Synthesis of the C1-C28 Portion of Spongistatin 1 (Altohyrtin A)

Article abstract of DOI:10.1021/jo9910987

A synthetic approach was developed to the C1-C28 subunit of spongistatin 1 (altohyrtin A, 65). The key step was the coupling of the AB and CD spiroketal moieties via an anti-aldol reaction of aldehyde 62 and ethyl ketone 57. The development of a method for the construction of the AB spiroketal fragment is described and included the desymmetrization of C₂-symmetric diketone 10 and the differentiation of the two primary alcohols of 16. Further elaboration of this advanced intermediate to the desired aldehyde 62 included an Evans' syn-aldol reaction and Tebbe olefination. The synthesis of the CD spiroketal fragment 56 involved the ketalization of a triol-dione, generated in situ by deprotection of 45, to provide a favorable ratio (6-7:1) of spiroketal isomers 46 and 47, respectively. The overall protecting group strategy, involving many selective manipulations of silyl protecting groups, was successfully developed to provide the desired C1-C28 subunit of spongistatin 1 (altohyrtin A) (65).

Full text of DOI:10.1021/jo9910987

J . Org. Chem. 1999, 64, 8267-8274
8267
Syn th esis of th e C1-C28 P or tion of Sp on gista tin 1 (Altoh yr tin A)
Michelle M. Claffey, Christopher J . Hayes, and Clayton H. Heathcock*
Department of Chemistry, University of California, Berkeley, California 94720
Received J uly 8, 1999
A synthetic approach was developed to the C1-C28 subunit of spongistatin 1 (altohyrtin A, 65).
The key step was the coupling of the AB and CD spiroketal moieties via an anti-aldol reaction of
aldehyde 62 and ethyl ketone 57. The development of a method for the construction of the AB
spiroketal fragment is described and included the desymmetrization of C2-symmetric diketone 10
and the differentiation of the two primary alcohols of 16. Further elaboration of this advanced
intermediate to the desired aldehyde 62 included an Evans’ syn-aldol reaction and Tebbe olefination.
The synthesis of the CD spiroketal fragment 56 involved the ketalization of a triol-dione, generated
in situ by deprotection of 45, to provide a favorable ratio (6-7:1) of spiroketal isomers 46 and 47,
respectively. The overall protecting group strategy, involving many selective manipulations of silyl
protecting groups, was successfully developed to provide the desired C1-C28 subunit of spongistatin
1 (altohyrtin A) (65).
In 1993 and 1994, a series of novel, marine-derived,
macrocyclic lactones with closely related structures,
including the spongistatins,1 cinachyrolide A,2 and the
altohyrtins,3 were reported. The altohyrtin/cinachyrolide/
spongistatin macrocyclic lactones are tremendously cy-
totoxic to various tumor lines and are therefore of interest
as potential cancer therapeutic agents. Spongistatin 1
itself has been characterized as “probably the best to date
in the NCI’s evaluation programs”,4 exhibiting 50%
growth inhibition against a range of tumor lines at
concentrations in the range of 10-10-10-12 mol/L! In
addition, spongistatin 1 showed potent activity against
a subset of highly chemoresistant tumor types.4 Spong-
istatin appears to inhibit microtubule assembly by bind-
ing to tubulin at the vinca alkaloid binding site.5 The
compound also has potent antifungal properties, inhibit-
ing the growth of many fungi, including strains resistant
to amphotericin B, ketoconazole, and flucytosine.6
currently no practical way to farm sponges to obtain
larger quantities of the metabolites. However, because
of their exceedingly high potency, it has been estimated
that a full clinical trial could be carried out with only a
few grams of material. We believe that, even despite their
great complexity, it is within the realm of feasibility that
organic synthesis could provide several-gram quantities
of the spongistatins, and it is the goal of the current
project to develop an efficient total synthesis to provide
several grams of the natural product.
