Novel preparation of chiral α-amino acids using the Mitsunobu-Tsunoda reaction

Article abstract of DOI:10.1039/c3cc44717k

An efficient synthesis of racemic or optically active α-amino acids by modified-Mitsunobu alkylation of a racemic or chiral glycine template from alcohols was developed. Libraries of amino acids were prepared in moderate to good yield with good to high enantioselectivity. This simple method widens the scope for preparation of structurally diverse amino acids.

Full text of DOI:10.1039/c3cc44717k

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DOI: 10.1039/C3CC44717K
Novel Preparation of Chiral -Amino Acids Using the Mitsunobu-
Tsunoda reaction
Anaïs F. M. Noisier,a Craig S. Harrisb and Margaret A. Brimble*a
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
An efficient synthesis of racemic or optically active α-amino
acids by modified-Mitsunobu alkylation of a racemic or chiral
glycine template from alcohols was developed. Libraries of
amino acids were prepared in moderate to good yield with
10 good to high enantioselectivity. This simple method widens
the scope for preparation of structurally diverse amino acids.
55
Scheme 1. General strategy for the synthesis of -AAs by direct
Mitsunobu-type alkylation with alcohol electrophiles.
Enantiopure non-proteinogenic -amino acids (-AAs) are of
great importance for pharmaceutical development.1 They are
15 essential for peptide synthesis and are indispensable in total
synthesis and ligand elaboration as either chiral building blocks
or chiral catalysts.2 The increasing demand for unnatural -AAs
has encouraged many research groups to focus their effort on the
development of novel methods for the rapid synthesis of a large
20 pool of enantiopure non-natural -AAs.
hamper the scope of nucleophiles which can be used efficiently.
Furthermore, difficulties in isolation often arise due to the
60 presence of triphenylphosphine oxide and hydrazine side-
products. In this regard considerable progress has been achieved
and modified Mitsunobu reagents have been developed.7 Notably,
cyanomethylene tributylphosphorane (CMBP) 1a and cyano-
methylene triphenylphosphorane (CMPP) 1b, reported by
65 Tsunoda et al.8 are capable of forming C-C bonds by effecting the
alkylation of alcohols by nucleophiles with a pKa <23.
We postulated that glycine derivatives should be suitable
nucleophiles to use in conjunction with these novel phosphoranes
(Scheme 1). Herein, we report the first Mitsunobu-Tsunoda
70 alkylation of glycine templates with a broad range of alcohols
providing -AAs in both racemic and enantioenriched forms.
Previous work by O’Donnell et al.9 focused on the structure of
the glycine templates, demonstrated that protection of the amine
functionality as a benzophenone imine was key for the success of
75 the phase-transfer catalyzed alkylation reaction. Not only does
the electron-withdrawing effect of the benzophenone Schiff base
increase the acidity of the methylene protons (pKa ≈ 18.7) but
also the steric bulk prevents undesired dialkylation at the
-carbon. Therefore, we decided to use O’Donnell’s scaffold for
80 our proposed Mitsunobu-Tsunoda alkylation study.
Initially, we examined the reaction of N-(diphenylmethylene)
glycine tert-butyl ester (2) with benzyl alcohol in order to
determine the optimum reaction conditions. Given that
elimination of acetonitrile is an entropic driving force for the
85 Mitsunobu-Tsunoda alkylation, the reaction was carried out at
high temperatures. Our first attempts using CMPP 1b afforded
only trace quantities of the desired product after heating in
toluene at 100 °C overnight. Unfortunately, changing the
temperature, time, concentration or equivalents of CMPP and
90 alcohol failed to improve the reaction outcome. At this point we
decided to investigate the more reactive phosphorane CMBP 1a.
Hence, treatment of 2 with one equivalent of benzyl alcohol and
one equivalent of 1a in toluene (0.5 M) at 100 °C afforded the
desired product 3a in 40% yield. Complete conversion could be
95 achieved by increasing the concentration to 1 M, the reaction
temperature to 120 °C and using two equivalents of both the
phosphorane and the alcohol. Pleasingly, under these conditions
no dialkylation side-product was detected and the desired product
3a was isolated in an improved 82% yield.
