Asymmetric synthesis of 3,5-bis(isopropyloxy)-4-methoxyphenyl glycine by way of a diastereoselective Strecker reaction and an Evans electrophilic amination reaction

Article abstract of DOI:10.1016/S0957-4166(98)00312-7

Two short syntheses of D-N-Boc-3,5-bis(isopropyloxy)-4-methoxyphenyl glycine, a central unit of vancomycin type antibiotics, have been developed. A diastereoselective Strecker reaction using (S)-phenylglycinol as a chiral inducer was the key step in the first synthesis, while Evans' electrophilic amination technology was employed for introducing both the amino function and the chirality in the second strategy.

Full text of DOI:10.1016/S0957-4166(98)00312-7

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 3095–3103
Asymmetric synthesis of 3,5-bis(isopropyloxy)-4-methoxyphenyl
glycine by way of a diastereoselective Strecker reaction and an
Evans electrophilic amination reaction
Caroline Vergne, Jean-Philippe Bouillon, Jacqueline Chastanet, Michèle Bois-Choussy and
Jieping Zhu ∗
Institut de Chimie des Substances Naturelles, CNRS, 91198 Gif-Sur-Yvette, France
Received 21 July 1998; accepted 31 July 1998
Abstract
Two short syntheses of D-N-Boc-3,5-bis(isopropyloxy)-4-methoxyphenyl glycine, a central unit of vancomycin
type antibiotics, have been developed. A diastereoselective Strecker reaction using (S)-phenylglycinol as a chiral
inducer was the key step in the first synthesis, while Evans’ electrophilic amination technology was employed for
introducing both the amino function and the chirality in the second strategy. © 1998 Elsevier Science Ltd. All
rights reserved.
The intramolecular SNAr-based cycloetherification reaction has been developed over recent years as
a powerful synthetic methodology for the construction of structurally diverse macrocycles with endo
aryl–aryl1–3 and aryl–alkyl ether4 linkages. To apply this reaction in the synthesis of vancomycin 1,5 an
important glycopeptide antibiotic, an easy access to D-N-Boc-3,5-dihydroxy-4-methoxyphenylglycine
2 in a suitably protected form was a prerequisite. Indeed, several asymmetric syntheses of this central
unit of the vancomycin structure have been reported. Thus, we have communicated two syntheses of
amino acid 2 by way of a diastereoselective Strecker reaction6 and Evans’ electrophilic amination
methodology7 in conjunction with our efforts toward the synthesis of the vancomycin C–O–D–O–E
ring. This latter strategy has also been employed independently by Pearson’s group8 for the synthesis
of this amino acid. Boger et al.9 have devised a concise synthesis of 2 in which Sharpless asymmetric
dihydroxylation10 served to introduce the required stereochemistry. Davis et al.11 very recently described
an elegant synthesis of 2 based on their chiral sulfinimine methodology. Furthermore, an alternative
chemoenzymatic synthesis has also been developed in this laboratory.12 We detail herein our syntheses
of 2a and 2b based on the diastereoselective Strecker and Evans’ electrophilic amination methodology
(Fig. 1).
∗
Corresponding author. Fax: 33-1-69077247; e-mail: zhu@icsn.cnrs-gif.fr
0957-4166/98/$ - see front matter © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00312-7
tetasy 2461 Article

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Fig. 1.
1. Asymmetric Strecker synthesis
The three component Strecker reaction is among one of the most convenient and efficient ways for the
construction of amino acids from readily available aldehydes. Several chiral auxiliary-based asymmetric
versions have been developed in which the chiral inducer was normally the amine moiety.13 Our synthesis
of amino acid 2 based on this strategy using (S)-phenyl glycinol as the chiral auxiliary14,15 is shown in
Scheme 1.
Scheme 1.
