Asymmetric Phase Transfer Catalysis
for the Production of Non-proteinogenic
a-Amino Acids:
Application of C2-Symmetric Chiral
1,1’-Binaphthyl-derived
Quaternary Ammonium Bromides
Masaya Ikunaka, Ph. D.
Principal of Technology Development
Fine Chemicals Division
Fine Chemicals Department, Nagase & Co., Ltd.
Keiji Maruoka, Ph.D.
Professor
Department of Chemistry
Graduate School of Science, Kyoto University
東北大学 農学部 化学工学概論（2009 年 12 月）
1
学んでほしいこと（Lessons that you will learn）
 What looks ordinary in the lab is out of the ordinary
in the plant.
（学術論文では当たり前に書かれていることが，工業的には実施できないことがあ
る）
 Be skeptical about any premise.
（実験や考察の前提がいつも正しいとは限らない．状況が変われば，前提も変化す
る）
 Discovery consists of seeing what everybody has seen
and thinking what nobody has thought.
Albert von Szent-Györgyi (1893–1986)
（同じ現象でも見る人が変われば，違う考察と違う結論が導かれる）
2
The Ballad of East and West
Rudyard Kipling (1865–1936)
Oh, East is East, and West is West,
and never the twain (two) shall meet,
Till Earth and Sky stand presently
at God’s great Judgment Seat;
But there is neither East nor West, Border,
Nor Breed, nor Birth,
When two strong men stand face to face,
though they come
from the ends of the earth!
3
Oil is Oil, and Salt is Salt,
But the two can engage in reaction,
When a phase transfer catalyst comes into play,
although they stay apart in different phases!
Phase transfer catalyst
Organic phase
Organic phase
Inorganic phase
Inorganic phase
4
C2-Symmetric chiral 1,1’-binaphthyl-derived quaternary
ammonium salts
Ar
Ar
F
N+
Br
-
Ar =
N+
F
F
N
R3
H
R5
O
OR4
Q*
Organic phase
N
Br
OR4
N
R
-
3
R
+
K OH
-
R3
1
R
+
H2O
K Br
-
N
+
-
R1 R5
OR4
R2
O K
OR4
3
R1
R2
O
R2
Br
-
+
-
Ar
Ar
R2
Br
O Q*
+
Interface
R1
Aqueous phase
Ikunaka, M.; Maruoka, K. In Asymmetric Catalysis on Industrial Scale, 2nd ed.;
Wiley-VCH: Weinheim, in press.
5
a-Amino acids and their derived drug candidates
O
O
Br
N
N
OH
Cl
NH2
O
F
Cl
+
H3N
TsO
Asymmetric
phase transfer
catalysis
(PTC)
-
-
+
H3N
CO2Et
H
CO2
O
H
H
O
+
N
EtO2C
F
O
H CO2H
-
NH3
6
Starks’ Extraction Mechanism
Aliquat® 336
(CH2)7Me
+
Me(CH2)7
N Me Cl
-
(CH2)7Me
C7H15
NaCN
+
Cl
+
C8H17-Cl + Q CN
C7H15
H2O
-
C8H17-CN
+
CN
+
Q Cl
-
Organic phase
Aqueous phase
+
Na Cl
-
Anion partitioning
+
+ Q CN
-
+
Na CN
-
Starks, C. M. J. Am. Chem. Soc. 1971, 93, 195.
+
+
Q Cl
-
7
Makosza’s Interfacial Mechanism
+
PhCH2NEt3 Cl
Ph
CN
+
Et
-
Et
Cl
Ph
50% aq NaOH
H H
Ph
CN
Cl
CN
+
Organic phase
Q Cl
-
N Q
-
Ph
+
Ph
C
CN
Lipophilic ion pair
Ph
C
-
N Na
+
Ph
C
Interface
-
N Q
+ -
Na
OH
H2O
+
Na Cl
-
+
Aqueous phase
Makosza, M.; Serafinowa, B. Rocz. Chem. 1965, 39, 1223.
8
The first efficient asymmetric phase transfer catalyst
Cl
O
Cl
HO
(10 mol%)
N
MeO
N
50% aq NaOH
toluene
20 C, 18 h
(95% yield)
Me Cl
Cl
Cl
MeO
92% ee
Br
-
H
N-[(4-trifluoromethyl)
benzyl]cinchoninium
bromide
CF3
Cl
O
+
1) AlCl3
PhMe, 45 C
2) ClCH2CO2Et
NaI, K2CO3
PhMe, reflux
3) aq NaOH
PhMe, reflux
O
Cl
O
O
HO
Uricosuric
(+)-indacrinone
(MK-0197)
Dolling, U.-H.; Davis P; Grabowski, E. J. J. Am. Chem. Soc. 1984, 106, 446.
9
The first successful asymmetric phase-transfer-catalytic
alkylation of benzophenone imine of tert-butyl glycinate
O
Ph
Br
+
N
Cl
Ot-Bu
Ph
HO
Cl
N
CH2Cl2
25 C
50% aq NaOH
15 h
(95% yield)
N
Ph
N
H
Ph
N-Benzylcinchoninium chloride
O
Ph
N
Ot-Bu
Ph
H
(R)
64% ee
+
(10 mol%)
O
Ph
-
Filtrate
(R) > 99% ee
Crystals
(R) 8% ee
Ot-Bu
H
Cl
Recrystallization from n-hexane
Cl
O’Donnell, M. J.; Bennett, W. D.; Wu, S. J. Am. Chem. Soc. 1989, 111, 2353.
10
The active form of catalyst
O
Ph
Ph
O
Ph
Br
N
N
Ot-Bu
Ph
50% aq NaOH
CH2Cl2, 25 C
Ph
Ot-Bu
H
Ph
Ph
O
N
-
N
Br
HO
N
+
61% ee
N
60% ee
+
N
Rapid N- and O-alkylation
N
HO
Ph
Br
-
Ph
60% ee
O’Donnell, M. J.; Wu, S.; Huffman, J. C. Tetrahedron 1994, 50, 4507.
11
N-Anthracenylmethyl-dihydrocinchonidinium chloride
O
Ph
N
Cl
Ot-Bu
Ph
-
N
+
Ph
Cl
+
N
Br
OH
O
N
rt, 18 h
toluene
N
(10 mol%)
50% aq KOH
The least uncatalyzed
alkylation in the use of aq KOH
Active form of the catalyst
generated in situ
N
Ph
O
O
Ph
+
Ot-Bu
H
Ph
H3O
(85%)
H2N
OH
H
Ph
Lygo, B.; Wainwright, P. G. Tetrahedron Lett. 1997, 38, 8595.
