Enantiodivergent deprotonation/acylation of α-amino nitriles

Article abstract of DOI:10.1002/anie.201306443

Back to 'base'ics: The title reaction of enantioenriched α-ureidonitriles was found to proceed in a highly enantiodivergent manner despite the intermediacy of stereolabile α-nitrile metallocarbanions. Enantiodivergence is dependent upon the base used. For the less basic hexamethyldisilazides (HMDS), deprotonation in which a metal (M) cation is precomplexed with an electrophile is proposed. LDA=lithium diisopropylamide. Copyright

Full text of DOI:10.1002/anie.201306443

.
Angewandte
Communications
DOI: 10.1002/anie.201306443
Carbanions
Enantiodivergent Deprotonation/Acylation of a-Amino Nitriles**
Michiko Sasaki, Tomo Takegawa, Kunihiro Sakamoto, Yuri Kotomori, Yuko Otani,*
Tomohiko Ohwada, Masatoshi Kawahata, Kentaro Yamaguchi, and Kei Takeda*
Although a-nitrile carbanions are outstanding nucleophiles
for carbon–carbon bond formation because of their powerful
nucleophilic character resulting from the small steric
demand,[1] the difficulties that have been associated with
their generation in an enantioselective manner have pre-
sented serious limitations to their usage in asymmetric
synthesis. A recent publication[2] from our laboratory has
shown that enantioselective in situ trapping of extremely
stereolabile[3,4] chiral a-oxycarbanions of acyclic nitriles is
possible at a practically promising level by taking advantage
of the powerful chelating ability of an O-carbamoyl group[5]
for configurational stabilization of a carbanion, where no
chiral elements other than a preexisting stereogenic center
are present (Scheme 1). Coldham and co-workers successfully
extended this approach to magnesiated nitriles.[6] Herein, we
report an enantiodivergent trapping of a chiral a-carbanion
generated from a-amino nitrile derivatives, in which the
stereogenecity of a single enantiomer can be used to produce
both enantiomers.
Our continuing studies in this area aim to further improve
and generalize the methodology through the design of even
more efficient fixation of a lithiocarbanion, and the use of
more readily available enantioenriched substrates. We
focused on enantioselective trapping of a chiral a-nitrile
carbanion adjacent to an a-ureido group, which would have
a more powerful fixing ability for a carbanion than an a-
carbamoyloxy group,[7,8] particularly on the basis of analogy
with N,N’-dimethylpropyleneurea.[9] Although a number of
reports concerning enantioselective carbamate- or ureido-
directed lithiation and substitution of carbanions adjacent to
a nitrogen atom have appeared in the literature,[10,11] most of
them have been limited to carbanions such as allylic and
benzylic systems, which are much more configurationally
stable than an a-nitrile carbanion, and to the processes using
a chiral auxiliary or a chiral ligand such as (À)-sparteine.[12]
For an enantioselective trapping of a-amino carbanions
adjacent to a conjugative electron-withdrawing group, it has
been reported that azyridynyllithiums a to an ester carbonyl
group are configurationally stable enough to undergo electro-
philic quenching with no loss of enantiomeric purity,[13,14] and
is explained in terms of enhanced angle strain in the transition
state of the inversion. For a-amino acid esters or cyclic
amides, Kawabata,[15] Carlier[16] and others have proposed the
concept of memory of chirality or self-regeneration of
stereocenters via stereolabile axially chiral intermediates,[17]
which allow for the enantioselective introduction of an
electrophile at an enolizable chiral center next to carbonyl
functions. However, such ideas would not be applicable to a-
nitrile carbanions, which probably cannot generate axially
chiral intermediates because of the linear nature of a keteni-
minate.[18]
We chose the N-carbamoyl a-amino nitrile (S)-4, which is
readily derived from l-phenylalanine (see the Supporting
Information), and investigated its enantioselective deproto-
nation/substitution reaction.[19] The optimized reaction con-
ditions[2] found for the carbamoyloxy derivative (S)-1 were
applied to (S)-4 and resulted in the formation of the acylated
product 6a in poor yield and with moderate enantioselectivity
(Table 1, entry 1) together with the recovery of a significant
amount of the starting material and no loss of enantiomeric
purity. This result was attributable to consumption of LDA
through reaction with ethyl cyanoformate, probably because
of lower reactivity of (S)-4 relative to (S)-1 toward deproto-
nation,[2] therefore less reactive electrophiles were examined.