Classical approaches to access these materials such as
resolution of racemic mixtures have quickly given way to the use
of more powerful asymmetric synthesis methods.3 Even though
the field of catalytic asymmetric synthesis has witnessed
25 impressive growth,4 the gold rush for the almighty catalyst so far
failed to deliver an inexpensive, readily available and universal
catalyst. The necessary screening for the optimum catalyst
renders the use of catalytic asymmetric synthesis laborious and
restricts its use for the preparation of libraries of compounds. On
30 the other hand, the introduction of the amino acid side-chain
using a diastereoselective approach offers access to a wide range
of chiral compounds from a single precursor. This is usually
achieved via the deprotometallation of an appropriate chiral
glycine auxiliary followed by reaction with an electrophile.5 To
35 be attractive, chiral auxiliaries must either be commercially
available or readily prepared in a few steps and should be
inexpensive or easily recycled. However, the alkylation process
often requires strong bases or cryogenic temperatures and to date,
only halides and pseudo-halides have been used as the
40 electrophilic partners. In many cases organohalides have limited
shelf-lives and are best used immediately after their preparation.
These restrictions are considerably limiting the use of the
diastereoselective approach for high throughput synthesis.
To the best of our knowledge, the synthesis of -AAs using
45 alcohols as pro-electrophiles has not been reported. Not only it
would save one step compared to using halides, but the vast pool
of structurally diverse commercially-available alcohols would
afford a significant increase in the number of non-proteinogenic
-AAs that become readily accessible. Such a process is therefore
50 highly desirable for both academic and industrial research.
Although the Mitsunobu reaction constitutes the most
commonly used reaction to effect the substitution of alcohols
with nucleophiles,6 it suffers serious limitations. The pKa
restrictions (nucleophile acidic hydrogen pKa ≤11) considerably

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DOI: 10.1039/C3CC44717K
CMBP 1a (2 eq)
ROH (2 eq)
biotechnological means and have so far proven difficult to access
by chemical synthesis, were readily prepared from thienyl-,
furanyl-, imidazolyl- and pyridyl- methanol in yields ranging
from 23-77% (3h-n). Furthermore, it was pleasing to observe that
35 both allylic and primary aliphatic alcohols reacted successfully
with 2 to form the desired allylglycine 3o, O-methylated
homoserine 3p and homo-tert-leucine 3q in 70%, 37% and 32%
yield, respectively. Interestingly, secondary alcohols were also
good substrates for the Mitsunobu-Tsunoda alkylation of 2 as
40 exemplified by the reaction of N-Boc-4-hydroxypiperidine which
afforded product 3r in 42% yield.
Ph
N
CO2tBu
Ph
N
CO2tBu
toluene
(c = 1 mol/L)
120 °C
Ph
Ph
R
2
3a-ra
Ph
N
CO2tBu Ph
N
CO2tBu Ph
N
CO2tBu
Cl
Ph
Ph
Ph
X
MeO
82%b (3a)
58%b (3b, X = H)
68% (3c, X = Cl)
77%b (3d, o-MeO)
63%b (3e, m-MeO)
68%b (3f, p-MeO)
Ph
N
CO2tBu
Ph
N
CO2tBu Ph
N
CO2tBu
We next focused on the extension of our methodology to the
asymmetric desymmetrisation of prochiral glycine equivalents for
the synthesis of optically active -amino acids. Although
45 diastereoselective alkylations most commonly proceed at sub-
zero to room temperatures,5 we were curious to see whether we
could control the diastereofacial selectivity in spite of the high
reaction temperatures required. We proposed that the nickel
complex developed by Belokon,10 and successfully used by our
50 laboratories and others for the synthesis of non-natural
enantiopure amino acids,11 would provide a suitable template for
the Mitsunobu-Tsunoda reaction, as only mild conditions are
required to effect its deprotonation. Furthermore, the high
diastereoselectivity observed during the alkylation of the Belokon
55 complex using NaOH as a base at room temperature are believed
to be the results of a thermodynamically favoured reaction
pathway.10b It was therefore hoped that the alkylation under
Mitsunobu-Tsunoda conditions would also take place under
thermodynamic control and lead to the same high diastereo-
60 selectivity despite the elevated temperature required.
