Enantioselective alkylation of acyclic α,α-disubstituted tributyltin enolates catalyzed by a {Cr(salen)} complex

Article abstract of DOI:10.1002/anie.200604901

Straighten out the mixture: A dynamic mixture of acyclic isomers of tributyltin enolates undergoes a {Cr(salen)}-catalyzed alkylation reaction to generate methyl ketones that contain α-carbonyl quaternary stereocenters in high yield and enantioselectivity

Full text of DOI:10.1002/anie.200604901

Angewandte
Chemie
DOI: 10.1002/anie.200604901
Asymmetric Catalysis
Enantioselective Alkylation of Acyclic a,a-Disubstituted Tributyltin
Enolates Catalyzed by a {Cr(salen)} Complex**
Abigail G. Doyle and Eric N. Jacobsen*
Dedicated to Professor Robert G. Bergman on the occasion of his 65th birthday
À
Catalytic a-carbonyl C C bond-forming reactions represent a
proven strategy for the construction of quaternary stereocen-
ters.[1] Most approaches involve the addition of enolates to
carbon-centered electrophiles in which both the p-facial
selectivity and the enolate geometry govern the stereoselec-
Z isomers, tin enolates are known to undergo tautomerization
between their O-stannyl and C-stannyl forms in solution.[12]
We were intrigued by the possibility that enantioselective
alkylation of acyclic enolates might be achievable by a
dynamic mechanism such as that outlined in Scheme 2,
[2–8]
À
tivity of the C C bond-forming event.
Unfortunately, the
synthesis of stereodefined enolates from simple a,a-disub-
stituted carbonyl compounds that lack either tethered sub-
stituents or specific chelating functionality remains a signifi-
cant challenge in organic synthesis.[9] As a result, successful
examples of asymmetric catalytic enolate addition reactions
that generate a-carbonyl quaternary stereocenters are limited
to b-cyano esters, b-keto esters, and cyclic ketones, and
relatively little progress has been made with simple acyclic
systems.[10] Our own efforts in the area of enantioselective
reactions with enolates have led to the recent discovery of a
{Cr(salen)}-catalyzed asymmetric a-alkylation of cyclic tin
Scheme 2. Strategy for the enantioselective alkylation of acyclic
tributyltin enolates 2.
enolates
to
provide
5-,
6-,
and
7-membered-
ring ketones that contain a quaternary stereocenters
(salen=N,N’-bis(salicylidene)ethylenediamine
dianion;
Scheme 1).[11] While the preparation of acyclic a,a-disubsti-
tuted tin enolates leads inevitably to mixtures of E and
wherein mixtures of acyclic tin enolates might undergo
reaction selectively through one geometric isomer under the
{Cr(salen)}-catalyzed alkylation conditions. Herein, we report
our progress to this end, and discuss how these studies have
enhanced our understanding of the mechanism of the
catalytic reaction.
Initial studies were performed using the tributyltin
enolate of 3-methyl-2-pentanone 2a, which was prepared as
a 1.8:1 mixture of E and Z isomers.[13] Treatment of 2a with
allyl bromide and the [Cr(salen)Cl] complex 1a at 48C
afforded the alkylation product 3a in 80% yield and 21% ee
(Table 1, entry 1). Variation of the substituents on the salen
ligand revealed that the OTIPS derivative 1b was both more
reactive and more enantioselective than the tBu derivative
(Table 1, entry 2, 84% yield, 36% ee).[14] A significant effect
of the catalyst counterion on enantioselectivity and conver-
sion was observed (Table 1, entries 2–4), with the iodide
complex 1d catalyzing the alkylation reaction in 93% yield
and 56% ee (3.6:1 e.r.).[15] This result established unambigu-
ously that the enantioselectivity of the alkylation product 3a
was not limited by the E/Z ratio of enolate isomers of 2a (see
below). Interestingly, a small increase in enantioselectivity
was observed in reactions run with 5 mol% Bu3SnOMe as an
additive (Table 1, entries 5 and 6), perhaps as a result of
acceleration of enolate tautomerization and equilibration.
