Stereoselective synthesis of protected (2S,3S)-N-methyl-5- hydroxyisoleucine, a component of halipeptins

Article abstract of DOI:10.1016/j.tet.2004.06.111

The stereocontrolled synthesis of the protected (2S,3S)-N-methyl-5- hydroxyisoleucine, a component of halipeptins A and B with potent anti-inflammatory activity, has been achieved. The key steps include (i) installation of a double bond to bicyclic lactam

Full text of DOI:10.1016/j.tet.2004.06.111

Tetrahedron 60 (2004) 8031–8035
Stereoselective synthesis of protected
(2S,3S)-N-methyl-5-hydroxyisoleucine, a component
of halipeptins
*
Sousuke Hara, Kazuishi Makino and Yasumasa Hamada
Graduate School of Pharmaceutical Sciences, Chiba University, Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
Received 28 May 2004; revised 16 June 2004; accepted 24 June 2004
Available online 29 July 2004
Abstract—The stereocontrolled synthesis of the protected (2S,3S)-N-methyl-5-hydroxyisoleucine, a component of halipeptins A and B with
potent anti-inflammatory activity, has been achieved. The key steps include (i) installation of a double bond to bicyclic lactam 4 using N-tert-
butyl phenylsulfinimidoyl chloride, (ii) highly exo-selective Michael reaction with lithium dimethylcuprate in the presence of
chlorotrimethylsilane, and (iii) Ru-catalyzed oxidative deprotection of N,O-benzylidene acetal to the acid anhydride.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
Riccardis reported the first synthesis of the NMeOHIle
derivative in 10 steps and 1.1% overall yield, in which a
diastereoselective silyl-assisted [3,3]-sigmatropic rear-
rangement was employed as a key step.3 We required a
practical synthesis of NMeOHIle for production of halipep-
tins and their analogues. Herein, we describe an enantio-
selective synthesis of protected (2S,3S)-NMeOHIle (3) based
on the strategy of stereocontrolled transformation of chiral
bicyclic lactam 4 and novel Ru-catalyzed oxidative depro-
tection of the benzylidene acetal originally developed by us.4j
Halipeptins A (1) and B (2)1 are novel 17-membered cyclic
depsipeptides isolated from the marine sponge Haliclona sp.
collected in waters off the Vanuatu Islands by Gomez-
Paloma and co-workers in 2001. In 2002, Gomez-Paloma
et al. corrected the original assignments for halipeptins and
reported the structural revision of an oxazetidine ring to the
thiazoline unit in halipeptins A and B (Fig. 1).2 Halipeptin A
is known to show strong anti-inflammatory activity in vivo,
causing 60% reduction of edema in mice at the dose of
300 mg/kg. In addition to their potent biological activities,
their intriguing structures containing (2S,3S)-N-methyl-5-
hydroxyisoleucine (NMeOHIle) and other unusual units
prompted us and another group to initiate efforts directed
towards the total synthesis. Very recently, Izzo and
2. Results and discussion
As the starting material for synthesis of (2S,3S)-N-methyl-5-
hydroxyisoleucine, we chose bicyclic lactam 4 derived from
Figure 1. Structure of halipeptins.
Keywords: Halipeptin; Bicyclic lactam; N-tert-Butyl phenylsulfinimidoyl chloride; (2S,3S)-N-Methyl-5-hydroxyisoleucine.
