Studies toward the total synthesis of pluraflavin A

Article abstract of DOI:10.1002/chem.201402254

A synthetic strategy towards the potent cytostatic agent pluraflavin A has been developed. Formation of the enantioenriched anthrapyran core bearing a halogen atom enabled the introduction of the α C-aryl glycoside by Stille cross-coupling and subsequent hydrogenation of the aryl glycal. Chemo- and stereoselective O-glycosylations of α oliose and β 3-epi vancosamine residues afforded a fully glycosylated aromatic core. Attempts to install the dimethylamino group of the C-disaccharide suggest that introduction of an azide group by displacement and subsequent reduction may pave the way to the total synthesis of pluraflavin A.

Full text of DOI:10.1002/chem.201402254

DOI: 10.1002/chem.201402254
Full Paper
&
Natural Product Synthesis
Studies Toward the Total Synthesis of Pluraflavin A
John Hartung,[a] Benjamin J. D. Wright,[a] and Samuel J. Danishefsky*[a, b]
Abstract: A synthetic strategy towards the potent cytostatic
agent pluraflavin A has been developed. Formation of the
enantioenriched anthrapyran core bearing a halogen atom
enabled the introduction of the a C-aryl glycoside by Stille
cross-coupling and subsequent hydrogenation of the aryl
glycal. Chemo- and stereoselective O-glycosylations of a o-
liose and b 3-epi vancosamine residues afforded a fully gly-
cosylated aromatic core. Attempts to install the dimethyla-
mino group of the C-disaccharide suggest that introduction
of an azide group by displacement and subsequent reduc-
tion may pave the way to the total synthesis of pluraflavin
A.
Introduction
tion of the pluramycins’ mechanism of action was provided by
Hurley’s study of the covalent modification of DNA by altromy-
cin B.[9] Ultimately, a consensus as to the general mode of
action of these natural products has been put forward involv-
ing nucleophilic attack of N7 of guanine onto the C14/C15 ox-
irane ring, resulting in DNA damage and subsequent cell
death.[10]
The first member and namesake of a family of antibiotics
known as the pluramycins was discovered in 1956 (1,
Figure 1).[1] Since then, a large collection of pluramycins have
been isolated and structurally characterized (Figure 1).
Amongst the structural characteristics that are conserved in
most members of this family, an anthrapyran core bearing C-
glycosidic appendages is both a necessary component for its
mechanism of biological activity and a synthetic roadblock to
assembling these targets in the laboratory. Thus, despite the
rapid discovery of many new entries in this natural product
family, there are relatively few approaches to their synthesis.
Efforts toward the synthesis of anthrapyran antibiotics have
culminated in the total synthesis of the aglycones of altromy-
cin (2) and kidamycin,[2] the indomycinones,[3] espicufolin,[4] and
related products.[5] Notably, the Martin group completed a syn-
thesis of the glycosylated pluramycin, isokidamycin (3), which
featured the application of a benzyne–furan cycloaddition to
append the C-glycosidic residue.[6]
In 2001, Vꢀrtesy and co-workers reported the isolation of
several new natural products from cultures of Saccharothrix sp.
DSM 12931 (4–6, Figure 1).[11] Due to their structural similarities
to the pluramycin family, the newly isolated products were
named the pluraflavins. The pluraflavins’ structures consist of
an anthrapyran core with appendages at the C2, C5, and C10
positions. The C-linked disaccharide, conserved amongst the
pluraflavins, is composed of a(1–4) oliose and a C-linked rho-
dosamine residues. Pluraflavins A and B possess a hydroxy-
methyl group at C5 bearing a b 3-epi vancosamine residue.
While pluraflavin A bears a trans epoxide at C2, its congeners
contain a diol of unknown relative and absolute stereochemis-
try. While the stereochemical relationships within the side
chains of pluraflavin A were determined by 2D NMR spectros-
copy, the absolute configurations of the widely separated sec-
tors with respect to each other remain undetermined. Total
synthesis of the putative structure and related structures bear-
ing enantiomeric side chains will enable definitive structural
elucidation; the current study employs D sugars.
In addition to antibiotic activity against gram-positive bacte-
ria, the isolation team found that the epoxide-bearing isolate,
pluraflavin A, demonstrated potent cytostatic activity against
a number of human cancer cell lines. Given our group’s long-
standing interest in the application of total synthesis to cancer
chemotherapy and the challenge posed by the architecture of
pluraflavin A, we embarked on the synthesis of this intriguing
molecule.
