Radical addition to oxime ethers for asymmetric synthesis of β-amino acid derivatives

Article abstract of DOI:10.1039/b208823a

The diastereoselective alkyl radical addition to chiral oxime ethers was studied with a view to preparing enantiomerically pure α,β-dialkyl-β-amino acid derivatives. The phase transfer-catalyzed alkylation of Oppolzer's camphorsultam derivative of oxime e

Full text of DOI:10.1039/b208823a

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Radical addition to oxime ethers for asymmetric synthesis of
ꢀ-amino acid derivatives
Hideto Miyabe,† Kayoko Fujii and Takeaki Naito*
Kobe Pharmaceutical University, Motoyamakita, Higashinada, Kobe 658-8558, Japan.
E-mail: taknaito@kobepharma-u.ac.jp
Received 10th September 2002, Accepted 21st October 2002
First published as an Advance Article on the web 16th December 2002
The diastereoselective alkyl radical addition to chiral oxime ethers was studied with a view to preparing
enantiomerically pure α,β-dialkyl-β-amino acid derivatives. The phase transfer-catalyzed alkylation of Oppolzer’s
camphorsultam derivative of oxime ether proceeded smoothly to give the alkylated N-(β-oximino)acyl derivatives. In
the presence of BF3ؒOEt2, radical addition to the oxime ethers proceeded using triethylborane as the radical initiator
to give α,β-dialkyl-β-amino acid derivatives with excellent diastereoselectivity.
Introduction
The control of stereochemistry in free radical-mediated reac-
tions has been of great importance in organic synthesis.1
Asymmetric induction, particularly in intermolecular carbon–
carbon bond-forming radical reactions of acyclic systems, is a
subject of current interest.1 Although a high degree of stereo-
control of radical reactions has been achieved in recent years,
stereocontrol in radical addition to imine derivatives has not
been widely studied.2 Only three studies have been directed
toward stereocontrol in the intermolecular carbon radical addi-
tion to imine derivatives.3–5 Bertrand’s and our groups recently
reported studies on stereocontrol in the radical addition to acti-
vated imine derivatives such as glyoxylic oxime ethers and
imines, which were successfully used for the novel asymmetric
synthesis of α-amino acids.3,4 More recently, Friestad and Qin
reported diastereoselective radical addition to acylhydrazone.5
Among the different types of radical acceptors containing a
carbon–nitrogen double bond, the oxime ethers are well known
to be excellent radical acceptors because of the extra stabiliz-
ation of the intermediate alkoxyaminyl radical provided by the
lone pair on the adjacent oxygen atom.6 However, studies on the
radical reaction of oxime ethers have concentrated on intra-
molecular reactions,6 and the difficulty of achieving the inter-
molecular construction of a carbon–carbon bond has remained
unresolved.7–10 Therefore, stereoselective carbon–carbon bond
formation based on intermolecular carbon radical addition to
oxime ethers is a challenging and promising task. We are inter-
ested in the stereoselective carbon–carbon bond-forming reac-
tions based on the intermolecular carbon radical addition to a
carbon–nitrogen double bond of acyclic oxime ethers.4 In this
paper, we describe full details of diastereoselective radical
addition to unactivated oxime ethers bearing Oppolzer’s
camphorsultam for the synthesis of the enantiomerically pure
β-amino acid derivatives.11
Scheme 1 Reagents and conditions: i, BnONH2ؒHCl, p-TsOH, THF,
60 ЊC, 88%; ii, BF3ؒOEt2, Et3B, CH2Cl2, 20 ЊC, 68%.
solution of oxime ether 2 and BF3ؒOEt2 in CH2Cl2 was added a
commercially available 1.0 M solution of Et3B in hexane, and
then the reaction mixture was stirred at 20 ЊC. As indicated in
our previous studies,10 oxime ether 2 exhibits good reactivity in
the presence of BF3ؒOEt2 to give the desired product 3 in 68%
yield. This result suggests that the radical addition to oxime
ethers is a highly promising approach to the synthesis of β-
amino acids.13 Additionally, it should be noted that the unacti-
vated oxime ether having an acidic α-hydrogen reacted
smoothly with a carbon radical. Nucleophilic addition to oxime
ether 2 would be expected to be plagued by undesired de-
protonation of the acidic α-hydrogen leading to the formation
of a tautomer of the substrate.
The auxiliary of choice was Oppolzer’s camphorsultam since
it had shown good characteristics in our previous work on
radical addition to glyoxylic oxime ethers.4 Oxime ether 4 was
readily prepared by treatment of ethyl 3-[N-(phenylmethoxy)-
imino]propionate 2 with (1S)-(Ϫ)-2,10-camphorsultam in the
presence of trimethylaluminium in boiling 1,2-dichloroethane
(Scheme 2). The camphorsultam derivative of oxime ether 4 has
Scheme 2 Reagents and conditions: i, Me3Al, (1S)-camphorsultam,
CH2ClCH2Cl, reflux, 95%.
Results and discussion
Prior to exploring issues of stereocontrol, we first investigated
the intermolecular carbon radical addition to achiral oxime
ether 2 (Scheme 1). Oxime ether 2 was prepared from com-
mercially available ethyl 3,3-diethoxypropionate and O-benzyl-
hydroxylamine hydrochloride.12 We recently reported the
potential of BF3ؒOEt2 as a Lewis acid in achieving the inter-
molecular radical addition to unactivated oxime ethers.10 To a
enough flexibility to allow access to a wide range of α,β-dialkyl-
β-amino acids.
We next investigated the anionic alkylation of sultam com-
pound 4 under several reaction conditions (Scheme 3, Table 1).
The methylation of 4 using LiHMDS (5 equiv.) gave the
undesired methylated product 5A in 61% yield with 15% yield
of the starting material 4 (Table 1, entry 1). The configuration
of the newly-formed stereocenter of 5A was not determined.
Methylation of 4 using NaHMDS (2.5 equiv.) gave a similar
result (entry 3). In the presence of MeOH (6 equiv.), methyl-
† Present address: Graduate School of Pharmaceutical Sciences, Kyoto
University, Yoshida, Sakyo-ku, Kyoto 606–8501, Japan.
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 3
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 8 1 – 3 9 0
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Table 1 Methylation of oxime ether 4
Yield (%)
Entry
Base (equiv.)
Additive (equiv.)
5a
5A
4
1a
2a
3a
4a
5a
6c
LiHMDS (5)
LiHMDS (2)
NaHMDS (2.5)
NaHMDS (1.5)
NaHMDS (6)
5 M NaOH
None
None
None
None
MeOH (6)
Bu4NBr (0.1)
61
78
15
90
80
59
19b
85 (13.1 : 1 : 1.2)b
1
a Reaction was carried out with MeI in THF at Ϫ78 ЊC. b Combined yields; ratio of (R,Z)-, (R,E)-, (S,Z)-isomers was determined by H NMR
analysis after PTLC. c Reaction was carried out with MeI (1.5 equiv.) and Bu4NBr (0.1 equiv.) in 5 M NaOH–CH2Cl2 at 20 ЊC.
diastereomerically pure alkylated products (R,Z)-5c, (R,Z)-5d,
and (R,Z)-5e could also be obtained under similar reaction
conditions after recrystallisation (entries 2–4). In contrast,
oxime ethers 5a, 5f, and 5g were obtained as an oil; thus, we
could not separate (R,Z)-, (R,E)-, and (S,Z)-isomers by either
medium-pressure column chromatography or recrystallisation
(Table 1, entry 6 and Table 2, entries 5 and 6). The absolute
configuration of major products 5a and 5c–g was assigned to
be R since their H NMR data showed similarity with that of
Scheme 3 Reagents and conditions: i, Base, MeI.
1
(R,Z)-5b. Although no isomerization of the newly-formed
chiral center of (R,Z)-5b was observed by treatment with tetra-
butylammonium bromide (0.1 equiv.) in 5 M NaOH–CH2Cl2,
(R,Z)-5b was isomerized to the more stable (R,E)-5b under
acidic conditions (Scheme 5).
ation of 4 using NaHMDS (6 equiv.) gave the desired methyl-
ated product 5a in 19% yield with 59% yield of the starting
material 4 (entry 5). These results suggest that a weak base such
as NaOMe is effective in the deprotonation of the acidic methyl-
ene in oxime ether 4. The phase transfer-catalyzed reaction was
an excellent method for the regioselective alkylation of the
acidic methylene in oxime ether 4 with no detection of the
undesired methylated product 5A (entry 6). Methylation of
sultam derivative 4 was carried out using MeI and tetrabutyl-
ammonium bromide as a phase-transfer catalyst in 5 M
NaOH–CH2Cl2 at 20 ЊC. The desired methylated oxime ether 5a
was obtained in 85% combined yield in a 13.1 : 1 : 1.2 ratio of
(R,Z)-, (R,E)-, and (S,Z)-isomers. The E : Z ratios of the oxime
1
ether group were deduced by H-NMR spectroscopy. In gen-
eral, 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.14
The phase transfer-catalyzed alkylation of sultam compound
4 using different alkylating reagents R1X was studied (Scheme
4). The results are summarized in Table 2. All alkylations of
Scheme 5 Reagents and conditions: i, Bu4NBr, 5 M NaOH, CH2Cl2,
20 ЊC; ii, 5% HCl, CH2Cl2, 20 ЊC.
As suggested by the studies on the camphorsultam derivative
by Oppolzer’s group,15 the stereochemical feature of this alkyl-
ation reaction can be rationalized in terms of the stereo-
electronic effect in the chelated (Z)-enolate anion of the
conformationally restricted oxime ether 4 (Fig. 1).