The unique structural complexity and stereochemical
diversity of these macrolides attracted the attention of
several research groups.7 To date, two groups have
published complete total syntheses. Evans and co-work-
ers reported the first total synthesis of a member of this
family of natural products and demonstrated that spong-
istatin 2 and altohyrtin C are identical (2).8 Further
confirmation that the altohyrtin and spongistatin families
were identical came from the publication of Kishi’s total
synthesis of altohyrtin A which proved to be identical to
spongistatin 1 (1).9
At the inception of our synthetic efforts, the quandary
surrounding the relationship of the spongistatins, alto-
hyrtins, and cinachyrolides led us to focus on altohyrtin
A (1), since it was the only structure whose absolute and
relative configuration was supported by adequate data.
Our strategy was designed around a macrolactonization
as the final key step. Further disconnection of the C28-
C29 double bond revealed two similarly complex frag-
ments, which were to be joined using a Wittig reaction.
The C1-C28 subunit, containing both spiroketal moi-
eties, was envisioned as arising from an anti-aldol
These exquisitely active marine natural products pro-
vide a good example of the power of Nature to point us
in the direction of organic structures of potential use in
chemotherapy. The problem is that they are available
from Nature in only minute amounts and there is
(1) (a) Pettit, G. R.; Cichacz, Z. A.; Herald, C. L.; Gao, F.; Boyd, M.
R.; Schmidt, J . M.; Hamel, E.; Bai, R. J . Chem. Soc., Chem. Commun.
1994, 1605-1606. (b) Pettit, G. R.; Herald, C. L.; Cichacz, Z. A.; Gao,
F.; Boyd, M. R.; Christie, N. D.; Schmidt, J . M. Nat. Prod. Lett. 1993,
3, 239-244. (c) Pettit, G. R.; Herald, C. L.; Cichacz, Z. A.; Gao, F.;
Schmidt, J . M.; Boyd, M. R.; Christie, N. D.; Boettner, F. E. J . Chem.
Soc., Chem. Commun. 1993, 1805-1807. (d) Pettit, G. R.; Cichacz, Z.
A.; Gao, F.; Herald, C. L.; Boyd, M. R. J . Chem. Soc., Chem. Commun.
1993, 1166-1168. (e) Pettit, G. R.; Cichacz, A. A.; Gao, F.; Herald, C.
L.; Boyd, M. R.; Schmidt, J . M.; Hooper, J . N. A. J . Org. Chem. 1993,
58, 1302-1304.
(2) Fusetani, N.; Shinoda, K.; Matsunaga, S. J . Am. Chem. Soc.
1993, 115, 3977-3981.
(3) (a) Kobayashi, M.; Aoki, S.; Kitagawa, I. Tetrahedron Lett. 1994,
35, 1243-1246. (b) Kobayashi, M.; Aoki, S.; Sakai, H.; Kawazoe, K.;
Kihara, N.; Sasaki, T.; Kitagawa, I. Tetrahedron Lett. 1993, 34, 2795-
2798.
(7) For a recent review, see: Pietruszka, J . Angew. Chem., Int. Ed.
Engl. 1998, 37, 2629-2636.
(8) (a) Evans, D. A.; Coleman, P. J .; Dias, L. C. Angew. Chem., Int.
Ed. Engl. 1997, 36, 2738-2741. (b) Evans, D. A.; Trotter, B. W.; Coˆte´,
B.; Coleman, P. J . Angew. Chem., Int. Ed. Engl. 1997, 36, 2741-2744.
(c) Evans, D. A.; Trotter, W. B.; Coˆte´, B.; Coleman, P. J .; Dias, L. C.;
Tyler, A. N. Angew. Chem., Int. Ed. Engl. 1997, 36, 2744-2747.
(9) (a) Guo, J .; Duffy, K. J .; Stevens, K. L.; Dalko, P. I.; Roth, R. M.;
Hayward, M. M.; Kishi, Y. Angew. Chem., Int. Ed. Engl. 1998, 37, 187-
192. (b) Hayward, M. M.; Roth, R. M.; Duffy, K. J .; Dalko, P. I.; Stevens,
K. L.; Guo, J .; Kishi, Y. Angew. Chem., Int. Ed. Engl. 1998, 37, 192-
196.
(4) Pettit, G. R. J . Nat. Prod. 1996, 59, 812-821.
(5) (a) Bai, R.; Cichacz, Z. A.; Herald, C. L.; Pettit, G. R.; Hamel, E.
