Zinc-mediated carbon radical addition to glyoxylic imines in aqueous media for the synthesis of α-amino acids

Article abstract of DOI:10.1039/b418726a

The addition of carbon radicals to glyoxylic imines was studied using zinc dust as a radical initiator. The zinc-mediated radical reaction of glyoxylic oxime ethers and hydrazones proceeded smoothly to give the alkylated products via a carbon-carbon bond-

Full text of DOI:10.1039/b418726a

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A R T I C L E
Zinc-mediated carbon radical addition to glyoxylic imines in aqueous
media for the synthesis of a-amino acids
Masafumi Ueda,a Hideto Miyabe,b Hisako Suginoa and Takeaki Naito*a
a Kobe Pharmaceutical University, Motoyamakita, Higashinada, Kobe, 658-8558, Japan.
E-mail: taknaito@kobepharma-u.ac.jp
b Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto,
606-8501, Japan
Received 13th December 2004, Accepted 2nd February 2005
First published as an Advance Article on the web 21st February 2005
The addition of carbon radicals to glyoxylic imines was studied using zinc dust as a radical initiator. The
zinc-mediated radical reaction of glyoxylic oxime ethers and hydrazones proceeded smoothly to give the alkylated
products via a carbon–carbon bond-forming process in aqueous media. The reaction of the oxime ethers and
hydrazones having an Oppolzer’s camphorsultam group provided the corresponding alkylated products, which could
be converted into enantiomerically pure a-amino acids. The diastereoselectivities observed in the reaction of
hydrazones were better than those obtained in the reaction of oxime ethers.
Table 1 Zinc-mediated radical additions to oxime ether 1a
Introduction
The use of water as a solvent has generated considerable interest
from both economical and environmental points of view.1
Particularly, carbon–carbon bond-formation in aqueous media
is a challenging problem.2 Thus, zinc-mediated carbon–carbon
bond-forming reactions in aqueous media have attracted
considerable interest.3 Among the various types of known
zinc-mediated reactions,3 radical reactions have captured much
recent attention because of their exceptional tolerance to
functional groups.4
The carbon–nitrogen double bond of imine derivatives has
emerged as a radical acceptor.5 However, the reactions of water-
sensitive imines have generally been performed in anhydrous
organic solvents. Therefore, zinc-mediated radical reactions of
imine derivatives in aqueous media have not been widely studied
to date. Our recent studies show that N-sulfonylimines are
excellent radical acceptors for the aqueous-medium reactions
using zinc as a single-electron transfer radical initiator.6 We
have a program directed toward the development of environ-
mentally benign synthetic reactions in aqueous media.7,8 As
part of this, we report here, for the first time in detail, zinc-
mediated radical addition to water-resistant glyoxylic oxime
ethers and hydrazones.9 We also report the diastereoselective
radical reaction of the oxime ether and hydrazone incorporating
Oppolzer’s camphorsultam.10
Entry RX
Solvent
Product Yield (%)b
1
2
3
4
5
6
7
PriI
Sat. NH4Cl : MeOH (2 : 1) 2a
H2O : MeOH (2 : 1)
Sat. NH4Cl : MeOH (2 : 1)
Sat. NH4Cl : MeOH (2 : 1) 2b
96
PriI
No reaction
No reaction
42
53
68
57
PriBr
BusI
c-Pentyl I Sat.NH4Cl : MeOH (2 : 1) 2c
c-Hexyl I Sat. NH4Cl : MeOH (2 : 1) 2d
ButI
Sat. NH4Cl : MeOH (2 : 1) 2e
a Reactions were carried out with RX (5 eq.) and zinc (7 eq.) at 20 ◦C
for 15 min. b Isolated yields.
◦
1
stirred vigorously at 20 C for 15 min (Table 1, entry 1). H
NMR measurement of the crude product showed an almost
quantitative conversion of 1 to the desired 2a. The product
2a was isolated in 96% yield after purification by preparative
TLC. It is important to note that no reaction of 1 occurred
in H2O–MeOH (Table 1, entry 2). These results suggest that
aqueous NH4Cl is important for the activation of unactivated
Zn. In contrast, the reaction with PriBr did not take place
because of the larger bond dissociation energy of the C–Br bond
(Table 1, entry 3). Secondary and tertiary alkyl radicals worked
well to give 2b–d after a 15 min reaction time (Table 1, entries 4–
7). These reactions are expected to proceed through the radical
pathway based on a single-electron transfer (SET) from zinc, as
reported previously (Scheme 2).4
Results and discussion
Among the different types of imines, the oxime ethers are
well-known to be excellent radical acceptors.5 As a prelimi-
nary experiment we first examined the zinc-mediated radical
addition to glyoxylic oxime ether 1, because it has shown
high reactivity toward radical addition reactions in our recent
studies (Scheme 1).7 To a suspension of oxime ether 1, metallic
unactivated Zn and PriI in MeOH was added dropwise sat.
aqueous NH4Cl at 20 ◦C and then the reaction mixture was
Scheme 2 Possible reaction pathway.
