Chemoenzymatic synthesis of D-N-Boc-3,5-dihydroxy-4- methoxyphenylglycine

Full text of DOI:10.1021/jo980233x

5662
J . Org. Chem. 1998, 63, 5662-5665
Ch em oen zym a tic Syn th esis of D-N-Boc-3,5-
d ih yd r oxy-4-m eth oxyp h en ylglycin e
Miche`le Bois-Choussy and J ieping Zhu*
Institut de Chimie des Substances Naturelles, CNRS,
91198 Gif-sur-Yvette, France
Received February 9, 1998
Vancomycin (1, Figure 1) and related glycopeptide
antibiotics, by virtue of their important antibacterial
activities, have spurred multidisciplinary interest over
the last four decades.1 Fully characterized in 1983,2 the
architectural complexity of vancomycin has captured the
imagination of synthetic chemists, and research in this
field has resulted in numerous new synthetic methodolo-
gies.3 The intramolecular SNAr-based cycloetherification
reaction has been developed during the last several years
as a powerful synthetic methodology for the construction
of structurally diverse macrocycles with endo aryl-
aryl4-6 and aryl-alkyl ether7 linkages. To apply this
reaction in the synthesis of vancomycin, an easy access
to D-N-Boc-3,5-dihydroxy-4-methoxyphenylglycine (2), the
central unit of its structure, was a prerequisite. Indeed,
several asymmetric syntheses of this moiety have been
reported. Thus, Boger et al.8 have devised a synthesis
of 2 in which Sharpless asymmetric dihydroxylation9
served to introduce the required stereochemistry. Pear-
son10 and our group11 have independently developed a
synthetic scheme wherein Evans’s electrophilic azidation
methodology12 was implemented as a key step for intro-
ducing both the chirality and the amino function. In an
earlier effort, we have accomplished a concise synthesis
of 213 by way of a diastereoselective Strecker reaction
using (S)-phenylglycinol as chiral auxiliary.14 Described
F igu r e 1.
herein is an efficient new chemoenzymatic synthesis of
this nonproteinogenic amino acid (2).
The Strecker reaction was used for the synthesis of
racemic amino acid derivatives 6a and 6b (Scheme 1).
Methyl 3,5-bis(isopropyloxy)-4-methoxybenzoate (3a ),
readily available in large quantities from methyl gal-
late,15 was converted into the corresponding aldehyde (4a )
by a standard reduction-oxidation sequence. Treatment
of this aldehyde with TMSCN in MeOH saturated with
16
NH3 gave the R-amino nitrile (5a ), which was then
transformed into compound 6a by way of methanolysis
and trifluoroacetylation. Compound 6b (R ) Me) was
synthesized following the same synthetic sequence start-
ing from ester 3b. Chemoselective removal of isopropyl
groups from 6a (BCl3, CH2Cl2) afforded compound 7 in
98% yield.17,18
(1) Glycopeptide Antibiotics; Nagarajan, R., Ed.; Marcel Dekker,
Inc.: New York, 1994.
(2) (a) Williamson, M. P.; Williams, D. H. J . Am. Chem. Soc. 1981,
103, 6580-6585. (b) Harris, C. M.; Kopecka, H.; Harris, T. M. J . Am.
Chem. Soc. 1983, 105, 6915-6922. (c) Williams, D. H. Acc. Chem. Res.
1984, 17, 364-369. (d) Nagarajan, R. J . Antiobiot. 1993, 46, 1181-
1195.
