The Spongistatins: Architecturally Complex Natural Products - Part One: A Formal Synthesis of (+)-Spongistatin 1 by Construction of an Advanced ABCD Fragment

Full text of DOI:10.1002/1521-3773(20010105)40:1<191::AID-ANIE191>3.0.CO;2-C

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The Spongistatins: Architecturally Complex
Natural ProductsÐPart One: A Formal
Synthesis of (‡)-Spongistatin 1 by Construction
of an Advanced ABCD Fragment**
OH
E
29
28
HO
H
O
OH
O
H
H
Amos B. Smith III,* Victoria A. Doughty, Qiyan Lin,
Linghang Zhuang, Mark D. McBriar, Armen M. Boldi,
William H. Moser, Noriaki Murase, Kiyoshi Nakayama,
and Masao Sobukawa
O
O
D
H
F
OMe
O
23
O
1
HO
H
C
O
OH
OH
H
H
O
The spongipyrans comprise an important family of archi-
tecturally unique bis-spiroketal macrolides that display ex-
traordinary (subnanomolar) antitumor activities against a
wide variety of human cancer cell lines, including melanoma,
lung, colon, and brain.[1] Three research groups (those of
Pettit,[1a, 2] Fusetani,[3] and Kitagawa[4]) independently isolated
members of the spongipyran family in minute amounts,
naming them in turn the spongistatins, cinachyrolide, and
the altohyrtins.[5] Whereas the carbon skeleton was common
to all three families, the structures differed in the assignment
of the relative stereochemical relationships. Kitagawa and co-
workers assigned the correct relative and absolute stereo-
chemistries based on extensive Mosher analysis and circular
dichroism studies.[4c] These assignments were subsequently
confirmed by the total syntheses of (‡)-altohyrtin C [spon-
gistatin 2 (2)] by Evans et al.[6] and (‡)-altohyrtin A [spon-
gistatin 1(1)] by Kishi and co-workers.[7] The elegant synthe-
ses at Harvard University demonstrated unequivocally that
the altohyrtins and spongistatins were indeed identical.
The spongistatins have attracted wide interest[8] as a result
of their architectural complexity, which includes two [6,6]
spiroketal moieties,[9] two highly substituted tetrahydropyran
rings encased in a 42 membered macrolide framework,
24 stereogenic centers, and a delicate triene side chain.
Particularly intriguing is the CD spiroketal possessing only a
single anomeric interaction in conjunction with an intra-
molecular hydrogen bond that stabilizes the axial ± equatorial
configuration.
12
O
A
X
13
AcO
B
OAc
OH
Spongistatin 1, X = Cl (1)
Spongistatin 2, X = H (2)
OTBS
P+Ph3I-
H
H
O
E
29
TESO
H
O
O
23
OMe
H
D
OMe
O
O
H
O
TBSO
C
F
+
O
H
OTMS
41
TIPSO
AcO
OTMS
OTBS
O
H
O
A
48
B
OAc
5
6
OH
BnO
51
28
H
O
OMe
D
1
TBSO
BPSO
C
O
H
3
O
MeO
H
O
12
OBOM
I
To assemble the complex spongipyran skeleton, we envi-
sioned Wittig union of 5 with 6 (Scheme 1), followed by
regioselective macrolactonization at C(41), first demonstrated
O
B
13
PhO2S
4
3
OTBS
ODMB
Scheme 1. Retrosynthetic analysis of spongistatin 2 (see ref. [20] for
abbreviations).
[*] Prof. A. B. Smith III, Dr. V. A. Doughty, Dr. Q. Lin, Dr. L. Zhuang,
Dr. M. D. McBriar, A. M. Boldi, Dr. W. H. Moser, Dr. N. Murase,
Dr. K. Nakayama, Dr. M. Sobukawa
Department of Chemistry
by Evans et al.[6] Advanced intermediate 6 would in turn arise
from a sulfone-mediated coupling of subunits 3 and 4 followed
by Julia methylenation,[10] elaboration of the AB spiroketal,
and oxidation at C(1) and C(28). Herein we report the
synthesis of an advanced C(1 ± 28) subunit for the spongista-
tins. Central to this venture was the development of epime-
rization conditions to control the C(23) configuration of the
CD spiroketal. In conjunction with this effort we achieved a
formal synthesis of spongistatin 1 (1). In the following
communication we describe the synthesis of 5, fragment
assembly, and final elaboration to (‡)-spongistatin 2 (2).
