Efficient synthesis of optically active α-quaternary amino acids by highly diastereoselective [2,3]-rearrangement of allylic ammonium ylides

Article abstract of DOI:10.1039/c2cc33027j

A pincer-like chiral auxiliary strategy for synthesizing various optically active α,α-disubstituted amino acids in high yields with excellent enantioselectivities is described.

Full text of DOI:10.1039/c2cc33027j

View Online / Journal Homepage / Table of Contents for this issue
Dynamic Article Links
ChemComm
Cite this: Chem. Commun., 2012, 48, 7274–7276
www.rsc.org/chemcomm
COMMUNICATION
Efficient synthesis of optically active a-quaternary amino acids by highly
diastereoselective [2,3]-rearrangement of allylic ammonium ylidesw
Ting-Shun Zhu and Ming-Hua Xu*
Received 27th April 2012, Accepted 17th May 2012
DOI: 10.1039/c2cc33027j
A pincer-like chiral auxiliary strategy for synthesizing various
optically active a,a-disubstituted amino acids in high yields with
excellent enantioselectivities is described.
Besides, the use of a bulky auxiliary simultaneously retarded
the formation of ammonium salts (it generally takes more than
72 h with allyl iodide). In another example,8 Somfai and
co-workers cleverly developed a BBr3/sulfonamide-mediated
asymmetric [2,3]-rearrangement, however, the prospect of
chiral catalysis in this type of rearrangement reaction remains
elusive due to the lack of coordination between a quaternary
nitrogen and a chiral catalyst. Moreover, with respect to
stereoselective [2,3]-rearrangement of allylic ammonium ylids
for constructing more challenging a-quaternary amino acids,
there have been no reports in the literature. Herein, we9
present a novel chiral auxiliary approach that addresses these
issues, giving access to various functionalized a,a-disubstituted
a-amino acids in a highly stereoselective manner.
As depicted in Scheme 1, we envisioned an unprecedented
chiral auxiliary strategy, in which a suitably functionalized
chiral auxiliary unit is attached to the substrate amine moiety
in a pincer-like manner. Notably, this strategy would offer
several significant advantages. We can expect that the incor-
poration of a chiral auxiliary more close to the rearrangement
center would result in advanced reaction stereoselectivity. We
also reasoned that this design, with tertiary amine in a ring
structure, should potentially reduce the difficulties in forming
the quaternary ammonium salt.10 Most importantly, the key
design element is that many commercially available, unpro-
tected, racemic a-amino acid esters could be directly used as
the starting substrates for further structural elaboration.
To carry out the idea, we thought of binding an axially
chiral C2-symmetric 2,20-dimethyl-1,10-binaphthyl bridge, as
the auxiliary, to the amine nitrogen atom. As shown in
Scheme 2, we first conducted reactions with a series of
commercially available L/racemic a-amino acid methyl ester
a,a-Disubstituted a-amino acids bearing a quaternary carbon
stereocenter at the a-position are an intriguing class of non-
natural amino acids of particular interest in bioorganic and
medicinal chemistry. They are often incorporated into peptides in
place of the natural amino acids for conformational constraint
and structural stability studies to understand the remarkable
protein flexibility and bioactivity changes.1 In addition,
a,a-disubstituted a-amino acids constitute a key structural
motif in natural products and bioactive compounds.2 Due to
their great importance, numerous attempts have been made by
synthetic organic chemists in the past decades to develop
efficient methodologies for the synthesis of these valuable,
optically active compounds.3–5 Among the wide range of
strategies employed, asymmetric rearrangement processes,
despite being comparatively less well documented,3j,5 have
proven to be one of the most powerful approaches in terms
of excellent intrinsic reaction efficiency and stereoselectivity
control. However, these rearrangement methods have frequently
suffered from limited reaction scopes and many requisite
substrates required multistep syntheses.