We next investigated diastereoselective radical additions to
oxime ether 3 which has camphorsultam as a chiral auxiliary
(Scheme 3). In our previous study, the radical addition to
oxime ether 3 proceeded with good diastereoselectivity using
triethylborane as a radical initiator.10a Additionally, we recently
Scheme 1 Reagents and conditions: i) RX (5 eq.), Zn (7 eq.), 20 ◦C,
15 min.
1 1 2 4
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 1 2 4 – 1 1 2 8
T h i s j o u r n a l i s
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5
©

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Table 3 Zinc-mediated radical additions to hydrazone 5a
Product Yield (%)b
Entry RX
Solvent
1
2
3
4
5
6
PriI
PriI
BusI
Sat. NH4Cl : MeOH (2 : 1) 6a
H2O : MeOH (2 : 1)
Sat. NH4Cl : MeOH (2 : 1) 6b
92
No reaction
89
63 (30)
89 (10)
95
c-Pentyl I Sat. NH4Cl : MeOH (2 : 1) 6c
c-Hexyl I Sat. NH4Cl : MeOH (2 : 1) 6d
ButI
Sat. NH4Cl : MeOH (2 : 1) 6e
Scheme 3 Reagents and conditions: i) RI, Zn (7 eq.).
a Reactions were carried out with RI (5 eq. × 2) and zinc (7 eq.) at 20 ◦C.
b Isolated yields; yields in parentheses are for the recovered starting
material 5.
reported the indium-mediated radical addition to 3 in aqueous
media.8a,8b Therefore, we expected that the comparison of zinc-
mediated reactions with indium-mediated reactions would lead
to insight into radical initiators such as triethylborane, indium
and zinc. The biphasic reaction of 3 with an isopropyl radical
in aqueous NH4Cl–CH2Cl2 (2 : 1, v/v) proceeded smoothly
to give 4a in 63% yield, after being stirred for only 0.5 h
(Table 2, entry 1). In the case of the indium-mediated reaction,
the isopropylated product 4a was obtained in 44% yield after
being stirred in H2O–CH2Cl2 for 72 h.8b These results indicate
that zinc exhibits good reactivity as a radical initiator, although
the zinc-mediated reactions need to be carried out under the
acidic reaction conditions using sat. aqueous NH4Cl. The
of 5 with PriI in aqueous NH4Cl–MeOH proceeded smoothly to
give 92% yield of 6a after being stirred for 1 h (Table 3, entry 1). In
contrast, no reaction took place in H2O–CH2Cl2 (Table 3, entry
2). The zinc-mediated reaction of 5 with other radical precursors
also proceeded to give the good yields of the products 6b–e
(Table 3, entries 3–6). These chemical yields were better than
those obtained in the reaction of oxime ether 1. In our previous
study on the radical addition to hydrazone 5 using triethylborane
the undesired C- and N-dialkylated products were obtained
as a result of additional N-alkylation.12 In contrast, the zinc-
mediated radical addition to 5 proceeded selectively to give the
desired C-monoalkylated products 6a–e with no detection of
C- and N-dialkylated products. A similar trend was observed
in the reaction of 5 using indium.8a Thus, zinc and indium
were found to be highly promising radical initiators for the
radical reactions of hydrazones in aqueous media. Additionally,
this methodology can be applied to the large-scale synthesis
of a-amino acid derivatives. The isopropyl radical addition to
1 g of hydrazone 5 afforded the desired product 6a in 91%
yield.
The task of controlling the stereochemistry in radical addi-
tions to glyoxylic hydrazones is an achievable one. Therefore, we
finally investigated the diastereoselective radical addition to hy-
drazone 7, having the camphorsultam group as a chiral auxiliary.
We expected that the bulky diphenyl amino group on the imino
nitrogen atom of 7 would enhance the diastereoselectivities. The
hydrazone 7 was easily prepared in 92% yield by condensation
of glyoxylic hydrazone 5 with (1R)-(+)-2,10-camphorsultam in
the presence of trimethylaluminum (Scheme 5).
