Scalable scny BRAnthesis of β-amino esters via reformatskcny BRA reaction with N-tert-butanesulfincny BRAl imines

Article abstract of DOI:10.1055/s-0028-1087964

The Reformatskcny BRA reagents derived from ethcny BRAl bromoacetate and tert-butcny BRAl bromoacetate add cleanlcny BRA, in high cny BRAield, and with good diastereoselectivitcny BRA to N-tert-butanesulfincny BRAl aldimines and ketimines. Importantlcny BRA, this reaction scales well (>50 mmol), and affords products upwards of 70% cny BRAield over three steps, starting from commerciallcny BRA available N-tert-butanesulfinamide, aldehcny BRAdes, and ketones.

Full text of DOI:10.1055/s-0028-1087964

LETTER
991
Scalable Synthesis of b-Amino Esters via Reformatsky Reaction with
N-tert-Butanesulfinyl Imines
Synthesis of
b
-Am
r
inoEste
i
rs stin Brinner,* Brandon Doughan, Daniel J. Poon*
Novartis Institutes for Biomedical Research, 4560 Horton St., MS 4.5, Emeryville, CA 94608-2916, USA
Fax +1(510)9233360; E-mail: daniel.poon@novartis.com
Received 16 December 2008
selectivities, the generation of titanium enolates and
reagent manipulation at low temperature rendered this
method impractical beyond multigram scale. Herein we
describe a report on the Reformatsky addition of acetate
Abstract: The Reformatsky reagents derived from ethyl bromoac-
etate and tert-butyl bromoacetate add cleanly, in high yield, and
with good diastereoselectivity to N-tert-butanesulfinyl aldimines
and ketimines. Importantly, this reaction scales well (>50 mmol),
and affords products upwards of 70% yield over three steps, starting enolates to N-tert-butanesulfinyl aldimines and ketimines
from commercially available N-tert-butanesulfinamide, aldehydes,
and ketones.
that overcome these limitations. The additions proceeded
at convenient temperatures, in good yields, and very high
Key words: diastereoselectivity, stereoselective synthesis, chiral
auxilaries, imines, amino acids
diastereoselectivities (94:6 to >99:1) and can be per-
formed on very large scale with no reduction in yield or
stereoselectivity.
We required a route that would allow us to access b-amino
esters rapidly on large scale (>50 g). Diastereoselective
imino-Reformatsky reactions have been used for a pro-
cess-scale synthesis of a b-amino ester intermediate, how-
ever, the use of Pb(OAc)4 for the deprotection of the chiral
auxiliary required to impart high levels of diastereoselec-
tivity detracted from this approach (Scheme 2).6
As b-amino acids are important chiral building blocks for
total synthesis and medicinal chemistry applications, their
asymmetric synthesis remains an active area of research.1
Many synthetic routes to b-amino acids employ the addi-
tion of ester enolate nucleophiles into ketimine or aldi-
mine electrophiles, however, these routes can suffer from
modest stereoselectivities or lack substrate generality.2 In
addition, N-substituents necessary for stereoselectivity
are often inconvenient to remove.3 Prompted by Davis’
success in the addition of the enolates of acetate esters to
a limited set of N-p-toluenesulfinyl imines,4 the method-
ology was extended to N-tert-butanesulfinyl imines.5
Ph
O
Ph
OH
OH
BrZn
N
N
Ot-Bu
Pb(OAc)4
HN
CO2t-Bu
Ar
Ar
Ph
The addition of the titanium enolate of methyl acetate to
aryl-, branched alkyl-, and unbranched alkyl-N-tert-butane-
sulfinyl aldimines and ketimines was shown to proceed in
high yields and diastereoselectivities with the advantage
of facile auxiliary removal. By extension, N-tert-butane-
sulfinyl-protected a,b-disubstituted, a,a,b- and a,b,b-
trisubstituted, and a,a,a,b-tetrasubstituted b-amino esters
are synthesized in good yields and diastereoselectivities
through addition of a variety of ester enolates to N-tert-
butanesulfinyl aldimines and ketimines (Scheme 1).
