Regioselective asymmetric aminohydroxylation approach to a β-hydroxyphenylalanine derivative for the synthesis of ustiloxin D

Full text of DOI:10.1021/jo010482c

J . Org. Chem. 2001, 66, 7223-7226
7223
Regioselective Asym m etr ic
Am in oh yd r oxyla tion Ap p r oa ch to a
â-Hyd r oxyp h en yla la n in e Der iva tive for th e
Syn th esis of Ustiloxin D
Haengsoon Park, Bin Cao, and Madeleine M. J oullie´*
Department of Chemistry, University of Pennsylvania,
Philadelphia, Pennsylvania 19104-6323
mjoullie@sas.upenn.edu
Received May 11, 2001
â-Hydroxy-R-amino acids are often found as key motifs
in biologically active natural products. For example,
â-hydroxytyrosine and â-hydroxyphenylalanine residues
are structural subunits of many important macrocyclic
peptide antibiotics such as vancomycin,1 bouvardin,2
orienticins,3 and phomopsins.4 These amino acids are also
useful building blocks for the synthesis of â-lactams.5 As
part of our synthetic studies toward ustiloxin D6a (1d ,
Figure 1), an efficient method was sought for the asym-
metric synthesis of a â-hydroxyphenylalanine derivative
(2, Scheme 1) as a key intermediate. Ustiloxins,6 whose
structures are closely related to those of phomopsins,
were isolated from the water extracts of false smut balls
caused on the panicles of the rice plant by a fungus,
Ustilaginoidea virens. They are potent inhibitors of
microtubule assembly and anticancer drug leads.6d,f
A literature survey revealed that several strategies
have been devised for the asymmetric syntheses of
â-hydroxy-R-amino acids: the alkylation of chiral eno-
lates from oxazolidinones, bis-lactims, oxazolines, oxazo-
lidines, and imidazolidinones; the cycloaddition of chiral
azomethine ylids; enzymatic transformations; and syn-
theses via catalytic asymmetric epoxidation, dihydroxy-
lation, aminohydroxylation, and aldol reactions.7 Since
most of these synthetic routes involve a multistep
F igu r e 1. Structures of ustiloxins.
Sch em e 1
* To whom correspondence should be addressed. E-mail: mjoullie@
sas.upenn.edu.
(1) (a) Williams, D. H. Acc. Chem. Res. 1984, 17, 364 and references
therein. (b) Kopecka, H.; Harris, T. M. J . Am. Chem. Soc. 1983, 105,
6915 and references therein.
(2) J olad, S. D.; Hoffmann, J . J .; Torrance, S. J .; Wiedhopf, R. M.;
Cole, J . R.; Arora, S. K.; Bates, R. B.; Gargiulo, R. D.; Kriek, G. R. J .
Am. Chem. Soc. 1977, 99, 8040.
(3) Tsuji, N.; Kobayashi, M.; Kamigauchi, T.; Yoshimura, Y.; Terui,
Y. J . Antibiot. 1988, 41, 819.
(4) (a) Mackay, M. F.; Donkelaar, A. V.; Culvenor, C. C. J . J . Chem.
Soc., Chem. Commun. 1986, 1219. (b) Lacey, E.; Edgar, J . A.; Culvenor,
C. C. J . Biochem. Pharmacol. 1987, 36, 2133. (c) Li, Y.; Kobayashi, H.;
Tokiwa, Y.; Hashimoto, Y.; Iwasaki, S. Biochem. Pharmacol. 1992, 43,
219.
preparation of each corresponding chiral auxiliary, in-
termediate, or a chiral catalyst system, rapid and efficient
methods for the synthesis of these important building
blocks are still desired. For the synthesis of â-hydroxy-
phenylalanine derivative 2, we investigated the Sharpless
asymmetric aminohydroxylation8 (AA) which could install
the requisite stereochemistry of the vicinal amino alcohol
function of 2 in a single step. Sharpless and co-workers
recently discovered that the use of the AQN ligand
(5) (a) Miller, M. J . Acc. Chem. Res. 1986, 19, 49. (b) Labia, R.;
Morin, C. J . Antibiot. 1984, 37, 1103. (c) Floyd, D. M.; Fritz, A. W.;
Pluscec, J .; Weaver, E. R.; Cimarusti, C. M. J . Org. Chem. 1982, 47,
5160.
