Synthesis of β-amino-α-hydroxy esters and β-amino-α- azido ester by sharpless asymmetric aminohydroxylation, byproducts analysis

Article abstract of DOI:10.1021/jo047772o

(Chemical Equation Presented) Synthesis of enantiomerically pure β-amino-α-hydroxy esters (1, 2) and β-amino-α-azido ester (3) using Sharpless AA as a key step is described. A hitherto unreported side reaction, the oxidation of the β-hydroxy-α-amino ester

Full text of DOI:10.1021/jo047772o

Synthesis of â-Amino-r-hydroxy Esters and
â-Amino-r-azido Ester by Sharpless
Asymmetric Aminohydroxylation,
Byproducts Analysis
Zuosheng Liu,† Nianchun Ma,† Yanxing Jia,†
Miche`le Bois-Choussy,† Adriano Malabarba,‡ and
Jieping Zhu*,†
Institut de Chimie des Substances Naturelles, CNRS,
91198 Gif-sur-Yvette Cedex, France, and Italy Research
Center, Vicuron Pharmaceuticals, via R. Lepetit, 34,
I-21040 Gerenzano (VA), Italy
FIGURE 1.
In connection with our ongoing project aiming at the
design and synthesis of compounds active against van-
comycin-resistant enteroccoci (VRE),10 an efficient syn-
thesis of suitably protected, enantiomerically pure
â-amino-R-hydroxy esters (1, 2) and â-amino-R-azido
ester (3, Figure 1) was required. For this purpose, the
Sharpless AA, which could install the vicinal amino
alcohol function of 1 in a single step with requisite
relative and absolute stereochemistry, seems to be ideal.
We report herein our studies on the Sharpless AA of
cinnamates 4 that lead to efficient syntheses of com-
pounds 1 to 3. The isolation of hitherto unreported
byproducts that are responsible for the decreased yields
of AA products in certain circumstances will also be
documented.
Initial experiments for the Sharpless AA of cinnamate
4 were carried out using tert-butyloxy carbamate as a
nitrogen source and the (DHQD)2PHAL11 as a ligand
(Scheme 1). In addition to AA products 1 and 5, careful
analysis of the reaction mixture led to the identification
of aldehyde (6), acid (7), and R,R-di-tert-butyloxycarbam-
oyl-â-ketone ester (8). It was noticed that the relative
ratio of these compounds was time-dependent. Prolonged
reaction time led to a decrease of the yield of both amino
alcohols 1 and 5, with the concurrent increase of the
amount of side products 6-8. Under optimized conditions
(n-PrOH/H2O ) 1/1, 10 °C, vigorous stirring, 1 h), the
desired amino alcohol 1 was isolated in 70% yield
together with its regioisomer 5 (11%), aldehyde 6 (7%),
acid 7 (2%), and R,R-di-tert-butyloxycarbamoyl-â-ketone
ester 8 (4%).
zhu@icsn.cnrs-gif.fr
Received December 21, 2004
Synthesis of enantiomerically pure â-amino-R-hydroxy esters
(1, 2) and â-amino-R-azido ester (3) using Sharpless AA as
a key step is described. A hitherto unreported side reaction,
the oxidation of the â-hydroxy-R-amino ester (5) into the R,R-
di-tert-butyloxycarbamoyl-â-ketoester (8) under AA condi-
tions, is documented.
The Sharpless asymmetric aminohydroxylation (AA)
provides an efficient one-step preparation of enantio-
merically pure â-amino alcohols from alkenes using
catalytic amounts of osmium, chiral ligands, and a
nitrogen source such as sulfonamides,1a,2 amides,3 car-
bamates,4 and aminoheterocycles.5 There has been rapid
improvement in both the scope and selectivity since
Sharpless’s initial reports.6-9
* Telefax: int code +33 1 69077247.
† Institut de Chimie des Substances Naturelles, CNRS.
‡ Vicuron Pharmaceuticals.
(1) (a) Li, G.; Chang, H.-T.; Sharpless, K. B. Angew. Chem., Int. Ed.
