Full text of DOI:10.1002/anie.200802158

Communications
DOI: 10.1002/anie.200802158
Asymmetric Synthesis
Configurational Control of Benzyl Carbanion–Copper Complexes by
Sulfinyl Groups: Synthesis of Optically Pure Allenes with Central and
Axial Chirality**
JosØ Luis García Ruano,* Vanesa Marcos, and JosØ Alemµn
Allenes are unique compounds that exhibit axial chirality,[1]
and they are present in a large number of medicinal and
natural products.[2] One of the most used methods for the
synthesis of optically pure allenes is based on the addition of
organocopper reagents to optically pure propargylic deriva-
tives (Scheme 1a),[3] in which almost complete stereoselec-
configurationally stable carbanion–copper complexes in these
reactions despite the interest in the resulting allenes, which
bear a chiral carbon center connected to the allenic system
and exhibit central and axial chirality, for studies of asym-
metric synthesis (Scheme 1b).[5]
During the course of our studies on the reactivity of the
lithium-chelated 2-p-tolylsulfinylbenzyl carbanions, we found
that the sulfinyl group, which is attached to the lithium ion,
can control the configuration of the benzylic carbon center.
This reagent reacts with electrophiles such as carbonyl
compounds,[6] N-sulfinylimines,[7] N-arylimines,[8] alkylating
reagents,[9] and other reagents[10] to form of C(sp ) C(sp )
bonds connecting two chiral centers. These results prompted
us to check the ability of the sulfinyl group to control the
configuration of benzyl carbanion–copper complex by inves-
tigating the reaction of the 2-p-tolylsulfinylbenzyl carbanion–
copper species with racemic propargylic derivatives. This
approach could provide a new entry into the synthesis of
allenes having chiral carbon centers directly attached to the
3
3
À
3
2
À
allenic moieties (C(sp ) C(sp ) bond). The results obtained
are reported herein.
Scheme 1. Different approaches for asymmetric syntheses of allenes:
a) classical approach, b) present work. LG=leaving group.
After trying different copper sources and reaction con-
ditions, we found that the best transmetalation conditions
involved the addition of CuCN/LiCl (2.5 equiv) in THF at
À108C to the optically pure lithium-chelated 2-p-tolylsulfi-
nylbenzyl carbanion ([Li]–1a) at À788C (Scheme 2). Under
these conditions, [Cu]–1a reacts with propargyl bromide (2a)
in a regioselective way to exclusively afford allene 4 in 92%
yield by an SN2’ process. A similar result was obtained by
using the corresponding propargyl mesylate (2b) instead of
bromide 2a as the starting material. The reaction of the [Li]–
1a with 2a at À788C yields the alkyne 3 in 90% yield, through
an SN2 process.
tivity is observed. The main limitation in the syntheses of
these chiral allenes is the availability of the optically pure
propargylic alcohols.[4] In this sense, the search for chiral
organocopper reagents for the kinetic resolution of racemic
propargylic esters is highly desirable. The use of optically pure
organocopper reagents having
a chiral center directly
attached to the metal should presumably provide an efficient
method for the kinetic resolution of racemic propargylic
esters. The efficiency of this resolution is expected to be
higher when the chiral elements involved in the asymmetric
induction are close in proximity. To the best of our knowledge,
there are no reports concerning the preparation and use of
[*] Prof. Dr. J. L. García Ruano, V. Marcos, Dr. J. Alemµn
Departamento de Química Orgµnica (C-I)
Universidad Autónoma de Madrid
Cantoblanco, 28049 Madrid (Spain)
Fax: (+34)91-497-466
E-mail: joseluis.garcia.ruano@uam.es
[**] Financial support of this work by the Ministerio de Educación y
Ciencia (CTQ2006-06741/BQU) is gratefully acknowledged. V.M.
thanks Ministerio de Educación y Ciencia for a predoctoral fellow-
ship.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200802158.
Scheme 2. SN2 versus SN2’ selectivity with lithium- and copper-chelated
benzyl carbanions.
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Chemie
Table 1: Reactions of 1b–1d with propargylic derivatives 2a–2e.[a]
Reactions of [Cu]–1a with C3-substituted propargylic
systems 2c–2e under similar conditions to afford 1,1-disub-
stituted allenes 5–7 with complete regioselectivity and in good
yields (Scheme 3). The reaction was performed on a larger
scale (up to 5.0 mmol) without loss in yield or selectivity.
Entry Reagent (R1)
Electrophile
(R2/LG)
Product Yield [%][b]
d.r.[c]
1
2
3
4
5
6
7
8
[Cu]–1b (Me) 2a (H/Br)
[Cu]–1b (Me) 2a (H/OMs)
[Cu]–1b (Me) 2c (Me/Br)
8
8
9
76
72
51
69
40[d]
68
64
75
94:6
94:6
88:12
>98:<2
>98:<2
>98:<2
85:15
[Cu]–1b (Me) 2e (Ph/OMs) 10
[Cu]–1c (Bn) 2a (H/Br)
[Cu]–1c (Bn) 2c (Me/Br)
[Cu]–1d (allyl) 2a (H/Br)
[Cu]–1d (allyl) 2c (Me/Br)
11
12
13
14
Scheme 3. Reactions of C3-substituted propargylic systems.
95:5
[a] All reactions were performed in a 0.2 mmol scale. LG=leaving group.
[b] Yield of isolated product as mixture of stereoisomers. [c] Determined
by 1H NMR spectroscopy of the crude mixture. [d] Conversion measured
by 1H NMR spectroscopy, in which allene 11 was inseparable from
sulfoxide 1c.
