Application of new chiral auxiliaries, trans-2-(N-arylsulfonyl-N-benzyl)cyclohexanols, in an asymmetric radical cyclization

Article abstract of DOI:10.1016/S0957-4166(00)00340-2

New chiral auxiliaries, trans-2-(N-arylsulfonyl-N-benzyl)cyclohexanols, were prepared and applied to an asymmetric radical cyclization. Copyright (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(00)00340-2

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 11 (2000) 3789–3805
Application of new chiral auxiliaries,
trans-2-(N-arylsulfonyl-N-benzyl)cyclohexanols, in an
asymmetric radical cyclization
Atsushi Nishida,* Fumie Shirato and Masako Nakagawa
Faculty of Pharmaceutical Sciences, Chiba University, 1-33 Yayoi-cho, Inage-ku, Chiba-shi 653-8522, Japan
Received 1 August 2000; accepted 23 August 2000
Abstract
New chiral auxiliaries, trans-2-(N-arylsulfonyl-N-benzyl)cyclohexanols, were prepared and applied to
an asymmetric radical cyclization. © 2000 Elsevier Science Ltd. All rights reserved.
1. Introduction
There have been important recent advances in radical chemistry, particularly in asymmetric
synthesis.1 We have reported a synthesis of chiral cycloalkenyl acetic acids using diastereoselective
radical cyclization with 8-phenylmenthol as the chiral auxiliary (Scheme 1).2 In this reaction, the
presence of a bulky Lewis acid such as methylaluminum bis(2,6-di-t-butyl-4-methylphenoxide)
(MAD)3 is essential for high selectivity.
Scheme 1.
8-Phenylmenthol is a cyclohexanol-type chiral auxiliary, and is widely used in asymmetric
synthesis. Both enantiomers are now commercially available and the synthesis of 8-phenyl-
menthol and its analogs have also been reported.4–6 Although several other cyclohexanol-type chiral
auxiliaries are commercially available, we needed a new cyclohexanol-type chiral auxiliary which
can be systematically tuned to adjust its asymmetrical circumstances with regard to both steric
* Corresponding author.
0957-4166/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00340-2

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and electronic characteristics. Therefore we designed new chiral cyclohexanols which have a
trans-amino group at the 2-position. Depending on the two substituents at the amino group,
both electronic and steric characteristics can be tuned (Fig. 1).
Figure 1. New chiral auxiliary based on trans-aminocyclohexanol
2. Results and discussion
Chiral trans-2-aminocyclohexanol can be readily obtained by several methods: (1) resolution
of racemic compounds as salts of tartaric acid,7 (2) ring-opening reaction of cyclohexene oxide
by chiral methylbenzylamine resulting in diastereomers that can be separated and debenzylated,8
and (3) the same ring-opening reaction by TMS-azide in the presence of chiral chromium
complex followed by reduction.9 We chose the second method because it was suitable for
synthesizing both enantiomers in enantiomerically pure form (Scheme 2).
Scheme 2.

A. Nishida et al. / Tetrahedron: Asymmetry 11 (2000) 3789–3805
3791
According to the procedure reported by Overman, cyclohexene oxide was reacted with
(+)-R-(1-phenylethyl)amine in the presence of trimethylaluminum in dichloromethane to give
two diastereomeric trans-2-(1-phenylethyl)aminocyclohexanols (2a and 2b), which were easily
separated by standard column chromatography. The stereochemistry of both 2a and 2b was
determined by comparison with reported spectral data. The phenylethyl group of 2a was
removed by hydrogenolysis to give (1S,2S)-3, which was converted to benzenesulfonamide 5
via 4. Using the same method, 2b was converted to sulfonamide 7, which has a 4-phenylben-
zyl group on nitrogen and was expected to show higher selectivity. Both 5 and 7 were
converted to iodo esters 11, 12 and 14 as reported previously2a (Scheme 3).
Scheme 3.
The conformation of the substrates in solution was studied before the radical reaction.
Chemical shifts obtained from 1H NMR studies of 12 and 14 are shown in Fig. 2, in
comparison to an achiral substrate. Olefinic protons in 12 and 14 appeared slightly
downfield. These results showed that neighboring aromatic rings should be situated near the
p-face of an unsaturated ester group.10 The same conclusion was supported by NOE studies
of crotonate of (1R,2R)-3 (Fig. 3). Therefore, we expected that this new auxiliary might be
effective for diastereoselective radical cyclization through a transition state, as shown in Fig.
1.

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A. Nishida et al. / Tetrahedron: Asymmetry 11 (2000) 3789–3805
1
Figure 2. Chemical shifts of chiral and achiral esters in the H NMR spectrum
Figure 3. NOE experiments using crotonate of (1R,2R)-3
When 11 was reacted with 1.6 equiv. of n-Bu3SnH in the presence of 1.1 equiv. of Et3B at
−78°C under aerobic conditions for 25 min, cyclized product 15 was obtained in quantitative
yield (Table 1, run 1). However, no diastereoselectivity was observed. The diastereoselectivity
was determined as discussed below.
Table 1
Radical cyclization of 11
Run
11 (mmol)
Additive (equiv.)
n-Bu3SnH (equiv.)
Time (min)
Yield (%)
de (major isomer, %)
1
2
3
0.5
0.4
1.2
None
BF3·Et2O (32)
MAD (4)
1.5
4.5
1.6
25
30
120
100
100
92
0
15b, 9
15a, 53

A. Nishida et al. / Tetrahedron: Asymmetry 11 (2000) 3789–3805
3793
In our previous study on the diastereoselective radical cyclization of 1, the presence of a bulky
Lewis acid was essential to obtain high selectivity. Therefore, the effect of a Lewis acid was
investigated in the radical cyclization of 11. In contrast to the cyclization of 1, a large excess of
BF3·Et2O did not improve the selectivity (run 2). However, in the presence of 4 equiv. of
methylaluminum bis(2,6-di-t-butyl-4-methylphenoxide) (MAD),3 15 was obtained in 92% yield
with 53% diastereomeric excess (de). The de value was determined as follows. A mixture of 15a
and 15b was hydrolyzed to 2-cyclopentenyl acetic acid 16 (75%) and the chiral alcohol 5 (73%).
The enantiomeric excess (ee) of 16 was determined to be 53% ee by comparison of its [h]D value
[[h]D +60 (c 1.0, CHCl3)] to the reported value [[h]D +113 (c 0.5, CHCl3)] for (S)-16.11 Therefore,
the absolute configuration of the major isomer was 15a in run 3 (Scheme 4).
In the presence of 4 equiv. of MAD, phenylbenzyl compound 12 gave 17 in 96% yield with
51% de. When the amount of MAD was increased to 8 equiv., the de (59% de) improved slightly
(Scheme 5). As Lewis acids, MgI2 and Zn(OTf)2 were not effective in the reaction of 12. Other
Lewis acids, such as EtAlCl2 and Et2AlCl, were also ineffective for obtaining high diastereoselec-
tivity (Scheme 6).
Scheme 4.
Scheme 5.

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A. Nishida et al. / Tetrahedron: Asymmetry 11 (2000) 3789–3805
Scheme 6.
Formation of a six-membered ring was also investigated. When 14 was treated with 1.1 equiv.
of n-Bu3SnH in the presence of 3.1 equiv. of Et3B and 4 equiv. of MAD at −40°C for 2 h,
cyclized product was obtained in 53% yield along with reduced product 19 (30% yield).
(R)-2-Cyclohexenyl acetic acid ester 18 was obtained as a major diastereomer with 38% de. This
diastereoselectivity was determined by comparing the [h]D value of 2-cyclohexenyl acetic acid
[[h]D −30 (c 0.8, CHCl3)], which was obtained by hydrolysis of 18, to the [h]D value [[h]D +84
(c 2.6, CHCl3)] reported for the (S)-isomer.12
The diastereoselectivity shown in the reaction of 11 was explained as before, considering the
transition state model shown in Fig. 1.
Further tuning of the structure of the auxiliary and its application to other reactions are now
underway.
3. Experimental
3.1. (1S,2S)-trans-2-[(R)-(h-Methylbenzyl)amino]cyclohexanol (2a) and (1R,2R)-trans-2-[(R)-
(h-methylbenzyl)amino]cyclohexanol 2b
To a solution of (+)-(R)-a-methylbenzylamine (12.1 mL, 94.1 mmol) in CH2Cl2 (80 mL) was
added dropwise a solution of Me3Al in n-hexane (93.2 mL, 94.1 mmol) at 0°C, and the mixture
was stirred for 1 h under the same conditions. To this mixture was added a CH2Cl2 (80 mL)
solution of cyclohexene oxide (10 mL, 98.8 mmol), and the mixture was stirred for 3 h at 0°C
and for 18 h at room temperature. The reaction was worked-up as reported to give 2a (9.7 g,
39%) and 2b (8.4 g, 45%). 2a: [h]1D9 −23.9 (c 1.0, MeOH); IR (neat) w cm−1: 3408, 3061, 3026,
1
2929, 2856, 1493, 1448, 1063, 762, 700; H NMR: 400 MHz (CDCl3) l: 0.78–0.88 (1H, m,
C3-H), 1.11–1.35 (4H, m), 1.33 (3H, d, J=6.4, CH3), 1.63–1.71 (2H, m, C4-H, C5-H), 1.91–2.07
(2H, m, C3-H, C6-H), 2.33 (1H, ddd, J=3.9, 9.3, 11.2, C2-H), 3.09 (1H, ddd, J=4.4, 9.5, 10.4,
C1-H), 3.91 (1H, q, J=6.3, CHMe), 7.21–7.34 (5H, m, Ph); 13C NMR: 100 MHz (CDCl3) l:
23.46 (CH3), 24.23 (C4), 25.38 (C5), 31.30 (C3), 32.97 (C6), 55.21 (ꢀCHMe), 61.55 (C1), 74.06
(C2), 126.40 (Ph), 127.02 (Ph), 128.46 (Ph), 146.79 (Ph); LR-FABMS m/z: 220 (M++H), 204.
HR-FABMS: calcd for C14H22NO (M++H), 220.1685; found: 220.1706. 2b: [h]1D9 +90.7 (c 1.0,
MeOH). IR (neat) w cm−1: 3298, 3062, 3026, 2931, 2858, 1739, 1493, 1450, 1371, 1271, 1240,
1
1124, 1066, 760, 702. H NMR: 400 MHz (CDCl3) l: 0.85–1.28 (4H, m), 1.34 (3H, d, J=6.6,
CH3), 1.63–1.67 (2H, m, C4-H, C5-H), 1.94–2.03 (2H, m, C3-H, C2-H), 2.13–2.18 (1H, m,