[2,3]-rearrangement of allylic ammonium ylids is an elegant
method to afford homoallylic tertiary amines.6 To our knowledge,
the use of this protocol for asymmetric synthesis of a-amino acids
has only been rarely reported. In 2005,7 a significant advancement
was achieved by Sweeney and co-workers with the successful
preparation of enantioenriched allyl glycine derivatives via highly
diastereoselective [2,3]-rearrangement of N,N,N-allyldimethyl
glycine salts bearing a pendant Oppolzer camphorsultam
auxiliary. However, the rather unique substrate specificity as
well as the difficulties in the removal and rupture of N,N-
dimethyl groups severely hamper it’s practical application.
State key Laboratory of Drug Research, Shanghai Institute of
Materia Medica, Chinese Academy of Sciences,
555 Zuchongzhi Road, Shanghai 201203, People’s Republic of China.
E-mail: xumh@mail.shcnc.ac.cn; Fax: +86 21 5080 7388;
Tel: +86 21 5080 7388
w Electronic supplementary information (ESI) available: Experimental
procedures and spectral data for new compounds. CCDC 865414 and
865415. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c2cc33027j
Scheme 1 ‘‘Pinch to work’’ auxiliary strategy for constructing
a-quaternary amino acids from unprotected racemic a-amino acid esters.
c
7274 Chem. Commun., 2012, 48, 7274–7276
This journal is The Royal Society of Chemistry 2012

View Online
Scheme 2 Synthesis of quaternary ammonium salts, 3.
Scheme 3 Expanding the reaction scope with a combined strategy.
hydrochloride salts with (R)-2,20-bis(bromomethyl)-1,10-
binaphthyl (1). After screening several reaction conditions,
we found that tertiary amines, 2, could be prepared in over
90% yields using NaHCO3 as the base in refluxing CH3CN.
Subsequently, these tertiary amines were subjected to reaction
with allylbromide. As expected, the corresponding quaternary
ammonium salts, 3, were formed in good to excellent yields
under very mild conditions using CH3CN as the solvent at
room temperature.
homophenylalanine, methionine, serine, tyrosine, tryptophan
and phenylglycine, were all successfully carried out, giving the
corresponding products in good yields and with excellent
diastereoselectivities (495% de) (entries 5–8, 10–15). It is
noteworthy that unprotected phenolic OH in the tyrosine
moiety and indole NH in the tryptophan moiety are well
tolerated in the current transformation. In these cases, the
use of 2.5 equiv. of NaH was required to ensure good yields.
Gratifyingly, for the substrates bearing less sterically hindered
R, such as that derived from alanine (3b, R = Me), the de
could be substantially improved by using modified ammonium
salt 3b0, in which two phenyl substituents were introduced
at the 3 and 30 positions of the chiral binaphthyl auxiliary.
This protocol was shown to be efficient for the synthesis of
a-monosubstituted amino acids, such as allylglycine, as well
(entry 2). The absolute stereochemistry of the major diastereomer
was determined as indicated by the X-ray crystallographic
analysis11 of 4a (entry 1) and 4k (in Scheme 3).
With quaternary ammonium salts 3 in hand, we chose
several to evaluate their [2,3]-sigmatropic rearrangement for
optimal conditions (see ESIw). After careful studies on solvent,
temperature and base, we found that the reaction proceeded
smoothly in the presence of 1.5 equiv. of NaH in DME at 0 1C.
When 3b (R = Me) was employed, the desired a-quaternary
amino acid product, 4b, was obtained in 92% yield with 85%
de (Table 1, entry 3). Notably, when the sterically more
demanding substrate 3c (R = Bn), derived from phenylalanine,
was examined under the same conditions, we were pleased to
find that both excellent yield (92%) and diastereoselectivity
(98% de) were achieved (entry 5).