Further variation of the reaction parameters led to identifi-
cation of conditions that provided 3a in 94% yield and
79% ee when the reaction was run at À278C in o-xylene with
Scheme 1. {Cr(salen)}-catalyzed alkylation of tetrasubstituted tin
enolates derived from cyclic ketones.
[*] A. G. Doyle, Prof. E. N. Jacobsen
Department of Chemistry and Chemical Biology
Harvard University, 12 Oxford St.
Cambridge, MA 02138 (USA)
Fax: (+1)617-496-1880
E-mail: jacobsen@chemistry.harvard.edu
[**] This work was supported by the NIH (GM-43214) and by a
predoctoral fellowship to A.G.D. from the National Science
Foundation. salen=N,N’-bis(salicylidene)ethylenediamine dianion.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Table 1: Optimization of the conditions for the asymmetric alkylation of tributyltin enolate 2a.[a]
substituent was investigated with
the tin enolate 2b (R1 = Me; R2 =
nBu), which was prepared as a
1.5:1 mixture of E and Z isomers.
Alkylation of 2b proved more
selective than alkylation of 2a with
a variety of electrophiles in spite of
the lower E/Z ratio of 2b (Table 2,
entries 5–8). For example, alkyla-
tion of 2b with allyl iodide provided
the ketone 3d in 92% yield and
87%ee. However, significant limi-
tations to the nucleophile scope
remain. For example, enolates con-
taining branched aliphatic substitu-
ents (for example, 2; R1 = Me; R2 =
iPr) underwent alkylation with low
enantioselectivity. Additionally, the
presence of aromatic substitution
on 2 (for example, R1 = Me; R2 =
Ph) led to reduced reactivity of the
Entry
Catalyst
X
R1
Solvent
m [equiv]
T [8C]
Yield [%][b]
ee [%][c]
1
2
3
4
1a
1b
1c
1d
1d
1d
1e
1e
Cl
Cl
Br
I
I
I
tBu
benzene
benzene
benzene
benzene
benzene
o-xylene
o-xylene
o-xylene
4
4
4
4
2
2
2
2
4
4
4
4
4
4
4
À27
80
84
90
93
90
95
94
94
21
36
49
56
60
65
68
79
OTIPS
OTIPS
OTIPS
OTIPS
OTIPS
OSiThMe2
OSiThMe2
5
6[d]
7[d]
8[d]
I
I
[a] Reactions were carried out with 1 (0.005 mmol) and 2a (0.1 mmol) in 250 mL of solvent; TIPS=
triisopropylsilyl, Th=thexyl=1,2,2-trimethylpropyl. [b] Determined by GC analysis using 1-decene as an
internal standard. [c] Determined by GC analysis on a chiral stationary phase compared with an
authentic racemic sample. [d] Bu3SnOMe (5 mol%, 0.005 mmol) was added.
catalyst 1e, in which the salen ligand contained a OSiThMe2
group (Table 1, entry 8).
enolate such that the alkylation proceeded only to very low
conversion.
Under the optimized conditions, the alkylation of enolate
2a with allyl iodide afforded 3a in 83% yield and 82% ee
(Table 2, entry 2). Alkylation of 2a with other common sp3-
hybridized electrophiles, which included benzyl bromide and
ethyl iodoacetate, proceeded in good yield and enantioselec-
tivity (Table 2, entries 3 and 4). Variation of the enolate
The methyl ketone products 3 have broad versatility as
chiral building blocks for organic synthesis (Scheme 3). For
example, ketone 3a was converted into acid 4a and tertiary
Table 2: Enantioselective alkylation of tributyltin enolates 2 with alkyl
halides.
Entry
Tin enolate
(E/Z ratio)
R3CH2X
Adduct
Yield
[%][a]
ee
[%][b]
Scheme 3. Elaboration of the methyl ketone products. mCPBA=meta-
chloroperoxybenzoic acid.