94% ee
12
Blockage of the second alkylation by the benzophenone imine
O
Ph
N
N
Ph
O
Ph
Ot-Bu
Ph
H H
O
Ph
Ph
OEt
H H
pKa 18.7 (DMSO)
-
Cl
OEt
H Me
pKa 22.8 (DMSO)
Ot-Bu
Ot-Bu
N
N
Ph
H
O
Ph
N
Ot-Bu
N
+
O Na
-
+
O Na
H
Cl
O’Donnell, M. J. Acc. Chem. Res. 2004, 37, 506.
13
Cinchona alkaloids in pseudoenantiomeric forms
N-Benzylcinchonidium
chloride
N-Benzylcinchoninium
chloride
H
+
+
Ph
OH
Ph
HO
-
N
Cl
N
-
Cl
H
N
N
(10% mol)
O
Ph
N
Ph
Ot-Bu
50% aq NaOH
CH2Cl2
N
Ph
20 C, 12 h
+
Br
Cl
O
Ph
82% yield
O
Ot-Bu
H
H3O
+
H 2N
OH
H
(S)
62% ee
Cl
O’Donnell, M. J.; Bennett, W. D.; Wu, S. J. Am. Chem. Soc. 1989, 111, 2353.
Cl
14
O-Allyl-N-anthracenylmethyl-cinchonidinium bromide
O
Ph
N
+
N
CH2Cl2
(87% yield)
CsOH•H2O
O
Ph
O
(10 mol%)
Br
-78 C, 23 h
N
Ph
N
Ot-Bu
Ph
Ph
Br
-
Ot-Bu
H
Ph
Use of solid base
to minimize the possibility of water
in the organic phase (CH2Cl2)
to apply lower temp (-60 to -78 C)
than are possible with 50% aq KOH
94% ee
Corey, E. J.; Xu, F.; Noe, M. C. J. Am. Chem. Soc. 1997, 119, 12414.
15
Cinchonidinium-induced enantioface selectivity
O
Ph
CsOH
Ph
N
N
-
O Q*
Ot-Bu
Ph
Q*
Br
Ot-Bu
CsBr
+
-
Br
Ph
H2O
+
Chiral ammonium E-enolate
The quinoline ring of the cinchonidinium moiety
blocks the re (front) face of the E-enolate.
-
N
+
Q*
+
-
E
Br
Br
O
N
Attack of the electrophile (E+) takes place
at the si (rear) face of the E-enolate.
• Corey, E. J.; et al.
J. Am. Chem. Soc. 1997, 119, 12414.
• Lygo, B.; et al.
Acc. Chem. Res. 2004, 37, 518.
O
Ph
N
Ot-Bu
Ph H E
16
Cinchonidine-derived ammonium salts
O
Ph
X
N
-
N
+
R1
O R
2
Ph
10 mol%
Ot-Bu
+
Ph
Br
O
Ph
base
solvent
N
temp
time
Ph
N
O’Donnell
(1989)
R1 = CH2Ph
R2 = H
(O-alkylation in situ)
X = Cl
Lygo
(1997)
R1 = Anthracenylmethyl
R2 = H
(O-alkylation in situ)
X = Cl
Corey
(1997)
R1 = Anthracenylmethyl
R2 = CH2CH=CH2
X = Br
Ot-Bu
H
Ph
20 C
12 h
82% yield
62% ee
(4-Cl-C6H4CH2Br)
50% aq KOH
toluene
rt
18 h
85% yield
94% ee
(after C- and Ndeprotection)
CsOH•H2O
CH2Cl2
-78 C
23 h
87% yield
94% ee
50% aq NaOH
CH2Cl2
17
Asymmetric alkylation of N,C-protected alanine
by the use of O’Donnell’s catalyst
Cl
R Br
(1.1 equiv)
O
N
Ot-Bu
O
N
CH2Cl2
25 C, 18 h
Mixed solid base
(10 mol%)
Ot-Bu
R
K2CO3/KOH
(R)
(10 equiv each)
Cl
HO
N
N
Cl
H
-
44% ee 80% yield
+
Ph
N-Benzylcinchoninium bromide
R=
48% ee 87% yield
Cl
36% ee 78% yield
O’Donnell, M. J.; Wu, S. Tetrahedron: Asymmetry 1992, 3, 591.
18
Asymmetric alkylation of N,C-protected alanine
by the use of Lygo’s catalyst
Cl
R Br
(1.2 equiv)
O
N
Cl
(S) O
N
toluene
rt, 30 min
Ot-Bu
Mixed solid base KOH fused with K2CO3
Ot-Bu
R
AcOH, THF-H2O
(O-alkylation in situ )
O
H2N
(10 mol%)
Ot-Bu
R
N
+
87% ee 95% yield
Br
OH
-
R=
N
N-Anthracenylmethyldihydrocinchonidinium chloride
77% ee 72% yield
Cl
Lygo, B.; Crosby, J.; Peterson, J. A. Tetrahedron Lett. 1999, 40, 8671.
19
Asymmetric alkylation of N,C-protected alanine
by the use of Jew and Park’s catalyst
R Br
(5 equiv)
O
O
N
N
Ot-Bu
Ot-Bu
toluene
-35 C
R
RbOH
(10 mol%)
(5.0 equiv)
Br
(S)
-
N
1N HCl, THF, rt
O
H2N
+
Ot-Bu
R
O
N
F
F
F
O-Allyl-N-(2,3,4-trifluorobenzyl)dihydrocinchonidinium chloride
95% ee 91% yield
R=
85% ee 87% yield
Jew, S-s.; et al. J. Org. Chem. 2003, 68, 4514.
20
a-Benzylalanine tert-butyl ester
O
R1
Br
O
Ph
N
Ot-Bu
R1
solvent
base
temp
N *
+
H3O
Ot-Bu
Ph
Ot-Bu
Ph
R1 = 4-C6H4
Lygo
(1999)
R1 = 4-C6H4
R2 = Anthracenylmethyl
R3 = H
(O-Benzylation in situ)
X = Cl
toluene
K2CO3/KOH
rt
87% ee (S)
95% yield
Jew &
Park
(2003)
R1 = 2-Naphthyl
R2 = 2,3,4-Trifluorobenzyl
R3 = Ally
X = Br
toluene
RbOH
-35 C
95% ee (S)
91% yield
Ph
HO
N
X
H2N *
CH2Cl2
44% ee (R)
K2CO3/KOH 80% yield
rt
(Schiff base)
H
N
O
+
O’Donnell
(1992)
-
+
N
R2
3
OR
N
Br
21
Cinchona alkaloid-derived chiral phase transfer catalysts
Q*
R2
-
+
X
N
R
X
-
N
+
R4
OR5
N
H
O
Q*
Ot-Bu
3
R1
R4
-
+
X
Br
O
R2
N *
R3
R4 = Reactive alkyl
(benzyl, allyl, etc.)