A. Nishida et al. / Tetrahedron: Asymmetry 11 (2000) 3789–3805
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C6-H), 3.14 (1H, ddd, J=3.9, 11.2, 13.0, C1-H), 3.98 (1H, q, J=6.6, CHMe), 7.21–7.34 (5H, m,
Ph). 13C NMR: 100 MHz (CDCl3) l: 24.20 (CH3), 24.96 (C4), 25.67 (C5), 30.43 (C3), 32.97
(C6), 54.05 (ꢀCHMe), 60.00 (C1), 74.16 (C2), 126.64 (Ph), 126.96 (Ph), 128.49 (Ph), 145.30 (Ph).
LR-FABMS: 220 (M++H), 204, 105. HR-FABMS: calcd for C14H22NO (M++H), 220.1762;
found: 220.1684 [lit. 2a: [h]D25 −15.5 (c 1.0, MeOH), 2b: [h]2D5 +86.7 (c 1.3, MeOH)].8
3.2. (1S,2S)-trans-2-Aminocyclohexanol (1S,2S)-3
A solution of 2a in MeOH (160 mL) was stirred for 3 days under a H2 atmosphere in the
presence of 10% Pd carbon (693 mg). Filtration and evaporation of the solvent followed by
column chromatography (SiO2, AcOEt:MeOH:NH4OH, 10:1:1) gave (1S,2S)-3 (1.49 g, 84%):
mp 91–92°C (Et2O), [h]2D6 +41.7 (c 1.08, MeOH) [lit. mp 88–89°C, [h]2D5 +48.2 (c 1.0, MeOH)].8
Using the same procedure, (1R,2R)-3 was obtained in 78% yield: mp 91–92°C (Et2O), [h]2D6 −40.9
(c 1.01, MeOH) [lit. mp 85–86°C, [h]2D5 −48.5 (c 1.0, MeOH)].8
3.3. (1S,2S)-trans-2-(N,O-Dibenzoyl)aminocyclohexanol
To a CH2Cl2 (95 mL) solution of (1S,2S)-3 (1.32 g, 11.5 mmol) was added triethylamine (8.0
mL, 57.4 mmol) and benzoyl chloride (4.0 mL, 34.4 mmol) at 0°C, and the mixture was stirred
for 3 h under the same conditions. The reaction was quenched by adding water (20 mL). The
aqueous layer was separated and extracted with AcOEt. The combined organic layers were
washed with brine, dried and concentrated in vacuo to give a crude product which was purified
by column chromatography (SiO2, AcOEt:n-hexane, 1:4) to give (1S,2S)-trans-2-(N,O-diben-
zoyl)aminocyclohexanol (3.81 g, 83%): mp 153–155°C. [h]1D2 +60.5 (c 1.0, CHCl3). IR (KBr) w
1
cm−1: 3068, 2939, 2866, 1718, 1631, 1543, 1491, 1452, 1321, 1286, 1272, 1115, 715, 702. H
NMR: 400 MHz (CDCl3) l: 1.29–1.50 (3H, m, CH2), 1.68–1.78 (2H, m, CH2), 1.87–1.90 (1H,
m, CH2), 2.15–2.18 (1H, m, C6-H), 2.32–2.35 (1H, m, C3-H), 4.19–4.27 (1H, m, C1-H), 5.05
(1H, ddd, J=4.4, 10.5, 10.8, C2-H), 6.46 (1H, d, J=8.3, ꢀNH), 7.32–7.52 (6H, m, Ph), 7.65 (2H,
d, J=7.3, Ph), 8.05 (2H, d, J=7.8, Ph). 13C NMR: 100 MHz (CDCl3) l: 24.24 (C4), 24.26 (C5),
31.26 (C3), 32.15 (C6), 53.71 (C1), 75.40 (C2), 126.77 (Ph), 128.31 (Ph), 128.40 (Ph), 129.70 (Ph),
129.74 (Ph), 129.84 (Ph), 130.02 (Ph), 131.19 (Ph), 133.11 (Ph), 134.47 (Ph), 167.10 (CꢁO),
167.69 (CꢁO). LR-FABMS: 324 (M++H), 202, 154, 105. Anal. calcd for C20H21NO3: C, 74.28;
H, 6.55; N, 4.33; found: C, 74.25; H, 6.53; N, 4.26.
3.4. (1S,2S)-trans-2-(N-Benzoyl)aminocyclohexanol
A mixture of (1S,2S)-trans-2-(N,O-dibenzoyl)aminocyclohexanol (2.97 g, 9.27 mmol) and
potassium carbonate (12.7 g, 92.7 mmol) in 90 mL of MeOH was heated to reflux for 1 h. After
the solvent was removed in vacuo, the product was partitioned between AcOEt and aq.
NaHCO3. The separated aqueous layer was extracted with AcOEt and the combined organic
layers were dried, filtered and concentrated to give a residue which was purified by recrystalliza-
tion from benzene. The mother liquor was concentrated to give a residue which was further
purified by column chromatography (SiO2, AcOEt:n-hexane, 1:1). (1S,2S)-trans-2-(N-Ben-
zoyl)aminocyclohexanol was obtained in an overall yield of 98% (1.99 g): mp 173–174°C
(benzene). [h]2D4.5 +38.6 (c 1.1, MeOH). IR (KBr) w cm−1: 3305, 3066, 2939, 2858, 1635, 1549,
1
1491, 1412, 1333, 1039, 860, 800, 694. H NMR: 400 MHz (CDCl3) l: 1.25–1.45 (4H, m, C3-H,