The scope of the reaction was further explored to synthesize
more challenging and structurally exceptional a-quaternary
amino acids. As illustrated in Scheme 3, a combined strategy
was successfully employed to convert binaphthyl amine 2a to
diastereomerically enriched a,a-disubstituted products by sequen-
tial a-alkylation, allylation and [2,3]-rearrangement. Since the
ammonium salt (3) unavoidably undergoes a-racemization upon
treatment with NaH, the stereochemical information gained from
the first alkylation has no impact on the final reaction stereo-
selectivity. Accordingly, in the examples of 4k and 4l, stereogenic
quaternary carbon centers with very high levels of stereocontrol
were efficiently constructed via rearrangement processes. It is also
notable that tolerated functionality, such as bromine or aldehyde,
would be useful for further elaboration.
With these promising results, we then turned our attention
to investigate the substrate generality of the reaction. A wide
range of natural a-amino acid derived quaternary ammonium
salts bearing different R substituents with diverse steric and
electronic properties were examined. As shown in Table 1, the
reaction was found to be general, and it appears that a-allylation
of various commercial available a-amino acids, including leucine,
Table 1 Asymmetric [2,3]-rearrangement of allylic ammonium salts
derived from different natural amino acidsa
Moreover, the advantage of the present approach was
further demonstrated by the application to the synthesis of
otherwise-more-difficult-to-access a-quaternary a-amino acids. As
shown in Scheme 4, three differently substituted allyl ammonium
salts (3m, 3n and 3o) underwent [2,3]-rearrangement smoothly
under standard conditions to give a-quaternary leucine derivatives
in good yields and with high diastereoselectivities. Thus, the
reaction substrate scope is largely expanded, indicating the
great compatibility and efficiency of the method.
Entry
3
R0
H
R
4
Yieldb (%) dec
76
76f
1d
2d
3
4
5
3a
3a0 Ph
H
H
Me
4a
4a0 68
4b
4b0 90
4c
4d
4e
4f
4g
4h
96
85
3b
H
92
3b0 Ph Me
96
98
498
498
498
98
96
498
498
3c
3d
3e
3f
3g
3h
3i
H
H
H
H
H
H
H
H
Bn
92
95
97
88
78
85
91
92
6
7
8
9
CH2CH(CH3)2
CH2CH2Ph
CH2CH2SCH3
CH2OMOM
4-OHC6H4CH2
Removal of the chiral binaphthyl auxiliary can be accom-
plished under hydrogenation conditions (H2, Pd/C) to afford
10e
11e
12
1H-indol-3-methylene 4i
Ph 4j
3j
a
Unless otherwise mentioned, all reactions were performed on
0.1 mmol scale with 1.5 equiv. of NaH and 100 mg of 4 A molecular
b
c
sieves in 5 mL of DME at 0 1C. Yield of isolated product. Determined
by H NMR and LC–MS. With 1 equiv. of NaH. With 2.5 equiv.
1
d
e
f
of NaH. Product 4a with 495% de was obtained after a single
crystallization of its HBr salt from CH2Cl2/MTBE.
Scheme 4 Expanding the reaction scope with other allyl reagents.
Chem. Commun., 2012, 48, 7274–7276 7275
c
This journal is The Royal Society of Chemistry 2012

View Online
70, 5339; (c) M. Ilies, L. D. Costanzo, D. P. Dowling, K. J. Thorn
and D. W. Christianson, J. Med. Chem., 2011, 54, 5432;
(d) G. M. Sambeth and R. D. Sussmuth, J. Pept. Sci., 2011,
17, 581.
3 For reviews on asymmetric synthesis of a,a-disubstituted a-amino
acids, see: (a) C. Cativiela and M. D. Dıaz-de-Villegas,
Tetrahedron: Asymmetry, 1998, 9, 3517; (b) C. Cativiela and
M. D. Dıaz-de-Villegas, Tetrahedron: Asymmetry, 2000, 11, 645;
(c) Y. Ohfune and T. Shinada, Eur. J. Org. Chem., 2005, 5127;
(d) H. Vogt and S. Brase, Org. Biomol. Chem., 2007, 5, 406; For
other related reviews, see: (e) H. Heimgartner, Angew. Chem.,
Int. Ed. Engl., 1991, 30, 238; (f) T. Wirth, Angew. Chem., Int. Ed.