Mol. Pharmacol. 1993, 44, 757-766. (b) Bai, R.; Cichacz, Z. A.; Herald,
C. L.; Pettit, G. R.; Hamel, E. Proc. Annu. Meet. Am. Assoc. Cancer
Res. 1993, 34: A2243. (c) Bai, R.; Taylor, G. F.; Cichaz, Z. A.; Herald,
C. L.; Kepler, J . A.; Pettir, G. R.; Hamel, E. Biochemistry 1995, 34,
9714-9721.
(6) Pettit, G. R. Patent Application WO97-US10200, 1997.
10.1021/jo9910987 CCC: $18.00 © 1999 American Chemical Society
Published on Web 10/14/1999

8268 J . Org. Chem., Vol. 64, No. 22, 1999
Claffey et al.
Sch em e 1
Sch em e 2
reaction that would establish the relative configuration
of the C15 and C16 stereocenters.
In order to exploit the methodology developed for the
model system,10 a key intermediate in the synthesis of
the AB spiroketal subunit would be a C2-symmetric
diketone (e.g., compound 10, Scheme 2), which would be
desymmetrized and further elaborated to the C1-C15
altohyrtin A system. Unraveling and disassembling the
diketone revealed keto-ester 3 as a starting material.
Following a literature procedure,11 ethyl acetoacetate was
treated with NaH followed by n-BuLi and the resulting
dianion was alkylated with benzyloxymethyl chloride
(BOMCl)12 to provide keto-ester 3 in moderate yield.
However, we developed a new route to generate ester 3
more efficiently and with greater purity. Swern-Moffatt
oxidation13 of 3-(benzyloxy)-1-propanol provided the crude
aldehyde, which was extended to â-keto-ester 3 by
treatment with ethyl diazoacetate in the presence of
catalytic SnCl2 in CH2Cl2.14 This more practical sequence
furnished keto-ester 3 in 57% overall yield.
hydroxy ester (S)-4 (91% ee). The resulting alcohol was
protected as silyl ether 5 in 94% yield by treatment with
triethylsilyl chloride and imidazole in dimethylforma-
mide. Subsequent reduction with diisobutylaluminum
hydride quantitatively generated crude aldehyde 6, which
was sufficiently pure to use in the next reaction. The two-
step elongation, involving the condensation of the alde-
hyde with acetone dimethylhydrazone followed by hy-
drazone cleavage, afforded the hydroxy ketone 7 in 86%
yield.
Extension of the chain through an aldol coupling was
most efficiently accomplished by treatment of methyl
ketone 7 with 2.5 equiv of trimethylsilyl triflate and
Hu¨nig’s base in CH2Cl2 to simultaneously protect the
alcohol and generate the silyl enol ether 8. A Mukiayama
aldol reaction, catalyzed by BF3‚Et2O, was performed
with the silyl enol ether and aldehyde 6. The resulting
aldol product 9 was treated with aqueous HF in CH3CN
to cleave the silicon protecting groups and promote acid-
catalyzed ketalization. The resulting mixture of spiroket-
al diols was then oxidized with Dess-Martin periodinane
to afford diketone 10 in 78% yield over the four steps with
a single purification.
Hydrogenation of keto-ester 3 was performed using a
modified protocol of Noyori and co-workers15 to provide
(10) Claffey, M. M.; Heathcock, C. H. J . Org. Chem. 1996, 61, 7646-
7647.
(11) Taylor, E. C.; LaMattina, J . L. J . Org. Chem. 1978, 43, 1200-
1204.
(12) Connor, D. S.; Klein, G. W.; Taylor, G. N.; Boeckman, J ., R. K.;
Medwid, J . B. Organic Syntheses; Wiley & Sons: New York, 1988;
Collect. Vol. 6, pp 101-103.
(13) Mancuso, A. J .; Huang, S.-L.; Swern, D. J . Org. Chem. 1978,
43, 2480-2483.
With an efficient route to diketone 10, we faced two
major challenges, desymmetrization and differentiation
of the two hydroxyethyl side chains. With utilization of
the methodology developed with the model system,
diketone 10 was treated with LDA in a mixture of THF
(14) Holmquist, C. R.; Roskamp, E. J . J . Org. Chem. 1989, 54, 4,
3258-3260.