* Corresponding author. Tel./fax: C81-4-3290-2987; e-mail: hamada@p.chiba-u.ac.jp
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.06.111

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S. Hara et al. / Tetrahedron 60 (2004) 8031–8035
(S)-glutamic acid (Scheme 1). Bicyclic lactam 4 is a
versatile synthon in the synthesis of a variety of natural
products4 and was prepared from (S)-pyroglutamic acid
according to Thottathil’s procedure.5 First, introduction of a
double bond to the lactam was performed by two-step
conversion, phenylselenylation-phenylselenoxide elimin-
ation, developed by us.4a,b This method, however, requires
highly toxic and expensive phenylselenium bromide or
chloride, and in addition its reproducibility is sometimes
problematic in large-scale production. In search of a
solution for this problem we investigated the possibility of
direct conversion using other less toxic reagents for the
synthesis of the bicyclic unsaturated lactam. However,
dehydrogenation of the lactam to give the unsaturated
lactam proved difficult. For example, use of Saegusa
method6 and IBX oxidation7 developed by Nicolaou for
preparation of a,b-unsaturated ketones gave no desired
product and/or recovery of the starting material. After
several experiments, N-tert-butyl phenylsulfinimidoyl
chloride (5) originally developed for ketonic compounds
by Mukaiyama and Matsuo8 was found to be effective and
reliable for large-scale production of highly strained a,b-
unsaturated lactam 6. Thus, 4 was deprotonated with lithium
diisopropylamide in tetrahydrofuran (K78 8C, 30 min) and
treated with 5 (K78 to K10 8C, 8 h) to afford, in addition to
a small amount of the starting material (11%), 6 in 71%
isolated yield (80% conversion yield, 4.5 g scale). As
expected, purification of 6 using silica gel column
chromatography was difficult due to contamination of 4
with similar polarity. Fortunately, the latent methyl
derivative 7 was found to be easily purified. Stereoselective
introduction of the methyl group at the 6 position of the
bicyclic lactam was carried out by using Hanessian’s
procedure.9 Treatment of 6 with lithium dimethylcuprate
(Me2CuLi) in the presence of chlorotrimethylsilane10 at
K78 8C afforded methylated product 7 in 86% yield in a
diastereomeric ratio of 95:5. The stereochemistry of the
newly formed stereocenter was unambiguously assigned by
1
NOE experiment using H NMR.4i For removal of N,O-
benzylidene acetal, we employed direct conversion to the
acid anhydride using oxidative cleavage developed by us.4j
Thus, acetal 7 was oxidized with a catalytic amount of
ruthenium chloride (5 mol%) in the presence of sodium
periodate in acetonitrile–carbon tetrachloride–water
(2:2:3)11 to give acid anhydride 8 in 65% yield, which
was transformed to benzyl ester 9 by treatment with benzyl
alcohol in the presence of p-toluenesulfonic acid in toluene
under refluxing conditions. For selective cleavage of the
lactam ring under coexistence of the benzyl ester, the
nitrogen of the lactam was protected with di-tert-butyl
dicarbonate (Boc2O) in the presence of N,N-dimethylami-
nopyridine (DMAP) to produce tert-butoxycarbonyl imide
10 in 87% yield. Functional group selective hydrolysis of
the g-lactam ring in 10 was carried out by using lithium
hydroxide in aqueous THF to afford carboxylic acid 11 in
excellent yield. Then 11 was converted to the mixed acid
anhydride by treatment with isobutyl chloroformate in the
presence of N-methylmorpholine and reduced to (2S,3S)-5-
Scheme 1. Stereoselective synthesis of (2S,3S)-N-methyl-5-hydroxyisoleucine (NMeOHlle).

S. Hara et al. / Tetrahedron 60 (2004) 8031–8035
8033
hydroxyisoleucine 12 with sodium borohydride in 62%
yield. After protection of the hydroxy group as a tert-
butyldimethylsilyl ether, N-methylation of 13 using iodo-
methane and potassium hexamethyldisilazide (KHMDS) in
THF furnished protected (2S,3S)-NMeOHIle 3 in 77% yield.
atmosphere was added a solution of MeLi in ether (0.8 M,
105 mL, 84 mmol) and the mixture was stirred at 0 8C for
30 min. The resulting colorless solution was cooled to
K78 8C and a solution of Me3SiCl (7.57 mL, 59 mmol) and
enone 6 (4.0 g, 19 mmol) in THF (30 mL) was added. After
stirring for 1 h, the reaction mixture was quenched with
saturated aqueous NH4Cl (250 mL). The aqueous phase was
extracted with ether (3!120 mL). The combined organic
extracts were washed with saturated aqueous NH4Cl (3!
100 mL), water (100 mL), and saturated brine (150 mL),
dried over sodium sulfate, and concentrated in vacuo. The
residue was purified by silica gel column chromatography
(120 g, n-hexane/ethyl acetateZ2/1) to give 7 (3.78 g, 86%)
as a colorless oil: [a]D22ZC228 (c 0.64, CHCl3) (lit.9 (6R)-
enantiomer: [a]DZK2.3 (c 1.47, CHCl3)); IR (neat) 2962,
3. Conclusion
In conclusion, we have achieved the stereoselective
synthesis of protected (2S,3S)-N-methyl-5-hydroxyiso-
leucine 3 in 9.9% overall yield by stereoselective trans-
formation of chiral bicyclic lactam 4 based on (i) installation
of a double bond using N-tert-butyl phenylsulfinimidoyl
chloride, (ii) highly exo-selective Michael reaction in the
presence of chlorotrimethylsilane, and (iii) Ru-catalyzed
oxidative deprotection of N,O-benzylidene acetal 7 to acid
anhydride 8 as the key steps. Further investigation toward
the total synthesis of halipeptins is actively under way.