PTSA, EtOH
4-TsOH ⋅
H2N
CO2t-Bu
CO2Et
Ar
Ar
Scheme 2 Process-scale diastereoselective imino-Reformatsky
reaction
Although the Reformatsky addition of unsubstituted ace-
tate enolates to N-sulfinyl imines had not previously been
disclosed, Staas had reported the Reformatsky reaction of
ethyl bromodifluoroacetate with alkyl- and aryl-substitut-
ed N-tert-butanesulfinyl imines to afford a,a-difluoro-b-
amino acid derivatives with good diastereoselectivity
(80:20 to 95:5).7 We therefore investigated addition of the
Reformatsky reagent derived from simple ethyl bromo-
acetate to N-tert-butanesulfinyl benzaldimine (1). We
were pleased to find that this reaction proceeded cleanly,
in high yield, and with excellent diastereoselectivity
(>99:1 dr). Removal of the sulfinyl protecting group of 2
OTi(Oi-Pr)3
R3
R1
R1 R2
O
S
O
O
S
OMe
R4
R2
N
OMe
N
H
R3 R4
Scheme 1 Addition of titanium ester enolates to N-tert-butanesulfi-
nyl aldimines and ketimines
While the sulfinamide-based route described above af- was easily effected by reaction with 1.0 M HCl in Et2O in
forded materials in good yields and with excellent diastereo- anhydrous ethanol to afford b-amino ester 3 after basic
aqueous workup in good yields (Scheme 3).
SYNLETT 2009, No. 6, pp 0991–0993
Advanced online publication: 16.03.2009
DOI: 10.1055/s-0028-1087964; Art ID: S12808ST
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x.
2
0
0
9
The reaction sequence can be increased to 50 mmol scale,
without the need for chromatographic purification at any
step. The absolute configuration of 3 was determined by

992
K. Brinner et al.
LETTER
ature is completely abrogated when tert-butyl bromozinc
acetate is employed (Table 1, entries 6–8).
O
O
S
O
S
H
PhCHO, Ti(OEt)4,
THF, r.t., 6 h
BrZn
OEt
NH2
N
Ph
In conclusion, the addition of Reformatsky reagents into
N-tert-butanesulfinyl imines, followed by N-tert-butane-
sulfinamide deprotection, affords highly enantioenriched
b-amino esters in good yield and purity. This reaction is
general and can afford monosubstituted and disubstituted
b-amino acids. Importantly, for the example shown (com-
pound 3), the stereoselective synthesis of b-amino acids
using this methodology can be easily scaled to access
large quantities of product in three steps from commer-
cially available starting materials, without the need for
chromatographic purification.
0 °C, 4 h
1 (95%)
Ph
O
O
S
Ph
O
1. 1.0 M HCl in Et2O
EtOH, r.t., 20 min
H2N
OEt
N
OEt
H
2. basic aqueous
workup
2 (97%, dr > 99:1)
3 (73%)
Scheme 3 Scaleable synthesis of (S)-3-amino-3-phenylpropionic
acid ethyl ester11–13
optical rotation which was found to be in good agreement
with literature values8,9 and commercially available mate-
rial.10 This result can be rationalized by invoking a closed
six-membered transition state arising from the E-sulfinyl
imine (Figure 1).7
Acknowledgment
We thank Professor Jonathan Ellman for helpful advice and editing
during preparation of this manuscript.
..
H
References and Notes
O
S
R1
N
(1) Davies, S. G.; Smith, A. D.; Price, P. D. Tetrahedron:
Asymmetry 2005, 16, 2833.
Zn
O
OR2
H
(2) (a) Brinner, K.; Ellman, J. A. Enantioselective Synthesis of
b-Amino Acids; Juaristi, E.; Soloshonok, V. A., Eds.; Wiley
and Sons: Hoboken, 2005. (b) Cole, D. C. Tetrahedron
1994, 50, 9517. (c) Juaristi, E.; Lopez-Ruiz, H. Curr. Med.
Chem. 1999, 6, 983. (d) Abele, S.; Seebach, D. Eur. J. Org.
Chem. 2000, 1, 1. (e) Hart, D. J.; Ha, D. C. Chem. Rev. 1989,
89, 1447.
Figure 1 Rationalization of observed diastereoselectivity
The Reformatsky reaction can be applied to ketimines to
provide diastereomerically pure or enriched N-sulfinyl-
protected quaternary substituted b-amino esters (Table 1,
entries 4, 5, and 8). When using the Reformatsky reagent
derived from ethyl bromoacetate, the reaction was per-
formed at 0 °C to prevent Claisen condensation with the
b-amino ester product; this side reaction at room temper-
(3) Ishitani, H.; Ueno, M.; Kobayashi, S. J. Am. Chem. Soc.