Continuing with the synthetic analysis, disconnection of
methylketal 3 (Scheme 2) revealed the opportunity to exploit
a one-pot unsymmetrical bisalkylation of 2-TBS-1,3-dithiane
Laboratory for Research on the Structure of Matter
and Monell Chemical Senses Center, University of Pennsylvania
Philadelphia, PA 19104 (USA)
Fax : (‡ 1)215-898-5129
E-mail: smithab@sas.upenn.edu
[**] Financial support was provided by the National Institutes of Health
(National Cancer Institute) through Grant CA-70329, NIH Postdoc-
toral Fellowships to A.M.B. and W.H.M.,
a Japan Society for
Promotion of Science Fellowship to N.M., and a Royal Society
Fulbright Fellowship to V.A.D. We also thank the Daiichi Pharma-
ceutical Co., Ltd, and the Tanabe Seiyaku Co., Ltd for financial
support. Finally we thank Dr. George T. Furst, Dr. Patrick J. Carroll,
Dr. Rakesh Kohli, and Mr John Dykins of the University of
Pennsylvania Spectroscopic Service Center for assistance in securing
and interpreting high-field NMR spectra, X-ray crystal structures, and
mass spectra.
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1
BnO
BnO
28
28
BPSO
3
H
H
O
O
O
MeO
H
OMe
D
12
OMe
D
O
I
TBSO
C
TBSO
C
O
B
O
H
O
H
S
S
+
12
17
3
OBOM
13
OTBS
18
I
13
PhO2S
O
O
11
ODMB
BnO
DMP
4
OH
OH
OTBS OH
S
S
OTs
OTBS OTBS S
OMe O
BSPO
S
O
(+)-9
(-)-15
OTES
O
S
S
O
6
O
1
+
+
O
BPSO
3
8
OTBS
O
12
TBS
O
O
S
S
(-)-7
(+)-8
BnO
O
28
18
TBS
Scheme 2. Retrosynthetic analysis of the AB subunit revealing a one-pot
unsymmetrical bis-alkylation disconnection (see ref. [20] for abbrevia-
tions).
(-)-14
(-)-13
Scheme 4. Retrosynthesis of the CD spiroketal 4 revealing a one-pot
unsymmetrical bis-alkylation disconnection (see ref. [20] for abbrevia-
tions).
with Brook rearrangement recently reported by our labora-
tory.[11] The development of this route and the synthesis of
fragments (ꢀ)-7, (‡)-8, and (‡)-9 were disclosed earlier.[8b]
Completion of subunit (ꢀ)-3[12] required four steps begin-
ning with (‡)-9[8b] (Scheme 3). Protection of the 1,3-diol as the
Assembly of the CD spiroketal required removal of both
the TBS and acetonide groups (HCl/MeOH) in (ꢀ)-15
(Scheme 5), followed by treatment with mercury perchlorate
buffered with calcium carbonate; the result was a
mixture of spiroketals (‡)-16 and (ꢀ)-17 (2:1).
After separation, NOE experiments revealed that
both spiroketals possessed an ªaxial ± equatorial
(AE)º configuration;[14] the ªaxial ± axial (AA')º
congener was not observed. Importantly, treat-
ment of the mixture with perchloric acid prior to
purification furnished only the desired spiroketal
(ꢀ)-17 (87%, two steps). Subsequent experi-
1) 2,2-dimethoxypropane,
PPTS, CH2Cl2, (95%)
2) Hg(ClO4)2, 2,6-lutidine,
MeOH:THF (1:1.5) 0 °C
(99%)
OH
OH
OTBS OH
S
S
OTs
BPSO
BPSO
3) HClO4, MeOH:CH2Cl2
(5:1), 0 °C (99%)
(+)-9
1
BPSO
ments[15] demonstrated that the calcium ion, a
LiI, MeCN,
70 °C (99%)
O
MeO
H
O
MeO
H
12
remnant of dithiane removal, stabilizes spiroketal
(ꢀ)-17, presumably through coordination with the
O
O
OTs
I
O
O
hydroxyl groups at C(18) and C(25) as well as the
(-)-3
C-ring pyran oxygen atom. This observation would
OTBS
(-)-10
OTBS
prove critical late in the synthesis (see below).
