Synthesis of AB and CD spiroketal of spongistatin 1

Article abstract of DOI:10.1055/s-2004-831334

The AB (C₁-C₁₃) and CD (C₁₇-C ₂₉) spiroketal of spongistatin 1 were prepared diastereoselectively from syn- and anti-3,5-dihydroxy-6-heptenoate derived from 2-deoxy-D-ribose.

Full text of DOI:10.1055/s-2004-831334

LETTER
2281
Synthesis of AB and CD Spiroketal of Spongistatin 1
Synthesis of
AB
and
CD
Spiro
e
ketal of Sp
u
ongistatin 1k Kun Lau,* Simon Crumpler, Kathy Macfarlane, Florence Lee, Carl Berthelette
Department of Medicinal Chemistry, Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Hwy, Kirkland, Quebec,
H9H 3L1, Canada
Fax +1(514)4284900; E-mail: lau@merck.com
Received 23 June 2004
The manuscript is dedicated to Professor Edward Piers of University of British Columbia for his retirement.
that the pseudo-C2-symmetric polyol 4 could be con-
structed from the sequential dithiane coupling of iodides
6 and 7, which are basically the same compound bearing
different protecting groups. The alcohols of the resulting
coupling product 4 are thus differentiated to facilitate fur-
ther elaboration (Scheme 1). Iodides 6 and 7 can be pre-
pared from (3R),(5S)-dihydroxy-6-heptenoate (8), whose
absolute stereochemistry was derived from its starting
material, 2-deoxy-D-ribose12 (Scheme 1).
Abstract: The AB (C1-C13) and CD (C17-C29) spiroketal of spongi-
statin 1 were prepared diastereoselectively from syn- and anti-3,5-
dihydroxy-6-heptenoate derived from 2-deoxy-D-ribose.
Key words: spiro compounds, natural products, stereoselective
synthesis, glycosides, alkylations
Spongistatins are a class of highly cytotoxic macrolides
isolated from marine sponges.1–3 These compounds have
been shown to exhibit potent antitumor activities against
a number of human multi-drug resistant cell lines.4 The
limited supply from natural sources has stimulated signif-
icant efforts in the synthesis of these compounds.5–11 Re-
cently, we published the synthesis of all four
diastereomers of syn- and anti-3,5-dihydroxy-6-hep-
tenoates as potential synthetic precursors to polyol natural
products.12 We now report the synthesis of the AB and CD
spiroketals of spongistatin 1 (Figure 1) starting from two
of these chiral diol precursors.
Based on previous work by other groups, acid-catalyzed
cyclization of 4 would give the expected thermodynami-
cally more stable AB spiroketal 3.8a,11a The C9 alcohol can
be readily oxidized to the corresponding ketone which can
then be alkylated to give the tertiary alcohol 2 stereoselec-
tively.5d,11a,p
OPMB
13
1
OH
Me
10
TBSO
OPMB
B
O
O
5
PMBO
HO
O
Me
Me
H
6
OTBS O
13
A
O
O
1
9
Me
OPMB
4
OH
Me
2
MeO
11
OAc
2
9
C
D
B
A
HO
O
O
9
7
5
1
13
O
OPMB
O
PMBO
HO
5
OPMB OH
OH
O
OPMB OH
OH
H
OH
OAc
OH
3
O
4
1
3
O
O
7
8
6
H
9
1
13
Me
HO
Me
OH
S
S
I
I
O
+
+
E
F
OPMB O
O
OPMB OTBS OTBS
O
5
7
6
OH
H
OH
Cl
1
EtO2C
Spongistatin 1, Altohyrtin A
OH
OH
Figure 1
8
Scheme 1 Retrosynthetic analysis of AB spiroketal.
The key to our approach to the synthesis of the AB
spiroketal 2 is the stereoselective preparation of the acy-
clic polyol precursor 4 from a single chiral syn-1,3-diol
synthon derived from 2-deoxy-D-ribose. We envisaged
Similar strategy can be employed to synthesize the CD
spiroketal 9 (Scheme 2). Since the stereo-configuration of
C25 and C27 of the CD spiroketal is the same as that of the
diol of iodide 7, dithiane coupling of 7 with the epoxide
12 would then give the spiroketal precursor 11. Epoxide
12 can be prepared from the (3S),(5S)-dihydroxy-6-hep-
tenoate (13).12 Earlier work by other groups suggested that
SYNLETT 2004, No. 13, pp 2281–2286
0
3
.1
1
.2
0
0
4
Advanced online publication: 24.09.2004
DOI: 10.1055/s-2004-831334; Art ID: S06104ST
© Georg Thieme Verlag Stuttgart · New York

2282
C. K. Lau et al.
LETTER
acid-catalyzed cyclization of 11 is expected to give the yield. The primary alcohol was transformed to the corre-
thermodynamically favored undesirable axial axial CD sponding iodide 7 via the tosylate (78%, 2 steps).14 Dis-
spiroketal 10 which can be equilibrated under Lewis acid placement of the iodide with 1,3-dithiane anion in the
catalysis to the desired axial equatorial isomer 9.5d,7a Es- presence of 2 equivalents of HMPA gave the key interme-
sentially, both the AB and CD spiroketals can be prepared diate 23 in 75% yield.
from the syn- and anti-diols 8 and 13.
