Spongipyran synthetic studies. Evolution of a scalable total synthesis of (+)-spongistatin 1

Article abstract of DOI:10.1016/j.tet.2009.04.003

Three syntheses of the architecturally complex, cytotoxic marine macrolide (+)-spongistatin 1 (1) are reported. Highlights of the first-generation synthesis include: use of a dithiane multicomponent linchpin coupling tactic for construction of the AB and CD spiroketals, and their union via a highly selective Evans boron-mediated aldol reaction en route to an ABCD aldehyde; introduction of the C(44)-C(51) side chain via a Lewis acid-mediated ring opening of a glucal epoxide with an allylstannane to assemble the EF subunit; and final fragment union via Wittig coupling of the ABCD and EF subunits to form the C(28)-C(29) olefin, followed by regioselective Yamaguchi macrolactonization and global deprotection. The second- and third-generation syntheses, designed with the goal of accessing 1 g of (+)-spongistatin 1 (1), maintain both the first-generation strategy for the ABCD aldehyde and final fragment union, while incorporating two more efficient approaches for construction of the EF Wittig salt. The latter combine the original chelation-controlled dithiane union of the E- and F-ring progenitors with application of a highly efficient cyanohydrin alkylation to append the F-ring side chain, in conjunction with two independent tactics to access the F-ring pyran. The first F-ring synthesis showcases a Petasis-Ferrier union/rearrangement protocol to access tetrahydropyrans, permitting the preparation of 750 mg of the EF Wittig salt, which in turn was converted to 80 mg of (+)-spongistatin 1, while the second F-ring strategy, incorporates an organocatalytic aldol reaction as the key construct, permitting completion of 1.009 g of totally synthetic (+)-spongistatin 1 (1). A brief analysis of the three syntheses alongside our earlier synthesis of (+)-spongistatin 2 is also presented.

Full text of DOI:10.1016/j.tet.2009.04.003

Tetrahedron 65 (2009) 6489–6509
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Spongipyran synthetic studies. Evolution of a scalable total synthesis
of (þ)-spongistatin 1
*
Amos B. Smith, III , Chris Sfouggatakis, Christina A. Risatti, Jeffrey B. Sperry, Wenyu Zhu,
Victoria A. Doughty, Takashi Tomioka, Dimitar B. Gotchev, Clay S. Bennett,
Satoshi Sakamoto, Onur Atasoylu, Shohei Shirakami, David Bauer,
Makoto Takeuchi, Jyunichi Koyanagi, Yasuharu Sakamoto
Department of Chemistry, Monell Chemical Senses Center and Laboratory of 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
Three syntheses of the architecturally complex, cytotoxic marine macrolide (þ)-spongistatin 1 (1) are
reported. Highlights of the first-generation synthesis include: use of a dithiane multicomponent linchpin
coupling tactic for construction of the AB and CD spiroketals, and their union via a highly selective Evans
boron-mediated aldol reaction en route to an ABCD aldehyde; introduction of the C(44)–C(51) side chain
via a Lewis acid-mediated ring opening of a glucal epoxide with an allylstannane to assemble the EF
subunit; and final fragment union via Wittig coupling of the ABCD and EF subunits to form the C(28)–
C(29) olefin, followed by regioselective Yamaguchi macrolactonization and global deprotection. The
second- and third-generation syntheses, designed with the goal of accessing 1 g of (þ)-spongistatin 1 (1),
maintain both the first-generation strategy for the ABCD aldehyde and final fragment union, while in-
corporating two more efficient approaches for construction of the EF Wittig salt. The latter combine the
original chelation-controlled dithiane union of the E- and F-ring progenitors with application of a highly
efficient cyanohydrin alkylation to append the F-ring side chain, in conjunction with two independent
tactics to access the F-ring pyran. The first F-ring synthesis showcases a Petasis–Ferrier union/re-
arrangement protocol to access tetrahydropyrans, permitting the preparation of 750 mg of the EF Wittig
salt, which in turn was converted to 80 mg of (þ)-spongistatin 1, while the second F-ring strategy, in-
corporates an organocatalytic aldol reaction as the key construct, permitting completion of 1.009 g of
totally synthetic (þ)-spongistatin 1 (1). A brief analysis of the three syntheses alongside our earlier
synthesis of (þ)-spongistatin 2 is also presented.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
this class of natural products have been achieved.3 While these
elegant syntheses have taught much about the intricacies of the
The spongistatin family of marine natural products comprises
some of the most potent antimiotic, growth inhibitory substances
discovered to date (Scheme 1).1 As such members of this remark-
able class hold great potential as exciting new leads for cancer
chemotherapy. The extremely low natural abundance of the
spongistatins,2 however, represents a major hurdle for clinical de-
velopment. Not surprisingly, the potent biological activities and
daunting molecular architectures of the spongistatins have attrac-
ted considerable interest in both the synthetic and biomedical
communities. To date seven total syntheses of representatives of
chemistry of the spongistatins, to date only the Heathcock
report3m,n on spongistatin 2 begins to address the need for suffi-
cient quantities of material for biomedical development.
Encouraged by our successful gram-scale synthesis of (þ)-
discodermolide,which led to phase I clinical development,4 we
initiated a program aimed at the evolution of a synthetic strategy
capable of delivering gram-quantities of (þ)-spongistatin 1 (1).
While we had already achieved a total synthesis of the closely re-
lated (þ)-spongistatin 2 (2), as outlined in the preceding paper,5,3h
the length and overall efficiencies of several critical trans-
formations would clearly not permit large-scale production. We
therefore reengineered our (þ)-spongistatin 2 (2) strategy, drawing
on lessons learned in our laboratory, as well as the experiences of
others, to permit access to (þ)-spongistatin 1 (1) on a preparative
scale.
* Corresponding author.
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.2009.04.003

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A.B. Smith III et al. / Tetrahedron 65 (2009) 6489–6509
the ABCD fragment 3, now at the C(15)–C(16) bond to reveal AB
OH
aldehyde 5 and CD ketone 6. Their union would call on an aldol
reaction similar to that employed in the pioneering Evans
(þ)-spongistatin 2 (2) synthesis.3a–d We were also cognizant of
the ever present possible loss of configurational control of the
C(23) CD spiroketal stereocenter via mild acid treatment both
during assembly of the ABCD aldehyde, as well as final elabora-
tion to (þ)-spongistatin 1 (1).3a–f
35
E
37
HO
H
28
H
O
OH
H
O
O
F
D
H
OMe
O
25
HO
41
O
44
C
O
H
OH
19
1
O
Even greater challenges were evident in our synthesis of the EF
Wittig salt 4a. Here, the low efficiency of the Julia union/methyl-
enation installation of the side chain, in conjunction with the dif-
ficulties associated with subsequent side chain elaboration were
clearly evident.3h We therefore again chose to abandon the Julia
tactic. In the end, three strategically independent approaches were
developed (vide infra). The first called for appending a fully elab-
orated side chain [cf. 8] exploiting chelation control to an advanced
EF intermediate (7) to afford 4b.
H
O
17
OH
H
13
A
O
B
R
AcO
OAc
51
OH
R = Cl, (+)-Spongistatin 1 (1)
R = H, (+)-Spongistatin 2 (2)
OTBS
P+Ph3I-
2.2. Construction of ABCD aldehyde 3 beginning with AB
spiroketal 5
28
E
O
H
H
O
TESO
H
29
O
H
OMe
As now well recognized,3 the AB spiroketal in the spongistatins
adopts the thermodynamically favorable axial–axial (AA) spiro
configuration at C(7); 5 was thus envisioned to be readily available
via spiroketalization under thermodynamic control of linear pre-
cursor 9 (Scheme 2). The requisite precursor in turn would arise via
our multicomponent linchpin tactic,7 in this case employing 2-
triethylsilyl-1,3-dithiane, epoxide 10 and epoxide 11, the latter
available by the addition of dithiane 13 to epoxide 12. By exploiting
more advanced epoxide coupling partners in the tri-component
linchpin event, extensive remodeling to arrive at an advanced AB
system would not be required.
D
OMe
O
O
F
H
C
O
TBSO
O
H
OTMS
OTMS
19
1
TIPSO
AcO
H
O
H
16
A
13
O
B
OTBS
15
X
OAc
4a, X = H
4b, X = Cl
51
OTES
3
BnO
OTBS
H
O
E
D
OMe
O
TESO
OTES
4
O
C
TBSO
ONap
H
O
OMe H
1
NapO
O
H
F
H
O
H
6
13
A
O
B
15
I
OTES
AcO
O
H
O
7
O
H
A
O
B
H
OTES
5
OTBS
AcO
O
Cl
8
5
OTES
Scheme 1.
OR OR
OR OH
S S
S S
1
15
OPMB
NapO
2. Results and discussion
2.1. Synthetic analysis
9, R = TES
Having in place a successful endgame for (þ)-spongistatin 2
(Scheme 1), comprising Wittig olefination of an advanced Wittig
salt (cf. 4a) with ABCD aldehyde 3, followed by macro-
lactonization and global deprotection,3h we turned to improve
acquisition of both 3 and the requisite chloro side chain fragment
4b for (þ)-spongistatin 1 (1). For the ABCD subunit 3, we rec-
ognized that, although the elegant Julia union/methylenation6
protocol proved to be a powerful method for uniting the AB and
CD subunits in our spongistatin 2 effort,3h this tactic relied on
a simplified AB precursor to permit high efficiency in the union
event. Extensive structural remodeling was then required to
obtain the fully functionalized ABCD subunit. Reasoning that
a more convergent strategy would be required for significant
material advancement, we turned to a revised disconnection of
OTES
10
SO
TE
S S
1
O
15
O
S
S
NapO
13
OPMB
11
TES
S S
OH
15
O
BPSO
H
OPMB
12
Scheme 2.
13