Ot-Bu
R1 R4
 Catalyst loading of 10 mol%
 R1 = H (a-alkyl glycine)
 Benzophenone imine (R2 = R3 = Ph)
for monoalkylation with little racemization
Cinchonidinium
 rt (aq KOH) to -78 C (solid CsOH•H2O)
R5O
N
N
-
X
+
R4
Cinchoninium
 R1 = Me (a-alkyl alanine)
 Aromatic aldehyde imine
(R2 = 4-Cl-C6H4, 2-naphthyl; R3 = H)
 Solid base:
rt (K2CO3/KOH) to -35 C (RbOH)
22
Denagliptin tosylate, a dipeptidyl IV (DPP-IV) inhibitor
O
BocHN
CONH2
OH
+
HN
p-TsOH
F
F
F
O C3H7
P
O
O
T3P =
Patterson, D. E.; et al.
Org. Process Res. Dev.
2009, 13, 900.
C3H7
P
O
O
P O
C3H7
1) T3P, i-Pr2NEt
AcOEt, 50 C
2) T3P, 78 C
3) p-TsOH, i-PrOH
70 C
4) ReX (iPrOH/H2O)
(78%)
CN
O
H2N
N
p-TsOH
DPP-IV inhibitor for the treatment
of type 2 diabetes that increases the levels
of active GLP-1 (glucagon-like peptide-1)
and GIP (glucose-dependent insulinotropic peptide),
both of which play important roles in regulating
blood glucose level
F
F
F
Denagliptin tosylate
23
Cinchonidine-derived phase transfer catalyst
O
Ph
N
Br
(10 mol%)
Ot-Bu
Ph
CH2Cl2 (5 vol)
45% aq KOH (10 equiv)
O
Br
cooling time
F
0 C
-
N
+
N
(1.5 equiv)
O
Ph
N
Ph
F
F
Ot-Bu
F
(S)/(R) (80:20)
Crystallization (AcOEt/heptane)
scale
cooling time
(S)/(R)
yield
Small
5 – 10 min
99 : 1
55%
large (kg)
30 – 60 min
50 : 50
65%
Patterson, D. E.; et al. Org. Process Res. Dev. 2007, 11, 624.
24
Decomposition of the catalyst in the absence of electrophile
Br
N
-
 Hofmann
degradation
+
O
H
N
45% aq KOH
CH2Cl2
O
N
CO2t-Bu
N
N
Ph
Ph
 Alkylation
 O-Deallylation
N
N
+
CO2t-Bu
N
O
N
N
Ph
HO
Ph
Patterson, D. E.; et al. Org. Process Res. Dev. 2007, 11, 624.
25
Optimized procedures for the use
of the cinchonidine-derived phase transfer catalyst
F
F
(1.5 equiv)
Br
Ph
N
Br
CO2t-Bu
O
-
N
+
Ph
CH2Cl2 (5 vol)
N
0 C
10 mol%
0–5 C
0–5 C
15–30 min
5h
Ph
45% aq KOH (10 equiv)
N
CO2t-Bu
(S)/(R) (80:20)
Ph
> 99% ee (56%)
after crystallization
(AcOEt/heptane)
F
F
Patterson, D. E.; et al.
Org. Process Res. Dev. 2007, 11, 624.
26
Issues to be addressed in up-scaling the asymmetric
phase-transfer-catalytic synthesis of a-amino acids
2
R
3
N
R3
H
1
O
Q*
4
OR
R1
4
+
R5
+
X
-
2
Base
X
Water-immiscible
organic solvent
O
R2
N *
R3
OR4
R1 R5
 Chiral quaternary ammonium salt catalyst should be base-proof
and exhibit supreme enantioselectivity even at its extremely low
loadings (« 1 mol%).
 Aqueous base should always be substituted for solid base, such as
CsOH•H2O, that is more expensive and difficult to handle on scale.
 Aromatic aldehyde imine (R3 = H) can be employed even when
R1 = H since it is much easier to prepare than benzophenone imine
(R2 = R3 = Ph).
 Amino acid esters should be produced that are easier to manipulate
in the ensuing steps than the corresponding tert-butyl ones.
27
BIRT-377, LFA-1 antagonist
O
Br
O
Br
N
N
Cl
H2N
O
Cl
OR
R = Et, Me
N-Aryl-substituted hydantoin
 identified as a potent inhibitor of the interaction between ICAM-1
(intercellular adhesion molecule-1) and LFA-1 (lymphocyte functionassociated antigen-1)
 nominated for a preclinical candidate in the treatment of inflammatory
and immune disorders
at Boehringer Ingelheim Pharmaceuticals Inc.
Yee, N. K. Org. Lett. 2000, 2, 2781.
28
(R)-a-(4-Bromobenzyl)alanine esters
 Seebach’s self-regeneration of stereocenters1
O
O
H
Br
BnO
N
H
BnO
CO2H
Cbz-L-Ala
N
O
H Ph
O
 Organocatalytic asymmetric amination2
Br
BnO2C
BnO2C
N
N
+
CO2R
R = Et, Me
N
N
H
H2N
N
+
HN N
(15 mol%)
CHO
1. Kapadia, S. R.; et al. J. Org. Chem. 2001, 66, 1903.
2. Barbas, III, C. F.; Chowadari, N. S. Org. Lett. 2005, 7, 867.
29
Self-regeneration of stereocenters
CO2H
BnO
O
PhC(OMe)2
ZnCl2, SOCl2
NH
THF
0 C, 4 h
(76%)
O
BnO
H
O
N
Br
O
Ph
Br
Cbz-L-Ala
cis/trans (25:1)
O
Br
BnO
N
O
O
H Ph
KN(SiMe3)2
THF
-27 C (1 h) to rt (1 h)
(75%)
1. 30% HBr, AcOH
rt, 20 h
2. HCl (g), EtOH
70 C, 34 h
(87%)
Br
H2N
CO2Et
> 99% ee
66% overall yield from Cbz-L-Ala over 4 steps
Kapadia, S. R.; et al. J. Org. Chem. 2001, 66, 1903.
30
3-(4-Bromophenyl)-2-methylpropanal
CHO
+
N CO2
CHO
-
H2N
LiAlH4, AlCl3
THF
CHO
+
65 C, 11 h
(85%)
rt, 48 h
(80%)
Br
Br
OH
Br
(COCl)2, Et3N
DMSO
CH2Cl2
-60 C, 5 min
(95%)
CHO
Br
(65% overall yield)
Barbas, III, C. F.; Chowadari, N. S. Org. Lett. 2005, 7, 867.