Engl. 1996, 35, 451-454. (b) Kolb, H. C.; Sharpless, K. B. Asymmetric
Aminohydroxylation. In Transition Metals for Organic Synthesis:
Building Blocks and Fine Chemicals; Beller, M., Bolm, C., Eds.; Wiley-
VCH: Weinheim, 1998; Vol. 2, pp 243-260.
While aldehydes have occasionally been isolated in
cinnamate aminohydroxylations,12,13 the formation of
compound 8 has never been reported under the Sharpless
AA conditions. To elucidate the origin of byproduct 8,
(2) Rudolph, J.; Sennhenn, P. C.; Vlaar, C. P.; Sharpless, K. B.
Angew. Chem., Int. Ed. Engl. 1996, 35, 2810-2813.
(3) (a) Bruncko, M.; Schlingloff, G.; Sharpless, K. B. Angew. Chem.,
Int. Ed. Engl. 1997, 35, 11483-1486. (b) Demko, Z. P.; Bartsch, M.;
Sharpless, K. B. Org. Lett. 2000, 2, 2221-2223.
(4) (a) Li, G.; Angert, H. H.; Sharpless, K. B. Angew. Chem., Int.
Ed. Engl. 1996, 35, 2813-2816. (b) Reddy, K. L.; Sharpless, K. B. J.
Am. Chem. Soc. 1998, 120, 1207-1217. (c) O’Brien, P.; Osborne, S. A.;
Parker, D. D. J. Chem. Soc., Perkin Trans. 1 1998, 2519-2526. (d)
Reddy, K. L.; Dress, K. R.; Sharpless, K. B. Tetrahedron Lett. 1998,
39, 3667-3670. (e) Montiel-Smith, S.; Cervantes-Mej´ıa, V.; Dubois, J.;
Gue´nard, D.; Gue´ritte, F.; Sandoval-Ram´ırez, J. Eur. J. Org. Chem.
2002, 2260-2264.
(5) Goossen, L. J.; Liu, H.; Dress, K. R.; Sharpless, K. B. Angew.
Chem., Int. Ed. 1999, 38, 1080-1083.
(6) For a highlight of Sharpless AA reaction, see: O’Brien, P. Angew.
Chem., Int. Ed. 1999, 38, 326-329.
(7) For a substrate-controlled Sharpless AA reaction, see: (a) Davey,
R. M.; Brimble, M. A.; McLeod, M. D. Tetrahedron Lett. 2000, 41,
5141-5145. (b) Han, H.; Cho, C.-W.; Janda, K. D. Chem. Eur. J. 1999,
5, 1565-1569. (c) Morgan, A. J.; Masse, C. E.; Panek, J. S. Org. Lett.
1999, 1, 1949-1952.
(8) For a tethered aminohydroxylation, see: (a) Donohoe, T. J.;
Johnson, P. D.; Pye, R. J.; Keenan, M. Org. Lett. 2004, 6, 2583-2585.
(b) Donohoe, T. J.; Cowley, A.; Johnson, P. D.; Keenan, M. J. Am. Chem.
Soc. 2002, 124, 12934-12925.
(9) For AA with immobilized catalyst, see (a) Song, C. E.; Oh, C. R.;
Lee, S. W.; Lee, S. G.; Canali, L.; Sherrington, D. C. J. Chem. Soc.,
Chem. Commun. 1998, 2435-2436. (b) Mandoli, A.; Pini, D.; Agostini,
A.; Salvadori, P. Tetrahedron: Asymmetry 2000, 11, 4039-4042. (c)
Yang, X. W.; Liu, H. Q.; Xu, M. H.; Lin, G. Q. Tetrahedron: Asymmetry
2004, 15, 1915-1918.
(10) Ma, N.; Jia, Y.; Liu, Z.; Gonzalez-Zamora, E.; Bois-Choussy, M.;
Malabarba, A.; Brunati, C.; Zhu, J. Bioorg. Med. Chem. Lett. 2005,
15, 743-746.
(11) (DHQD)2PHAL stands for 1,4-bis(dihydroquininyl)phthalazine.
(12) Wuts, P. G. M.; Anderson, A. M.; Goble, M. P.; Mancini, S. E.;
VanderRoest, R. J. Org. Lett. 2000, 2, 2667-2669.