We next investigated ethyl radical addition to the oxime ether
5a by using triethylborane as an ethyl radical source (Scheme 6).
Scheme 4 Reagents and conditions: i, R1X, Bu4NBr, 5 M NaOH,
CH2Cl2, 20 ЊC; ii, recrystallization.
sultam derivative 4 were carried out using alkyl bromides and
tetrabutylammonium bromide (0.1 equiv.) as phase-transfer
catalyst in 5 M NaOH–CH2Cl2 at 20 ЊC for 1 h. In the case of
benzylation using benzyl bromide, the desired benzylated oxime
ether 5b was obtained in 99% combined yield in favor of the
(R,Z)-isomer (Table 2, entry 1). The absolute configuration at
the newly-formed chiral center of the major product of 5b was
determined to be R by X-ray analysis of (R,Z)-5b. The other
Fig. 1 Transition-state model for the alkylation of 4.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 8 1 – 3 9 0
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Table 2 Alkylation of oxime ether 4
Entry
R1X
Product
Yield (%)a
Ratiob R,Z : R,E : S,Z
Purity after recrystallisationc
1d
2d
3d
4d
5e
6e
BnBr
4-NO2-Benzyl Br
Propargyl Br
5b
5c
5d
5e
5f
99
98
99
97
15.7 : 1.0 : 1.3
7.6 : 1.0 : 1.0
9.7 : 1.2 : 1.0
8.5 : 1.4 : 1.3
9.8 : 1.3 : 1.0
10.0 : 1.0 : —
95% de
95% de
95% de
95% de
—
Allyl I
4-Bromo-2-methylbut-2-ene
Methyl bromoacetate
91
5g
47 (42)f
—
a Combined yields. b Ratios were determined by 1H NMR analysis after PTLC. c Diastereomeric purities of 5b–e were determined after recrystallis-
ation. The diastereomerically pure materials (R,Z)-5b–e were obtained in ca. 60–80% yields after recrystallisation. d Alkylation was carried out with
R1X (1.1 equiv.) and Bu4NBr (0.1 equiv.) in 5 M NaOH–CH2Cl2 at 20 ЊC. e Alkylation was carried out with R1X (1.5 equiv.) and Bu4NBr (0.1 equiv.)
in 5 M NaOH–CH2Cl2 at 20 ЊC. f Yield in parentheses is that for starting material.
Table 3 Ethyl radical addition to (R,Z)-5b–e
Entry
Oxime ether
Solvent
T /ЊC
Product
Yield (%)a
Selectivityb
1c
2d
(R,Z)-5b
(R,Z)-5b
(R,Z)-5b
(R,Z)-5c
(R,Z)-5c
(R,Z)-5c
(R,Z)-5d
(R,Z)-5d
(R,Z)-5e
(R,Z)-5e
(R,Z)-5b
CH2Cl2
CH2Cl2
Toluene
CH2Cl2
Toluene
Toluene
CH2Cl2
Toluene
CH2Cl2
Toluene
CH2Cl2
Ϫ78
20
20
6bA
6bA
6bA
6cA
6cA
6cA
6dA
6dA
6eA
6eA
6bA
95
99
99
66
72
60
43 (37)
31 (45)
>95% de
>95% de
>95% de
>95% de
>95% de
>95% de
>95% de
>95% de
3d
4c
Ϫ78
Ϫ78
20
Ϫ78
Ϫ78
Ϫ78
Ϫ78
20
5c
6d
7c
8c
9c
Complex mixture
Complex mixture
No reaction
10c
11e
a Isolated yields; yield in parentheses is that for the recovered starting material. b Diastereoselectivities were determined by 1H NMR analysis.
c Radical addition at Ϫ78 ЊC was carried out with BF3ؒOEt2 (9 equiv.) and Et3B (9 equiv.). d Radical addition at 20 ЊC was carried out with BF3ؒOEt2
(5 equiv.) and Et3B (5 equiv.). e Radical addition at 20 ЊC was carried out with BF3ؒOEt2 (3 equiv.) and Et2Zn (3 equiv.).
and chemical yield were still maintained in the reaction at 20 ЊC
(entry 2). In regard to the solvent effect, replacement of CH2Cl2
by a nonpolar aromatic solvent such as toluene was also effect-
ive in the radical reaction giving the ethylated product 6bA in
99% yield with excellent diastereoselectivity (entry 3). The abso-
lute configuration at the newly-formed stereocenter of the
ethylated product 6bA was determined to be S by X-ray analy-
sis. Excellent diastereoselectivities were also observed in the
radical addition to different radical acceptors (R,Z)-5c and -5d
containing a 4-nitrobenzyl group or a carbon–carbon triple
bond, respectively, to afford the ethylated products 6cA and
6dA with relatively low efficiency (entries 4–8). In contrast, the
reaction of (R,Z)-5e did not give good results (entries 9 and
10). Although the ethyl radical addition to the oxime ether
(R,Z)-5b was studied by using diethylzinc as the ethyl radical
source, no reaction took place (entry 11).
In the case of the radical addition to the oxime ether 4, the
ethylated product 7 was obtained with low diastereoselectivity,
probably because the approaching radical was too far away
from the chiral sultam part (Scheme 8). Thus, the high stereo-
Scheme 6 Reagents and conditions: i, BF3ؒOEt2, Et3B, toluene, 20 ЊC,
70%.
In the presence of BF3ؒOEt2, the radical addition to the oxime
ether 5a proceeded smoothly to give the α,β-dialkyl-β-amino
acid derivative, while no reaction occurred in the absence of
BF3ؒOEt2. Although a mixture of (R,Z)-, (R,E)- and (S,Z)-
isomers 5a was used as the substrate, the ethylated product 6aA
was obtained as the major isomer in 70% isolated yield after
separation of isomers.
The ethyl radical addition to other oxime ethers (R,Z)-5b–5e
was also studied (Scheme 7). In the presence of BF3ؒOEt2, the
Scheme 7 Reagents and conditions: i, BF3ؒOEt2, Et3B.
Scheme 8 Reagents and conditions: i, BF3ؒOEt2, Et3B, Ϫ78 ЊC.
reaction of (R,Z)-5b with triethylborane in CH2Cl2 proceeded
smoothly within 15 min even at Ϫ78 ЊC to give a 95% yield of
the ethylated product 6bA (Table 3, entry 1). The diastereomeric
purity of 6bA was found to be not less than 95% de by 1H NMR
analysis of the crude products. The high diastereoselectivity
control in the alkyl radical addition to (R,Z)-5b–5d would be
regarded as the result of high 1,2-asymmetric induction.
In the case of (R,Z)-5b–5d, the conformer A minimizing
A1,3-strain effects would be favored (Fig. 2). Additionally, the
stable conformation was also supported by the crystal structure
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 8 1 – 3 9 0
383

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Fig. 2 1,2-Asymmetric induction.
resulting from X-ray analysis of (R,Z)-5b. Thus, ethyl radical
addition took place predominantly from the less-hindered
π-face of oxime ethers activated by BF3, in which the bulky
alkyl group (R1) shields the opposite face. After the radical
reaction in the presence of BF3ؒOEt2, isomerization of (Z)-5 to
(E)-5 was observed in the recovered starting materials 5. Thus,
both (Z)- and (E)-isomers would be important for the radical
reaction of 5.
To explore the issues of 1,2-asymmetric induction,16 we also
studied the radical addition to simple oxime ether 8 (Scheme 9).
Scheme 10 Reagents and conditions: i, H2, Pd(OH)2–C, MeOH, 20 ЊC;
ii, CbzCl, Na2CO3, acetone–H2O, 20 ЊC, 96% (2 steps); iii, LiOH, H2O,
THF, reflux, 62%.
Scheme 9 Reagents and conditions: i, BnBr, Bu4NBr, 5 M NaOH,
CH2Cl2, 20 ЊC, 78%; ii, BF3ؒOEt2, Et3B, CH2Cl2, 20 ЊC, 54%.
Scheme 11 Reagents and conditions: i, Bu3SnH, BF3ؒOEt2, PriI, Et3B,
CH2C12, 20 ЊC, 43%; ii, BF3ؒOEt2, PriI, Et3B, toluene, 50 ЊC, 71%.
Benzylation of oxime ether 2 was run by using benzyl bromide
and tetrabutylammonium bromide as a phase-transfer catalyst
in 5 M NaOH–CH2Cl2 at 20 ЊC. The desired benzylated oxime
ether (Z)-8 was obtained in 78% yield. In the presence of
BF3ؒOEt2, the reaction of (Z)-8 with triethylborane proceeded
smoothly to give a 54% yield of the ethylated product 9 in 83%
de. The relative configuration of 9 was not determined. These
results suggest that 1,2-asymmetric induction is responsible for
diastereocontrol in the radical reaction of (R,Z)-5a–5d.
Hydrogenolysis of the benzyloxy group of 6bA in the
presence of Pd(OH)2 in MeOH and subsequent protection of
the resulting amine with benzyloxycarbonyl chloride gave
10 in 96% yield from 6bA (Scheme 10). The removal of the
sultam auxiliary by standard hydrolysis17 afforded the
enantiomerically pure α,β-dialkyl-β-amino acid 11 in 62% yield
without any loss of stereochemical purity.
