Spongipyran synthetic studies. Total synthesis of (+)-spongistatin 2

Article abstract of DOI:10.1016/j.tet.2009.04.001

Evolution of a convergent synthetic strategy to access (+)-spongistatin 2 (2), a potent cytotoxic marine macrolide, is described. Highlights of the synthesis include: development of a multicomponent dithiane-mediated linchpin union tactic, devised and implemented specifically for construction of the spongistatin AB and CD spiro ring systems; application of a Ca^II ion controlled acid promoted equilibration to set the thermodynamically less stable axial-equatorial stereogenicity in the CD spiroketal; use of sulfone addition/Julia methylenation sequences to unite the AB and CD fragments and introduce the C(44)-C(51) side chain; and fragment union and final elaboration to (+)-spongistatin 2 (2) exploiting Wittig olefination to unite the advanced ABCD and EF fragments, followed by regioselective Yamaguchi macrolactonization and global deprotection. Correction of the CD spiro ring stereogenicity was subsequently achieved via acid equilibration in the presence of Ca^II ion to furnish (+)-spongistatin 2 (2). The synthesis proceeded with a longest linear sequence of 41 steps.

Full text of DOI:10.1016/j.tet.2009.04.001

Tetrahedron 65 (2009) 6470–6488
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Spongipyran synthetic studies. Total synthesis of (þ)-spongistatin 2
*
Amos B. Smith, III , Qiyan Lin, Victoria A. Doughty, Linghang Zhuang, Mark D. McBriar,
Jeffrey K. Kerns, Armen M. Boldi, Noriaki Murase, William H. Moser, Christopher S. Brook,
Clay S. Bennett, Kiyoshi Nakayama, Masao Sobukawa, Robert E. Lee Trout
Department of Chemistry, Monell Chemical Senses Center and Laboratory for Research on the Structure of Matter, University of Pennsylvania,
Philadelphia, PA 19104, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 6 March 2009
Received in revised form 30 March 2009
Accepted 1 April 2009
Available online 9 April 2009
Evolution of a convergent synthetic strategy to access (þ)-spongistatin 2 (2), a potent cytotoxic marine
macrolide, is described. Highlights of the synthesis include: development of a multicomponent dithiane-
mediated linchpin union tactic, devised and implemented specifically for construction of the spongis-
tatin AB and CD spiro ring systems; application of a CaII ion controlled acid promoted equilibration to set
the thermodynamically less stable axial–equatorial stereogenicity in the CD spiroketal; use of sulfone
addition/Julia methylenation sequences to unite the AB and CD fragments and introduce the C(44)–C(51)
side chain; and fragment union and final elaboration to (þ)-spongistatin 2 (2) exploiting Wittig olefi-
nation to unite the advanced ABCD and EF fragments, followed by regioselective Yamaguchi macro-
lactonization and global deprotection. Correction of the CD spiro ring stereogenicity was subsequently
achieved via acid equilibration in the presence of CaII ion to furnish (þ)-spongistatin 2 (2). The synthesis
proceeded with a longest linear sequence of 41 steps.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
OH
In 1993 the research groups of Pettit,1 Kitagawa,2 and Fusetani3
independently reported the isolation of a new class of cytotoxic
macrolides, termed, respectively, the spongistatins, altohyrtins, and
cinachyrolides.4 These macrolides, as well as a series of related
congeners subsequently reported by the Pettit5 and Kitagawa6
laboratories, possess architecturally novel spongipyran skeletons
endowed with 24 stereocenters, two [6.6] spiroketals, and a bis-
tetrahydropyranylmethane moiety embedded in a 42-membered
macrolactone, in conjunction with a delicate unsaturated side chain
(Fig. 1). While the initial reports were in agreement with respect to
the complete carbon skeleton, there were differences in the
assigned relative configurations at various sites. In 1994, the Kita-
gawa group, exploiting 2-D NMR experiments, in conjunction with
an elegant series of Mosher ester analyses and circular dichroism
measurements assigned the complete relative and absolute ste-
reochemistries of the spongipyrans,7 that were subsequently veri-
E
29
HO
H
28
H
O
O
OH
H
O
D
F
H
OMe
O
41
O
HO
H
C
O
H
1
OH
O
H
O
48
OH
AcO
12
A
O
13
R
B
OAc
51
OH
Spongistatin 1(1) R = Cl
Spongistatin 2(2) R = H
Figure 1. Structures of (þ)-spongistatin 1 and (þ)-spongistatin 2.
fied by the total syntheses of (þ)-spongistatin
2 (2) and
(þ)-spongistatin 1 (1), respectively, by the Evans and Kishi
groups.8,9
In addition to the daunting molecular architecture, the spon-
gistatins possess remarkable biological profiles. In the NCI panel of
60 human cancer cell line assays, mean GI50 values in the 0.04 to
1.1 nM range were observed.5,10 These results prompted Pettit to
state that the spongistatin family of natural products ‘appear to be
* Corresponding author. Tel.: þ1 215 898 4860; fax: þ1 215 898 5129.
E-mail address: smithab@sas.upenn.edu (A.B. Smith III).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.04.001

A.B. Smith III et al. / Tetrahedron 65 (2009) 6470–6488
6471
the most potent cancer cell inhibitory antimiotic substances dis-
OH
covered to date.’11 Even more promising than their in vitro activity
were the early in vivo results. Spongistatin 1 [(þ)-1] exhibited cu-
rative responses against human melanoma and ovarian xenografts
E
29
HO
H
OH
2H8
O
O
H
without observed toxicity at 25 m
g/kg.12 Although the spongistatins
O
clearly held considerable promise as chemotherapeutic leads, the
extreme low natural abundance [e.g., 400 kg of wet sponge yielded
only 13.8 mg of (þ)-spongistatin 1 (1)],1 represented a major ob-
stacle for biomedical development.
H
D
F
OMe
O
41
O
1
HO
H
C
O
H18
OH
O
H
O
17
48
OH
AcO
Not surprisingly the remarkable biological activities, low natural
abundances, and daunting molecular architectures, quickly en-
gendered considerable interest in the synthetic community. To date
seven total syntheses of the spongistatins have appeared,8,9,13–17
along with numerous reports describing the synthesis of various
advanced fragments.18 While major contributions in both our un-
derstanding of the chemistry of the spongistatins in particular, and
polyketide synthesis in general, have emanated from these efforts,
collectively these reports did little to augment access to this im-
portant class of natural products. As a result, both the Heathcock
group16 and our laboratory13c,d initiated programs aimed at the
development of synthetic routes capable of producing gram
quantities of (þ)-spongistatin 2 (2) and (þ)-spongistatin 1 (1). In
this full account, we provide a detailed description of our synthesis
of (þ)-spongistatin 2 (2).13a,b This synthetic venture provided the
foundation that has recently led to a scalable, gram-scale synthesis
of (þ)-spongistatin 1 (1). For a detailed account of the latter see the
following paper.19
A
O
R
B
OAc
51
OH
(+)-Spongistatin 1 (1) R = Cl
(+)-Spongistatin 2 (2) R = H
OTBS
P+Ph3I-
E
TBSO
H
29
O
OMe H
TESO 28
O
H
F
H
O
41 OBn
OMe
D
OTBS
5
TBSO
C
O
H
48
OTBS
4
18 I
OPMB
BPSO
1
2. Results and discussion
2.1. Synthetic analysis
S
H
S
17
O
H
O
B
A
TESO
Initial inspection of (þ)-spongistatin 2 (2) revealed a number of
synthetic challenges. First, a modular approach would be required
by which the molecule would ultimately be assembled under mild
conditions without compromising the anticipated sensitive triene
side chain. We therefore envisioned that completion of the fully
functionalized side chain would be required after construction of
the macrocyclic core. With this scenario in mind, dissection of the
molecule into three fragments of roughly equal complexity led to
the AB dithiane 3, the CD iodide 4, and the EF Wittig salt 5 lacking
the diene moiety (Scheme 1).20 In the forward direction, union of
dithiane 3 with iodide 4 would establish the ABCD ‘eastern pe-
rimeter’. Conversion of the C(28) TES ether to an aldehyde and
Wittig union with EF phosphonium salt 5 would then establish the
C(1)–C(48) carboskeleton, which would be transformed to
(þ)-spongistatin 2 (2) via macrolactonization, final side chain
elaboration and global deprotection.
OTES
OTBS
3
Scheme 1.
BPSO
1
1
BPSO
TESO
S
S
H
O
H
O
S
17
17
S
H
H
12
12
+
I
O
B
O
B
A
A
13
TESO
PhSO2 OTES
OTES
3
7
6
OTBS
OTBS
AB Fragment
CO2-i-Pr
HO HO
S
OTBS OH
S
O
1
OTs
B
17
BPSO
BPSO
CO2-i-Pr
12
12
O
13
8
+
2.2. Synthesis of the C(1) to C(17) AB dithiane (3)
CHO
OTBS
11
S
S
Further disconnection of the C(1)–C(17) subtarget at C(12)–
C(13) revealed the AB spiroketal 6 and sulfone 7 (Scheme 2). From
the synthetic perspective, the AB spiroketal possesses two
anomeric interactions,21 and as such was anticipated to be the
thermodynamically more stable of the two possible spiro epimers
at C(7), a conclusion supported by MM2 calculations.22 Spiroketal 6
was thus expected to be readily available from a linear precursor
such as dithiane 8, that in turn was envisioned to arise from the two
epoxides 9 and 10, employing the multicomponent dithiane-me-
diated linchpin coupling tactic involving a 1,4-Brook rearrange-
ment developed specifically for the spongistatin synthetic
venture.23 For the carbon backbone of sulfone 7, a Roush cro-
tylboration24 of known aldehyde (ꢀ)-1125 with (E)-crotylborane 12
appeared viable.24
OTES
O
O
O
O
TBS
9
10
Scheme 2.
We began with construction of epoxide 9. Addition of (þ)-allyl(-
diisopinocampheyl)borane26 to known aldehyde 1327 furnished
homoallylic alcohol (þ)-14 (Scheme 3), which was converted to the
corresponding tert-butyl carbonate and subjected to Bartlett car-
bonate cyclization28 employing IBr, an improvement introduced
during our synthesis of the (þ)-calyculins.29 Iodocarbonate (þ)-15
was obtained as a mixture of diastereomers (27:1). Basic meth-
anolysis of the carbonate functionality with concomitant epoxide

