Stereo- and regioselective glycosylates to the Bis-C-arylglycoside of kidamycin

Article abstract of DOI:10.1021/ol7014219

In explorations toward the total synthesis of the antitumor anthrapyran natural product kidamycin, the regioselective introduction of aminosugars angolosamine and vancosamine as C-arylglycosides has been accomplished onto hydroxylated anthrapyran aglycone

Full text of DOI:10.1021/ol7014219

ORGANIC
LETTERS
2007
Vol. 9, No. 18
3547-3550
Stereo- and Regioselective
Glycosylations to the
Bis-C-arylglycoside of Kidamycin
ZhongBo Fei and Frank E. McDonald*
Department of Chemistry, Emory UniVersity, Atlanta, Georgia 30322
fmcdona@emory.edu
Received June 18, 2007
ABSTRACT
In explorations toward the total synthesis of the antitumor anthrapyran natural product kidamycin, the regioselective introduction of aminosugars
angolosamine and vancosamine as C-arylglycosides has been accomplished onto hydroxylated anthrapyran aglycones. Specifically, the
9,11-dihydroxylated anthrapyran A undergoes sequential glycosylations with angolosamine synthon B and vancosamine synthon C to regio-
and stereoselectively afford bis-C-glycoside D corresponding to the C-glycoside pattern of kidamycin.
The pluramycins are a relatively large family of antitumor
antibiotic natural products containing the 4H-anthra[1,2-b]-
pyran-4,7,12-trione substructure, with variations in the side
chain and substitution patterns of carbohydrates on the
anthrapyran core aglycone.1 Kidamycin was isolated from
Streptomyces soil bacteria in the early 1970s, as one of the
earliest known members of the pluramycin antibiotics.2
Kidamycin demonstrates a wide spectrum of antimicrobial
activity against anaerobic bacteria, aerobic and facultative
bacteria, and yeasts3 and also has antitumor and cytotoxic
properties against leukemia L-1210 as well as life-prolonga-
tion activity on mice bearing ascites tumors at single i.p.
Figure 1. Structures of kidamycin and isokidamycin.
doses from just below the LD50 (18 mg/kg) to 1/16 of the
LD50.4 The structure and conformation of kidamycin (1,
Figure 1) was determined by NMR and X-ray crystal-
lographic studies, exhibiting a novel meta-arrangement of
two different C-arylglycosidic aminosugars, with equatorially
substituted angolosamine at C8 and axially substituted
vancosamine at C10.5 In the course of characterization stu-
dies, the acid sensitivity of the axial C-glycoside to ano-
merization was discovered to favor equatorially substituted
vancosamine in isokidamycin (2), which is attributed to occur
by protonation of the pyranose oxygen and elimination to a
(1) (a) Berdy, J. AdV. Appl. Microbiol. 1974, 18, 309. (b) Se´quin, U.
Prog. Chem. Org. Nat. Prod. 1986, 50, 57. (c) Rohr, J.; Thiericke, R. Nat.
Prod. Rep. 1992, 103. (d) Hansen, M. R.; Hurley, L. H. Acc. Chem. Res.
1996, 29, 249.
(2) Kanda, N. J. Antibiot. 1971, 24, 599.
(3) Kanda, N. J. Antibiot. 1972, 25, 557.
(4) Kanda, N.; Kono, M.; Asano, K. J. Antibiot. 1972, 25, 553.
10.1021/ol7014219 CCC: $37.00
© 2007 American Chemical Society
Published on Web 08/11/2007

