Copper-catalyzed preparation of ketones bearing a stereogenic center in α position

Article abstract of DOI:10.1002/anie.200600247

A highly enantioselective synthesis of α-alkylated and -arylated ketones can be achieved by using a reaction sequence consisting of a stereoselective anti-S_N2′ allylic substitution in the presence of CuCN·2LiCl following by the oxidation of an intermediate cycloalkenyl lithium species using (Me₃SiO)₂ or (MeO) ₃B/NaBO₃·4H₂O. (Chemical Equation Presented).

Full text of DOI:10.1002/anie.200600247

Communications
Asymmetric Synthesis
DOI: 10.1002/anie.200600247
Copper-Catalyzed Preparation of Ketones
Bearing a Stereogenic Center in a Position**
Darunee Soorukram and Paul Knochel*
Dedicated to Professor K. Peter C. Vollhardt
on the occasion of his 60th birthday
The enantioselective preparation of a-alkylated cyclic and
acyclic ketones is important,[1] since chiral a-alkylated
carbonyl moieties are present in numerous natural products.[2]
Recently, we have described a highly selective anti-SN2’
substitution of allylic benzoates and phosphates which allows
the preparation of chiral a-substituted alkenes[3,4] as well as
1,2-diols or 1,2-amino alcohols bearing a quaternary substi-
tuted carbon center.[5] Likewise, Breit et al. have reported
efficient syn-selective SN2’ substitutions using a directing
leaving group.[6]
Herein, we report the highly enantioselective preparation
of chiral ketones of type 1 having a stereogenic center in the a
position by two efficient oxidation procedures from the
intermediate chiral cycloalkenyl lithium species 2. These
organometallic intermediates are readily obtained from the
corresponding cycloalkenyl iodides 3 by I/Li exchange.[7] The
enantiomerically enriched cycloalkenyl iodides 3 are pre-
pared by a copper(i)-catalyzed anti-SN2’ allylic substitution
with organozinc compounds starting either from allylic
pentafluorobenzoates 4 or from the corresponding diethyl-
phosphates 5 (Scheme 1 and Tables 1 and 2).
Thus, the reaction of iPr2Zn (2.2 equiv) with (R)-2-iodo-2-
cyclohexen-1-yl pentafluorobenzoate (98% ee)[3a,c] in the
presence of CuCN·2LiCl (2.2 equiv) in THF/N-methylpyrro-
lidinone (NMP) (3:1) between À308C and À108C for 20 h
provided the expected iodide 3a in 97% yield and 94% ee.[8]
The reaction of 3a with tBuLi (2 equiv) at À788C in THF
provided the corresponding alkenyl lithium 2a, which readily
reacted with Me3SiOOSiMe3 [(TMSO)2; 1.5 equiv] at À788C
for 0.5 h. The resulting silyl enol ether was converted into the
ketone 1a using HF·pyridine in THF[9] (258C, 0.5 h, meth-
od A). This deprotection method provided the ketone 1a in
93% yield and 94% ee (entry 1, Table 1).[10] Similarly, the
[*] Dipl.-Chem. D. Soorukram, Prof. Dr. P. Knochel
Department Chemie and Biochemistry
Ludwig-Maximilians-Universität München
Butenandtstrasse 5–13, Haus F, 81377 München (Germany)
Fax: (+49)89-2180-77680
E-mail: paul.knochel@cup.uni-muenchen.de
[**] We thank the Fonds der Chemischen Industrie, the Deutsche
Forschungsgemeinschaft (KN347/6-2), and Merck Research Labo-
ratories for financial support. We also thank Chemetall GmbH
(Frankfurt), BASF AG (Ludwigshafen) for the generous gift of
chemicals.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Chemie
Table 1: Preparation of a-chiral ketones of type 1 by the oxidation method A
using (TMSO)2.
Entry Substrate of
Yield, ee
Product of type Yield [%][b] ee [%][c]
1
type 3
[%,%][a]
1
2
97, 94[g]
87, 96[g]
93
76
94
96
Scheme 1.
3
4
96, 94
90, 99
70
84
93[h]
93
seven-membered cycloalkenyl iodide 3b obtained in
96% ee[8] was converted into the chiral cycloheptanone 1b
in 76% yield and 96% ee (entry 2, Table 1). Five-membered
cyclic ketones can also be prepared by this procedure. Thus,
the cyclopentenyl iodide 3c furnished, with the oxidation
method A, (S)-2-pentylcyclopentanone (1c) in 70% yield and
93% ee (entry 3, Table 1). Various cyclohexanones with
primary and secondary alkyl substituents were obtained in
this way in 93–98% ee (entries 4–6, Table 1).