The pluramycins’ cytotoxic activity became apparent when
White and White identified both reversible interactions with
and irreversible modification of DNA by rubiflavin and hedamy-
cin.[7] Further research clarified this early work and assigned
the strong reversible interaction as intercalative in nature and
the irreversible modification a covalent attachment formed by
reaction with the epoxide group of the side chain.[8] Elucida-
[a] Dr. J. Hartung, Dr. B. J. D. Wright, Prof. Dr. S. J. Danishefsky
Department of Chemistry, Columbia University
3000 Broadway, New York, NY 10027 (USA)
[b] Prof. Dr. S. J. Danishefsky
Memorial Sloan-Kettering Cancer Center
1275 York Avenue, New York, NY 10065 (USA)
Fax: (+1)212-772-8691
Inspection of the pluraflavins’ structure suggested a few key
problems that would have to be solved before a successful
total synthesis could be carried out. In particular, the highly
functionalized aromatic core, epoxide side chain, and position
E-mail: s-danishefsky@ski.mskcc.org
Supporting information, which contains experimental details and com-
pound characterization, is available on the WWW under http://dx.doi.org/
10.1002/chem.201402254.
Chem. Eur. J. 2014, 20, 1 – 7
1
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Full Paper
Figure 1. Structures of representative pluramycins.
and orientation of the C-glycosidic bond in pluraflavin A pose
a formidable synthetic challenge. Our first subgoal was thus to
accomplish the synthesis of a suitable “aglycone,” which would
serve as a platform for the installation of the glycosidic appen-
dages. We were successful in accomplishing this goal and, in
the process, developed an approach featuring a key [3+2] cy-
cloaddition to form a functionalized isoxazoline, which could
be conferred into the pyrone ring of the natural structure.[12]
We describe herein an asymmetric synthesis of a late-stage in-
termediate en route to pluraflavin A.
The synthetic plan that previously succeeded in furnishing
the racemic pluraflavin A aglycone[12] has presently been
adapted to provide enantioenriched material (Scheme 1). Ac-
cordingly, the synthesis of [3+2] cycloaddition partner 8 was
modified to produce enantioenriched material by application
of the Sharpless asymmetric dihydroxylation.[13] Addition of
enantioenriched 8 to the nitrile oxide derived from 7, resulted
in cycloaddition to form isoxazoline 9 as an inconsequential
mixture of diastereomers. Cleavage of the NꢀO bond and hy-
drolysis of the resultant b-hydroxy imine proceeded in 68%
yield with Raney nickel and boric acid.[14]
Initial attempts to oxidize the b-hydroxy ketone were unsuc-
cessful. Treatment with pyridinium dichromate, pyridinium
chlorochromate, or tetrapropylammonium perruthenate and 4-
methylmorpholine-N-oxide all resulted in clean recovery of
starting material. At first, iodoxybenzoic acid (IBX) in ethyl ace-
tate appeared to be ineffective, but an increase in temperature
improved the rate of reaction. The insolubility of IBX in ethyl
acetate likely contributed to the lack of reaction at room tem-
perature. An optimized procedure (IBX, 658C, one recycle of
starting material.) furnished an 82% yield of the b-diketone
product 10. Cyclization of 10 in acetate buffer furnished the
pyrone of 11 in 86% yield.
A high-yielding (56% over seven steps) sequence converted
11 to the epoxide-containing intermediate 12. Treatment with
hydrochloric acid removed the acetonide and methoxymethyl
ether to afford a highly insoluble triol. The vicinal diol group-
ing was reprotected as the acetonide with inevitable formation
of the mixed ketal on the southeast alcohol. The mixed ketal
could be selectively hydrolyzed owing to its greater instability
in acid. Protection of the resultant benzylic alcohol with benzo-
yl chloride and pyridine afforded the benzoate. Treatment of
acetonide with HCl unveiled the cis diol, which was converted
to the trans epoxide in 60% yield by monomesylation and in-
tramolecular displacement with potassium carbonate. Finally,
CAN oxidation afforded intermediate 12.
Results and Discussion
In our global strategy, the aromatic core would be constructed
in the BC!ABC!ABCD direction. However, in contrast to the
prior syntheses of anthrapyran natural products, we decided to
store what would eventually become the A ring in the form of
an appropriately substituted isoxazoline intermediate. A subse-
quent ring-cleavage and oxidation reaction sequence would
unveil the desired b-diketone, which would readily condense
onto a phenol to form the pyrone ring of pluraflavin A. This
approach had the added benefit that formation of the isoxazo-
line could function as the union of the aromatic core and the
side chain that would eventually contain the epoxide.
