Synthesis of (R)-(4-methoxy-3,5-dihydroxyphenyl)glycine derivatives: The central amino acid of vancomycin and related agents

Full text of DOI:10.1021/jo960085f

J . Org. Chem. 1996, 61, 3561-3565
3561
Syn th esis of
(R)-(4-Meth oxy-3,5-d ih yd r oxyp h en yl)glycin e
Der iva tives: Th e Cen tr a l Am in o Acid of
Va n com ycin a n d Rela ted Agen ts
Dale L. Boger,* Robert M. Borzilleri, and Seiji Nukui
Department of Chemistry, The Scripps Research Institute,
10666 North Torrey Pines Road, La J olla, California 92037
Received J anuary 12, 1996
Vancomycin (1)1 was isolated in 1956 from Streptomy-
ces orientalis and its structure and stereochemistry were
ultimately secured over 25 years later by a combination
of chemical degradation,1b NMR,1d,e and X-ray crystal-
lography studies.1f This prototypic member of a large and
growing class of clinically effective glycopeptide anti-
biotics2-4 which includes teicoplanin,2a ristocetin,2b
â-avoparcin,2c actaplanin (A4696),2d and A33512B2e is
characterized by a polycyclic heptapeptide backbone
composed of two 16-membered biaryl ether ring systems
(CD and DE). Central to the characteristic bicyclic ring
system is a (R)-(3,4,5-trihydroxyphenyl)glycine in which
the meta 3,5-phenols form biaryl ethers to link the CD
and DE rings. Herein, we report an asymmetric synthe-
sis of 2-5 constituting selectively protected derivatives
of (R)-(3,4,5-trihydroxyphenyl)glycine5 which have been
utilized in our efforts6 on the development of synthetic
approaches4 to vancomycin and related agents.
Key to the approach which complements the disclosed
routes to the asymmetric synthesis of phenylglycines7
was the Sharpless asymmetric dihydroxylation8 of a
substituted styrene for introduction of the R-center
absolute stereochemistry as well as functionality for
subsequent elaboration to the phenylglycine carboxylate.
Following selective C4 O-methylation of methyl 3,4,5-
trihydroxybenzoate as detailed by Pedro,9 the remaining
C3 and C5 phenols were protected as benzyl ethers
(Scheme 1). Two-step conversion of the ester 6 to the
aldehyde 810 (95 × 90%) and subsequent Wittig reaction
with methylenetriphenylphosphorane provided the sub-
stituted styrene 9 (70%) and the key substrate for
asymmetric dihydroxylation. Treatment of 9 with AD-
mix-R8 (1:1 t-BuOH/H2O, 0.1 M, 25 °C, 20 h) provided 10
in superb conversions (97%) and high ee’s (87% ee). The
optical purity of 10 was assessed directly by chiral phase
HPLC separation of the enantiomers on an analytical
Diacel Chiralpak AD column (0.46 × 25 cm, 10% 2-pro-
panol-hexane, 0.5 mL/min) alongside racemic material.
The desired (S)-10 eluted with a retention time of 58.9
min and the enantiomer, (R)-10, eluted with a retention
time of 55.1 min (ratio ) 93.5:6.5). Following selective
protection of the primary alcohol of 10 as its TBDMS
ether 11, direct azide displacement of the secondary
alcohol upon Mitsunobu activation (2.5 equiv of DPPA,
2.5 equiv of DEAD, THF, -20 to 25 °C, 2 h)11 with clean
inversion of stereochemistry and subsequent reduction
of the crude azide 12 (2 equiv of Ph3P, THF-H2O, 45 °C,
21 h, 65% for two steps) provided the amine 13. Small
amounts of elimination (7%) but no loss of the stereo-
chemical integrity was observed during the displacement.
N-CBZ protection of 13 provided 14 (90%), and depro-
tection of the TBDMS ether provided the key alcohol 15
(92%). The optical purity of 15 obtained directly from
10 without intervening recrystallizations was 84-87%
ee indicating a maintenance of the stereochemical integ-
rity throughout the sequence and of the crystalline
intermediates, 15 proved to be the most convenient for
storage, assessment, and enrichment of the optical purity.
One recrystallization from 50% EtOAc-hexane routinely
enriched the optical purity of 15 from 87% ee to g94%
ee. The optical purity of 15 was assessed on a Chiralpak
AD HPLC column (0.46 × 25 cm, 30% 2-propanol-
hexane, 1.0 mL/min), (R)-15 tR ) 13.0 min and (S)-15 tR
) 7.9 min.
(1) (a) McCormick, M. H.; Stark, W. M.; Pittenger, G. F.; Pittenger,
R. C.; McGuire, G. M. Antibiot. Annu. 1955-1956, 606. (b) Harris, C.
M.; Kopecka, H.; Harris, T. M. J . Am. Chem. Soc. 1983, 105, 6915. (c)
Harris, C. M.; Harris, T. M. J . Am. Chem. Soc. 1982, 104, 4293. (d)
Williams, D. H.; Kalman, J . R. J . Am. Chem. Soc. 1977, 99, 2768. (e)
Williamson, M. P., Williams, D. H. J . Am. Chem. Soc. 1981, 103, 6580.
(f) Sheldrick, G. M.; J ones, P. G.; Kennard, O.; Williams, D. H.; Smith,
G. A. Nature 1978, 271, 223.
(2) (a) Cornell, I. C.; Bardone, M. R.; Deparli, A.; Ferrari, P.; Tuan,
G.; Gallo, G. G. J . Antibiot. 1984, 37, 621. (b) Harris, C. M.; Kibby, J .
J .; Fehlner, J . R.; Raabe, A. B.; Barber, T. A.; Harris, T. M. J . Am.