(7) For examples, see: (a) Evans, D. A.; Weber, A. E. J . Am. Chem.
Soc. 1986, 108, 6757. (b) Schollkopf, U.; Beulshausen, T. Liebigs Ann.
Chem. 1989, 223. (c) Seebach, D.; Aebi, J . D. Tetrahedron Lett. 1983,
24, 3311. (d) Seebach, D.; Aebi, J . D. Tetrahedron Lett. 1984, 24, 2545.
(e) Seebach, D.; J uaristi, E.; Miller, D. D.; Schickli, C.; Weber, T. Helv.
Chim. Acta 1987, 70, 237. (f) Alker D.; Hamblett, G.; Harwood, L. M.;
Robertson, S. M.; Watkin, D. J .; Williams, C. E. Tetrahedron 1998,
54, 6089. (g) Vassilev, V. P.; Uchiyama, T.; Kajimoto, T.; Wong, C.-H.
Tetrahedron Lett. 1995, 36, 4081. (h) J ung, M. E.; J ung, Y. H.
Tetrahedron Lett. 1989, 30, 6637. (i) Shao, H.; Goodman, M. J . Org.
Chem. 1996, 61, 2582. (j) Tao, B.; Schlingloff, G.; Sharpless, K. B.
Tetrahedron Lett. 1998, 39, 2507. (k) Ito, Y.; Sawamura, M.; Hayashi,
T. J . Am. Chem. Soc. 1986, 108, 6405. (l) Hayashi, T.; Sawamura, M.;
Ito, Y. Tetrahedron 1992, 48. 1999.
(6) (a) Koiso, Y.; Lin, Y.; Iwasaki, S.; Hanaoka, K.; Kobayashi, T.;
Sonoda, R.; Fujita, Y.; Yaegashi, H.; Sato, Z. J . Antibiot. 1994, 47, 765.
(b) Koiso, Y.; Natori, M.; Iwasaki, S.; Sato, S.; Sonoda, R.; Fujita, Y.;
Yaegashi, H.; Sato, Z. Tetrahedron Lett. 1992, 33, 4157. (c) Koiso, Y.;
Morisaki, N.; Yamashita, Y.; Mitsui, Y.; Shirai, R.; Hashimato, Y.;
Iwasaki, S. J . Antibiot. 1998, 51, 418. (d) Li, Y.; Koiso, Y.; Kobayashi,
T.; Hashimoto, Y.; Iwasaki, S. Biochem. Pharmacol. 1995, 49, 1367.
(e) Iwasaki, S. Med. Res. Rev. 1993, 13, 183. (f) Luduena, R. F.; Roach,
M. C.; Prasad, V.; Banerjee, M.; Koiso, Y.; Li, Y.; Iwasaki, S. Biochem.
Pharmacol. 1994, 47, 1593. (g) Morisaki, N.; Mitsui, Y.; Yamashita,
Y.; Koiso, Y.; Shirai, R.; Hashimoto, Y.; Iwasaki, S. J . Antibiot. 1998,
51, 423. (h) Hamel, E. Med. Res. Rev. 1996, 16, 207.
10.1021/jo010482c CCC: $20.00 © 2001 American Chemical Society
Published on Web 09/21/2001

7224 J . Org. Chem., Vol. 66, No. 21, 2001
Notes
Ta ble 1. AA Rea ction s Usin g TeocNH2
system in the osmium-catalyzed AA reaction of cinnama-
tes reversed the regiochemical outcomes of the previously
known PHAL ligand system, affording the N-protected
â-hydroxy-R-amino regioisomer as the major product (eq
1).7j Yet, the regioselectivities were moderate, ranging
from 4:1 to 3:1, and did not reach to the levels which can
be produced for the corresponding R-hydroxy-â-amino
regioisomers by the PHAL ligand. Electron-deficient
cinnamates were also found to be problematic substrates
with the AQN ligand; the AA of m-nitrocinnamate
afforded a 1:1 mixture of two regioisomers (enantiose-
lectivities not reported) and a substantial quantity of the
diol byproduct. Panek and co-workers, using the same
ligand, found that p-aryl esters substituted with strong
electron-withdrawing groups (e.g., p-NO2) precluded the
aminohydroxylation process.9 On the other hand, in the
AA of cinnamates, the PHAL ligand system appeared less
affected by the electronic properties of the substrates.
