Synthesis of the EF fragment of spongistatin 1

Article abstract of DOI:10.1055/s-2005-871960

The EF fragment of spongistatin 1 was prepared diastereoselectively from 3,4,5-tri-O-benzyl-D-glucal. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-871960

LETTER
2031
Synthesis of the EF Fragment of Spongistatin 1
Synthesis of th
h
e
EF Fragm
e
i
nt of
S
g
pongistatin
1eru Kawahara, Matthew J. Gaunt, Alessandra Scolaro, Shigeo Yamanoi, Steven V. Ley*
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK
Fax +44(1223)336442; E-mail: svl1000@cam.ac.uk
Received 16 June 2005
OH
H
Abstract: The EF fragment of spongistatin 1 was prepared diaste-
reoselectively from 3,4,5-tri-O-benzyl-D-glucal.
B
AcO
Cl
Key words: aldol, stereoselective synthesis, natural products, gly-
cosides, spongistatin 1, spongistatins
A
O
OH
O
H
AcO
O
HO
1
O
O
H
O
The spongistatins are a family of highly cytotoxic mac-
rolides that were isolated from marine sponges.1–3 These
compounds have been shown to exhibit potent antitumour
activities against a number of human multi-drug resistant
cell lines.4 The limited supply from natural sources has
stimulated significant efforts in the synthesis of these
compounds.5 Our route to spongistatin 1 calls for the as-
sembly of a C1–C29 ABCD aldehyde,6a,b coupling via a
Wittig process with a suitable EF fragment. This fragment
ideally derives from the union of three building blocks 1,
2, and 3, where the F-ring unit 2 acts as a core structure to
which the side chains are appended via aldol coupling re-
actions. We now report the successful completion of the
synthesis of the EF fragment based on this approach. Pre-
vious work in our group on a model system had estab-
lished the viability of this general strategy (Scheme 1).6c
F
H
O
H
HO
C
H
D
OMe
O
O
H
HO
E
HO
28
Spongistatin 1
OH
PPh3I
OPMB
PMBO
TBSO
O
F
E
O
OTBS
OMe
OPMB
H
Cl
EF fragment
N
O
O
OPMB
O
The synthetic effort began with the manipulation of glycol
derivative 4, which was prepared from 3,4,5-tri-O-benzyl-
D-glucal.6c Anomeric acetate formation, Mukaiyama-type
C glycosidation with 2-trimethylsilyloxy-propene and
subsequent isomerisation introduced the 2-oxo-propane
moiety of 5 in the required equatorial manner (Scheme 2).
Protection of the carbonyl group as its dioxolane deriva-
tive and further manipulation delivered iodide 6. Cyanide
displacement of the iodide afforded the corresponding ni-
trile 7, which was converted into ketone 2; the crucial step
of which is stereoselective introduction of the C38 hy-
droxyl group.
OPMB
OTES
F
H
Cl
+
+
O
H
O
O
Cl
PMBO
2
1
3
Scheme 1 Synthetic strategy for the EF fragment of spongistatin 1.
8. There is also a possibility that one of the two lone pairs
of the pyran oxygen might direct the catalyst through co-
ordination.
This was accomplished by Rubottom-type oxidation of
the thermodynamic silyl enol ether readily generated from
ketone 7, affording 8 as the sole C38 epimer (Scheme 2).7
The C29–C35 aldehyde fragment 3 was conveniently ob-
tained in 4 steps from commercially available oxazolidi-
Nuclear Overhauser effect (NOE) was observed between
C38–H and C40–H, and C36–Me and C38–H, respective-
ly (Figure 1). This clearly indicated that one face of the si-
lyl enol ether moiety was hindered by the C40 methyl
substituent. Therefore, the Rhenium catalyst most reason-
ably approaches the silyl enol ether moiety from the less
hindered front side, leading to the desired hydroxyketone
OTBS
37
39
Me
40
R
O
38
36
H
H
NOE
Figure 1 Proposed 3D structure of the silyl enol ether based on
NOE analysis; two PMBO groups are omitted and the CH2CON–
MeOMe moiety is represented by R for clarity.
SYNLETT 2005, No. 13, pp 2031–2034
Advanced online publication: 12.07.2005
DOI: 10.1055/s-2005-871960; Art ID: D16305ST
© Georg Thieme Verlag Stuttgart · New York
1
9
.0
8
.2
0
0
5

