Synthesis of the C(29)-C(45) bis-pyran subunit (E-F) of spongistatin 1 (altohyrtin A)

Article abstract of DOI:10.1021/jo001236o

A synthesis of the C(29)-C(45) bis-pyran subunit 2 of spongistatin 1 (1a) is described. The synthesis proceeds in 19 steps from the chiral aldehyde ent-7, and features highly diastereoselective α-alkoxyallylation reactions using the γ-alkoxy substituted allylstannanes 17 and 19, as well as a thermodynamically controlled intramolecular Michael addition to close the F-ring pyran. The E ring was assembled via the Mukaiyama aldol reaction of F-ring methyl ketone 3 and the 2,3-syn aldehyde 4.

Full text of DOI:10.1021/jo001236o

8730
J . Org. Chem. 2000, 65, 8730-8736
Syn th esis of th e C(29)-C(45) Bis-p yr a n Su bu n it (E-F ) of
Sp on gista tin 1 (Altoh yr tin A)
Glenn C. Micalizio, Anatoly N. Pinchuk, and William R. Roush*
Department of Chemistry, University of Michigan, Ann Arbor, Michigan 48109
roush@umich.edu
Received August 14, 2000
A synthesis of the C(29)-C(45) bis-pyran subunit 2 of spongistatin 1 (1a ) is described. The synthesis
proceeds in 19 steps from the chiral aldehyde ent-7, and features highly diastereoselective
R-alkoxyallylation reactions using the γ-alkoxy substituted allylstannanes 17 and 19, as well as a
thermodynamically controlled intramolecular Michael addition to close the F-ring pyran. The E
ring was assembled via the Mukaiyama aldol reaction of F-ring methyl ketone 3 and the 2,3-syn
aldehyde 4.
The spongistatins and altohyrtins, isolated in 1993 and
of spongistatin 2 (altohyrtin C, 1b) and spongistatin 1
(altohyrtin A, 1a ) have been completed by Evans36-39 and
Kishi,40,41 thereby confirming Kobayashi’s and Kitagawa’s
relative and absolute stereochemical assignments for
these compounds.3-5 We have previously published a
highly diastereoselective synthesis of the C(36)-C(45)
subunit,19 and now report the details of our efforts to
define a workable strategy for the synthesis of the fully
elaborated E-F bis-pyran portion of spongistatin 1 (1a ),
represented by structure 2.
1994 independently by the Pettit and Kitagawa groups
from Spongia sp. and Hyrtios altum, are members of a
class of highly cytotoxic sponge derived macrolide poly-
ethers possessing unparalleled inhibitory activity against
a subset of highly chemoresistant tumor types.1-5 Spong-
istatin 1 (1a ) is one of the most active members of the
spongipyran family, typically displaying IC50 values of
10-10 to 10-12 M against a number of human cancer cell
lines including colon, renal, ovarian, and breast cancer
cells.1,6 Spongistatin 1 (1a ) is an exquisitely complex
macrocyclic structure adorned with six highly oxygenated
heterocycles. Specifically, the 51 carbon chain incorpo-
rates two spiroketals (AB and CD rings), one hemiketal
(E ring), one pyran (F-ring), and 24 asymmetric centers.
The extremely meager natural supply (e.g., 14 mg of
1a from 400 kg of wet sponge),1 novel structural features,
and potent biological activities have defined the spong-
istatins as attractive targets for total synthesis. Several
groups are actively engaged in efforts to complete total
syntheses of members of this class.7-35 Total syntheses
We anticipated that the C(29)-C(45) subunit 2 could
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10.1021/jo001236o CCC: $19.00 © 2000 American Chemical Society
Published on Web 11/21/2000

Bis-pyran Subunit of Spongistatin 1
J . Org. Chem., Vol. 65, No. 25, 2000 8731
a 2:1 mixture of diastereomers 9a and 10a in 53% yield.
