Synthesis of the polyketomycin disaccharide

Article abstract of DOI:10.1016/j.tetasy.2003.07.023

The disaccharide portion of the anthracycline antibiotic polyketomycin consists of the trideoxy sugar D-amicetose attached to the methyl-branched sugar L-axenose. The polyketomycin disaccharide was synthesized from methyl 2,3,6-trideoxy-α-D-erythro-hexopyranoside (methyl α-D-amicetoside) and phenyl 3,4-di-O-benzyl-2,6-dideoxy-3-C-methyl-1-thio-α,β-L-xylo- hexopyranoside. The key coupling step was carried out by N-bromosuccinimide activation of the thioglycoside and gave the desired α (1→4) linked disaccharide exclusively in 71% yield, which was debenzylated by sodium and liquid ammonia.

Full text of DOI:10.1016/j.tetasy.2003.07.023

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 3183–3188
Synthesis of the polyketomycin disaccharide
Douglas S. Micalizzi, J. Patrick Dougherty, Lincoln A. Noecker, Garry R. Smith and
Robert M. Giuliano*
Department of Chemistry, Villanova University, Villanova, PA 19085, USA
Received 17 June 2003; accepted 17 July 2003
Abstract—The disaccharide portion of the anthracycline antibiotic polyketomycin consists of the trideoxy sugar
attached to the methyl-branched sugar -axenose. The polyketomycin disaccharide was synthesized from methyl 2,3,6-trideoxy-a-
-erythro-hexopyranoside (methyl a- -amicetoside) and phenyl 3,4-di-O-benzyl-2,6-dideoxy-3-C-methyl-1-thio-a,b- -xylo-
D-amicetose
L
D
D
L
hexopyranoside. The key coupling step was carried out by N-bromosuccinimide activation of the thioglycoside and gave the
desired a (1“4) linked disaccharide exclusively in 71% yield, which was debenzylated by sodium and liquid ammonia.
© 2003 Elsevier Ltd. All rights reserved.
1. Introduction
concern and several approaches have been taken to
develop more effective treatments, including the devel-
opment of more effective antibiotics and drug ana-
logues, some of which have modified sugar residues.4,5
Studies have shown that modification of the carbohy-
drate residues in other anthracycline antitumor antibi-
otics provides a viable means for the development of
more effective drug analogues, providing glycosides
that possess better bioavailability and lower toxicity
than the parent compounds.6 Our laboratory has
reported the synthesis of both amicetose and axenose.7,8
The synthesis of the disaccharide of polyketomycin is a
challenging problem owing to the presence of the 2-
deoxy glycosidic linkage and because multiple steps are
required to obtain suitably protected monosaccharide
derivatives. To date, neither the synthesis of the polyke-
tomycin disaccharide nor of other disaccharides which
contain the constituent sugars has been reported.
Polyketomycin (Fig. 1) is an anthracycline antibiotic
isolated from Streptomyces sp. MK277-AF1.1,2 Struc-
turally related to dutomycin,3 polyketomycin has been
found to possess cytotoxic activity against nine tumor
cell lines and against multi-drug resistant strains of
Gram-positive bacteria such as Staphylococcus aureus
MS9610, and methicillin-resistant S. aureus (MRSA).
The proliferation of MRSA has become a major health
Both polyketomycin and dutomycin are glycosylated
with a disaccharide that contains the trideoxy sugar
D
-amicetose9 and the methyl-branched sugar
L-
axenose,10 which are attached by an a (1“4) linkage.
Interestingly, the same two monosaccharides comprise
the disaccharide of the antibiotic axenomycin,10,11 but
the order of attachment is reversed, with amicetose
being the terminal sugar residue, and the linkage
between the two sugars is a b-linkage. Owing to the
extent of deoxygenation, especially at the C-2 positions,
synthesis of disaccharides of these unusual carbohy-
drates was anticipated to be difficult. Also, the lack of
a substituent at the 2-position precludes the use of
Figure 1. Polyketomycin.
