuONa, p-tol-BINAP, and PMHS, and this methodology was applied to the synthesis of (-)-Paroxetine.

Full text of DOI:10.1021/ja0351692

Published on Web 08/19/2003
Catalytic Enantioselective Conjugate Reduction of Lactones
and Lactams
Gregory Hughes, Masanari Kimura, and Stephen L. Buchwald*
Contribution from the Department of Chemistry, Massachusetts Institute of Technology,
Cambridge, Massachusetts 02139
Received March 14, 2003; E-mail: sbuchwal@mit.edu
Abstract: A dramatic acceleration of the enantioselective copper-catalyzed conjugate reduction of R,â-
unsaturated lactones, lactams, and esters is reported upon addition of alcohol additives. Good to excellent
yields and enantioselectivities were realized using a catalyst generated in situ from CuCl2‚H2O, t-BuONa,
p-tol-BINAP, and PMHS, and this methodology was applied to the synthesis of (-)-Paroxetine.
unsaturated six-membered lactams.6 There also have been
reports describing the enantioselective additions of n-alkyl
Grignard reagents or diethyl zinc to pentenolide using catalytic
amounts of chiral copper complexes.7
We have recently described the use of a Cu(I)/p-tolBINAP
catalyst for the enantioselective 1,4-reduction of acyclic R,â-
unsaturated esters and cyclic enones using PMHS (polymeth-
ylhydrosiloxane) as a stoichiometric reductant.8 We report herein
our efforts to extend this methodology to the conjugate reduction
of lactones and lactams. During the course of these studies,
mechanistic considerations led to the discovery that alcohol
additives improve the yields and dramatically increase the rates
of reduction of these substrates.9 This improved protocol has
allowed for an efficient synthesis of (-)-Paroxetine.
Introduction:
Chiral lactones and lactams possessing a â-stereocenter are
found within a number of biologically active compounds such
as the lignans (-)-Trachelogenin (1) and (-)-Arctigenin (2),
and antidepressant/PDE IV inhibitor (-)-Rolipram (3).1 Five-
and six-membered lactams also serve as precursors to pyrro-
lidines and piperidines, which are found within a number of
important pharmaceuticals such as the antidepressant (-)-
Paroxetine (4) (Figure 1).2
Despite recent developments in metal-catalyzed conjugate
addition methodology,3 there are few reports whereby these
compounds can be accessed in either racemic or enantiomeri-
cally enriched form by 1,4-addition of organometallic nucleo-
philes to unsaturated precursors. Conjugate addition to buteno-
lides typically requires the incorporation of an additional
activating substituent, such as a sulfide or a selenide, at the
R-position.4 In the only example of a catalytic enantioselective
addition to unsaturated five-membered ring lactones that we are
aware of, Hayashi has shown that a Rh(I)/(BINAP) complex
catalyzes the addition of phenyl boronic acid to butenolide in
33% yield and 97% ee.5 This methodology was also successful
for the addition of aryl boronic acids to pentenolide5 and to
Results
The starting materials for this investigation were prepared
as shown in Scheme 1. Our initial approach to â-substituted
butenolides involved ring-closing metathesis (RCM) of dienes
5a-c,10 prepared by esterification of allylic alcohols which were
either purchased from commercial sources or prepared by
copper-catalyzed addition of Grignard reagents to propargyl
alcohol.11 When these acrylates were treated with 5 mol % of
ruthenium carbene 7 for 18 h in refluxing dichloromethane, 65%
conversion to the desired product was observed. Interestingly,
increasing the catalyst loadings to 7 mol % led to only 35%
(1) For lead references regarding natural products containing chiral lactones,
see: (a) Connolly, J. D.; Hill, R. A. Dictionary of Terpenoids; Chapman
and Hall: London, 1991; Vol. 1, pp 476-541. (b) Peng, Z.-H.; Woerpel,
K. A. Org. Lett. 2001, 3, 675 and references therein. (c) For synthetic
approaches to Rolipram, see: Anada, M.; Mita, O.; Watanabe, H.; Kitagaki,
S.; Hashimoto, S. Synlett 1999, 1775 and references therein.
(2) For synthetic approaches to (-)-Paroxetine, see: (a) Christensen, J. A.;
Squires, R. F. German Patent 2,404,113, 1974. U.S. Patent 3,912,743, 1975.
U.S. Patent 4,007,196, 1977; Chem Abstr. 1974, 81, 152011q. (b) Faruk,
E. A.; Martin, R. T. EP Patent 223,334, 1986; Chem. Abstr. 1987, 107,
96594y. (c) Yu, M. S.; Lantos, I.; Peng, Z.-Q.; Yu, J.; Cacchio, T.
Tetrahedron Lett. 2000, 41. 5647. (d) de Gonzalo, G.; Brieva, R.; Sa´nchez,
V. M.; Bayod, M.; Gotor, V. J. Org. Chem. 2001, 66, 8947 and references
therein. For a formal synthesis of (-)-Paroxetine, see ref 6.
