Highly stereoselective intramolecular α-arylation of self-stabilized non-racemic enolates: Synthesis of α-quaternary α-amino acid derivatives

Article abstract of DOI:10.1039/b910326k

The 'one-pot' stereoselective conversion of N-(4-nitrobenzene)sulfonyl- α-amino acid tert-butyl esters into the corresponding N-alkyl-α-(4- nitrophenyl)-α-amino esters has been realized through N-alkylation of the starting amido esters, followed by N-C

Full text of DOI:10.1039/b910326k

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Highly stereoselective intramolecular a-arylation of self-stabilized
non-racemic enolates: synthesis of a-quaternary a-amino acid derivativesw
Vittoria Lupi,z*a Michele Penso,*b Francesca Foschi,a Federico Gassa,a Voichit-a Mihalia
and Aaron Tagliabuea
Received (in Cambridge, UK) 27th May 2009, Accepted 23rd June 2009
First published as an Advance Article on the web 13th July 2009
DOI: 10.1039/b910326k
The ‘one-pot’ stereoselective conversion of N-(4-nitrobenzene)-
sulfonyl-a-amino acid tert-butyl esters into the corresponding
N-alkyl-a-(4-nitrophenyl)-a-amino esters has been realized
through N-alkylation of the starting amido esters, followed by
N–Ca migration of the p-nitrophenyl group and the loss of
sulfur dioxide; the asymmetric induction is determined by an
intermediate non-racemic enolate, without the need of an
external source of chirality.
aromatic ring, bearing an electron-withdrawing group.
However, in order to display stereoselectivity, this process
required the presence of the expensive (ꢀ)-8-phenylmenthyl
ester that acts as a chiral auxiliary.
Here we report the stereoselective conversion of N-(4-nitro-
benzene)sulfonyl-a-amino acid tert-butyl esters 1 into the
corresponding N-alkyl-a-(4-nitrophenyl)-a-amino esters
2
(Scheme 1). These compounds are generated through the
N-alkylation of 1, followed by N–Ca migration of the
p-nitrophenyl group and the loss of sulfur dioxide.
Non-natural amino acids have attracted considerable
attention in biological and medicinal chemistry,1 because they
are powerful tools for the design of new oligopeptidic
fragments, capable of influencing the secondary structure of
proteins. In particular, a-quaternary a-amino acids are of
great interest for their potential intrinsic bioactivity.2 In
addition, new foldamers3 are formed by the introduction of
quaternary a-amino acids into peptidomimetics. This
procedure increases the lipophilicity of the oligomeric chain,
and restricts its conformational flexibility, thus making the
peptide more resistant to metabolic and chemical degradation.4
In the past few decades, a variety of synthetic strategies for
such important building blocks have been developed.5,6
Among these methods, the Kawabata approach—the
asymmetric alkylation of a-amino acid derivatives via a ‘chiral
non-racemic enolate’—emerges as one of the most appealing.7
Quaternary a-aryl-a-amino acids induce an enhanced
structural rigidity in peptides and hence attract particular
interest. Nevertheless, apart from the widely used Strecker
synthesis in its asymmetric variants2c,5d,8,9, only a few general
synthetic methods are available for their stereoselective
preparation.10 Tayama et al. recently described the straight-
forward application of the Stevens and Sommelet–Hauser
(S.–H.) rearrangements in the preparation of non-natural
amino acid derivatives.11 In particular, the S.–H. rearrangement
of N-benzylic a-ammonium acid esters gave quaternary
a-aryl-a-amino esters, through a [2,3]-sigmatropic shift of an
This degradative rearrangement was previously described
by Wilson et al.12 as the main process in the N-deprotection of
the series of N-alkyl-N-(p-nosyl)-a-amino acid tert-butyl esters
3, when 50% aqueous Bu4N+OHꢀ solution was used as a
base, but the resulting quaternary amino esters 2 were
completely racemic. Our interest in investigating the applicability
of this protocol to the enantioselective synthesis of quaternary
a-aryl-a-amino acids was stimulated by a survey of the
chemical literature, which did not evidence any further
attention to it as a practical synthetic method. To establish
the best alkylation–rearrangement conditions, L-tert-butyl
N-(p-nosyl)-phenylalaninate (1a) was reacted with allyl
bromide (Scheme 1, R1 = PhCH2, R2 = allyl; Table 1). The
best yields and ees of 2a were reached by using NaH as a base,
operating in dimethylacetamide (DMA) at ꢀ20 and 0 1C or in
DMF (entries 1–3). Other ‘non-hydrogen bonding donor’
solvents (entries 4–6), gave poor results.13 The unrearranged
optically pure N-allyl amido ester 3a was the sole product
isolated under solid–liquid phase-transfer catalytic (PTC)
conditions (entries 7, 8) or by using n-BuLi in THF at low
temperatures (entries 9, 10).