The 4-methoxy-3,5-bis(isopropyloxy)benzaldehyde 3 was readily available from gallic acid in large
quantities according to our recently developed procedures.16 Treatment of 3 with (S)-phenylglycinol in
CH2Cl2 at rt for 1 h followed by sequential addition of MeOH and TMSCN at 0°C afforded a mixture
of two readily separable diastereoisomers from which the desired stereoisomer 4a was isolated in 82%
yield. The stereoselectivity of this reaction can be explained based on the Felkin–Ahn model17 by analogy
with literature precedents.14 Hydrolysis of α-aminonitrile 4a to the corresponding amino acid under
acidic conditions was found to be troublesome in our case, and an alternative transformation to the
corresponding amino ester was thus sought. The methyl ester was unsuitable for our purpose since control
experiments showed that hydrolysis of N-Boc-4-methoxyphenyl glycine methyl ester under various
conditions led to partial racemization. In view of the mild, racemization free deprotection conditions

C. Vergne et al. / Tetrahedron: Asymmetry 9 (1998) 3095–3103
3097
of allyl esters,18 compound 4a was transformed into α-amino allyl ester 5 using gaseous HCl saturated
allyl alcohol in 95% yield. Neither the formation of γ-lactone resulting from the internal attack of the
primary hydroxy group onto the nitrile, nor the degradation to the starting aldehyde 3 was observed under
these conditions. Unfortunately, partial epimerization occurred leading to a mixture of two inseparable
diastereomers in a ratio of 9/1 (de 80%) which was used for the following transformations without further
purification. Oxidative cleavage of the chiral auxiliary with Pb(OAc)4,19 afforded the imine intermediate
which was immediately hydrolyzed to give the amino ester 6. Protection of the amino function as the
N-carbamate under classic conditions (Boc2O, CH2Cl2, or 2,2,2-trichloroethyl chloroformate, NaHCO3,
CH2Cl2–H2O) afforded compound 7 (P=Boc or Troc) in excellent yield. Deprotection of the allyl ester
was realized under reductive conditions [Pd(PPh3)4, NaBH4, THF]20 to provide the desired amino acid
2 in 79% yield whose enantiomeric excess was determined by conversion to the corresponding (S)-α-
methyl benzylamide 8. A diastereomeric excess of amide 8, hence an enantiomeric excess of 2a, was
estimated to be 80% by inspection of its 1H NMR spectrum. This value is in accord with the de of amino
ester 5 indicating that little, if any, racemization occurred in its conversion to amino acid 2 (Scheme 2).
Scheme 2.
2. Evans’ electrophilic azidation reaction
The moderate ee (80%) obtained with the above Strecker synthesis of amino acid 2a and 2b led us to
develop an alternative synthesis on the basis of Evans’ asymmetric azidation technology. The prerequisite
4-methoxy-3,5-bis(isopropyloxy)phenylacetic acid 10 was prepared from the known methyl 4-methoxy-
3,5-bis(isopropyloxy)benzoate 9 in a straightforward fashion. Formation of the mixed anhydride between
acid 10 and pivaloyl chloride followed by addition of the lithium salt of (4R)-4-phenylmethyl-2-
oxazolidinone gave the imide 11 in 85% yield. Subsequent treatment of its potassium enolate with 2,4,6-
triisopropylbenzenesulfonyl azide (TrisylN3) according to Evans21 provided the triazene intermediate
which was decomposed to the desired azide 12 under modified conditions (Me2CO, NaI, KOAc, room
temperature).22 The diastereoselectivity of this azidation reaction was found to be higher than 85% and

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the diastereomerically pure compound 12 can be isolated in 70–75% yield. Hydrogenolysis of azide in
the presence of Boc2O23 afforded directly the N-Boc carbamate derivative 13 which was then hydrolyzed
to furnish acid 2a in excellent overall yield. The ee of compound 2a prepared in this way was determined
to be greater than 95% by its transformation into the corresponding (S)-α-methyl benzylamide 8.
In conclusion, two efficient syntheses of the central amino acid of vancomycin type antibiotics have
been developed in which a diastereoselective Strecker reaction and an Evans’ electrophilic amination
were the key steps, respectively. Both syntheses allowed the preparation of the target in gram quantities.
However, the latter strategy is more efficient in terms of enantioselectivity.