We next investigated radical reactions using different radical
precursors. At first, isopropyl radical addition to oxime ether 2
was studied under different reaction conditions (Scheme 11). A
modest chemical yield was obtained in the stannyl radical-
mediated reaction of 2 using isopropyl iodide, Bu3SnH, and
Et3B in the presence of BF3ؒOEt2. Free radical synthetic
methods have largely relied on toxic organomercury or organo-
tin chemistry. From economic and ecological points of view, we
next investigated radical addition to oxime ether 2 in the
absence of Bu3SnH.18 Even in the absence of Bu3SnH, treat-
ment of 2 with isopropyl iodide and Et3B in toluene at 50 ЊC for
5 min gave the desired product 12 in 71% yield. The reaction
proceeded via a route involving an iodine atom-transfer process
between isopropyl iodide and an ethyl radical generated from
Et3B. In this reaction, Et3B acts as a radical initiator and a
radical terminator to trap the intermediate benzyloxyaminyl
radical.18 Thus, the radical chain reaction proceeds via the
regeneration of the ethyl radical by a simple procedure, which
does not require tedious workup to remove the tin residues
from the reaction mixture.
In order to investigate the generality and practicality of the
reaction, the present procedure was successfully extended to the
radical addition reactions to (R,Z)-5b–c (Scheme 12). The
isopropyl radical addition to (R,Z)-5b was run in toluene at
20 ЊC by using isopropyl iodide and Et3B in the presence of
BF3ؒOEt2 (Table 4, entry 1). As expected, the reaction proceeded
smoothly in the absence of tin hydride to give a good yield of
isopropylated product 6bB with a high level of diastereo-
selectivity. In this reaction, the formation of the ethylated
product 6bA was not observed. Other secondary alkyl radicals
also worked well under similar reaction conditions, allowing
facile incorporation of a variety of structures into the oxime
ether (entries 2–4). In the case of sec-butyl radical addition, a
1 : 1 diastereomeric ratio with regard the stereocenter on the
sec-butyl group was observed, although the radical addition
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 8 1 – 3 9 0
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Table 4 Alkyl radical addition to (R,Z)-5b–ca
Entry
Oxime ether
R2
Product
Yield (%)b
Selectivityc
1
2
3
4
5
6
(R,Z)-5b
(R,Z)-5b
(R,Z)-5b
(R,Z)-5b
(R,Z)-5b
(R,Z)-5c
Pri
6bB
6bC
6bD
6bE
6bF
6cB
70
57
59
50
>95% de
>95% de
>95% de
>95% de
>95% de
>95% de
c-Hexyl
c-Pentyl
Bus
Bui
20 (39)d
40 (16)
Pri
a Radical addition was carried out with R2I (30 equiv.), BF3ؒOEt2 (9 equiv.) and Et3B (9 equiv.) in toluene at 20 ЊC. b Isolated yields; yields in
parentheses are for the recovered starting material. c Diastereoselectivities were determined by 1H NMR analysis. d Ethylated product 6bA was also
obtained in 29% yield.
hexane, 0.678 mL, 0.678 mmol) under a nitrogen atmosphere at
20 ЊC. After being stirred at the same temperature for 15 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.
Purification by preparative TLC (AcOEt–hexane 1 : 15, 2-fold
development) afforded the alkylated products 3 (46.3 mg, 68%)
as a colorless oil.
3-[(Phenylmethoxy)amino]pentanoic acid ethyl ester (3)
IR (CHCl3) 3251, 2968, 1725, 1496 cmϪ1;1H NMR (CDCl3)
δ 7.39–7.21 (5H, m), 4.69 (2H, s), 4.11 (2H, q, J = 7.1 Hz), 3.24
(1H, m), 2.53 (1H, dd, J = 15.6, 7.4 Hz), 2.44 (1H, dd, J = 15.6,
Scheme 12 Reagents and conditions: i, BF3ؒOEt2, R2I, Et3B, toluene,
5.2 Hz), 1.71–1.32 (2H, m), 1.23 (3H, t, J = 7.1 Hz), 0.93 (3H, t,
J = 7.5 Hz);13C NMR (CDCl3) δ 172.4, 137.8, 128.2, 127.6, 76.4,
20 ЊC.
60.2, 58.9, 36.6, 24.6, 14.0, 10.3. HRMS: Calcd for C14H21NO3
proceeded with high diastereoselectivity. Low chemical yield
was obtained in the reaction using an unstable primary alkyl
(Mϩ): 251.1520. Found: 251.1501.
radical such as the isobutyl radical because of the competitive
formation of a significant amount of the ethylated product 6bA
Synthesis of oxime ether (4)
as a by-product, which was formed by the reaction with the
ethyl radical generated from Et3B (entry 5). Similar trends were
observed in our previous studies of radical addition to activated
glyoxylic oxime ethers.4,17 The isopropyl radical addition to an
oxime ether having a 4-nitrobenzyl group (R,Z)-5c also pro-
ceeded with excellent diastereoselectivity under similar reaction
conditions (entry 6).
In conclusion, we have demonstrated that the stereocontrol
in the intermolecular carbon radical addition to oxime ethers
presents new opportunities for stereoselective synthesis of
α,β-dialkyl-β-amino acid derivatives. In addition to the inter-
molecular radical reaction of glyoxylic oxime ether in the
asymmetric synthesis of α-amino acids,4 the radical reactions of
unactivated oxime ethers disclosed a broader aspect of the
utility of imine derivatives as a radical acceptor for the
synthesis of various types of chiral amino compounds.
To a solution of (1S)-(Ϫ)-2,10-camphorsultam (3.0 g, 13.9
mmol) and 2 (4.6 g, 20.8 mmol) in CH2ClCH2Cl (106 mL) was
added Me3Al (1.0 M in hexane, 20.8 mL, 20.8 mmol) under a
nitrogen atmosphere at room temperature. After being heated
at reflux for 9 h, the reaction mixture was diluted with 3% HCl
and then extracted with CH2Cl2. The organic phase was washed
with water, dried over MgSO4, and concentrated at reduced
pressure. Purification by flash chromatography (hexane–AcOEt
3 : 1) afforded 1 (5.1 g, 95%) as a colorless oil (2 : 3 mixture of
(E)–(Z)-oxime ether).
(3aS,6R,7aR)-1,4,5,6,7,7a-Hexahydro-8,8-dimethyl-1-{1-oxo-3-
[(phenylmethoxy)imino]propyl}-3H-3a,6-methano-2,1-benziso-
thiazole 2,2-dioxide (4)
[α]3D2 Ϫ84.5 (c 0.86, CHCl3); IR (CHCl3) 2964, 1698 cmϪ1; H
1
NMR (CDCl3) δ 7.58 (2/5H, t, J = 5.9 Hz), 7.38–7.25 (5H, m),
7.07 (3/5H, t, J = 4.7 Hz), 5.13 (6/5H, s), 5.08 (4/5H, s),
3.95–3.75 (11/5H, m), 3.68 (4/5H, d, J = 5.9 Hz), 3.49 (1H, br d,
J = 13.8 Hz), 3.48 (1H, br d, J = 13.8 Hz), 2.2–1.8 (5H, m), 1.45–
1.30 (2H, m), 1.14 (6/5H, s), 1.12 (9/5H, s), 0.96 (3H, s); 13C
NMR (CDCl3) δ 167.3, 167.0, 143.7, 142.6, 137.6, 137.3, 128.3,
128.1, 127.9, 127.8, 127.7, 75.93, 75.86, 65.1, 52.72, 52.66, 48.5,
47.7, 44.51, 44.47, 38.14, 38.08, 36.1, 32.7, 32.5, 26.3, 20.6, 19.7.
HRMS: Calcd for C20H26N2O4S (Mϩ): 390.1612. Found:
390.1624.
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 by the EI method. Preparative TLC separations
were carried out on precoated silica gel plates (E. Merck
60F254). Medium-pressure column chromatography was per-
formed using Lobar grösse B (E. Merck 310–25, Lichroprep
Si60). 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). [α]D values are meas-
Methylation of oxime ether (4)
For entry 1 in Table 1. To a solution of 4 (80.0 mg, 0.205
mmol) in THF (5 mL) was added LiHMDS (1 M in hexane,
1.08 mL, 1.08 mmol) under an argon atmosphere at Ϫ78 ЊC.
After being stirred at the same temperature for 30 min, MeI
(0.09 mL, 1.44 mmol) was added to the reaction mixture at
Ϫ78 ЊC. After being stirred at the same temperature for 45 min,
the reaction mixture was diluted with H2O and then extracted
with CH2Cl2. The organic phase was dried over MgSO4 and
ured in 10Ϫ1 deg cm2 gϪ1
.
Radical addition to oxime ether (2)
To a solution of 2 (60.0 mg, 0.271 mmol) in CH2Cl2 (3 mL) were
added BF3ؒOEt2 (0.068 mL, 0.542 mmol) and Et3B (1.0 M in
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 8 1 – 3 9 0
385

View Online
concentrated at reduced pressure. Purification by preparative
TLC (AcOEt–hexane 1 : 4, 2-fold development) afforded 5A
(51.9 mg, 61%) as a colorless oil and 4 (12.3 mg, 15%).
J = 5.9 Hz), 6.74 (1.2/15.3H, d, J = 5.3 Hz), 5.13 (2 × 13.1/
15.3H, s), 5.11 (2 × 1.2/15.3H, s), 5.08 (2 × 1/15.3H, s), 4.62–
4.30 (1H, m), 4.02 (1/15.3H, t, J = 6.4 Hz), 3.86 (1.2/15.3H,
t, J = 6.4 Hz), 3.83 (13.1/15.3H, t, J = 6.4 Hz), 3.51 (1H, d,
J = 13.9 Hz), 3.41 (1H, d, J = 13.8 Hz), 2.11–1.58 (5H, m),
1.48–1.22 (5H, m), 1.14 (3H, s), 0.97 (3 × 13.1/15.3H, s), 0.94
(3 × 1/15.3H, s), 0.92 (3 × 1.2/15.3H, s). HRMS: Calcd for
C21H28N2O4S (Mϩ): 404.1768. Found: 404.1759.
