Catalytic Asymmetric Synthesis of β-Hydroxy-α-amino Acids: Highly Enantioselective Hydrogenation of β-Oxy-α-acetamidoacrylates

Full text of DOI:10.1021/jo9722717

J . Org. Chem. 1998, 63, 3499-3503
3499
Sch em e 1a
Ca ta lytic Asym m etr ic Syn th esis of
â-Hyd r oxy-r-a m in o Acid s: High ly
En a n tioselective Hyd r ogen a tion of
â-Oxy-r-a ceta m id oa cr yla tes
Ryoichi Kuwano, Satoshi Okuda, and Yoshihiko Ito*
Department of Synthetic Chemistry and Biological
Chemistry, Graduate School of Engineering,
Kyoto University, Sakyo-ku, Kyoto 606-8501, J apan
Received December 15, 1997
Optically active â-hydroxy-R-amino acids are not only
important constituents of biologically active peptides and
related compounds1 but also useful chiral precursors in
organic synthesis.2 Various stereocontrolled syntheses
of optically active â-hydroxy-R-amino acids have been
reported.3 threo-â-Hydroxy-R-amino acids are conve-
niently prepared by highly enantioselective hydrogena-
tion of the corresponding ketone precursors or aldol
reaction of R-isocyanocarboxylates.4,5 However, erythro-
â-hydroxy-R-amino acids with high enantiomeric excess
have not been accessible by catalytic asymmetric syn-
thesis.6,7
a
(a) NaH, THF, -78 to 0 °C, 1 h then R′3SiCl, -78 °C to rt; (b)
NaBH4, EtOH, rt; (c) t-BuCOCl, Et3N, cat. DMAP, THF, rt; (d)
t-BuOCl, benzene, rt, then DABCO, rt.
In the preceding paper,8 we reported that trans-
chelating chiral diphosphine TRAPs9 with linear alkyl P
substituents (Et- and BuTRAP) are effective for asym-
acids. Herein, we describe a new efficient enantioselec-
tive synthesis of optically active erythro- and threo-â-
hydroxy-R-amino acids by TRAP-rhodium-catalyzed
asymmetric hydrogenation of the respective (Z)- and (E)-
â-oxy-R-acetamidoacrylates, which are both prepared
stereoselectively from the corresponding â-keto-R-(N-
acetylamino)carboxylate precursors.
According to Scheme 1, (Z)-â-siloxy-R-acetamidoacry-
lates (Z)-2a -i were synthesized with high stereoselec-
tivity in good yields by reaction of the sodium enolate of
1 with trialkylchlorosilane.11 The pure (Z)-2, which was
easily obtained through purification by flash column
chromatography on silica gel, was employed as the
starting olefinic substrate. On the other hand, (E)-â-
pivaloyloxy-R-acetamidoacrylates (E)-4 were prepared in
good yields as follows: The carbonyl group of 1 was
chemoselectively reduced with NaBH4 to give the corre-
sponding alcohol, which was esterified with pivaloyl
chloride, giving 3 as a mixture of diastereoisomers.
N-Chlorination of 3 with tert-butyl hypochlorite, followed
by dehydrochlorination with DABCO, resulted in the
formation of pure (E)-4 with migration of the C-N double
bond initially formed.
metric hydrogenation of â,â-dialkyl-substituted-R-aceta-
midoacrylates catalyzed by rhodium complexes.10 The
asymmetric hydrogenation provides an efficient synthetic
route to various optically active â-branched-R-amino
(1) (a) Parenti, F.; Cavalleri, B. Drugs of the Future 1990, 15, 57.
(b) Wenger, R. M.; Martin, K.; Tembers, C.; Tromelin, A. Chimia 1992,
46, 314.
(2) Coppola, G. M.; Schuster, H. F. Asymmetric Synthesis: Construc-
tion of Chiral Molecules Using Amino Acids; J ohn Wiley & Sons:
Toronto, 1987.
(3) Williams, R. M. Synthesis of Optically Active R-Amino Acids;
Pergamon: Oxford, 1989.
(4) For synthesis of threo-â-hydroxy-R-amino acids by catalytic
asymmetric hydrogenation of 2-(N-acetylamino)-3-ketoalkanoates,
see: (a) Noyori, R.; Ikeda, T.; Ohkuma, T.; Widhalm, M.; Kitamura,
M.; Takaya, H.; Akutagawa, S.; Sayo, N.; Saito, T.; Taketomi, T.;
Kumobayashi, H. J . Am. Chem. Soc. 1989, 111, 9134. (b) Genet, J . P.;
Pinel, C.; Mallart, S.; J uge, S.; Thorimbert, S.; Laffitte, J . A. Tetra-
hedron: Asymmetry 1991, 2, 555.
(5) For synthesis of threo-â-hydroxy-R-amino acids by catalytic
asymmetric aldol reaction of R-isocyanoacetates, see: (a) Ito, Y.;
Sawamura, M.; Hayashi, T. J . Am. Chem. Soc. 1986, 108, 6405. (b)
Sawamura, M.; Ito, Y. Catalytic Asymmetric Synthesis; Ojima, I., Ed.;
VCH: New York, 1993; Chapter 7.2, p 367.
(6) For synthetic transformations to optically active erythro-â-
hydroxy-R-amino acids, see: (a) Hale, K. J .; Manaviazar, S.; Delisser,
V. M. Tetrahedron 1994, 50, 9181. (b) Beaulieu, P. L. Tetrahedron Lett.
1991, 32, 1031.
(7) For noncatalytic asymmetric constructions of erythro-â-hydroxy-
R-amino acid skeleton, see: (a) Evans, D. A.; Sjogren, E. B.; Weber, A.
E.; Conn, R. E. Tetrahedron Lett. 1987, 28, 39. (b) Kanemasa, S.; Mori,
T.; Tatsukawa, A. Tetrahedron Lett. 1993, 34, 8293.
(8) Sawamura, M.; Kuwano, R.; Ito, Y. J . Am. Chem. Soc. 1995, 117,
9602.
