Total synthesis of isokidamycin

Article abstract of DOI:10.1021/ja107926f

The synthesis of isokidamycin, which represents the first total synthesis of a bis-C-aryl glycoside natural product in the pluramycin family, has been completed. The synthesis features the use of a silicon tether as a disposable regiocontrol element in an intramolecular Diels-Alder reaction between a substituted naphthyne and a glycosyl furan and a subsequent O→C-glycoside rearrangement.

Full text of DOI:10.1021/ja107926f

Published on Web 10/19/2010
Total Synthesis of Isokidamycin
B. Michael O’Keefe, Douglas M. Mans,† David E. Kaelin, Jr,‡ and Stephen F. Martin*
Department of Chemistry and Biochemistry, The UniVersity of Texas, Austin, Texas 78712
Received September 2, 2010; E-mail: sfmartin@mail.utexas.edu
Abstract: The synthesis of isokidamycin, which represents the
first total synthesis of a bis-C-aryl glycoside natural product in
the pluramycin family, has been completed. The synthesis
features the use of a silicon tether as a disposable regiocontrol
element in an intramolecular Diels-Alder reaction between a
substituted naphthyne and a glycosyl furan and a subsequent
OfC-glycoside rearrangement.
Kidamycin (1) is a member of the pluramycin class of C-aryl
glycoside antibiotics that was isolated from Streptomyces phae-
oVerticillatus and displays a broad range of antibacterial, antifungal,
and anticancer properties.1 Like other pluramycins, 1 binds to DNA,
leading to single strand cleavage.2 Kidamycin possesses an angular
anthrapyranone tetracyclic core that is adorned with a ꢀ-an-
golosaminyl C-glycoside substituent at C(8) and an R-N,N-
dimethylvancosaminyl C-glycoside group at C(10).3 Kidamycin (1)
is both light and acid sensitive and is easily transformed into
isokidamycin (2) upon treatment with acid.3a,4 No doubt owing to
their complex structures and labile functionality, none of the bis-
C-arylglycoside antibiotics of the pluramycin family have suc-
cumbed to total synthesis. Indeed, few have even dared to embark
on such a challenging enterprise.5
Figure 1. Retrosynthesis of kidamycin (1) and isokidamycin (2).
Several years ago we reported a unified strategy for preparing
the four major classes of C-aryl glycoside antibiotics.6 The approach
relies on the ring opening of glycosyl-substituted oxabicycles that
are produced by the Diels-Alder reactions of substituted arynes
with glycosyl furans. A significant feature of this novel entry to
C-aryl glycosides is that it couples the introduction of the C-aryl
glycoside moiety with the annelation of a new aromatic ring, thereby
leading to a rapid increase in complexity. We subsequently applied
this method to the syntheses of several C-aryl glycoside natural
products.7 However, we wished to extend this methodology to the
synthesis of a more complex member of the pluramycin family.
We now report our efforts in this area that resulted in the total
synthesis of isokidamycin (2), the first bis-C-arylglycoside antibiotic
to be prepared by total synthesis.
lecular naphthyne-furan cycloaddition that would be initiated
by reductive dehalogenation of 5, which would be assembled
via the union of the substituted naphthalene 6 and the protected
amino glycosyl furan 7.
The preparation of 7 began with the Friedel-Crafts alkylation
of furan with the known mixture of azidoacetates 9,9 which were
obtained from commercially available glycal 8 and subsequent
saponification of the acetate moiety of the intermediate furyl
glycoside to deliver 10 in 60% overall yield (Scheme 1). A
straightforward four-step sequence involving protection of the
Scheme 1a
The essential elements of our approach to kidamycin are outlined
in Figure 1. Given the known propensity for the N,N-dimethyl-
vancosamine moiety at C(10) of 1 to suffer epimerization at the
anomeric center to give 2, we favored the late stage introduction
of this residue from the advanced intermediate 3 using the OfC-
glycoside rearrangement that had been pioneered by Suzuki and
had been shown to be applicable to the preparation of some R-C-
aryl glycosides.8 We envisioned that anthrol 3 would be accessible
from 4 by cleavage of the disposable silicon tether, ring opening
of the oxabicycle, and annelation of the substituted pyranone ring.
