Synthesis of the Spirofungin B Core by a Reductive Cyclization Strategy

Article abstract of DOI:10.1021/ol050589c

(Chemical Equation Presented) A reductive decyanation approach to the synthesis of the core of spirofungin B has been developed. Spirofungin B has only one anomeric stabilization in the spiroacetal and was isolated along with its spiroacetal epimer, spiro

Full text of DOI:10.1021/ol050589c

ORGANIC
LETTERS
2005
Vol. 7, No. 9
1873-1875
Synthesis of the Spirofungin B Core by
a Reductive Cyclization Strategy
Thomas E. La Cruz and Scott D. Rychnovsky*
Department of Chemistry, 516 Rowland Hall, UniVersity of California, IrVine,
IrVine, California 92697-2025
srychnoV@uci.edu
Received March 17, 2005
ABSTRACT
A reductive decyanation approach to the synthesis of the core of spirofungin B has been developed. Spirofungin B has only one anomeric
stabilization in the spiroacetal and was isolated along with its spiroacetal epimer, spirofungin A. The cyclization precursor was constructed
from readily available starting materials. The reductive cyclization reaction was both efficient and stereoselective. The reductive cyclization
strategy to spiroacetals is convergent and effective.
The spirofungin family of natural products was isolated from
a Streptomyces strain Tu¨ 4113 collected in the Australian
Otway National Park as a 4:1 mixture of spirofungin A (1)
and spirofungin B (2).1 Rizzacasa and co-workers recently
reported the total synthesis of spirofungin B (2) and found
that NMR data for the natural product did not match that
for their synthetic material (Figure 1).2 Rizzacasa proposed
a revised structure for spirofungin B (3) that is epimeric with
spirofungin A (1) at the C15 spiroacetal center. Thus
spirofungin B (3) would be a spiroacetal with a single
anomeric stabilization. Rizzacasa’s reassignment of spiro-
fungin B was further supported by the report of Dias, who
synthesized a spirofungin A and B spiroacetal.3 Dias’
spirofungin model was isolated as a 30:70 equilibrium
mixture of spiroacetals 5 and 4, corresponding to the
spirofungin A and spirofungin B spiroacetals, respectively.3
The revised structure of spirofungin B (3) as a spiroacetal
with only one anomeric stabilization appears to be secure.
We recently reported a new reductive cyclization strategy
to access spiroketals with a single anomeric stabilization.4
The reductive cyclization method appears well suited to the
synthesis of the revised spirofungin B structure. Described
herein is a synthesis of the spirofungin B spiroacetal core
using a stereoselective reductive cyclization strategy.
(1) Holtzel, A.; Kempter, C.; Metzger, J. W.; Jung, G.; Groth, I.; Fritz,
T.; Fiedler, H.-P. J. Antibiot. 1998, 51, 699-707.
(2) Rizzacasa, M. A.; White, J. M.; Zanatta S. D. Org. Lett. 2004, 6,
1041-1044.
(3) Dias, L. C.; de Oliveira, L. G. Org. Lett. 2004, 6, 2587-2590.
(4) Buckmelter, A. J.; La Cruz, T. E.; Rychnovsky, S. D.; Takaoka, L.
R. J. Am. Chem. Soc. 2005, 127, 528-529.
Figure 1. The originally proposed structure of spirofungin B (2)
and Rizzacasa’s revised structure (3), as well as Dias’ synthetic
spirofungin A/B model (5/4).
10.1021/ol050589c CCC: $30.25
© 2005 American Chemical Society
Published on Web 04/05/2005

The disconnection strategy employed for the synthesis of
the spirofungin B spiroacetal 6 is illustrated in Scheme 1.
quenching of the organolithium species with diphenyl
disulfide, gave hemithio ketene acetal 10.6,7 Compound 10
was prepared with a TIPS protecting group because previous
experience had shown that it was suitable for both the
metalation reaction and the reductive cyclization.4
Scheme 1. Retrosynthetic Analysis
Scheme 3 summarizes the synthesis of diol 11. Homo-
Scheme 3. Synthesis of Chloro Diol 11
allylic alcohol 18 was synthesized by Brown crotylation of
aldehyde 17 in 86% yield and 94% ee.8 Alcohol 18 was
protected as the bis-TBS ether 19, which upon hydroboration
gave the primary alcohol 20. Treatment of this primary
alcohol with triphenylphosphine and carbon tetrachloride,
followed by removal of the TBS ethers under acidic
conditions, gave chloro diol 11.9
With the hemithio ketene acetal 10 and the diol 11 in hand,
synthesis of the spiroacetal could commence. The cyclization
precursor was assembled as outlined in Scheme 4. Acid-
The intermediate synthetic goal is the preparation of ortho
ester 9. Opening the ortho ester 9 to a cyano acetal 8,
followed by reductive lithiation using lithium di-tert-butyl-
biphenylide (LiDBB) would produce the axial organolithium
species 7. Intramolecular alkylation of organolithium 7
should deliver spiroacetal 6 stereoselectively, with a single
anomeric stabilization. The synthesis of ortho ester 9 derives
from the combination of hemithio ketene acetal 10 and diol
11, both of which should be readily available using standard
synthetic transformations.
Scheme 4. Combining the Fragments and Reductive
Synthesis of hemithio ketene acetal 10 began with known
alcohol 12, available in 91% ee using Brown’s enantio-
selective crotylation reaction.5,8a Alcohol 12 was esterified
with allyl bromide in 89% yield (Scheme 2). Ring closing
Cyclization
Scheme 2. Synthesis of Hemithio Ketene Acetal 10
metathesis of allyl ether 13 with Grubb’s first generation
catalyst generated dihydropyran 14 in 81% yield. Alkene
isomerization with Wilkinson’s catalyst to enol ether 15,
followed by lithiation of dihydropyran 15 with t-BuLi and
catalyzed addition of chloro diol 11 to hemithio ketene acetal
10 gave an inseparable mixture of ortho esters 22 consisting
(5) Dreher, S. D.; Leighton, J. L. J. Am. Chem Soc. 2001, 123, 341-
342.
(6) Leeuwenburgh, M. A.; Overkleeft, H. S.; van der Marel, G. A.; van
Boom, J. H. Synlett 1997, 1263-1264.
(7) Boeckman, R. K.; Bruza, K. J. Tetrahedron 1981, 37, 3997-4006.
(8) (a) Bhat, K. S.; Brown, H. C. J. Am. Chem. Soc. 1986, 108, 5919-
5923. (b) Gravel, M.; Hall, D. G.; Lachance, H.; Lu, X. J. Am. Chem. Soc.
2003, 125, 10160-10161. (c) Ardisson, J.; Berque, I.; Brion, J.-D.; Fe´re´zou,
J.-P.; Le Me´ne´z, P.; Mahuteau, J.; Pancrazi, A.; Razon, P. J. Org. Chem.
1999, 64, 373-381.
1874
Org. Lett., Vol. 7, No. 9, 2005