(3) For recent reviews of asymmetric conjugate addition, see: (a) Krause, N.;
Hoffmann-Ro¨der, A. Synthesis 2001, 171. (b) Sibi, M. P.; Manyem, S.
Tetrahedron 2000, 56, 8033.
(4) (a) Bella, M.; Piancatelli, G.; Pigro, M. C. Tetrahedron 1999, 55, 12387.
(b) Hollingworth, G. J.; Lee, T. V.; Sweeney, J. B. Synth. Commun. 1996,
26, 1117. (c) Watanabe, M.; Tsukazaki, M.; Hirakawa, Y.; Iwao, M.;
Furukawa, S. Chem. Pharm. Bull. 1989, 37, 2914.
(5) (a) Tayaka, Y.; Senda, T.; Kurushima, H.; Ogasawara, M.; Hayashi, T.
Tetrahedron:Assymetry 1999, 10, 4047. For catalytic enantioselective
approaches to γ-lactones and γ-lactams having a â-stereocenter featuring
Rh(II)-catalyzed intramolecular C-H insertions, see: (b) Bode, J. W.;
Doyle, M. P.; Protopopova, M. N.; Zhou, Q.-L. J. Org. Chem. 1996, 61,
9146. (c) Anada, M.; Hashimoto, S. Tetrahedron Lett. 1998, 39, 79. See
also ref 1d.
(6) Senda, T.; Ogasawara, M.; Hayashi, T. J. Org. Chem. 2001, 66, 6852.
(7) (a) Reetz, M. T.; Gosberg, A.; Moulin, D. Tetrahedron Lett. 2002, 43,
1189. (b) Kanai, M.; Nakagawa, Y.; Tomioka, K. Tetrahedron 1999, 55,
3843. (c) Yan, M.; Zhou, Z.-Y.; Chan, A. J. Chem. Soc., Chem. Commun.
2000, 115.
(8) (a) Appella, D. H.; Moritani, Y.; Shintani, R.; Ferreira, E. M.; Buchwald,
S. L. J. Am. Chem. Soc. 1999, 121, 9473. (b) Moritani, Y.; Appella, D. H.;
Jurkauskas, V.; Buchwald, S. L. J. Am. Chem. Soc. 2000, 122, 6797. (c)
Jurkauskas, V.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 2892.
Important related work: Lipshutz, B. H.; Papa, P. Angew. Chem., Int. Ed.
2002, 41, 4580.
9
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J. AM. CHEM. SOC. 2003, 125, 11253-11258
11253

A R T I C L E S
Hughes et al.
Figure 1. Biologically active compounds containing chiral lactones and lactams.
Scheme 1. Preparation of Unsaturated Lactones and Lactamsa
a (a) 7 (1-1.5 mol %), 10 h syringe pump addition, CH2Cl2, reflux, 40-90%. (b) HCOCO2H‚H2O (1 equiv), piperidine hydrochloride (1.1 equiv),
dioxane/H2O, reflux, 18 h. (c) NaBH4 (1 equiv), MeOH, 60-79% (two steps). (d) Ru(CO)(H)2(Ph3P)3 (5-20 mol %), CH2dCHSi(OEt)3 (2 equiv), toluene,
reflux, 0.5-3 h. (e) H2O2, NaF, NaHCO3, THF, 30-60%. (f) p-iodoanisole (1.1 equiv), K3PO4 (1.3 equiv), CuI (5 mol %), MeNH(CH2)2NHMe (20 mol %),
toluene 80 °C, 91%. (g) ClCOCH2CO2Et, Na2CO3, H2O/CH2Cl2. (h) EtONa (4 equiv), EtOH, reflux, 18 h, 70% (two steps).
conversion under otherwise identical conditions. When 2 mol
% of 7 was added in a single portion to a solution of 5 in
refluxing dichloromethane, 95% conversion was achieved after
2 h. Adding 1 mol % of 7 as a solution in dichloromethane
over 10 h resulted in complete conversion of 5a and 5b, with
slightly higher loadings (1.5 mol %) being required for complete
conversion of 5c.12 Pentenolide 6d was also prepared using this
protocol.
It was possible in some cases to use a condensation/reduction
strategy as an operationally simple and inexpensive alternative
to the RCM methodology. Hydroxy butenolides 9a-c, which
were prepared by condensation of aldehydes 8a-c and glyoxylic
acid in the presence of piperidine hydrochloride, could be treated
with sodium borohydride to afford the desired lactones 10a-
c.13
Pentenolides 12a and 12b were prepared from â-substituted
acrylates 11a and 11b using a minor variation of a literature
procedure involving Ru-catalyzed coupling with a vinyl silane,
followed by oxidation of the C-Si bond with concomitant
lactonization.14
(9) After this manuscript was submitted, we became aware of prior work of
Stryker. Specifically, he has reported three examples with three substrates
in which the use of t-BuOH as an additive (10-15 equiv) allowed for the
catalytic conjugate reduction to be carried out at 1 atm of hydrogen using
10-17 mol % Cu in 24-48 h. In the best case, the reduction of carvone
is reduced to a 87:13 ratio of the conjugate reduction product and the
overreduced saturated alcohol.1 The authors attribute the effect of the added
t-BuOH to “a protolytic transfer process to quench the unstable intermedi-
ates with concomitant transfer of the copper to a more stable alkoxide
moiety where hydrogen activation can proceed under lower pressure.”