We then studied reactions of the prochiral benzyl
carbanion–copper complex, derived from 2-p-tolylsulfinyl
ethylbenzene (1b), with propargyl derivatives. Reaction of
[Cu]–1b with 2a is completely regioselective, giving the
SN2’ products as a 94:6 mixture of diastereoisomers 8 and 8’,
which are epimeric at the benzylic position (Table 1, entry 1).
Identical results were obtained by using the propargyl
mesylate (2b), which indicated the lack of influence of the
leaving group on the stereoselective control (Table 2,
entry 2). After confirming that the sulfinyl group was efficient
in controlling the configuration at the benzylic position, we
studied the scope of this reaction with respect to 2. Accessing
different 1,1-disubstituted allenes, having a chiral center
connected to the allenic system, is important in for the
asymmetric syntheses of allenes. Reaction of 1b with 2c
afforded an 88:12 mixture of 9 and 9’ (Table 1, entry 3).
Interestingly, the reaction of 1b with 2e was completely
stereoselective, yielding 10 with a de value greater than 96%
(Table 1, entry 4). Complete stereoselective control was also
achieved in reactions of 1c with 2a and 2c, which afforded 11
and 12, respectively, as single diastereoisomers (Table 1,
entries 5 and 6). Reactions of allyl derivative [Cu]–1d with
propargylic bromides 2a and 2c gave the corresponding 1,2,6-
trienes 13 and 14, respectively, with good diastereomeric
ratios and high yields (Table 1, entries 7 and 8). These results
indicate that the configurational con-
(Scheme 4). The axial chirality of the products was assigned
by assuming the predominance of the anti attack observed in
most of the reactions of the anion–copper reactant with the
propargylic esters.[3] The reaction of [Cu]–1b with (R)-2 f
under mild conditions (À788C) almost instantaneously
afforded a 95:5 mixture of diastereoisomers 16 and 16’ in
88% yield (Scheme 4). This result provides evidence that
control of one of the two chiral elements (carbon center or
axis) can be achieved efficiently. On the basis of the complete
anti stereoselectivity observed in the reactions of [Cu]–1a, we
initially assumed that 16 and 16’ were epimers at the benzylic
position; this was additionally confirmed (see analysis for 17
below). Reaction of [Cu]–1b with (S)-2 f also gave a 95:5
mixture of 16 and 16’, however, the reaction times were longer
and the yield was much lower (18%) than those obtained
from (R)-2 f. Unreacted (S)-2 f was recovered as a mixture of
enantiomers. These results suggested that reaction of [Cu]–1b
with (S)-2 f did not take place and that mesylate 2 f was
racemized under the reaction conditions.[11]
trol of benzyl carbanion–copper species
can be achieved by having the 2-p-
tolylsulfinyl group act as a remote
chiral inducer.
Finally, we investigated the synthe-
sis of allenes having axial chirality. We
synthesized optically pure mesylates
(R)-2 f and (S)-2 f, derived from 4-
phenyl-3-butyn-2-ol by an enzymatic
resolution of the racemic alcohol.[4b]
The reactions of [Cu]–1a with (S)-2 f
and (R)-2 f are completely stereoselec-
tive and afford optically pure (SS, aS)-
15’ and (SS, aR)-15, respectfully; the
yields of the isolated products were
73%
and
76%,
respectively
Scheme 4. Asymmetric syntheses of allenes with axial chirality.
Angew. Chem. Int. Ed. 2008, 47, 6836 –6839
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6837

Communications
As expected, the reaction of [Cu]–1b with (rac)-2 f also
In summary, we have demonstrated that the reactions of
optically pure 2-p-tolylsulfinylbenzyl carbanion–copper
reagents with propargyl bromides and mesylates take place
in a completely regioselective way by a SN2’ process with
complete anti stereoselectivity in the formation of a chiral
axis. The sulfinyl group is very efficient in controlling the
configuration of the a-alkylbenzyl carbanion–copper reagent,
thus providing the first method to obtain optically pure
allenes having a chiral center directly attached to the allenic
system, which can also have a defined configuration of its
chiral axis. Additionally, complete kinetic resolution of
racemic propargylic mesylates can be achieved with sulfiny-
lated a-alkylbenzyl carbanion–copper reagents, which in turn
are moderately efficient for the dynamic kinetic resolution of
the mesylates. Additional studies for establishing the mech-
anism of these reactions are in progress and will be reported
at a later date.
gave a 95:5 mixture of 16 and 16’ (58%), as well as unreacted
1b (33%) and an alcohol resulting from the hydrolysis of
(rac)-2 f (42%), which can be reused in additional reactions
(Table 2, entry 1). A complete kinetic resolution and a
deficient dynamic kinetic resolution can be observed in this
reaction, and the main advantage derives from the lack of
reactivity of the S enantiomer. The synthesis of allenes with
axial and central chirality in high optical purity can be carried
out starting from racemic propargyl derivatives, thus avoiding
the tedious synthesis of optically pure propargylic alcohols.
Table 2: Reactions of 1b with racemic propargylic derivatives.[a]
Received: May 8, 2008
Published online: July 25, 2008
Entry
Electrophile (R1/R2)
Product
Yield [%][b]
d.r.[c]
1
2
3
4
5
2 f (Me/Ph)
2g (H/Me)
2h (Me/p-BrPh)
2i (Me/nBu)
2j (Et/Ph)
16
17
18
19
20
58
53
56
53
56
95:5[d]
90:10
85:15
93:7[d]
96:4[d]
Keywords: allenes · chirality · copper · sulfinyl groups ·
synthetic methods
.
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Chemie
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Angew. Chem. Int. Ed. 2008, 47, 6836 –6839
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