Efficient synthesis of N-acyl-α-arylglycines via palladium-catalyzed amidocarbonylation: Application to the central amino acid of chloropeptin

Full text of DOI:10.1021/jo980174n

5658
J . Org. Chem. 1998, 63, 5658-5661
of cobalt catalysts (eq 1).4 Up to now, this methodology
Efficien t Syn th esis of N-Acyl-r-a r ylglycin es
via P a lla d iu m -Ca ta lyzed
Am id oca r bon yla tion : Ap p lica tion to th e
Cen tr a l Am in o Acid of Ch lor op ep tin †
(1)
Matthias Beller,* Markus Eckert, and
E. Wolfgang Holla‡
has not found broad use in amino acid synthesis because
high catalyst concentrations of the cobalt catalyst HCo-
(CO)4 and harsh reaction conditions are required for the
reaction to take place. More important the substrate
variety is limited to nonfunctionalized aliphatic
aldehydesse.g., aromatic aldehyde derivatives cannot be
amidocarbonylated using cobalt catalysts to give aryl
glycine derivatives.5 To overcome the limitations of the
cobalt-catalyzed reaction, we developed recently a new
protocol for the amidocarbonylation utilizing palladium
catalysts.6 On the basis of our new amidocarbonylation
process herein, we report for the first time a general and
efficient catalytic amidocarbonylation of all kinds of
substituted benzaldehydes. The corresponding N-acyl-
R-arylglycines are obtained in one step in good to excel-
lent yields. The synthetic potential of the method is
illustrated by the asymmetric synthesis of the charac-
teristic amino acid derivative of chloropeptin: (S)-N-
acetyl-3,5-dichloro-4-hydroxyphenylglycine.
Our initial attempts focused on the amidocarbonylation
of benzaldehyde and 4-methoxybenzaldehyde with ac-
etamide. In the presence of only 0.25 mol % PdBr2, 0.5
mol % PPh3 as catalyst system, and 30 mol % LiBr and
1 mol % H2SO4 as cocatalysts, the reaction proceeded
smoothly in NMP as solvent to give (R,S)-N-acetyl-R-
phenylglycine and (R,S)-N-acetyl-R-(4-methoxyphenyl)-
glycine in 70% and 75% yields, respectively. These
results encouraged us to use the palladium-catalyzed
amidocarbonylation for a general synthesis of function-
alized arylglycine derivatives. Table 1 summarizes the
results obtained for the reaction of a variety of substi-
tuted benzaldehydes.
Anorganisch-chemisches Institut, Technische Universita¨t
Mu¨nchen, Lichtenbergstrasse 4,
D-85747 Garching, Germany
Received February 2, 1998
Arylglycines are of actual interest in organic and
medicinal chemistry because of their antimicrobial and
enzyme inhibitory properties.1 They constitute an im-
portant integral part of the growing class of clinically
effective glycopeptide antibiotics such as vancomycin,
â-avoparcin, and chloropeptin.2 Of key importance for
the practical synthesis of these cyclic peptides as well as
of pharmacologically interesting analogues is an easy and
general access to nonproteinogenic R-amino acids of the
arylglycine type. Although a number of elegant strate-
gies for stereoselective N-acyl amino acid synthesis were
published during the past decade,3 to our knowledge none
of them is applied in industry on a larger scale. This is
explained by the fact that most developed procedures use
fairly expensive starting materials and are limited to the
millimole scale.
Due to our interest to develop catalytic reactions for
organic synthesis which are applicable also in industry
on a larger scale, we looked for alternative methods for
the synthesis of amino acid derivatives. In this respect
the so-called amidocarbonylation developed by Waka-
matsu in 1971 seems to be an industrially feasible
procedure: starting from aldehydes, amides, and CO the
desired N-acyl R-amino acids are obtained in the presence
† Part
8 of the series Palladium-Catalyzed Reactions for Fine
Chemical Synthesis. For part 7, see: Beller, M.; Zapf, A. Synlett 1998,
in press.
The characteristic features of the results are as fol-
lows: (1) the palladium-catalyzed amidocarbonylation of
aromatic aldehydes takes place under much milder
conditions (e.g., 80 °C, 60 bar CO) compared to the
classical cobalt-catalyzed reaction7 of even more reactive
aliphatic aldehydes; (2) benzaldehydes bearing electron-
donating or weakly electron-withdrawing substituents
(entries 1-4) react more smoothly than those with strong
electron-withdrawing groups8 (entries 5-10); (3) never-
theless, deactivated benzaldehydes underwent success-
* To whom correspondence should be addressed. Tel: +89-28913096.
Fax: +89-28913473. E-mail: mbeller@arthur.anorg.chemie.tu-
muenchen.de.
‡ Hoechst Marion Roussel Deutschland GmbH, Chemical Research,
D-65926 Frankfurt am Main, Germany.