Intermediate 4 would then be formed by the pivotal intramo-
a Reaction conditions: (a) BF3 ·OEt2, furan, MeCN, 78%; (b) K2CO3,
MeOH, 60%; (c) BnBr, NaH, DMF; (d) LiAlH4, Et2O; (e) Boc2O, CH2Cl2;
(f) MeI, NaH, DMF, 90% (4 steps); (g) s-BuLi, THF, -78 f -50 °C;
chlorodimethylvinylsilane, -78 °C, 82%; (h) 9-BBN, THF; H2O2, NaOH,
84%.
† Current address: Glaxo Smith Kline, 709 Swedeland Rd., King of Prussia,
PA 19406.
‡ Current address: Merck & Co., Inc., 126 E. Lincoln Ave., Rahway, NJ 07065.
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C O M M U N I C A T I O N S
secondary alcohol in 10, reduction of the azide, protection of the
resultant primary amine, and N-methylation gave the carbamate 11
in 90% overall yield. The silicon tether, which was to be utilized
as the key regiocontrol element in the planned cycloaddition, was
then installed by reaction of the lithiated derivative of the glycosyl
furan 11 with chlorodimethylvinylsilane to give 12, and subsequent
hydroboration/oxidation delivered 7.
The synthesis of the substituted naphthol 6 commenced with
O-benzylation of the known naphthoquinone 1310 (Scheme 2).
Sequential bromination and dehydrobromination transformed 13 into
14, which underwent a second bromination and dehydrobromination
to provide the dibromonaphthoquinone 15. Reduction of the quinone
moiety and selective methylation of the sterically less hindered
hydroxyl group furnished naphthol 6 in 90% yield.
envisioned that 18 might be converted into 19 via a carbonylative
cross-coupling reaction that we had developed for transforming
hindered aryl halides into acetylenic ketones;13 however, all attempts
to extend this method to the problem at hand were unsuccessful.
On the other hand, subjection of 18 to metal-halogen exchange,
followed by trapping of the resultant aryl anion with aldehyde 20
and oxidation with BaMnO4, furnished ketone 19 in 72% overall
yield. Formation of the pyranone ring was then achieved by the
Lewis acid promoted cyclization of an intermediate vinylogous
diethylamide; subsequent removal of the phenolic TIPS protecting
group afforded 3 in about 50% overall yield from 19.
Scheme 4a
Scheme 2a
a Reaction conditions: n-BuLi, THF, -78 °C, 20 s; then (E)-4-methylhex-
4-en-2-ynal (20), 75%; (b) BaMnO4, PhH, 96%; (c) Et2NH, EtOH, >99%;
(d) LiBF4, 5% aq. MeCN, 82 °C, µW, 15 min; TBAF, THF, 0 °C, 50%.
a Reaction conditions: (a) BnBr, Ag2O, CHCl3, 91%; (b) Br2, CH2Cl2,
then NEt3, 97%; (c) PyHBr3, CH2Cl2, 0 °C, 90%; (d) Na2S2O4, CH2Cl2,
Et2O, H2O; Me3OBF4, proton sponge, 4 Å molecular sieves, CH2Cl2, 90%.
The stage was then set for introducing a vancosamine subunit
onto 3 via a OfC-glycoside rearrangement. It was first necessary
to prepare a suitable glycosyl donor, and we targeted 22 because
the protecting group strategy we had adopted was originally
designed to enable the simultaneous deprotection of multiple
functional groups later in the synthesis. Although there are de noVo
syntheses of vancosamine derivatives,14 we elected a more expedi-
ent approach that simply entailed degrading vancomycin by
straightforward modification of an established protocol,15 thereby
obtaining the vancosamine donor 22 as a mixture (10:1) of R- and
ꢀ-anomers, respectively, in 76% overall yield (Scheme 5).
The union of the requisite hydroquinone 6 and glycosyl furan 7
was achieved via a facile Mitsunobu etherification to give the key
intermediate 5 in 92% yield, thereby setting the stage for the key
intramolecular Diels-Alder reaction (Scheme 3). In the event,
dropwise addition of n-BuLi to a solution of 5 in THF at -25 °C
delivered oxabicycle 4 as a mixture of diastereomers in 92% yield.
Subsequent removal of the silicon tether and O-methylation of the
resultant naphthol gave 16. Treatment of 16 with TMSOTf induced
the opening of the oxabicyclic ring with concomitant cleavage of
the N-tert-butyl carbamate protecting group to furnish anthrol 17
in 85% yield. Processing of 17 by reductive N-methylation, TIPS
protection of the anthrol, chemoselective hydrogenolysis of the
phenolic benzyl group,11 ortho-bromination, and MOM protection
of the intermediate anthrol provided 18 in 47% overall yield.
