Synthesis of oxepines and 2-branched pyranosides from a D-glucal-derived gem-dibromo-1,2-cyclopropanated sugar

Article abstract of DOI:10.1021/jo902306a

(Chemical Equation Presented) The conversion of cyclopropane-fused carbohydrates into oxepines is an attractive method for accessing diverse members of the septanoside family of carbohydrate mimetics. 2-Bromooxepines are obtained through silver(I)-promoted thermal ring expansion of a D-glucal-derived gem-dihalocyclopropanated sugar. In contrast, cyclopropane ring cleavage under basic conditions leads to 2-C-branched pyranosides, not the 2-bromooxepine structures assigned in an earlier report.

Full text of DOI:10.1021/jo902306a

pubs.acs.org/joc
mimic the structures and functions of natural carbohydrates,
Synthesis of Oxepines and 2-Branched Pyranosides
from a D-Glucal-Derived gem-Dibromo-
1,2-cyclopropanated Sugar
while the conformations adopted by these homologues lead
to their binding and interaction with biological targets.3,4
Among the various strategies developed for the synthesis of
oxepines and septanosides,1,5,6 several methods have fea-
tured the homologation of pyranoses via cyclopropanes.3,7-9
Specifically, the cyclopropanation of unsaturated carbohy-
drate scaffolds10 and subsequent cyclopropane cleavage
leads to ring expansion. Alternatively, branched cyclic pro-
ducts can instead be generated depending on the cyclopro-
pane substituents and the reaction conditions.8,11
gem-Dihalocyclopropanes are readily synthesized by di-
halocarbene addition to the corresponding alkenes12 and
have been used in numerous synthetic applications.12,13
Nagarajan et al. described, inter alia, the conversion of
several glycal-derived gem-dihalocyclopropanated sugars
into 2-bromooxepines in the presence of methanol and
potassium carbonate in 1997 (for example, Scheme 1).8
Extension of this methodology by Ganesh and Jayaraman
led to the synthesis of a number of septanosides from
2-oxyglycals.9
Russell J. Hewitt and Joanne E. Harvey*
School of Chemical and Physical Sciences, Victoria University
of Wellington, P.O. Box 600, Wellington, New Zealand
joanne.harvey@vuw.ac.nz
Received October 28, 2009
The conversion of cyclopropane-fused carbohydrates
into oxepines is an attractive method for accessing diverse
members of the septanoside family of carbohydrate mi-
metics. 2-Bromooxepines are obtained through silver(I)-
promoted thermal ring expansion of a D-glucal-derived
gem-dihalocyclopropanated sugar. In contrast, cyclopro-
pane ring cleavage under basic conditions leads to 2-
C-branched pyranosides, not the 2-bromooxepine struc-
tures assigned in an earlier report.
SCHEME 1. Reported Base-Promoted Reaction of Cyclopro-
pane 18
Oxepines (aka oxepenes) are seven-membered oxacycles
with at least one double bond present in the ring.1 Interest in
the synthesis of substituted oxepines has been driven by their
inclusion in a number of bioactive natural products1 and the
ability to convert them into a diverse range of septanosides.2
These seven-membered-ring sugars have the potential to
In an effort to prepare a variety of oxepines containing the
2-bromoalkene functionality for further manipulations to
novel septanosides, we repeated the chemistry reported by
(1) (a) Snyder, N. L.; Haines, H. M.; Peczuh, M. W. Tetrahedron, 2006, 62,
9301-9320 and references cited therein. (b) Pakulski, Z. Pol. J. Chem. 2006, 80,
1293–1326.
(2) (a) Batchelor, R.; Harvey, J. E.; Northcote, P. T.; Teesdale-Spittle, P.;
Hoberg, J. O. J. Org. Chem. 2009, 74, 7627–7632. (b) DeMatteo, M. P.;
Snyder, N. L.; Morton, M.; Baldisseri, D. M.; Hadad, C. M.; Peczuh, M. W.
J. Org. Chem. 2005, 70, 24–38.
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9045. (b) Hoberg, J. O. J. Org. Chem. 1997, 62, 6615–6618.
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Chem. 2010, 75, 215–218. (b) Ganesh, N. V.; Jayaraman, N. J. Org. Chem.
