Cp2TiCl-mediated selective reduction of α,β-epoxy ketones

Full text of DOI:10.1021/jo001358g

1046
J . Org. Chem. 2001, 66, 1046-1048
Sch em e 1
Cp 2TiCl-Med ia ted Selective Red u ction of
r,â-Ep oxy Keton es
Christophe Hardouin, Floris Chevallier,
Bernard Rousseau, and Eric Doris*
CEA/ Saclay, Service des Mole´cules Marque´es, Baˆt. 547,
De´partement de Biologie Cellulaire et Mole´culaire,
91191 Gif sur Yvette Cedex, France
Ta ble 1. Exa m p les of Selective Red u ction of r,â-Ep oxy
Keton es
eric.doris@cea.fr
Received September 13, 2000
In tr od u ction
The selective reduction of R,â-epoxy ketones to â-hy-
droxy ketones is synthetically important because aldols
are key intermediates in the construction of numerous
natural products. Several methods have been developed
to perform this conversion. Examples include the follow-
ing: SmI2,1 Li/NH3,2 Al amalgam,3 Bu3SnH/AIBN,4 H2/
Pd/C,5 PET,6 and chalcogenide-based7-9 reductions. In
this paper, we disclose a novel reaction for the selective
reduction of R,â-epoxy ketones. Our approach relies on
the utilization of Cp2TiCl as the active species.10 Ti-
tanocene reagents are operative in pinacol coupling of
aldehydes and ketones.11 The reaction proceeds through
the formation of a ketyl radical that dimerizes readily.
Cp2TiCl also induces the deoxygenation of epoxides12 via
a â-alkoxy radical, which derives from the low-valent
metal complex through single electron transfer (SET).13
Thus, the treatment of a substrate in which a ketone
function resides adjacent to an epoxide function with 2
equivalents of Cp2TiCl should result in the selective
reduction of the oxirane moiety (Scheme 1).
* To whom correspondence should be addressed. Fax: +33-
169087991.
(1) Molander, G. A.; Hahn, G. J . Org. Chem. 1986, 51, 2596-2599.
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a
b
Isolated yields. Reaction time: 45 min from -78 to 0 °C.
c Enantiomeric excesses were determined by HPLC using
Chiralcel OD column. Product obtained as a 9/1 mixture of
epimers.
a
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d
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Resu lts a n d Discu ssion
(10) Gold, H. J . Synlett 1999, 159. For a recent application of Cp2-
TiCl, see: Ferna´ndez-Mateos, A.; Martin de la Nava, E.; Pascual Coca,
G.; Ramos Silvo, A.; Rubio Gonza´lez, R. Org. Lett. 1999, 1, 607-609.
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T.; Hatano, B.; Asahara, M.; Muguruma, Y.; Ogawa, A. Tetrahedron
Lett. 1998, 39, 5247-5248.
To investigate this conjecture, various R,â-epoxy ke-
tones were reacted with Cp2TiCl for 15 min at -78 °C in
THF/MeOH (Table 1). The low-valent titanium(III) com-
plex was readily prepared by the in situ reduction of 2.5
equiv of Cp2TiCl2 with 5 equiv of powdered zinc for 45
min at room temperature. In most cases, the overall
yields were satisfactory. The selective reduction of 2,3-
epoxy-1-phenylpropan-1-one afforded the expected aldol
product (entry 1). The reaction was also successfully
extended to di- and trisubstituted epoxy ketone systems
leading to primary (entry 2), benzylic (entry 4), and
(12) Schobert, R. Angew. Chem., Int. Ed. Engl. 1988, 27, 855-856.
RajanBabu, T. V.; Nugent, W. A.; Beattie, M. S. J . Am. Chem. Soc.
1990, 112, 6408-6409.
(13) RajanBabu, T. V.; Nugent, W. A. J . Am. Chem. Soc. 1989, 111,
4525-4527. RajanBabu, T. V.; Nugent, W. A. J . Am. Chem. Soc. 1994,
116, 986-997. Gansa¨uer, A.; Bluhm, H.; Pierobon, M. J . Am. Chem.
Soc. 1998, 120, 12849-12859.
