Asymmetric synthesis of α-amino acids based on carbon radical addition to glyoxylic oxime ether

Article abstract of DOI:10.1021/jo991353n

The first asymmetric synthesis of α-amino acids based on diastereoselective carbon radical addition to glyoxylic imine derivatives is reported. The addition of an isopropyl radical, generated from i-PrI, Bu₃SnH, and Et₃B in CH₂Cl₂ at 25 °C, to achiral glyoxylic oxime ether 1 proceeded regioselectively at the imino carbon atom of the oxime ether group to give an excellent yield of the C-isopropylated product 2. The competitive reaction using glyoxylic oxime ether 1 and aldoxime ether 4 showed that the reactivity of the glyoxylic oxime ether toward nucleophilic carbon radicals was enhanced by the presence of a neighboring electron-withdrawing substituent. Thus, the alkyl radical addition to glyoxylic oxime ether 1 proceeded smoothly even at -78 °C, in contrast to the unactivated aldoxime ether 4. A high degree of stereocontrol in the carbon radical addition to the glyoxylic oxime ether was achieved by using Oppolzer's camphorsultam as a chiral auxiliary. The stannyl radical-mediated reaction of the camphorsultam derivative 6 with an isopropyl radical at -78 °C afforded a 96:4 diastereomeric mixture, 7a, of the C-isopropylated product. The reductive removal of the benzyloxy group of the major diastereomer (R)-7a, by treatment with Mo(CO)₆ and the subsequent removal of the sultam auxiliary by standard hydrolysis, afforded the enantiomerically pure D-valine (R)-12 without any loss of stereochemical purity. To evaluate the new methodology, a variety of alkyl radicals were employed in the addition reaction which gave the alkylated products 7 with excellent diastereoselectivity, allowing access to a wide range of enantiomerically pure natural and unnatural α-amino acids. Even in the absence of Bu₃SnH, treatment of 6 with alkyl iodide and Et₃B at 20 °C gave the C-alkylated products 7 with moderate diastereoselectivities. The use of Et₂Zn as a radical initiator, instead of Et₃B, was also effective for the radical reaction. The enantioselective isopropyl radical addition to 1 using (R)-(+)-2,2'-isopropylidenebis(4-phenyl-2-oxazoline) and MgBr₂ gave excellent chemical yield of the valine derivative 2 in 52% ee.

Full text of DOI:10.1021/jo991353n

176
J . Org. Chem. 2000, 65, 176-185
Asym m etr ic Syn th esis of r-Am in o Acid s Ba sed on Ca r bon Ra d ica l
Ad d ition to Glyoxylic Oxim e Eth er
Hideto Miyabe, Chikage Ushiro, Masafumi Ueda, Kumiko Yamakawa, and Takeaki Naito*
Kobe Pharmaceutical University, Motoyamakita, Higashinada, Kobe 658-8558, J apan
Received August 25, 1999
The first asymmetric synthesis of R-amino acids based on diastereoselective carbon radical addition
to glyoxylic imine derivatives is reported. The addition of an isopropyl radical, generated from
i-PrI, Bu3SnH, and Et3B in CH2Cl2 at 25 °C, to achiral glyoxylic oxime ether 1 proceeded
regioselectively at the imino carbon atom of the oxime ether group to give an excellent yield of the
C-isopropylated product 2. The competitive reaction using glyoxylic oxime ether 1 and aldoxime
ether 4 showed that the reactivity of the glyoxylic oxime ether toward nucleophilic carbon radicals
was enhanced by the presence of a neighboring electron-withdrawing substituent. Thus, the alkyl
radical addition to glyoxylic oxime ether 1 proceeded smoothly even at -78 °C, in contrast to the
unactivated aldoxime ether 4. A high degree of stereocontrol in the carbon radical addition to the
glyoxylic oxime ether was achieved by using Oppolzer’s camphorsultam as a chiral auxiliary. The
stannyl radical-mediated reaction of the camphorsultam derivative 6 with an isopropyl radical at
-78 °C afforded a 96:4 diastereomeric mixture, 7a , of the C-isopropylated product. The reductive
removal of the benzyloxy group of the major diastereomer (R)-7a , by treatment with Mo(CO)6 and
the subsequent removal of the sultam auxiliary by standard hydrolysis, afforded the enantiomeri-
cally pure D-valine (R)-12 without any loss of stereochemical purity. To evaluate the new
methodology, a variety of alkyl radicals were employed in the addition reaction which gave the
alkylated products 7 with excellent diastereoselectivity, allowing access to a wide range of
enantiomerically pure natural and unnatural R-amino acids. Even in the absence of Bu3SnH,
treatment of 6 with alkyl iodide and Et3B at 20 °C gave the C-alkylated products 7 with moderate
diastereoselectivities. The use of Et2Zn as a radical initiator, instead of Et3B, was also effective for
the radical reaction. The enantioselective isopropyl radical addition to 1 using (R)-(+)-2,2′-
isopropylidenebis(4-phenyl-2-oxazoline) and MgBr2 gave excellent chemical yield of the valine
derivative 2 in 52% ee.
In tr od u ction
reactions based on the intermolecular carbon radical
addition to a carbon-nitrogen double bond of acyclic
imine derivatives.
The control of stereochemistry in free radical mediated
reactions has been of great importance to organic syn-
thesis.1 Hence, in recent years, a high degree of stereo-
control in radical reactions has been achieved, mainly in
the radical conjugate addition to the carbon-carbon
double bond of R,â-unsaturated carbonyl compounds, the
radical allyl-transfer reaction using allylstannane, the
reduction of alkyl halides using tributyltin hydride, and
so on.2-9 Asymmetric induction, particularly in the
carbon-carbon bond-forming radical reactions of acyclic
systems, is a subject of current interest.1 We are inter-
ested in the stereocontrol of carbon-carbon bond-forming
Among the different types of radical acceptors contain-
ing a carbon-nitrogen double bond, the oxime ethers are
well-known to be excellent radical acceptors because of
the extra stabilization of the intermediate alkoxyaminyl
radical provided by the lone pair on the adjacent oxygen
atom.10 However, studies on the radical reaction of oxime
ethers have concentrated on intramolecular reactions,10
and the difficulty in achieving the intermolecular con-
(5) (a) Guindon, Y.; Denis, R. C. Tetrahedron Lett. 1998, 39, 339-
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10.1021/jo991353n CCC: $19.00 © 2000 American Chemical Society
Published on Web 12/16/1999

Asymmetric Synthesis of R-Amino Acids
J . Org. Chem., Vol. 65, No. 1, 2000 177
struction of a carbon-carbon bond has remained un-
resolved.11-13 Therefore, stereoselective carbon-carbon
bond formation based on the intermolecular carbon
radical addition to oxime ethers is a challenging and
promising task. Hart’s group reported the first studies
on intermolecular alkyl radical additions to unhindered
O-benzylformaldoxime ethers.11a Recently, intermolec-
ular radical-mediated acylation using an R-sulfonyl oxime
ether has been reported by Kim’s group.12 In the course
of our investigations of the intramolecular radical reac-
tion of oxime ethers,14 we have succeeded in the develop-
ment of new efficient carbon-carbon bond-forming re-
actions based on intermolecular radical additions to BF3-
activated aldoxime ethers.15 This procedure is particularly
useful for the synthesis of a variety of primary amines
because of the exceptional tolerance of the functional
groups, such as aromatic heterocycle, alcohol, acetal,
ester, and amide moieties. We report here, in detail, the
diastereofacial stereocontrol in the carbon radical addi-
tion to Oppolzer’s camphorsultam derivatives of glyoxylic
oxime ethers.16 This reaction is the first reported example
of stereocontrol in the intermolecular carbon radical
addition to glyoxylic imine derivatives and is a convenient
method for preparing a wide range of enantiomerically
enriched R-amino acids.17,18
Resu lts a n d Discu ssion
Ca r bon Ra d ica l Ad d ition to Glyoxylic Oxim e
Eth er s. Glyoxylic imine derivatives are convenient start-
ing materials for the synthesis of natural and unnatural
R-amino acids and related compounds through ene reac-
tions, cycloadditions, or the nucleophilic additions of
organometallic reagents or enolate anion equivalents.19,20
Because glyoxylic imines have three electrophilic centers,
the nucleophilic addition of traditional organometallic
reagents takes place nonregioselectively at the imino
carbon and nitrogen atoms of the carbon-nitrogen double
bond, to give a mixture of C- and N-alkylated products.21
The few known examples of the regioselective nucleo-
philic addition of organometallic reagents to the imino
carbon atom of glyoxylic imines are limited to methods
using allyl zinc, stannane, or boron reagents and alkenyl/
aryl boronic acids.22-24 These reactions proceed under
mild conditions to give the corresponding R-amino acids
in high yield with high levels of stereoselectivity; how-
ever, it is important to note that aliphatic R-amino acids
would not be readily synthesized by applying these
methods. Thus, we have explored the intermolecular
carbon radical addition to glyoxylic oxime ethers as an
alternative synthetic route to allow ready access to a wide
range of aliphatic R-amino acids (Figure 1).25
Prior to exploring issues of stereocontrol, we investi-
gated the regioselectivity in the intermolecular carbon
radical addition to achiral glyoxylic oxime ether 1.26 At
first, we examined the addition of an isopropyl radical
to oxime ether 1 (Scheme 1). The reaction was run in
dichloromethane at 25 °C for 5 min by the use of i-PrI
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178 J . Org. Chem., Vol. 65, No. 1, 2000
Miyabe et al.
