Enantioselective synthesis of a potential key intermediate for the total synthesis of fumagillin

Article abstract of DOI:10.1016/j.tetasy.2006.12.018

Key intermediate, 7, of a projected total synthesis of the anti-angiogenesis compound Fumagillin 1 and the semi-synthetic analogue TNP-470 2, has been prepared in enantiomerically pure form by employing an early nucleophilic addition ring closure [NARC] s

Full text of DOI:10.1016/j.tetasy.2006.12.018

Tetrahedron: Asymmetry 18 (2007) 243–250
Enantioselective synthesis of a potential key intermediate
for the total synthesis of fumagillin
Marisa Ciampini,a Patrick Perlmuttera,* and Keith Watsonb
aSchool of Chemistry, Monash University, PO Box 23, Clayton, Victoria 3800, Australia
bBiota Holdings Inc., Monash University, Clayton, Victoria 3800, Australia
Received 11 December 2006; accepted 27 December 2006
Abstract—Key intermediate, 7, of a projected total synthesis of the anti-angiogenesis compound Fumagillin 1 and the semi-synthetic ana-
logue TNP-470 2, has been prepared in enantiomerically pure form by employing an early nucleophilic addition ring closure [NARC]
sequence to construct the cyclohexene backbone.
Crown Copyright ꢀ 2007 Published by Elsevier Ltd. All rights reserved.
1. Introduction
agillol 6, the saponification product of 1 have been
reported.11–17
Angiogenesis is the process by which new blood cells are
formed.1–4 Normally this process is regulated, however
cancer describes a range of diseases in which abnormal cells
proliferate and spread out of control. Surgery, radiother-
apy, chemotherapy, hormonal therapy, immunotherapy,
laser therapy and oral drugs can now treat cancer, alone
or in combination.5 There are several compounds, which
show inhibition of angiogenesis, which include fumagillin6
1, TNP-4707 2 a synthetic derivative of fumagillin, ovali-
2. Results and discussion
Due to the continuing importance of an anti-cancer drug,
we have chosen to develop a flexible route for the synthesis
of fumagillin 1 as well as new analogues. Our retrosynthe-
sis, outlined in Figure 2, produced keto-acetonide 7 as a
key target. The inclusion of a ketone at C10 (fumagillin
numbering) was seen as important given the recent evi-
dence that C10 planar fumagillin analogues, such as oxi-
mes, also exhibit potent anti-tumour activity18 as well as
being angiogenesis inhibitors.19 Thus the development of
a practical synthesis of 7 is the focus of this paper.
cin8 3, RK-8509 4, as well as 5-dimethyovalicin10
(Fig. 1). To date, seven syntheses of fumagillin 1 and fum-
5
1
2
O
O
O
OH
1'
3
6
4
O
2'
O
O
RO
H3CO
H3CO
O
O
R
O
O
O
OBPS
OH
O
[NARC]
HO2C
O
H
Xc
O
3
5
R = CH3
R = H
4
CO
H3CO
2
1
R =
R =
O
4
OH
O
H
N
Cl
2
Figure 2.
O
A central issue in this synthetic problem is the enantioselec-
tive construction of a cyclohexane bearing four contiguous
stereogenic centres.20 It was envisaged that this could be
achieved by diastereoselective dihydroxylation21 of a cyclo-
hexene such as 8. In turn, 8 might be prepared using a sim-
ple ‘NARC’22 sequence beginning with crotonyl sultam23 9.
6
R = H
Figure 1. Fumagillin and related analogues.
*
Corresponding author. Tel.: +61 3 9905 4522; fax: +61 3 9905 4597;
e-mail: patrick.perlmutter@sci.monash.edu.au
0957-4166/$ - see front matter Crown Copyright ꢀ 2007 Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.12.018

244
M. Ciampini et al. / Tetrahedron: Asymmetry 18 (2007) 243–250
O
OBPS
OH
O
OBPS
The successful execution of these ideas is outlined in this
paper.
(ii)
(i)
Xc
Xc
HO
16
14
Hence the Z-boron enolate of 9 (formed by c-deprotona-
tion) reacted exclusively at the a-carbon24 with aldehydes
5-phenyl-4-pentenal 10 or 4-pentanal 11 to give the corre-
sponding syn aldol adducts 12 and 13 in excellent yields
(Scheme 1).
15
(iii)
O
O
OBPS
OBPS
O
OBPS
(iv)
(v)
10%
Xc
HO
HO
O
O
O
OH
O
O
OH
O
O
O
(i)
(ii)
Xc
Xc
Y
19
18
17
9
Scheme 2. Reagents and conditions: (i) BPSCl, imidazole, DMAP (cat.)
DMF, rt; (ii) K2OsO4ÆH2O, t-BuOH/H2O (3:1); (iii) (CH3O)2C(CH3)2,
CSA (cat.); (iv) H2O2, LiOH; (v) LiAlH4.
R
14 Y = Xc
8 Y = OH
(iii)
12 R = Ph
13 R = H
N
= Xc
S
O2
Scheme 1. Reagents and conditions: (i) (a) Et2BOTf, (i-Pr)2NEt, CH2Cl2,
(b) 10 or 11; (ii) (Cy3P)2(Cl)2Ru@CHPh (cat.), CH2Cl2; (iii) H2O2, LiOH.
O
OBPS
OH
O
OR
H3CO
(iv)
(i)
(iii)
H3CO
(ii)
8
N
N
Surprisingly, ring closing metathesis of 12 failed. Fortu-
nately no such problems were encountered with diene 13,
which closed smoothly under standard Grubbs’ RCM con-
ditions.25 The X-ray crystal structure of 14 is shown in Fig-
ure 3. Hydrolysis of 14 provided enantiomerically pure
cyclohexene 8 in 63% yield from 9.
HO
22
20 R = H
21 R = BPS
O
OBPS
H3CO
(v)
N
7
O
23
O
Scheme 3. Reagents and conditions: (i) CH3O(CH3)NH, WSC hydro-
chloride; (ii) BPSCl, Im., DMAP (cat.) DMF, rt; (iii) K2OsO4ÆH2O,
t-BuOH/H2O (3:1); (iv) (CH3O)2C(CH3)2, CSA (cat.); (v) CH3Li.
cis-Diol 22 could then be converted into the target mole-
cule 7 by first protecting the diol as its acetonide, followed
by treatment with methyllithium.
Figure 3. X-ray crystal structure of RCM product 14.
The X-ray crystal structure of 7 is shown in Figure 4. The
conversion of 7 into fumagillin 1 will be reported in due
course.
Several approaches for the conversion of 14 into 7 were
explored. Initially 14 was protected as its BPS ether 15
(Scheme 2). Dihydroxylation then gave a single diastereo-
mer, cis-diol 16, but in moderate yield under standard con-
ditions21 (K2OsO4ÆH2O) employing a 1:1 mixture of DMF
and t-BuOH as solvent. Moving to a solvent consisting of a
3:1 mixture of t-BuOH and water gave an improved yield
of 90%. Many attempts were made to chemically manipu-
late 16 and its corresponding acetonide26 17 (formed quan-
titatively from diol 16 using 2,2-dimethoxypropane/
camphorsulfonic acid). However, only treatment of 17 with
lithium aluminium hydride gave any new product, alcohol
18, but in very low yield.