Stereochemistry was assigned to 9a and 10a after
conversion of the mixture to the p-methoxybenzylidene
acetals 13 and 14. The stucture of acetal 13 was assigned
based on the three small coupling constants observed for
C(40)-H (J 40,41 ) 2.2 Hz, J 39a, ) 1.5 Hz, and J 39b,
)
40
40
2.3 Hz). The structure of acetal 14 was assigned on the
basis of the large diaxial coupling observed between the
C(40) and C(41) protons (J 40,
) 12 Hz). Slightly
41
increased diastereoselectivity was realized in the BF3‚
OEt2-promoted reaction of 11 with the TBS-protected
aldehyde 8, which afforded a 3:1 mixture of isomers 9b
and 10b in 51% yield. The TBS-protected γ-alkoxyallyl-
stannane 1242 was also employed in an allylation reaction
with aldehyde 8 (MgBr2‚Et2O, CH2Cl2, -25 °C to +23 °C).
Surprisingly, this reaction provided 10c, the product of
chelation control, in 70% yield.50-54 Unfortunately, cy-
clopropane products predominated when the reaction of
8 and 12 was attempted using BF3‚Et2O as catalyst.44,55
be assembled via an aldol reaction between a suitably
functionalized F-ring methyl ketone 3 and the 2,3-syn
aldehyde 4. Further, our strategy called for the F-ring
pyran 3 to be synthesized by the intramolecular Michael
cyclization of an enoate such as 5, which in turn would
be constructed by a series of diastereoselective R-al-
koxyallylation42-46 reactions of a suitable synthetic equiva-
lent of methyl malondialdehyde 6. Although the allylation
reactions could be performed in two distinctly different
sequences, we decided to explore the C(41)-C(42) bond
construction first, since subsequent allylation of a C(39)
aldehyde with reagent 19 would lead directly to the C(39)
carbinol needed for the intramolecular Michael cycliza-
tion. Therefore, our initial efforts focused on developing
a highly diastereoselective synthesis of the C(40)-C(42)
syn,syn stereotriad substructure of 5.
Treatment of aldehyde 747 with γ-alkoxyallylstannane
1148,49 in the presence of BF3‚Et2O at -78 °C furnished
The modest diastereoselectivities observed for the
desired syn,syn diastereomer 9 in the reactions of
γ-alkoxyallylstannanes 11 and 12 with chiral aldehydes
(42) Keck, G. E.; Abbott, D. E.; Wile,: M. R. Tetrahedron Lett. 1987,
28, 139.
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28, 279.

8732 J . Org. Chem., Vol. 65, No. 25, 2000
Micalizio et al.
7 and 8 were insufficient for application of these reactions
to the projected total synthesis. Consequently we ex-
plored use of the chiral γ-alkoxyallylborane technology
developed by Brown.56 Although the asymmetric γ-alkoxy-
allylboration of achiral aldehydes with 16 has been
reported to be highly enantioselective (∼90% ee), we
found that the R-alkoxyallylation of 7 with 16 provided
an 8:1 diastereomeric mixture favoring the desired dif-
ferentially protected syn,syn diastereomer 9a . We pre-
sume that this reaction is stereochemically mismatched,57
since reactions of R-methyl branched aldehydes such as
7 with various (Z)-substituted allylboron reagents favors
production of the diastereomer represented by 10.58-60
Although this sequence offered an improvement in dias-
tereoselectivity as compared to substrate-based asym-
metric induction utilizing the γ-alkoxyallylstannane 11
or 12, large-scale production of 9a was impeded by
difficulties associated with diastereomer separation,
which was challenging even using HPLC.
addition of 19 to aldehyde ent-7 (MgBr2‚Et2O, CH2Cl2,
-25 °C to +23 °C) provided the anticipated homoallylic
alcohol 21 in 93% yield with greater than 20:1 stereose-
lectivity.42 The stereochemistry of the C(38)-C(39) diol
was deduced from 1H NOE studies of the acetonide 22,
prepared by sequential treatment of 21 with TBAF, then
dimethoxypropane and PPTS. The relative stereochem-
istry of the C(39) carbinol and C(40) methyl of 21 was
assigned after conversion to the p-methoxybenzylidene
acetal 23. The large coupling constant observed between
H(39) and H(40) indicated the diequatorial substitution
pattern of acetal 23 and hence the anti stereochemical
relationship in 21.