Motivated by the success of this strategy, we devised a plan
for the total synthesis of pluraflavin A (Scheme 2). We antici-
pated that the Diels–Alder cycloaddition could be used to
form the C10 halogenated D ring. This modification of our
original route to the pluraflavin aglycone, which took advant-
age of a known chlorojuglone synthesis to supply ample
amounts of starting material,[15] would aid in the stereoselec-
tive installation of the C-glycoside. Subsequent O-glycosyla-
Scheme 1. Synthesis of Diels–Alder precursor 12. Reaction conditions: a) 8
(2 equiv), chloramine-T, CH2Cl2/EtOH/H2O, 508C, 81%; b) Raney-Ni, B(OH)3, H2
(1 atm), EtOH/H2O, 68%; c) IBX, EtOAc, 658C, one starting material recycle,
82%; d) NaOAc, AcOH, 808C, 86%; e) HCl, THF/MeOH, 508C; f) 2,2-dimethox-
ypropane, pTsOH, acetone; g) AcOH/H2O; h) BzCl, Et3N, CH2Cl2, 08C, 86%
(over four steps); i) HCl, THF/MeOH, 508C; j) MsCl, iPr2NEt, CH2Cl2, 08C;
k) K2CO3, MeOH/THF, 08C, 60% (over three steps); l) CAN, 08C. Bz=benzoyl,
CAN=cerium ammonium nitrate, IBX=2-iodoxybenzoic acid, MOM=me-
thoxymethyl, Ms=methanesulfonyl, Ts=toluenesulfonyl.
&
&
Chem. Eur. J. 2014, 20, 1 – 7
www.chemeurj.org
2
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Full Paper
Scheme 2. Synthetic plan. TBS=tert-butyldimethylsilyl.
tions to append the oliose and 3-epi vancosamine residues
would proceed with judicious choice of mild glycosylation con-
ditions. Having accomplished introduction of the full comple-
ment of carbohydrate domains, a sequence to install the dime-
thylamino group onto the proximal C-glycosidic residue and
globally deprotect the resultant product would produce plura-
flavin A, itself.
With a viable approach to significant quantities of enan-
tioenriched tetracyclic core, we focused on the task of synthe-
sizing the halogenated pluraflavin A aglycone. It was conclud-
ed that a halogen atom would be a versatile precursor to in-
vestigate transition-metal-mediated transformations and could
be readily accommodated on a 1,3-butadiene fragment.[16]
Thus, the known[17] 2-bromo-1-trimethylsiloxy-1,3-butadiene
(13) was synthesized by treatment of 2-bromo crotonaldehyde
with a mixture of sublimed zinc chloride in triethylamine and
trimethylsilyl chloride. It was predicted that the regiochemistry
of Diels–Alder cycloaddition with chloroquinone 12 would be
governed by the substitution patterns on both reaction part-
ners. It has been shown that electron-releasing substituents on
C1 of 1,3-butadiene exert a stronger influence over the regio-
chemistry in Diels–Alder cycloadditions than substituents on
C2.[18] Moreover, the chloride substituent on the quinone dien-
ophile has been shown to bias bond formation at the distal
carbon atom.[19] The combination of these reactants was pre-
dicted to form a cycloadduct possessing the desired regio-
chemistry.
Scheme 3. Completion of the bromo “aglycone.” Reaction conditions: a) 13
(6 equiv), 1008C, toluene; b) Jones reagent, KF, acetone, 08C, 2 days; c) Et3N,
1 h, 52% (over three steps); d) benzoyl chloride, pyridine, CH2Cl2, 08C, 87%.
TMS=trimethylsilyl.
linked disaccharide residue. Glycal 20 (Scheme 4) was prepared
by adaptation of a known route (see the Supporting Informa-
tion for more details).[22] The silylated 6-deoxy glycal 20 was
metalated with Schlosser’s base[23] and quenched with excess
tributylstannyl chloride to yield the desired C1 stannylated
product. The triisopropylsilyl groups were required for success-
ful metalation; attempts with tert-butyldimethylsilyl groups re-
sulted in recovery of starting material.[24] Removal of the TIPS
groups with TBAF and selective monosilylation under standard
conditions provided the C3 protected stannyl glycal 21. Stille
In line with our hypothesis, cycloaddition of 13 and chloro-
quinone 12 proceeded cleanly to form a single adduct (17).
However, treatment of the cycloadduct with standard oxida-
tion/aromatization conditions yielded the deoxygenated prod-
uct 18.[20] While the Jones reagent is widely employed for the
desilylative oxidation of secondary alcohols, Diels–Alder adduct
17 was resistant to the reaction conditions. The subsequent ar-
omatization of 17 to form the aromatic D ring required that
the Jones oxidation be conducted in the presence of potassi-
um fluoride.[21] We propose that fluoride ion most likely assists
the desilylation of the trimethylsilyl ether to provide the alco-
hol in situ, which is converted to the unsaturated ketone by
the agency of chromic acid. Treatment of the crude oxidation
product with triethylamine provided the phenol 19 in 52%
yield over three steps. Subsequent protection of the free
phenol under standard conditions afforded the benzoylated ar-
omatic core (14) in 87% yield (Scheme 3).