Whereas reaction with ethyl chloroformate gave 6a in 83%
yield and in racemic form, the use of benzoyl chloride
improved both the yield and enantioselectivity to give 6b
(Table 1, entries 2 and 3). An X-ray analysis of a derivative of
Scheme 1. In situ deprotonation/acylation of (S)-1. LDA=lithium dii-
sopropylamide, THF=tetrahydrofuran.
[*] Dr. M. Sasaki, T. Takegawa, K. Sakamoto, Y. Kotomori,
Prof. Dr. K. Takeda
Graduate School of Medical Sciences, Hiroshima University
1-2-3 Kasumi, Minami-Ku, Hiroshima 734-8553 (Japan)
E-mail: takedak@hiroshima-u.ac.jp
Homepage: http://home.hiroshima-u.ac.jp/takedake/index-e.html
Dr. Y. Otani, Prof. Dr. T. Ohwada
Graduate School of Pharmaceutical Sciences
The University of Tokyo
7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
E-mail: otani@mol.f.u-tokyo.ac.jp
Dr. M. Kawahata, Prof. Dr. K. Yamaguchi
Pharmaceutical Sciences at Kagawa Campus
Tokushima Bunri University, Kagawa 769-2193 (Japan)
[**] This research was partially supported by a Grant-in-Aid for Scientific
Research (B) 22390001 (K.T), a Grant-in-Aid for Challenging
Exploratory Research 2365900700 (K.T.), a Grant-in-Aid for Young
Scientists (B) 22790011 (M.S.), and a Grant-in-Aid for Scientific
Research (C) 254600150 A (M.S.) from the Ministry of Education,
Culture, Sports, Science and Technology (MEXT), as well as the
Hoan Sha Foundation (M.S.), the Hayashi Memorial Foundation for
Female Natural Scientists (M.S.), and the Takeda Science Founda-
tion (M.S.). We thank the staff of the Natural Science Center for
Basic Research and Development (N-BARD), Hiroshima University
for the use of their facilities. The computations were performed at
the Research Center for Computational Science, Okazaki (Japan).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201306443.
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Chemie
Table 1: In situ deprotonation/electrophilic trapping of (S)-4 with LDA.
Although it may be considered that the structural differ-
ence between lithio- and sodiocarbanions plays a crucial role
in determining the enantioselectivity,[21] the fact that LDA
and LiHMDS lead to the opposite enantioselectivity suggests
the possibility that the deprotonation step as well as the
electrophilic quenching step is associated with determining
the enantioselectivity.[22]
Entry Electrophile
6
6a,b
4
Yield [%][a] e.r.
Yield [%][a]
e.r.
For the enantiodivergence observed, depending on the
base used, we propose the following stereochemical hypoth-
esis, taking into account the fact that the deprotonation is
carried out in the presence of benzoyl chloride. In the LDA-
induced reactions, the preferred attack of benzoyl chloride
can occur from the less-hindered and uncoordinated rear face
of a ureido-chelated lithiocarbanion intermediate as sug-
gested by Hoppe and co-workers for the corresponding O-
benzyl carbamates,[23] in which electron density significantly
increases because of the much more conjugated nature of an
a-nitrile carbanion relative to that of a benzyl carbanion, to
give an inversion product. For hexamethyldisilazide-induced
reactions, deprotonative metalation is conducted by a base in
which a metal cation is precomplexed[24] with two carbonyl
groups of a ureido group and benzoyl chloride, and a cyano
group, probably because of the less basic nature of a hexam-
ethyldisilazide than that of diisopropylamide.[25] Precomplex-
ation with benzoyl chloride in the transition state of
deprotonation would enhance the basicity and bring the
electrophilic center near the metalocarbanion, thus resulting
in retention of stereochemistry.