1
1710, 1453, 1350 cmK1; H NMR (CDCl3) d 1.22 (3H, d,
JZ6.8 Hz), 2.33–2.39 (1H, m), 2.46–2.69 (2H, m), 3.60
(1H, dd, JZ7.0, 8.0 Hz), 3.62–6.77 (1H, m), 4.20 (1H, dd,
JZ6.3, 8.3 Hz), 6.35 (1H, s), 7.30–7.44 (5H, m); 13C NMR
(100 MHz, CDCl3) d 19.16, 34.77, 42.31, 66.04, 70.77,
87.08, 125.95, 128.38, 128.49, 138.5, 177.5. HRMS (FAB,
NBA) calcd for C13H16NO2: 218.1181 (MCHC). Found:
218.1185.
4. Experimental
4.1. General
4.1.3. (2S,3S)-3-Methyl-5-oxo-pyrrolidine-2-carboxylic
benzoic anhydride (8). To a solution of bicyclic lactam 7
(0.351 g, 1.62 mmol) and NaIO4 (2.08 g, 9.72 mmol) in
carbon tetrachloride (2 mL), and H2O (3 mL) was added a
solution of added RuCl3$nH2O (91% purity, 18.5 mg,
81.2 mmol) in acetonitrile (2 mL). After stirring at room
temperature for 24 h, the reaction mixture was filtered
through a pad of celite, and the filtrate was extracted with
ethyl acetate, dried over sodium sulfate, filtered, and
concentrated in vacuo. The residue was purified by
recrystallization (ethyl acetate/n-hexane) to give 8
(0.260 g, 1.05 mmol, 65%) as colorless solids: mp 172–
174 8C; [a]2D3ZK18.9 (c 1.06, CHCl3); IR (KBr) 3854,
3821, 3745, 3676, 2966, 1741, 1680, 1291, 1247, 1212, 708,
Melting points were measured with a SHIBATA NEL-270
melting point apparatus. IR spectra were recorded on a
JASCO FT/IR-230 spectrometer. NMR spectra were
recorded on JEOL JNM GSX400A and JNM ECP400
spectrometers. FAB mass spectra were obtained with a
JEOL JMS-HX-110A spectrometer. Optical resolutions
were determined on a JASCO DIP-140 and JASCO
P-1020 polarimeter. Column chromatography was carried
out with silica gel BW-820MH (Fuji silysia). Analytical thin
layer chromatography was performed on Merck Kieselgel
60F254 0.25 mm thickness plates.
4.1.1. (2R,5S)-2-Phenyl-1-aza-3-oxabicyclo[3.3.0]oct-6-
en-8-one (6). To a solution of diisopropylamine (3.4 mL,
24.3 mmol) in THF (82 mL) at 0 8C was added dropwise a
solution of n-butyllithium in hexane (1.6 mol/L, 15.5 mL,
24.8 mmol) under argon atmosphere. After stirring at the
same temperature for 30 min, the solution was cooled to
K78 8C and a solution of 4 (4.49 g, 22.1 mmol) in THF
(14 mL) was added dropwise via canula. After 30 min, a
solution of N-tert-butyl benzenesulfinimidoyl chloride
(9.63 g, 44.6 mmol) in THF (14 mL) was added in one
portion. The reaction mixture was gradually warmed to
K10 8C. After 8.5 h, the reaction was quenched by addition
of saturated aqueous NH4Cl (100 mL) and diluted with ethyl
acetate (100 mL). The aqueous layer was extracted with
ethyl acetate (1!100 mL). The organic extract was washed
with saturated brine (100 mL), dried over sodium sulfate,
filtered and concentrated in vacuo. The residue was purified
by silica gel chromatography (200 g, n-hexane/ethyl
acetateZ1/1 to ethyl acetate only) to give 6 (3.33 g, 71%,
conversion yield 80%) as a brown oil along with a small
amount of the starting material 4 (0.506 g, 11.3%). The
spectra of 6 were identical with those of the reference.4b
1
633 cmK1; H NMR (CDCl3) d 1.38 (3H, d, JZ7.1 Hz),
2.29 (1H, dd, JZ5.4, 17.8 Hz), 2.62–2.66 (1H, m), 2.92
(1H, dd, JZ8.5, 17.8 Hz), 4.53 (1H, d, JZ4.9 Hz), 7.41–
7.45 (2H, m), 7.53–7.57 (1H, m), 7.66–7.68 (2H, m); 13C
NMR (CDCl3) d 20.0, 30.2, 39.9, 65.3, 127.9, 129.2, 132.5,
133.5, 170.7, 172.7, 175.2. Anal. calcd for C13H13NO4: C,
63.15, H, 5.30, N, 5.67. Found: C, 63.29, H, 5.39, N, 5.69.