Figure 4. X-ray crystal structure of target molecule 7.
Due to the problems encountered, dihydroxylation was
delayed until the acyl sultam manipulations had first been
completed. Thus 8 was converted into protected Weinreb
amide27 21 by successive treatment with CH3O(CH3)NH/
Al(CH3)3 and BPSCl/Et3N. Dihydroxylation of 21 again
occurred solely from the b-face (as drawn in Scheme 3) giv-
ing the new cis-diol 22 in 97% yield.
3. Conclusion
A concise, eight-step enantioselective synthesis of a key
precursor in our projected synthesis of fumagillol 6 and
its derivatives has been developed. Important steps involve

M. Ciampini et al. / Tetrahedron: Asymmetry 18 (2007) 243–250
245
syn-selective aldol followed by ring closing metathesis and
a completely facial-selective cis-dihydroxylation.
water (24 ml total) was added and the reaction allowed to
warm up to room temperature. It was poured into ethyl
acetate/water (200 ml total), extracted and the organic
phase washed with water (80 ml), dried over MgSO4 and
reduced in vacuo to give title compound 7 (2.34 g, 99%)
as a colourless oil, which was used without purification.
IR (CH2Cl2): 3068m, 3050m, 3023s, 3006s, 2928s, 1957m,
1885w, 1721m, 1684m, 1600m, 1574w, 1444s, 1447s,
1409m, 1358w, 1333w, 1202w, 1177w, 1137s, 1072s,
4. Experimental
Melting points were recorded on a Kofler hot stage appa-
ratus and are uncorrected. Elemental microanalyses were
performed by Chemical & Micro Analysis Services, Victo-
ria or the University of Otago, New Zealand. Optical rota-
tions were recorded at the sodium doublet on a Perkin
Elmer 141 Polarimeter. Infrared spectra were recorded on
a Perkin Elmer 1600 Series Fourier Transform spectro-
meter. Infrared band intensities of each frequency of absorp-
1028s, 968m, 916m, 787m, 688s, 668m cmꢀ1 1H NMR
.
(CDCl3): d 2.51–5.58 (m, 2H, CH2, H4); 2.59–2.74 (m,
2H, CH2, H3); 5.60 (dt, J 11.60, 11.67 Hz, 1H, H2); 6.47
(br d, J 11.60 Hz, 1H, H1); 7.24–7.26 (m, 5ArH; 9.75, t,
J 1.45 Hz, 1H, CHO).
1
tion are expressed as s (strong), w (weak) or b (broad). H
and 13C NMR spectra were recorded on a Bruker M 300
spectrometer and the chemical shifts recorded on the d
scale in parts per million (ppm). Deuteriochloroform
(CDCl3) was used as the internal standard. Mass Spectro-
metries were performed in methanol on a Micromass Plat-
form QMS spectrometer. High resolution mass spectra
were recorded on a Bruker BioApex 47e FTMS. The prin-
cipal ion peaks (m/z) are reported along with their intensi-
ties (in parentheses), expressed as a percentage of the base
peak (100%). M+ refers to the molecular ion. X-ray crystal-
lography was performed either on a Nonius Kappa CCD
or a Nicolet R3m/V diffractometer.
4.2. (2S)-N-[(2S,3R,7Z)-2-(Ethenyl)-3-(hydroxy)-7-phenyl-
6-heptenoyl]bornane-10,2-sultam 12
Freshly distilled triflic acid (156 ll, 1.76 mmol) was added
to triethylborane (1.76 ml, 1.76 mmol), which was vigor-
ously stirred, under a flow of N2. It was allowed to stir
for 0.5 h after which time the reaction became a homo-
geneous yellow solution. If not, the reaction was stirred at
40 ꢁC for 0.5 h to help initiate the reaction. The reaction
was cooled to 0 ꢁC and a solution of acyl sultam 6
(520 mg, 0.88 mmol) in CH2Cl2 (4.2 ml) was added and
the resulting mixture stirred for 10 min. N,N-Diisopro-
pyl(ethyl)amine (323 ll, 1.85 mmol) was then added drop-
wise while maintaining the internal temperature at 0 ꢁC.
The reaction was stirred for 0.5 h after which time it was
cooled to ꢀ78 ꢁC and a solution of 7 (282 mg, 1.76 mmol)
in CH2Cl2 (2 ml) was added. After stirring at ꢀ78 ꢁC for
2 h, aqueous phosphate buffer (pH 7, 4 ml) was added
and the mixture allowed to warm to room temperature
and then poured into Et2O (20 ml). The aqueous phase
was washed with Et2O (2 · 15 ml). The combined organic
extracts were dried over MgSO4 and the solvent was re-
moved in vacuo to afford a yellow solid. The crude product
was purified by flash column chromatography (SiO2, 5:1
4.1. (4Z)-5-Phenyl-4-pentenal 10
To a chilled solution (0–5 ꢁC) of (3-ethoxycarbonylprop-1-
yl)triphenylphosphonium bromide (10.27 g, 0.02 mol) in
THF (70 ml), NaN(TMS)2 (1 M, 25.0 ml, 25 mmol) was
added and stirred for 30 min. A solution of freshly distilled
benzaldehyde (2.8 ml, 0.03 mol) in THF (7 ml) was then
added and after 3 h was quenched with water (20 ml) and
poured into an ethyl acetate/water mixture (200/180 ml).