This ligand preferentially delivered the nitrogen to the
â position with good regioselectivity and enantioselec-
tivity to afford nitro-substituted R-hydroxy-â-amino de-
cat/liga
(mol %)
solvent
50% aq
selectivityb
6a :6b
% yieldc
6a , 6b
% eed
6a , 6b
entry
1
2
3
4/5
8/9
4/5
n-PrOH
n-PrOH
CH3CN
7:3
7:3
1:1
45, 21
37, 17
26, 27
57, 68
67, 75
71, 92
a
b
Catalyst ) K2OsO2(OH)4, Ligand ) (DHQD)2AQN. Ratio of
6a to 6b determined by 1H NMR (500 MHz) integration prior to
separation. c Isolated yield of 6a and 6b after separation by column
d
chromatography. Enantiomeric excesses of 6a and 6b determined
by HPLC analysis using a Chiralpak AD column with n-hexane/
i-PrOH as the eluent.
8b,10,11
rivatives.
using benzyl carbamate and the (DHQD)2AQN ligand (eq
2). The reaction provided a mixture of two regioisomers
(5a and 5b, ca. 1:1) in 44% combined yield and significant
amounts of the diol byproduct (∼8%). The enantioselec-
tivity obtained for the desired product 5a was only 25%.
To improve this result, other nitrogen sources were
screened. The reported 2-trimethylsilylethyl carbamate
(TeocNH2)10 seemed to be the reagent of choice for this
substrate.
In general, the selectivities of asymmetric catalytic
reactions are highly substrate dependent. Herein, we
wish to extend the scope of the Sharpless AA reaction to
electron-deficient olefinic substrates using the AQN
ligand for the synthesis of â-hydroxy-R-amino acid de-
rivatives. This method may prove useful for the asym-
metric syntheses of nitro- and/or fluoro-substituted aro-
matic amino acid building blocks12,13 as well as other
amino acids14 employed in organic synthesis.
Initial tests for the AA reactions were carried out with
The regioselectivities and enantioselectivities of the
aminohydroxylation reactions using TeocNH2 varied with
reaction conditions (Table 1). The AA reaction with 4 mol
% of the catalyst proceeded with a shorter reaction time
of 1.5 h and a regioselectivity of 7:3 for 6a and 6b,
affording a 45% isolated yield of the desired isomer 6a
in 57% ee (entry 1 of Table 1). Doubling the amount of
the osmium catalyst and the AQN ligand slightly en-
hanced the enantioselectivities of 6a and 6b to 67 and
75%, respectively (entry 2 of Table 1). On the other hand,
using CH3CN/H2O (1:1) as the solvent also led to a slight
improvement in the enantioselectivity but diminished the
regioselectivity to 1:1 (entry 3 of Table 1). Cinnamate 4
was unreactive to the aminohydroxylation at 0 °C. In all
three cases, the formation of a small amount of dihy-
droxylated byproduct (<5%) was observed.
p-nitrocinnamate 4 under standard carbamate conditions7j
(8) (a) Li, G.; Chang, H.-T.; Sharpless, K. B. Angew. Chem., Int. Ed.
Engl. 1996, 35, 451. (b) Li, G.; Angert, H. H.; Sharpless, K. B. Angew.
Chem., Int. Ed. Engl. 1996, 35, 2813. (c) Bruncko, M.; Schlingloff, G.;
Sharpless, K. B. Angew. Chem., Int. Ed. Engl. 1997, 36, 1483. (d) Kolb,
H. C.; Sharpless, K. B. Transition Metals for Organic Synthesis; Beller,
M., Bolm, C., Eds.; Wiley-VCH: Weinheim, 1998; Vol. 2, pp 243-260.