(1) Zinic, M.; Skaric, V. J . Org. Chem. 1988, 53, 2582-2588. J ames,
H. A. Amino Acids Peptides and Related Compounds; Organic Chem-
istry Series No. 6; Butterworth: London, 1973.
(2) Burgess, K.; Lim, D.; Martinez, C. I. Angew. Chem., Int. Ed. Engl.
1996, 35, 1077. Boger, D. L.; Borzilleri, R. M.; Nukui, S. J . Org. Chem.
1996, 61, 3561. Searle, M. S.; Westwell, M. S.; Mackay, J . P.; Groves,
P.; Beauregard, D. A. Chemtracts: Org. Chem. 1994, 7, 133-159. Rao,
A. V. R.; Gurjar, M.K.; Reddy, K. L.; Rao, A. S. Chem. Rev. 1995, 95,
2135.
(3) Chaari, M.; Lavergne, J .-P.; Viallefont, P. Synth. Commun. 1989,
19, 1211-1216. Koen, M. J .; Morgan, J .; Pinhey, J . T. J . Chem. Soc.,
Perkin Trans. 1993, 2383. O’Donnell, M. J .; Bennett, W. D.; J acobsen,
W. N.; Ma, Y. Tetrahedron Lett. 1989, 30, 3913. Weinges, K.; Reinel,
U.; Maurer, W.; Ga¨ssler, N. Liebigs Ann. Chem. 1987, 833-838.
Sheffer-Dee-Noor, S.; Ben-Ishai, D. Tetrahedron 1994, 50, 7009. Wirth,
T. Angew. Chem., Int. Ed. Engl. 1997, 36, 225. Petasis, N. A.; Zavialov,
I. A. J . Am. Chem. Soc. 1997, 119, 445-446. Park, Y. S.; Beak, P. J .
Org. Chem. 1997, 62, 1574-1575. Myers, A. G.; Gleason, J . L.; Yoon,
T.; Kung, D. W. J . Am. Chem. Soc. 1997, 119, 656-673. Williams, R.
M.; Sinclair, P. J .; Zhai, D.; Chen, D. J . Am. Chem. Soc. 1988, 110,
1547. Evans, D. A.; Britton, T. C.; Ellman, J . A.; Dorow, R. L. J . Am.
Chem. Soc. 1990, 112, 4011. Seebach, D.; Sting, A. R.; Hoffmann, M.
Angew. Chem. 1996, 108, 2880-2921; Angew. Chem., Int. Ed. Engl.
1996, 35, 2708-2748.
(4) Wakamatsu, H.; Uda, J .; Yamakami, N. J . Chem. Soc. Chem.
Commun. 1971, 1540. Ojima, I. Chem. Rev. 1988, 88, 1011-1030. Lin,
J . J .; Knifton, J . F. CHEMTECH 1992, 248-252. Beller, M.; Cornils,
B.; Frohning, C. D.; Kohlpaintner, C. W. J . Mol. Catal. 1995, 104, 17-
85. Parnaud, J .-J .; Campari, G.; Pino, P. J . Mol. Catal. 1979, 6, 341-
350.
(5) Magnus, P.; Slater, M. Tetrahedron Lett. 1987, 28, 2829-2832.
(6) Beller, M.; Eckert, M.; Vollmu¨ller, F.; Bogdanovic, S.; Geissler,
H. Angew. Chem. Int. Ed. Engl. 1997, 36, 1494-1496. Dyker, G. Angew.
Chem., Int. Ed. Engl. 1997, 36, 1700-1702. Beller, M.; Eckert, M.;
Vollmu¨ller, F. J . Mol. Catal. 1998, in press. Beller, M.; Eckert, M.;
Geissler, H.; Napierski, B.; Rebenstock, H.-P.; Holla, E. W. Chem. Eur.
J . 1998, 4, 935-941.
(7) Amidocarbonylations of benzaldehydes with cobalt catalysts did
not yield the desired N-acyl amino acid in any of our reference
experiments. Beside the aldehydes only hydrogenated starting material
could be detected in some cases.
S0022-3263(98)00174-1 CCC: $15.00 © 1998 American Chemical Society
Published on Web 07/10/1998

Notes
J . Org. Chem., Vol. 63, No. 16, 1998 5659
Ta ble 1. P a lla d iu m -Ca ta lyzed Am id oca r bon yla tion of
Ar om a tic Ald eh yd esa
bonylation of 4-tolylaldehyde with a reduced amount of
palladium(II)bromide (0.01 mol %). Turnover numbers
of 2800 and turnover frequency of 200 h-1 were obtained.
Thus, we recommend for these type of amidocarbonyla-
tions a catalyst load of 0.05-0.25 mol % in order to get
good yields.