31
Organocatalytic asymmetric amination
O
N
H
1.
N
H
HN N
(15 mol%)
+
Br
N
N
CO2Bn
CO2Bn
N
O
MeCN
rt, 3 h
H
HN
N
CO2Bn
CO2Bn
2. Recrystallization from
AcOEt/hexane (3:7)
(71%)
Br
N
N
N
BnO2C
N
> 99% ee
N N
H
N
CO2Bn
Br
Barbas, III, C. F.; Chowadari, N. S. Org. Lett. 2005, 7, 867.
32
(R)-a-(4-Bromobenzyl)alanine methyl ester
HN
OHC
N
CO2Bn
CO2Bn
2. Me3SiCHN2
(2 M in hexane)
PhMe/MeOH (2:1)
rt, 10 min (99%)
Br
HN
MeO2C
1. NaClO2, NaH2PO4
2-methyl-2-butene
t-BuOH/H2O (5:1)
4 C, 12 h (86%)
N
COCF3
CO2Bn
SmI2
(0.1 M in THF)
MeOH
MeO2C
HN
CO2Bn
(CF3CO)2O
Py
rt, 48 h
(99%)
Br
H
N
MeO2C
NH2
CO2Bn
HBr, AcOH
rt, 24 h
(99%)
rt, 30 min
(98%)
Br
Br
N
MeO2C
CO2Bn
Br
38% overall yield from 4-Br-C6H4CHO over 9 steps
Barbas, III, C. F.; Chowadari, N. S. Org. Lett. 2005, 7, 867.
33
Asymmetric phase-transfer-catalytic alkylation
Br
Br
H
N
F
F
MeO
N
CO2Et
PhMe, 0 C,10 h
Cl
CsOH•H2O
(5 equiv)
aq Citric acid (0.5 M)
THF, rt
Cl
MeO
(1.5 equiv)
Br
CO2Et
F
Br
(1 mol%)
MeO
N
MeO
H2N
+
CO2Et
90% ee
F
MeO
MeO
F
(S)
F
Br
-
2-step overall yield of 86%
• Self-regeneration of chiral centers:
66% (4 steps)
• Organocatalytic asymmetric amination: 38% (9 steps)
K. Maruoka, et al. Tetrahedron Lett. 2005, 46, 8555.
34
Issues to be addressed in up-scaling the asymmetric
phase-transfer-catalytic synthesis of a-amino acids
2
R
3
N
R3
H
1
O
Q*
4
OR
R1
4
+
R5
+
X
-
2
Base
X
Water-immiscible
organic solvent
O
R2
N *
R3
OR4
R1 R5
 Chiral quaternary ammonium salt catalyst should be base-proof
and exhibit supreme enantioselectivity even at its extremely low
loadings (« 1 mol%).
 Aqueous base should always be substituted for solid base, such as
CsOH•H2O, that is more expensive and difficult to handle on scale.
 Aromatic aldehyde imine (R3 = H) can be employed even when
R1 = H since it is much easier to prepare than benzophenone imine
(R2 = R3 = Ph).
 Amino acid esters should be produced that are easier to manipulate
in the ensuing steps than the corresponding tert-butyl ones.
35
Maruoka Catalysts®
3
R2
N
H
O
4
4
OR
toluene
+
5
R
X
2
1
R
48% aq KOH
O
R2
N
OR4
R1 R5
1
Ar
Ar
F
N
Ar
Ar =
+
Br
-
F
N
+
Br
-
F
Ar
C2-Symmetric chiral 1,1’-binaphthyl-derived quaternary ammonium bromides
work wonders
in the enantioselective synthesis of a-amino acids
by asymmetric alkylation
36
Maruoka Catalysts® offer solutions
3
R2
N
H
O
4
4
OR
R1
1
Maruoka CatalystTM
+ R5
X
2 48% aq KOH
toluene
O
R2
N
OR4
R1 R5

The catalyst, being invulnerable to the basic conditions applied,
shows excellent performance in both reactivity (TON) and
enantioselectivity such that 0.1–0.5 mol% of it suffices to obtain
alkylated products of high enantiomeric purity in good yield.

Easy-to-handle and inexpensive aq KOH solution can be used
irrespective of substrates used, whether R1 is H or not.

Easy-to-prepare aromatic aldehyde imine of glycinate (R1 = H)
can undergo mono-alkylation with high enantioselectivity.

Methyl and ethyl esters of N-protected a-amino acid (R4 = Me, Et)
of high ee can be produced in good yield, which are easier
to manipulate than the corresponding tert-butyl esters.
37
a-Amino acids and their derived drug candidates
O
O
Br
N
N
OH
Cl
NH2
O
F
Cl
+
H3N
TsO
Asymmetric
phase transfer
catalysis
(PTC)
-
-
+
H3N
CO2Et
H
CO2
O
H
H
O
+
N
EtO2C
F
O
H CO2H
-
NH3
38
(S)-N-Acetylindoline-2-carboxylic acid esters, intermediates
for potent angiotensin converting enzyme (ACE) inhibitors
H
H
EtO2C
H
H
N
N
H
O
Vincent, N.; et al. Tetrahedron Lett. 1982, 23, 1677.
H CO2H
Peridolpril
CO2R
N
H
Ac
H
N
EtO2C
O
Carba-analog
of peridolpril
H
R = Me, t-Bu
H CO2H
CO2R
H NHAc
Br
Stanton, J. L.; et al. J. Med. Chem. 1983, 26, 1277.
1. Buchwald, S. L.; et al. J. Am. Chem. Soc. 1997, 119, 8451.
2. Maruoka, K.; et al. J. Am. Chem. Soc. 2003, 125, 5139.
39
Asymmetric hydrogenation of eneamide
CO2Me
Br
I
Pd(OAc)2, Et3N
+
100 C, 2.5 h
(84%)
NHAc
CO2Me
NHAc
Br
(1.1 equiv)
+
rt
2.5 h
[(COD)Rh ]OTf
(0.1 mol%)
MeOH
H2 (30 psig)
(95%)
CO2R
H NHAc
Br
-
Et Et
P
P
Et
(S,S)-Et-DUPHOS
(0.1 mol%)
Et
Pd2(DBA)3 (10 mol% Pd)
P(o-tolyl)3 (20 mol%)
N
Cs2CO3, PhMe
100 C, 15 h (98%)
Ac
O
99% ee
2-step overall yield of 80%
CO2Me
DBA =
Ph
H
99% ee
Ph
Buchwald, S. L.; et al. J. Am. Chem. Soc. 1997, 119, 8451.