(e) O′Brian, P. Angew. Chem., Int. Ed. Engl. 1999, 38, 326.
(9) Morgan, A. D.; Masse, C. E.; Panek, J . S. Org. Lett. 1999, 1, 1949.
(10) Reddy, K. L.; Dress, K. R.; Sharpless, K. B. Tetrahedron Lett.
1998, 39, 3667.
(11) Barta, N. S.; Sidler, D. R.; Somerville, K. B.; Weissman, S. A.;
Larsen, R. D.; Reider, P. J . Org. Lett. 2000, 2, 2821.
(12) For nucleophilic aromatic substitution, see: (a) Burgess, K.;
Lim, D.; Martinez, C. I. Angew. Chem., Int. Ed. Engl. 1996, 35, 1077.
(b) Rao, R. A. V.; Gurjar, M. K.; Reddy, L.; Rao, A. S. Chem. Rev. 1995,
95, 2135. (c) Zhu, J .; La¨ıb, T.; Chastanet, J .; Beugelmans, R. Angew.
Chem., Int. Ed. Engl. 1996, 35, 2517. (d) Woiwode, T. F.; Rose, C.;
Wandless, T. J . J . Org. Chem. 1998, 63, 9594. (e) Raeppel, S.; Raeppel,
F.; Suffert, J . Synlett 1998, 794.
(13) Soloshonok, V. A.; Kacharov, A. D.; Hayashi, T. Tetrahedron
1996, 52, 245.
(14) Easton, C. J .; Hutton, C. A.; Roselt, P. D.; Tiekink, E. R. T.
Tetrahedron 1994, 50, 7327.
Encouraged by the results from the Teoc carbamate-
based aminohydroxylation, we decided to prepare the
desired â-hydroxyphenylalanine derivative 2 (Scheme 2).
Although previously reported as a side product,12e cin-

Notes
J . Org. Chem., Vol. 66, No. 21, 2001 7225
performed on 0.25 mm E. Merck silica gel 60 F254 plates. Merck
silica gel (60, particle size 0.040-0.063 mm) was used for flash
column chromatography. All 1H and 13C NMR spectra were
recorded at 500 and 125 MHz, respectively. High-resolution mass
Sch em e 2
spectra (HRMS) were recorded on
a Micromass AutoSpec
spectrometer using methane chemical ionization (CI) or electron
impact (EI). Optical rotations were recorded on a Perkin-Elmer
model 341 polarimeter at the sodium D line. Enantiomeric
excesses were determined by HPLC using a Chiralpak AD
column (conditions: 15% i-PrOH/hexane, 1 mL min-1, 254 nm).
Gen er a l P r oced u r e for th e Osm iu m -Ca ta lyzed AA Re-
a ction s. Sodium hydroxide (60 mg, 1.5 mmol) was dissolved in
water (4 mL), and 0.5 mL of this NaOH solution was transferred
to a small vial containing K2OsO2(OH)4 (0.020 mmol for 4 mol
% and 0.040 mmol for 8 mol %) for later use. To the remainder
of the NaOH solution were added the carbamate (1.55 mmol)
and n-PrOH (2 mL). The mixture was stirred for 2-3 min and
placed in a water bath before tert-butylhypochlorite16 (175 µL,
1.52 mmol) was slowly added with vigorous stirring. Then, the
resulting solution was sequentially treated with a solution of
(DHQD)2AQN (0.025 mmol for 5 mol % and 0.045 mmol for 9
mol %) in n-PrOH (1 mL), the cinnamate (0.50 mmol), the
previously prepared solution of K2OsO2(OH)4, and n-PrOH (1
mL). The reaction mixture was monitored by TLC to establish
completion, quenched by the addition of saturated aqueous
sodium sulfite (4 mL) while being cooled in an ice-water bath,
and stirred for an additional 30 min. The separated aqueous
phase was extracted with EtOAc (3 × 5 mL), and the combined
organic extracts were washed with water (3 mL) followed by
brine (5 mL), dried over MgSO4, and concentrated in vacuo. The
residue was purified by chromatography (EtOAc/hexanes) on a
silica gel column.