Asymmetric hydrogenations of (Z)-â-siloxy-R-acetami-
doacrylates (Z)-2a (R′3Si ) dimethylthexylsilyl (TDS))
were carried out at atmospheric pressure of hydrogen in
the presence of 1 mol % of rhodium catalyst generated
in situ by mixing [Rh(COD)2]ClO4 and (R,R)-(S,S)-TRAP
(1:1.1) bearing linear alkyl P substituents.12 The results
(9) General name for these diphosphines: (S,S)-2,2′′-bis[(R)-1-
(dialkylphosphino)ethyl]-1,1′-biferrocene: (a) Sawamura, M.; Hamash-
ima, H.; Ito, Y. Tetrahedron: Asymmetry 1991, 2, 593. (b) Sawamura,
M.; Hamashima, H.; Sugawara, M.; Kuwano, R.; Ito, Y. Organometal-
lics 1995, 14, 4549. (c) Kuwano, R.; Sawamura, M.; Okuda, S.; Asai,
T.; Ito, Y.; Redon, M.; Krief, A. Bull. Chem. Soc. J pn. 1997, 70, 2807.
(10) (a) Burk, M. J .; Feng, S.; Gross, M. F.; Tumas, W. J . Am. Chem.
Soc. 1995, 117, 8277. (b) Burk, M. J .; Gross, M. F.; Martinez, J . P. J .
Am. Chem. Soc. 1995, 117, 9375.
(11) (E)-2 was not found in 1H NMR spectrum of the crude product,
although a trace amount of (E)-2 was detected by TLC analysis.
S0022-3263(97)02271-8 CCC: $15.00 © 1998 American Chemical Society
Published on Web 04/30/1998

3500 J . Org. Chem., Vol. 63, No. 10, 1998
Notes
Ta ble 1. En a n tioselective Hyd r ogen a tion of (Z)-2
Ca ta lyzed by (R,R)-(S,S)-TRAP -Rh od iu m Com p lexa
Ta ble 2. Asym m etr ic Hyd r ogen a tion of (E)-4 Ca ta lyzed
by (R,R)-(S,S)-P r TRAP -Rh od iu m Com p lexa
entry
R (4)
product convn, %b yield, %c ee, %d(confign)
1
Me (4a )
Et (4b)
Bu (4c)
Ph (4d )
6a
6b
6c
6d
100
100
100
16
99
97
95
12e
97 (2S,3R)
91 (2S,3R)
89 (2S,3R)
73 (2S,3R)
2
3e
4
a
All reactions were carried out at 20 °C and 1 kg/cm2 of
hydrogen pressure in 2-propanol for 24 h unless otherwise noted.
b
4 (0.25 M):[Rh(COD)2]BF4:TRAP ) 100:1:1.1. Determined by 1H
NMR analysis of crude product. c Isolated yield by flash column
d
chromatography. Determined by HPLC analysis with SUM-
ICHIRAL OA-3000. e The reaction was carried out in 0.5 M
solution of 4.
erythro-5
temp, convn, yield,
ee, %d
b
c
entry
2
TRAP
°C
%
%
(confign)
yield (entry 8). Various erythro-â-hydroxyl-R-amino acid
derivatives 5f-h bearing a primary alkyl group at the
â-position were prepared with high enantioselectivity
from (Z)-2f-h by the asymmetric hydrogenation cata-
lyzed by the PrTRAP-rhodium complex (entries 9-11).
However, the hydrogenation of (Z)-2i with a secondary
alkyl â-substituent gave no hydrogenation product (entry
12). The hydrogenation product erythro-5a was easily
hydrolyzed to L-(2S,3S)-allo-threonine with 1 N hydro-
chloric acid in 77% yield.
1
2
3
4
5
6
7
8
9
2a
2a
2a
2a
2b
2c
2d
2e
2f
EtTRAP
PrTRAP
BuTRAP
PrTRAP
PrTRAP
PrTRAP
PrTRAP
PrTRAP
PrTRAP
PrTRAP
30
30
30
20
20
20
20
20
20
20
20
20
100
100
100
100
100e
16
75
95
96
98
48
7
88 (2S,3S)
93 (2S,3S)
88 (2S,3S)
95 (2S,3S)
94 (2S,3S)
92 (2S,3S)
0
100
100
100
100
0
93
93
89
99
95 (2S,3S)
94 (2S,3S)
97 (2S,3R)
94 (2S,3S)
10f
11
12
2g
2h g PrTRAP
2i
PrTRAP
(E)-â-Pivaloyloxy-R-acetamidoacrylates (E)-4 also were
hydrogenated with high enantioselectivity in the presence
of cationic PrTRAP-rhodium catalyst, giving threo-
(2S,3R)-6 (Table 2). The sense of enantioselection at the
R-carbon in the hydrogenation of (E)-4 is the same as that
of (Z)-2. Hydrogenation of (E)-4a led to 97% ee of
N-acetyl-O-pivaloyl-L-threonine methyl ester (6a ) in 99%
yield (entry 1). Et- and BuTRAP were less selective (87%
ee and 90% ee, respectively). Although â-alkyl substit-
uents of (Z)-2 did not affect enantioselectivity in the
asymmetric hydrogenations, the enantioselectivity of the
hydrogenation of (E)-4 slightly decreased with longer
â-alkyl substituents (entries 2 and 3). Disappointingly,
PrTRAP-rhodium catalyst showed low catalytic activity
for the hydrogenation of (E)-4d bearing a â-aromatic
substituent, giving threo-(2S,3R)-6d with moderate enan-
tiomeric excess (entry 4).
