Synthesis of spongistatin 2 employing a new route to the EF fragment

Article abstract of DOI:10.1039/c3sc50304f

An improved route to the EF fragment of the spongistatins has been developed and employed in a synthesis of spongistatin 2. The C48-C51 diene side chain, which lacks the chlorine substituent present in spongistatin 1, presented some compatibility issues d

Full text of DOI:10.1039/c3sc50304f

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Synthesis of spongistatin 2 employing a new route to
the EF fragment†
Cite this: DOI: 10.1039/c3sc50304f
Helmut Kraus,a Antoine Français,a Matthew O'Brien,ab James Frost,a
a
a
a
a
´
´
Alejandro Dieguez-Vazquez, Alessandra Polara, Nikla Baricordi, Richard Horan,
a
a
a
*
Day-Shin Hsu, Takashi Tsunoda and Steven V. Ley
Received 1st February 2013
Accepted 26th February 2013
An improved route to the EF fragment of the spongistatins has been developed and employed in a
synthesis of spongistatin 2. The C48–C51 diene side chain, which lacks the chlorine substituent present
in spongistatin 1, presented some compatibility issues during target assembly. These were overcome by
implementing a late stage Stille cross coupling to construct the diene portion of the natural product.
DOI: 10.1039/c3sc50304f
www.rsc.org/chemicalscience
For our total synthesis of spongistatin 1 we developed an
efficient and scalable route to the ABCD fragment which prof-
Introduction
According to recent WHO gures, cancer is the 4th largest cause
of death worldwide, accounting for 13% of total mortality in
2008.1 With an increasingly aging population, the incidence of
cancer is predicted to follow an upward trend.2 In the urgent
battle against this disease, natural products have (directly or
indirectly) delivered many important therapeutic advances and
remain an invaluable resource in this respect.3 Since they were
isolated independently by Pettit,4 Kitagawa5 and Fusetani6 in
1993, the spongistatins have attracted considerable scientic
interest, owing principally to their exceptional antitumour
activity against a variety of cell types. Indeed, all nine members of
the spongistatin family have displayed remarkable growth inhi-
bition characteristics against the US National Cancer Institute's
panel of60 human cancercelllines.7 Ofthe family, spongistatin 1
is the most active, having GI50 values between 0.025–0.035 nM
with particular efficacy against cell lines derived from human
melanoma.7 Unfortunately, due to the very low abundance of
these compounds, as well as the difficulties associated with
isolation and purication, obtaining signicant quantities of
natural material for further research is neither practical nor
economic. Consequently, signicant research efforts have been
made towards their total synthesis. The absolute stereochem-
istry of these complex 42 membered macrolides remained
unknown until the rst syntheses of spongistatin 2 by Evans8 in
1997 and spongistatin 1 by Kishi a year later.9 Since then, several
additional total syntheses have been established by Crimmins,10
Heathcock,11 Paterson,12 Smith13 and ourselves.14
ited from the pseudo-C2 symmetry of this fragment.14d It was
clear, however, that despite successfully completing the total
synthesis of spongistatin 1, access to biologically signicant
quantities of these natural products would require an improved
synthetic route to the EF fragment; one which was more scal-
able, required fewer synthetic steps and provided a higher
overall yield. We report herein our second generation synthesis
of the EF fragment and its subsequent employment in a total
synthesis of spongistatin 2.14e
Retrosynthesis
In line with previous syntheses of the spongistatins,8–14 our
initial retrosynthetic analysis begins with disconnection of the
C41(O)–C1 ester and the C28–C29 olen to afford the ABCD
aldehyde fragment, along with the corresponding EF phos-
phonium salt (3) (Fig. 1). As we already had a satisfactory route
to the ABCD fragment (with material in hand),14d as well as a
proven endgame strategy, we sought to use a similar protecting
group regime for this new synthesis. However, whilst our earlier
synthesis of spongistatin 1 used an EF fragment containing a
fully assembled C48–C51 chlorodiene appendage, the nor-
chlorodiene required for spongistatin 2 alerted us to potential
compatibility concerns during the subsequent removal of the
PMB protecting groups.11d Conjugated dienes are prone to
undergo side reactions when exposed to DDQ,15 the standard
reagent used for the oxidative cleavage of PMB groups, and it
seems the chlorine substituent in spongistatin 1 mitigates
this.12a,14d These concerns notwithstanding, we elected to
continue with PMB protecting groups for the EF fragment.