Sch em e 2
F igu r e 1. Radical addition to glyoxylic oxime ether.
withdrawing substituent, which would lower the LUMO
energy of the oxime ether as a radical acceptor.28 Thus,
the alkyl radical addition to glyoxylic oxime ether 1
proceeded smoothly even at -78 °C, in contrast to the
unactivated aldoxime ether 4.
Sch em e 1
Dia ster eoselective Ca r bon Ra d ica l Ad d ition to
Ca m p h or su lt a m Der iva t ive of Glyoxylic Oxim e
Eth er . Recent reports elucidate that control of the
stereochemistry is possible in free radical reactions, even
those found in acyclic systems.1-9 Of the chiral auxiliaries
used in acyclic systems, Oppolzer’s camphorsultam,
which is commercially available in both enantiomers and
is easily removed after use, has been employed exten-
sively in ionic and thermal cycloaddition reactions.30-33
We selected Oppolzer’s camphorsultam derivative of
glyoxylic oxime ether 6 as a radical acceptor which would
be flexible enough to allow access to a wide range of
natural and unnatural R-amino acids. Additionally, cam-
phorsultam derivative 6 was recently used in the asym-
metric synthesis of R-allylated R-amino acids by using
allyl zinc reagents.22 Therefore, we also expected that the
direct comparison of the radical reactions of 6 with the
related ionic reactions would lead to informative and
instructive suggestions regarding stereoselection in the
addition reactions.
(5.0 equiv), Bu3SnH (2.5 equiv), and commercially avail-
able 1.0 M solution of Et3B in hexane (5.0 equiv) as a
radical initiator. As expected, the radical addition took
place regioselectively at the imino carbon to give the
desired C-isopropylated product 2 in 79% yield.27 This is
a representative example of an aliphatic R-amino acid
derivative, which would be difficult to prepare by the
nucleophilic addition involving organometallic re-
agents.21-24 Only an 8% yield of the C-ethylated product
3 was formed as the result of a competitive reaction with
the ethyl radical generated from Et3B and O2. We could
not detect N-alkylated products, which may be formed
by the Michael-type addition reaction of an alkyl radical
to the imino nitrogen atom of oxime ether 1. These results
suggest that the radical addition to glyoxylic oxime ethers
is not only a highly promising approach to the synthesis
of R-amino acids but also complements the nucleophilic
addition of organometallic reagents.
To learn about the intermolecular reactivity of oxime
ether 1 with nucleophilic carbon radicals, we carried out
competitive reactions employing two types of oxime
ethers, 1 and 4 (Scheme 2). Treatment of a 1:1 mixture
of glyoxylic oxime ether 1 and aldoxime ether 415 with
i-PrI (1.1 equiv), Bu3SnH (1.1 equiv), and Et3B (1.1 equiv)
in CH2Cl2 at -78 °C for 30 min gave the isopropylated
product 2 (78% yield) and the ethylated product 315 (13%
yield) with no detection of the other possible adduct, 5.
Thus, the addition of an alkyl radical to 4 did not take
place, and 90% of the starting compound 4 was recovered.
In our more recent studies, we also found that the alkyl
radical addition to aldoxime ether 4 proceeded smoothly
in the presence of BF3‚OEt2 to give the alkylated benzyl-
oxyamines in high yields.15 These results show that the
reactivity of glyoxylic oxime ether 1 toward nucleophilic
carbon radicals is enhanced by the neighboring electron-
Compound 6 was readily prepared by treatment of
oxime ether 1 with the commercially available (1R)-(+)-
2,10-camphorsultam in the presence of trimethyl alumi-
num in boiling dichloroethane in 90% yield as a single E
isomer (Scheme 3).29 The reaction of 6 with i-PrI,
Bu3SnH, and Et3B in CH2Cl2 at 20 °C proceeded smoothly
to give an 86:14 diastereomeric mixture of the desired
(28) (a) Kim, S.; Yoon, K. S.; Kim, Y. S. Tetrahedron 1997, 53, 73-
80. (b) Kim, S.; Kim, Y.; Yoon, K. S. Tetrahedron Lett. 1997, 38, 2487-
2490.
(29) In general, the signals due to the imino hydrogen of the E-oxime
ether are shifted downfield by the influence of the alkoxy group of the
oxime ether moiety. See: McCarty, C. G. In The Chemistry of
Functional Groups; The chemistry of the carbon-nitrogen double bond;
Patai, S., Ed.; J ohn Wiley: New York, 1970; pp 383-392.
(30) For some reviews, see: (a) Kim, B. H.; Curran, D. P. Tetrahe-
dron 1993, 49, 293-318. (b) Oppolzer, W. Pure Appl. Chem. 1990, 62,
1241-1250. (c) Oppolzer, W. Pure Appl. Chem. 1988, 60, 39-48. (d)
Oppolzer, W. Tetrahedron 1987, 43, 1969-2004.
(31) For selected examples, see: (a) Oppolzer, W.; Tamura, O.;
Deerberg, J . Helv. Chim. Acta 1992, 75, 1965-1978. (b) Oppolzer, W.;
Tamura, O.; Sundarababu, G.; Signer, M. J . Am. Chem. Soc. 1992,
114, 5900-5902. (c) Oppolzer, W.; Bienayme´, H.; Genevois-Borella, A.
J . Am. Chem. Soc. 1991, 113, 9660-9661.
(32) For selected recent examples, see: (a) Brzezinski, L. J .; Rafel,
S.; Leahy, J . W. J . Am. Chem. Soc. 1997, 119, 4317-4318. (b) Mish,
M. R.; Guerra, F. M.; Carreira, E. M. J . Am. Chem. Soc. 1997, 119,
8379-8380. (c) Oppolzer, W.; Froelich, O.; Wiaux-Zamar, C.; Bernar-
dinelli, G. Tetrahedron Lett. 1997, 38, 2825-2828. (d) Ho, G.-J .;
Mathre, D. J . J . Org. Chem. 1995, 60, 2271-2273.
(33) For selected examples, see: (a) J ezewski, A.; Chajewska, K.;
Wielogo´rski, Z.; J urczak, J . Tetrahedron: Asymmetry 1997, 8, 1741-
1749. (b) Bauer, T. Tetrahedron: Asymmetry 1996, 7, 981-984. (c)
Bauer, T.; Chapuis, C.; J ezewski, A.; Kozak, J .; J urczak, J . Tetrahe-
dron: Asymmetry 1996, 7, 1391-1404.
(26) Glyoxylic oxime ether 1 was prepared by the treatment of
commercially available methyl 2-hydroxy-2-methoxyacetate with ben-
zyloxyamine hydrochloride in the presence of sodium acetate in
methanol. Oxime ether 1 was obtained as a single E isomer with
respect to the geometry of the oxime ether group. See: ref 15b.
(27) For the complete reaction, the excesses of reagents were
employed. The reactions were run without any special precautions such
as drying, degassing, or purification of solvents and reagents. The
reaction would proceed as follows: (1) The stannyl radical, generated
from Bu3SnH and Et3B, reacted with i-PrI to generate an isopropyl
radical. (2) The isopropyl radical then intermolecularly attacked
glyoxylic oxime ether 1 to afford the intermediate benzyloxyaminyl
radical as shown in Figure 1.

Asymmetric Synthesis of R-Amino Acids
J . Org. Chem., Vol. 65, No. 1, 2000 179
Ta ble 2. Isop r op yl Ra d ica l Ad d ition to 6
Sch em e 3
product 7a
product 7b
entry methoda yield (%)b selectivityc yield (%)b selectivityc
1
2
3
A
B
C
28
66
94:6
80:20
48
93:7
no reaction
a
Methods A-C. Reagents and conditions: Method A, i-PrI (5.0
equiv), (Me3Si)3SiH (2.5 equiv), Et3B (5.0 equiv), CH2Cl2, -78 °C.;
Method B, i-PrI (3.5 equiv), Bu3SnH (2.2 equiv), AIBN (0.2 equiv),
toluene, reflux.; Method C, i-PrI (3.5 equiv), Bu3SnH (2.2 equiv),
b
9-BBN (5.0 equiv), CH2Cl2, 20 °C. Isolated yields of major
diastereomer 7a ,b. c Diastereoselectivities were determined by 1H
NMR analysis.
is an effective Lewis acid for the activation of the carbon-
nitrogen double bond of oxime ethers in radical reac-
tions.15 The current observations suggest that oxime
ether 6 would be activated by BF3‚OEt2. Additionally,
CH2Cl2 and toluene were found to be most effective as
solvents for the present radical reaction.