A.B. Smith III et al. / Tetrahedron 65 (2009) 6489–6509
6491
Construction of 5 began with the elaboration of napthyl epoxide
10. We selected the rarely utilized 2-napthylmethyl protecting
group based on the reported potential for selective removal in the
presence of a benzyl ether,8 the latter employed to protect the C(28)
hydroxyl in CD spiroketal 6 (Scheme 1). Employing a sequence
similar to that developed for (þ)-spongistatin 2 (2), mono-
protection of 1,3-propanediol as the 2-napthylmethyl ether, followed
by oxidation furnished aldehyde 14 (Scheme 3). Brown allylbora-
tion9 then furnished homoallylic alcohol (þ)-15 in both high yield
and enantioselectivity (88% yield, 90% ee). Assignment of the C(3)
configuration of the major diastereomer entailed Mosher ester
analysis.10 Protection of the alcohol as a tert-butylcarbonate was
then followed by IBr-mediated cyclization exploiting our improved
protocol11 to furnish iodocarbonate (ꢀ)-16, which was then con-
verted to epoxide (ꢀ)-10.
followed by exposure of the requisite iodocarbonate to K2CO3 in
methanol led to epoxide (ꢀ)-12.
Completion of epoxide 11 began with a four-step synthesis of
dithiane (ꢀ)-13 employing the (þ)-Roche ester (Scheme 5). Alkyl-
ation with epoxide (ꢀ)-12 proceeded smoothly to provide diol
(ꢀ)-21, which was subjected to removal of the BPS group, Fraser-
Reid epoxidation,13 and protection of the secondary alcohol as a TES
ether to furnish (ꢀ)-11. The overall yield for the eight-step se-
quence was 31%.
OH
O
1) TEMPO, NaOCl,
CH2Cl2
1) PMBTCA, PPTS,
CH2Cl2-Benzene
OPMB
MeO
OH
2) 1,3-propanedithiol,
CSA, CH2Cl2
(77%, 2 steps)
2) LiAlH4, THF
(58%, 2 steps)
(+)-Roche Ester
(+)-20
a) t-BuLi, THF-HMPA
OH OH
S
S S
S
–78 °C 15min., –40 °C 45 min.
HO
OH
Br
(+)-Ipc BOMe,
2
H
OPMB
OPMB
b) THF
OH
1) KH, TBAI,
THF (95%)
+
O
MgBr
O
OBPS
BPSO
(–)-13
(–)-21
(–)-12 (1 equiv.)
Et O, –78 °C
2
2) TEMPO, NaOCl
NapO
H
(98%)
(88%)
CH Cl , 0 °C (90%)
2
2
14
1) TBAF, THF (93%)
2) NaH, p-TsImid.,
O
TESO
S
THF (83%)
S
O
8
15
1) NaHMDS, Boc O
2
OH
3) TESCl, Imid.,
THF (92%)
O
O
OPMB
THF, 0 °C
(–)-11
I
NapO
2) IBr, Tol., –78 °C
(91%, 2 steps)
NapO
OTES
(+)-15
(–)-16
Scheme 5.
With both epoxides in hand, we explored the multicomponent
linchpin union developed in our laboratory specifically for the
spongistatin program.7 Initially we employed epoxide (ꢀ)-11 as the
first electrophile, as this would permit in situ protection of
the tertiary C(9) hydroxyl as a TES ether.14 Unfortunately, all at-
tempts to achieve the union of 2-lithio-2-TES-1,3-dithiane with
epoxide (ꢀ)-11, followed by HMPA induced 1,4-Brook rearrange-
ment and alkylation with epoxide (ꢀ)-10 failed to produce the
desired product 22 (Scheme 6A). Instead, products corresponding to
mono- and bis-addition of (ꢀ)-10 to the dithiane were obtained
(structures not shown). Reversal of the order of epoxide addition
only led to a 13% yield of the desired adduct 23 (Scheme 6B).
1) K CO ,
2
3
MeOH (83%)
O
1
NapO
2) TESCl, Imid.,
THF (90%)
6
(–)-10
Scheme 3.
The synthesis of epoxide 11 began with Sharpless asymmetric
epoxidation12 of 2-methyl-2-propenol; in situ protection with
tert-butyldiphenylchlorosilane (BPSCl) afforded epoxide (ꢀ)-17
(Scheme 4). Treatment of the latter with vinylmagnesium bromide
in the presence of copper ion, followed by protection of the
resulting alcohol with Boc anhydride furnished carbonate (þ)-18.
Cyclic carbonate formation mediated by IBr proved less selective
than anticipated, initially furnishing a mixture (3:1) of syn- and
anti-iodocarbonates. However, by employing diethyl ether at
ꢀ100 ꢁC, the desired syn-iodocarbonate (þ)-19 was available as
a mixture of diastereomers (ca. 8:1). Chromatographic separation,
a) t-BuLi, Et2O, –78 to – 45 °C, 1 h
A
TESO
b)
S
Et2O, –78 to –25 °C,
2 h
S
O
OPMB
S S
TES
(–)-11
OTES
c)
O
Et2O-HMPA,
–78 to 0 °C, 3 h
NapO
(–)-10
a) Ti(Oi-Pr)4,
1)
MgBr
(–)-DIPT,
cumene
CuI, THF,
O
hydroperoxide
–45 °C (83%)
HO
BPSO
(–)-17
RO HO
OR OR
9
S S
b) Et3N, BPSCl,
DMAP (71%)
2) NaHMDS, Boc2O
THF, 0 °C (99%)
2-Methyl-2-propenol
NapO
R = TES, 22
S
S
O
OPMB
K2CO3,
O
O
IBr, Et2O, –100 °C
OBoc
MeOH
BPSO
I
Scheme 6A.
BPSO
(89%, 8:1 syn:anti)
(91%)
(+)-18
(+)-19
Undaunted, we turned to the stepwise alkylation of the lithiated
anion of TES dithiane with (ꢀ)-10 and (ꢀ)-11; treatment with
(ꢀ)-10 followed by addition of HMPA resulted in clean formation of
monoalkylation product (þ)-24 in 82% yield (Scheme 7). However,
attempts to carry out the analogous alkylation with (ꢀ)-11 failed.
Clearly epoxide (ꢀ)-11 was sterically too encumbered to permit
dithiane alkylation.
OH
O
BPSO
(–)-12
Scheme 4.

6492
A.B. Smith III et al. / Tetrahedron 65 (2009) 6489–6509
a) t-BuLi, Et2O, –78 to – 45 °C, 1 h
Recognizing that the dithiane in epoxide (ꢀ)-11 would ulti-
B
mately be converted to a methylene, we attempted to alleviate the
steric hindrance by installing the methylene prior to linchpin
union. Synthesis of the requisite coupling partner (þ)-30 began
with conversion of the p-methoxybenzyl (PMB) ether of Roche’s
ester15 to the corresponding Weinreb amide employing a Merck
protocol,16 followed by addition of methylmagnesium bromide to
furnish ketone (þ)-26 (Scheme 8). Condensation with 2,4,6-triiso-
propylbenzenesulfonyl hydrazide17 proceeded efficiently to afford
the hydrazone (ꢀ)-27 as a crystalline solid. The latter underwent
efficient Shapiro reaction18 to generate the corresponding vinyl-
lithium, which upon alkylation with epoxide (ꢀ)-12 led to diol
(þ)-28. Removal of the BPS protecting group followed by epoxide
ring formation, employing the Fraser-Reid protocol,13 and hydroxyl
protection completed construction of (þ)-30.
OTES
b)
O
Et2O, –78 to –25 °C,
2 h
NapO
O
S S
TES
(–)-10
Et2O-HMPA,
–78 to 0 °C, 3 h
c)
TESO
S
S
OPMB
(–)-11
OH
9
RO RO
OR
S S
NapO
S
R = TES, 23 (13%)
S
OPMB
Again, all attempts to employ (þ)-30 as the second electrophile
in the linchpin event failed to produce the desired product (Scheme
9). Instead, significant quantities of the intermediate dithiane
(þ)-24 (i.e., monoalkylation), as well as products arising from
elimination of the homoallylic TES ether (product not shown), were
observed. Steric hindrance of the epoxide was again presumed to be
the culprit. As a last resort, we explored the lithium alkoxide de-
rived from epoxide (þ)-29 as the second electrophile to lower
further the steric encumberance near the epoxide (Scheme 10). This
Scheme 6B.
a) t-BuLi, Et2O,
–78 to –45 °C, 1h
S S
RO RO
S S
A
OTES
b)
O
NapO
H
TES
NapO
R = TES, (+)-24
(–)-10
Et2O, –78 to –20 °C
c) HMPA (82%)
a) t-BuLi, Et2O, –78 to –45 °C, 1 h
OTES
O
b)
Et2O, –78 to –25 °C
2 h
NapO
O
S S
TES
(–)-10
a) t-BuLi, Et2O,
–78 to –45°C, 1 h
c)
OTES
THF-HMPA
–45 °C to rt
OR OR
S S
S S
S S
TES
OPMB
B
H
OPMB
(+)-30
TESO
S S
O
b)
R = TES, 25
OPMB
RO RO
OH OR
S
(–)-11
Et2O, –78 to –20 °C
c) HMPA
S
NapO
R = TES, 31
Scheme 7.
OPMB
Scheme 9.
1) Me (OMe) NH•HCl,
i-PrMgCl, –20 °C
THF
O
O
TrisNHNH2
Et2O (90%)
MeO
OPMB
OPMB
a) t-BuLi, Et2O, –78 to –45 °C, 1 h
2) MeMgBr, 0 °C
THF
(+)-26
OTES
(83%, 2 steps)
O
b)
c)
Et2O, –78 to –25 °C
2 h
NapO
O
S S
TES
(–)-10
NNHTris
a) t-BuLi (2equiv.), THF
–78 °C, 30 min., 0 °C 15 min.
OH OH
OLi
THF-HMPA
OPMB
OPMB
–45 to –25 °C, 16 h
OH
OPMB
O
b)
OBPS
(-)-27
BPSO
(+)-28
32
(–)-12
n-BuLi, THF-HMPA
n-BuLi, THF (90%)
–45 °C
OH
(+)-29
O
OH
O
1) TBAF, THF (98%)
OPMB
TESCl, Imid.
OPMB
2) TrisImid., NaH,
THF (74%)
THF (98%)
(+)-29
RO RO
OH OH
S S
NapO
OTES
O
15
R = TES, (+)-33
OPMB
8
(58%)
(+)-30
OPMB
Scheme 8.
Scheme 10.

A.B. Smith III et al. / Tetrahedron 65 (2009) 6489–6509
6493
tactic proved rewarding; coupled product (þ)-33 was obtained
NapO
HO
1
Hg (ClO4) 2•4H2O,
HClO4,
RO RO
OH OH
S
S
reproducibly in 55–58% yield on large scale (ca. 10 g). The above
sequence of events provides a showcase for how multicomponent
linchpin processes can be developed.
H
O
H
MeCN-H2O
O
15
OPMB
R = TES, (+)-33
ONap
(83%)
Removal of dithiane and the silyl protecting groups with mer-
curic perchlorate as employed for spongistatin 2 (2), proceeded
with concomitant spiroketalization to furnish AB spiroketal (ꢀ)-34
as a single isomer (Scheme 11); the stereochemistry was assigned
based on NOESY NMR experiments. While this one-pot depro-
tection/spiroketalization was attractive, the reaction sequence was
not readily reproducible on large scale. We therefore adopted
a two-step sequence involving TBAF-mediated desilylation to pro-
duce tetraol (þ)-35, which in turn was readily transformed to spi-
roketal (ꢀ)-34 by iodomethane-mediated hydrolysis of the
dithiane. The two-step sequence proceeded reproducibly in 76%
yield.
OPMB
OH
(–)-34
MeI,
MeCN-THF-H2O
(91%)
OH OH
OH OH
S
S
1
TBAF,THF
(84%)
NapO
(+)-35
15
OPMB
Scheme 11.
At this stage all that remained to complete the AB spiroketal 5
was adjustments of the protecting groups and oxidation state
(Scheme 12). Selective acetylation of the C(5) hydroxyl followed by
protection of the tertiary C(9) hydroxyl as a TES ether quickly
afforded (ꢀ)-36. Unfortunately, attempts to remove the C(15) PMB
protecting group under oxidative conditions resulted in competi-
tive removal of the napthyl and/or TES protecting group.
Unable to unmask the C(15) hydroxyl in the presence of the 2-
napthylmethyl ether (Scheme 13), we explored the possibility of
employing an ester at C(1) in the forthcoming aldol union of the AB
1) Ac2O, py,
NapO
NapO
DMAP,
H
O
H
O
CH2Cl2
(96%)
H
H
O
9
O
15
HO
AcO
2) TESOTf,
2,6-Lut.,
CH2Cl2
OPMB
OPMB
(–)-36
OH
OTES
(96%)
(–)-34
1
NapO
AcO
NapO
AcO
CAN
or
H
O
H
O
[O]
H
H
DDQ
O
O
15
A
B
O
OH
OTES
37
5
OTES
Scheme 12.
HO
NapO
AcO
H
O
H
O
Pd(OH)2,
CaCO3
,
H
H
O
O
AcO
EtOH (98%)
OPMB
OPMB
OTES
OTES
(–)-36
(–)-38
HO2C
H
O
1) TIPSCl, Et3N,
CH2Cl2 (99%)
1) Dess-Martin [O]
CH2Cl2
H
O
15
2) DDQ, CH2Cl2
H2O (91%)
2) NaClO2,NaH2PO4,
t-BuOH-H2O
(96%, 2 steps)
AcO
OPMB
OTES
(–)-39
TIPSO2C
H
TIPSO2C
1
H
O
H
Dess-Martin [O]
CH2Cl2 (95%)
O
H
O
O
B
A
15
AcO
AcO
OH
O
OTES
OTES
(–)-41
(–)-40
Scheme 13.