The catalytic mechanism of the palladium-catalyzed
amidocarbonylation has not yet been fully elucidated;
however, it is clear that the addition of halide ions is
prerequisite for catalysis. In contrast, even without acid
as cocatalyst the reaction takes place, albeit in lower
yield. The substrate profile of the benzaldehyde deriva-
tives (see Table 1) shows a clear but not essential
dependence of the electron properties of the substituents
on reactivity and only a small influence on the position
of substitution. In general, electron-rich aromatic alde-
hydes give better yields of the desired N-acyl amino acids.
This is explained by a better stabilization of an interme-
diate benzylic cation. According to these preliminary
mechanistic observations we propose the following mech-
anism: The reaction of acetamide and the aromatic
aldehyde in the presence of the acid and halide ions as
cocatalysts leads to several intermediates in equilibrium
(R-hydroxyamides, bisamides), most importantly a ben-
zylic R-haloamide. This benzylic R-haloamide undergoes
an oxidative addition to a coordinatively unsaturated
Pd(0) phosphine complex giving a palladium(II) alkyl
species. Subsequent insertion of CO and hydrolysis lead
to the N-acyl aryl amino acid.
To demonstrate the possibilities of the amidocarbon-
ylation as a powerful tool for natural product synthesis,
we turned our interest toward the synthesis of arylglycine
residues 13-15 which constitute key amino acid building
blocks found in pharmaceutically important natural
products such as vancomycin, â-avoparcin, and chlo-
ropeptins. Among these active agents the recently
isolated and characterized hexapeptide chloropeptin I,
which selectively inhibits HIV replication in peripheral
human lymphocytes,9 is particularly important. The
total synthesis of chloropeptin has not been reported,
although a synthetic approach toward subunits was very
recently disclosed.10 Two of the three different arylgly-
cine residues found in chloropeptin are 4-hydroxyphen-
ylglycine (13) and 3,5-dichloro-4-hydroxyphenylglycine
(15).
a
Reactions using 25.0 mL of a 1 M NMP (N-methylpyrrolidone)
solution of aldehyde and amide and 0.25 mol % PdBr2/2PPh3, 1
b
mol % H2SO4, and 35 mol % LiBr. Hammett para substituent
constants. c Isolated yield. Reaction using 0.025 mol % PdBr2/
d
2PPh3. e Reaction time 60 h. f TON ) turnover number.
ful amidocarbonylation with excellent yields when the
reaction temperature was slightly raised from 100 to 120
°C and the reaction time was prolonged; (4) in addition
to para-substituted benzaldehydes, meta- and ortho-
substituted benzaldehydes were amidocarbonylated in
the presence of the palladium catalyst without a signifi-
cant decrease in the yield (entries 5-7). Interestingly,
heteroaromatic aldehydes such as 3-thiophenecarbalde-
hyde also gave access to the corresponding N-acetyl
amino acid 12, albeit at lower yield (42%).
The only byproducts observed in the amidocarbonyla-
tion of substituted benzaldehydes in significant amounts
were the bisamides of the corresponding aldehydes.
Usually these bisamides were easily filtered off from
sodium bicarbonate solution.
It should be pointed out that most of the aforemen-
tioned reactions have not been optimized in detail. For
some derivatives (Table 1, entries 2, 3, 8, and 9) we
demonstrated that the rise of temperature and prolonga-
tion of reaction time increased the yield of desired
products to a synthetically useful level. However, we
believe that if someone has a particular interest in a
special N-acyl arylglycine, it should be possible to further
increase the yield by additional variations of the reaction
parameters, especially temperature and CO pressure. To
prove the catalyst efficiency we performed the amidocar-
13 was directly obtained by palladium-catalyzed ami-
docarbonylation in one step from inexpensive and readily
available 4-hydroxybenzaldehyde in excellent yield (90%).
3,5-Dichloro-4-hydroxyphenylglycine (15) was prepared
as follows: reduction of the commercially available ester
(8) Dean, J . A. Lange’s Handbook of Chemistry; 14th ed., McGraw-
Hill Book Co.: New York, 1992; 9.2-9.7.
(9) Gouda, H.; Matsuzaki, K.; Tanaka, H.; Hirono, S. J . Am. Chem.
Soc. 1996, 118, 13087-13088.
(10) Roussi, G.; Zamora, E. G.; Carbonnelle, A.-C.; Beugelmans, R.
Tetrahedron Lett. 1997, 38, 4401-4404.

5660 J . Org. Chem., Vol. 63, No. 16, 1998
Notes
Sch em e 1
Exp er im en ta l Section
Gen er a l. All high-pressure reactions were carried out with
a 300-mL stirred reactor (no. 4561 from Parr Co.) with a magnet-
driven propeller stirrer. Commercial reagents were used as
received without additional purification. 1H NMR (400 MHz)
and 13C NMR (100 MHz) spectra were recorded using solvent
shifts for calibration. Melting points are uncorrected.