Additionally, the NiII complex is easily accessible on a kilogram
scale and can be stored for months without degradation. NiII
complex 4 derived from (S)-2-[N-(N'-benzyl-prolyl) amino]
benzophenone (BPB) and glycine was prepared in excellent yield
65 in just three steps from inexpensive starting materials.12
Gratifyingly, the direct alkylation of Gly-Ni-(S)-BPB 4 with
various alcohols 5a-h using CMBP 1a took place providing the
desired products 6a-h with good yields and good diastereofacial
selectivity (Table 1). The diastereoisomeric ratios, determined by
70 1H NMR analysis, were found to be ≥86:14, and could be
increased to 99:1 after separation of the minor (S,R)-
diastereoisomer by column chromatography, except in the case of
6f, where the diastereoisomers were inseparable. Alkylation with
benzyl alcohol (5a), substituted benzyl alcohols (5b-c), heteroaryl
75 carbinols (5d-e) and allyl alcohol (5f) gave good yields (59-83%)
while unsaturated alcohols such as 5-hexen-1-ol afforded the
desired product 6g in a moderate 46% yield. The addition of an
unactivated long alkyl chain that is difficult to attain with
standard methods, also proceeded smoothly yielding 6h in 60%
80 yield.
Ph
Ph
N
Ph
N
CF3
51%c (3g)
54%b (3h)
37% (3i)
CO2tBu
Ph
N
CO2tBu Ph
N
CO2tBu Ph
N
Ph
Ph
Ph
Y
X
X
23% (3j, X = S)
62% (3k, X= O)
77% (3l, X = S, Y = H)
57% (3m, X = O, Y = H)
29% (3n, X = NMe, Y = N)
70% (3o)
Ph
N
CO2tBu Ph
N
CO2tBu Ph
N
CO2tBu
Ph
Ph
Ph
OMe
N
Boc
37% (3p)
32% (3q)
42% (3r)
Scheme 2. Scope of the Mitsunobu-Tsunoda alkylation for the racemic
synthesis of -AAs. a Yields were determined after semi-preparative
HPLC unless otherwise stated. b Yields were determined after flash
chromatography. c Yield was obtained using 3 equivalents of
4-(trifluoromethyl)benzyl alcohol and CMBP.
5
Encouraged by these promising results we next investigated
the scope of the reaction. A broad range of racemic -AA
derivatives were prepared by simply mixing alcohols with
10 N-(diphenylmethylene)glycine tert-butyl ester 2 and cyano-
methylene tributylphosphorane 1a in toluene and heating to
120 °C in a plain screwed-cap vial. The alkylated products were
easily purified from the highly polar tributylphosphine oxide and
volatile acetonitrile side-products, providing the -AA precursors
15 3a-r in good to moderate yields (Scheme 2).
Use of di-ortho substituted benzyl alcohols afforded
substituted phenylalanine analogue 3c in similar yield to the less
hindered 2-chlorophenylalanine 3b, indicating that the presence
of bulky substituents at the ortho position of the benzene ring
20 were well-tolerated. The reaction also proceeded smoothly when
the electron-withdrawing chlorine atom was replaced with an
electron-donating methoxy group providing 3d in 77% yield.
Furthermore, switching the methoxy group to the meta or para
position provided the pure products 3e and 3f in good yields
25 (63% and 68%, respectively). Perhaps surprisingly, when an
electron-withdrawing group was present in the para position such
as trifluoromethyl, the alkylation of 2 was found to be sluggish,
but 3g could still be obtained in 51% yield by adding additional
equivalents of CMPB and 4-(trifluoromethyl)benzyl alcohol.
30 Heteroaromatic derivatives, which remain mostly prepared by
Removal of the NiII complex under mild acidic conditions
followed by ion-exchange chromatography, afforded the free
amino acids 7a-g in good to excellent yields (67-99%). However,
the general procedure could not be applied to the preparation of
85 the lipophilic heptylglycine 7h, which could not be extracted into
the aqueous layer. In this case concentration of the reaction,
filtration of the precipitated BPB ligand, then reverse-phase
chromatography afforded the pure hydrochloride salt of the

Page 3 of 3
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DOI: 10.1039/C3CC44717K
support and AstraZeneca Research centre (France) for assistance.
Table 1. Scope of the Mitsunobu-Tsunoda alkylation for the
enantioselective synthesis of -AAs.
Notes and references
a School of Chemical Sciences and The Maurice Wilkins Centre for
Molecular Biodiscovery, The University of Auckland, 23 Symonds St,
40 Auckland Central 1010, New Zealand. E-mail: m.brimble@auckland.ac.nz
b Oncology iMed, AstraZeneca Pharma, ZI la Pompelle BP 1050, 51689
Reims Cedex 2, France. E-mail: craig.harris@galderma.com
† Electronic Supplementary Information (ESI) available: Experimental
details for the synthesis and characterization data, copies of 1H and 13C
45 NMR and chiral HPLC spectra. See DOI: 10.1039/b000000x/
1. G. M. Coppola and H. F. Schuster, in Asymmetric Synthesis:
Construction of Chiral Molecules Using Amino Acids. Wiley ed.; New-
York, 1987.