For entry 2 in Table 1. To a solution of 4 (80.0 mg, 0.205
mmol) in THF (5 mL) was added LiHMDS (1 M in hexane,
0.432 mL, 0.432 mmol) under an argon atmosphere at Ϫ78 ЊC.
After being stirred at the same temperature for 15 min, MeI
(0.05 mL, 0.72 mmol) was added to the reaction mixture at
Ϫ78 ЊC. After being stirred at the same temperature for 15 min,
the reaction mixture was diluted with H2O and then extracted
with CH2Cl2. The organic phase was dried over MgSO4 and
concentrated at reduced pressure. Purification by preparative
TLC (AcOEt–hexane 1 : 4, 2-fold development) afforded 4 (72.0
mg, 90%).
(3aS,6R,7aR)-1,4,5,6,7,7a-Hexahydro-3,8,8-trimethyl-1-
{1-oxo-3-[(phenylmethoxy)imino]propyl}-3H-3a,6-methano-2,1-
benzisothiazole 2,2-dioxide (5A). The configuration of the
newly-formed stereocenter of 5A was not determined. 1 : 2 mix-
ture of (E)–(Z)-oxime ether as a colorless oil. [α]3D0 Ϫ53.6
1
(c 2.00, CHCl3); IR (CHCl3) 2964, 1697, 1454 cmϪ1; H NMR
(CDCl3) δ 7.59 (1/3H, t, J = 5.9 Hz), 7.39–7.22 (5H, m), 7.07
(2/3H, t, J = 4.8 Hz), 5.13 (4/3H, s), 5.08 (2/3H, s), 3.96–3.67
(3H, m), 3.46 (1H, q, J = 7.4 Hz), 2.12–1.73 (5H, m), 1.41 (3H,
d, J = 7.4 Hz), 1.36–1.22 (2H, m), 1.12 (3/3H, s), 1.10 (6/3H, s),
0.94 (3H, s); 13C NMR (CDCl3) δ 167.6, 167.3, 143.8, 142.7,
137.6, 137.3, 128.2, 128.1, 127.8, 127.7, 127.6, 75.9, 75.8, 63.2,
57.03, 56.97, 52.0, 48.3, 44.6, 38.0, 37.9, 36.1, 32.5, 29.3, 25.8,
20.6, 19.7, 12.8. HRMS: Calcd for C21H28N2O4S (Mϩ):
404.1768. Found: 404.1763.
For entry 3 in Table 1. To a solution of 4 (80.0 mg, 0.205
mmol) in THF (5 mL) was added NaHMDS (1 M in THF,
0.51 mL, 0.51 mmol) under an argon atmosphere at Ϫ78 ЊC.
After being stirred at the same temperature for 30 min, MeI
(0.038 mL, 0.615 mmol) was added to the reaction mixture at
Ϫ78 ЊC. After being stirred at the same temperature for 30 min,
the reaction mixture was diluted with H2O and then extracted
with CH2Cl2. The organic phase was dried over MgSO4 and
concentrated at reduced pressure. Purification by preparative
TLC (AcOEt–hexane 1 : 4, 2-fold development) afforded 5A
(64.2 mg, 78%).
General procedure for the alkylation of 4 (Table 2)
To a solution of 4 (7.7 mmol) in CH2Cl2 (190 mL) were added
alkyl bromide (8.5 mmol), tetra-n-butylammonium bromide
(0.77 mmol), and 5 M NaOH (7.5 mL) under a nitrogen atmos-
phere at 20 ЊC. After being stirred at the same temperature for
1 h, the reaction mixture was diluted with saturated aqueous
NH4Cl and then extracted with CH2Cl2. The organic phase was
dried over MgSO4 and concentrated at reduced pressure. Purifi-
cation by flash column chromatography (AcOEt–hexane 1 : 4)
afforded the alkylated products 5b–g. The diastereomerically
pure products (R,Z)-5b–e were obtained by recrystallisation
from hexane–AcOEt.
For entry 4 in Table 1. To a solution of 4 (80.0 mg, 0.205
mmol) in THF (5 mL) was added NaHMDS (1 M in THF, 0.31
mL, 0.31 mmol) under an argon atmosphere at Ϫ78 ЊC. After
being stirred at the same temperature for 30 min, MeI (0.038
mL, 0.615 mmol) was added to the reaction mixture at Ϫ78 ЊC.
After being stirred at the same temperature for 15 min, the
reaction mixture was diluted with H2O and then extracted with
CH2Cl2. The organic phase was dried over MgSO4 and concen-
trated at reduced pressure. Purification by preparative TLC
(AcOEt–hexane 1 : 4, 2-fold development) afforded 4 (64.0 mg,
80%).
(3aS,6R,7aR)-1,4,5,6,7,7a-Hexahydro-8,8-dimethyl-1-{(2R,
3Z )-1-oxo-3-[(phenylmethoxy)imino]-2-(phenylmethyl)propyl}-
3H-3a,6-methano-2,1-benzisothiazole 2,2-dioxide [(R,Z )-5b].
Colorless crystals. Mp 121–122 ЊC (AcOEt–hexane); [α]2D3 Ϫ90.0
For entry 5 in Table 1. To a solution of 4 (80.0 mg, 0.205
mmol) in THF (5 mL) and CH2Cl2 (5 mL) were added MeOH
(0.05 mL, 1.23 mmol) and NaHMDS (1 M in THF, 1.23 mL,
1.23 mmol) under an argon atmosphere at Ϫ78 ЊC. After
being stirred at the same temperature for 15 min, MeI (0.08 mL,
1.23 mmol) was added to the reaction mixture at Ϫ78 ЊC. After
being stirred at Ϫ40 ЊC for 1 h, the reaction mixture was diluted
with H2O and then extracted with CH2Cl2. The organic phase
was dried over MgSO4 and concentrated at reduced pressure.
Purification by preparative TLC (AcOEt–hexane 1 : 4, 2-fold
development) afforded 5a (15.9 mg, 19%) and 4 (46.9 mg,
59%).
(c 0.98, CHCl3); IR (CHCl3) 2960, 1691 cmϪ1 1H NMR
;
(CDCl3) δ 7.36–7.12 (10H, m), 6.86 (1H, d, J = 6.4 Hz),
5.11 (1H, d, J = 8.1 Hz), 5.10 (1H, d, J = 8.1 Hz), 4.94 (1H,
br m), 3.68 (1H, br m), 3.38 (1H, d, J = 13.7 Hz), 3.32 (1H, d,
J = 13.7 Hz), 3.12 (1H, dd, J = 13.2, 8.4 Hz), 3.06 (1H, dd,
J = 13.2, 6.8 Hz), 1.92 (1H, dd, J = 13.5, 8.0 Hz), 1.84–16.5 (4H,
m), 1.26 (2H, br m), 0.87 (3H, s), 0.72 (3H, s); 13C NMR
(CDCl3) δ 170.5, 147.0, 137.7, 136.8, 129.2, 128.2, 128.1, 127.6,
127.4, 126.7, 75.8, 64.8, 52.8, 48.0, 47.4, 44.8, 44.5, 38.1, 37.1,
32.6, 26.2, 20.4, 19.6. HRMS: Calcd for C27H32N2O4S (Mϩ):
480.2081. Found: 480.2084. Anal. Calcd for C27H32N2O4S: C,
67.47; H, 6.71; N, 5.83; S, 6.67. Found: C, 67.65; H, 6.82; N,
5.82; S, 6.84%. Crystal data of (R,Z)-5b:‡ C27H32N2O4S, space
group monoclinic, P21 with a = 11.103 (11), b = 11.982 (14),
c = 9.962 (12) Å, V = 1251.6 (2) Å3, final R value 0.0297 for 3012
reflections
For entry 6 in Table 1. To a solution of 4 (80.0 mg, 0.205
mmol) in CH2Cl2 (5 mL) were added MeI (0.02 mL, 0.308
mmol), tetra-n-butylammonium bromide (6.8 mg, 0.023 mmol),
and 5 M NaOH (0.2 mL) under a nitrogen atmosphere at 20 ЊC.
After being stirred at the same temperature for 1 h, the reaction
mixture was diluted with saturated aqueous NH4Cl and then
extracted with CH2Cl2. The organic phase was dried over
MgSO4 and concentrated at reduced pressure. Purification by
preparative TLC (AcOEt–hexane 1 : 4, 2-fold development)
afforded 5a (70.3 mg, 85%).