The poor to moderate diastereoselection observed in
both the single and double asymmetric R-alkoxyallyla-
tions of the chiral aldehydes 7 and 8 prompted explora-
tion of an alternative approach to enoate 5 in which the
C(38)-C(40) stereotriad was formed first. This would
allow for the generation of the C(40)-C(42) all syn
stereotriad via Felkin addition of 17 to the 2,3-anti
aldehyde 18. The â-methyl-γ-alkoxyallylstannane 19 was
identified for construction of the differentially protected
C(38)-C(39) diol unit as well as the introduction of the
C(36)-C(37) alkene in 18, which we anticipated would
serve as a suitable precursor to the methyl ketone in the
targeted F ring pyran 3.
Precedent suggests that chelate-controlled allylation
reactions of γ-alkoxyallylstannanes lacking a â-methyl
substituent (i.e., 25) provide the syn-anti stereochemistry
present in 21.42,43 Therefore our result with 19 does not
appear surprising. However in comparison to the crot-
ylstannane literature, where a striking stereodivergence
has been observed in chelate controlled allylation reac-
tions between â-methylcrotylstannanes and the parent
crotylstannanes,61 our result is fundamentally interest-
ing.
Mikami has shown that the major product from the
chelate controlled addition of â-methyl-(Z)-crotylstannane
24 to aldehyde 26 is the 3,4-anti diastereomer 27,
whereas under similar conditions the reaction of 26 and
the unsubstituted crotylstannane 25 affords predomi-
nantly the 3,4-syn diastereomer 29.61 It has been pro-
posed that crotylstannane 25 prefers to adopt an anti-
periplanar orientation in transition state A, leading to
Metalation of tert-butyldimethylsilyl methallyl ether
20 followed by addition of Bu3SnCl afforded the â-methyl-
γ-alkoxyallylstannane 19 (64%). Chelation controlled
(55) Marshall, J . A.; J ablonowski, J . A.; Luke, G. P. J . Org. Chem.
1994, 59, 7825.
(56) Brown, H. C.; J adhav, P. K.; Bhat, K. S. J . Am. Chem. Soc.
1988, 110, 1535.
(59) Roush, W. R. In Comprehensive Organic Synthesis; Trost, B.
M., Fleming, I., Paquette, L. A., Eds.; Pergamon Press: Oxford, 1991;
Vol. 2, p 1.
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Chem., Int. Ed. Engl. 1985, 24, 1.
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1990, 112, 6348.
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Otera, J ., Ed.; Wiley-VCH: Weinheim, 2000; p 403.
(61) Mikami, K.; Kawamoto, K.; Loh, T.-P.; Nakai, T. J . Chem. Soc.,
Chem. Commun. 1990, 1161.

Bis-pyran Subunit of Spongistatin 1
J . Org. Chem., Vol. 65, No. 25, 2000 8733
the 3,4-syn stereochemistry in 29.62 Mikami suggests the
â-methylcrotylstannane 24 prefers to adopt a synclinal
geometry in transition state B, as a result of increased
steric demand imparted by the â-methyl substituent in
transition state A, and therefore that the 3,4-anti ster-
eochemistry in 27 is favored with 24.