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C4-H, C5-H, C6-H), 1.74–1.78 (2H, m, C4-H, C5-H), 2.09–2.11 (2H, m, C3-H, C6-H), 3.40–3.47
(1H, m, C2-H), 3.55 (1H, bs, ꢀOH), 3.80–3.88 (1H, m, C1-H), 6.17 (1H, bs, ꢀNH), 7.41–7.45
(2H, m, Ph), 7.49–7.53 (1H, m, Ph), 7.76–7.78 (2H, m, Ph). 13C NMR: 100 MHz (CDCl3) l:
24.01 (C4), 24.61 (C5), 31.63 (C3), 34.58 (C6), 56.28 (C1), 75.55 (C2), 127.01 (Ph), 128.31 (Ph),
128.58 (Ph), 131.72 (Ph), 134.13 (Ph), 169.27 (CꢁO). LR-FABMS: 220 (M++H), 154, 136, 105.
HR-FABMS: calcd for C13H18NO2 (M++H): 220.1369; found: 220.1329 [lit. mp 168–169°C, [h]2D5
+43.5 (c 2.0, EtOH)].7
3.5. (1S,2S)-trans-2-(N-Benzyl)aminocyclohexanol (1S,2S)-4
To a suspension of LiAlH4 (795 mg, 20.9 mmol) in THF (20 mL) was added a THF (200 mL)
solution of (1S,2S)-trans-2-(N-benzoyl)aminocyclohexanol (1.72 g, 7.84 mmol) at 0°C. The
mixture was then heated to reflux for 3 h. The reaction was quenched by adding water (1.6 mL)
and 10% aq. NaOH (1.27 mL) at 0°C. The mixture was refluxed for an additional 1 h. The
mixture was filtered through a Celite pad and the filtrate was concentrated to give a residue
which was purified by column chromatography (SiO2, AcOEt:n-hexane:triethylamine, 1:1:0.1) to
give (1S,2S)-4 (1.45 g, 90%): mp 70.5–71.5°C (n-hexane). [h]2D4.5 +83.7 (c 1.0, MeOH). IR (KBr)
1
w cm−1: 3294, 3060, 2937, 2856, 1498, 1450, 1431, 1360, 1338, 1099, 1078, 748, 698. H NMR:
400 MHz (CDCl3) l: 0.93–1.03 (1H, m, CH2), 1.18–1.33 (4H, m, CH2, NH), 1.71–1.74 (2H, m,
CH2), 2.00–2.06 (1H, m, CH2), 2.14–2.20 (1H, m, CH2), 2.29 (1H, ddd, J=3.6, 3.9, 9.3, NCH),
3.20 (1H, ddd, J=4.6, 9.5, 9.8, OCH), 3.35 (1H, bs, OH), 3.69 (1H, d, J=12.9, NHCH2Ph), 3.95
(1H, d, J=12.9, NHCH2Ph), 7.23–7.35 (5H, m, Ph). 13C NMR: 100 MHz (CDCl3) l: 24.29
(C4), 25.05 (C5), 30.45 (C3), 33.27 (C6), 50.71 (ꢀCH2Ph), 63.01 (C1), 73.75 (C2), 126.91 (Ph),
128.02 (Ph), 128.35 (Ph), 140.52 (Ph). LR-FABMS m/z: 206 (100, M++H). HR-FABMS: calcd
for C13H20NO (M++H): 206.1568; found: 206.1539.
3.6. (1S,2S)-trans-2-(N-Benzenesulfonyl-N-benzyl)aminocyclohexanol (1S,2S)-5
A mixture of (1S,2S)-4 (1.12 g, 5.45 mmol), triethylamine (0.92 mL, 6.54 mmol), and
benzenesulfonyl chloride (1.14 mL, 8.93 mmol) in CH2Cl2 (25 mL) was stirred at 0°C for 2.3 h.
The reaction mixture was partitioned between an aqueous saturated solution of NH4Cl and
AcOEt. The separated aqueous layer was extracted with AcOEt. The combined organic layers
were washed successively with 5% HCl, a saturated aqueous solution of NaHCO3, and brine.
Dried solvent was removed in vacuo to give a residue which was purified by column chromatog-
raphy (SiO2, AcOEt:n-hexane, 1:4) to give (1S,2S)-5 (1.68 g, 90%): mp 120–121°C (AcOEt/n-
hexane). [h]1D9 +3.2 (c 0.99, CHCl3). IR (KBr) w cm−1: 3531, 3061, 3029, 2942, 2861, 1454, 1445,
1
1321, 1164, 1149, 1036, 1023, 881, 859, 793. H NMR: 400 MHz (CDCl3) l: 0.98–1.24 (3H, m,
CH2), 1.28–1.38 (1H, m, CH2), 1.43–148 (1H, m, CH2), 1.57–1.63 (2H, m, CH2 and OH),
1.92–1.98 (2H, m, C3-H, C6-H), 3.20 (1H, ddd, J=4.4, 10.1, 14.9, C1-H), 3.50 (1H, ddd, J=3.9,
10.0, 12.1, C2-H), 4.28 (1H, d, J=15.6, NHCH2Ph), 4.63 (1H, d, J=15.6, NHCH2Ph),
7.26–7.33 (3H, m, Ph), 7.38–7.39 (2H, m, Ph), 7.46–7.50 (2H, m, Ph), 7.53–7.57 (1H, m, Ph),
7.82–7.85 (2H, m, Ph). 13C NMR: 100 MHz (CDCl3) l: 23.98 (C4), 25.37 (C5), 28.98 (C3), 34.46
(C6), 47.87 (CH2Ph), 64.54 (C1), 69.97 (C2), 126.95 (Ph), 127.84 (Ph), 128.01 (Ph), 128.70 (Ph),
129.08 (Ph), 132.56 (Ph), 137.74 (Ph), 140.77 (Ph). LR-FABMS: 346 (M++H), 204, 154, 91.
Anal. calcd for C17H23NO3S: C, 66.06; H, 6.71; N, 4.05; found: C, 66.07; H, 6.71; N, 3.97.

A. Nishida et al. / Tetrahedron: Asymmetry 11 (2000) 3789–3805
3797
3.7. (1R,2R)-trans-2-[N-(4-Phenylbenzoyl)]aminocyclohexanol
A mixture of (1R,2R)-3 (1.50 g, 13.0 mmol), triethylamine (2.75 mL, 19.5 mmol) and
4-phenylbenzoyl chloride (3.39 g, 15.6 mmol) in CH2Cl2 (130 mL) was stirred at 0°C for 1 h. The
reaction mixture was partitioned between water and CH2Cl2, and the aqueous layer was
extracted with CH2Cl2. The combined organic layers were washed successively with 5% HCl, a
saturated aqueous solution of NaHCO3, and brine. Dried solvent was removed in vacuo to give
a residue which was purified by recrystallization from benzene. The resulting mother liquor was
concentrated to give a residue which was further purified by column chromatography (SiO2,
AcOEt:n-hexane:CHCl3, 1:1:0.5). (1R,2R)-trans-2-[N-(4-Phenylbenzoyl)]aminocyclohexanol was
obtained in an overall yield of 86% (3.30 g): mp 238–239°C (benzene). [h]2D4 +1.2 (c 0.90, CHCl3).
IR (KBr) w cm−1: 3235, 3267, 3059, 3033, 2937, 2198, 2854, 1616, 1540, 1486, 1446, 1335, 1061,
1
1045, 850, 746, 698. H NMR: 400 MHz (CDCl3) l: 1.26–1.48 (4H, m, C3-H, C4-H, C5-H,
C6-H), 1.74–1.84 (2H, m, C4-H, C5-H), 2.08–2.20 (2H, m, C6-H, C3-H), 3.43–3.50 (m, C1-H),
3.53 (1H, d, J=4.4, ꢀOH), 3.83–3.92 (1H, m, C2-H), 6.16 (1H, d, J=7.6, CONH), 7.36–7.60
(3H, m, Ph), 7.60–7.67 (4H, m, Ph), 7.85–7.86 (2H, m, Ph). 13C NMR: 100 MHz (CDCl3) l:
23.48 (C4), 23.84 (C5), 30.47 (C3), 33.83 (C6), 55.12 (C1), 70.92 (C2), 125.73 (Ph), 126.25 (Ph),
127.26 (Ph), 127.37 (Ph), 128.34 (Ph), 133.76 (Ph), 139.02 (Ph), 142.08 (Ph), 165.70 (CꢁO).
LR-FABMS: 296 (M++H), 154. HR-FABMS: calcd for C19H22NO2 (M++H): 296.1698; found:
296.1631.
3.8. (1R,2R)-trans-2-[N-(4-Phenylbenzyl)]aminocyclohexanol (1R,2R)-6
A mixture of (1R,2R)-trans-2-[N-(4-phenylbenzoyl)]aminocyclohexanol (107 mg, 0.36 mmol)
and LiAlH4 (61 mg, 1.6 mmol) in THF (12 mL) was heated to reflux for 1.5 h. Excessive reagent
was quenched by adding water (0.12 mL) and 10% NaOH (0.01 mL) at 0°C. The mixture was
then refluxed for 30 min. Inorganic solid was removed by filtration through a Celite pad and the
filtrate was dried over Na2SO4. Evaporation of the solvent gave a residue, which was purified by
column chromatography (SiO2, AcOEt:n-hexane:triethylamine, 1:1:0.1) to give (1R,2R)-6 (93
mg, 91%): mp 137–138.5°C. [h]2D0 −54.1 (c 0.96, CHCl3). IR (KBr) w cm−1: 3294, 3082, 2927,
1
2848, 1489, 1448, 1429, 1080, 1059, 766, 696. H NMR: 400 MHz (CDCl3) l: 0.96–1.05 (1H, m,
CH2), 1.18–1.32 (3H, m, CH2), 1.46 (1H, bs, ꢀNH), 1.70–1.78 (2H, m, C4-H, C5-H), 2.03–2.07
(1H, m, CH2), 2.13–2.16 (1H, m, CH2), 2.32 (1H, ddd, J=3.9, 9.2, 11.3, C2-H), 3.22 (1H, ddd,
J=4.6, 9.7, 9.7, C1-H), 3.33 (1H, bs, ꢀOH), 3.74 (1H, d, J=13.2, NHCH2Ar), 4.00 (1H, d,
J=12.9, NHCH2Ar), 7.32–7.35 (1H, m, Ph), 7.40–7.40 (4H, m, Ph), 7.55–7.60 (4H, m, Ph). 13C
NMR: 100 MHz (CDCl3) l: 24.30 (C4), 25.11 (C5), 30.51 (C3), 33.27 (C6), 50.37 (CH2Ar),
63.06 (C1), 73.82 (C2), 127.00 (Ph), 127.14 (Ph), 128.48 (Ph), 128.69 (Ph), 139.58 (Ph).
LR-FABMS m/z: 282 (M++H), 167. HR-FABMS: calcd for C19H24NO (M++H): 282.1845;
found: 282.1863.
3.9. (1R,2R)-trans-2-[N-Benzenesulfonyl-N-(4-phenylbenzyl)]aminocyclohexanol (1R,2R)-7
A mixture of (1R,2R)-6 (2.11 g, 7.52 mmol), triethylamine (1.6 mL, 11.3 mmol) and
benzenesulfonyl chloride (1.95 mL, 15.2 mmol) in CH2Cl2 (75 mL) was stirred at 0°C and then
at room temperature for 2.3 h. The reaction was quenched by adding water, and the product
was extracted with AcOEt. The combined organic layers were washed successively with 5% HCl,