The phenylalanine derivative 1a (Scheme 1, R1 = PhCH2)
was then rearranged in the presence of a series of alkyl halides,
R2X, under the previously found best conditions (Table 2).
At 0 1C, the corresponding N-alkylated a-quaternary esters
2a–2h were obtained in good yields, with ees in the range of
51–82%. In particular, the N-methyl (2b) and N-propargyl
(2h) derivatives were isolated with the best yields and
a
`
Dipartimento di Chimica Organica e Industriale, Universita degli
Studi, Via Venezian 21, I-20133 Milano, Italy
b CNR Institute of Molecular Science and Technologies (ISTM),
Via Golgi 19, I-20133 Milano, Italy. Fax: +39 02 503 14159;
Tel: +39 02 503 14161; E-mail: michele.penso@istm.cnr.it
w Electronic supplementary information (ESI) available: Detailed
experimental procedures; characterization data for all new compounds
1a–e, 2a–h, 3a, 4b–e, 5c–e and (R)-2-amino-2-(4-nitrophenyl)-propionic
acid (R)-7; complete discussion of the migration stereochemical
outcome. See DOI: 10.1039/b910326k
Scheme
1 Alkylation–rearrangement of tert-butyl p-nosylamido
z Present address: Nerviano Medical Sciences, Viale Pasteur 10,
I-20014 Nerviano, Italy. E-mail: Vittoria.Lupi@nervianoms.com
esters 1.
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Table 1 Allylation–rearrangement of sulfonamido tert-butyl ester 1aa
Entry Base AllylBr/mmol Solvent t/h 2a (%) ee (%)
Table 3 Alkylation–rearrangement of tert-butyl esters 1a–e with allyl
and propargyl bromidea
1
2
3
4
5
6
7
8
9
10
NaH
NaH
NaH
NaH
NaH
NaH
K2CO3
NaOH/K2CO3 1.5
n-BuLi
n-BuLi
3
3
3
3
3
3
1.5
DMAb
DMAc 48 85
DMFb
78
DMSOd 72 71
5
87
62
74
75
48
20
—
—
—
—
—
6
DMPUb
NMPd 24
5
15
—
DMSOd 2.5 —f
e
g
h
DMSOd
THFi
5
24
24
—
—
—
3
3
N-Allyl derivative
THFj
Substrate
R1
At 0 1C
At ꢀ20 1C
t/h Yield (%) ee (%) t/h Yield (%) ee (%)
a
Reaction conditions: 1a (1 mmol), allyl bromide (1.5–3 mmol), NaH
d
b
c
Entry
(3 mmol), solvent (4 mL). At 0 1C. At ꢀ20 1C. At 25 1C.
e
ꢀ
1a (1 mmol), K2CO3 (4 mmol), Bu4N+HSO4 (0.1 mmol), DMSO
1
2
3
4
5
1a PhCH2
1b Ph
1c Me
1d i-Pr
1e s-Bu
5
2a 87
28 4b 92
4c 89
62
50
59
95
96
48 2a 85
48 4b 65b
16 4c 89
74
58
68
—
—
f
(4 mL). N-Allyl amido ester 3a was isolated in 85% yield and
g
ee
Z
99%.ꢀ 1a (1 mmol), NaOH (1 mmol), K2CO3 (3 mmol),
6
Bu4N+HSO4 (0.1 mmol), DMSO (4 mL). 3a was isolated in 75%
h
24 4d 99
26 4e 99
—
—
—
—
i
yield and ee Z 99%. At ꢀ78 1C; 3a was isolated in 15% yield.
j
At ꢀ20 1C; 3a was isolated in 32% yield.
Substrate
N-Propargyl derivativec
R1
t/h
Yield (%)
ee (%)
Entry
Table 2 Rearrangement of sulfonamido tert-butyl ester 1a with
several alkylating agents R2Xa
6
7
8
9
1a
1c
1d
1e
PhCH2
Me
i-Pr
8
5
20
26
2h 88
5c 93
5d 98
5e 97
80
68
96
98
At 0 1C
At ꢀ20 1C
t/h Yield (%) ee (%) t/h Yield (%) ee (%)
s-Bu
Entry R2X
a
Reaction conditions: p-nosylamido ester 1a–e (1 mmol), allyl or
b
propargyl bromide (3 mmol), NaH (3 mmol), DMA (4 mL). Starting
1
2
3
4
5
6
7
8
AllylBr
MeI
EtI
5
2
7
2a 87
2b 96
2c 99
62
82
57
57
62
61
51
80
48 2a 85
24 2b 90
74
91
—
—
—
—
61
—
c
material 1b (30%) was recovered. At 0 1C.