Chem. Soc. 1979, 101, 437. (c) McGahren, W. J .; Martin, J . H.; Morton,
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1984, 49, 635. (e) Debono, M.; Molloy, R. M.; Barnhart, M.; Dorman,
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1995, 5, 3091. Boger, D. L.; Nomoto, Y.; Teegarden, B. R. J . Org. Chem.
1993, 58, 1425.
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1994, 94, 2483. Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino,
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Chem. 1981, 20B, 770.
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Tetrahedron Lett. 1977, 18, 1977.
S0022-3263(96)00085-0 CCC: $12.00 © 1996 American Chemical Society

3562 J . Org. Chem., Vol. 61, No. 10, 1996
Notes
Sch em e 1
which provided 2 in comparable chemical yields (75-
77%) but with surprisingly little or no racemization (90-
94% ee). Because of the ease of scale up, this latter
procedure was used to routinely provide our material.13
In contrast, alcohol 15 underwent oxidation in the
presence of PDC (4.5 equiv, DMF, 25 °C, 21 h) to provide
2 in only modest yields (20-30%) with extensive decom-
position. Alternative oxidative conditions examined in-
cluding RuCl3 (0.2 equiv)-NaIO4 (3 equiv, CCl4-MeCN-
H2O, 3:1:1, 25 °C, 24 h) or J ones oxidation led to
decomposition, and Pt/C (0.1 equiv)-O2 (NaHCO3, H2O-
acetone, 25 °C, 22 h) led to recovered starting material.
Protection of 2 as its tert-butyl ester 3 (g94% ee),14 which
was selected over the methyl ester in order to minimize
potential racemization when employed in subsequent
synthetic efforts, followed by uneventful CBZ deprotec-
tion by hydrogenolysis provided 4. Similarly, CBZ depro-
tection of 2 followed by N-BOC protection of the free
amino acid provided 5.
Exp er im en ta l Section
Meth yl 3,5-Dih yd r oxy-4-m eth oxyben zoa te. This
compound was prepared by the procedure reported:9
white needles, mp 147-148 °C (30% EtOAc-hexane),
1
lit.15 mp 144-145 °C; H NMR (DMSO-d6, 400 MHz) δ
9.50 (s, 1H), 6.96 (s, 2H), 3.82 (s, 3H), 3.75 (s, 3H); 13C
NMR (DMSO-d6, 100 MHz) δ 166.1, 150.7, 139.7, 124.5,
108.5, 59.7, 51.9; IR (neat) νmax 3386, 2996, 1709 cm-1
;
FABHRMS (NBA-NaI) m/ z 221.0430 (M+ + Na, C9H10O5
requires 221.0426).
Meth yl 3,5-Bis(ben zyloxy)-4-m eth oxyben zoate (6).
A solution of methyl 3,5-dihydroxy-4-methoxybenzoate
(4.3 g, 22 mmol) in anhydrous DMF (25 mL) was
sequentially treated with K2CO3 (11 g, 83 mmol) and
PhCH2Cl (6.5 mL, 57 mmol). The reaction mixture was
warmed at 110 °C for 1 h, cooled to 25 °C, and quenched
by the addition of H2O (25 mL). The mixture was stirred
for 15 min while the product precipitated. The resulting
grey solid was collected by filtration and was washed with
H2O (3 × 15 mL), dried in a vacuum desiccator, and
purified by recrystallization from 20% EtOAc-hexane to
afford 6 (7.5 g, 92%) as white needles: mp 116.5-118.0
°C (25% EtOAc-hexane), lit. mp 116-11810 and 118-
119 °C;16 1H NMR (CDCl3, 250 MHz) δ 7.50-7.31 (m,
12H), 5.17 (s, 4H), 3.95 (s, 3H), 3.89 (s, 3H); 13C NMR
(CDCl3, 62.5 MHz) δ 166.5, 152.1 (2C), 143.5 (2C), 136.6,
128.5 (4C), 127.9 (2C), 127.3 (4C), 124.9, 109.1 (2C), 71.0
Direct oxidation of the primary alcohol to the desired
sensitive carboxylic acid 2 was accomplished best using
N-oxoammonium salts12 in combination with NaOCl in
a buffered solution (2 equiv of 4-6% NaOCl, 1.1 equiv of
TEMPO, 0.1 equiv of KBr, acetone-5% aqueous NaH-
CO3, 0 °C, 2 h, 78%). In the optimization of this reaction
it was found that 1.1 equiv of TEMPO was necessary to
obtain the desired oxidation product. If a catalytic
amount (ca. 0.1 equiv) of TEMPO was employed or Ca-
13
(OCl)2 was substituted for NaOCl, the chlorinated
aromatic derivative 16 was isolated as the major product
(eq 1). Presumably the TEMPO scavenges any chlorine
which is liberated during the reaction. Similarly, pro-
pylene oxide could be utilized as the chlorine scavenger;
however, the conversions to 15 were lower (40-50%).
Using this optimized procedure, 2 could be obtained in
good chemical yields (78%) with little or no racemization
(94% ee). This could also be accomplished by conducting
the oxidation in two separate steps without purification
of the sensitive intermediate aldehyde by Dess-Martin
oxidation (2 equiv, 30 min, CH2Cl2, 25 °C) followed by
NaClO2 treatment (9 equiv, 30% 0.7 M aqueous NaH2-
PO4-t-BuOH, excess 2-methyl-2-butene, 25 °C, 20 min)
(2C), 60.9, 52.1; IR (neat) νmax 3019, 2933, 1717 cm-1
;
FABHRMS (NBA-NaI) m/ z 401.1373 (M+ + Na, C23H22O5
requires 401.1365).
(13) Nwaukwa, S. O.; Keehn, P. M. Tetrahedron Lett. 1982, 23, 35.