Conversion of (ꢀ)-17 into iodide (ꢀ)-12 was then
Scheme 3. Synthesis of the AB subunit (ꢀ)-3 (see ref. [20] for abbreviations).
achieved in four steps: pivaloation of the primary
acetonide, mercury perchlorate mediated removal of the
dithiane[13] in the presence of methanol to furnish a mixture of
methyl ketals, and acid-catalyzed equilibration led to the
thermodynamically more stable ketal (ꢀ)-10 (d.r. > 10:1).
Treatment with lithium iodide completed the construction of
the AB fragment (ꢀ)-3; the overall yield was 92% (four
steps).
The CD fragment (4) was envisioned to arise through the
coupling of dithiane 11 with iodide 12 (Scheme 4). Discon-
nection of 12 at the spiroketal provided another opportunity
to employ the one-pot bis-alkylation tactic.[11] Indeed, the
coupling of (ꢀ)-13 and (ꢀ)-14 with the lithium anion of
2-TBS-1,3-dithiane followed by methylation furnished (ꢀ)-15
in 68% yield (two steps).[8m]
hydroxyl group, protection of the secondary hydroxyl group
(TBSCl), reductive removal of the pivaloate (DIBAL), and
conversion of the primary hydroxyl group into the iodide
completed the synthesis of (ꢀ)-12.
Construction of dithiane (‡)-11 (Scheme 6) required three
steps, beginning with (‡)-18;[8b] ozonolysis, introduction of the
dithiane with concomitant loss of the TBS group, and
protection of the diol (‡)-19 as the DMP acetal furnished
(‡)-11 in 85% yield (three steps).
The coupling of (‡)-11 and (ꢀ)-12 proceeded with high
efficiency (95%) to furnish (‡)-20 (Scheme 7). Removal of
the dithiane followed by reduction of the resultant ketone
(NaBH4) then led to a mixture of alcohols (3.5:1; 97% yield),
favoring the C(17) b-epimer 21. After protection of the
192
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The coupling of (‡)-4 with iodide (ꢀ)-3 also proceeded in
excellent yield to furnish an inconsequential mixture of
sulfone epimers (Scheme 8). In contrast to a system explored
earlier, which possessed a fully elaborated AB spiroketal,[16]
Julia methylenation[10] in this case proceeded smoothly to
furnish (‡)-23 (90%). Removal of the silicon protecting
groups with TBAF, followed in turn by reprotection of both
the primary and secondary hydroxyl groups as TBS ethers and
hydrolysis of the acetonide with concomitant spiroketaliza-
tion then furnished spiroketal (‡)-24. Although not surprising
in the retrospect that epimerization of the CD spiroketal had
occurred under the acidic conditions, this fact went undetect-
ed until the spectroscopic properties of the fully elaborated
23-epi-spongistatin was compared with those of an authentic
sample of (‡)-spongistatin 2 (1). Undaunted, we reasoned
that it should be possible to correct the CD spiroketal
stereochemistry by epimerization (for example, with HClO4/
Ca2‡) at a late stage in the synthesis.