6494
A.B. Smith III et al. / Tetrahedron 65 (2009) 6489–6509
with CD spiroketals. Selective removal of the napthyl group in
(ꢀ)-36 proceeded smoothly to furnish (ꢀ)-38, which was then
subjected to a two-step oxidation to provide acid (ꢀ)-39. Conver-
sion of the acid to the corresponding TIPS ester, followed by DDQ-
mediated removal of the C(15) PMB group led to alcohol (ꢀ)-40,
which was transformed to aldehyde (ꢀ)-41 via Dess–Martin
oxidation.19,20
1) BH3•THF
2) Et2C(OMe)2, p-TsOH,
DMF (93%, two steps)
O
O
O
O
OH
H
HO
3) SO3•Py, DMSO (85%)
(–)-45
OH
(L)-malic acid
O
1) Amberlite IR-120,
MeOH (92%)
46
SnBu3
2.3. Construction of the ABCD aldehyde 3 continued:
synthesis of the CD ketone 6
OH
O
2) Mesitylsulfonyl Chloride
Py (77%)
Ti(Oi-Pr)4, (R)-BINOL,
CH2Cl2, 4Å MS (81%)
O
19
(–)-47
In our (þ)-spongistatin 2 (2) venture, we discovered that the
requisite CD spiroketal fragment (cf. 6; Scheme 1), which possesses
the thermodynamically less stable axial–equatorial configuration at
the C(23) spiro center, could be generated by the treatment of the
more stable axial–axial congener with acid in the presence of CaII
ion.21 Accordingly, we anticipated that the desired spiroketal would
be available from the requisite linear precursor via a spiroketaliza-
tion/equilibration protocol involving dithiane 42, that in turn
would again arise taking advantage of our multicomponent linch-
pin tactic employing TBS-dithiane, epoxide (ꢀ)-43 [also utilized in
construction of the CD spiroketal during our (þ)-spongistatin 2
synthesis],3g and epoxide 44 (Scheme 14).
OH
OH
OTBS
a) NaH, THF
O
ArO2SO
Ar =
b) TBSCl, THF
(95%)
16
22
(–)-44
(–)-48
Scheme 15.
Again, we initially investigated the stepwise construction of the
C(16)–C(28) backbone to optimize each step of the pending multi-
component union. Lithiation of 2-triethylsilyl-1,3-dithiane fol-
lowed by addition of (ꢀ)-43 and subsequent treatment with
HMPA furnished dithiane (þ)-49 in good yield (Scheme 16). How-
ever, attempts to effect deprotonation of (þ)-49 led only to
decomposition of the substrate.
BnO
28
H
O
D
OMe
O
23
C
TBSO 25
O
a) t-BuLi, Et2O,
–78 to –45 °C, 1 h
b) Et2O,
H
6
R2O
R1O
S S
S S
–78 to –20 °C, 2 h
16
BnO
OTBS
O
H
TES
TES-1,3-Dithiane
BnO
R1 = TBS, (+)-49
(–)-43
R2 = TES
c) HMPA (79%)
TBSOTBSO
OTBS
OH
S S
R1O R2O
BnO
S S
D
a) Base
BnO
42
b) MeOD-d4
R1 = TBS, 50
2 = TES
R
Scheme 16.
TBSO
TBSO
28
To circumvent this problem, we reasoned that we could post-
pone the 1,4-Brook rearrangement until the second epoxide al-
kylation, thereby permitting a directed deprotonation of the
dithiane by the initially formed alkoxide. Toward this end, alkyl-
ation of the lithium anion of 2-TES-1,3-dithiane with (ꢀ)-43, now
in the absence of HMPA, furnished alcohol (þ)-51 (Scheme 17A).
With (þ)-51 in hand, deprotonation of the resultant alcohol fol-
lowed by addition of HMPA led to 1,4-Brook rearrangement;
subsequent C-alkylation with (ꢀ)-44 furnished (þ)-52. The yield
for the two-step sequence was 57%. With a successful stepwise
sequence in hand, we explored the one-pot scenario, in this case
employing the lithium anion derived from 2-TBS-1,3-dithiane.
Alkylation with epoxide (ꢀ)-43, followed by addition of epoxide
(ꢀ)-44 dissolved in THF/HMPA, furnished (þ)-42 (Scheme 17B).
Importantly, this reaction proceeded in 63–69% yield and could be
run reproducibly on large scale (10 g) permitting production of
>50 g of (þ)-42.
O
O
S
S
BnO
16
(–)-43
44
TBS
Scheme 14.
Construction of 44 began with the synthesis of aldehyde (ꢀ)-45
(Scheme 15),22 available in three steps from
-malic acid. Efforts to
utilize the
-oxygen in (ꢀ)-45 to direct formation of the C(19)
L
b
stereocenter via Lewis acid-catalyzed allylation failed to provide
the desired adduct with an acceptable level of selectivity. Instead,
reagent control was employed using allylstannane 46, in conjunc-
tion with the Ti(Oi-Pr)4/BINOL system reported by Keck and co-
workers;23 homoallylic alcohol (ꢀ)-47 was obtained in good yield
and with excellent selectivity (ca. 20:1).24 Removal of the ketal was
then followed by sequential treatment of the resulting primary
hydroxyl with trimethylbenzenesulfonyl chloride and NaH to
generate the epoxide, and TBSCl for in situ O-TBS protection to
complete the synthesis of (ꢀ)-44.
Having established both a reliable and scalable method for
construction of the C(16)–C(28) backbone, we turned to elaboration
of ketone 6 (Scheme 14). With the C(21) hydroxyl in (þ)-42 already

A.B. Smith III et al. / Tetrahedron 65 (2009) 6489–6509
6495
a) t-BuLi, Et2O, -78 to -45 °C, 1 h
A
S S
TES
TBSO HO
S S
BnO
OTBS
b)
TES
Et2O, –78
to –45 °C
O
BnO
(+)-51
(71%)
(–)-43
a) n-BuLi, Et2O,
TBSO RO
OH
21
OTBS
S S
–78 °C, 10 min
BnO
b) THF-HMPA
28
16
TBSO
O
R = TES, (+)-52
(–)-44
-78 to 0 °C
(80%)
B
a) t-BuLi, Et2O, –78 to –45 °C, 1 h
OTBS
b)
O
BnO
(–)-43
RO
RO
OH OR
S S
Et2O, –78 to –25 °C,
1h
S S
TBS
21
BnO
28
16
TBSO
c)
R = TBS, (+)-42
O
(63-69%)
(–)-44
THF-HMPA
–78 °C to rt
Scheme 17.
differentiated by the linchpin event, installation of the requisite
methyl ether was easily achieved employing iodomethane and
sodium hydride in the presence of 15-crown-5 to furnish (ꢀ)-53
(Scheme 18), which in turn was converted to triol (þ)-54 upon
treatment with p-TsOH. Removal of the dithiane proved to be even
more difficult than previously observed for (þ)-33, en route to the
AB spiroketal precursor. Standard mercuric perchlorate condi-
tions25 resulted in significant amounts of decomposition. We sur-
mised that the culprit was the C(17) alkene. To circumvent this
issue we examined a number of conditions to effect dithiane re-
moval with concomitant spiroketalization. In the end, we settled on
ceric ammonium nitrate (CAN), which furnished a mixture of spi-
roketals (þ)-55 and (ꢀ)-56 (ca. 4:1). As expected, NOESY NMR
experiments revealed that the major product was the undesired
axial–axial spiroketal (þ)-55 (Fig. 1).
MeI, NaH,
RO RO
OR
OR
OH
S S
15-crown-5, THF
21
BnO
BnO
28
16
(99%)
R = TBS, (+)-42
H
OBn
27
H
H
O
H
p-TsOH, CH3CN,
RO RO
OMe
S S
H
H
HO
H
H2O, THF
O
19
(95%)
21
(+)-55
OMe
R = TBS, (–)-53
Critical NOESY Correlations
HO HO
OMe OH
S S
Figure 1. Critical NOESY NMR correlations for spiroketal (þ)-55.
CAN, MeCN, THF
H2O (94%)
BnO
(+)-54
As discussed previously, a key discovery during our (þ)-spon-
gistatin 2 synthesis3g,h comprised an effective protocol to achieve
conversion of the CD axial–axial (AA) spiroketal to the axial–
equatorial (AE) congener in the presence of CaII ion, when appro-
priate chelation functionality was available. We surmised that the
methylene moiety in (þ)-55 and (ꢀ)-56 could be utilized to gen-
erate the required functionality. Toward this end, the mixture of
spiroketals was dihydroxylated with OsO4. Acid equilibration of the
diol mixture mediated by CaII, followed by oxidative cleavage of the
diols led to a mixture of spiroketals favoring the desired axial–
equatorial (AE) spiroketal (ꢀ)-58 (ca. 4:1; Scheme 19); confirma-
tion of both structures was achieved by NOESY NMR analysis upon
separation (Fig. 2).26
OBn
OH
28
BnO
28
O
O
HO
16
16
O
O
OMe
AE spiroketal
OMe
(+)-55
(–)-56
AA spiroketal
4:1 mixture
(+)-55: (–)-56
Scheme 18.