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DOI: 10.1021/jo902306a
r
Published on Web 01/12/2010
J. Org. Chem. 2010, 75, 955–958 955
2010 American Chemical Society

Hewitt and Harvey
JOCNote
Nagarajan,8 in which the D-glucal-derived gem-dibromocy-
clopropane 1 is treated with potassium carbonate in metha-
nol and heated at reflux. This provided a separable pair of
diastereoisomeric bromoalkenes in a 1.1:1 ratio and 67%
combined yield, and with NMR spectral data that match
those previously reported.8 The expected ring-expansion
mechanism would involve ejection of a bromide ion with
concomitant electrocyclic opening to give the oxygen-stabi-
lized allylic cation 2 (Scheme 1). Attack by methoxide at
C1 of this oxonium ion would result in formation of the
anomeric methyl 2-bromo-2,3-unsaturated oxepines 3 that
were reported.8 However, the absence of a significant cou-
pling between the proton of the benzyl-protected allylic
oxymethine and the alkene proton in both anomers cast
doubt upon structure 3. In addition, the chemical shifts of the
olefinic protons (ca. 6.8 ppm) were surprisingly high for
the alkene of structure 3. Moreover, the observation of
NOE correlations between the alkene and acetal protons
indicated that the products were actually the 2-C-branched
pyranosides 4r and 4β (Scheme 2), rather than the reported
2-bromooxepines.8 The anomeric stereochemistry was ten-
tatively assigned on the basis of small NOE enhancements
between H-1 and H-5 in the minor (β-) anomer, and between
H-1 and H-6 in the major (R-) anomer. More compelling
evidence was obtained through derivatization, in which the
major isomer was subjected to bromine-for-lithium ex-
change and a quench, generating the known 2-C-methylene
R-pyranoside 5 (Scheme 2).14 The spectroscopic data match
those previously reported,14 with the NMR spectra of the
resulting product showing distinctive signals for an exocyclic
methylene group, thus serving to confirm the revised structures.
facilitated by formation of an oxonium ion, would produce a
zwitterion that has the potential to convert to the products.16
The same 2-C-branched pyranosides 4r and 4β are also
generated from cyclopropane 1 by the action of methanolic
sodium methoxide in THF (Scheme 3). These conditions
allow faster reaction while maintaining a good yield (71%)
and have been adapted for the generation of allyl and benzyl
glycosides as shown in Scheme 3. The ratios of anomers in
the crude reaction mixtures range from 1.1:1 to 2.3:1, and the
isolated yields reflect these ratios.
SCHEME 3. Conversion of Cyclopropane 1 into 2-C-Branched
Pyranosides
2-C-Methylene glycosides,14,17 of which products 4, 6, and
7 are novel examples, are important modified sugars with
potential for transformation into a diverse range of carbohy-
drate mimetics by functionalization at the anomeric position,
the alkene, and, in this case, the bromide. Derivatizations of
these 2-C-branched pyranosides are currently underway.
The use of silver(I) salts is widely favored in promoting
ring expansion of gem-dihalocyclopropanes.12,13 The result-
ing allylic cation can be trapped by the ejected halide ion, the
silver counterion, or an intra- or intermolecular nucleo-
phile.12,13,18 However, we found that reaction of gem-diha-
locyclopropane 1 with silver tetrafluoroborate or silver
acetate in methanol at reflux was extremely sluggish. Never-
theless, acetal and alkenyl proton resonances were detected
in the NMR spectrum after several days’ reaction, and small
quantities of the ring-expanded 2-bromooxepine anomers
3r and 3β were isolated in 11% and 4% yields, respectively
(Scheme 4). The NMR spectra of these materials were
distinctly different from those of the base-derived products.
Specifically, the alkene protons were in the expected region
(δ 6.44 and 6.33 for 3r and 3β, respectively), and the
expected homonuclear 3-bond couplings between the alkene
SCHEME 2. Revised Product Structures from Base-Promoted
Reaction of Cyclopropane 1
1
(H3) and allylic (H4) protons were observed in the H and
COSY spectra of both anomers.