1) HCl, MeOH (85%)
OTBS OTBS S
OMe
O
S
2) Hg(ClO4)2, CaCO3,
CH3CN:H2O (9:1)
BnO
O
23
28
18
(-)-15
BnO
BnO
1) PivCl, Et3N,
CH2Cl2 (87%)
2) TBSCl, imid.,
H
O
H
O
DMF (99%)
OMe
OMe
3) DIBAL, CH2Cl2,
-78 °C (100%)
4) PPh3, I2, imid.,
PhH (90%)
HO
HO
+
O
H
O
H
(2 : 1)
(-)-17
(+)-16
OH
OH
HClO4, CH2Cl2:CH3CN
(10:1), (87%, 2 steps)
BnO
H
H
25
H
O
O
OMe
BnO
To confirm rigorously the stereochemistry of (‡)-24, we
prepared (ꢀ)-27, an advanced intermediate employed in the
total synthesis of (‡)-spongistatin 1 (1) by Kishi and co-work-
ers.[7] Toward this end, oxidative removal of the DMB ether
(DDQ), followed by bis-acylation of the triol gave diacetate
(ꢀ)-25. Removal of the C(25) TBS group (HF/CH3CN) set
H
CaII
O
TBSO
O
H
O
O
18
(-)-12
MeO
I
tridentate complex
of Ca2+ and 17
BnO
25
27
27
OH
OBn
24
H
H
H
H
H
BnO
27
O
O
H
OH
HO
HO
OH
BnO
H
O
O
19
MeO
H
O
22
21
22
O
MeO
MeO
(+)-16
(-)-17
HO
AE'
O
OMe
AE
AA'
S
S
TBSO
tBuLi, THF, HMPA,
-78 °C; then (-)-12, THF
Scheme 5. Synthesis of the CD spiroketal iodide (ꢀ)12 (see ref. [20] for
O
H
abbreviations).
-78 °C to 0 °C (95%)
S
O
O
S
(+)-11
1) O3, CH2Cl2:
MeOH (1:1),
DMP
O
O
then PPh3,
S
S
-78 °C to RT
(+)-20
BnO
H
DMP
2) 1,3-propane
dithiol, BF3•OEt2,
CH2Cl2 (97%,
two steps)
HO
TBSO
OH
OH
O
OMe
OH
(+)-18
(+)-19
TBSO
O
1) Hg(ClO4)2, CaCO3,
MeOH:H2O (9:1),
0 °C (71%)
1) PhCH2OCH2Cl,
iPr2NEt, CH2Cl2 (94%)
H
3,4-DMPCHO,
PPTS, 4Å MS,
CH2Cl2 (88%)
S
S
17
2) DIBAL, PhMe:
tBuOMe (3:1),
2) NaBH4, MeOH:
CH2Cl2 (2:1) (97%)
-78 °C to 0 °C (78%)
O
O
O
O
21
(+)-11
DMP
DMP
C(17) α/β = 1 : 3.5
Scheme 6. Synthesis of dithiane (‡)-11 (see ref. [20] for abbreviations).
BnO
H
BnO
H
secondary hydroxyl group (BOMCl), the mixture was sepa-
rated, and although both epimers were potentially useful, only
the major b-epimer was carried forward. Regioselective
reduction (DIBAL) of the acetal led to (‡)-22. The weakly
coordinating co-solvent, tert-butylmethyl ether, proved essen-
tial to minimize reduction of the spiroketal. Conversion of
(‡)-22 into the iodide and subsequent introduction of the
phenyl sulfone completed the assembly of the CD fragment
(‡)-4.
O
O
1) I2, PPh3, imid.,
PhH:MeCN
OMe
OMe
(4:1) (96%)
TBSO
TBSO
O
H
O
H
2) PhSO2Na,
DMF, 50 °C
(77%)
OBOM
OBOM
(+)-22
(+)-4
OH
PhO2S
ODMB
ODMB
Scheme 7. Synthesis of sulfone (‡)-4 (see ref. [20] for abbreviations).
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treatment with HF/CH3CN then afforded the
desired spiroketal (ꢀ)-27 along with the epimer
(‡)-26 (ca. 1:1.3) in 92% yield. Importantly,
epimerization of (‡)-26 (HClO4/Ca2‡) proceed-
ed consistently with high mass recovery (ca. 80 ±
84%), although the ratio of spiroketals was
variable (2.6 ± 4.5:1). In this fashion (ꢀ)-27
could be obtained in approximately 75% yield.
