Synthesis of the branched C-glycoside substructure of altromycin B

Article abstract of DOI:10.1021/ol050975u

(Chemical Equation Presented) Tungsten-catalyzed cycloisomerization of alkynyl alcohols including 8 provides only the endocyclic enol ether (11) as a key intermediate for the branched Oglycoside substructure (2) of altromycin B. A sequence of Stille cross

Full text of DOI:10.1021/ol050975u

ORGANIC
LETTERS
2005
Vol. 7, No. 17
3621-3624
Synthesis of the Branched C-Glycoside
Substructure of Altromycin B
Bonsuk Koo and Frank E. McDonald*
Department of Chemistry, Emory UniVersity, Atlanta, Georgia 30322
fmcdona@emory.edu
Received April 29, 2005
ABSTRACT
Tungsten-catalyzed cycloisomerization of alkynyl alcohols including 8 provides only the endocyclic enol ether (11) as a key intermediate for
the branched C-glycoside substructure (2) of altromycin B. A sequence of Stille cross-coupling reaction and regio- and stereoselective functional
group transformations affords each C13-diastereomer of the branched C-arylglycoside (2a and 2b).
Altromycin B (1, Figure 1), a member of the family of
pluramycin antibiotics isolated from a South African bush-
veld soil, was first reported to have selective antibiotic
activities against Gram-positive bacteria in the early 1990s
and later reported to possess anticancer activity including in
vivo activity against P388 leukemia, as well as colon, lung,
and ovarian tumors.1 The structure of altromycin B has been
elucidated primarily by NMR spectroscopy, and thus the
absolute stereochemistry of each of the widely separated
chiral subunits has not been unambiguously assigned. Along
with the studies on the biological activities, interactions
between altromycin B with DNA2 and its metal complex3
have been reported. Despite the attractive biological activity
of altromycin B and various congener natural products, none
of the altromycin natural products have been prepared by
total synthesis. Pasetto and Franck recently reported the
synthesis of both possible C13 isomers (2a, 2b) of the north-
west quadrant of altromycin B, beginning with D-glucose.4
However, their efforts to assign C13 stereochemistry on the
basis of the NMR comparison of their synthetic compounds
2a and 2b with altromycin B (1) were unsuccessful because
of the complexity of the natural product structure. In support
of our ongoing studies directed at the total synthesis of
altromycins, we report herein a different synthesis of
substructures 2a and 2b arising from non-carbohydrate
precursors.5
Our retrosynthetic analysis of 2a and 2b (Figure 1)
envisioned a cross-coupling reaction6 to form the C13 1,1-
methylene linking the carbohydrate and aglycone sectors in
3, with the carbohydrate coupling product 4 arising from
the product of tungsten-catalyzed alkynol cycloisomerization
of 5.7
(1) (a) Jackson, M.; Karwowski, J. P.; Theriault, R. J.; Hardy, D. J.;
Swanson, S. J.; Barlow, G. J.; Tillis, P. M.; McAlpine, J. B. J. Antibiot.
1990, 43, 223. (b) Brill, G. M.; McAlpine, J. B.; Whittern, D. N.; Buko, A.
M. J. Antibiot. 1990, 43, 229.
(2) (a) Sun, D.; Hansen, M.; Clement, J. J.; Hurley, L. H. Biochemistry
1993, 32, 1068. (b) Hansen, M.; Hurley, L. J. Am. Chem. Soc. 1995, 117,
2421. (c) Hansen, M.; Yun, S.; Hurley, L. Chem. Biol. 1995, 2, 229. (d)
Nakatani, K.; Okamoto, A.; Matsuno, T. Saito, I. J. Am. Chem. Soc. 1998,
120, 11219.
(3) (a) Menidiatis, C.; Methenitis, C.; Nikolis, N.; Peumatikakis, G. J.
Inorg. Biochem. 2004, 98, 1795. (b) Nikolis, N.; Methenitis, C.; Pneuma-
tikakis, G. J. Inorg. Biochem. 2003, 95, 177. (c) Nikolis, N.; Methenitis,
C.; Pneumatikakis, G.; Fiallo, M. L. J. Inorg. Biochem. 2002, 89, 131.
(4) Pasetto, P.; Franck, R. W. J. Org. Chem. 2003, 68, 8042.
(5) For synthesis of the altromycin aglycone substructure, see the
preceding communication: Fei, Z.; McDonald, F. E. Org. Lett. 2005, 7,
3617.
10.1021/ol050975u CCC: $30.25
© 2005 American Chemical Society
Published on Web 07/20/2005