1
diastereomeric ratio of 4a was determined by H NMR and
was assumed to be 77% de. This is lower than the de obtained in
the previous indium-mediated reactions.8b The major product
could be easily isolated by preparative TLC. Based on our
previous work,10a the absolute configuration at the newly formed
stereocenter of the major product 4a was assumed to be R.11 The
monophasic reaction of 3 in aqueous NH4Cl–MeOH (2 : 1, v/v)
proceeded slowly to give 4a in 20% yield with 67% de (Table 2,
entry 2). The reaction also proceeded effectively in the absence of
organic cosolvent to give 4a in 64% yield with 75% de (Table 2,
entry 3). Lowering the temperature from 20 to 0 ◦C led to a
moderate increase in diastereoselectivity, to 83% de (Table 2,
entry 4). We have observed no remarkable effect of additive
on either the chemical yield or stereoselectivity by employing
CTAB, SDS and Yb(OTf)3 (Table 2, entries 5–7). Not only the
secondary cyclopentyl radical but also the bulky tertiary butyl
radical worked well under similar reaction conditions to give the
corresponding adducts 4c and 4e in good yields (Table 2, entries
8 and 9).
We next investigated zinc-mediated alkyl radical additions to
glyoxylic hydrazone 5 (Scheme 4). The zinc-mediated reaction
Scheme 4 Reagents and conditions: i) RI (5 eq. × 2), Zn (7 eq.), 20 ◦C,
Scheme
5
Reagents and conditions: i) Me3Al, (1R)-(+)-2,10-
1 h.
camphorsultam, CH2ClCH2Cl, reflux, 92%.
Table 2 Zinc-mediated radical additions to oxime ether 3
Entry
RI
Solvent
Additive/eq.
Time/h
Yield (%)d
de (%)e
1a
2a
3a
4b
5a
6a
7a
8c
9a
PriI
Sat. NH4Cl : CH2Cl2 (2 : 1)
Sat. NH4Cl : MeOH (2 : 1)
Sat. NH4Cl
Sat. NH4Cl
Sat. NH4Cl
Sat. NH4Cl
Sat. NH4Cl
Sat. NH4Cl
Sat. NH4Cl
None
None
None
None
CTAB (0.2)
SDS (0.2)
Yb(OTf)3 (1.0)
None
0.5
0.5
0.5
1
1
1
1
2
1
63
20
64
56
56
47
30
74
81
77
67
75
83
73
72
68
78
73
PriI
PriI
PriI
PriI
PriI
PriI
c-Pentyl I
ButI
None
a Reactions were carried out with RI (5 eq.) and zinc (7 eq.) at 2◦0 ◦C. b Reaction was carried out with PriI (5 eq.) and zinc (7 eq.) at 0 ◦C. c Reaction
was carried out with c-pentyl I (5 eq. × 2) and zinc (7 eq.) at 20 C. d Isolated yields. e Diastereoselectivities were determined by 1H NMR analysis.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 1 2 4 – 1 1 2 8
1 1 2 5

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The diastereoselective radical addition to hydrazone 7 was
examined under several reaction conditions (Scheme 6). The
biphasic reaction of 7 with an isopropyl radical in aqueous
NH4Cl–CH2Cl2 (4 : 1, v/v) proceeded slowly to give 8a in
73% yield after being stirred for 22 h (Table 4, entry 1). Some
starting material was also recoverd in 7% yield. As expected,
the diastereoselectivity observed in the reaction of hydrazone
7 was better than that obtained in the reaction of oxime ether
3, although the reaction of hydrazone 7 was slower than the
reaction of oxime ether 3. In contrast to the reaction of achiral
hydrazone 5, the monophasic reaction of 7 in aqueous NH4Cl–
MeOH (2 : 1, v/v) did not proceed effectively (Table 4, entry 2).
In the absence of organic cosolvent, the product 8a was obtained
in 26% yield with 83% de after being stirred in sat. aqueous
NH4Cl for 48 h (Table 4, entry 3). This is in contrast to the
reaction of oxime ether 3. The major diastereomer 8a could be
easily isolated by preparative TLC. The absolute configuration
at the newly formed stereocenter of major product 8a was
determined to be R by conversion into the known a-amino
acid 10. Thus, the stereochemical course of the diastereoselective
radical addition to hydrazone 7 was found to be the same as that
for the reaction of oxime ether 3. The cleavage of the N–N bond
of diastereomerically pure product 8a was successfully achieved
by hydrogenolysis in the presence of Pearlman catalyst and cam-
phorsulfonic acid (CSA). Subsequently, protection with CbzCl
and hydrolysis using 1 M LiOH gave N-Cbz-D-valine 10 in 61%
yield from 8a without any loss of optical purity. The cyclopentyl
radical addition also worked well (Table 4, entry 4). In the case
of tert-butyl radical addition, 84% yield of the desired product
8e was obtained as a single diastereomer (Table 4, entry 5).