Next, we examined the addition of an isopropyl radical
to 6 under different reaction conditions. Treatment of 6
with i-PrI (5.0 equiv) and Et3B (5.0 equiv) in the presence
of (Me3Si)3SiH (2.5 equiv) gave a 94:6 diastereomeric
mixture of 7a in 28% combined yield along with a
significant amount of the ethylated product 7b (Table 2,
entry 1). From the result, it was ascertained that the use
of Bu3SnH is effective to achieve successful alkylation.
Low diastereoselectivity was observed in the reaction of
6 with i-PrI and Bu3SnH in the presence of AIBN (0.2
equiv) in boiling toluene to afford an 80:20 diastereomeric
mixture of 7a in 66% yield (Table 2, entry 2). Because
9-BBN has been reported to potentially induce a stannyl
radical-mediated reaction,34 we attempted the reaction
using i-PrI, Bu3SnH, and 9-BBN as a radical initiator,
which however, did not proceed (Table 2, entry 3). Thus,
both the stannyl radical-mediated generation of an alkyl
radical from Et3B and a low reaction temperature are
important for obtaining high selectivity.
Ta ble 1. Isop r op yl Ra d ica l Ad d ition to 6 by u sin g Et3Ba
entry Lewis acidb
solvent
CH2Cl2
CH2Cl2
toluene
Et2O
T (°C) yieldc (%) selectivityd
1
2
3
4
+20
-78
-78
-78
-78
-78
-78
76
73
74
71
80
57
81
73
74
72
86:14
94:6
93:7
96:4
96:4
90:10
94:6
91:9
92:8
86:14
5
6
BF3‚OEt2 CH2Cl2
Et2AlCl
CH2Cl2
CH2Cl2
CH2Cl2, THF -78
CH2Cl2 -78
CH2Cl2, THF -78
7
8
9
10
Zn(OTf)2
Zn(OTf)2
Yb(OTf)3
Yb(OTf)3
a
All reactions were carried out with i-PrI (5.0 equiv), Bu3SnH
b
(2.5 equiv), and Et3B (5.0 equiv). 2 equiv of Lewis acid was used.
c Isolated yields of major diastereomer 7a ; A small amount of the
d
ethylated product 7b was also obtained. Diastereoselectivities
were determined by 1H NMR analysis.
The absolute configuration at the newly formed ste-
reocenter of the major product of mixture 7a was
determined to be R by converting the diastereomerically
pure major isomer of 7a into the authentic N-Cbz-D-
valine 11 (Scheme 4).35 The reductive cleavage of the
N-O bond of (R)-7a by treatment with Mo(CO)6 in boiling
CH3CN/H2O gave the amine hydrochloride (R)-9 in 88%
yield.36 The amine was protected as the N-Cbz derivative
(R)-10 in 92% yield by treatment with CbzCl. Mild
hydrolysis of (R)-10 with LiOH in THF/H2O afforded the
enantiomerically pure N-Cbz-D-valine (R)-11 in 73%
yield, which was found to be identical to an authentic
sample, upon comparison of their spectral data and
optical rotations.35 D-Valine (R)-12 itself was also ob-
tained by the reductive removal of the benzyloxy group
of (R)-7a followed by the subsequent removal of the
sultam auxiliary by standard hydrolysis without any loss
of stereochemical purity. It is noteworthy that the
absolute stereochemical couse of the radical addition to
the oxime ether 6 is the same as that for the allylation
by the addition of zinc reagents to 6.22
C-alkylated product 7a accompanied by a small amount
of the C-ethylated product 7b (Table 1, entry 1). Dia-
stereoselectivity was determined by 1H NMR analysis of
the alkylated products obtained after rough purification
to remove the tin residue from the reaction mixture.
Diastereomer 7a could be separated and purified by
preparative TLC to afford the pure major isomer in 76%
yield. To optimize the reaction conditions, we then
investigated the effect of temperature, solvent, and Lewis
acid on the reaction. The degree of stereoselectivity was
shown to be dependent on the reaction temperature; thus,
changing the temperature from +20 to -78 °C led to a
moderate increase in diastereoselectivity to 94:6 (Table
1, compare entry 1 with entry 2). The replacement of
CH2Cl2 with Et2O as a solvent led to higher selectivity
(Table 1, entry 4). These diastereoselectivities were
comparable to or better than that obtained by the known
addition of allyl zinc reagents to glyoxylic oxime ether
6.22 Curran has shown that high levels of stereoselectivity
can be obtained in the reaction of chiral R-carbonyl
radicals derived from camphorsultam.8 We have now
demonstrated that high stereoselectivity can be achieved
in radical additions to the R-imino carbon atom on a
camphorsultam derivative of oxime ether 6. Although the
addition of Lewis acids as an additive did not dramati-
cally influence the degree of stereoselectivity, the pres-
ence of BF3‚OEt2 in CH2Cl2 slightly enhanced chemical
yields (Table 1, entry 5). We have reported that BF3‚OEt2
(34) Perchyonok, V. T.; Schiesser, C. H. Tetrahedron Lett. 1998, 39,
5437-5438.
(35) (a) Oki, K.; Suzuki, K.; Tuchida, S.; Saito, T.; Kotake, H. Bull.
Chem. Soc. J pn. 1970, 43, 2554-2558. (b) Sarges, R.; Witkop, B. J .
Am. Chem. Soc. 1965, 87, 2020-2027.
(36) (a) Cicchi, S.; Goti, A.; Brandi, A.; Guarna. A.; De Sarlo, F.
Tetrahedron Lett. 1990, 31, 3351-3354. (b) Nitta, M.; Kobayashi, T.
J . Chem. Soc., Perkin Trans. 1 1985, 1401-1406.

180 J . Org. Chem., Vol. 65, No. 1, 2000
Miyabe et al.
Sch em e 4
Sch em e 5
Ta ble 3. Dia ster eoselective Alk yl Ra d ica l Ad d ition to 6a
Lewis
acidb
product
entry
RI
solvent (% yieldc) selectivityd
halides as alkyl radical precursors. As was expected from
the nature of the radical reaction, alkyl iodides containing
an ester moiety or a chlorine atom underwent the
addition reactions to give the corresponding functional-
ized R-amino acid derivatives (R)-7g and (R)-8 in 41 and
15% yields, respectively (Table 3, entries 10 and 11). In
the case of 1-chloro-3-iodopropane, the proline derivative
(R)-8 was obtained as a result of the concomitant in-
tramolecular N-alkylation of (R)-7h which was formed
as an intermediate.
1
2
3
4
5
6
7
8
9
EtI
EtI
Et2O
BF3‚OEt2 CH2Cl2 7b (80)
Et2O
7c (25)e
BF3‚OEt2 CH2Cl2 7c (83)e
Et2O
7d (39)e
BF3‚OEt2 CH2Cl2 7d (83)e
7b (54)
96:4
95:5
>98:2
>98:2
97:3
t-BuI
t-BuI
i-BuI
i-BuI
c-HexylI
c-HexylI
s-BuI
AcO(CH2)4I
Cl(CH2)3I
97:3
Et2O
7e (74)e
96:4
BF3‚OEt2 CH2Cl2 7e (86)e
CH2Cl2 7f (69)e
96:4
>98:2
>98:2
>98:2
10
11
CH2Cl2 7g (41)f
CH2Cl2 8 (15)f
Ch ir a l Lew is Acid -Ca ta lyzed En a n tioselective
Ca r bon Ra d ica l Ad d ition to Glyoxylic Oxim e Eth er .
We next investigated the enantioselective radical addi-
tion to oxime ether 1 in the presence of chiral Lewis acids
(Scheme 5). Several combinations of chiral ligands and
Lewis acids were initially evaluated. The isopropyl radi-
cal addition to 1 was run in CH2Cl2 at -78 °C by using
i-PrI, Bu3SnH, and Et3B in the presence of chiral ligand
and Lewis acid, and then the enantiomeric purity of 2
was checked by chiral column chromatography (Chiral
Pack OJ column) eluting with ethanol/hexane (15:85, v/v).
The results obtained by using (R)-(+)-2,2′-isopropylidene-
bis(4-phenyl-2-oxazoline) as a chiral ligand are shown in
Table 4. Excellent chemical yield and moderate enantio-
selectivity were obtained when a stoichiometric amount
of a chiral ligand and MgBr2 in CH2Cl2 was employed
(Table 4, entry 4). In this combination, the replacement
of CH2Cl2 with toluene or diethyl ether as a solvent led
to lower selectivity (Table 4, entries 5 and 6). The
absolute configuration at the stereocenter of the major
enantiomer was determined to be R by converting the
adduct 2 into the MTPA derivative 13. Hydrogenolysis
of the benzyloxyamino group of 2 in the presence of
Pd(OH)2 in MeOH followed by N-acylation of the result-
ing crude amine with (R)-2-methoxy-2-(trifluoromethyl)-
phenylacetyl ((-)-MTPA) chloride afforded the MTPA
derivative 13. A re face radical addition to complex A
accounts for the observed absolute configuration of the
product 2.
a
All reactions were carried out with RX (5.0 equiv), Bu3SnH
b
(2.5 equiv), and Et3B (5.0 equiv) at -78 °C. 2 equiv of Lewis acid
was used. c Isolated yields of major diastereomer (R)-7b-8. Dia-
d
stereoselectivities were determined by 1H NMR analysis. e A small
amount of the ethylated product 7b was also obtained. f A sub-
stantial amount of the ethylated product 7b was obtained in 55%
(entry 10) and 69% (entry 11) yields, respectively.
