A method for constructing the C18-C28 dispiroacetal moiety of altohyrtin A

Full text of DOI:10.1021/jo9701703

2678
J . Org. Chem. 1997, 62, 2678-2679
Sch em e 1
A Meth od for Con str u ctin g th e C18-C28
Disp ir oa ceta l Moiety of Altoh yr tin A
Christopher J . Hayes and Clayton H. Heathcock*
Department of Chemistry, University of California,
Berkeley, California 94720
Received J anuary 30, 1997
The altohyrtins,1,2 the spongistatins,3 and cinachyrolide
A4 represent a growing group of related marine-derived
macrolides, which show extremely potent cancer cell
growth inhibitory activity. It is of particular interest that
many of these compounds have displayed extreme cyto-
toxicity toward a subset of chemoresistant tumor types.
Altohyrtin A (1) is the only member of this family for
which the absolute stereochemistry has been determined.
Profound biological activity and unusual chemical struc-
ture couple to make 1 a desirable target for total
synthesis.
Sch em e 2a
a
Reagents: (a) HF(48% aqueous), MeCN (91%); (b) KHMDS,
PhCHO, THF, 0 °C (73%); (c) DIBALH, CH2Cl2, -95 °C (94%); (d)
MeMgBr, Et2O, 0 °C; (e) Dess-Martin, CH2Cl2 (94%).
We envisioned 5 as being readily derived from the
known ester 66 and aldehyde 85a (Scheme 2). Thus,
deprotection of 6 with 48% aqueous HF in acetonitrile
first provided the corresponding secondary alcohol. Ste-
reoselective installation of the C3 stereocenter and
concomitant benzylidene acetal formation were achieved
using the method developed by Evans and co-workers.7
Reduction of the resultant ethyl ester with 1 equiv of
DIBALH afforded the aldehyde 7. The synthesis of 9
from 8 was readily accomplished in two steps by addition
of methylmagnesium bromide and Dess-Martin perio-
dinane oxidation.8 Condensation of 7 with the lithium
enolate of 9 afforded the corresponding aldol product,
which was oxidized with Dess-Martin periodinane to
yield the dione 10 in good yield (Scheme 3). The
synthesis of 5 was completed by deprotection of the
TBDPS ether with tetrabutylammonium fluoride fol-
lowed by removal of the benzylidene acetal using catalytic
hydrogenation. A number of solvents were screened for
the hydrogenation reaction, and it was found that in ethyl
acetate spiroacetalization of 5 occurred in situ. The
acetalization is presumably catalyzed by trace amounts
of acid present in the solvent. Our original prediction
regarding the stereoselective acetalization of 5 was shown
to be correct. A 1H NMR spectrum of the crude reaction
mixture showed that the diastereomeric spiroacetals 3
and 11 were formed in a ratio of approximately 5:1.
Owing to problems associated with the volatility of 11
and particularly 3, the diastereoisomers were not sepa-
rated at this stage. Treatment of a mixture of 3 and 11
with tert-butyldimethylsilyl trifluoromethanesulfonate
and 2,6-lutidine at low temperature (-78 °C) afforded a
5:1 mixture of the corresponding silyl ethers 12 and 13
As part of our research directed toward a total syn-
thesis of 1,5 we had reason to synthesize the spiroacetal
2, which is a model for the C-D, C18-C28 fragment of
1. Retrosynthetic analysis of 2 (Scheme 1) revealed the
triol 4 as a potential precursor. Preliminary molecular
mechanics and semiempirical calculations, however, sug-
gested that the spiroacetalization of 4 might result in low
selectivity for the desired acetal configuration. Therefore,
we decided to explore an alternative approach. Thus,
disconnection of 2 revealed the ketohydroxy spiroacetal
3 as a key intermediate, which might result from
spiroacetalization of the triol-dione 5. In this case,
molecular modeling suggested that the desired R-spiro-
acetal configuration should be favored. In order to test
this hypothesis, we required an expedient synthesis of
the triol-dione 5.
(1) Kobayashi, M.; Aoki, S.; Kitagawa, I. Tetrahedron Lett. 1994,
35, 1243.
(2) Kobayashi, M.; Aoki, S.; Sakai, H.; Kawazoe, K.; Kihara, N.;
Sasaki, T.; Kitagawa, I. Tetrahedron Lett. 1993, 34, 2795.
(3) Bai, R.; Taylor, G. F.; Cichacz, Z. A.; Herald, C. L.; Kepler, J . A.;
Pettit, G. R.; Hamel, E. Biochemistry 1995, 34, 9714. See also
references cited therein.
(4) Fusetani, N.; Shinoda, K.; Matsunaga, S. J . Am. Chem. Soc.
1993, 115, 3977.
(5) (a) Claffey, M. M.; Heathcock, C. H. J . Org. Chem. 1996, 61, 7646.
See also: (b) Paterson, I.; Oballa, R. M.; Norcross, R. D. Tetrahedron
Lett. 1996, 37, 8581.
(6) Keck, G. E.; Palani, A.; McHardy, S. F. J . Org. Chem. 1994, 59,
3113.
(7) Evans, D. A.; Gauchet-Prunet, J . A. J . Org. Chem. 1993, 58, 2446.
(8) Dess, D. B.; Martin, J . C. J . Org. Chem. 1983, 48, 4155.
S0022-3263(97)00170-9 CCC: $14.00 © 1997 American Chemical Society