The organic phase was extracted and the aqueous layer
re-extracted with ethyl acetate (200 ml). The organic ex-
tracts were combined, dried over MgSO4 and reduced in
vacuo. The crude product was purified using flash column
chromatography (SiO2, 15:1 light petroleum/ethyl acetate)
to yield ethyl (4Z)-5-phenyl-4-pentenoate as a colourless oil
(3.28 g, 71%). Found 205.123. C13H6O2(H+) requires
205.123. IR (CH2Cl2): 3510m, 3153w, 3086m, 3063m,
2893m, 2964m, 2929m, 2856m, 2739w, 2361w, 2342w,
2254m, 1728s, 1704s, 1599m, 1585m, 1494m, 1448m,
1419m, 1375s, 1350m, 1270m, 1204m, 1182m, 1169m,
1110w, 1097m, 1072w, 1056m, 1028m, 912s, 828w, 738s,
light petroleum/ethyl acetate) to firstly give
a 3:1
(291 mg, 56%, Rf 0.53) inseparable mixture of unreacted
6 and its isomerised product followed by title compound
12 (152 mg, 39%, Rf 0.17) as a colourless oil. IR (CH2Cl2):
3510m, 3086w, 3046w, 3006m, 2959s, 2925s, 2885m,
2845m, 1684m, 1634m, 1600w, 1494m, 1456m, 1443m,
1412m, 1376m, 1334s, 1267m, 1236m, 1214s, 1166m,
1135s, 1117m, 1063m, 992m, 929w, 878w, 765m, 668w
1
cmꢀ1. H NMR (CDCl3): d 0.93 (s, 1H, CH3, H8 or H9);
1.09 (s, 1H, CH3, H8 or H9); 1.27–1.43 (m, 2H and 1.51–
1.61, m, 1H and 1.65–1.77, m, 2H and 1.85–2.02, m, 4H,
total 9H, 1(CH), H4 and 4(CH2), H3, H5, H6, H16);
2.38–2.53 (m, 2H, CH2, H17; 3.26, br s, 1H, OH); 3.45,
3.48 (ABq, J 13.81 Hz, 2H, CH2, H10); 3.74 (dd, J 8.70,
3.51 Hz, 1H, CHN, H2) 3.89 (t, J 6.18 Hz, 1H, CH, H12)
4.03–4.09 (m, 1H, CH, H15); 5.33–5.41 (m, 2H, CH2,
H14); 5.62–5.71 (m, 1H, H18); 5.92 (qd, J 17.40, 9.92,
8.70 Hz, 1H, H13); 6.41–6.49 (m, 1H, H19); 7.18–7.42
(m, 5ArH). 13C NMR (CDCl3): d 19.90, CH3, C8 or C9;
20.75, CH3, C8 or C9; 24.93, CH2, C17; 26.42, CH2, C5;
32.82, CH2, C6; 34.34, CH2, C16; 38.15, CH2, C3; 44.63,
CH, C4; 47.70, C(CH3)2, C7; 48.35, C, C1; 53.10, CH2,
C10; 54.62, CH, C12; 64.85, CH, C2; 70.39, CH, C15;
1
701m cmꢀ1. H NMR (CDCl3): d 1.22 (t, J 7.17 Hz, 3H,
CH3CH2); 2.38–2.45 (m, 2H, CH2, H4); 2.60–2.68 (m,
2H, CH2, H3); 4.11 (q, J 7.17 Hz, 2H, OCH2CH3); 5.61
(dt, J 11.75, 7.17 Hz, 1H, CH, H2); 6.44 (br d, J
11.60 Hz, 1H, H1); 7.17–7.34 (m, 5ArH). 13C NMR
(CDCl3): d 14.23, CH3; 24.07, CH2; 60.36, CH2; 125.38,
CH, C2; 126.56, 128.03, 128.52, 129.92, ArCH (C20, C30,
C40, C50); 134.27, CH, C1; 136.99, ArC, C10; 172.76, CO.
To a cooled solution (ꢀ78 ꢁC) of the above ester (3.00 g,
14.7 mmol) in toluene (60 ml), DIBAL-H (1.5 M solution
in toluene, 15.6 ml, 23.5 mmol) was added. After comple-
tion of the reaction (TLC, 2 h), a 1:1 mixture of acetone/

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M. Ciampini et al. / Tetrahedron: Asymmetry 18 (2007) 243–250
1
121.44, CH2, C14; 126.31, CH, C18; 127.96, ArCH (C20,
C60 or C30, C50); 128.60, ArCH (C20, C60 or C30, C50);
129.12, ArCH (C40); 130.66, CH, C13; 131.86, CH, C19;
137.35, ArC (C10); 173.08, CO, C11. MS: 444.3
([M+H]+, 20%), 466.2 ([M+Na]+, 100). HRMS calcd for
C25H33NO4S(H+) requires 444.221, found 444.220.
C25H33NO4S(Na+) requires 466.203, found 466.201. Anal.
856m, 805w, 765m, 737s, 703m cmꢀ1. H NMR (CDCl3):
d 0.97 (s, 1H, CH3, H8 or H9); 1.18 (s, 1H, CH3, H8 or
H9); 1.21–2.54 (m, 11H, 5(CH2), H16, H15, H6, H5, H3
and 1(CH), H4); 3.45 (d, J 3.51 Hz, 1H, OH); 3.49, 3.52
(ABq, J 13.88 Hz, 2H, CH2, H10); 3.86–3.96 (m, 2H,
2(CH), H2, H12); 4.12–4.20 (m, CH, H17); 5.54 (dp, J
5.80, 2.14 Hz, 1H, CH, H14); 5.92 (dq, J 5.95, 3.36 Hz,
1H, CH, H13). 13C NMR (CDCl3): d 19.21, CH3, C8 or
C9; 20.96, CH3, C8 or C9; 22.83, CH2, C15; 26.45, CH2,
C5; 27.06, CH2, C16; 32.88, CH2, C6; 38.39, CH2, C3;
44.63, CH, C4; 46.87, CH, C12; 47.77, C(CH3)2, C7;
48.27, C, C1; 53.19, CH2, C10; 65.33, CHN, C2; 66.52,
CH, C17; 120.97, CH, C14; 130.89, CH, C13; 172.62,
CO, C11. MS: 340.3 ([M+H]+, 5%), 362.2 ([M+Na]+,
100), 701.4 ([2M+Na]+, 90). HRMS calcd for
C17H25NO4S(H+) requires 340.158, found 340.159.
C17H25NO4S(Na+) requires 362.140, found 362.140. Anal.
Calcd (443.2): C, 67.69; H, 7.50; N, 3.16. Found: C, 67.79;
25
H, 7.35; N, 3.22. ½aꢁD ¼ þ12:5 (c 2, CHCl3).
4.3. (+)-(2S)-N-[(2S,3R)-2-(Ethenyl)-3-(hydroxy)-6-hepteno-
yl]bornane-10,2-sultam 13
In a manner similar to that for 12, aldol addition of acyl
sultam
9 (320 mg, 1.13 mmol) with 4-pentenal 11
(124 mg, 1.47 mmol) afforded, upon work-up, a yellow so-
lid. Purification by flash column chromatography (SiO2,
4:1 light petroleum/ethyl acetate) gave title compound 13
(393 mg, 87%, Rf 0.31 in 3:1 light petroleum/ethyl acetate),
as colourless crystals (mp 140–141 ꢁC). IR (CH2Cl2):
3519m, 3072m, 2961s, 2890s, 1728m, 1682s, 1640s,
1478m, 2961s, 2890s, 1728m, 1682s, 1640s, 1478m,
1456m, 1415m, 1376m, 1334s, 1267s, 1237s, 1215s, 1166s,
1135s, 1064m, 994m, 924w, 877w, 824w, 764w, 738m,
Calcd (339.2): C, 60.15; H, 7.94; N, 4.13; S, 9.45. Found: C,
24
59.94; H, 7.94; N, 4.07; S, 9.25. ½aꢁD ¼ þ270:0 (c 0.7,
CHCl3).