10.1021/jo001358g CCC: $20.00 © 2001 American Chemical Society
Published on Web 01/11/2001

Notes
J . Org. Chem., Vol. 66, No. 3, 2001 1047
Sch em e 2
Sch em e 3
tertiary (entry 3) alcohols, respectively. The effect of the
stereochemistry of the starting epoxide was also stud-
ied: Both trans- (entry 5) and cis-2,3-epoxy-1-phenyl-
heptan-1-one (entry 6) reacted similarly toward Cp2TiCl
to give comparable yields of reduced 3-hydroxy-1-phen-
ylheptan-1-one. Since the stereochemical integrity of the
â-position should remain intact during the reductive
process, the synthesis of optically enriched aldols ap-
peared feasible. Accordingly, treatment of (2R,3S)-epoxy-
1-phenylheptan-1-one14 (80% ee) under the aforemen-
tioned conditions led to (S)-3-hydroxy-1-phenylheptan-
1-one in 81% yield without any loss of optical purity
(entry 7). The procedure worked equally well on aliphatic
(entry 8) and cyclic ketone (entry 9) systems. It was
gratifying that our method worked on a carvone-derived
epoxide (entry 10) for which a previous SmI2-mediated
attempt had failed.1
Exp er im en ta l Section
Gen er a l Meth od s. 1H NMR and 13C NMR spectra were
recorded at 300 and 75 MHz using residual CHCl3 (7.25 ppm)
and CDCl3 (77 ppm) as internal standard, respectively. Flash
column chromatography was performed on Merck silica gel (60
Å, 230-400 mesh). All reactions were performed under Ar using
freshly distilled THF (over Na/benzophenone). Reagents were
purchased from Aldrich Chemical Co.
Gen er a l P r oced u r e for th e Selective Red u ction of r,â-
Ep oxy Keton es: 3-Hyd r oxy-1-p h en ylp r op a n -1-on e16 4 (En -
tr y 1). Stoich iom etr ic P r oced u r e. THF (5 mL) was added to
a mixture of Cp2TiCl2 (0.42 g, 2.5 equiv) and powdered Zn (0.22
g, 5.0 equiv) in an oven-dried flask purged with argon. The
heterogeneous solution was stirred vigorously for 45 min at room
temperature. The green slurry of Cp2TiCl was cooled to -78 °C,
and a solution of 2,3-epoxy-1-phenylpropan-1-one (0.1 g, 0.68
mmol, 1 equiv) in THF/MeOH (1.3 mL/0.7 mL) was added
dropwise. After 15 min at -78 °C, the reaction was transferred
to an Erlenmeyer flask and quenched, at room temperature, with
10 mL of 10% K2CO3. The mixture was filtered through a fritted
glass funnel, and the aqueous layer was extracted twice with
Et2O and once with CH2Cl2. The combined organic layers were
dried over Na2SO4, filtered, and concentrated under reduced
pressure. The residue was subjected to column chromatography
over silica gel (eluent: hexane/AcOEt ) 1/1) to yield 3-hydroxy-
1-phenylpropan-1-one: oil, 0.087 g, 86%.
A postulated reaction mechanism is illustrated in
Scheme 2 for the reductive ring opening of 2,3-epoxy-1-
phenylpropan-1-one 1. The sequential single electron
transfer from Cp2TiCl to the oxirane and thereafter to
the carbonyl generates, in the first step, a radical
intermediate 2 which, upon reaction with a second
equivalent of Cp2TiCl, produces enolate â-alcoholate 3.
Subsequent protonation of 3 by methanol affords 3-hy-
droxy-1-phenylpropan-1-one 4. The emergence of 3 as
intermediate during this transformation was prompted
by the observation that, when methanol-d was used as
cosolvent instead of MeOH, the reduced product 4 was
deuterated R to the carbonyl (65% isotopic enrichment).
A similar result (84% yield) was obtained on substrate
1 when a catalytic amount of Cp2TiCl2 (20 mol %) in THF
was used in the presence of powdered Zn (5 equiv) and
collidine hydrochloride (3 equiv). The latter served not
only for the double protonation of intermediate 3, but also
for the regeneration15 of the starting titanocene(IV)
dichloride reagent which is in situ reduced by stoichio-
metric Zn to redox-active Cp2TiCl. This completes the
catalytic cycle (Scheme 3).
Ca ta lytic P r oced u r e. THF (5 mL) was added to a mixture
of Cp2TiCl2 (0.034 g, 0.2 equiv, cat.), powdered Zn (0.22 g, 5
equiv), and collidine hydrochloride (0.32 g, 3 equiv) in an oven-
dried flask purged with argon. The heterogeneous solution was
stirred vigorously for 45 min at room temperature. The green
slurry of Cp2TiCl was cooled to -78 °C, and a solution of 2,3-
epoxy-1-phenylpropan-1-one (0.1 g, 0.68 mmol, 1 equiv) in 2 mL
of THF was added dropwise. After 15 min at -78 °C, the reaction
was slowly warmed to -30 °C over a period of 1 h. The reaction
was worked up as before (vide supra) to yield 3-hydroxy-1-
1
phenylpropan-1-one: 0.085 g, 84%; H NMR δ 2.83 (t, J ) 5.5
Hz, 1H), 3.21 (t, J ) 5.5 Hz, 2H), 4.01 (q like, J ) 5.5 Hz, 2H),
7.42-7.48 (m, 2H), 7.53-7.60 (m, 1H), 7.92-7.96 (m, 2H).
