Synthesis of optically active α-arylglycines: Stereoselective Mannich-type reaction with a new chiral template

Article abstract of DOI:10.1055/s-2001-15168

Mannich-type reaction of phenols with iminolactone 4, readily prepared from commercially available phenylglycine, proceeded with high stereoselectivity to give α-arylglycine derivatives. The reaction was also applicable to other electron-rich aromatic compounds and aryl boronic acids. These adducts could be readily converted to the corresponding optically active α-arylglycines.

Full text of DOI:10.1055/s-2001-15168

LETTER
1179
Synthesis of Optically Active -Arylglycines: Stereoselective Mannich-Type
Reaction with a New Chiral Template
Shigemitsu Tohma, Atsushi Endo, Toshiyuki Kan, Tohru Fukuyama*
Graduate School of Pharmaceutical Sciences, The University of Tokyo, CREST, The Japan Science and Technology Corporation (JST),
7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Fax +81-3-5802-8694; E-mail: fukuyama@mol.f.u-tokyo.ac.jp
Received 7 May 2001
tone 4 is stable enough to be isolated and thus amenable
Abstract: Mannich-type reaction of phenols with iminolactone 4,
to large-scale preparations.
readily prepared from commercially available phenylglycine, pro-
ceeded with high stereoselectivity to give -arylglycine derivatives.
The reaction was also applicable to other electron-rich aromatic
compounds and aryl boronic acids. These adducts could be readily
H
H
converted to the corresponding optically active -arylglycines.
NH2
OH
NH2
OH
a, b, c, d
Key words: -arylglycines, Mannich-type reaction, iminolactone,
phenol, arylboronic acid
O
1
2
-Arylglycines constitute an important class of nonprotei-
nogenic -amino acids.1,2 These compounds have been
found in numerous natural products such as amoxicillin
and vancomycin, to name a few. In addition, -hy-
droxyarylglycines have been shown to be highly potent
agonists or antagonists for the glutamate receptors of the
central nervous system.3,4 The growing need for -arylg-
lycines has attracted much interests from synthetic chem-
ists.5,6 It is difficult to synthesize this class of compounds
in optically pure form because the benzylic chiral center
is prone to racemization. While the methodology reported
by Williams appears to be quite attractive, it may not be
particularly suited for large-scale preparations of highly
functionalized -arylglycines.7 During the course of our
synthetic study on ecteinascidin 743, we found that an in-
termolecular Mannich-type reaction of phenol with cyclic
imine proceeded with high stereoselectivity.8 Inspired by
this finding, we launched an investigation on the scope of
such -arylglycine synthesis, using simple cyclic imines
with readily removable chiral auxiliaries. After prelimi-
nary investigation of electrophilic glycine equivalents,
lactone 4 was found to be sufficiently robust and suitable
for this purpose. Herein we report stereoselective Man-
nich-type reaction with a new chiral template 4 and its
conversion to optically active -arylglycines.
H
H
N
H
N
g
e, f
O
O
O
O
3
4
Scheme 1 Reagents and conditions: a) SOCl2 (5.0 eq), MeOH, r.t.;
b) (Boc)2O (1.0 eq), MeCN, r.t., 88% in 2 steps; c) MeMgBr (3.2 eq),
THF, r.t., 82%; d) SOCl2 (5.0 eq), MeOH, r.t., 91%; e) phenyl bro-
moacetate (1.1 eq), propylene oxide (5.0 eq), MeCN, 50 °C, 81%; f)
toluene, , 86%; g) Pb(OAc)4 (1.2 eq), MeCN, r.t., 89%.
With the requisite iminolactone 4 in hand, we then exam-
ined the Mannich-type reaction with various phenols (5a-
5g).9a,b Under acidic conditions, the addition reactions
proceeded with excellent stereoselectivity and in near
quantitative yields to give the corresponding phenylgly-
cine derivatives (6a-6g).10 The reaction conditions, yields
and diastereoselectivities are given in the Table. It is note-
worthy that highly substituted phenols such as 5a,b,g
serve as excellent substrates in this reaction. In addition,
the iminolactone 4 reacts with other electron-rich aromat-
ic ethers (5h and 5i). The high stereoselectivity of the ad-
dition reactions can be explained by a preferential
approach of the nucleophiles from the opposite face of the
bulky phenyl group. The stereochemistry of the adduct 6g
was confirmed by X-ray analysis of 7 (Figure).11
As illustrated in Scheme 1, iminolactone 4 was readily
prepared in a seven-step sequence from phenylglycine (1),
which is commercially available in both enantiomeric
form and relatively inexpensive. After conversion to the
N-Boc-phenylglycine methyl ester, treatment with
MeMgBr followed by removal of the Boc group furnished
the alcohol 2. N-Alkylation of 2 with phenyl bromoacetate
and subsequent lactonization afforded the desired lactone
3, which, upon treatment with Pb(OAc)4 smoothly under-
went oxidation to provide highly crystalline iminolactone
4. Because of the geminal dimethyl group, the iminolac-
Moreover, the imine 4 was applicable to boronic acid
Mannich reaction, which was first reported by Petasis et
al.12 As shown in Scheme 2, treatment of arylbronic acid
8 with trifluoroacetic acid resulted in diastereo- and regi-
oselective addition to 4, giving 9 in high yield. Since nu-
merous arylboronic acid derivatives can be easily
synthesized, this protocol can be applied to synthesis of a
wide variety of -arylglycines.
Synlett 2001, No. 7, 1179–1181 ISSN 0936-5214 © Thieme Stuttgart · New York