(15) Kitamura, M.; Ohkuma, T.; Inoue, S.; Sayo, N.; Kumobayashi,
H.; Akutagawa, S.; Ohta, T.; Takaya, H.; Noyori, R. J . Am. Chem. Soc.
1988, 110, 629-631.

Synthesis of the C1-C28 Portion of Spongistatin 1
J . Org. Chem., Vol. 64, No. 22, 1999 8269
Sch em e 3
Sch em e 4
and HMPA and the resulting enolate was trapped with
triisopropylsilyl chloride to provide the desired mono(silyl
enol) ether 11 (64%) accompanied by the bis(silyl enol)
ether 12 (26%) and recovered starting material (8%).
Despite the moderate yield, the good mass recovery and
the potential to recycle material made this transforma-
tion practical. Treatment of the bis(silyl enol) ether with
TBAF‚3H2O at low temperature regenerated the diketone
10 in 92% yield. Therefore, with one recycle operation,
the mono(silyl enol) ether 11 was obtained in 84% yield
(Scheme 3).
Functionalization of the spiroketal rings was performed
without complications. Reduction of ketone 11 was
performed with L-Selectride to give solely the axial
alcohol 13. The silyl enol ether was smoothly cleaved with
TBAF‚3H2O in THF at -78 °C to provide the desymme-
trized spiroketal 14 in 94% yield. Addition of the meth-
ylcerium reagent to ketone 14 occurs in a highly stereo-
selective manner, providing the axial tertiary alcohol
(15), which was selectively silylated on the less hindered
hydroxy group by reaction with TBSOTf and Et3N in
CH2Cl2 at -78 °C to provide silyl ether 15 in 84% yield
for the two steps. Subsequent hydrogenation of the benzyl
ethers afforded the desired triol 16 (Scheme 4).
At this point we were faced with the second major
challenge: differentiation of the two hydroxyethyl side
chains. The one subtle difference between the two alco-
hols is the capability of the C13 alcohol to form an
intramolecular hydrogen bond with an ether oxygen of
the spiroketal:
bonded to the axial tertiary hydroxy group. On the basis
of this hypothesis, we thought the two primary hydroxy
groups might have different reactivity.
Initial efforts to differentiate the side chains were
performed on the analogous C5-acetate derivative and
included treatments with either benzoyl chloride or
TESCl in CH2Cl2 in the presence of DMAP and Et3N.
Modest selectivity was observed with the major isomers
resulting from reaction at the C1 alcohol. This selectivity
indicated that the C1 alcohol was sterically less encum-
bered than the C13 alcohol in agreement with the
prediction that the C13 alcohol participated in intramo-
lecular hydrogen bonding.
We speculated that a greater difference in reactivity
of the two primary hydroxy groups might be observed
by generation of the monoanion. Although two primary
alkoxides can form, the C13 alkoxide should predominate
in the equilibrium because the associated cation can be
chelated by the proximal spiroketal oxygen. Reaction of
the monoalkoxide with a silyl halide should lead to
reaction predominately at the C13 hydroxy group. In the
event, treatment of 16 with 1 equiv of LDA in THF,
followed by addition of triethylsilyl chloride, afforded the
expected silyl ether 17 as the major regioisomer in 72%
yield, accompanied by 4% of isomer 18, 9% of the bis-
silylated product 19, and 12% of recovered starting
material. Treatment of the two undesired products, 18
and 19, with TBAF‚3H2O in THF gave 92% yield of triol
16, thus providing the desired product 17 in a net yield
of 89% for the silylation and one recycle of the recovered
starting material and undesired silylation products
(Scheme 5).
Alcohol 17 was oxidized with Dess-Martin periodinane
to aldehyde 20. Homonuclear decoupling experiments
with aldehyde 20 confirmed its structure, thus firmly
establishing the regiochemistry of the silylation reaction
shown in Scheme 5. The primary triethylsilyl ether was
cleaved with aqueous camphorsulfonic acid in THF.
Further oxidation of the aldehyde at C1 with sodium
The other primary alcohol at C1 is less able to form a
similar intramolecular hydrogen bond because the cor-
responding ether oxygen of the spiroketal is hydrogen

8270 J . Org. Chem., Vol. 64, No. 22, 1999
Claffey et al.