Scheme 5a
Scheme 3a
a Reaction conditions: Cbz-O-Succ, NaHCO3, dioxane, H2O; (b) HCl,
MeOH, 89% (2 steps); (c) HOAc, H2O, 100 °C, 71%; (d) Ac2O, pyridine,
DMAP, CH2Cl2, 85%.
We were cognizant of the fact that there were only a few
examples of OfC-glycoside rearrangements that delivered R-C-
aryl glycosides, because the highly Lewis acidic reaction conditions
typically promotes epimerization of the kinetically formed R-gly-
coside to the thermodynamically more stable ꢀ-C-aryl glycoside.5c,16
In exploratory work using model systems, we experienced some
success in intercepting the desired R-anomer of a vancosamine-
derived C-arylglycoside. However, these model studies did not
transfer to the real system. Namely, when anthrol 3 and the
vancosamine donor 22 were coupled using a number of Lewis acid
promoters, the ꢀ,ꢀ-bis-C-aryl glycoside was the major, if not
exclusive, product. After extensive experimentation and optimiza-
tion, we discovered that reaction of 3 and 22 in the presence of
Sc(OTf)3 as the promoter, followed by O-acetylation of the
intermediate phenol, furnished 23 in about 80% overall yield
(Scheme 6); none of the desired R-anomer was detected. Although
the adverse stereochemical outcome of this reaction would not
enable us to complete the total synthesis of kidamycin (1), our
disappointment was attenuated by the realization that 23 might serve
as a viable precursor of isokidamycin (2).
a Reaction conditions: (a) DIAD, PPh3, toluene, 92%; (b) n-BuLi, THF,
-25 °C, 92%; (c) TBAF ·3H2O, DMF, 70 °C; MeI, NaH, 0 °C, 85%; (d)
TMSOTf, 2,6-tBu2Py, CH2Cl2, 0 °C f rt, 85%; (e) formalin, NaBH(OAc)3,
DCE, 95%; (f) TIPSOTf, 2,6-lutidine, CH2Cl2, 80%; (g) H2, Pd(OH)2/C
(20 mol %), pyridine, MeOH, EtOAc, 90%; (h) NBS, CH2Cl2, -78 °C f
rt, 77%; (i) MOMCl, NaH, THF, 89%.
At this juncture, it was necessary to annelate a pyranone ring,
and we opted for an approach entailing the cyclization of a phenolic
acetylenic ketone derived from 18 (Scheme 4).12 We originally
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C O M M U N I C A T I O N S
Scheme 6a
of McDonald suggests that the application of OfC-glycoside
rearrangements involving other vancosamine derivatives might lead
to a solution to this problem. Further applications of our general
approach to complex C-aryl glycoside natural products are in
progress, and the results of these investigations will be reported in
due course.
Acknowledgment. We thank the National Institutes of Health
(GM31077) and the Robert A. Welch Foundation (F-652) for
generous support of this research. We are grateful to Eli Lilly and
Abbott Laboratories for their generous gifts of vancomycin•HCl.
We also thank Prof. Urs Se´quin (Univ. of Basel, Switzerland) for
providing authentic samples of 1 and 2 for comparison. We also
thank Yoshitaka Ichikawa (Kyoto University) for the preparation
of starting materials.
Supporting Information Available: Experimental procedures and
spectral data for compounds 2-5, 7, 10, 12, 16, 17, 19, 20, 23, 24;
copies of 1H and 13C NMR spectra for all new compounds; and a tabular
comparison for synthetic 2 with an authentic sample. This material is
available free of charge via the Internet at http://pubs.acs.org.
a Reaction conditions: 22 (4 equiv), Sc(OTf)3, Drierite, DCE, -30 f 0
°C, 67 h, 80%; (b) Ac2O, pyridine, DMAP, CH2Cl2, >99%; (c) BBr3,
CH2Cl2, -90 °C; TMSI, 2,6-tBu2Py, CH2Cl2, 0 °C, then MeOH, pH ) 7
phosphate buffer; NaCNBH3, formalin, HOAc, MeOH, CH2Cl2; K2CO3,
MeOH, 3 h; MeOH, 3 d, 39%; (d) Ce(SO4)2, MeCN, H2O (9:1), 0 °C, 51%.
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