While important progress has been made in the
enzymatic synthesis of chiral amino acid derivatives in
general, studies on the resolution of arylglycine are
relatively rare, and the conditions developed have been
often less than satisfactory and limited in scope.19 One
exception is the highly efficient dynamic resolution of
hydantoins by D-specific hydantoinases. However, the
low availability, high cost, and instability at elevated
temperature of hydantoinases compared to other hydro-
lases have significantly limited their potential applica-
tions in organic synthesis.20 In preliminary experiments,
we first examined the protease (from Bacillus licheni-
formis, P5459 from Sigma)-mediated ester hydrolysis21,22
of 6b (R ) Me) in phosphate buffer and with various
organic cosolvents such as CH2Cl2, 1,4-dioxane, MeCN,
(3) Rama Rao, A. V.; Gurjar, M. K.; Reddy, L.; Rao, A. S. Chem.
Rev. 1995, 95, 2135-2167.
(4) For a review, see: Burgess, K.; Lim, D.; Martinez, C. I. Angew.
Chem., Int. Ed. Engl. 1996, 35, 1077-1078.
(5) For a short account, see: Zhu, J . Synlett 1997, 133-144 and
references therein.
(6) For recent selected examples, see: (a) Boger, D. L.; Borzilleri,
R. M.; Nukui, S.; Beresis, R. T. J . Org. Chem. 1997, 62, 4721-4736.
(b) Evans, D. A.; Barrow, J . C.; Watson, P. S.; Ratz, A. M.; Dinsmore,
C. J .; Evrard, D. A.; DeVries, K. M.; Ellman, J . A.; Rychnovsky, S. D.;
Lacour, J . J . Am. Chem. Soc. 1997, 119, 3419-3420. (c) Nicolaou, K.
C.; Boddy, C. N. C.; Natarajan, S.; Yue, T.-Y.; Li, H.; Bra¨se, S.;
Ramanjulu, J . M. J . Am. Chem. Soc. 1997, 119, 3421-3422. (d)
Pearson, A. J .; Zhang, P.; Bignan, G. J . Org. Chem. 1997, 62, 4536-
4538. (e) Bois-Choussy, M.; Vergne, C.; Neuville, L.; Beugelmans, R.;
Zhu, J . Tetrahedron Lett. 1997, 38, 5795-5798 and references therein.
(7) La¨ıb, T.; Zhu, J . Tetrahedron Lett. 1998, 39, 283-286.
(8) Boger, D. L.; Borzilleri, R. M.; Nukui, S. J . Org. Chem. 1996,
61, 3561-3565.
(9) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev.
1994, 94, 2483-2547.
(10) Pearson, A. J .; Mariappan, V. C.; Bignan, G. C. Synthesis 1997,
536-540.
(11) Beugelmans, R.; Bois-Choussy, M.; Vergne, C.; Bouillon, J . P.;
Zhu, J . J . Chem. Soc., Chem. Commun. 1996, 1029-1030.
(12) Evans, D. A.; Britton, T. C.; Ellman, J . A.; Dorow, R. L. J . Am.
Chem. Soc. 1990, 112, 4011-4030.
(13) Zhu, J .; Bouillon, J . P.; Singh, G. P.; Chastanet, J .; Beugelmans,
R. Tetrahedron Lett. 1995, 36, 7081-7084.
(14) Chakraborty, T. K.; Reddy, G. V.; Hussain, K. A. Tetrahedron
Lett. 1991, 32, 7597-7600.
(15) Zhu, J .; Chastanet, J .; Beugelmans, R. Synth. Commun. 1996,
26, 2479-2486.
(16) (a) Mai, K.; Patil, G. Organic Preparation and Procedures Int.
1985, 17, 183-186. (b) Zhu, J .; Beugelmans, R.; Bigot, R.; Singh, G.
P.; Bois-Choussy, M. Tetrahedron Lett. 1993, 34, 7401-04.
(17) Vergne, C.; Bois-Choussy, M.; Beugelmans, R.; Zhu, J . Tetra-
hedron Lett. 1997, 38, 1403-1406.