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A. Nishida et al. / Tetrahedron: Asymmetry 11 (2000) 3789–3805
saturated NaHCO3 solution, and brine. Dried solvent was removed in vacuo to give a residue
which was purified by recrystallization from AcOEt. The resulting mother liquor was concen-
trated to give a residue, which was further purified by column chromatography (SiO2, AcOEt:n-
hexane, 1:4). The total yield of (1R,2R)-7 was 3.02 g (95%): mp 175.0–176.0°C
(AcOEt/n-hexane). [h]2D3 −7.78 (c 1.04, CHCl3). IR (KBr) w cm−1: 3541, 3059, 3032, 2939, 2862,
1
1489, 1446, 1410, 1319, 1165, 1149, 1080, 1036, 752, 685. H NMR: 400 MHz (CDCl3) l:
1.00–1.28 (3H, m, CH2), 1.30–1.48 (2H, m, CH2), 1.58–1.65 (2H, m, CH2, ꢀOH), 1.95–2.00 (1H,
m, CH2), 2.08 (1H, d, J=3.9, CH2), 3.18–3.26 (1H, m, C1-H), 3.55 (1H, ddd, J=3.9, 9.8, 11.8,
C2-H), 4.30 (1H, d, J=15.6, NHCH2Ar), 4.70 (1H, d, J=15.7, NHCH2Ar), 7.32–7.37 (1H, m,
Ph), 7.42–7.60 (11H, m, Ph), 7.84–7.87 (2H, m, Ph). 13C NMR: 100 MHz (CDCl3) l: 23.97 (C4),
25.34 (C5), 29.10 (C3), 34.50 (C6), 47.54 (CH2Ar), 64.55 (C1), 70.00 (C2), 126.94 (Ph), 127.30
(Ph), 128.44 (Ph), 128.71 (Ph), 129.06 (Ph), 132.53 (Ph), 136.72 (Ph), 140.41 (Ph), 140.60 (Ph),
140.75 (Ph). LR-FABMS: 280 (M++H), 167, 136. Anal. calcd for C25H27NO3S: C, 71.23; H,
6.46; N, 3.32; found: C, 71.36; H, 6.50; N, 3.22.
3.10. 5-Iodo-4-penten-1-ol
To a benzene (85 mL) solution of 4-pentyn-1-ol (2.0 mL, 21.2 mmol) was added tri-n-butyltin
hydride (5.7 mL, 21.2 mmol) and azobisisobutyronitrile (AIBN, 352 mg, 2.1 mmol), and the
mixture was heated to reflux for 1 h. After the reaction was cooled to room temperature,
benzene was evaporated to give a residue which was dissolved in CH2Cl2 (50 mL). To this
solution was added dropwise a CH2Cl2 (150 mL) solution of iodine (8.23 g, 63.6 mmol) at 0°C,
and the mixture was stirred for 1.3 h. The reaction was quenched by adding a saturated aqueous
solution of sodium thiosulfate. The product was extracted with ether and the combined extracts
were washed successively with water and brine. The extracts were then dried and concentrated
in vacuo to give a residue which was purified by column chromatography (SiO2, AcOEt:n-hex-
ane, 1:2) to give 5-iodo-4-penten-1-ol (4.36 g, 97%). IR (neat) w cm−1: 3336, 3047, 2937, 2873,
1
1606, 1437, 1277, 1219, 1057, 947, 658. H NMR: 400 MHz (CDCl3) l: 1.35 (1H, bs, ꢀOH),
1.63–1.75 (2H, m, C2-H), 2.17 (1.64H, tdd, J=1.2, 7.5, 7.4, C3-H for (E)-isomer), 2.25 (0.46H,
dt, J=7.3, 13.9, C3-H for (Z)-isomer), 3.63–3.71 (2H, m, C1-H), 6.05 (0.79H, dt, J=14.4, 1.5,
C5-H for (E)-isomer), 6.18–6.25 (0.42H, m, C4-H and C5-H for (Z)-isomer), 6.53 (0.79H, dt,
J=14.4, 7.1, C4-H for (E)-isomer). 13C NMR: 100 MHz (CDCl3) l: 30.77 (C2 for (Z)-isomer),
31.09 (C2 for (E)-isomer), 32.26 (C1 for (E)-isomer), 61.73 (C3 for (E)-isomer), 62.00 (C3 for
(Z)-isomer), 75.02 (C4 for (E)-isomer), 83.01 (C4 for (Z)-isomer), 140.52 (C5 for (Z)-isomer),
145.69 (C5 for (E)-isomer). LR-EIMS: 212 (M++H), 194, 167, 127, 85, 67. HR-EIMS: calcd for
C5H9IO: 211.9768; found: 211.9679.
3.11. (1S,2S)-trans-2-(N-Benzenesulfonyl-N-benzyl)aminocyclohexyl bromoacetate
To a THF (27 mL) solution of (1S,2S)-5 (93.5 mg, 2.71 mmol) was added bromoacetyl
bromide (1.92 mL, 22.5 mmol) at 0°C, and the mixture was stirred for 5.5 h under the same
conditions. The reaction was quenched by adding a saturated aqueous solution of NaHCO3, and
the product was extracted with AcOEt. The combined extracts were washed with brine and
dried. The solvent was removed in vacuo to give a residue which was purified by column
chromatography (SiO2, AcOEt:n-hexane, 1:6) to give (1S,2S)-trans-2-(N-benzenesulfonyl-N-
benzyl)aminocyclohexyl bromoacetate (1.21 g, 96%): mp 85.0–85.5°C (Et2O/n-hexane). [h]2D0 −1.9