In conclusion, we succeeded in the highly enantiose-
lective synthesis of erythro- and threo-â-hydroxy-R-amino
acids (up to 97% ee) by PrTRAP-rhodium catalyzed
asymmetric hydrogenation of (Z)- and (E)-â-oxy-R-aceta-
midoacrylates, both of which were stereoselectively pre-
pared from the corresponding â-keto-R-(N-acetylami-
no)alkanoate precursors.
a
All reactions were carried out at 1 kg/cm2 of hydrogen pressure
in 1,2-dichloroethane for 24 h unless otherwise noted. 2 (0.5 M):
[Rh(COD)2]ClO4:TRAP ) 100:1:1.1. Determined by 1H NMR
b
analysis of crude product. c Isolated yield by flash column chro-
d
matography. Determined by HPLC analysis with SUMICHIRAL
OA-3000. e 1H NMR analysis of the workup mixture indicated that
the hydrogenation product, erythro-5, was accompanied by the
hydrolysis product (38%). f 2 mol % of catalyst was used. g Diethyl
ester was used.
are summarized in Table 1. The hydrogenations pro-
ceeded stereospecifically to yield erythro-(2S,3S)-5a, which
was isolated by flash column chromatography. PrTRAP
gave higher enantioselectivity than Et- and BuTRAP
(entries 1-3). The enantioselectivity increased up to 95%
ee by carrying out the hydrogenation at 20 °C with
PrTRAP ligand on the rhodium complex (entry 4).
Hydrogenation of TBDMS enol ether (Z)-2b provided
erythro-5b (94% ee) in 48% yield, which was accompanied
by the hydrolysis product, methyl 2-(N-acetylamino)-3-
oxobutanoate (1a , R ) Me) (entry 5). The hydrogenation
reaction of tert-butyldiphenylsilyl (TBDPS) enol ether (Z)-
2c proceeded sluggishly (entry 6), probably because a
larger silyl substituent such as the TBDPS group inter-
fered with the coordination of (Z)-2c to the rhodium
complex. The crucial role of the silyl group is also
observed in the asymmetric hydrogenation of (Z)-3-siloxy-
2-(N-acetylamino)-2-pentenoate (2d and 2e, R ) Et). The
hydrogenation of TDS ether (Z)-2d did not work at all
(entry 7). However, the TBDMS ether (Z)-2e, whose silyl
group may be slightly less bulky than that of 2d , was
subjected to the hydrogenation at 20 °C for 24 h to
furnish erythro-(2S,3S)-5e with 95% ee in 93% chemical
Exp er im en ta l Section
Ma ter ia ls. Unless otherwise noted, materials were obtained
from commercial suppliers and used without further purification.
1,2-Dichloroethane and 2-propanol were distilled from CaH2
under nitrogen. Tetrahydrofuran (THF) and benzene were
distilled from sodium-benzophenone ketyl. MeOH was distilled
from Mg(OMe)2. [Rh(COD)2]ClO4,13 [Rh(COD)2]BF4,13 PrTRAP9c
,
and 2-(N-acetylamino)-3-ketocarboxylates 14b were prepared
(12) Use of [Rh(COD)2]BF4 and [Rh(COD)2]OTf as catalyst precursor
accelerated hydrolysis reaction to give 1.
(13) Schenck, T. G.; Downes, J . M.; Milne, C. R. C.; Mackenzie, P.
B.; Boucher, H.; Whelan, J .; Boshnich, B. Inorg. Chem. 1985, 24, 2334.

Notes
J . Org. Chem., Vol. 63, No. 10, 1998 3501
according to the literature procedures. Flash column chroma-
tography was performed with silica gel 60 (230-400 mesh, E.
Merck) except for purifications of 2a -i, which were performed
with silica gel 60 N (spherical, neutral) (40-100 µm, Kanto
Chemical).
3184, 1728, 1654 cm-1; HRMS(FAB) calcd for C14H28NO5Si (M
+ H)+ 318.1737, found 318.1734.
Dieth yl (Z)-2-(N-Acetyla m in o)-3-(ter t-bu tyld im eth ylsi-
loxy)-2-h ep ten ed ioa te (2h ). In 55% yield: colorless oil; 1H
NMR (300 MHz, CDCl3, TMS) δ 0.21 and 0.22 (a pair of s, 6 H),
0.96 (s, 9 H), 1.25 (t, J ) 7.2 Hz, 3 H), 1.27 (t, J ) 7.2 Hz, 3 H),
1.82-1.98 (m, 2 H), 2.03 and 1.87 (a pair of s, 3 H), 2.34 and
2.38 (a pair of t, J ) 7.5 and 7.5 Hz, 2 H), 2.69 and 2.81 (a pair
of t, J ) 7.8 and 7.7 Hz, 2 H), 4.12 (q, J ) 7.2 Hz, 2 H), 4.20 (q,
J ) 7.2 Hz, 2 H), 6.48 and 6.05 (a pair of br s, 1 H); 13C NMR
(75 MHz, CDCl3) δ -4.1, 14.1, 18.2 and 19.9 (a pair of s), 22.8,
22.9, 25.4, 25.5, 32.0 and 32.9 (a pair of s), 33.4 and 33.6 (a pair
of s), 60.2, 60.6, 112.6, 159.5, 165.3, 168.3, 173.2; IR (neat) 3268,
Meth yl (Z)-2-(N-Acetyla m in o)-3-(d im eth ylth exylsiloxy)-
2-bu ten oa te (2a ). A solution of methyl 2-(N-acetylamino)-3-
ketobutanoate (346 mg, 2.0 mmol) in THF (3.0 mL) was added
to a suspension of NaH (52.8 mg, 2.2 mmol) in THF (4.0 mL) at
-78 °C. After 1 h of stirring at 0 °C, dimethylthexylsilyl chloride
(395 mg, 2.2 mmol) was added to the mixture at -78 °C. After
1 h of stirring at room temperature, the mixture was filtered
through Celite pad and evaporated under reduced pressure. The
residue was purified by flash column chromatography (n-hexane/
AcOEt ) 1/1), giving 461 mg (73%) of 2a : white solid; mp 64-
65 °C; 1H NMR (300 MHz, CDCl3, TMS) δ 0.26 and 0.27 (a pair
of s, 6 H), 0.90 (d, J ) 6.9 Hz, 6 H), 0.91 (s, 6 H), 1.69 (septet,
J ) 6.9 Hz, 1 H), 2.04 and 1.85 (a pair of s, 3 H), 2.29 and 2.40
(a pair of s, 3 H), 3.73 (s, 3 H), 6.42 and 6.03 (a pair of br s, 1
H); 13C NMR (75 MHz, CDCl3) δ -1.7, 18.4, 19.7 and 19.8 (a
pair of s), 20.1 and 20.9 (a pair of s), 23.0, 25.1, 33.8, 51.7, 111.0,
1740, 1668 cm-1
. Anal. Calcd for C19H35NO6Si: C, 56.83; H,
8.78; N, 3.49. Found: C, 56.88; H, 8.92; N, 3.46.