Scheme 4. Glycosyl donor synthesis and Stille coupling. Reaction conditions:
a) nBuLi, KOtBu, Bu3SnCl, THF, ꢀ78–238C, 82%; b) TBAF, THF, 0–238C;
c) TBSCl, imidazole, DMF, 49% (over two steps); d) 21 (2 equiv), [Pd(tBu3P)2]
(10 mol%), 808C, 80%; e) K2CO3, CH2Cl2/MeOH, 0–238C; f) TBSCl, imidazole,
DMF, 73% (over two steps). TBAF=tetra-n-butylammonium fluoride, TIP-
S=triisopropylsilyl.
With the functionalized aromatic core in hand, our next ob-
jective was the synthesis of a carbohydrate precursor to the C-
Chem. Eur. J. 2014, 20, 1 – 7
www.chemeurj.org
3
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Full Paper
coupling of 14 with the monoprotected stannyl glycal 21 cata-
lyzed by bis(tri-tert-butylphosphine) palladium[25] proceeded
rapidly (30 min) and afforded 22 in 72% yield.[26]
which could be used to form the a C-aryl glycoside of plurafla-
vin A.
Encouraged by the results of the model study, we sought to
transform glycal 23 into the desired a glycoside. Low solubility
of 23 in hexanes precluded the use of this solvent, and toluene
was required to achieve any reactivity. Heterogeneous hydro-
genation of 23 afforded a 3:1 mixture of aryl C-glycosides 26
favoring the desired a isomer (Scheme 6). The dimethyl ketal
conferred stability during reduction of the glycal double bond
as compared to substrates lacking this protecting group. Con-
version of the dimethyl ketal into the corresponding carbonyl
occurred cleanly when 26 was stirred with silica gel at elevated
temperature for 34 h. Protection of the phenol with allyl bro-
mide in the presence of cesium carbonate provided 15. Alkyla-
Initial attempts to hydrogenate compound 22 resulted in
hydrogenolysis of the southeast benzyl ester. Accordingly, the
protecting group scheme was altered to avoid the formation
of this product. Treatment of 22 with potassium carbonate in
methanol and dichloromethane resulted in clean formation of
the debenzoylated dimethyl ketal. Selective protection of the
primary hydroxyl as its tert-butyldimethylsilyl derivative afford-
ed an intermediate (23) better suited for the investigation of
the glycal reduction step.
Given the thermodynamic preference for formation of the
undesired b C-glycoside, due to the absence of stabilization af-
forded by the anomeric effect, we considered approaches for
the directed functionalization of the glycal double bond. It was
proposed that coordination of a suitable reagent with the free
C4 hydroxyl would override the strong preference and afford
the desired a glycoside. Initial studies were conducted on
a simple model system, bearing an identical protecting group
scheme and an unfunctionalized naphthalene ring.
Model glycal 24, which possesses a free hydroxyl group at
C4, presented an opportunity to conduct a hydroxyl-directed
homogeneous hydrogenation.[27] However, treatment of 24
with [Rh(PPh3)3Cl] or [Ir(cod)PCy3(pyr)]PF6 under high H2 pres-
sures resulted in recovery of starting material. It was discov-
ered that heterogeneous conditions (Pd/C, H2) were more ef-
fective at reducing the glycal double bond (Scheme 5). A rela-
tionship between solvent polarity and stereoselectivity was ob-
served (Table 1). An equal amount of both stereoisomers 25a
and 25b formed in methanol. In less polar media, hydrogena-
Scheme 6. Stereoselective reduction of C-aryl glycal and oliose glycosylation.
Reaction conditions: a) Pd/C (10%), H2 (1 atm), toluene, 60% (3:1 a/b);
b) SiO2, C6H6, 408C, 83%; c) allyl bromide, Cs2CO3, DMF/acetone, 08C, 60%;
d) 27 (4 equiv), AgPF6, 2,6-tert-butyl-3-methyl pyridine, 4 ꢂ MS, CH2Cl2, 08C,
83% (yield after desilylation to 33).
tion yields were improved by employing a large excess of allyl
bromide in order to avoid prolonged reaction times, which re-
sulted in decomposition likely due to the formation of an un-
stable ortho quinone methide species.
Scheme 5. Hydrogenation of a model C-aryl glycal (see Table 1 for more de-
Up to this point in the synthesis, the epoxide side chain
present in our synthetic intermediates posed no issues of ad-
verse reactivity. For example, no byproducts derived from acid-
catalyzed epoxide opening were observed in the oxidation/ar-
omatization sequence in Scheme 3. However, when consider-
ing the possible glycosyl donors and modes of activation for
the installation of the oliose residue, it became clear that che-
moselective activation of a suitable donor would be advanta-
geous to prevent degradation of our core structure. A report
from the Hirama group came to our attention that appeared
to address these concerns during the glycosylation of a particu-
larly sensitive intermediate en route to kedarcidin.[28] Equally
encouraging was the high stereoselectivity observed in this
method, especially in the case of 2-deoxy glycosyl donors, a no-
toriously unselective class of substrates for a variety of
common glycosylation methods.[29] Alcohol 15 appeared to be
the ideal intermediate to attempt such a glycosylation. While
chemoselectivity was assured due to the protecting group
scheme, it was still unclear whether this method would afford
tails).
tion from the same face as the free hydroxyl became increas-
ingly favored to afford the desired a-glycoside 25a. The best
stereoselectivity (a/b 14:1) was obtained when conducting the
reduction in hexanes. Hydrogenation of related substrates
bearing a methoxymethyl ether instead of a free alcohol
showed low stereoselectivity and no solvent dependence.