Gen er a l P r otocol. A 25.0-mL portion of a N-methylpyrroli-
done (NMP) solution (1 M) in aldehyde and amide, 0.25 mol %
(PPh3)2PdBr2, 1 mol % H2SO4, and 35 mol % LiBr were allowed
to react at 60 bar CO and 100 °C for 12 h. After the reaction
mixture had cooled, the volatile components were removed in
vacuo, and the residue was taken up in a saturated aqueous
solution of sodium bicarbonate and then washed with chloroform
and ethyl acetate. The aqueous phase was adjusted to pH 2 with
phosphoric acid and extracted five times with ethyl acetate. The
combined organic phases were dried over magnesium sulfate,
and the solvent was removed in vacuo. The product was
recrystallized from water/2-propanol mixtures or ethyl acetate.
(R,S)-N-Acetyl-r-(4-m eth oxyp h en yl)glycin e (1): mp 210
°C; 1H NMR (DMSO-d6) δ 12.7 (bs, 1H), 8.50 (d, J ) 7.03 Hz,
1H), 7.30 (d, J ) 8.53 Hz, 2H), 6.93 (d, J ) 8.53 Hz, 2H), 5.24
(d, J ) 7.53 Hz, 1H), 3.75 (s, 3H), 1.88 (s, 3H); 13C NMR (DMSO-
d6) δ 172.2, 169.0, 159.0, 129.3, 128.8, 113.9, 55.7, 55.2, 22.3;
FT-IR (KBr) ν ) 3341s, 1718s, 1600s, 1545s, 1514s; CI-MS m/z
224 (M + H+). Anal. Calcd for C11H13NO4: C, 59.19; H, 5.87;
N, 6.27. Found: C, 58.98; H, 5.97; N, 6.30.
16 with LiAlH4 and selective oxidation with DDQ lead
to 3,5-dichloro-4-hydroxybenzaldehyde (17) in almost
quantitative yield (Scheme 1).11 Palladium-catalyzed
amidocarbonylation (yield 73%) and enzymatic resolution
provided the chiral arylglycine 18 with >99.5% ee in 19%
overall yield (and the (R)-enantiomer of 15 in >99.5% ee
in 18% overall yield). To increase the yield of 18 it should
be possible to racemize and additionally enzymatically
hydrolyze the (R)-enantiomer of 15.6 The efficiency of
the amidocarbonylation as a key step for complex aryl
amino acid synthesis is demonstrated unambiguously if
one compares the shown reaction sequence with the
preparation of the related N-Boc-3,5-dichloro-4-methox-
yphenylglycine. The synthesis of this latter compound
was reported in five reaction steps starting from 3,5-
dichloro-4-methoxybenzaldehyde!10
Antibiotics such as vancomycin12 and â-avoparcin13 are
characterized by a central arylglycine residue bearing a
3,5-dialkoxy-4-hydroxy substitution pattern on the aro-
matic ring. Thus, we prepared 3,5-dimethoxy-4-hydrox-
yphenylglycine (14) via amidocarbonylation of the com-
mercially available 3,5-dimethoxy-4-hydroxybenzaldehyde.
The reaction proceeded in good yield (65%). Initially the
purification of the desired hydroxy-substituted N-acetyl
aryl amino acids turned out to be more difficult. How-
ever, by applying longer reaction times (48 h) and in the
case of 14 2 equiv of aldehyde, minor amounts of
bisamides were produced, which could be removed by
recrystallization.
(R,S)-N-Acetyl-r-(4-tolyl)glycin e (2): mp 230 °C; 1H NMR
(DMSO-d6) δ 12.5 (bs, 1H), 8.35 (d, J ) 7.53 Hz, 1H), 7.08 (d, J
) 8.03 Hz, 2H), 6.98 (d, J ) 8.03 Hz, 2H), 5.06 (d, J ) 7.53 Hz,
1H), 2.10 (s, 3H), 1.69 (s, 3H); 13C NMR (DMSO-d6) δ 172.3,
169.2, 137.3, 134.4, 129.1, 127.6, 124.3, 56.1, 22.4, 20.8; FT-IR
(KBr) ν ) 3338s, 1718s, 1601s, 1545s; CI-MS m/z 208 (M + H+).
Anal. Calcd for C11H13NO3: C, 63.76; H, 6.32; N, 6.76. Found:
C, 63.66; H, 6.54; N, 6.79.
