Asymmetric α-arylation of amino acid derivatives by clayden rearrangement of ester enolates via memory of chirality

Article abstract of DOI:10.1021/ja406653n

A method for asymmetric α-arylation of amino acid derivatives has been developed. The arylation was performed by Clayden rearrangement of ester enolates via memory of chirality to give hydantoins with an aryl-substituted tetrasubstituted carbon with up to 99% ee.

Full text of DOI:10.1021/ja406653n

Communication
pubs.acs.org/JACS
Asymmetric α‑Arylation of Amino Acid Derivatives by Clayden
Rearrangement of Ester Enolates via Memory of Chirality
Keisuke Tomohara, Tomoyuki Yoshimura, Ryuichi Hyakutake, Pan Yang, and Takeo Kawabata*
Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011, Japan
S
* Supporting Information
Scheme 2. Strategy for Asymmetric Aryl Migration of Chiral
Enolates via Memory of Chirality
ABSTRACT: A method for asymmetric α-arylation of
amino acid derivatives has been developed. The arylation
was performed by Clayden rearrangement of ester enolates
via memory of chirality to give hydantoins with an aryl-
substituted tetrasubstituted carbon with up to 99% ee.
e have developed methods for asymmetric construction
Wof α,α-disubstituted amino acid derivatives via memory of
chirality (MOC).1,2 Since the reactions take place via axially
chiral enolate intermediates with limited half-lives of racemiza-
tion, reactions of the chiral enolates with electrophiles compete
with racemization of the chiral enolates themselves. Therefore,
carefully controlled conditions are required for intermolecular
alkylation,3 conjugate addition,4 and aldol reactions,5 which must
be performed at low temperatures (−78 to −60 °C) to minimize
racemization of the intermediary chiral enolates. On the other
hand, asymmetric intramolecular reactions via MOC can be
performed at ambient or even higher temperature in the case
where the intermediary chiral enolates can react immediately
after they are generated.6 Intramolecular alkylation,6a,7 conjugate
addition,6b,c,8 and acyl migration9 have been successfully
developed. However, we have had difficulties in developing
asymmetric α-arylation of amino acid derivatives even by
employing the intramolecular protocol.10 We have now focused
on the intramolecular aryl migration process. Clayden and co-
workers reported intramolecular electrophilic arylation of
lithiated ureas.11 Aryl groups on the nitrogen of the urea moiety
were reported to migrate to the benzylic position with retention
of configuration via an ipso SNAr process (Scheme 1). This
pioneering work on anionic aryl migration prompted us to
develop an asymmetric arylation of chiral enolates derived from
amino acid esters via MOC.12−14
addition to the N-aryl group to give Meisenheimer-type complex
B. Although the conversion of enolate A to anionic species B was
expected to be difficult because the less stable (more basic)
anionic species is to be generated, upon formation B would
readily be transformed to the more stable urea anion C. To
facilitate the transformation of A into B, we initiated the study
using I with R1 = p-NO2 (2).
The preparation of urea 2 is shown in Scheme 3. Condensation
of the HCl salt of L-phenylalanine ethyl ester with p-nitrophenyl
Scheme 3. Preparation of Urea Derivative 2
isocyanate gave urea 1 in 91% yield. Introduction of a
methoxymethyl (MOM) group onto the anilinic NH group
under acidic conditions followed by introduction of the second
MOM group onto the NH group of the phenylalanine moiety
under basic conditions gave 2 in 65% yield without racemization.
According to our previous studies, the MOM group on the
nitrogen of the amino acid moiety in 2 was assumed to be critical
for the generation of the axially chiral enolate with high
enantiomeric purity.