Excellent chemical yield and high diastereoselectivity
were also obtained in the addition of different radical
precursors to 6 (Table 3).37 The reaction was run in
CH2Cl2 or Et2O at -78 °C for 30 min by the use of RI
(5.0 equiv), Bu3SnH (2.5 equiv), and commercially avail-
able 1.0 M solution of Et3B in hexane (5.0 equiv). Not
only did the secondary alkyl radicals, such as sec-butyl
and cyclohexyl radicals, work well, but the bulky tert-
butyl in CH2Cl2 radical also worked well (Table 3, entries
3-9). Modest chemical yields were obtained in reactions
using functionalized primary alkyl radicals such as
4-acetoxybutyl and 3-chloropropyl radicals because of the
competitive formation of a significant amount of the
ethylated byproduct 7b (Table 3, entries 10 and 11).
Expecting that the addition of radicals generated from
multifunctionalized precursors would yield products that
would serve as more synthetically useful building blocks,
we investigated the reaction employing bifunctional
(37) The absolute configuration of major products 7b-g and 8 was
assigned to have R-configuration since their 1H NMR data were similar
to that of (R)-7a .

Asymmetric Synthesis of R-Amino Acids
J . Org. Chem., Vol. 65, No. 1, 2000 181
Ta ble 4. En a n tioselective Isop r op yl Ra d ica l Ad d ition to
1a
Ta ble 5. Eth yl Ra d ica l Ad d ition to 6a
product 7b
entry
Lewis acidb
solvent
yield (%)c
ee (%)d
config
entry
initiator
solvent
T (°C) yield (%)b
selectivityc
1
2
3
4
5
6
Zn(OTf)2
Yb(OTf)3
Mg(OTf)2
MgBr2
MgBr2
MgBr2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Et2O
73
92
85
97
98
98
10
24
2
52
13
10
R
R
R
R
R
R
1
2
3
4
5
6
7
8
9
Et3B
Et3B
Et3B
Et3Zn
Et3Zn
Et2Zn
Et2Zn
Me2Zn
Me2Zn
Me2Zn
CH2Cl2
CH2Cl2
toluene
CH2Cl2
CH2Cl2
toluene
toluene
CH2Cl2
toluene
toluene
+20
-78
-78
+20
-78
+20
-78
-78
+20
-78
82
99
98
76
84
83
99
89:11
94:6
93:7
79:21
92:8
69:31
86:14
toluene
a
All reactions were carried out with i-PrI (10 equiv), Bu3SnH
no reaction (71)d
no reaction (73)d
no reaction (99)d
b
(5 equiv), and Et3B (10 equiv). 1 equiv amounts of Lewis acid
and of chiral ligand were used. c Isolated yields. Stereoselectivi-
d
10
ties were determined by chiral HPLC analysis using Chiralcel OJ
(Daicel Chemical Industries, LTD.) eluting with ethanol/hexane
(15:85, v/v).
a
All reactions were carried out with radical initiator (5.0 equiv).
Combined yields of diastereomers. c Diastereoselectivities were
b
determined by 1H NMR analysis. Yields in parentheses are for
d
Sch em e 6
the recovered starting material.
Sch em e 7
79:21 diastereomeric mixture of 7b was obtained in 76%
yield (Table 5, entry 4). Although the use of Et2Zn led to
a small decrease in diastereoselectivity, it is noteworthy
that the reaction proceeded even at -78 °C (Table 5,
entries 5 and 7). These observations suggest that Et2Zn
acts as well as Et3B in its utility as a radical initiator,
Lewis acid, and radical terminator. Surprisingly, the
reaction using Me2Zn did not take place and the starting
compound 6 was recovered (Table 5, entries 8-10).
We next investigated the isopropyl radical addition to
oxime ether 6 using i-PrI and Et3B or Et2Zn in the
absence of Bu3SnH (Scheme 7). Treatment of 6 with i-PrI
(10 equiv) and Et3B (2.5 equiv) in the absence of Bu3SnH
gave a 93:7 diastereomeric mixture of 7a in 35% com-
bined yield, along with a significant amount of the
ethylated product 7b (Table 6, entry 1). The formation
of the isopropylated product 7a was found to be depend-
ent on the reaction temperature. Thus, changing the
temperature from -78 °C to +20 °C led to an effective
increase in the yield of 7a (Table 6, entry 2). These results
indicate that the reaction proceeded effectively at 20 °C
via a route involving the iodine atom-transfer process
between the isopropyl iodide and the ethyl radical gener-
ated from Et3B;40 the predominant addition of the more
nucleophilic and stable isopropyl radical was observed.
Although the reaction proceeded with moderate dia-
stereoselectivity, the major diastereomer (R)-7a could be
easily isolated by preparative TLC. Therefore, this radical
reaction has a tremendous practical advantage over the
stannyl radical-induced reaction, which requires tedious
workup to remove the tin residues from the reaction
Ca r bon Ra d ica l Ad d ition in th e Absen ce of Tin
Hyd r id e. Free radical synthetic methods largely relied
on toxic organomercury or organotin chemistry. From
economical and ecological points of view, we next inves-
tigated the radical addition to oxime ether 6 in the
absence of Bu3SnH (Scheme 6).38 Recently, Ryu and
Komatsu reported that a diethylzinc-air system can
serve as an initiator of tin hydride-mediated radical
reaction.39 To test the viability of Et3B and Et2Zn, we first
investigated the simple addition of an ethyl radical,
generated from Et3B or Et2Zn and O2, to oxime ether 6
(Table 5). In the absence of Bu3SnH, treatment of 6 with
Et3B (5.0 equiv) in CH2Cl2 at 20 °C for 5 min gave an
89:11 diastereomeric mixture of 7b in 82% yield (Table
5, entry 1). Changing the temperature from +20 to -78
°C led to a moderate increase in diastereoselectivity to
94:6 (Table 5, compare entry 1 with entry 2). The
replacement of CH2Cl2 with toluene as a solvent was also
effective for the reaction (Table 5, entry 3). A com-
mercially available 1.0 M solution of Et2Zn in hexane was
added to a solution of oxime ether 6 in CH2Cl2, and then
the reaction mixture was stirred at 20 °C for 5 min. A
(38) We recently reported that the treatment of 1 with RI and Et3B
is an effective method for the synthesis of R-amino acids when the
stable tertiary and secondary alkyl radicals were employed. In this
reaction, Et3B acts multiply as a radical initiator, a Lewis acid, and a
radical terminator by trapping the intermediate benzyloxyaminyl
radical. Therefore, more than a stoichiometric amount of Et3B is
required. See: ref 17b.
(40) (a) Nozaki, K.; Oshima, K.; Utimoto, K. Bull. Chem. Soc. J pn.
1991, 64, 403-409. (b) Miura, K.; Ichinose, Y.; Nozaki, K.; Fugami,
K.; Oshima, K.; Utimoto, K. Bull. Chem. Soc. J pn. 1989, 62, 143-147.
(39) Ryu, I.; Araki, F.; Minakata, S.; Komatsu, M. Tetrahedron Lett.
1998, 39, 6335-6336.

182 J . Org. Chem., Vol. 65, No. 1, 2000
Ta ble 6. Isop r op yl Ra d ica l Ad d ition to 6 via Iod in e Atom -Tr a n sfer P r ocessa
product 7a
selectivityc
Miyabe et al.
product 7b
entry
initiator
solvent
T (°C)
yield (%)b
yield (%)b
selectivityc
1
2
3
4
5
6
7
8
Et3B
Et3B
Et3B
Et3B
Et3Zn
Et2Zn
Et2Zn
Et2Zn
CH2Cl2
CH2Cl2
toluene
toluene
CH2Cl2
CH2Cl2
toluene
toluene
-78
+20
-78
+20
-78
+20
-78
+20
35
78
51
78
19
75
26
64
93:7
53
13
41
16
66
18
65
19
92:8
87:13
90:10
89:11
95:5
88:12
95:5
87:13
90:10
89:11
95:5
88:12
94:6
86:14
86:14
a
b
All reactions were carried out with i-PrI (10 equiv) and radical initiator (2.5 equiv). Combined yields of diastereomers.
c Diastereoselectivities were determined by 1H NMR analysis.