3-Hyd r oxy-2-m eth yl-1-p h en ylp r op a n -1-on e17 (en tr y 2):
oil, 90%; 1H NMR δ 1.24 (d, J ) 7.3 Hz, 3H), 2.26-2.34 (m, 1H),
3.62-3.98 (m, 3H), 7.45-7.61 (m, 3H), 7.94-7.98 (m, 2H).
In conclusion, we have shown that low-valent Cp2TiCl
selectively reduces selected R,â-epoxy ketones to the
corresponding aldol products under mild conditions. The
procedure was applied to the synthesis of a chiral,
nonracemic â-hydroxy ketone. A catalytic titanocene
system was also developed to accomplish the reductive
conversion.
3-Hydr oxy-3-m eth yl-1-ph en ylbu tan -1-on e18 (en tr y 3): oil,
74%; 1H NMR δ 1.34 (s, 6H), 3.44 (s, 2H), 4.16 (s, 1H), 7.44-
7.50 (m, 2H), 7.55-7.61 (m, 1H), 7.92-7.96 (m, 2H).
3-Hyd r oxy-1,3-d ip h en ylp r op a n -1-on e19 (en tr y 4): oil,
59%; 1H NMR δ 3.37 (d, J ) 6.1 Hz, 2H), 3.60 (d, J ) 3.0 Hz,
1H), 5.35 (dt, J ) 3.0, 6.1 Hz, 1H), 7.25-7.61 (m, 8H), 7.93-
7.97 (m, 2H).
(14) This compound was prepared by the Sharpless asymmetric
epoxidation of (E)-1-phenylhept-2-en-1-ol, followed by MnO2 oxidation
of the resulting epoxy alcohol, see: Gao, Y.; Hanson, R. M.; Klunder,
J . M.; Ko, S. O.; Masamune, H.; Sharpless, K. B. J . Am. Chem. Soc.
1987, 109, 5765-5780.
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Gansa¨uer, A.; Bauer, D. Eur. J . Org. Chem. 1998, 2673-2676.
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82-87.
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(18) Guthrie, J . P.; Wang, X. Can. J . Chem. 1991, 69, 339-344.
(19) Orsini, F. J . Org. Chem. 1997, 62, 1159-1163.

1048 J . Org. Chem., Vol. 66, No. 3, 2001
Notes
3-Hyd r oxy-1-p h en ylh ep ta n -1-on e20 (en tr ies 5-7): oil,
79-83%; 1H NMR δ 0.91 (t, J ) 7.3 Hz, 3H), 1.23-1.63 (m, 6H),
3.02 (dd, J ) 8.5, 17.7 Hz, 1H), 3.16 (dd, J ) 2.4 Hz, 17.7 Hz,
1H), 3.28 (d, J ) 3.0 Hz, 1H), 4.15-4.24 (m, 1H), 7.43-7.60 (m,
3H), 7.92-7.96 (m, 2H).
(oil): 1H NMR δ 1.10 (d, J ) 6.8 Hz, 3H), 1.65 (m 1H), 1.74 (s,
3H), 1.84 (m, 1H), 2.14 (m, 1H), 2.26 (t, J ) 12.7 Hz, 1H), 2.44-
2.57 (m, 2H), 2.84 (m, 1H), 4.30 (m, 1H), 4.75 (s, 1H), 4.77 (s,
1H).
1-Hyd r oxyocta n -3-on e9 (en tr y 8): oil, 89%; 1H NMR δ 0.86
(t, J ) 7.0 Hz, 3H), 1.18-1.33 (m, 4H), 1.51-1.61 (m, 2H), 2.41
(t, J ) 7.3 Hz, 2H), 2.61 (brs, 1H), 2.64 (t, J ) 5.2 Hz, 2H), 3.81
(m, 2H).
Ack n ow led gm en t. Dr. J . Albert Ferreira is grate-
fully acknowledged for reviewing this manuscript. Mr.
Alain Valleix is also acknowledged for HPLC and MS
analyses. This work was partly supported by “Pierre
Fabre Me´dicaments” through a grant to C.H.
1
3-Hyd r oxycycloh exa n on e16 (en tr y 9): oil, 80%; H NMR
δ 1.66-2.34 (m, 7H), 2.40 (dd, J ) 7.3, 14.0 Hz, 1H), 2.65 (dd,
J ) 4.3, 14.0 Hz, 1H), 4.14-4.22 (m, 1H).
(3R,5R)-3-H yd r oxy-5-isop r op en yl-2-m et h ylcycloh exa -
n on e8 (En tr y 10). This compound was obtained as a 9:1 mixture
of epimers in a combined yield of 65%. For the major isomer:
(2R,3R,5R)-3-Hydroxy-5-isopropenyl-2-methyl-cyclohexanone
Su p p or tin g In for m a tion Ava ila ble: Reproductions of 1H
NMR spectra of the products described in entries 1-10. This
material is available free of charge on the Internet at
http://pubs.acs.org.
(20) Curran, D. P. J . Am. Chem. Soc. 1983, 105, 5826-5833.
J O001358G