Experiments (including model studies) conrmed that the
diene would likely not survive the conditions used to remove the
PMB groups. For this reason we chose to append a vinyl iodide
substituent which we hoped to transform at a late stage (aer
aDepartment of Chemistry, University of Cambridge, Lenseld Road, Cambridge, CB2
1EW, UK. E-mail: svl1000@cam.ac.uk; Fax: +44 (0)1223 336442; Tel: +44 (0)1223
336398
bLennard-Jones Laboratories, Keele University, Keele, Staffordshire, ST5 5BG, UK.
E-mail: m.obrien@keele.ac.uk; Tel: +44 (0)1782 734371
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c3sc50304f
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Horner reaction with known phosphonate 1318 yielded 14,
which underwent selective dihydroxylation (dr ¼ 86 : 14, single
isomer aer chromatography) to afford diol 15 (Scheme 1). We
next focused on the construction of the F ring by means of an
oxy-Michael cyclisation reaction.
Encouraged by studies undertaken by Paterson and co-
workers,12d our initial efforts centred on removal of the aceto-
nide protecting group in 15 under acidic conditions, which we
hoped would be accompanied by spontaneous cyclisation to
form the F ring in a one-pot procedure. However, although the
acetonide could cleanly be removed (using MP-TsOH), the
resulting tetraol 7 was resistant to subsequent cyclisation,
despite assaying a range of conditions for this transformation
(inc. Amberlyst A-15, TFA, Tf2NH, TfOH, AcOH, TMSCl : EtOH
(0.3 M)). This being the case, we focussed our attention on the
cyclisation process itself. The use of a variety of different bases
(TBAF, NaH, KHMDS, t-BuOK, DBU, Et3N, NaHCO3) under
different conditions (solvent and temperature) either failed to
promote any reaction or afforded the desired product only in
low yield (#50%).19 In many instances the desired thermody-
namic pyran 16 was formed in varying ratio with products
resulting from epimerisation at C42 or C43, the latter of which
tended to form the 6,5-cis fused bicyclic lactone 17. Having
achieved little success with bases, we turned instead to the use
of Lewis acids in order to affect this crucial transformation.
Although such methods to construct densely functionalised
tetrahydropyran rings are not widely reported,20 it seemed
reasonable that a Lewis acid might activate the enoate towards
nucleophilic attack. A selection of the additives which were
screened are shown in Table 1.
Fig. 1 Retrosynthetic analysis of spongistatin 2 and the EF fragment.
PMB deprotection) into the diene using a Stille coupling with
tributyl(vinyl)tin.16 Further disconnection of EF fragment 3 via
two aldol reactions leads to trans vinyl iodide 4, F ring-con-
taining fragment 5 and aldehyde 6 as potential coupling part-
ners. Fragment 5 would then derive from the intramolecular
oxy-Michael cyclisation of substrate 7. Development of a
sequence capable of furnishing multigram quantities of frag-
ment 5 was therefore key to a scalable route to the EF fragment
and thereaer the completion of spongistatin 2 (2) (Fig. 1).
Results and discussion
Our synthesis began from the commercially available (S)-Roche
ester 8. This was protected as its p-methoxybenzyl ether,
reduced to the corresponding aldehyde and reacted with
Ph3PCHCO2Et to furnish enoate 9 in excellent yield as a single
(E)-isomer. Dihydroxylation using the Sharpless17 AD-mix-b
provided 10 with excellent diastereoselectivity (dr ¼ 94 : 6).