Dess, D. B.; Martin, J . C. J . Org. Chem. 1983, 48, 4155. Corey, E. J .;
Kania, R. S. J . Am. Chem. Soc. 1996, 118, 1229 and references cited
therein. Smith, A. B., III; Leenay, T. L. J . Am. Chem. Soc. 1989, 111,
5761.
(14) Anderson, G. W.; Callahan, F. M. J . Am. Chem. Soc. 1960, 82,
3359.
(12) (a) Anelli, P. L.; Biffi, C.; Montanari, F.; Quici, S. J . Org. Chem.
1987, 52, 2559. (b) Inokuchi, T.; Matsumoto, S.; Nishiyama, T.; Torri,
S. J . Org. Chem. 1990, 55, 462. (c) Miyazawa, T.; Endo, T.; Shiihashi,
S.; Okawara, M. J . Org. Chem. 1985, 50, 1332.
(15) Krauss, A. S.; Taylor, W. C. Aust. J . Chem. 1991, 44, 1307.
(16) Haslam, E.; Uddin, M. Tetrahedron 1968, 24, 4015.
(17) Degraw, J . I.; Christensen, J . C.; Brown, V. H.; Cory, M. J . J .
Heterocycl. Chem. 1974, 11, 363.

Notes
This reaction has also been conducted on large scale
with 115 g of 6 (92%) obtained from 65 g of starting
phenol.
J . Org. Chem., Vol. 61, No. 10, 1996 3563
62.5 MHz) δ 152.6 (2C), 140.1, 137.1, 136.5 (2C), 133.1,
128.5 (4C), 127.8 (2C), 127.2 (4C), 113.2, 106.1 (2C), 71.1
(2C), 61.0; IR (neat) νmax 3033, 2938, 1580, 1505, 915, 842
cm-1; FABHRMS (NBA-NaI) m/ z 347.1662 (M+ + H,
C23H22O3 requires 347.1647). Anal. Calcd for C23H22O3:
C, 79.81; H, 6.40. Found: C, 80.10; H, 6.29.
3,5-Bis(ben zyloxy)-4-m eth oxyben zyl Alcoh ol (7).
A cooled suspension of LiAlH4 (1.2 g, 32 mmol) in
anhydrous THF (30 mL) at 0 °C was treated dropwise
with a solution of 6 (6.1 g, 16 mmol) dissolved in THF
(25 mL). The resulting mixture was warmed to 25 °C,
stirred for 40 min, and recooled to 0 °C before saturated
aqueous NH4Cl (10 mL) was added slowly. The reaction
mixture was then filtered, and the remaining solid was
washed with EtOAc (4 × 15 mL). The volatiles were
removed in vacuo, and the remaining residual white solid
was purified by recrystallization from 50% EtOAc-
hexane to afford 7 (5.4 g, 95%) as white prisms: mp
104.0-104.5 °C (40% EtOAc-hexane), lit. mp 104-10510
and 105-106 °C;17 1H NMR (CDCl3, 250 MHz) δ 7.48-
7.32 (m, 10H), 6.64 (s, 2H), 5.11 (s, 4H), 4.52 (d, 2H, J )
5.7 Hz), 3.90 (s, 3H); 13C NMR (CDCl3, 62.5 MHz) δ 152.5
(2C), 138.5, 137.0 (2C), 136.5, 128.4 (4C), 127.8 (2C),
127.1 (4C), 106.2 (2C), 70.9 (2C), 65.1, 60.9; IR (neat) νmax
3313, 3065, 3033, 2937 cm-1; FABHRMS (NBA-NaI)
m/ z 373.1404 (M+ + Na, C22H22O4 requires 373.1416).
Anal. Calcd for C22H22O4: C, 75.46; H, 6.33. Found: C,
75.67; H, 6.16.
1(S)-[3,5-Bis(ben zyloxy)-4-m eth oxyp h en yl]-2-h y-
d r oxyeth a n ol (10). A stirred suspension of AD-mix-R8
(Aldrich, 8.1 g, 1.4 g/mmol) in t-BuOH-H2O (1:1, 58 mL)
was treated with 9 (2.0 g, 5.8 mmol) at 25 °C, and the
resulting two-phase reaction mixture was stirred vigor-
ously at 25 °C for 20 h. Sodium sulfite (Na2SO3, 8.7 g,
1.5 g/mmol) was added, and the mixture was stirred for
30 min and diluted with EtOAc (50 mL). After separa-
tion of the layers, the aqueous phase was further
extracted with EtOAc (3 × 25 mL). The combined
organic layers were washed with H2O (50 mL) and
saturated aqueous NaCl (50 mL), dried (MgSO4), and
concentrated in vacuo. The crude, white solid was
purified by recrystallization from 50% EtOAc-hexane to
afford 10 (2.1 g, 97%, 87% ee) as white needles: mp 103-
104 °C (20% EtOAc-hexane); [R]25 +21 (c 1.0, CHCl3);
D
1H NMR (CDCl3, 250 MHz) δ 7.44-7.28 (m, 10H), 6.61
(s, 2H), 5.07 (s, 4H), 4.61 (dd, 1H, J ) 3.4, 7.8 Hz), 3.87
(s, 3H), 3.53 (ddd, 2H, J ) 3.4, 7.8, 11.3 Hz), 3.05 (br s,
1H, OH), 2.48 (br s, 1H, OH); 13C NMR (CDCl3, 62.5 MHz)
δ 152.4 (2C), 138.6, 136.9 (2C), 136.2, 128.4 (4C), 127.8
(2C), 127.3 (4C), 105.4 (2C), 74.4, 70.9 (2C), 67.9, 60.8;
IR (neat) νmax 3386, 3066, 3033, 2933, 2871 cm-1; FAB-
HRMS (NBA-CsI) m/ z 513.0661 (M+ + Cs, C23H24O5
requires 513.0678). Anal. Calcd for C23H24O5: C, 72.67;
H, 6.36. Found: C, 72.56; H, 6.37.