1
(R,S)-N-Acetyl-r-p h en ylglycin e (3): mp 199 °C; H NMR
(DMSO-d6) δ 12.6 (bs, 1H), 8.50 (d, J ) 7.03 Hz, 1H), 7.30 (d, J
) 8.53 Hz, 2H), 6.93 (d, J ) 8.53 Hz, 2H), 5.24 (d, J ) 7.53 Hz,
1H), 3.75 (s, 3H), 1.88 (s, 3H); 13C NMR (DMSO-d6) δ 172.1,
169.2, 137.4, 128.7, 128.0, 127.6, 56.4, 22.4; FT-IR (KBr) ν )
3342s, 1716s, 1669s, 1604s, 1540s; CI-MS m/z 194 (M + H+).
Anal. Calcd for C10H11NO3: C, 62.17; H, 5.74; N, 7.25. Found:
C, 62.45; H, 5.99; N, 7.30.
(R,S)-N-Acetyl-r-(4-flu or op h en yl)glycin e (4): mp 188 °C;
1H NMR (DMSO-d6) δ 12.8 (bs, 1H), 8.59 (d, J ) 7.03 Hz, 1H),
7.41 (dd, J ) 8.53, 5.52 Hz, 2H), 7.19 (m, 2H), 5.32 (d, J ) 7.53
Hz, 1H), 1.88 (s, 3H); 13C NMR (DMSO-d6) δ 171.8, 169.0, 160.5,
133.7, 129.7, 115.2, 55.5, 22.2; FT-IR (KBr) ν ) 3341s, 1724s,
1616s, 1542s, 1512s; CI-MS m/z 212 (M + H+). Anal. Calcd for
C
10H10FNO3: C, 56.87; H, 4.77; N, 6.63. Found: C, 56.47; H,
In conclusion, we have developed a general synthetic
strategy for the preparation of N-acetylarylglycines based
on the palladium-catalyzed amidocarbonylation. Utiliz-
ing the ubiquitous commercially available feedstock of
benzaldehydes, this atom economic multicomponent reac-
tion offers the most efficient straightforward route to
various racemic arylglycines. In combination with en-
zymatic hydrolysis also enantiomerically pure arylgly-
cines are available. The usefulness of the methodology
for organic synthesis is demonstrated by the synthesis
of naturally occurring arylglycines 13-15, which consti-
tute key structural components of important cyclopep-
tides.
4.96; N, 6.62.
(R,S)-N-Acetyl-r-(4-ch lor op h en yl)glycin e (5): mp 196 °C;
1H NMR (DMSO-d6) δ 12.9 (bs, 1H), 8.70 (d, J ) 7.53 Hz, 1H),
7.42 (m, 4H), 5.33 (d, J ) 7.53 Hz, 1H), 1.90 (s, 3H); 13C NMR
(DMSO-d6) δ 171.5, 169.3, 135.5, 133.2, 129.8, 129.6, 129.2,
127.6, 53.2, 22.3; FT-IR (KBr) ν ) 3339s, 1717s, 1602s, 1541s;
CI-MS m/z 227/229 (M + H+). Anal. Calcd for C10H10ClNO3:
C, 52.76; H, 4.43; N, 6.15. Found: C, 52.50; H, 4.20; N, 6.20.
(R,S)-N-Acetyl-r-(2-ch lor op h en yl)glycin e (6): mp 160 °C;
1H NMR (DMSO-d6) δ 12.6 (bs, 1H), 8.69 (d, J ) 7.53 Hz, 1H),
7.3-7.5 (m, 4H), 5.76 (d, J ) 8.03 Hz, 2H), 1.88 (s, 3H); 13C NMR
(DMSO-d6) δ 171.4, 169.2, 135.5, 133.1 129.8, 129.6, 129.2, 127.6,
53.2, 22.3; FT-IR (KBr) ν ) 3359s, 1717s, 1609s, 1538s; CI-MS
m/z 227/229 (M + H+). Anal. Calcd for C10H10ClNO3: C, 52.76;
H, 4.43; N, 6.15. Found: C, 53.02; H, 4.51; N, 6.18.
(R,S)-N-Acetyl-r-(3-ch lor op h en yl)glycin e (7): mp 169 °C;
1H NMR (DMSO-d6) δ 12.6 (bs, 1H), 8.70 (d, J ) 6.53 Hz, 1H),
7.4 (m, 4H), 5.39 (d, J ) 7.03 Hz, 1H), 1.89 (s, 3H); 13C NMR
(DMSO-d6) δ 171.6, 169.3, 139.9, 133.2, 130.5, 128.0, 127.5,
126.6, 55.8, 22.4; FT-IR (KBr) ν ) 3348s, 1719s, 1607s, 1534s;
CI-MS m/z 227/229 (M + H+). Anal. Calcd for C10H10ClNO3:
C, 52.76; H, 4.43; N, 6.15. Found: C, 52. 92; H, 4.15; N, 6.30.
(R,S)-N-Acet yl-r-(4-(m et h oxyca r b on yl)p h en yl)glycin e
(11) Becker, H.-D.; Bjo¨rk, A.; Adler, E. J . Org. Chem. 1980, 45,
1596-1600.