6496
A.B. Smith III et al. / Tetrahedron 65 (2009) 6489–6509
OBn
O
HO
17
17
O
1) OsO4, NMO,
Acetone-H2O
OMe
(+)-55
4:1 mixture
2) HClO4, Ca(ClO4)2•4H2O,
CH2Cl2-MeCN
(+)-55: (–)-56
OH
3) NaIO4, MeOH, H2O
(95%, 3 steps)
BnO
O
O
OMe
(–)-56
OBn
O
O
17
HO
O
H
OMe
(+)-57
25
OH
Separable
1:4 mixture
(+)-57: (–)-58
H
II
O
Ca
BnO
17
O
OH
BnO
O
O
O
17
OMe
O
O
OMe
(–)-58
Scheme 19.
only a minor role in the outcome of the equilibration event. For
material advancement, as well as cost considerations, we employed
dihydroxylation with OsO4/NMO, followed by oxidative cleavage to
furnish (þ)-57 and (ꢀ)-58 (1:4) in 90% yield.
H
OBn
OH
H
H
H
H
H
O
BnO
O
H
O
H
H
H
HO
H
O
O
H
O
OMe
OMe
57
(+)-
OBn
HO
OBn
(–)-58
OH
OH
BnO
O
1. HClO4,
Ca(ClO4)2
O
O
O
O
Critical NOESY Correlations
+
HO
HO
O
O
O
O
O
R
2. NaIO4
(90%)
MeO
MeO
Figure 2. Relevant NOESY data for (þ)-57 and (ꢀ)-58.
MeO
59
OBn
(+)-57
(–)-58
OH
1 : 3
BnO
Intrigued by the possibility that the C(17) configuration might
play a significant role in the equilibration process, we prepared the
C(17) diastereomeric diols. Sharpless asymmetric dihydroxy-
OBn
O
OH
OH
1. HClO4,
Ca(ClO4)2
O
O
O
+
HO
HO
O
O
S
2. NaIO4
(90%)
lation27 with AD-mix-
a
provided access to a mixture (5:1) favoring
the S-isomer 59 at C(17) (Scheme 20).28 Alternatively, AD-mix-
proved highly selective, producing triol 60 (10:1); the latter
MeO
MeO
MeO
(–)-58
60
(+)-57
1 : 5
b
Scheme 21.
clearly represents a matched case.
Completion of CD ketone (ꢀ)-6 was achieved by protection of the
free hydroxyl in (ꢀ)-58 as the TBS ether (Scheme 22). The overall
OBn
OBn
HO
OH
sequence to (ꢀ)-6 proceeded in 16 steps from
L-malic acid with an
O
AD-mix-α
HO
O
overall yield of 20%. A total of 15 g of spiroketal (ꢀ)-6 was prepared.
HO
O
O
O
(80%, dr = 5:1)
(S)
MeO
MeO
59
(+)-55
OH
OTBS
BnO
O
BnO
O
O
O
TBSOTf, 2,6-Lut.
CH2Cl2, (97%)
OBn
OBn
O
O
OH
OH
O
AD-mix-β
HO
O
OMe
OMe
(-)-58
(–)-6
HO
O
(88% - 99%, dr = 10:1)
(R)
MeO
MeO
60
(+)-55
BnO
28
Scheme 20.
H
O
Exposure of the mixture enriched in the S-isomer (59) to the
now standard CaII equilibration conditions,3g,h followed by oxida-
tive cleavage of the diol, produced a 1:3 mixture of spiroketals
favoring the required axial–equatorial ketone (ꢀ)-58 (Scheme 21).
Alternatively, exposure of the diol mixture rich in the R-isomer (60)
to the identical conditions furnished a mixture (5:1) of di-
astereomers, once again favoring the desired (ꢀ)-58. Taken to-
gether, these results suggest that the configuration at C(17) plays
D
OMe
C
TBSO
O
H
O
(–)-6
16
Scheme 22.

A.B. Smith III et al. / Tetrahedron 65 (2009) 6489–6509
6497
R1O
28
BnO
O
28
H
H
H
O
O
O
D
OMe
O
D
OMe
O
OMe
TBSO
TBSO
C
O
1
TBSO
C
O
O
O
O
a) c-Hex2BCl, Et3N, Et2O
Dess-Martin [O]
(97%)
OTIPS
1
TIPSO
AcO
H
TIPSO
AcO
H
H
(–)-6
H
O
O
H
O
b) H2O2, MeOH, pH 7 buffer
(72%, dr >9:1 )
O
H
O
H
H
O
A
16
15
O
H
O
B
B
A
OR2
OAc
AcO
O
(–)-3
OTES
OTES
(–)-61, R1 = Bn, R2 = H
(–)-62, R1 = Bn, R2 = Ac
(–)-63, R1 = H, R2 = Ac
OTES
(–)-41
AcCl, Py
CH2Cl2 (88%)
, Pd(OH)2/C, CaCO3
EtOH (98%)
Scheme 23.
2.4. Fragment union and completion of the C(1)–C(28)
ABCD aldehyde (3)
treatment with TESCl led to pyran (þ)-73. Oxidative removal of the
PMB moiety, followed by the Swern protocol34 then furnished
model F-ring ketone (þ)-74 (Scheme 26).
Having ample quantities of both (ꢀ)-41 and (ꢀ)-6, we pro-
ceeded to the Evans aldol to unite the two fragments. As antici-
pated, the aldol reaction3c proceeded smoothly to afford the
desired ABCD product (ꢀ)-61 (Scheme 23), both in good yield and
with high diastereoselectivity (9:1). Acetylation followed by re-
moval of the benzyl group furnished alcohol (ꢀ)-63, which was
readily oxidized to (ꢀ)-3.29 From the preparative perspective,
construction of the ABCD subunit (ꢀ)-3 now entails a longest linear
sequence of 22 steps and proceeds with an overall yield of 6.5%.
This sequence is 15 steps shorter than our approach to the epimeric
C(23) ABCD aldehyde employed in our spongistatin 2 synthesis, and
as such represents a major synthetic advance.
Initial attempts to effect alkylation of (þ)-74 employing kinetic
deprotonation and treatment with either allyl bromide or allyl io-
dide failed to provide the desired adduct 75 (Scheme 27). Silyl enol
ether 76, however, could be prepared by deprotonation of (þ)-74
with LiHMDS, followed by addition of TMSCl. Pleasingly, alkylation
with allyl iodide promoted by silver trifluoroacetate then furnished
75 as a mixture of isomers (ca. 7.5:1), favoring the desired equa-
torial product.
OTBS
P+Ph3I-
E
29
TESO
O
2.5. Synthesis of the EF Wittig salt 4: a most challenging
synthetic target
H
O
OMe H
F
H
43
OTMS
OTMS
Development of effective synthetic routes to appropriately
functionalized EF Wittig salts for the spongistatins has proved
challenging to all who have engaged in the spongistatin synthetic
enterprise. We report here three strategically different syntheses of
this advanced intermediate, each taking advantage of the stereo-
controlled E ring construction developed in our spongistatin 2
synthetic venture,5 involving cerium(III) mediated addition of
dithiane (ꢀ)-6430 to an appropriate F-ring aldehyde employing
zinc(II) chelation control. The first approach (Scheme 24) entailed
introduction of a fully functionalized side chain via alkylation of
ketone 7 with allyl iodide 8. Further analysis of 7 reveals pro-
genitors dithiane (ꢀ)-64 and aldehyde 65. The requisite allyl iodide
side chain in turn would arise ultimately by allylation of chlor-
odiene aldehyde 66 with allyl(diisopinocampheyl)borane 67, fol-
lowed by functional group adjustments.
OTBS
Cl
4
51
OTBS
I
E
TESO
O
OTES
H
O
OMe H
OTBS
F
Cl
Construction of (þ)-65 began via Brown crotylboration31 of
known aldehyde (ꢀ)-6832 to furnish homoallylic alcohol (ꢀ)-69,
followed by protection as a benzyl ether and exposure to cam-
phorsulfonic acid (CSA) in methanol to deliver diol (ꢀ)-70 in 55%
yield (three steps; Scheme 25). Selective sulfonation of the primary
alcohol with 2,4,6-triisopropylbenzenesulfonyl chloride (TrisCl)
and protection of the secondary alcohol as a PMB ether afforded
alkene (þ)-71, that was in turn converted to the F-ring pyran via
Sharpless asymmetric dihydroxylation27 and base promoted cycli-
zation to furnish alcohol (þ)-72 in 85% yield. Parikh–Doering33
oxidation then completed construction of (þ)-65.
OTES
8
O
7
O
O
O
S
S
H
OBn
Cl
(–)-64
66
CHO
H
O
OPMB
F
At this stage, we explored a model alkylation study prior to
attempted union of aldehyde (þ)-65 with dithiane (ꢀ)-64. Con-
version of the primary hydroxyl in (þ)-72 to the TBS ether, followed
by transfer hydrogenolysis to remove the benzyl group and
B(-)-Ipc2
67
OBn
OPMB
65
Scheme 24.

6498
A.B. Smith III et al. / Tetrahedron 65 (2009) 6489–6509
a) (+)-Ipc2BOMe, n-BuLi
O
OH
KOtBu, cis-2-Butene
–78 °C
1) BnBr, NaH, THF
H
O
O
b) BF3•OEt2, –78 °C
c) NaOH, H2O2
2) CSA, MeOH-H2O
(55%, 3 steps)
O
O
(–)-68
(–)-69
OBn
OBn
1) TrisCl, Et3N, DMAP
CH2Cl2 (86%)
HO
TrisO
PMBO
2) PMBOC(NH)CCl3
0.03 mol% TfOH
Et2O (93%)
OH
(–)-70
(+)-71
a) (DHQD)2-PYR, K3Fe(CN)6,
K2CO3, K2OsO2(OH)4,
t-BuOH-H2O, 0 °C
OH
CHO
SO3•Py,
H
O
H
O
CH2Cl2, DMSO
F
b) NaOMe
(85%)
0 °C (95%)
OBn
OBn
OPMB
OPMB
(+)-72
(+)-65
Scheme 25.
OH
OTBS
OTBS
H
O
O
H
OH
O
OH
1) DDQ, CH2Cl2,
pH 7.0 buffer (96%)
2) Swern [O] (85%)
MgCl
1) TBSCl, Imid.,
THF (88%)
2) 10% Pd/C, EtOH
H
O
H
O
NaIO4
O
O
O
(–)-Ipc2BOMe
Et2O, –78 °C
O
CH2Cl2,
H2O
OBn
OPMB
OTES
OPMB
O
O
OTES
O
(+)-74
O
OH
(+)-78
(86%)
3) TESCl, Imid.,
THF (93%)
(+)-77
(+)-72
(+)-73
1) NaIO4, CH2Cl2,
H2O (91%)
1) TBSCl, Imid.,
DMF, rt, 60 h
2) 50% TFA,
CH2Cl2-H2O
(59%, 4 steps)
OTBS
OH
OTBS
Scheme 26.
OH
2) In, DMF, rt
Cl
80
(+)-79
Cl
OH
(86%)
Cl
OTBS
OTBS
H
O
H
O
LDA, THF
a) SeO2 (0.1 equiv.),
TBHP (1 equiv.),
CH2Cl2, rt
1) MsCl, Et3N,
CH2Cl2, 0°C
OTBS
X
OTES
O
(+)-74
OTES
X = I or Br
b) NaBH4, MeOH, 0 °C
(24%, 49% BORSM)
O
75
2) DBU, benzene
reflux
(–)-81
Cl
(89%, 2 steps)
OTBS
a) Ms2O, Et3N, THF
b) LiI
OTBS
OTBS
OTBS
OTBS
HO
I
CF3CO2Ag,
–70 to 20°C
H
O
H
O
H
O
(+)-82
(63%)
LiHMDS, THF
TMSCl, Et3N
(+)-8
Cl
Cl
I
OTES –78 °C (99%)
Scheme 28.
OTES
OTMS
76
OTES
(53%, dr = 7.5:1)
O
O
(+)-74
75
Scheme 27.
with LiI completed the synthesis of what proved to be an unstable
iodide (þ)-8. Unfortunately, attempts to alkylate enol ether 76 with
(þ)-8, employing the model conditions, proved unsuccessful
(Scheme 29).37
Encouraged by these results, we turned to construction of the
requisite fully functionalized side chain (þ)-8 (Scheme 28), begin-
ning with oxidative cleavage of l,2,5,6-di-O-isopropylidene-
D
-
OTBS
OTBS
mannitol to provide aldehyde (þ)-77. Brown allylboration9
furnished homoallylic alcohol (þ)-78, which was subjected to
a protection/deprotection sequence to yield diol (þ)-79. Cleavage of
the diol, followed by indium-mediated allylation35 provided 80 as
an inconsequential mixture of alcohols (ca. 1:1). Without separa-
tion, elimination of the hydroxyl groups furnished triene (ꢀ)-81,
which upon Riley oxidation with SeO2,36 employing a reductive
workup led to alcohol (þ)-82, albeit in low yield (24%, 49% BORSM).
Notwithstanding the modest yield, conversion of the allylic alcohol
to the corresponding mesylate, followed by in situ displacement
OTBS
H
O
Conditions
H
O
+
I
(+)-8
OTES
Cl
OTES
OTMS
76
O
83
Conditions:
OTBS
a) CF3CO2Ag, –70 to 20 °C
b) CF3CO2Ag, –70 to 20 °C, in the dark
c) TASF, –70 to –10 °C, in the dark
Cl
Scheme 29.