A. Nishida et al. / Tetrahedron: Asymmetry 11 (2000) 3789–3805
3799
(c 1.0, CHCl3). IR (neat) w cm−1: 3087, 3057, 3031, 2935, 2860, 1734, 1446, 1362, 1338, 1277,
1
1157, 1115, 1091, 1022, 933, 887, 806, 744, 688. H NMR: 400 MHz (CDCl3) l: 1.06–1.34 (4H,
m, C3-H, C4-H, C5-H, C6-H), 1.58–1.68 (2H, m, C4-H, C5-H), 1.74–1.82 (1H, m, C6-H),
2.06–2.14 (1H, m, C3-H), 3.36 (d, J=12.2, CH2Br), 3.60 (d, J=12.2, CH2Br), 3.94–3.88 (1H, m,
OCH), 4.18 (1H, d, J=15.8, NCH2Ph), 4.50 (1H, d, J=15.6, NCH2Ph), 4.72 (1H, ddd, J=4.6,
10.6, 10.8, NCHꢀ), 7.30–7.24 (5H, m, Ph), 7.46–7.56 (3H, m, Ph), 7.80–7.82 (2H, m, Ph). 13C
NMR: 100 MHz (CDCl3) l: 23.62 (C4), 25.08 (C5), 25.82 (CH2Br), 31.45 (C3), 31.78 (C6), 48.00
(CH2Ph), 60.64 (C1), 73.71 (C2), 127.12, 127.75, 128.30, 128.48, 128.94, 132.24, 137.12, 141.39,
166.27 (CꢁO). LR-FABMS m/z: 466 (M+), 328, 91. HR-FABMS: calcd for C21H25NO4S81Br
(M++H): 468.0710; found: 468.0630.
3.12. (1S,2S)-trans-2-(N-Benzenesulfonyl-N-benzyl)aminocyclohexyl (triphenylphosphoranyli-
dene)acetate (1S,2S)-8
A toluene (7.5 mL) solution of (1S,2S)-trans-2-(N-benzenesulfonyl-N-benzyl)aminocyclohexyl
bromoacetate (1.0 g, 2.15 mmol) and triphenylphosphine (567 mg, 2.15 mmol) was heated to
reflux for 3 h. After solvent was removed, the product was solidified by adding ether. The
product was washed with ether (5 mL, three times) and dissolved in water (10 mL). 1N NaOH
was added until the product solution was basic, and the product was extracted with CHCl3. The
combined extracts were washed with brine and dried. The solvent was removed in vacuo to give
(1S,2S)-8 (1.2 g, 91%), which was used in the next step without further purification: [h]2D0 −26.7
(c 0.97, CHCl3). IR (neat) w cm−1: 3059, 2935, 2858, 1612, 1437, 1377, 1333, 1153, 1107, 887, 752,
1
690, 592, 515. H NMR: 400 MHz (CDCl3) l: 0.73–1.26 (4H, m, C3-H, C4-H, C5-H, C6-H),
1.41–1.59 (2H, m, C4-H, C5-H), 1.81–1.84 (1H, m, C6-H), 2.05–2.07 (1H, m, C3-H), 3.85–3.91
(1H, m, C1-H, and 1H, d, J=15.9, NCH2Ph), 4.67–4.77 (2H, m, C2-H, NCH2Ph), 7.03–7.07
(1H, m, CHꢁPPh3), 7.20–7.25 (4H, m, Ph), 7.40–7.58 (19H, m, Ph), 7.75 (2H, d, J=7.3, Ph). 13C
NMR: 100 MHz (CDCl3) l: 24.03 (C4), 31.69 (C5), 33.35 (C3), 34.29 (C6), 47.23 (CH2Ph),
61.80 (C1), 68.23 (C2), 127.10, 127.25, 127.57, 128.18, 128.50, 128.62, 128.74, 131.43, 132.03,
132.85, 132.94, 138.56, 141.48, 170.10 (CꢁO). LR-FABMS: 648 (M++H), 321, 154, 136.
HR-FABMS: calcd for C39H39NO4PS (M++H): 648.2339; found: 648.2335.
3.13. (1S,2S)-trans-2-(N-Benzenesulfonyl-N-benzyl)aminocyclohexyl (2E)-7-iodo-2,6-
heptadienoate (1S,2S)-11
A mixture of (1S,2S)-8 (2.59 g, 4.00 mmol) and crude 5-iodo-4-penten-1-al 10 (1.42 g, 6.78
mmol), which was prepared by oxidation of 5-iodo-4-penten-1-ol using PCC, in CH2Cl2 (15 mL)
was stirred at room temperature for 2.3 h. The solvent was removed in vacuo to give a residue
which was purified by column chromatography (SiO2, AcOEt:n-hexane, 1:6) to give (1S,2S)-11
(770.5 mg, 82%): [h]2D0 +15.1 (c 1.05, CHCl3). IR (neat) w cm−1: 3062, 3028, 2939, 2860, 1714,
1
1652, 1604, 1495, 1446, 1327, 1269, 1155, 1092, 1028, 754, 690. H NMR: 400 MHz (CDCl3) l:
1.03–1.27 (4H, m, C3%-H, C4%-H, C5%-H, C6%-H), 1.54–1.62 (2H, m, C4%-H, C5%-H), 1.72–1.74
(1H, m, C6%-H), 2.08–2.10 (1H, m, C3%-H), 2.19–2.32 (4H, m, C4-H, C5-H), 3.90–4.00 (1H, m,
C1%-H), 4.11 (1H, d, J=15.6, NCH2Ph), 4.51 (1H, d, J=15.9, NCH2Ph), 4.70 (1H, ddd, J=4.6,
10.4, 10.4, C2%-H), 5.27 (1H, d, J=15.4, C2-H), 6.12 (0.83H, d, J=14.4, C7-H for (E)-isomer),
6.21 (0.18H, dt, J=7.3, 7.3, C6-H for (Z)-isomer), 6.32 (0.17H, d, J=7.3, C7-H for (Z)-isomer),
6.81 (1H, dt, J=15.6, 6.6, C3-H), 7.24–7.28 (2H, m, Ph), 7.33–7.37 (2H, m, Ph), 7.45–7.58 (3H,

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A. Nishida et al. / Tetrahedron: Asymmetry 11 (2000) 3789–3805
m, Ph), 7.80–7.82 (2H, m, Ph). 13C NMR: 100 MHz (CDCl3) l: 23.73 (C4%), 25.20 (C5%), 30.86
(C5), 31.94 (C3%, C6%), 34.26 (C4), 47.71 (CH2Ph), 60.74 (C1%), 71.58 (C2%), 76.06 (C7 for
(E)-isomer), 83.84 (C7 for (Z)-isomer), 121.84 (C2), 127.11, 127.60, 128.33, 128.41, 128.86,
131.91, 137.75, 139.35 (C6 for (Z)-isomer), 141.59, 144.46 (C6 for (E)-isomer), 147.52 (C3 for
(E)-isomer), 147.78 (C3 for (Z)-isomer), 165.30 (CꢁO). LR-FABMS: 580 (M++H), 438, 328, 238,
91. HR-FABMS: calcd for C26H32INO4S (M++H): 580.1027; found: 580.1008.
3.14. (1R,2R)-trans-2-[N-Benzenesulfonyl-N-(4-phenylbenzyl)]aminocyclohexyl bromoacetate
To a THF (70 mL) solution of (1R,2R)-7 (2.80 g, 6.65 mmol) in an ice bath was added
bromoacetyl bromide (4.7 mL, 53.9 mmol), and the mixture was stirred for 2 h under the same
conditions. The reaction was quenched by adding a saturated aqueous solution of NaHCO3, and
the product was extracted with AcOEt. The combined extracts were washed with brine and
dried. The solvent was removed in vacuo to give a residue which was purified by column
chromatography (SiO2, AcOEt:n-hexane, 1:10) to give (1R,2R)-trans-2-[N-benzenesulfonyl-N-
(4-phenylbenzyl)]aminocyclohexyl bromoacetate (3.60 g, 99%): [h]2D3 −8.0 (c 1.04, CHCl3). IR
(neat) w cm−1: 3057, 3030, 2939, 2862, 1736, 1489, 1446, 1333, 1277, 1155, 1090, 1018, 760, 689.
1H NMR: 400 MHz (CDCl3) l: 1.12–1.34 (4H, m, C3-H, C4-H, C5-H, C6-H), 1.62–1.68 (2H,
m, C4-H, C5-H), 1.80–1.82 (1H, m, C6-H), 2.08–2.14 (1H, m, C3-H), 3.36 (d, J=12.4, CH2Br),
3.42 (d, J=12.4, CH2Br), 3.94–4.00 (1H, m, C1-H), 4.18 (1H, d, J=15.9, NCH2C6H4Ph), 4.55
(1H, d, J=15.8, NCH2C6H4Ph), 4.75 (1H, ddd, J=4.6, 10.6, 10.9, C2-H), 7.33–7.38 (3H, m,
Ph), 7.42–7.51 (6H, m, Ph), 7.54–7.59 (3H, m, Ph), 7.80–7.83 (2H, m, Ph). 13C NMR: 100 MHz
(CDCl3) l: 23.66 (C4), 25.10 (C5), 25.85 (CH2Br), 31.49 (C3), 31.96 (C6), 47.74 (CH2Ph), 60.72
(C1), 73.73 (C2), 127.01, 127.15, 127.34, 128.75, 128.77, 128.93, 132.22, 136.12, 140.55, 141.46,
166.35 (CꢁO). LR-FABMS m/z: 542 (M++H). HR-FABMS: calcd for C27H29NO4S81Br (M++H):
544.1030; found: 544.0921.
3.15. (1R,2R)-trans-2-[N-Benzenesulfonyl-N-(4-phenylbenzyl)]aminocyclohexyl
(triphenylphosphoranylidene)acetate (1R,2R)-9
A
toluene (60 mL) solution of (1R,2R)-trans-2-[N-benzenesulfonyl-N-(4-phenylben-
zyl)]aminocyclohexyl bromoacetate (3.17 g, 6.00 mmol) and triphenylphosphine (2.05 g, 7.81
mmol) was heated to reflux for 4.5 h. After the solvent was removed, the product was solidified
by adding ether. The product was washed with ether (20 mL, three times) and dissolved in water
(20 mL). 1N NaOH was added until the product solution was basic, and the product was
extracted with CHCl3. The combined extracts were washed with brine and dried. The solvent
was removed in vacuo to give (1R,2R)-9 (4.0 g, 95%), which was used in the next step without
further purification: [h]1D1 +10.0 (c 1.32, CHCl3). IR (neat) w cm−1: 3057, 3027, 2936, 2860, 1611,
1
1485, 1437, 1377, 1333, 1152, 1107, 894, 756, 691. H NMR: 400 MHz (CDCl3) l: 0.85–1.22
(4H, m, C3-H, C4-H, C5-H, C6-H), 1.44–1.60 (2H, m, C4-H, C5-H), 1.86–1.90 (1H, m, C6-H),
2.04–2.13 (1H, m, C3-H), 3.85–3.96 (1H, m, C1-H, and 1H, d, J=15.6, NCH2C6H4Ph),
4.70–4.80 (1H, m, C2-H, and 1H, d, J=15.6, NCH2C6H4Ph), 7.04–7.07 (1H, m, CHꢁPPh3),
7.21–7.26 (3H, m, Ph), 7.31–7.34 (1H, m, Ph), 7.40–7.48 (12H, m, Ph), 7.53–7.59 (11H, m, Ph),
7.91–7.93 (2H, m, Ph). 13C NMR: 100 MHz (CDCl3) l: 24.05 (C4), 30.50 (C5), 33.37 (C3), 34.34
(C6), 46.95 (CH2Ph), 61.86 (C1), 68.30 (C2), 126.85, 127.00, 127.14, 127.60, 128.02, 128.51,
128.64, 128.67, 128.76, 129.18, 131.46, 132.05, 132.85, 132.95, 137.63, 140.03, 140.83, 141.48,