1
2
2a (1.8:1)
3a
3a
80
83
79
82
alcohol 4b both with complete preservation of enantiomeric
excess (Scheme 3).[16] Very few efficient catalytic routes to
products with structures such as 4a and 4b have been
identified because of the inherent difficulty associated with
enantiodifferentiation of three sp3-hybridized substituents.[17]
The Cr-catalyzed alkylation reaction generates a-quater-
nary ketones 3 in high yield with e.r. values significantly
exceeding the E/Z ratios of the enolate starting material. This
result requires that either: 1) both enolate isomers undergo
alkylation to generate the same enantiomer of product
preferentially (scenario 1, Scheme 4), or 2) the enolate iso-
mers undergo rapid equilibration under the reaction condi-
tions with selective reaction of one geometric isomer (sce-
nario 2, Scheme 4). Acyclic a-monosubstituted tin enolates
have been shown to undergo tautomerization between their
O-stannyl and C-stannyl forms in solution.[18] In the present
3
3b
86
81
4
5
6
3c
3d
3e
73
92
83
76
87
86
2b (1.5:1)
7
8
3 f
77
97
84[c]
78[d]
3g
[a] Yield of isolated product after chromatography on silica gel.
[b] Determined by GC or HPLC analysis on a chiral stationary phase
compared with an authentic racemic sample. [c] Analysis of the ee value
was performed on the Weinreb amide. [d] Analysis of the ee value was
performed on the desilylated alkyne.
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Figure 1. Enantioselectivity over the course of the reaction.
plex as the only role of the {(salen)Cr} catalyst (mechanism A,
Scheme 5).[20] Preliminary studies reveal a first-order kinetic
dependence on the chromium catalyst, which suggests that a
mechanism in which the catalyst serves a dual role as a Lewis
acid activator of the alkyl halide and as a counterion for the
enolate is not operative.[21]
Nucleophilic activation of tin enolates can occur not only
by transmetalation but also by coordination of a Lewis base
such as hexamethylphosphoramide (HMPA) or Bu4NBr to
the metal to generate pentacoordinate anionic (ate) com-
plexes.[22] Thus, chromium catalyst 1 could act in an analogous
fashion to Bu4NBr, by activating the tin enolate through
halide addition, thus generating a tin ate complex with a
cationic {(salen)Cr} counterion (mechanism B, Scheme 5).[23]
It is particularly relevant in this context that neutral
tetracoordinate tin enolates have been shown to add to a-
halocarbonyl electrophiles at the carbonyl group, whereas
pentacoordinate tin enolates react by halide displacement.[24]
In mechanism B, enantioselectivity would be imparted solely
Scheme 4. Possible pathways for the enantioselective alkylation of
geometric mixtures of 2a.
context, enolate tautomerization could serve as a viable
mechanism for E/Z equilibration as long as the C tautomer is
accessible from a,a-disubstituted tin enolates. Furthermore,
differences in reactivity of E and Z enolates have ample
literature precedent.[19] When the course of the alkylation
reaction of 2a with allyl bromide was monitored from 5% to
100% conversion, the ee value of the product 3a was
observed to remain invariant (Figure 1). This is fully consis-
tent with scenario 2 in Scheme 4, but is only possible within
the constraint of scenario 1 if the E and Z isomers undergo
alkylation with identical enantiose-
lectivity or at exactly the same rate.
Given the implausibility of such
scenarios, the equilibration mecha-
nism in scenario 2 appears most
likely.
The pronounced influence of
the counterion to the chromium
catalyst 1 on the ee value of the
alkylation reaction (Table 1) holds
clear mechanistic implications. A
similar observation was made in the
alkylation of cyclic tin enolates,
however the trend was in the oppo-
site direction, with catalyst 1a
being more enantioselective than
the corresponding [(salen)CrBr] or
[(salen)CrI] complexes. Evidently,
the counterion of the chromium
catalyst 1 is part of the enantiode-
termining step in the catalytic cycle.
This rules out a mechanism for
catalysis that involves the genera-
tion of a [(salen)Cr(enolate)] com-
Scheme 5. Possible mechanisms for the {(salen)Cr}-catalyzed alkylation of tributyltin enolates 2 with
alkyl halides. L=salen ligand.