(13) Also observed in the OsO4-catalyzed dihydroxylation of strained
olefines, see: Tsui, H.-C.; Paquette, L. A. J. Org. Chem. 1998, 63, 8071.
10.1021/jo047772o CCC: $30.25 © 2005 American Chemical Society
Published on Web 02/25/2005
J. Org. Chem. 2005, 70, 2847-2850
2847

SCHEME 1
identical conditions, we suspected that the overall process
might be triggered by the oxidation of benzylic alcohol.
Control experiments have shown that the same trans-
formation did not proceed in the absence of osmium
tetraoxide or N-chloro-N-sodio tert-butyl carbamate. It
is thus possible that oxidation of the benzylic alcohol to
ketone may be promoted by the complex formed between
these two species in analogy with the chemistry of
chloroamine-T.16 Reaction of phenoxyacetamidopenicil-
lanate with ethyl N-chloro-N-sodiocarbamate to provide
6,6-diacylaminopenicillinate has previously been reported
17
by Campbell and co-workers.
The conversion of â-hydroxy-R-amino ester to the
corresponding â,â-di-tert-butyloxycarbamoyl ketoester
under Sharpless AA conditions is not restricted to
compound 5 with an electron-rich aromatic ring. Thus,
the N-Boc DL-threophenylserine (15) was partially trans-
formed into the same type of compound under identical
conditions (Scheme 4). Although more detailed studies
are required, these results indicated a generality of this
undesired reaction that may reduce the efficiency of the
AA process.
With the efficient one-step preparation of amino alcohol
1 in hand, compounds 2 and 3 were readily synthesized,
as is shown in Scheme 5. Mesylation of the secondary
alcohol (MsCl, pyridine) gave the corresponding mesylate
17 in 98% yield.18 Reaction of 17 with cesium acetate in
benzene in the presence of 18-crown-6 followed by selec-
tive hydrolysis of acetate provided the (2R,3R)-2 in 54%
overall yield. On the other hand, nucleophilic displace-
ment of mesylate by azide (NaN3, DMSO, 50 °C) afforded
the azido derivative (2R,3R)-3 in 91% yield.19
SCHEME 2
In summary, we have developed efficient syntheses of
enantiomerically pure â-amino-R-hydroxy esters (1, 2)
and â-amino-R-azido ester (3) using Sharpless AA as a
key step. Oxidation of one of the AA products, the
â-hydroxy-R-amino ester, into the R,R-di-tert-butyloxy-
carbamoyl-â-ketoester under AA conditions was reported
for the first time and might decrease the yield of AA or
give an incorrect estimation of the real regioisomeric
ratio. This will be particularly true if â-hydroxy-R-amino
acid was the desired regioisomer. Indeed, analysis of
literature data indicated that the Sharpless AA of cin-
namate using anthraquinone ligands [(DHQD)2AQN or
(DHQ)2AQN] leading to â-hydroxy-R-amino ester as a
major regioisomer usually proceeded with lower chemical
yield.20 The partial decomposition of this regioisomer
following the pathway shown in Scheme 3 may partially
account for the reduced yield. We suspect that any effort
pure amino alcohols 1, 5, and diol 9 (Scheme 1) were
resubmitted to the Sharpless AA conditions (3 h). It was
found that 1, 5, and 9 decomposed under these conditions,
yielding different product mixtures. Besides a transes-
terification product (methyl ester to propyl ester), 4-meth-
oxy-3,5-diisopropyloxy benzoic acid (7) was produced from
all these reactions, while 4-methoxy-3,5-diisopropyloxy
benzaldehyde was isolated only from the diol (9) and,
more importantly, the ketone ester 8 was generated only
from the â-hydroxy-R-amino ester 5 (Scheme 2). From
this observation, the following mechanistic hypothesis
was proposed to account for the formation of ketone ester
8 from 5 (Scheme 3). Oxidation of benzylic alcohol
followed by N-chlorination gave intermediate 11, which
upon deprotonation and elimination of chloride should
provide imine 12. Nucleophilic addition of tert-butyl
carbamidate anion onto the resulting imine would pro-
vide the observed compound 8. In this transformation,
the N-chloro-N-sodiocarbamate acted as a chloronium ion
donor, as a base, and then as a nucleophile. Alterna-
tively,14 enolization of â-keto ester (10) followed by second
aminohydroxylation on the resulting enolate (13) would
lead to the intermediate 14, which upon hydrolysis would
afford the observed compound 8.15 Since amino alcohols
1 and 5 did not follow the same reaction paths under the
(15) Osminium tetroxide-catalyzed aminohydroxylation of silyl enol
ethers has been reported; see: Phukan, P.; Sudalai, A. Tetrahedron:
Asymmetry 1998, 9, 1001-1005.