These results strongly suggest a hydroxyl-directed process,
Table 1. Solvent dependence of stereoselectivity.
Solvent
a/b ratio
methanol
ethyl acetate
benzene
1:1
5:1
11:1
14:1
hexanes
&
&
Chem. Eur. J. 2014, 20, 1 – 7
www.chemeurj.org
4
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Full Paper
the desired a-oliose residue. Gratifyingly, glycosylation with thi-
oglycosyl donor 27 promoted by silver hexafluorophosphate
proceeded to give the desired O-glycoside 16 in 83% yield as
a single diastereomer.
34 as a single diastereomer (Scheme 8).[31] Glycosylations con-
ducted with an excess of BF3·OEt2 resulted in better conversion
than reactions carried out with TMSOTf or Bu2BOTf. HF·pyridine
was subsequently employed to aid in purification by desilyla-
tion of the glycosylation product and to prepare for the intro-
duction of the azide by intermolecular displacement. The opti-
mized sequence gave a 48% yield of 35 from 33.
With product 35 in hand, we attempted the introduction of
the dimethylamino group present in pluraflavin A. Triflation of
the free alcohol proceeded cleanly, requiring 10 min at 08C for
completion (Scheme 8). Addition of 3 equivalents of tetrabuty-
lammonium azide to the crude triflate in benzene at room
temperature afforded the desired azide 36 in 4 h and 96%
yield. Although introduction of the azide was facile, its reduc-
tion to the primary amine posed a considerable challenge. No
reaction was observed with many known reducing agents,
such as propanedithiol,[32] dithiothreitol, [Et3NH][SnSPh3],[33]
SnCl2·2H2O,[34] HSnBu3, and H2SnBu2.[33] Reduction did occur
with H2 in the presence of Pd/C or Lindlar’s catalyst[35] and
zinc/acetic acid[36] but these conditions were incompatible with
the pluraflavin core, resulting in decomposition.
While an additional challenge remained in the conversion of
the C-linked 2,6-dideoxy gulose into the native rhodosamine
present in the natural product, the issue was postponed in
order to take advantage of the ready deprotection of the pri-
mary TBS ether (HF·pyridine, 08C, 8 h, 83% yield, see
Scheme 8) in the southeast region. This reactivity was seen to
be highly convenient, as it would bias the chemoselectivity of
the final glycosylation reaction to install the 3-epi vancosamine
residue. We also required the identification of suitable glycosyl
donors; although syntheses of 3-epi vancosamine have been
published,[30] to the best of our knowledge, glycosylations of
the monosaccharide have not been reported. Thus, our atten-
tion turned to the synthesis of a suitable glycosyl donor in the
3-epi vancosamine series and its evaluation in the glycosylation
of primary alcohol glycosyl acceptors. An intermediate in Mat-
sushima’s synthesis (28)[30 g] was converted to glycosyl acetate
30 by N-Cbz formation, reduction of the lactone, and acetyla-
tion of the crude mixture of lactols (Scheme 7).
We sought recourse to the highly chemoselective Staudinger
reduction.[37] However, treatment of 36 with triphenylphos-
phine in wet tetrahydrofuran did not provide the desired
amine. This was attributed to the slow rate of hydrolysis of the
iminophosphorane intermediate. Indeed, peaks corresponding
to the mass of the iminophosphorane were observed in mass
spectral analysis of the crude reaction mixture.
Glycosyl acetate 30 proved to be a versatile starting material
for the synthesis of several glycosyl donors. Hydrolysis of the
anomeric acetate yielded the free lactol 31, which was convert-
ed to a trichloroacetimidate 32 by treatment with cesium car-
bonate and an excess of trichloroacetonitrile. Although the tri-
chloroacetimidate was unstable to silica, this procedure provid-
ed material of sufficient purity to undergo productive glycosy-
lation.
We reasoned that hydrolysis of the iminophosphorane pro-
duced during Staudinger reduction of the azide with triphenyl-
phosphine was difficult and could be accelerated by reducing
the steric bulk imposed by the phosphine substituents. In
accord with this hypothesis, reduction with methyldiphenyl-
phosphine provided some primary amine, which was reduc-
tively methylated with sodium triacetoxyborohydride and for-
malin to provide the dimethylamino compound in low yield
(30% NMR). Future work on the total synthesis will be directed
at the optimization of the azide reduction and the optimal pro-
cedure for protecting group removal.