I
CO2Et
O
I
CO2Et
O
a
HO
17
94%
20
C
MeO
22
PMBO
OH
15
HO
14
O
b
OH
88%
O
O
PMBO
24
OH
O
D
OTBS
c, d
76%
MeO
Et
CO2
28
9
26
OPMB OH
OPMB OTBS
16
OPMB
17
e
89%
OPMB
6
1
OTBS
25
23
21
19
17
29
OTBS
f, g
77%
I
O
HO
OPMB OTBS
OH
OPMB OH
OH
O
OMe OH
OH
HO
OPMB OTBS
O
6
11
18
MeO
29
OPMB O
10
Scheme 3 Synthesis of iodide 6. Reagents and conditions: a)
PMBOC=NHCCl3, CSA, CH2Cl2, r.t., 20 h; b) Zn, EtOH, 70 °C, 1 h;
c) DIBALH, toluene, –78 °C to r.t., 1.5 h; d) TBDMSCl, DMAP,
Et3N, CH2Cl2, r.t., 72 h; e) O3, CH2Cl2, MeOH, –78 °C; then NaBH4,
r.t., 1.5 h; f) TsCl, DMAP, Et3N, CH2Cl2, 1.5 h; g) NaI, NaHCO3,
butanone, D, 3 h.
25
21
19
17
I
S
+
S
+
O
O
OTBS OTBS
12
7
EtO2C
CO2Et
OH
OH
OH
OH
I
CO2Et
a, b
O
EtO2C
8
13
OH
OTBS
86%
19
c
Scheme 2 Retrosynthetic analysis of CD spiroketal.
14
HO
89%
PMBO
EtO2C
d, e
The synthesis of the C1-C6 iodo intermediate 6 began with
the iodofuran 14 (Scheme 3) which was prepared from 2-
deoxy-D-ribose in 3 steps.12 The secondary alcohol was
protected as the p-methoxybenzyl (PMB) ether 15 (94%).
Reductive ring-opening of 15 with zinc dust in refluxing
dry ethanol gave 16, the mono-protected derivative of 8,
in 88% yield. The ester was reduced by DIBALH (84%)
and the resulting diol was protected as the bis-t-butyldi-
methylsilyl (TBS) ether 17 (90%). Ozonolysis of the ter-
minal olefin, followed by reductive workup with NaBH4
gave the primary alcohol 18 in 89% yield. The primary al-
cohol was transformed to the iodide 6 via the correspond-
ing tosylate (77%, 2 steps).13
O
O
O
O
76%
20
21
71%
O
f
PMBO
g, h
78%
PMBO
I
OH
O
O
O
7
22
i
75%
PMBO
7
13
S
S
O
O
23
The synthesis of the C7-C13 intermediate 7 also starts from
14 (Scheme 4). Protection of the alcohol as a TBS ether
followed by ring opening with zinc/ethanol gave the
mono-protected diol 19 in 86% yield over two steps.
Treatment of 19 with dimethoxypropane in the presence
of a catalytic amount of p-toluenesulfonic acid cleaved the
TBS ether in situ and formed the acetonide 20 in 89%
yield. A better yield of the ring opening reaction was ob-
tained when the alcohol 14 was protected as TBS ether.
The ester was reduced by LiAlH4 in THF and the resulting
alcohol was protected as the PMB ether 21 (76%). Ozo-
nolysis of the terminal olefin, followed by reductive
workup with NaBH4 gave the primary alcohol 22 in 71%
Scheme 4 Synthesis of dithiane 23. Reagents and conditions: a)
TBDMSCl, DMAP, Et3N, CH2Cl2, r.t., 20 h; b) Zn, EtOH, 70 °C, 1 h;
c) dimethoxypropane, TsOH, DMF, r.t., 7 d; d) LiAlH4, THF, 0 °C,
10 min; e) PMBOC=NHCCl3, CSA, CH2Cl2, r.t., 20 h; f) O3, CH2Cl2,
–78 °C; then NaBH4, EtOH, H2O, r.t., 1.5 h; g) TsCl, DMAP, Et3N,
CH2Cl2, r.t., 1.5 h; h) NaI, NaHCO3, 2-butanone, D, 8 h; i) 1,3-dithi-
ane, n-BuLi, HMPA, THF, –20 °C, 1 h then 7, –20 °C, 1 h.
Coupling of 6 and 23 was achieved by treating 23 with 1.2
equivalents of t-butyllithium in THF at –78 °C in the pres-
ence of 2 equivalents of HMPA followed by the addition
of 6 (Scheme 5). The coupled product 24 was obtained in
88% yield. Sequential coupling of dithiane with iodide 6
Synlett 2004, No. 13, 2281–2286 © Thieme Stuttgart · New York

LETTER
Synthesis of AB and CD Spiroketal of Spongistatin 1
2283
first and then with iodide 7 was also attempted. The over- DDQ in aqueous CH2Cl2 gave the secondary alcohol 31
all yield was only 50%. Furthermore, dithiane 7 can also (79%, 2 steps). Treatment of 31 with NaOEt in EtOH gave
be used in the synthesis of the CD spiroketal, making this the epoxide 12 in 80% yield.18
sequence more attractive. Reaction of thioacetal 24 with
O
OEt
Hg(ClO4)2 in MeCN–H2O gave an 84% yield of the ke-
tone 25.15 Treatment of 25 with HF in aqueous MeCN
deprotected both the TBS ethers and the acetonide with
concomitant cyclization to give the spiroketal 3 as the
only product in 78% yield. Protection of the primary alco-
hol followed by oxidation of the secondary alcohol to the
ketone with Dess–Martin periodinane (DMP) gave the ke-
tone 26 (76%, 2 steps). 1H NMR, 2D-COSY and NOESY
spectra of 26 is consistent with the stereochemistry of the
AB spiroketal of spongistatin 1.16 Alkylation of the ketone
26 with MeMgI in diethyl ether gave only 66% yield of
the desired axial alcohol 2a. In contrast to similar reac-
tions reported in literature,8a,9a the epimer 2b was also iso-
lated in 23% yield. The axial configuration of the tertiary
alcohol of 2a was confirmed by NOE experiments.17 Oth-
er alkylation method will be investigated in the future to
improve the selectivity. The two primary alcohols of 2a
are differentiated and deprotection of the primary vs. the
secondary PMB ether should be possible.