Treatment of (‡)-26 with only HClO4 estab-
lished the critical requirement for a calcium ion;
both (‡)-26 and (ꢀ)-27 (6.1:1, 81%) were
obtained. The synthesis of (ꢀ)-27, which was
identical to that prepared by Kishi and co-
workers, constitutes both a formal total syn-
thesis of (‡)-spongistatin 1 (1) and confirms our
stereochemical assignments.[7, 17]
Continuing with the synthesis of the advanced
ABCD fragment (‡)-29 (Scheme 9) for spon-
gistatin 2 (2; see accompanying communica-
tion), protection of the tertiary hydroxyl group
as a TES ether[18] was followed by selective
removal of the primary TBS group in the
presence of both the secondary TBS and tertiary
TES ethers. A two-step oxidation (Dess ± Mar-
tin periodinane[19] and buffered NaClO2), fol-
lowed by silylation of the resulting carboxylic
acid led to (ꢀ)-28 (67%, five steps). Removal of
the benzyl and benzyloxymethyl groups in the
presence of the exo-methylene group (transfer
hydrogenolysis) then proceeded smoothly. Fi-
nally, Dess ± Martin oxidation furnished alde-
hyde (‡)-29. In the following communication we
describe the synthesis of the C(29 ± 51) subunit
(5), its coupling with (‡)-29, and final elabo-
ration to afford (‡)-spongistatin 2 (2).
BnO
1) nBuLi,
THF, HMPA,
BnO
H
O
H
O
-78 °C; then
iodide (-)-3,
THF, -78 °C
to RT (92%)
OMe
OMe
D
23
TBSO
OBPS
TBSO
C
O
H
O
H
2) nBuLi,
THF, HMPA,
-78 °C; then
OBOM
OBOM
(+)-4
CH2I2, iPrMgCl,
THF, HMPA,
-78 °C (90%)
O
MeO
H
O
O
B
PhO2S
ODMB
ODMB
(+)-23
OTBS
BnO
H
O
OMe
D
23
TBSO
C
1) DDQ, CH2Cl2,
H2O, 0 °C (95%)
1) TBAF, DMF, THF,
70 °C, (88%)
O
H
TBSO
OBOM
2) Ac2O, DMAP,
pyr, THF (96%)
2) TBSCl, imid.,
DMF, (91%)
3) 3.5% HClO4 (aq),
CH2Cl2 (82%)
O
H
O
A
HO
B
ODMB
(+)-24
OH
BnO
H
O
1) 1-methyl-1,4-
cyclohexadiene,
OMe
Pd(OH)2/C, CaCO3,
EtOH (100%)
25
TBSO
2) PMBMCl, iPr2NEt,
CH2Cl2 (87%)
O
H
TBSO
AcO
OBOM
3) Dess-Martin
periodinane, pyr,
CH2Cl2 (88%)
4) HF, CH3CN,
0 °C (92%)
17
O
H
O
OAc
(-)-25
OH
PMBMO
PMBMO
H
O
H
Received: October 12, 2000 [Z15947]
O
OMe
O
OMe
O
23
HO
H
HO
H
O
H
O
H
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HO
HO
+
O
O
O
O
AcO
AcO
OAc
OAc
(-)-27
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(+)-26
OH
OH
HClO4, Ca(ClO4)2, CH2Cl2:CH3CN
(10:1) (84%)
(+)-26 : (-)-27 (1:2.6-4.5)
Scheme 8. C(23) Epimerization attempts: Completion of
spongistatin 1 (1) (see ref. [20] for abbreviations).
a
formal synthesis of (‡)-
the stage for spiroketal correction. Unfortunately, all attempts
to effect epimerization at C(23) employing our previously
optimized conditions failed. We reasoned that the bulky C(17)
BOM group precluded epimerization. Accordingly, the BOM
and benzyl groups were removed (transfer hydrogenolysis).