2032
S. Kawahara et al.
LETTER
OBn OBn
OBn OBn
OBn
O
OH
O
OBn
i
i, ii
N
Cl
H
O
N
H
O
O
O
H
O
O
O
OMe
9
10
5
4
O
iii
ii
O
OTES
O
OTES
iv
I
OPMB
CN OPMB
OPMB
Cl
Cl
H
EtS
35
OPMB
41
29
H
H
O
iii
3
11
O
H
H
O
Scheme 3 Reagents and conditions: i) n-Bu2BOTf, i-Pr2NEt,
CH2Cl2, –78 °C to 0 °C, 30 min, followed by addition of 5-chloropen-
tanal, –78 °C to 0 °C, 1.5 h, 78%; ii) TESCl, imidazole, DMF, r.t., 2
h, 78%; iii) EtSH, n-BuLi, THF, 0 °C, 0.5 h, 80%; iv) 10% Pd/C,
Et3SiH, CH2Cl2, r.t., 10 min, 98%.
O
6
7
O
iv
N
O
N
O
The acid-catalysed removal of the triethylsilyl group from
the C33 hydroxyl of 13 revealed the EF-ring system 14 via
spontaneous cyclisation and in situ protection of the
resulting hemiketal in the presence of MeOH as solvent.
Silyl protection of the C35 hydroxyl group was best per-
formed using tert-butyldimethylsilyl trifluoromethane-
sulfonate/2,6-lutidine and conversion of the Weinreb
amide into methyl ketone 15 was effected by treatment
with MeLi–CeCl3. The organocerium reagent was chosen
due to its reduced basicity compared with the analogous
organolithium, successfully preventing competing unpro-
ductive enolisation.11
MeO
OPMB
38
MeO
OPMB
OPMB
O
OPMB
O
H
H
v
O
H
O
H
38
HO
PMBO
8
2
Scheme 2 Synthesis of the F-ring fragment 2. Reagents and condi-
tions: i) (a) concd HCl, 1,4-dioxane, r.t., 4 h, 65%; (b) Ac2O, pyridine,
r.t., 5 h, 98%; (c) 2-trimethylsilyloxy-propene, TMSOTf, CH2Cl2,
–78 °C to –40 °C, 25 h, 75%; (d) NaOMe, MeOH, r.t., 18 h, then 1,2-
ethanediol, PPTS, benzene, (azeotropic), 85% over 2 steps; ii) (a)
10% Pd/C, H2, AcOH, EtOH, r.t., 10 h, then TIPSCl, imidazole,
DMF, r.t., 3 h, 97%, over 2 steps; (b) PMBCl, NaI, NaH, THF–DMF,
r.t., 18 h, 98%; (c) TBAF, THF, r.t., 2 h, 88%; (d) I2, PPh3, imidazole,
MeCN–Et2O, quant; iii) (a) KCN, 18-crown-6, DMF, r.t., 3 h, 92%;
(b) DIBAL-H, CH2Cl2, –78 °C, 2 h, 84%; (c) NaClO2, 2-methyl-2-bu-
tene, pH 7 buffer–t-BuOH–THF, r.t., 1 h, then MeNHOMe·HCl,
TEA, EDCI, HOBt, CH2Cl2, 93% over 2 steps; (d) PPTS, acetone–
H2O, reflux, 1 h, 90%; iv) (a) t-BuOK, t-BuOH, THF, –78 °C, 20 min,
followed by addition of TBSCl, –78 °C, 1 h, quant.; (b) MTO, pyridi-
ne, H2O2, CH2Cl2, 0 °C to r.t., 4 h, then TBAF, CH2Cl2, 0 °C, 30 min,
78%, over 2 steps; v) (a) PMBTCA, BF3·OEt2, CH2Cl2, r.t., 50–80%.
The chlorodiene fragment 1 was prepared in just four
steps from commercially available orthoester 16
(Scheme 5). Johnson–Claisen rearrangement through the
intermediacy of allylvinyl ether 17 afforded a-chloroester
18.12 Basic elimination with DBU in benzene provided an
intermediate conjugated diene ester which was reduced
with DIBAL-H and oxidised with MnO2 to furnish chlo-
rodiene 1. This sequence represents the most efficient so-
lution to the synthesis of the problematic chlorodienal
MTO = methyltrioxorhenium; PMBTCA = para-methoxybenzyl tri- aldehyde.
chloroacetoimidate.
Coupling of chlorodiene 1 to methyl ketone 15 was
achieved through a highly selective boron aldol reaction.
Owing to its instability, immediate protection of the new-
ly formed C47 alcohol was necessary to access 20 in ex-
cellent yield (Scheme 6). Interestingly, we found that the
C35 tert-butyldimethylsilyl ether was essential for high
selectivity in this reaction;5m,6c use of the corresponding
C35 para-methoxybenzyl ether 19 resulted in poor dia-
stereoselectivity in the side chain coupling reaction. The
seemingly remote nature of the C35 protecting group in-
dicates a key conformational requirement for the installa-
tion of the side chain motif via aldol coupling protocols.
none 9 using Evans’ aldol chemistry.8 Stereoselective
aldol coupling and protection of the resulting alcohol gave
the protected syn-aldol product 10. Substitution of the
oxazolidinone with EtSLi afforded the thiol 11, which
was conveniently reduced to the corresponding C29–C35
aldehyde 3 with Et3SiH in the presence of Pd/C9
(Scheme 3).
The boron-mediated aldol coupling of ketone 2 with alde-
hyde 3 proceeded with high diastereocontrol, providing
the desired aldol adduct 13 under Felkin–Ahn control
(Scheme 4). This excellent diastereoselectivity suggests
that 1,2 Felkin–Ahn control overrides the competing 1,3
effect of the chiral aldehyde.10
Takai olefination installed the desired exo-methylene
group at the C45 position affording 22 (Scheme 7).13
Finkelstein conditions in the presence of n-PrI, which act-
ed as a chloride scavenger, enabled us to obtain the corre-
sponding iodide 23 as the sole product. Phosphonium salt
Synlett 2005, No. 13, 2031–2034 © Thieme Stuttgart · New York