a, b
OEt
I
OPMB OH
O
71%
O
28
HO
27
70%
c, d
e
OTBS
OTBS
HO
89%
OPMB OTBS
OPMB OTBS
30
f, g
29
79%
22
O
h
OTBS
17
OTBS
TsO
80%
OH
OTBS
OTBS
12
31
Scheme 6 Synthesis of epoxide 12. Reagents and conditions: a)
PMBOC=NHCCl3, CSA, CH2Cl2, r.t., 20 h; b) Zn, EtOH, 70 °C, 1.5
h; c) DIBALH, toluene, –78 °C to 0 °C, 30 min; d) TBDMSCl,
DMAP, Et3N, CH2Cl2, D, 3.5 h; e) O3, CH2Cl2, MeOH, –78 °C; then
NaBH4, r.t. 1 h; f) TsCl, DMAP, Et3N, CH2Cl2, 20 h; g) DDQ,
CH2Cl2–H2O (9:1), 0 °C, 3 h; h) NaOEt, EtOH, r.t., 15 min.
For the CD spiroketal, synthesis of the C17-C22 fragment
12 followed the same synthetic sequence as that of 6 due
to the similarity between the two compounds. Thus, pro-
tection of the secondary alcohol of 27 (the C1 a-isomer of
14)12 with a PMB ether followed by zinc/ethanol ring-
opening gave the mono-protected anti-diol 28 (71% in 2
steps, Scheme 6). The ester was reduced by DIBALH and
the resulting diol was protected as the bis-TBS ether 29
(70%, 2 steps). Ozonolysis of the terminal olefin, fol-
lowed by reductive workup with NaBH4 gave the primary
alcohol 30 in 89% overall yield. Tosylation of the primary
alcohol followed by deprotection of the PMB ether with
As mentioned earlier, the C7-C13 fragment 23 also repre-
sent the C23-C29 fragment of the CD spiroketal. Coupling
of the dithiane anion of 23 with the epoxide 12, under the
same reaction conditions described above for the forma-
tion of 6, gave the key intermediate 32 in 54% yield. Sig-
nificant amount of starting materials 23 and 6 (28% and
40%, respectively) were recovered in the reaction. At-
tempts to push the reaction to completion by raising the
reaction temperature were not successful. Dethioacetali-
zation of 32 with Hg(ClO4)2 gave a 52% yield of the hy-
droxyketone 33. A mixture of the primary and secondary
S
S
OPMB O
O
a
S
S
23
OPMB O
O
OPMB OTBS OTBS
88%
I
24
OPMB OTBS OTBS
6
b
84%
HO
c
OPMB
O
PMBO
HO
78%
OPMB O
O
O
OPMB OTBS OTBS
H
O
25
3
1
TBSO
OPMB
TBSO
3
d, e
f
O
PMBO
HO
OPMB
O
76%
PMBO
H
H
O
O
6
11
Me
8
O
66%
23%
2a
26
2b equatorial OH
Scheme 5 Synthesis of AB spiroketal 2. Reagents and conditions: a) 23, t-BuLi, 2 equiv HMPA, THF, –78 °C, 30 min, then 6, –78 °C, 0.5
h; b) Hg(ClO4)2, THF–H2O (5:1), 10 min; c) HF, MeCN–H2O (2:1), r.t., 6 h; d) TBDMSCl, DMAP, Et3N, CH2Cl2, r.t., 20 h; e) DMP, CH2Cl2,
r.t., 4 h; f) MeMgI, Et2O, –78 °C to –10 °C, 5 h.
Synlett 2004, No. 13, 2281–2286 © Thieme Stuttgart · New York

2284
C. K. Lau et al.
LETTER
S
S
OPMB O
O
a
S
S
23
OPMB O
O
OH
OTBS OTBS
54%
O
OTBS OTBS
32
12
c
69%
b
52%
OPMB O
O
O
OH
OTBS OTBS
33
d
100%
OPMB O
O
O
OMe OTBS OTBS
34
OPMB
25
27
OH
H
H
O
O
25
H
H
H
O
H
H
HO
OH
O
19
PMBO
19
H
H
+
21
22
21
H
MeO
OMe
(1 : 4.6)
H
HO
9
10
NOESY
NOESY
e 79%
H19-H21
H24-H22
H22eq-H27
H24-H25
H19-H24eq
H21-H24eq
H22-H24
(3.4 : 1)
H19-H21
Scheme 7 Synthesis of CD spiroketal 9. Reagents and conditions: a) 23, t-BuLi, 2 equiv HMPA, THF, –78 °C, 30 min, then 12, –20 °C, 4 h;
b) Hg(ClO4)2, CaCO3, THF–H2O (5:1), 10 min; c) Me3O+BF4 , 2,6-di-t-butyl-4-methylpyridine, CH2Cl2, r.t., 6 h; d) HF, MeCN–H2O (2:1), r.t.,
–
3 h; e) ZnBr2, CH2Cl2, r.t., 1 h.