Table 1. Cycloisomerizations of Alkynyl Alcohols 7 and 8
products
(ratio)a
combined
yield (%)
substrate
R3N
solvent
7
8
8
8
8
DABCO
Et3N
DABCO
Et3N
THF
THF
THF
toluene
toluene
9, 10 (4:1)
33
52
68
64
72b
11, 12 (7:1)
11, 12 (10:1)
11, 12 (8:1)
11 (endo only)
DABCO
1
a Determined by H NMR (400 MHz). b Isolated yield with 10 mol %
W(CO)6.
The tungsten-catalyzed cycloisomerization was initially
conducted with substrate 7 (Table 1). In contrast to other
alkynol substrates explored in our laboratory, the preparation
of six-membered glycal 9 could be optimized to provide only
1
33% yield. The crude H NMR spectrum of the product
Figure 1. Retrosynthetic analysis.
mixture suggested the formation of a minor amount of the
exocyclic methylene regioisomer 10, but this byproduct could
not be isolated.8 However, cycloisomerization of the aceto-
nide-protected substrate 8 gave better results. After optimiza-
tion of the tertiary amine base and choice of solvent,9 we
obtained glycal 11 as the only regioisomeric product in good
isolated yield.
Glycal 11 with the acetonide protective group also proved
ideal for conversion into the stannylated glycal 13 (Scheme
2), due to the tolerance of the acetonide upon reaction with
Our synthesis began with the known diol 6 (Scheme 1).7a
We observed regioselective formation of the methyl ether
from the propargylic alcohol using cyclic stannylene activa-
tion of the diol, followed by silylation of the remaining
alcohol and removal of the benzoate protective group with
DIBAL reduction to afford alkynyl alcohol 7. Alternatively,
Scheme 1. Preparation of Alkynyl Alcohols 7 and 8
Scheme 2. Synthesis of Diols 15a and 15b
protection of diol 6 with 2,2-dimethoxypropane in the
presence of catalytic p-TsOH, followed by DIBAL reduction
of the benzoate ester provided the cyclic acetonide-protected
alkynol 8.
tert-butyllithium as well as solubility for subsequent trans-
formations, relative to silyl ether protected glycals including
(8) Wipf and Graham have also noted substituent effects on regioselec-
tivity of this transformation: Wipf, P.; Graham, T. H. J. Org. Chem. 2003,
68, 8798.
(9) Iwasawa has observed dramatic solvent effects on the regioselectivity
of mechanistically related tungsten carbonyl-promoted carbacyclizations:
(a) Iwasawa, N.; Maeyama, K.; Kusama, H. Org. Lett. 2001, 3, 3871. (b)
Kusama, H.; Yamabe, H.; Iwasawa, N. Org. Lett. 2002, 4, 2569. (c)
Maeyama, K.; Iwasawa, N. J. Am. Chem. Soc. 1998, 120, 1928.
(6) (a) Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508. (b) Stille,
J. K. Pure Appl. Chem. 1985, 57, 1771.
(7) (a) McDonald, F. E.; Reddy, K. S.; D´ıaz, Y. J. Am. Chem. Soc. 2000,
122, 4304. (b) McDonald, F. E.; Reddy, K. S. Angew. Chem., Int. Ed. 2001,
40, 3653. (c) Alca´zar, E.; Pletcher, J. M.; McDonald, F. E. Org. Lett. 2004,
6, 3877.
3622
Org. Lett., Vol. 7, No. 17, 2005

9. Although the Stille cross coupling reaction between 13
and R-iodostyrene was initially irreproducible under the usual
conditions recommended for stannyl glycal partners,10 es-
pecially on millimole scales, the synergistic effect of copper-
(I) salts and fluoride ion11 [Pd(PPh3)4 (2 mol %), CuI (10
mol %), CsF (2 equiv), DMF, 45 °C] provided a robust
solution for this important transformation in our synthesis,
affording C13-disubstituted diene 14 in 66% yield.12 Dihy-
droxylation13 of 14 using AD-mix R or â regioselectively
occurred at the less-substituted alkene and produced a
separable mixture of diastereomers 15a and 15b (15a:15b
) 0.9:1 with AD-mix R; 3.6:1 with AD-mix â).
(Scheme 3), with stereochemistry of 16 consistent with
sterically controlled addition of borane to the convex face
of the acetonide-protected glycal 15a. However, the other
diastereomer 15b produced a hydroxyl group syn to the
adjacent acetonide protected group as the major product
under the same reaction conditions. We postulate that the
primary C19-alcohol may be directing the stereochemistry
of hydroboration,14 since the mono-TBS ether 17 provided
the expected stereoisomer 18 consistent with sterically
controlled addition.
Compounds 16 and 18 were separately treated with TBSCl
and imidazole to afford bis-TBS-protected compounds 19a
and 19b, for which the primary alcohols were then selectively
deprotected with catalytic CSA to provide 20a and 20b.15
The synthesis of the altromycin branched glycoside
substructure 2a was completed from diol 20a, beginning with
Parikh-Doering oxidation followed by I2/KOH oxidation of
the intermediate aldehyde to the methyl ester 21a (Scheme
4).16 Sequential removal of acetonide and silyl ether protec-
tive groups resulted in only trace formation of the tetraol-
methyl ester 22a but rather the bicyclic lactone 23a as the
major product. The rigidity of the fused bicyclic structure
differentiated the remaining secondary alcohols of 23a so
that the C4′ equatorial alcohol was regioselectively converted
into the methyl ether 24a via the cyclic stannylene interme-
diate.17 Opening of the lactone to the methyl ester of target
compound 2a was initially accomplished by acidic metha-
nolysis (Amberlyst-15, MeOH), but better yields were
consistently obtained under basic conditions.18 An identical
series of transformations was conducted from the diastere-
omeric diol 20b to provide 2b.
Scheme 3. Synthesis of Diols 20a and 20b
The C13 hydroxyl stereochemistry was confirmed by
X-ray crystallography of intermediate 23b, and NOE studies
with diastereomer 23a allowed unambiguous stereochemical
assignments for all synthetic products.19 The 1H NMR spectra
for our synthetic compounds 2a and 2b matched the data
published by Pasetto and Franck for these two compounds.4
Treatment of diol 15a with borane‚THF followed by
NaOH/H2O2 oxidation provided triol 16 in 75% yield
Scheme 4. Conversion of Diols 20a and 20b to the Corresponding Altromycin Branched Glycoside Substructures 2a and 2b
Org. Lett., Vol. 7, No. 17, 2005
3623