6472
A.B. Smith III et al. / Tetrahedron 65 (2009) 6470–6488
1a) (+)-Ipc2BOMe
MgBr
O
1
OH
S S
R
Tol., –78°C
BPSO
Et2O
R Si
3
Li
CHO
BPSO
(+)-14 (84% ee)
b) NaOH, H2O2
(98%)
13
LiO
R SiO
3
S S
S S
O
HMPA
SiR or DMPU
1) K2CO3, MeOH
(73%, 2 steps)
1) Boc2O, NaHMDS,
THF, 0 °C (99%)
2) IBr, Tol., –80 °C
(dr = 27:1)
1
1
Li
R
R
3
O
O
2) TESCl, TMEDA,
DMF (98%)
Solvent-controlled
Brook Rearrangement
I
BPSO
BPSO
(+)-15
O
2
R SiO
3
OH
S S
R
OTES
O
1
2
Et2O
R
R
(–)-9
OH OH OH
Scheme 3.
1
2
R
R
*
*
*
formation, followed by treatment with TESCl in the presence of
TMEDA furnished epoxide (ꢀ)-9.
Access to all possible diastereomers
of the 1,3,5-polyol system
Construction of epoxide 10 began with Wittig olefination of the
isopropylidene derivative of L
-glyceraldehyde (16),30 followed by
Figure 2. Mechanism of the solvent controlled multicomponent linchpin coupling.
DIBAL-H reduction to furnish allylic alcohol (ꢀ)-17 (Scheme 4).
Sharpless asymmetric epoxidation31 next provided epoxide (þ)-18
in high yield as a mixture (3:1) of diastereomers. Although the
selectivity was less than optimal due to a mismatched reagent–
substrate pair,32 the reaction proved reproducible on large scale (cf.
50 g), and thus remained the method of choice for installation of
the epoxide. Lewis acid-mediated hydride opening of the epoxide
in alcohol (þ)-18,33 followed by ring closure of the resultant diol via
a modification of the Fraser-Reid cyclization protocol34 furnished
epoxide (þ)-10.
provide polyol (ꢀ)-19 in good yield (Scheme 5). Acid-mediated
removal of both the acetonide and the TES protecting group, fol-
lowed by treatment of the resultant polyol with p-toluenesulfonyl
chloride in the presence of DMAP then provided triol (þ)-8.
Pleasingly, the Stork mercury perchlorate-mediated hydrolysis of
the dithiane, our method of choice to remove dithianes, next pro-
ceeded with concomitant spiroketalization to afford the AB spiro-
ketal as a mixture (26:1) of isomers, favoring the desired spiroketal
(ꢀ)-21 as determined by NOESY NMR studies (Fig. 3). On large scale,
the minor axial–equatorial congener (ꢀ)-20 could be isolated and
converted to the desired spiroketal (ꢀ)-21 via acid equilibration for
purposes of material advancement. Protection of the C(5) hydroxyl
as the TES ether and subsequent iodide formation completed the
construction of (ꢀ)-6.
Ph3P
1)
TBHP, (–)-DET,
CO2Et
CH2Cl2 (92%)
O
i
Ti(O- -Pr)4
O
O
H
CH2Cl2, –20 °C
(77%, dr = 3:1)
O
2) DIBAL-H, CH2Cl2
(96%)
HO
O
16
(–)-17
TsO
1) LiBH4, Ti(O-i-Pr)4,
Tol., –25 °C (96%)
nOe
R = OTBS
H
O
O
H
O
O
R
O
O
AcO
O
2)Tosylimidazole, NaH,
THF, 0 °C (93%)
HO
O
H
8
BPSO
H
12
(+)-18
(+)-10
nOe
(−)-21
Scheme 4.
Figure 3. Relevant NOESY data for (ꢀ)-21.
With both epoxide coupling partners in hand, the stage was set
for the linchpin union. The solvent controlled multicomponent
dithiane-mediated linchpin union of diverse epoxides, developed
for the spongistatin project, was based on earlier precedent from
the Tietze laboratory.35 Specifically, reaction of a 2-lithio-2-silyl-
1,3-dithiane (Fig. 2) with an epoxide to generate the lithium alk-
oxide intermediate, followed upon complete reaction, by treatment
of the intermediate with a highly polar aprotic solvent (such as
HMPA, DMPU, THF, and/or DMF) results in a solvent promoted 1,4-
Brook rearrangement36 to generate the corresponding silyl ether
and a new 2-lithio-1,3-dithiane, which can be reacted with a sec-
ond different epoxide.37 By proper choice of the epoxide linchpins,
followed by careful removal of the dithiane and directed reduction
of the carbonyl group, all possible diastereomers of the 1,3,5-polyol
system encountered in a wide variety of polyketide natural prod-
ucts can be accessed. Extension of this multicomponent union
tactic, now recognized as Type I Anion Relay Chemistry (ARC),
comprises a technique that holds considerable potential for di-
versity oriented synthesis.38
Having developed an effective route to (ꢀ)-6, we turned to the
synthesis of sulfone 7. Known aldehyde (ꢀ)-1125 was subjected to
Roush crotylboration24 to provide homoallylic alcohol (þ)-22
(Scheme 6). Removal of the TBS protecting group, followed by
treatment with 3,4-dimethoxybenzaldehyde led to benzylidene
acetal (þ)-23, which upon DIBAL-H-mediated reduction, and con-
version of the resultant primary alcohol to the sulfone furnished
(ꢀ)-24. Oxidative cleavage of the alkene then produced aldehyde
(þ)-25, which was readily converted to dithiane (þ)-7.
Completion of the C(1) to C(17) AB dithiane was envisioned to
occur via application of the elegant Julia sulfone addition/methy-
lenation39 protocol. A model study of this tactic had already been
established in our laboratory.40 Thus, treatment of AB iodide (ꢀ)-6
with the lithiated anion of sulfone (þ)-7, followed in turn by
in situ treatment with CH2I2/i-PrMgCl and a second equivalent of
n-butyllithium furnished the complete C(1)–C(17) backbone of
dithiane (þ)-3 (Scheme 7). The yield of the methylenation reaction
however was low, due presumably to the crowded environment of
the AB ring system. Despite numerous attempts to optimize this
The Type I ARC union between 2-(tert-butyldimethylsilyl)-1,3-
dithiane, epoxide (þ)-10 and epoxide (ꢀ)-9 proceeded smoothly to

A.B. Smith III et al. / Tetrahedron 65 (2009) 6470–6488
6473
Scheme 5.
reaction, we were unable to improve the yield. Given our interest in
verifying the viability of the subsequent union of dithiane (þ)-3
with CD iodide (ꢀ)-4, we decided to press forward and address the
Julia methylenation issue later.
spongistatin macrocyclic ring, the axial–axial to axial–equatorial
equilibrium might be perturbed in favor of the latter. This suppo-
sition proved correct (vida infra). Alternatively, it might be possible
both to construct an advanced CD spiroketal fragment under ki-
netically controlled conditions and to maintain the integrity of the
C(23) stereogenicity throughout the synthesis (vida infra).
We approached construction of the CD spiroketal 4 in a fashion
similar to the AB spiroketal. Two routes were envisioned. First,
a stepwise approach, involved alkylation of epoxide 27 with
dithiane 28 (Scheme 8), the latter prepared by thioacetalization of
the corresponding aldehyde. Alternatively, application of our
multicomponent dithiane-mediated linchpin protocol involving 2-
TBS-1,3-dithiane, epoxide 27, and epoxide 29 held promise of
providing a viable route to the desired target. Although we
2.3. Construction of the C(18)–C(28) CD spiroketal 4:
a serendipitous discovery
From the outset, we recognized that construction of any CD
spiroketal fragment (cf. 4) possessing the thermodynamically less
stable axial–equatorial configuration at C(23) would represent
a challenge given that a single anomeric effect is present. Molecular
mechanics calculations indeed confirmed our concern (4.5 kJ/mol
energy difference with MM2 forcefield). Nonetheless, we reasoned
that when the spiroketal structural motif is embedded in the
1) n-BuLi, THF-HMPA, –78 °C, 1h
CO2i-Pr
BPSO
H
O
CO2i-Pr
B
O
H
1) TBAF, THF (94%)
O
A
O
B
CHO
(–)-11
I
TESO
2) 3,4-(MeO)2PhCHO,
TsOH, CH2Cl2 (94%)
Tol., –78 °C
(86%)
TBSO
TBSO
OH
(+)-22
S
(–)-6
OTBS
S
(76%)
1) OsO4, Me3NO,
2) n-BuLi, THF, CH2I2, i-PrMgCl
Acetone, H2O
1) DIBAL-H(94%)
PhSO
OTES
(23%)
(94%)
2
2) Pb(OAc)4,
2) TsCl, Et3N( 98%)
3) PhSO2Na, NaI,
DMF( 87%)
(+)-7
PhO S
ODMB
(–)-24
2
O
O
Benzene (92%)
(+)-23
DMP
BPSO
TESO
S
S
H
O
S
17
S
1) 1,3-Propanedithiol,
TsOH, CH2Cl2 (70%)
H
CHO
A
O
B
13
2) TESOTf, iPr2NEt,
CH2Cl2 (80%)
OTES
(+)-3
PhO S
OTES
(+)-7
2
PhO S
2
ODMB
(+)-25
OTBS
Scheme 6.
Scheme 7.