Asymmetric migration of the enolate generated from 2 was
examined (Table 1). We previously found that a base system
[potassium hexamethyldisilazide (KHMDS) in dimethylforma-
mide/tetrahydrofuran (DMF/THF) at −60 °C] is suitable for
highly enantioselective intramolecular alkylation of chiral
The strategy for asymmetric α-arylation of amino acid
derivatives is shown in Scheme 2. Treatment of N-MOM-N-
C(O)-substituted amino acid esters I (readily prepared from
α-amino acids according to Clayden’s protocol11a) with a base
would generate axially chiral enolate A according to our
protocol.3−9 A would undergo intramolecular nucleophilic
Scheme 1. Clayden’s Anionic Aryl Migration
Received: June 30, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja406653n | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Table 1. Asymmetric Aryl Migration of Phenylalanine−Urea
Table 2. Scope of Aryl Groups in Asymmetric Aryl Migration
of Phenylalanine−Urea Derivative
a
a
Derivative 2
c
product:
b
b
entry
substrate: Ar
base, solvent
% yield (% ee)
% yield (% ee ) % yield
entry
1
base, solvent
T (°C), t (h)
−60, 0.5
of 3
of 4
d
1
2: 4-NO2C6H4
LiHMDS,
3: 68 (97)
4:1 DMF/THF
KHMDS,
3:2 DMF/THF
93 (83)
−
2
3
5: 4-CNC6H4
7: 4-BrC6H4
LiHMDS,
6: 90 (98)
8: 97 (95)
5:1 DMF/THF
2
3
4
NaHMDS,
8:1 DMF/THF
−60, 0.5
64 (93)
59 (99)
68 (97)
24
15
−
LiHMDS,
5:1 DMF/THF
LiHMDS,
4:1 DMF/THF
−60, 0.5
e
f
4
9: 4-MeOC6H4 KHMDS, 1:1 DMF/THF
10: 0 (−)
LiHMDS,
4:1 DMF/THF
−60 to 15, 0.5
5
11: 1-naphthyl
LiHMDS,
12: 47 (84)
5:1 DMF/THF
g
5
6
KHMDS, THF
−78, 0.5
−78, 0.5
−78, 0.5
0, 0.5
80 (7)
8
20
−
42
29
26
11
6
7
13: C6H5
KHMDS, 3:2 DMF/THF
KHMDS, 1:1 DMF/THF
14: 73 (55)
h
i
NaHMDS, THF
LiHMDS, THF
62 (73)
15: C6H5
16: 46 (73)
c
a
b
7
18 (−23 )
55 (−25 )
51 (−83 )
62 (−61 )
Reactions were run at a substrate concentration of 0.1 M. Both
LiHMDS and KHMDS were examined for each substrate. Only the
conditions that gave the product with the higher ee are shown.
Absolute configurations were tentatively assigned by analogy to 22,
24, and 26. The reaction was run at −60 to 15 °C. Run for 24 h.
The substrate was recovered. The substrate was recovered in 37%
c
8
KHMDS, toluene
NaHMDS, toluene
NaHMDS, toluene
LiHMDS, toluene
c
9
0, 0.5
c
c
10
11
−78, 3.5
0, 1
d
e
c
37 (−74 )
f
g
a
The reactions were run at a substrate concentration of 0.1 M under
an Ar atmosphere. Absolute configurations were tentatively assigned
by analogy to 22, 24, and 26. 3 was obtained with the absolute
h
b
yield. Substrate 15 had an N,N-diphenyl group (no N-MOM group).
i
c
The substrate was recovered in 40% yield.
configuration opposite to that in entries 1−6.
hydantoin 12 with 84% ee in 47% yield (entry 5). While
asymmetric aryl migration proceeded even in N-phenylurea
derivative 13 to give α-phenylhydantoin 14 with a moderate 55%
ee, the corresponding reaction of the N,N-diphenyl derivative 15
gave the product with an improved 73% ee (entries 6 and 7).
The asymmetric aryl migration was further examined using
various N-aryl-N-MOM-urea derivatives derived from L-valine
and L-methionine (Table 3). 4-Bromophenyl- and 4-nitrophenyl
derivatives derived from L-methionine, 17 and 19, underwent
asymmetric aryl migration with high enatioselectivity upon
treatment with LiHMDS in DMF/THF at −60 °C to give α-
arylated hydantoins 18 and 20 with 96% ee (86% yield) and 96%
ee (71% yield), respectively (entries 1 and 2). Asymmetric aryl
migration in 4-bromophenyl derivative 21 derived from L-valine
upon treatment with LiHMDS afforded hydantoin 22 with 99%
ee (25% yield) and the initial arylated product before cyclization
in 66% yield (entry 3). The corresponding reaction at higher
temperature (−60 to 20 °C) gave hydantoin 22 as the sole
product in 80% yield with 98% ee (entry 4). The use of KHMDS
instead of LiHMDS at −60 °C gave hydantoin 22 in quantitative
yield but with a moderate 56% ee (entry 5). α-Arylated
hydantoin 24 was obtained with high enantioselectivity (99%
ee) in quantitative yield upon treatment of 4-nitrophenyl
derivative 23 derived from L-valine with LiHMDS at −60 to 20
°C (entry 6). The corresponding N-phenyl derivative 25 gave α-
arylated hydantoin 26 with 61% ee in 86% yield (entry 7). The
absolute configuration of 26 was determined to be S by its
conversion and comparison with known (R)-27.16 The absolute
configuration of hydantoins 22 and 24 were also determined to
be S by their chemical correlation to (R)-27 [see the Supporting
Information (SI)]. Thus, asymmetric aryl migration in 21, 23,
and 25 was found to proceed with inversion of configuration.