Meth yl (2S,3R)-2-[N-[(Ben zyloxy)ca r bon yl]a m in o]-3-h y-
dr oxy-3-(4-n itr oph en yl)pr opion ate (5a) an d Meth yl (2S,3R)-
3-[N-[(Ben zyloxy)ca r b on yl]a m in o]-2-h yd r oxy-3-(4-n it r o-
p h en yl)p r op ion a te (5b). The reaction mixture (ca. 5a :5b )
1:1) was chromatographed using 3:7 EtOAc/hexanes to yield 160
mg (44% combined yield) of the mixture of 5a and 5b. 5a : ee )
25% [30.4 min (2S, 3R), 37.1 min (2R, 3S)]; Rf ) 0.52 (1:1 EtOAc/
namate 8 was prepared from commercially available
3-fluoro-4-nitrotoluene by chromium trioxide oxidation
followed by acidic hydrolysis15 and Horner-Emmons
olefination. The following aminohydroxylation of cin-
namate 8, similar to the previous case, afforded two
regioisomers 9a and 9b with a regioselectivity of 7:3 (50%
of 9a , 20% of 9b). However, the enantioselectivity ob-
served for 9a (89% ee)was higher than that for 6a (67%
ee). The preparation of the desired amino alcohol 2 was
achieved by removal of the Teoc protective group from
9a with TFA in 85% yield.
In conclusion, the use of 2-trimethylsilylethyl carbam-
ate as the nitrogen source in the Os(VIII)/(DHQD)2AQN-
catalyzed AA provided an efficient route to fluoro-, nitro-
substituted â-hydroxyphenylalanine derivatives, which
are useful building blocks12 in synthetic and medicinal
chemistry. Therefore, we have expanded the scope of the
AA to electron-deficient aromatic substrates. Nitro-
substituted phenyl â-hydroxyamino acid derivatives will
allow the incorporation not only of the hydroxyl group
but also of other nitrogen functional groups into natural
products.1 The method will be generally applicable for
the asymmetric synthesis of other substituted aromatic
amino acids13,14 required for diverse purposes. Further
studies toward the total synthesis of ustiloxin D based
on these results will be reported in due course.
1
hexanes); H NMR (CDCl3) δ 8.17 (d, J ) 8.2 Hz, 2H), 7.55 (d,
J ) 8.5 Hz, 2H), 7.40-7.25 (m, 5H), 5.55 (d, J ) 8.1 Hz, 1H),
5.45 (s, 1H), 5.04 (d, J AB ) 12.2 Hz, 1H), 4.96 (d, J AB ) 12.2 Hz,
1H), 4.71 (d, J ) 8.3 Hz, 1H), 3.88 (s, 3H), 2.86 (br s, 1H);13
C
NMR (CDCl3) δ 170.5, 156.1, 147.7, 146.6, 135.9, 128.5, 128.4,
128.1, 126.9, 123.6, 72.9, 67.3, 59.4, 53.0; HRMS (CI) calcd for
C
18H19N2O7 (M + H+) 375.1192, found 375.1208. 5b: ee ) 38%
[50.3 min (2S, 3R), 28.0 min (2R, 3S)]; Rf ) 0.58 (1:1 EtOAc/
hexanes); H NMR (CDCl3) δ 8.23 (d, J ) 8.4 Hz, 2H), 7.59 (d,
1
J ) 8.2 Hz, 2H), 7.40-7.36 (m, 5H), 5.79 (d, J ) 9.3 Hz, 1H),
5.39 (d, J ) 8.9 Hz, 1H), 5.14-5.08 (m, 2H), 4.51 (br s, 1H),
3.86 (s, 3H), 3.30 (d, J ) 3.4 Hz, 1H);13C NMR (CDCl3) δ 172.5,
155.6, 147.6, 146.2, 135.9, 128.5, 128.3, 128.1, 127.8, 123.8, 72.8,
67.3, 56.0, 53.4; HRMS (CI) calcd for C18H19N2O7 (M + H+)
375.1192, found 375.1196.
