Oxabicyclo[3.2.1]oct-6-enes as templates for the stereoselective synthesis of polypropionates: Total synthesis of callystatin a and C19-epi-callystatin A

Article abstract of DOI:10.1055/s-2002-34386

The total synthesis of the polyketide natural product callystatin A and its novel analog C19-epi-callystatin A is described. Our strategy features the use of an enantiomerically pure oxabicyclo[3.2.1]oct-6-ene as a template for the stereocontrolled preparation of the C15-C21 polypropionate region.

Full text of DOI:10.1055/s-2002-34386

PAPER
1993
Oxabicyclo[3.2.1]oct-6-enes as Templates for the Stereoselective Synthesis of
Polypropionates: Total Synthesis of Callystatin A and C19-epi-Callystatin A
O
xabicyclo[3.2.1]oct-6
a
-enes as Te
r
m
plates
k
for Polypropionate
L
s: Total Synthe
a
sis of Cally
u
statin
A
tens,* Timothy A. Stammers
Davenport Research Laboratories, Department of Chemistry, University of Toronto, Toronto, Ontario, M5S 3H6, Canada
Fax +1(416)9786083; E-mail: mlautens@chem.utoronto.ca
Received 16 June 2002
Dedicated to Professor D. Seebach in recognition of his diverse contributions to organic chemistry.
relationships.14 These studies suggested the pharmacoph-
Abstract: The total synthesis of the polyketide natural product
ore of callystatin A is the unsaturated lactone which has
callystatin A and its novel analog C19-epi-callystatin A is de-
been confirmed as the pharmacophore of the related com-
scribed. Our strategy features the use of an enantiomerically pure
pound leptomycin B.15 The SAR studies by Kobayashi
oxabicyclo[3.2.1]oct-6-ene as a template for the stereocontrolled
preparation of the C15–C21 polypropionate region.
and co-workers also demonstrated that the remainder of
the molecule contributed significantly to activity of
callystatin A emphasizing the importance of synthetic an-
alogues of the natural product.
Key words: total synthesis, natural products, asymmetric synthe-
sis, ring opening, stereoselectivity
Our retrosynthetic analysis is outlined in Scheme 1 and
employed an E-selective tributylphosphonium Wittig type
reaction16 to join the known C1–C12 aldehyde 3 and the
C13–C22 polypropionate fragments 4 and 5. This cou-
pling strategy has been shown to be effective in three pre-
vious total syntheses.8,9,13 The work reported in this article
primarily focuses on our studies towards the efficient
preparation of C13–C22 phosphonium salts 4 and 5. The
structural element of callystatin A 1 which initially at-
tracted our attention to this series of natural products was
the C15–C21 polypropionate region containing the 1,3,5-
syn,syn-trimethyl configuration. We anticipated that the
C13–C22 fragments would be derived from tetraol inter-
mediate 6, which contains the desired 1,3,5-syn,syn-tri-
methyl configuration, that we had reported in an earlier
The structure of the marine polyketide callystatin A (1)
was reported by Kobayashi and co-workers in 19971 and
was followed shortly thereafter by the confirmation of its
relative and absolute configuration.2 Callystatin A is one
of several structurally related polyketide natural products
that display potent and diverse biological activities that in-
clude the anguinomycins,3 kazusamycin,4 leptofuranins,5
leptomycins6 and leptolstatin.7 Callystatin A has been the
target of significant synthetic research interest including
total syntheses published by the research groups of
Kobayashi,8 Crimmins,9 Smith,10 Kalesse,11 Marshall,12
and Enders.13 Recent efforts from Kobayashi and co-
workers have involved the preparation of several structur-
al analogues of callystatin A to develop structure–activity
Scheme 1 Retrosynthetic analysis of callystatin A
Synthesis 2002, No. 14, Print: 07 10 2002.
Art Id.1437-210X,E;2002,0,14,1993,2012,ftx,en;C03302SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

1994
M. Lautens, T. A. Stammers
PAPER
communication.17 Tetraol 6 had been prepared in four cycloaddition. The stereoselectivity of the cycloaddition
steps (Scheme 4) from enantiomerically pure [3.2.1]oxa- is rationalized by the extended transition state depicted in
bicycle 7.18
Scheme 3 where the zinc not only chelates (furan-2-yl)cy-
clohexylmethoxide, but also the incoming oxyallyl cation
providing [3.2.1]oxabicyclooctanone 7 with diaxial meth-
yl groups (relative to the chair conformation drawn for 7
in Scheme 3) in high selectivity, a feature which is unique
among [4 + 3] cycloadditions.31 The key benefit associat-
ed with the formation of 7 is that a methyl-NRO reaction
will result in the desired 1,3,5-syn,syn-trimethyl arrange-
ment in contrast to the transition metal catalyzed NRO of
meso-[3.2.1]oxabicycle illustrated in Scheme 2. Exten-
sive studies on the reduction of the ketone in 7 have al-
lowed selective access to cis-alcohol 8. The consequence
of forming this diastereomer is the stereochemistry at
what will become C19 of callystatin A is epimeric to the
natural product [C19-epi-callystatin A (2)] necessitating
an inversion of the hydroxyl stereochemistry at the C19-
position at a later stage in the synthesis in order to access
callystatin A (1).
Work in our group and others has focused on the use of
[3.2.1]oxabicycles as a templates for the synthesis of acy-
clic polypropionates.19–21One of the key issues relating to
the use of [3.2.1]oxabicycles is the need to generate enan-
tiomerically pure intermediates. Strategies reported in the
literature include asymmetric hydroboration,22 asymmet-
ric deprotonation,23 enzymatic resolution,24 a tandem cat-
alytic asymmetric cyclopropanation/Cope rearangement25
and diastereoselective [4 + 3] cycloadditions.18,26 Recent
efforts in our own laboratories have focused on transition
metal catalyzed asymmetric methods such as reductive
ring opening (RRO)27 and nucleophilic ring opening
(NRO, Scheme 2)28 reactions of meso-[3.2.1]oxabicycles.
However, neither of these methodologies are suitable for
the preparation of the C15–C21 1,3,5-syn,syn-trimethyl
substituted fragment of callystatin A (2). For example, the
catalytic asymmetric methyl-NRO of the meso-[3.2.1]-
oxabicycle shown in Figure 2 results in a functionalized The methyl-NRO reaction of 9, which secured the desired
cycloheptene which corresponds to a 1,3,5-syn,anti-trim- 1,3,5-syn,syn-trimethyl arrangement, was studied in de-
ethyl relationship.28b
tail.17 Silyl ether 9 was prepared selectively from diol 8 in
90% yield in the presence of triisopropylsilyl triflate and
2,6-lutidine as shown in Scheme 4. Cerium(III) chloride
was found to be crucial for the NRO reaction to proceed
with methyllithium and further optimization of tempera-
ture effects has led to a slightly improved yield of cyclo-
heptene 10.17 Oxidative rupture of cycloheptene 10 with
ozone followed by reductive work-up with sodium boro-
We relied upon a previously described diastereoselective
[4 + 3] cycloaddition18 to generate the enantiomerically
pure [3.2.1]oxabicycle 7 as illustrated in Scheme 3. Non-
racemic (furan-2-yl)cyclohexylmethanol, prepared from a
Sharpless asymmetric epoxidation resolution,29 was treat-
ed with diethylzinc and 2,4-dibromopentanone30 to gener-
ate the respective reactive species that undergoes the
Me2Zn, Zn(OTf)2,
Pd(CH3CN)2Cl2
OTIPS
O
ClCH2CH2Cl, reflux
HO
OH
OH
O
N
OTIPS
TIPSO
OH
73% yield
93% ee
ref.22b
PPh3
Fe
Scheme 2 Catalytic enantioselective NRO of a meso-[3.2.1]oxabicycle
Zn
THF, ZnEt2,
-15 to 25 oC
O
O
OH
O
O
HO
19
O
O
O
H
7
Br Br
O
HO
OH
19
O
OH
8
Scheme 3 Diastereoselective [4 + 3] cycloaddition and ketone reduction
Synthesis 2002, No. 14, 1993–2012 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Oxabicyclo[3.2.1]oct-6-enes as Templates for Polypropionates: Total Synthesis of Callystatin A
1995
OTIPS
O
O
a
b
HO
HO
OH
OH
OTIPS
HO
8
9
10
c
OH
Cy
HO
OH OR OH
6: R=TIPS
Scheme 4 a) TIPSOTf, CH2Cl2, 2,6-lutidine, 0 °C, 90%; b) MeLi, CeCl3,THF–Et2O, –78 to –15 °C, 85%; c) O3, CH2Cl2–MeOH, –78 °C;
then NaBH4, 69 h, 20 °C, 91%
hydride afforded tetraol 6 as a single diasteriomer in 91% While lactol 12 was unreactive towards olefination it
yield.
could be reduced to acyclic diol 13 in the presence of
LiBH4 at 50 °C in a servicable yield of 71% (Scheme 6).
The hydroxyls of diol 13 were differentiated through
acetylation then a selective saponification of the less hin-
dered acetate to yield alcohol 14. Installation of the C22
methyl moiety was first attempted by activating the pri-
mary hydroxyl as a tosylate (95% yield) then treating the
intermediate with Me2CuCNLi2. There was no observed
reaction with the tosylate until warming to 0 °C where py-
ran 15 was obtained as the major product in 38% yield.
Presumably, upon decomposition of the cuprate reagent
the acetate at C17 was cleaved and the resulting alkoxide
underwent the intramolecular cyclization. The one carbon
homologation could be accomplished by oxidation of 14
followed by Wittig olefination to afford alkene 16 in 61%
yield. Hydrogenation of the alkene and the subsequent se-
lective hydrolysis of the primary tert-butyldimethylsilyl
group provided the advanced intermediate 17 in 71%
yield over two steps. While this route was successful, we
were discouraged by the number of protecting group ma-
nipulations. In addition, the route did not present an ap-
pealing opportunity to invert the stereochemistry at C19.
A key challenge in our synthesis was developing a pro-
tecting group strategy for the multiple hydroxyls of tetraol
6 that allowed for an efficient route to the C13–C22 frag-
ments for C19-epi-callystatin A 4 and callystatin A 5. A
number of strategies were explored and are discussed be-
low. In our initial report,17 the vicinal diol in tetraol 6 was
oxidatively cleaved in the presence of periodic acid result-
ing in a lactol that could be masked efficiently as methyl
lactol 11, Scheme 5. While the primary hydroxyl of 11
was readily manipulated, the methyl lactol proved highly
resistent to hydrolysis without concomitant removal of the
triisopropylsilyl ether. Instead we sought to utilize the lac-
tol directly after its formation. To this end we selectivily
silylated the primary hydroxyl of 6 then treated the result-
ing diol with lead(IV) acetate to afford lactol 12 in 98%
yield over the two steps. Unfortunately, the lactol proved
unreactive towards olefination with a variety of reagents
under various conditions.
It is interesting to note that the acyclic polypropionate in-
termediate A, the open conformation of lactol 11, is pseu-
do-symmetric, diffentiated only by protecting groups and
oxidation state. Thus, depending on the absolute configu-
ration of oxabicycle 7, the polypropionate fragment could
be extended in either direction.
The complications associated with the lactol intermedi-
ates prompted us to pursue a strategy, which completely
circumvented lactol formation. Selective formation of a
cyclic carbonate was investigated and our results are
OH
a, b
c,d
TIPSO
TIPSO
O
HO
OH
OTBS
HO
Cy
O
O
OH OR OH
11
6: R=TIPS
12
O
HO
OH OTIPS
A
Scheme 5 a) H5IO6, NaHCO3, THF–H2O, 24 °C, 0.25 h, 94%; b) MeOH, TsOH, 24 °C, 8 h, 84%; c) TBSCl, CH2Cl2, Im, 0 to 20 °C, 1 h,
98%; d) Pb(OAc)4, PhH–MeOH, 0 °C, 0.5 h, >99%
Synthesis 2002, No. 14, 1993–2012 ISSN 0039-7881 © Thieme Stuttgart · New York

1996
M. Lautens, T. A. Stammers
PAPER
TIPSO
OTBS
b, c
a
17
TBSO
OH
TBSO
OH
O
HO
OH OTIPS
AcO
OTIPS
14
12
13
f, g
d, e
TIPSO
h, i
22
HO
TBSO
O
17
AcO
OTIPS
AcO
OTIPS
H
OTBS
17
16
15
Scheme 6 a) LiBH4, THF, 50 °C, 3 h, 71%; b) Ac2O, Et3N, cat. DMAP, CH2Cl2, 20 °C, 1.5 h, 96%; c) K2CO3, MeOH, 1 h, 20 °C, 92%; d)
TsCl, cat. DMAP, Et3N, CH2Cl2, 20 °C, 17 h, 95%; e) Me2CuCNLi2, Et2O, –15 to 0 °C, 1 h, 38%; f) TPAP, NMO, CH2Cl2, 20 °C, 0.75 h, 95%;
g) Ph3C=CH2, THF, –15 °C, 0.33 h, 64%; h) H2, 10% Pd/C, EtOAc, 20 °C, 0.33 h, >99%; i) PPTS, EtOH, 50 °C, 24 h, 71%
shown in Scheme 7. Acylation of the primary hydroxyl of shown in Scheme 8. We found the desired reactivity by
6 with (4-nitrophenyl)chloroformate proceeded selective- employing 4-methoxybenzaldehyde dimethylacetal33 and
ly at 0 °C and upon consumption of the starting material, catalytic acid. Initial attempts, Entry 1, Table 1, demon-
dimethylaminopyridine was added and the mixture was strated that the reaction in DMF was partially selective to-
allowed to warm to ambient temperature to form the cy- wards the formation of 6-membered benzylidene 20 (49%
clic carbonate. Oxidative cleavage of the vicinal diol pro- yield) but bis-benzylidene 21, 5-membered benzylidenes
vided aldehyde 18 in 86% yield over the two steps. The 22a–b, as well as recovered starting material 6 were also
C22 methyl terminus was introduced through Wittig ole- observed. Unfortunately, in DMF, 20 was formed as a
fination and hydrogenation to afford 19. Though this strat- mixture of diasteriomers at the benzylidene carbon. The
egy significantly reduced the number of steps compared to product distribution was essentially unaffected by chang-
the previous route described in Scheme 6, intrinsic prob- ing solvent but less polar solvents such as toluene and
lems were identified with the carbonate. The leading is- dichloromethane (Entry 2) favored the formation of a sin-
sues were the selective opening of the carbonate, the low gle diasteriomer of 20. We have tentatively assigned the
yield of the Wittig olefination and the questionable com- relative stereochemistry of 20 such that the substituents
patibility of the cyclic carbonate with an oxidation/reduc- are disposed equatorially on the six-membered ring. We
tion sequence necessary for the correction of the C19 hypothesized that the 5-membered benzylidene would be
hydroxyl stereochemistry.
favored under kinetic conditions and we observed this to
be true at –35 °C based on thin layer chromatography
analysis. It then followed that the 6-membered ben-
zylidene may be favored under equilibrating conditions.
However, heating the reaction mixture in toluene at 90 °C
over a prolonged period resulted in the unfavorable distri-
bution of the observed products reported in Entry 3. We
were dismayed to find that when the reaction was per-
formed on a larger scale (4.1 mmol of 6, Entry 4) the prod-
uct distribution differed substantially from that shown in
Entry 2 (0.4 mmol). Acceptable and reproducible yields
were observed at ambient temperature (Entry 5). Further
experimentation demonstrated improved reaction perfor-
mance at higher concentration (Entries 6 and 7). The mod-
est overall yield of 20 necessitated the recycling of the
unwanted benzylidenes 21 and 22, which was done effi-
As an alternative to the cyclic carbonate, we investigated
the use of a 4-methoxybenzylidene to selectively protect
the 1,3-diol of tetraol 6. The benzylidene was predicted to
be stable to the conditions for the oxidation/reduction se-
quence required for the inversion of the C19-hydroxyl as
well as the other anticipated transformations. In addition,
benzylidenes have been shown to be versatile in terms of
their removal or opening to the corresponding benzyl
ethers. The selective formation of acetals and ketals on
acyclic polyhydroxylated compounds does appear in the
literature.32 Generally, it has been established that ace-
tonides and pentanolides will selectively protect 1,2-diols
but examples exist where a benzylidene was selectively
formed on a 1,3-diol in the presence of a 1,2-diol.32f With
these examples in mind we investigated the reaction
OH
c, d
O
a, b
HO
Cy
O
O
OTIPS
O
O
OTIPS
OH OR OH
6: R=TIPS
18
19
O
O
Scheme 7 a) (4-NO2PhO)COCl, CH2Cl2, Et3N, 0 °C, 1 h; then DMAP, 24 °C, 60 h, 92%; b) Pb(OAc)4, PhH, MeOH, 0 °C, 10 min, 94% c)
Ph3C=CH2, THF, –78 °C, 0.33 h, 49%; d) H2, 10% Pd/C, Et2O, 20 °C, 0.5 h, 90%
Synthesis 2002, No. 14, 1993–2012 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Oxabicyclo[3.2.1]oct-6-enes as Templates for Polypropionates: Total Synthesis of Callystatin A
1997
Scheme 8
ments 4 and 5. Our initial foray is described in Scheme 9.