Scheme 1. Syntheses of Glycosyl Donors 6 and 10 via Alkynol Cycloisomerization
quinomethide intermediate, followed by reclosure of the
lent of base. However, we recognized the advantages of the
cyclic carbamate in avoiding carbonyl group participation
of the acyclic Cbz group in glycosylations as well as the
convex nature of compound 9 in stereoselective glycosylation
and were able to optimize preparation of 9 by using excess
base until complete conversion to the cyclic carbamate had
occurred, followed by addition of iodomethane. Further
derivatization of glycal 9 to glycosyl acetate 1016 broadened
the choice of conditions for glycosylations.
In 2005, we reported the synthesis of kidamycin aglycone
via the advanced intermediate 11.7 Friedel-Crafts-type
glycosylation17 of 11 with angolosamine synthon 5 stereo-
and regioselectively provided C8-glycoside 13, albeit with
low conversion (Scheme 2). Similar results were observed
with the C12-thioethyl analogue 12.19 The regioselectivity
of these glycosylations was assigned by the disappearance
of the C8 hydrogen resonance in comparing 1H NMR spectra
for compounds 11-14 and confirmed by the observation of
a nuclear Overhauser effect between H7 and the anomeric
hydrogen H1′ in compound 14.18 This glycosylation was not
further optimized after we found that the O-methyl groups
could not be removed from the aglycone nucleus in the
presence of the fragile benzylic carbon-oxygen bond of the
angolosamine carbohydrate, but we did demonstrate reduc-
tion of the azide of 13 to amine which was characterized as
peracetylated 15.
pyran ring.5a Despite the interesting biological activity of
kidamycin, this structurally complex compound has, to date,
resisted total synthesis. Two syntheses of the kidamycin agly-
cone have been recorded,6,7as well as the development of
several methods for the regioselective construction of meta-
bis-C-arylglycosides.8 In this report, we will disclose the first
cases in which the angolosamine and vancosamine sugars
have been stereo- and regioselectively introduced onto an
aglycone bearing most of the features of the natural product
kidamycin. Our synthetic strategy features late-stage sequen-
tial C-glycosylation at C8 of kidamycin aglycone or the re-
lated anthrapyran synthon with a suitably protected angolos-
amine synthon and at C10 with the vancosamine synthon.
Both carbohydrate components leading to angolosamine
and vancosamine were prepared utilizing tungsten-catalyzed
alkynol cycloisomerization to form pyranosyl glycal inter-
mediates. For D-angolosamine synthon 6 (Scheme 1), cyclo-
isomerization9 of alkynyl alcohol 3 provided glycal 4.10
Removal of the silyl ether protective group allowed direct
SN2 substitution11 to introduce an azide group with inversion
of stereochemistry to produce 5, with nonbasic nitrogen in
the azide functional group.12 Treatment of this glycal 5 with
hot aqueous acid13 effected one-pot hydrolysis of vinyl ether
and cleavage of MOM ether to produce the diol, which was
acylated to generate 6 as the angolosamine glycosyl donor.
Likewise, the synthesis of L-vancosamine synthon 10 began
with alkynol cycloisomerization of 7 to 8.10,14 N-Methylation
of 8 was complicated by formation of bicyclic carbamate
9,15 which could be prevented by using exactly one equiva-
Introduction of vancosamine was also explored with
several substrates, with C11 phenol 16 as a representative
example (Scheme 2).19,20 Initial results in SnCl4-promoted
glycosylation with vancosamine synthon 10 provided a
mixture of C10-glycoside anomers 17 and 18,18 with the
(5) (a) Furukawa, M.; Iitaka, Y. Tetrahedron Lett. 1974, 15, 3287. (b)
Furukawa, M.; Hayakawa, I.; Ohta, G.; Iitaka, Y. Tetrahedron 1975, 31,
2989.
(13) Meyers, A. I.; Durandetta, J. L.; Munavu, R. J. Org. Chem. 1975,
40, 2025.
(6) Hauser, F. M.; Rhee, R. P. J. Org. Chem. 1980, 45, 3061.
(7) Fei, Z.; McDonald, F. E. Org. Lett. 2005, 7, 3617.
(8) (a) Dubois, E.; Beau, J.-M. Carbohydr. Res. 1992, 228, 103. (b)
Parker, K. A.; Koh, Y.-h. J. Am. Chem. Soc. 1994, 116, 11149. (c) Kaelin,
D. E.; Lopez, O. D.; Martin, S. F. J. Am. Chem. Soc. 2001, 123, 6937. (d)
Kaelin, D. E.; Sparks, S. M.; Plake, H. R.; Martin, S. F. J. Am. Chem. Soc.
2003, 125, 12994. (e) Yamauchi, T.; Watanabe, Y.; Suzuki, K.; Matsumoto,
T. Synthesis 2006, 2818.
(9) (a) McDonald, F. E.; Reddy, K. S.; D´ıaz, Y. J. Am. Chem. Soc. 2000,
122, 4304. (b) Koo, B.; McDonald, F. E. Org. Lett. 2007, 9, 1737.
(10) See Supporting Information for details on the preparation of alkynyl
alcohols 3 and 7.
(14) Cutchins, W. W.; McDonald, F. E. Org. Lett. 2002, 4, 749.
(15) Parker, K. A.; Chang, W. Org. Lett. 2003, 5, 3891.
(16) Lam, S. N.; Gervay-Hague, J. Org. Lett. 2003, 5, 4219.
(17) (a) Matsumoto, T.; Katsuki, M.; Suzuki, K. Tetrahedron Lett. 1989,
30, 833. (b) Kuribayashi, T.; Ohkawa, N.; Satoh, S. Tetrahedron Lett. 1998,
39, 4537. (c) Kuribayashi, T.; Ohkawa, N.; Satoh, S. Tetrahedron Lett.
1998, 39, 4541. (d) Shuto, S.; Horne, G.; Marwood, R. D.; Potter, B. V. L.
Chem.-Eur. J. 2001, 7, 4937.
(18) See Supporting Information for more details on the positional and
stereochemical assignments for C-glycosylation products.
(19) Compound 12 arose from an unsuccessful attempt to remove methyl
ethers from 11 with AlCl3/EtSH (ref 20).
(11) Thompson, A. S.; Humphrey, G. R.; DeMarco, A. M.; Mathre, D.
J.; Grabowski, E. J. J. J. Org. Chem. 1993, 58, 5886.
(12) Parker, K. A.; Ding, Q.-j. Tetrahedron 2000, 56, 10255.
(20) Node, M.; Nishide, K.; Fuji, K.; Fujita, E. J. Org. Chem. 1980, 45,
4275.
3548
Org. Lett., Vol. 9, No. 18, 2007