4.5. (+)-(1S,2R)-2-Hydroxy-5-cyclohexenecarboxylic acid 8
Hydrogen peroxide (0.51 ml, 30% solution, 4.50 mmol) was
added to a chilled (0 ꢁC) solution of 14 (318 mg,
0.94 mmol) in THF/H2O (6:1, total 21 ml). This was fol-
lowed by incremental addition of lithium hydroxide
(51.0 mg, 1.22 mmol). The reaction was warmed to room
temperature overnight, quenched with Na2SO3Æ7H2O
(940 mg, 9.4 ml H2O) and CH2Cl2 (15 ml) added. The
aqueous phase was washed with CH2Cl2 (2 · 10 ml). The
organics were combined, dried over MgSO4 and reduced
under vacuum to yield a quantitative recovery of camphor-
sultam (203 mg). The aqueous layer was acidified with 1 M
HCl and extracted with ethyl acetate (5 · 10 ml). The
organics were combined, dried over MgSO4 and reduced
in vacuo to give title compound 8 (110 mg, 82%) as an or-
ange oil (Rf 0.44 in ethyl acetate), which was used without
further purification. IR (CH2Cl2): 3442m, 3339m, 3055s,
2987m, 2899m, 2306m, 1711s, 1431m, 1422s, 1265s,
1087m, 1070m, 1034m, 982w, 936w, 896m, 865w, 643m,
1
703m cmꢀ1. H NMR (CDCl3): d 0.95 (s, 1H, CH3, H8
or H9); 1.08 (s, 1H, CH3, H8 or H9); 1.15–2.31 (m, 11H,
5(CH2) H16, H17, H6, H5, H3 and 1(CH), H4); 3.31 (br
s, 1H, OH); 3.45, 3.48 (ABq, J 13.81 Hz, 2H, CH2, H10);
3.73 (dd, J 3.51, 8.70 Hz, 1H, CHN, H2); 3.89 (br t, J
6.26 Hz, 1H, CH, H12); 3.98–4.05 (m, 1H, CH, H15);
4.94 (dp, J 10.22, 2.14,1.98 Hz, 1H, CH of CH2; H19a);
5.03 (dq, J 3.51, 1.68 Hz, 1H, CH of CH2, H19b); 5.31–
5.41 (m, 2H, CH2, H14); 5.80, ddt (J 17.90, 14.70,
10.38 Hz, 1H, H18); 5.91 (qd, J10.07, 8.70 Hz, 1H, H13).
13C NMR (CDCl3): d 19.91, CH3, C8 or C9; 20.75, CH3,
C8 or C9; 26.45, CH2, C5; 29.81, CH2, C17; 32.83, CH2,
C6; 32.23, CH2, C16; 38.16, CH2, C3; 44.64, CH, C4;
47.72, C(CH3)2, C7; 48.36, C, C1; 53.11, CH2, C10;
54.35, CH, C12; 64.87, CHN, C2; 70.19, CH, C15;
114.75, CH2, C19; 121.39, CH2, C14; 130.60, CH, C18;
137.93, CH, C13; 173.25, CO, C11. MS: 390.3 ([M+Na]+,
80%), 757.3 ([2M+Na]+, 100). HRMS calcd for
C19H29NO4S(H+) requires 368.190, found 368.190.
C19H29NO4S(Na+) requires 390.172, found 390.172. Anal.
738s, 704s cmꢀ1. H NMR (CDCl3): d 1.73–1.82, m, 1H,
1
CH of CH2, H4 or H5; 1.93–1.21, m, 2H, H4 or H5;
2.22–2.30, m, 1H, CH of CH2, H4 or H5; 3.33, br s, 1H,
CH, H1; 4.28, br s, 1H, CH, H6; 5.70, br d, J 10.07 Hz,
1H, CH, H3; 5.87, qd, J 10.07, 2.43 Hz, 1H, CH, H2,
6.83; br s, 2H, 2(OH). 13C NMR (CDCl3): d 21.88, CH2,
C4; 27.70, CH2, C5; 38.73, CH, C1; 66.43, CH, C6;
121.15, CH, C3; 129.58, CH, C2; 167.66, CO. MS: 142.7
([M]+, 5%), 164.8 ([M+Na]+, 100). HRMS calcd for
C7H10O3(Na+) requires 165.053, found 165.052. Anal.
Calcd (367.2): C, 65.10; H, 7.95; N, 3.81. Found: C, 65.60;
24
H, 8.18; N, 3.73. ½aꢁD ¼ þ95:35 (c 1.3, CHCl3).
4.4. (+)-(2S)-N-[(1R,2S)-1-Hydroxy-3-cyclohexen-2-car-
bonyl]bornane-10,2-sultam 14
Grubbs’ catalyst (231 mg, 0.27 mmol), in degassed CH2Cl2
(50 ml), was added to a solution of 13 (2.00 g, 5.44 mmol)
in degassed CH2Cl2 (450 ml) under a flow of argon and the
resulting solution was stirred at room temperature for 24 h.
The solvent was removed in vacuo and the crude material
was purified by column chromatography (SiO2, 4:1 light
petroleum/ethyl acetate) to give title compound 13
(1.62 g, 88%, Rf 0.16) as colourless crystals (mp 139–
140.5 ꢁC). IR (CH2Cl2): 3526s, 3053s, 3024s, 2981s,
2880s, 3841s, 1686s, 1478m, 1456m, 1429m, 1410m,
1391m, 1377m, 1332s, 1267s, 1237s, 1213s, 1165m, 1134s,
1122m, 1078m, 1064s, 991m, 977m, 953w, 893m, 871w,
Calcd (142.1): C, 59.14; H, 7.09. Found: C, 58.58; H,
22
6.87. ½aꢁD ¼ þ95:45 (c 4, CHCl3).
4.6. (+)-(2S)-N-[(1R,2S)-1-(((tert-Butyldiphenyl)silyl)oxy)-
3-cyclohexen-2-carbonyl]bornane-10,2-sultam 15
Imidazole (20.2 mg, 0.30 mmol) and BPSCl (40.8 mg,
37.0 ll) were added to a solution of 14 (310.0 mg,
0.91 mmol) in CH2Cl2 (2 ml) at room temperature. Follow-
ing stirring overnight the reaction was quenched with water
(1 ml) and then poured into Et2O (5 ml). The aqueous

M. Ciampini et al. / Tetrahedron: Asymmetry 18 (2007) 243–250
247
phase was washed with Et2O (2 · 5 ml). The organic ex-
tracts were combined, dried (MgSO4) and the solvent was
removed in vacuo to afford a white solid. The crude prod-
uct was purified by flash column chromatography (SiO2,
5:1 light petroleum/ethyl acetate) to yield the title com-
pound 15 (455 mg, 87%, Rf 0.55 in 8:1 light petroleum/ethyl
acetate) as colourless crystals (mp 158–159 ꢁC). IR
(CH2Cl2): 3066m, 3046m, 2959s, 2946s, 2957s, 1707s,
1472w, 1458w, 1428m, 1391m, 1362w, 1332s, 1268s,
1236m, 1219m, 1199m, 1164m, 1133s, 1111s, 1063m,
–BPS; 19.84, CH3, C8 or C9; 20.97, CH3, C8 or C9;
25.00, CH2, C15; 26.20, CH2, C5; 26.33, 3(CH3) –BPS;
27.20, CH2, C16; 32.82, CH2, C6; 38.57, CH2, C3; 44.64,
CH, C4; 47.65, CH, C12; 48.32, C(CH3)2, C7; 50.46, CH,
C17; 52.91, CH, C1; 53.02, CH2, C10; 65.27, CHN, C2;
68.75, CH, C14; 68.97, CH, C13; 69.41, CH, C14; 127.35,
127.45, ArCH, 2(C20, C60 or C30, C5) –BPS; 129.52,
129.57 ArCH, 2(C40) –BPS; 134.02, 134.96, ArC, 2(C10)
–BPS; 136.24, 138.64, ArCH, 2(C20, C60 or C30, C5)
–BPS; 169.79, CO, C11. MS: 612.4 ([M+H]+, 25%), 634.3
([M+Na]+, 100), 644.3 ([M+MeOH(H)]+, 50). HRMS
calcd for C33H45NO6SSi(Na+) requires 634.264, found
990w, 895w, 840w, 822w, 788w, 766w, 740w, 704m cmꢀ1
.