Oxidative cleavage of the vicinal diol of 20 with lead(IV)
acetate and subsequent Wittig homologation of the alde-
hyde produced alkene 23 in excellent yield. After consid-
erable experimentation it was found that selective
hydrogenation of the terminal alkene of 23 could be car-
ried out with 10% Pd/C in ethyl acetate without any ob-
servable reduction of the benzylidene to cleanly afford 24.
Selective reductive opening of the benzylidene with
DIBAL-H34 in CH2Cl2 released the primary hydroxyl,
which was then oxidized in the presence of PCC resulting
in aldehyde 25 in 80% yield after chromatography. At-
tempts to homologate aldehyde 25 to the desired (E)-un-
saturated ester were frustrated by elimination of the C17
4-methoxybenzylalkoxide to form enal 26 or epimeriza-
tion of the C16-methyl group employing either Horner–
Wadsworth–Emmons protocols or stabilized ylides.
Marshall12a and Dias35 reported a lack of reactivity with a
similar intermediate in their synthesis of the polypropi-
onate region of callystatin A (intermediate B, Scheme 9).
Table 1 Optimization for the Formation of the 1,3-Benzylidene 20
En- Conditions
try
20a
21a
19
11
26
38
27
27
37
22a
6a
19
20
22
12
6
1
2
3
4
5
6
7
DMF, 0 °C, CSA (10 mol%), 49b
acetal (1.2 equiv)
3
CH2Cl2, 0 °C, CSA
(5 mol%, 0.4 mmol)
52
22
21
47
11
23
17
19
13
28
PhMe, 90 °C, PPTS
(5 mol%), acetal (1.1 equiv)
CH2Cl2, 0 °C, CSA
(3 mol%, 4.1 mmol)
CH2Cl2 (0.093 M), 20 °C,
CSA (3 mol%, 1.9 mmol)
CH2Cl2 (0.7 M), 20 °C, CSA 52
(3 mol%, 2.1 mmol)
9
CH2Cl2 (0.01 M), 20 °C,
CSA (3 mol%, 2.1 mmol)
18
27
Leaving the C17 hydroxyl unprotected provided a direct
solution to the elimination problem with the homologa-
tion of aldehyde 25. Elimination of hydroxide under basic
conditions should be less facile compared to the 4-meth-
oxybenzylalkoxide and the lack of the protecting group
may perturb the conformation of the molecule to make the
elimination less favorable.36 Thus, the desired 1,3-diol 27
was synthesized from intermediate 23 employing Pearl-
a Isolated yields (%).
b Mixture of benzylidene isomers.
ciently through hydrogenolysis with Pearlman’s catalyst
and H2 (1 atm) in 2-propanol allowing a 90% recovery of
tetraol 6.
With the appropriately protected intermediate 20 in hand man’s catalyst in i-PrOH under one atmosphere of H2
we could address the synthesis of the polypropionate frag- which simultaneously hydrogenated the alkene as well as
OH
a, b
c
Cy
O
H
O
OTIPS
23
O
H
O
OTIPS
24
O
H
O
OR OH
20: R=TIPS
PMP
PMP
PMP
d, e
elimination
O
17
16
O
O
O
PMBO
OTBS
OTIPS
PMBO
OTIPS
EtO
B
26
25
PPh3
Scheme 9 a) Pb(OAc)4, PhH–MeOH, 0 °C, 0.5 h, 97%; b) Ph3P=CH2, THF, –15 to 25 °C, 18 h, 95%; c) 10% Pd/C, EtOAc, H2, 0.5 h, 25 °C,
99%; d) DIBALH, CH2Cl2, –78 °C, 98%; e) PCC, CH2Cl2, 25 °C, 3 h, 80%
Synthesis 2002, No. 14, 1993–2012 ISSN 0039-7881 © Thieme Stuttgart · New York

1998
M. Lautens, T. A. Stammers
PAPER
reductively removed the benzylidene in 97% yield as the reductive ring opening could be suppressed by per-
shown in Scheme 10.37 It was then necessary to selective- forming the reaction in less polar solvents (Entries 7 and
ly oxidize the 1,3-diol 27. After experimenting with vari- 8). Under the optimized conditions, 31-(R) can be isolated
ous oxidizing agents it was found that Swern conditions38 cleanly in 68% under the conditions described in Entry 8.
cleanly provided the -hydroxy aldehyde 28 contaminat-
ed with ~5% of the starting diol.13,39,40Aldehyde 28 elimi-
Table 2 Selective Reduction of Ketone 30
nated to enal 26 during silica gel chromatography but
could be used directly after an aqueous work up without
further purification. Fortunately, 28 underwent successful
olefination with (1-ethoxycarbonyl)ethylidenetriphe-
nylphosphorane to form unsaturated ester 29 as the only
observed geometrical isomer. The C13–C22 phosphoni-
um salt 4 was obtained in essentially quantitative yield
following DIBAL-H reduction of 29 to the allylic alcohol,
conversion to the allylic bromide and treatment of the al-
lylic bromide with tributylphosphine.
Entry Conditions
31-(R/S)a
~1:10
~1:4b
32 (%)
1
2
3
4
5
6
7
8
LiAlH4, THF, –78 °C
Red-Al, PhMe, –78 to 0 °C
LiBH4, THF, 0 °C
~1:4b
DIBAL-H, CH2Cl2, –78 °C
NaBH4, MeOH, reflux
L-Selectride, THF, 20 °C
L-Selectride, Et2O, 20 °C
L-Selectride, PhMe, 20 °C
~1:2
decomp.
>10:1
>10:1
>10:1c
~60
5–10
0
Having established access to the C19-epi-C13–C22 frag-
ment 4, we turned our attention to the inversion of the C19
stereochemistry. Ketone 30 was readily prepared through
fluoride induced removal of the silyl protecting group of
intermediate 24 followed by tetrapropylammonium perru-
thenate (TPAP) oxidation41 of the resulting alcohol as
shown in Scheme 11. Our hypothesis for the selectivity of
the C19-ketone reduction was based on Lewis acid chela-
tion of the C17 ether and C19 carbonyl of 30, which
would allow the C18 methyl to influence the facial selec-
tivity of the hydride delivery towards the Si-face as illus-
trated in Scheme 11. Reduction of 30 was carried out with
a variety of reagents and the results are shown in Table 2.
We found the selectivity of the reduction was highly de-
pendent on the nature of the reducing agent. Lithium alu-
minum hydride reduction favored the original
stereochemistry 31-(S) almost exclusively (Entry 1). Re-
ducing agents including Red-Al, LiBH4, DIBAL-H and
NaBH4 provided discouraging results (Entries 2–5). L-Se-
lectride was shown to be an ideal reagent for the selective
reduction but was observed to be sluggish and did not pro-
ceed until the mixture was allowed to warm to ambient
temperature. Analysis of the products showed that the re-
duction proceeded with the desired selectivity to 31-(R)
but was contaminated with a major byproduct presumed
to be the diol 32 arising from reductive opening of the
benzylidene. Further experimentation demonstrated that
a Ratios determined crude 1H NMR.
b Reaction did not go to completion.
c 68% isolated yield.
The same series of transformations used to prepare 4
(Scheme 10) could be applied to prepare phosphonium
salt 5 epimeric at C19 as outlined in Scheme 12. Silylation
of the free alcohol 31-(R) with tert-butyldimethylsilyl trif-
late and 2,6-lutidine was followed by hydrogenolysis of
the benzylidene providing diol 33 in 88% and 97% yield,
respectively. The diol was selectively oxidized under
Swern conditions and the resulting -hydroxy aldehyde
was homologated to unsaturated ester 34 in yields similar
to those with the epimeric intermediate 29. From the un-
saturated ester 34, the same series of manipulations shown
in Scheme 10 were used to synthesize phosphonium salt
5.
The synthesis of the C1–C12 aldehyde fragment 3 began
with the assembly of a C1–C6 lactone precursor. Our ap-
proach, shown in Scheme 13, was inspired by a prepara-
tion of the compactin lactone reported in the literature,42
and is similar to that recently reported by Marshall and
a
b
17
O
HO
O
H
O
OTIPS
HO
OTIPS
HO
OTIPS
23
27
28
PMP
c
d, e, f
Br- Bu3P+
O
HO
OTIPS
O
HO
OTIPS
4
29
Scheme 10 a) Pd(OH)2/C, H2 (1 atm), 20 °C, i-PrOH, 12 h, 97%; b) (COCl)2, DMSO, CH2Cl2, –78 °C, Et3N, 95%; c) (Me)(Ph3P=)CCO2Et,
CH2Cl2, reflux, 16 h, 81%; d) DIBAL-H, CH2Cl2, –78 °C, 99%; e) Ph3P, CBr4, MeCN, 2,6-lutidine, 25 °C, 10 min., >99%; f) Bu3P, MeCN,
24 °C, 3 h
Synthesis 2002, No. 14, 1993–2012 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Oxabicyclo[3.2.1]oct-6-enes as Templates for Polypropionates: Total Synthesis of Callystatin A
1999
O
H
O
OH
31-(R)
a, b
c
PMP
O
H
O
OTIPS
O
H
O
O
24
30
PMP
PMP
O
H
O
OH
31-(S)
PMP
O
O
O
CH3
CH3
Ar
L.A.
PMBO
H
H3C
H-
OH OH
H
32
H2CH3C
Scheme 11 a) TBAF, THF, 25 °C, 66 h, 99%; b) TPAP, NMO, CH2Cl2, 2.5 h, 97%; c) Table 2
a, b
c, d
19
HO
O
O
H
O
OH
31-(R)
OH OTBS
O
HO
OTBS
33
34
PMP
e, f, g
Br- Bu3P+
HO
OTBS
5
Scheme 12 a) TBSOTf, CH2Cl2, 2,6-lutidine, –15 °C, 2 h, 88%; b) Pd(OH)2/C, H2 (1 atm), i-PrOH, 20 °C, 1 h, 97%; c) (COCl)2, DMSO,
CH2Cl2, –78 °C, Et3N, ~95%; d) (Me)(Ph3P=)CCO2Et, CH2Cl2, reflux, 13.5 h, 78%; e) DIBAL-H, CH2Cl2, –78 °C, 10 min., 96%; f) Ph3P, CBr4,
MeCN, 2,6-lutidine, 25 °C, 5 min., 79%; g) Bu3P, MeCN, 24 °C, 1 h
Bourbeau in their synthesis of callystatin A.12a The C5 ste- to the desired lactol was more difficult than initially anti-
reogenic center was derived from (S)-glycidol which was cipated. Under optimized conditions, oxidation to the lac-
utilized as its silyl ether 35. The tetrahydropyranyl ether tol proceeded in 75% yield based on 67% conversion in
of propargylic alcohol was treated with butyllithium fol- the presence of 15 equivalents of manganese(IV) oxide.44
lowed by boron trifluoride etherate to generate a boryl nu- Known isopropyl lactol 388,9,45could be obtained in 93%
cleophile,43 which was used to open epoxide 35 and form yield by stirring the lactol with catalytic acid and 2-pro-
homoalkynyl alcohol 36 in 78% yield. Selective hydroly- panol. The relative stereochemistry of the dihydropyran
sis of the tetrahydropyranyl ether 36 followed by semi-hy- 38 was in agreement with that presented in the literature.46
drogenation proceeded in essentially quantitative yield to
Z-alkenyl diol 37. Selective allylic oxidation of the diol 37
Lastly, we turned our attention to the synthesis of the C7–
C12 fragment of callystatin A. The key intermediate is the
OH
OH
b, c
OH
a
THPO
OTHP
OTBDPS
OTBDPS
O
OTBDPS
36
37
35
d, e
O
H
O
OTBDPS
H
38
Scheme 13 a) BuLi, THF, –78 °C; then BF3 Et2O; then 35, 78%; b) PPTS, EtOH, 50 °C, 3 h, 99%; c) Lindlar cat., PhMe, H2 (1 atm), 20 °C,
3 h, 99%; d) MnO2, CH2Cl2, 20 °C, 13 h, 75% (based on converstion); e) i-PrOH, PPTS, 20 °C, 0.75 h, 93%
Synthesis 2002, No. 14, 1993–2012 ISSN 0039-7881 © Thieme Stuttgart · New York

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M. Lautens, T. A. Stammers
PAPER
C9–C12 chiral synthon 41 which had been utilized in pre- Completion of the synthesis of the C1–C12 fragment of
vious synthesis of this fragment of callystatin A.8,9,13 We callystatin A 3 is illustrated in Scheme 15 and was per-
sought to find a more efficient route than those reported in formed analogously to protocols described in the litera-
the literature and found the functional, direct approach ture.2,8,9,11,12a,13,49 Silyl ether 38 was converted to C1–C6
shown in Scheme 14. The C10 stereochemistry arises aldehyde 42 by removal to the tert-butyldiphenylsilyl
from the commercially available (R)- -methylsuccinic group and oxidation of the resulting alcohol under Swern
acid. The diacid was reduced with lithium aluminum hy- conditions.38 The C9–C12 aldehyde 41 was homologated
dride to diol 39 in 87% yield. Selective protection of the with butyrophosphonate 43. The use of the Still protocol50
less hindered of the two hydroxy groups of 39 was exam- for securing the Z-geometry of the C8–C9 alkene is ubiq-
ined with tert-butylchlorodiphenylsilane (TBDPSCl) uitous among syntheses of this class of natural products.
since the TBDPS group would be compatible with the The C7–C12 phosphonium salt 44 was then prepared us-
subsequent steps, we could employ it stoichiometrically ing conventional transformations. The E-selective tribu-
and the chlorosilane is reactive at low temperatures. Most tylphosphonium Wittig type coupling16 between aldehyde
importantly, the two mono-silylated isomers were separa- 42 and phosphonium salt 44 was carried out under the
ble by flash chromatography, a feature lacking with other conditions reported by Crimmins and King9 to provide the
protecting groups investigated. Under the optimized con- C1–C12 portion of callystatin A 45 as a single isomer in
ditions with 5 mmol of 39, we were able to isolate 61% of 82% yield. Cleavage of the tert-butyldiphenylsilyl ether in
purified alcohol 40 as well as 14% of bis-silylated materi- the presence of TBAF followed by Swern oxidation pro-
al and an additional 6% of a mixture of two mono-silylat- vided aldehyde 3 in high yield.
ed alcohols. A 16:1 selectivity was observed for the
We sought to employ the E-selective tributylphosphoni-
silylation of the less hindered alcohol.47 The two mono-si-
um Wittig type reaction16 that had been shown to be effec-
lylated alcohols were observed to have nearly overlapping
tive for the coupling of the C1–C12 and C13–C22
1H NMR spectra and could not be conclusively identified
fragments in previous total syntheses of callystatin A.8,9,13
until oxidation to aldehyde 41. Overall this route required
The coupling reaction is shown in Scheme 16 and our ob-
servations, which are in contrast to those reported in the
literature, are shown in Table 3. Our initial attempt to cou-
six fewer steps and resulted in a 23% higher overall yield
of 41 compared to the literature route.48
O
a
b
HO
HO
HO
OH
OH
OTBDPS
39
40
O
c
O
OTBDPS
41
Scheme 14 a) LiAlH4, THF, 0 °C to 24 °C, 17.5 h, 87%; b) TBDPSCl, DBU, DMF, –50 °C, 0.5 h, 61%; c) DMSO, CH2Cl2, (COCl)2, –78 °C,
Et3N, 99%
Scheme 15 Preparation of the C1–C12 aldehyde 3
Synthesis 2002, No. 14, 1993–2012 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Oxabicyclo[3.2.1]oct-6-enes as Templates for Polypropionates: Total Synthesis of Callystatin A
2001
H
O
O
3
H
O
H
O
O
H
Br- Bu3P+
17
17
R2
R1
R1 R2
R3O
R3O
4, 5, 48, 49
46, 47, 50, 51
Scheme 16
ple C1–C12 aldehyde 3 with the C19-epi-C13–C22 phos- of protecting the C17 hydroxyl (R3). The corresponding
phonium salt 4 under conditions described by Crimmins phosphonium salts 48,49 were prepared from allylic bro-
and King8 resulted in the coupled product 46 in a modest mides 52,53 as shown in Scheme 17. We were pleased to
yield of 46% and as a 2:1 mixture of inseparable E/Z iso- find that phosphonium salts 48 and 49 coupled with alde-
mers, Entry 1. Coupling with the C13–C22 phosphonium hyde 3 in excellent yields in the presence of potassium
salt 5 proceeded in high yield to afford 47 but with essen- tert-butoxide with high E-selectivity to provide C19-epi-
tially no E/Z selectivity (Entry 2). We were surprised by C1–C22 intermediate 50 and C1–C22 intermediate 51 as
the poor selectivity of the olefination as Kobayashi and shown in Entries 7 and 8. These observations emphasize
Crimmins had reported obtaining the (E)-alkenes exclu- the remarkable effect of the C17-substitution on this Wit-
sively. Interestingly, the C13–C22 phosphonium salt used tig coupling.
by Kobayshi and co-workers was identical to 5 expect the
stereochemistry of the free hydoxyl at C17. We are unable
to account for dramatic effect on E/Z selectivity from this
relatively remote stereochemistry. Experimenting with
With the C1–C22 skeletons of C19-epi-callystatin 50 and
callystatin A 51 assembled, we began to study the final
manipulations required to attain the targets shown in
Scheme 18. Hydrolysis of the i-Pr-lactol proved challeng-
different bases, solvents and temperatures resulted in re-
ing with the major byproduct of the reaction being isomer-
duced yields with essentially no affect on E/Z selectivity
ization of the lactol to an (E)-enal 56,57. Under the
for the coupling reaction as illustrated by examples shown
optimized conditions, 50 was treated with acetic acid in a
in Entries 3–6 in Table 3. We then investigated the option
Table 3 Coupling of the C1–C12 and C13–C22 Fragments
Entry
P-Salt
Conditions
R1
R2
R3
H
Product
46
Yield (%)
E/Za
2:1
1
2
3
4
5
6
7
8
4
5
PhMe–THF, 0 °C, t-BuOK
PhMe–THF, 0 °C, t-BuOK
PhMe–THF, 0 °C, LHMDS
THF, 0 °C, LHMDS
H
OTIPS
H
46
92
29
43
27
n/a
99
94
OTBS
H
H
47
1:1.3
2:1
4
OTIPS
OTIPS
H
H
46
4
H
H
47
1:1
5
DMF, 0 °C, t-BuOK
OTBS
OTBS
H
H
49
1:1.3
n/a
5
DMSO, 0 °C, t-BuOK
PhMe–THF, 0 °C, t-BuOK
PhMe–THF, 0 °C, t-BuOK
H
H
decomp.