This reaction has also been conducted on a large scale
with 77 g of 7 (79%) obtained from 115 g of 6.
3,5-Bis(ben zyloxy)-4-m eth oxyben za ld eh yd e (8). A
solution of 7 (5.2 g, 15 mmol) in anhydrous CH2Cl2 (60
mL) was treated with activated MnO2 (25 g) at 25 °C,
and the resulting suspension was stirred for 2 h. The
reaction mixture was filtered through a Celite pad (CH2-
Cl2, 5 × 50 mL), and the solvent was removed in vacuo.
The crude residue was purified by recrystallization from
50% EtOAc-hexane to afford 8 (4.4 g, 90%) as a white
powder: mp 85.5-87.5 °C (50% EtOAc-hexane), lit. mp
87-8810 and 85-88 °C;15 1H NMR (CDCl3, 250 MHz) δ
9.79 (s, 1H), 7.49-7.33 (s, 10H), 7.18 (s, 2H), 5.19 (s, 4H),
3.99 (s, 3H); 13C NMR (CDCl3, 62.5 MHz) δ 190.9, 152.9
(2C), 144.9, 136.4 (2C), 131.5, 128.7 (4C), 128.1 (2C),
127.3 (4C), 109.0 (2C), 71.1 (2C), 61.0; IR (neat) νmax 3064,
3032, 2939, 2830, 2731, 1693, 1587 cm-1; FABHRMS
(NBA-NaI) m/ z 349.1435 (M+ + H, C22H20O4 requires
349.1440). Anal. Calcd for C22H20O4: C, 75.90; H, 5.79.
Found: C, 76.17; H, 5.49.
1(S)-2-[(ter t-Bu tyldim eth ylsilyl)oxy]-1-[3,5-bis(ben -
zyloxy)-4-m eth oxyp h en yl]eth a n ol (11). A solution of
10 (1.8 g, 4.7 mmol) in anhydrous DMF (20 mL) was
treated with t-BuMe2SiCl (0.86 g, 5.7 mmol) and imida-
zole (0.45 g, 6.6 mmol) at 0 °C under Ar. The resulting
reaction mixture was warmed to 25 °C and stirred for 5
h before H2O (40 mL) was added. The aqueous phase
was extracted with EtOAc (3 × 30 mL), and the combined
extracts were washed with H2O (75 mL), saturated
aqueous NaCl (75 mL), dried (MgSO4), and concentrated
in vacuo. Flash chromatography (SiO2, 5 × 25 cm, 10-
20% EtOAc-hexane gradient elution) afforded 11 (2.0 g,
85%) as a colorless oil: [R]25D +12 (c 0.6, CHCl3); 1H NMR
(CDCl3, 250 MHz) δ 7.48-7.28 (m, 10H), 6.66 (s, 2H),
5.14 (s, 4H), 4.60 (ddd, 1H, J ) 2.0, 3.6, 8.1 Hz), 3.89 (s,
3H), 3.66 (dd, 1H, J ) 3.6, 10.1 Hz), 3.44 (dd, 1H, J )
8.1, 10.1 Hz), 2.99 (d, 1H, J ) 2.0 Hz), 0.94 (s, 9H), 0.08
(s, 6H); 13C NMR (CDCl3, 62.5 MHz) δ 152.4 (2C), 138.9,
137.1 (2C), 135.7, 128.4 (4C), 127.7 (2C), 127.3 (4C), 105.9
(2C), 74.1, 71.0 (2C), 68.8, 60.8, 25.8 (3C), 18.2, -5.4 (2C);
This reaction has also been conducted on a large scale
with PCC (CH2Cl2) with 64 g of 8 (85%) obtained from
77 g of 7.
3,5-Bis(ben zyloxy)-4-m eth oxystyr en e (9). A sus-
pension of methyltriphenylphosphonium bromide (12.3
g, 34.5 mmol) in anhydrous THF (70 mL) at -40 °C was
treated with n-BuLi (1.9 M solution in hexane, 18.1 mL,
34.5 mmol) dropwise over 15 min, and the resulting
solution was allowed to warm to -10 °C. After 40 min,
the mixture was cooled to -30 °C and a solution of 8 (4.00
g, 11.5 mmol) in THF (7 mL) was added dropwise over 5
min. The resulting orange reaction mixture was warmed
to 25 °C, stirred for 1.5 h, quenched by the addition of
H2O (40 mL), and extracted with EtOAc (4 × 20 mL).
The combined organic phases were washed with H2O (2
× 30 mL) and saturated aqueous NaCl (75 mL), dried
(MgSO4), and concentrated in vacuo. Chromatography
(SiO2, 4 × 24 cm, 10-20% EtOAc-hexane gradient
elution) afforded 9 (3.58 g, 90%) as white needles: mp
68.0-68.5 °C (20% EtOAc-hexane); 1H NMR (CDCl3, 250
MHz) δ 7.50-7.31 (m, 10H), 6.71 (s, 2H), 6.58 (dd, 1H, J
) 10.8, 17.5 Hz), 5.58 (d, 1H, J ) 17.5 Hz), 5.18 (d, 1H,
J ) 10.8 Hz), 5.16 (s, 4H), 3.92 (s, 3H); 13C NMR (CDCl3,
IR (film) νmax 3475, 3064, 3032, 2952, 2927, 2856 cm-1
;
FABHRMS (NBA-CsI) m/ z 627.1570 (M+ + Cs, C29H38O5-
Si requires 627.1543).