Scheme 2. Glycosylations of Anthrapyrans 11, 12, and 16
formation of equatorially substituted 18 attributed to Lewis
reaction temperature increased stereoselectivity as well as
the isolated yield for production of 17,21 but under these
conditions, we also observed formation of the para-C8-
glycoside isomer 19, characterized by the absence of the C8
hydrogen and the presence of the C10 hydrogen in com-
parison with compounds 16-18.18
At this stage, we modified our aglycone synthesis to
introduce an additional hydroxyl substituent at C9, which
might be advantageous in more easily forming C-glycosides
at C8 as well as C10. Ortho-lithiation22 of amide 21 and
addition to the aldehyde 22, followed by desilylation,
acid catalyzed anomerization in a mechanism analogous to
that proposed for the isomerization of kidamycin (1) to
isokidamycin (2). The positional selectivity for this glyco-
sylation at C10 was evident by the disappearance of the C10
hydrogen resonance in the formation of compounds 17 and
18, and the anomeric stereochemistry was assigned in
analogy with kidamycin (1) and isokidamycin (2), with the
1
anomeric H resonance of δ 5.48 for 17 consistent with a
pseudoequatorial hydrogen, relative to the shielded pseudo-
axial anomeric hydrogen of 18 at δ 5.09. Lowering the
Scheme 3. Synthesis of Anthrapyrans Bearing a 9-Hydroxyl Substituent
Org. Lett., Vol. 9, No. 18, 2007
3549