—
—
—
—
—
—
—
—
n-PrI
n-BuI
C8H17
BnBr
16 2d 80
2e 86c
4
3a reacted under these conditions with good yield but,
I
16 2f 73d
2g 75e
2h 88
48 2g 84
—
unexpectedly, the product 2a showed
a very low ee
4
8
PrgBrb
—
(Table 4, entry 1). The addition of increasing amounts of
optically pure 1a produced a progressive increment of optical
purity of 2a (entries 2–4) up to 57% ee. When racemic
non-alkylated rac-1a was used as an additive, 2a was isolated
with analogous yield and ee (entry 5). These results indicate
that, in the ‘one-pot’ process, the stereochemical information
is directly transferred from the N-alkylated sulfonamide 3 to
the final rearranged product 2 via a non-racemic enolate B
(Scheme 2). As suggested by the data in Table 4, the aza-anion
derived from 1a or rac-1a, does not act as an external chiral
source but stabilizes the enolate conformer B. This
a
Reaction conditions: 1a (1 mmol), alkyl halide R2X (3 mmol), NaH
b
(3 mmol), DMA (4 mL). Propargyl bromide. 3e: 7%.
d
c
e
3f: 21%. 3g: 20%.
enantioselectivities (entries 2, 8), whereas 1-iodooctane and
benzyl bromide gave large amounts of intermediated
unrearranged N-alkyl p-nosylamido esters 3f and 3g (entry 6,
footnote d; entry 7, footnote e). To prove the influence of the
reaction temperature, 1a was reacted at ꢀ20 1C with the more
activated alkylating agents; together with longer reaction
times, only modest ee increments (9–12%) were found (entries
1, 2, 7). On these bases, allyl bromide and propargyl bromide
were used as alkylating agents to study the reactivity of several
representative a-(p-nosylamido)acid tert-butyl esters (Table 3).
Quantitative yields and very high ees of the corresponding
rearranged products ( Z 95%) were reached with strongly
hindered valine (1d) and isoleucine (1e) derivatives (entries 4,
5, 8, 9). The phenylglycine derivative 1b was very sensitive to
basic conditions and reacted with poor enantioselectivity
(entry 2). Due to the ready N-deallylation, (see 4c example
in ESIw), the N-allyl derivatives 2a and 4 are useful inter-
mediates for the preparation of the N-unsubstituted
a-quaternary a-amino acids. Furthermore, the N-propargyl
derivatives 2h and 5 have been used14 in click reactions.15
Whereas the non-alkylated 1a did not react in the absence of
the alkylating agent and was recovered with unchanged
enantiopurity, the optically pure N-allylated sulfonamido ester
Table 4 Rearrangement of the N-allyl sulfonamido esters 3a using 1a
as an additivea
Entry
1a/mmol
NaH/mmol
t/h
2a (%)
ee (%)
1
2
3
4
5
—
0.5b
1b
3
3
6
6
6
2
1
1
1
1
87
87
88
91
89
28
40
55
57
55
2b
2c
a
b
Reaction conditions: 3a (1 mmol), DMA (4 mL), 0 1C. Ester 1a
was quantitatively recovered with 100% ee. Using rac-1a.
c
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Scheme 2 Proposed mechanism and stereochemical course.
intermediate, through a Re-face attack, evolves into a chiral
spiro-Meisenheimer complex that, in turn, undergoes the
stereoselective N–Ca migration of the aryl group. The
formation of the species B can be ascribed to the deprotonation
of the less crowded conformer A, in which the arylsulfonyl
group is far from the tert-butyl ester.w
In conclusion, a series of N-(p-nosyl)-a-amino esters 1 have
been stereoselectively transformed under mild reaction
conditions into the new quaternary N-alkyl-a-p-nitrophenyl-
a-amino acid derivatives 2. Practically quantitative yields and
very high enantioselectivities were reached in the case of
sterically crowded a-amino acid derivatives, which are difficult
to obtain through other synthetic protocols. The asymmetric
induction is determined by an intermediate non-racemic
enolate, without need of an external source of chirality.
Further research to improve the enantioselectivity of the
process in the case of less crowded compounds, and for its
application to different EWG-activated a-arylsulfonamido
acid derivatives is in progress.
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This research was carried out within the framework of the
National Project ‘Nuovi metodi catalitici stereoselettivi
e sintesi stereoselettiva di molecole funzionali’, and it is
supported by MIUR (Rome) and CNR (Italy).
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this process.
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5014 | Chem. Commun., 2009, 5012–5014