3. Experimental section
3.1. (3,5-Bisisopropyloxy-4-methoxy-phenyl)-(2-hydroxy-1-phenyl-ethylamino)-acetonitrile 4a
To a solution of aldehyde 3 (1.00 g, 3.97 mmol) in CH2Cl2 (27 mL) was added (S)-phenylglycinol
(0.65 g, 4.76 mmol) at room temperature. After being stirred at room temperature for 2 h, the reaction
mixture was cooled to 0°C, methanol (3.3 mL) and TMSCN (0.79 mL, 5.96 mmol) were then introduced
successively. After being stirred at 0°C for 1 h and at room temperature for 12 h, the reaction mixture
was carefully quenched by addition of aqueous citric acid solution (caution: generating toxic HCN) and
stirring was continued for another 30 min. The aqueous phase was then neutralized with phosphate buffer
(pH=7) and extracted with CH2Cl2. The combined organic extracts were washed with brine, dried and
evaporated to dryness. Purification by flash chromatography (SiO2, eluant: Et2O/heptane=5/6 then 5/4
afforded compound 4a (1.30 g, 82%) and its diastereomer 4b (170.00 mg, 11%). Compound 4a: [α]D
1
+49 (c 0.7, CHCl3); IR (CHCl3) ν 3400–3500, 2975, 2944, 2230, 1581, 1500, 1438, 1325 cm−1; H
NMR (CDCl3, 200 MHz) δ 1.35 (d, J=6.2 Hz, 12H), 1.88 (br s, 1H, OH), 2.50 (br s, 1H, NH), 3.62
(m, 1H), 3.80 (s, 3H), 3.85 (m, 1H), 4.22 (dd, J=3.9, 9.1 Hz, 1H), 4.38 (d, J=10.8 Hz, 1H), 4.51 (septet,
J=6.2 Hz, 2H), 6.70 (s, 2H), 7.30–7.50 (m, 5H); 13C NMR (CDCl3) δ 22.2, 52.0, 60.5, 63.4, 67.2, 72.0,
108.4, 118.9, 127.8, 128.6, 129.0, 130.2, 138.3, 152.2; MS (EI) m/z 398 (M+), 371, 340, 298. Anal. calcd
for C23H30N2O4: C, 69.32; H, 7.59; N, 7.03; found: C, 68.98; H, 7.22; N, 6.78. Compound 4b: [α]D +32
(c 0.6, CHCl3); IR (CHCl3) ν 3334, 2983, 2932, 2230, 1594, 1496, 1387, 1324 cm−1; 1H NMR (CDCl3,
200 MHz) δ 1.35 (d, J=6.1 Hz, 12H), 1.95 (br s, 1H, OH), 2.46 (br s, 1H, NH), 3.60–3.90 (m, 3H), 3.80
(s, 3H), 4.47 (septet, J=6.1 Hz, 2H), 4.52 (brs, 1H), 6.53 (s, 2H), 7.25–7.45 (m, 5H); 13C NMR (CDCl3)
δ 22.3, 51.9, 60.6, 61.9, 66.9, 71.9, 108.6, 119.2, 127.7, 128.4, 128.9, 130.0, 138.9, 152.4; MS (EI) m/z
398 (M+), 371, 340, 298.
3.2. (3,5-Bisisopropyloxy-4-methoxy-phenyl)-(2-hydroxy-1-phenyl-ethylamino)-acetic acid allyl ester 5
To a solution of amino nitrile 4a (1.01 g, 2.54 mmol) in a minimum amount of allyl alcohol was
added allyl alcohol saturated with gaseous HCl at 0°C. After being stirred at 0°C for 2 h and at room
temperature for 8 h, the volatiles were removed and the residue was redissolved in water, neutralized
first with aqueous NaHCO3 solution (to pH=5–6) then with phosphate buffer (pH=7) and extracted
with CH2Cl2. The combined organic extracts were washed with brine, dried and evaporated to dryness.
Purification by flash chromatography (SiO2, eluant: EtOAc/heptane=1/5 then 1/2) afforded compound
5 (1.10 g, 95%): [α]D −6.0 (c 0.3, CHCl3); IR (CHCl3) ν 3400–3500, 3341, 2982, 2938, 1735, 1592,
1492, 1456, 1437, 1319 cm−1; 1H NMR (CDCl3, 200 MHz) δ 1.32 (d, J=6.0 Hz, 12H), 1.60 (brs, 2H,
NH, OH), 3.58–3.82 (m, 3H), 3.78 (s, 3H), 4.20 (s, 1H), 4.47 (septet, J=6.0 Hz, 2H), 4.62 (dt, J=1.3,

C. Vergne et al. / Tetrahedron: Asymmetry 9 (1998) 3095–3103
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5.3 Hz, 2H), 5.18 (qd, J=1.3, 16.4 Hz, 1H), 5.21 (qd, J=1.3, 10.5 Hz, 1H), 5.81 (tdd, J=5.3, 10.5, 16.4
Hz, 1H), 6.51 (s, 2H), 7.30 (m, 5H); 13C NMR (CDCl3) δ 22.2, 60.4, 62.9, 63.3, 65.6, 67.1, 71.7, 108.5,
118.4, 127.5, 127.6, 127.8, 128.9, 131.6, 133.3, 140.0, 152.0, 173.1; MS (EI) m/z 457 (M+), 426, 372,
321, 252. Anal. calcd for C26H35NO6: C, 68.25; H, 7.71; N, 3.06; found: C, 67.81; H, 7.582; N, 3.15.