1H NMR (CDCl3): d 0.98 (s, 3H, CH3, H8 or H9); 1.04
(s, 9H, 3(CH3) –BPS; 1.09, s, 3H, CH3, H8 or H9); 1.22–
2.60 (m, 11H, 5(CH2), H16, H15, H6, H5, H3 and
1(CH), H4); 3.49, 3.51 (ABq, J 13.89 Hz, 2H, CH2, H10);
3.91–4.02 (m, 3H, 3(CH), H2, H12, H17); 5.61–5.65 (m,
1H, H14); 5.72–5.76 (m, 1H, H13); 7.32–7.46 (m, 6ArH
–BPS); 7.71–7.79 (m, 4ArH –BPS). 13C NMR (CDCl3): d
19.24, C(CH3)3 –BPS; 19.98, CH3, C8 or C9; 20.93, CH3,
C8 or C9; 24.92, CH2, C15; 26.52, CH2, C5; 26.93,
C(CH3)3 –BPS; 27.32, CH2, C16; 32.85, CH2, C6; 38.35,
CH2, C3; 44.59, CH, C4; 47.56, CH, C12; 47.78, C(CH3)3
–BPS, C7; 48.20, C, C1; 53.13, CH2, C10; 65.20, CHN,
C2; 70.39, CH, C17; 122.29, CH, C14; 127.22, 127.39,
ArCH, 2(C20, C60 or C30, C50) –BPS; 129.23, 129.23,
ArCH, 2(C40) –BPS; 130.87, CH, C13; 133.47, 134,85,
ArC, 2(C10) –BPS; 135.87, ArCH, 2(C20, C60 or C30, C50)
–BPS; 169.25, CO, C11. MS: 578.4 ([M+H]+, 40%), 600.4
([M+Na]+, 90). HRMS calcd for C33H43NO4SSi(Na+)
requires 600.258 found 600.256. Anal. Calcd (577.3): C,
634.262. Anal. Calcd (611.4): C, 64.78; H, 7.41; N, 2.29.
22
Found: C, 64.57; H, 7.26; N, 2.29. ½aꢁD ¼ þ5:4 (c 0.73,
CHCl3).
4.8. (+)-(2S)-N-[(3aS,4S,5R,7aR)-2,2-Dimethyl-5-(((tert-
butyldiphenyl)silyl)oxy)hexahydro[1,3]benzodioxol-4-car-
bonyl]bornane-10,2-sultam 17
2,2-Dimethoxypropane (80.4 ll, 0.65 mmol) followed by
camphorsulfonic acid (2.0 mg, 0.0082 mmol) was added
to a solution of 16 (50 mg, 0.082 mmol) in acetone
˚
(0.5 ml), which contained 4 A molecular sieves at room
temperature. After completion of the reaction (TLC 1 h),
NEt3 (0.1 ml) was added. Stirring for a further 15 min
was followed by evaporation under vacuum. Water (1 ml)
and Et2O (5 ml) were added and the aqueous phase was
further washed with Et2O (3 · 5 ml). The organic extracts
were combined, dried over MgSO4 and evaporated in va-
cuo. The crude product was purified using flash column
chromatography (SiO2, 4:1 light petroleum/ethyl acetate)
to yield title compound 17, as colourless crystals (50 mg,
94%, Rf 0.75, mp 203–205 ꢁC). IR (CH2Cl2): 3077w,
3049w, 2946s, 2932s, 2890m, 2857m, 1698s, 1459w,
1471w, 1428m, 1407w, 1392m, 1330s, 1265m, 1234m,
1213s, 1164m, 1134m, 1112s, 1067s, 1047s, 1000w, 982w,
68.59; H, 7.50; N, 2.42. Found: C, 68.66; H, 7.32; N,
22
2.53. ½aꢁD ¼ þ81:0 (c 0.2, CHCl3).
4.7. (+)-(2S)-N-[(1R,2R,3S,4R)-1-(((tert-Butyldiphenyl)-
silyl)oxy)-3,4-(dihydroxy)cyclo-hexan-2-carbonyl]bornane-
10,2-sultam 16
NMO (332 mg, 2.84 mmol) followed by K2OsO4ÆH2O
(52.2 mg, 0.142 mmol) was added to a solution of 15
(480 mg, 1.42 mmol) in a 3:1 mixture of t-BuOH/H2O
(12 ml total), at room temperature and allowed to stir over-
night. The pale orange solution was quenched with
Na2S2O3 (1 M, 1.5 ml) and allowed to stir for an additional
0.5 h. The solution was evaporated to dryness, and an ethyl
acetate (20 ml) and water (5 ml) mixture added. The aque-
ous phase was washed with ethyl acetate (2 · 20 ml). The
organic extracts were combined, dried over MgSO4 and
the solvent was removed in vacuo to afford a yellow solid.
The crude product was purified using flash column chro-
matography (SiO2, 4:1 light petroleum/ethyl acetate) to
yield title compound 16 (470 mg, 92%, Rf 0.14, mp 215–
216 ꢁC), as colourless crystals. IR (CH2Cl2): 3484s, 3073s,
3072s, 2932s, 2858, 1702m, 1472m, 1428s, 1391w, 1362w,
874w, 860w, 824w, 799w, 767w, 735m, 703s cmꢀ1 1H
.