1180
S. Tohma et al.
LETTER
N
O
Ph
OMe
Table Mannich-type reaction of 5 with iminolactone 4
MeO
4
H
H
N
O
H
N
H
(1.0 eq)
N
Ph
Ar
Ph
TFA
Ph
(R)
+
Ar-H 5 (a-i)
TFA (5 eq)
CH2Cl2
0 °C
(1.0 eq)
O
O
O
O
ClCH2CH2Cl
50 °C, 30 min
B
O
O
O
OH
6 (a-i)
4
(1.05 eq)
9
8
(1.5 eq)
TFA (eq)
time (h)
85%
dr=19:1
yields (%)
reaction site
dr (R:S)
ArH
5
97 (6a)
83 (6b)
11:1
12:1
5a
5b
5c
5d
5e
Scheme 2
0.5
Y
Y
2
24
5
5
*
R (single isomer)
88 (6c)
Y
A representative example of the removal of the chiral aux-
iliary and the conversion to the corresponding -arylgly-
cine is shown in Scheme 3. Acidic cleavage of
aminolactone 6g with SOCl2 in methanol, followed by
protection of the phenol as the TBS ether afforded methyl
ester 11. Oxidative cleavage of amino alcohol 11 with
Pb(OAc)4 and the subsequent treatment with hydroxy-
lamine led to aminoester 12. Examination of the 1H NMR
spectra of the corresponding MTPA amide revealed that
12 did not racemize under these reaction conditions.
5
2.5
95 (6d)
98 (6e)
96 (6f)
>20:1
4:1
X
X
10
10
5
3
5f
5g
5h
X:Y=1:1
>20:1
R (single isomer)
10:1
5
0.5
*
93 (6g)
X
Z
5
3
96 (6h)
98 (6i)
5
0.5
5i
>20:1
X
*after recrystallization
OMe
X
OMe
OMe
HO
Me
Me
Me
Ph
H
OH
5a: X=OMs, Y=H
5b: X=OMOM
Y=H
a
5g: X=H
H
H
N
Ph
NH
Y
MeO
X
MeO
MeO
O
O
OH
X
OH
O
6g
OR CO2Me
10: R= H
11: R= TBS
O
OH
b
X
MeO
Z
OMe
OMe
5h: X=Me,
Y=Z=H
5i: X=Z=H
Y=OMe
5c: X=Me, Y=H
5d: X=H, Y=Me
5e: X=H,Y=Br
5f: X=Y=H
Me
c
11
H
NH2
Y
Y
MeO
12
OR CO2Me
Scheme 3 Reagents and conditions: a) SOCl2 (2.0 eq), MeOH,
,
92%; b) TBSCl (1.2 eq), imidazole (3.0 eq), DMF, , 93%; c)
Pb(OAc)4 (1.5 eq), toluene, 0 °C; NH2OH HCl (5.0 eq), NaOAc (5.0
eq), EtOH, r.t., 82%.
In conclusion, we have developed a novel synthesis of op-
tically active -arylglycines by means of stereoselective
Mannich-type reaction of a versatile imine 4 with various
aromatic compounds. The choice of appropriate aromatic
compounds would allows us to synthesize a variety of
highly functionalized arylglycines. Further applications
of the chiral template 4 to the syntheses of a range of op-
tically active amino acids are under investigation in our
laboratories
Acknowledgement
We wish to thank Mr. R. Akiyama (Graduate School of Pharmaceu-
tical Sciences, The University of Tokyo) for kind support of the X-
ray analysis of 7.
Figure ORTEP drawing of adduct 7