A.B. Smith III et al. / Tetrahedron 65 (2009) 6489–6509
6499
Recognizing the instability of allyl iodide (þ)-8, we turned
instead to a Lewis acid promoted addition of an allylstannane to
a glucal epoxide for side chain attachment, as employed in the
Evans (þ)-spongistatin 2 synthesis.3a–d However, given the an-
ticipated sensitive nature of both the glucal and the side chain,
we decided to first construct the E ring, again employing the
tactic used in our spongistatin 2 synthesis. To this end, addition
of the cerium salt of dithiane (ꢀ)-64 to aldehyde (þ)-65 pro-
vided (þ)-84 in a highly stereocontrolled fashion (51%, dr>20:1)
via the aforementioned chelation-controlled process (Scheme
30).
O
O
OH
35
1) CSA (86%)
HO
H
O
HO
H
O
2) Hg(ClO4)2,
CH3CN/H2O
(95%)
S
BnO
O
S
OH
H
BnO
OBn
OPMB
OBn
OPMB
(+)-84
(+)-85
OH
Hydrolysis of the acetonide and in turn removal of the dithiane
proceeded as expected with concomitant cyclization to furnish
(þ)-85 (Scheme 31). Acid-catalyzed methyl ketal installation was
then achieved in near quantitative yield to furnish (þ)-86 as a sin-
gle isomer. Protection of the axial C(35) hydroxyl as the TBS ether,
however, proved more difficult than initially anticipated due to
extensive elimination of the methyl ketal to furnish the corre-
sponding dihydropyran (structure not shown).
HO
O
0.2 equiv. PPTS
MeOH-CH2Cl2
(98%)
H
O
H
OMe
BnO
OBn
OPMB
(+)-86
Scheme 31.
After extensive experimentation, we decided to install the
mixed methyl ketal at a later stage. Pleasingly, protection of the
C(35) hydroxyl in (þ)-85 proceeded selectively to furnish (þ)-87
(Scheme 32). Selective removal of the benzyl groups was then
achieved using transfer hydrogenolysis in methanol employing
2,6-lutidine38 to provide (þ)-88 as a mixture of methyl and
hemiketals. Exposure of this mixture to PPTS in methanol led to
complete mixed methyl ketal formation; exhaustive silylation
then led to TES ether (þ)-89 in high yield. Removal of the PMB
group was next achieved using medium-pressure hydro-
genolysis (500 psi) to furnish alcohol (þ)-90, which was con-
verted without purification to the corresponding triflate and
then to coupling partner (þ)-91 by treatment with LDA. The
overall yield of (þ)-91, requiring 17 steps from known aldehyde
(ꢀ)-68, was 3%.
OTBS
OH
35
1) 10% Pd/C,
HO
H
O
HO
H
O
TBSOTf, 2,6-Lut.
2,6-Lut., MeOH, 45 °C
(81%)
O
O
CH2Cl2, –78 °C
(90%)
OH
H
OH
H
2) 0.02 equiv. PPTS,
MeOH (85%)
BnO
BnO
OBn
OPMB
OBn
OPMB
(+)-85
(+)-87
OTBS
OTBS
10% Pd/C,
500 psi H2,
EtOAc (74%)
HO
H
O
TESOTf,
TESO
O
O
2,6-Lut., CH2Cl2
H
OR
H
O
OMe H
–78 °C (86%)
HO
TESO
OH
OPMB
2.6. Side chain construction, union with the EF fragment (D)-
91, and elaboration to Wittig salt (D)-103
OTES
OPMB
(+)-89
(+)-88
R= Me
Having secured a viable route to the EF dihydropyran (þ)-91, we
turned to construction of the requisite stannane side chain required
for the proposed Evans coupling. Although we had in hand
a pathway to access the corresponding iodide (þ)-8 (Scheme 28),
the route proved inefficient for large-scale synthesis. We therefore
designed an alternative approach.
OTBS
O
OTBS
1) Tf2O, Py,
CH2Cl2
TESO
TESO
OTES
H
O
OMe H
O
OMe
H
O
H
2) LDA, HMPA
(51%, 2 steps)
TESO
OTES
We began with BiCl3-mediated allylation39 of ethyl glyoxalate to
furnish homoallylic alcohol 92 as an inconsequential mixture (ca.
1:1) of isomers (Scheme 33). Conversion of the alcohol to a mesy-
late, followed by DBU-mediated elimination to provide 93, and
a two-step reduction/oxidation sequence furnished aldehyde 94.
OTES (+)-91
OH
(+)-90
Scheme 32.
S
O
O
S
OBn
O
O
i) n-BuLi, THF/HMPA
–78 °C to –50 °C,
40 min
ii) CeCl3, THF
iii) ZnCl2, (+)-65
–78 °C
S S
38
HO
H
O
(–)-64
OBn
CHO
H
O
OBn
OPMB
(+)-84
(51%)
OBn
OPMB
(+)-65
Scheme 30.

6500
A.B. Smith III et al. / Tetrahedron 65 (2009) 6489–6509
BiCl3, Al,
O
1) MsCl, Et3N, THF
EtO C
TBAI, H2O
EtO C
2
2
EtO C
H
2
2) DBU, Benzene
(89%, 2 steps)
Cl
Cl
OH Cl
92
93
Cl
(62%)
PivO
SnBu3
O
1) DIBAL-H, CH2Cl2
95
H
(S)-BINOL/Zr(Oi-Pr)4
4,4'-Dimethoxy-2,2'-dihydroxybenzophenone
CH2Cl2, (69%)
2) MnO2, CH2Cl2
(89%, 2 steps)
Cl
94
OH
TMSCl,
Imid.
1) DIBAL-H
OTMS
CH2Cl2, –78 °C
PivO
PivO
2) DCBCl, Py,
CH2Cl2
CH2Cl2
(78%)
(–)-96
(+)-97
Cl
Cl
(70%, 2 steps)
5% Pd(PPh3)4,
OTMS
OTMS
Bu3SnAlEt2, THF
DCBO
Bu3Sn
–78 °C to rt (40%)
Cl
DCB =2,4-Dichlorobenzoyl
Cl
(+)-99
(+)-98
Scheme 33.
Initial attempts to couple 94 with allylstannane 95 employing the
Keck protocol23 produced (ꢀ)-96 with excellent selectivity (98%
ee); however, the yield was at best modest (33%). Employing a bis-
zirconium catalyst,40 in place of the Keck catalyst, led to marked
improvement (69%) without loss of selectivity. Silylation with
TMSCl then furnished (þ)-97, which was converted to the primary
2,4-dichlorobenzoate (þ)-98 in two steps. Displacement of the
benzoate with Bu3SnAlEt2 mediated by Pd0 employing the
conditions of Trost41 completed construction of allylstannane
(þ)-99.42 The overall yield for the 10-step sequence from ethyl
glyoxalate was 7.4%.
Having secured both coupling partners, we turned to the
Evans union.3a–c Epoxidation of (þ)-91 with dimethyldioxirane
followed without purification by treatment with stannane
(þ)-99 in the presence of Bu3SnOTf furnished (þ)-100 as a single
isomer in excellent yield (Scheme 34). Removal of the sterically
OTBS
O
OTBS
O
OTES
OH
OTBS
TESO
TESO
H
H
O
OMe H
OMe H
KF
1) DMDO, CH2Cl2
2) Bu3SnOTf
OTES
E
O
MeOH-THF
(95%)
TESO
H
H
O
H
O
OMe H
OTES
OH
OTMS
Bu3Sn
OH
OH
OH
F
(+)-91
(+)-100
(+)-101
(+)-99
(77%, 2 steps)
Cl
OTES
OTMS
Cl
Cl
OTBS
OTBS
E
TESO
+
-
OTris
O
P Ph I
3
1) LiI, 2,6-Lut.
H
O
OMe H
TrisCl,
TESO
2) TMSOTf, 2,6-Lut.
DtBMP, DMAP
O
H
O
H
OMe
H
F
3) PPh3, Li2CO3,
MeCN-Benzene
(88%, 3 steps)
(93%)
OTMS
OTMS
H
OH
OH
OH
OTMS
(+)-102
(+)-103
Cl
Cl
Scheme 34.