Stryker has also demonstrated that the addition of t-BuOH often favors
1,2-reduction. (a) Lipshutz, B. H. In Modern Organocopper Chemistry;
Krause, N., Ed.; Wiley-VCH: Weinheim, 2002; p 167. (b) Stryker, J. M.;
Mahoney, W. S.; Daeuble, J. F.; Brestensky, D. M. In Catalysis in Organic
Synthesis; Pascoe, W. E., Ed.; Marcel Dekker: New York, 1992; p 29. (c)
Daeuble, J. F.; Stryker, J. M. In Catalysis of Organic Reactions; Scaros,
M., Prunier, M. L., Eds.; Marcel Dekker: New York, 1995; p 235. (d)
Chen, J. X.; Daeuble, J. F.; Brestensky, D. M.; Stryker, J. M. Tetrahedron
2000, 56, 2153. (e) Chen, J. X.; Daeuble, D. M.; Stryker, J. M. Tetrahedron
2000, 56, 2789.
(10) (a) Chatterjee, A. K.; Morgan, J. P.; Scholl, M.; Grubbs, R. H. J. Am. Chem.
Soc. 2000, 122, 3783. (b) Fu¨rstner, A.; Thiel, O. R.; Ackermann, L.; Schanz,
H.-J.; Nolan, S. P. J. Org. Chem. 2000, 65, 2204.
(11) Buboudin, J. G.; Jousseaume, B. J. Organomet. Chem. 1979, 168, 1.
(12) This behavior is suggestive of a catalyst decomposition pathway that is
second order in Ru. For a discussion of the mechanism of Ru carbene
decomposition pathways, see: Choi, T.-L.; Lee, C. W.; Chatterjee, A.;
Grubbs, R. H. J. Am. Chem. Soc. 2001, 123, 10417.
Five-membered lactams 13 and 14a were prepared according
to literature procedures.15 Conversion of 14a to 15 was affected
by our recently developed Cu-catalyzed amide arylation meth-
odology.16 Six-membered lactam 17 was prepared from 16 by
amidation with ethylmalonyl chloride, followed by intramo-
lecular Knovenagel condensation and a retro-Claisen decar-
boxylation.
(13) (a) Bourguignon, J. J.; Wermuth, C. G. J. Org. Chem. 1981, 46, 4889. (b)
Bourguignon, J. J.; Schoenfelder, A.; Schmitt, M.; Wermuth, C. G.; Hechler,
V.; Charlier, B.; Maitre, M. J. Med. Chem. 1988, 31, 893.
(14) Trost, B. M.; Imi, K.; Davies, I. W. J. Am. Chem. Soc. 1995, 117, 5371.
(15) (a) Barluenga, J.; Fan˜ana´s, F. J.; Foubelo, F.; Yus, M. Tetrahedron Lett.
1988, 29, 4859. (b) Corriu, R. J. P.; Bolin, G.; Iqbal, J.; Moreau, J. J. E.;
Vernhet, C. Tetrahedron 1993, 49, 4603.
(16) (a) Klapers, A.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124,
7421. (b) Klapars, A.; Antilla, J. C.; Huang, X.; Buchwald, S. L. J. Am.
Chem. Soc. 2001, 123, 7727.
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Conjugate Reduction of Lactones and Lactams
A R T I C L E S
Table 1. Optimization of Lactone Reduction Protocol
pump over 4 h allowed for complete consumption of lactone,
with the product being isolated in 90% yield and 93% ee (Table
1, entry 4). Switching from EtOH to i-PrOH obviated the need
for slow addition. We also found that air-stable CuCl2‚2H2O
could replace CuCl as the copper source, allowing the reaction
to be set up without the aid of a drybox (Table 1, entry 5).
These conditions allowed for the reduction of n-alkyl (Table
2, entry 1), secondary (Table 2, entry 2), and benzyl (Table 2,
entries 4,5) substituted butenolides in good yields with good to
excellent levels of enantioselectivity. The reduction of 10c
represents a formal synthesis of lignans 119 and 2.5b Phenyl
substituted butyrolactone was formed with only modest enan-
tiomeric excess (entry 3).20
Initial attempts to extend this methodology to the reduction
of pentenolides were again hampered by poor mass balance.
For instance, the reduction of 12a at -20 °C with 4 equiv of
i-PrOH resulted in a GC yield of only 25% at 100% conversion.