50
48
49
OTIPS
H
TMS
TMS
~10:1
>19:1
OTBS
51
a Measured by 1H NMR comparison of the C14 methyl integrations.
Scheme 17 a) TMSOTf, 2,6-lutidine,CH2Cl2, –78 °C; b) Bu3P, MeCN, 20 °C
Synthesis 2002, No. 14, 1993–2012 ISSN 0039-7881 © Thieme Stuttgart · New York

2002
M. Lautens, T. A. Stammers
PAPER
mixture of tetrahydrofuran and H2O to afford lactol 54 in and 13C NMR spectra. Although we were unable to sepa-
63% yield along with 7% of enal 56. The trimethylsilyl rate the compounds we suspect that the C16-methyl group
ether was concomitantly hydrolyzed under these condi- had epimerized under the reaction conditions. Using pyri-
tions. Application of the identical conditions to the com- dine as a co-solvent, as reported by Kalesse and co-work-
pound with the correct C19-stereochemistry 51, led to a ers,11,45 with HF pyridine (70:30, Aldrich) we were able to
disappointing yield of lactol 55 along with 29% of isomer- cleanly recover C19-epi-callystatin A (1) and callystatin
ized enal 57. Attempts to oxidize both the lactol and the A (1).
C17-hydroxyl simultaneously failed thus the oxidations
were carried out sequentially. Optimal yields were ob-
tained when the lactols of 54 and 55 were first oxidized in
In summary we were able efficiently synthesize C19-epi-
callystatin in 22 steps from furan and the total synthesis of
callystatin A was accomplished in 27 steps including a
successful inversion of the C19-hydroxyl stereochemis-
the presence of manganese(IV) oxide followed by treat-
ment with the Dess–Martin periodinane51 to provide the
try. Application of the [3.2.1]oxabicycle methodology de-
corresponding keto-lactone intermediates. Lastly, the silyl
veloped in our laboratories allowed us to generate an
protecting groups were cleaved in the presence of hydro-
acyclic intermediate 6 with the required 1,3,5-syn,syn-tri-
methyl arrangement for the C15–C21 polypropionate re-
gion. Evaluation of several protecting group strategies for
tetraol 6 allowed us to develop a route that required a min-
gen fluoride pyridine complex to produce C19-epi-callys-
tatin A (1) and callystatin A (1) in good yields over the
final three steps. Interestingly, use of HF pyridine (70:30
mixture, Fluka) has been reported in the literature.9,10
imum number of manipulations while also providing the
When we attempted the deprotection leading to callystatin
opportunity to selectively invert the C19 stereochemistry.
A (1) with HF pyridine (70:30 mixture, Aldrich) and we
cleanly obtained what appeared to be the natural product.
All chemicals were purchased from Aldrich Chemical Company
However, upon closer examination, we determined that
and used as received unless otherwise noted. THF, Et2O and toluene
two compounds were present with nearly overlapping 1H
were distilled over sodium in the presence of benzophenone.
Scheme 18 a) HOAc, THF–H2O, 20 °C; b) MnO2, CH2Cl2, 20 °C; c) Dess–Martin periodinane, CH2Cl2, 20 °C; d) HF pyridine, pyridine–
THF, 0 to 20 °C
Synthesis 2002, No. 14, 1993–2012 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Oxabicyclo[3.2.1]oct-6-enes as Templates for Polypropionates: Total Synthesis of Callystatin A
2003
CH2Cl2 was distilled over calcium hydride. Anhyd DMF and
DMSO were distilled under reduced pressure over calcium hydride
then stored over molecular sieves before use. Cerium(III) chloride
heptahydrate (Strem) was crushed into a fine powder then dried at
120 °C under high vacuum for at least 6 h before use in the methyl-
lithium NRO reactions. 1H NMR spectra were referenced from an
internal standard of tetramethylsilane ( = 0.00) and 13C signals
were referenced from CDCl3 ( = 77.23). Spectral features are tab-
ulated in the following order: chemical shift ( , ppm); multiplicity
(s-singlet, d-doublet, t-triplet, q-quartet, m-complex multiplet, AB,
ABX); number of protons; coupling constants (J, Hz). IR spectra
were obtained on a Perkin–Elmer Spectrum 1000 FT-IR spectrom-
eter using NaCl plates. Optical rotations were measured on a Per-
kin–Elmer 243B polarimeter equiped with a sodium lamp (D-line,
J = 7.2 Hz), 1.83–1.73 (m, 4 H), 1.65 (d, 1 H, J = 10.1 Hz), 1.56 (d,
2 H, J = 11.4 Hz), 1.60–1.48 (m, 2 H), 1.39 (dq, 1 H, J = 12.4, 3.1),
1.32–1.24 (m, 1 H), 1.22 (d, 3 H, J = 7.1 Hz), 1.20–1.06 (m, 21 H),
0.94 (d, 3 H, J = 7.0 Hz), 0.93 (d, 3 H, J = 7.0 Hz).
13C NMR (100 MHz, CDCl3): = 79.0, 76.5, 75.8, 75.5, 64.0, 41.1,
40.1, 38.4, 34.6, 31.2, 27.0, 26.8, 26.24, 26.21, 18.1, 15.9, 14.7,
12.6, 11.8.
HRMS (EI+, MH+): m/z calcd for C26H55O5Si: 475.3819; found:
475.3796.
[1S,2R,3R,4R,5R,5(4R),5(5R)]-1-Cyclohexyl-5-{2-(4-methoxy-
phenyl)-5-methyl[1,3]dioxan-4-yl}-3-methyl-4-(triisopropylsil-
anyloxy)hexan-1,2-diol (20)
T
Tetraol 6 (0.991 g, 2.1 mmol) was combined with p-anisaldehyde
dimethylacetal (0.456 g, 2.5 mmol) in freshly distilled CH2Cl2 (3
mL) under an N2 atmosphere. Camphorsulfonic acid (0.015 g, 0.1
mmol) was added and the solution was stirred 10 min before being
quenched by pouring into sat. aq NaHCO3 (75 mL). The mixture
was partitioned with Et2O (100 mL) and the organic phase was
washed with brine (75 mL). The organic phase was dried (MgSO4),
filtered and concentrated. The residue was subjected to flash chro-
matography (EtOAc–hexanes; 1:19, 1:9, 1:4, 1:3, 1:2, 1:1, 2:1). Re-
covered bis-benzylidene 21 (0.399 g, 27%), the high Rf 5-
memebered benzylidene 22a (0.053 g, 4%) and the low Rf 5-mem-
bered benzylidene 22b (0.105 g, 7%), starting tetraol 6 (0.084 g,
9%) as well and the desired 6-membered benzylidene 20 were ob-
tained.
= 589 nm) and are reported as follows: [ ]D (c g/100 mL, sol-
vent).
[1S,1(1S),2R,3R,4S,5R]-1-(Cyclohexylhydroxymethyl)-2,4-di-
methyl-3-(triisopropylsilanyloxy)-8-oxabicyclo[3.2.1]oct-6-ene
(9)
Diol 8 (1.082 g, 4.1 mmol) was dissolved in freshly distilled CH2Cl2
(20 mL). The solution was chilled to 0 °C and triisopropylsilyl trif-
luoromethanesulfonate (2.18 mL, 8.1 mmol) was added followed by
the slow addition of 2,6-lutidine (1.18 mL, 10.2 mmol). The reac-
tion was stirred for 1 h at 0 °C before being diluted in EtOAc (125
mL) and washed with sat. aq NH4Cl (75 mL) and brine (75 mL).
The organic phase was dried (MgSO4), filtered and concentrated.
Purification by flash chromatography (EtOAc–hexanes; 1:19, 1:9;
1:4; 1:3) afforded [3.2.1]oxabicycle 9.
20
Yield: 0.644 g (52%); Rf 0.51 (EtOAc–hexanes, 1:3); [ ]D –36.3
(c 1.4, CHCl3).
Yield: 1.532 g (89%); colorless oil; Rf 0.29 (EtOAc–hexanes, 1:9);
[ ]D20 +29.5 (c 1.4, CHCl3).
IR (neat): 3492, 2939, 2847, 1739, 1614, 1589, 1714, 1468, 1390,
1248, 1172, 1124 cm–1.
IR (neat): 3479, 2911, 1652, 1458, 1386, 1111 cm–1.
1H NMR (CDCl3, 400 MHz): = 7.39 (d, 2 H, J = 8.8 Hz), 6.90 (d,
2 H, J = 8.8 Hz), 5.37 (s, 1 H), 4.33 (t, 1 H, J = 3.6 Hz), 4.13 (dd, 1
H, J = 11.3, 4.7 Hz), 3.89–3.84 (m, 1 H), 3.82 (s, 3 H), 3.55–3.51
(m, 1 H), 3.49–3.42 (m, 1 H), 3.40–3.33 (m, 1 H), 2.78 (d, 1 H,
J = 8.5 Hz), 2.31–2.23 (m, 1 H), 2.22–2.14 (m, 1 H), 2.13–2.02 (m,
1 H), 1.94–1.85 (m, 1 H), 1.78–1.56 (m, 3 H), 1.50–1.38 (m, 3 H),
1.22 (d, 3 H, J = 7.2 Hz), 1.15–1.05 (m, 21 H), 0.96 (d, 3 H, J = 6.8
Hz), 0.88 (d, 3 H, J = 6.6 Hz).
1H NMR (CDCl3, 400 MHz): = 6.14 (ddd, 1 H, J = 6.2, 1.6, 0.9
Hz), 6.08 (d, 1 H, J = 6.2 Hz), 4.54, (s, 1 H), 4.15 (t, 1 H, J = 6.5
Hz), 3.69 (d, 1 H, J = 1.8 Hz), 2.13 (br, 1 H), 1.88–0.94 (m, 13 H),
1.14 (3 H, d, J = 7.1 Hz), 1.08 (d, 3 H, J = 7.0 Hz), 1.04 (s, 21 H).
13C NMR (100 MHz, CDCl3): = 132.7, 131.3, 92.2, 82.6, 75.4,
68.0, 38.5, 37.4, 35.1, 32.1, 27.1, 26.8, 26.3, 26.1, 18.0, 13.7, 12.3,
10.1.
HRMS (EI+, M+): m/z calcd for C25H46O3Si: 422.3216; found:
422.3230.
13C NMR (100 MHz, CDCl3): = 160.1, 131.3, 127.4, 113.8, 101.7,
68.3, 78.3, 76.0, 75.4, 73.5, 55.4, 42.8, 39.0, 37.7, 32.1, 31.3, 27.0,
26.9, 26.6, 26.4, 18.5, 18.4, 16.8, 13.5, 13.1, 12.8.
Anal. Calcd for C25H46O3Si: C, 71.03; H, 10.97. Found: C, 71.00;
H, 11.05.
HRMS (EI+, MH+): m/z calcd for C34H61O6Si: 593.4237; found:
593.4209.
(1S,2R,3S,4R,5R,6R,7R)-1-Cyclohexyl-1,2,6,8-tetrahydroxy-4-
(triispropylsilanyloxy)-3,5,7-trimethyloctane (6)
[3S,4S,5R,5(2R),5(4R),5(5R)]-5-{2-(4-Methoxyphenyl)-5-meth-
yl[1,3]dioxan-4-yl}-3-methyl-4-(triisopropylsilanyloxy)hex-1-
ene (23)
Diol 20 (0.856 g, 1.4 mmol) was dissolved in benzene and MeOH
(9:1, 20 mL). The solution was chilled to 0 °C and lead(IV) acetate
(0.960 g, 2.2 mmol) was added. The heterogeneous mixture was
stirred for 1 h at 0 °C before being diluted in Et2O (20 mL). The sus-
pension was filtered through silica gel (Et2O) and the filtrate was
concentrated. Purification by flash chromatography (EtOAc–hex-
anes; 1:19, 1:9, 1:4) afforded the aldehyde.
Cycloheptene 10 (4.06 g, 9.3 mmol) was dissolved in CH2Cl2–
MeOH (1:1, 50 mL) with stirring. The solution was cooled to
–78 °C and ozone was bubbled through until the characteristic blue
color persisted. The solution was purged with nitrogen for 1 h be-
fore NaBH4 (0.346 g, 93 mmol) was added. The mixture was al-
lowed to warm r.t. and stirred for 69 h. The reaction was quenched
by pouring into sat. aq NH4Cl (250 mL). The aq phase was extracted
with CH2Cl2 (3 100 mL) and combined organic extracts were
dried (MgSO4), filtered and concentrated. Purification by flash
chromatography (EtOAc–hexanes; 1:3, 1:2, 1:1) afforded tetraol 6.
Yield: 0.667 g (97%); colorless oil; Rf 0.54 (EtOAc–hexanes, 1:4);
Yield: 4.013 g (91%); white foam which could be crystallized from
hexanes; mp. 116.5–118.5 °C (hexanes); Rf 0.16 (EtOAc–hexanes,
20
[ ]D –45.9 (c 1.5, CHCl3).
20
IR (neat): 2838, 2718, 1726, 1711, 1612, 1513, 1468, 1382, 1302,
1249 cm–1.
1H NMR (CDCl3, 400 MHz): = 9.89 (d, 1 H, J = 2.2 Hz), 7.35 (d,
2 H, J = 8.4 Hz), 6.88 (d, 2 H, J = 8.1 Hz), 5.35 (s, 1 H), 4.42–4.39
(m, 1 H), 4.08 (dd, 1 H, J = 11.2, 4.4 Hz), 3.80 (s, 3 H), 3.50–3.41
(m, 2 H), 3.01–2.93 (m, 1 H), 2.28–2.20 (m, 1 H), 2.04–1.94 (m, 1
1:2 ); [ ]D –7.2 (c 1.5, CHCl3).
IR (neat): 3391, 2879, 1459, 1265, 1068 cm–1.
1H NMR (400 MHz, CDCl3): = 4.52 (t, 1 H, J = 4.3 Hz), 4.23 (br,
1 H), 4.01 (dd, 1 H, J = 10.8, 2.8 Hz), 3.70 (dd, 1 H, J = 10.6, 2.8
Hz), 3.63–3.55 (m, 2 H), 3.49 (s, 1 H), 3.29 (br, 1 H), 3.16 (br, 1 H),
2.38 (br, 1 H), 2.17–2.10 (1 H, m), 2.09–2.05 (m, 1 H), 1.96 (d, 1 H,
Synthesis 2002, No. 14, 1993–2012 ISSN 0039-7881 © Thieme Stuttgart · New York

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M. Lautens, T. A. Stammers
PAPER
H), 1.20 (d, 3 H, J = 7.1 Hz), 1.17 (d, 3 H, J = 7.1 Hz), 1.10–1.07
(m, 21 H), 0.86 (d, 3 H, J = 6.5 Hz).