Meth yl (Z)-2-(N-Acetyla m in o)-3-(ter t-bu tyld im eth ylsi-
loxy)-4-m eth yl-2-p en ten oa te (2i). In 37% yield: white solid;
1H NMR (300 MHz, CDCl3, TMS) δ 0.21 and 0.23 (a pair of s, 6
H), 1.00 and 0.99 (a pair of s, 9 H), 1.11 and 1.13 (a pair of d, J
) 6.8 and 6.3 Hz, 6 H), 2.05 and 1.85 (a pair of s, 3 H), 2.40
(septet, J ) 6.8 Hz, 1 H), 3.73 (s, 3 H), 6.34 and 5.89 (a pair of
br s, 1 H); 13C NMR (75 MHz, CDCl3) δ -3.8 and -3.7 (a pair of
s), 18.9 and 19.0 (a pair of s), 19.3 and 19.9 (a pair of s), 19.6,
23.2, 25.9, 30.5 and 30.7 (a pair of s), 51.8, 110.2 and 109.3 (a
pair of s), 165.1, 166.7, 169.1.
158.5, 166.2, 168.5; IR (KBr) 3240, 1724, 1660 cm-1
, Anal.
Calcd for C15H29NO4Si: C, 57.11; H, 9.27; N, 4.44. Found: C,
56.89; H, 9.38; N, 4.29.
Meth yl (Z)-2-(N-Acetyla m in o)-3-(ter t-bu tyld im eth ylsi-
loxy)-2-bu ten oa te (2b). In 63% yield: white solid; 1H NMR
(300 MHz, CDCl3, TMS) δ 0.22 and 0.23 (a pair of s, 6 H), 0.95
(s, 9 H), 2.04 and 1.85 (a pair of s, 3 H), 2.30 and 2.41 (a pair of
s, 3 H), 3.73 (s, 3 H), 6.42 and 6.05 (a pair of br s, 1 H); 13C
NMR (75 MHz, CDCl3) δ -3.8, 18.0, 20.1, 23.0, 25.4 and 25.3 (a
pair of s), 51.7, 110.8, 158.8, 166.2, 168.5.
Met h yl (Z)-2-(N-Acet yla m in o)-3-(ter t-b u t yld ip h en ylsi-
loxy)-2-bu ten oa te (2c). In 78% yield: white solid; 1H NMR
(300 MHz, CDCl3, TMS) δ 1.04 (s, 9 H), 1.88 (s, 3 H), 2.09 and
2.14 (a pair of s, 3 H), 3.69 (s, 3 H), 6.35 and 6.16 (br s, 1 H),
7.39-7.53 (m, 6 H), 7.65-7.74 (m, 4 H); 13C NMR (75 MHz,
CDCl3) δ 19.3, 20.5, 22.8, 26.2, 51.6, 110.2, 128.2, 130.5, 132.3,
135.1, 159.8, 166.2, 168.7.
Meth yl (Z)-2-(N-Acetyla m in o)-3-(d im eth ylth exylsiloxy)-
2-p en ten oa te (2d ). In 76% yield: white solid; 1H NMR (300
MHz, CDCl3, TMS) δ 0.24 and 0.25 (a pair of s, 6 H), 0.87-0.94
(m, 12 H), 1.13 and 1.18 (a pair of t, J ) 7.4 and 7.4 Hz, 3 H),
1.73 (septet, J ) 6.9 Hz, 1 H), 2.04 and 1.85 (a pair of s, 3 H),
2.63 and 2.78 (a pair of q, J ) 7.4 and 7.4 Hz, 2 H), 3.73 (s, 3 H),
6.45 and 6.04 (a pair of br s, 1 H); 13C NMR (75 MHz, CDCl3) δ
-2.0, 12.3 and 12.0 (a pair of s), 18.4, 19.8 and 19.7 (a pair of s),
23.0, 25.2, 26.2 and 27.2 (a pair of s), 33.7, 51.7, 111.1, 162.5,
165.9, 168.5.
Meth yl 2-(N-Acetyla m in o)-3-p iva loyloxybu ta n oa te (3a ).
NaBH4 (96 mg, 2.5 mmol) was added to a solution of methyl
2-(N-acetylamino)-3-ketobutanoate (877 mg, 5.1 mmol) in MeOH
(10 mL) at 0 °C. The solution was stirred at room temperature
for 1 h. After NH4Cl solid was added, the mixture was
evaporated under reduced pressure. The residue was passed
through a short silica gel column (AcOEt), giving 730 mg (82%)
of crude methyl 2-(N-acetylamino)-3-hydroxybutanoate. A mix-
ture of the crude product and DMAP (26 mg, 0.22 mmol) was
diluted with THF (8 mL) and Et3N (548 mg, 5.4 mmol). Pivaloyl
chloride (655 mg, 5.4 mmol) was added to the solution at 0 °C.
The mixture was stirred at room temperature for 2 h. After
saturated aqueous NaHCO3 was added, the mixture was ex-
tracted three times with AcOEt. The organic layer was washed
with brine, dried over Na2SO4, and evaporated under reduced
pressure. The residue was purified by flash column chroma-
tography (n-hexane/AcOEt ) 1/1), giving 790 mg (60% from 1a )
of 3a as a mixture of diastereoisomers (erythro/threo ) 82/18).