* Corresponding author. E-mail: robert.guiliano@villanova.edu
0957-4166/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2003.07.023

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D. S. Micalizzi et al. / Tetrahedron: Asymmetry 14 (2003) 3183–3188
neighboring group participation for the control of
stereochemistry in glycoside bond formation. Our ini-
tial attempts at disaccharide synthesis based on cou-
pling glycosyl donors of axenose with methyl
amicetoside were met with limited success, in particular
low yields in the glycosylation and poor stereoselectiv-
ity. Herein, we report an efficient and stereoselective
synthesis of the polyketomycin disaccharide 10, based
on the NBS-activation12 of the thioglycoside of
axenose.
not separated at this stage.15 Cleavage of the benzyli-
dene acetal with N-bromosuccinimide16 gave a separa-
ble mixture of anomers of bromo ester 3. While it is
assumed that both a- and b-anomers (or the anomeric
mixture) of methyl amicetoside would be suitable as
glycosyl acceptors, we selected the a-anomer for further
studies since it was the major one formed. We found
that reduction of 3 could be carried out by two meth-
ods, either with tributyltin hydride or with tetra-
butylammonium
borohydride.17
The
use
of
tetrabutylammonium borohydride avoids the hazards
of handling organotin reagents, however, some deester-
ification occurs along with reduction. The alcohol 5 is
easily separated from the ester 4 by straightforward
column chromatography. Hydrolysis of 4 gave methyl
2. Results and discussion
Both the glycosyl donor for axenose and the acceptor
for amicetose were synthesized from carbohydrate
starting materials. Several syntheses of amicetose from
carbohydrate and non-carbohydrate precursors have
been reported.13 Horton and Albano synthesized
a- -amicetoside 5 in 20–25% overall yield, depending
D
on which reduction method is used.
The glycosyl donors of axenose used in this study were
phenyl thioglycosides, which were prepared by the
route we have previously reported.8 Methyl 3-O-benzyl-
methyl a-
D
-amicetoside from methyl 4,6-O-benzyli-
-erythro-hex-2-enopyranoside,
dene-2,3-dideoxy-a-
D
2,6-dideoxy-3-C-methyl-b- -xylo-hexopyranoside 6 was
L
which was obtained from methyl a-D-glucopyran-
oside.14 NBS cleavage of the a-anomer of benzylidene
acetal 2 is a key step in this route, as it provides for
deoxygenation of the C-6 via hydrogenolysis of an iodo
synthesized from 2-deoxyribose, benzylated at the C-4
hydroxyl, and treated with phenylthiotrimethylsilane
and TMS-triflate to give an anomeric mixture of phenyl
thioglycosides 7 (Scheme 2).12 We chose thioglycosides
as the glycosyl donor for axenose because they can be
activated under mild reaction conditions either with
halonium electrophiles or by several other methods.18
The versatility of thioglycosides would provide multiple
options in what was considered to be a difficult glycosyl-
ation step. The results of our study of coupling reac-
derivative. Our synthesis of methyl ab-
D-amicetoside is
similar, except that 2 was prepared from tri-O-acetyl-
D
-
glucal, and the deoxygenation of C-6 was carried out
directly on the 6-bromo sugar, using either of two
methods that were found to be suitable for this reduc-
tion (Scheme 1).
tions are shown in Scheme 3. Methyl a-D-amicetoside
We utilized an efficient, three-step sequence of Ferrier
rearrangement, deacetylation, and reduction to prepare
was reacted with thioglycoside 7 under a variety of
conditions and with the sulfoxide derivative 8. In one of
the first attempts at disaccharide synthesis, a 3:2 ratio
methyl 4,6-O-benzylidene-2,3-dideoxy-a,b-
D-erythro-
hexopyranoside 2 as a mixture of anomers which were
Scheme 1. Synthesis of methyl a-D-amicetoside.

D. S. Micalizzi et al. / Tetrahedron: Asymmetry 14 (2003) 3183–3188
3185
Scheme 2. Synthesis of glycosyl donors of axenose.
of a and b glycosides of 9 was obtained using N-iodo-
succinimide/triflic acid to activate the thioglycoside.20
These conditions had been used previously with differ-
ent substrates in our synthesis of the cororubicin trisac-
charide, in which the major product was the
b-anomer.21 It was the only method in this study that
was found to produce any of the b-anomer, and while
the natural configuration of the disaccharide is a, we
remain interested in the synthesis of 2-deoxy-b-gly-
cosides owing to their occurrence in the disaccharides
found in other antibiotics, for example, axenomycin.11
It was interesting to observe that activation with N-
iodosuccinimide in the polar solvent N-methylpyrrolidi-
ence of 2,6-di-tert-butyl-4-methylpyridine. While the
selectivity of the reaction was exclusive for the desired
a-anomer, higher yields were obtained with NBS acti-
vation. Attempted debenzylation of 9a by catalytic
hydrogenolysis over palladium-on-carbon was not suc-
cessful; however, treatment with sodium in liquid
ammonia gave the polyketomycin disaccharide as its
methyl glycoside 10 in 71% yield (Scheme 4).