Sch em e 8
Ta ble 7. Alk yl Ra d ica l Ad d ition to 6 via Iod in e
Atom -Tr a n sfer P r ocessa
yield
entry
RX
c-HexylI Et3B
s-BuI Et3B
c-HexylI Et3B
s-BuI Et3B
c-HexylI Et2Zn
s-BuI Et2Zn
initiator solvent product (%)b selectivityc
1
2
3
4
5
6
CH2Cl2
CH2Cl2
toluene
toluene
toluene
toluene
7e
7f
7e
7f
7e
7f
63
74
69
76
57
65
87:13
87:13
80:20
86:14
81:19
83:17
a
All reactions were carried out with RX (10 equiv) and radical
b
initiator (2.5 equiv) in toluene at 20 °C. The ethylated product
7b was also obtained in 10-25 yields. c Combined yields of
F igu r e 2. Radical addition to camphorsultam derivative of
diastereomers. Diastereoselectivities were determined by 1H
d
glyoxylic oxime ether.
NMR analysis.
Con clu sion s
mixture. The replacement of CH2Cl2 with a nonpolar
aromatic solvent such as toluene was also effective for
the reaction (Table 6, entries 3 and 4). It is noteworthy
that similar trends were observed in the reaction using
Et2Zn (Table 6, entries 5-8).
We have succeeded in the asymmetric synthesis of
R-amino acids based on the intermolecular carbon radical
addition to Oppolzer’s camphorsultam derivatives of the
glyoxylic oxime ether with excellent diastereoselectivities.
The new methodology provides a synthetic approach to
a wide range of enantiomerically pure natural and
unnatural R-amino acids, including aliphatic R-amino
acids. Therefore, the free radical-mediated carbon-
carbon bond-forming reaction complements the nucleo-
philic addition of organometallic reagents.
To evaluate the generality of the radical reaction, we
investigated the reaction using different radical precur-
sors, such as sec-butyl and cyclohexyl iodides, which
afforded the alkylated respective products 7e and 7f with
moderate diastereoselectivities (Scheme 8, Table 7). The
reactions were run at 20 °C for 10 min by the use of RI
(10 equiv) and 1.0 M solution of Et3B in hexane (2.5
equiv) or 1.0 M solution of Et2Zn in hexane (2.5 equiv).
Curran has suggested that in imides derived from
camphorsultam, dipole-dipole interactions control the
C(O)-N rotamer population and is responsible for the
observed stereoselection in radical reactions.8 In our
reaction, the rotamer having the carbonyl group anti to
the sulfonyl group would be favored in order to minimize
dipole-dipole interactions between these groups (Figure
2). As suggested by the studies on the camphorsultam
derivative of glyoxylic acid,33 it is expected that the
sterically more stable s-cis planar conformation between
the carbonyl group and the oxime ether group would be
favored. Therefore, the anti and s-cis planar rotamer A
should be preferred over rotamers B-D, and the radical
addition to the re (bottom) face is favored, presumably
due to steric interactions with the axial oxygen of the
sulfonyl group, which effectively prevents addition to the
si face.
Exp er im en ta l Section
Gen er a l Meth od s. Melting points are uncorrected. 1H and
13C NMR spectra were recorded at 200, 300, or 500 MHz and
at 50 or 125 MHz, respectively. IR spectra were recorded using
FTIR apparatus. Mass spectra were obtained by EI, CI, or
SIMS methods. Preparative TLC separations were carried out
on precoated silica gel plates (E. Merck 60F254). Medium-
pressure column chromatography was performed using Lobar
gro¨sse B (E. Merck 310-25, Lichroprep Si60). Flash column
chromatography was performed using E. Merck Kieselgel 60
(230-400 mesh).
[3a S -[1(E ),3a r,6r,7a â]]-H e xa h yd r o-8,8-d im e t h yl-1-
[[(p h en ylm et h oxy)im in o]a cet yl]-3H -3a ,6-m et h a n o-2,1-
ben zisoth ia zole-2,2-d ioxid e (6). To a solution of (1R)-(+)-
2,10-camphorsultam (1.0 g, 4.6 mmol) and glyoxylic oxime
ether 1 (1.33 g, 6.9 mmol) in CH2ClCH2Cl (40 mL) was added
Me3Al (1.0 M in hexane, 6.9 mL, 6.9 mmol) under a nitrogen
atmosphere at room temperature. After being heated at reflux
for 5 h, the reaction mixture was diluted with 1 N HCl and

Asymmetric Synthesis of R-Amino Acids
J . Org. Chem., Vol. 65, No. 1, 2000 183
then extracted with CH2Cl2. The organic phase was washed
with water, dried over MgSO4, and concentrated at reduced
pressure. Purification of the residue by flash chromatography
(hexane/AcOEt 4:1) afforded 6 (1.56 g, 90%) as colorless
the alkylated products (R)-7b as colorless crystals and (S)-7b
as a white solid, respectively:41 mp 99-100 °C (Et2O/hexane);
[R]28 +107.4 (c 0.95, CHCl3); IR (CHCl3) 3271, 2966, 1693,
D
1455 cm-1; H NMR (CDCl3) δ 7.36-7.24 (5H, m), 6.18 (1H,
1
crystals: mp 133-134 °C (Et2O/hexane); [R]27 +88.9 (c 1.01,
br d, J ) 10.5 Hz), 4.71, 4.66 (each 1H, d, J ) 12.0 Hz), 4.27
(1H, br m), 3.97 (1H, br t, J ) 6.5 Hz), 3.50, 3.47 (each 1H, d,
J ) 14.0 Hz), 2.09 (2H, br d, J ) 6.5 Hz), 1.93-1.86 (3H, m),
1.72-1.35 (4H, m), 1.13, 0.97 (each 3H, s), 0.95 (3H, t, J ) 7.5
Hz); 13C NMR (CDCl3) δ 174.1, 137.9, 128.6, 128.1, 127.6, 75.8,
65.0, 64.4, 53.1, 48.6, 47.8, 44.6, 38.3, 32.8, 26.4, 24.0, 20.7,
19.9, 10.5; HRMS calcd for C21H31N2O4S (M+ + H) 407.2002,
found 407.1997. Anal. Calcd for C21H30N2O4S: C, 62.04; H,
7.44; N, 6.89; S, 7.89. Found: C, 62.12; H, 7.58; N, 6.71; S,
7.92.
D
1
CHCl3); IR (CHCl3) 2962, 1693, 1456 cm-1; H NMR (CDCl3)
δ 8.21 (1H, s), 7.42-7.28 (5H, m), 5.32 (2H, s), 3.98 (1H, dd, J
) 5.2, 7.4 Hz), 3.52, 3.45 (each 1H, d, J ) 13.7 Hz), 2.20-2.02
(2H, m), 1.98-1.82 (3H, m), 1.48-1.29 (2H, m), 1.16, 0.97 (each
3H, s); 13C NMR (CDCl3) δ 159.0, 140.8, 135.8, 128.5, 128.4,
128.3, 78.2, 65.1, 52.9, 48.8, 47.7, 44.5, 38.1, 32.7, 26.2, 20.7,
19.7; HRMS calcd for C19H25N2O4S (M+ + H) 377.1543, found
377.1538. Anal. Calcd for C19H24N2O4S: C, 60.62; H, 6.43; N,
7.44; S, 8.52. Found: C, 60.42; H, 6.34; N, 7.34; S, 8.67.
[3aS-[1(S*),3ar,6r,7aâ]]-Hexah ydr o-8,8-dim eth yl-1-[3,3-
dim eth yl-1-oxo-2-[(ph en ylm eth oxy)am in o]bu tyl]-3H-3a,6-
m eth a n o-2,1-ben zisoth ia zole-2,2-d ioxid e [(R)-7c]. Further
careful purification by preparative TLC (hexane/AcOEt 11:1)
afforded the alkylated products (R)-7c as a colorless oil and
Gen er a l P r oced u r e for Bu 3Sn H-Med ia ted Ra d ica l Ad -
d ition to Ca m p h or su lta m Der iva tive 6. To a solution of 6
(100 mg, 0.27 mmol) in CH2Cl2 (20 mL) were added Lewis acid
(0.53 mmol), alkyl iodide (1.33 mmol), Bu3SnH (0.18 mL, 0.66
mmol), and Et3B (1.0 M in hexane, 1.33 mL, 1.33 mmol) under
a nitrogen atmosphere at -78 °C. After being stirred at the
same temperature for 30 min, the reaction mixture was diluted
with saturated aqueous NaHCO3 and then extracted with
CH2Cl2. The organic phase was dried over MgSO4 and con-
centrated at reduced pressure. The diastereoselectivity was
determined by the 1H NMR analysis of the diastereomeric
mixtures obtained after rough purification (hexane/AcOEt 11:
1) to remove the tin residues from the reaction mixture.
Further careful purification by preparative TLC afforded the
alkylated products (R)-7a -h and their diastereomers.