A. Nishida et al. / Tetrahedron: Asymmetry 11 (2000) 3789–3805
3801
170.27 (CꢁO). LR-FABMS m/z: 724 (M++H). HR-FABMS: calcd for C45H44NO4PS (M++H):
724.2646; found: 724.2662.
3.16. (1R,2R)-trans-2-[N-Benzenesulfonyl-N-(4-phenylbenzyl)]aminocyclohexyl (2E)-7-iodo-2,6-
heptadienoate (1R,2R)-12
A mixture of (1R,2R)-9 (189.2 mg, 0.26 mmol) and crude 5-iodo-4-penten-1-al 10 (54.1 mg,
0.258 mmol), which was prepared by oxidation of 5-iodo-4-penten-1-ol using PCC, in CH2Cl2 (3
mL) was stirred at room temperature for 4.5 h. The solvent was removed in vacuo to give a
residue which was purified by column chromatography (SiO2, AcOEt:n-hexane, 1:6) to give
(1R,2R)-12 (130 mg, 77%): [h]1D7 −49.1 (c 1.05, CHCl3). IR (neat) w cm−1: 3421, 3059, 3030, 2935,
1
2860, 1718, 1655, 1604, 1489, 1448, 1340, 1277, 1157, 1092, 1033, 756, 690. H NMR: 400 MHz
(CDCl3) l: 1.10–1.30 (4H, m, C3%-H, C4%-H, C5%-H, C6%-H), 1.60–1.64 (2H, m, C4%-H, C5%-H),
1.78–1.80 (1H, m, C6%-H), 2.10–2.15 (1H, m, C3%-H), 2.16–2.30 (4H, m, C4-H, C5-H), 3.90–4.19
(1H, m, C1%-H), 4.15 (1H, d, J=15.8, NCH2C6H4Ph), 4.56 (1H, d, J=15.6, NCH2C6H4Ph), 4.70
(1H, ddd, J=4.6, 10.4, 10.4, C2%-H), 5.29 (1H, d, J=15.6, C2-H), 6.10 (0.82H, d, J=15.6, C7-H
for (E)-isomer), 6.17–6.22 (1H, m, C6-H for (Z)-isomer), 6.30 (0.18H, d, J=7.3, C7-H for
(Z)-isomer), 6.48 (1H, dt, J=15.6, 6.6, C3-H), 7.31–7.59 (12H, m, Ph), 7.80–7.82 (2H, m, Ph).
13C NMR: 100 MHz (CDCl3) l: 23.75 (C4%), 25.20 (C5%), 30.35 (C5 for (Z)-isomer), 30.86 (C5
for (E)-isomer), 31.98 (C3%), 32.07 (C6%), 33.05 (C4 for (Z)-isomer), 34.25 (C4 (E)-isomer), 47.42
(CH2C6H4Ph), 60.83 (C1%), 71.59 (C2%), 76.06 (C7 for (E)-isomer), 83.85 (C7 for (Z)-isomer),
121.66 (C2 for (Z)-isomer), 121.82 (C2 for (E)-isomer), 127.00, 127.08, 127.14, 128.27, 128.83,
131.89, 136.40, 139.33 (C6 for (Z)-isomer), 140.42, 140.65, 141.67, 144.45 (C6 for (E)-isomer),
147.56 (C3 for (E)-isomer), 147.87 (C3 for (Z)-isomer), 166.34 (CꢁO for (E)-isomer), 165.40
(CꢁO for (Z)-isomer). LR-FABMS: 656 (M++H). HR-FABMS: calcd for C32H35INO4S (M++
H): 656.1334; found: 656.1298.
3.17. 6-Iodo-5-hexen-1-ol
To a benzene (25 mL) solution of 5-hexen-1-ol (0.5 mL, 4.53 mmol) were added tri-n-butyltin
hydride (1.25 mL, 4.53 mmol) and AIBN (75.2 mg, 0.45 mmol). The mixture was heated to
reflux for 3.5 h. After the reaction was cooled to room temperature, benzene was evaporated to
give a residue which was dissolved in CH2Cl2 (10 mL). To this solution was added dropwise a
CH2Cl2 (40 mL) solution of iodine (1.74 g, 13.6 mmol) at 0°C, and the mixture was stirred for
1.3 h. The reaction was quenched by adding an aqueous saturated solution of sodium
thiosulfate. The product was extracted with ether and the combined extracts were washed
successively with water and brine. The extracts were then dried and concentrated in vacuo to
give a residue which was purified by column chromatography (SiO2, AcOEt:n-hexane, 1:2) to
give 6-iodo-5-hexen-1-ol (1.07 g, 100%). IR (neat) w cm−1: 3337, 3048, 2933, 2860, 1604, 1458,
1
1214, 1066, 949, 660. H NMR: 400 MHz (CDCl3) l: 1.28–1.39 (1H, m, C2-H), 1.44–1.64 (4H,
m, C2-H, C3-H, ꢀOH), 2.13–2.07 (1.6H, m, C4-H for (E)-isomer), 2.16–2.21 (0.4H, m, C4-H for
(Z)-isomer), 3.63–3.69 (2H, m, C1-H), 6.01 (0.74H, dt, J=14.4, 1.4, C6-H for (E)-isomer),
6.15–6.23 (0.33H, m, C5-H for (Z)-isomer, C6-H for (Z)-isomer), 6.51 (0.7H, dt, J=14.4, 7.3,
C5-H for (E)-isomer). 13C NMR: 100 MHz (CDCl3) l: 24.12 (C), 24.51 (C), 31.85 (C), 32.01,
34.33 (C), 35.68, 62.50, 62.59, 74.75, 82.65, 140.92, 146.19. LREIMS m/z: 225 (M++H).
HR-EIMS: calcd for C6H11IO: 225.9871; found: 225.9850.