In combination with concurrent research into the synthesis
of the altromycin aglycone,5 further studies directed toward
the total synthesis of the altromycin natural products are in
progress.
Acknowledgment. We thank the National Institutes of
Health (CA 59703) for support of this research. We also
acknowledge use of shared instrumentation provided by
grants from the National Institutes of Health, National
Science Foundation, and the Georgia Research Alliance
(NMR spectroscopy, mass spectrometry, X-ray diffractom-
etry) as well as the University Research Committee of Emory
University (polarimeter). We also appreciate the work of Dr.
Kenneth I. Hardcastle and Mr. Xikui Fang for crystal
structure determinations of 23b and 24b.
(10) (a) MacLeod, D.; Moorcroft, D.; Quayle, P.; Dorrity, M. R. J.;
Malone, J. F.; Davies, G. M. Tetrahedron Lett. 1990, 31, 6077. (b) Abas,
A.; Beddoes, R. L.; Conway, J. C.; Quayle, P.; Urch, C. J. Synlett 1995,
12, 1264.
(11) (a) Mee, P. H.; Lee, V.; Baldwin, J. E. Angew. Chem., Int. Ed. 2004,
43, 1132. For effect of Cu(I) in the Stille cross-coupling reaction, see: (b)
Liebeskind, L. S.; Fengl, R. W. J. Org. Chem. 1990, 55, 5359. (c) Kapadia,
V. F. S.; Krishnan, B.; Wang, C.; Liebeskind, L. S. J. Org. Chem. 1994,
12, 1047. (d) Casado, A. L.; Espinet, P. Organometallics 2003, 22, 1305.
(e) Han, X.; Stoltz, B. M.; Corey, E. J. J. Am. Chem. Soc. 1999, 121, 7600.
(12) In all cases formation of the undesired homodimerization byproduct
from glycal 13 could not be completely suppressed (ca. 20% yield). The
attempted Stille cross coupling reaction with the bis-TBS-protected stannyl
glycal corresponding to 13 was unsuccessful, perhaps as a result of the
poor solubility of this stannylated glycal in DMF.
(13) (a) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem.
ReV. 1994, 94, 2483. (b) Stereochemical assignments for 15a and 15b are
based on conversions to bicyclic lactones 23a and 23b, respectively.
(14) Transition metal catalyzed hydroborations: (a) Evans, D. A.; Fu,
G. C.; Hoveyda, A. H. J. Am. Chem. Soc. 1988, 110, 6917. (b) Evans, D.
A.; Fu, G. C. J. Am. Chem. Soc. 1991, 113, 4042. An unsuccessful attempt
to achieve hydroxyl-directed hydroboration has been reported: (c) Smith,
A. B., III; Yokoyama, Y.; Huryn, D. M.; Dunlap, N. K. Tetrahedron Lett.
1987, 28, 3659.
Supporting Information Available: Experimental pro-
cedures and characterization data for new compounds,
including data in CIF format. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL050975U
(16) (a) Parikh, J.; Doering, W. J. Am. Chem. Soc. 1967, 89, 5505. (b)
Yamada, S.; Morizono, D.; Yamamoto, K. Tetrahedron Lett. 1992, 33, 4329.
Chromium(VI) oxidations resulted in oxidative cleavage of the C13-C19
bond.
(17) Grindley, T. B. AdV. Carbohydr. Chem. Biochem. 1998, 53, 17.
(18) (a) Kamenecka, T. M.; Danishefsky, S. J. Chem. Eur. J. 2001, 7,
41. (b) Anand, R. C.; Selvapalam, N. Synth. Commun. 1994, 24, 2743.
(19) See Supporting Information for NOE studies on 23a, as well as
crystallographic information for 23b and 24b.
(15) Paterson, I.; Florence, G. J.; Gerlach, K.; Scott, J. P.; Sereinig, N.
J. Am. Chem. Soc. 2001, 123, 9535.
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