Synthesis of the bis-spiroacetal C25-C40 moiety of the antimitotic agent spirastrellolide B using a bis-dithiane deprotection/spiroacetalisation sequence

Article abstract of DOI:10.1039/c0cc00056f

Use of a bis-dithiane deprotection-tandem bis-spiroacetalisation sequence was key to the successful synthesis of the [5,6,6]-bis-spiroacetal of the antimitotic agent spirastrellolide B, achieved in a highly convergent fashion involving successive dithiane alkylations.

Full text of DOI:10.1039/c0cc00056f

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Synthesis of the bis-spiroacetal C25–C40 moiety of the antimitotic agent
spirastrellolide B using a bis-dithiane deprotection/spiroacetalisation
sequencew
Jack Li-Yang Chen and Margaret A. Brimble*
Received 22nd February 2010, Accepted 12th April 2010
First published as an Advance Article on the web 5th May 2010
DOI: 10.1039/c0cc00056f
Use of a bis-dithiane deprotection–tandem bis-spiroacetalisation
sequence was key to the successful synthesis of the [5,6,6]-bis-
spiroacetal of the antimitotic agent spirastrellolide B, achieved
in a highly convergent fashion involving successive dithiane
alkylations.
The spirastrellolides are a family of polyketide macrolides first
isolated in 2003 by Andersen and co-workers from the marine
sponge Spirastrella coccinea.1 Spirastrellolides A (1) and B (2)
exhibited antimitotic activity which was later attributed to the
potent (IC50 = 1 nM) inhibition of Ser/Thr protein phosphatase
2A (PP2A). PP2A is emerging as a novel medicinal target for
the treatment of cancer,2 and the isolation of the spirastrello-
lides is thus important not only for its potential as a therapeutic
agent, but also for its use as a biological tool in the investigation
of PP2A function.
The complex structure of the spirastrellolides and its unique
biological activity has generated intense interest within the syn-
thetic community.3 Of particular interest to our research group is
the intriguing [5,6,6]-bis-spiroacetal ring system (Fig. 1).4 We
sought to prepare this unit using a double dithiane deprotection/
spiroacetalisation strategy.5 The simultaneous deprotection of
Scheme 1 Retrosynthesis of DEF bis-spiroacetal 3.
two dithiane moieties with concomitant cyclisation to form a
bis-spiroacetal is hitherto unprecedented in the context of natural
C31 and C35 should therefore result from bis-dithiane deprotec-
product synthesis.
tion of acyclic precursor 4 under equilibrating conditions to
form the desired bis-spiroacetal 3 (Scheme 1). Acyclic precursor
4 is accessible via alkylation of dithiane 6 with iodide 5, which in
turn is prepared via union of dithiane 7 with epoxide 8. These
two successive dithiane alkylations considerably simplify the
carbon backbone of the target into three smaller fragments,
thereby facilitating a highly convergent approach to DEF
bis-spiroacetal 3.
The structure of the DEF bis-spiroacetal moiety benefits
from full anomeric stabilisation with all of its substituents
occupying equatorial positions. The desired configuration at
Fig. 1 Spirastrellolides A and B and the DEF bis-spiroacetal.
Scheme
2
Reagents and conditions: (i) Ti(O-i-Pr)4, D-(À)-DET,
TBHP, 4 A MS, CH2Cl2, À30 1C, then 9, À25 1C, 92% yield,
495% ee; (ii) Me3Al, CH2Cl2–hexanes (1 : 1), 78%; (iii) NaIO4,
THF–H2O (1 : 1), rt, 99%; (iv) 1,3-propanedithiol, CoCl2, CH3CN,
rt, 80%; (v) BF3ÁOEt2, Me2S, CH2Cl2, rt, then 7, 80%; (vi) TBSCl,
NEt3, DMAP, CH2Cl2, 85%.
Department of Chemistry, University of Auckland, 23 Symonds
Street, Auckland, New Zealand. E-mail: m.brimble@auckland.ac.nz
w Electronic supplementary information (ESI) available: Characterisa-
tion and spectral data for major intermediates. See DOI: 10.1039/
c0cc00056f
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Scheme 3 Reagents and conditions: (i) NCS, DMS, CH2Cl2, then 9,
0 1C to rt, 93%; (ii) (DHQ)2AQN, OsO4, K3[Fe(CN)6], CH3SO2NH2,
K2CO3, NaHCO3, t-BuOH–H2O (1
: 1), 0 1C, 98%, 94% ee;
(iii) NaOH, THF, 0 1C, 91%; (iv) EOMCl, i-Pr2EtN, DMAP, CH2Cl2,
rt, 87%.