Meth yl (2S,3R)-3-Hyd r oxy-3-(4-n itr op h en yl)-2-[N-[(tr i-
m eth ylsilyleth oxy)ca r bon yl]a m in o]p r op ion a te (6a ) a n d
Meth yl (2S,3R)-2-Hyd r oxy-3-(4-n itr op h en yl)-3-[N-[(tr im -
eth ylsilyleth oxy)ca r bon yl]a m in o]p r op ion a te (6b) (En tr y
1, Ta ble 1). The reaction mixture (ca. 6a :6b ) 7:3) was
chromatographed using EtOAc/hexanes (2:8 f 4:6, gradient
elution) to yield 86 mg (45% yield) of 6a and 41 mg (21% yield)
of 6b. 6a (major isomer): [R]20 ) -14.0 (c 0.56, CHCl3); ee )
D
57% [14.4 min (2S, 3R), 21.4 min (2R, 3S)]; Rf ) 0.52 (1:1 EtOAc/
1
hexanes); H NMR (CDCl3) δ 8.24 (d, J ) 8.7 Hz, 2H), 7.60 (d,
J ) 8.6 Hz, 2H), 5.44 (s, 1H), 5.39 (br d, J ) 8.0 Hz, 1H), 4.68
(br d, J ) 7.3 Hz, 1H), 4.07 (br m, 2H), 3.84 (s, 3H), 2.98 (s, 1H),
0.91 (br m, 2H), 0.02 (s, 9H);13C NMR (CDCl3) δ 170.6, 156.5,
147.7, 146.8, 126.9, 123.6, 73.0, 64.0, 59.4, 52.9, 17.6, -1.6;
HRMS (CI) calcd for C16H25N2O7Si (M + H+) 385.1430, found
Exp er im en ta l Section
Gen er a l. Reactions requiring air-sensitive manipulations
were conducted under nitrogen. Unless stated otherwise, all
reagents were purchased from commercial sources and used
without additional purification. Methylene chloride was distilled
from calcium hydride. The literature procedure was used to
prepare 2-trimethylsilylethyl carbamate.10 Analytical TLC was
385.1455. 6b (minor isomer): [R]20 ) -17.3 (c 0.55, CHCl3); ee
D
) 68% [20.8 min (2S, 3R), 12.8 min (2R, 3S)]; Rf ) 0.60 (1:1
EtOAc/hexanes); 1H NMR (CDCl3) δ 8.25 (d, J ) 8.5 Hz, 2H),
7.60 (d, J ) 8.4 Hz, 2H), 5.60 (d, J ) 9.1 Hz, 1H), 5.37 (d, J )
(15) Lieberman, S. V.; Connor, R. Organic Syntheses; Wiley: New
York, 1943; Collect. Vol. 2, pp 441-443.
(16) Mintz, M. J .; Walling, C. Organic Syntheses; Wiley: New York,
1973; Collect. Vol. 5, pp 183-187.

7226 J . Org. Chem., Vol. 66, No. 21, 2001
Notes
8.6 Hz, 1H), 4.51 (s, 1H), 4.17 (t, J ) 8.5 Hz, 2H), 3.91 (s, 3H),
3.26 (br s, 1H), 1.00 (br t, J ) 8.1 Hz, 2H), 0.05 (s, 9H);13C NMR
(CDCl3) δ 172.6, 155.8, 147.6, 146.5, 127.9, 123.8, 72.9, 63.9, 55.9,
53.5, 17.6, -1.5; HRMS (CI) calcd for C16H25N2O7Si (M + H+)
385.1430, found 385.1433.
NMR (CDCl3) δ 172.4, 155.8, 155.6 (d, J ) 265.7 Hz), 148.4,
136.6, 126.3, 123.0, 117.1 (d, J ) 21.6 Hz), 72.6, 64.0, 55.6, 53.5,
17.6, -1.5; HRMS (EI) calcd for C16H23N2O7FNaSi (M + Na+)
425.1155, found 425.1175.