6474
A.B. Smith III et al. / Tetrahedron 65 (2009) 6470–6488
intended to examine both routes, the latter approach appeared
more desirable, considering the higher convergency (Scheme 8).
1) NaH, 4-bromobenzyl
bromide, THF
1) Vinyllithium,
CuCN, THF
–78 °C
2) HCl, MeOH
O
O
(90%, 2 steps)
p-BrBnO
(–)-34
TESO
28
O
HO
2) n-BuLi, –78 °C
Boc2O
3a) (MeO)3CMe, PPTS
b) TMSCl, CH2Cl2
c) K2CO3, MeOH (86%)
H
O
(+)-33
OMe
23
TBSO
O
O
H
K2CO3,
MeOH
(54%, 4 steps)
IBr, Tol.
OBoc
O
O
18
– 80
°C
I
p-BrBnO
4
p-BrBnO
I
TBSO
BnO
O
(–)-36
(–)-35
28
27
TBSO
O
OH
1) TBSCl, TMEDA (76%)
O
OR OR
OMe O
S
S
BnO
p-BrBnO
S
23
S
2) t-BuLi, THF, –78 °C; MeOH (92%)
O
BnO
23
(–)-37
28
18
(–)-27
26
TBS
Scheme 10.
R = TBS
O
O
furnish epoxide (ꢀ)-37. Protection of the free alcohol as a TBS ether,
followed by tert-butyllithium-mediated removal of the bromide
completed construction of epoxide (ꢀ)-27.
O
18
29
For dithiane 28, we began with known allylic alcohol (ꢀ)-38,42
prepared in four steps from (S)-(ꢀ)-malic acid. Conversion to the
methyl ether and ozonolysis led to aldehyde (ꢀ)-39 (Scheme 11).
Thioketalization under Lewis acidic conditions then proceeded
with concomitant removal of the acetonide to produce a diol that
was converted to isopropylidene acetal (ꢀ)-28.
Multicomponent Coupling
TBSO
BnO
S
OMe O
S
O
O
23
28
18
27
28
Stepwise Approach
Scheme 8.
1) NaH, MeI, 15-crown-5
(98%)
OH
O
Nonetheless, with the stepwise approach initially in mind,
construction of CD spiroketal 4 began with the synthesis of epoxide
27, as this epoxide could be employed in both the stepwise and
multicomponent tactics. Reaction of (R)-(ꢀ)-benzyl glycidol ether
with the cuprate derived from vinyllithium, followed by protection
of the derived alcohol with BOC anhydride furnished carbonate
(ꢀ)-30 (Scheme 9). Unfortunately, all attempts to effect the
IBr-mediated iodocarbonate cyclization employing a variety of
conditions, led to a mixture of (ꢀ)-31 and tetrahydrofurans 32a/b,
favoring the tetrahydrofurans by 2–4:1.
OMe O
(–)-39
O
O
;
2) O3,CH2Cl2, –78 °C
O
PPh3 (96%)
(–)-38
1) 1,3-propanedithiol
BF3•OEt2 (89%)
OMe
S
O
S
O
2) Me2C(OMe)2, PPTS
(90%)
23
18
(–)-28
Scheme 11.
1) Vinyllithium, CuCN,
THF, –78°C
2) n-BuLi, –78°C
Boc2O
(93%, 2 steps)
OBoc
With both coupling partners in hand, lithiation of (ꢀ)-28 with t-
BuLi in THF/HMPA, followed by treatment with epoxide (ꢀ)-27
produced the desired C(18)–C(28) adduct, albeit in disappointing
yield, presumably due to incomplete lithiation (Scheme 12). Sily-
lation of the resulting free alcohol completed construction of the
spiroketalization precursor (ꢀ)-26. However, despite extensive ef-
fort to optimize the alkylation, we were unable to improve the yield
above 20%. We therefore turned to the multicomponent route.
O
BnO
BnO
(R)-(–) benzyl
(–)-30
glycidol ether
O
OBoc
IBr, Tol.
–80°C
O
O
BnO
I
I
O
1a) t-BuLi, THF-HMPA (9:1),
(–)-31
32a/b
–78 °C, 30 min.
31%
62%
b)
OTBS
O
Scheme 9.
BnO
(–)-27
MeO
O
S S
(20%)
We reasoned that furan formation could be suppressed by de-
creasing the electron density on the benzyl ether oxygen. Examina-
tion of a number of electron deficient benzyl ethers eventually led to
a 4-bromobenzyl group. Protection of (þ)-33 (Scheme 10) as the 4-
bromobenzyl ether, followed by acid-mediated hydrolysis of the
acetonide and epoxide formation via the Sharpless protocol41 thus
led to glycidol ether (ꢀ)-34, which upon treatment with vinyllithium
in the presence of copper cyanide; protection of the resultant alcohol
as a tert-butyl carbonate then furnished (ꢀ)-35. Pleasingly, the IBr-
mediated cyclization now proceeded smoothly to give exclusively
iodocarbonate (ꢀ)-36, which was subjected to basic methanolysis to
O
2) TBSOTf, 2,6-lut.
CH2Cl2 (95%)
(–)-28
RO RO
OMe
O
S S
O
BnO
28
18
(–)-26
R = TBS
Scheme 12.

A.B. Smith III et al. / Tetrahedron 65 (2009) 6470–6488
6475
The required epoxide 29 was prepared by treatment of known
-glyceraldehyde
spiroketalization to produce a mixture (2:1) of the undesired axial–
axial spiroketal (þ)-42 and the desired axial–equatorial product
(ꢀ)-43. Surprisingly however, exposure of the unpurified reaction
mixture to perchloric acid in CH2Cl2/MeCN (10:1) resulted in the
formation of only the desired spiroketal (ꢀ)-43. The configuration
at the C(23) stereocenter was established by silylation of the pri-
mary hydroxyl, followed by a NOESY NMR study, which proved
consistent with the enhancements observed by both the Kitagawa2
and Fusetani3 groups in (þ)-spongistatin 1 (Fig. 4).
alcohol (þ)-40 (available in three steps from
D
acetonide)43 with tosyl chloride, followed by hydride-mediated
epoxide opening44 to furnish a readily separable mixture (3:1) of 2-
and 3-hydroxyl substituted tosylates (Scheme 13). Basic meth-
anolysis of the major isomer led to epoxide (ꢀ)-29 in good yield.
1) TsCl, py., CH2Cl2
0 °C (88%)
O
O
O
O
O
HO
2) DIBAL-H, CH2Cl2,– 78 °C
(84%, 3:1 mixture of
regioisomers)
O
(+)-40
(–)-29
OH
H
3) K2CO3, MeOH (71%)
H
O
H
BnO
H
OBPS
Scheme 13.
O
H
OMe
Alkylation of 2-lithio-2-(tert-butyldimethylsilyl)-1,3-dithiane
with epoxide (ꢀ)-27, followed by HMPA-mediated 1,4-Brook rear-
rangement and unionwithepoxide(ꢀ)-29led tothe desired coupling
product, which upon O-methylation furnished (ꢀ)-26 in 72% yield for
thetwosteps(Scheme 14). Importantly, themulticomponentstrategy
not only eliminated two steps from the earlier sequence, but also
proved far more efficient than the stepwise process.
(–)-44
Figure 4. Relevant NOESY Data for (ꢀ)-44.
To understand the equilibration, we attempted to isomerize both
pure (þ)-42 and the purified mixture of (þ)-42 and (ꢀ)-43 to the
desired spiroketal, employing conditions identical to those used with
the unpurified mixture. Only a 1:1 mixture (at best) of the isomeric
spiroketals resulted. After considerable analysis, we surmised that
Ca(ClO4)2 generated during the dithiane hydrolysis might play a sig-
nificant role in the equilibration process. Indeed, treatment of the
purified mixture (2:1) of (þ)-42 and (ꢀ)-43 with perchloric acid in
the presence of 1 equiv of Ca(ClO4)2 led to a 9:1 mixture of isomers
favoring the desired spiroketal (ꢀ)-43 (Scheme 16). Although this
ratio was moderately lower than that obtained when the crude
mixture was employed, clearly CaII was playing a significant role in
the equilibration process. Subsequent MM2 calculations22 suggested
that the CaII ion could coordinate to the C(18) and C(25) hydroxyls, as
well as to the C-ring pyran, thus driving the equilibrium to favor
(ꢀ)-43 via chelation of the desired C(23) congener. Careful work-up
to prevent isomerization furnished (ꢀ)-43 (Fig. 5).
t
1a) -BuLi, Et2O
–78 to –45 °C,1 h
b)
TBSO
O
BnO
(–)-27 (1 eq.)
RO RO
OMe
O
S
S
S
S
O
–78 to –25 °C, 1 h
BnO
c)
O
28
18
O
TBS
O
(–)-26, R = TBS
(–)-29 (2 eq.)
Et2O, HMPA (9:1)
–78 °C to rt.
,
2) NaH, MeI, 15-crown-5
THF( 72%, 2 steps)
Scheme 14.
H
Ca
Having established a viable route to the C(18)–C(28) carbon
skeleton, we turned to completion of iodide 4 (Scheme 1). Treat-
ment of (ꢀ)-26 with methanolic HCl resulted in removal of both the
acetonide and silyl ethers to furnish tetraol (þ)-41 in good yield
(Scheme 15). The Stork mercury (II) perchlorate-promoted removal
of the dithiane proceeded, as anticipated, with concomitant
O
BnO
O
II
O
H
O
MeO
Figure 5. Model for how CaII templates the formation of the desired spiroketal.
Scheme 15.