A.B. Smith III et al. / Tetrahedron 65 (2009) 6489–6509
6501
more accessible TES and the TMS protecting groups generated
2.8. Second- and third-generation scalable syntheses of (D)-
spongistatin 1
tetraol (þ)-101, which was selectively converted to (þ)-102 upon
treatment with TrisCl, DMAP, and Dt-BMP (2,6-di-tert-butyl-4-
methylpyridine). Interestingly, use of Et3N or Hu¨ nig’s base
resulted in lower yields of the primary sulfonate, in conjunction
with loss of the methyl ketal. Conversion of the trisylate to the
corresponding iodide, global TMS protection, and displacement
of the primary iodide with PPh3 completed the synthesis of the
EF Wittig salt (þ)-103.
While our first-generation synthesis entailed a significant im-
provement over our spongistatin 2 (2) synthetic venture, two
significant obstacles remained prior to initiating a large-scale
synthetic campaign. These include the modest yield observed
during the dehydration required to furnish dihydropyran (þ)-91,
and the overall length and inefficiency required to access the
highly unstable stannane (þ)-99. Since both problems were en-
countered during construction of the EF side chain, redesign of
this fragment was imperative. Two new strategies were developed
(e.g., second- and third-generation syntheses). The modified tar-
get, EF Wittig salt 105, employed in both was envisioned to differ
from (þ)-103 in that the side chain hydroxyl would now be
protected as a TBS ether, in order to permit selective endgame
deprotection to reveal the seco-acid and thereby eliminate
a reprotection step. With this scenario in mind, initial dissection
of Wittig salt 105 at C(46)–C(47) revealed allyl bromide 107 and
aldehyde 106 (Scheme 36). By not employing a fully elaborated
side chain, a number of options for bond construction would be
possible, including both nucleophilic allylation or use of an
umpolung44 tactic (vide infra) without having to significantly
reengineer the coupling fragments. Such a scenario was of course
appealing.
2.7. Fragment union and elaboration to (D)-spongistatin 1:
a first-generation synthesis
In our spongistatin 2 synthesis, we employed the Kishi ti-
tration protocol3m to effect the critical union between (þ)-4a
(X¼H) and (ꢀ)-3; however, in our hands the yield was less than
satisfactory. In an effort to improve this transformation, we
examined the modified conditions of Paterson (THF/HMPA) to
unite (þ)-103 with (ꢀ)-3.3j seco-Acid (þ)-104 was obtained in
64% yield, after treatment with KF in methanol (Scheme 35).
Selective protection of the side chain hydroxyl as the TES ether,
followed by Yamaguchi macrolactonization43 employing 2,4,6-
trichlorobenzoyl chloride (2,4,6-TCBCl) and global deprotection
with HF completed the synthesis of (þ)-spongistatin 1, which
was identical in all respects (500 MHz 1H NMR, 125 MHz 13C
NMR, HRMS, IR, and chiroptic properties) with literature
data.3i,m The synthesis proceeded with a longest linear se-
quence of 29 steps (based on the EF subunit) with an overall
yield of 0.5%. Importantly, this route represents a significant
improvement over our spongistatin 2 synthesis (ca. 18 fewer
steps)!
Continuing with this analysis, disconnection of 107 led to
dithiane (ꢀ)-64 and aldehyde 108. We first envisioned 108 to
arise from cis-4-heptanal and acid 109 via a Petasis–Ferrier45
union/rearrangement (path A), an effective tactic developed in
our phorboxazole synthetic program to access 2,6-cis-di-
substituted tetrahydropyrans.46 Alternatively, an organocatalyzed
OTBS
OTBS
E
+
-
TESO
H
P Ph I
3
O
OMe H
TESO
O
4
1) LHMDS
HMPA/THF
ABCD(–)-3
(64%)
O
H
O
OMe H
H
O
H
F
OTMS
H
OMe
O
OTMS
OTMS
(+)-103
OH
TBSO
O
H
2) KF
OH
CO H
2
MeOH-THF
(98%)
H
O
Cl
OH
H
O
Cl
AcO
OAc
(+)-104
OTES
OH
E
1) TESCl, Et3N
HO
H
O
2) 2,4,6-TCBCl, i-Pr2NEt,
OH
H
H
Tol.; then DMAP
O
O
D
H
OMe
F
3) HF•Py, MeCN-H2O
(41%, 3 steps)
C
O
HO
H
O
H
OH
O
H
O
O
OH
A
O
Cl
B
AcO
OAc
OH
(+)-Spongistatin 1 (1)
Scheme 35.

6502
A.B. Smith III et al. / Tetrahedron 65 (2009) 6489–6509
protection, removal of the p-methoxyphenyl (PMP) group, and
oxidation.
OTBS
E
29
TESO
H
2.10. Path B: the organocatalytic aldol approach
O
P+Ph3I-
38
OMe H
O
While the Petasis–Ferrier approach to the F-ring pyran suc-
cessfully led to 700 mg of the desired EF ring system [ca. 80 mg of
(þ)-spongistatin 1 from 450 mg], we were intrigued that the two-
step MacMillan47 carbohydrate synthesis might further shorten our
route to (þ)-108. Initially, we sought to combine the MacMillan
cross-aldol reaction of aldehyde 118 with a Mukaiyama aldol re-
action involving silyl enol ether 111 to access 110 (Scheme 38).
Lactol 110 would then be elaborated to the desired F-ring pyran 108
in four chemical operations. Unfortunately, the Mukaiyama aldol
reaction on large scale (ca. 100 g) was hampered both by the in-
H
F
OTES
46OTES
47
OTBS
105
Cl
OTBS
O
stability of the intermediate b
-hydroxyaldehyde 11251 and the ap-
parent sensitivity to impurities generated in the organocatalytic
aldol process.
TESO
CHO
H
O
OMe H
However, encouraged by the efficiency of the organocatalytic
anti-aldol reaction (Scheme 39), 112 was directly subjected as
a syn/anti (w1/5) mixture to a Horner–Wadsworth–Emmons
reaction with methyl (triphenylphosphoranylidene)acetate to
provide ester 119. Sharpless asymmetric dihydroxylation, fol-
lowed by lactonization then led to lactone (ꢀ)-120, which was
isolated as a single isomer in good yield. Only the desired
product arising from the anti-aldol reaction underwent cycli-
zation, thereby permitting facile separation from the syn-aldol
byproduct. Bis-benzylation was then followed by addition of
the Grignard derived from bromide 122, reduction of the re-
sultant lactol with Et3SiH/BF3$Et2O,52 the latter occurring with
concomitant removal of the O-TBDPS protecting group, and
Parikh–Doering oxidation to furnish aldehyde (þ)-108. This
eight-step reaction sequence proceeded with an overall yield of
50% from BPS-protected aldehyde 118. In contrast, the Petasis–
TESO
50
+
Cl
H
106
OTES
OTES
45
107
Br
OPMP
O
38
HO
H
O
HO
O
Path A
H
F
O
O
S S
+
109
OBn
H
46OBn
+
29
BnO
(–)-64
108
O
cis-4-heptenal
Path B
OTMS
OBPS
Ferrier approach, requiring
a
total of 12 steps from
OBn
H
O
H
p-methoxyphenoxy acetaldehyde [two steps to (ꢀ)-109], pro-
ceeded in 26% overall yield. Clearly, the organocatalytic route
would be more applicable for the gram-scale production of
(þ)-spongistatin 1 (1).3j
111
+
HO
OH
OH
O
n
OB
BPSO
H
110
2.11. Construction of ring E
112
Scheme 36.
As with our earlier approaches to the spongistatins, fragment
union to furnish (þ)-124 was achieved via addition of the cerium
dithiane anion derived from (ꢀ)-64 to aldehyde (þ)-108 premixed
with zinc chloride. Although providing the desired adduct, a sig-
aldol approach (path B), patterned after the elegant work of
MacMillan and co-workers47 for the preparation of carbohydrates,
held promise of a viable approach to the F ring pyran 108.
nificant amount of what was presumed to be b-isomer 125 resulted
(Scheme 40). Subsequent experiments revealed that by increasing
the amount of metal additives, in conjunction with decreasing the
amount of HMPA, the amount of 125 could be reduced. However, in
the process we began to observe a third product (126) of un-
determined stereochemistry at C(38). Eventually, we discovered
that formation of both 125 and 126 could be suppressed by
warming the initially generated aldehyde (þ)-108–ZnII reaction
mixture to ꢀ20 ꢁC prior to addition of the cerium dithiane, using
a minimal amount of HMPA (1.5 equiv). Under these conditions,
(þ)-124 was reproducibly generated in 65–68% yield on large scale
(cf. 10 g).
With a reliable route to (þ)-124 securely in hand, we turned to
elaborate ring E. Hydrolysis of the acetonide, followed by iodo-
methane-mediated dithiane removal proceeded with concomitant
hemiketalization to furnish EF diol (þ)-127 in 77% for the two
steps (Scheme 41). Selective silylation of the C(35) hydroxyl, fol-
lowed by exposure to methanolic PPTS then led to methyl ketal
(þ)-128. Removal of the benzyl protecting groups via hydro-
genolysis, however, proved to be more challenging than we had
2.9. Path A: the Petasis–Ferrier union/rearrangement
approach
Preparation of aldehyde 108 began with the TMSOTf-promoted
condensation48 of acid (ꢀ)-109 (prepared in two steps employing
the Evans oxazolidinone chemistry) with cis-4-heptanal to furnish
dioxanone (ꢀ)-113 (Scheme 37). Methylenation49 and exposure of
the enol ether to Me2AlCl led via Petasis–Ferrier rearrangement to
pyranone (ꢀ)-114 as a single isomer. After considerable experi-
mentation, introduction of the C(42) hydroxyl was achieved by
treatment of the potassium enolate of (ꢀ)-114 with the Davis
oxaziridine (þ)-11550 to provide alcohol (þ)-116 in good yield after
epimerization of the C(40) methyl substituent. Silylation of the
newly generated hydroxyl was then followed by selective axial-
reduction and desilylation to furnish diol (þ)-117, which was con-
verted to F-ring aldehyde (þ)-108 in three additional steps: diol

A.B. Smith III et al. / Tetrahedron 65 (2009) 6489–6509
6503
OPMP
O
OPMP
1) Cp2TiMe2,
THF, 65 °C
2) Me2AlCl, CH2Cl2
(77%, 2 steps)
a) HMDS, CH2Cl2
b) cis-4-heptenal
DTBMP
HO
HO
Et
O
TMSOTf, CH2Cl2
(86%, dr=12:1)
O
O
(–)-109
(–)-113
PMP = p-Methoxyphenyl
Me
Me
Me
PMPO
PMPO
R
PMPO
R
O
O
O
O
AlMe2Cl
O
R
Al(III)
O
Al(III)
1) KHMDS; then
OPMP
OPMP
OMe
OMe
40
Et
O
Et
O
N (+)-115
S
O
O2
42
O
O
2) K2CO3, MeOH
(78%, 2 steps)
OH
(+)-116
(–)-114
OPMP
CHO
38
1) NaH, BnBr
1) TM SCl
Et
40
Et
O
F
2) CAN, MeCN
O
2) Bu4NBH4;
then HCl
(85%, 2 steps)
3) SO3•Py
(99%, 3 steps)
42
OBn
OH
46
OBn
(+)-108
OH
O
(+)-117
Scheme 37.
O
O
OH
10% L-Proline
BPSO
118
+
BPSO
H
H
H
DMF, +4 °C
anticipated, being plagued with competitive olefin reduction. Use
of LiDBB, however, proved highly effective to furnish (þ)-129 in
96% yield.
112
(lit: 84%, anti:syn = 5:1, 99% ee)
OTMS
OBn
111
To set the stage for final elaboration of the F-ring side chain,
(þ)-129 was globally protected as the tetra-TES ether (þ)-130
(Scheme 42). Ozonolysis employing reductive workup, followed
without purification by treatment with Eschenmoser’s salt53 next
furnished (þ)-131. Selective 1,2-reduction with DIBAL-H then led to
alcohol (þ)-132, which was converted to bromide (þ)-107 with
CBr4 in the presence of PPh3. Alternatively, the corresponding
OBPS
CHO
OBn
H
O
H
O
H
Et
H
MgBr2•Et2O
Et2O
HO
OH
OBn
OBn
110
108
Scheme 38.
1) Propanal
1) AD-mix β, MeSO2NH2
10% L-Proline
DMF, 4 °C
O
OH
O
t-BuOH-H2O
BPSO
BPSO
H
OMe
2) PPh3= CHCO2Me
(94%, 2 steps)
2) PPTS, Tol., rt
(81%; based on anti)
118
119
OBPS
OH
OBPS
1)
H
O
Br
122
H
O
BnBr, Ag2O
Mg, Et2O
CaSO4,DCE
40 to 60 °C
(78%)
O
2) Et3SiH, BF3•Et2O
(89%, 2 steps)
O
OBn
OH
OBn
(–)-120
(–)-121
OH
CHO
H
H
O
SO3•Py,
O
H
H
F
DMSO, i-Pr2EtN
OBn
OBn
(94%)
OBn
OBn
(+)-123
(+)-108
Scheme 39.