Switching to a larger alcohol additive, tert-amyl alcohol
(t-AmOH), and lowering the reaction temperature to -40 °C
significantly improved the GC yields (80-90%), although the
isolated yields for these substrates are moderate (55-70%, Table
2, entries 6-8), and separation of the reduced products from
byproducts required two chromatographic columns. As was the
case for the reduction of cyclohexenones, BIPHEMP was found
to be the ligand of choice for the reduction of pentenolides.
We next examined the asymmetric conjugate reduction of
lactams. While N-H and N-benzyl lactams 14a and 14b did
not undergo reduction, N-p-methoxyphenyl lactam 15 was
reduced in 94% yield and 94% ee after 3 h at 0 °C (Table 2,
entry 9). The reduction of 4-methyl lactam 13, which was
considerably slower than that of 15, was accelerated by
switching solvents from 50/50 c-hexane/toluene to c-hexane/
THF, presumably due to its insolubility in the former solvent
system (entry 10). In contrast to cyclohexenones and penteno-
lides, reduction of unsaturated six-membered lactam 17 proceeds
with excellent ee using p-tolBINAP as the ligand (entry 11).
The reduction of acyclic unsaturated esters was also acceler-
ated by the addition of alcohols. Treatment of ethyl trans-â-
methylcinnamate (18) with PMHS (4 equiv) and t-AmOH (4
equiv) with as little as 0.1 mol % Cu/(S)-p-tolBINAP allowed
for complete consumption of 18 in 36 h (eq 1). By contrast,
reduction of 18 with catalyst loadings of 1 mol % in the absence
of alcohol additives required 48 h to achieve 95% conversion.
temp (°C)
% yield
(% ee)b
entry
Cu/silane
solvent (ROH)
(time (h))a
1
2
3
4
5
CuCl/PMHS
CuCl/Ph2SiH2
CuCl/PMHS
CuCl/PMHS
PhCH3
23 (48)
50 (80)
Et2O/pentc
-15 (24) 34d (91)
c-hex (EtOH)e
THF/pent (EtOH)c,e,g
23 (5 min) 89f (-)
-40 (4)
90 (93)
90 (92)
CuCl2‚2H2O/PMHS PhCH3/pent (i-PrOH)e,h -20 (3)
a >95% conversion. b Isolated yields. % ee determined by HPLC. c 80%
pentane. d 75% conversion. e 4 equiv of ROH. f GC yield, 10% residual
starting material. g EtOH added by syringe pump over 4 h. h 20 mol %
t-BuONa was used. 50/50 PhCH3/pentane.
Scheme 2. Proposed Mechanism for the Copper-Catalyzed
Lactone Reduction
When 6b was subjected to the reaction conditions described
in our initial report (Table 1, entry 1),8a the desired product
was isolated in 50% yield and 80% ee, along with 5% residual
starting material after 48 h (Table 1, entry 1). Using Ph2SiH2
in place of PMHS and switching to a predominantly hydrocar-
bon solvent system accelerated the reaction such that it could
be performed at -15 °C (entry 2). While the enantiomeric
excess improved to 91%, the isolated yield was still low (34%
at 75% conversion).
We have previously suggested that these conjugate reductions
proceed via a copper enolate that undergoes σ-bond metathesis
with a Si-H bond to form a silylketene acetal.8a If the poor
mass balance was due to side reactions of either the copper
enolate or the silylketene acetal, we postulated that better yields
might be realized upon addition of an alcohol to protonate the
enolate.17 This would generate the lactone product (D, Scheme
2) and a copper alkoxide (C). We reasoned that C should be
capable of undergoing σ-bond metathesis more rapidly than B
to regenerate catalytically active A (vide infra).
We were pleased to find that adding EtOH (4 equiv) to a
room temperature mixture of substrate, catalyst, and PMHS gave
an 89% GC yield of the desired product at 90% conversion
after 5 min (Table 1, entry 3). The reaction did not proceed
beyond 90% conversion, presumably due to competitive sily-
lation of EtOH with concomitant release of H2.18 Lowering the
reaction temperature to -40 °C and adding EtOH via syringe
A series of alcohols of various sizes (EtOH, i-PrOH,
3-pentanol, t-AmOH) were screened to identify the optimal
additive (Figure 1). The alcohols (4 equiv) were added via
syringe pump over an hour to a mixture of 18 (1 equiv), CuCl2
(0.5 mol %), t-BuONa (1 mol %), (S)-p-tolBINAP (0.5 mol
(17) For other examples of alcohols and amines accelerating metal-catalyzed
silane reductions, see: (a) Verdaguer, X.; Lange, U. E. W.; Buchwald, S.
L. Angew. Chem., Int. Ed. 1998, 37, 1103. (b) Yun, J.; Buchwald, S. L. J.
Am. Chem. Soc. 1999, 121, 5640. (c) Hays, D. S.; Fu, G. C. Tetrahedron
1999, 55, 8815.
(18) In support of this, vigorous gas evolution, presumably H2, was observed
upon addition of EtOH.
(19) Moritani, Y.; Fukushima, C.; Ukita, T.; Miyagishima, T.; Ohmizu, H.;
Iwasaki, T. J. Org. Chem. 1996, 61, 6922.