6476
A.B. Smith III et al. / Tetrahedron 65 (2009) 6470–6488
BnO
OBPS
BnO
1) t-BuLi, THF/HMPA (9:1),
O
O
O
S
H
O
OMe
OMe
–78 °C , 30 min
17
25
S
23
O
H
HO
HO
+
O
2) TESO
TESO
28
OTES
18
(–)-43
OH
H
O
OH
(+)-42
OTBS
(+)-3
2:1
OMe
23
TBSO
O
H
HClO4, Ca(ClO4)2
CH2Cl2, CH3CN (10:1)
I
(–)-4
TESO
H
O
BnO
BnO
OMe
O
O
O
O
OBPS
TBSO
OMe
OMe
O
H
HO
HO
+
H
O
S
S
H
OH
OH
O
(+)-42
(–)-43
TESO
1:9
Scheme 16.
OTES
OTBS
47
With the discovery of a preparatively viable route to the
desired spiroketal in hand, we turned to completion of the
synthesis of CD iodide 4. Acylation of the primary hydroxyl in
(ꢀ)-43 with pivaloyl chloride, followed by protection of the
C(25) hydroxyl as a TBS ether and conversion of the C(28)
benzyl ether to a TES ether furnished (ꢀ)-45 (Scheme 17). Re-
moval of the pivaloate was then followed by treatment with
tosyl chloride to provide (ꢀ)-46. Displacement of the tosylate
with sodium iodide proceeded with concomitant removal of the
TES group, which was reinstalled with TESOTf to complete
coupling partner (ꢀ)-4.
Scheme 18.
(ꢀ)-4 precludes fragment union. Our inability to effect this trans-
formation thus forced us to revisit our synthetic plan.
2.5. A second-generation synthetic strategy for (D)-
spongistatin 2
In redesigning our initial approach to a more appropriate ABCD
aldehyde, we reasoned that reducing the steric bulk of the C(l)–
C(12) fragment, by postponing elaboration of the A ring until after
the Julia union/exomethylene tactic might permit an effective
union. Toward this end, a C(13)–C(17) fragment bearing a phenyl
sulfone would be incorporated in the CD fragment prior to union,
now with a simplified AB fragment (Scheme 19). A second signifi-
cant change from our first-generation strategy would involve the
EF side chain. Successful studies during the construction of a series
of simplified spongistatin analogues40 possessing the C(44)–C(51)
2.4. Attempted fragment union: a significant frustration
Having developed routes to the AB and CD spiroketals, we
turned to the dithiane-mediated ABCD fragment union. Un-
fortunately, multiple attempts to unite (þ)-3 with (ꢀ)-4 met with
failure (Scheme 18). At low temperature (ꢀ78 ꢁC) no reaction was
observed; on the other hand, carefully raising the temperature led
only to decomposition. Presumably steric hinderance in iodide
BnO
TESO
28
1) PivCl, py. (70%)
O
O
O
O
2) TBSCl, Imid.,
DMF (89%)
1) DIBAL-H,
OMe
OMe
THF, –50 °C
BSO
T
HO
3) Pd/C, H2,
CaCO3,
2) TsCl, Et3N
0 °C
(87%, 2 steps)
18
EtOH/EtOAc (1:4)
4) TESCl, Imid., DMF
(92%, 2 steps)
OH
OPiv
(–)-45
(–)-43
TESO
TESO
28
1) NaI, Imid.,
O
O
OMe
OMe
Acetone, 50 °C
TBSO
TBSO
2) TESOTf, 2,6-Lut.
THF, 0°C
O
O
18 I
(76%, 2 steps)
OTs
(–)-46
(–)-4
Scheme 17.

A.B. Smith III et al. / Tetrahedron 65 (2009) 6470–6488
6477
OH
2.6. Synthesis of iodide 48
E
The revised C(l)–C(12) fragment 48 (Scheme 20) was envisioned
to arise from the same dithiane (þ)-8 employed in our previous
approach (Scheme 5). Thus, acetonide formation, followed by HgII
mediated dithiane removal with concomitant cyclization, furnished
the B ring methyl ketal as a mixture of anomers, that could be
29
HO
H
OH
H
2H8
O
O
O
D
H
F
OMe
O
41
43
O
HO
H
C
O
H
1
OH
readily converted to the desired
a
-anomer (ꢀ)-51 upon treatment
O
H
O
with perchloric acid in methanol. Displacement of the tosylate with
LiI completed construction of the iodide (ꢀ)-48. The four-step se-
quence proved highly efficient proceeding in 92% yield.
48
OH
AcO
12
A
O
13
B
OAc
51
2.7. Construction of C(13)–C(28) spiroketal 49
OH
(+)-Spongistatin 2 (2)
Disconnection of the C(17)–C(18)
s-bond in 49 revealed two
new fragments, the CD iodide 52 and dithiane 53 (Scheme 21). As in
the case of fragment (ꢀ)-48, both were envisioned to arise from
previously available advanced intermediates.
OTBS
+
-
P Ph I
3
E
29
TBSO
H
O
BnO
28
H
O
OMe H
BnO
28
H
O
O
H
F
D
OMe
41 OBn
D
OMe
TBSO
C
OTBS
OTBS
1
O
H
TBSO
C
50
O
H
18
S
48
51
S
S
S
17
13
13
PhO2S
ODMB
BnO
BPSO
PhO S
ODMB
2
3
49
O
MeO
H
12
49
O
B
I
O
H
O
48
S
S
OTBS
Scheme 19.
D
OMe
C
TBSO
52
O
H
O
O
side chain convinced us that a fully elaborated side chain would not
be a major liability in the proposed Wittig union required to unite
the ABCD and EF fragments. Thus, we dissected (þ)-spongistatin 2
(2) into three new fragments: the AB iodide 48, the CD sulfone 49,
and the fully elaborated EF Wittig salt 50.
53
DMP
I
Scheme 21.
For the new CD spiroketal 52 we began with diol (ꢀ)-43
(Scheme 22). Conversion of the primary hydroxyl to the corre-
sponding pivalate, followed by TBS ether formation provided the
fully protected CD spiroketal (ꢀ)-54. Removal of the pivalate was
then followed by conversion of the alcohol to the corresponding
iodide to furnish (ꢀ)-52. By retaining the C(28) hydroxyl protection
(e.g., benzyl ether), we were able to limit the number of protecting
HO HO
S
OTBS OH
S
OTs
BPSO
(+)-8
BnO
BnO
BPSO
1) PivCl, Et3N,
CH2Cl2 (87%)
H
O
H
O
1) 2,2-Dimethoxypropane
PPTS, CH2Cl2 (95%)
2) Hg(ClO4)2, 2,6-Lut.,
MeOH, THF (99%)
3) HClO4, MeOH, CH2Cl2
(99%)
,
O
MeO
H
O
OMe
OMe
D
D
OTs
2) TBSCl, Imid.,
DMF (99%)
O
TBSO
HO
(–)-43
C
C
O
H
O
H
(–)-51
OTBS
(–)-54
OPiv
OH
1
BPSO
LiI,
BnO
1) DIBAL-H, CH2Cl2
–70 °C (99%)
2) PPh3, I2, Imid.,
Benzene(90%)
H
O
CaCO3
O
MeO
H
O
B
12
I
OMe
D
CH3CN
70 °C
O
TBSO
(–)-52
C
O
H
(99%)
OTBS
(–)-48
Scheme 20.
I
Scheme 22.

6478
A.B. Smith III et al. / Tetrahedron 65 (2009) 6470–6488
1) O3, MeOH, CH2Cl2;
Ph3P
S
S
3,4-Dimethoxy-
benzaldehyde
S
S
2) HS(CH2)3SH,
BF3 OEt2,
PPTS, CH2Cl2
(88%)
TBSO
OH
O
O
OH OH
(+)-55
CH2Cl2
(+)-22
(97%, 2 steps)
(+)-53
DMP
Scheme 23.
group manipulations, thereby reducing the length of the synthetic
sequence by three steps.
generated in moderate yield via a modified Mitsunobu protocol.45
Displacement of the derived iodide with sodium benzenesulfonate
completed construction of CD sulfone (ꢀ)-49.
Construction of the requisite C(13)–C(17) dithiane (53) began
with homoallylic alcohol (þ)-22, an intermediate available from our
first-generation approach (Scheme 23). Ozonolysis, followed by
thioketalization with concomitant removal of the TBS group afforded
diol (þ)-55; benzylidene acetal formation next led to (þ)-53.
In contrast to our first-generation route, union of the CDspiroketal
iodide (ꢀ)-52 employing the lithium salt of dithiane (þ)-53 pro-
ceeded smoothly to produce (þ)-56 in excellent yield (Scheme 24).
Presumably, the increase in efficiency is due to the predicted de-
creased steric bulk in dithiane (þ)-53, relative to the fully elaborated
C(l)–C(17) ABdithiane (þ)-3. Reduction of the benzylidineacetalwith
DIBAL-H however, proved more problematic. In non-coordinating
solvents such as methylene chloride, low yields were obtained due to
competing reduction of the spiroketal. Polar coordinating solvents,
such as THF on the other hand completely inhibited the reaction.
Eventually we discovered that the use of a weakly coordinating sol-
vent (cf. t-BuOMe) with toluene proved optimal, furnishing primary
alcohol (ꢀ)-57 in 70% yield. Conversion of the latter to iodide (ꢀ)-58
was also not trivial. After considerable effort, iodide (ꢀ)-58 was
2.8. Fragment union and elaboration of ABCD aldehyde 65
With ample quantities of AB iodide (ꢀ)-48 and CD sulfone
(ꢀ)-49 in hand, we turned our focus to the revised union strategy.
Pleasingly, lithiation of (ꢀ)-49 followed by reaction with iodide
(ꢀ)-48 proceeded in excellent yield to furnish the complete C(1)–
C(28) carbon skeleton (Scheme 25). Our prediction that decreasing
the steric bulk of the AB system would increase the yield of the Julia
methylenation39 proved correct; a 93% yield of exo olefin (ꢀ)-59
was obtained. We next replaced the C(1) BPS protecting group with
a TBS group [(a) KH and 18-crown-6 in THF/water; (b) TBSCl, im-
idazole],46 anticipating that the basic conditions required for BPS
removal would not be compatible with more advanced in-
termediates. Oxidative removal of the 3,4-dimethoxybenzyl (DMB)
group in (ꢀ)-60, followed by acetonide hydrolysis with concomi-
tant spiroketal formation under acidic conditions then furnished
the AB spiroketal (ꢀ)-61 after acetylation of the C(15) hydroxyl. The
acidic conditions however led to epimerization of the CD spiroketal.
While in hindsight this result is not surprising, the epimerization
event went undetected until the spectroscopic properties of the
synthetic material were found not to be identical to those
(þ)-spongistatin 2 (vida infra).
BnO
O
S
OMe
a) t-BuLi,THF-HMPA,
S
–50°C 30min.
TBSO
O
Continuing with the C(23)-epimeric spiroketal (ꢀ)-61, we next
found, much to our dismay, that the C(17) dithiane was resistant to
mercury-mediated hydrolysis (Scheme 26). A number of other
conditions, including oxidative, alkylative, and/or heavy metal
based protocols, also proved ineffective. We were thus forced to
conclude that the C(17) dithiane would have to be removed at an
earlier stage.
b)
BnO
S
O
O
S
O
O
OMe
DMP
TBSO
O
O
(+)-53
(–)-52
I
(+)-56
–78 °C to 0 °C, 3h (95%)
DMP
Reasoning that removal of the dithiane might prove more facile
prior to union of the AB and CD fragments, we attempted the hy-
drolysis after coupling of the CD iodide (ꢀ)-52 with the C(13)–C(17)
dithiane (þ)-53. Pleasingly, treatment of the previously prepared
dithiane (þ)-56 (Scheme 24) with mercury perchlorate furnished
the corresponding ketone, which was converted to an inseparable
mixture (3.5:1) of alcohols 63a/b upon reduction with NaBH4
(Scheme 27). Generation of the corresponding BOM ethers next
BnO
O
PPh3, DEAD, MeI,
Benzene, 80 °C
OMe
DIBAL-H
TBSO
O
Tol. / t-BuOMe
(60%)
(4:1)
(86% BORSM)
S
S
(70%)
permitted facile separation. The major
b-isomer, possessing the
C(17) stereogenicity required for the spongistatins was in turn
subjected to DIBAL-H-mediated acetal reduction to furnish primary
alcohol (þ)-64,47,48 which was converted to the corresponding CD
sulfone (þ)-65 as previously described.
HO
ODMB
(–)-57
BnO
O
BnO
28
As expected, both the union of CD sulfone (þ)-65 with AB iodide
(ꢀ)-48 and the subsequent Julia methylenation proceeded efficiently
to furnish alkene (þ)-66 in 83% yield for the two steps (Scheme 28).
The primary BPS ether was next exchanged for a TBS ether to provide
(þ)-67, which in turn was converted to the AB spiroketal (ꢀ)-68 via
DDQ-mediated removal of the 3,4-dimethoxybenzyl (DMB) moiety,
acetonide hydrolysis, and acetate formation, as previously described
for (ꢀ)-61. Epimerization of the C(23) stereocenter, which occurred
during the acetonide hydrolysis under acidic conditions, again went
undetected. Selective removal of the primary TBS ether was now
followed by a two-step oxidation to provide acid (ꢀ)-69, which was
O
OMe
D
OMe
C
TBSO
O
TBSO
PhSO2Na
DMF, 75 °C
(92%)
O
S
S
S
S
13
I
ODMB
(–)-58
PhO S
ODMB
2
(–)-49
Scheme 24.