NMR (CDCl3): d 0.92 (s, 3H, CH3, H8 or H9); 1.08 (s,
9H, 3(CH3) –BPS); 1.11 (3H, CH3, H8 or H9); 1.32 (3H,
CH3, C(CH3)2); 1.44 (3H, CH3, C(CH3)2); 1.56–2.18 (m,
11H, 5(CH2), H16, H15, H6, H5, H3 and 1(CH), H4);
3.16 (d, J 9.46 Hz, 1H, CH, H12); 3.36, 3.43 (ABq, J
13.51 Hz, 2H, CH2, H10); 3.42 (t, J 6.33 Hz, 1H, CH,
H2); 4.36 (br s, 1H, CH, H14); 4.84 (br s, 1H, CH, H17);
4.92 (dd, J 9.38, 4.60 Hz, 1H, CH, H13); 7.32–7.43 (m,
6H, 6ArH –BPS). 13C NMR (CDCl3): d 19.51, C(CH3)
–BPS; 19.94, CH3, C8 or C9; 20.82, CH3, C8 or C9; 21.02,
CH2, C15; 26.51, CH2, C5; 26.62, CH3, C(CH3)2; 26.96,
CH2, C16; 27.27, 3(CH3) –BPS; 27.83, CH3 (CH3)2;
32.79, CH2, C6; 38.54, CH2, C3; 44.57, CH, C4; 47.73,
C(CH3)2, C7; 48.39, C, C1; 51.15, CH, C12; 52.98, CH2,
C10; 65.27, CHN, C2; 68.46, CH, C17; 72.76, CH, C14;
74.94, CH, C13; 108.11, C(CH3)2; 127.13, 127.26, ArCH,
2(C20, C60 or C30, C5) –BPS; 129.29, 129.35, ArCH,
2(C40) –BPS; 133.61, 134.69, ArC, 2(C10) –BPS; 135.92,
136.45, ArCH, 2(C20, C60 or C30, C50) –BPS; 169.33, CO,
C11. MS: 652.3 ([M+H]+, 100%), 674.2 ([M+Na]+, 28).
HRMS calcd for C36H49NO6SSi(Na+) requires 674.295,
1332m, 1266s, 1199w, 822s, 739s, 703s cmꢀ1 1H NMR
.
(CDCl3): d 0.92 (s, 3H, CH3, H8 or H9); 1.08 (9H, 3CH3
–BPS); 1.09 (s, 3H, CH3, H8 or H9); 1.18–2.36 (m, 11H,
5(CH2), H16, H15, H6, H5, H3 and 1(CH), H4); 3.23,
3.46 (ABq, J 13.73 Hz, 2H, CH2, H10); 3.34–3.41 (m,
2H, 2(CH), H2, H12); 4.08 (br d, J 2.59 Hz, 1H, CH,
H14); 4.54 (dd, J 10.07, 2.90 Hz, 1H, CH, H17); 4.82 (br
s, 1H, CH, H13); 7.31–7.44 (m, 6ArH –BPS); 7.61–7.71
(m, 4ArH –BPS). 13C NMR (CDCl3): d 19.44, C(CH3)
found 674.294. Anal. Calcd (651.3): C, 66.32; H, 7.58; N,
24
2.15. Found: C, 66.47; H, 7.34; N, 2.12. ½aꢁD ¼ þ8:2 (c 1,
CHCl3).

248
M. Ciampini et al. / Tetrahedron: Asymmetry 18 (2007) 243–250
4.9. (3aS,4R,5R,7aR)-2,2-Dimethyl-4-(hydroxymethyl)-5-
(((tert-butyldiphenyl)silyl)oxy)hexahydro[1,3]benzodioxole
18
13C NMR (CDCl3): d 22.15, CH2, C4; 27.81, CH2, C5;
42.27, CH, C1; 61.37, CH3, NCH3, OCH3; 66.36, CH,
C6; 121.35, CH, C3; 130.01, CH, C2; 174.18, CO. MS:
185.8 ([M+H]+, 20%), 207.9 ([M+Na]+, 100). HRMS calcd
LiAlH4 (7.3 mg, 0.193 mmol) was added to a solution of 17
(60 mg, 0.09 mmol) in CH2Cl2 (1 ml) at 0 ꢁC. After stirring
for 4 h at room temperature, TLC indicated the presence of
unreacted starting material. Therefore, extra LiAlH4
(15 mg, 0.4 mmol) was added at room temperature and
the mixture left to stir overnight. Addition of a mixture
of Na2S2O6Æ10H2O (10 mg) in water (1 ml) was followed
by washing with CH2Cl2 (3 · 5 ml). The organics were
combined, dried over MgSO4 and reduced in vacuo. The
crude reaction mixture was purified by column chromato-
graphy (SiO2, 4:1 light petroleum/ethyl acetate) to give
firstly BPSOH (20 mg), followed by title compound 18
for C9H15NO3(Na+) requires 208.095, found 208.095.
23
½aꢁD ¼ þ108:9 (c 7.5, CHCl3).
4.11. (+)-(1S,2R)-2-(((tert-Butyldiphenyl)silyl)oxy)-5-
cyclohexenecarboxylic acid (N-methoxy-N-methyl)amide 21
Alcohol 20 (415 mg, 2.25 mmol) was silylated in a manner
similar to that for 15. The crude product was purified via
column chromatography (SiO2, 6:1 light petroleum/ethyl
acetate), to give title compound 21 (650 mg, 68%, Rf
0.22, in 10:1 in light petroleum/ethyl acetate) as a colour-
less oil. IR (CH2Cl2): 3071m, 3046m, 2931w, 2895m,
2857s, 1642m, 1472m, 1428s, 1390w, 1363w, 1113s,
1
(9 mg, 10%), isolated as a white solid. H NMR (CDCl3):
d 1.07 (s, 9H, 3(CH3) –BPS); 1.35 (s, 3H, CH3, C(CH3)2);
1.45 (s, 3H, CH3, C(CH3)2); 1.51–1.57 (m, 2H, H1, H2 or
H3); 1.61–1.69 (m, 1H, H1, H2 or H3); 1.90–1.96 (m,
1H, H1, H2 or H3); 2.14–2.27 (m, 1H, H1, H2 or H3);
3.43 (dd (ABX), J7a–7e 10.76 Hz, J7a–6 7.10 Hz, 1H CH of
CH2, H7); 3.75 (dd (ABX), J7a–7e 10.76 Hz, J7e–6 6.49 Hz,
1H, CH of CH2, H7); 4.13–4.18 (m, 2H, 2(CH), H4, H5);
4.30–4.34 (m, 1H, CH, H6; 4.81, br d, J4.42 Hz, 1H,
OH); 7.35–7.48 (m, 6ArH –BPS); 7.60–7.68 (m, 4ArH
–BPS). 13C NMR (CDCl3): d 19.83, C(CH3)3 –BPS; 21.85,
CH2, C4; 26.85, CH3, C(CH3)2; 27.39, CH2, C5; 27.50,
CH3, 3(CH3) –BPS; 28.82, CH3, C(CH3)2; 46.94, CH, C1;
63.97, CH2, C7; 69.06, CH, C6; 73.28, CH, C3; 76.86,
CH, C2; 108.40, C, C(CH3)2; 127.86, 128.01, ArCH,
2(C20, C40 or C30, C50) –BPS; 130.10, 130.17, ArCH,
2(C40) –BPS; 133.54, 134.05, ArC, 2(C10) –BPS; 136.07,
136.09, ArCH, 2(C20, C40 or C30, C50) –BPS. MS: 441.2
([M+H]+, 15%), 463.2 ([M+Na]+, 100). HRMS calcd for
C26H36O4Si(Na+) requires 463.228, found 463.228.