The first fragment dithiane 7 was prepared using Sharpless
asymmetric epoxidation6 of allylic alcohol 9 (Scheme 2). Sub-
sequent epoxide opening using trimethylaluminium,7 followed
by oxidative cleavage and treatment with 1,3-propanedithiol
Scheme 5 Reagents and conditions: (i) KHMDS, 0 1C, THF, then
N-(2,4,6-triisopropylbenzenesulfonyl)imidazole; (ii) EOMCl, i-Pr2EtN,
DMAP, CH2Cl2, rt, 53% over 2 steps; (iii) 1,3-dithiane, n-BuLi, THF,
À20 1C, then 16, 0 1C, 88%; (iv) t-BuOK, MeI, THF, rt, 82%;
(v) n-BuLi/Bu2Mg (4 : 1), THF, rt, then 13, 78% (3 : 2 ratio of
diastereomers).
8
in the presence of CoCl2 furnished dithiane 7. Dithiane 7
however, proved ineffective for subsequent alkylation reactions
and deuterium exchange experiments indicated incomplete
lithiation of the 1,3-dithiane to be the problem. In view of
previous reports of interactions between p systems and the
C–S s* orbital,9 the PMB ether was replaced with a TBS ether
(Scheme 2). Dithiane 10 was efficiently lithiated, with 80%
deuterium incorporation being observed.
subsequent alkylation resulted only in decomposition of
the starting material.13 Alcohol 12 was therefore converted
to aldehyde 13 using TPAP/NMO,14 with the hope that the
superfluous hydroxyl group formed following hydroxyalkyl-
ation could be readily removed via Barton–McCombie15
deoxygenation.
The synthesis of epoxide 8 began with chlorination of allylic
alcohol 9, followed by Sharpless dihydroxylation10 to install
the stereocentres at C37 and C38 (Scheme 3). Use of the AQN11
linker allowed access to the diol in 94% ee, higher than the
previously reported example using PHAL (88% ee).12 Treatment
with NaOH to form the epoxy alcohol, followed by protection as
an ethoxymethyl (EOM) ether provided epoxide 8 in 72% over
the 4 steps.
The third fragment dithiane 6 was synthesised from triol 15,
which in turn was available from D-(+)-ribono-g-lactone
14 (Scheme 5).16 Epoxide formation using KHMDS and
N-(2,4,6-triisopropylbenzenesulfonyl)imidazole,17 followed by
EOM protection furnished epoxide 16 in 53% yield over the
2 steps. Alkylation of epoxide 16 with 1,3-dithiane, followed by
methylation provided the desired dithiane 6.
Union of dithiane 10 and epoxide 8 was efficiently achieved
by treatment of dithiane 10 (1.6 eq.) with n-BuLi at rt,
followed by the addition of epoxide 8 (Scheme 4). The coupled
product 11 was isolated in quantitative yield, with the excess
dithiane 10 fully recovered. Benzyl protection of the resulting
alcohol, followed by removal of the primary TBS group
provided alcohol 12 in 82% yield over the 2 steps. Attempts
to convert alcohol 12 into the corresponding iodide for
Deuterium exchange experiments demonstrated effective
lithiation of dithiane 6 using n-BuLi as well as t-BuLi in
THF/HMPA, but both of these methods failed to effect the
union of dithiane 6 with aldehyde 13. Further experiments
suggested that the lifetime of the anion was relatively short at
the temperatures required for successful alkylation. Therefore
a n-BuLi/Bu2Mg18 mixture was employed to extend the life-
time of the lithiated species. Use of this mixed organometallic
reagent allowed effective coupling of dithiane 6 with aldehyde
13 in 78% yield (3 : 2 ratio of diastereomers).
Several methods were investigated for the deoxygenation of
alcohol 17, including Barton–McCombie conditions. Formation of
the xanthate derivative of alcohol 17 was successful, but sub-
sequent treatment with Bu3SnH and AIBN and heating in toluene
resulted in decomposition of the starting material. Attempts to
form the thiocarbonyldiimidazole derivative met with failure.
The desire to progress with the synthesis led to the decision
to postpone the deoxygenation of the C32 secondary alcohol to
allow investigation of the critical bis-dithiane deprotection–
bis-spiroacetalisation sequence. To this end, the two diastereo-
1
meric alcohols were separated to facilitate H NMR and 13C
NMR interpretation in the following steps. However, steric
hindrance at the C32 alcohol prevented introduction of bulky
protecting groups capable of withstanding the acidic con-
ditions required for removal of the EOM groups.