TBS deprotected alcohols was also isolated (38%). The
poor yield of this reaction in contrast to that of 24 → 25
may be attributed to the presence of the adjacent hydroxy-
ketone. The secondary alcohol was then methylated with
References
(1) (a) Pettit, G. R.; Cichacz, Z. A.; Gao, F.; Herald, C. L.; Boyd,
M. R.; Schmidt, J. M.; Hooper, J. N. A. J. Org. Chem. 1993,
58, 1302. (b) Pettit, G. R.; Cichacz, Z. A.; Gao, F.; Herald,
C. L.; Boyd, M. R. J. Chem. Soc., Chem. Commun. 1993,
1166. (c) Pettit, G. R.; Herald, C. L.; Cichacz, Z. A.; Gao, F.;
Boyd, M. R.; Christie, N. D.; Schmidt, J. M. Nat. Prod. Lett.
1993, 3, 239. (d) Pettit, G. R.; Herald, C. L.; Cichacz, Z. A.;
Gao, F.; Schmidt, J. M.; Boyd, M. R.; Christie, N. D.;
Boettner, F. E. J. Chem. Soc., Chem. Commun. 1993, 1805.
(e) Pettit, G. R.; Cichacz, Z. A.; Herald, C. L.; Gao, F.; Boyd,
M. R.; Schmidt, J. M.; Hamel, E.; Bai, R. J. Chem. Soc.,
Chem. Commun. 1994, 1605.
(2) (a) Kobayashi, M.; Aoki, S.; Sakai, H.; Kawazon, K.;
Kihara, N.; Sasaki, T.; Kitagawa, I. Tetrahedron Lett. 1993,
34, 1993. (b) Kobayashi, M.; Aoki, S.; Sakai, H.; Kawazon,
K.; Kihara, N.; Sasaki, T.; Kitagawa, I. Chem. Pharm. Bull.
1993, 41, 989. (c) Kobayashi, M.; Aoki, S.; Kitagawa, I.
Tetrahedron Lett. 1994, 35, 1243.
–
Me3O+BF4 to give a 69% yield of 34 (Scheme 7).19
Treatment of 34 with HF in aqueous MeCN gave quanti-
tatively a mixture of the spiroketals 9 and 10 in the ratio
of 1:4 favoring the undesirable axial axial isomer 10. The
mixture was treated with 1.2 equivalents of anhydrous
ZnBr2 in CH2Cl2 for 1 hour5d,10a to give 61% of the desired
isomer 9 and 18% of 10 after chromatography. The con-
figurations of the spiroketals 9 and 10 were confirmed via
1H NMR, 2D-COSY and NOESY experiments.20
Spiroketal 9 exhibits diagnostic strong NOEs between
H19-H21, H19-H24eq, H21-H24eq and H22eq-H24ax. For
spiroketal 10,21 strong NOE was observed between H19-
H21, confirming the chair conformation of the C19-C22
segment. The second ring (C23-C27) adopts a more boat
like conformation as defined by NOEs observed between
H22-H24, H24-H25, and the most telling NOE between
H22eq and H27.11p
(3) Fusetanai, N.; Shinoda, K.; Matsunaga, S. J. Am. Chem. Soc.
1993, 115, 3977.
(4) Pettit, G. R. J. Nat. Prod. 1996, 59, 812.
(5) (a) Evans, D. A.; Coleman, P. J.; Dias, L. C. Angew. Chem.,
Int. Ed. Engl. 1997, 36, 2738. (b) Evans, D. A.; Trotter, B.
W.; Côté, B.; Coleman, P. J. Angew. Chem., Int. Ed. Engl.
1997, 36, 2741. (c) Evans, D. A.; Trotter, B. W.; Côté, B.;
Coleman, P. J.; Dias, L. C.; Tyler, A. N. Angew. Chem., Int.
Ed. Engl. 1997, 36, 2744. (d) Evans, D. A.; Trotter, B. W.;
Coleman, P. J.; Côté, B.; Dias, L. C.; Rajapakse, H. A.;
Tyler, A. N. Tetrahedron 1999, 55, 8671.
In summary, we have achieved a highly stereoselective
and convergent synthesis of both the AB and CD spiroket-
als of spongistatin 1 starting from derivatives of the syn-
and anti-3,5-dihydroxy-6-heptenoates of predefined ste-
reo configuration that were derived from 2-deoxy-D-ri-
bose.
Synlett 2004, No. 13, 2281–2286 © Thieme Stuttgart · New York

LETTER
Synthesis of AB and CD Spiroketal of Spongistatin 1
2285
(6) (a) Guo, J.; Duffy, K. J.; Stevens, K. L.; Dalko, P. I.; Roth,
R. M.; Hayward, M. M.; Kishi, Y. Angew. Chem. Int. Ed.
1998, 37, 187. (b) Hayward, M. M.; Roth, R. M.; Duffy, K.
J.; Dalko, P. I.; Stevens, K. L.; Guo, J.; Kishi, Y. Angew.
Chem. Int. Ed. 1998, 37, 192.
W. R. Org. Lett. 2002, 4, 3719. (q) Holson, E. B.; Roush,
W. R. Org. Lett. 2002, 4, 3723.
(12) Lau, C. K.; Zakrewski, P. Synlett 2003, 2, 215.