S0022-3263(98)00233-3 CCC: $15.00 © 1998 American Chemical Society
Published on Web 07/17/1998

Notes
J . Org. Chem., Vol. 63, No. 16, 1998 5663
a
Sch em e 1
and DMF. Among these, only DMF was found to be
suitable, leading to the acid 8b, with moderate enantio-
selectivity. However, under identical conditions, com-
pound 6a (R ) i-Pr) was resistant to hydrolysis, while
compound 7 was transformed into the corresponding acid
8c in high chemical yield (>95%, 6 h) without enantio-
selectivity. These results indicated that the phenoxy
protecting groups can dramatically influence both the
reactivity and the enantioselectivity of the enzymatic
process.23 Although no chiral discrimination was ob-
served, this protease-catalyzed hydrolysis of 7 was found
to be the method of choice to prepare acid 8c (Scheme 1)
as other chemical methods (e.g., HOAc/4N HCl ) 1/1, 65
°C, 65%) gave only moderate yields due to the lability of
the trifluoroacetyl group under both basic and acidic
conditions.
We then turned our attention to the aminoacylase-
catalyzed24 hydrolysis of N-(trifluoroacetyl)amino acids
8a -c25 based on Goldsworthy’s work26 concerning the
enzymatic resolution of N-(chloroacetyl)-3,5-dihydroxy-
phenylglycine. The trifluoroacetyl group was chosen
since it can be removed under much milder conditions22
than the chloroacetyl function, whose chemical hydrolysis
leads to the erosion of enantiopurity.26 Experimentally,
large differences in the hydrolysis rate of compounds 7
and 8a -c were once again observed under a given set of
conditions. Indeed, hydrolysis of 7 and 8a employing the
acylase AMANO 3000027 under various conditions was
not appreciable even after prolonged reaction time, while
compounds 8b and 8c were smoothly hydrolyzed. For
(18) A significant difference in reactivity between BCl3 in CH2Cl2
and BCl3 in hexane (1 M solution, both from Aldrich) was observed.
While the former displayed excellent chemoselectivity leading to the
formation of compound 7 in quantitative yield [1 equiv (mol ratio: BCl3/
6a ) 2/1) of BCl3, room temperature, 3 h], the latter afforded a mixture
of 7, A, and B depending upon the reaction temperature.
a
Key: (a) (i) LAH, THF; (ii) PDC, CH2Cl2, 85-90%; (b) NH3,
MeOH, TSCN; (c) MeOH, HCl; (d) TEA, trifluoroacetic anhydride,
CH2Cl2, 88%; (e) BCl3, CH2Cl2, 98% from 6a ; (f) protease from
Bacillus licheniformis (Sigma), phosphate buffer, DMF, (g) AMANO
30000, phosphate buffer, NaN3, CoCl2, 42% for two enzymatic
steps; (h) HOAc, 6 N HCl; (i) Boc2O, dioxane, H2O, Na2CO3, 83%;
(j) L-R-methylbenzylamine, EDC, HOBt, CH2Cl2, 90%.
the present purpose, the hydrolysis of 8c was studied in
detail since this would directly furnish the amino acid
required for further synthetic elaboration. Thus, hy-
drolysis of 8c in phosphate buffer (pH 7) with acylase
AMANO 30000 in the presence of a catalytic amount of
CoCl2 and NaN3 at 25 °C26 gave L-9 and unhydrolyzed
amide D-8c in 48% yield. Hydrolysis was initially fol-
lowed by reversed-phase HPLC and was found to be
highly stereoselective. In fact, under these conditions,
the enantiomer selectivity is so high that no tedious
HPLC monitoring was required, making the resolution
step very practical. Removal of the trifluoroacetyl group
from D-8c under mild acidic conditions followed by
formation of N-(tert-butyloxy)carbamate gave then D-N-
(19) Wong, C. H.; Whitesides, G. M. Enzymes in Synthetic Organic
Chemistry. In Tetrahedron Organic Series; Baldwin, J . E., Magnus,
P. D., Eds.; Pergamon: Elmsfrd, NY, 1994; Vol. 12. (b) Williams, R.
M.; Hendrix, J . A. Chem. Rev. 1992, 92, 889-917.