The preparation of 2-arylcyclohexanones is more difficult,
since the protons in the position a to both the phenyl ring and
the carbonyl group are much more acidic. Thus, the prepa-
ration of (R)-2-phenylcyclohexanone by method A and an
SN2 substitution mediated by the lithium cuprate
(PhMe2CCH2)(Ph)CuLi in THF[11] (À308C, 48 h) furnished
the crude product 1g with 90% ee. However, during the
chromatographic purification some racemization occurred,
and the ketone 1g was obtained in pure form (70% yield)
with 86% ee (entry 7, Table 1). Iodocyclohexene 3i was
5
6
7
8
90, 99
90, 98[g]
60, 93
90, 98
91
88
70
81
97
98
86
86
prepared by an anti-SN2’ substitution using PhCu in
9
53, 96
69
92
[12]
CH2Cl2
and the corresponding phosphate as substrate
(see the Experimental Section). The oxidation procedure A
furnished ketone 1i in 69% yield and 92% ee after chromato-
graphic purification (entry 9, Table 1). Interestingly, the
cyclohexanone bearing an a-para-methoxyphenyl substituent
(1h) proved to be especially sensitive toward racemization,
and attempts to purify the ketone 1h by chromatography
either on silica gel or alumina led to considerable racemiza-
tion (5–24% ee). However, the recrystallization of this ketone
from diethyl ether provided the pure product 1h in 81% yield
and 86% ee.
[a] Yield of isolated produce. The enantiomeric excess was determined by
either HPLC or GC analysis. In each case the racemic compound was also
prepared for calibration. [b] Overall yield after oxidation and desilylation.
[c] The enantiomeric excess was determined by either HPLC or GC analysis. In
each case the racemic compound was also prepared for calibration.
[d] Prepared from the corresponding pentafluorobenzoate (see the Supporting
Information). [e] Prepared from the corresponding diethylphosphate (see the
Supporting Information). [f] Prepared from the corresponding acetate (SN2
substitution; see the Supporting Information). [g] Determined from the
corresponding ketone. [h] Determined from the corresponding lactone (see
the Supporting Information).
Although the oxidation of the alkenyl lithium derivatives
of type 2 proceeded in good yields and excellent enantiose-
lectivities, we were concerned with the scale-up and the safety
of this oxidation procedure since it requires the use of the
sensitive peroxide (TMSO)2 (see the Experimental Section).
Thus, we examined an alternative procedure in which the
lithium intermediate of type 2 is transmetalated by reaction
with B(OMe)3 (2.5 equiv, À788C to 258C, 24 h) to give the
cycloalkenyl(dimethoxy)borane, which is then oxidized with
NaBO3·4H2O (258C, 24 h).[13] Under these conditions, several
cyclohexenyl iodides of type 3 were converted into the chiral
ketones of type 1 in good yields and enantioselectivities
(Scheme 1 and Table 2). A comparison of the two methods
(entries 1–4 of Table 1 and Table 2) shows that similar high
enantioselectivities were obtained for cyclohexanones and
cycloheptanones, whereas for the cyclopentanone 1c an
enantioselectivity of only 81% ee was obtained with meth-
od B (entry 3, Table 2). Various chiral cyclohexanones bear-
ing either a primary or a secondary alkyl substituent in a
position were prepared in this way in 46–65% yield and 90–
98% ee (entries 5–8, Table 2). Interestingly, ketones bearing a
quaternary center in the position a to the carbonyl center
were obtained by this method. Thus, the reaction of the
pentafluorobenzoate 6 with Pent2Zn (2.4 equiv) and CuCN·2
LiCl (1.2 equiv) in THF for 4 h at 258C provided the SN2’-
substitution product 7 in 93% yield and 95% ee. Less than
5% of the SN2-substitution product was found. Application of
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Table 2: Preparation of a-chiral ketones of type 1 by method B by
transmetalation with (MeO)3B and further oxidation with NaBO3·4H2O.
Entry Substrate of
Yield, ee
Product of
type 1
Yield [%][b] ee [%][c]
type 3
[%,%][a]
1
2
97, 97[f]
87, 98[f]
90
86
97
98
Scheme 2. Application of method B to provide 8.
3
4
96, 94
90, 99
90
86
81[g]
98
5
6
95, 98[f]
95, 98
56
65
98
97
Scheme 3. Application to the preparation of 9. mCPBA=m-chloroper-
benzoic acid.
chiral ketones with an stereogenic center in a position.
Extensions of this method to more complex substrates are
underway in our laboratory.
7
8
85, 99
85, 98
61
46
95
90
Experimental Section
Typical procedure for the preparation 1a (entry 1, Table 1) with
(TMSO)2 (method A): A flame-dried 25-mL flask equipped with a
magnetic stirring bar, an argon inlet, and a septum was charged with
3a (125 mg, 0.5 mmol, 1 equiv) and THF (4 mL). The mixture was
cooled at À788C, then tBuLi (1.6m in pentane, 0.63 mL, 1 mmol,
2 equiv) was added dropwise. The reaction mixture was stirred at
À788C for 30 min, then (TMSO)2 (neat, 0.16 mL, 0.75 mmol,
1.5 equiv) was added (Caution: Explosive![15] The reagent must be
transferred with a plastic syringe and teflon needle and added slowly).