Scheme 4 Reagents and conditions: (i) n-BuLi, THF, rt, 5 min, then 8,
98%; (ii) KH, BnBr, THF, rt, 85%; (iii) TBAF, THF, rt, 97%;
(iv) TPAP, NMO, 4 A MS, CH2Cl2, rt, 86%.
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2007, 72, 9842; D. E. Williams, M. Roberge, R. V. Soest and
R. J. Andersen, J. Am. Chem. Soc., 2003, 125, 5296.
2 A. McCluskey, A. T. R. Sim and J. A. Sakoff, J. Med. Chem., 2002,
45, 1151.
3 For total syntheses of the spirastrellolides, see: I. Paterson,
E. A. Anderson, S. M. Dalby, J. H. Lim, J. Genovino, P. Maltas
and C. Moessner, Angew. Chem., Int. Ed., 2008, 47, 3016; I. Paterson,
E. A. Anderson, S. M. Dalby, J. H. Lim, J. Genovino, P. Maltas and
C. Moessner, Angew. Chem., Int. Ed., 2008, 47, 3021; G. W. O’Neil,
J. Ceccon, S. Benson, M.-P. Collin, B. Fasching and A. Furstner,
¨
Angew. Chem., Int. Ed., 2009, 48, 9940; S. Benson, M.-P. Collin,
G. W. O’Neil, J. Ceccon, B. Fasching, M. D. B. Fenster,
C. Godbout, K. Radkowski, R. Goddard and A. Furstner, Angew.
¨
Chem., Int. Ed., 2009, 48, 9946; For contributions towards the
spirastrellolides, see: I. Paterson, E. A. Anderson, S. M. Dalby and
O. Loiseleur, Org. Lett., 2005, 7, 4121; I. Paterson, E. A. Anderson,
S. M. Dalby and O. Loiseleur, Org. Lett., 2005, 7, 4125; J. Liu and
R. P. Hsung, Org. Lett., 2005, 7, 2273; Y. Pan and J. K. De Brabander,
Synlett, 2006, 853; I. Paterson, E. A. Anderson, S. M. Dalby,
J. H. Lim, P. Maltas and C. Moessner, Chem. Commun., 2006, 4186;
C. Wang and C. J. Forsyth, Org. Lett., 2006, 8, 2997; J. Liu,
J. H. Yang, C. Ko and R. P. Hsung, Tetrahedron Lett., 2006, 47,
Scheme 6 Reagents and conditions: (i) PPTS, t-BuOH, reflux, 63%;
(ii) HgCl2, CH3CN–H2O (4 : 1), rt, 74%; (iii) C(S)Im2, THF, reflux,
78%; (iv) Bu3SnH, AIBN, toluene, reflux, 40% 3 and 30% 18.
6121; A. Furstner, M. D. B. Fenster, B. Fasching, C. Godbout and
¨
¨
K. Radkowski, Angew. Chem., Int. Ed., 2006, 45, 5506; A. Furstner,
M. D. B. Fenster, B. Fasching, C. Godbout and K. Radkowski,
Angew. Chem., Int. Ed., 2006, 45, 5510; I. Paterson, E. A. Anderson,
S. M. Dalby, J. Genovino, J. H. Lim and C. Moessner, Chem.
Commun., 2007, 1852; A. B. Smith and D.-S. Kim, Org. Lett., 2007,
9, 3311; C. Wang and C. J. Forsyth, Heterocycles, 2007, 72, 621;
As a result, unprotected alcohol 17a was carried through the
bis-dithiane deprotection–spiroacetalisation sequence with the
intent of removing the superfluous hydroxyl group at a late
stage.19 The best results for EOM deprotection was obtained
by use of PPTS in t-BuOH20 at reflux to furnish the corres-
ponding triol in 63% yield (Scheme 6). Gratifyingly, the
critical bis-dithiane deprotection step was accomplished by
treatment of the bis-dithiane with HgCl2, resulting in con-
comitant bis-spiroacetalisation to generate the desired bis-
spiroacetal 18 in 74% yield. Bis-spiroacetal 18 was formed
as a single diastereomer, with no sign of competing cyclisa-
tions. The double anomerically stabilised configuration was
confirmed by a strong NOE correlation between the C27 and
C38 methine protons.
A. Furstner, B. Fasching, G. W. O’Neil, M. D. B. Fenster, C. Godbout
¨
and J. Ceccon, Chem. Commun., 2007, 3045; K. A. Keaton and
A. J. Phillips, Org. Lett., 2008, 10, 1083; S. Chandrasekhar,
C. Rambabu and A. S. Reddy, Org. Lett., 2008, 10, 4355;
J.-H. Yang, J. Liu and R. P. Hsung, Org. Lett., 2008, 10, 2525; For
a review see: I. Paterson and S. M. Dalby, Nat. Prod. Rep., 2009, 26,
865.