Fig. 1 Stereochemical feature.
In conclusion, we have established the diastereoselective zinc-
mediated alkyl radical addition to imine derivatives such as
oxime ethers and hydrazones in aqueous media. The reactions
proceeded with good diastereoselectivities, providing access to
potentially a large range of a-amino acids.
Experimental
Melting points are uncorrected. 1H and 13C NMR spectra
were recorded at 500, 300, and 200 MHz and at 125, 75, and
50 MHz, respectively; chemical shifts are measured in ppm. IR
spectra were recorded using FTIR apparatus. Mass spectra were
obtained using the EI method. Preparative TLC separations
were carried out on precoated silica gel plates (E. Merck
60F254). Flash column chromatography was performed using
E. Merck Kieselgel 60 (230–400 mesh). Optical rotations were
recorded on a Jasco polarimeter with a path length of 1 cm;
concentrations are quoted in mg (2 mL). [a]D values were
measured in 10−1 deg cm2 g−1.
General procedure for alkyl radical addition to glyoxylic oxime
ether 1
To a micro tube containing 1 (50 mg, 0.26 mmol), RI (1.3 mmol),
zinc (119 mg, 1.82 mmol) and MeOH (0.2 mL) was added
dropwise aqueous sat. NH4Cl (0.4 mL) at 20 ◦C over 5 min. After
being stirred at the same temperature for 10 min, the reaction
mixture was diluted with 36% potassium sodium (+)-tartrate
and then extracted with CH2Cl2. The organic phase was washed,
dried over MgSO4 and concentrated at a reduced pressure.
Purification of the residue by preparative TLC (hexane–AcOEt,
10 : 1) afforded 2a–e14 in the yields shown in Table 1.
Scheme 6 Reagents and conditions: i) RI, Zn (7 eq.), 20 ◦C; ii) H2,
Pd(OH)2/C, CSA, MeOH, 20 ◦C; iii) CbzCl, Na2CO3, acetone–H2O,
0 ◦C (84%, 2 steps); iv) 1 M LiOH, THF, 20 ◦C (73%).
General procedure for alkyl radical addition to chiral oxime
ether 3
To a micro tube containing 3 (50 mg, 0.13 mmol), RI
(0.65 mmol), zinc (59.5 mg, 0.91 mmol) and cosolvent (0.2 mL)
was added dropwise aqueous sat. NH4Cl (0.4 mL) at 20 ◦C
over 5 min. After being stirred at the same temperature for 1 h,
the reaction mixture was diluted with 36% potassium sodium
(+)-tartrate and then extracted with CH2Cl2. The organic
phase was washed, dried over MgSO4 and concentrated at a
reduced pressure. Purification of the residue by preparative TLC
(hexane–AcOEt, 3 : 1) afforded 4a–e10a in the yields shown in
Table 2.
As shown in Fig. 1, the rotamer having the carbonyl group
anti to the sulfonyl group would be favored in order to
minimize dipole–dipole interactions between these groups. As
suggested by the studies on the camphorsultam derivatives of
glyoxylic acid,13 it is expected that the sterically more stable s-
cis planar conformation between the carbonyl group and the
diphenylhydrazino group would be favored. This would lead to
alkyl radical attack from a-face which is not hindered by the
S–O group.
Table 4 Zinc-mediated radical additions to hydrazone 7a
Entry
RI/eq.
Solvent
Time
Product
Yield (%)b
de (%)c
1
2
3
4
5
PriI (5.0)
Sat. NH4Cl : CH2Cl2 (4 : 1)
Sat. NH4Cl : MeOH (2 : 1)
Sat. NH4Cl
Sat. NH4Cl : CH2Cl2 (4:1)
Sat. NH4Cl : CH2Cl2 (4 : 1)
22
4
48
22
22
8a
8a
8a
8c
8e
73 (7)
4 (86)
26 (68)
58 (40)
84
86
—
83
86
>95
PriI (5.0 × 4)
PriI (10)
c-Pentyl I (5.0)
ButI (5.0)
a Reactions were carried out with RI and zinc (7 eq.) at 20 ◦C. b Isolated yields; yields in parentheses are for the recovered starting material 7.
c Diastereoselectivities were determined by 1H NMR analysis.