(20) It should be noted that the reduction of â-methyl substituted butenolide
continues to suffer from poor mass balance, even under optimized
conditions.
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A R T I C L E S
Hughes et al.
Table 2. Enantioselective Conjugate Reduction of Lactones and Lactamsa
a Conditions from Table 1, entry 5. b Isolated yields, >95% pure. c % ee determined by GC or HPLC. d 20% CH2Cl2 was used to facilitate solvation. e 6
h was required for 100% conversion. f Recrystallized (S)-BIPHEMP, -40 °C, 2 equiv of PMHS and t-AmOH. g CuCl2‚2H2O (5 mol %), t-BuONa (20 mol
%), (S)-p-tolBINAP (5 mol %), PMHS (4 equiv), EtOH (4 equiv), toluene/THF (50/50), 0 °C. h 1 h was required for 100% conversion.
We have applied this methodology to a catalytic enantiose-
lective synthesis of 4, which is outlined in Scheme 3. p-
Anisidine and 4-fluoro-3′-chloropropiophenone were mixed with
triethylamine in refluxing THF to afford 19 in 77% yield. The
crude amidation product 20 was dissolved in an ethanolic
solution of NaOEt. After being refluxed for 30 min, the mixture
was added to cold water, from which lactam 21 was isolated in
76% yield after filtration and azeotropic removal of residual
water. 1H NMR analysis revealed a 20:1 mixture of the desired
product and the â,γ-unsaturated isomer. The reduction of 21
was considerably slower than other lactams, with ∼20%
conversion being realized after 18 h. In an ongoing investigation,
Figure 2. Reduction of 18 in the presence of various alcohol additives
a further acceleration in the conjugate reductions has been noted
when the reactions are performed open to the atmosphere.21 We
were gratified to find that running the reaction in air and use of
16 equiv each of PMHS and t-AmOH allowed for 22 to be
isolated in 90% yield and 90% ee with as little as 0.5 mol %
(R)-p-tolBINAP.22
This intermediate was converted to 24 in two steps (81%
overall yield) using previously reported conditions for a similar
substrate.2c Because of complications with the oxidative removal
of the PMP functionality in the presence of a second electron-
rich aromatic ring, a protecting group switch to Boc was
performed, affording 26 in 75% yield over two steps.
Figure 3. Reduction of 18 after complete addition of alcohols.
During the course of ongoing efforts to develop transition
metal-catalyzed methods for coupling alcohols with aryl tosy-
lates,23 control experiments revealed that heating primary
alcohols and aryltosylates in the presence of a base afforded
%), and PMHS (4 equiv) in c-hexane. While EtOH and i-PrOH
accelerate the reduction to similar degrees, the reduction with
3-pentanol is slightly slower and is significantly slower with
t-AmOH (Figure 2).
(21) Hughes, G.; Buchwald, S. L., unpublished results. For related effects in
catalytic enantioselective copper-hydride reductions of ketones, see: Sirol,
S.; Courarcel, J.; Mostefai, N.; Riant, O. Org. Lett. 2001, 3, 4111.
(22) We have noted that a larger excess of alcohol and silane is required in the
air-accelerated reactions as the alcohol silylation side reaction appears to
be accelerated more dramatically than conjugate reduction by the presence
of air. This effect is less pronounced with larger alcohols such as t-AmOH
than it is with smaller ones such as EtOH. In air, optimal rates and
conversions are achieved with 5 equiv of CuCl2 and 10 equiv of t-BuONa
per ligand, whereas an excess of Cu and base per ligand under anaerobic
conditions was found to give poor conversions.
When the degree of conversion to product was monitored
after the 60 min alcohol-addition time, the reaction with EtOH
showed no further progress (Figure 3). With i-PrOH, the reaction
continued from 95% conversion at 60 min to 97% after 90 min,
and then proceeded no further. With 3-pentanol, the reduction
proceeds from 85% conversion after 60 min to 99% after 300
min. With t-AmOH, the reaction proceeded from 77% at 60
min to 100% conversion after ∼300 min.
(23) Huang, X.; Buchwald, S. L., unpublished results.
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Conjugate Reduction of Lactones and Lactams
A R T I C L E S
Scheme 3. Synthesis of (-)-Paroxetinea
a (a) PMPNH2(1.1 equiv), Et3N (1.2 equiv), THF, reflux, 75%. (b) ClCOCH2CO2Et (1.1 equiv), Na2CO3 (sat), CH2Cl2. (c) NaOEt (4 equiv), EtOH,
reflux, 74% (two steps). (d) PMHS (16 equiv), t-AmOH (16 equiv), (S)-p-tol-BINAP (0.5 mol %), CuCl2 (2.5 mol %), t-BuONa (5 mol %), C6H5F, air, 23
°C 90%, 90% ee. (e) NaH (6 equiv), MeOH (3 equiv), (MeO)2CO (3 equiv), toluene, reflux, 86%. (f) BH3‚THF, reflux, 97%. (g) CAN (4 equiv), CH3CN/
H2O (3/1). (h) Boc2O (2.0 equiv), NaOH (1.5 equiv), toluene, H2O, 75% (two steps). (i) (1) 27 (1.3 equiv), Cs2CO3 (1.5 equiv), xylene, 130 °C; (2)
TFA/CH2Cl2, 52% (two steps).