3.3. (D)-3,5-Bis(isopropyloxy)-4-methoxyphenyl glycine allyl ester 6
To a solution of Pb(OAc)4 (1.01 g, 2.33 mmol) in MeOH (20 mL) cooled at 0°C was added a solution
of ester 5 (866.70 mg, 1.90 mmol) in CH2Cl2 precooled at 0°C. After being stirred at 0°C for 30 min,
volatiles were removed under reduced pressure. The residue was redissolved in water, neutralized with
phosphate buffer (pH=7) and extracted with CH2Cl2. The combined organic extracts were washed with
brine, dried and evaporated to give the crude imine which was used directly for the next step. The so
obtained crude imine, dissolved in Et2O (4 mL) was treated with 6 N HCl for 90 min at room temperature.
The volatiles were removed and the residue was redissolved in water and extracted with Et2O–heptane
to remove the neutral chemicals. The aqueous phase was then neutralized with phosphate buffer and
extracted with CH2Cl2. The combined organic extracts were washed with brine, dried and evaporated to
give 6 (556.00 mg, 87%): [α]D −48 (c 0.2, CHCl3); IR (CHCl3) ν 3392, 2981, 2936, 1739, 1591, 1499,
1436, 1385, 1316 cm−1; 1H NMR (CDCl3, 250 MHz) δ 1.34 (d, J=6.0 Hz, 12H), 1.95 (br s, 2H, NH2),
3.79 (s, 3H), 4.51 (septet, J=6.0 Hz, 3H), 4.62 (td, J=1.3, 5.6 Hz, 2H), 5.16 (qd, J=1.4, 16.0 Hz, 1H),
5.22 (qd, J=1.4, 10.3 Hz, 1H), 5.83 (tdd, J=5.6, 10.3, 16.0 Hz, 1H), 6.58 (s, 2H); 13C NMR (CDCl3) δ
22.4, 58.9, 60.6, 65.9, 71.9, 108.3, 118.6, 131.8, 141.1, 152.2, 179.3; MS (EI) m/z 337 (M+), 321, 252.
This compound was not very stable and was better protected directly in the form of carbamate.
3.4. (D)-N-Boc-3,5-bis(isopropyloxy)-4-methoxyphenyl glycine allyl ester 7a
To a solution of amino ester 6 (330 mg, 0.98 mmol) in CH2Cl2 was added Boc2O (321.0 mg, 1.47
mmol). After being stirred at room temperature for 8 h, the volatiles were removed under reduced
pressure and the crude product was purified by flash chromatography (SiO2, eluant: EtOAc/heptane=1/5)
to afford product 7a (411.0 mg, 96%): [α]D −63 (c 0.2, CHCl3); IR (CHCl3) ν 3443, 2983, 2938, 1743,
1713, 1593, 1493, 1438, 1373, 1328 cm−1; 1H NMR (CDCl3, 200 MHz) δ 1.40 (d, J=6.0 Hz, 12H), 1.48
(s, 9H), 3.76 (s, 3H), 4.50 (septet, J=6.0 Hz, 2H), 4.62 (br d, J=5.4 Hz, 2H), 5.10–5.30 (m, 3H), 5.48
(br d, J=7.1 Hz, 1H, NH), 5.82 (tdd, J=5.4, 10.6, 16.0 Hz, 1H), 6.52 (s, 2H); 13C NMR (CDCl3) δ 22.2,
28.3, 57.6, 60.4, 66.1, 71.7, 80.2, 108.3, 118.6, 131.4, 131.8, 152.1, 170.8; MS (EI) m/z 437 (M+), 381,
364, 352, 336. Anal. calcd for C23H35NO7: C, 63.14; H, 8.06; N, 3.20; found: C, 62.84; H, 8.23; N, 3.38.
3.5. (D)-N-Troc-3,5-bis(isopropyloxy)-4-methoxyphenyl glycine allyl ester 7b
To a solution of amino ester 6 (170.0 mg, 0.5 mmol) in CH2Cl2 (3.0 mL) and water (3 mL) were
added 2,2,2-trichloroethyl chloroformate (103.2 µL, 0.75 mmol) and NaHCO3 (60.0 mg, 0.75 mmol).