(2S,3S,4S,5S,6S)-3-(4-Methoxybenzyloxy)-5-(triisopropylsilan-
yloxy)-2,4,6-trimethyloctanal (25)
In an oven-dried flask under an N2 atmosphere, benzylidene 24
(0.333 g, 0.7 mmol) was dissolved in freshly distilled CH2Cl2 (5
mL). The solution was chilled to 0 °C and DIBAL-H (1.0 M in hep-
tanes; 2.78 mL, 2.8 mmol) was added. The mixture was allowed to
warm to r.t. and stirred for 2 h. The reaction was quenched by pour-
ing into H2O (30 mL) and the aluminum salts were solubilized by
acidification with 10% aq HCl (2 mL). The aq phase was extracted
with CH2Cl2 (3 20 mL) and the combined organic extracts were
dried (MgSO4), filtered and concentrated in vacuo to cleanly afford
the alcohol.
13C NMR (100 MHz, CDCl3): = 205.8, 160.1, 131.2, 127.4, 113.8,
101.8, 86.0, 75.7, 73.4, 55.5, 49.4, 42.4, 32.6, 18.5, 18.4, 14.2, 13.2,
13.1, 13.0.
HRMS (EI+, MH+): m/z calcd for C27H45O5Si: 477.3036; found:
477.3030.
Freshly dried methyltriphenylphosphonium bromide (0.157 g, 0.4
mmol) was suspended in freshly distilled THF (2 mL). The mixture
was chilled to –15 °C and butyllithium (1.27 M in hexanes; 0.347
mL, 0.4 mmol) was added. The solution was stirred for 10 min at
–15 °C before the aldehyde (0.141 g, 0.3 mmol) was added to the
yellow solution via cannula as a solution in freshly distilled THF (2
mL plus a 2 mL wash). The heterogeneous mixture was stirred for
2 h between –15 °C and –10 °C then allowed to warm to r.t. for an
additional 14 h. The mixture was diluted in Et2O (25 mL) and
washed with H2O (15 mL) and brine (15 mL). The organic phase
was dried (MgSO4), filtered and concentrated. Purification by flash
chromatography (EtOAc–hexanes; 1:19, 1:9) afforded alkene 23.
Yield: 0.335 g (>99%); colorless oil; Rf 0.62 (EtOAc–hexanes,
1:2); [ ]D20 –9.9 (c 1.0, CHCl3).
IR (neat): 3435, 2950, 2868, 1614, 1514, 1462, 1249, 1058 cm–1.
1H NMR (CDCl3, 400 MHz): = 7.23 (d, 2 H, J = 8.6 Hz), 6.85 (d,
2 H, J = 8.6 Hz), 4.54 (A of an ABX, 1 H, J = 10.4 Hz), 4.50 (B of
an ABX, 1 H, J = 10.4 Hz), 4.04 (t, 1 H, J = 3.5 Hz), 3.88 (dt, 1 H,
J = 11.0, 3.7 Hz), 3.79 (s, 3 H), 3.58–3.52 (m, 1 H), 3.47 (dd, 1 H,
J = 9.2, 2.7 Hz), 2.93 (d, 1 H, J = 7.5 Hz), 2.20–2.10 (m, 1 H), 1.98–
1.91 (m, 1 H), 1.77–1.67 (m, 1 H), 1.63–1.55 (m, 1 H), 1.21 (d, 3 H,
J = 7.1 Hz), 1.13–1.03 (m, 22 H), 1.00 (d, 3 H, J = 6.8 Hz), 0.96 (d,
3 H, J = 7.1 Hz), 0.89 (t, 3 H, J = 7.5 Hz).
13C NMR (100 MHz, CDCl3): = 159.4, 130.5, 129.3, 113.9, 87.2,
77.1, 74.9, 64.9, 55.4, 43.5, 38.3, 36.2, 25.4, 18.5, 18.4, 18.3, 16.6,
13.2, 12.6, 12.3.
HRMS (EI+, MH+): m/z calcd for C28H53O4Si: 481.3713; found:
481.3730.
Yield: 0.1322 (95%); colorless oil; Rf 0.66 (EtOAc–hexanes, 1:9 );
[ ]D20 –26.5 (c 1.5, CDCl3).
IR (neat): 2962, 2855, 1614, 1514, 1462, 1384, 1302, 1250, 1119,
1039, 883 cm–1.
1H NMR (CDCl3, 400 MHz): = 7.41 (d, 2 H, J = 8.6 Hz), 6.88 (d,
2 H, J = 8.6 Hz), 6.18–6.08 (m, 1 H), 5.37 (s, 1 H), 4.93–4.85 (m, 2
H), 4.16–4.13 (m, 1 H), 4.07 (dd, 1 H, J = 11.4, 4.8 Hz), 3.81 (s, 3
H), 3.49–3.43 (m, 2 H), 2.85–2.75 (m, 1 H), 2.18–2.08 (m, 1 H),
2.06–1.95 (m, 1 H), 1.12–1.03 (m, 27 H), 0.84 (d, 3 H, J = 6.6 Hz).
The alcohol (0.0337 g, 0.1 mmol) was combined with activated mo-
lecular sieves (~100 mg, 3 Å) in freshly distilled CH2Cl2 (2 mL).
PCC (0.030 g, 0.1 mmol, 2 equiv) was added and the mixture was
stirred for 3.5 h at r.t. The reaction mixture was concentrated under
reduced pressure and the resulting residue was filtered through a
plug of silica gel (EtOAc–hexanes, 1:1) to afford aldehyde 25.
13C NMR (100 MHz, CDCl3): = 159.9, 142.7, 131.6, 127.5, 113.6,
113.2, 101.5, 86.0, 75.8, 73.6, 55.5, 43.2, 41.4, 32.5, 21.3, 18.6,
13.3, 12.8.
HRMS (EI+, MH+): m/z calcd for C28H48O4Si: 476.3322; found:
476.3298.
Yield: 0.0304 g (91%); colorless oil; Rf 0.59 (EtOAc–hexanes, 1:3);
[3S,4S,5R,5(2R),5(4R),5(5R)]-5-{2-(4-Methoxyphenyl)-5-meth-
yl[1,3]dioxan-4-yl}-3-methyl-4-(triisopropylsilanyloxy)hexane
(24)
Alkene 23 (0.334 g, 0.7 mmol) was dissolved in EtOAc (5 mL) un-
der an N2 atmosphere before palladium on carbon (10% by weight,
~50 mg) was added. Hydrogen was bubbled through the mixture for
45 min after which the solution was purged with N2 for 15 min. The
catalyst was removed by filtration through a pad of Celite. The fil-
trate was concentrated in vacuo to afford 24 cleanly.
[ ]D20 +3.0 (c 1.0, CHCl3).
IR (neat): 2960, 2868, 1724, 1614, 1514, 1464, 1384, 1301, 1249,
1175, 1059, 883, 823 cm–-1.
1H NMR (CDCl3, 400 MHz): = 9.81 (d, 1 H, J = 1.8 Hz), 7.23 (d,
2 H, J = 8.6 Hz), 6.86 (d, 2 H, J = 8.8 Hz), 4.49 (A of an AB, 1 H,
J = 10.8 Hz), 4.45 (B of an AB, 1 H, J = 11.0 Hz), 4.01 (t, 1 H,
J = 4.0 Hz), 3.82–3.78 (m, 4 H), 2.76 (qt, 1 H, J = 7.0, 2.2 Hz),
2.17–2.08 (d, 1 H), 1.68-1.48 (m, 3 H), 1.19 (d, 3 H, J = 7.1 Hz),
1.11–1.00 (m, 21 H), 0.93 (d, 3 H, J = 7.0 Hz), 0.87 (t, 3 H, J = 7.5
Hz), 0.86 (d, 3 H, J = 7.1 Hz).
Yield: 0.333 g (>99%); colorless oil; Rf 0.66 (EtOAc–hexanes,
1:9); [ ]D20 –23.5 (c 1.4, CHCl3).
IR (neat): 2961, 2863, 1614, 1514, 1462, 1384, 1302, 1250, 1117,
883 cm–1.
13C NMR (100 MHz, CDCl3): = 204.2, 159.0, 130.5, 128.9, 113.8,
82.4, 77.0, 72.3, 55.6, 48.8, 42.3, 38.9, 25.9, 18.8, 17.8, 13.6, 12.9,
12.3, 11.2.
HRMS [EI+, (M – C3H7)+]: m/z calcd for C25H43O4Si: 435.2931;
found: 435.2922.
1H NMR (CDCl3, 400 MHz): = 7.39 (d, 2 H, J = 8.6 Hz), 6.87 (d,
2 H, J = 8.2 Hz), 5.35 (s, 1 H), 4.09–4.02 (m, 2 H), 3.80 (s, 3 H),
3.50–3.42 (m, 2 H), 2.18–2.09 (m, 1 H), 2.06–1.95 (m, 1 H), 1.88–
1.79 (m, 1 H), 1.78–1.57 (m, 2 H), 1.12 (d, 3 H, J = 7.3 Hz), 1.11–
1.03 (m, 21 H), 0.95 (d, 3 H, J = 6.8 Hz), 0.85 (t, 3 H, J = 7.1 Hz),
0.84 (d, 3 H, J = 6.4 Hz).
(2R,3R,4R,5S,6S)-2,4,6-Trimethyl-5-(triisopropylsilanyloxy)oc-
tane-1,3-diol (27)
Alkene 23 (0.369 g, 0.8 mmol) was dissolved in 2-propanol (5 mL)
under an N2 atmosphere. Pearlman’s catalyst (0.075 g) was added
before H2 was bubbled through the solution for 10 min. The mixture
was then stirred for 14 h under 1 atm of H2. The mixture was purged
with N2 for 10 min before the catalyst was removed by filtration
through Celite. After concentration, the crude product was purified
by flash chromatography (EtOAc–hexanes; 1:9, 1:4) to afford diol
27.
13C NMR (100 MHz, CDCl3): = 160.0, 131.7, 127.5, 113.8, 101.5,
85.7, 76.6, 73.6, 55.5, 43.5, 38.7, 32.6, 24.8, 18.7, 18.61, 18.57,
18.2, 13.4, 13.2, 12.7, 12.6.
HRMS [EI+, (M – C3H7)+]: m/z calcd for C25H43O4Si: 435.2931;
found: 435.2930.
Yield: 0.267 g (96%); colorless oil; Rf 0.22 (EtOAc–hexanes, 1:9 );
[ ]D20 +10.6 (c 1.0, CHCl3).
Synthesis 2002, No. 14, 1993–2012 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Oxabicyclo[3.2.1]oct-6-enes as Templates for Polypropionates: Total Synthesis of Callystatin A
2005
IR (neat): 3347, 2962, 2863, 1462, 1383, 1250, 1112, 1059, 975,
883 cm–1.
(E)-(4R,5R,6R,7S,8S)-1-Tributylphosphonium-2,4,6,8-tetrame-
thyl-7-(triisopropylsilanyloxy)dec-2-en-5-ol Bromide (4)
Unsaturated ester 29 (0.218 g, 0.5 mmol) was dissolved in freshly
distilled CH2Cl2 (4 mL). The solution was cooled to –78 °C under
an N2 atmosphere and DIBAL-H (1.0 M in heptane;1.23 mL) was
added. The solution was stirred for10 min at –78 °C before being
quenched with MeOH (~1 mL). The mixture was allowed to warm
to r.t. before being diluted in H2O (30 mL). Aluminum salts were
hydrolyzed with 10% aq HCl (~2 mL) before the aq phase was ex-
tracted with CH2Cl2 (3 20 mL). Combined organic extracts were
dried (MgSO4), filtered and concentrated in vacuo. Allylic alcohol
was recovered cleanly.
1H NMR (CDCl3, 400 MHz): = 4.29 (s, 1 H), 4.00 (d, 1 H, J = 11.2
Hz), 3.90 (t, 1 H, J = 4.0 Hz), 3.66 (d, 1 H, J = 10.1 Hz), 3.57–3.50
(m, 1 H), 3.35 (d, 1 H, J = 8.2 Hz), 2.05–1.95 (m, 1 H), 1.79–1.72
(m, 1 H), 1.71–1.63 (m, 1 H), 1.47–1.36 (m, 1 H), 1.21 (d, 3 H,
J = 7.1 Hz), 1.10–1.05 (m, 22 H), 0.96 (d, 3 H, J = 6.8 Hz), 0.94 (t,
3 H, J = 7.0 Hz), 0.86 (d, 3 H, J = 7.0 Hz).
13C NMR (100 MHz, CDCl3): = 82.5, 79.4, 64.2, 42.5, 37.3, 35.2,
26.1, 18.4, 18.3, 17.9, 16.0, 13.7, 13.0, 12.6.
HRMS (EI+, MH+): m/z calcd for C20H45O3Si: 361.3138; found:
361.3155.
Yield: (0.194 g, 99%); colorless oil; Rf 0.42 (EtOAc–hexanes, 1:3);
[ ]D20 +7.9 (c 3.4, CHCl3).
(2S,3S,4R,5S,6S)-3-Hydroxy-2,4,6-trimethyl-5-(triisopropylsil-
anyloxy)octanal (28)
IR (neat): 3388, 2947, 2869, 1462, 1453, 1384, 1242, 1112, 1057,
1002, 883 cm–1.
In an oven-dried flask under an N2 atmosphere, DMSO (0.111 mL,
1.6 mmol) was dissolved in freshly distilled CH2Cl2 (2 mL). The so-
lution was cooled to –78 °C and (COCl)2 (0.075 mL, 0.9 mmol) was
added dropwise. After 5 min, diol 27 (0.267 g, 0.8 mmol) was added
via cannula as a solution in CH2Cl2 (2 mL plus 1 mL wash). The
white slurry was stirred 10 min at –78 °C before Et3N (0.433 g, 3.1
mmol) was added dropwise. The solution was allowed to warm to
r.t. before being diluted in Et2O (100 mL) and washed with sat. aq
NH4Cl (75 mL), NaHCO3 (75 mL) and brine (75 mL). The organic
phase was dried (MgSO4), filtered and concentrated in vacuo to pro-
vide -hydroxy aldehyde 28.
1H NMR (CDCl3, 300 MHz): = 5.61 (dq, 1 H, J = 9.9, 1.1 Hz),
4.02 (d, 2 H, J = 2.8 Hz), 3.84 (t, 1 H, J = 4.4 Hz), 3.69 (s, 1 H), 3.53
(dt, 1 H, J = 9.9, 1.9 Hz), 2.63–2.51 (m, 1 H), 1.68 (d, 3 H, J = 1.4
Hz), 1.72–1.55 (m, 2 H), 1.47–1.32 (m, 2 H), 1.11–1.08 (m, 21 H),
1.07 (d, 3 H, J = 6.9 Hz), 0.92 (d, 3 H, J = 6.6 Hz), 0.90 (t, 3 H,
J = 7.2 Hz), 0.80 (d, 3 H, J = 6.9 Hz).
13C NMR (75 MHz, CDCl3): = 135.0, 127.1, 82.1, 77.7, 69.5, 42.3,
37.9, 34.4, 26.1, 18.7, 18.43, 18.37, 17.4, 14.0, 13.9, 13.0, 12.7.
HRMS (EI+, MH+): m/z calcd for C23H49O3Si: 401.3451; found:
401.3438.
Yield: 0.261 g (98%); colorless oil; Rf 0.54 (EtOAc–hexanes, 1:9 );
[ ]D20 +22.3 (c 2.2, CHCl3).
The allylic alcohol (0.0561 g, 0.1 mmol) and 2,6-lutidine (0.025
mL, 0.2 mmol) were combined in freshly distilled MeCN (1.5 mL).
Carbon tetrabromide (0.070 g, 0.2 mmol) was added followed by
Ph3P (0.055 g, 0.2 mmol). The reaction was stirred for 10 min at r.t.
before being diluted in Et2O (30 mL). The organic phase was
washed with H2O (20 mL) and brine (20 mL) before being dried
(MgSO4), filtered and concentrated. The resulting residue was fil-
tered through a plug of silica gel (EtOAc–hexanes, 1:19) and con-
centrated in vacuo to cleanly afford the allylic bromide.
IR (neat): 3506, 2954, 2868, 1721, 1462, 1385, 1116, 1058, 1013,
990, 883 cm–1.
1H NMR (CDCl3, 400 MHz): = 9.84 (d, 1 H, J = 2.9 Hz), 4.05 (s,
1 H), 3.89 (dd, 1 H, J = 4.6 Hz), 3.81 (d, 1 H, J = 10.1 Hz), 1.26 (d,
3 H, J = 7.0 Hz), 1.14–1.06 (m, 21 H), 0.95–0.88 (m, 9 H).
13C NMR (100 MHz, CDCl3): = 206.0, 82.3, 76.8, 48.8, 42.5, 37.6,
26.1, 18.4, 18.3, 17.7, 13.7, 13.0, 12.6, 12.0.
Yield: 0.0646 g (>99%); colorless oil; Rf 0.65 (EtOAc–hexanes,
HRMS (EI+, MH+): m/z calcd for C20H43O3Si: 359.2981; found:
359.2990.
1:19 ); [ ]D20 –14.6 (c 1.1, CHCl3).
IR (neat): 3504, 2947, 2868, 1462, 1385, 1208, 1055, 1012, 883
cm–1.