of two predominant isomers (1.5:1 ratio) that were epimeric
at the spiro center. We found this mixture to be contaminated
with at least one other diastereomeric ortho ester (∼5%) that
would arise from the coupling of the minor enantiomer of
hemithio ketene acetal 10 or chloro diol 11. Treatment of
the ortho ester mixture 22 with TMSCN and BF3 etherate
afforded cyano acetals 23 and 24 in 77% yield as a 6:1
mixture of epimers. However, once again a third minor
isomer was present in this mixture. The major cyano acetal
23 could be readily separated from the other cyano acetals
by flash chromatography and was carried forward as a single
diastereomer.10 The primary hydroxyl group was protected
as the TBS ether to give the cyclization precursor 25.
Cyano acetal 25 was treated with LiDBB in THF at -78
°C to generate an axial organolithium reagent corresponding
to compound 7 in Scheme 1. The organolithium reagent
cyclized to give the spiroacetal core of spirofungin B,
compound 6. Spiroacetal 6 was produced as a single
diastereomer. The relative configuration of spiroacetal 6 was
determined by 1D and 2D NMR analysis11,12 and by
comparing the spectroscopic data of 6 with Dias’ spirofungin
B segment (Figure 2).3 The chemical shift of the spiro carbon
of 6 was found to be 97.4 ppm (CDCl3), which is in good
agreement with both the structure of spirofungin B (97.1
ppm), and of Dias’ spiroacetal (97.5 ppm).13 The methyl
groups of 6 also shared similar chemical shifts as those
reported for Dias’ spiroacetal. When spiroacetal 6 was
dissolved in CDCl3, equilibration ensued to produce a 70:
30 mixture of 6 and its C15 epimer. This outcome is in
Figure 2. Spectroscopic data for spiroacetal 6 and Dias’ analogue.
accord with the behavior Dias observed with his spirofungin
B spiroacetal and lends further support to the structural
assignment of spiroacetal 6.11,13
A reductive cyclization approach to the synthesis of the
spirofungin B spiroacetal was developed. The spiroacetal has
only a single anomeric stabilization, and it has not been
prepared as a single diastereomer previous to this work. The
reductive cyclization strategy is inherently convergent, and
in this example the cyclization precursor was constructed
efficiently from readily available starting materials. The
cyclization reaction was highly stereoselective and produced
the spirofungin B core as a single diastereomer. We will
continue to investigate the potential of reductive cyclization
strategies in natural product syntheses.
(9) Garegg, P. J.; Johansson, R.; Samuelsson, B. Synthesis 1984, 168-
170.
(10) The configuration of the nitrile motif is inconsequential to the
outcome of the cyclization reaction (ref 4).
(11) 1D and 2D proton NMR data of spiroacetal 6 were collected in
C6D6. However, the spectroscopic data shown in Figure 2 was collected in
CDCl3, the same solvent used by Dias. In CDCl3 spiroacetal 6 equilibrated
with its C15 epimer rapidly, and equilibrium was achieved in approximately
10 min.
(12) Equilibration of spiroacetal 6 with its C15 epimer was prevented if
1H NMR and 13C NMR data were obtained using C6D6.
(13) The chemical shift of the C15 epimer of 6 was observed to be 96.6
ppm (CDCl3). Dias’ spirofungin A model showed an identical 13C NMR
shift at the corresponding carbon atom (ref 3).
Acknowledgment. This work was supported by the
National Institute of General Medical Sciences (GM-65338).
Brian Patterson initially developed the route to enol ether
15 in this laboratory.
Supporting Information Available: Preparation and
characterization of the described compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL050589C
Org. Lett., Vol. 7, No. 9, 2005
1875