A.B. Smith III et al. / Tetrahedron 65 (2009) 6470–6488
6479
1a) n-BuLi, THF-HMPA
–78 °C 15 min, –45 °C 15 min
b)
BPSO
BnO
O
O
BnO
OMe
O
MeO
H
TBSO
O
O
O
Hg(ClO4)2, CaCO3,
CH3CN-H2O (10:1), 0 °C
OMe
I
O
TBSO
AcO
S
TBSO
S
OTBS
(93%)
O
H
(–)-48
–78 °C to 7 °C
S
O
S
OAc
2a) n-BuLi, THF-HMPA, –78 °C
b) i-PrMgCl, CH2I2,THF-HMPA
OTBS
(–)-61
–78 °C
(93%)
PhO S
ODMB
2
(–)-49
BnO
BnO
28
1) KH, H2O,
O
O
18-crown-6,THF
OMe
OMe
(98%)
TBSO
TBSO
1
O
O
2) TBSCl, Imid.,
DMF (98%)
TBSO
AcO
BPSO
S
O
S
O
H
O
MeO
H
13
O
O
O
OAc
ODMB
OTBS
OTBS
(–)-59
62
Scheme 26.
BnO
O
OMe
1) DDQ, CH2Cl2-H2O
(89%)
TBSO
O
2) 3.5% HClO4 (aq),
Ca(ClO4)2, CH2Cl2
TBSO
S
S
BnO
BnO
O
MeO
H
(70%)
O
15
3) Ac2O, DMAP, Py,
O
O
O
O
CH2Cl2 (93%)
1) Hg(ClO4)2, CaCO3,
MeOH-H2O (9:1)
0 °C (71%)
ODMB
OMe
OH
OMe
TBSO
TBSO
OTBS
(–)-60
O
2) NaBH4,
MeOH-CH2Cl2 (2:1)
(97%, a/b 1:3.5)
S
S
BnO
O
O
O
C(23)-Epimer
OMe
O
O
O
D
DMP
DMP
63a,b
TBSO
C
(+)-56
TBSO
AcO
BnO
S
S
O
H
O
A
O
B
OMe
TBSO
OAc
1) PhCH2OCH2Cl,
O
iPr2NEt, CH2Cl2 (94%)
OTBS
(–)-61
OBOM
2) DIBAL-H, Tol.,
t-BuOMe (3:1)
–78 to 0 °C (78%)
Scheme 25.
HO
ODMB
protected as the corresponding triisopropylsilyl (TIPS) ester. Removal
of the benzyl protecting groups and Dess–Martin oxidation49 of the
resulting diol then furnished ABCD aldehyde (þ)-70. From the per-
spective of material advancement, synthesis of the ABCD aldehyde
required a longest linear sequence of 34 steps and proceeded with an
overall yield of 1.5%.
(+)-64
BnO
28
1) I2, PPh3, Imid.,
Benzene-MeCN (4:1)
(96%)
O
D
OMe
C
TBSO
2.9. Construction of the C(29)–C(51) EF Wittig salt
O
2) PhSO2Na, DMF
50 °C (75%)
OBOM
Taking advantage of our success with the Julia union/methyle-
nation protocol to construct the ABCD fragment, we envisioned
elaboration of the EF Wittig salt 50 via addition of sulfone 71 to iodide
72, followed by a similar Julia methylenation (Scheme 29).39 Iodide
72 in turnwould arise via chelation-controlled addition of dithiane 74
to aldehyde 73, followed by E-ring formation and further elaboration.
13
ODMB
PhO S
2
(+)-65
Scheme 27.

6480
A.B. Smith III et al. / Tetrahedron 65 (2009) 6470–6488
BnO
BnO
BnO
1a) n-BuLi,
THF-HMPA
O
O
O
1) DDQ,
CH2Cl2/H2O
1) KH, H2O, 18-crown-6,
(9:1)
b) (–)-48 (92%)
O
O
OMe
OMe
OMe
THF (97%)
TBSO
TBSO
OBPS
TBSO
OTBS
O
2) HClO4 (aq.),
Ca(ClO4)2
2) i-PrMgCl,
CH2I2,
THF-HMPA
(9:1) (90%)
2) TBSCl, Imid., DMF
(98%)
OBOM
OBOM
OBOM
CH2Cl2
3) Ac2O, Py,
DMAP, THF
(74%, 3 steps)
O
O
MeO
H
O
O
MeO
H
O
O
PhO S
ODMB
ODMB
ODMB
2
(+)-65
OTBS
(+)-66
(+)-67
OTBS
BnO
BnO
O
O
O
O
O
O
OMe
OMe
OMe
TBSO
TBSO
TBSO
O
O
OTBS
1) HF•Py,
1) TIPSCl, Et3N,
THF (99%)
O
Py-THF (88%)
TIPSO
AcO
HO
OBOM
O
OBOM
OAc
2) Dess-Martin [O]
CH2Cl2 (98%)
3) NaClO2,
NaH2PO4,
t-BuOH-H2O
(96%)
2)
Pd(OH)2/C,
CaCO3,
EtOH (90%)
O
H
O
H
O
H
O
O
O
AcO
AcO
3) Dess-Martin [O]
CH2Cl2 (95%)
OAc
OAc
(–)-69
(–)-68
OTBS
OTBS
OTBS
(+)-70
ABCD
Aldehyde
Scheme 28.
Construction of aldehyde 73 began with Brown crotylboration50
of known silyloxy aldehyde 7551 (Scheme 30) to yield homoallylic
alcohol (þ)-76 (91%, 89% ee).48 Protection as the benzyl ether,
followed by removal of the primary BPS group provided allylic
alcohol (þ)-77, which was subjected to Sharpless asymmetric ep-
oxidation31 to produce the corresponding epoxy alcohol (dr
>15:1). Regioselective opening of the epoxide with benzoic acid in
the presence of titanium isopropoxide next furnished diol (þ)-78
as the only isolable product. Mercuric acetate-mediated cycliza-
tion, in conjunction with an aqueous sodium bromide work-up,
followed by acetylation and oxidation52 of the intermediate or-
ganomercurial with O2 led to the E-ring pyran, as a mixture of
diastereomers 79a/b (ca. 8:1) favoring the trans-pyran isomer.
Methanolysis followed by acetonide formation then provided al-
cohol 80a/b. Pleasingly the major isomer (þ)-80a proved crystal-
line, thereby permitting structure verification via X-ray analysis.
Clearly epimerization at C(39) would be required. Initially we
OTBS
P+Ph3I-
E
TBSO
cis
n
-2-Butene, -BuLi,
i)
29
O
OH
O
t
KO Bu,[(+)-Ipc]2BOMe
H
O
OMe H
BPSO
BPSO
H
Et2O, THF, -78 °C
ii) NaOH, H2O2
(91%)
H
F
(+)-76
44
75
OBn
OTBS
45
OBn
OTBS
1) KHMDS,
1) (-)-DET, Ti(O-i-Pr)4,
BnBr, THF
TBHP, CH2Cl2 (84%)
HO
50
2) TBAF, THF
(94%, 2 steps)
i
2) PhCO2H, Ti(O- -Pr)4,
THF (80%)
(+)-77
OTBS
O
OH
H
O
OBPS
SO2Ph
HO
OBn
1) Hg(OAc)2, THF,
sat. NaBr
TBSO
HO
+
H
O
OMe H
H
2) Ac2O, Et3N,
DMAP, CH2Cl2
3) NaBH4, O2,
DMF, CH2Cl2
(86%, 3 steps)
OBz
(+)-78
OBn
OTBS
OPMB
(-)-71
H
I
AcO
OBz
79a/b
OBn
OTBS
72
trans cis
:
(
=8 : 1)
OH
CHO
H
O
H
O
39
1) NaOMe, MeOH
CHO
Swern [O]
H
O
H
O
H
O
2) Acetone,Benzene,
PPTS, reflux
(90%, 2 steps)
S
O
O
OBn
S
i
-Pr2NEt
OBn
OBn
H
O
+
(92%)
O
O
OBn
O
73
74
(+)-80a
Scheme 30.
(+)-73
Scheme 29.