It appeared likely that the silver-promoted reaction would
proceed more efficiently at a higher temperature.19 The use
of alternative nucleophiles and solvents would allow ex-
ploration of higher temperatures than methanol provides.
In agreement with the results reported by Nagarajan et al.,
we found that reaction of cyclopropane 1 with silver acetate
The mode of cyclopropane ring-opening observed here is
unusual, but related reactions in which gem-dichlorocyclo-
propanes are converted, using potassium tert-butoxide, to
dienes incorporating a chloromethylidene branch have been
reported by Banwell and co-authors.11c,g There are several
possible mechanisms that would account for the course of
these reactions. For example, a cyclopropene, formed from 1
by alkoxide-induced elimination of the elements of HBr,12b,15
may ring open to provide, in a stereoselective manner, the
observed branched products. Alternatively, direct opening of
the cyclopropane to an exocyclic dibromomethyl anion,11g
(16) The presence of a hydrogen atom at the 2-position is necessary for
formation of the observed branched products by all of the plausible
mechanistic pathways, and therefore the oxepine structures assigned by
Ganesh and Jayaraman9 in the more substituted 2-oxyglycal-derived systems
are assumed to be correct.
(17) (a) Kashyap, S.; Vidadala, S. R.; Hotha, S. Tetrahedron Lett. 2007, 48,
8960-8962 and references cited therein. (b) Sato, K.; Sekiguchi, T.; Hozumi, T.;
Yamazaki, T.; Akai, S. Tetrahedron Lett. 2002, 43, 3087–3090.
ꢀ
(18) Verhe, R.; De Kimpe, N. In The Chemistry of the Cyclopropyl Group;
(14) Booma, C.; Balasubramanian, K. K. J. Chem. Soc., Chem. Commun.
1993, 1394–1395.
(15) Baird, M. S. In Advances in Strain in Organic Chemistry; Halton, B.,
Ed.; JAI Press Ltd: London, UK, 1991; Vol. 1, pp 65-116.
Rappoport, Z., Ed.; John Wiley & Sons: Chichester, UK, 1987; Vol. 1, pp
445-564.
(19) Reactions in a sealed vessel under microwave irradiation generate
several new products, and will be discussed in a future publication.
956 J. Org. Chem. Vol. 75, No. 3, 2010

Hewitt and Harvey
JOCNote
SCHEME 4. Silver-Promoted Ring Expansions of Cyclopro-
pane 1
127.5 (CH), 112.6 (CH), 98.9 (CH), 79.3 (CH), 76.1 (CH), 73.1
(CH2), 71.5 (CH2), 71.4 (CH), 70.8 (CH2), 69.5 (CH2), 55.2
(CH3); IR (KBr) 3054, 3027, 2961, 2865, 1629, 1496, 1453, 1345,
1261, 1094, 1072, 802, 735, 697 cm-1
.
4r: Rf 0.25 (1:9 EtOAc/hexanes); [R]17 þ18 (c 1.0, CHCl3)
D
[lit.8 [R]25D þ26.7 (c 1, CHCl3)]; 1H NMR (500 MHz, CDCl3) δ
7.36-7.24 (complex m, 15H), 6.78 (s, 1H), 5.05 (s, 1H), 4.71
(d, J =11.5 Hz, 1H), 4.69 (d, J = 3.7 Hz, 1H), 4.62 (d, J = 11.7 Hz,
1H), 4.52 (complex m, 2H), 4.50 (d, J = 11.7 Hz, 1H), 4.48
(d, J = 11.7 Hz, 1H), 3.91 (dd, J = 5.0, 3.8 Hz, 1H), 3.85
(m, 1H), 3.83 (dd, J = 10.0, 5.2 Hz, 1H), 3.77 (dd, J = 10.0, 5.1 Hz,
1H), 3.47 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 138.4 (C),
138.3 (C), 137.8 (C), 137.0 (C), 128.4 (CH), 128.33 (CH), 128.25
(CH), 127.9 (CH), 127.8 (CH), 127.7 (CH), 127.56 (CH), 127.55
(CH), 114.7 (CH), 101.1 (CH), 76.0 (CH), 74.9 (CH), 74.6 (CH),
73.3 (CH2), 72.2 (CH2), 70.9 (CH2), 70.6 (CH2), 55.8 (CH3); IR
(KBr) 3060, 3030, 2912, 2865, 1629, 1496, 1453, 1363, 1303,
1205, 1097, 1072, 1027, 818, 735, 697 cm-1; HRMS m/z
C29H31O579BrK [M þ K]þ calcd 577.0992, found 577.0988.