The reaction mixture was stirred continuously at À788C for 30 min,
and then poured into water, extracted with pentane, and dried over
MgSO4. The solvents were removed, and the crude product was used
in the next step without purification.
A flame-dried 25-mL flask equipped with a magnetic stirring bar,
an argon inlet, and a septum was charged with dry pyridine (0.4 mL)
and HF·pyridine complex (70%) (0.02 mL, 0.5 mmol, 1 equiv). A
solution of the previously prepared silyl enol ether (see above) in
THF (2 mL) was added dropwise at room temperature. The reaction
mixture was stirred for 30 min, poured into water, extracted with
Et2O, washed with brine, and dried over MgSO4. The solvents were
removed, and the crude product was purified by column chromatog-
raphy (silica gel, 10% Et2O/pentane) to yield the chiral ketone 1a
(65 mg, 93% yield, 94% ee) as a colorless oil.
[a] Yield of isolated product. The enantiomeric excess was determined by
either HPLC or GC analysis. In each case the racemic compound was
also prepared for calibration. [b] Overall yield of the two-step oxidation
procedure. [c] The enantiomeric excess was determined by HPLC or GC
analysis. In each case the racemic compound was also prepared for
calibration. [d] Prepared from the corresponding pentafluorobenzoate
(see the Supporting Information). [e] Prepared from the corresponding
diethylphosphate (see the Supporting Information). [f] Determined from
the corresponding ketone. [g] Determined from the corresponding
lactone (see the Supporting Information).
method B provided the ketone 8 in 70% yield and 95% ee
(Scheme 2).
As an application of this methodology, we prepared (R)-
10-methyl-6-undecanolide (9), a caprolactone recently iso-
lated from
a
marine streptomycete (isolate B6007)[14]
(Scheme 3). Thus, the reaction of (CH3)2CH(CH2)3ZnI
(2 equiv) with compound 10 (98% ee)[3a,c] in the presence of
CuCN·2 LiCl (2 equiv) in THF/NMP (3:1) between À308C
and room temperature for 15 h provided the anti-SN2’-
substitution product 11 in 88% yield and 96% ee. The
oxidation procedure A furnished the ketone 12 in 89%
yield and 95% ee. Baeyer–Villiger oxidation of 12 with m-
chloroperbenzoic acid in CH2Cl2 gave the caprolactone 9 in
91% yield and 95% ee.
Typical procedure for the preparation of 1a with B(OMe)3
(method B): A flame-dried 25-mL flask equipped with a magnetic
stirring bar, an argon inlet, and a septum was charged with 3a
(125 mg, 0.5 mmol, 1 equiv) and THF (4 mL). The mixture was cooled
at À788C, then tBuLi (1.6m in pentane, 0.63 mL, 1 mmol, 2 equiv)
was added dropwise. The reaction mixture was stirred at À788C for
30 min, then B(OMe)3 (neat, 0.14 mL, 1.25 mmol, 2.5 equiv) was
added dropwise. The reaction mixture was slowly warmed up to RT
In summary, we have developed a short synthetic
sequence for the enantioselective preparation of various
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and stirred for 24 h, then a suspension of NaBO3·4H2O (10 equiv,
769 mg, 5 mmol) in H2O (6 mL) was added. After the mixture had
been stirred at RT for 24 h, it was poured into water, extracted with
Et2O, washed with brine, and dried over MgSO4. The solvents were
removed, and the crude product was purified by column chromatog-
raphy (silica gel, 10% Et2O/pentane) to yield the chiral ketone 1a
(63 mg, 90% yield, 97% ee) as a colorless oil.
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[8] Determined from the corresponding ketone.
[9] D. A. Evans, S. W. Kaldor, T. K. Jones, J. Clardy, T. J. Stout, J.
Am. Chem. Soc. 1990, 112, 7001.
[10] When tetrabutylammonium fluoride in THF was used (08C, 1 h),
partial racemization of the ketone 1a was observed (86% yield,
65% ee; see the Supporting Information.
[11] M. I. Calaza, X. Yang, D. Soorukram, P. Knochel, Org. Lett.
2004, 6, 529.
Received: January 20, 2006
Published online: April 28, 2006
[12] For the use of (Ph)2CuLi in the presence of tetramethylsilyl
chloride in CH2Cl2 for 1,4-addition reactions see: T. Hirata, K.
Shimoda, T. Kawano, Tetrahedron: Asymmetry 2000, 11, 1063.
[13] A. Winqvist, R. Strꢀmberg, Eur. J. Org. Chem. 2001, 4305.
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b) Bis(trimethylsilyl)peroxide [(TMSO)2] was purchased from
ABCR Product List. Please refer to the warnings in the catalog.
Keywords: allylic substitution · asymmetric synthesis ·
carbonyl compounds · copper · zinc
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