(S)-7c as a white solid, respectively:41 [R]29 +87.2 (c 3.37,
D
CHCl3); IR (CHCl3) 3291, 2962, 1687, 1455 cm-1
;
1H NMR
(CDCl3) δ 7.41-7.23 (5H, m), 6.20 (1H, br d, J ) 9.5 Hz), 4.69,
4.60 (each 1H, d, J ) 12.0 Hz), 4.12 (1H, br d, J ) 9.5 Hz),
4.01 (1H, br t, J ) 6.0 Hz), 3.49 (2H, br s), 2.16-2.02 (2H, br
m), 1.94-1.83 (3H, m), 1.43-1.32 (2H, m), 1.13 (3H, s), 0.98
(9H, s), 0.96 (3H, s); 13C NMR (CDCl3) δ 174.8, 138.2, 128.8,
128.0, 127.4, 75.3, 69.6, 65.5, 53.3, 47.8, 47.7, 44.6, 38.6, 34.7,
33.0, 27.0, 26.5, 20.6, 20.0; HRMS calcd for C23H35N2O4S (M+
+ H) 435.2315, found 435.2307.
[3a S-[1(S*),3a r,6r,7a â]]-Hexa h yd r o-8,8-d im eth yl-1-[4-
m eth yl-1-oxo-2-[(p h en ylm eth oxy)a m in o]p en tyl]-3H-3a ,6-
m eth a n o-2,1-ben zisoth ia zole-2,2-d ioxid e [(R)-7d ]. Further
careful purification by preparative TLC (hexane/AcOEt 11:1)
afforded the alkylated products (R)-7d as a colorless oil and
Isop r op yl Ra d ica l Ad d ition to 6 Usin g (Me3Si)3SiH. To
a solution of 6 (100 mg, 0.27 mmol) in CH2Cl2 (20 mL) were
added i-PrI (0.13 mL, 1.35 mmol), (Me3Si)3SiH (0.21 mL, 0.66
mmol), and Et3B (1.0 M in hexane, 1.33 mL, 1.33 mmol) under
a nitrogen atmosphere at -78 °C. After being stirred at the
same temperature for 30 min, the reaction mixture was diluted
with saturated aqueous NaHCO3 and then extracted with
CH2Cl2. The organic phase was dried over MgSO4 and con-
centrated at reduced pressure. Purification was performed
using the protocol described in the general procedure.
Isop r op yl Ra d ica l Ad d ition to 6 Usin g AIBN. To a
boiling solution of 6 (100 mg, 0.27 mmol) and i-PrI (0.09 mL,
0.945 mmol) in toluene (10 mL) was added a solution of
Bu3SnH (0.18 mL, 0.59 mmol) and AIBN (9 mg, 0.054 mmol)
in toluene (5 mL) under a nitrogen atmosphere. After being
heated at reflux for 5 min, the reaction mixture was diluted
with saturated aqueous NaHCO3 and then extracted with
AcOEt. The organic phase was dried over MgSO4 and concen-
trated under reduced pressure. Purification was performed
using the protocol described in the general procedure.
(S)-7d as a white solid, respectively:41 [R]27 +48.6 (c 6.70,
D
CHCl3); IR (CHCl3) 3270, 2962, 1693, 1455 cm-1
;
1H NMR
(CDCl3) δ 7.39-7.24 (5H, m), 6.15 (1H, br m), 4.69, 4.66 (each
1H, d, J ) 12.0 Hz), 4.42-4.35 (1H, br m), 3.97 (1H, t, J ) 6.0
Hz), 3.48, 3.47 (each 1H, d, J ) 14.0 Hz), 2.07 (2H, br m), 1.94-
1.83 (3H, m), 1.78 (1H, m), 1.43-1.18 (4H, m), 1.13, 0.97 (each
3H, s), 0.86 (6H, d, J ) 7.0 Hz); 13C NMR (CDCl3) δ 174.7,
138.0, 128.7, 128.1, 127.5, 75.8, 65.0, 61.9, 53.0, 48.6, 47.8, 44.6,
39.2, 38.2, 32.8, 26.4, 25.2, 23.4, 21.3, 20.8, 19.9; HRMS calcd
for C23H35N2O4S (M+ + H) 435.2315, found 435.2292.
[3aS-[1(S*),3ar,6r,7aâ]]-1-[Cycloh exyl[(ph en ylm eth oxy)-
a m in o]a cetyl]-h exa h yd r o-8,8-dim eth yl-3H-3a ,6-m eth a n o-
2,1-ben zisoth ia zole-2,2-d ioxid e [(R)-7e]. Further careful
purification by preparative TLC (hexane/AcOEt 11:1) afforded
the alkylated products (R)-7e as a colorless oil and (S)-7e as
a colorless oil, respectively:41 [R]30 +85.4 (c 4.00, CHCl3); IR
D
[3a S-[1(S*),3a r,6r,7a â]]-Hexa h yd r o-8,8-d im eth yl-1-[3-
m eth yl-1-oxo-2-[(p h en ylm eth oxy)a m in o]bu tyl]-3H-3a ,6-
m eth a n o-2,1-ben zisoth ia zole-2,2-d ioxid e [(R)-7a ]. Further
careful purification by preparative TLC (hexane/AcOEt 8:1)
afforded the alkylated products (R)-7a as colorless crystals and
(S)-7a as a white solid, respectively:41 mp 83-84 °C (Et2O/
hexane); [R]29D +103.6 (c 1.11, CHCl3); IR (CHCl3) 3288, 2966,
(CHCl3) 3275, 2931, 1691, 1453 cm-1; 1H NMR (CDCl3) δ 7.39-
7.24 (5H, m), 6.21 (1H, br m), 4.68, 4.62 (each 1H, d, J ) 11.5
Hz), 4.15 (1H, br m), 3.98 (1H, br t, J ) 6.5 Hz), 3.49, 3.47
(each 1H, d, J ) 14.0 Hz), 2.07 (2H, m), 1.95-1.84 (3H, m),
1.78-1.02 (13H, m), 1.13, 0.97 (each 3H, s); 13C NMR (CDCl3)
δ 174.2, 138.1, 128.7, 128.1, 127.5, 75.6, 68.0, 65.1, 53.1, 48.4,
47.7, 44.6, 40.0, 38.5, 32.8, 29.9, 28.7, 26.5, 26.3, 26.2, 26.0,
20.6, 20.0; HRMS calcd for C25H37N2O4S (M+ + H) 461.2471,
found 461.2479.
1
1692, 1455 cm-1; H NMR (CDCl3) δ 7.39-7.24 (5H, m), 6.22
(1H, d, J ) 11.0 Hz), 4.69, 4.63 (each 1H, d, J ) 14.0 Hz),
4.17-4.10 (1H, br m), 3.99 (1H, br t, J ) 6.0 Hz), 3.49, 3.48
(each 1H, d, J ) 14.0 Hz), 2.15-2.03 (2H, m), 1.95-1.83 (4H,
m), 1.48-1.30 (2H, m), 1.13, 0.97 (each 3H, s), 1.01, 0.86 (each
3H, d, J ) 7.0 Hz); 13C NMR (CDCl3) δ 174.3, 138.0, 128.8,
128.1, 127.5, 75.6, 68.1, 65.1, 53.1, 48.4, 47.8, 44.6, 38.5, 32.9,
30.3, 26.5, 20.7, 20.0, 17.9; HRMS calcd for C22H33N2O4S (M+
+ H) 421.2159, found 421.2150. Anal. Calcd for C22H32N2O4S:
C, 62.83; H, 7.67; N, 6.66; S, 7.62. Found: C, 62.67; H, 7.60;
N, 6.38; S, 7.68.
[3a S-[1(S*),3a r,6r,7a â]]-Hexa h yd r o-8,8-d im eth yl-1-[3-
m eth yl-1-oxo-2-[(p h en ylm eth oxy)a m in o]p en tyl]-3H-3a ,6-
m eth a n o-2,1-ben zisoth ia zole-2,2-d ioxid e [(R)-7f]. Further
careful purification by preparative TLC (hexane/AcOEt
(10:1), 2-fold development) afforded the alkylated products (R)-
7f as a colorless oil and as a 1:1 diastereomeric mixture
concerning the chiral carbon on the sec-butyl group: [R]28
D
+84.2 (c 0.75, CHCl3); IR (CHCl3) 3300, 2966, 1691, 1455 cm-1
;
1H NMR (CDCl3) δ 7.45-7.20 (5H, m), 6.25 (1H, br s), 4.67
(1/2H, d, J ) 12.0 Hz), 4.66 (1/2H, d, J ) 12.0 Hz), 4.63 (1H, d,
J ) 12.0 Hz), 4.29, 4.18 (each 1/2H, br m), 3.98 (1H, br t, J )
6.5 Hz), 3.47 (2H, m), 2.18-1.98 (2H, br m), 1.98-1.82 (3H,
br m), 1.82-1.23 (5H, m) 1.12, 0.96 (each 3H, br s), 0.87, 0.81
(each 3/2H, t, J ) 7.5 Hz), 0.82, 0.76 (3/2H, d, J ) 7.0 Hz); 13C
NMR (CDCl3) δ 174.3, 174.0, 138.0, 137.9, 128.6, 128.0, 127.4,
75.53, 75.45, 67.6, 66.3, 65.0, 64.9, 52.9, 48.4, 48.3, 47.6, 44.4,
[3a S-[1(S*),3a r,6r,7a â]]-Hexa h yd r o-8,8-d im eth yl-1-[1-
oxo-2-[(p h en ylm eth oxy)a m in o]bu tyl]-3H-3a ,6-m eth a n o-
2,1-ben zisot h ia zole-2,2-d ioxid e [(R)-7b ]. Further careful
purification by preparative TLC (hexane/AcOEt 11:1) afforded
(41) The characterization data of the minor diasteromers (S)-7a -e
are given in the Supporting Information.