Methyl 3,4,6-Tri-O-benzyl-2-deoxy-2-C-methylene-r-D-ara-
bino-hexopyranoside (5). A solution of bromide 4r (20 mg,
0.037 mmol) in THF (0.5 mL) was cooled to -78 °C and treated
with n-butyllithium (50 μL, 1.6 M in hexanes) and then stirred at
this temperature for 1 h. The reaction mixture was then treated
with water (50 μL), and immediately allowed to warm to room
temperature. After 30 min of additional stirring, the reaction
mixture was diluted with water, then extracted with diethyl
ether. The ethereal fractions were combined, dried, and con-
centrated to provide a colorless oil, which was purified by flash
chromatography (1:9 EtOAc/hexanes) to provide known alkene
514 (5 mg, 29% yield) as a colorless oil: Rf 0.25 (1:9 EtOAc/
hexanes); [R]17 þ13 (c 0.3, CHCl3) [lit.14 [R]25 þ32 (c 1,
in refluxing acetic acid caused extensive decomposition.8
However, optimization of the reaction conditions provided
the anomeric acetates 8r and 8β in 52% yield and a 3.5:1
ratio after treatment with silver(I) acetate in acetic acid at
100 °C (Scheme 4). Replacing the acetic acid with toluene
and adding sodium acetate (5 equiv) to the reaction led to
improved results (65% combined yield, 4.3:1 ratio of 8r
and 8β). The anomeric stereochemistries of the oxepines
8 were tentatively assigned on the basis of an NOE enhance-
ment (ca. 5%) between H1 and H6 in the minor isomer. The
presence of the anomeric acetate provides an opportunity for
the formation of alternative glycosidic linkages. The alkenyl
bromide moiety provides scope for further derivatizations to
a range of septanosides.
In summary, several 2-C-branched pyranosides and
septanoside precursors have been prepared. The product
structures previously reported8 for the reaction of D-glucal-
derived cyclopropane 1 with potassium carbonate in metha-
nol have been revised as 2-C-branched pyranose sugars.
Additionally, conditions involving silver(I) salts that suc-
cessfully produce 2-bromooxepines are provided.
D
D
CH2Cl2)]; 1H NMR (500 MHz, CDCl3) δ 7.40-7.15 (complex
m, 15H), 5.30 (s, 1H), 5.16 (s, 1H), 5.06 (s, 1H), 4.87 (d, J = 10.7
Hz, 1H), 4.76 (d, J = 11.2 Hz, 1H), 4.70 (d, J = 11.2 Hz, 1H),
4.63 (d, J = 12.0 Hz, 1H), 4.51 (d, J = 12.2 Hz, 1H), 4.49 (d, J =
10.7 Hz, 1H), 4.42 (dd, J = 9.0, 2.0 Hz, 1H), 3.92 (ddd, J = 9.9,
3.8, 1.9 Hz, 1H), 3.75 (dd, J = 10.6, 3.9 Hz, 1H), 3.69 (dd, J =
10.6, 1.9 Hz, 1H), 3.60 (t, J = 9.4 Hz, 1H), 3.38 (s, 3H); 13C
NMR (125 MHz, CDCl3) δ 142.3 (C), 138.32 (C), 138.27 (C),
138.1 (C), 128.4 (CH), 128.3 (CH), 127.9 (CH), 127.8 (CH),
127.7 (CH), 127.63 (CH), 127.61 (CH), 110.7 (CH2), 102.4 (CH),
81.2 (CH), 79.9 (CH), 74.9 (CH2), 73.5 (CH2), 73.4 (CH2), 71.5
(CH), 68.8 (CH2), 54.5 (CH3); IR (KBr) 3029, 2907, 1496, 1454,
1359, 1102, 1067, 1026, 968, 736, 697 cm-1; HRMS m/z
C29H32O5Na [M þ Na]þ calcd 483.2147, found 483.2145.