After being stirred at room temperature for 1 h, the reaction mixture was extracted with CH2Cl2. The
combined organic extracts were washed with brine, dried (Na2SO4) and evaporated. Purification by flash
chromatography (SiO2, eluant: EtOAc/heptane=1/5) afforded product 7b (233.0 mg, 91%): [α]D −60
1
(c 0.3, CHCl3); IR (CHCl3) ν 3427, 2985, 2939, 1736, 1592, 1498, 1441, 1384, 1327 cm−1; H NMR
(CDCl3, 200 MHz) δ 1.35 (d, J=6.1 Hz, 12H), 3.79 (s, 3H), 4.50 (septet, J=6.0 Hz, 2H), 4.65 (br d, J=5.6
Hz, 2H), 4.73 (s, 2H), 5.10–5.30 (m, 3H), 5.81 (tdd, J=5.6, 10.6, 16.0 Hz, 1H), 5.98 (br d, J=7.2 Hz, 1H,
NH), 6.55 (s, 2H); 13C NMR (CDCl3) δ 22.3, 58.3, 60.5, 66.5, 72.1, 75.0, 95.5, 108.9, 119.0, 131.0,

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131.3, 143.0, 152.4, 153.3, 170.2; MS (EI) m/z 517, 515, 512, 511 (M+). Anal. calcd for C21H28Cl3NO7:
C, 49.19; H, 5.50; N, 2.73; found: C, 49.41; H, 5.32; N, 2.61.
3.6. (D)-N-Boc-3,5-bis(isopropyloxy)-4-methoxyphenyl glycine 2a
A solution of compound 7a (172 mg, 0.39 mmol) and Pd(PPh3)4 (9.1 mg, 7.87 µmol) in THF (5 mL)
was stirred at room temperature for 10 min. The reaction mixture was cooled to 0°C and NaBH4 (30
mg, 0.78 mmol) was introduced. After being stirred at 0°C for 1 h, the reaction mixture was diluted
with aq. NH4Cl, acidified with 1 N HCl and extracted with EtOAc. The combined organic extracts were
washed with brine, dried (Na2SO4) and evaporated. Purification by flash chromatography (SiO2, eluant:
EtOAc/heptane=1/3 then CH2Cl2/MeOH=20/1) afforded product 2a (124.0 mg, 79%): IR (CHCl3) 3437,
3382, 2982, 2936, 2878, 1707, 1666, 1591, 1492, 1439, 1364 cm−1; 1H NMR (CDCl3, 200 MHz) mixture
of two rotamers δ 1.27 (d, J=5.9 Hz, 12H), 1.42 (s, 9H), 3.79 (s, 3H), 4.50 (septet, J=5.9 Hz, 2H), 5.00,
5.19 (d, J=4.5 Hz, 1H), 5.50 (d, J=4.5 Hz, 1H), 6.60 (s, 2H); 13C NMR (CDCl3, 50 MHz) δ 22.4, 28.4,
58.5, 60.5, 71.9, 80.0, 108.9, 131.5, 140.9, 152.1, 154.9, 175.6; MS (EI) m/z 397; HRMS m/z 397.2100
(C20H31NO7 requires 397.2100).
3.7. (D)-N-Troc-3,5-bis(isopropyloxy)-4-methoxyphenyl glycine 2b
Compound 2b was prepared following the procedure described for the preparation of 2a. Compound
2b: [α]D −40 (c 0.1, CHCl3); IR (CHCl3) ν 3419, 3338, 2982, 2933, 1726, 1595, 1502 cm−1; 1H NMR
(CD3COCD3, 200 MHz) δ 1.32 (d, J=6.1 Hz, 12H), 3.72 (s, 3H), 4.49 (septet, J=6.1 Hz, 2H), 4.68, 4.82
(AB system, J=12.2 Hz, 2H), 5.12 (d, J=6.8 Hz, 1H), 6.72 (s, 2H), 7.30 (brs, 2H, NH, COOH); 13C NMR
(CDCl3) δ 22.6, 60.7, 70.9, 72.3, 75.3, 97.2, 109.9, 133.9, 141.8, 155.2, 155.5, 173.9; MS (EI) m/z 477,
475, 473, 471 (M+, isotope).