(E)-(4R,5R,6R,7S,8S)-5-Hydroxy-2,4,6,8-tetramethyl-7-(triiso-
propylsilanyloxy)dec-2-enoic Acid Ethyl Ester (29)
1H NMR (CDCl3, 300 MHz): = 5.83 (d, 1 H, J = 9.9 Hz), 4.03 (A
of an AB, 1 H, J = 9.3 Hz), 3.98 (B of an AB, 1 H, J = 9.3 Hz), 3.85
(t, 1 H, J = 4.3 Hz), 3.76 (t, 1 H, J = 1.4 Hz), 3.55 (dt, 1 H, J = 10.0,
1.9 Hz), 2.60–2.47 (m, 1 H), 1.77 (d, 3 H, J = 1.4 Hz), 1.75–1.55 (m,
2 H), 1.46–1.38 (m, 1 H), 1.13–1.08 (m, 22 H), 1.07 (d, 3 H, J = 7.0
Hz), 0.94 (d, 3 H, J = 6.7 Hz), 0.91 (t, 3 H, J = 7.0 Hz), 0.81 (d, 3
H, J = 6.9 Hz).
13C NMR (100 MHz, CDCl3): = 132.5, 131.9, 82.4, 77.8, 42.5,
77.8, 42.5, 42.2, 37.6, 35.2, 26.1, 18.44, 18.38, 18.1, 18.0, 17.7,
15.0, 13.9, 13.0, 12.7.
Aldehyde 28 (0.128 g, 0.4 mmol) and (1-ethoxycarbonyleth-
ylidene)triphenylphosphorane (0.324 g, 0.9 mmol) were combined
in freshly distilled CH2Cl2 (5 mL). The solution was heated to reflux
and stirred for 16 h. The reaction mixture was concentrated and the
resulting residue was purified by flash chromatography (hexanes,
1:19; EtOAc–hexanes, 1:9, 1:4) to afford unsaturated ester 29 in ad-
dition to diol 27 (0.007 g, 5%).
Yield: 0.129 g (81%); waxy white solid; Rf 0.54 (EtOAc–hexanes,
1:9); [ ]D20 +12.0 (c 1.6, CHCl3).
IR (neat): 3519, 2962, 2858, 1720, 1711, 1692, 1462, 1384, 1367,
1242, 1138, 1114, 1087, 1059, 1003, 883 cm–1.
HRMS (EI+, MH+): m/z calcd for C23H46O2SiBr: 461.2450; found:
461.2448.
1H NMR (CDCl3, 400 MHz): = 7.01 (d, 1 H, J = 10.3 Hz), 4.25–
4.14 (m, 2 H), 3.85 (t, 1 H, J = 4.0 Hz), 3.80 (s, 1 H), 3.59 (d, 1 H,
J = 9.9 Hz), 2.73–2.64 (m, 1 H), 1.85 (d, 3 H, J = 1.3 Hz), 1.69–1.58
(m, 3 H), 1.44–1.31 (m, 2 H), 1.29 (t, 3 H, J = 7.0 Hz), 1.12–1.01
(m, 21 H), 0.94 (d, 3 H, J = 6.8 Hz), 0.90 (t, 3 H, J = 7.5 Hz), 0.80
(d, 3 H, J = 7.0 Hz).
13C NMR (100 MHz, CDCl3): = 168.5, 142.8, 127.7, 82.2, 60.5,
42.3, 38.2, 35.9, 26.2, 18.5, 18.43, 18.38, 18.33, 17.5, 14.5, 13.9,
13.0, 12.6.
Allylic bromide (0.0435 g, 0.1 mmol) was dissolved in freshly dis-
tilled CH2Cl2 (1 mL) under an N2 atmosphere. Tributylphosphine
(0.047 mL, 0.2 mmol, Strem) was added and the solution was stirred
for 3 h at 20 °C. Solvent and excess phosphine were removed in
vacuo and the material was recovered as a colorless oil which solid-
ified on standing. Phosphonium salt 4 was utilized without further
purification or characterization.
[3S,5R,5(2R),5(4R),5(5R)]-5-{2-(4-Methoxyphenyl)-5-meth-
yl[1,3]dioxan-4-yl}-3-methylhexan-4-one (30)
Silyl ether 24 (0.534 g, 1.1 mmol) was dissolved in freshly distilled
THF (5 mL) under an N2 atmosphere. TBAF (1.0 M in THF; 2.24
HRMS [EI+, (M-C3H7)+]: m/z calcd for C22H43O4Si: 399.2931;
found: 399.3615.
Synthesis 2002, No. 14, 1993–2012 ISSN 0039-7881 © Thieme Stuttgart · New York

2006
M. Lautens, T. A. Stammers
PAPER
mL) was added and the solution was stirred for 66 h at r.t. The mix-
ture was then diluted in Et2O (125 mL) and washed with sat. aq
NH4Cl (75 mL) and brine (75 mL). The organic phase was dried
(MgSO4), filtered and concentrated. Purified by flash chromatogra-
phy (EtOAc–hexanes; 1:19, 1:9, 1:4, 1:3) afforded the alcohol.
1 H, J = 11.0 Hz), 3.35–3.32 (m, 1 H), 2.29–2.20 (m, 1 H), 2.11–
2.04 (m, 1 H), 1.57–1.49 (m, 1 H), 1.46–1.37 (m, 1 H), 1.08 (d, 3 H,
J = 7.1 Hz), 1.01 (d, 3 H, J = 7.3 Hz), 0.91 (t, 3 H, J = 7.3 Hz), 0.78
(d, 3 H, J = 6.6 Hz).
13C NMR (100 MHz, CDCl3): = 160.2, 130.9, 127.4, 113.9, 102.2,
89.7, 74.3, 73.2, 55.5, 37.3, 33.9, 30.9, 25.4, 15.6, 12.4, 11.2, 11.1.
Yield: 0.356 g (99%); as a colorless oil; Rf 0.18 (EtOAc–hexanes,
1:9); [ ]D20 –22.3 (c 1.3, CHCl3).
HRMS (EI+, M+): m/z calcd for C19H30O4: 322.2144; found:
IR (neat): 3532, 2962, 2870, 2832, 1614, 1518, 1462, 1391, 1303,
1250, 1171, 1112, 1035 cm–1.
322.2143.
(2R,3R,4R,5R,6S)-2,4,6-Trimethyl-5-(tert-butyldimethylsilan-
yloxy)octane-1,3-diol (33)
1H NMR (CDCl3, 400 MHz): = 7.38 (d, 2 H, J = 8.2 Hz), 6.88 (d,
2 H, J = 7.9 Hz), 5.40 (s, 1 H), 4.08 (dd, 1 H, J = 11.4, 4.6 Hz), 3.80
(s, 3 H), 3.54–3.48 (m, 1 H), 3.43 (t, 1 H, J = 11.2 Hz), 2.53 (d, 1 H,
J = 5.1 Hz), 2.39–2.28 (m, 1 H), 2.10–2.01 (m, 1 H), 1.63–1.52 (m,
2 H), 1.23–1.09 (m, 1 H), 1.04 (d, 3 H, J = 7.1 Hz), 0.98 (d, 3 H,
J = 6.6 Hz), 0.91 (t, 3 H, J = 7.3 Hz), 0.83 (d, 3 H, J = 6.6 Hz).
13C NMR (100 MHz, CDCl3): = 160.1, 131.3, 127.5, 113.8, 101.8,
88.7, 78.8, 73.8, 55.5, 37.6, 37.3, 33.1, 22.4, 17.5, 17.0, 12.9, 12.2.
HRMS (EI+, M+): m/z calcd for C19H30O4: 322.2144; found:
Alcohol 31-(R) (0.211 g, 0.7 mmol) was dissolved in freshly dis-
tilled CH2Cl2 (5 mL). The solution was cooled to –15 °C under an
N2 atmosphere and 2,6-lutidine (0.153 g, 1.3 mmol) was added fol-
lowed by tert-butyldimethilsilyl trifluoromethanesulfonate (0.196
mL, 0.9 mmol). The mixture was stirred at –15 °C for 2 h before be-
ing quenched with 2-propanol (~1 mL). The solution was then di-
luted in Et2O (100 mL) and washed with sat. aq NH4Cl 75 mL and
brine (75 mL). The organic phase was dried (MgSO4), filtered and
concentrated. Purification by flash chromatography (hexanes;
EtOAc–hexanes, 1:19) afforded the silyl ether as a colorless oil. A
322.2153.
The alcohol (0.0469 g, 0.1 mmol) was dissolved in freshly distilled
CH2Cl2 (2 mL). Tetrapropylammonium perruthenate (0.005 g, 0.01
mmol) and N-methylmorpholine oxide (0.026 g, 0.2 mmol) were
added and the dark solution was stirred at r.t. for 2.5 h. The reaction
mixture was concentrated then filtered through a plug of silica gel
(EtOAc–hexanes, 1:1). The filtrate was concentrated in vacuo to af-
ford ketone 30.
1
1:1 mixture of benzylidene isomers was observed by H NMR:
Rf 0.54 (EtOAc–hexanes, 1:9). This compound has been reported
but not characterized previously as a single stereoisomer.35
The silyl ether (0.252 g, 0.6 mmol) was dissolved in 2-propanol (3
mL) under an N2 atmosphere. Palladium hydroxide on carbon
(0.030 g) was added and H2 was bubbled through the mixture for 10
min. The mixture was stirred an additional 50 min under 1 atm of
H2 before being deemed complete by TLC. The catalyst was re-
moved by filtration though Celite. After concentration, the crude
material was subjected to flash chromatography (EtOAc–hexanes;
1:9, 1:4, 1:3) to afford diol 33.
Yield: 0.0453 (97%); colorless oil; Rf 0.46 (EtOAc–hexanes, 1:3 );
[ ]D20 –21.3 (c 1.2, CHCl3).
IR (neat): 2968, 2870, 2840, 1710, 1613, 1589, 1514, 1462, 1391,
1303, 1248, 1173, 1116, 1082, 1034, 834 cm–1.
1H NMR (CDCl3, 300 MHz): = 7.36 (d, 2 H, J = 8.6 Hz), 6.87 (d,
2 H, J = 8.6 Hz), 5.39 (s, 1 H), 4.05 (dd, 1 H, J = 11.4, 4.8 Hz), 3.80
(s, 3 H), 3.69 (dd, 1 H, J = 10.0, 4.5 Hz), 3.47 (t, 1 H, J = 11.2 Hz),
2.97 (dq, 1 H, J = 7.1, 4.5 Hz), 2.73 (dq, 1 H, J = 6.7 Hz), 2.07–1.92
(m, 1 H), 1.72–1.58 (m, 1 H), 1.38–1.27 (m, 1 H), 1.26 (d, 3 H,
J = 7.1 Hz), 1.06 (d, 3 H, J = 6.9 Hz), 0.81 (t, 3 H, J = 6.7 Hz), 0.80
(d, 3 H, J = 6.7 Hz).
13C NMR (75 MHz, CDCl3): = 216.6, 160.1, 131.2, 127.6, 113.7,
101.6, 84.9, 73.2, 55.5, 49.8, 46.3, 32.7, 26.0, 16.4, 13.5, 13.1, 11.9.
HRMS (EI+, M+): m/z calcd for C19H28O4: 320.1987; found:
Yield: 0.179g (97%); colorless oil; Rf 0.29 (EtOAc–hexanes, 1:9);
[ ]D20 +2.7 (c 1.1, CHCl3).
IR (neat): 3374, 3958, 2870, 1462, 1383, 1254, 1070, 1025, 975,
837, 773 cm–1.
1H NMR (CDCl3, 400 MHz): = 3.92 (d, 1 H, J = 10.3 Hz), 3.83 (t,
1 H, J = 2.6 Hz), 3.70 (dd, 1 H, J = 9.2, 2.8 Hz), 3.57 (dd, 1 H,
J = 10.4, 3.5 Hz), 2.08–2.00 (m, 1 H), 1.76–1.68 (m, 1 H), 1.62–
1.55 (m, 1 H), 1.47–1.37 (m, 1 H), 1.26–1.16 (m, 1 H), 1.13 (d, 3 H,
J = 7.1 Hz), 0.96 (d, 3 H, J = 6.8 Hz), 0.91 (s, 9 H), 0.89 (t, 3 H,
J = 7.5 Hz), 0.82 (d, 3 H, J = 7.0 Hz), 0.14 (s, 3 H), 0.09 (s, 3 H).
320.1988.
13C NMR (100 MHz, CDCl3): = 80.3, 79.8, 64.7, 40.4, 36.9, 35.9,
28.6, 26.1, 18.3, 15.8, 15.5, 14.0, 12.4, –4.0, –4.3.
HRMS [EI+, (M – C4H9)+] m/z calcd for C13H29O3Si: 261.1886;
[3S,4R,5R,5(2R), 5(4R),5(5R)]-5-{2-(4-Methoxyphenyl)-5-meth-
yl[1,3]dioxan-4-yl}-3-methylhexan-4-ol [31-(R)]
found: 261.1891.
Ketone 30 (0.178 g, 0.6 mmol) was dissolved in freshly distilled tol-
uene (3 mL) under an N2 atmosphere. The solution was chilled to
0 °C and L-Selectride (0.78 mL, 0.8 mmol) was added. The mixture
was allowed to warm to r.t. and stirred for 1 h. The solution was
chilled to 0 °C once again and quenched by the dropwise addition
of aq H2O2 (30%; ~2 mL). The biphasic mixture was allowed to
warm to r.t. and stirred for an additional 15 min. The mixture was
diluted in sat. aq NH4Cl (30 mL) and extracted with CH2Cl2 (3 20
mL). The combined organic extracts were dried (MgSO4), filtered
and concentrated. Purification by flash chromatography (EtOAc–
hexanes; 1:9, 1:4) afforded alcohol 31-(R) as a single stereoisomer.
(E)-(4R,5R,6R,7R,8S)-5-Hydroxy-2,4,6,8-tetramethyl-7-(tert-
butyldimethylsilanyloxy)-dec-2-enoic Acid Ethyl Ester (34)
In an oven-dried flask under an N2 atmosphere, DMSO (0.049 mL,
0.7 mmol) was dissolved in freshly distilled CH2Cl2 (1 mL). The so-
lution was cooled to –78 °C before oxalyl chloride (0.033 mL) was
added dropwise. After stirring for 5 min at –78 °C, diol 33 (0.1047
g, 0.3 mmol) was added via cannula as a solution in CH2Cl2 (1.5 mL
plus 1.5 mL wash). The white slurry was stirred 10 min at –78 °C
before Et3N (0.190 mL, 1.4 mmol) was added slowly. After the ad-
dition was complete the solution was allowed to warm to r.t. before
being diluted in Et2O (30 mL). The organic phase was washed with
sat. aq solutions of NH4Cl (20 mL) NaHCO3 (20 mL) and brine (20
mL). The organic phase was dried (MgSO4), filtered and concen-
trated in vacuo. The -hydroxy aldehyde was obtained cleanly.
Characterization data is in agreement with that reported in the liter-
ature for the identical compound synthesized by an independent
route.12a
Yield: 0.121 g (68%); Rf 0.28 (EtOAc–hexanes, 1:9); [ ]D20 –8.6
(c 1.8, CHCl3).
IR (neat): 3519, 2964, 2924, 2878, 2832, 1614, 1518, 1462, 1391,
1303, 1251, 1172, 1109, 1035 cm–1.
1H NMR (CDCl3, 400 MHz): = 7.36 (d, 2 H, J = 8.2 Hz), 6.86 (d,
2 H, J = 7.9 Hz), 5.38 (s, 1 H), 4.14 (dd, 1 H, J = 11.2, 4.8 Hz), 3.79
(d, 3 H), 3.68 (d, 1 H, J = 9.3 Hz), 3.56 (d, 1 H, J = 9.9 Hz), 3.50 (t,
Synthesis 2002, No. 14, 1993–2012 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Oxabicyclo[3.2.1]oct-6-enes as Templates for Polypropionates: Total Synthesis of Callystatin A
2007
Yield: 0.097 g (94%); colorless oil.
13C NMR (100 MHz, CDCl3): = 132.4, 132.0, 80.9, 77.7, 42.1,
41.6, 35.91, 35.88, 29.3, 26.1, 18.3, 17.7, 15.6, 15.0, 14.1, 12.3, –
4.0, –4.6.
HRMS [EI+, (M – C4H9)+]: m/z calcd for C16H32O2SiBr: 363.1355;
In a clean dry flask, (1-ethoxycarbonylethylidene)triphenylphos-
phorane (0.279 g, 0.8 mmol, Lancaster) was combined with the
-
hydroxy aldehyde (0.0974 g, 0.3 mmol) in freshly distilled CH2Cl2
(4 mL). The solution was heated to reflux and stirred for 13.5 h be-
fore being concentrated under reduced pressure. The resulting resi-
due was purified by flash chromatography (hexanes; EtOAc–
hexanes, 1:19) to afford unsaturated ester 34. This compound has
been synthesized previously under different conditions but the char-
acterization was incomplete.12a
found: 363.1365.