(13) Physical data of 6: [a]D25 –16.5 (c 1.79, CHCl3). 1H NMR
(500 MHz, acetone-d6): d = 7.31 (d, 2 H, J = 8.7 Hz), 6.90
(d, 2 H, J = 8.7 Hz), 4.58 (d, 1 H, J = 11.1 Hz), 4.42 (d, 1 H,
J = 11.2 Hz), 4.07–4.01 (m, 1 H), 3.78 (s, 3 H), 3.74–3.66
(m, 2 H), 3.56–3.52 (m, 1 H), 3.41–3.39 (m, 2 H), 1.87–1.81
(m, 1 H), 1.77–1.69 (m, 2 H), 1.65–1.58 (m, 1 H), 0.88 (s, 18
H), 0.08 (s, 6 H), 0.05 (s, 6 H). 13C NMR (100 MHz, acetone-
d6): d = 170.5, 141.6, 140.4, 124.7, 85.1, 81.3, 77.5, 70.6,
65.7, 53.8, 51.2, 36.5, 28.9, 28.8, 22.3, 6.1, 5.9, 5.1. HRMS:
m/z calcd for C26H48O4Si2I: for [M – H] 607.2136. Found:
607.2138.
(7) (a) Smith, A. B. I. I. I.; Zhuang, L.; Brook, C. S.; Lin, Q.;
Moser, W. H.; Trout, R. E. L.; Boldi, A. M. Tetrahedron
Lett. 1997, 38, 8671. (b) Smith, A. B. III.; Doughty, V. A.;
Lin, Q.; Zhuang, L.; McBriar, M. D.; Boldi, A. M.; Moser,
W. H.; Murase, N.; Nakayama, K.; Sobukawa, M. Angew.
Chem. Int. Ed. 2001, 40, 191. (c) Smith, A. B. III.; Lin, Q.;
Doughty, V. A.; Zhuang, L.; McBriar, M. D.; Kerns, J. K.;
Brook, C. S.; Murase, N.; Nakayama, K. Angew. Chem. Int.
Ed. 2001, 40, 196. (d) Smith, A. B. III.; Doughty, V. A.;
Sfouggatakis, C.; Bennett, C. S.; Koyanagi, J.; Takeuchi, M.
Org. Lett. 2002, 4, 783. (e) Smith, A. B. III.; Zhu, W.;
Shirakami, S.; Sfouggatakis, C.; Doughty, V. A.; Bennett, C.
S.; Sakamoto, Y. Org. Lett. 2003, 5, 761.
(14) Physical data of 7: [a]D25 –0.9 (c 4.47, CHCl3). 1H NMR
(500 MHz, acetone-d6): d = 7.28 (d, 2 H, J = 8.6 Hz), 6.92
(d, 2 H, J = 8.6 Hz), 4.42 (q, 2 H, J = 9.6 Hz), 4.12–4.06 (m,
1 H), 3.94–3.87 (m, 1 H), 3.80 (s, 3 H), 3.58–3.48 (m, 2 H),
3.26 (dd, 1 H, J = 4.8, 10.1 Hz), 3.17 (dd, 1 H, J = 6.4, 10.2
Hz), 1.82–1.74 (m, 1 H), 1.71 (q, 2 H, J = 6.2 Hz), 1.43 (s, 3
H), 1.32 (s, 3 H), 1.10 (q, 1 H, J = 11.8 Hz). 13C NMR (100
MHz, acetone-d6): d = 164.3, 136.1, 134.2, 118.7, 103.9,
77.2, 74.1, 70.9, 70.7, 59.8, 41.9, 41.5, 34.6, 24.5, 15.2.
(15) Physical data of 25: [a]D25 –7.3 (c 3.75, CH2Cl2). 1H NMR
(500 MHz, acetone-d6): d = 7.27 (m, 4 H), 6.91 (m, 4 H),
4.46 (d, 2 H, J = 11.0 Hz), 4.42 (d, 2 H, J = 10.6 Hz), 4.39–
4.34 (m, 1 H), 4.08–4.02 (m, 3 H), 3.83 (s, 3 H), 3.81 (s, 3
H), 3.78–3.70 (m, 2 H), 3.55–3.47 (m, 2 H), 2.69–2.61 (m, 2
H), 2.48 (dd, 1 H, J = 5.0, 15.6 Hz), 1.83–1.76 (m, 2 H),
1.68–1.58 (m, 6 H), 1.42 (s, 3 H), 1.27 (s, 3 H), 1.09 (m, 1
H), 0.94 (s, 9 H), 0.91 (s, 9 H), 0.10 (m, 6 H), 0.08 (s, 6 H).
13C NMR (100 MHz, acetone-d6): d = 206.91, 159.61,
131.46, 131.43, 129.52, 129.40, 113.92, 113.86, 98.57,
72.80, 72.46, 70.95, 66.89, 66.28, 66.13, 65.99, 59.86,
55.00, 50.38, 48.83, 43.18, 40.52, 37.23, 37.00, 25.86,
19.60, 18.31, 18.10, –4.55, –4.77, –5.56, –5.58. HRMS: m/z
calcd for C44H74O9Si2K: for [M + K+] 841.4508. Found:
841.4505.
(8) (a) Paterson, I.; Oballa, R. M.; Norcross, R. D. Tetrahedron
Lett. 1996, 37, 8581. (b) Paterson, I.; Gibson, K. R.; Oballa,
R. M. Tetrahedron Lett. 1996, 37, 8585. (c) Paterson, I.;
Keown, L. E. Tetrahedron Lett. 1997, 38, 5727.