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Communications
(0.5 mL) at 08C. Solid potassium fluoride (ca. 1 g) was added,
accompanied by the formation of white precipitate. The mixture
was filtered through a bed of sodium sulfate (rinsing with pentane)
into a flask cooled to 08C, and was concentrated to around 1.5 mL by
rotary evaporation with a bath at 48C. The residue was purified by
column chromatography on silica gel, with 2% diethyl ether in
pentane as the eluent. Concentration of the desired fractions was
again performed with a bath at 48C and the product was isolated as a
clear oil (58.2 mg, 83% yield). The enantiomeric excess was
determined to be 82% by GC analysis on a chiral stationary phase
(g-TA 508C (isothermal), tr(minor) = 61.1 min, tr(major) = 58.0 min);
[a]2D4 = À0.65 (c = 6.7, CHCl3); IR (thin film): n˜ = 3070 (w), 2955 (m),
2910 (m), 2860 (w), 1706 (s), 1461 (w), 1355 cmÀ1 (m); 1H NMR
(400 MHz, CDCl3): d = 5.71–5.61 (1H, m), 5.07–5.02 (2H, m), 2.34
(1H, dd, J = 14.4, 7.6 Hz), 2.19 (1H, dd, J = 12.8, 7.6 Hz), 2.10 (3H, s),
1.65 (1H, dq, J = 14, 7.6 Hz), 1.50 (1H, dq, J = 14 Hz, 7.6 Hz), 1.07
(3H, s), 0.79 ppm (3H, t, J = 7.4 Hz); 13C NMR (100 MHz, CDCl3):
d = 208.6, 134.2, 118.1, 51.8, 42.2, 31.0, 22.6, 20.5, 8.9 ppm; LRMS
(ES): 141 (100%) [M+H]+.
by ion pairing; consistent with this possibility, the enantiose-
lectivities of alkylation reactions were found to be strongly
solvent dependent, with reactions that were carried out in
nonpolar solvents such as benzene or o-xylene affording
better results than those carried out in polar solvents such as
acetonitrile or tetrahydrofuran.
Alternatively, the Cr-catalyzed alkylation reaction could
proceed by activation of the alkyl halide by the neutral Cr
catalyst (mechanism C, Scheme 5). However, neutral metal
complexes of alkyl halides find no precedent in the literature.
By contrast, coordination complexes of alkyl halides with
cationic transition metals are known and have been shown to
accelerate SN2 alkylation reactions.[25] An intriguing variant to
mechanism B would thus involve activation of the alkyl halide
by the cationic chromium complex formed upon halide
transfer to the tin atom (mechanism D, Scheme 5). At this
stage we have been unable to obtain definitive experimental
evidence to rule out either of the mechanisms B or D, but
several compelling aspects of mechanism D justify its careful
consideration. First, the mechanism invokes minimal charge
separation in the association of the leaving group of the
electrophile with the chromium catalyst to close the catalytic
cycle. Second, it suggests a basis for stereoinduction in the
enolate alkylation reaction that has strong precedent in
epoxidation and epoxide-opening reactions, in which the
enantioselectivity results from nucleophilic addition to a
metal-bound electrophile located within the chiral salen
framework.[26]
In conclusion, we have identified a system for the catalytic
asymmetric alkylation of acyclic tetrasubstituted tin enolates
to generate a-carbonyl quaternary stereocenters. We are able
to use tin enolates prepared as their thermodynamic E and
Z mixtures under the alkylation conditions and obtain high
yields and good enantioselectivities with a variety of sp3-
hybridized electrophiles. Catalysis likely proceeds by gener-
ation of a tin ate species from the [Cr(salen)X] catalyst,
perhaps with concomitant activation of the alkyl halide by the
cationic chromium complex generated in situ. Alkyl halide
activation is unprecedented in alkylation catalysis, and future
studies will be necessary to ascertain the validity of this
proposal.