with DIBAL64 followed by Swern oxidation.65 The γ-alkoxy-
allylstannane 17 needed for homologation of 31 was
generated by alkylation of p-methoxyphenol 32 with
allylbromide followed by metalation with s-BuLi and
addition of Bu3SnCl. Unfortunately, attempted allylation
of 2,3-anti-aldehyde 31 with γ-alkoxyallylstannane 17 in
the presence of BF3‚OEt2 gave a complex mixture of
products lacking disubstituted olefins. We speculated
that 31 may have undergone an intramolecular Prins
reaction owing to the nucleophilicity of the C(37) alk-
ene.66,67
While Mikami’s results suggest that the â-methyl
substituent of 24 provides an overriding steric component
in the chelate controlled reaction with 26, it appears that
the â-substituent of 19 plays a much diminished role in
the reaction of ent-7 and 19, and that a different control
element is operational in this case. In accord with an SE′
mechanism,63 the dihedral angle of the Sn-C-CdC unit
of 19 should be approximately 90° in the transition state,
thereby maximizing overlap between the Sn-C σ bond
and the π* orbital of the double bond. MM2 calculations
of 19 indicate that the O-Si bond remains coplanar with
the CdC, and that the t-Bu substituent is positioned anti
to the Bu3Sn- group as in 19a . Therefore, the Lewis acid
complex of ent-7 must be oriented in the transition state
for allylation with 19 in such a way as to minimize
interactions with the t-Bu of the TBS ether protecting
group of 19.
It is conceivable that the antiperiplanar transition
state C is preferred in this case compared to the synclinal
transition state D because it can better accommodate the
large t-Bu substituent of the γ-alkoxyallylstannane 19.
Inspection of models clearly indicates that the tert-butyl
group of the TBS ether interacts with the aldehyde C(R)
substituents in transition state D.
Due to the sensitivity of enal 31 to Lewis acids, we
attempted to use the γ-alkoxyallylaluminate 34, a re-
agent that does not require the addition of an external
Lewis acid for allylation to occur.45 However, treatment
of 31 with allylaluminate 34 afforded a 1:1 mixture of
stereoisomeric homoallylic alcohols tentatively assigned
as 35 and 36.
In view of these difficulties, we decided to modify the
C(37) olefin of 31 before proceeding with the synthesis.
Accordingly, treatment of the homoallylic alcohol 21 with
triethylsilyl triflate (TESOTf) followed by asymmetric
dihydroxylation68 provided an 8:1 mixture of diastereo-
meric diols in a combined 81% yield. The major diaste-
reomer was assigned the stereochemistry shown by
application of Sharpless' empirical mnemonic.68 The
major diol was treated with triphosgene and pyridine in
Conversion of the PMP acetal 23 to the C(41) aldehyde
31 was achieved via regioselective reduction of the acetal
(63) Denmark, S. E.; Hosoi, S. J . Org. Chem. 1994, 59, 5133.
(64) Takano, S.; Akiyama, M.; Sato, S.; Ogasawara, K. Chem. Lett.
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(65) Tidwell, T. T. Synthesis 1990, 857.

8734 J . Org. Chem., Vol. 65, No. 25, 2000
Micalizio et al.
the newly liberated C(39) alcohol underwent 1,4-addition
to the enoate. This one pot olefination, silyl migration,
1,4-addition reaction sequence furnished the targeted
pyran system as a 10:1 mixture of diastereomers 40 and
1
41 in 68% yield. However, H NOE studies of the dia-
stereomeric pyrans indicated that the major product 40
possessed the incorrect (axial) stereochemistry at C(43).
CH2Cl2 to give the corresponding carbonate 37 in 99%
yield. Removal of the PMB ether by exposure of 37 to
DDQ69 in wet CH2Cl2 provided the primary alcohol which
was oxidized to the aldehyde 38 using the standard
Swern protocol.65
Initial attempts to equilibrate the mixture of diaster-
eomeric pyrans were unsuccessful (BnMe3N+ -OMe,
MeOH, THF, 0 °C; KOt-Bu, THF, 0-23 °C; DBU, DMF,
100 °C); in general, pyran 40 was recovered without
significant equilibration to 41. We speculated that the
inability to equilibrate this mixture was due to a remote
steric effect of the C(41)-triethylsilyl ether, which causes
the C(42) p-methoxyphenyl ether to adopt a conformation
anti to the C(41)-C(42) bond, thereby destabilizing 41
with an equatorial acetate side chain, compared to 40.