The allylic bromide (0.070 g, 0.2 mmol) was dissolved in freshly
distilled MeCN (1.5 mL) under an N2 atmosphere. Tributylphos-
phine (0.082 mL, 0.3 mmol, Strem) was added and the reaction was
stirred at r.t. until the starting material was consumed (~1 h). The
solution was concentrated in vacuo and the resulting phosphonium
salt 5 was used in the subsequent coupling reaction without further
purification or characterization.
Yield: 0.096 g (78%); white solid; Rf 0.53 (EtOAc–hexanes, 1:9);
[ ]D20 +30.9 (c 1.0, CHCl3).
IR (neat): 3485, 2959, 2855, 1711, 1462, 1413, 1387, 1299, 1252,
1139, 1097, 1004, 837 cm–1.
(2R)-1-(tert-Butyldiphenylsilanyloxy)-6-(tetrahydropyran-2-
yloxy)hex-4-yn-2-ol (36)
1H NMR (CDCl3, 400 MHz): = 6.98 (dq, 1 H, J = 10.3, 1.5 Hz),
4.47 (s, 1 H), 4.20–4.11 (m, 2 H), 3.71–3.68 (m, 2 H), 2.64–2.54 (m,
1 H), 1.86 (d, 3 H, J = 1.3 Hz), 1.75–1.65 (m, 1 H), 1.64–1.44 (m, 1
H), 1.39–1.17 (m, 2 H), 1.28 (t, 3 H, J = 7.1 Hz), 1.11 (d, 3 H,
J = 7.1 Hz), 1.01 (d, 3 H, J = 6.6 Hz), 0.92 (s, 9 H), 0.88 (t, 3 H,
J = 7.5 Hz), 0.71 (d, 3 H, J = 7.0 Hz), 0.11 (s, 3 H), 0.06 (s, 3 H).
13C NMR (100 MHz, CDCl3): = 168.4, 142.8, 127.7, 81.0, 77.4,
60.5, 41.9, 36.6, 35.7, 29.4, 26.1, 18.3, 17.0, 15.5, 14.5, 14.2, 12.7,
12.3, –3.9, –4.7.
Tetrahydropyranyl propargylic ether (0.673 g, 4.8 mmol) was dis-
solved in freshly distilled THF (10 mL) in an oven-dried flask under
an N2 atmosphere. The solution was cooled to –78 °C and BuLi
(1.92 mL, 4.8 mmol) was added. The mixture was allowed to warm
to 0 °C for 15 min before being cooled to –78 °C once again.
BF3 Et2O (0.607 mL, 4.8 mmol) was added slowly and the mixture
was allowed to stir for 5 min before epoxide 35 (1.00 g, 3.2 mmol)
was added via cannula as a solution in THF (5 mL plus 5 mL wash).
The mixture was allowed to warm to r.t. before being diluted in
EtOAc (150 mL) and washed with sat. aq NH4Cl (100 mL) and
brine (100 mL). The organic phase was dried (MgSO4), filtered and
concentrated. Purification by flash chromatography (EtOAc–hex-
anes; 1:9, 1:4, 1:3) afforded alkynyl alcohol 36. Although THP di-
asteriomers were expected only a single set of 13C NMR signals was
observed.
HRMS [EI+, (M – C4H9)+]: m/z calcd for C18H35O4Si: 343.2305;
found: 343.2324.
(E)-(4R,5R,6R,7R,8S)-1-Tributylphosphonium-2,4,6,8-tetrame-
thyl-7-(tert-butyldimethylsilanyloxy)dec-2-en-5-ol Bromide (5)
Unsaturated ester 34 (0.096 g, 0.2 mmol) was dissolved in freshly
distilled CH2Cl2 (1 mL) under an N2 atmosphere. The solution was
cooled to –78 °C and DIBAL-H (1.0 M in toluene; 0.840 mL) was
added. The solution was stirred 10 min at –78 °C before being
quenched with MeOH (~0.5 mL). The mixture was allowed to warm
to r.t. before being diluted in H2O (30 mL). The aluminum salts
were hydrolyzed with 10% aq HCl (~2 mL) before the aq phase was
extracted with CH2Cl2 (3 15 mL). The combined organic extracts
were dried (MgSO4), filtered and concentrated. The allylic alcohol
(0.083 g, 96%) was recovered cleanly as a colorless oil. Character-
ization data are in agreement with that reported in the literature for
the identical compound.12a
Yield: 1.137 (79%); colorless oil; Rf 0.45 (EtOAc–hexanes, 1:3).
IR (neat): 3455, 3071, 2931, 2246, 1740, 1428, 1113, 871, 740, 703
cm–1.
1H NMR (CDCl3, 300 MHz): 7.72–7.66 (m, 4 H), 7.50–7.37 (m,
6 H), 4.79 (t, 1 H, J = 3.3 Hz), 4.34–4.14 (m, 2 H), 3.77–3.66 (m, 6
H), 3.59–3.48 (m, 1 H), 2.57–2.51 (m, 2 H), 1.90–1.49 (m, 6 H),
1.10 (s, 9 H).
13C NMR (75 MHz, CDCl3): = 135.7, 133.2, 130.0, 128.0, 97.1,
82.4, 78.4, 70.5, 66.6, 62.2, 54.8, 30.5, 27.0, 25.5, 23.9, 19.5, 19.3.
(Z)-(5R)-6-(tert-Butyldiphenylsilanyloxy)hex-2-ene-1,5-diol
(37)
The allylic alcohol (0.094 g, 0.3 mmol) and 2,6-lutidine (0.046 mL,
0.4 mmol) were combined in freshly distilled CH2Cl2 (3 mL). Car-
bon tetrabromide (0.131 g, 0.4 mmol) was added and the solution
was chilled to 0 °C. Ph3P (0.104 g, 0.4 mmol) was added and the
mixture was allowed to warm to r.t. After stirring for 5 min, the re-
action was quenched by pouring into H2O (30 mL). The aq phase
was extracted with Et2O (2 20 mL) and the combined organic ex-
tracts were dried (MgSO4), filtered and concentrated. The residue
was filtered through a plug of silica gel (EtOAc–hexanes, 1:19) and
concentrated to afford the allylic bromide.
Tetrahydropyranyl ether 36 (0.813 g, 1.8 mmol) was dissolved in
absolute EtOH (10 mL). PPTS (0.045 g, 0.2 mmol) was added and
the reaction was heated to 50 °C. After 3 h the mixture was diluted
in EtOAc (150 mL) and washed with H2O (100 mL) and brine (100
mL). The aq washes were back extracted with EtOAc (50 mL) and
the combined organic phases were dried (MgSO4), filtered and con-
centrated. Purification by flash chromatography (EtOAc–hexanes;
1:2, 1:1, 2:1) afforded the alkynyl diol.
Yield: 0.672 g (>99%); colorless oil which solidified upon standing.
The solid could be recrystallized from hexanes–Et2O to provide a
crystalline white solid; mp 79–82 °C (hexanes–Et2O); Rf 0.14
(EtOAc–hexanes, 1:3 ); [ ]D20 –1.2 (CHCl3, c 6.0).
Yield: 0.087 g (79%); colorless oil; Rf 0.76 (EtOAc–hexanes, 1:4);
[ ]D20 –9.4 (c 0.9, CHCl3).
IR (neat): 3485, 2959, 2855, 1462, 1379, 1255, 1211, 1123, 1004,
837, 771 cm–1.
IR (neat): 3382, 3071, 2931, 2858, 2246, 1472, 1428, 1391, 1113,
909, 824 cm–1.
1H NMR (CDCl3, 400 MHz): = 7.69–7.64 (m, 4 H), 7.48–7.35 (m,
6 H), 4.19 (s, 2 H), 3.90–3.83 (m, 1 H), 3.71 (dq, 2 H, J = 12.7, 4.2),
2.56 (br, 1 H), 2.49 (dt, 2 H, J = 6.2, 2.2 Hz), 1.60 (br, 1 H), 1.07 (s,
9 H).
1H NMR (CDCl3, 400 MHz): = 5.80 (d, 1 H, J = 9.9 Hz), 4.26 (s,
1 H), 4.01 (A of an AB, 1 H, J = 9.3 Hz), 3.97 (B of an AB, 1 H,
J = 9.3 Hz), 3.69 (t, 1 H, J = 3.1 Hz), 3.64 (d, 1 H, J = 10.3 Hz),
2.49–2.41 (m, 1 H), 1.78 (d, 3 H, J = 1.1 Hz), 1.77–1.67 (m, 1 H),
1.65–1.55 (m, 1 H), 1.38–1.30 (m, 1 H), 1.27–1.17 (m, 1 H), 1.06
(d, 3 H, J = 7.0 Hz), 1.00 (d, 3 H, J = 6.8 Hz), 0.93 (s, 9 H), 0.88 (t,
3 H, J = 7.3 Hz), 0.73 (d, 3 H, J = 7.1 Hz), 0.12 (s, 3 H), 0.07 (s,
3H).
13C NMR (100 MHz, CDCl3): = 135.8, 133.2, 130.1, 128.0, 82.4,
80.7, 70.5, 66.6, 51.5, 27.1, 23.7, 19.5.
Synthesis 2002, No. 14, 1993–2012 ISSN 0039-7881 © Thieme Stuttgart · New York

2008
M. Lautens, T. A. Stammers
PAPER
HRMS [EI+, (M – C4H9)+]: m/z calcd for C18H19O3Si: 311.1103;
found: 311.1104.
The mixture stirred at r.t. for 17.5 h before being filtered through a
pad of Celite washing with copious amounts of THF. The filtrate
was concentrated under reduced pressure and the crude material
was purified by flash chromatography (EtOAc) to afford diol 39.
Yield: 1.68 g (87%); colorless oil; Rf 0.37 (EtOAc); [ ]D20 +24.5
(c 2.2, CHCl3).
Alkynyl diol (10.716 g, 29.4 mmol) was dissolved in freshly dis-
tilled toluene (100 mL) under an N2 atmosphere. Lindlar’s catayst
(0.956 g) was added and flask was flushed with H2 and kept under
1 atm of H2. After stirring for 3 h at r.t. the reaction mixture was fil-
tered through a pad of Celite then concentrated in vacuo to cleanly
afford alkenyl diol 37 with no apparent over-reduction.
IR (neat): 3300, 2953, 2876, 1462, 1451, 1431, 1384, 1062, 1037,
1006 cm–1.
Yield: 10.710 g (99%); colorless oil; Rf 0.47 (EtOAc–hexanes, 1:1);
1H NMR (CDCl3, 300 MHz): = 3.81–3.60 (m, 2 H), 3.56 (A of an
ABX, 1 H, J = 10.6, 4.6 Hz), 3.41 (B of an ABX, 1 H, J = 10.6, 7.2
Hz), 3.19 (br, 2 H), 1.91–1.70 (m, 1 H), 1.63–1.53 (m, 2 H), 0.92 (d,
3 H, J = 6.8 Hz)
[ ]D20 +8.6 (CHCl3, c 3.7).
IR (neat): 3356, 3071, 2931, 1739, 1472, 1428, 1243, 1113, 824,
740, 702 cm–1.
1H NMR (CDCl3, 300 MHz): = 7.69–7.63 (m, 4 H), 7.49–7.36 (m,
6 H), 5.91–6.80 (m, 1 H), 5.65–5.54 (m, 1 H), 4.17 (A of an ABX,
1 H, J = 12.4, 7.6 Hz), 4.04 (B of an ABX, 1 H, J = 12.4, 6.6 Hz),
3.81–3.71 (m, 1 H), 3.65 (A of an ABX, 1 H, J = 10.1, 3.9 Hz), 3.56
(B of an ABX, 1 H, J = 10.1, 7.6 Hz), 2.88 (br, 1 H), 2.51 (b, 1 H),
2.37–2.14 (m, 2 H).
13C NMR (75 MHz, CDCl3): = 135.5, 133.0, 131.4, 129.9, 128.6,
127.8, 70.8, 67.5, 57.6, 30.6, 26.8, 19.2.
HRMS [EI+, (M – C4H9)+]: m/z calcd for C18H21O3Si: 313.1260;
13C NMR (75 MHz, CDCl3): = 68.1, 60.9, 37.6, 34.2, 17.4.
HRMS (EI+, MH+): m/z calcd for C5H13O2: 105.0916; found:
105.0910.
(R)-4-(tert-Butyldiphenylsilanyloxy)-2-methylbutan-1-ol (40)
In an oven dried flask under an N2 atmosphere, diol 39 (0.518 g, 5.0
mmol) and tert-butylchlorodiphenylsilane (1.36 mL, 5.2 mmol)
were combined in anhyd DMF (20 mL). The solution was cooled to
–50 °C before DBU (1.12 mL, 7.5 mmol) was added dropwise. Stir-
ring was continued at –50 °C for 25 min before the solution was di-
luted in EtOAc (150 mL) and washed with sat. aq solutions of
NH4Cl (100 mL), NaHCO3 (100 mL) and brine (100 mL). The or-
ganic phase was dried (MgSO4), filtered and concentrated. Purifica-
tion by flash chromatography (EtOAc–hexanes; 1:19, 1:9, 1:4)
afforded alcohol 40 along with bis-silated material (0.413 g, 14%;
Rf 0.81, EtOAc–hexanes, 1:4) and mixed mono-silated material
(0.101 g, 6%; unwanted; Rf 0.27, EtOAc–hexanes, 1:4) as a 2:1
mixture favoring unwanted isomer material by NMR.
found: 313.1254.
(6R)-6-(tert-Butyldiphenylsilanyloxymethyl)-2-isopropoxy-5,6-
dihydro-2H-pyran (38)
The (Z)-alkenyl diol 37 (4.97 g, 13.5 mmol) was dissolved in fresh-
ly distilled CH2Cl2 (150 mL). Manganese(IV) oxide (11.73 g, 134.9
mmol) was added and the heterogeneous mixture was stirred at r.t.
for 13 h. The mixture was then filtered through Celite and concen-
trated. The residue was subjected to flash chromatography (EtOAc–
hexanes; 1:4, 1:3, 1:2, 1:1) to afford the lactol as well as starting diol
37 (1.630 g, 33%) and isomerized (E)-enal (0.168 g, 3%), each as a
viscous oils.
Yield: 1.038 g (61%); [ ]D20 +6.6 (c 1.9, CHCl3), identical to mate-
rial synthesized by the literature route.9
(E)-(4R,5R,6R,7S,8S)-1-Tributylphosphonium-2,4,6,8-tetrame-
thyl-7-(triisopropylsilanyloxy)-5-(trimethylsilanyloxy)dec-2-
ene Bromide (48)
Yield: 2.474 g (50%); Rf 0.43 (EtOAc–hexanes, 1:3); [ ]D20 +36.5
(CHCl3, c 1.9).
IR (neat): 3408, 3061, 2930, 1428, 1184, 1113, 1005, 708 cm–1.
1H NMR (CDCl3, 400 MHz): = 7.71–7.63 (m, 4 H), 7.45–7.32 (m,
6 H), 6.06–6.00 (m, 1 H), 5.77 (dq, 1 H, J = 4.2, 1.7 Hz), 5.39–5.36
(m, 1 H), 4.16–4.09 (m, 1 H), 3.79 (A of an ABX, 1 H, J = 10.4, 5.3
Hz), 3.66 (B of an ABX, 1 H, J = 10.4, 5.3 Hz), 3.01 (d, 1 H, J = 4.9
Hz), 2.11–1.97 (m, 3 H), 1.06 (d, 9 H).
13C NMR (100 MHz, CDCl3): = 135.8, 133.7, 129.8, 128.8, 127.8,
126.3, 89.2, 67.3, 66.8, 27.2, 27.0, 19.4.
Alcohol 52 (0.0204 g, 0.04 mmol) was combined with 2,6-lutidine
(0.008 mL, 0.07 mmol) in freshly distilled CH2Cl2 (0.5 mL) under
an inert atmosphere. The solution was cooled to –78 °C and trime-
thylsilyl trifluoromethanesulfonate (0.009 mL, 0.05 mmol) was
added. After 10 min, the reaction was quenched with 2-propanol be-
fore being allowed to warm to r.t. and concentrated under a stream
of N2. The residue was filtered through a pipette column of SiO2
(hexanes).
Yield of the silyl ether: 0.0223 g (95%); colorless oil; Rf 0.95
HRMS [EI+, (M – C4H9)+]: m/z calcd for C18H19O3Si: 311.1103;
found: 311.1099.
(EtOAc–hexanes, 1:19); [ ]D20 –16.3 (c 1.2, CHCl3).
IR (neat): 2960, 2870, 1461, 1453, 1383, 1251, 1212, 1093, 1037,
883, 842, 731 cm–1.