4.1.4. (2S,3S)-3-Methyl-5-oxo-pyrrolidine-2-carboxylic
acid benzyl ester (9). To a solution of 8 (0.197 g,
0.797 mmol) and benzyl alcohol (0.83 mL, 8.02 mmol) in
toluene (4 mL) was added TsOH$H2O (18.6 mg,
0.098 mmol). The reaction mixture was heated to reflux
for 14.5 h. After cooling, the reaction was quenched by
addition of saturated aqueous sodium hydrogen carbonate
and the resulting mixture was extracted with ethyl acetate.
The organic layer was washed with saturated brine, dried
over sodium sulfate, filtered, and concentrated in vacuo. The
residue was purified by silica gel column chromatography
(n-hexane/ethyl acetateZ1/1 to CHCl3/CH3OHZ4/1) to
afford 9 (0.121 g, 65%) as a brown oil. The analytical
sample was obtained by recrystallization (n-hexane/ether)
as colorless needles: mp 79 8C; [a]1D9ZC21.1 (c 0.66,
CHCl3); IR (KBr) 3218, 1701, 1669, 1457, 1264, 1090,
1005, 752, 699 cmK1; 1H NMR (CDCl3) d 1.29 (3H, d, JZ
4.1.2.
(2R,5S,6S)-6-Methyl-2-phenyl-1-aza-3-oxa-
bicyclo[3.3.0]octan-8-one (7). To a suspension of CuI
(11.4 g, 59 mmol) in THF (344 mL) at K78 8C under argon

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S. Hara et al. / Tetrahedron 60 (2004) 8031–8035
6.6 Hz), 1.98–2.08 (1H, m), 2.53–2.65 (2H, m), 3.86 (1H, d,
JZ5.4 Hz), 5.18 (1H, d, JZ12.2 Hz), 5.22 (1H, d, JZ
12.2 Hz), 5.94 (1H, s), 7.33–7.41 (5H, m); 13C NMR
(CDCl3) d 20.1, 34.1, 37.8, 62.4, 67.3, 128.3, 128.6, 128.7,
135.1, 171.4, 176.7. Anal. calcd for C13H15NO3: C, 66.94,
H, 6.48, N, 6.00. Found: C, 66.97, H, 6.51, N, 5.96.
column chromatography (n-hexane/ethyl acetateZ1/1) to
give 12 (75.5 mg, 62%) as a colorless oil: [a]2D2ZC5.49 (c
1.52, CHCl3); IR (neat) 3382, 2974, 1710, 1560, 1499,
1457, 1366, 1250, 1163, 1057, 697 cmK1 1H NMR
;
(CDCl3) d 0.916 (3H, d, JZ6.8 Hz), 1.43 (9H, s), 1.55–
1.63 (1H, m), 2.16–2.17 (2H, m), 3.59 (1H, m), 3.70 (1H,
m), 4.34–4.37 (1H, m), 5.13 (1H, d, JZ12.2 Hz), 5.22 (1H,
d, JZ12.2 Hz), 5.36 (1H, d, JZ7.8 Hz), 7.31–7.37 (5H, m);
13C NMR (CDCl3) d 16.0, 28.3, 33.2, 35.0, 57.3, 60.0, 67.0,
77.2, 79.9, 128.4, 128.5, 128.6, 135.3, 155.7, 171.9. HRMS
(EI) calcd for C18H28NO5: 338.1967 (MHC). Found:
338.1935.