3. Conclusion
In conclusion, we have developed an efficient and
stereoselective synthesis of the polyketomycin disaccha-
none
or
with
NBS
in
a
mixture
of
acetonitrile–dichloromethane gave exclusively the
desired a-anomer. High selectivity for a-glycosylation
with NBS-activation of thioglycosides in acetonitrile
has been reported by Nicolaou et al.12 In the coupling
of thioglycoside 7 and 5, temperature control was
found to be critical, with reductions in yield being
observed for reactions run at higher temperatures.
ride, by coupling methyl a-D-amicetoside with a thio-
glycoside derivative of axenose. Best results in the key
coupling step were obtained by activation of the thio-
glycoside with NBS in acetonitrile–dichloromethane. A
feature of this approach that is worth noting is that the
glycosyl donor could be substituted with groups other
than benzyl at the C-4 hydroxyl. In polyketomycin, this
position is acylated with a salicylate group. Also, com-
pound 6, the precursor to thioglycoside 7, is unpro-
tected at C-4 and could therefore be used as the
acceptor in the synthesis of the axenomycin disaccha-
ride. Further studies are in progress in these areas.
Glycosylation by the sulfoxide method was also
attempted.19 Thioglycoside 7 was oxidized to its sulfox-
ide 8 and the mixture of isomers was treated with
methyl amicetoside with triflic anhydride in the pres-
Scheme 3. Coupling of
D-amicetose and L-axenose derivatives.
Scheme 4. Debenzylation of polyketomycin disaccharide.

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D. S. Micalizzi et al. / Tetrahedron: Asymmetry 14 (2003) 3183–3188
4. Experimental
28.7, 23.9; b-anomer: recrystallized from hexanes/ethyl
acetate to give white needles, mp 104–105°; [a]D +14.6
(c 1.00, chloroform); Rf 0.60 (3:1 hexanes/ethyl acetate);
1H NMR l 8.06–8.01 (m, 2H, Ar), 7.63-7.42 (m, 3H,
Ar), 4.94 (m, 1H, H-4), 4.54 (m, 1H, H-1), 3.84 (ddd,
1H, J4,5 8.7, J5,6 7.5, 3.3 Hz, H-5), 3.62 (dd, 1H, J6,6% 9.9
Hz, H-6), 3.56 (dd, 1H, H-6%), 3.49 (s, 3H, OCH3), 2.33
(m, 1H), 1.96 (m, 1H), 1.71 (m, 2H); 13C NMR l 165.3,
137.9, 133.2, 129.5, 128.3, 102.3, 76.6, 70.4, 56.3, 32.1,
29.2, 26.4. Anal. calcd for C14H17O4Br: C, 51.04; H,
5.21. Found: C, 51.14; H, 5.05.
4.1. General methods
1H NMR spectra were recorded at 300 MHz with TMS
as an internal reference in CDCl3, and 13C NMR
spectra were recorded at 75 MHz and referenced with
CDCl3, unless otherwise noted. Melting points were
determined in an open capillary tube with a Thomas
Hoover apparatus and are uncorrected. TLC analyses
were conducted on aluminum-backed silica gel
Kieselgel 60 F254 plates and visualized by UV 254 nm
or with ammonium molybdate-ceric sulfate reagent.
Flash chromatography was carried out with ‘Baker’
silica gel. Optical rotations were recorded on a Perkin
Elmer 241 polarimeter at 23°C. Elemental analyses
were carried out at Merck Research Laboratories. High
resolution mass spectra were measured at Merck
Research Laboratories using ES-FT/ICR/MS with pro-
pylene glycol as the internal standard or at the Univer-
sity of Pennsylvania by electrospray ionization.