Methyl 4,5,7-Tri-O-benzyl-2-bromo-2,3-dideoxy-r-D-arabi-
no-hept-2-enoseptanoside (3r) and Methyl 4,5,7-Tri-O-benzyl-
2-bromo-2,3-dideoxy-β-D-arabino-hept-2-enoseptanoside (3β). A
solution of cyclopropane 1 (104 mg, 0.177 mmol) in methanol
(1.7 mL) was treated with silver acetate (37 mg, 0.22 mmol) and
refluxed for 5 days in the dark. The reaction mixture was then
diluted with diethyl ether, and filtered through a pad of Celite,
then the ethereal filtrate was washed with water. The aqueous
wash was further extracted with diethyl ether, then the ethereal
solutions were combined, dried (MgSO4), filtered, and concen-
trated to provide a pale-yellow oil. Purification of this crude
product by column chromatography (silica, 1:9 EtOAc/hexanes)
delivered recovered starting material 1 (63 mg, 61%), plus ox-
epines 3β (4 mg, 4%) as a colorless oil and 3r (11 mg, 11%) as a
colorless oil.
Experimental Section
General Procedure for the Synthesis of 2-C-Branched Pyrano-
sides. A solution of sodium alkoxide (ca. 1.5 equiv) in the
corresponding alcohol (ca. 5 equiv), prepared by dissolution
of metallic sodium in the alcohol, was diluted with THF (10 mL/
mmol of cyclopropane). Cyclopropane 1 (1 equiv) was added
and the resulting solution was refluxed until the starting ma-
terial was consumed. The reaction mixture was then cooled,
diluted with water, and extracted with dichloromethane. The
combined organic fractions were dried (MgSO4), filtered, and
concentrated. The crude products were separated with flash
chromatography.
Methyl (2E)-3,4,6-Tri-O-benzyl-2-C-(bromomethylene)-2-deoxy-
r-D-arabino-hexopyranoside (4r) and Methyl (2E)-3,4,6-Tri-O-
benzyl-2-C-(bromomethylene)-2-deoxy-β-D-arabino-hexopyrano-
side (4β). Use of sodium (6.5 mg, 0.3 mmol), methanol (63 μL,
1.6 mmol), THF (1.7 mL), and cyclopropane 1 (100 mg, 0.17
mmol) as described above yielded a yellow oil after 75 min.
Chromatography of this oil (silica, 1:9 EtOAc/hexanes) af-
forded compounds 4β (20 mg, 22%) as a colorless oil and 4r
(45 mg, 49%) as a colorless oil.
4β: Rf 0.35 (1:9 EtOAc/hexanes); [R]17 þ57 (c 1.0, CHCl3)
D
1
[lit.8 [R]25 þ69 (c 2, CHCl3)]; H NMR (500 MHz, CDCl3) δ
D
7.41-7.18 (complex m, 15H), 6.81 (d, J = 1.7 Hz, 1H), 5.19 (d,
J = 1.7 Hz, 1H), 4.73 (d, J = 1.2 Hz, 1H), 4.64 (d, J = 12.2 Hz,
1H), 4.60 (d, J = 12.2 Hz, 1H), 4.52 (d, J = 11.5 Hz, 1H), 4.50
(d, J = 12.2 Hz, 1H), 4.43 (d, J = 12.2 Hz, 1H), 4.29 (d, J = 11.5
Hz, 1H), 3.74 (dd, J = 9.0, 1.5 Hz, 1H), 3.69 (ddd, J = 8.8, 5.1,
2.4 Hz, 1H), 3.65 (dd, J = 10.9, 2.5 Hz, 1H), 3.62 (dd, J = 10.9,
5.3 Hz, 1H), 3.47 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 138.3
(C), 138.1 (C), 137.7 (C), 137.5 (C), 128.32 (CH), 128.27 (CH),