3.8. [(3,5-Bis(isopropyloxy)-4-methoxy-phenyl)-(1-phenyl-ethylcarbamoyl)-methyl]-carbamic acid tert-
butyl ester 8a
To a solution of amino acid 2a (41 mg, 0.10 mmol) in CH2Cl2 (1 mL), cooled at 0°C, were added
HOBt (14.0 mg, 0.1 mmol), (S)-α-methylbenzylamine (15.0 µL, 0.12 mmol), and EDC (22.0 mg, 0.11
mmol). After being stirred at 0°C for 5 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 chromatography (SiO2, eluant: EtOAc/heptane=1/3) afforded product
8a (46.8 mg, 93%): mp 150–153°C (EtOAc/hexane); [α]D −65 (c 0.1, CHCl3); IR (CHCl3) ν 3422,
2984, 2937, 1708, 1679, 1587, 1448, 1373, 1321 cm−1; 1H NMR (CDCl3, 200 MHz) δ 1.32 (d, J=6.0
Hz, 12H), 1.40 (d, J=7.2 Hz, 3H), 1.42 (s, 9H), 3.78 (s, 3H), 4.47 (septet, J=6.1 Hz, 2H), 4.94 (d, J=5.4
Hz, 1H), 5.10 (quintet, J=7.2 Hz, 1H), 5.65 (br s, 1H, NH), 5.95 (br d, J=7.2 Hz, 1H, NH), 6.52 (s,
2H), 7.20–7.40 (m, 5H); 13C NMR (CDCl3) δ 21.5, 22.3, 28.4, 49.3, 59.1, 60.5, 72.0, 80.2, 108.8, 126.3,
127.6, 128.8, 133.6, 142.8, 152.4, 154.6, 169.3; MS (EI) m/z 500, 444, 427, 399, 384.
3.9. (4R)-3-[2-(4-Methoxy-3,5-bisisopropyloxy)phenyl-1-oxoethyl]-4-(phenylmethyl)-2-oxazolidinone
11
A solution of 10 (5.35 g, 18.98 mmol) in dry THF was cooled to −78°C, whereupon Et3N (3.5 mL,
24.90 mmol) and redistilled pivaloyl chloride (2.6 mL, 21.11 mmol) were added successively via syringe

C. Vergne et al. / Tetrahedron: Asymmetry 9 (1998) 3095–3103
3101
with stirring. The resulting slurry was stirred at −78°C for 15 min and at 0°C for 45 min and then
cooled again to −78°C. In a separate flask, (4R)-4-phenylmethyl-2-oxazolidinone (4.10 g, 23.16 mmol)
was dissolved in dry THF (40 mL) and cooled to −78°C, a solution of butyllithium in hexane (1.6 M,
16.6 mL, 26.56 mmol) was added slowly and stirred at −78°C for another 5 min after completion of
the addition. The so formed metallated oxazolidinone (yellow colored) was transferred via cannula to
the flask containing the mixed anhydride. The resulting slurry was stirred for 15 min at −78°C and then
warmed up to room temperature over 90 min. The reaction was quenched by addition of aqueous NH4Cl,
the volatiles were removed in vacuo and the aqueous solution was extracted with EtOAc. The combined
organic phases were washed with brine, dried (Na2SO4) and evaporated in vacuo. The crude product
was purified by flash chromatography (SiO2, EtOAc/heptane=1/2) to afford compound 11 as a yellow oil
(7.12 g, 85%): [α]D −40 (c 1.0, CHCl3); IR (CHCl3) 3050, 1780, 1720, 1585 cm−1; 1H NMR (CDCl3,
200 MHz) δ 1.33 (d, J=6.0 Hz, 12H), 2.78 (dd, J=9.1, 13.4 Hz, 1H), 3.21 (dd, J=3.2, 13.4 Hz, 1H), 3.81
(s, 3H), 4.1–4.3 (m, 4H), 4.50 (septet, J=6.0 Hz, 2H), 4.68 (m, 1H), 6.60 (s, 2H), 7.1–7.3 (m, 5H); 13C
NMR (CDCl3) δ 22.9, 38.3, 42.1, 55.8, 61.1, 66.7, 72.3, 111.6, 128.0, 129.1, 129.6, 130.1, 135.7, 140.9,
152.5, 154.0, 171.8; MS (EI) m/z 441. Anal. calcd for C25H31ON6: C, 68.00; H, 7.07; N, 3.17; found: C,
67.51; H, 7.19; N, 2.72.