2000, 122, 8180.
(4) Davis, F. A.; Szewczyk, J. M.; Reddy, R. E. J. Org. Chem.
1996, 61, 2222; and references cited therein.
(5) Tang, T. P.; Ellman, J. A. J. Org. Chem. 2002, 67, 7819; and
references cited therein.
(6) Clark, J. D.; Weisenburger, G. A.; Anderson, D. K.; Colson,
P.-J.; Edney, A. D.; Gallagher, D. J.; Kleine, H. P.; Knable,
C. M.; Lantz, M. K.; Moore, C. M. V.; Murphy, J. B.;
Rogers, T. E.; Ruminsky, P. G.; Shah, A. S.; Storer, N.;
Wise, B. E. Org. Process Res. Dev. 2004, 8, 51.
(7) Staas, D. D.; Savage, K. L.; Homnick, C. F.; Tsou, N. N.;
Ball, R. G. J. Org. Chem. 2002, 67, 8276.
Table 1 Reformatsky Reaction with N-tert-Butanesulfinylimines
O
R1
R1 R2
O
O
S
O
S
BrZn
OR3
2.5 equiv
R2
N
OR3
N
H
(8) Koizumi, T.; Hirai, H.; Yoshii, E. J. Org. Chem. 1982, 47,
4004.
1.0 equiv
70–100% yield
dr > 94:6
(9) Graf, E.; Boeddeker, H. Justus Liebigs Ann. Chem. 1958,
613, 111.
(10) Acros: (S)-3-amino-3-phenylpropionic acid ethyl ester
hydrochloride; CAS 167834-24-4.
Entry
R1
H
R2
Ph
R3
Et
Temp (°C) Yield (%) dra
1
2
3
4
5
6
7
8
0
97
>99:1
94:6
(11) Preparation of Zn/Cu
H
i-Bu Et
i-Pr Et
0
82
Large-scale reactions require the preparation of Zn as
previously described.15,16 The zinc was then thoroughly
dried in a vacuum oven at 70 °C for at least 24 h. The dried
Zn dust and CuCl were then combined in appropriate
amounts in a dry mortar, ground to a fine powder, then
transferred to the reaction vessel.
H
0
75
95:5
Me
Me
H
Ph
Et
0
quant.
65
>99:1
96:4
i-Pr Et
0
(12) Compound 2
Ph
t-Bu
r.t.
r.t.
r.t.
86
>99:1
96:4
A three-necked 1 L round-bottom flask, reflux condenser,
and addition funnel were oven-dried overnight, assembled
with a mechanical stirrer under positive argon pressure and
allowed cool to r.t. The flask was charged with Zn dust (31.3
g, 478 mmol, 10 equiv) and CuCl (4.7 g, 47.8 mmol, 1.0
equiv). The two solids were mixed under a slow stream of
nitrogen while the flask was dried with a flame. The flask
H
i-Bu t-Bu
88
Me
Ph
t-Bu
quant.
>99:1
a The dr was determined by HPLC analysis of crude b-amino ester
products.14
Synlett 2009, No. 6, 991–993 © Thieme Stuttgart · New York

LETTER
was allowed to cool to r.t. and dry THF (100 mL) was added
Synthesis of b-Amino Esters
993
concentrated in vacuo, the resultant residue dissolved in 100
mL 0.1 M aq HCl. The solution was washed with Et2O (100
mL) and hexanes (100 mL), and aqueous layer was basified
to pH = 9 by the addition of solid Na2CO3. The solution was
extracted with EtOAc (2 × 100 mL), washed with brine
(1 × 100 mL), the organics dried (Na2SO4), and concentrated
to afford (S)-3-amino-3-phenylpropionic acid ethyl ester (3)
as a colorless oil (6.05 g, 31.4 mmol, 73%). 1H NMR (300
MHz, CDCl3): d = 7.33–7.23 (m, 5 H), 4.41 (dd, J = 7.0 Hz,
6.7, 1 H), 4.15 (q, J = 7.0 Hz, 2 H), 2.64 (d, J = 6.7 Hz, 2 H),
1.92 (br s, 2 H), 1.23 (3 H, J = 7.0 Hz, 3 H). 13C NMR (300
MHz, CDCl3): d = 172.2, 144.8, 128.8, 127.6, 126.4, 66.7,
52.8, 44.4, 14.4. [a]D22 –3.8 (c 1.0, EtOH); lit. [a]D22 –2.4
(c 0.13, EtOH)8; [a]D22 –3.6 (c 1.0, EtOH).9
to produce a dark slurry. The resulting reaction mixture was
heated to reflux temperature and stirred vigorously for 30
min. The heating bath was then removed while maintaining
vigorous stirring, and the addition funnel was then charged
with ethyl bromoacetate (17.7 mL, 119.5 mmol, 2.5 equiv)
and dry THF (44 mL). CAUTION: EXOTHERMIC
REACTION. The ethyl bromoacetate solution was slowly
and carefully added dropwise until reflux was re-initiated.