128.0 (CH), 127.9 (CH), 127.8 (CH), 127.72 (CH), 127.67 (CH),
3β: Rf 0.30 (1:9 EtOAc/hexanes); 1H NMR (500 MHz,
CDCl3) δ 7.36-7.15 (complex m, 15H), 6.33 (d, J = 5.1 Hz,
1H), 5.14 (s, 1H), 4.68 (d, J = 12.0 Hz, 1H), 4.65 (d, J = 11.2 Hz,
1H), 4.59 (d, J = 11.7 Hz, 1H), 4.59 (d, J = 12.2 Hz, 1H), 4.51
(d, J = 12.0 Hz, 1H), 4.45 (d, J = 11.2 Hz, 1H), 4.17-
4.14 (complex m, 2H), 3.77 (dd, J = 8.9, 5.7 Hz, 1H), 3.70 (dd,
J = 10.5, 5.6 Hz, 1H), 3.61 (dd, J = 10.5, 2.7 Hz, 1H), 3.46 (s, 3H);
J. Org. Chem. Vol. 75, No. 3, 2010 957

Hewitt and Harvey
JOCNote
13C NMR (125 MHz, CDCl3) δ 138.2 (C), 138.1 (C), 137.9 (C),
132.1 (CH), 128.5 (CH), 128.4 (CH), 128.3 (CH), 127.90 (CH),
127.87 (CH), 127.85 (CH), 127.76 (CH), 127.71 (CH), 127.6
(CH), 124.7 (C), 102.1 (CH), 80.5 (CH), 78.9 (CH), 73.7 (CH2),
73.2 (CH2), 72.1 (CH2), 71.5 (CH), 70.4 (CH2), 56.5 (CH3).
3r: Rf 0.25 (1:9 EtOAc/hexanes); 1H NMR (500 MHz,
CDCl3) δ 7.37-7.14 (complex m, 15H), 6.44 (dd, J = 7.1, 1.0
Hz, 1H), 5.05 (s, 1H), 4.68 (d, J = 12.2 Hz, 1H), 4.57-4.56 (com-
plex m, 2H), 4.51 (d, J = 12.4 Hz, 1H), 4.49 (d, J = 12.2 Hz, 1H),
4.33 (d, J = 11.5 Hz, 1H), 4.09 (dd, J = 7.1, 1.2 Hz, 1H), 3.70-
3.69 (complex m, 2H), 3.65-3.63 (complex m, 2H), 3.47 (s, 3H);
13C NMR (125 MHz, CDCl3) δ 138.2 (C), 137.9 (C), 137.4 (C),
132.2 (CH), 128.5 (CH), 128.42 (CH), 128.37 (CH), 128.0 (CH),
127.93 (CH), 127.85 (CH), 127.7 (CH), 127.6 (CH), 123.5 (C),
104.2 (CH), 80.0 (CH), 77.4 (CH), 75.3 (CH), 73.3 (CH2),
72.7 (CH2), 71.3 (CH2), 71.0 (CH2), 55.8 (CH3); HRMS m/z
C29H31O579BrNa [M þ Na]þ calcd 561.1253, found 561.1256.
Acetyl 4,5,7-Tri-O-benzyl-2-bromo-2,3-dideoxy-r-D-arabino-
hept-2-enoseptanoside (8r) and Acetyl 4,5,7-Tri-O-benzyl-2-bromo-
2,3-dideoxy-β-D-arabino-hept-2-enoseptanoside (8β). Method A:
A solution of cyclopropane 1 (101 mg, 0.17 mmol) in acetic
acid (1.7 mL) was treated with silver acetate (39 mg, 0.23 mmol)
and then stirred at 100 °C for 25 h. The resulting cooled solution
was diluted with dichloromethane and filtered through a pad of
Celite, then the filtrate was washed with water. The aqueous
phase was extracted further with dichloromethane, then the
organic fractions were combined, dried (MgSO4), filtered, and
concentrated to provide a mixture of compounds 8r and 8β
(3.5:1 ratio) as a light-yellow oil. Purification by column chro-
matography (1:14 EtOAc/hexanes) yielded the major oxepine
8r (14 mg, 14%) as a clear, colorless oil, and a mixture of 8r and
8β (37 mg, 38% yield).
81.1 (CH), 77.2 (CH), 74.4 (CH), 73.4 (CH2), 73.2 (CH2), 71.7
(CH2), 70.3 (CH2), 20.7 (CH3); IR (KBr) 3086 3058, 3030, 2863,
1753, 1639, 1496, 1454, 1368, 1221, 1071, 1005, 952, 737, 698
cm-1; HRMS m/z C30H31O679BrNa [M þ Na]þ calcd 589.1202,
found 589.1202.