(d) Paterson, I.; Oballa, R. M. Tetrahedron Lett. 1997, 38,
8241. (e) Paterson, I.; Wallace, D. J.; Gibson, K. R.
Tetrahedron Lett. 1997, 38, 8911. (f) Paterson, I.; Chen, D.
Y.-K.; Coster, M. J.; Aceña, J. L.; Bach, J.; Gibson, K. R.;
Keown, L. E.; Oballa, R. M.; Trieselmann, T.; Wallace, D.
J.; Hodgson, A. P.; Norcross, R. D. Angew. Chem. Int. Ed.
2001, 40, 4055.
(9) (a) Crimmins, M. T.; Washburn, D. G. Tetrahedron Lett.
1998, 39, 7487. (b) Crimmins, M. T.; Katz, J. D.; McAtee,
L. C.; Tabet, E. A.; Kirincich, S. J. Org. Lett. 2001, 3, 949.
(c) Crimmins, M. T.; Katz, J. D. Org. Lett. 2000, 2, 957.
(d) Crimmins, M. T.; Katz, J. D.; Washburn, D. G.; Allwein,
S. P.; McAtee, L. F. J. Am. Chem. Soc. 2002, 124, 5661.
(10) (a) Hubbs, J. L.; Heathcock, C. H. J. Am. Chem. Soc. 2003,
125, 12836. (b) Heathcock, C. H.; McLaughlin, M.; Medina,
J.; Hubbs, J. L.; Wallace, G. A.; Scott, R.; Claffey, M. M.;
Hayes, C. J.; Ott, G. R. J. Am. Chem. Soc. 2003, 125, 12844.
(c) Wallace, G. A.; Scott, R. W.; Heathcock, C. H. J. Org.
Chem. 2000, 65, 4145. (d) Claffey, M. M.; Hayes, C. J.;
Heathcock, C. H. J. Org. Chem. 1999, 64, 8267.
(11) For a comprehensive list of leading references to synthetic
approaches from other laboratories, see the references cited
in ref.10a and the following: (a) Zuev, D.; Paquette, L. A.
Org. Lett. 2000, 2, 679. (b) Terauchi, T.; Nakata, M.
Tetrahedron Lett. 1998, 39, 3795. (c) Lemaire-Audoire, S.;
Vogel, P. Tetrahedron Lett. 1998, 39, 1345. (d) Lemaire-
Audoire, S.; Vogel, P. J. Org. Chem. 2000, 65, 3346.
(e) Zemribo, R.; Mead, K. T. Tetrahedron Lett. 1998, 39,
3895. (f) Fernandez-Megia, E.; Gourlaouen, N.; Ley, S. V.;
Rowlands, G. J. Synlett 1998, 991. (g) Gaunt, M. J.; Hook,
D. F.; Tanner, H. R.; Ley, S. V. Org. Lett. 2003, 5, 4815.
(h) Gaunt, M. J.; Jessiman, A. S.; Orsini, P.; Tanner, H. R.;
Hook, D. F.; Ley, S. V. Org. Lett. 2003, 5, 4819.
(16) Physical data of 26: [a]D25 –67.4 (c 6.5, CH2Cl2). 1H NMR
(500 MHz, acetone-d6): d = 7.36 (d, 2 H, J = 8.5 Hz), 7.17
(d, 2 H, J = 8.5 Hz), 6.92 (d, 2 H, J = 8.6 Hz), 6.88 (d, 2 H,
J = 8.6 Hz), 4.61 (d, 1 H, J = 11.1 Hz), 4.43 (d, 1 H, J = 11.1
Hz), 4.27 (d, 1 H, J = 11.4 Hz), 4.16 (d, 1 H, J = 11.4 Hz),
4.13–4.08 (m, 1 H, H3), 4.07–4.03 (m, 1 H, H11), 3.90 (br s,
1 H), 3.79 (s, 3 H), 3.77 (s, 3 H), 3.72–3.68 (m, 1 H), 3.66–
3.60 (m, 2 H), 3.54–3.50 (m, 1 H), 2.54 (d, 1 H, J = 14.1 Hz,
H8ax), 2.34 (d, 1 H, J = 8.5 Hz, H6ax), 2.29–2.23 (m, 3 H),
1.89 (d, 1 H, J = 13.9 Hz, H4ax), 1.84–1.80 (m, 2 H), 1.62–
1.55 (m, 3 H), 1.52–1.46 (m, 1 H, H4eq), 0.89 (s, 9 H), 0.03
(s, 6 H). 13C NMR (150 MHz, acetone-d6): d = 204.78,
159.89, 159.35, 132.36, 129.66, 129.24, 128.96, 113.64,
113.63, 99.82, 72.51, 70.88, 69.66, 66.61, 66.15, 62.44,
59.88, 54.89, 54.86, 52.24, 46.94, 38.97, 36.17, 36.13,
35.74, 25.84, 18.20, –5.67. The stereochemistry of AB
spiroketal was determined by 2D-COSY and NOESY
experiments. NOEs were observed between H6ax and H8ax,
H6eq and H8eq as well as H3ax and H11ax which were
consistent with the proposed spiroketal junction reported in
the literature. HRMS: m/z calcd for C35H52O8SiK: for [M +
K+] 667.3069. Found: 667.3066.
(i) Micalizio, G. C.; Pinchuk, A. N.; Roush, W. R. J. Org.
Chem. 2000, 65, 8730. (j) Anderson, J. C.; McDermott, B.