Selective protection of the primary hydroxyl group with
PMBMCl, oxidation of the secondary hydroxyl group, and
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194
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Angew. Chem. Int. Ed. 2001, 40, No. 1

COMMUNICATIONS
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BnO
H
O
1) TESOTf, 2,6-lutidine,
THF (93%)
2) HF•pyr, pyr, THF (80%)
3) Dess-Martin periodinane,
pyr, CH2Cl2 (97%)
OMe
25
TBSO
O
H
TBSO
AcO
4) NaClO2, 2-methyl-
2-butene, NaH2PO4,
tBuOH:H2O (95%)
5) TIPSCl, Et3N, THF
(98%)
OBOM
17
O
H
O
OAc
(-)-25
OH
BnO
O
H
H
O
H
O
D
OMe
OMe
O
25
C
O
TBSO
O
TBSO
O
H
O
H
TIPSO
AcO
TIPSO
AcO
OBOM
O
O
H
O
H
O
A
B
OAc
OAc
(+)-29
(-)-28
OTES
OTES
1) 1-methyl-1,4-cyclohexadiene,
Pd(OH)2/C, CaCO3, EtOH (90%)
à Â
Trotter, B. Cote, Tetrahedron Lett. 1998, 39, 1709.
[9] For a review of spiroketals, see F. Perron, K. F. Albizati,
Chem. Rev. 1989, 89, 1617.
2) Dess-Martin periodinane,
pyr, CH2Cl2 (93%)
[10] C. De Lima, M. Julia, J.-N. Verpeaux, Synlett 1992, 133.
[11] A. B. Smith III, A. M. Boldi, J. Am. Chem. Soc. 1997, 119,
6925.
Scheme 9. Synthesis of (‡)-29 (see ref. [20] for abbreviations).
Bull. 1993, 41, 989; d) M. Kobayashi, S. Aoki, K. Gato, I. Kitagawa,
Chem. Pharm. Bull. 1996, 44, 2142.
[12] Satisfactory spectroscopic data (
1H and 13C NMR, LR-MS, HR-MS,
[a], and IR) were obtained for all new compounds.
[13] E. Fujita, Y. Nagao, K. Kaneko, Chem. Pharm. Bull. 1978, 26, 3743.
[14] Nuclear Overhauser experiments (NOE) studies were carried out
after selective BPS protection of the primary hydroxyl group (BPSCl,
imid., DMF) in both 16 and 17 (80 and 83%, respectively). For the
spiroketal derived from 17, diagnostic NOE observations were seen
between H(19a) to H(24e), H(19a) to OH (C25), H(21a) to H(24e),
and H(22e) to H(24a). For the spiroketal derived from 16, a diagnostic
NOE was seen between H(22e) and H(27a), which demonstrates that
an axial ± equatorial rather than an axial ± axial configuration exists.
[15] Treatment of a purified mixture of (‡)-16 and (ꢀ)-17 (2:1) with
HClO4 afforded a 1:1 mixture of spiroketals. Addition of Ca(ClO4)2 to
the reaction provided a 9:1 mixture favoring the desired spiroketal
(ꢀ)-17.
[5] Since Pettit and co-workers were the first to isolate members of the
spongipyran family, we have adopted the spongistatin nomenclature.
[6] a) D. A. Evans, P. J. Coleman, L. C. Dias, Angew. Chem. 1997, 109,
2951; Angew. Chem. Int. Ed. Engl. 1997, 36, 2738; b) D. A. Evans,
à Â
B. W. Trotter, B. Cote, P. J. Coleman, Angew. Chem. 1997, 109, 2954;
Angew. Chem. Int. Ed. Engl. 1997, 36, 2741; c) D. A. Evans, B. W.
à Â
Trotter, B. Cote, P. J. Coleman, L. C. Dias, A. N. Tyler, Angew. Chem.
1997, 109, 2957; Angew. Chem. Int. Ed. Engl. 1997, 36, 2744; d) D. A.
à Â
Evans, B. W. Trotter, P. J. Coleman, B. Cote, L. C. Dias, H. A.
Rajapakse, A. N. Tyler, Tetrahedron 1999, 55, 8671.
[7] a) J. Guo, K. J. Duffy, K. L. Stevens, P. I. Dalko, R. M. Roth, M. M.
Hayward, Y. Kishi, Angew. Chem. 1998, 110, 198; Angew. Chem. Int.
Ed. 1998, 37, 187; b) M. M. Hayward, R. M. Roth, K. J. Duffy, P. I.