However, MM2 calculations suggest that 41 is more
stable than 40 by ca. 1 kcal/mol. Therefore, our inability
to equilibrate 40 to 41 must reflect a kinetic and not a
thermodynamic problem. Nevertheless, removal of the
C(41) TES ether (PPTS in methanol, 93%) followed by
subjection of the resulting pyranols to basic conditions
(DBU, DMF, 80 °C) resulted in an equilibrated 9:1
mixture of the desired pyran 43 (now major) and the
C(43) axial epimer 42 in 56% yield.
We now were in position to revisit the R-alkoxyallyla-
tion of the C(41) aldehyde. Gratifyingly, treatment of
aldehyde 38 with allylstannane reagent 17 and BF3‚Et2O
in CH2Cl2 at -78 °C gave the desired alcohol 39 in 93%
yield with >20:1 diastereoselectivity. The terminal olefin
of 39 was oxidatively cleaved via a two step procedure
(OsO4, NMO70 followed by NaIO4, 84%), and the resulting
crude aldehyde was subjected to a Horner-Wadsworth-
Emmons reaction using (EtO)2POCH2CO2Me, LiCl, and
DBU in acetonitrile.71 When the Horner-Wadsworth-
Emmons reaction was performed in the presence of
excess LiCl at room temperature, the TES group mi-
grated from the C(39) hydroxyl to the C(41) hydroxyl, and
Armed with the insight provided by these equilibration
studies, the synthesis of 43 was improved as follows.
When the HWE olefination of 44 was performed using 3
equiv of (EtO)2POCH2CO2Me, 3 equiv of LiCl and 3 equiv
of DBU in CH3CN at -35 °C to -10 °C, the corresponding
enoate was isolated in 88% yield. Subsequent deprotec-
tion of the TES ether via exposure to PPTS in methanol
then gave diol 45 in 94% yield. Finally, the 1,4-addition
was accomplished by treatment of 45 with DBU under
thermodynamic conditions (DMF, 95 °C, 22 h), from
(66) Ziegler, F. E.; Wang, T.-F. J . Am. Chem. Soc. 1984, 106, 718.
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Chem. 1987, 52, 5419.
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2183.

Bis-pyran Subunit of Spongistatin 1
J . Org. Chem., Vol. 65, No. 25, 2000 8735
which the desired pyran 43 was obtained in 65% yield
with 25:1 diastereoselectivity.
In planning the coupling of 3 and 4, we were aware of
a report by Ley that an analogous aldol reaction using
the lithium enolate provided the anti-Felkin aldol pref-
erentially.30,74 As a means to access the desired Felkin
diastereomer, Ley ultimately employed chiral boron
enolate (Ipc2BCl) technology which provided the desired
compound as a single diastereomer, but in low yield. We
were also aware of reports by Evans that 2,3-syn alde-
hydes 50 exhibit high Felkin diastereoselectivity in
Mukaiyama aldol reactions75 with sterically demanding
enol silanes 51 and 52, leading to the preferential
formation of the syn, syn stereotriad in 53.74 In addition,
Trost has demonstrated that the Mukaiyama aldol reac-
tion of R-silyloxy enol silanes 56 with isobutyraldehyde,
affords predominantly the 1,4-syn adduct 57 (2:1 ds).76
These data suggested that the Mukaiyama aldol coupling
of 3 and 4 would be stereochemically mismatched.57
Nevertheless, we anticipated that the facial bias of the
2,3-syn aldehyde 4 would dominate that of the enol silane
generated from 3 in the aldol reaction, thereby providing
diastereoselective access to the desired aldol 59.