3.10. 3-[2-Azido-2-(4-methoxy-3,5-bisisopropyloxy)phenyl-1-oxoethyl]-4-(phenylmethyl)-2-oxazolidi-
none 12
To a solution of imide 11 (6.50 g, 14.70 mmol) in THF (30 mL), stirred at −78°C under Ar was added
a solution of KHMDS (0.5 M in toluene, 40 mL). The solution was stirred for 30 min at −78°C, then a
precooled (−78°C) solution of triisopropylbenzenesulfonylazide (5.50 g, 17.80 mmol) in THF (30 mL)
was added via cannula. After being stirred for 5 min, the reaction was quenched with acetic acid, warmed
to 0°C and diluted with saturated aqueous NH4Cl. The volatiles were removed in vacuo and the aqueous
phase was extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4)
and evaporated. The resulting residue was dissolved in acetone (30 mL), then NaI (11.00 g, 73.39 mmol)
and KOAc (4.50 g, 45.91 mmol) were added. The mixture was stirred overnight at room temperature,
then filtered through a short pad of Celite. The volatiles in the filtrate were removed and the residue was
dissolved in an aqueous solution of Na2S2O3 and extracted with EtOAc. The combined organic extracts
were washed with brine, dried (Na2SO4), and evaporated. Purification by flash chromatography (SiO2,
EtOAc/heptane: 1/5 then 1/4) afforded the azide 12 (5.04 g, 71%): [α]D −162 (c 1.5, CHCl3); IR (CHCl3)
3010, 2110, 1784, 1716, 1583, 1386, 1114 cm−1; 1H NMR (CDCl3, 300 MHz) δ 1.34 (d, J=6.0 Hz, 6H),
1.35 (d, J=6.0 Hz, 6H), 2.85 (dd, J=9.6, 13.4 Hz, 1H), 3.40 (dd, J=3.1, 13.4 Hz, 1H), 3.71 (s, 3H), 4.15
(m, 2H), 4.51 (septet, J=6.0 Hz, 2H), 4.61 (m, 1H), 6.02 (s, 1H), 6.65 (s, 2H), 7.2–7.5 (m, 5H); 13C NMR
(CDCl3, 50 MHz) δ 22.3, 37.8, 55.9, 60.6, 63.6, 66.5, 71.9, 109.8, 127.6, 127.7, 129.2, 129.5, 134.9,
152.3, 152.5, 169.5; HRMS m/z 483.2282 (M+H), [(C25H30N4O6+H) requires 483.2244].
3.11. [2-(4-Benzyl-2-oxo-oxazolidin-3-yl)-1-(3,5-bisisopropyloxy-4-methoxy-phenyl)-2-oxo-ethyl]-
carbamic acid acid tert-butyl ester 13
A suspension of azide 12 (3.70 g, 7.66 mmol), Boc2O (2.50 g, 11.45 mmol) and a catalytic amount of
10% Pd/C in EtOAc was hydrogenated at 1 atm for 4 h. The reaction mixture was filtered through a short
pad of Celite, the filtrate was evaporated in vacuo and the residue was purified by flash chromatography
(SiO2, EtOAc/heptane: 1/4) to afford 13 (3.62 g, 85%) as white crystals: mp 50–52°C; [α]D −129 (c 0.5,
CHCl3); IR (CHCl3) 3010, 1795, 1702, 1589, 1477 cm−1; 1H NMR (CDCl3, 200 MHz) δ 1.35 (d, J=6.1

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C. Vergne et al. / Tetrahedron: Asymmetry 9 (1998) 3095–3103
Hz, 12H), 1.48 (s, 9H), 2.86 (dd, J=9.7, 13.3 Hz, 1H), 3.38 (dd, J=3.1, 13.3 Hz, 1H), 3.78 (s, 3H), 4.11
(m, 2H), 4.50 (septet, J=6.1 Hz, 2H), 4.51 (m, 1H), 5.47 (d, J=7.5 Hz, 1H), 6.48 (d, J=7.5 Hz, 1H), 6.65
(s, 2H), 7.2–7.4 (m, 5H); 13C NMR (CDCl3) δ 22.3, 28.4, 37.8, 55.9, 56.0, 60.5, 66.3, 71.7, 80.3, 109.3,
127.5, 129.1, 130.7, 135.3, 152.2, 152.5, 155.0, 171.7; MS (EI) m/z 556. Anal. calcd for C30H40N2O8:
C, 64.73; H, 7.24; N, 5.03: found: C, 64.54; H, 7.51; N, 4.81.