The mixture was used without further purification: white solid.
erythro-3a : 1H NMR (200 MHz, CDCl3, TMS) δ 1.18 (s, 9 H),
1.34 (d, J ) 6.6 Hz, 3 H), 2.04 (s, 3 H), 3.78 (s, 3 H), 4.81 (dd, J
) 8.4, 3.5 Hz, 1 H), 5.10 (dq, J ) 3.5, 6.6 Hz, 1 H), 6.35 (br d, 1
H). threo-3a : 1H NMR (200 MHz, CDCl3, TMS) δ 1.17 (s, 9 H),
1.26 (d, J ) 6.3 Hz, 3 H), 2.11 (s, 3 H), 3.72 (s, 3 H), 4.83 (dd, J
) 9.3, 3.0 Hz, 1 H), 5.37 (dq, J ) 3.0, 6.3 Hz, 1 H), 6.05 (br d, 1
H).
Meth yl 2-(N-Acetylam in o)-3-pivaloyloxypen tan oate (3b).
In 67% yield (erythro/threo ) 80/20): white solid. erythro-3b:
1H NMR (200 MHz, CDCl3, TMS) δ 0.95 (t, J ) 7.5 Hz, 3 H),
1.19 (s, 9 H), 1.60-1.90 (m, 2 H), 2.03 (s, 3 H), 3.76 (s, 3 H),
4.78-4.96 (m, 2 H), 6.44 (br d, 1 H).
Meth yl 2-(N-Acetylam in o)-3-pivaloyloxyh eptan oate (3c).
In 57% yield (erythro/threo ) 79/21): white solid. erythro-3c:
1H NMR (200 MHz, CDCl3, TMS) δ 0.84-0.95 (m, 3 H), 1.19 (s,
9 H), 1.23-1.42 (m, 4 H), 1.47-1.85 (m, 2 H), 2.03 (s, 3 H), 3.76
(s, 3 H), 4.82 (dd, J ) 8.3, 2.9 Hz, 1 H), 4.98 (ddd, J ) 9.1, 5.0,
2.9 Hz, 1 H), 6.44 (br d, 1 H).
Meth yl (Z)-2-(N-Acetyla m in o)-3-(ter t-bu tyld im eth ylsi-
loxy)-2-p en ten oa te (2e). In 78% yield: white solid; mp 65-
66 °C; 1H NMR (300 MHz, CDCl3, TMS) δ 0.21 and 0.22 (a pair
of s, 6 H), 0.96 and 0.95 (a pair of s, 9 H), 1.13 and 1.18 (a pair
of t, J ) 7.5 and 7.5 Hz, 3 H), 2.04 and 1.86 (a pair of s, 3 H),
2.64 and 2.78 (a pair of q, J ) 7.5 and 7.5 Hz, 2 H), 3.73 (s, 3 H),
6.43 and 6.05 (a pair of br s, 1 H); 13C NMR (75 MHz, CDCl3) δ
-4.0, 12.2 and 11.9 (a pair of s), 18.2, 23.0, 25.5 and 25.3 (a
pair of s), 26.3 and 27.1 (a pair of s), 51.7, 110.9, 162.9, 165.9,
168.5; IR (KBr) 3260, 1734, 1660 cm-1; HRMS(FAB) calcd for
C
14H28NO4Si (M + H)+ 302.1787, found 302.1791.
Meth yl (Z)-2-(N-Acetyla m in o)-3-(ter t-bu tyld im eth ylsi-
loxy)-2-h exen oa te (2f). In 58% yield: white solid; mp 52-54
1
°C; H NMR (300 MHz, CDCl3, TMS) δ 0.20 and 0.21 (a pair of
s, 6 H), 0.93 and 0.99 (a pair of t, J ) 7.5 and 7.2 Hz, 3 H), 0.96
and 0.95 (a pair of s, 9 H), 1.50-1.70 (m, 2 H), 2.04 and 1.86 (a
pair of s, 3 H), 2.61 and 2.75 (a pair of t, J ) 7.7 and 7.8 Hz, 2
H), 3.73 (s, 3H), 6.47 and 6.04 (a pair of br s, 1 H); 13C NMR (75
MHz, CDCl3, TMS) δ -4.0, 13.6 and 13.8 (a pair of s), 18.2, 21.0,
23.0, 25.5, 34.7 and 35.5 (a pair of s), 51.7, 111.7, 161.1, 165.9,
Meth yl 2-(N-Acetyla m in o)-3-p h en yl-3-p iva loyloxyp r o-
p a n oa te (3d ). In 76% yield (erythro/threo ) 90/10): white solid.
erythro-3c: 1H NMR (200 MHz, CDCl3, TMS) δ 1.24 (s, 9 H),
2.00 (s, 3 H), 3.72 (s, 3 H), 5.22 (dd, J ) 8.9, 4.3 Hz, 1 H), 5.94
(br d, 2 H), 6.13 (d, J ) 4.3 Hz, 1 H), 7.25-7.42 (m, 5 H).
Meth yl (E)-2-(N-Acetylam in o)-3-pivaloyloxy-2-bu ten oate
(4a ). tert-Butyl hypochlorite (229 mg, 2.1 mmol) was added to
a solution of 3a (493 mg, 1.9 mmol) in benzene (4 mL). After
the solution was stirred at room temperature for 120 h, DABCO
(256 mg, 2.3 mmol) was added at 0 °C. After being stirred at
room temperature for 3 h, the mixture was filtered through
Celite pad and evaporated under reduced pressure. The residue
was purified by flash column chromatography (n-hexane/AcOEt
) 1/1), giving 351 mg (72%) of 4a : white solid; mp 110-113 °C;
1H NMR (300 MHz, CDCl3, TMS) δ 1.29 (s, 9 H), 1.99 (s, 3 H),
168.4; IR (KBr) 3252, 1734, 1654 cm-1. Anal. Calcd for C15H29
-
NO4Si: C, 57.11; H, 9.27; N, 4.44. Found: C, 56.81; H, 9.12; N,
4.37.