40
N-Spiro-C2-symmetric bis-1,1’-binaphthyl-derived
chiral ammonium bromide
O
Ph
N
Ar
F
Ot-Bu
Ph
1 mol%
Br
Ar
PhMe/50% aq KOH (1:3)
0 C, 24 h under Ar
F
Ar =
N
H
-
F
(R,R)
AcHN
Ot-Bu
Ph
Br
O
O
Br
+
(1.2 equiv)
Br
Ph
N
1. 1 M aq citric acid
THF, rt, 3 h
2. AcCl, Et3N, CH2Cl2
0 C, 0.5 h
Ot-Bu
H
99% ee
Br
86% overall yield over 3 steps
Maruoka, K.; et al. J. Am. Chem. Soc. 2003, 125, 5139.
41
Alkylation of protected Gly using N-Spiro-C2-symmetric
chiral ammonium bromide of bis-1,1’-binaphthyl structure
O
Ph
Ar
F
N
Ot-Bu
Ph
N+
R-X (1.2 equiv)
PhMe/50% aq KOH (1:3)
0 C under Ar
O
Ph
N
Ph
Br
-
F
Ar =
F
Ar
(S, S)
Ot-Bu
H R
Ph
1 mol%
99% ee
90% (12 h)
0.5 mol%
99% ee
85% (36 h)
Br
R -X
1 mol%
99% ee
80% (24 h)
Br
0.2 mol%
99% ee
72% (48 h)
I
(5 equiv)
-15 C
sat aq CsOH
1 mol%
Maruoka, K. et al. J. Am. Chem. Soc. 2003, 125, 5139.
98% ee
89% (10 h)
42
Alkylation of protected a-alkyl a-amino acids using N-Spiro-C2symmetric chiral ammonium bromide of bis-1,1’-binaphthyl structure
4-Cl-Ph
N
CO2t-Bu
F
R1
(0.25 M)
PhMe/CsOH•H2O (5 equiv)
R2-X (1.2 equiv)
0 C under Ar
4-Cl-Ph
Ar
N
CO2t-Bu
Ar
Br
F
Ar =
N+
1 mol%
F
-
(S, S)
4-Cl-Ph = 4-Cl-C6H4-
R1 R2
R1 = Me
0.5 M aq
citric acid
THF
H2N
R2-X
CO2t-Bu
Ph
Br
85% (0.5 h)
98% ee
R1 = Me
I
(5 equiv)
71% (0.3 h)
99% ee
R1 = CH2CH(Me)2
Br
70% (1 h)
93% ee
R1 R2
Maruoka, K. et al. J. Am. Chem. Soc. 2000, 122, 5228.
43
Sequential double alkylation using N-spiro-C2-symmetric
chiral ammonium bromide of bis-1,1’-binaphthyl structure
4-Cl-Ph
N
Ar
CO2t-Bu
F
4-Cl-Ph = 4-Cl-C6H4(0.25 M)
PhMe
1.
(1 equiv)
CsOH•H2O
- 10 C
(5 equiv)
2
2. R -X (1.2 equiv) under Ar
0 C
R1-X
4-Cl-Ph
N
Br
F
(S, S)
R2-X
R1-X
Br
R1 R2
0.5 M aq citric acid
THF
-
Ar
CO2t-Bu
(3.5 h)
H2N
F
Ar =
N+
1 mol%
Ph
Br
(0.5 h)
98% ee (R)
80%
CO2t-Bu
R1 R2
Ph
(2 h)
Br
Br
(0.3 h)
Maruoka, K. et al. J. Am. Chem. Soc. 2000, 122, 5228.
92% ee (S)
74%
44
Alkylation of simple esters of Gly benzophenone imine
O
Ph
Ar
N
Ph
R1-X (1.2 equiv)
PhMe/50% aq KOH (1:3)
0 C under Ar
1 mol%
N
Ar (S, S)
Br
F
Br
OR
H R1
R1-X
F
Ar =
N+
-
O
Ph
Ph
F
OR
Ph
I (5 equiv)
sat aq CsOH
- 15 C
Br
R = Me
82% (3 h)
97% ee
R = Et
96% (2 h)
98% ee
99% (2 h)
97% ee
Maruoka, K. et al. Tetrahedron Lett. 2004, 45, 1675.
75% (3 h)
93% ee
45
Alkylation of simple esters of Ala 4-Cl-benzaldehyde imine
O
4-Cl-Ph
Ar
N
F
OR
R1-X (1.2 equiv)
PhMe/CsOH•H2O (5 equiv)
-20 C, 3–5 h under Ar
F
Ar =
N+
1 mol%
F
-
Br
Ar (S, S)
O
N
4-Cl-Ph
OR
Br
4-Cl-Ph = 4-Cl-C6H4-
R1
R1-X
1 M HCl
THF
O
H2N
R
Ph
Br
R = Me
81%
85% ee
R = Et
82%
98% ee
OR
1
Ph
Maruoka, K. et al. Tetrahedron Lett. 2004, 45, 1675.
89%
88% ee
Br
80%
82% ee
46
Manipulations of the ethyl functionalities
Ph
N
Ph
CO2Et
H
40% MeNH2
in MeOH
a-Np =
a-Np
O
BocHN
rt, 8 h
(98%)
97% ee
1. 1 M HCl/THF, rt, 2 h
BocHN
2. (Boc)2O, sat aq NaHCO3
THF, rt, 30 min
(quant)
CO2Et
H
a-Np
NHMe
H
a-Np
DIBAL-H
PhMe
97% ee
O
BocHN
-78 C, 2 h
(95%)
H
H
a-Np
97% ee
O
H2N
CO2Et
Ph
98% ee
(Boc)2O, NaHCO3 BocHN
THF, rt, 12h
(97%)
CO2Et
Ph
DIBAL-H
BocHN
PhMe
-78 C, 2 h
(81%)
Maruoka, K. et al. Tetrahedron Lett. 2004, 45, 1675.
H
Ph
98% ee
47
N-Protection of Gly esters for monoalkylation
Ph
NH
+
-
O
+
Cl H3N
N
OR
Ph
NH4 Cl
(81%)
Ph
O
H2N
Ph
-
Ph
N
OR
N
H
MgBr
OR
Ph
+
MeOH
O
Ph
CH2Cl2
H
O
OR
*
Ph
R1
Ar
O
PhMgBr
Et2O
Ph C
N
H2O
O
Ar
N
Ar
OR
N
H
O
*
OR
R1
1. O’Donnell, M.; Polt, R. T. J. Org. Chem. 1982, 47, 2663.
2. Pickard, P. L.; Tolbert, T. L. Org. Syntheses; Wiley-VCH: New York, 1973;
Coll. Vol. V, pp 520-522.