Fortunately, this diol was highly crystalline and recrystallisation
Scheme 1 Synthesis of fragment 7. Reagents and conditions: (a) PMB-tri-
furnished a diastereomerically pure product in 92% yield. chloroacetimidate, PPTS, CH2Cl2, r.t., quant.; (b) DIBAL-H, CH2Cl2, ꢀ78 ꢁC; (c)
Ph3PCHCO2Et, CH2Cl2, r.t., 94% over 2 steps; (d) AD-mix-b, MeSO2NH2, t-BuOH–
Protection as the acetonide followed by addition of MeLi$LiBr to
the ester and Wittig reaction of the resulting ketone afforded 11.
This 7 step sequence was carried out on large scale (100 mmol
batches), allowing for the generation of 11 in substantial
H2O (1 : 1), 4 ꢁC, 92%; (e) 2,2-dimethoxypropane, CSA, r.t., 96%; (f) MeLi$LiBr,
Et2O, ꢀ78 ꢁC, 95%; (g) CH3PPh3Br, n-BuLi, THF, 0 ꢁC to r.t., 96%; (h) DDQ, pH 7
buffer, CH2Cl2, r.t.; (i) Dess–Martin periodinane, CH2Cl2, 0 ꢁC to r.t.; (j) 13, LiHMDS,
THF, ꢀ78 ꢁC then 12, ꢀ78 ꢁC to r.t.; 80% over 3 steps; (k) AD-mix-b, MeSO2NH2, t-
amounts. Removal of the PMB group, oxidation and Wittig– BuOH–H2O (1 : 1), 0 ꢁC, 89%; and (l) MP-TsOH, EtOH–H2O (1 : 1), 82 ꢁC, 98%.
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Table 1 Selected Lewis acidic additives for the key oxy-Michael cyclisation
investigated initially since experience gained from the
preceding oxy-Michael cyclisation had revealed the C43 stereo-
centre to be highly prone to epimerisation. However, despite
trying a variety of different acid catalysts (TfOH, La(OTf)3,
BF3$OEt2, Ph3CBF4) these efforts were met with decomposition
or only low yields of the desired tris-PMB ether 18. Little
improvement was observed using tried-and-tested basic condi-
tions. Wishing to avoid the daunting prospect of reworking our
protecting group strategy, we persevered. Aer investigating a
plethora of reagents and workarounds, we were pleased to nd
that a respectable 72% yield of 18 could be obtained using PMB-
lepidine in the presence of MeOTs.25 Use of this reagent offered
several advantages compared to PMB-TCA: (a) it was stable at
room temperature and could be easily prepared,25 (b) the reac-
tive intermediate could be formed under non-acidic conditions
and (c) the lepidine byproduct could be easily removed by silica
gel chromatography.
Hydrolysis of the ester functionality and formation of the
corresponding Weinreb amide26 proceeded smoothly. There-
aer dihydroxylation of the alkene and Pb(OAc)4-mediated
cleavage of the resulting diols furnished ketone 5; allowing for
interception of our rst generation synthesis of spongistatin 1
(Scheme 2).14e
With ketone 5 in hand, our efforts shied to the construction
of the E ring. The boron mediated aldol coupling of ketone 5
and aldehyde 1927 was achieved in high yield (82%) and in
Entry
Lewis acid
Temp. [ꢁC]
Methoda
Result
1
2
3
4
5
6
7
8
9
TiCl4
PtCl4
AuCl3
CeCl3
ZnCl2
PtCl4
AuCl3
CeCl3
ZnCl2
ZnX2
Zn(OTf)2
Zn(OTf)2
TfOH
80
80
80
80
80
110
140
120
180
140
100
100
100
A
A
A
A
A
B
B
B
B
B
B
C
C
Decomposition
No reaction
No reaction
No reaction
No reaction
Decomposition
Decomposition
Decomposition
16 (65%) + 17 (15%)
Decomposition
16 (75%) + 17 (15%)
16 (88%) + 17 (8%)c
No reaction
10b
11
12
13
a
Method A ¼ conventional heating using a reux condenser; Method
B ¼ microwave heating in a sealed vessel; Method C ¼ sealed Schlenk
b
c
tube. X ¼ F, Br, I. The reaction was also conducted at r.t. at
elevated pressure (50 bar) with no conversion observed.