Scheme 4. Bisglycosylations of 9-Hydroxyl-Substituted Anthrapyrans 30 and 31
provided the lactone 23. The phenol of 23 underwent
amine unit,18 as well as the white color of product 33,
consistent with interruption of conjugation in the C ring at
C7. Thus, the aglycone substrate 31 without protective groups
at either C9 or C11 phenols was subjected to glycosylation
with angolosamine donor 6, providing C8-glycoside 34 in
good yield, which in turn underwent regio- and stereoselec-
tive glycosylation with vancosamine synthon 10 to provide
the C10-glycoside 35,18 possessing a meta-bisglycosylated
anthrapyran with considerable structural similarity to kida-
mycin (1).
Although we have not yet completed the synthesis of
kidamycin, we have demonstrated a number of interesting
and informative glycosylation transformations which have
culminated in the successful preparation of the bis-C-
arylglycoside 35 closely corresponding to most of the
structural features of kidamycin. Continuing efforts will focus
on completing the total synthesis either from the doubly
glycosylated intermediate 35 or, less aggressively, by remov-
ing the C9 oxygen from intermediate 34 prior to the second
glycosylation to introduce the C-vancosamine glycoside.
addition-elimination23 with â-chlorodienoate (24)7,24 to form
compound 25, although forcing conditions were required as
phenolate reactivity was diminished due to conjugation with
the ester carbonyl. Reductive opening of the doubly benzylic
C7 lactone also resulted in removal of the isopropyl ethers,
but global O-benzylation of both phenols and the carboxylic
acid provided 26, which was easily purified. After saponi-
fication of both esters to dicarboxylic acid 27, double
Friedel-Crafts cyclization25 provided the anthrapyran 28,
which was converted into a variety of O-protected congeners
29-31 (Scheme 3).
Glycosylation was first conducted with the bromoethyl
ether protected 30 bearing a single phenol at C9, which was
anticipated to direct ortho-C-glycosylation26 at both C8 and
C10. Introduction of angolosamine synthon 6 proceeded in
good yield and with apparent complete stereo- and regiose-
lectivity for C8-glycosylation17,18 in product 32 (Scheme 4).
However, the attempted introduction of vancosamine via the
C9-hydroxyl group instead provided the surprising result of
C7-glycosylation to provide the anthrone 33, which was
Acknowledgment. This research was supported by the
National Institutes of Health (R01 CA59703). 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), as well as the
University Research Committee of Emory University (po-
larimeter).
1
characterized by observation of H-1H coupling between
the C7 hydrogen and the anomeric hydrogen of the vancos-
(21) The C-vancosamine glycosylation product 17 undergoes partial
anomerization to a mixture of 17 and 18 upon the prolonged reaction time
or higher temperature required for complete conversion of starting materials.
(22) Falk, H.; Mayr, E. Monatsh. Chem. 1995, 126, 699.
(23) (a) Hormi, O. E. O. J. Org. Chem. 1988, 53, 880. (b) Hormi, O. E.
O.; Hirvela, L. Tetrahedron Lett. 1993, 34, 6463.
(24) Andrews, J. F. P.; Regan, A. C. Tetrahedron Lett. 1991, 32, 7731.
(25) (a) Bycroft, B. W.; Roberts, J. C. J. Chem. Soc. 1963, 4868. (b)
Devos, A.; Frisque-Hesbain, A.-M.; Colens, A.; Ghosez, L. J. Chem. Soc.,
Chem. Commun. 1979, 1180.
(26) (a) Matsumoto, T.; Maeta, H.; Suzuki, K.; Tsuchihashi, G.-i.
Tetrahedron Lett. 1988, 29, 3567. (b) Matsumoto, T.; Katsuki, M.; Suzuki,
K. Tetrahedron Lett. 1988, 29, 6935. (c) Matsumoto, T.; Hosoya, T.; Suzuki,
K. Tetrahedron Lett. 1990, 31, 4629. (d) Ben, A.; Yamauchi, T.; Matsumoto,
T.; Suzuki, K. Synlett 2004, 225.
Supporting Information Available: Experimental pro-
cedures and characterization data for new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL7014219
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Org. Lett., Vol. 9, No. 18, 2007