184 J . Org. Chem., Vol. 65, No. 1, 2000
Miyabe et al.
38.4, 38.3, 36.6, 36.2, 32.6, 27.0, 26.3, 24.4, 20.5, 20.4, 19.8,
15.9, 14.0, 11.5, 11.3; HRMS calcd for C23H35N2O4S (M+ + H)
435.2315, found 435.2297.
Hz), 2.29 (1H, br m), 2.08 (1H, dd, J ) 7.5, 13.5 Hz), 2.03-
1.85 (3H, br m), 1.46-1.32 (2H, m), 1.13, 0.97 (each 3H, s),
1.04, 0.80 (each 3H, d, J ) 7.0 Hz); 13C NMR (CDCl3) δ 171.9,
156.0, 136.4, 128.5, 128.2, 128.1, 67.1, 64.9, 59.1, 53.0, 48.6,
47.8, 44.6, 38.4, 32.8, 32.0, 26.5, 20.6, 19.9, 19.8, 15.9; HRMS
calcd for C23H32N2O5S (M+) 448.2030, found 448.2031. Anal.
Calcd for C23H32N2O5S: C, 61.61; H, 7.14; N, 6.25; S, 7.14.
Found: C, 61.60; H, 7.24; N, 6.25; S, 7.34.
[3aS-[1(S*),3ar,6r,7aâ]]-1-[6-Acetyloxy-1-oxo-2-[(ph en yl-
m eth oxy)a m in o]h exyl]h exa h yd r o-8,8-d im eth yl-3H-3a ,6-
m eth a n o-2,1-ben zisoth ia zole-2,2-d ioxid e [(R)-7g]. Further
careful purification by preparative TLC (hexane/AcOEt (5:1),
2-fold development) afforded the alkylated products (R)-7g as
a colorless oil: [R]31 +64.9 (c 1.01, CHCl3); IR (CHCl3) 3300,
N-[(P h en ylm eth oxy)ca r bon yl]-D-va lin e [(R)-11]. A solu-
tion of (R)-10 (174 mg, 0.39 mmol) in 1 N LiOH-THF (1:4, 10
mL) was stirred at room temperature for 4 h. After the reaction
mixture was concentrated at reduced pressure, the resulting
residue was diluted with water, acidified to a pH between 4
and 5 with diluted HCl, and then extracted with CH2Cl2. The
organic phase was dried over Na2SO4 and concentrated at
reduced pressure. Purification of the residue by flash column
chromatography (hexane/AcOEt 1:2) afforded (R)-11 (71 mg,
73%) as a colorless oil: [R]27D +5.6 (c 1.78, MeOH); IR (CHCl3)
D
2963, 1727, 1693, 1455 cm-1
;
1H NMR (CDCl3) δ 7.40-7.23
(5H, m), 6.18 (1H, br d, J ) 10.5 Hz), 4.69, 4.65 (each 1H, d,
J ) 12.0 Hz), 4.28 (1H, m), 4.04-3.93 (3H, m), 3.49, 3.47 (each
1H, d, J ) 13.0 Hz), 2.11-1.28 (13H, m), 2.03 (3H, s), 1.12,
0.97 (each 3H, s); 13C NMR (CDCl3) δ 174.0, 171.1, 137.9, 128.7,
128.2, 127.6, 75.8, 65.0, 64.2, 63.1, 53.0, 48.7, 47.8, 44.6, 38.2,
32.8, 30.1, 28.1, 26.4, 22.5, 21.0, 20.7, 19.9; HRMS calcd for
C
25H37N2O6S (M+ + H) 493.2370, found 493.2393.
[3a S-[1(S*),3a r,6r,7a â]]-Hexa h yd r o-8,8-d im eth yl-1-[1-
1
oxo-[2-[N-(p h en ylm eth oxy)p yr r olid in yl]]]-3H-3a ,6-m eth -
a n o-2,1-ben zisoth ia zole-2,2-d ioxid e [(R)-8]. In the case of
product (R)-8, the reaction mixture was stirred at -78 °C for
30 min and then stirred at room temperature for an additional
30 h. Further careful purification by preparative TLC (hexane/
AcOEt (6:1), 2-fold development) afforded the alkylated product
3438, 2968, 1715, 1466, 1456 cm-1; H NMR (CDCl3) δ 7.39-
7.28 (5H, m), 5.27 (1H, br m), 5.12, 5.11 (each 1H, br d, J )
12.0 Hz), 4.34 (1H, br m), 2.22 (1H, br m), 1.00, 0.93 (each
3H, d, J ) 7.5 Hz); 13C NMR (CDCl3) δ 176.2, 156.4, 136.2,
128.6, 128.3, 128.2, 67.2, 58.9, 31.0, 19.0, 17.4; HRMS calcd
for C13H17NO4 (M+) 251.1157, found 251.1152.
(R)-8 as a yellow solid: [R]27 +131.0 (c 0.60, CHCl3); IR
D-Va lin e [(R)-12]. A solution of (R)-9 (60 mg, 0.17 mmol)
in 1 N LiOH-THF (1:4, 7 mL) was stirred at room temperature
for 3 h. After the reaction mixture was concentrated at reduced
pressure, the resulting residue was diluted with CH2Cl2 and
extracted with water. After the aqueous phase was acidified
to a pH between 4 and 5 with the diluted HCl, Amberlite IR-
120B ion-exchange resin (200 mg) was added to the aqueous
phase at room temperature. After being stirred at same
temperature for 15 h, the reaction mixture was filtered. After
the resin was washed well with water, a solution of the resin
in 30% NH3 (10 mL) was stirred at room temperature for 4 h.
The reaction mixture was filtered, and the filtrate was
concentrated at reduced pressure to afford (R)-12 (17.6 mg,
D
(CHCl3) 2964, 1703, 1454 cm-1; 1H NMR (CDCl3) δ 7.38-7.23
(5H, m), 4.86, 4.81 (each 1H, d, J ) 11.0 Hz), 4.40 (1H, dd, J
) 8.0, 10.0 Hz), 3.97 (1H, dd, J ) 5.0, 7.0 Hz), 3.49, 3.48 (each
1H, d, J ) 14.0 Hz), 3.28 (1H, m), 2.97 (1H, m), 2.41 (1H, m),
2.14-2.00 (2H, m), 1.97-1.83 (4H, m), 1.81 (1H, m), 1.68 (1H,
m), 1.47-1.32 (2H, m), 1.13, 0.97 (each 3H, s); 13C NMR
(CDCl3) δ 171.7, 137.9, 128.6, 128.2, 127.6, 75.7, 69.8, 65.1,
56.1, 53.1, 48.6, 47.8, 44.6, 38.2, 32.8, 27.7, 26.4, 21.2, 20.7,
19.9; HRMS calcd for C22H31N2O4S (M+ + H) 419.2001, found
419.2024.
[3a S-[1(S*),3a r,6r,7a â]]-1-[(2-Am in o-3-m et h yl-1-oxo)-
bu tyl]h exah ydr o-8,8-dim eth yl-3H-3a,6-m eth an o-2,1-ben z-
isoth ia zole-2,2-d ioxid e Mon oh yd r och lor id e [(R)-9]. To a
solution of (R)-7a (120 mg, 0.286 mmol) in H2O (0.29 mL) and
MeCN (4.3 mL) was added Mo(CO)6 (52.8 mg, 0.20 mmol)
under a nitrogen atmosphere at room temperature. After being
heated at reflux for 2 h, the reaction mixture was concentrated
at reduced pressure. The resulting residue was diluted with
CH2Cl2 and washed with saturated aqueous NaHCO3 and
water. The organic phase was extracted with 1 N HCl. The
aqueous phase was concentrated at reduced pressure to afford
88%) as a white powder: [R]28 -26.0 (c 0.97, 6 N HCl); IR
D
(Nujol) 2890, 1605 cm-1; 1H NMR (D2O) δ 3.05 (1H, d, J ) 5.2
Hz), 1.92 (1H, m), 0.94, 0.87 (each 3H, d, J ) 7.0 Hz); 13C NMR
(D2O) δ 171.3, 64.8, 34.7, 22.0, 19.6; HRMS calcd for C5H12
NO2 (M+ + H) 118.0867, found 118.0883.
-
En a n tioselective Ra d ica l Ad d ition to 1. To a solution
of 1 (30 mg, 0.155 mmol) and (R)-(+)-2,2′-isopropylidenebis-
(4-phenyl-2-oxazoline) (52 mg, 0.155 mmol) in CH2Cl2 (4 mL)
were added Lewis acid (0.155 mmol), isopropyl iodide (0.155
mL, 1.55 mmol), Bu3SnH (0.209 mL, 0.776 mmol), and Et3B
(1.0 M in hexane, 1.55 mL, 1.55 mmol) under a nitrogen
atmosphere at -78 °C. After being stirred at the same
temperature for 30 min, the reaction mixture was diluted with
saturated aqueous NaHCO3 and then extracted with CH2Cl2.