(12) Boger, D. L.; Borzilleri, R. M.; Nukui, S.; Beresis, R. T. J . Org.
Chem. 1997, 62, 4721-4736. Boger, D. L.; Borzilleri, R. M.; Nukui, S.
J . Org. Chem. 1997, 61, 3561-3565. Nicolaou, K. C.; Chu, X.-J .;
Ramanjulu, J . M.; Natarajan, S.; Bra¨se, S.; Ru¨bsam, F.; Boddy, C. N.
C. Angew. Chem., Int. Ed. Engl. 1997, 36, 1539-1540. Burgess, K.;
Lim, D.; Martinez, C. I. Angew. Chem., Int. Ed. Engl. 1996, 35, 1077-
1078.
1
(8): mp 227 °C; H NMR (DMSO-d6) δ 12.8 (bs, 1H), 8.73 (d, J
) 7.53 Hz, 1H), 7.95 (d, J ) 8.53 Hz, 2H), 7.55 (d, J ) 8.03 Hz,
(13) Stone, M. J .; van Dyk, M. S.; Booth, P. M.; Williams, D. H. J .
Chem. Soc., Perkin Trans. I 1991, 1629.
2H), 5.44 (d, J ) 7.53 Hz, 1H), 3.83 (s, 3H), 1.90 (s, 3H); 13C

Notes
J . Org. Chem., Vol. 63, No. 16, 1998 5661
NMR (DMSO-d6) δ 171.7, 169.3, 166.1, 143.0, 129.6, 129.4, 128.0,
56.2, 52.3, 22.4; FT-IR (KBr) ν ) 3338s, 1727s, 1610m, 1545s;
CI-MS m/z 252 (M + H+). Anal. Calcd for C12H13NO5: C, 57.37;
H, 5.22; N, 5.58. Found: C, 57.46; H 5.31; N, 5.56.
atmosphere. As the mixture stirred vigorously a solution of 6.0
g (25 mmol) of methyl 3,5-dichloro-4-hydroxybenzoate hydrate
(16) (Aldrich, #38,909-9) in 50 mL of dry THF was added
dropwise, and the suspension was heated under reflux for 12 h.
After the mixture cooled to room temperature water was added
dropwise till hydrogen formation stopped; then aqueous sulfuric
acid (10%) was added to dissolve the precipitation. Extraction
with ether, combining the organic layers, drying over sodium
sulfate, and removing the solvent yielded 4.6 g (24 mmol) of 3,5-
(R,S)-N-Acet yl-r-(4-(t r iflu or om et h yl)p h en yl)glycin e
1
(9): mp 211 °C; H NMR (DMSO-d6) δ 12.7 (bs, 1H), 8.78 (d, J
) 7.53 Hz, 1H), 7.75 (d, J ) 8.03 Hz, 2H), 7.60 (d, J ) 8.03 Hz,
2H), 5.49 (d, J ) 7.53 Hz, 1H), 1.88 (s, 3H); 13C NMR (DMSO-
d6) δ 171.5, 169.3, 142.3, 128.8, 125.5, 56.0, 22.4; FT-IR (KBr) ν
) 3358s, 1725s, 1600s, 1539s; CI-MS m/z 262 (M + H+). Anal.
Calcd for C11H10F3NO3: C, 50.58; H, 3.86; N, 5.36. Found: C,
50.96; H, 4.08; N, 5.35.
1
dichloro-4-hydroxybenzyl alcohol: mp 86 °C; H NMR (DMSO-
d6) δ 9.95 (s, 1H), 7.29 (s, 2H), 5.24 (t, J ) 5.52 Hz, 1H), 4.48 (d,
J ) 5.52 Hz, 2H); 13C NMR (DMSO-d6) δ 147.6, 135.8, 126.6,
122.1, 61.5; FT-IR (KBr) ν ) 3332s, 2959m, 2928m, 2871m,
2606m, 2468m, 1700s, 1623s, 1559s, 1448m, 1439m; CI-MS m/z
194 (M + H+). 3,5-Dichloro-4-hydroxybenzyl alcohol (4.6 g, 24
mmol) was dissolved in 150 mL of dioxane, and 5.5 g (24 mmol)
of DDQ was added to this solution. The reaction mixture was
stirred for 12 h at room temperature, then the solvent was
removed, and the precipitation was dissolved in 150 mL of
methylene chloride. After filtration the solution was dried over
MgSO4, and the solvent was removed. Recrystallization from
ethyl acetate yielded 4.4 g (23 mmol) of 17: mp 157 °C; 1H NMR
(DMSO-d6) δ 9.95 (s, 1H), 7.29 (s, 2H), 5.24 (t, J ) 5.52 Hz, 1H),
4.48 (d, J ) 5.52 Hz, 2H); 13C NMR (DMSO-d6) δ 147.6, 135.8,
126.6, 122.1, 61.5; FT-IR (KBr) ν ) 3355s, 2966m, 2928m, 1700s,
1557s, 1448m, 1375m; CI-MS m/z 191 (M + H+).