48
Intermediacy of mono-alkylation product in the sequential
asymmetric double alkylation
Cl
1. R1-X (1 equiv)
- 10 C
N
CO2t-Bu
PhMe
CsOH•H2O
(5 equiv)
under Ar
Ar
N+
Br
-
Cl
N
CO2t-Bu
1 mol%
H R1
2. R2-X (1.2 equiv)
0 C
Ar
F
(S, S)
F
Ar =
Cl
N
F
CO2t-Bu
R1 R2
Maruoka, K. et al. J. Am. Chem. Soc. 2000, 122, 5228.
49
Intermediacy of mono-alkylation product in the sequential
asymmetric double alkylation
Cl
1. R1-X (1 equiv)
- 10 C
N
CO2t-Bu
PhMe
CsOH•H2O
(5 equiv)
under Ar
Ar
Cl
N
N+
Br
-
F
F
Ar =
H R1
2. R2-X (1.2 equiv)
0 C
Ar
(S, S)
1 mol%
CO2t-Bu
F
Maruoka, K. et al.
J. Am. Chem. Soc. 2000, 122, 5228.
Cl
N
CO2t-Bu
R1 R2
50
Mono-alkylation of
4-chlorobenzaldehyde imine of glycine t-butyl ester
Cl
1 mol%
N
Ar
CO2t-Bu
F
(0.15 M)
R-X (1.2 equiv)
N
+
F
Ar =
PhMe/50% aq KOH (3:1)
0 C under Ar
Ar
Cl
N
Br
-
F
(R,R)
CO2t-Bu
R-X
H R
Ph
Br
Br
I
(10 equiv)
1 M HCl
THF
0 C, 0.5 h
H2N
CO2t-Bu
H R
2h
99%
98% ee
2h
84%
92% ee
5h
93%
99% ee
Maruoka, K. et al. Tetrahedron: Asymmetry 2006, 17, 603.
51
Enantiofacial differentiation of the prochiral enolate
R5 X
can approach only the re (front)
face of the (E)-enolate
(S,S)-BBN
F
F
+
N
F
F
R3
R1
N
(E)-Enolate
R2
F
-
O
OR4
R3 R1
F
R2
R5
OR4
N
(R)
O
The two 3,4,5-F3-C6H2 groups create
a chiral molecular pocket shielding the si (rear) face of the (E)-enolate
1. Maruoka, K.; et al. J. Am. Chem. Soc. 1999, 121, 6519.
2. Maruoka, K.; et al. J. Am. Chem. Soc. 2003, 125, 5139.
52
C2-Symmetric mono-1,1’-binaphthyl-derived
chiral ammonium bromide
Ar
Ar
F
N
+
Br
-
N
F
Ar =
+
Br
-
F
Ar
Ar
(S)-MBN
(S,S)-BBN
Ph
Ph
N
Br (1.2 equiv)
CO2t-Bu
50% aq KOH/PhMe (1:1)
0 C
Ph
(S)-MBN
(S,S)-BBN
Ph
N
Ph
H
CO2t-Bu
Ph
0.05 mol%
2h
98% yield
99% ee
0.01 mol%
9h
92% yield
98% ee
0.05 mol%
24 h
22% yield
85% ee
Maruoka, K.; et al. Angew. Chem. Int. Ed. 2005, 44, 1549.
53
The less lipophilic catalyst can enter the interface more easily
Ar
Ar
F
N+
Br
Ar =
-
F
N+
Br
-
F
Ar
Q*
(S)-MBN
-
+
Ar
Br
(S,S)-BBN
The Makosza interfacial mechanism
R
2
N
R3
H
R5
O
OR4
Q*
Organic phase
Br
-
+
O
R2
N
Br
R
R1 R5
R1
OR4
R2
N
-
3
R
+
K OH
-
O Q*
3
R
R1
K Br
-
N
+
+
H2O
OR4
R2
O K
-
OR4
3
Interface
+
R1
Aqueous phase
Maruoka, K.; et al. Angew. Chem. Int. Ed. 2005, 44, 1549.
54
Powerful chiral phase transfer catalyst
F
 At least 20 times more active than
the N-spiro-bis-binaphthyl-derived catalyst
F
F
N
+
Br
 Effective in the asymmetric alkylation of
4-chlorobenzaldehyde imine of Ala esters
-
(Angew. Chem. Int. Ed. 2005, 44, 1549)
 Effective in the asymmetric alkylation of
4-chlorobenzaldehyde imine of Gly esters
F
(Tetrahedron: Asymmetry 2006, 17, 603.)
F
(S)-MBN
F
Ar
N
CO2t-Bu
Ar = 4-Cl-C6H4
Ar
N
CO2t-Bu
(R) (1 mol%)
PhMe/50% aq KOH
0 C, 2 h under Ar
(S) (0.05 mol%)
CsOH•H2O (5 equiv)
PhMe, -20 C, 1 h
H2N
H2N
CO2t-Bu
Ph
98% ee (63%)
CO2t-Bu
98% ee (95%)
55
ortho-Magnesiation for the catalyst synthesis
CO2H
CO2H
Mg(TMP)2
THF
1) SOCl2
CO2i-Pr
0 C–rt
CO2i-Pr
2) i-PrOH
Py
(94%)
TMP =
Br
MgTMP
CO2i-Pr
CO2i-Pr
N
Br2
CO2i-Pr
-78 C–rt
(89%)
CO2i-Pr
MgTMP
1. Maruoka, K.; et al. J. Org. Chem. 2003, 68, 4576.
2. Maruoka, K.; et al. Angew. Chem. Int. Ed. 2005, 44, 1549.
Br
56
Suzuki-Miyaura cross coupling for the catalyst synthesis
Br
CO2i-Pr
CO2i-Pr
Br
Ar
ArB(OH)2
Pd(OAc)2
PPh3
CO2i-Pr
F
CO2i-Pr
K2CO3
DMF, 90 C
(94%)
Ar
Ar =
F
F
1) LiAlH4
THF
0 C–rt
2) PBr3
THF
0 C–rt
(91%)
Ar
Ar
Br
Br
Ar
Bu2NH
MeCN
+
N
reflux
(89%)