The presence of a variety of Lewis acids (20 mol%) at 80 ꢁC in excellent diastereoselectivity (dr > 95 : 5), giving the Felkin–Anh
ethanol either led to no reaction or to decomposition (entries 1– product (20).28 Presumably the 1,2-stereochemical induction
5). The results for Pt(IV) and Au(III) were disappointing as we predicted by the Felkin–Anh model overrides any 1,3-asym-
speculated that the propensity of these metals to activate metric induction favoured by the chiral aldehyde.29 Treatment
ynones toward intramolecular reactions would extend to of 20 with PPTS in the presence of trimethyl orthoformate and
enones.21 In order to investigate the use of higher temperatures MeOH effected C33(OH) silyl deprotection and triggered
with the same solvent, a microwave reactor was used to conve-
niently allow the solvent to be superheated under pressure
(ethanol b.p. ¼ 78.4 ꢁC at 1 atm) (entries 6–11).22 Extensive
decomposition was observed in several cases (entries 6–8).
However, ZnCl2, which had no effect at 80 ꢁC, afforded at 180 ꢁC
the desired product 16 in 65% yield, in addition to lactone 17
(15%). Whilst the use of other zinc(II) halogenide additives
(ZnF2, ZnBr2, ZnI2) were ineffective (entry 10), Zn(OTf)2 proved
to be the optimal choice, with the desired product produced in
75% yield (entry 11). Fortunately, this reaction proved to be both
higher yielding (88%) and more scalable when performed in a
sealed Schlenk tube, using conventional heating (oil bath) at
100 ꢁC. Negating the need for a microwave reactor allowed
multigram batches of material to be processed (entry 12). The
origins of the superiority of Zn(OTf)2 as a catalyst for this
reaction are not clear, although it seems unlikely that any
residual TfOH is acting as a catalyst (entry 13).
Having developed an effective procedure to ensure scalable
and efficient access to the F-ring scaffold we required a method
that would allow for the protection of all three hydroxyl groups
present in 16. PMB protection of hydroxyl groups is typically
achieved using one of two sets of conditions: (a) base in
conjunction with PMB-Cl/Br and a catalytic amount of TBAI/
NaI23 or (b) PMB-trichloroacetimidate (TCA) combined with a
Brønsted or Lewis acid catalyst.24 The latter method was lutidine, THF, ꢀ78 ꢁC, 99%; and (i) MeLi, CeCl3, ꢀ78 ꢁC, quant.
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Scheme 2 Synthesis of EF fragment 21. Reagents and conditions: (a) PMBO-
lepidine, MeOTs, PhMe, 40 ꢁC, 72%; (b) LiOH$H2O, THF, H2O, r.t.; (c) HCl$HN(OMe)
Me, HOBt–EDCI, Et3N, THF, r.t, 86% over 2 steps; (d) OsO4, NMO, acetone–H2O
(1 : 1), r.t., 98%; (e) Pb(OAc)4, PhMe, r.t., 98%; (f) cHex2BCl, Et3N, Et2O, 0 ꢁC, 2 h,
then 19, ꢀ78 ꢁC, 2 h, 82%; (g) PPTS, CH(OMe)3, MeOH, r.t., 89%; (h) TBSOTf, 2,6-
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spontaneous E ring cyclisation with concomitant formation of considerable experimentation, a Wittig olenation reaction
the C37 methyl acetal. The C35(OH) was then protected as its between the corresponding phosphonium salt 3 (1.0 equiv.) and
TBS ether, and the Weinreb amide functionality converted to ABCD aldehyde 24 (1.3 equiv.)14d in the presence of LiHMDS (3.0
the corresponding ketone (21) in quantitative yield by reaction equiv.) at ꢀ78 ꢁC resulted in a 56% yield of the (Z)-alkene. The
with a methylcerium reagent prepared in situ from methyl- three PMB protecting groups in this compound were then
lithium and anhydrous ceric chloride.30 Completion of EF oxidatively cleaved in 71% yield using DDQ.