(16) Campbell, M. M.; Johnson, G. Chem. Rev. 1978, 78, 65-79.
(17) Campbell, M. M.; Johnson, G. J. Chem. Soc., Chem. Commun.
1975, 479-480.
(18) (a) Lee, S. H.; Yoon, J.; Nakamura, K. Org. Lett. 2000, 2, 1243-
1246. (b) Milicevic, S.; Matovic, R.; Saicic, R. N. Tetrahedron Lett. 2004,
45, 955-957.
(19) Enantiomeric excess (ee) of these compounds was found to be
higher than 95% by analyzing their tripeptide derivatives. A copy of a
1HNMR spectrum of one of these derivatives can be found in Support-
ing Information.
(14) This mechanism has been proposed by one of the referees; we
are grateful for this suggestion. However, at the present time, we do
not have any experimental evidence to differentiate these two alterna-
tives.
(20) (a) Tao, B.; Schlingloff, G.; Sharpless, K. B. Tetrahedron Lett.
1998, 39, 2507-2510. (b) Kim, I. H.; Kirk, K. L. Tetrahedron Lett. 2001,
42, 8401-8403. (c) Park, H.; Cao, B.; Joullie´, M. M. J. Org. Chem. 2001,
66, 7223-7226.
2848 J. Org. Chem., Vol. 70, No. 7, 2005

SCHEME 3
room temperature for 5 min, the reaction flask was cooled in a
cold-water bath. To the reaction mixture was added ester 1 (616
mg, 2 mmol) in n-PrOH and H2O (1:1, 10.0 mL) and K2OsO2-
(OH)4 (29.4 mg, 0.08 mmol). After the mixture was stirred for 1
h at 10 °C (the color of solution turned from green to green-
yellow), Na2SO3 (1.0 g) was added to the reaction mixture and
the mixture was stirred for 10 min. The reaction mixture was
extracted with EtOAc. The organic phase was washed with 5%
K2CO3, saturated NaHCO3, H2O, and brine and dried over
anhydrous Na2SO4. The volatile was removed under reduced
pressure, and the residue was purified by flash chromatography
(Hept/AcOEt ) 8:1 to 2:1) to afford compound 1 (620.0 mg, 70%),
the regioisomer 5 (96.0 mg, 11%), the aldehyde 6 (37.0 mg, 7.3%),
and keto ester 8 (40.0 mg, 3.6%). The aqueous phase was
acidified with aqueous HCl (5%) and extracted with EtOAc; the
organic phase was washed with H2O and brine and dried over
anhydrous Na2SO4. After evaporation of solvent, the residue was
purified by flash chromatography (Hept/AcOEt ) 4:1) to afford
SCHEME 4
SCHEME 5a
acid 7 (11.0 mg, 2.1%). Compound 1: [R]23 -9 (c 0.6, CHCl3);
D
IR (CHCl3) ν 3525, 3035, 2981, 2936, 2831, 1750, 1710, 1590,
1493, 1368, 1320, 1273, 1165, 1116 cm-1 1H NMR (250 MHz,
;
CDCl3) δ 6.57 (s, 2H), 5.33 (d, 1H, J ) 9.4 Hz), 5.07 (m, 1H),
4.50 (hept, 2H, J ) 6.1 Hz), 4.43 (m, 1H), 3.83 (s, 3H), 3.79 (s,
3H), 3.16 (d, 1H, J ) 3.8 Hz), 1.41 (s, 9H), 1.33 (d, 12H, J ) 6.1
Hz); 13C NMR (62.5 MHz, CDCl3) δ 173.2, 155.2, 151.7 (2C),
140.5, 134.4, 108.1 (2C), 79.8, 73.6, 71.6 (2C), 60.3, 54.8, 52.7,
28.2 (3C), 22.1 (4C); MS (ESI) m/z 464 (M + Na); HRMS (ESI)
m/z calcd for C22H35NO8Na (M + Na) 464.2260, found 464.2252.