Meth yl (Z)-2-(N-Acetyla m in o)-3-(ter t-bu tyld im eth ylsi-
loxy)-4-m eth oxy-2-bu ten oa te (2g). In 58% yield: pale yellow
solid; mp 63-67 °C; 1H NMR (300 MHz, CDCl3, TMS) δ 0.22 (s,
6 H), 0.95 (s, 9 H), 2.07 (s, 3 H), 3.32 (s, 3 H), 3.76 (s, 3 H), 4.35
(s, 2 H), 6.61 (br s, 1 H); 13C NMR (75 MHz, CDCl3) δ -4.3, 18.4,
22.9, 25.6, 51.9, 57.6, 68.5, 113.3, 153.6, 165.5, 168.3; IR (KBr)

3502 J . Org. Chem., Vol. 63, No. 10, 1998
Notes
2.13 (s, 3 H), 3.72 (s, 3 H), 6.69 and 6.33 (a pair of br s, 1 H); 13
C
Calcd for C15H31NO4Si: C, 56.74; H, 9.84; N, 4.41. Found: C,
57.03; H, 9.83; N, 4.23.
NMR (75 MHz, CDCl3) δ 18.5, 22.9, 26.8, 39.0, 52.1, 117.3, 155.5,
163.5, 169.2, 175.9; IR (KBr) 3312, 1746, 1670 cm-1
.
Anal.
Meth yl (2S,3R)-2-(N-Acetyla m in o)-3-(ter t-bu tyld im eth -
ylsiloxy)-4-m eth oxybu a n oa te (5g). Yellow oil; [R]20D ) +43.6
Calcd for C12H19NO5: C, 56.02; H, 7.44; N, 5.44. Found: C,
55.72; H, 7.49; N, 5.40.
1
(c 1.00, CHCl3); H NMR (300 MHz, CDCl3, TMS) δ 0.065 (s, 3
Meth yl (E)-2-(N-Acetylam in o)-3-pivaloyloxy-2-pen ten oate
(4b). In 69% yield: white solid; mp 87-89 °C; 1H NMR (300
MHz, CDCl3, TMS) δ 1.06 and 1.08 (a pair of t, J ) 7.6 and 7.5
Hz, 3 H), 1.31 and 1.34 (a pair of s, 9 H), 2.12 and 2.00 (a pair
of s, 3 H), 2.40 and 2.51 (a pair of q, J ) 7.6 and 7.5 Hz, 2 H),
3.71 and 3.74 (a pair of s, 3 H), 6.80 and 6.39 (a pair of br s, 1
H); 13C NMR (75 MHz, CDCl3) δ 9.61, 22.8, 24.8, 27.0, 39.1, 52.0,
116.7, 159.0, 163.6, 169.8, 175.8; IR (KBr) 3292, 1756, 1734, 1668
cm-1. Anal. Calcd for C13H21NO5: C, 57.55; H, 7.80; N, 5.16.
Found: C, 57.50; H, 8.05; N, 5.01.
H), 0.069 (s, 3 H), 0.87 (s, 9 H), 2.03 (s, 3 H), 3.36 (s, 3 H), 3.39
(dd, J ) 10.1, 5.9 Hz, 1 H), 3.53 (dd, J ) 10.1, 5.3 Hz, 1 H), 3.75
(s, 3 H), 4.13 (dt, J ) 3.5, 5.6 Hz, 1 H), 4.76 (dd, J ) 8.3, 3.5 Hz,
1 H), 6.38 (br d, 1 H); 13C NMR (75 MHz, CDCl3) δ -5.3, -4.7,
18.0, 23.1, 25.6, 52.2, 55.7, 59.0, 72.1, 74.6, 169.6, 170.4; IR (neat)
3304, 1754, 1662 cm-1. Anal. Calcd for C14H29NO5Si: C, 52.63;
H, 9.14; N, 4.38. Found: C, 52.45; H, 9.41; N, 4.27.
Dieth yl (2S,3S)-2-(N-Acetyla m in o)-3-(ter t-bu tyld im eth -
ylsiloxy)p im ela te (5h ). Colorless oil; [R]20 ) +42.3 (c 1.03,
D
1
CHCl3); H NMR (300 MHz, CDCl3, TMS) δ 0.05 (s, 3 H), 0.06
Meth yl (E)-2-(N-Acetylam in o)-3-pivaloyloxy-2-h epten oate
(4c). In 68% yield: white solid; mp 91-94 °C; 1H NMR (300
MHz, CDCl3, TMS) δ 0.89 (t, J ) 7.3 Hz, 3 H), 1.18-1.53 (m, 4
H), 1.30 (s, 9 H), 2.11 and 2.00 (a pair of s, 3 H), 2.36 and 2.47
(a pair of t, J ) 7.6 and 7.3 Hz, 2 H), 3.71 and 3.73 (a pair of s,
3 H), 6.83 and 6.41 (a pair of br s, 1 H); 13C NMR (75 MHz,
CDCl3) δ 13.7, 22.4, 23.0, 27.0, 27.5, 31.3, 39.1, 52.1, 117.1, 158.7,
(s, 3 H), 0.87 (s, 9 H), 1.26 (t, J ) 7.2 Hz, 3 H), 1.29 (t, J ) 7.1
Hz, 3 H), 1.59-1.83 (m, 4 H), 2.03 (s, 3 H), 2.34 (t, J ) 7.2 Hz,
2 H), 3.94 (dt, J ) 2.7, 6.6 Hz, 1 H), 4.13 (q, J ) 7.1 Hz, 2 H),
4.19 (dq, J ) 10.8, 7.2 Hz, 1 H), 4.25 (dq, J ) 10.8, 7.2 Hz, 1 H),
4.61 (dd, J ) 2.7, 7.7 Hz, 1 H), 6.26 (br d, 1 H); 13C NMR (75
MHz, CDCl3) δ -4.8, -4.6, 14.1, 17.9, 21.1, 23.2, 25.6, 33.8, 34.1,
56.5, 60.2, 61.4, 73.7, 169.4, 169.8, 173.4; IR (neat) 3320, 1740,
1666 cm-1. Anal. Calcd for C19H37NO6Si: C, 56.54; H, 9.24; N,
3.47. Found: C, 56.64; H, 9.52; N, 3.42.
163.6, 169.6, 175.7; IR (KBr) 3296, 1762, 1734, 1668 cm-1
;
HRMS(FAB) calcd for C15H26NO5 (M + H)+ 300.1811, found
300.1815.