Elaboration of the cis-pyran 43 to the targeted methyl
ketone 3 was straightforward. Silylation of the C(41)
carbinol, followed by simultaneous reduction of the C(45)
ester and the carbonate, oxidative cleavage of the result-
ing diol (NaIO4), and protection of the primary carbinol
(TBDPSCl, Et3N, DMAP) afforded the fully functionalized
F-ring methyl ketone 3 in an overall 77% yield.
With a route to the C(36)-C(45) methyl ketone frag-
ment 3 secured, we directed our efforts to the synthesis
of the 2,3-syn aldehyde 4.36 Syn-aldol 48 was prepared
in 81% yield (>95:5 ds) from the aldol reaction between
N-propionyl oxazolidinone 46 and aldehyde 47.72,73 Aldol
48 was converted to the Weinreb amide 49 via a two step
procedure (AlMe3, MeNH(OMe)‚HCl followed by TES-
Cl, imidazole) in 79% yield. Reduction of amide 49 with
DIBAL afforded the crude aldehyde 4 which was used in
subsequent aldol reactions without purification.
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8736 J . Org. Chem., Vol. 65, No. 25, 2000
Micalizio et al.
Toward this end methyl ketone 3 was treated with
kaiyama aldol reaction of less functionalized partners
were also ineffective.
TMSCl, Et3N and LiHMDS to afford the TMS enol ether
61 as a chromatographically stable oil in 83% yield.77
A
In final analysis, it is clear that the stereoselectivity
of the aldol reaction of 61 and 4 leading to 59 suffers
from the dissonant stereochemical pairing of the two
components.57 While it should be possible to utilize the
minor aldol adduct (60) in the synthesis by epimerization
of the C(35) center,13 alternative strategies for control of
this center will be explored in future studies. Despite this
one blemish in stereochemical control, the present syn-
thesis of the E-F bis-pyran unit 2 is accomplished in 19
steps and 10.1% overall yield. The use of the γ-alkoxy-
allylstannane reagents 17 and 19 in highly stereoselec-
tive R-alkoxyallylation reactions is noteworthy, as is the
insight gained in the development of a thermodynami-
cally controlled intramolecular Michael addition to close
the F-ring pyran. Additional progress on the synthesis
of the spongistatins will be reported in due course.
solution of enol silane 61 and aldehyde 4 was then
treated with BF3‚Et2O at -78 °C. The mixture of crude
aldol products was treated with PPTS in methanol
resulting in deprotection of the C(35) and C(41) trieth-
ylsilyl ethers and formation of the methyl hemiketal. This
sequence provided a mixture of diastereomeric pyrans 2
and 62 (2.5:1 d.s.), which after chromatographic separa-
tion afforded the desired diastereomer 2 in 52% yield.
After our studies of this reaction were complete, Heath-
cock reported an analogous Mukaiyama aldol coupling
in his synthesis of the spongistatin E-F bis pyran unit.13
Ack n ow led gm en t. Support provided by the Na-
tional Institutes of Health (GM 38436 to W.R.R. and
CA 78333 to A.N.P.) is gratefully acknowledged. We also
thank Eli Lilly and the ACS Division of Organic
Chemistry for a Graduate Fellowship to G.C.M.
Su p p or tin g In for m a tion Ava ila ble: Complete experi-
mental details and copies of 1H NMR spectra of compounds 2,
3, 17, 19, 31, 38-44, 61, 62, 68, 70, and 71. This material is
available free of charge via the Internet at http://pubs.acs.org.
J O001236O
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Increased Felkin diastereoselectivity has been observed
in the reactions of 2,3-syn-aldehydes and enol silanes
using trityl salts as the promoter.74,78-80 However, ap-
-
plication of (C6H5)3C+SnCl5 to the present case merely
led to extensive decomposition of both the highly func-
tionalized enol silane 61 and aldehyde 4. Similarly,
attempted use of other Lewis acids (TiCl4, SnCl4, MeAlCl2,
TMSOTf, TBSOTf) commonly employed in the Mu-
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447.