Sch em e 5
Sch em e 7
Sch em e 6
Sch em e 8
chlorite16 provided the corresponding acid, which was
converted to the tert-butyl ester using excess N,N′-
diisopropyl-O-tert-butylisourea17 in CH2Cl2. The opti-
mized conditions resulted in an 82% yield of tert-butyl
ester 21 for the four steps with only a single purification
necessary. The side chain manipulations were completed
with the oxidation of alcohol 21 with Dess-Martin
periodinane to afford aldehyde 22 in excellent yield
(Scheme 6).
Our next task was installation of the linker between
the AB and CD spiroketals. As shown in Scheme 7, the
requisite two-carbon extension and methyl substituent
were appended diastereoselectively to the aldehyde 22
by employing Evans’ syn-aldol methodology.18 The crude
aldol product 23 was reduced with LiBH4 in EtOH and
THF to cleave the chiral auxiliary to provide the primary
alcohol 24 in 78% yield for the two steps. The selective
protection of the primary alcohol occurred without inci-
dent to give silyl ether 25 in nearly quantitative yield.
Subsequent oxidation with Dess-Martin periodinane
provided ketone 26.
Although several methylenation protocols were em-
ployed to convert ketone 26 into the corresponding olefin,
the Tebbe reagent19 proved to be the preferred method
for this transformation. As shown in Scheme 8, treatment
of ketone 26 with Tebbe reagent in THF provided olefin
27 in 64% yield, accompanied by acid 28 and recovered
(16) Lindgren, B. O.; Nilsson, T. Acta Chem. Scand. 1973, 27, 888-
890.
(17) (a) Mathias, L. J . Synthesis 1979, 561-576. (b) Schmidt, E.;
Moosmu¨ller, F. J ustus Liebigs Ann. Chem. 1955, 597, 235-240.
(18) Gage, J . R.; Evans, D. A. Org. Synth. 1989, 68, 83-91.
(19) (a) Pine, S. H.; Kim, G.; Lee, V. Org. Synth. 1990, 69, 72-79.
(b) Pine, S. H.; Zahler, R.; Evans, D. A.; Grubbs, R. H. J . Am. Chem.
Soc. 1980, 102, 3270-3272.
starting material. The formation of this side product was
circumvented by protection of the tertiary alcohol prior

Synthesis of the C1-C28 Portion of Spongistatin 1
J . Org. Chem., Vol. 64, No. 22, 1999 8271
Sch em e 9
Sch em e 10
to the olefination. Thus, treatent of 26 with triethylsilyl
triflate and 2,6-lutidine in CH2Cl2 gave the bis-TES ether
29 in nearly quantitative yield. The ketone was converted
to the corresponding 1,1-disubstituted olefin by utilizing
the Tebbe reagent. The protection of the alcohol prior to
Tebbe reaction proved to be advantageous, since the
formation of the acid side product was eliminated and
olefin 30 was isolated in 67% yield along with 33%
recovered ketone 29. Selective desilylation of 30 with
aqueous camphorsulfonic acid in THF and subsequent
Dess-Martin oxidation provided the target aldehyde 31
in 88% yield for the two steps. At this point, the requisite
AB spiroketal fragment was synthesized and ready for
the key anti-aldol coupling with the ethyl ketone of the
CD spiroketal subunit.
Sch em e 11
A model system was investigated to explore the ket-
alization of the CD spiroketal,20 and the methodology
developed was subsequently applied to the synthesis of
the C16-C28 subunit of altohyrtin A. The construction
of the ketalization precursor began with the hydroxy
ester (R)-4, the enantiomer of hydroxy ester (S)-4 used
in the synthesis of the AB-spiroketal fragment. The
benzyl ether of (R)-4 was removed and replaced with a
tert-butyldimethylsilyl ether by hydrogenation with Pd/C
in EtOH followed by treatment of the crude diol with
TBSCl and imidazole in THF at 0 °C to provide TBS ether
32 in 80% yield for the two steps. Treatment of 32 with
(p-methoxybenzyl)trichloroacetimidate21 in the presence
of catalytic BF3‚OEt2 afforded the p-methoxybenzyl ether
33, which was reduced by diisobutylaluminum hydride
to obtain aldehyde 34. Addition of methylmagnesium
bromide in ether at 0 °C, followed by oxidation of the
resulting diastereomeric mixture of alcohols with Dess-
Martin periodinane, provided methyl ketone 35 (Scheme
9).