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A. Nishida et al. / Tetrahedron: Asymmetry 11 (2000) 3789–3805
3.18. (1R,2R)-trans-2-[N-Benzenesulfonyl-N-(4-phenylbenzyl)]aminocyclohexyl (2E)-8-iodo-2,7-
octadienoate [(1R,2R)-14]
A mixture of (1R,2R)-9 (1.49 g, 2.06 mmol) and crude 6-iodo-5-hexen-1-al 13 (556 mg, 2.48
mmol), which was prepared by oxidation of 6-iodo-5-hexen-1-ol using PCC, in CH2Cl2 (5 mL)
was stirred at room temperature for 17 h. The solvent was removed in vacuo to give a residue
which was purified by column chromatography (SiO2, AcOEt:n-hexane, 1:10) to give (1R,2R)-14
(1.13 g, 82%): [h]1D6 −44.4 (c 1.03, CHCl3). IR (neat) w cm−1: 3058, 3029, 2938, 2860, 1717, 1653,
1
1604, 1489, 1446, 1332, 1154, 1092, 1038, 892, 754, 689. H NMR: 400 MHz (CDCl3) l:
1.12–1.35 (4H, m, C3%-H, C4%-H, C5%-H, C6%-H), 1.51–1.68 (4H, m, C4%-H, C5%-H, C5-H),
1.79–1.85 (1H, m, C6%-H), 2.06–2.20 (5H, m, C3%-H, C4-H, C6-H), 3.95–4.02 (1H, m, C1%-H),
4.19 (1H, d, J=15.6, NCH2Ph), 4.53 (1H, d, J=15.6, NCH2Ph), 4.73 (1H, ddd, J=4.6, 10.3,
10.4, C2%-H), 5.36 (1H, dt, J=15.6, 1.5, C2-H), 6.06 (0.82H, d, J=14.4, C8-H for (E)-isomer),
6.18 (0.18H, dt, J=7.0, 7.0, C7-H for (Z)-isomer), 6.27 (0.18H, d, J=7.3, C8-H for (Z)-isomer),
6.51 (1H, dt, J=14.2, 7.1, C7-H), 6.83 (1H, dt, J=15.6, 7.1, C3-H), 7.30–7.57 (12H, m, Ph),
7.78–7.81 (2H, m, Ph). 13C NMR: 100 MHz (CDCl3) l: 23.78 (C4%), 25.22 (C5%), 26.58 (C5),
31.17 (C6), 32.03 (C3%, C6%), 35.25 (C4), 47.41 (CH2Ph), 60.83 (C1%), 71.49 (C2%), 75.40 (C8 for
(E)-isomer), 83.31 (C8 for (Z)-isomer), 121.45 (C2), 127.14, 128.81, 131.92, 136.42, 140.42,
140.68, 141.68, 145.52 (C7 for (E)-isomer), 148.72 (C3), 165.51 (CꢁO). LR-FABMS m/z: 167
(100), 670 (M++H). HR-FABMS: calcd for C33H38INO4S (M++H): 670.1509, found: 670.1447.
3.19. Radical cyclization of (1S,2S)-11 (a representative procedure for Table 1)
3.19.1. Run 1
To a mixture of (1S,2S)-11 (280 mg, 0.49 mmol) and tri-n-butyltin hydride (0.2 mL, 0.73
mmol) in toluene (9.7 mL) with stirring at −78°C was added a toluene solution of triethylborane
(1.0 M solution, 0.5 mL, 0.5 mmol), and the mixture was stirred for 25 min under the same
conditions. The mixture was warmed to room temperature and concentrated in vacuo to give a
residue which was treated with 10% aqueous potassium fluoride for 12 h after dissolving in
CH2Cl2 (15 mL). The resulting suspension was filtered through a Celite pad and the filtrate was
extracted with AcOEt. The combined organic layers were washed with an aqueous saturated
solution of NaHCO3 and brine. Dried solvent was removed in vacuo to give a residue which was
purified by column chromatography (SiO2, AcOEt:n-hexane, 1:6) to give an inseparable mixture
of 15a and 15b (220 mg, 100%). Spectral data for a mixture of 15a and 15b: IR (neat) w cm−1:
1
3060, 3032, 2941, 2862, 1734, 1446, 1340, 1259, 1157, 1092, 1026, 930, 887, 741, 690. H NMR:
400 MHz (CDCl3) l: 1.07–1.40 (6H, m, C3¦-H, C4¦-H, C5¦-H, C6¦-H, C2%-H, C5-H), 1.56–1.62
(2H, m, C4%-H, C5%-H), 1.78–1.89 (2H, m, C2%-H, C6¦-H), 1.94–2.09 (2H, m, C3¦-H, C5-H),
2.24–2.35 (2H, m, C4-H), 2.85–2.92 (1H, m, C1-H), 3.86–3.95 (1H, m, C1%-H), 4.29 (1H, d,
J=15.6, NCH2Ph), 4.56 (1H, d, J=15.9, NCH2Ph), 4.74 (1H, dddd, J=2.5, 4.6, 10.5, 10.5,
C2¦-H), 5.55–5.60 (1H, m, C3-H), 5.73–5.76 (1H, m, C2-H), 7.21–7.51 (8H, m, Ph), 7.80 (2H, m,
Ph). 13C NMR: 100 MHz (CDCl3) l: 23.87 (C4¦), 25.35 (C5¦), 29.58 (C5), 31.83 (C4), 32.17
(C3¦), 32.56 (C6¦), 40.22 (C2%), 41.86 (C1), 48.06 (CH2Ph), 61.09 (C1¦), 71.62 (C2¦), 127.30,
127.67, 128.43, 128.60, 128.81, 131.35 (C3), 131.97, 133.57 (C2), 137.57, 141.90, 171.98 (CꢁO).
LR-FABMS m/z: 454 (M++H), 328, 312, 238, 154, 91. HR-FABMS: calcd for C26H32NO4S
(M++H): 454.2041; found: 454.2061.

A. Nishida et al. / Tetrahedron: Asymmetry 11 (2000) 3789–3805
3803
3.19.2. Run 2
To a mixture of (1S,2S)-11 (200 mg, 0.35 mmol) and BF3·Et2O (1.4 mL, 11.1 mmol) in toluene
(3.2 mL) with stirring at −78°C were successively added tri-n-butyltin hydride (0.42 mL, 1.56 mmol)
and triethylborane (1.01 M solution in n-hexane, 0.38 mL, 0.38 mmol). The reaction mixture was
stirred under the same conditions for 30 min and worked-up as in run 1 to give a mixture of 15a
and 15b (157 mg, 100%).
3.19.3. Run 3
To a solution of (1S,2S)-11 (695 mg, 1.20 mmol) in toluene (12 mL) with stirring at −78°C
was added a toluene solution of MAD (0.4 M solution, 12 mL, 4.8 mmol), which was prepared
by adding trimethylaluminum (1 M in n-hexane, 5 mL, 5 mmol) to a toluene (7.5 mL) solution
of butylhydroxytoluene (2.2 g, 10 mmol) at 0°C. To this mixture were added tri-n-butyltin hydride
(0.48 mL, 1.80 mmol) and triethylborane (1 M solution in n-hexane, 1.25 mL, 1.25 mmol), and
the mixture was stirred for 150 min. After adding tri-n-butyltin hydride (0.03 mL, 0.12 mmol)
and triethylborane (1 M solution in n-hexane, 0.12 mL, 0.12 mmol), the mixture was stirred for
30 min. The reaction was quenched and worked-up as in run 1 to give a mixture of 15a and 15b
(501 mg, 92%).
3.20. Hydrolysis of 15
A mixture of 15 (run 3, 457 mg, 0.99 mmol) and NaOH (794 mg, 19.8 mmol) in MeOH:H2O
(4:1, 12.5 mL) was heated to reflux for 2 h. After the mixture was cooled to room temperature,
the solvent was removed under reduced pressure and the aqueous layer was extracted with ether.
The combined organic layers were washed with brine and dried. The solvent was removed in vacuo
to give a residue which was purified by column chromatography (SiO2, AcOEt:n-hexane, 1:4) to
give 5 (258 mg, 75%). The aqueous layer was acidified with 1N HCl and extracted with ether.
The combined extracts were washed with brine and dried. The solvent was removed in vacuo to
give a residue which was purified by column chromatography (SiO2, ether:n-hexane, 1:4, then
ether) to give 16 (91 mg, 73%). The enantiomeric excess of 16 was calculated to be 53% ee by
comparison of the [h]D value.
[h]2D0 +60.0 (c 1.01, CHCl3) [lit [h]D +113 (c 0.5, CHCl3)].11 IR (neat) w cm−1: 3053, 2931, 2679,
1
1707, 1408, 1290, 1217, 928, 723. H NMR: 400 MHz (CDCl3) l: 1.42–1.53 (1H, m, C5%-H),
2.10–2.19 (1H, m, C5%-H), 2.31–2.46 (4H, m, CH2COOH, C4%-H), 3.05–3.13 (1H, m, C1-H),
5.67–5.70 (1H, m, C2%-H), 5.77–5.80 (1H, m, C3%-H), 10.4 (1H, m, ꢀCOOH). 13C NMR: 100 MHz
(CDCl3) l: 29.62 (C5%), 31.79 (C4%), 40.19 (C2), 41.73 (C1%), 131.74 (C3%), 133.37 (C2%), 179.55
(ꢀCOOH). LR-EIMS: 127 (M++H), 108, 79, 67, 66. HR-EIMS: calcd for C7H10O2: 126.0607;
found: 126.0691.
3.21. Radical cyclization of (1R,2R)-12
To a mixture of (1R,2R)-12 (263 mg, 0.40 mmol) and MAD (0.8 M solution in toluene, 4 mL,
3.2 mmol) were successively added tri-n-butyltin hydride (0.16 mL, 0.6 mmol) and triethylborane
(1.0 M solution in n-hexane, 0.42 mL, 0.42 mmol), and the mixture was stirred for 3 h at −78°C.
The reaction was quenched by adding 1N HCl (3 mL) and worked-up as above to give (1R,2R)-17
(201 mg, 95%): IR (neat) w cm−1: 3057, 2935, 2862, 1718, 1489, 1448, 1340, 1020, 891, 862, 806,
1
688. H NMR: 400 MHz (CDCl3) l: 1.05–1.44 (6H, m, C3¦-H, C4¦-H, C5¦-H, C6¦-H, C2%-H,