1(R)-2-[(ter t-Bu tyldim eth ylsilyl)oxy]-1-[3,5-bis(ben -
zyloxy)-4-m eth oxyp h en yl]eth yla m in e (13). A solu-
tion of 11 (0.94 g, 1.9 mmol) in anhydrous THF (14 mL)
at -20 °C was treated sequentially with Et3N (1.3 g, 4.8
mmol) diphenyl phosphorazidate (DPPA, 1.0 mL, 4.8
mmol), and diethyl azodicarboxylate (DEAD, 0.75 mL,
4.8 mmol). The reaction mixture was warmed to 25 °C,
stirred for 2 h, and concentrated in vacuo. Chromatog-
raphy (SiO2, 4 × 24 cm, 5-10% EtOAc-hexane gradient
elution) afforded 0.9 g of an inseparable 9:1 mixture of
azide 12 and the corresponding elimination product,
respectively, as a colorless oil which was carried on

3564 J . Org. Chem., Vol. 61, No. 10, 1996
Notes
together into the subsequent step. For 12: 1H NMR
(CDCl3, 400 MHz) δ 7.46-7.31 (m, 10H), 6.55 (s, 2H),
5.12 (s, 4H), 4.42 (dd, 1H, J ) 4.2, 8.3 Hz), 3.87 (s, 3H),
3.67 (dd, 1H, J ) 4.2, 10.6 Hz), 3.61 (dd, 1H, J ) 8.3,
10.6 Hz), 0.89 (s, 9H), 0.04 (s, 6H); 13C NMR (CDCl3, 100
MHz) δ 152.6 (2C), 139.4, 137.0 (2C), 132.3, 128.5 (4C),
127.9 (2C), 127.4 (4C), 106.8 (2C), 71.2 (2C), 68.3, 67.3,
60.9, 26.0 (3C), 18.3, -5.4 (2C); IR (film) νmax 3065, 3032,
2928, 2857, 2099 cm-1; MS (electrospray) m/ z 542 (M+
+ Na).
THF (0.43 mL, 0.43 mmol) under Ar. The resulting
reaction mixture was warmed to 25 °C, stirred for 2 h,
poured into H2O (10 mL), and extracted with EtOAc (3
× 10 mL). The combined organic extracts were washed
with H2O (20 mL), saturated aqueous NaCl (25 mL),
dried (Na2SO4), and concentrated in vacuo. Flash chro-
matography (SiO2, 3.5 × 10 cm, 20-50% EtOAc-hexane
gradient elution) afforded 15 (0.17 g, 92%) as a white
powder. Recrystallization (50% EtOAc-hexane) provided
15 (0.16 g, 88%, g94% ee): mp 118-119 °C (50% EtOAc-
hexane); [R]23D -21 (c 0.50, CHCl3); 1H NMR (CDCl3, 400
MHz) δ 7.42-7.29 (m, 15H), 6.52 (s, 2H), 5.40-5.36 (br
s, 1H, NH), 5.09 (s, 6H), 4.69-4.64 (m, 1H), 3.89 (s, 3H),
3.78-3.74 (m, 2H), 1.78 (br s, 1H, OH); 13C NMR (CDCl3,
100 MHz) δ 156.3, 152.6 (2C), 138.6, 136.8 (2C), 136.1,
134.7, 128.4 (6C), 128.2, 127.9 (2C), 127.3 (6C), 106.1
(2C), 71.0 (2C), 66.8, 66.1, 60.8, 56.9; IR (neat) νmax 3332,
3041, 2950, 1685, 1595, 1535, 1509 cm-1; FABHRMS
(NBA-CsI) m/ z 646.1229 (M+ + Cs, C31H31NO6 requires
646.1206). Anal. Calcd for C31H31NO6: C, 72.55; H, 6.08;
N, 2.73. Found: C, 72.55; H, 6.11; N, 2.71.
The mixture of azide 12 and the elimination product
from the previous reaction (0.9 g) in THF (17 mL) was
treated with Ph3P (0.91 g, 3.5 mmol) and H2O (0.31 mL,
0.017 mol) at 25 °C. The resulting reaction mixture was
warmed at 45 °C for 21 h. The volatiles were removed
in vacuo, and the residue was purified by flash chroma-
tography (SiO2, 4 × 24 cm, 5-20% EtOAc-hexane
gradient elution) to afford 13 (0.61 g, 65% based on
starting alcohol 11) and the elimination product (68 mg,
7%) as colorless oils. For 13: [R]25 -9.7 (c 2.7, CHCl3);
D
1H NMR (CDCl3, 400 MHz) δ 7.45-7.30 (m, 10H), 6.66
(s, 2H), 5.18 (s, 4H), 3.93 (dd, 1H, J ) 3.9, 8.6 Hz), 3.87
(s, 3H), 3.57 (dd, 1H, J ) 3.9, 9.8 Hz), 3.37 (dd, 1H, J )
8.6, 9.8 Hz), 0.88 (s, 9H), 0.02 (s, 6H); 13C NMR (CDCl3,
62.5 MHz) δ 152.3 (2C), 138.5, 138.0, 137.1 (2C), 128.3
(4C), 127.7 (2C), 127.2 (4C), 106.4 (2C), 70.9 (2C), 69.4,
60.7, 57.5, 25.8 (3C), 18.2, -5.5 (2C); IR (film) νmax 3383,
3064, 3032, 2953, 2928, 2856 cm-1; FABHRMS (NBA-
CsI) m/ z 626.1723 (M+ + Cs, C29H39NO4Si requires
626.1703).