The aldehyde necessary to perform an aldol reaction
with methyl ketone 35 was derived initially from D-malic
acid. Esterification was accomplished by reaction with
thionyl chloride in absolute ethanol, providing diethyl
malate (36), which was reduced to diol 37 using borane
dimethyl sulfide complex and catalytic sodium borohy-
dride.22 Selective silylation of the resulting diol with
triisopropylsilyl triflate and 2,6-lutidine in CH2Cl2 gener-
ated the TIPS ether 38 in 80% yield. Reduction of ester
38 with diisobutylaluminum hydride followed by reaction
with ethyl triphenylphosphoranylidine acetate afforded
the desired (E)-R,â-unsaturated ester 39, accompanied
by 7% of the Z isomer. Installation of the benzylidene
acetal was performed as in our model study, in which it
worked reasonably well to give the desired model dioxane
derivative in 73% yield.20 Unfortunately, this protocol did
not translate well to the requisite acetal 40, which was
isolated in only 20-40% yield (Scheme 10). Many efforts
to optimize this procedure failed to furnish a practical,
isolated yield of product. As a result, a new route to the
aldehyde was required.
As shown in Scheme 11, a precedented 23 mixed Claisen
condensation of the lithium enolate of tert-butyl acetate
with ester 38 provided â-keto ester 41. Although this
reaction was complicated by competitive enolization of
the starting ester, we found that by forming the enolate
at -78 °C and adding it to a solution of ester 38 in THF
at 0 °C, followed by warming to room temperature, the
desired â-keto ester 41 was obtained in 84% yield. The
ketone carbonyl group was stereoselectively reduced with
Et2BOMe and NaBH4 in THF/MeOH,24 and the resulting
syn-1,3-diol was converted into the benzylidine acetal by
reaction with benzaldehyde dimethyl acetal in the pres-
ence of pyridinium p-toluenesulfonate (PPTS) in refluxing
CH2Cl2; acetal 42 was obtained in a yield of 80% for the
two-step process. Reduction of 42 with diisobutylalumi-
num hydride provided the desired aldehyde 43 in 88%
yield.
(20) Hayes, C. J .; Heathcock, C. H. J . Org. Chem. 1997, 62, 2678-
2679.
(21) Audia, J . E.; Boisvert, L.; Patten, A. D.; Villalobos, A.; Dan-
ishefsky, S. J . J . Org. Chem. 1989, 54, 3738-3740.
(22) Saito, S.; Ishikawa, T.; Kuroda, A.; Koga, K.; Moriwake, T.
Tetrahedron 1992, 48, 4067-4086.
(23) Wess, G.; Kesseler, K.; Baader, E.; Bartmann, W.; Beck, G.;
Bergmann, A.; J endralla, H.; Bock, K.; Holzstein, G.; Kleine, H.;
Schnierer, M. Tetrahedron Lett. 1990, 31, 2545-2548.
(24) Chen, K.-M.; Hardtmann, G. E.; Prasad, K.; Repic, O.; Shapiro,
M. J . Tetrahedron Lett. 1987, 28, 155-158.

8272 J . Org. Chem., Vol. 64, No. 22, 1999
Claffey et al.
Sch em e 12
Sch em e 13
Sch em e 14
Methyl ketone 35 was treated with LDA followed by
the addition of aldehyde 43 to provide the aldol product
44 in 80% yield. Careful oxidation with Dess-Martin
periodinane resulted in the formation of 45,25 the ketal-
ization precursor, in 87% yield. Following the precedent
set in the ketalization of the model system, the dione was
anticipated to ketalize with an acceptable degree of
selectivity, generating the dispiroketal. However, initial
attempts to deprotect 45 and promote acid-catalyzed
spiroketalization met with only minimal success. Hydro-
genation of the dione with Pearlman’s catalyst in EtOAc
removed both the benzylidene acetal and the PMB ether.