3804
A. Nishida et al. / Tetrahedron: Asymmetry 11 (2000) 3789–3805
C5-H), 1.58–1.63 (2H, m, C4%-H, C5%-H), 1.75–1.87 (2H, m, C2%-H, C6¦-H), 2.02–2.09 (2H,
m, C3¦-H, C5-H), 2.27–2.35 (2H, m, C4-H), 2.83–2.91 (1H, m, C1-H), 3.92–3.96 (1H, m,
C1%-H), 4.04 (1H, d, J=15.9, NCH2Ph), 4.63 (1H, d, J=15.9, NCH2Ph), 4.77 (1H, ddd,
J=4.4, 10.4, 10.5, C2¦-H), 5.54–5.59 (1H, m, C3-H), 5.72–5.76 (1H, m, C2-H), 7.32–7.36
(1H, m, Ph), 7.39–7.51 (9H, m, Ph), 7.57–7.59 (2H, m, Ph), 7.79–7.81 (2H, m, Ph). 13C
NMR: 100 MHz (CDCl3) l: 23.75 (C4¦), 25.19 (C5¦), 29.38 (C5), 31.80 (C4), 32.59 (C3¦),
32.66 (C6¦), 40.01 (C2%), 41.74 (C1), 47.45 (CH2Ph), 60.89 (C1¦), 71.42 (C2¦), 126.97, 127.04,
127.15, 127.30, 128.72, 128.81, 128.90, 128.81, 131.41 (C3), 131.99, 133.45 (C2), 136.43,
140.46, 140.60, 141.53, 172.02 (CꢁO). LR-FABMS: 530 (M++H). HR-FABMS: calcd for
C32H36NO4S: 530.2370; found: 530.2359.
A mixture of (1R,2R)-17 (201 mg, 0.381 mmol) and NaOH (93 mg, 2.34 mmol) in
MeOH:water (4:1, 4 mL) was refluxed for 1.5 h. The usual work-up gave 2-cyclopentenyl
acetic acid (31 mg, 64%) with [h]D19 −67.1 (c 0.86, CHCl3), 59% ee. IR (neat) w cm−1: 3053,
1
2931, 2679, 1707, 1408, 1290, 1217, 928, 723. H NMR: 400 MHz (CDCl3) l: 1.42–1.53 (1H,
m, C5%-H), 2.10–2.19 (1H, m, C5%-H), 2.31–2.46 (4H, m, CH2COOH, C4%-H), 3.05–3.13 (1H,
m, C1-H), 5.67–5.70 (1H, m, C2%-H), 5.77–5.80 (1H, m, C3%-H), 10.4 (1H, m, ꢀCOOH). 13C
NMR: 100 MHz (CDCl3) l: 29.62 (C5%), 31.79 (C4%), 40.19 (C2), 41.73 (C1%), 131.74 (C3%),
133.37 (C2%), 179.55 (ꢀCOOH). LR-EIMS: 127 (M++H), 108, 79, 67. HR-EIMS: calcd for
C7H10O2: 126.0607; found: 126.0691.
3.22. Radical cyclization of (1R,2R)-14
To a mixture of (1R,2R)-14 (268 mg, 0.40 mmol) and MAD (0.4 M solution in toluene, 4
mL, 1.6 mmol) with stirring at −78°C were successively added tri-n-butyltin hydride (0.21
mL, 0.78 mmol) and triethylborane (1.0 M solution in n-hexane, 0.93 mL, 0.93 mmol), and
the mixture was stirred for 2 h at −78°C. The reaction was quenched by adding 1N HCl (3
mL). The reaction was worked-up as above to give (1R,2R)-18 (85 mg, 39%) and (1R,2R)-19
(76 mg, 35%). (1R,2R)-18: IR (neat) w cm−1: 3027, 2934, 2861, 1730, 1489, 1447, 1340, 1156,
1
1092, 891, 759, 716, 689. H NMR: 400 MHz (CDCl3) l: 0.85–1.26 (6H, m, C3¦-H, C4¦-H,
C5¦-H, C6¦-H, C2%-H, C5-H), 1.48–1.80 (4H, m, C4%-H, C5%-H), 1.81–1.89 (3H, m, C2%-H,
C6¦-H), 1.96–1.97 (1H, m), 2.09–2.12 (1H, m, C3¦-H, C5-H), 2.39–2.43 (1H, m, C4-H), 3.93
(1H, ddd, J=4.6, 10.9, 10.9, C1%-H), 4.10 (1H, d, J=15.8, ꢀNꢀCH2ꢀPh), 4.61 (1H, d,
J=15.6, ꢀNꢀCH2ꢀPh), 4.80 (1H, ddd, J=4.6, 10.3, 10.4, C2¦-H), 5.44 (1H, dd, J=2.2, 10.1,
C3-H), 5.69 (1H, ddd, J=3.4, 10.0, 5.9, C2-H), 7.30–7.34 (1H, m, Ph), 7.38–7.58 (11H, m,
Ph), 7.79–7.81 (2H, m, Ph). 13C NMR: 100 MHz (CDCl3) l: 20.90 (C6), 23.74 (C4¦), 24.95
(C5), 25.17 (C5¦), 28.66 (C4), 31.88 (C3¦), 32.04 (C1), 32.59 (C6¦), 40.34 (C2%), 47.45
(CH2Ph), 60.86 (C1¦), 71.45 (C2¦), 126.96, 127.03, 127.14, 127.28, 128.07, 128.71, 128.81,
128.90, 129.83, 132.01 (C2), 136.45, 140.44, 140.57, 141.50, 171.92 (CꢁO). LR-FABMS m/z:
544 (M++H). HR-FABMS: calcd for C33H38NO4S (M++H): 544.2553; found: 544.2484.
(1R,2R)-19: [h]1D6 −42.1 (c 1.0, CHCl3). IR (neat) w cm−1: 3061, 3029, 2935, 2860, 1714, 1654,
1
1489, 1446, 1331, 1264, 1155, 1092, 1038, 892, 760, 689. H NMR: 400 MHz (CDCl3) l:
1.20–1.29 (4H, m, C3%-H, C4%-H, C5%-H, C6%-H), 1.51–1.65 (4H, m, C4%-H, C5%-H, C5-H),
1.80–1.85 (1H, m, C6%-H), 2.06–2.18 (5H, m, C3%-H, C4-H, C6-H), 3.93–4.00 (1H, m, C1%-H),
4.16 (1H, d, J=15.6, NCH2Ph), 4.56 (1H, d, J=15.8, NCH2Ph), 4.76 (1H, ddd, J=4.6, 10.5,
10.5, C2%-H), 4.99–5.07 (2H, m, C8-H), 5.33 (1H, dt, J=15.6, 1.5, C2-H), 5.81 (1H, ddt,
J=10.2, 17.1, 6.6, C7-H), 6.83 (1H, dt, J=15.9, 6.8, C3-H), 7.32–7.34 (1H, m, Ph), 7.38–7.57

A. Nishida et al. / Tetrahedron: Asymmetry 11 (2000) 3789–3805
3805
(11H, m, Ph), 7.79–7.81 (2H, m, Ph). 13C NMR: 100 MHz (CDCl3) l: 20.90 (C4%), 23.75 (C5%),
25.19 (C5), 31.44 (C6%), 32.01 (C3%), 32.26 (C6%), 33.07 (C4), 47.41 (CH2Ph), 60.86 (C1%), 71.38
(C2%), 115.14 (C8), 121.02 (C2), 126.97, 127.04, 127.13, 127.23, 128.68, 128.80, 13188, 136.48,
137.90 (C7), 140.38, 140.65, 141.60, 149.44 (C3), 165.65 (CꢁO). LR-FABMS: 544 (M++H), 167.
HR-FABMS: calcd for C33H38NO4S (M++H): 544.2546; found: 544.2491.
A mixture of (1R,2R)-18 (85 mg, 0.16 mmol) and NaOH (91 mg, 2.28 mmol) in MeOH:water
(4:1, 1.6 mL) was refluxed for 6 h. The usual work-up gave 2-cyclohexenyl acetic acid (15.1 mg,
68%) with [h]1D4 −30 (c 0.76, CHCl3), 35% ee [lit. [h]D27 +84 (c 2.6, CHCl3) for (S)-isomer].12
3.22.1. 2-Cyclohexenyl acetic acid
1
IR (neat) w cm−1: 2927, 1707, 1410, 1292, 1202, 941, 721, 680. H NMR: 400 MHz (CDCl3)
l: 1.35–1.26 (1H, m, C5%-H), 1.52–1.62 (1H, m, C5%-H), 1.68–1.73 (1H, m, C6%-H), 1.83–1.90 (1H,
m, C6%-H), 1.95–2.02 (2H, m, C4%-H), 2.30 (1H, dd, J=8.0, 15.2, CH2COOH), 2.37 (1H, dd, J=6.8,
15.1, CH2COOH), 2.55–2.62 (1H, m, C1%-H), 5.57 (1H, dd, J=2.2, 9.9, C2%-H), 5.74 (1H, ddd,
J=3.4, 5.8, 9.8, C3%-H), 10.6–12.0 (1H, bs, ꢀCOOH). 13C NMR: 100 MHz (CDCl3) l: 20.90 (C5%),
24.96 (C6%), 28.73 (C4%), 32.01 (C1%), 40.57 (C2), 128.39 (C3%), 129.79 (C2%), 179.25 (ꢀCOOH).
LR-EIMS: 140 (M++H), 122, 80, 79, 67. HR-EIMS: calcd for C8H12O2: 140.0782; found: 140.0846.
Acknowledgements
This study was supported by a Grant-in-Aid for Scientific Research from the Ministry of Science,
Education, Sports and Culture.
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