(R)-N-[(Ben zyloxy)ca r bon yl]-[3,5-bis(ben zyloxy)-
4-m eth oxyp h en yl]glycin e (2). Method A: A solution
of 15 (84 mg, 0.16 mmol) in acetone (0.4 mL) at 0 °C was
added to an aqueous 5% NaHCO3 solution (0.4 mL), and
additional acetone (ca. 0.4 mL), was added until stirring
became possible. This heterogeneous mixture was treated
sequentially with KBr (1.9 mg, 0.016 mmol) and TEMPO
(28 mg, 0.18 mmol). Sodium hypochlorite (NaOCl, Ald-
rich 4-6% or ca. 0.5 M solution, 0.40 mL, 0.21 mmol)
was added dropwise over 10 min, and the mixture was
stirred at 0 °C. After 1 h, additional NaOCl (0.20 mL,
0.10 mmol) was added. The reaction mixture was stirred
for 1 h before the addition of H2O (10 mL), and EtOAc
(10 mL). The aqueous phase was extracted with EtOAc
(3 × 10 mL), and the combined organic layers were
washed with H2O (20 mL) and saturated aqueous NaCl
(20 mL), dried (Na2SO4), and concentrated in vacuo.
Chromatography (SiO2, 3.5 × 10 cm, 2-10% CH3OH-
CHCl3 gradient elution) afforded 2 (67 mg, 78%, g94%
For the elimination product: 1H NMR (CDCl3, 250
MHz) δ 7.54-7.32 (m, 10H), 6.77 (d, 1H, J ) 12.1 Hz),
6.49 (s, 2H), 5.90 (d, 1H, J ) 12.1 Hz), 5.15 (s, 4H), 3.90
(s, 3H), 0.96 (s, 9H), 0.20 (s, 6H); 13C NMR (CDCl3, 62.5
MHz) δ 152.6 (2C), 141.9, 137.3 (2C), 133.8, 132.0, 128.5
(4C), 127.8 (2C), 127.2 (4C), 112.6, 105.2 (2C), 71.2 (2C),
61.0, 25.6 (3C), 18.3, -5.2 (2C); IR (film) νmax 3032, 2953,
2928, 2857, 1758, 1645 cm-1
.
1(R)-N-[(Ben zyloxy)ca r bon yl]-2-[(ter t-bu tyld im e-
th ylsilyl)oxy]-1-[3,5-bis(ben zyloxy)-4-m eth oxyp h e-
n yl]eth yla m in e (14). A solution of 13 (0.20 g, 0.41
mmol) in THF-H2O (1:1, 4.0 mL) was treated with Na2-
CO3 (86 mg, 0.81 mmol) and benzyl chloroformate (64
µL, 0.46 mmol) at 25 °C under Ar. After 2.5 h, the
reaction mixture was poured into H2O (10 mL) and
extracted with EtOAc (4 × 10 mL). The combined
organic layers were washed with H2O (3 × 10 mL) and
saturated aqueous NaCl (3 × 10 mL), dried (MgSO4),
filtered, and concentrated in vacuo. Chromatography
(SiO2, 3.5 × 10 cm, 10-25% EtOAc-hexane gradient
elution) afforded 14 (0.22 g, 90%) as a white solid: mp
ee)18 as a white solid: mp 128.5-130.0 °C (EtOH-
1
hexane); [R]25 -72 (c 1.0, CH3OH); H NMR (CD3OD,
D
400 MHz) δ 7.45-7.16 (m, 15H), 6.75 (s, 2H), 5.05 (s, 1H),
4.99 (s, 2H), 4.96 (s, 4H), 3.67 (s, 3H); 13C NMR (CD3OD,
100 MHz) δ 173.8, 158.0, 153.9 (2C), 140.0, 138.4 (2C),
138.1, 134.2, 129.5 (6C), 129.0, 128.9 (2C), 128.8 (6C),
108.1 (2C), 72.0 (2C), 67.8, 61.3, 59.3; IR (neat) νmax 3316,
3016, 2937, 1717, 1592 cm-1; FABHRMS (NBA-CsI) m/ z
660.1023 (M+ + Cs, C31H29NO7 requires 660.0998).
Method B: A solution of 15 (56 mg, 0.11 mmol) in CH2-
Cl2 (1.1 mL) at 0 °C was treated with Dess-Martin 12-
I-5 periodinane reagent13 (92 mg, 0.22 mmol), and the
resulting heterogeneous mixture was gradually warmed
to 25 °C. After 30 min of stirring, the suspension was
diluted with Et2O (2 mL), poured into a saturated
aqueous solution of NaHCO3 (5 mL) containing Na2S2O3-
84.5-85.0 °C (20% EtOAc-hexane); [R]25 -15.2 (c 1.0,
D
CHCl3); 1H NMR (CDCl3, 400 MHz) δ 7.44-7.29 (m, 15H),
6.58 (s, 2H), 5.40 (d, 1H, NH, J ) 7.4 Hz), 5.08 (s, 6H),
4.65-4.60 (m, 1H), 3.87 (s, 3H), 3.80 (dd, 1H, J ) 4.0,
10.2 Hz), 3.65-3.58 (m, 1H), 0.88 (s, 9H), -0.08 (s, 3H),
-0.10 (s, 3H); 13C NMR (CDCl3, 100 MHz), δ 156.4, 152.5
(2C), 138.6, 136.7 (2C), 134.0, 132.4, 128.4 (6 C), 128.0,
127.9 (2C), 127.4 (6C), 106.3 (2C), 71.0 (2C), 66.1, 66.7,
60.8, 56.6, 26.1 (3C), 18.5, -5.5 (2C); IR (neat) νmax 3358,
3064, 3032, 2928, 2856, 1688, 1593, 1532 cm-1; FAB-
HRMS (NBA-CsI) m/ z 760.2042 (M+ + Cs, C37H45NO6-
Si requires 760.2070). Anal. Calcd for C37H45NO6Si: C,
70.84; H, 7.22; N, 2.23. Found: C, 70.66; H, 7.28; N, 2.21.