P. Tetrahedron Lett. 1999, 40, 7135. (k) Samadi, M.;
Munoz-Letelier, C.; Poigny, S.; Guyot, M. Tetrahedron Lett.
2000, 41, 3349. (l) Terauchi, T.; Terauchi, T.; Sato, I.;
Tsukada, T.; Kanoh, N.; Nakata, M. Tetrahedron Lett. 2000,
41, 2649. (m) Kary, P. D.; Roberts, S. M. Tetrahedron:
Asymmetry 1999, 10, 217. (n) Kim, H.; Hoffmann, M. R.
Eur. J. Org. Chem. 2000, 2195. (o) Barrett, A. G. M.;
Braddock, D. C.; de Koning, P. D.; White, A. J. P.; Williams,
D. J. J. Org. Chem. 2000, 65, 375. (p) Holson, E. B.; Roush,
(17) Physical data of 2a: [a]D25 –50.0 (c 1.2, CH2Cl2). 1H NMR
(500 MHz, acetone-d6): d = 7.33 (d, 2 H, J = 8.5 Hz), 7.17
(d, 2 H, J = 8.4 Hz), 6.89 (dd, 4 H, J = 8.6, 11.4 Hz), 4.56 (d,
1 H, J = 11.1 Hz), 4.38 (d, 1 H, J = 11.1 Hz), 4.28 (d, 1 H,
J = 11.4 Hz), 4.23–4.15 (m, 3 H), 4.01 (t, 1 H, J = 10.5 Hz),
3.85 (s, 1 H), 3.79 (s, 3 H), 3.76 (s, 3 H), 3.76–3.73 (m, 1 H),
3.71–3.61 (m, 2 H), 3.53–3.47 (m, 1 H), 2.11 (s, 1 H, H6),
Synlett 2004, No. 13, 2281–2286 © Thieme Stuttgart · New York

2286
C. K. Lau et al.
LETTER
1.89 (d, 1 H, J = 12.6 Hz, H4), 1.75–1.65 (m, 5 H), 1.56–
1.49 (m, 4 H), 1.29 (t, 1 H, J = 12.3 Hz, H10), 1.10 (s, 3 H,
CH3), 0.90 (s, 9 H), 0.06 (s, 6 H). 13C NMR (150 MHz,
acetone-d6): d = 160.48, 160.44, 132.35, 132.31, 129.14,
129.04, 113.95, 113.91, 98.56, 72.30, 70.90, 69.63, 69.16,
66.85, 62.94, 62.81, 60.41, 54.85, 54.83, 46.45, 44.53,
39.18, 37.00, 36.04, 29.95, 25.79, 18.15, –5.18. The
stereochemistry of the axial C9-OH was determined by 2D-
COSY and NOESY experiments. NOE was observed
between H11ax and C9-OH, CH3 and H8eq as well as CH3 and
H10eq. HRMS: m/z calcd for C36H56O8SiK: for [M + K+]
1.62–1.58 (m, 1 H), 1.55–1.49 (m, 1 H), 1.44 (s, 3 H), 1.28
(s, 3 H), 1.13–1.05 (m, 1 H), 0.96 (s, 9 H), 0.92 (s, 9 H), 0.13
(s, 6 H), 0.08 (s, 6 H). 13C NMR (100 MHz, acetone-d6): d =
206.62, 159.62, 131.43, 129.39, 113.92, 98.57, 74.04, 72.45,
67.11, 66.29, 66.01, 65.98, 59.67, 55.82, 54.99, 50.23,
48.15, 43.15, 41.48, 37.22, 37.00, 25.90, 25.81, 19.59,
18.27, 18.15, –4.48, –4.71, –5.64. HRMS: m/z calcd for
C37H68O8Si2K: for [M + K+] 735.4090. Found: 735.4087.
(20) Physical data of 9: [a]D25 –26.8 (c 0.67, CH2Cl2). 1H NMR
(500 MHz, acetone-d6): d = 7.31 (d, 2 H, J = 8.5 Hz), 6.91
(d, 2 H, J = 8.5 Hz), 4.59–4.53 (m, 1 H), 4.45 (q, 2 H,
J = 10.1 Hz), 4.18 (d, 1 H, J = 5.3 Hz), 4.11 (s, 1 H), 3.94 (t,
1 H, J = 6.3 Hz, OH), 3.85–3.81 (m, 2 H), 3.80 (s, 3 H),
3.59–3.51 (m, 4 H), 3.30 (s, 3 H), 2.37 (d, 1 H, J = 14.6 Hz,
H24eq), 2.04–2.00 (m, 2 H), 1.74–1.59 (m, 5 H), 1.53–1.45
(m, 2 H), 1.21 (t, 1 H, J = 11.9 Hz, H22ax), 1.08 (q, 1 H,
J = 11.7 Hz, H20ax). 13C NMR (150 MHz, acetone-d6): d =
159.20, 131.01, 129.04, 114.01, 99.09, 74.00, 72.51, 67.69,
66.36, 64.04, 62.21, 58.39, 54.91, 54.58, 43.74, 38.92,
38.60, 38.38, 36.52, 34.11. The stereochemistry of CD
spiroketal was determined by 2D-COSY and NOESY
experiments. NOEs were observed between H19ax and
H24eq, H21 and H24eq, H22eq and H24ax as well as H21 and
H-19. HRMS: m/z calcd for C22H34O7K: for [M + K+]