While glycosylations employing acetate 30 produced
anomeric mixtures, treatment of a mixture of acceptor 33 and
donor 32 in the presence of BF3·OEt2 afforded the b glycoside
Scheme 7. Synthesis of 3-epi vancosamine glycosyl donors. Key: a) benzyl
chloroformate, NaHCO3 (aq.), THF, 82%; b) DIBAL, THF, ꢀ308C; c) Ac2O, Et3N,
DMAP, CH2Cl2, 0–238C, 50% (over two steps); d) 5% HCl (aq.), THF, 62%; e)
Cl3CCN, Cs2CO3, CH2Cl2, 75%. Cbz=benzyloxycarbonyl, DIBAL=diisobutyl-
aluminum hydride, DMAP=N,N-4-dimethylaminopyridine.
Conclusion
In summary, an approach to the synthesis of pluraflavin A has
been developed that succeeded in installing the C- and O-
Scheme 8. Synthesis of azide 36. Reaction conditions: a) HF·pyridine, THF, 08C, 8 h, 83%; b) 32 (1.5 equiv), BF3·OEt2, CH2Cl2, ꢀ408C; c) HF·pyridine, THF, 238C,
48% (over two steps); d) Tf2O, pyridine, CH2Cl2, 08C; e) Bu4NN3, C6H6, 96% (over two steps). Tf=trifluoromethanesulfonyl.
Chem. Eur. J. 2014, 20, 1 – 7
www.chemeurj.org
5
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Full Paper
[11] L. Vꢀrtesy, F. P. Barbone, E. Cashmen, H. Decker, K. Ehrlich, B. Jordan, M.
Knauf, D. Schummer, M. P. Segeth, J. Wink, G. Seibert, J. Antibiot. 2001,
54, 718–729.
[12] B. J. D. Wright, J. Hartung, F. Peng, R. Van de Water, H. Liu, Q.-H. Tan, T.-
C. Chou, S. J. Danishefsky, J. Am. Chem. Soc. 2008, 130, 16786–16790.
[13] a) K. B. Sharpless, W. Amberg, Y. L. Bennani, G. A. Crispino, J. Hartung,
K. S. Jeong, H. L. Kwong, K. Morikawa, Z. M. Wang, D. Q. Xu, X. L. Zhang,
J. Org. Chem. 1992, 57, 2768–2771; b) H. C. Kolb, M. S. Vannieuwenhze,
K. B. Sharpless, Chem. Rev. 1994, 94, 2483–2547.
[14] D. P. Curran, J. Am. Chem. Soc. 1982, 104, 4024–4026.
[15] J. L. Bloomer, J. A. Gazzillo, Tetrahedron Lett. 1989, 30, 1201–1204.
[16] a) M. H. D. Postema, Tetrahedron 1992, 48, 8545–8599; b) Y. G. Du, R. J.
Linhardt, I. R. Vlahov, Tetrahedron 1998, 54, 9913–9959; c) D. E. Levy, C.
Tang, in Tetrahedron Organic Chemistry Series, Vol. 13 (Eds.: J. E. Baldwin,
P. D. Magnus), Elsevier, Tarrytown, New York, 1995; d) M. H. D. Postema,
C-Glycoside Synthesis, CRC Press, Boca Raton, FL, 1995.
linked sugar residues in a stereo- and regioselective manner.
Stille coupling proved to be a robust method for the function-
alization of the pluraflavin bromo “aglycone.” Experimental evi-
dence supports the hydroxyl directed hydrogenation of the C-
aryl glycal to form the synthetically challenging a glycoside
linkage present in pluraflavin A.
Ongoing efforts are focused on the installation of the dime-
thylamino group of the rhodosamine residue and the global
deprotection of the resulting product. While initial attempts at
Staudinger reduction of the azide and subsequent methylation
have met with measureable success, we are optimistic that fur-
ther experimentation will result in a successful route to the
potent anti-cancer agent.
[17] J.-C. Combret, J.-L. Klein, J. L. Gaillard, US 5,113,007, 1992.
[18] a) B. M. Trost, J. Ippen, W. C. Vladuchick, J. Am. Chem. Soc. 1977, 99,
8116–8118; b) B. M. Trost, W. C. Vladuchick, A. J. Bridges, J. Am. Chem.
Soc. 1980, 102, 3554–3572; c) P. V. Alston, M. D. Gordon, R. M. Otten-
brite, T. Cohen, J. Org. Chem. 1983, 48, 5051–5054.
[19] a) J. Banville, J. Grandmai, G. Lang, P. Brassard, Can. J. Chem. 1974, 52,
80–87; b) L. Boisvert, P. Brassard, J. Org. Chem. 1988, 53, 4052–4059.