Compound 5: [R]23D -2 (c 0.5, CHCl3); IR (CHCl3) ν 3446, 3007,
2980, 2936, 2831, 1753, 1714, 1590, 1493, 1439, 1368, 1320, 1273
1
cm-1; H NMR (300 MHz, CDCl3) δ 6.53 (s, 2H), 5.34 (d, 1H, J
) 9.4 Hz), 5.07 (brs, 1H), 4.52-4.42 (m, 3H), 3.73 (s, 3H), 3.70
(s, 3H), 3.28 (brs, 1H), 1.31 (s, 9H), 1.30 (d, 12H, J ) 6.1 Hz);
13C NMR (50.3 MHz, CDCl3) δ 171.4, 155.6, 151.4 (2C), 140.3,
135.2, 107.2 (2C), 79.8, 73.3, 71.4 (2C), 60.3, 59.4, 52.4, 28.1 (3C),
22.1 (4C); MS (ESI) m/z 464 (M + Na); HRMS (ESI) m/z calcd
for C22H35NO8Na (M + Na) 464.2260, found 464.2252. Com-
pound 8: IR (CHCl3) ν 3418, 2982, 2937, 2854, 1754, 1717, 1709,
a Reagents and conditions: (a) MsCl, Py, 0 °C, 98%; (b) CsOAc,
PhH, 18-C-6, reflux; (c) K2CO3, MeOH-H2O, rt, 15 min, 54%; (d)
NaN3, DMSO, 50 °C, 91%.
aiming at avoiding this side reaction will increase the
chemical efficiency of the Sharpless AA process.
1481, 1468, 1369, 1252, 1168, 1114, 1078, 1023, 1001, 863 cm-1
;
1H NMR (300 MHz, CDCl3) δ 7.42 (s, 2H), 7.01 (s, 2H), 4.53 (hept,
2H, J ) 6.0 Hz), 3.86 (s, 3H), 3.73 (s, 3H), 1.35 (d, 12H, J ) 6.0
Hz), 1.34 (s, 18H); 13C NMR (75 MHz, CDCl3) δ 186.3, 168.1,
154.2 (2C), 151.5 (2C), 146.2, 127.5, 110.8 (2C), 80.1(2C), 73.9,
72.0 (2C), 60.9, 54.5, 28.4 (6C), 22.4 (4C); MS (ESI) m/z 577 (M
+ Na), 593 (M + K); HRMS (ESI) m/z calcd for C27H42N2O10Na
(M + Na) 577.2737, found 577.2751.
2,2-Bis-tert-butoxycarbonylamino-3-oxo-3-phenyl-proion-
ic Acid Methyl Ester (16). IR (CHCl3) ν 3418, 3032, 3011, 2983,
2933, 1755, 1714, 1599, 1481, 1471, 1448, 1394, 1369, 1277,
Experimental Section
Sharpless AA of Cinnamate 4. To a solution of tert-butyl
carbamate (741.0 mg, 6.2 mmol) in n-PrOH (8.0 mL) was
sequentially added a solution of NaOH (249.0 mg, 6.1 mmol in
15.0 mL water) and t-BuOCl (fresehly prepared, 0.7 mL, 6.1
mmol). After the reaction mixture was stirred at room temper-
ature for 3 min, a solution of (DHQD)2PHAL (82 mg, 0.1 mmol)
in n-PrOH (7.0 mL) was added, and the solution was stirred at
J. Org. Chem, Vol. 70, No. 7, 2005 2849

1256, 1156, 1051, 1017, 876 cm-1; 1H NMR (300 MHz, CDCl3) δ
8.13 (d, 2H, J ) 7.0 Hz), 7.54 (t, 1H, J ) 7.0 Hz), 7.40 (t, 2H, J
) 7.7 Hz), 7.02 (brs, 2H), 3.74 (s, 3H), 1.33 (s, 18H); 13C NMR
(75 MHz, CDCl3) δ 187.3, 167.4, 153.9 (2C), 133.6, 132.8, 129.3
(2C), 128.4 (2C), 80.8 (2C), 73.6, 54.1, 28.0 (6C); MS (ESI) m/z
431.0 (M + Na), 447.0 (M + K); HRMS (ESI) m/z calcd for
C20H28N2O7Na (M + Na) 431.1794, found 431.1784.