fragment 21 via this new route resulted in a signicantly shorter
At this stage the C48–C51 diene side chain could be
reaction sequence (22 linear steps) and a much higher overall completed. Pleasingly, the necessary Stille cross coupling reac-
yield of 20% compared to our rst generation synthesis tion was not perturbed by the C1 allyl ester protecting group. A
(27 linear steps and 5.6% overall yield).14e This enabled the one-pot Stille-coupling/deprotection sequence36 was effected
production of 6.4 g of highly functionalised compound 21, and using Pd2dba3 (10 mol%), AsPh3(40 mol%), tributyl(vinyl)tin
compares favourably with other routes reported towards similar (5.0 equiv.) and morpholine (10.0 equiv.), affording 26 in an
EF fragments.12,13
excellent yield of 84%. By installing the diene unit at this late
At this stage the route diverges from our original spongis- stage, we effectively avoided the side reactions (oxidation,
tatin 1 synthesis. Aldol coupling of 21 with an excess31 of 3-iodo- cycloadduct formation11d), that we and others had previously
acrolein 2232 furnished compound 23 in high diaster- observed using DDQ on a similar diene substrate.11d Yamaguchi
eoselectivity (dr > 95 : 5) and good yield (65%) (Scheme 3).33 This macrolactonisation37 of seco-acid 26 using the conditions
was then TBS-protected, and subjected to the Takai–Lombardo developed by Heathcock11 led to a mixture of the desired
1
methylenation34 conditions followed by Finkelstein reaction35 in product as well as some byproducts. From the H NMR of the
a highly efficient 3 step sequence in 74% overall yield. Following crude product mixture, it appeared that partial hydrolysis of the
Scheme 3 Completion of spongistatin 2. Reagents and conditions: (a) Cy2BCl, Et3N, Et2O, ꢀ55 ꢁC, then 22, ꢀ70 ꢁC, Et2O, 65%; (b) TBSCl, imidazole, DMF, r.t.; (c) Zn,
PbI2, TMSCl, CH2I2, 0 ꢁC to r.t., then TiCl4, CH2Cl2, r.t., followed by ketone, THF, r.t.; (d) NaI, NaHCO3, Na2SO3, 1-iodopropane, acetone, 67 ꢁC, 74% over 3 steps; (e) PPh3,
DIPEA, MeCN, 90 ꢁC; (f) 3, THF, r.t. then LiHMDS, ꢀ78 ꢁC, followed by aldehyde 24, ꢀ78 ꢁC, 56% over 2 steps; (g) DDQ, pH 7 phosphate buffer, CH2Cl2, 0 ꢁC, 71%; (h)
Pd2dba3 (10 mol%), AsPh3(40 mol%), tributyl(vinyl)tin (5.0 equiv.), morpholine (10.0 equiv.), DMF–THF (1 : 1), r.t., 84%; (i) 2,4,6-trichlorobenzoyl chloride, DIPEA, DMAP,
PhMe, 90 ꢁC; and (j) 47–51% aq. HF, MeCN, ꢀ20 ꢁC, 42% over 2 steps.