6504
A.B. Smith III et al. / Tetrahedron 65 (2009) 6489–6509
a) n-BuLi, THF-HMPA
O
O
S S
–78 to –45 °C, 30 min
38
b) CeCl3, THF, –78 °C, 1 h
O
O
HO
H
OBn
S S
4
OBn
O
c) ZnCl2, THF
H
Et
O
4
H
–78 °C
Et
H
(+)-124
O
F
H
OBn
(–)-64
OBn
OBn
+
(+)-108
(68%)
OBn
O
O
S S
HO 38
Result:
equiv. (+)-124 125 126
ZnCl2
equiv.
HMPA
equiv.
CeCl3
OBn
Entry
4
1
2
3
4
5
1.2
1.2
2.1
2.1
1.2*
7.5
6.0
3.0
2.0
1.5
3.2
3.5
5.0
4.5
3.5
50% 46%
51% 37%
53% 9%
-
125
-
+
25%
61% 17% 13%
O
O
S S
38
HO
68% 19% 12%
*Aldehyde/ZnCl2 mixture warmed
to –20 °C prior to addition
126
Scheme 40.
OH
O
O
S S
38
35
1) p-TsOH,
MeCN-H2O
(95%)
HO
H
OBn
E
HO
OBn
4
O
H
O
H
OH
4
Et
O
2) MeI, CaCO3,
MeCN-H2O
(81%)
H
Et
H
F
OBn
OBn
OBn
(+)-127
OBn
(+)-124
OTBS
35
1) TBSOTf, 2, 6-Lut.,
CH2Cl2 (84%)
LiDBB, THF,
–78 to –45 °C
(96%)
HO
O
OBn
H
O
H
OMe
4
2) PPTS, MeOH
(96%)
Et
H
OBn
OBn
(+)-128
OTBS
O
OH
OH
H
O
H
OMe
4
Et
H
OH
OH
(+)-129
Scheme 41.
iodide (þ)-133 could be prepared by treatment with I2 in the
C(47) alcohols. The yield, however, was only modest (ca. 42%). We
therefore turned to an umpolung approach.56
presence of PPh3.
In this scenario, we envisioned addition of an O-protected
cyanohydrin57 to either bromide (þ)-107 or iodide (þ)-133
(Scheme 42). Accordingly, aldehyde 106 was treated with trime-
thylsilyl cyanide in the presence of ZnI2 to furnish cyanohydrin
135 (Scheme 44).58 Attempts to deprotonate 135 and trap the
resulting ion with either (þ)-107 or (þ)-133, however, resulted
only in decomposition of the cyanohydrin or recovery of the allyl
halide.
2.12. Elaboration of the EF side chain
Our initial approach focused on a tin-mediated Barbier allylation
protocol54 between known chlorodiene aldehyde 10655 and bro-
mide (þ)-107 (Scheme 43). To this end, treatment of a premixed
solution of bromide (þ)-107 and aldehyde 106 with SnCl2$2H2O in
the presence of NaI proceeded to furnish 134 as a mixture (1:1) of

A.B. Smith III et al. / Tetrahedron 65 (2009) 6489–6509
6505
OTBS
OTBS
OH
H
OH
4
TESCl,
O
TESO
H
OTES
4
OMe
H
Imid., DMF
O
OMe H
Et
O
(99%)
H
Et
O
H
OH
OTES
OH
(+)-129
OTES
(+)-130
OTBS
a) O3,CH2Cl2,
b) Me2S, Et3N
DIBAL-H,
CH2Cl2
TESO
OTES
4
O
OMe H
H
O
c) CH2=N+Me2I-
(76%, one-pot)
–78 °C (97%)
H
OTES
O
OTES
(+)-131
OTBS
O
OTBS
CBr4, PPh3, Et3N,
CH2Cl2 (98%)
TESO
H
OTES
4
TESO
OTES
O
OMe H
H
H
O
OMe
4
or
O
I2, PPh3,
Imid.,
THF (98%)
H
H
46
OTES
OTES
OTES
OTES
OH
X
(+)-132
X = Br, (+)-107
X = I, (+)-133
Scheme 42.
OTBS
OTBS
SnCl2•2H2O, NaI,
Et3N, DMF
TESO
H
OTES
TESO
OTES
O
O
H
OMe H
OMe
H
O
4
4
CHO
O
H
H
106
Cl
OTES
OTES
(42%, dr = ~1:1)
Br
OTES
(+)-107
OTES
134
OH
Cl
Scheme 43.
Reasoning that the extended conjugation of the cyanohydrin
might be responsible for decomposition via an elimination path-
Conversion of the C(29) hydroxyl to the corresponding iodide then
fortuitously proceeded with concomitant elimination of the C(49)
hydroxyl to provide (þ)-143, which upon Corey reduction60 with
(R)-Me-CBS afforded allylic alcohol (þ)-144 with good diaster-
eoselectivity (dr>10:1). Protection of the free hydroxyl, followed
by treatment with PPh3 completed construction of Wittig salt
(þ)-105.
way, we opted to mask the olefin as a protected
b-hydroxyl.
Construction of the revised cyanohydrin 141 began with an aldol
reaction between the lithium enolate of tert-butyl acetate 137 and
aldehyde 138 (generated in situ via Swern oxidation of the cor-
responding alcohol)59 to furnish racemic 139 (Scheme 45). Pro-
tection of the alcohol without purification with TESCl provided
140, which was converted to cyanohydrin 141 in two additional
steps.
Pleasingly, cyanohydrin 141 underwent clean deprotonation
and union with allylic iodide (þ)-133 to furnish diol 142, after
removal of the silyl groups at C(29) and C(49) (Scheme 46).
Comparison of the three approaches to the EF Wittig salts [cf.
(þ)-103 and (þ)-105] from the prospective of step economy reveals
near equivalency; the Evans glucal epoxide approach 24 steps, the
Petasis–Ferrier tactic 26 steps, and organocatalytic aldol approach 24
steps. However, the efficiencies are markedly different, being 1.8, 8.3,
and9.4%, respectively, inoverallyieldsfromknownstartingmaterials.

6506
A.B. Smith III et al. / Tetrahedron 65 (2009) 6489–6509
O
OTMS
CN
TMSCN, ZnI2, CH2Cl2
H
(68%)
Cl
Cl
106
135
OTBS
O
OTES
a) LiHMDS, THF, –78 °C
TESO
H
OMe
H
b)
OTBS
O
H
OTES
TESO
H
OTES
O
H
OMe
OTES
OTMS
THF
–78 °C to rt
O
H
OTES
OTES
CN
Cl
(+)-107: X = Br
(+)-133: X = I
136
X
Scheme 44.
OH
O
O
a) LDA, THF
–78 °C
quantity of (þ)-spongistatin 1 comprises more of the natural
product than has arisen from all the isolation and synthetic
studies combined.
TESCl, Imid., THF
Ot-Bu
137
Ot-Bu
b)
(97%, 2 steps)
O
138
Cl
139
Cl
1) DIBAL-H, Tol.
–78 °C (85%)
TESO
Cl
O
TESO
OTMS
1) LiHMDS, THF, –78 °C to rt;
then (+)-133
OTBS
O
2) KF, MeOH-THF
(97%, 2 steps)
Ot-Bu
CN
OTMS
CN
TESO
Cl
2) TMSCN, ZnI2
CH2Cl2 (81%)
TESO
H
OH
140
Cl
141
OTBS
H
OMe
4
141
Scheme 45.
O
H
TESO
H
OTES
OTES
OTES
O
OMe H
4
O
H
142
O
OTES
OTES
45
Cl
2.13. Fragment union and completion of the second- and
third-generation total syntheses
OH
I
(+)-133
OTBS
OTBS
Having improved our approach to EF Wittig salt (þ)-105, all
that remained was union with aldehyde (ꢀ)-3 and final elabo-
ration to the natural product (Scheme 47). Wittig reaction be-
tween (þ)-105 and (ꢀ)-3 proceeded smoothly to provide alkene
(þ)-145 as a single isomer in 62% yield when utilizing LHMDS61
or in 64% when relying on MeLi$LiBr.62 Removal of the TES and
TIPS protecting groups was then achieved with TBAF in THF3m,n
to furnish seco-acid (þ)-146, which upon regioselective Yama-
guchi macrolactonization3c furnished macrolactone (þ)-147 in
85% yield.
TESO
H
I
TESO
I
O
O
H
OMe
H
O
4
OMe
4
H
(R)-Me-CBS,
I2, PPh3
O
BH3•THF, THF
Imid., THF
H
H
(80%, dr > 10:1)
–45 to 0 °C
(88%)
OTES
OTES
OTES
OTES
O
(+)-144
OH
(+)-143
Cl
Cl
Completion of the total synthesis now only required global
deprotection. While we had previously relied upon dilute HF/
acetonitrile in our first-generation synthesis of (þ)-spongistatin 1
(1), yields were highly variable. We therefore explored the
Heathcock conditions,3m,n calling on a higher concentration of
acid at lower temperature, as developed in their (þ)-spongistatin
OTBS
E
29
TESO
H
P+Ph3I-
1) TBSOTf, 2,6-Lut.,
THF(99%)
O
H
OMe
O
2) PPh3, Li2CO3,
MeCN-Benzene, 70 °C
(98%)
H
F
2
synthesis. These conditions furnished an 87% yield of
OTES
OTES
(þ)-spongistatin 1 (1). As such, the third-generation synthesis
requires a longest linear sequence of 31 steps and proceeds with
an overall yield of 3.1%. Using this protocol we have been able to
prepare 80 mg of (þ)-spongistatin 1 (1) via Petasis–Ferrier union
tactic and 929 mg via the organocatalytic aldol strategy for a total
of 1.009 g of synthetic (þ)-spongistatin 1 (1). Importantly, this
(+)-105
OTBS
Cl 50
Scheme 46.