(3aS,6R,7aR)-1,4,5,6,7,7a-Hexahydro-8,8-dimethyl-
1-{(2R,3Z )-2-[(4-nitrophenyl)methyl]-1-oxo-3-[(phenyl-
methoxy)imino]propyl}-3H-3a,6-methano-2,1-benzisothiazole
2,2-dioxide [(R,Z )-5c]. Colorless crystals. Mp 130–132 ЊC
(AcOEt–hexane); [α]2D4 Ϫ86.9 (c 1.54, CHCl3); IR (CHCl3) 2964,
1690 cmϪ1; 1H NMR δ 8.05 (2H, d, J = 8.4 Hz), 7.40–7.22 (7H,
(3aS,6R,7aR)-1,4,5,6,7,7a-Hexahydro-8,8-dimethyl-1-
{2-methyl-1-oxo-3-[(phenylmethoxy)imino]propyl}-3H-3a,6-
methano-2,1-benzisothiazole 2,2-dioxide (5a). (R,Z : R,E : S,Z =
13.1 : 1 : 1.2) as a colorless oil. [α]2D7 Ϫ95.9 (c 1.08, CHCl3); IR
(CHCl3) 2964, 2884, 1694, 1456 cmϪ1; 1H NMR (CDCl3) δ 7.59
(1/15.3H, d,J = 6.1 Hz), 7.40–7.21 (5H, m), 6.98 (13.1/15.3H, d,
‡ CCDC reference number 135458. See http://www.rsc.org/suppdata/
ob/b2/b208823a/ for crystallographic files in .cif or other electronic
format.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 8 1 – 3 9 0
386

View Online
m), 6.87 (1H, d, J = 6.6 Hz), 5.11 (1H, d, J = 12.8 Hz), 5.06 (1H,
d, J = 12.8 Hz), 5.08–4.96 (1H, m), 3.82–3.73 (1H, m), 3.43 (1H,
d, J = 14.0 Hz), 3.38 (1H, d, J = 14.0 Hz), 3.22 (1H, dd, J = 13.2,
8.3 Hz), 3.12 (1H, dd, J = 13.2, 6.8 Hz), 2.05–1.68 (5H, m),
1.40–1.22 (2H, m), 0.89 (3H, s), 0.68 (3H, s); 13C NMR (CDCl3)
δ 169.9, 146.9, 146.0, 144.5, 137.3, 130.2, 128.2, 127.8, 127.7,
123.4, 76.0, 65.0, 52.8, 48.2, 47.4, 44.4, 44.0, 38.0, 36.6, 32.6,
26.1, 20.1, 19.5. HRMS: Calcd for C27H31N3O6S (Mϩ):
525.1931. Found: 525.1953. Anal. Calcd for C27H31N3O6S: C,
61.70; H, 5.94; N, 7.99; S, 6.10. Found: C, 61.75; H, 5.91; N,
8.05; S, 6.21%.
Ethyl radical addition to oxime ethers
General procedure for ethyl radical addition to 5 at 20 ؇C
(Scheme 6, Table 3). To a solution of 5 (0.083 mmol) in toluene
or CH2Cl2 (2 mL) were added BF3ؒOEt2 (0.052 mL, 0.417
mmol) and Et3B (1.0 M in hexane, 0.417 mL, 0.417 mmol) at
20 ЊC. After being stirred at the same temperature for 15 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.
Purification by preparative TLC (AcOEt–hexane 1 : 3) afforded
the alkylated products 6.
(3aS,6R,7aR)-1,4,5,6,7,7a-Hexahydro-8,8-dimethyl-1-{(2R)-
1-oxo-2-[(Z )-(phenylmethoxy)iminomethyl]pent-4-ynyl}-3H-
3a,6-methano-2,1-benzisothiazole 2,2-dioxide [(R,Z )-5d]. Color-
less crystals. Mp 101–103 ЊC (AcOEt–hexane); [α]2D4 Ϫ89.4
(c 1.12, CHCl3); IR (CHCl3) 2964, 1697 cmϪ1; 1H NMR δ 7.70–
7.25 (5H, m), 7.01 (1H, d, J = 5.9 Hz), 5.14 (2H, s), 4.67 (1H, br
q, J = 6.1 Hz), 3.90–3.83 (1H, m), 3.49 (1H, d, J = 13.7 Hz), 3.42
(1H, d, J = 13.7 Hz), 2.84 (1H, ddd, J = 17.0, 5.6, 2.7 Hz), 2.74
(1H, ddd, J = 17.0, 6.4, 2.7 Hz), 2.18–1.80 (6H, m), 1.44–1.22
(2H, m), 1.17 (3H, s), 0.96 (3H, s); 13C NMR (CDCl3) δ 169.2,
146.1, 137.5, 128.2, 127.7, 127.6, 79.0, 76.0, 71.4, 65.0, 52.8,
48.4, 47.6, 44.4, 41.2, 38.0, 32.5, 26.3, 20.5, 20.4, 19.7. HRMS:
Calcd for C23H28N2O4S (Mϩ): 428.1768. Found: 428.1740.
Anal. Calcd for C23H28N2O4S: C, 64.46; H, 6.59; N, 6.54; S,
7.48. Found: C, 64.62; H, 6.61; N, 6.58; S, 7.56%.
General Procedure for Ethyl Radical Addition to 5 or 4 at
؊78 ؇C (Table 3, Scheme 8). To a solution of 5 or 4 (0.208
mmol) in toluene or CH2Cl2 (8 mL) were added BF3ؒOEt2
(0.078 mL, 0.625 mmol) and Et3B (1.0 M in hexane, 0.625 mL,
0.625 mmol) under a nitrogen atmosphere at Ϫ78 ЊC, and then
air was passed into the solution. After being stirred at the same
temperature for 3 min, BF3ؒOEt2 (0.078 mL, 0.625 mmol) and
Et3B (0.625 mL, 0.625 mmol) were added twice, and then air
was passed into the solution. After being stirred at the same
temperature for 3 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. Purification by preparative TLC (AcOEt–
hexane 1 : 3) afforded the alkylated products 6 and 7 from 5 and
4, respectively.
(3aS,6R,7aR)-1,4,5,6,7,7a-Hexahydro-8,8-dimethyl-1-{(2R)-
1-oxo-2-[(Z )-(phenylmethoxy)iminomethyl]pent-4-enyl}-3H-
3a,6-methano-2,1-benzisothiazole 2,2-dioxide [(R,Z )-5e]. Color-
less crystals. Mp 105–108 ЊC (AcOEt–hexane); [α]2D5 Ϫ98.9
(3aS,6R,7aR)-1,4,5,6,7,7a-Hexahydro-8,8-dimethyl-1-
{(2R,3S )-2-methyl-1-oxo-3-[(phenylmethoxy)amino]pentyl}-
3H-3a,6-methano-2,1-benzisothiazole 2,2-dioxide (6aA).
A
colorless oil. [α]2D8 Ϫ62.5 (c 0.69, CHCl3); IR (CHCl3) 3290,
2965, 1688, 1455 cmϪ1; 1H NMR (CDCl3) δ 7.45–7.20 (5H, m),
6.15–5.72 (1H, br s), 4.68 (2H, s), 3.87 (1H, t, J = 6.3 Hz), 3.55–
3.1 (3H, m), 2.95 (1H, dt, J = 12.6, 4.5 Hz), 2.09–1.63 (6H, m),
1.5–1.32 (3H, m), 1.28 (3H, d, J = 7.1 Hz), 1.15 (3H, s), 0.97
(3H, s), 0.94 (3H, t, J = 7.4 Hz); 13C NMR (CDCl3) δ 175.5,
138.1, 128.2, 127.5, 76.2, 64.9, 63.2, 53.0, 48.1, 47.6, 44.5, 42.3,
38.3, 32.7, 26.3, 23.2, 20.7, 19.7, 15.3, 10.8. HRMS: Calcd for
C23H34N2O4S (Mϩ): 434.2237. Found: 434.2220.
1
(c 0.92, CHCl3); IR (CHCl3) 2964, 1692, 1455 cmϪ1; H NMR
(CDCl3) δ 7.42–7.20 (5H, m), 6.90 (1H, d, J = 6.2 Hz), 5.88 (1H,
m), 5.14 (2H, s), 5.15–4.98 (1H, m), 4.68 (1H, dd, J = 6.5, 13
Hz), 3.83 (1H, t, J = 6.2 Hz), 3.50 (1H, d, J = 13.7 Hz), 3.40 (1H,
d, J = 13.8 Hz), 2.73–2.46 (2H, m), 2.08–1.78 (6H, m), 1.47–1.20
(2H, m), 1.14, 0.96 (each 3H, s); 13C NMR (CDCl3) δ 170.5,
147.2, 133.4, 128.1, 127.7, 127.5, 118.0, 75.8, 65.0, 52.9, 48.2,
47.6, 44.5, 42.3, 38.2, 35.6, 32.7, 26.2, 20.6, 19.7. HRMS: Calcd
for C23H30N2O4S (Mϩ): 430.1924. Found: 430.1945. Anal.
Calcd for C23H30N2O4S: C, 64.16; H, 7.02; N, 6.51; S, 7.45.
Found: C, 63.94; H, 6.94; N, 6.45; S, 7.60%.
(3aS,6R,7aR)-1,4,5,6,7,7a-Hexahydro-8,8-dimethyl-1-
{(2R,3S )-1-oxo-3-[(phenylmethoxy)amino]-2-(phenylmethyl)-
pentyl}-3H-3a,6-methano-2,1-benzisothiazole 2,2-dioxide (6bA).
Colorless crystals. Mp 136–137 ЊC (AcOEt–hexane); [α]2D8 Ϫ6.8
(c 1.07, CHCl3); IR (CHCl3) 2965, 1679 cmϪ1; 1H NMR δ 7.40–
7.20 (10H, m), 6.32 (1H, br m), 4.730 (1H, d, J = 12.0 Hz), 4.725
(1H, d, J = 12.0 Hz), 3.65 (2H, m), 3.29 (2H, br s), 3.11 (1H, dd,
J = 13.4, 4.4 Hz), 3.09 (1H, m), 2.95 (1H, dd, J = 13.4, 10.7 Hz),
2.00–1.50 (7H, m), 1.29–1.16 (2H, m), 1.01 (3H, t, J = 7.4 Hz),
0.81 (3H, s), 0.43 (3H, s); 13C NMR (CDCl3) δ 174.0, 138.3,
138.0, 129.5, 128.2, 128.1, 127.5, 126.3, 76.5, 65.0, 62.8, 52.9,
48.3, 47.6, 47.3, 44.5, 38.3, 35.2, 32.7, 26.2, 23.1, 20.2, 19.6,
11.0. HRMS: Calcd for C29H38N2O4S (Mϩ): 510.2550. Found:
510.2522. Anal. Calcd for C29H38N2O4S: C, 68.21; H, 7.50; N,
5.49; S, 6.28. Found: C, 67.99; H, 7.48; N, 5.35; S, 6.50. data of
6bA:§ C29H38N2O4S, space group monoclinic, P21 with a =
12.240 (15), b = 20.564 (14), c = 10.904 (16) Å, V = 2737.1 (6) Å3,
final R value 0.0416 for 6927 reflections.