3.12. (D)-N-Boc-3,5-bis(isopropyloxy)-4-methoxyphenyl glycine 2a
To a solution of 13 (3.02 g, 5.43 mmol) in THF/H2O (60/20 mL) was added LiOH·H2O (0.45 g, 10.71
mmol) at 0°C. After being stirred at 0°C for 3 h, the solvent was removed and the aqeous phase was
extracted with Et2O. The combined organic layers were washed with brine, dried and concentrated in
vacuo to recover the Evans’ oxazolidinone. The aqueous phase was then acidified with citric acid and
extracted with EtOAc. The combined organic extracts were washed with brine, dried and evaporated
under reduced pressure to afford the compound 2a (2.05 g, 95%) as a white film: [α]D −92 (c 1.5,
CHCl3).
Acknowledgements
One of us (C. Vergne) thanks the ‘Ministère de la Recherche et de l’Enseignement Superieur’ for a
doctoral fellowship.
References
1. Rama Rao, A. V.; Gurjar, M. K.; Reddy, L.; Rao, A. S. Chem. Rev. 1995, 95, 2135–2167.
2. Burgess, K.; Lim, D.; Martinez, C. I. Angew. Chem., Int. Ed. Engl. 1996, 35, 1077–1078.
3. For a short account, see: Zhu, J. Synlett 1997, 133–144 and references cited therein.
4. Laïb, T.; Zhu, J. Tetrahedron Lett. 1998, 39, 283–286.
5. (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.
6. Zhu, J.; Bouillon, J. P.; Singh, G. P.; Chastanet, J.; Beugelmans, R. Tetrahedron Lett. 1995, 36, 7081–7084.
7. Beugelmans, R.; Bois-Choussy, M.; Vergne, C.; Bouillon, J. P.; Zhu, J. J. Chem. Soc., Chem. Commun. 1996, 1029–1030.
8. Pearson, A. J.; Chelliah, M. C.; Bignan, G. C. Synthesis 1997, 536–540.
9. Boger, D. L.; Borzilleri, R. M.; Nukui, S. J. Org. Chem. 1996, 61, 3561–3565.
10. Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994, 94, 2483–2547.
11. Davis, F. A.; Fanelli, D. L. J. Org. Chem. 1998, 63, 1981–1985.
12. Bois-Choussy, M.; Zhu, J. J. Org. Chem. 1998, 63, 5662–5665.
13. (a) Williams, R. M. Synthesis of Optically Active α-Amino Acids. In Organic Chemistry Series; Baldwin, J. E., Magnus,
P. D., Eds. Pergamon: Oxford, 1989, Vol. 7; (b) Williams, R. M.; Hendrix, J. A. Chem. Rev. 1992, 92, 889–917.
14. Chakraborty, T. K.; Reddy, G. V.; Hussain, K. A. Tetrahedron Lett. 1991, 32, 7597–7600; (b) Inaba, T.; Kozono, I.; Fujita,
M.; Ogura, K. Bull. Chem. Soc. Jpn. 1992, 65, 2359–2365.
15. For a review on the use of phenyl glycinol as chiral auxiliary, see: Husson, H.-P.; Royer, J. Chemistry of Potential and
Reversed Imminium Systems. In Advances in the Use of Synthons in Organic Chemistry, JAI Press Inc., 1995.
16. Zhu, J.; Chastanet, J.; Beugelmans, R. Synth. Commun. 1996, 26, 2479–2486.
17. Chérest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968, 2199–2204; (b) Chérest, M.; Felkin, H. Tetrahedron Lett.
1968, 2204–2208.
18. For reviews, see: Guibé, F. Tetrahedron 1997, 53, 13509–13555 and ibid. 1998, 54, 2967–3042.
19. Mokhallalati, M. K.; Pridgen, L. N. Synth. Commun. 1993, 23, 2055–2064.

C. Vergne et al. / Tetrahedron: Asymmetry 9 (1998) 3095–3103
3103
20. Beugelmans, R.; Bourdet, S.; Bigot, A.; Zhu, J. Tetrahedron Lett. 1994, 35, 4349–4350; (b) Beugelmans, R.; Neuville, L.;
Bois-Choussy, M.; Chastanet, J.; Zhu, J. Tetrahedron Lett. 1995, 36, 3129–3132.
21. Evans, D. A.; Britton, T. C.; Ellman, J. A.; Dorow, R. L. J. Am. Chem. Soc. 1990, 112, 4011–4030.
22. Evans, D. A.; Evrard, D. A.; Rychnovsky, S. D.; Früh, T.; Whittingham, W. G.; Devries, K. M. Tetrahedron Lett. 1992, 33,
1189–1192.
23. Saito, S.; Nakajima, H.; Inaba, M.; Moriwake, T. Tetrahedron Lett. 1989, 30, 837–838.