Meth yl (2S,3R)-2-Am in o-3-h yd r oxy-3-[(3-flu or o-4-n itr o)-
p h en yl]p r op ion a te (2). A solution of 9a (20 mg, 0.050 mmol)
in CH2Cl2 (80 µL) was treated with trifluoroacetic acid (80 µL,
1.0 mmol) at 0 °C under nitrogen. The reaction mixture was
stirred for 1 h, diluted with EtOAc (10 mL), and neutralized with
saturated aqueous NaHCO3. The separated aqueous layer was
extracted with EtOAc (3 × 15 mL). The combined organic layers
were washed with water followed by brine, dried over MgSO4,
and concentrated in vacuo. The residue was chromatographed
using 1:10 MeOH/CHCl3 to yield 11 mg (85% yield) of amino
alcohol 2 as a white solid. 2: 1H NMR (CDCl3) δ 8.06 (t, J ) 8.0
Hz, 1H), 7.38-7.27 (m, 2H), 4.95 (d, J ) 4.5 Hz, 1H), 3.75 (s,
3H), 3.62 (d, J ) 4.5 Hz, 1H), 1.65 (br s, 3H);13C NMR (DMSO-
d6) δ 173.7, 154.3 (d, J ) 260.8 Hz), 153.1 (d, J ) 7.9 Hz), 135.3,
125.5, 122.9 (d, J ) 3.1 Hz), 116.1 (d, J ) 21.3 Hz), 72.6, 60.0,
51.7; HRMS (EI) calcd for C10H11N2O5FNa (M + Na+) 281.0549,
found 281.0544.
Meth yl (2S,3R)-3-[(3-F lu or o-4-n itr o)p h en yl]-3-h yd r oxy-
2-[N-[(tr im eth ylsilyleth oxy)car bon yl]am in o]pr opion ate (9a)
an d Meth yl (2S,3R)-3-[(3-Flu or o-4-n itr o)ph en yl]-2-h ydr oxy-
3-[N-[(t r im et h ylsilylet h oxy)ca r b on yl]a m in o]p r op ion a t e
(9b). The reaction mixture (ca. 9a :9b ) 7:3) was chromato-
graphed using EtOAc/hexanes (2:8 f 3:7, gradient elution) to
yield 100 mg (50% yield) of 9a and 39 mg (20% yield) of 9b. 9a
(major isomer): [R]20 ) -25.6 (c 0.44, CHCl3); ee ) 89% [11.0
D
min (2S, 3R), 16.3 min (2R, 3S)]; Rf ) 0.36 (4:6 EtOAc/hexanes);
1H NMR (CDCl3) δ 8.09 (t, J ) 8.0 Hz, 1H), 7.43-7.32 (m, 2H),
5.42 (s, 1H), 5.36 (br d, J ) 8.8 Hz, 1H), 4.67 (br d, J ) 7.8 Hz,
1H), 4.10 (t, J ) 8.3 Hz, 2H), 3.85 (s, 3H), 3.00 (s, 1H), 0.93 (br
m, 2H), 0.03 (s, 9H);13C NMR (CDCl3) δ 170.4, 155.9, 155.5 (d,
J ) 265.5 Hz), 148.9 (d, J ) 7.8 Hz), 136.6, 126.1, 121.9 (d, J )
3.7 Hz), 116.2 (d, J ) 21.9 Hz), 72.3, 64.1, 59.2, 53.0, 17.6, -1.6;
HRMS (EI) calcd for C16H23N2O7FNaSi (M + Na+) 425.1155,
found 425.1184. 9b (minor isomer): [R]20 ) -21.4 (c 0.56,
D
CHCl3); ee ) 92% [13.8 min (2S, 3R), 9.5 min (2R, 3S)]; Rf )
0.48 (4:6 EtOAc/hexanes); 1H NMR (CDCl3) δ 8.06 (t, J ) 8.0
Hz, 2H), 7.37-7.33 (m, 2H), 5.56 (d, J ) 9.2 Hz, 1H), 5.29 (br d,
J ) 8.7 Hz, 1H), 4.47 (s, 1H), 4.15 (t, J ) 8.5 Hz, 2H), 3.88 (s,
3H), 3.25 (d, J ) 3.1 Hz, 1H), 0.99-0.95 (m, 2H), 0.02 (s, 9H);13C
Ack n ow led gm en t. We thank the NIH (CA-40081)
and NSF (CHE-9901449) for financial support of this
work.
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