(3aS,6R,7aR)-1,4,5,6,7,7a-Hexahydro-8,8-dimethyl-1-
{5-methyl-1-oxo-2-[(phenylmethoxy)iminomethyl]hex-4-enyl}-
3H-3a,6-methano-2,1-benzisothiazole 2,2-dioxide [(R,E )-5f].
R,Z : R,E : S,Z = 9.8 : 1.3 : 1 as a colorless oil. [α]2D9 Ϫ59.6
1
(c 1.44, CHCl3); IR (CHCl3) 2962, 1692, 1455 cmϪ1; H NMR
(CDCl3) δ 7.51 (1.3/12.1H, d, J = 6.8 Hz), 7.48–7.21 (5H, m),
6.85 (9.8/12.1H, d, J = 6.3 Hz), 6.69 (1/12.1H, d, J = 6 Hz), 5.12
(2 × 9.8/12.1H, s), 5.10 (2 × 1/12.1H, s), 5.08 (2 × 1.3/12.1H, s),
5.04–4.97 (1/12.1H, m), 4.64 (9.8/12.1H, br q, J = 6.9 Hz), 3.99
(1.3/12.1H, br q, J = 6.9 Hz), 3.94–3.77 (1H, m), 3.54–3.34 (2H,
m), 2.73–2.34 (2H, m), 2.15–1.79 (6H, m), 1.63, 1.57 (each 3H,
s), 1.43–1.24 (2H, m), 1.14, 0.95 (each 3H, br s). HRMS: Calcd
for C25H34N2O4S (Mϩ): 458.2238. Found: 458.2227.
(3aS,6R,7aR)-1,4,5,6,7,7a-Hexahydro-8,8-dimethyl-1-
{3-(methoxycarbonyl)-1-oxo-2-[(phenylmethoxy)iminomethyl-
]propyl}-3H-3a,6-methano-2,1-benzisothiazole
2,2-dioxide
[(R,Z )-5g]. R,Z : R,E = 10 : 1 as a colorless oil. [α]3D0 Ϫ47.1
(3aS,6R,7aR)-1,4,5,6,7,7a-Hexahydro-8,8-dimethyl-1-
{(2R,3S )-2-[(4-nitrophenyl)methyl]-1-oxo-3-[(phenylmethoxy)-
amino]pentyl}-3H-3a,6-methano-2,1-benzisothiazole 2,2-dioxide
(6cA). A colorless oil. [α]2D8 Ϫ3.3 (c 1.02, CHCl3); IR (CHCl3)
2966, 1680 cmϪ1; 1H NMR δ 8.06 (2H, br d, J = 8.8 Hz), 7.40–
(c 0.52, CHCl3); IR (CHCl3) 2959, 1737, 1692, 1455 cmϪ1; H
1
NMR (CDCl3) δ 7.56 (1/11H, d, J = 7.5 Hz), 7.40–7.25 (5H, m),
6.81 (10/11H, d, J = 7.5 Hz), 5.15 (2 × 10/11H, s), 5.00 (2 ×
1/11H, s), 4.85–4.74 (1H, m), 3.95–3.85 (1H, m), 3.65 (3H, s),
3.52, 3.42 (each 1H, br d, J = 15 Hz), 2.96 (1H, br dd, J = 7.5,
15 Hz), 2.81(1H, br dd, J = 6, 15 Hz), 2.2–1.8 (5H, m), 1.64–
1.2 (2H, m), 1.21, 0.98 (each 3H, s). HRMS: Calcd for
C23H30N2O6S (Mϩ): 462.1822. Found: 462.1825.
§ CCDC reference number 135459. See http://www.rsc.org/suppdata/
ob/b2/b208823a/ for crystallographic files in .cif or other electronic
format.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 8 1 – 3 9 0
387

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7.22 (7H, m), 6.22 (1H, br m), 4.72 (2H, br s), 3.80–3.62 (2H,
m), 3.31 (2H, s), 3.23 (1H, dd, J = 13.4, 4.6 Hz), 3.14–2.98 (2H,
m), 2.14–1.40 (7H, m), 1.32–1.10 (2H, m), 1.01 (3H, t, J = 7.4
Hz), 0.80 (3H, s), 0.32 (3H, s); 13C NMR (CDCl3) δ 173.2,
146.7, 146.4, 137.8, 130.5, 128.2, 127.6, 123.3, 76.5, 65.2, 63.0,
52.9, 48.1, 47.7, 47.2, 44.3, 38.3, 35.5, 32.7, 26.1, 23.1, 19.7,
19.4, 11.0. HRMS: Calcd for C29H37N3O6S (Mϩ): 555.2401.
Found: 555.2402.
126.0, 76.0, 63.5, 60.0, 48.7, 34.5, 21.8, 13.9, 11.0. HRMS:
Calcd for C21H27NO3 (Mϩ): 341.1990. Found: 341.2001.
Synthesis of ꢀ-amino acid 11
(3aS,6R,7aR)-1,4,5,6,7,7a-Hexahydro-8,8-dimethyl-1-
{(2R,3S )-1-oxo-3-[(phenylmethoxy)carbonylamino]-2-(phenyl-
methyl)pentyl]-3H-3a,6-methano-2,1-benzisothiazole
2,2-di-
oxide (10). A suspension of 20% Pd(OH)2–C (2.13 mg) in
MeOH (2 mL) was stirred under a hydrogen atmosphere
(1 atm) at 20 ЊC for 40 min. To this suspension was added a
solution of 6bA (50.0 mg, 0.10 mmol) in MeOH (2 mL). After
being stirred under a hydrogen atmosphere at the same temper-
ature for 1 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 acetone (4 mL)
was added a solution of Na2CO3 (20.8 mg, 0.20 mmol) in H2O
(0.3 mL) under a nitrogen atmosphere at 20 ЊC. After benzy-
loxycarbonyl chloride (33.4 mg, 0.20 mmol) in acetone (0.5 mL)
was added to the reaction mixture at 20 ЊC, the reaction mixture
was stirred at the same temperature for 1 h. After the reaction
mixture was concentrated at 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 reduced pressure. Purification by preparative
TLC (hexane–AcOEt 3 : 1) afforded 10 (50.9 mg, 96%) as color-
less crystals. Mp 158–160 ЊC (AcOEt–hexane); [α]2D1 Ϫ18.8
(c 0.98, CHCl3); IR (CHCl3) 3434, 3032, 2965, 1719, 1512, 1456
cmϪ1; 1H NMR (CDCl3) δ 7.45–7.10 (10H, m, Ar), 5.16 (1H, d,
J = 12.3 Hz), 5.05 (1H, d, J = 12.1 Hz), 4.80–4.64, 4.20–
3.92 (each 1H, m), 3.60–3.44 (1H, m), 3.32 (2H, s), 3.04–2.88
(2H, m), 2.20–1.48 (8H, m), 1.32–1.20 (2H, m), 0.95 (3H, t,
J = 7.3 Hz), 0.82, 0.48 (each 3H, s); 13C NMR (CDCl3) δ 172.4,
156.3, 137.6, 129.4, 128.2, 127.9, 126.4, 77.1, 66.6, 65.1, 54.4,
52.9, 50.9, 47.7, 47.3, 44.5, 38.3, 36.1, 32.6, 26.4, 26.2, 20.3,
19.6, 10.8. HRMS: Calcd for C30H38N2O5S (Mϩ): 538.2500.
Found: 538.2517.
(3aS,6R,7aR)-1,4,5,6,7,7a-Hexahydro-8,8-dimethyl-1-{(2R)-
1-oxo-2-[(1S )-1-(phenylmethoxy)aminopropyl]pent-4-ynyl}-3H-
3a,6-methano-2,1-benzisothiazole 2,2-dioxide (6dA). Colorless
crystals. Mp 101–102 ЊC (AcOEt–hexane); [α]2D3 Ϫ149.5 (c 0.24,
1
CHCl3); IR (CHCl3) 2965, 1694 cmϪ1; H NMR δ 7.40–7.20
(5H, m), 5.95 (1H, br m), 4.67 (2H, s), 3.90 (1H, dd, J = 7.6,
5.1 Hz), 3.49 (1H, d, J = 13.7 Hz), 3.45 (1H, d, J = 13.7 Hz),
3.50–3.40 (1H, m), 3.15 (1H, td, J = 8.5, 4.4 Hz), 2.80 (1H, ddd,
J = 17.3, 7.2, 2.7 Hz), 2.69 (1H, ddd, J = 17.3, 4.4, 2.7 Hz), 2.20–
1.32 (10H, m), 1.19 (3H, s), 0.97 (3H, s), 0.96 (3H, t, J = 7.4 Hz);
13C NMR (CDCl3) δ 172.5, 137.9, 128.2, 127.6, 80.4, 77.1, 76.4,
70.9, 65.2, 61.0, 53.1, 48.2, 47.7, 45.9, 44.5, 38.3, 32.7, 26.4,
23.0, 20.7, 19.8, 19.0, 10.8. HRMS: Calcd for C25H34N2O4S
(Mϩ): 458.2237. Found: 458.2209. Anal. Calcd for C25H34N2-
O4S: C, 65.47; H, 7.47; N, 6.11; S, 6.99. Found: C, 65.18; H,
7.43; N, 6.00; S, 7.08%.