The behavior of the intermediary chiral enolates toward
racemization was investigated (Scheme 4). We previously
determined the barrier to racemization of the axially chiral
enolates generated from amino acid esters.7−9 Treatment of 2
with 2.0 equiv of KHMDS in 3:2 DMF/THF at −60 °C for 0.5 h
gave hydantoin 3 as the sole product (93% yield) with 83% ee
(entry 1).
Hydantoin 3 was expected to form by intramolecular acylation
of the in situ-generated N-anion of 4. Use of NaHMDS gave 3 in
64% yield with 93% ee and 4 in 24% yield (entry 2). While the use
of LiHMDS gave 3 with a further-improved 99% ee, the yield of 3
was diminished to 59% (entry 3). Raising the temperature from
−60 to 15 °C afforded 3 as the sole product in 68% yield with
97% ee (entry 4). This indicates that the anion of 4 is the initial
product in the formation of 3. The use of THF as the solvent
resulted in a decrease in the enantioselectivity (entries 5−7). The
reactions of 2 in toluene at elevated temperature (0 °C) gave 3
with the absolute configuration opposite to that obtained by the
reactions in DMF/THF (entries 8, 9, and 11). The reaction of 2
with NaHMDS in toluene at 0 °C gave 3 with higher
enantioselectivity (83% ee) than obtained at −78 °C (61% ee)
(entry 9 vs 10). Similar solvent and temperature effects were
observed in enantiodivergent cyclization of amino acid esters via
MOC.7b,15
Asymmetric α-arylation of N-aryl-N-MOM-phenyalanine−
urea derivatives with various aryl groups was also examined
(Table 2). The reactions of urea derivatives possessing an N-aryl
group substituted with an electron-withdrawing group pro-
ceeded with high enantioselectivity (95−98% ee; entries 1−3). 4-
Cyanophenyl and 4-bromophenyl derivatives 5 and 7 gave α-
arylated hydantoins 6 and 8 with 98% ee (90% yield) and 95% ee
(97% yield), respectively (entries 2 and 3). The aryl migration
was not observed in substrate 9 with an electron-donating aryl
group (4-OMe-C6H4) (entry 4). To our surprise, anionic aryl
migration was also observed in substrates 11, 13, and 15 with
unactivated aryl groups (entries 5−7). The reaction of N-(1-
naphthyl)urea derivative 11 with LiHMDS gave α-arylated
B
dx.doi.org/10.1021/ja406653n | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
a
Table 3. Asymmetric Aryl Migration in Various Urea Derivatives Derived from L-Valine and L-Methionine
entry
substrate: R
Ar
M
T (°C), t (h)
−60, 0.5
−60, 0.5
−60, 0.5
−60 to 20, 0.5−12
−60, 0.5
product: % yield (% ee)
b
1
2
3
4
5
6
7
17: MeS(CH2)2
19: MeS(CH2)2
21: i-Pr
4-BrC6H4
4-NO2C6H4
4-BrC6H4
4-BrC6H4
4-BrC6H4
4-NO2C6H4
C6H5
Li
Li
Li
Li
K
18: 86 (96)
b
20: 71 (96)
c
d
22: 25 (99)
e
e
c
21: i-Pr
22: 80 (98)
c
21: i-Pr
22: 99 (56)
c
23: i-Pr
Li
K
−60 to 20, 0.5−12
−60, 3
24: 99 (99)
c
25: i-Pr
26: 86 (61)
a
b
c
Reactions were run at a substrate concentration of 0.1 M. Absolute configurations were tentatively assigned by analogy to 22, 24, and 26. S
d
e
isomer. The α-arylated product before cyclization was obtained in 66% yield. After being stirred for 30 min at −60 °C, the mixture was gradually
warmed to 20 °C over a period of 12 h.