(20) For a recent report on thermally stable hydantoinases, see:
Keil, O.; Schneider, M. P.; Rasor, J . P. Tetrahedron: Asymmetry 1995,
6, 1257-1260.
(21) Chen, S. T.; Wang, K. T.; Wong, C. H. J . Chem. Soc., Chem.
Commun. 1986, 1514-1516.
(22) Vergne, C.; Bois-Choussy, M.; Ouazzani, J .; Beugelmans, R.;
Zhu, J . Tetrahedron: Asymmetry 1997, 8, 391-398.
(23) Lemke, K.; Lemke, M.; Theil, F. J . Org. Chem. 1997, 62, 6268-
6273.
(24) Chenault, H. K.; Dahmer, J .; Whitesides, G. M. J . Am. Chem.
Soc. 1989, 111, 6354-6364.
(25) Compounds 8a and 8b were prepared in moderate yield by
treatment of esters 6a and 6b, respectively, with acid (HOAc/4 N HCl
) 1/1, 65 °C). Alternatively, full deprotection of 6a and 6b to the
corresponding free amino acid (6 N HCl, reflux) followed by reprotection
of amine as the trifluoroacetamide (ethyl trifluoroacetate, triethyl-
amine, MeOH) gave 8a and 8b in similar yields (60%). See: Curphey,
T. J . J . Org. Chem. 1979, 44, 2805-2807.
Boc-3,5-dihydroxy-4-methoxyphenylglycine (2) [[R]D
)
-90° (MeOH, c 2.0); lit.8 [R]D ) -89° (MeOH, c 0.8); lit10
[R]D ) -86° (MeOH, c 0.5)]. Both D-2 and its racemic
form DL-2 were transformed into the corresponding L-R-
1
methylbenzylamide. Inspection of the H NMR spectra
(26) Baker, S. R.; Goldsworthy, J .; Harden, R. C.; Salhoff, C. R.;
Schoepp, D. D. Bioorg. Med. Chem. Lett. 1995, 5, 223-228.
(27) Acylase AMANO 30000 was from AMANO pharmaceutical Co.
LTD, Nagoya, J apan.
(in DMSO) of 10 and its diastereoisomeric amide re-
vealed that the de of 10, hence the ee of D-2, was about
90%.

5664 J . Org. Chem., Vol. 63, No. 16, 1998
Notes
g, 17.20 mmol) in dry CH2Cl2 (60 mL) was added, at -78 °C, a
solution of BCl3 in CH2Cl2 (1 M, 36.12 mL, 36.12 mmol). The
cooling bath was removed, and the reaction mixture was stirred
at room temperature for 3 h before being recooled to 0 °C and
quenched by careful addition of dry MeOH. Removal of volatile
at reduced pressure gave compound 7 (5.44 g, 98%): mp 148-
150 °C (CHCl3); IR (CHCl3) ν 3600, 3400, 1735, 1600, 1525, 1170
A one-pot sequential treatment of amino ester 7 by
protease (from B. licheniformis) followed by acylase was
also briefly investigated. However, it seems that the
catalytic property of acylase was poisoned by the presence
of the protease as only optically inactive acid 8c ([R]D )
0) was isolated with this two-enzyme, one-reactor pro-
cedure.