4.4. Methyl 4-O-benzoyl-2,3,6-trideoxy-a- -erythro-
D
hexopyranoside 4
Method A: To a solution of methyl 4-O-benzoyl-6-
bromo-2,3,6-trideoxy-a- -erythro-hexopyranoside
D
3
(1.0 g, 3.0 mmol) in anhydrous benzene (10 mL) under
nitrogen was added tributyltin hydride (900 mL, 3.3
mmol) and 2,2%-azobisisobutyronitrile (5 mg) with the
mixture left to stir under reflux for 20 h. After cooling
to rt, the mixture was concentrated and purified by
flash chromatography, eluting first with hexanes to
separate the alkyltin by-products, then with 9:1 hex-
anes/ethyl acetate to afford 0.73 g (96%) of 4 as a
colorless oil: [h]D +161 (c 1.28, chloroform) lit.22 [a]D26
+170 (c 1.0, chloroform); Rf 0.61 (4:1 hexanes/ethyl
4.2. Methyl 4,6-O-benzylidene-2,3-dideoxy-a/b-
thro-hexopyranoside 2
D
-ery-
To a stirred solution of methyl 2,3-dideoxy-a/b-D-ery-
thro-hexopyranoside 1 (14 g, 86 mmol, 4:1 a/b) in
N,N-dimethylformamide (80 mL) was added benzalde-
hyde dimethyl acetal (16.8 mL, 112 mmol) and pyri-
dinium p-toluenesulfonate (1.4 g) and the resulting
solution was heated at 80–85°C under reduced pressure
(26 mm) for 2 h. After cooling, the reaction mixture
was poured into sat. aq. NaHCO3 (200 mL) and
extracted with ethyl acetate (3×200 mL). The combined
organic phases were washed with sat. aq. NaCl, dried
over MgSO4, and concentrated to a syrup that was
purified by flash chromatography using hexanes/ethyl
1
acetate); H NMR l 8.06–8.01 (m, 2H, Ar), 7.62–7.40
(m, 3H, Ar), 4.76 (m, 1H, H-4), 4.70 (m, 1H, H-1), 3.96
(dq, 1H, J4,5 9.4, J5,6 6.3 Hz, H-5), 3.41 (s, 3H, OCH3),
2.10–1.86 (m, 2H), 1.62 (m, 1H), 1.36 (m, 1H), 1.23 (d,
3H, H-6); 13C NMR l 165.6, 132.8, 129.5, 128.2, 97.4,
73.9, 66.4, 54.4, 29.0, 24.1, 17.9.
Method B: To a solution of bromo ester 3 (6.6 g, 20.0
mmol) in anhydrous benzene (66 mL) under nitrogen
was added tetrabutylammonium borohydride (10.3 g,
40 mmol) with the mixture left to stir under reflux for
3 h. After cooling to 0°C, the excess borohydride was
decomposed by the addition of ice until bubbling
ceased. The mixture was then extracted with ethyl
acetate and the combined extracts washed with sat. aq.
NH4Cl and sat. aq. NaCl, dried over MgSO4 and
concentrated to a residue that was purified by flash
chromatography with 9:1 hexanes/ethyl acetate to give
1
acetate (9:1–8:2) to yield 16.4 g (76%) of a/b 2. The H
NMR spectrum of the a-anomer matched that
reported.14
4.3. Methyl 4-O-benzoyl-6-bromo-2,3,6-trideoxy-a/b-
erythro-hexopyranoside 3
D-
A suspension of methyl 4,6-O-benzylidene-2,3-dideoxy-
a/b- -erythro-hexopyranoside 2 (15.5 g, 62 mmol), N-
D
3.8 g (76%) of 4 and 350 mg (12%) of methyl a-
D
-
bromosuccinimide (13.2 g, 74.3 mmol), and barium
carbonate (18.3 g, 93 mmol) in anhydrous carbon tetra-
chloride (300 mL) was stirred under reflux for 1 h.
After cooling to room temperature, the mixture was
filtered and the solids were washed with
dichloromethane (200 mL). The combined organic solu-
tions were washed successively with sat. aq. NaHCO3
(200 mL) and sat. aq. NaCl (100 mL), dried over
MgSO4, and concentrated under reduced pressure to
give a syrup that was purified by flash chromatography
(480 g silica gel) with 9:1 hexanes/ethyl acetate to give
13.0 g of a-anomer and 3.5 g of b-anomer (81% com-
bined yield). a-Anomer: [h]D +124 (c 1.25, chloroform)
lit.14 [h]D21 +133 (c 1.1, chloroform); Rf 0.63 (3:1 hex-
anes/ethyl acetate); The 1H NMR spectrum of the
a-anomer of 3 matched that reported;14 13C NMR l
165.3, 133.2, 129.7, 128.4, 97.6, 70.9, 70.0, 54.8, 32.9,
amicetoside 5.