4.1.5. (2S,3S)-3-Methyl-5-oxo-pyrrolidine-1,2-dicarb-
oxylic acid 2-benzyl ester 1-tert-butyl ester (10). A
solution of 9 (0.200 g, 0.857 mmol), Boc2O (0.565 g,
2.59 mmol), and DMAP (21.8 mg, 0.178 mmol) in
CH3CN (4.3 mL) was stirred at room temperature. After
9.5 h, the reaction mixture was diluted with ethyl acetate,
washed with saturated brine, dried over Na2SO4, filtered,
and concentrated in vacuo. The residue was purified by
silica gel column chromatography (n-hexane/ethyl acetate-
Z1/1) to give 10 (0.249 g, 87%) as a colorless oil:
[a]2D2ZK14.7 (c 1.03, CHCl3); IR (neat) 2977, 1793,
1752, 1715, 1499, 1456, 1369, 1314, 1154, 1087, 1021, 911,
4.1.8. (2S,3S)-2-tert-Butoxycarbonylamino-5-(tert-butyl-
dimethylsiloxy)-3-methylpentanoic acid benzyl ester
(13). To a solution of TBSCl (0.230 g, 1.53 mmol) and
imidazole (0.180 g, 2.64 mmol) in CH2Cl2 (1 mL) was
added a solution of 12 (0.171 g, 0.507 mmol) in CH2Cl2
(1.5 mL) via cannula and the reaction mixture was stirred at
room temperature for 10.5 h. The reaction was diluted with
ethyl acetate, washed with saturated brine, dried over
sodium sulfate, filtered, and concentrated in vacuo. The
residue was purified by silica gel column chromatography
(n-hexane/ethyl acetateZ5/1) to give 13 (0.218 g, 95%) as a
colorless oil: [a]2D4ZC1.72 (c 0.99, CHCl3); IR (neat) 3356,
2929, 1718, 1560, 1499, 1365, 1255, 1163, 1099, 836,
776 cmK1; 1H NMR (CDCl3) d 0.030 (6H, s), 0.876 (9H, s),
0.940 (3H, d, JZ7.0 Hz), 1.28–1.36 (1H, m), 1.43 (9H, s),
1.53–1.60 (2H, m), 2.17 (1H, m), 3.54–3.60 (1H, m), 3.62–
3.67 (1H, m), 4.25–4.28 (1H, m), 5.13 (1H, d, JZ12.5 Hz),
5.18 (1H, d, JZ12.5 Hz), 5.32 (1H, d, JZ8.8 Hz), 7.32–
7.36 (5H, m); 13C NMR (CDCl3) d K5.43, K5.40, 16.3,
18.3, 25.9, 28.3, 32.9, 35.0, 58.3, 60.5, 66.8, 79.6, 128.3,
128.5, 135.5, 155.7, 172.2. HRMS (FAB, NBA) calcd for
C24H42NO5Si: 452.2832 (MCHC). Found: 452.2838.
1
839, 750, 698 cmK1; H NMR (CDCl3) d 1.23 (3H, d, JZ
6.8 Hz), 1.42 (9H, s), 2.14 (1H, dd, JZ4.2 Hz, 17.3 Hz),
2.31–2.40 (1H, m), 2.77 (1H, dd, JZ8.5, 17.3 Hz), 4.22
(1H, d, JZ3.4 Hz), 5.19 (1H, d, JZ12.2 Hz), 7.33–7.40
(5H, m); 13C NMR (CDCl3) d 20.5, 27.8, 29.7, 39.4, 66.0,
67.3, 83.7, 128.5, 128.6, 128.7, 135.0, 149.3, 170.7, 172.7.
HRMS (FAB, NBA) calcd for C18H24NO5: 334.1654 (MC
HC). Found: 334.1628.
4.1.6. (2S,3S)-2-tert-Butoxycarbonylamino-3-methyl-1,5-
pentanedioic acid 1-benzyl ester (11). To a solution of 10
(0.249 g, 0.747 mmol) in THF (3.2 mL) and water (0.8 mL)
at 0 8C was added LiOH$H2O (36.3 mg, 0.865 mmol) and
the reaction mixture was stirred at 0 8C for 1 h. The reaction
mixture was neutralized by addition of acetic acid and
concentrated in vacuo. The residue was purified by silica gel
column chromatography (CHCl3/CH3OHZ9/1) to give 11
(0.238 g, 91%) as a yellow oil: IR (neat) 3330, 2976, 1718,
4.1.9.