Received: December 4, 2006
Revised: January 1, 2007
Published online: April 3, 2007
Keywords: alkylation · asymmetric catalysis · chromium ·
.
enolates · N,O ligands
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[3] For a-allylation of enolates, see: a) T. Hayashi in Catalytic
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[4] For the a-alkylation reaction of enolates, see: a) U.-H. Dolling,
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Experimental Section
3-Ethyl-3-methyl-hex-5-en-2-one (3a): A Schlenk flask (10 mL) was
flame dried under vacuum, cooled to 238C, and charged with the
catalyst (R,R)-1e (23.7 mg, 0.0025 mmol, 5 mol%) under nitrogen.
The flask was evacuated for 10 min and then flushed with nitrogen.
Then o-xylene (500 mL) and allyl iodide (91 mL, 1 mmol, 2 equiv)
were added by syringe. The solution was stirred at À278C under
nitrogen in an immersion cooler for 10 min. A solution of tin enolate
(195 mg, 0.5 mmol, 1 equiv) and tributyltin methoxide (7 mL,
0.025 mmol, 5 mol%) in o-xylene (0.75 mL) was prepared in a
flame-dried 2-dram vial. The solution was cooled to À278C in an
acetone/dry-ice bath with vigorous stirring under nitrogen for 5 min
and was then added in one portion by syringe to the Schlenk flask.
The rubber septum on the Schlenk flask was exchanged for a greased
glass stopper, the nitrogen inlet was sealed shut, and the reaction was
stirred at À278C for 48h. The reaction was diluted with pentane
(2 mL) and transferred into a disposable test tube (durex borosilicate
glass, 18” 150 mm), which contained saturated NaCl solution
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h) T. Ooi, T. Miki, M. Taniguchi, M. Shiraishi, M. Takeuchi, K.
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[16] The absolute configuration of 4a was assigned by hydrogenation
to 2-ethyl-2-methylpentanoic acid and by comparison of its
optical rotation to literature values, see reference [10f] and also:
a) W. v. E. Doering, K. B. Wiberg, J. Am. Chem. Soc. 1950, 72,
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3789 – 3794; c) F. S. Prout, B. Burachinsky, W. T. Brannen, H. L.
Young, J. Org. Chem. 1960, 25, 835 – 838. The absolute config-
urations of products 3 were inferred from this assignment.
[17] For state-of-the-art preparations of 4a and 4b, see: a) H. Leuser,
S. Perrone, F. Liron, F. F. Kneisel, P. Knochel, Angew. Chem.
2005, 117, 4703 – 4707; Angew. Chem. Int. Ed. 2005, 44, 4627 –
4631, and references therein; also see: b) J. Wu, D. M. Mam-
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4585; c) K. E. Murphy, A. H. Hoveyda, Org. Lett. 2005, 7,
1255 – 1258.
[6] For additions of enolates to nitroolefins, see: a) T. Okino, Y.
Hoashi, T. Furukawa, X. Xu, Y. Takemoto, J. Am. Chem. Soc.
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Guo, B. M. Foxman, L. Deng, Angew. Chem. 2005, 117, 107 –
110; Angew. Chem. Int. Ed. 2005, 44, 105 – 108; for additions of
enolates to vinyl sulfones, see: c) T.-Y. Liu, J. Long, B.-J. Li, L.
Jiang, R. Li, Y. Wu, L.-S. Ding, Y.-C. Chen, Org. Biomol. Chem.
2006, 4, 2097 – 2099.
[7] For acylation reactions of enolates, see: a) A. H. Mermerian,
G. C. Fu, J. Am. Chem. Soc. 2003, 125, 4050 – 4051.
[18] Efforts to ascertain if the E/Z ratio of 2a changed over the
1
[8] For Mannich reactions, see: a) A. Ting, S. Lou, S. E. Schaus, Org.
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A. Kjærsgaard, K. Juhl, N. Gathergood, K. A. Jørgensen, Chem.
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[9] For the synthesis of tetrasubstituted tributyltin ketone enolates,
see: a) F. GuibØz, Y. T. Xian, A. N. Zigna, G. Balavoine,
Tetrahedron Lett. 1985, 26, 3559 – 3562; for the synthesis of
tetrasubstituted silyl enol ethers from ketenes, see: b) R. Hꢀner,
T. Laube, D. Seebach, J. Am. Chem. Soc. 1985, 107, 5396 – 5403;
for purification by distillation using a spinning-band column,
see: c) S. Yamago, D. Machii, E. Nakamura, J. Org. Chem. 1991,
56, 2098– 2106.