1 1 2 6
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 1 2 4 – 1 1 2 8

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General procedure for alkyl radical addition to glyoxylic
hydrazone 5
1486 cm−1. 1H NMR (CDCl3) d 7.45–7.21 (10H, m), 7.11
(1H, s), 4.01 (1H, dd, J = 8, 5.5 Hz), 3.41, 3.37 (each 1H, d,
J = 13.5 Hz), 2.15–2.08 (2H, m), 1.91–1.86 (3H, m), 1.45–1.34
(2H, m), 1.14, 0.95 (each 3H, s). 13C NMR (CDCl3) d 162.1,
129.9, 124.6, 65.4, 53.1, 48.6, 47.7, 44.8, 38.5, 32.9, 26.5, 21.0,
19.9. HRMS calcd for C24H27N3O3S (M+) 437.1772, found:
437.1773. Anal. calcd for C24H27N3O3S: C, 65.88; H, 6.22; N,
9.60; S, 7.33%. Found: C, 65.62; H, 6.19; N, 9.59; S, 7.49%.
To a micro tube containing 5 (50 mg, 0.2 mmol), RI (2.0 mmol),
zinc (92 mg, 1.4 mmol) and MeOH (0.2 mL) was added dropwise
aqueous sat. NH4Cl (0.4 mL) at 20 ◦C over 5 min. After being
stirred at the same temperature for 1 h, the reaction mixture
was diluted with 36% potassium sodium (+)-tartrate and then
extracted with CH2Cl2. The organic phase was washed, dried
over MgSO4 and concentrated at a reduced pressure. Purification
of the residue by preparative TLC (hexane–AcOEt, 5 : 1)
afforded 6a–e in the yields shown in Table 3.
General procedure for alkyl radical addition to chiral hydrazone 7
To a micro tube containing 7 (50 mg, 0.11 mmol), RI
(0.55 mmol), zinc (50.3 mg, 0.77 mmol) and CH2Cl2 (0.1 mL)
was added dropwise aqueous sat. NH4Cl (0.4 mL) at 20 ◦C over
5 min. After being stirred at the same temperature for 22 h,
the reaction mixture was diluted with 36% potassium sodium
(+)-tartrate and then extracted with CH2Cl2. The organic
phase was washed, dried over MgSO4 and concentrated at a
reduced pressure. Purification of the residue by preparative TLC
(hexane–AcOEt, 3 : 1) afforded 8a–c in the yields shown in
Table 4.
2-(2,2-Diphenylhydrazino)-3-methylbutanoic acid methyl ester
(6a). Colorless crystals. Mp 43–43.5 ◦C (hexane). IR (CHCl3)
1
3012, 1731, 1589, 1489 cm−1. H NMR (CDCl3) d 7.29–6.98
(10H, m), 4.40 (1H, br s), 3.45 (3H, s), 3.41 (1H, d, J = 6.3 Hz),
2.03–1.96 (1H, m), 1.07 (3H, d, J = 6.6 Hz), 0.97 (3H, d, J =
6.6 Hz). 13C NMR (CDCl3) d 173.8, 148.0, 129.0, 122.7, 120.9,
67.7, 51.2, 30.5, 19.2, 18.8. HRMS calcd for C18H22N2O2 (M+)
298.1680, found 298.1696. Anal. calcd for C18H22N2O2: C, 72.46;
H, 7.43; N, 9.39%. Found: C, 72.70; H, 7.44; N, 9.28%.
(3aR,6S,7aS)-Hexahydro-8,8-dimethyl-1-[(2R)-1-oxo-2-(2,2-
diphenylhydrazino)-3-(methyl)butyl]-3H-3a,6-methano-2,1-benz-
isothiazole 2,2-dioxide [(R)-8a]. Colorless crystals. Mp 145.5–
2-(2,2-Diphenylhydrazino)-3-methylpentanoic acid methyl es-
ter (6b). A 1 : 1 mixture of diastereomers with regard the sec-
butyl group. A colorless oil. IR (CHCl3) 3029, 3010, 2965, 1730,
◦
146.5 C (AcOEt–hexane). [a]2D3 +20.1 (c 1.00, CHCl3). IR
1
1589 cm−1. H NMR (CDCl3) d 7.29–6.98 (10H, m), 4.41 (1H,
(CHCl3) 3010, 2966, 1691, 1589, 1492 cm−1. 1H NMR (CDCl3)
d 7.28–7.15 (10H, m), 4.59 (1H, br s), 4.17 (1H, br s), 3.64
(1H, dd, J = 7.5, 5 Hz), 3.42, 3.38 (each 1H, d, J = 13.5 Hz),
2.18–2.14 (1H, m), 1.97–1.82 (5H, m), 1.39–1.28 (2H, m), 1.16,
0.90 (each 3H, d, J = 7 Hz), 1.07, 0.93 (each 3H, s). 13C NMR
(CDCl3) d 173.6, 149.1, 129.0, 122.8, 121.5, 67.8, 65.0, 52.9,
48.5, 47.8, 44.4, 38.4, 32.8, 32.1, 26.4, 20.7, 20.6, 19.9, 16.3.