1(R)-N-[(Ben zyloxy)car bon yl]-1-[3,5-bis(ben zyloxy)-
4-m eth oxyp h en yl]-2-h yd r oxyeth yla m in e (15). A so-
lution of 14 (0.22 g, 0.36 mmol) in THF (5 mL) at 0 °C
was treated dropwise with a 1.0 M solution of Bu4NF in
(18) The optical purity of 3 (94% ee) derived from 10 (87% ee) was
assessed by chiral phase HPLC separation of the enantiomers on a
Chiralpak AD HPLC column (0.46 × 25 cm, 30% 2-propanol-hexane,
1.0 mL/min) alongside racemic material, tR ) 13.0 min for (R)-3 and
tR ) 21.0 min for (S)-3 (97:3), in which the enrichment of the optical
purity (g94% ee) was accomplished by recrystallization of intermediate
15. Consequently, the optical purity of 2, the precursor to 3, following
oxidation of 15 must be g94% ee. The optical purity of 4 (94% ee) was
established upon conversion to the Mosher amide upon treatment with
(-)-(R)-MTPCl and 19F and 1H NMR analysis alongside racemic
material: 19F NMR (CDCl3) δ -70.0 (3.0), -70.2 (97.0); 1H NMR
(CDCl3, 400 MHz) δ 6.52 (s, 1.94), 6.39 (s, 0.06 H). Due to its
chromatographic polarity, the optical purity of 5 was not assessed by
chiral phase HPLC, but its use in subsequent efforts6 indicated that
little or no racemization occurred in its preparation.

Notes
J . Org. Chem., Vol. 61, No. 10, 1996 3565
H2O (0.19 g, 0.76 mmol), and stirred until two distinct
layers were observed. The two layers were separated,
and the aqueous phase was extracted with Et2O (3 × 7
mL). The combined organic extracts were washed with
saturated aqueous NaHCO3 (2 × 7 mL) and saturated
aqueous NaCl (7 mL), dried (Na2SO4), and concentrated
in vacuo to afford crude aldehyde (54 mg, 99%) which
was sufficiently pure to use in the subsequent step. A
buffered solution of NaClO2 (Aldrich, 80%, 0.11 g, 0.99
mmol) and NaH2PO4 (0.10 g, 0.74 mmol) in H2O (1 mL)
was added dropwise to a solution of the aldehyde (54 mg,
0.11 mmol) in 2-methyl-2-butene (0.65 mL) and t-BuOH
(2.6 mL, 1:4) at 25 °C. After stirring the reaction mixture
for 20 min at 25 °C, the volatiles were removed in vacuo,
and the residue was diluted with H2O (10 mL) and
extracted with EtOAc (3 × 10 mL). The combined
organic layers were dried (Na2SO4) and concentrated in
vacuo. Flash chromatography (SiO2, 2.5 × 10 cm, 5-10%
CH3OH-CHCl3 gradient elution) afforded 2 (43 mg, 75%
(CDCl3, 100 MHz) δ 169.6, 155.3, 152.7 (2C), 139.3, 136.9
(2C), 136.2, 132.7 (2C), 128.5 (6C), 128.2 (2C), 127.9 (4C),
127.3 (2C), 106.5 (2C), 82.7, 71.0 (2C), 67.0, 60.9, 58.3,
27.8 (3C); IR (film) νmax 3346, 3056, 2978, 2929, 1721,
1529 cm-1; FABHRMS (NBA-CsI) m/ z 716.1604 (M+
+
Cs, C35H37NO7 requires 716.1624).
ter t-Bu tyl (R)-(3,5-Dih yd r oxy-4-m eth oxyp h en yl)-
glycin e (4). A solution of 3 (0.13 g, 0.22 mmol) in CH3-
OH (2.5 mL) at 25 °C was treated with 10% Pd-C (13
mg) and was stirred under 1 atm of H2 for 5 h. The
reaction mixture was filtered through a pad of Celite
(10% CH3OH-CHCl3, 3 × 10 mL), and the solvent was
removed in vacuo. Chromatography (SiO2, 3.5 × 10 cm,
5-10% CH3OH-CHCl3 gradient elution) afforded 4 (59
mg, 98%) as a white film: [R]25 -53 (c 0.27, CH3OH);18
D
1H NMR (CD3OD, 400 MHz) δ 6.24 (s, 2H), 4.07 (s, 1H),
3.64 (s, 3H), 1.30 (s, 9H); 13C NMR (CD3OD, 100 MHz) δ
172.2, 149.9 (2C), 135.3, 134.5, 105.2 (2C), 80.6, 58.8,
57.8, 26.1 (3C); IR (neat) νmax 3349, 3269, 2958, 2912,
1712, 1560, 1523 cm-1; FABHRMS (NBA-NaI) m/ z
292.1156 (M+ + Na, C13H19NO5 requires 292.1161).