A.B. Smith III et al. / Tetrahedron 65 (2009) 6489–6509
6507
OTBS
O
OTBS
O
OTBS
TESO
H
29
TESO
H
P+Ph3I-
TESO
OH
H
H
O
O
OMe H
H
O
OMe H
H
O
4
LiHMDS, THF-HMPA;
ABCD (–)-3 (62%)
or
O
2,4,6-TCBCl, i-Pr2NEt,
H
OMe
O
41
Tol.; thenDMAP
H
H
OMe
O
O
TBSO
O
H
1
OTES
OTES
41
1
(85%)
OR
TBSO
2
MeLi•LiBr, THF;
OH
O
H
O
ABCD (–)-3 (64%)
OR
CO R
2
H
O
2
H
OTBS
AcO
O
H
O
OTBS
(+)-105
OTBS
AcO
O
H
Cl
O
Cl 50
50
Cl
OAc
(+)-147
OAc
OTES
OTES
(+)-145: R1=TES, R2=TIPS
TBAF, THF
(71%)
(+)-146: R1, R2=H
OH
E
HO
H
O
OH
H
H
O
O
5M HF, –20 °C
CH3CN-H2O
D
H
OMe
F
C
O
HO
O
H
(87%)
OH
O
H
O
O
OH
H
O
B
A
Cl
AcO
OAc
OH
(+)-Spongistatin 1 (1)
Scheme 47.
3. Conclusion
the (þ)-spongistatin 2 synthesis proved inefficient. In contrast,
elaboration of the partially functionalized side chain prior to union
to the EF ring system proved more efficient as evidenced by the
increase in the overall yield of this fragment from 0.3% in our
(þ)-spongistatin 2 synthesis to 1.8% in our first-generation ap-
proach to (þ)-spongistatin 1. Despite these improvements, the te-
dious nature of the EF dihydropyran construction, in conjunction
with the sensitivity of the side chain, compromised large-scale
advancement of the material. We therefore developed an approach,
which incorporated an efficient cyanohydrin alkylation to complete
the F-ring side chain. This approach proved to be much more ef-
fective than the earlier two tactics, removing the need to perform
extensive manipulations on advanced intermediates and/or the
synthesis of highly sensitive coupling partners. The improved effi-
ciency is best exemplified by the fact that that we can now con-
struct the EF Wittig salt with an overall yield of 9.5% from known
materials. Finally, the integrity of the C(23) spiroketal stereocenter
was maintained throughout the synthesis.
Three stereocontrolled total syntheses of (þ)-spongistatin 1
have been achieved. Comparison of the three routes reveals that the
third-generation route is roughly four times more efficient in terms
of overall yield than the first-generation route. Given that the
endgames of all three routes are similar, the differences in the
overall efficiencies reside in the tactics employed to arrive at
the subtargets. For the ABCD aldehyde (ꢀ)-3, our dithiane-medi-
ated multicomponent linchpin coupling proved to be an extremely
powerful method for construction of the AB and CD subunits.
Clearly, the different fragment union protocols played a critical role
in the outcome of the different syntheses. For example, the Julia
union/methylenation process proceeded in high yield in our origi-
nal (þ)-spongistatin 2 (2) synthesis, a result of the simplified nature
of the coupling partners. A large number of transformations,
however, were required after fragment union to complete the ABCD
aldehyde. By comparison, the boron aldol approach in the
(þ)-spongistatin 1 (1) synthesis permitted advancement with more
highly functionalized fragments, thereby increasing both the con-
vergency and overall efficiency for the ABCD aldehyde, as evi-
denced by an increase in the overall yield of this fragment from 1.4%
to 6.5%.
An even more dramatic improvement in terms of efficiency can
be seen in the diverse strategies to construct the EF Wittig salt. In
both our (þ)-spongistatin 2 (2) and (þ)-spongistatin 1 (1) synthe-
ses, ring F was constructed from a linear precursor, coupled to an E-
ring fragment precursor and then subjected to cyclization prior to
side chain introduction. Unfortunately, side chain installation in the
(þ)-spongistatin 2 (2) synthesis was compromised by an un-
expected low yield of the Julia union/methylenation tactic. This
information in conjunction with the extensive number of trans-
formations required to evolve the fully elaborated EF side chain in
Acknowledgements
Financial Support was provided by the National Institute of
Health (National Cancer Institute) through Grant No. CA-70329,
and by Postdoctoral Fellowships from the Uehara Memorial Foun-
dation and the Japanese Society for the Promotion of Science to S.S.,
the Royal Society Fulbright Fellowship to V.A.D., the American
Cancer SocietydMichael Schmidt Fellowship to C.A.R., and the
Ruth L. Kirschstein National Research Service Award FCA121716A
from the National Cancer Institute to J.B.S. We also thank Dr. George
T. Furst, Dr. Patrick J. Carroll, and Dr. Rakesh Kohli of the University
of Pennsylvania Spectroscopic Center for assistance in securing and
interpreting high-field NMR, X-ray crystal structures, and mass
spectra, respectively.

6508
A.B. Smith III et al. / Tetrahedron 65 (2009) 6489–6509
22. Smith, A. B., III; Chen, S. S.-Y.; Nelson, F. C.; Reichert, J. M.; Salvatore, B. A. J. Am.
Supplementary data
Chem. Soc. 1995, 117, 12013.
23. (a) Keck, G. E.; Krishnamurthy, D.; Grier, M. C. J. Org. Chem. 1993, 58, 6543; (b)
Keck, G. E.; Tarbet, K. H.; Geraci, L. S. J. Am. Chem. Soc. 1993, 115, 8467; (c)
Molinski, T. F.; Searle, P. A.; Brzezinski, L. J.; Leahy, J. W. J. Am. Chem. Soc. 1996,
118, 9422.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tet.2009.04.003.
24. The configuration of the newly formed stereocenter was assigned using the
Mosher’s ester analysis. See Ref. 10.
25. Fujita, E.; Nagao, Y.; Kaneko, K. Chem. Pharm. Bull. 1978, 26, 3743.
26. Attempts to equilibrate the undesired ketone (þ)-57, employing the same
conditions, produced only a 1:1.2 mixture of spiroketals (Scheme 20), sug-
gesting that (þ)-57 does not possess the proper combination of geometry and
functionality to coordinate effectively with calcium ion and thereby lead to the
desired (AE) product.
27. Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A.; Hartung, J.; Jeong,
K. S.; Kwong, H.-L.; Morikawa, K.; Wang, Z.-M.; Xu, D.; Zhang, X.-L. J. Org. Chem.
1992, 57, 2768.
References and notes
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28. Diol stereochemistry was assigned based on the Sharpless precedent. See: Ref. 27.
29. Assignment of the structure of (ꢀ)-3, specifically the C(15) and C(16) stereo-
centers was achieved via extensive NMR studies (see Supplementary data). In
addition, we preformed a chemical correlation involving spectroscopic com-
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3. (a) Evans, D. A.; Coleman, P. J.; Dias, L. C. Angew. Chem., Int. Ed. 1997, 36, 2738;
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unit to the conditions used for the purification.
43. (a) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull. Chem. Soc.
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46. (þ)-Phorboxazole: (a) Smith, A. B., III; Verhoest, P. R.; Minbiole, K. P.; Lim, J. J.
Org. Lett. 1999, 1, 909; (b) Smith, A. B., III; Minbiole, K. P.; Verhoest, P. R.;
Beauchamp, T. J. Org. Lett. 1999, 1, 913; (c) Smith, A. B., III; Minbiole, K. P.;
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Ferrier tactic has also been employed by us in the synthesis of (þ)-zampanolide
and (þ)-dactylolide: (d) Smith, A. B., III; Safonov, I. G.; Corbett, M. R. J. Am.
Chem. Soc. 2001, 123, 12426; (e) Smith, A. B., III; Safonov, I. G.; Corbett, R. M.
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E. F.; Meyer, E. A. J. Am. Chem. Soc. 2006, 128, 5292; (ꢀ)-Clavosolide A: (g) Smith,
A. B., III; Simov, V. Org. Lett. 2006, 8, 3315; (ꢀ)-Okilactomycin: (h) Smith, A. B.,
III; Basu, K.; Bosanac, T. J. Am. Chem. Soc. 2007, 129, 14872; For a review see: (i)
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43, 2152.
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13. Hicks, D. R.; Fraser-Reid, B. Synthesis 1974, 3, 203.
14. Work from our (þ)-spongistatin 2 synthesis had shown that the TES ether was
the optimal protecting group for the C(9) hydroxyl. See Ref. 5.
15. Walkup, R. D.; Kane, R. R.; Boatman, P. D., Jr.; Cunningham, R. T. Tetrahedron Lett.
1990, 31, 7587.
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991.
56. Although unable to orchestrate a satisfactory allylation strategy, the separable
mixture of diastereomers (þ)-134
confirm rigorously the stereochemical assignments of our advanced in-
, the ‘slower moving
b
and (þ)-134
a did provide an opportunity to
20. Over the years we have also deployed a stepwise coupling approach for the
synthesis of the AB aldehyde. Both the multicomponent linchpin coupling
tactic, as well as the stepwise approach have contributed significant amounts
of material toward the gram-scale effort.
21. Smith, A. B., III; Zhuang, L.; Brook, C. S.; Lin, Q.; Moser, W. H.; Trout, R. E. L.;
Boldi, A. M. Tetrahedron Lett. 1997, 38, 8671.
termediates via chemical correlation. Polyol (þ)-135
a
isomer’ (in reference to the TLC motilities of the two isomers), was identical in
all respects (500 MHz 1H NMR, 125 MHz 13C NMR, HRMS, IR, and chiroptic
properties) to our first-generation EF Wittig salt intermediate (þ)-101.

A.B. Smith III et al. / Tetrahedron 65 (2009) 6489–6509
6509
57. (a) Stork, G.; Maldonado, L. J. Am. Chem. Soc. 1971, 93, 5286; (b) Stork, G.;
Maldonado, L. J. Am. Chem. Soc. 1974, 96, 5272.
OTBS
O
OTBS
OTES
OH
58. Evans, D. A.; Truesdale, L. K.; Carroll, G. L. J. Chem. Soc., Chem. Commun. 1973, 55.
59. Ireland, R. E.; Norbeck, D. W. J. Org. Chem. 1985, 50, 2198.
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1987, 109, 7925.
61. Excess ABCD aldehyde (ꢀ)-3 can be recovered and purified following conver-
sion to the corresponding ABCDCH2OH with NaBH(OAc)3.
62. Excess EF Wittig salt (þ)-105 can be recovered with 94% purity via col-
umn chromatography, followed by precipitation of excess Ph3P(O) with
hexane.
TESO
H
TESO
H
O
KF
OMe H
H
OMe
MeOH/THF
O
O
H
H
(78%)
OTES
OTES
OH
OH
OH
(+)-135α = (+)-101
47
47
OH
(+)-134α
"lower isomer"
Cl
Cl