3-tert-(2R,3R)Butoxycarbonylamino-3-(3,5-diisopropoxy-
4-methoxy-phenyl)-2-hydroxy-propionic Acid Methyl Es-
ter (2). To a solution of compound 17 (230 mg, 0.44 mmol) in
anhydrous benzene (10 mL) was added CsOAc (340.0 mg, 1.77
mmol) and 18-crown-6 (118.0 mg, 0.44 mmol). After being
refluxed for 24 h under Ar, the reaction mixture was cooled to
room temperature and then filtered. The filtrate was concen-
trated, and the residue was purified by flash chromatography
(Hept/AcOEt ) 4:1) to afford the desired ester (145.0 mg, 80%);
3-tert-(2S,3R)Butoxycarbonylamino-3-(3,5-diisopropoxy-
4-methoxy-phenyl)-2-methanesulfonyloxy-propionic Acid
Methyl Ester (17). To a solution of alcohol 1 (1.0 g, 2.28 mmol)
in anhydrous pyridine (freshly distilled over CaH2, 11.0 mL) was
added dropwise MsCl (0.21 mL, 2.73 mmol) at 0 °C. After being
stirred at 0 °C for 2 h and at room temperature for 2 h, the
reaction mixture was quenched by addition of MeOH (2 mL) and
extracted with EtOAc. The organic phase was washed with 5%
HCl, saturated NaHCO3, H2O, and brine and dried over anhy-
drous Na2SO4. The solvent was evaporated, and the residue was
purified by flash chromatography (Hept/AcOEt ) 3:1) to afford
starting material (35.0 mg) was also recovered: [R]23 -18 (c
D
0.3, CHCl3); IR (CHCl3) 3448, 3020, 2981, 2937, 1751, 1712, 1589,
1493, 1438, 1370, 1317, 1230, 1224, 1211, 1159, 1116, 1006 cm-1
;
1H NMR (250 MHz, CDCl3) δ 6.51 (s, 2H), 5.36 (d, 1H, J ) 4.7
Hz), 5.30-5.10 (m, 2H), 4.49 (hept, 2H, J ) 6.1 Hz), 3.80 (s,
3H), 3.64 (s, 3H), 2.15 (s, 3H), 1.44 (s, 9H), 1.33 (d, 12H, J ) 6.1
Hz); 13C NMR (62.5 MHz, CD3OD) δ 169.9, 168.1, 154.8, 151.7,
141.2, 132.0, 109.0, 80.1, 74.8, 74.2, 71.7, 60.4, 54.7, 52.3, 28.3,
22.2, 20.6; MS (ESI) m/z 506 (M + Na); HRMS (ESI) m/z calcd
for C24H37NO9Na (M + Na) 506.2366, found 506.2360. To a
solution of the acetate (220.0 mg, 0.46 mmol) in MeOH (30.0
mL) and H2O (3.0 mL) was added K2CO3 (188.0 mg, 1.37 mmol).