The lactol (0.235, 0.6 mmol) was dissolved in 2-propanol and PPTS
(0.008 g, 0.03 mmol) was added. The mixture was stirred at r.t. for
0.75 h before being diluted in Et2O (100 mL) and washed with H2O
(75 mL) and brine (75 mL). The organic phase was dried (MgSO4),
filtered and concentrated. Purification by flash chromatography
(EtOAc–hexanes; 1:9, 1:4, 1:3) afforded i-Pr-lactol 38. Spectra and
properties matched those described in the literature.9
1H NMR (CDCl3, 400 MHz): = 5.70 (d, 1 H, J = 9.5 Hz), 3.96 (s,
2 H), 3.93 (t, 1 H, J = 4.0 Hz), 3.62 (dd, 1 H, J = 9.0, 1.8 Hz), 2.61–
2.53 (m, 1 H), 1.83–1.76 (m, 1 H), 1.75 (d, 3 H, J = 1.3 Hz), 1.71–
1.61 (m, 1 H), 1.52–1.43 (m, 1 H), 1.16–1.09 (m, 1 H), 1.08–1.00
(m, 21 H), 0.97 (d, 3 H, J = 7.0 Hz), 0.96 (d, 3 H, J = 6.8 Hz), 0.87
(t, 3 H, J = 7.5 Hz), 0.82 (d, 3 H, J = 7.3 Hz), 0.14 (s, 9 H).
13C NMR (100 MHz, CDCl3): = 133.0, 131.1, 79.1, 76.6, 45.3,
42.2, 38.5, 36.0, 25.6, 18.8, 18.6, 17.5, 15.0, 13.3, 12.6, 11.4, 1.3.
HRMS [EI+, (M – Me)+]: m/z calcd for C25H52O2Si2Br: 519.2689;
Yield: 0.243 g (95%); colorless oil.
(R)-2-Methyl-1,4-butandiol (39)
In an oven dried flask under an N2 atmosphere, (R)-(+)- -methyl-
succinic acid (2.45 g, 18.5 mmol) was dissolved in freshly distilled
THF (60 mL). The solution was chilled to 0 °C and LiAlH4 (2.11 g,
55.6 mmol) was added portionwise over 1.5 h. After the addition
was complete the heterogeneous mixture was allowed to warm to
r.t. and stirred for 10 h. Sodium potassium tartrate (31.4 g, 111.3
mmol) was added followed by the cautious addition of H2O (5 mL).
found: 519.2704.
The allylic bromide (0.0416 g, 0.1 mmol) was dissolved in freshly
distilled CH2Cl2 (1.5 mL) under an N2 atmosphere. Tributylphos-
phine (0.047 mL, 0.2 mmol, Strem) was added and the solution was
stirred for 2.5 h at 20 °C. Solvent and excess phosphine were re-
Synthesis 2002, No. 14, 1993–2012 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Oxabicyclo[3.2.1]oct-6-enes as Templates for Polypropionates: Total Synthesis of Callystatin A
2009
moved in vacuo and the phosphonium salt 48 was utilized without
(m, 1 H), 1.06–1.00 (m, 21 H), 0.99 (d, 3 H, J = 7.1 Hz), 0.96 (d, 3
further purification or characterization.
H, J = 7.0 Hz), 0.95 (d, 3 H, J = 7.0 Hz), 0.86 (t, 3 H, J = 7.3 Hz),
0.84 (t, 3 H, J = 7.3 Hz), 0.13 (s, 9 H).
(E)-(4R,5R,6R,7R,8S)-1-Tributylphosphonium-2,4,6,8-tetrame-
thyl-7-(tert-butyldimethylsilanyloxy)-5-(trimethylsilanyloxy)-
dec-2-ene Bromide (49)
13C NMR (100 MHz, CDCl3): = 136.9, 135.95, 135.92, 132.8,
132.3, 128.8, 128.7, 127.6, 126.4, 125.2, 93.5, 79.7, 76.5, 69.9,
67.4, 45.3, 41.2, 38.4, 36.0, 32.3, 31.1, 26.6, 25.6, 24.1, 22.4, 20.7,
19.2, 18.6, 18.5, 17.5, 13.7, 13.3, 12.9, 12.6, 11.5, 1.4.
HRMS (EI+, M+): m/z calcd for C44H82O4Si2: 730.5752; found:
730.5764.
Alcohol 53 (0.0237 g, 0.1 mmol) was combined with Et3N (0.020
mL, 0.1 mmol) in freshly distilled CH2Cl2 (1 mL) under an inert at-
mosphere. The solution was cooled to –78 °C and trimethylsilyl tri-
fluoromethanesulfonate (0.013 mL, 0.1 mmol) was added. After 10
min, the mixture was diluted in Et2O (20 mL) and washed with sat.
aq solutions of NH4Cl (10 mL), NaHCO3 (10 mL) and brine (10
mL). The organic phase was dried (MgSO4), filtered then concen-
trated. Purification by flash chromatography (hexanes; EtOAc–hex-
anes, 1:19) afforded the trimethylsilyl ether as well as alcohol 53
(0.0053 g, 22%).
(8E,10E,14Z,16E)-[3S,4R,5R,6R,7R,13R,17(2R),17(6R)]-4-(tert-
Butyldimethylsilanyloxy)-15-ethyl-17-(6-isopropoxy-3,6-dihy-
dro-2H-pyran-2-yl)-3,5,7,9,13-pentamethyl-6-(trimethylsilany-
loxy)-heptadeca-8,10,14,16-tetraene (51)
Phosphonium salt 49 (0.04 mmol) and aldehyde 3 (0.013 g, 0.04
mmol) were combined in freshly distilled toluene (1 mL). The solu-
tion was chilled to 0 °C and t-BuOK (1.0 M in THF; 0.042 mL, 0.04
mmol) was added dropwise. The mixture was stirred 5 min at 0 °C
before being diluted in Et2O (20 mL). The organic phase was
washed with H2O (10 mL) and brine (10 mL) before being dried
(MgSO4), filtered and concentrated. Purification by flash chroma-
tography (hexanes; Et2O–hexanes, 1:19) afforded coupled material
51.
Yield: 0.0195g (70%); colorless oil; Rf 0.82 (EtOAc–hexanes,
1:19); [ ]D20 –6.1 (c 1.8, CHCl3).
IR (neat): 2958, 2865, 1462, 1380, 1251, 1209, 1091, 1060, 1036,
963, 882, 841, 774 cm–1
1H NMR (CDCl3, 400 MHz): = 5.73 (d, 1 H, J = 9.7 Hz), 4.01 (A
of an AB, 1 H, J = 9.3 Hz), 3.98 (B of an AB, 1 H, J = 9.3 Hz), 3.61
(t, 1 H, J = 3.8 Hz), 3.50 (dd, 1 H, J = 7.7, 2.2 Hz), 2.52–2.44 (m, 1
H), 1.76 (d, 3 H, J = 1.3 Hz), 1.66–1.58 (m, 1 H) 1.53 (m, 1 H),
1.39–1.32 (m, 1 H), 1.15–1.04 (m, 1 H), 0.95 (d, 3 H, J = 7.0 Hz),
0.90 (s, 9 H), 0.88 (t, 3 H, J = 7.3 Hz), 0.83 (d, 3 H, J = 6.8 Hz), 0.75
(d, 3 H, J = 7.1 Hz), 0.15 (s, 9 H), 0.05 (s, 6 H).
13C NMR (100 MHz, CDCl3): = 133.4, 130.6, 79.4, 76.4, 42.5,
41.8, 41.5, 35.6, 29.9, 26.4, 19.0, 18.8, 15.0, 13.8, 12.7, 12.5, 1.3, –
3.1, –3.4.
Yield: 0.0271 g (94%); colorless oil; Rf 0.41 (EtOAc–hexanes,
1:19); [ ]D20 +53.9 (c 2.3, CHCl3).
IR (neat): 2960, 2926, 2878, 1462, 1451, 1381, 1316, 1252, 1182,
1101, 1057, 1031, 1003, 966, 841, 773 cm–1.
1H NMR (CDCl3, 400 MHz): = 6.59 (d, 1 H, J = 15.9 Hz), 6.08–
5.99 (m, 2 H), 5.76–5.70 (m, 2 H), 5.51–5.42 (m, 2 H), 5.19 (d, 1 H,
J = 9.5 Hz), 5.13 (s, 1 H), 4.53–4.48 (m, 1 H), 4.02 (sept, 1 H,
J = 6.2 Hz), 3.66 (t, 1 H, J = 3.5 Hz), 3.48 (dd, 1 H, J = 7.7, 2.2 Hz),
2.81–2.73 (m, 1 H), 2.71–2.55 (m, 2 H), 2.44–2.34 (m, 1 H), 2.23–
2.16 (m, 2 H), 2.15–2.00 (m, 4 H), 1.70 (s, 3 H), 1.68–1.60 (m, 1 H),
1.42–1.34 (m, 1 H), 1.25 (d, 3 H, J = 6.2 Hz), 1.18 (d, 3 H, J = 6.2
Hz), 1.08–1.00 (m,1 H), 1.05 (t, 3 H, J = 7.5 Hz), 1.00–0.93 (m, 6
H), 0.89 (s, 9 H), 0.87 (t, 3 H, J = 7.3 Hz), 0.82 (d, 3 H, J = 6.8 Hz),
0.74 (d, 3 H, J = 7.0 Hz), 0.14 (s, 9 H), 0.04 (s, 3 H), 0.03 (s, 3 H).
13C NMR (100 MHz, CDCl3): = 136.9, 136.0, 135.9, 132.43,
132.37, 128.7, 128.6, 127.6, 126.4, 125.0, 93.5, 80.1, 76.2, 69.8,
67.3, 41.8, 41.5, 41.1, 35.4, 32.3, 31.1, 26.6, 26.4, 24.6, 24.4, 24.1,
22.4, 20.8, 19.6, 18.8, 13.8, 13.7, 12.8, 12.6, 1.4, –3.1, –3.5.
HRMS [EI+, (M – C4H9)+]: m/z calcd for C29H40O2Si2Br: 435.1750;
found: 435.1741.
The allylic bromide (0.0207 g, 0.04 mmol) was dissolved in freshly
distilled MeCN (1.5 mL) under an N2 atmosphere. Tributylphos-
phine (0.016 mL, 0.1 mmol, Strem) was added and the reaction was
stirred at r.t. until the starting material was consumed (~1 h). The
solution was concentrated in vacuo and the resulting phosphonium
salt 49 was used in the subsequent coupling reaction without further
purification or characterization.
(8E,10E,14Z,16E)-[3S,4S,5R,6R,7R,13R,17(2R),17(6R)]-15-Eth-
yl-17-(6-isopropoxy-3,6-dihydro-2H-pyran-2-yl)-3,5,7,9,13-
pentamethyl-4-(triisopropylsilanyloxy)-6-(trimethylsilanyl-
oxy)heptadeca-8,10,14,16-tetraene (50)
Phosphonium salt 48 (0.1 mmol) and aldehyde 3 (0.0248 g, 0.1
mmol, 1.1 equiv) were combined in freshly distilled toluene (1.5
mL). The solution was chilled to 0 °C and t-BuOK (1.0 M in THF;
0.078 mL, 0.1 mmol, 1 equiv) was added dropwise. The mixture
was stirred 5 min at 0 °C before being diluted in Et2O (20 mL) and
washed with H2O (10 mL) and brine (10 mL). The organic phase
was dried (MgSO4), filtered and concentrated. Purification by flash
chromatography (hexanes; Et2O–hexanes, 1:19) afforded coupled
material 50.
(8E,10E,14Z,16E)-[3S,4S,5R,6R,7R,13R,17(2R)]-15-Ethyl-17-
(6-hydroxy-3,6-dihydro-2H-pyran-2-yl)-3,5,7,9,13-pentameth-
yl-4-(triisopropylsilanyloxy)heptadeca-8,10,14,16-tetraen-6-ol
(54)
Silyl ether/i-Pr-lactol 50 (0.0088 g, 0.01 mmol) was dissolved in
THF (0.5 mL). H2O (0.2 mL) was added followed by glacial HOAc
(0.2 mL) and the solution was stirred at r.t. for 24 h. The reaction
was quenched by pouring into sat. aq NaHCO3 (15 mL). The aq
phase was extracted with EtOAc (2 10 mL) and the combined or-
ganic extracts were dried (MgSO4), filtered and concentrated. Puri-
fication by flash chromatography (Et2O–hexanes; 1:19, 1:9, 1:4)
afforded lactol 54 as well as (E)-enal 56 (0.0005 g, 7%). Yield:
0.0047 g (63%); colorless oil; Rf 0.50 (EtOAc–hexanes, 1:3);
[ ]D20 +63.0 (c 0.86, CHCl3).
Yield: 0.0560 g (99%); colorless oil; Rf 0.49 (EtOAc–hexanes,
1:19); [ ]D20 +38.4 (c 2.1, CHCl3).
IR (neat): 2964, 2870, 1462, 1453, 1381, 1251, 1180, 1101, 1055,
1033, 1002, 968, 883, 831 cm–1.
IR (neat): 3418, 2960, 2872, 1462, 1453, 1384, 1256, 1182, 1094,
1056, 993, 969, 939, 885 cm–1.
1H NMR (CDCl3, 400 MHz): = 6.59 (d, 1 H, J = 15.9 Hz), 6.07–
5.98 (m, 2 H), 5.77–5.69 (m, 2 H), 5.49–5.41 (m, 2 H), 5.19 (d, 1 H,
J = 9.3 Hz), 5.13 (s, 1 H), 4.54–4.48 (m, 1 H), 4.03 (sept, 1 H,
J = 6.2 Hz), 3.95 (t, 1 H, J = 3.8 Hz), 3.59 (dd, 1 H, J = 9.0, 2.0 Hz),
2.71–2.60 (m, 2 H), 2.20 (q, 2 H, J = 7.5 Hz), 2.15–1.97 (m, 4 H),
1.86–1.78 (m, 1 H), 1.72–1.64 (m, 1 H), 1.70 (s, 3 H), 1.52–1.45 (m,
1 H), 1.26 (d, 3 H, J = 6.2 Hz), 1.18 (d, 3 H, J = 6.0 Hz), 1.14–1.08
1H NMR (CDCl3, 400 MHz): = 6.63 (d, 1 H, J = 15.9 Hz), 6.13–
5.98 (m, 2 H), 5.86–5.81 (m, 1 H), 5.74 (dd, 1 H, J = 15.9, 6.6 Hz),
5.58 (d, 1 H, J = 9.7 Hz), 5.53–5.43 (m, 2 H), 5.19 (d, 1 H, J = 9.7
Hz), 4.59–4.53 (m, 1 H), 3.85 (t, 1 H, J = 3.8 Hz), 3.68 (s, 1 H), 3.55
(d, 1 H, J = 9.9 Hz), 2.99 (d, 1 H, J = 4.8 Hz), 2.75–2.61 (m, 2 H),
2.19 (q, 2 H, J = 7.5 Hz), 2.14–2.01 (m, 4 H), 1.70 (s, 3 H), 1.66–
Synthesis 2002, No. 14, 1993–2012 ISSN 0039-7881 © Thieme Stuttgart · New York

2010
M. Lautens, T. A. Stammers
PAPER
1.58 (m, 1 H), 1.45–1.35 (m, 2 H), 1.13–1.08 (m, 22 H), 1.07 (d, 3
H, J = 7.0 Hz), 1.05 (t, 3 H, J = 7.3 Hz), 0.98 (d, 3 H, J = 6.8 Hz),
0.94 (d, 3 H, J = 6.8 Hz), 0.94 (d, 3 H, J = 6.8 Hz), 0.92 (t, 3 H,
J = 7.1 Hz), 0.79 (d, 3 H, J = 7.0 Hz).
13C NMR (100 MHz, CDCl3): = 136.6, 136.3, 135.8, 133.5, 131.2,
129.0, 128.4, 128.0, 126.4, 125.3, 89.5, 82.2, 77.9, 67.9, 42.3, 41.0,
38.1, 35.0, 32.1, 31.1, 26.7, 26.1, 21.1, 18.8, 18.5, 18.4, 17.4, 14.1,
13.8, 13.1, 12.8, 12.7.
35.0, 32.5, 30.3, 26.6, 26.1, 21.0, 18.8, 18.5, 18.4, 17.3, 14.1, 13.7,
13.1, 12.75, 12.67.
HRMS (EI+, MH+): m/z calcd for C28H67O3Si: 615.4809; found:
615.4825.
The alcohol (0.0040 g, 0.006 mmol) was dissolved in freshly dis-
tilled CH2Cl2 (0.5 mL) and Dess–Martin periodinane (0.006 g, 0.01
mmol) was added. The heterogeneous mixture was stirred at r.t. for
45 min. The reaction mixture loaded directly onto a flash column
(EtOAc–hexanes; 1:19, 1:9) to afford C19-epi-C19-triisopropylsi-
lyl callystatin A.
(8E,10E,14Z,16E)-[3S,4R,5R,6R,7R,13R,17(2R)]-4-(tert-Butyl-
dimethylsilanyloxy)-15-ethyl-17-(6-hydroxy-3,6-dihydro-2H-
pyran-2-yl)-3,5,7,9,13-pentamethylheptadeca-8,10,14,16-tet-
raen-6-ol (55)
Colorless film: Rf 0.30 (EtOAc–hexanes, 1:9); [ ]D20 –4.3 (c 0.7,
CHCl3).