Engl., 1997, 36, 225; (g) K. Maruoka and T. Ooi, Chem. Rev., 2003,
103, 3013; (h) C. Najera and J. M. Sansano, Chem. Rev., 2007,
107, 4584; (i) K. Undheim, Amino Acids, 2008, 34, 357;
(j) J. Clayden, M. Donnard, J. Lefranc and D. J. Tetlow, Chem.
Commun., 2011, 47, 4624.
4 For selected recent examples, see: (a) S. Masumoto, H. Usuda,
M. Suzuki, M. Kanai and M. Shibasaki, J. Am. Chem. Soc., 2003,
125, 5634; (b) N. S. Chowdari, J. T. Suri and C. F. Barbas III,
Org. Lett., 2004, 6, 2507; (c) M. Kitamura, S. Shirakawa and
K. Maruoka, Angew. Chem., Int. Ed., 2005, 44, 1549;
(d) M. C. Jones, S. P. Marsden and D. M. M. Subtil, Org. Lett.,
2006, 8, 5509; (e) D. Uraguchi, K. Koshimoto and T. Ooi, J. Am.
Chem. Soc., 2008, 130, 10878; (f) S. Cabrera, E. Reyes, J. Aleman,
A. Milelli, S. Kobbelgaard and K. A. Jørgensen, J. Am. Chem.
Soc., 2008, 130, 12031; (g) M. Branca, S. Pena, R. Guillot, D. Gori,
V. Alezra and C. Kouklovsky, J. Am. Chem. Soc., 2009,
131, 10711; (h) T.-J. Lu and C.-K. Lin, J. Org. Chem., 2011,
76, 1621; (i) S. Shirakawa, S. J. Terao, R. He and K. Maruoka,
Chem. Commun., 2011, 47, 10557.
5 (a) J. C. Ruble and G. C. Fu, J. Am. Chem. Soc., 1998, 120, 11532;
(b) E. Tayama, S. Nanbara and T. Nakai, Chem. Lett., 2006,
35, 478; (c) K. Tamooka, J. Sakamaki, M. Harada and R. Wada,
Synlett, 2008, 683; (d) E. Tayama, K. Orihara and H. Kimura,
Org. Biomol. Chem., 2008, 6, 3673; (e) P. Tuzina and P. Somfai,
Org. Lett., 2009, 11, 919; (f) V. Iosub, A. R. Haberl, J. Leung,
M. Tang, K. Vembaiyan, M. Parvez and T. G. Back, J. Org.
Chem., 2010, 75, 1612; (g) D. Uraguchi, K. Koshimoto, S. Miyake
and T. Ooi, Angew. Chem., Int. Ed., 2010, 49, 5567; (h) C. K. De,
N. Mittal and D. Seidel, J. Am. Chem. Soc., 2011, 133, 16802;
(i) E. Tayama, K. Takedachi, H. Iwamoto and E. Hasegawa,
Tetrahedron Lett., 2012, 53, 1373.
Scheme 5 An alternative auxiliary approach to highly optically
active a-allyl a-quaternary amino acids.
the corresponding quaternary carbon-containing a-amino
acids in high yields without loss of the optical purities.12
Despite that the allylic double bond can be pre-elaborated
or derivatized before hydrogenation,13 we realized that it is
necessary to identify an alternative, equally effective chiral
auxiliary that could be easily removed while preserving the
alkene functionality in the molecule. For this purpose, we
investigated the use a of more electron-rich, axially chiral dial
614 (98% ee, Scheme 5). Similarly, we found that the allyl
ammonium salts represented by 7a and 7b, formed from
phenylalanine and leucine, were capable of efficient [2,3]-
rearrangement under the above same conditions, furnishing
products 8a and 8b in high yields as well as excellent diastereo-
selectivities. Significantly, the auxiliary was cleanly removed
by oxidative debenzylation with cerium(IV) ammonium
nitrate (CAN), and highly enantiomerically enriched (R)-allyl
phenylalanine (9a) and (S)-allyl leucine (9b) were satisfactorily
accessed.