After the mixture was stirred at room temperature for 20 min,
it was then acidified with citric acid to pH ) 2-3 and concen-
trated under reduced pressure. The residue was diluted with
H2O and extracted with EtOAc. The combined organic phase was
washed with H2O and brine and dried over Na2SO4. The solvent
was evaporated, and the residue was purified by flash chroma-
tography (Hept/AcOEt ) 2:1) to afford compound 2 (134.0 mg,
67%): [R]23D -14 (c 2, CHCl3); IR (CHCl3) 3529, 3444, 3020, 3013,
2981, 2935, 2832, 1740, 1710, 1589, 1493, 1440, 1368, 1317,
compound 15 (1.16 g, 98%): mp 66-69 °C; [R]23 -1. (c 0.2,
D
CHCl3); IR (CHCl3) ν 3662, 3549, 3433, 3021, 2983, 2936, 2673,
2578, 1760, 1719, 1583, 1454, 1438, 1393, 1369, 1218, 1175, 1115
1
cm-1; H NMR (300 MHz, CDCl3) δ 6.53 (s, 2H), 5.30 (m, 2H),
5.17 (brs, 1H), 4.52 (hept, 2H, J ) 5.9 Hz), 3.82 (s, 3H), 3.78 (s,
3H), 2.86 (s, 3H), 1.41 (s, 9H), 1.32 (d, 12H, J ) 5.9 Hz); 13C
NMR (62.5 MHz, CD3OD) δ 169.4, 159.8, 153.3, 142.0, 134.6,
109.6, 82.1, 80.1, 73.0, 61.3, 57.2, 53.6, 38.9, 29.0, 22.8; MS (ESI)
m/z 542 (M + Na); HRMS (ESI) m/z calcd for C23H37NO10NaS
(M + Na) 542.2036, found 542.2034.
3-tert-(2R,3R)Butoxycarbonylamino-3-(3,5-diisopropoxy-
4-methoxy-phenyl)-2-azido-propionic Acid Methyl Ester
(3). To a solution of compound 17 (1.17 g, 2.25 mmol) in
anhydrous DMSO (7.4 mL) was added NaN3 (293.0 mg, 4.5
mmol). After being stirred at 50 °C for 24 h under Ar, the
reaction mixture was cooled to room temperature, diluted with
H2O, and extracted with EtOAc; the organic phase was washed
with H2O and brine and dried over anhydrous Na2SO4. The
solvent was evapotated, and the residue was purified by flash
chromatography (Hept/AcOEt ) 4:1) to afford azide 3 (954.0 mg,
1275, 1232, 1162, 1117, 1080, 1052, 1006 cm-1 1H NMR (250
;
MHz, CDCl3) δ 6.46 (s, 2H), 5.47 (d, 1H, J ) 8.2 Hz), 4.97 (m,
1H), 4.57 (m, 1H), 4.48 (m, 2H), 3.79 (s, 3H), 3.72 (s, 3H), 1.64
(brs, 1H), 1.44 (s, 9H), 1.33 (d, 6H, J ) 6.0 Hz), 1.31 (d, 6H, J )
6.0 Hz); 13C NMR (62.5 MHz, CD3OD) δ 172.3, 155.1, 151.8,
141.3, 131.9, 109.2, 108.4, 80.0, 73.7, 73.4, 71.8, 60.5, 56.7, 52.6,
28.4, 22.3; MS (ESI) m/z 464 (M + Na); HRMS (ESI) m/z calcd
for C22H35NO8Na (M + Na) 464.2260, found 464.2252.
91%): [R]23 -3 (c 0.5, MeOH); IR (CHCl3) ν 3441, 2982, 2937,
D
Acknowledgment. Financial support from Vicuron
Pharmaceuticals (Postdoctoral Fellowships to Drs. Z. S.
Liu, N. C. Ma, and Y. X. Jia) and CNRS is gratefully
acknowledged.
2832, 2117, 1720, 1711, 1589, 1492, 1438, 1368, 1317, 1247,
1160, 1110, 1082, 1005 cm-1; 1H NMR (300 MHz, CDCl3) δ 6.49
(s, 2H), 5.31 (d, 1H, J ) 8.1 Hz), 5.08 (m, 1H), 4.49 (hept, 2H, J
) 5.9 Hz), 4.42 (d, 1H, J ) 3.7 Hz), 3.78 (s, 3H), 3.69 (s, 3H),
1.43 (s, 9H), 1.32 (d, 12 H, J ) 5.9 Hz); 13C NMR (50.3 MHz,
CDCl3) δ 171.8, 159.2, 152.0, 148.4, 135.6, 109.0, 80.5, 71.9, 66.9,
65.3, 60.6, 55.7, 52.8, 28.4, 22.3; MS (ESI) m/z 489 (M + Na);
HRMS (ESI) m/z calcd for C22H34N4O7Na (M + Na) 489.2325,
found 489.2329.
1
Supporting Information Available: Copies of H NMR
spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO047772O
2850 J. Org. Chem., Vol. 70, No. 7, 2005