HRMS calcd for C27H35N3O3S (M+) 481.2397, found 481.2402.
Anal. calcd for C27H35N3O3S: C, 67.33; H, 7.32; N, 8.72; S,
6.66%. Found: C, 67.30; H, 7.40; N, 8.62; S, 6.88%.
br s), 3.53–3.50 (1H, br m), 3.47 (3H, s), 1.84–1.72 (1H, m),
1.66–1.52 (1H, m), 1.38–1.16 (1H, m), 1.04–0.87 (6H, m). 13C
NMR (CDCl3) d 174.1, 169.9, 148.2, 148.1, 129.0, 122.7, 121.0,
66.1, 66.0, 51.3, 51.2, 37.4, 37.0, 26.0, 25.9, 15.5, 15.3, 11.7, 11.4.
HRMS calcd for C19H24N2O2 (M+) 312.1836, found 312.1847.
a-(2,2-Diphenylhydrazino)cyclopentaneacetic acid methyl ester
◦
(6c). Colorless crystals. Mp 52.5–53 C (AcOEt–hexane). IR
(CHCl3) 2953, 1732, 1589, 1497 cm−1. 1H NMR (CDCl3) d 7.29–
7.00 (10H, m), 4.28 (1H, br s), 3.42 (3H, s), 3.42 (1H, br m),
2.13–2.02 (1H, m), 1.98–1.88 (1H, m), 1.66–1.28 (7H, m). 13C
NMR (CDCl3) d 174.3, 148.0, 129.0, 122.7, 120.9, 66.9, 51.3,
41.6, 30.0, 29.0, 25.1, 24.9. HRMS calcd for C20H24N2O2 (M+)
324.1836, found 324.1836. Anal. calcd for C20H24N2O2: C, 74.04;
H, 7.46; N, 8.64%. Found: C, 74.05; H, 7.45; N, 8.62%.
(3aR,6S,7aS)-Hexahydro-8,8-dimethyl-1-[(2S)-1-oxo-2-(2,2-
diphenylhydrazino)-3-(methyl)butyl]-3H-3a,6-methano-2,1-benz-
isothiazole 2,2-dioxide [(S)-8a]. A yellow solid. [a]2D3 +34.5 (c
1.15, CHCl3). IR (CHCl3) 3018, 2966, 1685, 1589, 1493 cm−1.
1H NMR (CDCl3) d 7.27–7.12 (10H, m), 4.57 (1H, br s), 4.05
(1H, d, J = 4.5 Hz), 3.75 (1H, dd, J = 7.4, 4.2 Hz), 3.41, 3.34
(each 1H, d, J = 13.8 Hz), 2.20–2.09 (1H, m), 1.92–1.70 (5H,
m), 1.36–1.26 (2H, m), 1.13, 1.00 (each 3H, d, J = 6.9 Hz),
0.88, 0.85 (each 3H, s). 13C NMR (CDCl3) d 173.8, 148.7, 129.0,
122.7, 121.1, 66.9, 65.6, 53.0, 48.2, 47.6, 44.5, 38.5, 33.0, 30.1,
26.3, 21.0, 19.8, 16.9. HRMS calcd for C27H35N3O3S (M+)
481.2397, found 481.2404.
a-(2,2-Diphenylhydrazino)cyclohexaneacetic acid methyl ester
(6d). A white solid. IR (CHCl3) 2932, 1731, 1589, 1497 cm−1.
1H NMR (CDCl3) d 7.30–6.98 (10H, m), 4.35 (1H, br s), 3.43
(3H, s), 3.41 (1H, br d), 1.96–1.92 (1H, m), 1.78–1.59 (5H, m),
1.27–1.09 (5H, m). 13C NMR (CDCl3) d 174.1, 148.1, 129.0,
122.8, 121.0, 67.5, 51.3, 40.1, 29.8, 29.4, 26.2, 26.1. HRMS calcd
for C21H26N2O2 (M+) 338.2037, found 338.2015.