4.5. Methyl 2,3,6-trideoxy-a-
D
-erythro-hexopyranoside
(methyl a- -amicetoside) 5
D
A solution of methyl 4-O-benzoyl-2,3,6-trideoxy-a-
D
-
erythro-hexopyranoside 4 (250 mg, 0.98 mmol) in etha-
nol (3 mL) and 2 M NaOH (4.5 mL) was stirred at
90°C for 15 min. Progress was monitored by TLC (3:1
hexanes/ethyl acetate), until it was shown no starting
material remained. Water (6 mL) was then added and
the mixture extracted with dichloromethane (4×10 ml).
The combined organic phases were washed with satd.
aq. NaCl dried over Na2SO4 and concentrated under
reduced pressure to give an oil; yield, 119 mg (83%):
[a]D +145 (c 1.14, H2O) lit.14 [h]D18 +142 (c 1.2, H2O); Rf
1
0.48 (1:1 hexanes/ethyl acetate); H NMR l 4.63 (d,

D. S. Micalizzi et al. / Tetrahedron: Asymmetry 14 (2003) 3183–3188
3187
1H, J1,2 1.7 Hz, H-1), 3.55 (dq, 1H, J4,5 9.1, J5,6 6.3 Hz,
H-5), 3.28 (m, 1H, H-4), 3.34 (s, 3H, OCH3), 1.81–1.66
(m, 4H), 1.27 (d, 3H, H-6); 13C NMR l 97.2, 71.9, 69.1,
54.2, 29.4, 27.4 (2C), 17.8.
(dd, 1H, H-2%eq), 1.33 (s, 3H, 3%-CH3), 1.16 (d, 3H,
H-6%), 1.14 (d, 3H, H-6); 13C NMR (100 MHz) l 128.2,
128.1, 128.1, 127.8, 127.7, 127.2, 99.0, 97.3, 81.6, 80.4,
77.4, 75.9, 67.6, 63.6, 63.3, 52.2, 32.1, 29.4, 26.12, 22.4,
18.2, 17.1. HRMS calcd for C28H38O6Na (M+Na):
493.2560. Found: 493.2565.
4.6. Phenyl 3,4-di-O-benzyl-2,6-dideoxy-3-C-methyl-1-
(RS)-sulfinyl-a,b- -xylo-hexopyranoside 8
L
4.8. Methyl 2,6-dideoxy-3-C-methyl-a-
L
-xylo-hexopy-
m-Chloroperoxybenzoic acid (64 mg, 57–86%, 1.0–1.3
equiv.) was added to a stirred solution of phenyl 3,4-di-
O-benzyl-2,6-dideoxy-3-C-methyl-1-thio-a/b-L-xylo-
ranosyl-(1“4)-2,3,6-trideoxy-a-D
-erythro-
hexopyranoside 10
hexopyranoside (124 mg, 0.29 mmol, 3:1 b/a) in
anhydrous dichloromethane (6 mL) at −78°C. The reac-
tion was allowed to warm to 0°C over 2 h, then poured
into sat. aq. NaHCO3 and extracted with
dichloromethane. The organic phase was washed with
sat. aq. NaCl, dried over Na2SO4, concentrated, and
purified by flash chromatography (4:1 hexanes/ethyl
acetate) to give the syrupy sulfoxide (98 mg, 76%) as a
Sodium metal (12 mg, 0.54 mmol) was added to a
stirred solution of ammonia (5 mL) at −78°C under
argon. Blue color appeared within 5 min and a solution
of 9a (51 mg, 0.108 mmol) in anhydrous THF (1.5 mL)
was added in one portion. Additional sodium was
added in small pieces until the color persisted. The
reaction was then stirred for 30 min. Solid ammonium
chloride was added until the color dissipated at which
point the reaction was allowed to warm to room
temperature.
1
mixture of a,b/R,S isomers that was not separated: H
NMR l 7.68–7.12 (m, 15H, Ar), 4.66 (ABq, J 11.9 Hz,
2H, OCH2Ph), 4.34 (br d, 1H, J1,2 6.0 Hz, H-1), 4.28
(ABq, J 11.6 Hz, 2H, OCH2Ph), 4.05 (dq, 1H, J4,5 0.9,
J5,6 6.5 Hz, H-5), 3.08 (br s, 1H, H-4), 2.09–2.04 (m,
2H, H-2), 1.37 (s, 3H, 3-CH3), 1.19 (d, 3H, H-6); 13C
NMR l 141.5 (ipso SOPh), 138.2, 138.7 (Ar ipso),
128.61-124.8 (Ar), 91.8 (C-1), 80.2 (OBn), 76.1 (C-3),
75.8 (C-4), 72.8 (C-5), 63.1 (OBn), 28.2 (C-2), 21.6
(3-CH3), 16.8 (C-6).