Silyl ether/i-Pr-lactol 51 (0.0235 g, 0.03 mmol) was dissolved in
THF (1 mL). H2O (0.2 mL) and glacial HOAc (0.2 mL) were added
and the solution was stirred at r.t. for 96 h. The reaction was
quenched by pouring in sat. aq NaHCO3 (25 mL). The aq phase was
extracted with EtOAc (2 20 mL) and the combined organic ex-
tracts were dried (MgSO4), filtered and concentrated. Purification
by flash chromatography (hexanes; EtOAc–hexanes; 1:19, 1:9, 1:4,
1:3) afforded lactol 55 as well as (E)-enal 57 (0.0057 g, 29%) both
as colorless oils.
IR (neat) 2964, 2865, 1737, 1727, 1712, 1698, 1462, 1453, 1382,
1242, 1058, 1017, 996, 966, 885 cm–1.
1H NMR (CDCl3, 400 MHz): = 6.90 (dt, 1 H, J = 9.9, 4.4 Hz), 6.64
(d, 1 H, J = 15.9 Hz), 6.07 (dt, 1 H, J = 9.9, 1.6 Hz), 6.02 (d, 1 H,
J = 15.6 Hz), 5.77 (dd, 1 H, J = 15.7, 6.8 Hz), 5.53 (dt, 1 H,
J = 15.6, 7.5 Hz), 5.40 (d, 1 H, J = 9.5 Hz), 5.26 (d, 1 H, J = 9.7 Hz),
4.99 (q, 1 H, J = 7.3 Hz), 4.10 (dd, 1 H, J = 6.0, 3.8 Hz), 3.65 (dq,
1 H, J = 9.7, 7.0 Hz), 2.91 (quintet-like, 1 H, J = 7.0 Hz), 2.70–2.62
(m, 1 H), 2.49–2.45 (m, 2 H), 2.22–2.14 (m, 2 H), 2.11–2.03 (m, 2
H), 1.76 (d, 3 H, J = 1.1 Hz), 1.61–1.49 (m, 2 H), 1.13 (d, 3 H,
J = 7.0 Hz), 1.11–1.02 (m, 28 H), 0.96 (d, 3 H, J = 6.6 Hz), 0.88 (t,
3 H, J = 7.0 Hz), 0.86 (t, 3 H, J = 7.0 Hz).
13C NMR (100 MHz, CDCl3): = 213.8, 164.2, 144.8, 137.6, 136.1,
135.3, 134.6, 129.9, 129.8, 126.7, 125.0, 121.9, 79.0, 77.6, 49.9,
45.3, 41.1, 40.7, 32.4, 30.3, 26.6, 26.4, 20.9, 18.6, 18.5, 17.6, 15.2,
13.7, 13.4, 13.1, 12.9, 12.8.
Yield: 0.0089 g (45%); Rf 0.49 (EtOAc–hexanes, 1:3); [ ]D20 +66.0
(c 0.5, CHCl3).
IR (neat): 3480, 3405, 2959, 2919, 2872, 1465, 1377, 1255, 1185,
1094, 1060, 1030, 1003, 966 cm–1.
1H NMR (CDCl3, 400 MHz): = 6.62 (d, 1 H, J = 15.9 Hz), 6.09–
5.97 (m, 2 H), 5.84–5.79 (m, 1 H), 5.74 (dd, 1 H, J = 15.9, 6.6 Hz),
5.55–5.44 (m, 3 H), 5.20 (d, 1 H, J = 9.5 Hz), 4.59–4.53 (m, 1 H),
4.05 (b, 1 H), 3.70 (t, 1 H, J = 2.9 Hz), 3.62 (d, 1 H, J = 10.1 Hz),
2.83 (d, 1 H, J = 4.4 Hz), 2.73–2.62 (m, 1 H), 2.60–2.52 (m, 1 H),
2.20 (q, 2 H, J = 7.5 Hz), 2.15–2.02 (m, 4 H), 1.78–1.63 (m, 1 H),
1.72 (s, 3 H), 1.39–1.31 (m, 1 H), 1.24–1.17 (m, 1 H), 1.06 (d, 3 H,
J = 7.1 Hz), 1.05 (t, 3 H, J = 6.8 Hz), 0.99 (d, 3 H, J = 6.8 Hz), 0.97
(d, 3 H, J = 6.6 Hz), 0.92 (s, 9 H), 0.88 (t, 3 H, J = 7.5 Hz), 0.72 (d,
3 H, J =& nbsp;7.0 Hz), 0.10 (s, 3 H), 0.06 (s, 3 H).
13C NMR (100 MHz, CDCl3): = 136.7, 136.3, 135.8, 133.6, 131.3,
129.0, 128.4, 128.0, 126.4, 125.4, 89.5, 80.6, 78.0, 67.8, 41.6, 41.1,
36.3, 35.7, 32.3, 31.0, 29.9, 29.1, 26.6, 26.2, 21.0, 18.4, 15.6, 14.0,
13.8, 12.9, 12.3, –3.9, –4.5.
In a plastic vial, C19-epi-C19-triisopropylsilyl callystatin A was
dissolved in freshly distilled THF (0.2 mL) and pyridine (0.2 mL).
The solution was chilled to 0 °C and HF pyridine (70:30; 0.1 mL,
Aldrich) was added dropwise. The solution was immediately al-
lowed to warm to r.t. and was stirred for 85 h. The reaction was
quenched by pouring into sat. aq NaHCO3 (10 mL). The aq phase
was extracted with EtOAc (3 5 mL) and the combined organic ex-
tracts were dried (MgSO4), filtered and concentrated. Purification
by flash chromatography (EtOAc–hexanes; 1:4, 1:3) afforded C19-
epi-callystatin A (2).
Yield: 0.0024 g (81%, 2 steps); colorless oil; Rf 0.20 (EtOAc–hex-
anes, 1:3); [ ]D20 –90.8 (c 0.2, CHCl3).
C19-epi-Callystatin A (2)
IR (neat): 3500, 2966, 2925, 2865, 1728, 1714, 1465, 1454, 1384,
1243, 1131, 1057, 1017, 963 cm–1.
Lactol 54 (0.0017 g, 0.003 mmol) and manganese(IV) oxide (0.005
g, 0.1 mmol, 20 equiv) were combined in freshly distilled CH2Cl2
(0.5 mL). The mixture was stirred at r.t. for 13 h before being fil-
tered through Celite and concentrated in vacuo to cleanly provide
the lactone.
1H NMR (CDCl3, 400 MHz): = 6.90 (dt, 1 H, J = 9.9, 4.0 Hz), 6.63
(d, 1 H, J = 15.7 Hz), 6.06 (dt, 1 H, J = 9.9, 1.8 Hz), 6.03 (d, 1 H,
J = 15.8 Hz), 5.76 (dd, 1 H, J = 15.4, 7.0 Hz), 5.58 (dt, 1 H,
J = 15.4, 7.3 Hz), 5.25 (d, 1 H, J = 9.9 Hz), 5.16 (d, 1 H, J = 10.1
Hz), 4.98 (q, 1 H, J = 7.3 Hz), 3.65 (dq, 1 H, J = 10.1, 6.6 Hz), 3.32–
3.27 (m, 1 H), 2.94–2.86 (m, 2 H), 2.66 (dq, 1 H, J = 9.5, 6.8Hz),
2.49–2.45 (m, 2 H), 2.22–2.15 (m, 2 H), 2.08 (t, 2 H, J = 7.0 Hz),
1.81 (d, 3 H, J = 1.3 Hz), 1.66–1.58 (m, 1 H), 1.46–1.35 (m, 1 H),
1.20 (d, 3 H, J = 7.3 Hz), 1.14 (d, 3 H, J = 6.6 Hz), 1.05 (t, 3 H,
J = 7.3 Hz), 0.97 (d, 3 H, J = 6.6 Hz), 0.87 (t, 3 H, J = 7.3 Hz), 0.80
(d, 3 H, J = 6.8 Hz).
13C NMR (125 MHz, CDCl3): = 217.7, 164.3, 144.9, 137.4, 136.4,
135.7, 135.5, 130.2, 128.7, 127.8, 125.0, 121.9, 79.1, 79.0, 46.1,
45.9, 41.0, 38.3, 32.4, 30.3, 26.6, 24.1, 21.0, 16.5, 16.1, 15.7, 13.7,
13.3, 11.5.
HRMS (EI+, M+): m/z calcd for C29H45O4: 457.3318; found:
457.3323.
Yield: 0.0014 g (83%); colorless film; Rf 0.39 (EtOAc–hexanes,
1:3); [ ]D20 +46.8 (c 0.4, CHCl3).
IR (neat): 3507, 2960, 2865, 1737, 1728, 1462, 1382, 1243, 1148,
1114, 1055, 1020, 963, 882 cm–1.
1H NMR (CDCl3, 400 MHz): = 6.89 (dt, 1 H, J = 9.7, 4.0 Hz), 6.64
(d, 1 H, J = 15.7 Hz), 6.10–6.03 (m, 2 H), 5.77 (dd, 1 H, J = 15.7,
6.8 Hz), 5.59 (d, 1 H, J = 10.1 Hz), 5.46 (dt, 1 H, J = 15.6, 7.9 Hz),
5.27 (d, 1 H, J = 9.7 Hz), 4.99 (q, 1 H, J = 7.3 Hz), 3.85 (t, 1 H,
J = 4.2 Hz), 3.60 (s, 1 H), 3.55 (dd, 1 H, J = 9.9, 1.0 Hz), 2.70–2.60
(m, 2 H), 2.49–2.45 (m, 2 H), 2.49–2.45 (m, 2 H), 2.24–1.93 (m, 2
H), 2.08 (t, 2 H, J = 7.0 Hz), 1.70 (d, 3 H, J = 0.9 Hz), 1.65–1.58 (m,
1 H), 1.45–1.35 (m, 2 H), 1.14–1.10 (m, 1 H), 1.10 (s, 21 H), 1.09–
1.03 (m, 6 H), 0.98 (d, 3 H, J = 6.6 Hz), 0.93 (d, 3 H, J = 6.8 Hz),
0.90 (t, 3 H, J = 7.0 Hz), 0.78 (d, 3 H, J = 7.0 Hz).
13C NMR (100 MHz, CDCl3): = 164.3, 144.9, 137.8, 137.0, 135.3,
133.5, 131.4, 125.0, 124.9, 121.9, 82.1, 79.1, 77.8, 42.2, 41.0, 38.2,
Callystatin A (1)
Lactol 57 (0.0039 g, 0.007 mmol) was dissolved in freshly distilled
CH2Cl2 (1 mL). Manganese(IV) oxide (0.012 g, 0.1 mmol) was add-
Synthesis 2002, No. 14, 1993–2012 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Oxabicyclo[3.2.1]oct-6-enes as Templates for Polypropionates: Total Synthesis of Callystatin A
2011
ed and the mixture was stirred at r.t. for 19 h. The mixture was fil-
tered through Celite and concentrated in vacuo to afford lactone
126.
(9) Crimmins, M. T.; King, B. W. J. Am. Chem. Soc. 1998, 120,
9084.
(10) Smith, A. B.; Brandt, B. M. Org. Lett. 2001, 3, 1685.
(11) Kalesse, M.; Quitschalle, M.; Khandavalli, C. P.; Saeed, A.
Org. Lett. 2001, 3, 3107.
(12) (a) Marshall, J. A.; Bourbeau, M. P. J. Org. Chem. 2002, 67,
2751. (b) Marshall, J. A.; Schaaf, G. M. J. Org. Chem. 2001,
66, 7825. (c) Marshall, J. A.; Fitzgerald, R. N. J. Org. Chem.
1999, 64, 4477.
(13) Vicario, J. L.; Job, A.; Wolberg, M.; Muller, M.; Enders, D.
Org. Lett. 2002, 4, 1023.
(14) (a) Murakami, N.; Sugimoto, M.; Kobayashi, M. Bioorg.
Med. Chem. 2001, 9, 57. (b) Murakami, N.; Sugimoto, M.;
Nakajima, T.; Kawanishi, M.; Tsutsui, Y.; Kobayashi, M.
Bioorg. Med. Chem. 2000, 8, 2651.
(15) Kudo, N.; Matsumori, N.; Taoka, H.; Fujiwara, D.;
Schreiner, E. P.; Wolff, B.; Yoshida, M.; Horinouchi, S.
Proc. Natl. Acad. Sci. U.S.A. 1999, 96, 9112.
(16) Tamura, R.; Saegusa, K.; Kakihana, M.; Oda, D. J. Org.
Chem. 1988, 53, 2723.
(17) Lautens, M.; de Frutos, O.; Stammers, T. A. Tetrahedron
Lett. 1999, 40, 9028.
(18) Lautens, M.; Aspiotis, R.; Colucci, J. J. Am. Chem. Soc.
1996, 118, 10930.
Yield: 0.0028 g (72%); colorless film; Rf 0.39 (EtOAc–hexanes,
1:3); [ ]D20 +52.5 (c 0.3, CHCl3).
IR (neat): 3493, 2960, 1725, 1465, 1381, 1252, 1057, 1021, 966
cm–1.
1H NMR (CDCl3, 400 MHz): = 6.89 (dt, 1 H, J = 9.9, 4.0 Hz), 6.65
(d, 1 H, J = 15.9 Hz), 6.08–5.98 (m, 2 H), 5.76 (dd, 1 H, J = 15.7,
6.8 Hz), 5.55 (d, 1 H, J = 10.1 Hz), 5.46 (dt, 1 H, J = 15.6, 7.7 Hz),
5.27 (d, 1 H, J = 9.5 Hz), 4.99 (q, 1 H, J = 7.3 Hz), 4.10 (br, 1 H),
3.69 (t, 1 H, J = 1.0 Hz), 3.62 (d, 1 H, J = 9.9 Hz), 2.69–2.61 (m, 1
H), 2.60–2.52 (m, 1 H), 2.49–2.45 (m, 2 H), 2.19 (q, 1 H, J = 7.3
Hz), 2.18 (q, 1 H, J = 7.5 Hz), 2.08 (t, 2 H, J = 7.1 Hz), 1.78–1.73
(m, 1 H), 1.72 (s, 3 H), 1.63–1.54 (m, 1 H), 1.40–1.30 (m, 1 H),
1.28–1.15 (m, 1 H), 1.06 (d, 3 H, J = 7.0 Hz), 1.05 (t, 3 H, J = 7.0
Hz) 0.99 (d, 3 H, J = 7.1 Hz), 0.97 (d, 3 H, J = 7.0 Hz), 0.92 (s, 9
H), 0.88 (t, 3 H, J = 7.3 Hz), 0.71 (d, 3 H, J = 7.1 Hz), 0.10 (s, 3 H),
0.07 (s, 3 H).
13C NMR (125 MHz, CDCl3): = 164.3, 144.9, 137.8, 137.0, 135.3,
133.5, 131.5, 130.1, 125.1, 124.9, 121.9, 80.7, 79.1, 78.0, 41.6,
41.1, 36.2, 35.7, 32.5, 30.3, 29.9, 29.2, 26.6, 26.2, 20.9, 18.4, 15.6,
14.1, 13.7, 12.9, 12.3, –3.9, –4.5.
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(b) Lautens, M.; Chiu, P.; Colucci, J. T. Angew. Chem., Int.
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HRMS [EI+, (M – C4H9)+]: m/z calcd for C31H51O4Si: 515.3557;
found: 515.3572.
The alcohol (0.0028 g, 0.005 mmol) was dissolved in freshly dis-
tilled CH2Cl2 (0.5 mL) and Dess–Martin periodinane (0.006 g, 0.01
mmol) was added. The mixture was stirred 30 min at r.t. before be-
ing loaded directly onto a flash column and eluted (hexanes;
EtOAc–hexanes; 1:19, 1:9, 1:4) to provide C19-tert-butyldimethyl-
silyl callystatin A. Data collected is in agreement with that reported
in the literature.8–10
Yield: 0.0023 g (82%); colorless oil.
(21) (a) Vogel, P.; Cossy, J.; Plumet, P.; Arjona, O. Tetrahedron
1999, 55, 13521. (b) Lautens, M.; Chiu, P. Top. Curr. Chem.
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Acknowledgement
This research was financially supported by Natural Sciences and
Engineering Research Council of Canada, the University of Toronto
and the Walter C. Sumner foundation. We thank Dr. Alan Lough for
obtaining the X-ray structure of compound 10, Dr. Timothy Burrow
for assistance with NMR spectroscopy and Dr. Alex Young and co-
workers in the University of Toronto Mass Spectroscopy lab for ob-
taining HRMS data.
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Scheme 20
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LiOH, MeOH
HO
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O
O
OTIPS
HO
OTIPS
27
19
O
Scheme 19
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Synthesis 2002, No. 14, 1993–2012 ISSN 0039-7881 © Thieme Stuttgart · New York