over two steps) as a white solid: [R]25 -72 (c 0.9, CH3-
D
OH), g94% ee).18
(R)-N-[(Ben zyloxy)ca r bon yl]-[3,5-bis(ben zyloxy)-
2-ch lor o-4-m eth oxyp h en yl]glycin e (16). A solution
of 15 (25 mg, 0.049 mmol) in acetone (0.2 mL) at 0 °C
was added to an aqueous 5% NaHCO3 solution (0.2 mL),
and additional acetone was added (0.3 mL) until stirring
became possible. This heterogeneous mixture was treated
with TEMPO (0.08 mg, 0.005 mmol) followed by Ca(OCl)2
(17 mg, 0.12 mmol). The resulting reaction mixture was
stirred at 0 °C for 2 h, poured into H2O (5 mL), and
extracted with EtOAc (3 × 5 mL). The combined organic
layers were washed with H2O (10 mL) and saturated
aqueous NaCl (20 mL), dried (Na2SO4), and concentrated
in vacuo. Chromatography (SiO2, 2.5 × 10 cm, 2-10%
(R)-N-[(ter t-Bu tyloxy)ca r bon yl]-(3,5-d ih yd r oxy-4-
m eth oxyp h en yl)glycin e (5). A solution of 2 (45 mg,
0.085 mmol) in CH3OH (0.9 mL) at 25 °C was treated
with 10% Pd-C (4.5 mg, 0.10 wt equiv), and the mixture
was stirred under 1 atm of H2 for 8 h. The reaction
mixture was filtered through a pad of Celite (CH3OH,
50 mL), the solvent was removed in vacuo, and the
product was dried under vacuum to afford the depro-
tected amino acid (18 mg, 0.085 mmol) which was used
directly in the following reaction.
A solution of the amino acid (18 mg, 0.085 mmol) in
THF-H2O (1:1, 1.7 mL) was treated with NaHCO3 (22
mg, 0.26 mmol) and di-tert-butyl dicarbonate (41 mg, 0.19
mmol) at 25 °C under Ar. After 10 h, aqueous citric acid
(pH ) 3-4, 1.7 mL) was added to the reaction mixture,
and the mixture was extracted with EtOAc (2 × 10 mL).
The combined organic layers were washed with saturated
aqueous NaCl (1 × 2 mL), dried (Na2SO4), filtered, and
concentrated in vacuo. Chromatography (SiO2, 3 × 14
cm, CH2Cl2-CH3OH-HOAc 88:10:6) afforded 5 (22 mg,
CH3OH-CHCl3 gradient elution) afforded 16 (14 mg,
1
52%) as a colorless oil: [R]25 -56 (c 0.025, CH3OH); H
D
NMR (CD3OD, 400 MHz) δ 7.38-7.14 (m, 15H), 6.89 (s,
1H), 5.60 (s, 1H), 4.98 (s, 2H), 4.95 (s, 2H), 4.90 (s, 2H),
3.72 (s, 3H); 13C NMR (CD3OD, 100 MHz) δ 174.0, 158.1,
152.8 (2C), 150.3, 146.0, 138.5, 138.0 (2C), 132.5, 129.6
(2C), 129.5 (4C), 129.4 (2C), 129.2, 129.1 (2C), 129.0,
128.9 (2C), 111.0 (2C), 76.6 (2C), 72.2, 67.8, 61.7; IR (neat)
ν
max 3393, 1701, 1485, 1414, 1369, 1338, 1218, 1097 cm-1
;
FABHRMS (NBA-CsI) m/ z 694.0621 (M+ + Cs, C31H28
-
ClNO7 requires 694.0609).
78%) as a white film: [R]25 -89 (c 0.8, CH3OH);18 1H
D
ter t-Bu t yl (R)-N-[(Ben zyloxy)ca r b on yl]-[3,5-b is-
(ben zyloxy)-4-m eth oxyp h en yl]glycin e (3). A sealed
tube reaction vessel was charged with 2 (0.14 g, 0.27
mmol), anhydrous CH2Cl2 (2.7 mL), and concentrated H2-
SO4 (2.8 µL, 0.053 mmol) at -15 °C. Before the tube was
sealed, excess isobutylene gas was bubbled through the
suspension until the volume tripled (9 mL, ca. 5 min).
The reaction vessel was sealed, and the mixture was
warmed to 25 °C and stirred for 24 h. The tube was then
cooled to -78 °C, opened to the atmosphere, and allowed
to slowly warm to 25 °C. N2 was bubbled through the
solution to remove the residual isobutylene. A 5%
aqueous NaHCO3 solution (10 mL) and EtOAc (10 mL)
were added and the mixture was extracted with EtOAc
(3 × 10 mL). The combined organic phases were washed
with 5% aqueous NaHCO3 (20 mL) and saturated aque-
ous NaCl (20 mL), dried (Na2SO4), and concentrated in
vacuo. Chromatography (SiO2, 3.5 × 10 cm, 10-40%
NMR (CD3OD, 400 MHz) δ 6.41 (s, 2H), 4.92 (s, 1H), 3.76
(s, 3H), 1.43 (s, 9H); 13C NMR (CD3OD, 100 MHz) δ 175.3,
157.3, 151.8, 136.5, 135.1, 107.8, 80.6, 60.7, 28.7, 28.5;
IR (neat) νmax 3345, 2976, 2932, 1694, 1600, 1504, 1455,
1161 cm-1; FABHRMS (NBA-NaI) m/ z 336.1069 (M+
+ Na, C14H19NO7 requires 336.1059).
Ack n ow led gm en t. We gratefully acknowledge the
financial support of the National Institutes of Health
(CA41101) and the award of a NIH postdoctoral fellow-
ship (RMB, GM17548), and we wish to thank Professor
Sharpless for use of the Diacel Chiralpak AD HPLC
column.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra of
6, 11, 13, 16, and 2-5 are provided (8 pages). This material
is contained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
EtOAc-hexane gradient elution) afforded 3 (0.13 g, 87%,
1
94% ee18) as a white film: [R]25 -60 (c 1.3, CHCl3); H
D
NMR (CDCl3, 400 MHz) δ 7.44-7.25 (m, 15H), 6.64 (s,
2H), 5.78 (d, 1H, NH, J ) 7.2 Hz), 5.12 (s, 1H), 5.10 (s,
4H), 5.09 (s, 2H), 3.90 (s, 3H), 1.32 (s, 9H); 13C NMR
J O960085F