(R,S)-N-Acetyl-r-(4-cya n op h en yl)glycin e (10): mp 232 °C;
1H NMR (DMSO-d6) δ 12.8 (bs, 1H), 8.79 (d, J ) 8.03 Hz, 1H),
7.85 (d, J ) 8.03 Hz, 2H), 7.59 (d, J ) 8.03 Hz, 2H), 5.49 (d, J
) 7.53 Hz, 1H), 1.91 (s, 3H); 13C NMR (DMSO-d6) δ 171.3, 169.4,
143.2, 132.5, 128.7, 118.8, 110.8, 56.1, 22.4; FT-IR (KBr) ν )
3329s, 2234s, 1729s, 1616s, 1533s; CI-MS m/z 219 (M + H+).
Anal. Calcd for C11H10N2O3: C, 60.55; H, 4.62; N, 12.84.
Found: C, 60.08; H, 4.33; N, 12.70.
(R,S)-N-Acetyl-r-(â-n a p h th yl)glycin e (11): mp 208 °C; 1H
NMR (DMSO-d6) δ 12.6 (bs, 1H), 8.80 (d, J ) 7.53 Hz, 1H), 8.0
(m, 4H), 7.6 (m, 3H), 5.58 (d, J ) 7.53 Hz, 1H), 1.95 (s, 3H); 13
C
NMR (DMSO-d6) δ 172.1, 169.2, 135.1, 132.7, 132.5, 128.2, 127.9,
127.6, 126.5, 126.4, 56.6, 22.4; FT-IR (KBr) ν ) 3394s, 1734s,
1617s, 1534s; CI-MS m/z 244 (M + H+). Anal. Calcd for C14H13
-
NO3: C, 69.12; H, 5.39; N, 5.76. Found: C, 69.25; H, 5.48; N,
5.70.
(S)-r-(3,5-Dich lor o-4-h yd r oxyp h en yl)glycin e (18). (R,S)-
N-Acetyl-3,5-dichloro-4-hydroxyphenylglycine (0.89 g, 3.2 mmol)
was dissolved at 20-25 °C in a mechanically stirred solution of
NaOH pellets (0.25 g, 6.25 mmol) in water (20 mL). After
addition of CoCl2‚6H2O (1.7 mg, 0.007 mmol) the clear solution
was adjusted to pH 7.9 with hydrochloric acid (2 N) and heated
to 37-40 °C. Acylase from Aspergillus sp. (30 mg of Amano
30.000, 30 U/mg) was added, and the reaction mixture was
stirred at 37-40 °C for 94 h (pH was controlled periodically and
kept at ∼7.9 with 1 N NaOH). The resulting reaction mixture
was stirred for 1 h at 0-5 °C, but no precipitation occurred. The
reaction mixture was concentrated under reduced pressure to
10 mL, 2-5 mL of ethanol was added, and the reaction mixture
was concentrated under reduced pressure to 5-10 mL. Filtra-
tion of the precipitate under suction and drying in vacuo afforded
0.2 g (26.5%) of the desired (S)-3,5-dichloro-4hydroxyphenyly-
(R,S)-N-Acetyl-r-(3-th iop h en eyl)glycin e (12): departing
from general protocol, the reaction was allowed to react for 60
1
h; mp 190 °C; H NMR (DMSO-d6) δ 12.8 (bs, 1H), 8.61 (d, J )
7.53 Hz, 1H), 7.52 (m, 1H), 7.48 (m, 1H), 7.12 (d, J ) 5.02 Hz,
1H), 5.43 (d, J ) 7.53 Hz, 1H), 1.88 (s, 3H); 13C NMR (DMSO-
d6) δ 172.0, 169.3, 137.3, 127.3, 126.7, 123.5, 52.3, 22.4; FT-IR
(KBr) ν ) 3339s, 1717s, 1652s, 1602s, 1538s; CI-MS m/z 200 (M
+ H+). Anal. Calcd for C8H9NO3S: C, 48.23; H, 4.55; N, 7.03.
Found: C, 48.00; H, 4.80; N, 6.93.