The subsequent acid-catalyzed ketalization proved to be
challenging and was investigated by subjecting the crude
hydrogenation product to a series of protic acid condi-
tions, keeping in mind the acid-labile silicon protecting
groups on the terminal hydroxyl groups. Treatment of
the triol-dione with acetic acid and aqueous HCl in
CHCl3 displayed encouraging results. Using this two-step
sequence, two spiroketals (46 and 47) were isolated in
yields of 64% and 6%, respectively. However, these
results were not reproducible on various batches of the
ketalization precursor with yields ranging from 26 to
64%. After the screening of a variety of other protic acids
and solvents, the best conditions for the ketalization were
PPTS in CH2Cl2 to provide 46% yield of the desired
spiroketal. Our attention then shifted to Lewis-acid-
catalyzed ketalizations. Several relatively strong Lewis
acids [Ti(Oi-Pr)4, Me2AlCl, BF3‚OEt2] resulted solely in
decomposition, while weaker Lewis acids [MgBr2, Mg-
(O2CCF3), ZnCl2] proved to be impractically slow. Moder-
ate success was achieved with 1.2 equiv of anhydrous
ZnBr2 in CH2Cl2 for 30 min warming from -78 to 0 °C.
The desired isomer was isolated in 53% yield accompa-
nied by 8% of the minor isomer possessing the opposite
configuration at the spiroketal carbon (Scheme 12). The
low mass recovery was attributed to cleavage of the
terminal silicon protecting groups under the acidic condi-
tions. Despite the moderate yield for this ketalization
sequence, the 6-7:1 ratio of spiroketal products (46:47)
is impressive. Molecular mechanics calculations (which
indicate no clear thermodynamic preference for one
spiroketal configuration) and control equilibrations (which
gave an approximate equimolar mixture of 46 and 47)
prove that the observed product ratio is kinetic.
Elaboration of the spiroketal to the target CD-
spiroketal subunit began by dissolving metal reduction
of the ketone 46 to obtain diol 48 (Scheme 13). The
reduction was performed by adding the ketone in 1:2
Et2O‚MeOH to the K/NH3 slurry and quenching with
solid NH4Cl to provide 74% of 48 along with 15% of the
minor isomer 49. This byproduct obviously results from
isomerization of the spiroketal center, at some stage in
the process. However, we have thus far not been able to
eliminate its formation in this reduction. The assigned
configuration was based on analysis of its 1H NMR
spectrum and confirmed by the observation that it is also
produced by reduction of compound 47, the minor isomer
of the spiroketalization.
As shown in Scheme 14, the equatorial hydroxy group
of diol 48 was selectively methylated by reaction with
excess Meerwein’s salt (Me3O‚BF4) and 2,6-di-tert-butyl-
4-methylpyridine in CH2Cl2 at 0 °C, affording methyl
ether 50 in 84% yield. NOESY experiments on compound
50 showed unequivocally that the spiroketal center has
the desired (R)-configuration. The axial hydroxy group
was protected as a PMB ether by deprotonation with
KHMDS in THF followed by alkylation with PMBCl to
provide 51 in 87% yield.
The fully protected spiroketal was then transformed
to the key ethyl ketone necessary for the anti-aldol
coupling of the two spiroketal fragments. We first at-
tempted to selectively deprotect the TBS ether by treat-
ment with TBAF‚3H2O in THF at -10 °C, but to our
surprise, the TIPS ether was removed preferentially
(25) Compound 45 is seen by NMR spectroscopy to exist completely
in an enolic form, either that shown or the isomer in which the OH
and CdO groups are reversed.

Synthesis of the C1-C28 Portion of Spongistatin 1
J . Org. Chem., Vol. 64, No. 22, 1999 8273
Sch em e 15
Sch em e 17
Sch em e 16
Sch em e 18
under these conditions. However, use of aqueous CSA in
THF gave the desired alcohol 52 with good selectivity and
in 78% yield. Optimum conditions were found in which
51 was treated with fluorosilic acid (H2SiF6) in t-BuOH
and CH3CN at 0 °C to provide 52 in 86% yield. The
synthesis of ethyl ketone 54 was completed by a three-
step conversion of the primary alcohol into the ethyl
ketone. Dess-Martin periodinane oxidation yielded al-
dehyde 53, which was treated with EtMgBr in ether at
0 °C. The temperature of this reaction is crucial to effect
complete conversion of the starting material, since ad-
dition at low temperature (-78 °C) resulted in substan-
tial amounts of recovered aldehyde. The resulting dia-
stereomeric mixture of secondary alcohols was oxidized
with Dess-Martin periodinane to afford the ethyl ketone
54 in 78% yield for the three steps with one final
purification.