Br
-
Ar
1. Maruoka, K.; et al. J. Org. Chem. 2003, 68, 4576.
2. Maruoka, K.; et al. Angew. Chem. Int. Ed. 2005, 44, 1549.
57
Exquisite compounds derived from (S)-allylglycine
OH
N-Acylimminium
ion cyclization
Iodolactonization
O
H
N
CO2H
H2N
Boc
CO2H
H
R1
Heck reaction
N
H
OR2
O
Rh-catalyzed
hydroformylation
Ar
H
Boc
N
H
CO2t-Bu
N
CO2Me
Boc
1. Rutjes, F. P. J. T.; et al. Org. Biol. Chem. 2005, 3, 3435.
2. Rutjes, F. P. J. T.; et al. J. Chem. Soc. Perkin Trans. I 2000, 4197.
58
Synthetic plan for (S)-allylglycine ester
-
O
+
Cl H3N
-
X H3N
F
4
OR
OR4
F
R4  t-Bu
Base
F
Base•HCl
N+
Br
O
-
H2N
O
H2N
Ar
O
+
OR4
F
4
OR
F
(R)-MBN
O
F
Ar
HX
H2O
O
H2O
O
O
Ar
N
aq KOH/PhMe
4
OR
Aromatic aldehyde imine
Ar
N
OR4
Br
59
Production of ethyl (S)-allylglycinate on scale
Cl
- +
H3N
CO2Et
PhMe
Ph
O
(1.0 equiv)
-
+
TsO H3N
CO2Et
H
Et3N (1.0 equiv)
H2O
Aq layer
Et3N•HCl
99.6% ee (70% yield)
PhMe layer
ReX from EtOH/AcOEt
Ph
N
CO2Et
(94%)
• 48% aq KOH (2.5 equiv)
• (R)-MBN (0.1 mol%)
•
Br (1.1 equiv)
TsOH•H2O (1.1 equiv)/AcOE
5 C, 6 h
(94%)
Ph
N
CO2Et
H
92.3% ee
60
Asymmetric phase transfer catalysts
of a C2-symmetric chiral 1,1’-binaphthyl type
O
3
 BBN: effective at not more than 1 mol%.
Ar
MBN: effective at not more than 0.5 mol%.
MBN is at least 20 times more active than BBN.
N
4
OR4
H H
R4  t-Bu
 Mono-alkylation is possible
with aromatic aldehyde imine of glycinate
O
Ar
 Esters other than t-butyl ones are tolerated
N
4
OR4
H R1
Ar
Ar
F
N+
Br
-
Ar =
N+
F
Br
-
F
Ar
(S,S)-BBN
Ar
(S)-MBN
61
Chiral analog of FTY720
O
HO
Novartis Pharmaceutical Corporation
H2N
Prasad, R.; et al. Org. Process Res. Dev. 2008, 12, 1164.
Sphingosine
kinase
FTY720 (Fingolimod)
7
HO
(S)-FTY720-phosphate
7
in vivo
O
(HO)2P
HO
H2N
HO
O
H2N
 Immunomodulator acting via sphingosine 1-phosphate (S 1 P) receptor agonism
 The first S 1 P receptor modulator being evaluated in a phase-III clinical study
 Potential therapeutic agent to treat autoimmune diseases such as multiple sclerosis
62
Enantioselective synthesis of a-alkyl alanine derivative
O
Chiral analog of FTY720
HO
H2N
O
RO2C
H2N
Diastereoselective alkylation
using Schölkopf chiral template
Asymmetric alkylation
using chiral phase transfer catalyst
O
N
OMe
+
MeO
I
(S)-MBN
+
N
N
CO2t-Bu
n-BuLi
Cl
Prasad, R.; et al. Org. Process Res. Dev. 2008, 12, 1164.
63
Synthesis of 2-(2-propoxynaphth-6-yl)ethyl iodide
n-PrI
K2CO3
HO
Br
O
O
O
+
acetone
59 C, 48 h
(95%)
Br
Pd(OAc)2 (1 mol%)
K3PO4 (3.5 equiv)
PhMe
O
OEt
LiBH4, THF
65 C, 4 h
(80%)
90 C (2 h)
100 C (2 h)
(80%)
I2 (1.5 equiv)
Ph3P (1.3 equiv)
O
OH
imidazole
(1.5 equiv)
THF, rt, 0.25 h
(90%)
Prasad, R.; et al. Org. Process Res. Dev. 2008, 12, 1164.
O
OEt
(1.3 equiv)
P(t-Bu)2
(2 mol%)
O
I
64
Research synthesis using Schölkopf’s chiral template
O
O
I
HO
H2N
N
MeO
OMe
n-BuLi/hexane
THF, -70 C
(71%)
N
LiAlH4, THF
(60%)
Diastereoselectivity: 90–95%
O
MeO2C
Elimination of HI
N
MeO
O
OMe
N
H2N
TFA (20 equiv)
MeCN, H2O (59%)
Prasad, R.; et al. Org. Process Res. Dev. 2008, 12, 1164.
65
Asymmetric phase-transfer-catalytic alkylation
Et3N
MgSO4
Ar
N
CO2t-Bu
MeOH
(94%)
(S)-MBN
(1.3 mol%)
CsOH•H2O
(5 equiv)
0 C, 10 h
Ar
+
O
- +
Cl H3N
CO2t-Bu
Ar = 4-Cl-C6H4
O
(S)-MBN
F
(1.3 equiv)
I
F
F
PhMe/t-BuOMe (17:1)
N+
Br
-
O
F
t-BuO2C
F
N
Ar
96% ee
Prasad, R.; et al. Org. Process Res. Dev. 2008, 12, 1164.
F
66
Deprotection and reduction
O
1. 6 M HCl/i-PrOH, H2O (68%)
2. slurrying in EtOH/PhMe (82%)
t-BuO2C
N
O
HO2C
Cl
-
+
Cl H3N
> 99% ee
56% overall yield
from protected Ala
O
LiAlH4 (4 equiv)
HO
H2N
THF, 56 C, 4–5 h
(79%)
Prasad, R.; et al. Org. Process Res. Dev. 2008, 12, 1164.
67
The last issue to be addressed: asymmetric phase-transfercatalytic alkylation of protected alanine using liquid base
Ar
N
PhMe/t-BuOMe
(17:1)
CO2t-Bu
O
I
0 C
(S)-MBN
O
t-BuO2C
N
Ar = 4-Cl-C6H4
Ar
CsOH•H2O
 Less costly
 Easier to handle
2
aq KOH
Cl
Cl
PhMe
R5-X
+
N
 t-Bu
N
F
H
R4
+
O
OR4
F
F
Br
F
-
F
F
O
R4 O
N
R5
68
(R)-a-(4-Fluorobenzyl)alanine
F
F
Br
Phase-transfer-catalytic
asymmetric benzylation of
N- and C-protected alanine
using liquid base phase
+
CO2
F
Cl
Kinetic resolution
with Lipase L (Amano)
 100% by weight
of enzyme
 5 days at rt
F
S
N
CO2Et
-
H3N
H2N
N
AcHN
CO2H
F
AcHN
CO2H
Boehringer Ingelheim Pharmaceuticals, Inc.
Spero, D. M.; Kapadia, S. R. J. Org. Chem. 1996, 61, 7398.