The following data were obtained for 8β by subtracting the
NMR signals for 8r from those of the mixture obtained. 8β: Rf
0.15 (1:9 EtOAc/hexanes); 1H NMR (500 MHz, CDCl3) δ
7.36-7.14 (complex m, 15H), 6.45 (m, 1H), 6.33 (s, 1H), 4.69-
4.37 (complex m, 6H), 4.15 (m, 1H), 3.92 (dd, J = 11.0, 5.9 Hz,
1H), 3.80 (dd, J = 6.3, 4.4 Hz, 1H), 3.67-3.52 (complex m, 2H),
2.15 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 169.0 (C), 138.1 (C),
137.8 (C), 137.5 (C), 133.4 (CH), 128.45 (CH), 128.40 (CH),
128.33 (CH), 127.93 (CH), 127.88 (CH), 127.81 (CH), 125.6 (C),
94.4 (CH), 79.2 (CH), 78.6 (CH), 75.4 (CH), 73.3 (CH2), 72.7
(CH2), 71.6 (CH2), 70.4 (CH2), 20.9 (CH3).
Method B: A solution of cyclopropane 1 (102 mg, 0.173
mmol) in toluene (1.7 mL) was treated with sodium acetate
(72 mg, 0.88 mmol) and silver acetate (41 mg, 0.25 mmol) and
then stirred at reflux for 28 h. The resulting cooled solution was
filtered through a pad of silica gel, further eluted with dichlor-
omethane, then the fractions were combined, dried (MgSO4),
filtered, and concentrated to provide a mixture of compounds
8r and 8β (4.3:1 ratio) as a colorless oil. Purification by column
chromatography (1:14 EtOAc/hexanes) yielded a mixture of 8r
and 8β (64 mg, 65% combined yield).
Acknowledgment. The Cancer Society of New Zealand is
gratefully acknowledged for the provision of a Ph.D. scho-
larship (R.J.H.). The Faculty of Science and the School of
Chemical and Physical Sciences, VUW, provided conference
funding and scholarship assistance (R.J.H.). We sincerely
thank Assoc Prof. Peter Northcote, Dr. Brendan Burkett,
Em. Prof. Brian Halton, and Assoc. Prof. Paul Teesdale-
Spittle for helpful discussions and proof-reading during the
course of this research.
8r: Rf 0.15 (1:9 EtOAc/hexanes); [R]19D -23 (c 0.7, CHCl3);
1H NMR (500 MHz, CDCl3) δ 7.36-7.16 (complex m, 15H),
6.57 (s, 1H), 6.46 (dd, J = 6.3, 1.2 Hz, 1H), 4.68 (d, J = 12.0 Hz,
1H), 4.57 (d, J = 11.2 Hz, 1H), 4.56 (d, J = 12.0 Hz, 1H), 4.51
(d, J = 11.7 Hz, 1H), 4.45 (d, J = 11.7 Hz, 1H), 4.38 (d, J = 11.2
Hz, 1H), 4.17-4.14 (complex m, 2H), 3.74 (dd, J = 9.1, 4.2 Hz,
1H), 3.61 (dd, J = 10.5, 2.4 Hz, 1H), 3.54 (dd, J = 10.5, 7.1 Hz,
1H), 1.93 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 169.3 (C),
138.0 (C), 137.8 (C), 137.5 (C), 133.5 (CH), 128.5 (CH), 128.4
(CH), 128.3 (CH), 128.0 (CH), 127.95 (CH), 127.93 (CH),
127.88 (CH), 127.8 (CH), 127.6 (CH), 123.9 (C), 93.4 (CH),
Supporting Information Available: General experimental
methods, experimental procedures, and compound character-
ization data for all products (3-8), copies of 1H and 13C NMR
spectra for 3-8, copies of NOE spectra for 4, and copies of
COSY spectra for 3, 4, and 8. This material is available free of
charge via the Internet at http://pubs.acs.org.
958 J. Org. Chem. Vol. 75, No. 3, 2010