The residue was dissolved in ethyl acetate (75 mL),
extracted with water, dried over Na2SO4 and concen-
trated to give a solid product (29 mg) which was
triturated with diethyl ether (0.5 mL) and dried under
high vacuum; yield, 24 mg (75%). Recrystallization
from ethyl acetate–hexane gave needles: mp 130–132°C;
[h]D +44.7 (c 0.94, chloroform); Rf 0.61 (3:2 hexanes/
1
ethyl acetate) H NMR l 5.00 (dd, 1H, J1%,2a% 4.1, J1%,2e%
1.2 Hz, H-1%), 4.61 (br d, 1H, J 2.9 Hz, H-1), 4.43 (br
q, 1H, J5%,6% 6.7 Hz, H-5%), 3.93 (br s, 1H, OH), 3.65 (m,
1H, J5,6 6.3 Hz, H-5), 3.35 (s, 3H, OCH3), 3.22 (m, 1H,
J4,5 9.7, J3a,4 10.4 Hz, H-4), 3.15 (dd, 1H, J2e,4 1.2, J4,5
0, J4,OH 5.7 Hz, H-4%), 2.02–1.64 (m, 7H, J2a%,2e% 14.4 Hz,
H-2%, H-2, H-3, OH), 1.25 (s, 3H, 3%-CH3), 1.24 (d, 3H,
H-6%), 1.21 (d, 3 H, H-6); 13C NMR l 99.8, 96.9, 80.1,
74.5, 70.0, 67.3, 63.0, 54.6, 36.2, 29.7, 26.4, 26.3, 18.5,
17.0. HRMS calcd for C14H26O6Na (M+Na): 313.1627.
Found: 313.1630.
4.7. Methyl 3,4-di-O-benzyl-2,6-dideoxy-3-C-methyl-a-
L
-xylo-hexopyranosyl-(1“4)-2,3,6-trideoxy-a- -erythro-
D
hexopyranoside 9a
A mixture of methyl a- -amicetoside 5 (24.5 mg, 0.17
D
mol) and thioglycoside 7 (68 mg, 0.15 mmol) was
azeotropically dried with benzene (3×2 mL) and dis-
solved in 1:1 CH3CN–CH2Cl2 (2 mL). Molecular sieves
,
(4 A, 40 mg) were added and the mixture stirred under
argon at room temperature for 25 min and then cooled
to −78°C. N-Bromosuccinimide (32 mg, 0.18 mmol, 1.2
equiv., recrys from H2O and dried) was added in one
portion and progress of the reaction was monitored by
TLC (3:1 hexanes/ethyl acetate). After 2 h, the major
component of the reaction was the disaccharide (Rf
0.38). The reaction was diluted with dichloromethane
(10 mL), filtered, and the filtrate extracted with 5% aq.
NaHSO3, sat. aq. NaCl, dried over Na2SO4, and con-
centrated to a syrup that was purified by chromatogra-
phy on a Waters Vacuum Manifold on a silica gel
cartridge (2 g) with 5–25% ethyl acetate/hexanes as the
eluant. Obtained was 52 mg (71%) of disaccharide 9a as
a colorless oil: [h]D −63 (c 0.33, chloroform); Rf 0.42
(3:1 hexanes/ethyl acetate) 1H NMR (400 MHz) l
7.60–7.22 (m, 10H, Ar), 4.94 (br d, 1H, J1%,2% 3.3 Hz,
H-1%), 4.67 (ABq, 2H, J 11.2 Hz, OCH2Ph), 4.60 (br d,
1H, J1,2 2.9 Hz, H-1), 4.56 (br q, 1H, J5,6 6.6 Hz, H-5%),
4.50 (ABq, 2H, J 10 Hz, OCH2Ph), 3.56 (dq, 1H, J5,6
6.1 Hz, H-5), 3.32 (s, 3H, OCH3), 3.15 (dt, 1H, J3,4 4.8,
J4,5 9.2 Hz, H-4), 3.10 (br s, 1H, H-4%), 2.06 (br d, 1H,
J2,2% 14.9 Hz, H-2%ax), 1.90–1.71 (m, 4H, H-2, H-3), 1.82
Acknowledgements
We thank the Petroleum Research Fund, administered
by the American Chemical Society, the Howard Hughes
Medical Institute, Merck Research Laboratories and
Villanova University for their financial support of this
research. We also thank the Villanova Honors Program
for support for Douglas Micalizzi and J. Patrick
Dougherty.
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