Yielda %
drb
Yieldc % eed %
(7)
Entry
R
(6)
75
72
90/10 (99/1)
87/13 (99/1)
79
67
95
a
2. (a) Jr, J. J. Nestor, Curr. Med. Chem., 2009, 16, 4399; (b) L.-W. Xu
50 and Y. Lu, Org. Biomol. Chem., 2008, 6, 2047.
>99
b
3. (a) M. A. Blaskovich, in Handbook on syntheses of amino acids :
General routes for the syntheses of amino acids First ed.; Oxford
University Press, New York, 2010; (b) A. David, in Process Chemistry in
the Pharmaceutical Industry, CRC Press, 2007, vol. 2, pp 157-179.
55 4. (a) C. Najera and J. M. Sansano, Chem. Rev., 2007, 107, 4584; For
reviews on asymmetric hydrogenation: (b) P. Etayo and A. Vidal-Ferran,
Chem. Soc. Rev., 2013, 42, 728; (c) W. Tang and X. Zhang, Chem. Rev.,
2003, 103, 3029; For reviews on Strecker reaction: (d) J. Wang, X. Liu
and X. Feng, Chem. Rev., 2011, 111, 6947; (e) P. Merino, E. Marqués-
60 López, T. Tejero and R. P. Herrera, Tetrahedron, 2009, 65, 1219; (f) S. J.
Connon, Angew. Chem. Int. Ed., 2008, 47, 1176; For reviews on phase-
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2008, 12, 679; (i) M. J. O'Donnell, Acc. Chem. Res., 2004, 37, 506.
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T. Abellán, R. Chinchilla, N. Galindo, G. Guillena, C. Nájera and J. M.
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59
68
90/10 (99/1)
96/4 (99/1)
87
79
96
92
c
d
83
87/13 (99/1)
quant.
96
e
78
46
60
90/10
quant.
quant.
64
81
95
97
f
89/11 (99/1)
86/14 (99/1)
g
h
a
Yields were determined after isolation of the major isomer by flash
chromatography. dr were determined by 1H NMR analysis of crude
b
5 reaction mixtures (dr of the major isomer isolated by flash chromato-
c
graphy). Yields were determined after ion-exchange chromatography.
d ee were determined by chiral HPLC on Chirobiotic T column.
desired amino acid 7h in 64% yield. The enantiomeric purities
were determined by chiral HPLC, confirming that little to no
10 racemization occurred during the cleavage step. While hydrolysis
of the pure (S,S)-diastereoisomers afforded the amino acids in
92-99% enantiomeric purity (7a-e, 7g-h), cleavage of the
diastereoisomeric mixture of 6f gave the free amino acid 7f in
81% ee. The BPB ligand was also recovered in quantitative yield
15 by simple extraction with dichloromethane.
In conclusion, we have developed a novel methodology for the
synthesis of -AAs, using readily available alcohol substrates and
an inexpensive glycine chiral auxiliary. Thanks to the variety,
ready availability and stability of the alcohol electrophilic
20 partners and the facile reaction set-up, this new method allows
access to a wide range of novel optically active -AAs in a
simple library-style operating manner. Furthermore, neither
cryogenic temperatures nor expensive chiral ligands were
necessary to achieve consistently high ee. The methodology
25 reported herein therefore, provides a powerful addition to the
armoury of existing methods to effect the synthesis of novel
chiral non-proteinogenic -AAs.
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G. Ezernitskaya, S. R. Harutyunyan, R. Hrdina, H. B. Kagan, P.
Kocovsky, K. A. Kochetkov, O. V. Larionov, K. A. Lyssenko, M. North,
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U. Boettiger, S. B. Bolene and V. A. Soloshonok, J. Org. Chem., 2003,
68, 7104.
The alkylation of NiII complexes derived from other -AAs
(for the synthesis of dialkylated -AAs), is currently under
30 examination. Further investigations into the effect of modifying
the Tsunoda reagent are also in progress in our laboratory.
The authors thank Auckland Uniservices Ltd., whose interests
in this study are protected under US patent application
nº 61/729,810, the 2011-2012 Dumont D’Urville NZ-France
35 Science & Technology Support Programme for their financial