In summary, we have developed an unprecedented, unique
chiral auxiliary strategy to access various highly optically
active a,a-disubstituted quaternary amino acids, including
structurally exceptional and functionalized ones through
an efficient, stereospecific [2,3]-sigmatropic rearrangement
process under very simple and mild conditions. A particularly
remarkable design element is that many commercially avail-
able unprotected racemic amino acid esters could be directly
used as the starting substrates for a-allylation with great
stereocontrol. Given the broad scope and generality, and high
efficiency for creation of all-carbon quaternary stereocenters,
this method is expected to be of great interest and to have
significant applications in organic synthesis.
6 I. Marko, in Comprehensive Organic Synthesis, ed. B. M. Trost and
I. Fleming, Pergamon, Oxford, 1991, vol. 3, p. 913.
7 J. A. Workman, N. P. Garrido, J. Sancuon, E. Roberts, H. P. Wessel
and J. B. Sweeney, J. Am. Chem. Soc., 2005, 127, 1066.
8 J. Blid, O. Panknin and P. Somfai, J. Am. Chem. Soc., 2005,
127, 9352.
9 For our recent involvement in asymmetric synthesis of optically
active non-proteinogenic amino acids, see: (a) X.-W. Sun, M. Liu,
M.-H. Xu and G.-Q. Lin, Org. Lett., 2008, 10, 1259; (b) M. Liu,
A. Shen, X.-W. Sun, F. Deng, M.-H. Xu and G.-Q. Lin, Chem.
Commun., 2010, 46, 8460; (c) D.-M. Ji and M.-H. Xu, Chem.
Commun., 2010, 46, 1550; (d) S.-S. Jin and M.-H. Xu, Adv. Synth.
Catal., 2010, 352, 3136; (e) Y. Li, D.-M. Ji and M.-H. Xu, Org.
Biomol. Chem., 2011, 9, 8452; (f) Y. Li and M.-H. Xu, Org. Lett.,
2012, 14, 2062.
10 For a review of the Menshutkin reaction, see: J.-L. M. Abboud,
R. Notario, J. Betran and M. Sola, Prog. Phys. Org. Chem., 1993,
19, 1.
11 CCDC 865414 (4a.HBr) and 865415 (4k) contain the supple-
mentary crystallographic data.
This work was generously supported by the NSFC (21021063),
the State Key Laboratory of Drug Research, SIMM and the
CAS.
12 See ESIw for details. It is worth noting that the auxiliary derivative
(2,20-dimethyl-1,10-binapthene) can be recovered in over 90%
yield, and reused after bromination with NBS.
Notes and references
1 (a) J. Venkatraman, S. C. Shankaramma and P. Balaram, Chem.
Rev., 2001, 101, 3131; (b) M. Tanaka, Chem. Pharm. Bull., 2007,
55, 349; (c) M. Crisma, M. Saviano, A. Moretto, Q. B.
Broxterman, B. Kaptein and C. Toniolo, J. Am. Chem. Soc.,
2007, 129, 15471.
2 (a) C. S. V. Houge-Frydrych, M. L. Gilpin, P. W. Skett and
J. W. Tyler, J. Antibiot., 2000, 53, 364; (b) Y. Matsukawa,
M. Isobe, H. Kotsuki and Y. Ichikawa, J. Org. Chem., 2005,
13 For example, double bond elaboration of product 4d via Heck
reaction with either electron-rich or electron-poor aryl iodide was
successfully performed, see ESIw for details.
14 Chiral dial 6 can be easily obtained by either resolution or
asymmetric coupling as shown in our earlier work, see:
(a) C. Zhu, Y. Shi, M.-H. Xu and G.-Q. Lin, Org. Lett., 2008,
10, 1243; (b) W.-W. Chen, Q. Zhao, M.-H. Xu and G.-Q. Lin,
Org. Lett., 2010, 12, 1072.
c
7276 Chem. Commun., 2012, 48, 7274–7276
This journal is The Royal Society of Chemistry 2012