4 For
a review on the synthesis of bis-spiroacetals, see:
M. A. Brimble and F. A. Fares, Tetrahedron, 1999, 55, 7661.
5 For examples of dithiane chemistry in natural product synthesis,
see: A. B. Smith, III and W. M. Wuest, Chem. Commun., 2008,
5883; A. B. Smith, III and C. M. Adams, Acc. Chem. Res., 2004,
´
37, 365; M. Y. Yus, C. Najera and F. Foubelo, Tetrahedron, 2003,
59, 6147; A. B. Smith, III, S. M. Condon and J. A. McCauley, Acc.
Chem. Res., 1998, 31, 35.
An attempt to form the xanthate derivative of 18 in
readiness for a Barton–McCombie deoxygenation reaction
met with failure. However, the thiocarbonylimidazole derivative
of bis-spiroacetal 18 was successfully formed, presumably due
to the lower steric encumbrance at C32 following bis-spiroacetal
formation. Treatment of the thiocarbonylimidazole derivative
of 18 with Bu3SnH and AIBN in toluene under reflux
furnished the desired DEF bis-spiroacetal of spirastrellolide
B (3) in 40% yield, with 30% recovered bis-spiroacetal 18.
Efforts towards improving the efficiency of the deoxygenation
step are ongoing and will be reported in due course.
6 Y. Gao, R. M. Hanson, J. M. Klunder, S. Y. Ko, H. Masamune
and B. Sharpless, J. Am. Chem. Soc., 1987, 109, 5765.
7 T. Suzuki, H. Saimoto, H. Tomioka, K. Oshima and H. Nozaki,
Tetrahedron Lett., 1982, 23, 3597.
8 S. K. De, Tetrahedron Lett., 2004, 45, 1035.
9 A. B. Smith, III, G. K. Friestad, J. Barbosa, E. Bertounesque,
K. G. Hull, M. Iwashima, Y. Qiu, B. A. Salvatore, P. G. Spoors
and J. J.-W. Duan, J. Am. Chem. Soc., 1999, 121, 10468.
10 H. C. Kolb, M. S. VanNieuwenhze and K. B. Sharpless, Chem.
Rev., 1994, 94, 2483.
11 H. Becker and K. B. Sharpless, Angew. Chem., Int. Ed. Engl., 1996,
35, 448.
12 W. H. Pearson and B. W. Lian, Angew. Chem., Int. Ed., 1998, 37, 1724.
13 For a similar example, see: A. B. Smith, III, S. M. Condon,
J. A. McCauley, J. L. Leazer, Jr., J. W. Leahy and
R. E. Maleczka, Jr., J. Am. Chem. Soc., 1997, 119, 947.
14 S. V. Ley, J. Norman, W. P. Griffith and S. P. Marsden, Synthesis,
1994, 639.
15 D. H. R. Barton and S. W. McCombie, J. Chem. Soc., Perkin
Trans. 1, 1975, 1574.
16 S. V. Attwood and A. G. M. Barrett, J. Chem. Soc., Perkin Trans. 1,
1984, 1315.
In summary, the successful synthesis of the DEF bis-
spiroacetal ring system of spirastrellolide
B has been
achieved using a novel bis-dithiane deprotection–tandem bis-
spiroacetalisation strategy. Features of this highly convergent
synthesis include the use of successive dithiane alkylations and a
late stage Barton–McCombie deoxygenation reaction. This
methodology can also be used to access C32 analogues of the
DEF bis-spiroacetal in order to investigate their PP2A activity.
17 E. J. Corey, L. O. Weigel, A. R. Chamberlin and B. Lipshutz,
J. Am. Chem. Soc., 1980, 102, 1439.
18 M. Ide and M. Nakata, Bull. Chem. Soc. Jpn., 1999, 72, 2491.
19 The final steps in this synthesis were initially investigated using the
diastereomer of 17a and there is no indication that this diastereo-
mer cannot also be carried through the synthesis. Research is
ongoing and full results will be presented in due course.
20 H. Monti, G. Leandri, M. Klos-Ringuet and C. Corriol, Synth.
Commun., 1983, 13, 1021.
Notes and references
1 K. Warabi, D. E. Williams, B. O. Patrick, M. Roberge and
R. J. Andersen, J. Am. Chem. Soc., 2007, 129, 508;
D. E. Williams, R. A. Keyzers, K. Warabi, K. Desjardine,
J. L. Riffell, M. Roberge and R. J. Andersen, J. Org. Chem.,
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Chem. Commun., 2010, 46, 3967–3969 | 3969