1
cm-1; H NMR (acetone-d6) δ 3.71 (s, 3H), 3.78 (s, 3H), 5.37 (d,
J ) 7.0 Hz, 1H), 6.48 (s, 2H), 8.21 (br s, 2H), 8.95 (br d, 1H); 13
C
In summary, we have described an efficient synthesis
of nonproteinogenic amino acid 2, an important building
block in the synthesis of vancomycin-type antibiotics. The
chirality was introduced by AMANO acylase-catalyzed
enantioselective hydrolysis, and the overall yield of 2 was
36% starting from aldehyde 4a . It was observed in the
course of these studies that the efficiency of both pro-
tease- and acylase-catalyzed hydrolysis reactions depends
significantly on the protecting groups used for the two
phenoxy functions on the aromatic ring. Besides the
steric reason, the beneficial effect of the free hydroxy
groups in compound 8c may be attributed to their
hydrogen bonding donor property as well as to the
possible dipole-dipole interactions in the binding region
of the enzyme.23 To the best of our knowledge, the
trifluoroacetyl group has been used for the first time as
the acyl group in aminoacylase-catalyzed hydrolysis of
amides, the main advantages being its easy preparation
and mild chemical hydrolysis. The synthetic route
described here is amenable to the synthesis of D-2 on a
multigram scale.
NMR (DMSO-d6) δ 52.6, 56.7, 59.8, 107.6, 115.9 (q, J ) 286.5
Hz), 129.5, 135.9, 151.0, 156.5 (q, J ) 37.5 Hz), 169.8; MS (CI)
m/z 324 [M + 1]. Anal. Calcd for C12H12F3NO6: C, 44.59; H,
3.74; N, 4.33. Found: C, 44.46; H, 3.91; N, 4.23.
P r otea se (fr om B. lich en ifor m is)-Ca ta lyzed Hyd r olysis
of 7: d,L-N-(Tr iflu or oacetyl)-3,5-dih ydr oxy-4-m eth oxyph en -
ylglycin e (8c). To a solution of compound 7 (5.00 g, 15.48
mmol) in DMF (20 mL) and phosphate buffer pH ) 7 (500 mL)
was added protease (from B. licheniformis, Sigma) (15 mL).
After being stirred at 37 °C overnight, the reaction mixture
was acidified to pH ) 3 and extracted with ethyl acetate. The
combined organic extracts were washed with brine, dried
(Na2SO4), and evaporated to dryness, which was used directly
for the next enzymatic reaction.
Acyla se-Ca ta lyzed En a n tioselective Hyd r olysis of Acid
DL-8c. To a solution of crude acid dl-8c, so obtained from the
above protease-mediated hydrolysis of 7, in phosphate buffer pH
) 7 (400 mL) were added CoCl2 (7 mL, 2.5 mM in water), NaN3
(1 mL, 154 mM), and acylase AMANO 30000 (1.4 g), successively.
After being stirred at 25 °C overnight (no monitoring was
required as the hydrolysis is highly enantioselective), the
reaction was acidified by addition of aqueous citric acid solution,
and the mixture was extracted with EtOAc. The combined
organic extracts were washed with brine, dried (Na2SO4), and
evaporated. Purification by flash chromatography (SiO2, eluent
heptane/EtOAc/AcOH ) 2/1/0.01) gave D-8c as a colorless oil
(2.01 g, 42% based on compound 7): [R]D ) -110° (MeOH, c 0.4);
1H NMR (DMSO-d6) δ 3.44 (s, 3H), 4.91 (d, J ) 6.1 Hz, 1H),
6.16 (s, 2H), 9.02 (br s, 2H), 9.80 (d, J ) 6.1 Hz, 1H); 13C NMR
(DMSO-d6) δ 56.7, 59.9, 107.6, 107.8, 116.0 (q, J ) 286.0 Hz),
130.4, 135.8, 150.9 (2C), 156.4 (q, J ) 37.5 Hz), 174.5; MS (CI)
m/z 310 [M + 1], 266. Anal. Calcd for C11H10F3NO6: C, 42.73;
H, 3.26. Found: C, 42.89; H, 3.33.
