A method for constructing the C44-C51 side chain of altohyrtin C.

Article abstract of DOI:10.1021/ol990281j

[formula: see text] A method to construct the C44-C51 side chain of altohyrtin C has been developed and applied to a model aldehyde derived from D-glucose. The approach relies on a Wittig reaction to couple the side chain to an aldehyde and utilizes an al

Full text of DOI:10.1021/ol990281j

ORGANIC
LETTERS
1999
Vol. 1, No. 9
1475-1478
A Method for Constructing the C44−C51
Side Chain of Altohyrtin C
Gregory R. Ott and Clayton H. Heathcock*
Department of Chemistry, UniVersity of California, Berkeley, California 94720
chh@steroid.cchem.berkeley.edu
Received September 13, 1999
ABSTRACT
A method to construct the C44−C51 side chain of altohyrtin C has been developed and applied to a model aldehyde derived from D-glucose.
The approach relies on a Wittig reaction to couple the side chain to an aldehyde and utilizes an allylic diazene rearrangement to place the C45
double bond in the correct position.
The altohyrtins (1-3),1 spongistatins,2 and cinachrylide A3
represent a growing class of sponge-derived macrolides that
display unique, highly complex architecture and very potent
cytotoxicity. The above criteria have made these molecules
attractive targets for total synthesis.4 As part of our research
directed toward the total synthesis of the altohyrtins,5 we
have developed a method for introducing the side chain
moieties to an appropriate F-ring model compound. This
method uses a Wittig olefination of an appropriate aldehyde
and an allylic diazene rearrangement to introduce the side
chain geminal olefin.
(1) (a) Kobayashi, M.; Aoki, S.; Sakai, H.; Kawazoe, K.; Kihara, N.;
Sasaki, T.; Kitigawaw, I. Tetrahedron Lett. 1993, 34, 2795. (b) Kobayashi,
M.; Aoki, S.; Kitigawa, I. Tetrahedron Lett. 1994, 35, 1243.
(2) Bai, R.; Taylor, G. F.; Cichacz, Z. A.; Herald, C. L.; Kepler, J. A.;
Pettit, G. R.; Hamel, E. Biochemistry 1995, 34, 9741.
(3) Fusetani, N.; Shinoda, K.; Matsunaga, S. J. Am. Chem. Soc. 1993,
115, 3977.
(4) (a) Evans, D. A.; Coleman, P. J.; Dias, L. C. Angew. Chem., Int. Ed.
Engl. 1997, 36, 2738. (b) Evans, D. A.; Trotter. B. W.; Cote, B.; Coleman,
P. J. Angew. Chem., Int. Ed. Engl. 1997, 36, 2741. (c) Evans, D. A.; Trotter,
B. W.; Cote, B.; Coleman, P. J.; Dias, L. C.; Tyler, A. N. Angew. Chem.,
Int. Ed. Engl. 1997, 36, 2744. (d) Guo, J. S.; Duffy, K. J.; Stevens, K. L.;
Dalko, P. I.; Roth, R. M.; Hayward, M. M.; Kishi, Y. Angew. Chem., Int.
Ed. Engl. 1997, 37, 187. (e) Hayward, M. M.; Roth, R. M.; Duffy, K. J.;
Dalko, P. I.; Stevens, K. L.; Guo, J. S.; Kishi, Y. Angew. Chem., Int. Ed.
Engl. 1998, 37, 192.
(5) (a) Claffey, M. M.; Heathcock, C. H. J. Org. Chem. 1996, 61, 7646.
(b) Hayes, C. J.; Heathcock, C. H. J. Org. Chem. 1997, 62, 2678. (c) Claffey,
M. M.; Hayes, C. J.; Heathcock, C. H. J. Org. Chem., in press.
The advanced F-ring in our synthesis is ultimately be
derived from tri-O-acetyl-D-glucal, with the C6 position of
10.1021/ol990281j CCC: $18.00 © 1999 American Chemical Society
Published on Web 09/28/1999