A.B. Smith III et al. / Tetrahedron 65 (2009) 6470–6488
6481
employed Swern oxidation53 followed by epimerization of the re-
sultant aldehyde with DBU to produce (þ)-73, albeit in modest
yield. Best results were obtained upon modification of the oxida-
tion protocol to include use of Hu¨nigs base (i-Pr2NEt). Under these
conditions, near quantitative epimerization occurred.
Construction of the requisite dithiane 74 began with the mon-
obenzyl derivative of 1,5-propanediol (Scheme 31); PCC oxidation
to provide aldehyde 81 followed by Brown crotylboration50 fur-
nished homoallylic alcohol (þ)-82 in excellent yield and enantio-
selectivity (90%, 96% ee), the latter determined by Mosher ester
analysis.48 Protection of (þ)-82 as the tert-butyl carbonate, fol-
lowed by IBr-mediated cyclization,29 and exposure to K2CO3 in
methanol then yielded epoxy carbonate (þ)-84, which upon
treatment with 2-lithio-1,3-dithiane led to epoxide ring opening
with concomitant removal of the methyl carbonate to furnish the
corresponding diol. Acetonide formation was next accomplished
without difficulty to give dithiane (ꢀ)-74.
were modest. Reasoning that the low efficiency might be due to
enolization of (þ)-73, we examined the use of CeCl3.55 While CeCl3
improved the yield to 72%, a drop in selectivity to 3.7:1 occurred, still
favoring the desired diastereomer. Since the increase in yield might
be due to the formation of an organocerium species, we explored
pregeneration of the cerium dithiane, followed by addition to alde-
hyde (þ)-73 precomplexed with ZnCl2. These conditions proved re-
warding; a reproducible 65% yield of a single diastereomer (þ)-85
was obtained (Scheme 33).56 To the best of our knowledge, this ob-
servation represents the first example of employing a cerium
dithiane species in the context of complex molecule synthesis.57
O
O
OBn
n
-BuLi, –78 °C,
–50 °C, 40 min.
1.5 equiv. HMPA
O
S
O
OBn
HO
H
CHO
S
38 S
H
O
H
O
1) NaH, BnBr, TBAI,
S
H
OBn
(+)-73
THF (87%)
HO
OH
OBn
O
O
OBn
OHC
(–)-74
(+)-85
2) PCC, NaOAc,
Celite, CH2Cl2
(83%)
O
O
81
Lewis Acid,
THF, –78 °C
cis
i)
-2-Butene,(–)-Ipc2BOMe,
1) NaHMDS, Boc2O,
THF, 0 oC (98%)
Additive
OH
Selectivity (a/b)
Yield (%)
OBn
n
t
-BuLi, KO Bu, Et2O,
THF, –78 °C
MgBr2
>20:1
20:1
58
40
45
72
2) IBr, Tol., –78 °C
(77%)
ii) NaOH, H2O2 (90%)
ZnCl2
(+)-82
10:1
ZnCl2, –50 °C
CeCl3
3.7:1
O
O
K2CO3,
MeOH, H2O
Scheme 32.
O
OMe OBn
O
O
OBn
O
I
Protection of the newly formed hydroxyl as a TBS ether, followed
(80%, dr = 12:1)
by hydrolysis of the acetonides led to tetraol (þ)-86 (Scheme 34).
Mercuric perchlorate-promoted dithiane removal then proceeded
with concomitant methyl ketal formation to furnish (þ)-87, after
protection of the primary hydroxyl as a pivalate. Exhaustive silyla-
tion employing TBSCl under forcing conditions generated the fully
protected EF ring system (þ)-88. A series of NOESY experiments
(+)-83
(+)-84
OBn
1) 1,3-dithiane, n-BuLi,
1.5% HMPA-THF
–50 °C (80%)
O
O
S
S
2) Me2C(OMe)2, PPTS,
CH2Cl2 (92%)
verified the
a-configuration of the methyl ketal (Fig. 6).
nOe
(–)-74
Scheme 31.
56
H
H
CH3
36
TBSO
H
H
O
With both coupling partners (þ)-73 and (ꢀ)-74 in hand, we
turned to their union. The major challenge here was to effect a che-
lation-controlled process in the presence of HMPA,54 the latter re-
quired for efficient dithiane metalation. A number of Lewis acid
additives were therefore examined. Use of both MgII and ZnII pro-
vided excellent selectivity (10–20:1, Scheme 32), however yields
TBSO
OCH3
H
OBn
nOe
Figure 6. Critical NOESY data for (þ)-88.
O
O
OBn
n
a) -BuLi, CeCl3,
HO
O
S
O
OBn
THF-HMPA, –78 °C
S
38 S
H
O
CHO
b)
H
O
H
O
H
S
OBn
(–)-74
(+)-85
OBn
(+)-73
O
O
O
ZnCl2/THF
(65%)
Scheme 33.

6482
A.B. Smith III et al. / Tetrahedron 65 (2009) 6470–6488
O
O
OBn
OH OH
OBn
1) TBSOTf, 2,6-Lut.,
CH2Cl2 (99%)
HO
H
TBSO
H
S
S
S
S
2) TFA-CH2Cl2-H2O
(1:4:4) (68%)
O
O
H
H
OBn
OBn
O
O
OH OH
OBn
(+)-85
(+)-86
OH
TBSO
O
1) Hg(ClO4)2, 2,6-Lut.,
THF, MeOH, 0 °C
2) PivCl, Py,
(70%, 2 steps)
TBSCl, TMEDA,
HMPA, 80 °C
H
O
OMe H
H
(70%)
OBn
PivO
OH
(+)-87
OTBS
OBn
TBSO
H
O
OMe H
O
H
41
OBn
PivO
OTBS
(+)-88
Scheme 34.
At this juncture, before attempting further elaboration of the
fully functionalized EF side chain, we subjected (þ)-88 to a series of
model studies to test the viability of our proposed endgame. This
proved to be a wise decision, as attempts to remove the C(41)
benzyl protecting group were plagued by both silyl group migration
and low yields. Even more disappointing, all attempts to convert
the resultant C(41) alcohol to the corresponding acetate met with
failure, presumably due to steric crowding at C(41). During the
course of these model studies, the Evans group reported a remark-
able result: macrolactonization of the seco-acid of spongistatin 2
proceeded chemoselectively at the C(41) hydroxyl in the presence
of an unprotected C(42) hydroxyl.8 Based on these results, we de-
cided to alter our protecting group strategy so that the C(41) and
C(42) hydroxyls would possess the same protecting group, thereby
eliminating both the possibility of unwanted silyl migration and
steric hindrance in the macrolactonization event.
Construction of the newly envisioned EF fragment began with
pivalate (þ)-87 (Scheme 35). Selective protection of the axial C(35)
hydroxyl employing TBS triflate, followed by removal of the benzyl
ethers under transfer hydrogenation conditions furnished triol
(þ)-89 in 97% yield. Conversion of the liberated primary hydroxyl to
a BPS ether, followed by exhaustive silylation and removal of the
pivalate protecting group then provided alcohol (þ)-90 in good
yield. Completion of the EF iodide (þ)-91, the side chain precursor,
was then achieved by treatment with triphenylphosphine
and iodine.
the enol ether by varying the metal ion, introduction of additives,
and/or temperature and solvent regimes proved unrewarding.
While this result was clearly disappointing, we were able to recycle
(þ)-93 to alcohol (þ)-90 via a hydroboration–oxidation sequence,
thereby minimizing loss of valuable material.
With sulfone (þ)-92 in hand, elaboration to the EF Wittig salt
proved more difficult than we had initially anticipated. Julia
methylenation39 of (þ)-92 failed to proceed to completion, pro-
ducing olefin (þ)-94 in only modest yield (Scheme 37). In addi-
tion, removal of the C(48) primary PMB protecting group to
generate alcohol (þ)-95 required the use of a buffer (pH 6) to
prevent hydrolysis of the E-ring methyl ketal. Dess–Martin49
oxidation of (þ)-95, followed by Horner–Wadsworth–Emmons
olefination then led to triene (þ)-96, possessing the fully func-
tionalized side chain. Notwithstanding the modest yield of the
olefination (cf. 37%), we decided to continue forward and explore
the viability of the fully functionalized side chain in the key
Wittig union. Toward this end, removal of the BPS and TES pro-
tecting groups, followed by a two-step conversion of the derived
primary alcohol to the iodide furnished (þ)-97. Protection of the
C(41) and C(42) hydroxyls as the TMS ethers and displacement of
the iodide with triphenylphosphine completed the synthesis of
the EF Wittig salt (þ)-98. The longest linear sequence required 32
steps from commercially available starting materials.
2.10. Union followed by macrolactonization
Further development of the side chain now required sulfone
(ꢀ)-71, available in three steps from commercially available (R)-
(þ)-glycidol (Scheme 36). Union of (ꢀ)-71 with iodide (þ)-91
proceeded in moderate yield to furnish (þ)-92 as a mixture of di-
astereomers (ca. 1:1) at C(45), along with a significant amount of
elimination product (þ)-93. Attempts to minimize the formation of
Having achieved syntheses of ABCD aldehyde (þ)-70 and EF
Wittig salt (þ)-98, we proceeded with the endgame. Wittig re-
action between (þ)-98 and (þ)-70 under the titration conditions
initially reported by Kishi9 provided alkene (þ)-99 in 66% yield
(Scheme 38). Clean removal of the TMS ethers and TIPS groups