(3aR,6S,7aS)-1-[(2R)-2-Cyclopentyl-2-(2,2-diphenylhydrazino)-
acetyl]hexahydro-8,8-dimethyl-3H -3a,6-methano-2,1-benziso-
thiazole 2,2-dioxide [(R)-8c]. A colorless oil. [a]2D4 +39.5 (c
1.04, CHCl3). IR (CHCl3) 2961, 1692, 1589, 1493 cm−1. 1H
NMR (CDCl3) d 7.29–6.97 (10H, m), 4.60 (1H, br s), 4.28 (1H,
br s), 3.66 (1H, t, J = 6.3 Hz), 3.43, 3.37 (each 1H, d, J =
13.5 Hz), 2.30–2.22 (1H, m), 1.98–1.26 (15H, m), 1.08, 0.93
(each 3H, s). 13C NMR (CDCl3) d 174.0, 149.1, 128.9, 122.7,
121.4, 65.6, 65.1, 53.0, 48.3, 47.7, 44.4, 43.3, 38.3, 32.8, 29.2,
27.9, 26.4, 25.5, 25.4, 20.6, 19.9. HRMS calcd for C29H37N3O3S
(M+) 507.2553, found 507.2565.
2-(2,2-Diphenylhydrazino)-3,3-dimethylbutanoic acid methyl
ester (6e). A white solid. IR (CHCl3) 2955, 1729, 1589,
1
1498 cm−1. H NMR (CDCl3) d 7.32–6.98 (10H, m), 4.35 (1H,
br s), 3.36 (3H, s), 3.36 (1H, br d), 1.03 (9H, s). 13C NMR (CDCl3)
d 174.0, 148.5, 129.1, 122.9, 121.3, 71.4, 51.0, 34.2, 27.0. HRMS
calcd for C19H24N2O2 (M+) 312.1836, found 312.1840.
(3aR,6S,7aS)-Hexahydro-8,8-dimethyl-1-[(2E)-(diphenylhydra-
zono)acetyl]-3H-3a,6-methano-2,1-benzisothiazole 2,2-dioxide
(7). To a solution of (1R)-(+)-2,10-camphorsultam (1.0 g,
4.6 mmol) and 5 (1.8 g, 7.0 mmol) in CH2ClCH2Cl (60 mL)
was added Me3Al (1.0 M in hexane, 7.1 mL, 7.0 mmol) under a
nitrogen atmosphere at room temperature. After being heated
at reflux for 10 h, the reaction mixture was diluted with 36%
potassium sodium (+)-tartrate and then extracted with CH2Cl2.
The organic phase was washed with water, dried over MgSO4
and concentrated at a reduced pressure. Purification by flash
chromatography (CHCl3–hexane, 10 : 1) afforded 7 (1.23 g,
61%). Colorless crystals. mp 226–227 ◦C (AcOEt–hexane).
[a]2D1 +51 (c 1.00, CHCl3); IR (CHCl3) 3010, 2964, 1676, 1536,
((3aR,6S,7aS)-1-[(2S)-2-Cyclopentyl-2-(2,2-diphenylhydra-
zino)acetyl]hexahydro-8,8-dimethyl-3H-3a,6-methano-2,1-benz-
isothiazole 2,2-dioxide [(S)-8c]. A yellow solid. IR (CHCl3)
1
2959, 1691, 1589, 1493 cm−1. H NMR (CDCl3) d 7.27–6.96
(10H, m), 4.42 (1H, br s), 4.15 (1H, br d, J = 6.3 Hz), 3.82–3.77
(1H, m), 3.41, 3.34 (each 1H, d, J = 13.8 Hz), 2.35–2.28 (1H,
m), 1.94–1.25 (15H, m), 0.86, 0.80 (each 3H, s). HRMS calcd
for C29H37N3O3S (M+) 507.2554, found 507.2548.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 1 2 4 – 1 1 2 8
1 1 2 7

View Article Online
(3aR,6S,7aS)-Hexahydro-8,8-dimethyl-1-[(2R)-3,3-dimethyl-
1-oxo-2-(2,2-diphenylhydrazino)butyl]-3H-3a,6-methano-2,1-
benzisothiazole 2,2-dioxide [(R)-8e]. A colorless oil. [a]2D4 +50.6
Acknowledgements
This work was supported in part by Grant-in-Aid for Scientific
Research (B) (T. N.) and for Young Scientists (B) (M. U.
and H. M.) from the Ministry of Education, Culture, Sports,
Science and Technology of Japan. We thank the Science Re-
search Promotion Fund of the Japan Private School Promotion
Foundation for reseach grants and Fuji Photo Film Award in
Synthetic Organic Chemistry, Japan (M. U.).