1
2
3
NCCO2Et
ClCO2Et
PhC(O)Cl
6a 25
6a 83
6b 79
79:21 72
100:0
–
–
51:49
91:9
0
0
[a] Yield is that of isolated product.
6b indicated that the substitution occurs with inversion of
configuration, which is the same as the case of (S)-1.
The different behaviors toward an electrophile led us to
examine variables of the reaction including temperature,
solvent, and additives by using benzoyl chloride as an
electrophile. Although Et2O could not be used because of
the poor solubility of (S)-4, the use of THF at À1008C gave
better enantioselectivity and addition of HMPA did not
significantly lower the enantioselectivity (Table 2, entries 1–
5). Since it is well documented that a metal cation can control
the geometry of metalated nitriles,[20] effects of the base and
Table 2: In situ deprotonation/benzoylation of (S)-4 by amide bases.
In fact, treatment of (S)-4 with LiHMDS in THF at À1008
and À908C for 10 minutes in the absence of benzoyl chloride
resulted in recovery of 4 with e.r. = 99:1 and e.r. = 90:10,
respectively, thus indicating that, correspondingly, only 2%
and 20% of the substrate were deprotonated under the
reaction conditions (see Table 2, entries 7 and 8).[26] Conse-
quently, the rate of deprotonation can be enhanced by the
presence of benzoyl chloride. This result prompted us to test
this hypothesis by conducting reactions using other aroyl
chlorides whose carbonyl group may have potentially differ-
ent abilities to complex a metal cation and different reactivity
toward a metalocarbanion, and may thus cause changes in the
e.r. values. The results are shown in Table 3.
Entry
Base
X
Solvent
Yield [%][a]
e.r.[b]
1
2
3
4
5
6
7
8
9
10
LDA
LDA
LDA
LDA
3
3
3
3
3
5
5
5
5
5
THF/Et2O (2:1)
Et2O
77
–
92:8
–
THF
81
85
39
82
14[e]
29[f]
95
88
96:4
95:5
92:8
92:8
13:87
25:75
3:97
3:97
THF[c]
THF[d]
THF
LDA
LiTMP
LiHMDS
LiHMDS
NaHMDS
KHMDS
THF
THF
THF
THF
[a] Yield is that of isolated product. [b] (R)-6/(S)-6. Determined by HPLC
on a chiral stationary phase. [c] Added 4 equiv of HMPA. [d] Added
10 equiv of HMPA. [e] Recovered 73% of the starting material with no
loss of enantiopurity. [f] Reaction was carried out at À908C for 10 min
and 66% of the starting material was recovered with no loss of
enantiopurity. HMDS=hexamethyldisilazide, TMP=tetramethylpiperi-
dine.
Table 3: In situ deprotonation/quenching by aroyl chlorides.
Entry
Base
X
Ar
6
Yield [%][a]
e.r.[b]
counter cation on the enantioselectivity were examined. The
most striking feature is enantiodivergence: hexamethyldisi-
lazide bases dramatically changed the stereochemical out-
come of substitution from inversion to retention to give the
enantiomeric product (S)-6b (Table 2, entries 7–10), for
which the best chemical and enantiomeric yields were
obtained with NaHMDS. The same trend was also observed
for the carbamoyloxy derivative (S)-1, albeit in much lower
enantioselectivity [LDA: 86% (60:40); NaHMDS: 92%
(46:54)].