the of the glucal eventually becoming C44 (altohyrtin
numbering). This would require formation of the carbon-
carbon bond of the side chain at the C44-C45 linkage.
Compound 4 (Scheme 1) was chosen as an appropriate target
allylation using the Luche protocol8 gave the homoallylic
alcohol 13 as mixture of diastereomers (ca. 2-3:1). The
mixture of isomers was treated with Martin’s sulfurane
dehydrating reagent9 to yield the trans diene 14. Completion
of the Horner-Emmons reagent 7 entailed installation of
the carbomethoxy group (LDA, dimethyl carbonate) to give
the substituted phosphonoacetate as a 1:1 mixture of dia-
stereomers.
Scheme 1
The F-ring model is available in three steps from methyl
4,6-O-(4-methoxybenzylidene)-â-D-glucopyranoside (Scheme
3).10 Methylation of the free hydroxyls gave 16 which was
Scheme 3
to model the introduction of our side chain. We envisioned
disconnecting the C44-C45 (altohyrtin numbering) linkage
as a double bond; thus our approach relies on an allylic
transposition of the C45 geminal olefin to give the ester 5.
The R,â-unsaturated ester 5 can arise through a Horner-
Emmons or Wittig reaction with either 7 or 8 and the model
F-ring aldehyde 6.
subjected to lithium aluminum hydride reduction in the
presence of AlCl3 yielding primary alcohol 17 (64%).11
Swern oxidation afforded the unstable aldehyde 6 which was
prepared fresh and used directly in the olefin-forming
reactions.
Coupling of 6 and 7 proved to be more difficult than
expected. For example, when treated with bases such as NaH,
LiCl/DBU,12 or KHMDS/18-C-6,12 olefin formation required
several hours to several days at room temperature for
completion and was complicated by elimination of the
OPMB group. Use of LDA as the base helped to suppress
elimination of the OPMB group (Scheme 4), but the reaction
still required 16 h at room temperature for completion and
suffered from poor mass recovery (40%). It was apparent
that the Horner-Emmons approach was not going to be
viable.
The Horner-Emmons reagent 7 (Scheme 2) was available
from PMB-protected glycidol 96 by epoxide opening with
the lithium anion of diethyl methylphosphonate.7 The
secondary alcohol was subsequently protected as the tert-
butyldimethylsilyl (TBDMS) ether. Unmasking of the pri-
mary alcohol (DDQ) followed by Swern oxidation and
Scheme 2
At this stage, we decided to focus on the stabilized Wittig
reagent 8 (Scheme 5). Hydroxy ester 19,13 available from
(6) Smith, A. B.; Zhuang, L. H.; Brook, C. S.; Boldi, A. M.; McBriar,
M. D.; Moser, W. H.; Murase, N.; Nakayama, K.; P. R., V.; Lin, Q.
Tetrahedron Lett. 1997, 38, 8667.
(7) Li, Z. G.; Racha, S.; Dan, L.; Elsubbagh, H.; Abushanab, E. J. Org.
Chem. 1993, 58, 5779.
(8) Petrier, C.; Luche, J.-L. J. Org. Chem. 1985, 50, 910.
(9) Martin, J. C.; Arhart, R. J.; Franz, J. A.; Perozzi, E. F.; Kaplan, L.
J. Org. Synth. 1977, 57, 22.
(10) Classon, B.; Liu, Z. J. Org. Chem. 1988, 53, 6126.
(11) Stick, R. V.; Tilbrook, D.; Matthew, G. Aust J. Chem. 1990, 43,
1643.
(12) Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.;
Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron Lett. 1984, 25, 2138.
1476
Org. Lett., Vol. 1, No. 9, 1999