The organic phase was dried over MgSO4 and concentrated at
reduced pressure. After rough purification of the residue by
preparative TLC (hexane/AcOEt 12:1) to remove the tin
residues from the reaction mixture, further careful purification
by preparative TLC (CHCl3) afforded the alkylated product 2.
(2S)-N-(3,3,3-Tr iflu or o-2-m eth oxy-1-oxo-2-p h en ylp r o-
p oxy)-D-va lin e Meth yl Ester [(R)-13] a n d (2S)-N-(3,3,3-
Tr iflu or o-2-m et h oxy-1-oxo-2-p h en ylp r op oxy)-L-va lin e
Meth yl Ester [(S)-13]. A suspension of 20% Pd(OH)2 (30 mg)
in MeOH (1 mL) was stirred under a hydrogen atmosphere at
20 °C for 1 h. To this suspension was added a solution of 2
(100 mg, 0.42 mmol) in MeOH (2 mL). After being stirred
under a hydrogen atmosphere at 20 °C for 3 h, the reaction
mixture was filtered and the filtrate was concentrated at
reduced pressure to afford the crude amine. To a solution of
the resulting crude amine in pyridine (0.5 mL) were added
DMAP (12 mg, 0.1 mmol) and (R)-R-methoxy-R-(trifluoro-
methyl)phenylacetyl chloride (150 mg, 0.59 mmol) under a
nitrogen atmosphere at 20 °C. After being stirred at the same
temperature for 15 min, the reaction mixture was extracted
with AcOEt. The organic phase was washed with 3% HCl,
water, and brine; dried over MgSO4; and concentrated at
reduced pressure. Purification of the residue by preparative
TLC (AcOEt/hexane 1:3) afforded (R)-13 (85 mg, 59%) as a
(R)-9 (88 mg, 88%) as a white powder: [R]29 +61.3 (c 1.06,
D
MeOH); IR (CHCl3) 3423, 1654 cm-1; 1H NMR (CD3OD) δ 4.29
(1H, br d, J ) 4.5 Hz), 3.99 (1H, dd, J ) 5.0, 7.5 Hz), 3.80,
3.69 (each 1H, d, J ) 13.7 Hz), 2.46 (1H, m), 2.16-1.85 (5H,
m), 1.55-1.32 (2H, m), 1.14, 1.03 (each 3H, s), 1.12, 0.98 (each
3H, d, J ) 7.0 Hz); 13C NMR (CD3OD) δ 169.5, 66.4, 59.6, 53.6,
50.2, 48.9, 46.1, 39.1, 33.5, 31.7, 27.3, 21.2, 20.1, 19.5, 16.4;
HRMS calcd for C15H27N2O3S (M+ + H) 315.1740, found
315.1721.
[3a S-[1(S*),3a r,6r,7a â]]-Hexa h yd r o-8,8-d im eth yl-1-[3-
m eth yl-1-oxo-2-[[(ph en ylm eth oxy)car bon yl]am in o]bu tyl]-
3H -3a ,6-m et h a n o-2,1-b en zisot h ia zole-2,2-d ioxid e [(R)-
10]. To a solution of (R)-9 (168 mg, 0.48 mmol) in acetone (2
mL) was added a solution of Na2CO3 (153 mg, 1.44 mmol) in
H2O (1 mL) under a nitrogen atmosphere at room temperature.
After a solution of CbzCl (119 mg, 0.70 mmol) in acetone (0.5
mL) was added dropwise at 0 °C, the reaction mixture was
stirred at room temperature for 1 h. After the reaction mixture
was concentrated at reduced pressure, the resulting residue
was diluted with water and then extracted with CH2Cl2. The
organic phase was dried over Na2SO4 and concentrated at
reduced pressure. Purification of the residue by medium-
pressure column chromatography (hexane/AcOEt 6:1 to 4:1)
afforded (R)-10 (197 mg, 92%) as colorless crystals: mp 169-
170 °C (AcOEt/Et2O/hexane); [R]29 +62.0 (c 1.50, MeOH); IR
D
(CHCl3) 3435, 2966, 1725, 1697, 1456 cm-1; 1H NMR (CDCl3)
δ 7.41-7.29 (5H, m), 5.35 (1H, br d, J ) 9.0 Hz), 5.08, 5.14
(each 1H, br d, J ) 12.0 Hz), 4.94 (1H, br dd, J ) 3.0, 9.0 Hz),
3.91 (1H, br t, J ) 6.0 Hz), 3.49, 3.47 (each 1H, br d, J ) 14.0

Asymmetric Synthesis of R-Amino Acids
J . Org. Chem., Vol. 65, No. 1, 2000 185
colorless oil and (S)-13 (26 mg, 18%) as a colorless oil (R)-13:
[R]27D -486 (c 1.20, CHCl3); IR (CHCl3) 2969, 1740, 1698, 1514
hexane, 0.33 mL, 0.332 mmol) under a nitrogen atmosphere
at +20 or -78 °C. After being stirred at the same temperature
for 10 min, the reaction mixture was diluted with saturated
aqueous NaHCO3 and then extracted with CH2Cl2. The organic
phase was dried over MgSO4 and concentrated at reduced
pressure. After the separation of the alkylated products 7a ,e,f
and the ethylated product 7b by preparative TLC (hexane/
AcOEt 4:1, 2-fold development), diastereoselectivities were
determined by 1H NMR analysis. The pure diastereomers (R)-
7a , (R)-7e, and (R)-7f could be also isolated by preparative
TLC (hexane/AcOEt 4:1, 2-fold development).
1
cm-1; H NMR (CDCl3) δ 7.60-7.50 (2H, m), 7.45-7.35 (3H,
m), 4.59 (1H, m), 3.74 (3H, s), 3.39 (3H, br s), 2.23 (1H, m),
0.99, 0.94 (each 3H, d, J ) 6.9 Hz); 13C NMR (CDCl3) δ 171.8,
166.1, 131.7, 129.4, 128.5, 127.9, 123.7 (q, J ) 289 Hz, CF3),
84.1 (q, J ) 27 Hz, CF3C), 57.0, 54.8, 52.1, 31.0, 18.9, 17.5;
HRMS calcd for C16H21F3NO4 (M+ + H) 248.1421, found
348.1427. (S)-13: [R]27D -2713 (c 2.50, CHCl3); IR (CHCl3) 2968,
1740, 1698, 1514 cm-1; 1H NMR (CDCl3) δ 7.65-7.55 (2H, m),
7.50-7.35 (3H, m), 4.61 (1H, m), 3.76 (3H, s), 3.50 (3H, br s),
2.19 (1H, m), 0.87, 0.80 (each 3H, d, J ) 6.9 Hz); 13C NMR
(CDCl3) δ 171.7, 166.4, 132.9, 129.4, 128.3, 127.2, 123.4 (q, J
) 289 Hz, CF3), 83.9 (q, J ) 29 Hz, CF3C), 56.7, 55.6, 52.2,
31.1, 18.8, 17.4; HRMS calcd for C16H20F3NO4 (M+ + H)
248.1421, found 348.1432.
Ack n ow led gm en t. We wish to thank the Ministry
of Education, Science, Sports and Culture of J apan and
the Science Research Promotion Fund of the J apan
Private School Promotion Foundation for research grants.
Partial support for this work was also provided by the
Nissan Chemical Industries Award in Synthetic Organic
Chemistry, J apan.
Eth yl Ra d ica l Ad d ition to 6 Usin g Et3B or Et2Zn . To a
solution of 6 (50 mg, 0.133 mmol) in CH2Cl2 or toluene (3 mL)
were added Et3B or Et2Zn (1.0 M in hexane, 0.664 mL, 0.664
mmol) under a nitrogen atmosphere at +20 or -78 °C. After
being stirred at the same temperature for 5 min, the reaction
mixture was diluted with saturated aqueous NaHCO3 and then
extracted with CH2Cl2. The organic phase was dried over
MgSO4 and concentrated at reduced pressure. Diastereoselec-
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures for the isopropyl radical addition to glyoxylic oxime
ether 1 and the competitive reaction. The characterization data
1
tivity was determined by H NMR analysis of crude products.
1
Purification of the residue by preparative TLC (hexane/AcOEt
4:1) afforded (R)-7b and (S)-7b.
Gen er a l P r oced u r e for Ra d ica l Ad d ition to 6. To a
solution of 6 (50 mg, 0.133 mmol) in CH2Cl2 or toluene (3 mL)
were added RI (1.33 mmol) and Et3B or Et2Zn (1.0 M in
of the minor diastereomers (S)-7a -e and H NMR data for 2,
6, (R)-7a -g, (S)-7a -e, and (R)-8-12. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
J O991353N