1
(c 1.11, CHCl3). IR (CHCl3) 2958, 1685, 1589, 1467 cm−1. H
NMR (CDCl3) d 7.29–6.97 (10H, m), 4.63 (1H, br s), 4.11
(1H, s), 3.66 (1H, t, J = 6.3 Hz), 3.43, 3.37 (each 1H, d, J =
13.5 Hz), 2.05–2.01 (2H, br m), 1.93–1.81 (3H, br m), 1.35–1.20
(3H, br m), 1.08 (12H, m), 0.93 (each 3H, s). 13C NMR (CDCl3)
d 174.1, 149.3, 128.7, 122.6, 121.4, 69.3, 65.9, 53.2, 47.6, 47.5,
44.5, 38.6, 35.8, 33.2, 27.1, 26.4, 20.6, 20.0. HRMS calcd for
C28H37N3O3S (M+) 495.2554, found 495.2546.
References
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[(1R)-2-Methyl-1-[[(3aR,6S,7aS)-tetrahydro-8,8-dimethyl-2,2-
dioxide-3H-3a,6-methano-2,1-benzisothiazol-1(4H)-yl]carbonyl]-
propyl]carbamic acid 2,2-dioxide phenylmethyl ester (9).
A
suspension of 20% Pd(OH)2/C (208 mg) in MeOH (5 mL)
◦
was stirred under a hydrogen atmosphere (1 atm) at 20 C for
45 min. To this suspension was added a solution of (R)-8a
(100 mg, 0.20 mmol) and 10-camphorsulfonic acid (100 mg,
0.40 mmol) in MeOH (10 mL). After being stirred under a
hydrogen atmosphere at the same temperature for 30 min, the
reaction mixture was filtered and the filtrate was concentrated
at a reduced pressure to afford the crude amine. To a solution
of the resulting crude amine in acetone (5 mL) was added
a solution of Na2CO3 (106 mg, 1.00 mmol) in H2O (2 mL)
under a nitrogen atmosphere at 20 ◦C. After a solution of
benzyloxycarbonyl chloride (0.9 mL, 0.60 mmol) in acetone
(1 mL) was added to the reaction mixture at 20 ◦C, the reaction
mixture was stirred at the same temperature for 5 h. After
the reaction mixture was concentrated at a reduced pressure,
the resulting residue was diluted with CH2Cl2 and water and
then extracted with CH2Cl2. The organic phase was dried over
MgSO4 and concentrated at a reduced pressure. Purification by
preparative TLC (hexane–AcOEt, 4 : 1) afforded 9 (75.1 mg,
84%). Colorless crystals. Mp 169–170 ◦C (AcOEt–hexane).
[a]2D9 +62 (c 1.50, CHCl3). IR (CHCl3) 3010, 2966, 1691, 1589,
1
1492 cm−1. H NMR (CDCl3) d 7.41–7.29 (5H, m), 5.35 (1H,
br d, J = 9 Hz), 5.14, 5.08 (each 1H, br d, J = 12 Hz), 4.94
(1H, br dd, J = 9, 3 Hz), 3.91 (1H, br t, J = 6 Hz), 3.49, 3.47
(each 1H, br d, J = 14 Hz), 2.29 (1H, br m), 2.08 (1H, dd, J =
13.5), 2.03–1.85 (4H, br m), 1.46–1.32 (2H, m), 1.13, 0.97 (each
3H, s), 1.04, 0.80 (each 3H, d, J = 7 Hz). 13C NMR (CDCl3) d
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, 61.6; H, 7.24; N, 6.25; S, 7.34%.
N-[(Phenylmethoxy)carbonyl]-D-valine (10). A solution of 9
(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 a reduced pressure, the resulting residue was
diluted with water, acidified to a pH between 4 and 5 with
diluted HCl, then extracted with CH2Cl2. The organic phase
was dried over Na2SO4 and concentrated at a reduced pressure.
Purification of the residue by flash column chromatography
(hexane–AcOEt, 1 : 2) afforded 10 (71 mg, 73%). A colorless oil.
[a]2D7 +5.6 (c 1.78, CHCl3). IR (CHCl3) 3438, 1715, 1456 cm−1.
1H NMR (CDCl3) d 7.39–7.28 (5H, m), 5.27 (1H, br m), 5.12,
5.11 (each 1H, br d, J = 12 Hz), 4.34 (1H, br m), 2.22 (1H, br
m), 1.00, 0.93 (each 3H, J = 7.5 Hz). 13C NMR (CDCl3) d 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 C13H17N2O4 (M+) 251.1157, found 251.1152.
14 H. Miyabe, M. Ueda, N. Yoshioka, K. Yamakawa and T. Naito,
Tetrahedron, 2000, 56, 24131.
1 1 2 8
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 1 2 4 – 1 1 2 8