Scheme 4
Scheme 5
Scheme 6
L-malic acid in three steps, was protected as its TBDMS ether
temperatures generally used for these reactions (ca. 80-100
°C). At ambient temperature, however, olefin formation was
quite clean, albeit a bit slow (ca. 3-5 days) yielding 18 as
a single isomer in 70% yield (Scheme 6). Now that we had
secured a reliable protocol for formation of the R,â-
unsaturated ester, we next required a method for allylic
transposition of the R,â-unsaturated ester to the geminal
olefin.
and subjected to hydrogenolysis to afford primary alcohol
21. Swern oxidation followed by a two-step Wittig protocol
(Ph3PCHCHO; Ph3PdCH2) installed the requisite trans diene.
Ester 24 was reduced (DIBAL), and the derived alcohol was
converted to the iodide and then to the phosphonium salt.
Deprotonation of phosphonium salt 27 with excess NaHMDS
and trapping with methyl chloroformate provided the phos-
phorylidene species 8.14
To address this issue, we had hoped to take advantage of
recent advances in the area of allylic diazene rearrangements.
Specifically, we wished to utilize those introduced by Myers
and co-workers15 which entail Mitsunobu displacement of
an allylic alcohol with o-nitrobenzenesulfonyl hydrazine
With the stabilized Wittig reagent in hand, we proceeded
onto the coupling with our model F-ring aldehyde. The
instability of aldehyde 6 precluded the use of elevated
(13) Thiam, M.; Slassi, A.; Chastrette, F.; Amouroux, R. Synth. Commun.
1992, 22, 83.
(14) Bestmann, H. J. Angew. Chem., Int. Ed. Engl. 1965, 4, 645.
(15) Myers, A. G.; Zheng, B. Tetrahedron Lett. 1996, 37, 4841.
Org. Lett., Vol. 1, No. 9, 1999
1477

(NBSH).16 Toward this end, the ester was reduced (DIBAL)
to provide the allylic alcohol 28 (Scheme 7). Unfortunately,
ment of an allylic iodide with hydrazine followed by air
oxidation to the diazene intermediate.17 This was achieved
by conversion of the alcohol to the iodide (MsCl; NaI)
followed by treatment with NH2NH2‚H2O in deoxygenated
1-hexene/ethanol (1:1) at 40 °C for 1 h. Following consump-
tion of the starting iodide, and aqueous workup, the crude
allylic hydrazine was stirred in dichloromethane/1-hexene
under an air atmosphere to oxidize 30 to the diazene
intermediate which undergoes 1,5-hydride transfer with loss
of dinitrogen to produce 4 in 51% yield for the two-step
procedure. The 1-hexene was added to suppress concomitant
reduction of the remaining olefins caused by adventitious
diimide.
Scheme 7
In summary, a stereoselective synthesis of the desired
model 4 has been achieved. We have developed an efficient
coupling process to attach the altohyrtin side chains to a
model F-ring aldehyde. We have also demonstrated that we
can introduce the geminal olefin using an allylic diazene
rearrangement. The strategies developed in this model study
are directly applicable for the introduction of the altohyrtin
side chains to an advanced EF, C29-C44 aldehyde. Studies
directed toward this goal are currently underway.
Acknowledgment. This work was supported by a re-
search grant from the National Instutes of Health (GM15027).
Supporting Information Available: Experimental pro-
cedures and full characterization for all compounds reported.
This material is available free of charge via the Internet at
http://pubs.acs.org.
28 was completely unreactive toward Mitsunobu displace-
ment with NBSH, yielding only recovered alcohol. This led
us to consider a more traditional approach, namely displace-
OL990281J
(17) (a) Corey, E. J.; Wess, G.; Xiang, Y. B.; Singh, A. K. J. Am. Chem.
Soc. 1987, 109, 4717. (b) Corey, E. J.; Xiang, Y. B. Tetrahedron Lett. 1987,
28, 5403.
(16) Myers, A. G.; Zheng, B.; Movassaghi, M. J. Org. Chem. 1997, 62,
7507.
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Org. Lett., Vol. 1, No. 9, 1999