Scheme 4. Racemization Behavior of Chiral Enolate A
Derived from 9
Scheme 5. A Possible Stereochemical Course for Asymmetric
Aryl Migration
enolate generated from an N-MOM-N-Boc-L-phenylalanine
derivative by periodic quenching of the chiral enolate with
methyl iodide.1b,3,6a However, this protocol could not be applied
to the enolates generated from the present substrates because
they underwent aryl migration immediately after they were
generated. We chose to use compound 9 to estimate the
racemization barrier of the chiral enolate because enolate A
(Scheme 2) generated from 9 was expected not to undergo aryl
migration (Table 2, entry 4). The barrier to racemization of
lithium enolate A generated from 9 in 2:1 DMF/THF at −78 °C
was determined through the periodic quenching of the enolate
with methyl iodide (Scheme 4; for details, see the SI). The barrier
was found to be 15.2 kcal/mol at −78 °C. The half-life of
racemization of the chiral enolate at −60 °C (the reaction
temperature) was roughly estimated to be 5 min from the
racemization barrier at −78 °C on the basis of the assumption
that ΔS⧧ ≈ 0 for the unimolecular racemization process (bond
rotation along the chiral C−N axis).
A rationale for the stereochemical course of the asymmetric
aryl migration of 23 is shown in Scheme 5. A conformational
search of 23 gave the stable conformers 23-I and 23-II.17
Deprotonation of 23-I with LiHMDS, where the C(α)−H
(shown in red) bond is antiperiplanar with respect to the
neighboring N−(CO)N(MOM)Ar bond, would be preferable
to that of 23-II, where the C(α)−H (shown in red) bond is
antiperiplanar with respect to the neighboring N−C(MOM)
bond. This was assumed on the basis of our previous
stereochemical results, in which deprotonation of N-Boc-N-
alkyl-α-amino acid derivatives preferentially took place from the
conformer in which the C(α)−H bond is antiperiplanar with
respect to the N−C(Boc) bond.1b,3−9 Deprotonation of
conformer 23-I would give enantiomerically enriched enolate
D, which would undergo intramolecular addition to the
neighboring N-aryl group to give Meisenheimer-type complex
E. Collapse of E followed by intramolecular N-acylation would
give α-arylated hydantoin 24 with inversion of configuration.
In conclusion, we have developed a method for asymmetric α-
arylation of amino acid derivatives. The reaction involves
Clayden rearrangement of chiral enolates generated from α-
amino acid esters via the protocol of MOC. This method
provides chiral hydantoins with an aryl-substituted tetrasub-
stituted carbon, which are potentially useful chiral building
blocks in the field of medicinal chemistry18 and are structural
equivalents to amino acids with aryl-substituted tetrasubstituted
carbons.19
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and spectroscopic data. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
kawabata@scl.kyoto-u.acjp
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Professor Jonathan Clayden (University of Man-
chester) for the valuable discussion, and generous guidance on
the occasion of Dr. Keisuke Tomohara’s visit to his laboratory.
C
dx.doi.org/10.1021/ja406653n | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Chem. 2011, 7, 1570. (f) Jones, E. P.; Jones, P.; Barrett, A. M. G. Org.
Lett. 2011, 13, 1012.
This work was partially supported by KAKENHI (B) and by a
Grant-in-Aid for JSPS Fellows to K.T.
(14) For pioneering reports on racemic synthesis of α-arylated amino
acid derivatives via Pd-catalyzed arylation of enolates, see: (a) Lee, S.;
Beare, N. A.; Hartwig, J. F. J. Am. Chem. Soc. 2001, 123, 8410.
(b) Gaertzen, O.; Buchwald, S. L. J. Org. Chem. 2002, 67, 465. (c) Liu,
X.; Hartwig, J. F. Org. Lett. 2003, 5, 1915. (d) Hama, T.; Hartwig, J. F.
Org. Lett. 2008, 11, 1549.
(15) A possible explanation for the solvent dependence is as follows:
Deprotonation of 23-I (Scheme 5) is basically preferable to give
enantiomerically enriched enolate D followed by the product with
inversion of configuration. Deprotonation of 23-II seems to be
preferential only in less-coordinative solvents such as toluene because
coordination of the countercation of the base with the urea carbonyl
group would become crucial in a less-coordinative solvent and would
give chiral enolate ent-D followed by the product with retention of
configuration.
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