449.1942. Found: 449.1940.
25
683.3382. Found: 683.3382. Physical data of 2b: [a]D
–46.0 (c 0.43, CH2Cl2). 1H NMR (500 MHz, acetone-d6):
d = 7.33 (d, 2 H, J = 8.6 Hz), 7.18 (d, 2 H, J = 8.6 Hz),
6.89–6.87 (m, 4 H), 4.56 (d, 1 H, J = 11.1 Hz), 4.36 (d, 1 H,
J = 11.1 Hz), 4.29 (d, 1 H, J = 11.5 Hz), 4.18 (d, 1 H,
J = 11.5 Hz), 4.11–4.05 (m, 1 H, H3), 3.85–3.81 (m, 2 H),
3.79 (s, 3 H), 3.76 (s, 3 H), 3.73–3.67 (m, 2 H), 3.64–3.58
(m, 1 H), 3.51–3.47 (m, 2 H), 2.10–2.08 (m, 1 H, H6), 1.86–
1.82 (m, 1 H, H4), 1.74–1.59 (m, 6 H), 1.53–1.45 (m, 3 H),
1.41 (s, 3 H, CH3), 1.38–1.31 (m, 1 H, H10), 0.90 (s, 9 H),
0.05 (s, 6 H). 13C NMR (150 MHz, acetone-d6): d = 159.60,
159.54, 131.60, 131.48, 129.71, 129.65, 114.06, 113.99,
97.71, 72.23, 71.10, 69.63, 67.16, 64.80, 61.92, 60.63,
54.83, 54.82, 49.75, 46.32, 39.71, 37.69, 36.54, 36.12,
29.14, 26.10, 18.16, –5.18. NOEs were observed between
H11ax and CH3, H8eq and CH3 as well as H3ax and H11ax
which were consistent with the spiroketal structure with the
equatorial C9-OH. HRMS: m/z calcd for C36H56O8SiNa: for
[M + Na+] 667.3642. Found: 667.3638.
(21) Physical data of 10: [a]D25 +0.3 (c 1.7, CH2Cl2). 1H NMR
(500 MHz, acetone-d6): d = 7.30 (d, 2 H, J = 8.3 Hz), 6.92
(d, 2 H, J = 8.4 Hz), 4.48–4.41 (m, 2 H), 4.20–4.18 (m, 1 H,
H25), 4.17–4.11 (m, 1 H, H27), 4.08–4.05 (m, 1 H, H19),
3.80 (s, 3 H), 3.80–3.79 (m, 1 H, OH), 3.69–3.62 (m, 3 H),
3.58–3.50 (m, 2 H), 3.37 (t, 1 H, J = 5.1 Hz, OH), 3.24 (s, 3
H), 2.69 (d, 1 H, J = 10.2 Hz, H22eq), 2.08–2.03 (m, 1 H,
H20), 1.84–1.78 (m, 3 H), 1.73–1.58 (m, 5 H), 1.07–0.99 (m,
2 H). 13C NMR (150 MHz, acetone-d6): d = 159.23, 130.98,
129.05, 113.52, 98.95, 72.98, 72.10, 66.68, 66.64, 66.51,
62.38, 58.68, 54.60, 54.40, 43.65, 39.96, 39.26, 38.19,
37.62, 35.99. The stereochemistry of CD spiroketal was
determined by 2D-COSY and NOESY experiments. NOEs
were observed between H19 and H21, H24 and H25, H22
and H24 as well as H22eq and H27ax which was consistent
with the spiroketal junction with a chair conformation for the
C19-C22 fragment and a boat like conformation for the C24-
C27 segment. HRMS: m/z calcd for C22H34O7K: for [M +
K+] 449.1942. Found: 449.1940.
(18) Physical data of 12: [a]D25 –2.53 (c 4.5, CH2Cl2). 1H NMR
(500 MHz, acetone-d6): d = 4.17–4.11 (m, 1 H), 3.75 (t, 2 H,
J = 6.3 Hz), 2.98–2.96 (m, 1 H), 2.72 (t, 1 H, J = 4.6 Hz),
2.44 (dd, 1 H, J = 2.5, 5.2 Hz), 1.77–1.71 (m, 2 H), 1.71–
1.61 (m, 2 H), 0.95 (s, 9 H), 0.92 (s, 9 H), 0.14 (m, 6 H), 0.09
(s, 6 H). 13C NMR (100 MHz, acetone-d6): d = 67.81, 59.66,
49.26, 46.92, 41.19, 41.03, 25.83, 25.80, 18.28, 18.11,
–4.80, –4.88, –5.62. HRMS: m/z calcd for C18H41O3Si2: for
[M + H+] 361.2594. Found: 361.2593.
(19) Physical data of 34: [a]D25 –19.3 (c 0.15, CH2Cl2). 1H NMR
(500 MHz, acetone-d6): d = 7.28 (d, 2 H, J = 8.5 Hz), 6.92
(d, 2 H, J = 8.5 Hz), 4.43–4.36 (m, 3 H), 4.10–4.05 (m, 2 H),
3.89–3.83 (m, 1 H), 3.80 (s, 3 H), 3.77–3.71 (m, 2 H), 3.56–
3.48 (m, 2 H), 3.28 (s, 3 H), 2.82–2.78 (m, 1 H), 2.63 (dd, 1
H, J = 7.5, 15.9 Hz), 2.56–2.46 (m, 2 H), 1.72–1.66 (m, 5 H),
Synlett 2004, No. 13, 2281–2286 © Thieme Stuttgart · New York