LETTER
Synthesis of the EF Fragment of Spongistatin 1
2033
OPMB
PMBO
O
Cl
O
O
OTBS
OPMB
N
47
O
H
2
H
OPMB
O
OMe
OPMB
OPMB
H
O
i
OPMB
i, ii
H
H
H
O
O
H
PMBO
MeO
OPMB
H
O
PMBO
O
35
OBCy2
PMBO
MeO
OR
Cl
N
O
H
35
H
R = TBS 15
R = PMB 19
12
OMe
OPMB
OR
R = TBS 20 95% (sole product)
R = PMB 21 90% (4:1 d.r. in favour of 21)
Cl
ii
Felkin–Ahn
1,3 syn (1,3 anti preferred)
OPMB
Scheme 6 Reagents and conditions: i) (a) Cy2BCl, TEA, Et2O, –78
°C, 3 h, followed by addition of aldehyde 1, –78 °C, 16 h; (b) TBSCl,
imidazole, DMF, r.t., 2 h, 97% over 2 steps.
PMBO
O
OH OTES
O
40
39
38
35
N
O
H
Cl
36
H
13
OMe
OPMB
to counteranion exchange between iodide and presumably
HO– or MeO–. In order to avoid the problematic purifica-
tion, we intend to use the crude salt in the following key
Wittig coupling.
1,5 anti
1,4 anti
OMe
N
iii
O
O
OPMB
OPMB
In summary, we have completed an efficient synthesis of
the EF fragment of spongistatin 1. Our route has produced
gram quantities of the key fragment and we are currently
optimising the completion of the synthesis of spongistatin
1. We are also developing a second-generation synthesis
of the EF fragment which will be reported in due course.
OPMB
OPMB
H
H
O
H
O
H
iv, v
H
O
H
O
PMBO
MeO
PMBO
MeO
35
35
OH
Cl
OTBS
Cl
15
14
Cl
Cl
Scheme 4 Reagents and conditions: i) Cy2BCl, TEA, Et2O, 0 °C,
1.5 h; ii) 3, –78 °C to 0 °C, 3 h, 96%; iii) PPTS, TMOF, MeOH–THF,
r.t., 20 min, 89%; iv) t-BuMe2SiOTf, 2,6-lutidine, THF, –78 °C, 20
min, 86%; v) CeCl3, MeLi, THF, –78 °C, 20 min, 96%.
OTBS
OTBS
OPMB
OPMB
OPMB
45
45
OPMB
H
H
iii
i
spongistatin 1
O
H
O
H
20
Cl
Cl
Cl
Cl
H
i
H
O
ii, iii
O
OEt
PMBO
MeO
PMBO
MeO
CHO
EtO
OEt
OEt
O
16
18
1
OTBS
PPh3I
OTBS
X
X = Cl 22
X = I 23
Cl
Cl
EF Fragment
ii
Scheme 7 Reagents and conditions: i) Zn, PbI2, Me3SiCl, CH2I2,
TiCl4, CH2Cl2–THF, r.t., 4 h, 75%; ii) NaI, n-PrI, NaHCO3, Na2SO3,
acetone, 18 h, 93%; iii) PPh3, i-Pr2NEt, MeCN, 85 °C, quant.
O
OEt
17
Scheme 5 Reagents and conditions: i) pivalic acid, 2-chloro-2-pro-
pene-1-ol, o-xylene, 140 °C, 17 h, 78%; ii) (a) DBU, benzene, 0 °C to
r.t., 4 h; (b) DIBAL-H, CH2Cl2, –78 °C, 30 min, 74% over 2 steps; iii)
MnO2, CH2Cl2, r.t., 1 h, 81%.
Acknowledgment
We thank Pharmacia, Italy (A.S.), Ajinomoto Co. Inc. (S.K.), and
Novartis for a fellowship (S.V.L.), as well as Dr. Matthew Ball,
Adam Talbot and Huw Tanner for other important contributions to
this work. We also gratefully acknowledge the work of Dr. Felix
Rodriguez in performing crucial EF model studies.
formation was easily achieved with PPh3 in the presence
of i-Pr2NEt, however, silica gel purification of the salt led
Synlett 2005, No. 13, 2031–2034 © Thieme Stuttgart · New York

2034
S. Kawahara et al.
LETTER
Scott, R.; Claffey, M. M.; Hayes, C. J.; Ott, G. R. J. Am.
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Synlett 2005, No. 13, 2031–2034 © Thieme Stuttgart · New York