(2S,3S)-2-(N-tert-Butoxycarbonyl-N-methyl-
1560, 1508, 1457, 1369, 1160, 1069, 1017, 753, 698 cmK1
;
amino)-5-(tert-butyldimethylsiloxy)-3-methyl pentanoic
acid benzyl ester (3). To a solution of 13 (52.9 mg,
0.117 mmol) in THF (1 mL) under Ar atmosphere was
added 0.5 M solution of KHMDS in toluene (0.26 mL,
0.130 mmol) at K78 8C and the mixture was stirred at the
same temperature for 30 min. Then iodomethane
(0.070 mL, 1.12 mmol) was added and the reaction
temperature was gradually warmed to room temperature.
After 18.5 h, the reaction was quenched by addition of
saturated aqueous NH4Cl, and the resulting mixture was
extracted with ethyl acetate. The organic layer was washed
with saturated brine, dried over sodium sulfate, filtered, and
concentrated in vacuo. The residue was purified by silica gel
column chromatography (n-hexane/ethyl acetateZ5/1) to
give 3 (42.0 mg, 77%) as a colorless oil: [a]1D9ZK42.2 (c
0.52, CHCl3); IR (neat) 2930, 1740, 1700, 1473, 1366,
1H NMR (CDCl3) d 0.982 (3 H, d, JZ6.4 Hz), 1.43 (9H, s),
2.21–2.22 (1H, m), 2.42–2.46 (2H, m), 4.34 (1H, brs), 5.09–
5.22 (3H, m), 7.30–7.39 (5H, m); 13C NMR (CDCl3) d 16.5,
28.2, 33.5, 57.6, 67.2, 77.2, 80.2, 128.4, 128.5, 128.6, 135.1,
155.5, 171.6; [a]2D2ZC5.49 (c 1.52, CHCl3). HRMS (EI)
calcd for C18H25NO6: 351.1682. Found: 351.1693.
4.1.7. (2S,3S)-2-tert-Butoxycarbonylamino-5-hydroxy-3-
methylpentanoic acid benzyl ester (12). To a solution of
11 (0.126 g, 0.359 mmol) in 1,2-dimethoxyethane (DME,
0.5 mL) at K15 8C were successively added a solution of
N-methyl morpholine (40.9 mg, 0.404 mmol) in DME
(0.5 mL) and isobutyl chloroformate (53.9 mg,
0.395 mmol) in DME (0.5 mL), and the reaction mixture
was stirred at K15 to K10 8C for 15 min. The precipitated
N-methyl morpholine hydrochloride was removed by
filtration and washed with DME, and the combined filtrates
were chilled to K15 8C in an ice–salt bath. Then, a solution
of NaBH4 (41.0 mg, 1.08 mmol) in water (0.5 mL) was
added in one portion at K15 8C. After stirring at K15 to
K10 8C for 10 min, the reaction was quenched by addition
of saturated aqueous NH4Cl, and the resulting mixture was
extracted with ethyl acetate. The organic layer was washed
with saturated brine, dried over sodium sulfate, filtered, and
concentrated in vacuo. The residue was purified by silica gel
1
1313, 1256, 1172, 1096, 1004, 836, 775, 697 cmK1; H
NMR (CDCl3, 50 8C) d 0.031 (6H, s), 0.880 (9H, s), 0.928
(3H, d, JZ6.6 Hz), 1.20–1.26 (1H, m), 1.43 (9H, s), 1.65–
1.67 (1H, m), 2.21 (1H, m), 2.80–2.84 (3H, m), 3.59–3.72
(3H, m), 5.12 (1H, d, JZ12.7 Hz), 5.17 (1H, d, JZ
12.4 Hz), 7.28–7.33 (5H, m); 13C NMR (125 MHz, CDCl3,
45 8C, a mixture of conformational isomers) d K5.40,
K5.34, 16.3, 16.5, 18.3, 25.5, 25.7, 25.9, 28.4, 29.1, 30.3,
33.1, 35.2, 35.6, 51.5, 60.5, 60.7, 61.0, 62.4, 64.1, 66.2,
66.8, 80.1, 128.0, 128.1, 128.3, 128.5, 135.9, 155.7, 171.2.

S. Hara et al. / Tetrahedron 60 (2004) 8031–8035
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HRMS (FAB, NBA) calcd for C25H44NO5Si: 466.2989
(MCHC). Found: 466.2945. Anal. calcd for C25H43NO5Si:
C, 64.48, H, 9.31, N, 3.01. Found: C, 64.21, H, 9.31, N, 3.04.
References and notes
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