the enolate protonation step is expected to be slower with
t-AmOD, the protonation of the copper-hydride catalyst (leading
to alcohol silylation) should also be slower. As a result, one
might expect to see a higher concentration of the active catalyst
and hence a faster reaction which would counteract the
hindrance in the enolate protonation step. It is also possible that
the rates of protonation of σ-bond metathesis are similar. A more
detailed kinetic study will be required to distinguish between
these possibilities.
We attribute the fact that higher conversions are realized with
larger alcohols to the rate of alcohol silylation being hampered
Figure 4. Rationale for the acceleratory effect of alcohol additives.
to a greater extent than the rate of conjugate reduction by an
increase in the size of the alcohol.
aryl ethers in the absence of metallic catalysts.24 Thus, treating
26 with tosylate 27 in the presence of Cs2CO3 at 130 °C in
xylene afforded the desired aryl ether. Removal of the Boc group
afforded 4 in 52% yield from 26.
Conclusion
In conclusion, we have developed a conjugate reduction
protocol that allows for the catalytic enantioselective formation
of five- and six-membered lactones and lactams possessing a
â-stereocenter. The addition of alcoholic additives was found
to be crucial for higher yields of the desired products. In addition
to improved yields, a dramatic increase in the reaction rate was
also observed. Finally, we have applied this methodology to a
brief, catalytic enantioselective approach to (-)-Paroxetine.
Discussion
It was found that the rate of the conjugate reduction was
dramatically accelerated upon inclusion of alcohol additives. If
the slow step in the absence of alcohols were σ-bond metathesis,
this would suggest that the silylation of copper alkoxides is much
faster than the silylation of copper enolates. As there seems to
be no obvious steric or electronic basis for this acceleration,
we speculate that the sluggishness of the enolate silylation might
be the result of a preference for C-bound versus O-bound copper
enolate (Figure 4). One might expect that the C-bound tautomor
would be impervious to σ-bond metathesis, requiring conversion
to the O-enolate prior to catalyst turnover. The addition of
alcohols alleviates this problem by protonating the enolate to
give an alkoxide that readily undergoes σ-bond metathesis.
We also observed that the rate of reduction is dependent on
the size of the alcohol additive. While EtOH and i-PrOH give
rise to similar rates, the use of larger alcohols (s-BuOH and
particularly t-AmOH) results in progressively slower reaction
rates. This suggests that, at least with larger alcohols, the rate-
limiting step is either protonation of the copper enolate or
σ-bond metathesis. A modest kH/kD of 1.8 was observed when
the conjugate reductions were performed with t-AmOH versus
t-AmOD; however, this result is difficult to interpret. While
Experimental Section
The following are representative procedures for conjugate reduction.
A full account of the reaction conditions and characterization of
substrates and products can be found in the Supporting Information.
4-Butyldihydrofuran-2-one. CuCl2‚2H2O (4.8 mg, 0.036 mmol, 5
mol %), (S)-p-tolBINAP (24.2 mg, 0.0356 mmol, 5 mol %), and
t-BuONa (14.0 mg, 0.143 mmol, 20 mol %) were added to a Schlenk
tube which was then evacuated and charged with an argon atmosphere.
PMHS (171 µL, 2.85 mmol, 4 equiv) and pentane (1.0 mL) were added,
and the mixture was stirred for 2 h before cooling to -20 °C. A solution
of 10a (100 mg, 0.713 mmol, 1 equiv), dodecane (100 µL), and i-PrOH
(220 µL, 2.85 mmol, 4 equiv) in toluene (1.0 mL) was added via
syringe. After 3 h, GC analysis showed complete conversion, and the
mixture was partitioned between 10% HCl and ethyl acetate. The
aqueous layer was extracted two times with fresh portions of ethyl
acetate, and the organic layers were combined, washed with brine, dried
over MgSO4, filtered, and concentrated to dryness. The residue was
purified by flash chromatography (15 f 20% ethyl acetate/hexanes)
to afford the title compound as a colorless oil (90 mg, 89% yield).
Chiral GC analysis (GTA column, 1 mL/min, 90 °C, 60 min, then 1
°C/min to 120 °C, hold for 20 min, retention times: 93.9 min (major),
(24) We presume that tosyl transfer occurs between 26 and 27 to produce a
primary tosylate and a phenol. In the presence of base, the phenol displaces
the primary tosylate to afford the desired coupling product. For similar
examples of transfer of activation, see: (a) Sobolov, S. B.; Sun, J.; Cooper,
B. A. Tetrahedron Lett. 1998, 39, 5685. (b) Kim, T. H.; Lee, G.-J. J. Org.
Chem. 1999, 65, 2941.