The addition was continued at a rate that maintained a
controllable reflux. Once addition was complete, the
reaction mixture was stirred for an additional 30 min at
ambient temperature, then at 50 °C for 30 min. The reaction
mixture was then cooled to 0 °C, and the addition funnel
charged with N-tert-butanesulfinyl benzaldimine (1,
prepared as previously described,17 10.0 g, 47.8 mmol. 1.0
equiv) and dry THF (50 mL). This solution was then added
dropwise to the reaction mixture, which was stirred for an
additional 4 h at 0 °C. The reaction mixture was filtered
through a pad of Celite, washing the Zn and the filter pad
with Et2O (2 × 100 mL). The filtrate was washed with 0.25
M aq citric acid (200 mL), sat. aq NaHCO3 (2 × 200 mL),
sat. aq NaCl (1 × 100 mL), dried (Na2SO4), and concentrated
in vacuo to afford the N-tert-butanesulfinyl-protected b-
amino ester (13.8 g, 46.5 mmol, 97%) as a clear oil that
solidified upon standing. 1H NMR (300 MHz,CDCl3): d =
7.34–7.26 (m, 5 H), 4.78 (m, 1 H), 4.69 (m, 1 H), 4.09 (q,
J = 6.9 Hz, 2 H), 2.86 (d, J = 6.3 Hz, 2 H), 1.25 (m, 12 H).
13C NMR (75.5 MHz, CDCl3): d = 171.5, 140.9, 128.8,
128.2, 127.5, 61.1, 55.9, 42.5, 22.8, 14.3. ESI-LR: m/z calcd
for C15H23NO3S [M + H]+: 298.1; found: 298.0.
(14) Synthesis of Authentic Diastereomeric Mixtures
The crude reaction material of N-sulfinyl b-amino ester
products (5 mg) was dissolved in EtOH (0.5 mL) and 1.0 M
HCl in Et2O (0.5 mL). After stirring at r.t. for 1 h, the
reaction was concentrated, the residue dissolved in EtOH (2
mL), and concentrated again. The crude b-amino ester was
then dissolved in CH2Cl2 (1.0 mL) and DIPEA (0.3 mL), and
racemic tert-butanesulfinyl chloride (0.15 mL) was added.
The reaction was stirred overnight, then concentrated, and
filtered through a short SiO2 column (EtOAc–hexanes, 3:1).
The products were resolved by LC-MS and HPLC (20–70%
MeCN, 10 min).
(15) Perrin, D. D.; Armarego, W. L. F.; Perrin, D. R. Purification
of Laboratory Chemicals, 2nd ed.; Pergamon: Oxford, 1980,
547.
(16) Fürstner, A. In Organozinc Reagents: A Practical
Approach; Knochel, P.; Jones, P., Eds.; The Practical
Approaches in Chemistry Series, Oxford University Press:
Oxford, 1999, 287.
(13) Compound 3
A 500 mL round-bottom flask was charged with compound
2 (13.0 g, 43 mmol), EtOH (48 mL, 1.1 equiv), and 1 M HCl
in Et2O (87 mL, 87 mmol, 2.0 equiv). The reaction mixture
was stirred at r.t. for 30 min. The reaction mixture was
(17) Liu, G.; Cogan, D. A.; Owens, T. D.; Tang, T. P.; Ellman,
J. A. J. Org. Chem. 1999, 64, 1278.
Synlett 2009, No. 6, 991–993 © Thieme Stuttgart · New York