69
(±)-2-(Acetylamino)-2-methyl3-(3-fluorophenyl)-propionic acid ethyl ester
- +
1. Et3N, H2O
rt, 0.5 h
H
Cl H3N
CO2Et
F
rt, 48 h
t-Bu
N
H
t-Bu
2. t-BuCHO
MgSO4
CH2Cl2
rt, 20 h
1 N HCl
CO2Et
KOt-Bu (1 M/THF)
toluene
N
CO2Et
F
(90%)
Br
-3 C
2h
Ac2O, Py
rt, 20 h
F
- +
Cl H3N
Spero, D. M.; Kapadia, S. R.
J. Org. Chem. 1996, 61, 7398.
CO2Et
(93%)
F
AcHN
CO2Et
(70%)
70
(S)-2-(Acetylamino)-2-methyl-3-(3-fluorophenyl)propionic acid
100% by weight of
Lipase L (Amano)
t-BuOH
F
AcHN
phosphate buffer
pH 6.5 (2 N KOH)
rt, 5d
CO2Et
5-step overall yield of
59% from (±)-Ala-OEt•HCl
pH 8.8 (2 N NaOH)
F
Extraction with AcOEt
pH 7.0 (2 N HCl)
F
AcHN
Concentration to dryness
AcHN
CO2H
(S)-Acid
> 95.6% ee
(37%)
CO2Et
(R)-Ester
> 99.9% ee
(47%)
SiO2 Chromatog
22% from (±)-Ala-OEt•HCl
Spero, D. M.; Kapadia, S. R. J. Org. Chem. 1996, 61, 7398.
71
Production of (R)-4-fluorobenzylalanine on scale
Cl
- +
H3N
CO2Et
H
O (1.0 equiv)
Ar
PhMe
99.7% ee
Ar = 4-Cl-C6H4
+
H3N
-
CO2
F
Et3N (1.1 equiv)
H2O
(63% overall yield)
Aq layer
PhMe layer
Ar
N
Et3N•HCl
Isoelectric precipitation (pH 5.9) (87%)
aq KOH (Et ester hydrolysis)
CO2Et
(85%)
H
aq HCl (imine hydrolysis)
(93%)
• 48% aq KOH (4.7 equiv)
• (S)-MBN (0.1 mol%)
•
F
(1.0 equiv)
Br
Ar
8 C
6h
(93%)
N
CO2Et
F
87% ee
72
Scalable asymmetric PTC
for the production of a-amino acids
F
F
R2
F
N
+
F
(S)-MBN
F
O
H
4
OR
R1
Br
F
N
-
R5 X
PhMe
O
R2
N
48% aq KOH
(S)-MBN
OR4
R1 R5
With C2-symmetric chiral mono-1,1’-binaphthyl
derived quaternary ammonium bromide, MBN,
(1) 0.1–0.5 mol% of it suffices to drive
the reaction to completion with high
enantioselectivity;
(2) Any chiral centers, including quaternary ones, can be built enantioselectively under liquid-liquid biphasic conditions using aq KOH;
(3) benzaldehyde imine of Gly esters (R1 = H, R2 = Ph) can undergo
enantioselective mono-alkylation without incident;
(4) esters simpler than tert-butyl ones (R4 = Me, Et) can be used
without compromising enantioselectivity or yield.
73
Conformationally constrained b-methyl-a-amino acids
Introduction of a b-methyl group can
restrict conformational freedom around the side chain in c space
O
O
OH
OH
NH2
NH2
anti-(2S, 3S)
Component of bottromycin, a peptidic antibiotic
produced by Streptomyces bottropensis
syn-(2S, 3R)
Component of sst4-selective
somatostatin (SRIF) agonist
Bull. Chem. Soc. Jpn. 1976, 49, 1081.
J. Med. Chem. 2003, 46, 5587.
O
*
*
O
-
+
F
NH3
74
Double enantioselection by chiral quaternary ammonium ion
Selection of
a chiral center
of racemic bromide
(S)-MBN
Selection of a prochiral
enolate enantioface
F
O
-
R3
N
F
R2
4
OR
N
F
F
F
si-face
Ar
3
(S)
H
H
H
Br
Ar
2
F
+
Ar
R6
Br
(R)
CO2t-Bu
R2
N
R3
anti-(2R,3R)
Br
SN2
Ar
2
CO2t-Bu
N
R2
3
syn-(2R,3S)
R3
75
Double enantioselection
by C2-symmetric chiral phase transfer catalyst
Ot-Bu
O
H
2
Br
F
(2 equiv)
(S)-MBN
(0.5 mol%)
PhMe
50% aq KOH
3
N
NH2
F
Ph
Ph
anti-(2R,3R):
99% ee
anti/syn (81:19): 73% yield
1 M aq HCl
EtOH
0 C, 3 h
Q*
+ -
O
Ot-Bu
Br
H
F
CO2t-Bu
SN2
N
+
Ph
(S)
CO2t-Bu
Ph
si (front) face
F
N
Ph
Ph
76
Production of anti-(2R,3R)-b-methyl-4-fluorophenylalanine on scale
F
F
O
Ph
N
F
H
Br
(1.5 equiv)
OEt
F
(S)-MBN
PhMe, (S)-MBN (0.1 mol%)
48% aq KOH (5 equiv)
5 C, 6.5 h
N
F
O
OEt
1. aq HCl
(80%)
2. K2CO3
Br
-
F
F
N
F
+
O
Ph
OEt
O
2
O
3
-
1. aq NaOH
2. aq HCl
(46%)
F
+
F
NH3
anti/syn (99:1)
anti-(2R,3R): > 99% ee
NH2
anti/syn (94.5:5.5)
anti-(2R,3R): 99% ee
77
Streamlined production of chiral a-amino acids on scale
Aromatic aldehyde imine formation
(toluene)
R2
N
Direct use of the toluene solution
without isolating the imine formed
Asymmetric phase-transfer-catalytic alkylation
H
CO2R4
R1
(toluene/48% aq KOH)
Liquid/liquid biphasic mixture
R2
R5
N
CO2R4
*
R1
Phase separation and extraction
Facile isolation of N- and C-protected a-amino acid products
R6
CO2R4
*
* R1
N
R2
Manipulations with N- or C-protecting groups
R5
7
R HN
Purification by (re)crystallization
*
R1
CO2R8
4
CO
R
2
*
R6
R1
7
R HN
*
Isoelectric precipitation: free a-amino acids
Formation of crystalline salts: N-acyl a-amino acids or a-amino esters
78
Conclusion
 What looks ordinary in the lab is out of the ordinary
in the plant.
 Be skeptical about any premise.
 Discovery consists of seeing what everybody has seen
and thinking what nobody has thought.
Albert von Szent-Györgyi (1893–1986)
79
Thank you
80