(3aS,6R,7aR)-1,4,5,6,7,7a-Hexahydro-8,8-dimethyl-1-
{1-oxo-3-[(phenylmethoxy)amino]pentyl}-3H-3a,6-methano-2,1-
benzisothiazole 2,2-dioxide (7). 9 : 10 mixture of diastereomers
as a colorless oil. [α]3D1 Ϫ63.1 (c 3.39, CHCl3); IR (CHCl3) 2964,
1693 cmϪ1; 1H NMR δ 7.40–7.20 (5H, m), 5.83 (1H, br m), 4.68
(18/19H, s), 4.66 (20/19H, s), 3.89–3.78 (1H, m), 3.53–3.30 (3H,
m), 3.05–2.70 (2H, m), 2.18–1.25 (9H, m), 1.13 (27/19H, s), 1.11
(30/19H, s), 0.950 (27/19H, s), 0.945 (30/19H, s), 0.933 (30/19H,
t, J = 6.4 Hz), 0.930 (27/19H, t, J = 6.4 Hz); 13C NMR (CDCl3)
δ 170.72, 170.67, 137.90, 137.86, 128.24, 128.18, 128.1, 127.5,
76.20, 76.15, 65.0, 58.7, 58.6, 52.84, 52.77, 48.2, 47.5, 44.5, 38.3,
38.2, 37.61, 37.56, 32.7, 26.3, 24.8, 24.7, 20.7, 20.6, 19.7, 10.3,
10.2. HRMS: Calcd for C22H32N2O4S (Mϩ): 420.2081. Found:
420.2107.
(ꢁR)-ꢁ-{(1S )-1-[(Phenylmethoxy)carbonylamino]propyl}-
benzenepropanoic acid (11). A solution of 10 (33.5 mg, 0.07
mmol) in 1 M LiOH–THF (1 : 1, 4 mL) was stirred at reflux for
3 h. After the reaction mixture was concentrated at reduced
pressure, the resulting residue was acidified with dilute HCl,
and then extracted with CH2Cl2. The organic phase was dried
over Na2SO4 and concentrated at reduced pressure. Purification
by preparative TLC (hexane–AcOEt 3 : 1) afforded 11 (71 mg,
73%) as a white powder. [α]2D5 Ϫ23.7 (c 1.18, CHCl3); IR (CHCl3)
(3Z )-3-[(Phenylmethoxy)imino]-2-(phenylmethyl)propanoic acid
ethyl ester (8)
According to the general procedure for the alkylation of 4,
compound 8 was prepared as a colorless oil. IR (CHCl3) 3024,
1729, 1455 cmϪ1; 1H NMR (CDCl3) δ 7.42–7.11 (10H, m), 6.84
(1H, d, J = 6.8 Hz), 5.09 (2H, s), 4.2 (1H, q, J = 7.1 Hz), 4.08
(2H, q, J = 7.1 Hz), 3.14 (1H, dd, J = 7.3, 14.1 Hz), 3.02 (1H, dd,
J = 7.3, 13.8 Hz), 1.15 (3H, t, J = 7.1 Hz); 13C NMR (CDCl3)
δ 171.1, 147.7, 137.5, 137.5, 128.9, 128.33, 128.26, 127.8, 127.7,
126.7, 76.0, 60.9, 44.0, 36.0, 13.9. HRMS: Calcd for C19H21NO3
(Mϩ): 311.1520. Found: 311.1530.
1
2969, 1716 cmϪ1; H NMR δ 7.45–7.13 (10H, m), 5.12 (1H,
d, J = 12.4 Hz), 5.06 (1H, d, J = 12.4 Hz), 4.94 (1H, br d,
J = 10.0 Hz), 3.87 (1H, m), 3.10–2.75 (4H, m), 1.68 (1H, m),
1.42 (1H, m), 0.95 (3H, t, J = 7.1 Hz); 13C NMR (CDCl3)
δ 177.3, 156.2, 138.6, 136.3, 128.6, 128.4, 128.1, 128.0, 126.4,
77.1, 66.8, 54.0, 51.6, 34.4, 24.9, 10.6. HRMS: Calcd for
C20H23NO4 (Mϩ): 341.1626. Found: 341.1630.
3-[(Phenylmethoxy)amino]-2-(phenylmethyl)pentanoic acid ethyl
ester (9)
Isopropyl radical addition to oxime ether 2
Reaction in the presence of Bu3SnH. To a solution of 2 (80.0
mg, 0.362 mmol) in CH2Cl2 (4 mL) were added isopropyl iodide
(0.720 mL, 7.24 mmol), Bu3SnH (0.097 mL, 0.362 mmol), and
Et3B (1.0 M in hexane, 0.850 mL, 0.905 mmol) at 20 ЊC. After
being stirred at the same temperature for 1 min, BF3ؒOEt2
(0.090 mL, 0.724 mmol) was added at 20 ЊC. After being stirred
at the same temperature for 15 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. Purification by preparative
TLC (AcOEt–hexane 1 : 15, 2-fold development) afforded 12
(41.6 mg, 43%) as a colorless oil.
To a solution of 8 (109 mg, 0.351 mmol) in toluene (8 mL) were
added BF3ؒOEt2 (0.130 mL, 1.05 mmol) and Et3B (1.0 M in
hexane, 1.05 mL, 1.05 mmol) at 20 ЊC. After being stirred at the
same temperature for 15 min, the reaction mixture was diluted
with saturated aqueous NaHCO3 and then extracted with
CH2Cl2. The organic phase was dried over MgSO4 and concen-
trated at reduced pressure. Purification by preparative TLC
(CHCl3) afforded the alkylated products 9 (64.5 mg, 54%) as a
colorless oil. For the major isomer of 9: IR (CHCl3) 2966, 1724,
1
1454 cmϪ1; H NMR (CDCl3) δ 7.39–7.13 (10H, m), 5.8 (1H,
br s, NH), 4.70, 4.64 (each 1H, d, J = 11.6 Hz), 4.01 (2H, q,
J = 7.2 Hz), 3.18–3.02 (1H, m), 3.02–2.82 (3H, m), 1.64–1.24
(2H, m), 1.09 (3H, t, J = 7.2 Hz), 0.94 (3H, t, J = 7.3 Hz); 13C
NMR (CDCl3) δ 173.9, 139.6, 137.8, 128.8, 128.3, 128.2, 127.6,
Reaction in the absence of Bu3SnH. To a solution of 2 (80.0
mg, 0.362 mmol) in CH2Cl2 (4 mL) were added isopropyl iodide
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 8 1 – 3 9 0
388

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(0.720 mL, 7.24 mmol), BF3ؒOEt2 (0.090 mL, 0.724 mmol), and
Et3B (1.0 M in hexane, 0.850 mL, 0.905 mmol) at 50 ЊC. 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. Purification by
preparative TLC (AcOEt–hexane 1 : 15, 2-fold development)
afforded 12 (68.6 mg, 71%) as a colorless oil.
(1H, br m), 4.77 (1H, d, J = 11.5 Hz), 4.72 (1H, d, J = 11.5 Hz),
3.73–3.66 (2H, m), 3.30 (1H, d, J = 13.5 Hz), 3.27 (1H, d,
J = 13.5 Hz), 3.18 (1H, dd, J = 2.5, 9.5 Hz), 3.15–3.07 (2H,
m), 2.36–2.26 (1H, m), 2.05–1.97 (1H, m), 1.92–1.84 (2H, m),
1.82–1.20 (12H, m), 0.81 (3H, s), 0.37 (3H, s); 13C NMR
(CDCl3) δ 173.8, 138.9, 138.2, 129.5, 128.3, 128.2, 128.1,
127.5, 126.3, 75.9, 65.2, 64.8, 53.1, 49.3, 47.9, 47.4, 44.5,
41.8, 38.3, 34.2, 32.8, 31.4, 30.1, 26.4, 25.2, 25.0, 20.2, 19.7.
HRMS: Calcd for C32H42N2O4S (Mϩ): 550.2863. Found:
550.2885.
4-Methyl-3-[(phenylmethoxy)amino]pentanoic acid ethyl ester
(12). IR (CHCl3) 3250, 2964, 1725, 1454 cmϪ1 1H NMR
;
(CDCl3) δ 7.23–7.41 (5H, m), 6.2–5.5 (1H, m), 4.67 (2H, s), 4.11
(2H, q, J = 7 Hz), 3.15 (1H, m), 2.42 (2H, m), 1.92 (1H, m), 1.23
(3H, t, J = 7 Hz), 0.94, 0.90 (each 3H, d, J = 7 Hz); 13C NMR
(CDCl3) δ 172.9, 137.9, 128.3, 128.2, 127.6, 76.1, 62.6, 60.2,
33.9, 28.9, 19.1, 18.1, 14.0. HRMS: Calcd for C15H23N1O3
(Mϩ): 265.1627. Found: 265.1652.