Communications
J . Org. Chem., Vol. 62, No. 9, 1997 2679
Sch em e 3a
Ta ble 1
condns
ratio 15:2
condns
ratio 15:2
TFA, CH2Cl2
HCl, CDCl3
45:55
45:55
TFA, hexanes
HFaq, MeCN
55:45
85:15
established (Table 1). A number of equilibration condi-
tions were examined in an attempt to favor 2 over 15.
The best conditions were found to be trifluoroacetic acid
in methylene chloride, giving a ratio of 55:45 of 2 and 15
at equilibrium. Since the two isomers were readily
separable by column chromatography, we had a method
to convert the undesired spiroacetal isomer 15 into the
desired product 2. Thus, three equilibration/separation
cycles allowed us to convert isomerically pure 15 into
isomerically pure 2 in 90% isolated yield. Subsequent
to the aforementioned studies, we found that the separa-
tion of 12 and 13 was not necessary. The mixture of
diastereoisomers could be carried through the reduction,
methyl ether formation and deprotection reactions, pro-
ducing 2 and 15 in a ratio paralleling the initial ratio of
12 and 13 used. For example, a 5:1 mixture of 12 and
13 produced a 5:1 mixture of 2 and 15 in 64% overall
yield. The separated 15 was then converted into 2 using
two equilibration/separation cycles. This overall process
afforded the desired acetal 2 in 60% isolated yield (from
the mixture of 12 and 13) along with 2% of 15. Although
we were hoping for a better ratio than 55:45 of 2:15 in
the equilibration step, this result supports our original
prediction that the spiroacetalization of 4 would not be
selective for the desired acetal configuration.
a
Reagents: (a) LDA, -78 °C, THF then 7, THF (81%); (b) Dess-
Martin, CH2Cl2 (84%); (c) TBAF, THF (92%); (d) H2, Pd(OH)2,
EtOAc; (e) TBSOTf, 2,6-lutidine, CH2Cl2, -78 °C (74%, two steps).
Sch em e 4a
In summary, a stereoselective synthesis of the desired
model 2 has been accomplished. We have shown that
acetalization of the triol 5 leads to selective formation of
the spiroacetal 3 possessing the desired R-spiroacetal
configuration and how this intermediate can be elabo-
rated into 2. In addition, we have described how the
minor S-spiroacetal isomer 11 can also be used to access
the desired target 2 in good yield. The strategy developed
for stereocontrolled synthesis of 2 is directly applicable
to the synthesis of the C-D, C18-C28 spiroacetal of
altohyrtin A (1), and studies directed toward this end are
currently underway.
a
Reagents: (a) K/NH3, MeOH; (b) NaH, MeI, THF; (c) TBAF,
THF.
in excellent yield. The diastereoisomers were easily
separated at this point by column chromatography.
Reduction of 12 using potassium in liquid ammonia at
low temperature (-78 °C) resulted in the selective
formation of the equatorial secondary alcohol 14 (Scheme
4). Methyl ether formation and removal of the TBS
protecting group, following standard procedures, yielded
the desired spiroacetal target 2. The relative configura-
tion of 2 was confirmed by a series of NOE difference
NMR experiments. In addition to the synthesis of 2, we
were able to synthesize the diastereomeric spiroacetal 15
from 13 using an identical sequence of reactions to those
described above. We found that under a variety of acidic
conditions, an equilibrium between 15 and 2 could be
Ack n ow led gm en t. This work was supported by a
research grant from the United States Public Health
Service (GM 15067).
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and spectral data for all compounds (13 pages).
J O9701703