We were now ready to examine the major anti-aldol
union of the two spiroketal subunits. With utilization of
the methodology developed by Brown and co-workers,26
treatment of the ketone 54 with a mixture of dicyclo-
hexylboron chloride and triethylamine in pentane at 0
°C was followed by addition at -78 °C of 1.1 equiv of
aldehyde 31. After 3.5 h the reaction was quenched and
worked-up to provide two aldol products (65%), recovered
ketone 54 (27%), and recovered aldehyde 31 (44%). HPLC
separation of the aldol products revealed a 1.3:1 ratio of
products. The slightly favored, less-polar isomer 55
proved to be a product resulting from reaction of the
aldehyde with the boron enolate possessing the wrong
regiochemistry. The more-polar isomer was the desired
anti-aldol product 56 (Scheme 15).
C,8 which was based partly on the same key anti-aldol
disconnection. The Evans anti-aldol reaction was very
similar to ours, differing mainly in the protecting groups;
in their case the C25 secondary alcohol was protected as
a TBS ether and the C28 primary alcohol as a trityl
group. We suspected that the different regiochemical
outcome of our aldol reaction was due to the C25 PMB
group. To test this hypothesis, the PMB group was
removed by hydrogenolysis and subsequent silylation
with TBS-triflate to provide ethyl ketone 57 in 81% yield
(Scheme 16).
Concurrent with our early aldol couplings, Evans and
co-workers published their total synthesis of altohyrtin
(26) Ganesan, K.; Brown, H. C. J . Org. Chem. 1993, 58, 7162-7169.

8274 J . Org. Chem., Vol. 64, No. 22, 1999
Claffey et al.
Because of this change, it was also necessary to change
the protecting groups in aldehyde 31, since the secondary
alcohol at C5 must be orthogonal to the one at C25. To
accomplish this change with material available, we
retreated to compound 30 (see Scheme 8). Global desi-
lylation occurred in almost quantitative yield when this
material was treated with H2SiF6 in t-BuOH/CH3CN
(Scheme 17). Reprotection with triethylsilyl triflate pro-
vided the tris(silyl ether) 59 in 73% yield. Selective
deprotection of the primary TES ether by reaction with
aqueous camphorsulfonic acid in THF at 0 °C did not
proceed smoothly and provided an unoptimized 56% yield
of the desired alcohol 60 along with 40% of diol 61.
Alcohol 60 was oxidized with Dess-Martin periodinane
to provide the TES-protected aldehyde 62 in 92% yield.
Investigation of the anti-aldol reaction with the newly
protected substrates 57 and 62 (1.18 equiv) afforded the
desired aldol product in approximately 70% yield, along
with recovered aldehyde (35%) and another diastereomer
(ca. 9%). Since the aldol product 63 was contaminated
with a small amount of the copolar ketone 57, a selective
deprotection of the TES ether was performed on the
mixture with HF‚pyridine in THF at 0 °C to provide the
desired diol 64 in a combined yield of 57% for the two
steps. Acetylation with acetic anhydride and DMAP in
pyridine gave diacetate 65 in 92% yield (Scheme 18).
At this point, we have in hand several hundred
milligrams of compound 65, corresponding to the ABCD
subunit of spongistatin 1 (altohyrtin A). The final pro-
tecting group array has proven feasible for the synthesis
of this subunit and is consistent with our plans for the
remainder of the synthesis. The protecting group shuffle
at the end of the route is obviously not optimal, but this
can easily be remedied by installation of the appropriate
protecting groups when larger quantities of 56 and 61
are prepared for future development of the synthesis.
Investigations on the coupling of 64 to the EF subunit
and completion of the total synthesis of spongistatin 1
are currently underway and will be reported in due
course.
Ack n ow led gm en t. This work was supported by a
research grant from the United States Public Health
Service (AI15027).
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and characterization for all new compounds reported
in this paper. This material is available free of charge via the
Internet at http://pubs.acs.org.
J O9910987