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methyl acetal at C37 had occurred, somewhat hampering full 1H
NMR analysis. However, treatment of the crude mixture with
and M. R. Boyd, J. Chem. Soc., Chem. Commun., 1993, 1166;
(c) G. R. Pettit, C. L. Herald, Z. A. Cichacz, F. Gao,
J. M. Schmidt, M. R. Boyd, N. D. Christie and
F. E. Boettner, J. Chem. Soc., Chem. Commun., 1993, 1805;
(d) G. R. Pettit, C. L. Herald, Z. A. Cichacz, F. Gao,
M. R. Boyd, N. D. Christie and J. M. Schmidt, Nat. Prod.
Lett., 1993, 3, 239; (e) G. R. Pettit, Z. A. Cichacz,
C. L. Herald, F. Gao, M. R. Boyd, J. M. Schmidt, E. Hamel
and R. L. Bai, J. Chem. Soc., Chem. Commun., 1994, 1605.
5 (a) M. Kobayashi, S. Aoki, H. Sakai, K. Kawazoe, N. Kihara,
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ꢁ
47–51% aq. HF at ꢀ20 C resulted in global silyl deprotection
and methyl acetal hydrolysis to deliver spongistatin 2 (2) in 42%
over the two steps. The synthetic material was found to be
identical to the natural product in all respects (1H NMR, 13C
NMR, IR, mass spectrometry, optical rotation).4b,5c
Conclusions
In summary we have developed a highly scalable and efficient
preparation of the EF fragment of the spongistatins. This was
made possible by the design of a route that gave access to
multigram quantities of tetraol 7. Satisfactory conditions for the
F ring cyclisation initially proved elusive but this key trans-
formation was eventually achieved in a yield of 88% using
Zn(OTf)2. Further synthetic manipulation brought about inter-
ception with our rst generation synthesis, leading to
compound 21 in 22 steps (longest linear sequence) and 20%
overall yield. With 5 fewer steps and a greater than threefold
increase in yield, this clearly represents a signicant gain in
efficiency. A boron mediated aldol reaction using 3-iodo-acro-
lein (22) allowed us to install a truncated vinyl iodide side chain.
By extending this to the diene at a late stage via a Stille cross
coupling with tributyl(vinyl)tin, we managed to avoid serious
incompatibility issues related to PMB deprotection and were
able to complete a total synthesis of spongistatin 2 (2) with an
overall yield of 1.3% (from Roche ester) over 32 steps (longest
linear sequence). To date, 6.4 g of 21 have been prepared. With
scalable routes to both the EF and ABCD fragments at our
disposal, we are now in a position to synthesise spongistatin 2
(and other members of the family) in quantities useful for
further biological investigation.
6 N. S. Fusetani, K. Shinoda and S. Matsunaga, J. Am. Chem.
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ˆ ´
B. Cote and P. J. Coleman, Angew. Chem., Int. Ed., 1997, 36,
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Acknowledgements
We gratefully acknowledge the Cambridge European Trust for a
partially funded studentship (H.K.), the EPSRC (A.F., M.O.B., 10 (a) M. T. Crimmins and D. G. Washburn, Tetrahedron Lett.,
R.H. grant number: EP/F0693685/1), Novartis (J.F., A.P.), the
1998, 39, 7487; (b) M. T. Crimmins and J. D. Katz, Org.
Lett., 2000, 2, 957; (c) M. T. Crimmins, J. D. Katz,
D. G. Washburn, S. P. Allwein and L. F. McAtee, J. Am.
Chem. Soc., 2002, 124, 5661.
´
Ministerio de Educacion y Ciencia (Spain) for a postdoctoral
`
fellowship (A.D.V), Universita di Ferrara (N.B.) the Taiwan Merit
Scholarship Program for a postdoctoral fellowship (D.S.H.),
Astellas Pharma Inc. (T.T.) and the B.P. 1702 endowment 11 (a) M. M. Claffey, C. J. Hayes and C. H. Heathcock, J. Org.
(S.V.L.) for generous funding.
Chem., 1999, 64, 8267; (b) G. A. Wallace, R. W. Scott and
C. H. Heathcock, J. Org. Chem., 2000, 65, 4145; (c)
J. L. Hubbs and C. H. Heathcock, J. Am. Chem. Soc., 2003,
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J. Medina, J. L. Hubbs, G. A. Wallace, R. Scott,
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