Gen er a l P r oced u r e of Asym m etr ic Hyd r ogen a tion of 4.
A solution of [Rh(COD)2]BF4 (1.0 mg, 2.5 µmol) and (R,R)-(S,S)-
PrTRAP (1.8 mg, 2.7 µmol) in 2-propanol (1.0 mL) was stirred
at room temperature for 10 min, and 4 (0.25 mmol) was added.
Immediately, the flask was cooled at -78 °C, successively
evacuated, and filled with hydrogen in the flask. After 24 h of
stirring at 20 °C, the solution was evaporated under reduced
pressure. The residue was purified by flash column chroma-
tography, giving optically active threo-6.
Meth yl (E)-2-(N-Acetyla m in o)-3-p h en yl-3-p iva loyloxy-2-
p r op en oa te (4d ). In 91% yield: white solid; 1H NMR (300
MHz, CDCl3, TMS) δ 1.27 (s, 9 H), 1.99 (s, 3 H), 3.79 (s, 3 H),
6.93 and 6.46 (a pair of br s, 1 H), 7.34-7.47 (m, 5 H); 13C NMR
(75 MHz, CDCl3) δ 22.7, 26.8, 38.9, 52.4, 118.7, 127.8, 128.7,
130.0, 133.3, 148.6, 164.0, 169.2, 175.6.
Gen er a l P r oced u r e of Asym m etr ic Hyd r ogen a tion of 2.
A solution of [Rh(COD)2]ClO4 (4.2 mg, 10 µmol) and (R,R)-(S,S)-
PrTRAP (7.2 mg, 11 µmol) in 1,2-dichloroethane (2.0 mL) was
stirred at room temperature for 10 min, and 2 (1.0 mmol) was
added. Immediately, the flask was cooled at -78 °C, successively
evacuated, and filled with hydrogen in the flask. After 24 h of
stirring at 20 °C, the mixture was directly purified by flash
column chromatography, giving optically active erythro-5.
Meth yl (2S,3S)-2-(N-Acetyla m in o)-3-(d im eth ylth exylsi-
Meth yl (2S,3R)-2-(N-Acetyla m in o)-3-p iva loyloxybu ta n o-
a te (6a ). Colorless oil; [R]20 ) +60.7 (c 1.03, CHCl3). The
D
optical rotation of authentic (2S,3R)-6a was [R]20 ) +61.5 (c
D
1.01, CHCl3). 1H NMR (300 MHz, CDCl3, TMS) δ 1.17 (s, 9 H),
1.26 (d, J ) 6.3 Hz, 3 H), 2.11 (s, 3 H), 3.72 (s, 3 H), 4.83 (dd, J
) 9.3, 3.0 Hz, 1 H), 5.37 (dq, J ) 3.0, 6.3 Hz, 1 H), 6.05 (br d, 1
H); 13C NMR (75 MHz, CDCl3) δ 16.7, 23.1, 27.0, 38.7, 52.6, 55.4,
70.2, 170.4, 170.5, 177.3; IR (neat) 3320, 1756, 1740, 1660. Anal.
Calcd for C12H21NO5: C, 55.58; H, 8.16; N, 5.40. Found: C,
55.36; H, 8.14; N, 5.36.
loxy)bu ta n oa te (5a ). Colorless oil; [R]20 ) +54.3 (c 1.01,
D
1
CHCl3); H NMR (300 MHz, CDCl3, TMS) δ 0.07 (s, 3 H), 0.08
(s, 3 H), 0.82 (s, 3 H), 0.83 (s, 3 H), 0.86 (d, J ) 6.9 Hz, 3 H),
0.87 (d, J ) 6.9 Hz, 3 H), 1.27 (d, J ) 6.5 Hz, 3 H), 1.59 (septet,
J ) 6.9 Hz, 1 H), 2.02 (s, 3 H), 3.75 (s, 3 H), 4.09 (dq, J ) 6.5,
Met h yl (2S,3R)-2-(N-Acet yla m in o)-3-p iva loyloxyp en -
ta n oa te (6b). White solid; mp 49-53 °C; [R]20 ) +73.0 (c
3.3 Hz, 1 H), 4.52 (dd, J ) 8.0, 3.3 Hz, 1 H), 6.22 (br d, 1 H); 13
C
D
1
0.996, CHCl3); H NMR (300 MHz, CDCl3, TMS) δ 0.93 (t, J )
NMR (75 MHz, CDCl3) δ -3.2, -2.7, 18.4, 18.5, 20.0, 20.2, 20.6,
7.5 Hz, 3 H), 1.19 (s, 9 H), 1.57-1.69 (m, 2 H), 2.09 (s, 3 H),
3.72 (s, 3 H), 4.88 (dd, J ) 9.3, 2.7 Hz, 1 H), 5.23 (ddd, J ) 7.5,
6.6, 2.7 Hz, 1 H), 6.00 (br d, 1 H); 13C NMR (75 MHz, CDCl3) δ
9.6, 23.1, 24.3, 27.1, 38.9, 52.6, 53.9, 74.6, 170.3, 170.8, 177.5;
23.1, 24.7, 34.1, 52.0, 58.3, 69.9, 169.4, 170.5; IR (neat) 3304,
1756, 1660 cm-1
. Anal. Calcd for C15H31NO4Si: C, 56.74; H,
9.84; N, 4.41. Found: C, 56.50; H, 10.00; N, 4.28.
Meth yl (2S,3S)-2-(N-Acetyla m in o)-3-(ter t-bu tyld im eth -
IR (KBr) 3308, 1762, 1738, 1658 cm-1
C
.