[10] For successful diastereoselective examples, see: a) D. Enders, A.
Zamponi, T. Schꢀfer, C. Nꢁbling, H. Eichenauer, A. S. Demir, G.
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f) A. H. Mermerian, G. C. Fu, J. Am. Chem. Soc. 2005, 127,
5604 – 5607.
course of the reaction by H and 13C NMR spectroscopy have
been inconclusive.
[19] For observations of reactions of E and Z enolates that react with
2- to 8-fold differences in rate, see: a) D. A. Evans, J. V. Nelson,
E. Vogel, T. R. Taber, J. Am. Chem. Soc. 1981, 103, 3099 – 3111;
b) J. E. Dubois, P. Felmann, Tetrahedron Lett. 1975, 16, 1225 –
1228. Assuming that the isomeric mixture of the tin enolates
undergo alkylation with identical enantioselectivity, a maximum
9-fold difference in rate is necessary to explain the observed
levels of enantioselectivity for the alkylation of a 1.5:1 mixture
of E/Z tin enolates.
[20] The possibility of a [(salen)Cr(enolate)] intermediate finds
indirect precedent in mechanistic studies on the {(salen)Co}-
catalyzed phenolic kinetic resolution (PKR) of epoxides, in
which [(salen)Co(phenoxide)] intermediates are strongly impli-
cated; see: J. M. Ready, E. N. Jacobsen, J. Am. Chem. Soc. 1999,
121, 6086 – 6087.
[21] A dual-activation mechanism in which the cooperative bimet-
allic step is not rate limiting cannot be ruled out.
[22] a) M. Yasuda, Y. Katoh, I. Shibata, A. Baba, H. Matsuda, N.
Sonoda, J. Org. Chem. 1994, 59, 4386 – 4392; b) M. Yasuda, K.
Hayashi, Y. Katoh, I. Shibata, A. Baba, J. Am. Chem. Soc. 1998,
120, 715 – 721; c) M. Yasuda, S. Tsuji, Y. Shigeyoshi, A. Baba, J.
Am. Chem. Soc. 2002, 124, 7440 – 7447.
[23] The ability of [(salen)CrX] complexes to effect halide addition to
epoxides has been established; see: K. B. Hansen, J. L. Leighton,
E. N. Jacobsen, J. Am. Chem. Soc. 1996, 118, 10924 – 10925.
[24] See references [22a] and [22b].
[25] For examples, see: R. J. Kulawiec, J. W. Faller, R. H. Crabtree,
Organometallics 1990, 9, 745 – 755, and references therein.
[26] For reviews, see: a) E. N. Jacobsen, M. H. Wu in Comprehensive
Asymmetric Catalysis, Vol. 3 (Eds.: E. N. Jacobsen, A. Pfaltz, H.
Yamamoto), Springer, Berlin, 1999, chap. 35; b) E. N. Jacobsen,
M. H. Wu in Comprehensive Asymmetric Catalysis, Vol. 2 (Eds.:
E. N. Jacobsen, A. Pfaltz, H. Yamamoto), Springer, Berlin, 1999,
chap. 18.2.
[11] A. G. Doyle, E. N. Jacobsen, J. Am. Chem. Soc. 2005, 127, 62 –
63.
[12] K. Kobayashi, M. Kawanisi, T. Hitomi, S. Kozima, Chem. Lett.
1984, 497 – 500.
[13] See the Supporting Information for details.
[14] The para-siloxy salen ligands were prepared in three steps and in
high overall yield (70–80%) from the commercially available
tert-butylhydroquinone; see the Supporting Information for
details.
[15] Treatment of the [(salen)CrCl] complex 1b with NaI at room
temperature resulted in the quantitative exchange of the
counterion; see the Supporting Information for details
Angew. Chem. Int. Ed. 2007, 46, 3701 –3705
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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