[20] a) K. Bowden, I. M. Heilbron, E. R. H. Jones, B. C. L. Weedon, J. Chem. Soc.
1946, 39–45; b) R. Baker, V. B. Rao, P. D. Ravenscroft, C. J. Swain, Synthe-
sis 1983, 572–574.
[21] H. J. Liu, I. S. Han, Synth. Commun. 1985, 15, 759–764.
[22] a) K. M. Engstrom, M. R. Mendoza, M. Navarro-Villalobos, D. Y. Gin,
Angew. Chem. 2001, 113, 1162–1164; Angew. Chem. Int. Ed. 2001, 40,
1128–1130; b) R. L. Halcomb, S. H. Boyer, M. D. Wittman, S. H. Olson,
D. J. Denhart, K. K. C. Liu, S. J. Danishefsky, J. Am. Chem. Soc. 1995, 117,
5720–5749.
Acknowledgements
This work was financially supported by the NIH grant R01
HL025848. The authors thank the Guthikonda family for their
generous support (fellowship to J.H.), Rebecca Wilson for help
in editing the manuscript, Arthur Han for experimental assis-
tance, and John Decatur and Yasuhiro Itagaki for NMR and
mass spectrometric assistance, respectively.
Keywords: anti-cancer agents · C-glycoside · glycosylation ·
pluraflavin A · pluramycins
[23] M. Schlosser, Pure Appl. Chem. 1988, 60, 1627–1634.
[24] R. W. Friesen, L. A. Trimble, J. Org. Chem. 1996, 61, 1165–1168.
[25] A. F. Littke, L. Schwarz, G. C. Fu, J. Am. Chem. Soc. 2002, 124, 6343–
6348.
[26] a) E. Dubois, J. M. Beau, Carbohydr. Res. 1992, 228, 103–120; b) R. W.
Friesen, R. W. Loo, C. F. Sturino, Can. J. Chem. 1994, 72, 1262–1272.
[27] A. H. Hoveyda, D. A. Evans, G. C. Fu, Chem. Rev. 1993, 93, 1307–1370.
[28] M. J. Lear, F. Yoshimura, M. Hirama, Angew. Chem. 2001, 113, 972–975;
Angew. Chem. Int. Ed. 2001, 40, 946–949.
[1] K. Maeda, T. Takeuchi, K. Nitta, K. Yagishita, R. Utahara, T. Osato, M.
Ueda, S. Kondo, Y. Okami, H. Umezawa, J. Antibiot. 1956, 9, 75–81.
[2] a) F. M. Hauser, R. P. Rhee, J. Am. Chem. Soc. 1979, 101, 1628–1629;
b) Z. B. Fei, F. E. McDonald, Org. Lett. 2005, 7, 3617–3620.
[3] a) D.-S. Hsu, T. Matsumoto, K. Suzuki, Chem. Lett. 2006, 35, 1016–1017;
b) L. F. Tietze, R. R. Singidi, K. M. Gericke, Org. Lett. 2006, 8, 5873–5876;
c) K. Krohn, H. T. Tran-Thien, J. Vitz, A. Vidal, Eur. J. Org. Chem. 2007,
1905–1911; d) L. F. Tietze, R. R. Singidi, K. M. Gericke, Chem. Eur. J. 2007,
13, 9939–9947; e) K. Krohn, T.-T. Hoan Trang, I. Ahmed, Eur. J. Org.
Chem. 2011, 2223–2225.
[4] a) H. Uno, K. Sakamoto, E. Honda, N. Ono, Chem. Commun. 1999, 1005–
1006; b) H. Uno, K. Sakamoto, E. Honda, K. Fukuhara, N. Ono, J. Tanaka,
M. Sakanaka, J. Chem. Soc. Perkin Trans. 1 2001, 229–238; c) L. F. Tietze,
K. M. Gericke, R. R. Singidi, I. Schuberth, Org. Biomol. Chem. 2007, 5,
1191–1200.
[5] a) K. Krohn, J. Vitz, Eur. J. Org. Chem. 2004, 209–219; b) L. F. Tietze, K. M.
Gericke, R. R. Singidi, Angew. Chem. 2006, 118, 7146–7150; Angew.
Chem. Int. Ed. 2006, 45, 6990–6993; c) L. F. Tietze, R. R. Singidi, K. M.
Gericke, H. Boeckemeier, H. Laatsch, Eur. J. Org. Chem. 2007, 5875–
5878; d) S. Gattinoni, L. Merlini, S. Dallavalle, Tetrahedron Lett. 2007, 48,
1049–1051; e) S. Dallavalle, S. Gattinoni, S. Mazzini, L. Scaglioni, L. Merli-
ni, S. Tinelli, G. L. Beretta, F. Zunino, Bioorg. Med. Chem. Lett. 2008, 18,
1484–1489; f) M. A. Elban, S. A. Hecht, J. Org. Chem. 2008, 73, 785–793;
g) P. A. Zaleski, R. Maini, S. J. Leiris, M. A. Elban, S. M. Hecht, J. Nat. Prod.