1
2
3
4
5
6
7
8
LDA
LDA
LDA
LDA
NaHMDS
NaHMDS
NaHMDS
NaHMDS
3
3
3
3
5
5
5
5
4-MeOC6H4
4-NO2C6H4
2-FC6H4
6c
6d
6e
6 f
6c
6d
6e
6 f
83
–
84
69
90
–
81:19
–
94:6
93:7
5:95
–
2-ClC6H4
4-MeOC6H4
4-NO2C6H4
2-FC6H4
91
90
3:97
2:98
2-ClC6H4
[a] Yield is that of isolated product. [b] (R)-6/(S)-6. Determined by HPLC
on a chiral stationary phase.
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In the case of LDA, the use of 4-methoxybenzoyl chloride,
which forms a strong complex but has low electrophilicity,
resulted in decreased enantioselectivity (Table 3, entry 1).
However, for NaHMDS, which requires complexation for
deprotonation, the reaction led to almost the same enantio-
selectivity as that with benzoyl chloride (Table 3, entry 5). In
the case of 4-nitrobenzoyl chloride, unfortunately the reac-
tions with both the bases resulted in recovery of the starting
material (Table 3, entries 2 and 6), presumably
as a consequence of consumption of 4-nitro-
benzoyl chloride by reaction with the base.
Anticipating an increase in an inversion prod-
uct with NaHMDS because of its reduced
ability to form a complex, we attempted
reactions with 2-fluoro- and 2-chloro deriva-
tives and they afforded almost the same
enantioselectivity (Table 3, entries 3, 4, 7, and
8), probably because the enhanced reactivity
of the 2-halognated derivatives toward an
anionic species compensates for the reduced
ability to complex a sodium cation. The results,
however, show the generality of the enantio-
divergent process that is dependent upon
a base.
role in determining the enantioselectivity. The results with
LDA are consistent with the general trend that attack on
carbon electrophiles by a relatively stable lithiocarbanion can
occur from the less-hindered and uncoordinated backside of
the molecule in which the electron density increases because
of the partially flattened nature of the carbanion.[23] This
behavior is not the case with LiHMDS, which despite having
the same counter cation shows an energetic profile similar to
Since, to the best of our knowledge, there is
no literature precedent for intermolecular
electrophile-assisted deprotonation,[24] ener-
getics for deprotonation were examined
using a-(trimethylureido)propiononitrile (7;
Scheme 2) as a model compound (DFT at the
B3PW91/6-311 ++ G(d,p) level) to estimate
the possibilities of the participation of benzoyl
chlorides in the transition-state structures of
the deprotonation step by forming a precom-
plex with the metal cation of hexamethyldisi-
lazide. It was found that in the case of
NaHMDS, the benzoyl-chloride-assisted tran-
sition-structure 7-TS-Na is 1.7 kcalmolÀ1 more
favorable than a nonassisted one, thus leading
to the intermediate 7-I-Na (DHrel = À1.7 kcal
molÀ1), which is 5.1 kcalmolÀ1 more favorable
than an intermediate not involving benzoyl
chloride (DHrel =+ 3.4 kcalmolÀ1). In contrast,
in the case of LDA, both a PhCOCl-assisted
deprotonation leading to the transition-struc-
ture 7-TS-LDA and a non-assisted deprotona-
tion leading to the transition structure 7’-TS-
LDA were found to be much less endothermic
than those of the sodium counterpart. These
deprotonation processes generated thermody-
namically stable intermediates, 7-I-LDA and
7’-I-LDA (À12.3 and À13.1 kcalmolÀ1), which
have about the same relative energy. It should
also be noted that the carbanion species in 7’-I-
LDA is almost planarized and the pyramidal-
ization angle is 208. Consequently, it is reason-
able to assume that in LDA-induced deproto-
Scheme 2. DFT optimized structures for PhCOCl-assisted deprotonation of 7 and for
formation of metalated anions by NaHMDS, LDA, and LiHMDS and their relative
nation/acylation, a precomplexed base with
benzoyl chloride does not play an important energies in simulated THF. Selected bond lengths [ꢀ].