Anal. Calcd for
13H23NO5: C, 57.12; H, 8.48; N, 5.12. Found: C, 56.95; H, 8.63;
N, 4.84.
ylsiloxy)bu ta n oa te (5b). Colorless oil; [R]20 ) +47.1 (c 0.32,
D
1
CHCl3); H NMR (300 MHz, CDCl3, TMS) δ 0.04 (s, 3 H), 0.05
(s, 3 H), 0.87 (s, 9 H), 1.27 (d, J ) 6.6 Hz, 3 H), 2.03 (s, 3 H),
3.76 (s, 3 H), 4.09 (dq, J ) 3.3, 6.6 Hz, 1 H), 4.53 (dd, J ) 8.3,
3.3 Hz, 1 H), 6.26 (br d, 1 H); 13C NMR (75 MHz, CDCl3) δ -5.2,
-4.7, 17.8, 20.6, 23.2, 25.5, 52.1, 58.3, 69.9, 169.5, 170.6; IR
Met h yl (2S,3R)-2-(N-Acet yla m in o)-3-p iva loyloxyh ep -
ta n oa te (6c). Pale yellow oil; [R]20 ) +69.8 (c 1.02, CHCl3);
D
1H NMR (300 MHz, CDCl3, TMS) δ 0.89 (t, J ) 6.9 Hz, 3 H),
1.19 (s, 9 H), 1.24-1.36 (m, 4 H), 1.51-1.64 (m, 2 H), 2.09 (s, 3
H), 3.71 (s, 3 H), 4.85 (dd, J ) 9.5, 2.7 Hz, 1 H), 5.29 (ddd, J )
7.7, 6.3, 2.7 Hz, 1 H), 5.97 (br d, 1 H); 13C NMR (75 MHz, CDCl3)
δ 13.8, 22.2, 23.1, 27.1, 27.2, 30.7, 38.8, 52.5, 54.2, 73.2, 170.2,
170.8, 177.4; IR (neat) 3320, 1740, 1660 cm-1. Anal. Calcd for
(neat) 3292, 1750, 1660 cm-1
.
Meth yl (2S,3S)-2-(N-Acetyla m in o)-3-(ter t-bu tyld im eth -
ylsiloxy)p en ta n oa te (5e). Colorless oil; [R]20D ) +47.2 (c 1.02,
1
CHCl3); H NMR (300 MHz, CDCl3, TMS) δ 0.05 (s, 3 H), 0.06
(s, 3 H), 0.88 (s, 9 H), 0.98 (t, J ) 7.5 Hz, 3 H), 1.50-1.73 (m, 2
H), 2.03 (s, 3 H), 3.75 (s, 3 H), 3.85 (dt, J ) 3.2, 6.7 Hz, 1 H),
4.67 (dd, J ) 7.8, 3.2 Hz, 1 H), 6.20 (br d, 1 H); 13C NMR (75
MHz, CDCl3) δ -4.8, -4.5, 9.9, 17.9, 23.2, 25.6, 27.2, 52.0, 56.2,
75.4, 169.4, 170.6; IR (neat) 3296, 1750, 1660 cm-1. Anal. Calcd
for C14H29NO4Si: C, 55.41; H, 9.63; N, 4.62. Found: C, 55.14;
H, 9.80; N, 4.57.
C
15H27NO5: C, 59.78; H, 9.03; N, 4.65. Found: C, 59.67; H, 8.96;
N, 4.51.
Meth yl (2S,3R)-2-(N-Acetyla m in o)-3-p iva loyloxy-3-p h en -
ylp r op a n oa te (6d ). White solid; 1H NMR (200 MHz, CDCl3,
TMS) 1.24 (s, 9 H), 1.94 (s, 3 H), 3.69 (s, 3H), 5.10 (dd, J ) 9.4,
4.3 Hz, 1 H), 6.00 (br d, 1 H), 6.23 (d, J ) 4.3 Hz, 1 H), 7.21-
7.49 (m, 5 H).
Meth yl (2S,3S)-2-(N-Acetyla m in o)-3-(ter t-bu tyld im eth -
ylsiloxy)h exa n oa te (5f). Colorless oil; [R]20 ) +49.6 (c 1.00,
Hyd r olysis of er yth r o-(2S,3S)-5a (L-(2S,3S)-a llo-Th r eo-
n in e). A mixture of erythro-(2S,3S)-5a (79 mg, 0.25 mmol, 95%
ee) and 1 N hydrochloric acid (1.0 mL) was heated at 100 °C for
3 h. After evaporation under reduced pressure, the residue was
purified by ion exchange column (Amberlite IR-120B, H+ form),
D
1
CHCl3); H NMR (300 MHz, CDCl3, TMS) δ 0.05 (s, 3 H), 0.06
(s, 3 H), 0.87 (s, 9 H), 0.94 (t, J ) 7.2 Hz, 3 H), 1.25-1.66 (m, 4
H), 2.03 (s, 3 H), 3.75 (s, 3 H), 3.93 (dt, J ) 3.0, 6.5 Hz, 1 H),
4.65 (dd, J ) 7.8, 3.0 Hz, 1 H), 6.22 (br d, 1 H); 13C NMR (75
MHz, CDCl3) δ -4.8, -4.6, 14.0, 17.9, 18.7, 23.2, 25.6, 36.5, 52.1,
56.7, 73.8, 169.4, 170.5; IR (neat) 3304, 1750, 1660 cm-1. Anal.
giving 33 mg (77%) of L-allo-threonine: [R]26 ) +8.5 (c 0.45,
D
H2O), lit.14 [R]24 ) +9.3 (c 3.8, H2O); 1H NMR (300 MHz, D2O,
D

Notes
J . Org. Chem., Vol. 63, No. 10, 1998 3503
1,4-dioxane as external std at δ 3.55) δ 0.61 (d, J ) 6.6 Hz, 3
H), 2.95 (br s, 1 H), 3.62 (br q, 1 H).
Su p p or tin g In for m a tion Ava ila ble: Assignments of
1
stereochemistry of 2, 4, 5, and 6 and H and 13C NMR spectra
of 2e, 2g, and 4c (6 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.
Ack n ow led gm en t. This research is supported by
Ciba-Geigy J apan Limited Award in Synthetic Organic
Chemistry, J apan.
(14) Elliot, D. F. J . Chem. Soc. 1950, 62.
J O9722717