1008w, 821m, 740m, 701s cmꢀ1 1H NMR (CDCl3): d
.
(1.04, s, 9H, 3(CH3) –BPS); 1.60 (pd, J 9.08, 3.13 Hz, 1H,
CH of CH2, H4 or H5); 1.77–1.87 (m, 1H, CH of CH2,
H4 or H5); 2.14 (br dd, J 18.47, 2.90 Hz, 1H, CH of
CH2, H4 or H5); 2.29–2.44 (m, 1H, H4 or H5); 3.20 (s,
3H, NCH3); 3.61 (3H, OCH3); 3.81 (br s, 1H, CH, H1);
4.15 (dq, J 5.73 3.74 Hz, 1H, CH, H6); 5.45–5.50 (m, 1H,
CH, H3); 5.80–5.83 (m, 1H, CH, H2); 7.34–7.45 (m,
6ArH –BPS); 7.69–7.71 (m, 4ArH –BPS). 13C NMR
(CDCl3): d 19.25, C(CH3)3 –BPS; 24.28, CH2, C4; 26.92
(CH3) –BPS; 27.13, CH2, C5; 42.38, CH, C1; 61.25,
NCH3, OCH3; 70.44, CH, C6; 122.65, CH, C3; 127.29,
127.30, ArCH, 2(C20, C60 or C30, C60) –BPS; 129.36,
ArCH, 2(C40) –BPS; 130.02, CH, C2; 133.95, 134.49,
ArC, 2(C10) –BPS; 135.75, 135.77, ArCH, 2(C20, C60 or
C30, C50) –BPS; 172.70, CO. MS: 424.2 ([M+H]+, 25%),
446.2 ([M+Na]+, 85). HRMS calcd for C25H33NO3Si(Na+)
requires 446.213, found 446.212. Anal. Calcd (423.2): C,
70.88; H, 7.85; N, 3.31. Found: C, 70.89; H, 7.84; N,
23
3.27. ½aꢁD ¼ þ83:6 (c 1.95, CHCl3).
4.10. (+)-(1S,2R)-2-(Hydroxy)-5-cyclohexenecarboxylic
acid (N-methoxy-N-methyl)amide 20
4.12. (ꢀ)-(1S,2S,3R,6R)-2,3-(Dihydroxy)-6-(((tert-butyldi-
phenyl)silyl)oxy)cyclohexane-carboxylic acid (N-methoxy-
N-methyl)amide 22
N,O-Dimethylhydroxylamine
hydrochloride
(38 mg,
0.51 mmol), followed by N-methylmorpholine (40 mg,
43 ll, 0.51 mmol) was added to a cooled (0 ꢁC) solution
of 8 (54 mg, 0.39 mmol) in CH2Cl2 (1 ml). N-(3-Dimethyl-
aminopropyl)-N-ethylcarbodiimide hydrochloride (75 mg,
0.51 mmol) was added incrementally and allowed to stir
at this temperature for 2 h. The reaction was quenched
with 1 M HCl (1.5 ml), extracted and the aqueous phase
re-extracted with CH2Cl2 (2 ml). The organics were com-
bined, washed with satd NaHCO3 (2 ml) and the aqueous
phase was washed with CH2Cl2 (2 ml). The organics were
combined, dried over MgSO4 and reduced in vacuo to give
title compound 20 (50 mg, 77%). IR (CH2Cl2): 3428s,
3054s, 2926s, 2850s, 1654s, 1642s, 1458m, 1439m, 1423m,
1388m, 1318w, 1266s, 1192w, 1179w, 1112w, 1073w,
Alkene 21 (163 mg, 0.38 mmol), dissolved in t-BuOH
(1.8 ml), DMF (1.8 ml), was dihydroxylated in a manner
similar to that for diol 16. After work-up title compound
22 was isolated as a colourless oil (170 mg, 97%, Rf 0.10
in 2:1 light petroleum/ethyl acetate). Recrystallisation from
light petroleum/ CH2Cl2 gave title compound 22 as colour-
less crystals (mp 50–51 ꢁC). IR (CH2Cl2): 3440s, 3053s,
2933s, 2858s, 1963w, 1895w, 1750w, 1737m, 1644s,
1590m, 1428m, 1391m, 1266s, 1193m, 1112m, 1050m,
965m, 928w, 895w, 863w, 823m, 739s, 704s cmꢀ1 1H
.
NMR (CDCl3): d 1.04 (s, 9H, 3(CH3) –BPS); 1.54–1.72
(m, 2H, CH2, H5); 1.90–2.20 (m, 2H, CH2, H4); 3.00 (br
s, 1H, CH, H1); 3.04 (s, 3H, NCH3); 3.47 (s, 3H, OCH3);
4.18 (q, J 2.29 Hz, 1H, CH, H6); 4.57 (dd, J 10.48,
2.83 Hz, 1H, CH, H2); 4.61 (br s, 1H, CH, H3); 4.61 (br
s, OH, 7.32, m, 6ArH –BPS); 7.59–7.63 (m, 4ArH –BPS).
13C NMR (CDCl3): d 19.47, C(CH3)2; 24.65, CH2, C4;
26.52, CH2, C5; 27.04, CH3, 3(CH3) –BPS; 48.15, CH,
C1; 60.87, CH3, OCH3 and NCH3; 67.95, CH, C6; 68.73,
CH, C3; 69.71, CH, C2; 127.30, 127.34, ArCH, 2(C20,
1
1034w, 1012w, 895w, 739s, 704m, 673m cmꢀ1. H NMR
(CDCl3): d 1.70–1.77 (m, 1H, CH of CH2, H4 or H5);
1.99–2.15 (m, 2H, CH2, H4 or H5); 2.24–2.34 (m, 1H,
CH of CH2, H4 or H5); 3.16 (br s, 1H, OH); 3.21 (s, 3H,
NCH3); 3.61–3.70 (m, 1H, CH, H1); 3.73 (s, 3H, OCH3);
4.09–4.14 (m, 1H, CH, H6); 5.52 (br dd, J 10.07, 2.45 Hz,
1H, CH, H3); 5.88 (bqd, J 6.28, 2.45 Hz, 1H, CH, H2).

M. Ciampini et al. / Tetrahedron: Asymmetry 18 (2007) 243–250
249
C60 or C30, C50) –BPS; 129.48, ArCH, 2(C40) –BPS; 133.43,
134.29, ArC, 2(C10) –BPS; 135.79, 136.05, ArCH, 2(C20,
C60 or C30, C50) –BPS; 172.45, CO. MS: 458.4 ([M+H]+,
100%), 480.3 ([M+Na]+, 80). HRMS calcd for C25H35NO5-
Si(H+) requires 458.236, found 458.241. C25H35NO5Si-
(Na+) requires 480.215, found 480.220. Anal. Calcd
with NH4Cl aq (2 ml), extracted and the aqueous phase
re-extracted with Et2O (3 · 5 ml). The organics were com-
bined, dried over MgSO4 and reduced under vacuum.