1
95.5 min (minor)) showed 86% ee. H NMR (300 MHz, CDCl3) δ:
0.91 (t, J ) 7 Hz, 3H), 1.23-1.41 (m, 4H), 1.44-1.54 (m, 2H), 2.19
(dd, J ) 16.5, 7.5 Hz, 1H), 2.46-2.68 (m, 2H), 3.93 (ABX, dd, J )
9
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A R T I C L E S
Hughes et al.
9, 7 Hz, 1H), 4.42 (ABX, dd, J ) 9, 7, Hz, 1H). 13C NMR (100 MHz,
CDCl3) δ: 14.06, 22.71, 29.67, 32.95, 34.70, 35.86, 73.61, 177.49. RD
(589 nm, 38.5 mg/mL CHCl3) ) +5.25
(major), 24.4 min (minor)) showed 93% ee. mp (CH2Cl2): 49-51 °C.
1H NMR (500 MHz, CDCl3) δ: 1.20 (d, J ) 6.8 Hz, 3H), 2.22 (ABX,
dd, J ) 16.7, 7.4 Hz, 1H), 2.55 (hextet, J ) 7.4 Hz, 1H), 2.72 (ABX,
dd, J ) 16.7, 8.4 Hz, 1H), 3.41 (ABX, dd, J ) 9.4, 6.4 Hz, 1H), 3.90
(ABX, dd, J ) 9.4, 7.6 Hz, 1H), 6.89 (ABX, dm, J ) 9.1 Hz, 2H),
7.47 (ABX, J ) 9.1 Hz, 2H). 13C NMR (300 MHz, CDCl3) δ: 19.42,
26.25, 40.61, 55.36, 56.26, 113.91, 121.72, 132.47, 156.43, 173.49.
IR (film, cm-1): 1688, 1513, 1397, 1266, 1034. Elemental analysis:
%C (calc.) ) 70.22, %C (found) ) 70.06, %H (calc.) ) 7.37, %H
(found) ) 7.31. RD (589 nm, 23.8 mg/mL CHCl3) ) -4.2.
(4S)-4-Propyltetrahydropyran-2-one. CuCl2‚2H2O (4.8 mg, 0.036
mmol, 5 mol %), (S)-BIPHEMP (24.2 mg, 0.0356 mmol, 5 mol %),
and t-BuONa (14.0 mg, 0.143 mmol, 20 mol %) were added to a
Schlenk tube which was then evacuated and charged with an argon
atmosphere. PMHS (86 µL, 1.426 mmol, 2 equiv) and toluene (0.5
mL) were added via syringe, and the mixture was stirred for 30 min.
Pentane (1 mL) was added, and the mixture was cooled to -40 °C. A
solution of 12a (100 mg, 0.713 mmol, 1 equiv) and dodecane (100
µL) in toluene (0.5 mL) was added via syringe, followed by t-AmOH
(156 µL, 1.43 mmol, 2 equiv). After 3 h, GC analysis showed complete
conversion, and the reaction was quenched by the addition of 10%
hydrochloric acid. The aqueous layer was extracted three times with
ether. The organic layers were combined, washed with brine, dried over
MgSO4, filtered, and concentrated to dryness. Purification by flash
chromatography (25% ethyl acetate/hexanes) afforded a mixture of the
title compound and an unidentified byproduct. A second flash chro-
matography (80% ether/hexanes) afforded the title compound as a
colorless liquid (71 mg, 70% yield). Chiral GC analysis (GTA column,
1 mL/min, 120 °C, 50 min, retention times: 41.3 min (major), 46.2
min (minor)) showed 86% ee. 1H NMR (300 MHz, CDCl3) δ: 0.88-
1.00 (m, 3H), 1.29-1.42 (m, 4H), 1.44-1.60 (m, 1H), 1.90-2.04 (m,
2H), 2.14 (ABX, dd, J ) 17, 10 Hz, 1H), 2.70 (ABX, ddd, J ) 17, 4,
1.5 Hz, 1H), 4.26 (ABX, ddd, J ) 11, 10, 3.5, 1H), 4.42 (ABX, ddd,
J ) 11, 5, 4 Hz, 1H). 13C NMR (300 MHz, CDCl3) δ: 14.16, 19.72,
29.06, 31.37, 36.74, 38.51, 68.78, 171.76. RD (589 nm, 23.8 mg/mL
CHCl3) ) -21.4.26
(4R)-4-Methyl-1-(4-methoxyphenyl)pyrrolidin-2-one. A solution
of 13 (50 mg, 0.267 mmol, 1 equiv) and i-PrOH (82 µL, 1.1 mmol, 4
equiv) in THF (0.50 mL) was added to a 0 °C slurry of CuCl2‚2H2O
(1.8 mg, 0.013 mmol, 5 mol %), (S)-p-tol-BINAP (9.1 mg, 0.013 mmol,
5 mol %), t-BuONa (5.2 mg, 0.053 mmol, 20 mol %), and PMHS (64
µL, 1.1 mmol, 4 equiv) in c-hexane (0.50 mL). The mixture was stirred
at 0 °C for 1 h. The reaction was quenched by the addition of 10%
hydrochloric acid, and the aqueous layer was extracted three times with
ethyl acetate. The organic layers were combined, washed with brine,
dried over MgSO4, filtered, and concentrated to dryness. Purification
by flash chromatography (70% ethyl acetate/hexanes) afforded the title
compound as a white crystalline solid (48 mg, 95%). Chiral HPLC
analysis (Daicel Chiralpak OB-H column (0.46 cmØ × 25 cm), 0.5
mL/min, 40% i-PrOH/hexane, 254, 280 nm, retention times: 18.4 min
(4R)-4-(4-Fluorophenyl)-1-(4-methoxyphenyl)piperidin-2-one (22).