(R,S)-N-Acetyl-r-(4-h yd r oxyp h en yl)glycin e (13): depart-
ing from general protocol, the reaction was allowed to react for
1
48 h; mp 199 °C; H NMR (DMSO-d6) δ 12.6 (bs, 1H), 9.48 (bs,
1H), 8.44 (d, J ) 7.53 Hz, 1H), 7.17 (d, J ) 8.53 Hz, 2H), 6.75
(d, J ) 8.53 Hz, 2H), 5.16 (d, J ) 7.03 Hz, 1H), 1.90 (s, 3H); 13
C
20
NMR (DMSO-d6) δ 172.5, 169.1, 157.3, 129.0, 127.4, 115.3, 55.9,
22.3; FT-IR (KBr) ν ) 3342s, 1716s, 1669s, 1604s, 1540s; CI-
MS m/z 210 (M + H+). Anal. Calcd for C10H11NO4: C, 57.41;
H, 5.30; N, 6.70. Found: C, 57.15; H, 5.62; N, 6.55.
glycine: mp 204 °C dec; [R]D +104 (c ) 1, 1 N HCl); >99.5%
ee (HPLC on Crownpak CR (+) 15 cm × 0.4 cm (Daicel Chemical
Industries), monitoring at 205/280 nm, eluting with 0.016 M
HClO4, pH ) 2.06; flow rate 1 mL/min; 40 °C); 1H NMR (300
MHz, TFA) δ 5.4 (s, 1H), 7.52 (s, 2H), 11.5 (s, 1H); MS (ESI)
m/z (%) 235.9 (M + H+, 100).
(R,S)-N-Acet yl-r-(3,5-d im et h oxy-4-h yd r oxyp h en yl)gly-
cin e (14): departing from general protocol, the reaction was
allowed to react for 48 h and 2 equiv of aldehyde was used; mp
> 240 °C; 1H NMR (DMSO-d6) δ 12.6 (bs, 1H), 8.46 (d, J ) 7.53
Hz, 1H), 8.45 (s, 1H), 6.66 (s, 2H), 5.16 (d, J ) 7.03 Hz, 1H),
3.76 (s, 6H), 1.89 (s, 3H); 13C NMR (DMSO-d6) δ 172.4, 169.1,
147.9, 135.5, 126.8, 105.5, 56.2, 56.1, 22.4; FT-IR (KBr) ν )
3373s, 1729s, 1616s, 1569s, 1520s, 1216s; CI-MS m/z 270 (M +
H+). Anal. Calcd for C12H15NO6: C, 53.53; H, 5.62; N, 5.20.
Found: C, 54.00; H, 5.75; N, 5.23.
(R,S)-N-Acet yl-r-(3,5-d ich lor o-4-h yd r oxyp h en yl)gly-
cin e (15): departing from general protocol, the reaction was
allowed to react for 48 h; mp 232 °C; 1H NMR (DMSO-d6) δ 12.9
(bs, 1H), 10.24 (bs, 1H), 8.57 (d, J ) 7.53 Hz, 1H), 7.35 (s, 2H),
5.23 (d, J ) 7.53 Hz, 1H), 1.86 (s, 3H); 13C NMR (DMSO-d6) δ
171.6, 169.2, 148.9, 130.3, 127.9, 122.2, 54.9, 22.4; FT-IR (KBr)
ν ) 3356s, 1717s, 1622m, 1559s, 1490m, 1419m; CI-MS m/z 279
(M + H+). Anal. Calcd for C10H9Cl2NO4: C, 43.19; H, 3.26; N,
5.04. Found: C, 42.91; H, 3.35; N, 5.30.
The remaining solution was acidified to pH ∼ 1.5 with
concentrated hydrochloric acid and extracted with ethyl acetate.
The combined extracts were dried with MgSO4 and concentrated
in vacuo. Trituration with tert-butyl methyl ether and drying
afforded 0.223 g (25%) of (R)-N-acetyl-3,5-dichloro-4-hydroxy-
phenylyglycine as an off-white solid: mp 234 °C dec; [R]D20 -28°
(c ) 1, MeOH); >99.5% ee (HPLC on (S,S)-Whelk-O 1 (E. Merck,
Darmstadt), monitoring at 225/215 nm, eluting with hexane/
ethanol, 4/1, + 0.1% HOAc; flow rate 1 mL/min; 25 °C); MS (ESI)
1
m/z (%) 278.0 (M + H+, 100); H NMR data were in agreement
with data from (R,S)-N-acetyl-3,5-dichloro-4-hydroxyphenylgly-
cine.
Ack n ow led gm en t. We thank Prof. Dr. K. Ku¨hlein
and Dr. H. Geissler (Hoechst AG) for stimulating
discussions and H.-P. Rebenstock and R. Saric (Hoechst
Marion Roussel) for experimental assistance regarding
the enzymatic resolution.
3,5-Dich lor o-4-h yd r oxyben za ld eh yd e (17). A 1.4-g (38
mmol) portion of lithium aluminum hydride in a 250-mL three-
necked flask equipped with a reflux condenser and a dropping
funnel was suspended in 100 mL of dry THF under nitrogen
J O980174N