A.B. Smith III et al. / Tetrahedron 65 (2009) 6470–6488
6483
1) TBSOTf,
OTBS
OH
2,6-Lut.,
CH2Cl2,
–78 °C
(99%)
OBn
OH
35
TBSO
H
TBSO
H
O
O
OMe H
H
OMe
2) HCO2NH4,
Pd/C,
O
O
H
H
42
MeOH
OBn
OH
(+)-89
65 °C
(+)-87
PivO
OH
PivO
OH
(97%)
OTBS
OBPS
1) BPSCl, Imid.,
DMF (99%)
TBSO
H
PPh3, I2, Imid.,
O
OMe H
MeCN-Tol.
2) TESCl, TMEDA,
HMPA, 80 °C
(99%)
70 °C (96%)
O
H
,
3) DIBAL-H, CH2Cl2
–50 °C (90%)
OTES
OH OTES
(+)-90
OTBS
O
OBPS
TBSO
H
H
OMe
O
H
I
OTES
OTES
(+)-91
Scheme 35.
45
a) n-BuLi, –50 °C,
1) NaH, PMBCl,
PhO S
2
O
HMPA-THF (1:4)
n-Bu4NI, THF (82%)
48
OTBS
b) –20 °C
OTBS
2) n-BuLi, PhSO2CH3,
THF (98%)
3) TBSOTf, 2,6-Lut.,
CH2Cl2 (99%)
OH
OPMB
(–)-71
(R)-(+)-Glycidol
OBPS
TBSO
H
O
H
OMe
(+)-91
O
H
I
OTES
OTES
OTBS
OTBS
OBPS
TBSO
H
OBPS
O
H
TBSO
OMe
O
O
H
O
H
OMe
H
+
OTES
OTES
OTES
OTES
PhO S
2
(+)-92
OTBS
OPMB
(+)-93
(50%)
(43%)
OTBS
OTBS
OBPS
OBPS
TBSO
TBSO
H
O
O
a) BH3•THF,
THF, 0 °C
H
O
H
OMe
OMe H
O
H
b) H2O2, NaOH
(72%)
OTES
OTES
(+)-93
OTES
OTES
(+)-90
HO
Scheme 36.

6484
A.B. Smith III et al. / Tetrahedron 65 (2009) 6470–6488
OTBS
stage protecting group strategy for both the ABCD aldehyde and the
EF Wittig salt, employing TES groups at C(9) and C(38).
OTBS
O
TBSO
H
OBPS
TBSO
H
OBPS
a) -BuLi,
THF-HMPA (1:1)
O
4
2.11. A second-generation protecting group strategy
for the ABCD and EF subunits
n
4
H
OMe
H
OMe
O
O
H
H
b) i-PrMgCl, CH2I2
OTES
OTES
OTES
OTES
(46%, 76% BORSM)
Construction of the revised ABCD aldehyde (þ)-105 began
with the Julia union/methylenation product (þ)-66 (vide supra).
Global removal of the silyl groups using TBAF was followed in
turn by protection of both the resultant primary and secondary
hydroxyls as TBS ethers and acid removal of the acetonide; the
latter proceeded with concomitant spiroketalization to provide
ABCD bisspiroketal (þ)-102 (Scheme 39). As in the earlier case,
complete undetected epimerization of the CD spiroketal occurred
during the acetonide removal. Exchange of the C(15) DMB pro-
tecting group for an acetate was then followed by protection of
the C(9) hydroxyl as a TES ether to furnish the fully protected
ABCD fragment (ꢀ)-103. Final elaboration of the Wittig union
precursor, aldehyde (þ)-105 then proceeded in six straightforward
transformations (Scheme 39). The yield for this 12-step sequence
proved excellent (cf. 34%).
PhO2S
(+)-94
(+)-92
48
OTBS
OTBS
OPMB
OPMB
OTBS
TBSO
H
OBPS
O
OMe H
4
1) Dess-Martin [O]
Py, CH2Cl2 (96%)
DDQ, CH2Cl2
O
pH 6 buffer, 0 °C
H
2) n-BuLi,
(51%, 89% BORSM)
OTES
OTES
diethyl allyl phosphate
THF (37%)
Construction of the revised EF-Wittig salt (þ)-112 (Schemes 40
and 41) began with dithiane coupling product (þ)-85 (vide supra).
Removal of the acetonides, followed by dithiane hydrolysis with
concomitant cyclization and subsequent protection of the C(44) pri-
mary hydroxyl with pivaloyl chloride furnished pivalate (þ)-106
(Scheme 40). The C(35) axial hydroxyl was then protected as a TBS
ether and the benzyl groups removed via hydrogenolysis. Com-
pletion of EF iodide (þ)-108 was achieved in four straightforward
steps. The overall yield for the nine-step sequence was again good
(cf. 24%).
A number of additional problems were encountered in our
original synthesis of the EF Wittig side chain (þ)-98 (Scheme 37),
including inefficient Julia methylenation, difficult removal of the
PMB protecting group, and a low yield upon installation of the diene
moiety. We reasoned that coupling of a more elaborate sulfone unit
to EF iodide (þ)-108 (Scheme 41) would circumvent these problems
by reducing the number of transformations on advanced in-
termediates. The new side chain precursor, envisioned to be sulfone
(ꢀ)-109, was constructed beginning with our first-generation sul-
fone (ꢀ)-71, via a five-step sequence. Pleasingly, union of sulfone
(ꢀ)-109 to iodide (þ)-108 proved to be much more efficient, pro-
ducing a mixture (ca. 1:1) of sulfones in 80% yield. The efficiency of
the Julia methylenation, however did not improve despite consid-
erable effort, producing only a 25% yield of diene (þ)-110 (e.g., a 50%
yield based on recovered starting material). Continuing with the
synthesis, reductive removal of the primary benzyl group in (þ)-110
was followed by Dess–Martin oxidation, Wittig methylenation and
removal of the BPS ether to furnish triene (þ)-111 in 46% yield for the
four steps. Completion of the EF Wittig salt (þ)-112 was then ach-
ieved in four straightforward transformations.
OTBS
(+)-95
OH
OTBS
OTBS
TBSO
O
OBPS
TBSO
O
I
4
H
O
OMe H
4
H
O
OMe H
1) KH, 18-crown-6, THF (81%)
2) TsCl, Et3N, DMAP,
CH2Cl2 (80%)
3) LiI, 2,6-Lut., CH3CN,
(99%)
H
H
OTES
OTES
OH
OH
OTBS
(+)-97
OTBS
(+)-96
OTBS
E
TBSO
O
P+Ph3I-
H
O
OMe H
1)TMSOTf, 2,6-Lut.,
CH2Cl2 (98%)
2) PPh3, Li2CO3,
CH3CN-Benzene
(96%)
F
H
41
OTMS
OTMS
(+)-98
EF Wittig Salt
OTBS
Scheme 37.
2.12. Wittig union, macrolactonization, and anticipated
final elaboration of (D)-spongistatin 2 (2)
mediated by KF then led to seco-acid (þ)-100, which underwent
smooth Yamaguchi macrolactonization58 to furnish protected
macrocycle (þ)-101. Macrolactonization of C(41) was based on the
Evans/Kishi8,9 precedent, in conjunction with careful NMR com-
parisons with 23-epi-spongistatin 2 (vide infra). Unfortunately, all
attempts at global deprotection proved challenging as de-
composition of the substrate occurred at a rate faster than the re-
moval of the TBS group to free the axial C(9) hydroxyl. Analysis of
the successful routes to (þ)-spongistatin 2 revealed that the Evans
group employed TES groups at the C(9) and C(38) hydroxyls, while
Kishi and co-workers chose to leave these positions unprotected.
Based upon these observations, we were forced to redesign the late
With the EF Wittig salt (þ)-112 and the ABCD aldehyde (þ)-105 in
hand, we turned our attention toward the Wittig olefination. How-
ever, in contrast to the earlier results, we were unable to obtain better
than a 35% yield of alkene (þ)-113 in the key Wittig step (Scheme 42).
The reason for this dramatic drop in yield, upon what was only a mi-
nor change in the protecting groups remains unclear. Nonetheless,
selective removal of the TIPS and TMS protecting groups provided the
corresponding seco-acid, which then underwent smooth Yamaguchi
macrolactonization58 to provide macrocycle (þ)-114.
As foreshadowed, global deprotection of (þ)-114 did not afford
pure (þ)-spongistatin 2 (2), but instead a mixture (1:3) of (þ)-2