Synlett 2001, No. 7, 1179–1181 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Synthesis of Optically Active -Arylglycines
1181
(10) Typical experimental procedure: To a mixture of 510 mg
(3.0 mmol) of 5g and 650 mg (3.2 mmol, 1.05 equiv) of 4 in
6 ml of CH2Cl2 was added 0.23 ml (15 mmol, 5 equiv) of TFA
at 0 °C. The reaction mixture was stirred at same temperature
until 5g was consumed. The reaction mixture was poured into
saturated NaHCO3 solution, and extracted with CH2Cl2. The
extracts were washed with brine, dried over anhydrous
MgSO4, filtered, and evaporated under reduced pressure.
Purification of the crude product by recrystallization (AcOEt-
Hexane) yielded 1.04 g (2.8 mmol, 93%) of 6g as white
crystal.
(11) Compound 7 was prepared from 6g by the treatment with
MsCl and Et3N in 85% yield. X-ray crystallographic data for
the structure reported in this paper have been deposited with
the Cambridge Crystallographic Data Base (Deposition No.
162231). Copies of the data can be obtained free of charge on
application to the CCDC, 12 Union Road, Cambridge
CB21EZ, UK (fax+44-1223-336-033; E-mail:
References and Notes
(1) Williams, R. M. Synthesis of Optically Active -Amino Acids;
Pergamon Press: Oxford, 1989.
(2) For a review of asymmetric synthesis of arylglycines, see:
Williams, R. M.; Hendrix, J. A. Chem. Rev. 1992, 92, 889.
(3) Watkins, J.; Collingridge, G. Trends Pharm. Sci. 1994, 15,
333.
(4) Bendingfield, J. S.; Kemp M. C.; Jane, D. E.; Tse, H. W.;
Roberts, P. J.; Watkins, J. Br. J. Pharmacol. 1995, 116, 3323.
(5) a) Evans, D. A.; Britton, T. C.; Dorow, R. L.; Dellaria, J. F. J.
Am. Chem. Soc. 1986, 108, 6395. b) Evans, D. A.; Britton, T.
C.; Dorow, R. L.; Dellaria, J. F. Tetrahedron 1988, 44, 5525.
(6) Caron, M.; Carlier, P. R.; Sharpless, K. B. J. Org. Chem. 1988,
53, 5185.
(7) Williams, R. M.; Hendrix, J. A. J. Org. Chem. 1990, 55, 3723.
(8) Endo, A.; Kan, T.; Fukuyama, T. Synlett 1999, 1103.
(9) (a) Preparation of phenols 5a and 5b, see: ref 6.
(b) Preparation of phenol 5g, see: Fukuyama, T.; Sachleben,
R. A. J. Am. Chem. Soc. 1982, 104, 4957.
deposit@ccdc.cam.ac.uk).
(12) Petasis, N. A.; Goodman, A.; Zavialov, I. A. Tetrahedron
1997, 48, 16463.
Article Identifier:
1437-2096,E;2001,0,07,1179,1181,ftx,en;Y09801ST.pdf
Synlett 2001, No. 7, 1179–1181 ISSN 0936-5214 © Thieme Stuttgart · New York