Exp er im en ta l Section
General procedures and methods for characterization of new
compounds have been described previously. Melting points are
uncorrected.28
D,L-N-(Tr iflu or oa cetyl)-3,5-bis(isop r op yloxy)-4-m eth oxy-
p h en ylglycin e Meth yl Ester (6a ). To a solution of 3,5-bis-
(isopropyloxy)-4-methoxybenzaldehyde (4a) (12.00 g, 47.62 mmol)
in MeOH (100 mL) saturated with NH3 was added TMSCN
(71.43 mmol, 9.55 mL) dropwise at 0 °C. The resulting solution
was then heated to 45 °C for 5 h and evaporated in vacuo to
dryness. The crude amino nitrile 5a , dissolved in dry MeOH
(80 mL), was saturated with gaseous hydrogen chloride. After
being stirred at room temperature for 12 h, thionyl chloride (4
mL) was added, and the solution was heated to 55 °C for 3 h in
order to convert a small amount of free amino acid to the desired
amino ester. The volatile was removed under reduced pressure
to give the analytically pure hydrogen chloride salt of amino
ester: 1H NMR (CD3OD) δ 1.31 (d, J ) 6.1 Hz, 6H), 1.34 (d, J )
6.1 Hz, 6H), 3.76 (s, 3H), 3.80 (s, 3H), 4.59 (septet,
J ) 6.1 Hz, 2H), 5.10 (br s, 1H), 6.75 (s, 2H). To a solution of
the hydrogen chloride salt of amino ester in CH2Cl2 (120 mL)
were added triethylamine (13.24 mL, 95.24 mmol) and trifluo-
roacetic anhydride (13.45 mL, 95.24 mmol), successively. After
being stirred at room temperature for 2 h, the reaction mixture
was diluted with aqueous NH4Cl solution and extracted with
CH2Cl2. The combined organic extracts were washed with brine,
dried (Na2SO4), and evaporated. Purification by flash chroma-
tography (SiO2, eluent: CH2Cl2) gave 6a as white crystals
(17.06 g, 88% overall yield from aldehyde 4a ): mp 109-110 °C
(CH2Cl2-pentane); IR (CHCl3) ν 3412, 1735, 1600, 1450, 1285,
1175, 1100 cm-1; 1H NMR (CDCl3) δ 1.33 (d, J ) 6.1 Hz, 12 H),
3.78 (s, 3H), 3.81 (s, 3H), 4.51 (septet, J ) 6.1 Hz, 2H), 5.41 (d,
J ) 7.1 Hz, 1H), 6.53 (s, 2H), 7.28 (d, J ) 7.1 Hz, 1H); 13C NMR
(DMSO-d6) δ 21.9, 52.5, 56.5, 59.5, 70.6, 108.5, 115.7 (q, J )
285.0 Hz), 129.6, 139.9, 151.2, 156.2 (q, J ) 38.0 Hz), 169.6; MS
(CI) m/z 408 [M + 1], 366, 324. Anal. Calcd for C18H24F3NO6:
C, 53.07; H, 5.94; N, 3.44. Found: C, 53.05; H, 5.91; N, 3.80.
D,L-N-(Tr iflu or oa cetyl)-3,5-d ih yd r oxy-4-m eth oxyp h en yl-
glycin e Meth yl Ester (7). To a solution of compound 6a (7.00
D-N-Boc-3,5-d ih yd r oxy-4-m eth oxyp h en ylglycin e (2). A
solution of D-8c (1.00 g, 3.24 mmol) in HOAc (10 mL) and 6 N
HCl (10 mL) was heated to 65 °C for 6 h. Evaporation of the
volatile at reduced pressure gave the hydrogen chloride salt of
crude amino acid that was redissolved in dioxane (40 mL), and
a solution of Na2CO3 (687.0 mg, 6.48 mmol) in H2O (20 mL) and
Boc2O (1.41 g, 6.48 mmol) were added successively. After being
stirred at room temperature for 3 h, the reaction mixture was
extracted with EtOAc. The combined organic extracts were
washed with brine, dried (Na2SO4), and evaporated. Purification
by flash chromatography (SiO2, eluent heptane/EtOAc/HOAc )
2/1/0.01) gave D-2 (843 mg, 83%): [R]D ) -90° (MeOH, c 0.2)
[lit.8 [R]D ) -89° (MeOH, c 0.8); lit.10 [R]D ) -86° (MeOH, c 0.5)];
mp 85-87° (ether); IR (CHCl3) ν 3530, 3440, 3240, 1724, 1600,
1500, 1370, 1164 cm-1; 1H NMR (acetone-d6) δ 1.39 (s, 9H), 3.77
(s, 3H), 5.08 (d, J ) 7.7 Hz, 1H), 6.38 (br d, J ) 7.7 Hz, 1H),
6.51 (s, 2H); 13C NMR (CD3OD) δ 28.4, 28.6, 59.0, 60.5, 80.7,
107.4, 108.0, 133.9, 136.5, 151.6 (2C), 157.2, 174.2; MS (FAB
NaCl) m/z 336 [M + 23], 258. Anal. Calcd for C14H19NO7: C,
53.67; H, 6.11; N, 4.47. Found: C, 53.38; H, 6.14; N, 4.43.