The crude product (90 mg) was purified via column chro-
matography (SiO2, 6:1 light petroleum/ethyl acetate) to
give title compound 7 (66 mg, 80%, Rf 0.31 in 8:1 light
petroleum/ethyl acetate) as a colourless oil, which solidifies
on standing. Recrystallisation from light petroleum/
CH2Cl2 afforded colourless crystals (mp 75–76 ꢁC). IR
(CH2Cl2): 3076m, 3046m, 2986s, 2946s, 2931s, 2885m,
2855s, 1718s, 1472w, 1373m, 1369m, 1245m, 1217m,
1160m, 1111m, 1062s, 965w, 874w, 861w, 822m, 799w,
(457.2): C, 65.61; H, 7.71; N 3.06, 7. Found: C, 65.60; H,
24
7.80; N, 3.01. ½aꢁD ¼ ꢀ17:95 (c 2, CHCl3).
4.13. (ꢀ)-(3aS,4S,5R,7aR)-5-(((tert-Butyldiphenyl)-
silyl)oxy)-2,2-dimethylhexahydro-[1,3]benzodioxol-4-car-
boxylic acid (N-methoxy-N-methyl)amide 23
1
776w, 741m, 702s, 678m, 668s cmꢀ1. H NMR (CDCl3):
To a solution of 22 (666 mg, 1.57 mmol) in acetone (6 ml),
which contained 4 A molecular sieves, 2,2-dimethoxypro-
d 1.03 (s, 9H, CH3, 3(CH3) –BPS); 1.37 (s, 3H, CH3,
C(CH3)2); 1.41–1.53 (m, 1H, CH of CH2, H4 or H5);
1.57 (s, 3H, CH3, C(CH3)2); 1.82–1.88 (m, 2H, CH2, H4
or H5); 1.89 (s, 3H, CH3, CO(CH3)); 2.10–2.22 (m, 1H,
CH of CH2, H4 or H5); 2.47 (dd, J 8.85, 2.29 Hz, 1H,
CH, H1); 4.39 (qd, J 4.58, 3.05 Hz, 1H, CH, H6); 4.46
(dt, J 4.43, 4.27 Hz, 1H, CH, H3); 4.82 (dd, J 8.93,
5.11 Hz, 1H, CH, H2); 7.34–7.46 (m, 6ArH –BPS); 7.58–
7.61 (4ArH –BPS). 13C NMR (CDCl3): d 19.37, C(CH3)3
–BPS; 21.67, CH2, C4; 26.38, CH3, C(CH3)2; 27.07, CH3,
3(CH3) –BPS; 27.20, CH2, C5; 28.63, CH3, C(CH3);
29.48; CH3, CO(CH3)2; 58.34, CH, C1; 69.83, CH, C6;
72.59, 2(CH), C2 and C3; 107.81, C, C(CH3)2; 127.45,
127.54, ArCH, 2(C20, C60 or C30, C50) –BPS; 129.70,
129.80, ArCH, 2(C40) –BPS; 132.68, 133.80, ArC, 2(C10)
–BPS; 135.73, 135.98, ArCH, 2(C20, C60 or C30, C50) –
BPS; 206.98, CO. MS: 475.3 ([M+Na]+, 100%). HRMS
calcd for C27H36O4Si(Na+) requires 475.228, found
475.228. C27H36O4Si(K+) requires 491.202, found
˚
pane (1.54 ml, 13 mmol) followed by camphor sulfonic acid
(40.0 mg, 0.16 mmol) was added at room temperature.
After completion of the reaction (TLC 1 h) NEt3 (2.0 ml)
was added, allowed to stir for 15 min and reduced under
vacuum. A water (20 ml) and Et2O (100 ml) mixture was
added, it was extracted and the aqueous phase re-extracted
with Et2O (3 · 100 ml). The organic extracts were com-
bined, dried over MgSO4 and reduced under pressure.
The crude product was purified using flash column chro-
matography (SiO2, 2:1 light petroleum/ethyl acetate) to
give 23 (764 mg, 98%, Rf 0.28 in 4:1 light petroleum/ethyl
acetate) as a colourless oil, which solidified on standing.
Recrystallisation from CH2Cl2/light petroleum gave the
title compound 23 as colourless crystals (mp 89–90 ꢁC).
IR (CH2Cl2): 3072s, 3046s, 2932s, 2885s, 2858s, 1966w,
1906w, 1850w, 1736w, 1648s, 1589w, 1473m, 1428m,
1390m, 1363w, 1348w, 1266m, 1194w, 1112s, 1052s,
1027m, 1007m, 965m, 928w, 894w, 881w, 863w, 823m,
780w, 741m, 703s cmꢀ1 1H NMR (CDCl3): d 1.05 (s, 9H,
CH3, 3(CH3) –BPS); 1.36 (s, 3H, CH3, C(CH3)2); 1.44 (s,
3H, CH3, C(CH3)2); 1.81 (br dd, J 16.31, 3.21 Hz, 2H,
CH2, H4); 2.9–2.14 (m, 2H, CH2, H5); 2.79 (dd, J 9.16,
1.68 Hz, 1H, CH, H1); 3.11 (s, 3H, NCH3); 3.50 (s, 3H,
OCH3); 4.41 (q, J 6.87, 4.43 Hz, 1H, CH, H6); 4.48 (br
d, J 1.68 Hz, 1H, CH, H3); 4.99 (dd, J 9.24, 4.96 Hz, 1H,
CH, H2); 7.32–7.44 (m, 6ArH –BPS); 7.58–7.64 (4ArH –
BPS). 13C NMR (CDCl3): d 19.39, C(CH3)3 –BPS; 21.36,
CH2, C4; 26.39, CH3, 3(CH3)2; 26.89, CH2, C5; 27.06,
CH3; 3(CH3) –BPS; 28.75, CH3, C(CH3)2; 48.33, CH, C1;
60.94, CH3, NCH3, OCH3; 69.34, CH, C6; 72.60, CH,
C3; 73.29, CH, C2; 107.52, C, C(CH3)2; 127.26, 127.35,
ArCH, 2(C20, C60 or C30, C50) –BPS; 129.45, ArCH,
2(C40) –BPS; 133.26, 134.37, ArC, 2(C10) –BPS; 135.68,
136.02, ArCH, 2(C20, C60 or C30, C50) –BPS; 171.30, CO.
HRMS calcd for C28H39NO5Si(H+) requires 498.268,
491.204. Anal. Calcd for C27H36O4Si (452.2): C, 71.64;
25
H, 8.02. Found: C, 71.53; H, 7.94. ½aꢁD ¼ ꢀ74:9 (c 1.25,
CHCl3).
Acknowledgements
M.C. thanks the Australian Research Council for an
Australian Post-Graduate Award (Industry) and Biota
Holdings Inc. for financial support.
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