Dalko, K. L. Stevens, J. Guo, Y. Kishi, Angew. Chem. 1998, 110, 202;
Angew. Chem. Int. Ed. 1998, 37, 192.
[16] See ref. [8b]. With the fully formed spiroketal in place, only modest
yields for the installation of the exo-methylene group could be
obtained.
[8] For
a discussion of synthetic studies towards the spongistatins/
[17] We thank Prof. Y. Kishi for providing the 1H NMR spectra of
advanced intermediates 26 and 27.
altohyrtins/cinachyrolide and their biology, see a) J. Pietruszka,
Angew. Chem. 1998, 110, 2773; Angew. Chem. Int. Ed. 1998, 37,
2629; for synthetic approaches to the AB spiroketal, see b) A. B.
Smith III, Q. Lin, K. Nakayama, A. M. Boldi, C. S. Brook, M. D.
McBriar, W. H. Moser, M. Sobukawa, L. Zhuang, Tetrahedron Lett.
1997, 38, 8675; c) M. M. Claffey, C. H. Heathcock, J. Org. Chem. 1996,
61, 7646; d) M. M. Claffey, C. J. Hayes, C. H. Heathcock, J. Org.
Chem. 1999, 64, 8267; e) I. Paterson, R. M. Oballa, R. D. Norcross,
Tetrahedron Lett. 1996, 37, 8581; f) I. Paterson, R. M. Oballa,
Tetrahedron Lett. 1997, 38, 8241; g) I. Paterson, D. J. Wallace, R. M.
Oballa, Tetrahedron Lett. 1998, 39, 8545; h) L. A. Paquette, D. Zuev,
Tetrahedron Lett. 1997, 38, 5115; i) D. Zuev, L. A. Paquette, Org. Lett.
2000, 2, 679; j) M. T. Crimmins, D. G. Washburn, Tetrahedron Lett.
1998, 39, 7487; k) T. Terauchi, M. Nakata, Tetrahedron Lett. 1998, 39,
3795; l) A. G. M. Barrett, D. C. Braddock, P. D. de Koning, A. J. P.
White, D. J. Williams, J. Org. Chem. 2000, 65, 375; for synthetic
approaches to the CD spiroketal, see m) A. B. Smith III, L. Zhuang,
C. S. Brook, Q. Lin, W. H. Moser, R. E. L. Trout, A. M. Boldi,
Tetrahedron Lett. 1997, 38, 8671; n) C. J. Hayes, C. H. Heathcock, J.
[18] Initially the corresponding compound with TBS protection on the
tertiary hydroxyl group was carried through to the end of the
synthesis. However, the TBS group could not be removed.
[19] D. B. Dess, J. C. Martin, J. Am. Chem. Soc. 1991, 113, 7277.
[20] Abbreviations used: PG ˆ protecting group; Ac ˆ acetyl; TES ˆ tri-
ethylsilyl; TBS ˆ tert-butyldimethylsilyl; TMS ˆ trimethylsilyl; BPS ˆ
tert-butylbiphenylsilyl; TIPS ˆ triisopropylsilyl; DMB ˆ 3,4-dime-
thoxybenzyl; Bnˆ benzyl; BOM ˆ benzyloxymethyl; Tsˆ tosyl ˆ tol-
uene-4-sulfonyl; DMP ˆ dimethoxyphenyl; Piv ˆ pivaloyl ˆ 2,2-dime-
thylpropanoyl; PPTS ˆ pyridinium p-toluenesulfonate; DIBAL ˆ
diisobutylaluminum hydride; imid. ˆ imidazole; MS ˆ molecular
sieves; DDQˆ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone; DMAP ˆ
4-dimethylaminopyridine; pyr ˆ pyridine; HMPA ˆ hexamethylphos-
phoramide; DMF ˆ dimethylformamide; PMBM ˆ para-methoxy-
benzyloxymethyl; TBAF ˆ tetrabutylammonium fluoride; THF ˆ
tetrahydrofuran.
Angew. Chem. Int. Ed. 2001, 40, No. 1
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