2012, 75, 577–585; h) J. E. Rixson, B. W. Skelton, G. A. Koutsantonis,
K. M. Gericke, S. G. Stewart, Org. Lett. 2013, 15, 4834–4837.
[29] a) C. H. Marzabadi, R. W. Franck, Tetrahedron 2000, 56, 8385–8417; b) D.
Hou, T. L. Lowary, Carbohydr. Res. 2009, 344, 1911–1940; c) A. Borovika,
P. Nagorny, J. Carbohydr. Chem. 2012, 31, 255–283.
[30] a) G. Fronza, C. Fuganti, P. Grasselli, G. Pedrocchifantoni, Tetrahedron
Lett. 1981, 22, 5073–5076; b) J. S. Brimacombe, R. Hanna, L. C. N.
Tucker, Carbohydr. Res. 1982, 105, C1–C3; c) J. Yoshimura, T. Yasumori,
T. Kondo, K.-I. Sato, Carbohydr. Res. 1982, 106, C1–C3; d) J. S. Brima-
combe, R. Hanna, L. C. N. Tucker, J. Chem. Soc. Perkin Trans. 1 1983,
2277–2280; e) T. Yasumori, K. Sato, H. Hashimoto, J. Yoshimura, Bull.
Chem. Soc. Jpn. 1984, 57, 2538–2542; f) B. M. Trost, C. H. Jiang, K.
Hammer, Synthesis 2005, 3335–3345; g) Y. Matsushima, J. Kino, Tetrahe-
dron 2008, 64, 3943–3952.
[31] a) R. R. Schmidt, G. Effenberger, Liebigs Ann. Chem. 1987, 825–831;
b) R. R. Schmidt, M. Hoffmann, Tetrahedron Lett. 1982, 23, 409–412.
[32] H. Bayley, D. N. Standring, J. R. Knowles, Tetrahedron Lett. 1978, 19,
3633–3634.
[33] M. Bartra, F. Urpi, J. Vilarrasa, Tetrahedron Lett. 1987, 28, 5941–5944.
[34] S. N. Maiti, M. P. Singh, R. G. Micetich, Tetrahedron Lett. 1986, 27, 1423–
1424.
[35] E. J. Corey, K. C. Nicolaou, R. D. Balanson, Y. Machida, Synthesis 1975,
590–591.
[36] D. N. Kirk, M. A. Wilson, J. Chem. Soc. C 1971, 414–424.
[37] a) H. Staudinger, J. Meyer, Helv. Chim. Acta 1919, 2, 635–646; b) E. F. V.
Scriven, K. Turnbull, Chem. Rev. 1988, 88, 297–368.
[6] a) B. M. O’Keefe, D. M. Mans, D. E. Kaelin, Jr., S. F. Martin, J. Am. Chem.
Soc. 2010, 132, 15528–15530; b) B. M. O’Keefe, D. M. Mans, D. E. Kae-
lin, Jr., S. F. Martin, Tetrahedron 2011, 67, 6524–6538.
[7] H. L. White, J. R. White, Biochemistry 1969, 8, 1030–1042.
[8] H. M. Jernigan, J. L. Irvin, J. R. White, Biochemistry 1978, 17, 4232–4239.
[9] a) D. Y. Sun, M. Hansen, J. J. Clement, L. H. Hurley, Biochemistry 1993, 32,
8068–8074; b) M. Hansen, L. Hurley, J. Am. Chem. Soc. 1995, 117, 2421–
2429; c) D. Y. Sun, M. Hansen, L. Hurley, J. Am. Chem. Soc. 1995, 117,
2430–2440.
Received: February 19, 2014
[10] M. R. Hansen, L. H. Hurley, Acc. Chem. Res. 1996, 29, 249–258.
Published online on && &&, 0000
&
&
Chem. Eur. J. 2014, 20, 1 – 7
www.chemeurj.org
6
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Full Paper
FULL PAPER
A synthetic strategy towards the
potent anti-cancer agent pluraflavin A
(see figure) has been developed. Forma-
tion of the halogenated aromatic core
enabled the installation of the a C-aryl
glycoside linkage, which was forged by
the Stille coupling of a stannyl glycal
and subsequent hydrogenation of the
cross-coupling product.
&
Natural Product Synthesis
J. Hartung, B. J. D. Wright,
S. J. Danishefsky*
&& – &&
Studies Toward the Total Synthesis of
Pluraflavin A
Chem. Eur. J. 2014, 20, 1 – 7
www.chemeurj.org
7
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