CuCl2 (13.3 mg, 0.0992 mmol, 2.5 mol %) and t-BuONa (19.1 mg,
0.198 mmol, 5 mol %) were added to a mixture of 21 (1.18 g, 3.97
mmol, 1.0 equiv), (R)-p-tolBINAP (13.5 mg, 0.0198 mmol, 0.5 mol
%), PMHS (3.81 mL, 63.5 mmol, 16 equiv), and t-AmOH (6.95 mL,
63.5 mmol, 16 equiv) in fluorobenzene (8 mL). After 45 min, 10%
hydrochloric acid was added, and the mixture was extracted three times
with ethyl acetate. The organic layers were combined, washed with
brine, dried over MgSO4, filtered, and concentrated to dryness. The
residue was purified by flash chromatography (60% f 100% ethyl
acetate/hexanes) to afford the title compound as a crystalline solid (1.00
g, 89%, based on 95% pure starting material). Chiral HPLC analysis
(Daicel Chiralpak OD column (0.46 cmØ × 25 cm), 1.0 mL/min, 25%
i-PrOH/hexane, retention times: 19.4 min (minor), 22.3 min (major))
showed 90% ee. mp (Et2O): 183-186 °C. 1H NMR (300 MHz, CDCl3)
δ: 2.02-2.27 (m, 2H), 2.64 (ABX, dd, J ) 17, 11 Hz, 1H), 2.86 (ABX,
ddd, J ) 17, 5, 2 Hz, 1H), 3.18-3.30 (m, 1H), 6.62 (ABX, ddd, J )
12, 5, 4 Hz, 1H), 3.68-3.83 (m, 1H), 3.80 (s, 3H), 6.92 (ABX, dt, J
) 9, 2 Hz, 2H), 7.03 (tt, J ) 9, 2 Hz, 2H), 7.16 (AB, dt, J ) 9, 2 Hz,
2H), 7.21 (ABX, dd, J ) 9, 5.5 Hz, 2H). 13C NMR (300 MHz, CDCl3)
δ: 30.98, 38.31, 40.21, 51.06, 55.64, 114.61, 115.65 (d, J ) 19 Hz,
2C), 127.41, 128.01 (d, J ) 8 Hz, 2C), 135.74, 139.08 (d, J ) 3 Hz,
2C), 158.19, 161.60 (d, J ) 244 Hz, 2C), 169.16. IR (neat film, cm-1):
1642, 1511, 1266. Elemental analysis: %C (calc.) ) 72.22, %C
(found) ) 72.22, %H (calc.) ) 6.06, %H (found) ) 6.05. RD (589 nm,
12.8 mg/mL CHCl3) ) +8.
Acknowledgment. We thank the National Institutes of Health
(GM 46059) for funding and Pfizer, Merck, and Bristol-Myers
Squibb for additional unrestricted support. G.H. thanks the
Natural Sciences and Engineering Research Council (NSERC)
of Canada for a postdoctoral fellowship. We are grateful to Dr.
Rudy Schmid (Roche) for a generous gift of (S)-BIPHEMP.
We also thank Prof. Jeff Stryker for helpful comments.
(25) Spectral data and optical rotation were consistent with literature values.
1H/13C NMR: Roeder, E.; Krauss, H. Liebigs Ann. Chem. 1992, 177. Optical
rotation: Kosugi, H.; Tagami, K.; Takahashi, A.; Kanna, H.; Uda, H. J.
Chem. Soc., Perkin Trans. 1 1989, 935.
(26) Spectral data and optical rotation were consistent with literature values.
1H/13C NMR: Kayser, M. M.; Chen, G.; Stewart, J. D. J. Org. Chem. 1998,
63, 7103. Optical rotation: Jones, J. B.; Lok, K. P. Can. J. Chem. 1979,
57, 1025.
Supporting Information Available: Preparation and charac-
terization of all substrates and products (PDF). This material is
available free of charge via the Internet at http://pubs.acs.org.
JA0351692
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11258 J. AM. CHEM. SOC. VOL. 125, NO. 37, 2003