(3aS,6R,7aR)-1,4,5,6,7,7a-Hexahydro-8,8-dimethyl-1-
{(2R,3S )-4-methyl-1-oxo-3-[(phenylmethoxy)amino]-2-(phenyl-
methyl)hexyl}-3H-3a,6-methano-2,1-benzisothiazole 2,2-dioxide
(6bE). 1 : 1 mixture of diastereomers, with regard the sec-butyl
group, as a colorless oil. [α]2D6 Ϫ4.1 (c 1.04, CHCl3); IR (CHCl3)
1
2964, 1681 cmϪ1; H NMR δ 7.38–7.09 (10H, m), 6.45 (1H, br
m), 4.73 (1/2H, d, J = 11.5 Hz), 4.716 (1/2H, d, J = 11.5 Hz),
4.715 (1/2H, d, J = 11.0 Hz), 4.712 (1/2H, d, J = 11.0 Hz), 3.75–
3.64 (2H, m), 3.33–3.28 (2H, m), 3.26 (1/2H, t, J = 5.5 Hz), 3.20
(1/2H, dd, J = 8.0, 3.5 Hz), 3.13 (1/2H, dd, J = 8.0, 3.5 Hz),
3.09–2.99 (3/2H, m), 1.96–1.56 (7H, m), 1.35–1.20 (3H, m), 1.10
(3/2H, d, J = 7.0 Hz), 1.05 (3/2H, d, J = 6.5 Hz), 0.95 (3H, br t,
J = 7.5 Hz), 0.81 (3H, br s), 0.40 (3/2H, s), 0.38 (3/2H, s); 13C
NMR (CDCl3) δ 174.1, 138.9, 138.6, 138.15, 138.13, 129.5,
129.4, 128.3, 128.19, 128.16, 128.11, 127.52, 127.48, 126.4,
126.3, 75.8, 75.7, 65.3, 65.2, 64,2, 64.0, 53.06, 53.04, 48.1, 47.84,
47.81, 47.76, 47.6, 47.4, 44.51, 44.48, 38.29, 38.28, 36.4, 35.7,
35.3, 34.6, 32.8, 27.1, 26.4, 26.0, 20.2, 19.7, 16.2, 15.8, 12.1,
11.4. HRMS: Calcd for C31H42N2O4S (Mϩ): 538.2863. Found:
538.2861
General procedure for alkyl radical addition to (R,Z )-5b,c
(Table 4)
To a solution of (R,Z)-5b,c (2.08 mmol) in toluene (15 mL)
were added alkyl iodide (62.5 mmol), BF3ؒOEt2 (6.25 mmol),
and Et3B (1.0 M in hexane, 6.25 mmol) at 20 ЊC. After being
stirred at the same temperature for 3 min, BF3ؒOEt2 (6.25
mmol) and Et3B (6.25 mmol) were added twice. After being
stirred at the same temperature for 3 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. Purification by
preparative TLC (AcOEt–hexane 1 : 4) afforded the alkylated
products 6bB–6bF,6cB.
(3aS,6R,7aR)-1,4,5,6,7,7a-Hexahydro-8,8-dimethyl-1-
{(2R,3S )-4,4-dimethyl-1-oxo-3-[(phenylmethoxy)amino]-2-
(phenylmethyl)pentyl}-3H-3a,6-methano-2,1-benzisothiazole
2,2-dioxide (6bF). A colorless oil. [α]2D9 Ϫ17.3 (c 1.20, CHCl3);
(3aS,6R,7aR)-1,4,5,6,7,7a-Hexahydro-8,8-dimethyl-1-
{(2R,3S )-4-methyl-1-oxo-3-[(phenylmethoxy)amino]-2-(phenyl-
methyl)pentyl}-3H-3a,6-methano-2,1-benzisothiazole
2,2-di-
oxide (6bB). A colorless oil. [α]2D7 ϩ1.7 (c 1.16, CHCl3); IR
(CHCl3) 2964, 1679 cmϪ1; 1H NMR δ 7.39–7.09 (10H, m), 6.55
(1H, br m), 4.76 (1H, d, J = 11.5 Hz), 4.72 (1H, d, J = 11.5 Hz),
3.76–3.67 (2H, m), 3.30 (1H, d, J = 13.5 Hz), 3.28 (1H, d,
J = 13.5 Hz), 3.12–3.05 (3H, m), 2.18–2.11 (1H, m), 1.88
(1H, dd, J = 13.5, 7.5 Hz), 1.83–1.73 (1H, m), 1.67–1.55 (3H,
m), 1.30–1.20 (2H, m), 1.28 (6H, t, J = 5.5 Hz), 0.81 (3H, s),
0.38 (3H, s); 13C NMR (CDCl3) δ 174.0, 138.8, 138.1, 129.5,
128.3, 128.2, 128.1, 127.5, 126.3, 75.7, 65.5, 65.2, 53.0, 47.8,
47.7, 47.4, 44.5, 38.3, 34.6, 32.8, 29.2, 26.4, 20.5, 20.3, 20.2,
19.7. HRMS: Calcd for C30H40N2O4S (Mϩ): 524.2706. Found:
524.2721.
1
IR (CHCl3) 2960, 1682 cmϪ1; H NMR δ 7.38–7.09 (10H, m),
6.21 (1H, br m), 4.71 (2H, s), 3.64 (1H, br m), 3.32–3.23 (3H,
m), 3.12 (1H, dd, J = 13.5, 5.0 Hz), 2.97 (1H, dd, J = 13.5, 10.5
Hz), 1.91–1.46 (7H, m), 1.33–1.18 (3H, m), 0.95 (3H, d, J = 6.0
Hz), 0.89 (3H, d, J = 6.5 Hz), 0.81 (3H, s), 0.92–0.77 (1H, m),
0.44 (3H, br s); 13C NMR (CDCl3) δ 174.0, 138.4, 138.2, 129.6,
128.3, 128.24, 128.18, 127.6, 126.4, 76.5, 65.2, 59.3, 53.0, 49.4,
47.7, 47.4, 44.6, 39.7, 38.4, 35.8, 32.8, 26.4, 24.9, 23.3, 22.3,
20.4, 19.8. HRMS: Calcd for C31H42N2O4S (Mϩ): 538.2863.
Found: 538.2855.
(3aS,6R,7aR)-1,4,5,6,7,7a-Hexahydro-8,8-dimethyl-1-
{(2R,3S )-4-methyl-2-[(4-nitrophenyl)methyl]-1-oxo-3-[(phenyl-
methoxy)amino]pentyl}-3H-3a,6-methano-2,1-benzisothiazole
2,2-dioxide (6cB). A yellow oil. [α]2D7 ϩ10.5 (c 0.57, CHCl3); IR
(CHCl3) 2964, 1681 cmϪ1; 1H NMR δ 8.06 (2H, d, J = 8.5 Hz),
7.42–7.20 (7H, m), 6.36 (1H, br m), 4.73 (2H, s), 3.80–3.68 (2H,
m), 3.31 (3H, s), 3.30–3.07 (3H, m), 2.20–2.15 (1H, m), 1.97–
0.68 (6H, m), 1.12 (3H, d, J = 6.6 Hz), 1.11 (3H, d, J = 6.9 Hz),
0.80 (3H, s), 0.33 (3H, br s); 13C NMR (CDCl3) δ 173.2, 146.9,
146.7, 137.9, 130.3, 128.2, 128.0, 127.5, 123.3, 75.7, 65.4, 65.2,
52.9, 47.9, 47.3, 44.3, 38.2, 34.7, 32.6, 28.8, 26.2, 20.4, 19.9,
19.6, 19.5. HRMS: Calcd for C30H39N3O6S (Mϩ): 569.2557.
Found: 569.2580.
(3aS,6R,7aR)-1-{(2R,3S )-3-Cyclohexyl-1-oxo-3-[(phenyl-
methoxy)amino]-2-(phenylmethyl)propyl}-1,4,5,6,7,7a-hexa-
hydro-8,8-dimethyl-3H-3a,6-methano-2,1-benzisothiazole 2,2-
dioxide (6bC). A colorless oil. [α]2D8 Ϫ10.1 (c 1.00, CHCl3); IR
(CHCl3) 2930, 1679 cmϪ1 1H NMR δ 7.38–7.09 (10H, m),
;
6.55 (1H, br m), 4.75 (1H, d, J = 11.5 Hz), 4.70 (1H, d,
J = 11.5 Hz), 3.77–3.66 (2H, m), 3.30 (1H, d, J = 13.5 Hz), 3.27
(1H, d, J = 13.5 Hz), 3.14 (1H, dd, J = 3.5, 7.5 Hz), 3.06 (2H, d,
J = 8.0 Hz), 2.11–2.04 (1H, m), 1.92–1.56 (10H, m), 1.32–1.10
(7H, m), 0.81 (3H, s), 0.39 (3H, s); 13C NMR (CDCl3) δ 174.1,
138.8, 138.1, 129.4, 128.3, 128.2, 127.5, 126.3, 75.7, 65.2, 64.8,
53.0, 47.8, 47.4, 47.3, 44.5, 38.9, 38.3, 34.6, 32.8, 30.53, 30.46,
26.7, 26.51, 26.48, 26.38, 20.2, 19.7. HRMS: Calcd for
C33H44N2O4S (Mϩ): 564.3020. Found: 564.3002.
Acknowledgements
We thank the Japan Society for the Promotion of Science
for a Grant-in-Aid for Scientific Research (B) and the
Science Research Promotion Fund of the Japan Private School
Promotion Foundation for research grants. We also thank
Dr H. Hiramatsu and Dr K. Aoe, Tanabe Seiyaku Co. Ltd, for
X-ray analysis.
(3aS,6R,7aR)-1-{(2R,3S )-3-Cyclopentyl-1-oxo-3-[(phenyl-
methoxy)amino]-2-(phenylmethyl)propyl}-1,4,5,6,7,7a-hexa-
hydro-8,8-dimethyl-3H-3a,6-methano-2,1-benzisothiazole 2,2-
dioxide (6bD). A colorless oil. [α]2D8 Ϫ12.2 (c 1.36, CHCl3); IR
(CHCl3) 2960, 1679 cmϪ1; 1H NMR δ 7.39–7.10 (10H, m), 6.70
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 8 1 – 3 9 0
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