A.B. Smith III et al. / Tetrahedron 65 (2009) 6470–6488
OTBS
6485
OTBS
+
-
P Ph I
3
TBSO
H
TBSO
H
O
H
O
O
H
H
O
H
H
O
OMe
OMe
O
O
+
NaHMDS,
Tol.
(66%)
H
OMe
O
H
KF, MeOH
(95%)
OMe
O
OTMS TBSO
OTMS
OTMS
OTMS
O
H
O
TBSO
CO2TIPS
H
O
H
TIPSO
H
O
OTBS
OTBS
AcO
O
H
O
H
(+)-98
O
OAc
AcO
OAc
OTBS
OTBS
(+)-99
(+)-70
OTBS
OTBS
38
TBSO
TBSO
H
O
O
H
O
H
H
O
OMe
H
H
O
OMe
O
H
OMe
2,4,6-trichloro-
H
OMe
O
HF
CH3CN-H2O
benzoyl chloride
O
TBSO
OH TBSO
O
H
O
H
OH
Et3N, Tol., DMAP
(85%)
CO2H
H
OH
O
H
O
OTBS
AcO
O
H
OTBS
AcO
O
H
O
O
9
OAc
OAc
OTBS
(+)-101
OTBS
(+)-100
OH
E
HO
O
C(23)
H
O
H
OH
H
O
H
F
D
OMe
O
C
O
HO
O
H
OH
O
H
O
OH
A
O
B
H
AcO
OAc
OH
23-Epi-Spongistatin 2
Scheme 38.
and (ꢀ)-C(23)-epi-spongistatin 2 (115). It was only at this point
that we recognized that epimerization of the C(23) stereocenter
had occurred. Indeed, epimerization had taken place on two
fronts; first during the synthesis of the ABCD aldehyde and then
again upon global deprotection, as we had entered deprotection
with a single diastereomer. Fortunately, the loss of configuration
at C(23) could be corrected by taking advantage of our previous
experience with the interconversion of CD spiroketals (þ)-42 and
(ꢀ)-43. Specifically, exposure of (ꢀ)-115 to CaII ion in the presence
of perchloric acid furnished a 3.9–2.3:1 mixture of C(23) spi-
roketal epimers favoring the natural product.59 Synthetic
systems), and HPLC] with an authentic sample kindly provided by
Professor Evans.60
In summary, we achieved the total synthesis of (þ)-spongistatin
2 (2) in 41 steps (longest linear sequence). Similar to other ap-
proaches, our synthesis takes advantage of a late stage Wittig
coupling with EF salt followed by Yamaguchi macrolactonization to
furnish (þ)-spongistatin 2. Unique to our approach was the use of
the multicomponent dithiane coupling protocol mediated by Brook
rearrangement and the Julia union/methylenation protocols for
complex fragment assembly. While the former tactic permitted
reliable and rapid construction of both the AB and CD ring systems
[(ꢀ)-4 and (ꢀ)-52], the latter proved reliable only for the synthesis
of the ABCD aldehyde.
(þ)-spongistatin 2 (2) proved to be identical in all respects
26
[500 MHz 1H NMR, LRMS, HRMS,
[a] , TLC (three solvent
D

6486
A.B. Smith III et al. / Tetrahedron 65 (2009) 6470–6488
BnO
BnO
BnO
O
O
O
O
O
OMe
OMe
OMe
1) TBAF, DMF, THF
70 °C (88%)
1) DDQ, CH2Cl2, H2O
0 °C (95%)
TBSO
TBSO
OTBS
OBPS
OTBS
TBSO
O
2) TBSCl, Imid.,
DMF (91%)
3) 3.5% HClO4 (aq.),
CH2Cl2 (82%)
2) Ac2O, Py, DMAP,
THF (96%)
3) TESOTf, 2,6-Lut.,
THF, 0 °C (93%)
OBOM
OBOM
OBOM
O
MeO
H
O
H
O
H
O
O
O
15
O
AcO
HO
ODMB
OAc
ODMB
9
OTBS
(+)-66
OTES
(–)-103
OH
(+)-102
BnO
O
H
O
O
OMe
D
OMe
O
23
TBSO
O
1) HF·Py., Py.-THF
0 °C (80%)
2) Dess-Martin [O],
Py, CH2Cl2 (97%)
O
C
1) TIPSCl, Et3N,
THF (98%)
TBSO
O
O
HO
TIPSO
OBOM 2) 1-methyl-1,4-cyclohexadiene,
Pd(OH)2/C, CaCO3, EtOH (90%)
3) Dess-Martin [O], Py, CH2Cl2
(93%)
O
H
O
H
O
3) NaClO2, NaH2PO4,
t-BuOH, H2O (95%)
A
O
B
AcO
AcO
OAc
OAc
OTES
(+)-105
OTES
(–)-104
Scheme 39.
Significant drawbacks of the synthetic route entail a lengthy
approach to the ABCD aldehyde (þ)-105, coupled with a low
yielding Julia methylenation required to complete of the EF side
chain. While not sufficiently disabling to prevent completion of
(þ)-spongistatin 2 (2), these drawbacks would certainly prevent
1) DDQ, CH2Cl2,
H2O (90%)
2) Dess-Martin [O]
Py, CH2Cl2 (87%)
3) Ph3P=CHCO2Et,
1a)n-BuLi,
HMPA-THF
PhO S
PhO S
2
2
b) EF (+)-108
benzene, reflux (84%)
(80%)
OTBS
OTBS
OPMB
2a)n-BuLi,
HMPA-THF
b) CH2I2,
i-PrMgCl
(25%)
4) DIBAL-H, CH2Cl2,
–78 to 0 °C
OBn
O
O
OBn
(–)-71
5) NaH, BnBr, TBAI,
THF (99%)
OH
35
(–)-109
OBn
HO
H
S
HO
H
1) CSA, MeOH (93%)
2) Hg(ClO4)2,
S
OTBS
O
OTBS
O
H
OMe
O
H
OBPS
OH
O
F
2,6-Lut., MeOH-TH
(63%)
H
OBn
TESO
H
TESO
H
O
(+)-85
OBn
3) PivCl, Py, DMAP
(76%)
O
O
H
H
OMe
OMe
OH
(+)-106
1) LiDBB, THF (90%)
2) Dess-Martin [O] (91%)
PivO
O
O
H
H
OTES
OTES
OH
3) CH2=PPh3, THF (94%)
4) NaOH, DMPU-H2O (60%)
OH
OTBS
O
(+)-110
(+)-111
OBPS
1) TBSOTf, 2,6-Lut.,
CH2Cl2,– 78 °C (95%)
OTBS
OTBS
HO
H
H
OMe
2) HCO2NH4, Pd/C,
MeOH, reflux (91%)
3) BPSCl, Imid. (82%)
OBn
O
H
OH
OTBS
(+)-107
PivO
OH
E
TESO
H
+
-
O
P Ph I
3
H
OMe
O
OTBS
1) TsCl, Et3N, DMAP (81%)
2) LiI, 2,6-Lut., MeCN( 93%)
H
F
OTMS
OBPS
1) TESOTf, 2,6-Lut.
CH2Cl2,– 78 °C (99%)
3) TMSOTf, 2,6-Lut., THF (100%)
4) PPh3, Li2CO3
MeCN-benzene (4:1) (93%)
OTMS
TESO
H
O
H
2) DIBAL-H, THF
OMe
)
-78 to 0 °C (81%
OTBS
O
3) PPh3, I2, Imid.
Tol. (95%)
H
I
(+)-112
EF Phosphonium Salt
OTES
(+)-108
OTES
Scheme 40.
Scheme 41.

A.B. Smith III et al. / Tetrahedron 65 (2009) 6470–6488
6487
OTBS
O
OTBS
+
-
P Ph I
3
TESO
H
TESO
O
O
H
H
O
H
H
O
H
H
O
OMe
OMe
O
NaHMDS,
Tol.
+
1) KF, MeOH-THF,
(75%)
H
H
OMe
O
OMe
O
OTMS
OTMS
OTMS TBSO
–5 °C
O
H
2) 2,4,6-trichloro-
benzoyl chloride,
i-Pr2NEt, Tol.
O
TBSO
CO TIPS
OTMS
2
(34%)
O
H
H
TIPSO
AcO
then DMAP (81%)
H
O
OTBS
OTBS
AcO
O
H
O
H
O
OAc
(+)-112
OAc
(+)-105
OTES
OTES
(+)-113
OTBS
OH
O
TESO
H
HO
H
O
OMe H
H
OH
H
H
O
O
O
O
H
OMe
H
OMe
O
23
HClO4, Ca(ClO4)2,
HF, CH3CN-H2O,
0 °C (66%)
O
TBSO
O
HO
H
O
H
CH2Cl2-CH3CN
(10:1) (55%)
O
H
OH
OH
O
O
H
O
H
O
OTBS
AcO
O
H
OH
O
O
AcO
OAc
OAc
OTES
OH
(+)-114
(–)-C(23)-epi-Spongistatin 2 ( (–)-115)
OH
E
HO
H
O
OH
H
H
O
O
F
D
H
OMe
O
HO
H
C
O
H
OH
O
H
O
O
OH
A
O
AcO
B
OAc
OH
(+)-Spongistatin 2 (2)
Scheme 42.
large-scale production of the spongistatins. Clearly, significant re-
design would be required to achieve our ultimate goal, a pre-
parative scale synthesis of spongistatin. Evolution of a revised
strategy leading to a gram-scale synthesis of (þ)-spongistatin 1 is
described in the accompanying paper.19
crystal structures, and mass spectra, respectively. This and the next
paper are dedicated to Professor Larry E. Overman, outstanding sci-
entist, scholar and friend, on the occasion of receipt of the 2009
Tetrahedron Prize.
Supplementary data
Acknowledgements
Spectroscopic and analytical data and selected experimental
procedure associated with this article can be found, in the online
version. Crystallographic data (excluding structure factors) for the
structures in this paper have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication nos.
CCDC 725651. Copies of the data can be obtained, free of charge, on
application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK, (fax:
þ44 (0)1223 336033 or e-mail: deposit@ccdc.cam.ac.uk). Supple-
mentary data associated with this article can be found in the online
version, at doi:10.1016/j.tet.2009.04.001.
Financial Supportwasprovidedby theNational Institute ofHealth
(National Cancer Institute) through grant CA-70329, NIH post-
doctoral fellowships to A.M.B., C.S.B., and W.H.M., a Japan Society for
Promotion of Science Fellowship to N.M., and a Royal Society Ful-
bright Fellowship to V.A.D. We also thank Daiichi Pharmaceutical Co.,
Ltd., and the Tanabe Seiyaku Co. Ltd. for financial support. Finally, we
thank Dr. George T. Furst, Dr. Patrick J. Carroll, and Dr. Rakesh Kohli of
the University of Pennsylvania Spectroscopic Service Center for as-
sistance in securing and interpreting high-field NMR spectra, X-ray

6488
A.B. Smith III et al. / Tetrahedron 65 (2009) 6470–6488
22. The 1987 version of the MM2 force field was employed in conjunction with the
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