[(1-P h en ylet h ylca r b a m oyl)(3,5-d ih yd r oxy-4-m et h oxy-
p h en yl)m eth yl]ca r ba m ic Acid ter t-Bu tyl Ester (10). To a
solution of D-2 (31.0 mg, 0.1 mmol) in CH2Cl2 (10 mL) were
added, at 0 °C, L-R-methylbenzylamine (20 µL, 0.15 mmol), EDC
(21 mg, 0.11 mmol), and HOBt (15 mg, 0.11 mmol) successively.
After being stirred at 0 °C for 4 h, the reaction mixture was
diluted with a saturated aqueous solution of NH4Cl and ex-
tracted with EtOAc. The combined organic extracts were
washed with brine, dried (Na2SO4), and evaporated. Purification
by flash chromatography (SiO2, eluent heptane/EtOAc ) 1/1)
gave amide 10 (37.5 mg, 90%): de 90%; [R]D ) -55° (MeOH, c
0.3); mp 80-85° (ether); IR (CHCl3) ν 3550, 3430, 1710, 1680,
1
1500, 1360, 1270 cm-1; H NMR (DMSO-d6) δ 1.29 (d, J ) 7.0
Hz, 3H), 1.35 (s, 9H), 3.63 (s, 3H), 4.84 (q, J ) 7.0 Hz, 1H), 4.99
(d, J ) 8.6 Hz, 1H), 6.34 (s, 2H), 6.89 (d, J ) 8.6 Hz, 1H), 7.28
(28) Beugelmans, R.; Singh, G. P.; Bois-Choussy, M.; Chastanet, J .;
Zhu, J . J . Org. Chem. 1994, 59, 5535-5542.

Notes
J . Org. Chem., Vol. 63, No. 16, 1998 5665
(m, 5H), 8.50 (d, J ) 7.7 Hz, 1H), 9.00 (s, 2H); 13C NMR (DMSO-
d6) δ 22.6, 28.4, 48.4, 56.6, 59.9, 77.8, 106.5, 128.3, 126.9, 128.5,
134.4, 136.0, 144.5, 150.7, 156.0, 169.5; MS (CI) m/z 417 [M +
1]. Anal. Calcd for C22H28N2O6: C, 63.44; H, 6.78; N, 6.72.
Found: C, 63.06; H, 7.10; N, 6.46.
generous gift of AMANO 30000. Note Ad d ed in P r oof.
Very recently, an elegant synthesis of D-N-Boc-3,5-
dihydroxy-4-methoxyphenylglycine (2) was reported
from Professor Davis’s group; see: Davis, F. A.; Fanelli,
D. L. J . Org. Chem. 1998, 63, 1981-1985.
Ack n ow led gm en t. We are grateful to Dr. J . Ouaz-
zani of this institute for helpful discussions and a
J O980233X