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Chemie
Gao, P. R. Carlier, Chem. Eur. J. 2011, 17, 12250 – 12253; f) also
see ref. [3].
that obtained with NaHMDS. Thus, a PhCOCl-assisted
deprotonation to generate the transition structure 7-TS-
LiHMDS is 3.0 kcalmolÀ1 more favorable than a nonassisted
one, and the relative energy of the lithio anion intermediate 7-
I-LiHMDS is much higher than that of the corresponding
intermediate generated by LDA (7-I-LDA), and even higher
than that obtained by NaHMDS. This data is consistent with
the experimental observation that the LiHMDS procedure is
a rather low-yielding process. Although further detailed
theoretical and structural investigations are required before
definitive conclusions can be drawn, the present computa-
tional studies along with our experimental work provide
support for the proposed hypothesis.
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In conclusion, we have demonstrated that the deprotona-
tion/benzoylation of a-ureidonitriles proceeds in a highly
enantiodivergent manner, depending on the base used, to give
both enantiomers of a benzoylated product in the absence of
any further chiral elements. Based on the reactions using
benzoyl halides which bear electronically different substitu-
ents and based on DFT calculations, a stereochemical ration-
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precomplexation to the countercation of the base used in
deprotonation, for the enantiodivergence was proposed.
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Experimental Section
General procedure for acylation of (S)-4: Reaction of (S)-4 with LDA
and benzoylchloride: A solution of LDA (1.2m in THF, 433 mL,
0.51 mmol) was added dropwise over a period of 2 min to a cooled
(À1008C) solution of (S)-4 (40 mg, 0.17 mmol) and benzoyl chloride
(60 mL, 0.51 mmol) in THF (2.97 mL). The mixture was stirred at the
same temperature for 10 min before addition of CH3COOH (1.0m in
THF, 0.51 mL, 0.51 mmol). The mixture was diluted with H2O
(10 mL) and extracted with Et2O (10 mL ꢀ 3). The combined organic
phases were washed with saturated brine (10 mL), dried, and
concentrated. The white solid was subjected to column chromatog-
raphy (silica gel 10 g, elution with Et2O) to give (S)-6b (51 mg, 87%,
e.r. = 94:6) as a white solid.
[14] V. Alezra, M. Bonin, L. Micouin, H.-P. Husson, Tetrahedron Lett.
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Received: July 24, 2013
Revised: September 3, 2013
Published online: October 9, 2013
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Keywords: asymmetric synthesis · carbanions · cyanides ·
lithium · metalation
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[22] Kawabata et al. reported enantiodivergent intramolecular alky-
lation of N-Boc-N-w-bromoalkyl-a-amino esters by memory of
chirality, in which the enantiodivergent outcome depends on
whether deprotonation is carried out with KHMDS in DMF or
LiTMP in THF. They rationalize the enantiodivergent outcome
by invoking a different chelation ability of lithium ion and
potassium ion to a carbonyl oxygen atom in deprotonative
transition structures. T. Kawabata, S. Matsuda, S. Kawakami, D.
Monguchi, K. Moriyama, J. Am. Chem. Soc. 2006, 128, 15394 –
15395. Also, see ref. [17b].
[26] We assume that (S)-4 immediately racemizes after deprotona-
tion unless an electrophile exists. This assumption is based on the
fact that deprotonation by LDA or NaHMDS over a 2 min
period at À1008C, followed by proton quenching by precooled
AcOH in THF led to recovery of completely racemized starting
material.
[23] a) A. Carstens, D. Hoppe, Tetrahedron 1994, 50, 6097 – 6108;
b) D. Hoppe, D. F. Marr, M. Brꢃggemann in Organolithiums in
Enantioselective Synthesis (Eds. D. M. Hodgson) Springer: New
York, 2003, pp. 61 – 137; c) H. Ikemoto, M. Sasaki, M. Kawahata,
K. Yamaguchi, K. Takeda, Eur. J. Org. Chem. 2011, 6553 – 6557.
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