A diastereoselective unique route to cyclopropanes functionalized at all three ring carbon atoms from acyclic vinyl sulfone-modified carbohydrates

Article abstract of DOI:10.1021/jo802709q

In a departure from the current trend of using metal-catalyzed routes to cyclopropanation, pentosyl and hexosyl vinyl sulfone-modified carbohydrates having the terminal double bond and a suitably positioned leaving group are reacted in a stereoselective f

Full text of DOI:10.1021/jo802709q

A Diastereoselective Unique Route to Cyclopropanes Functionalized
at All Three Ring Carbon Atoms from Acyclic Vinyl
Sulfone-Modified Carbohydrates†
Ananta Kumar Atta and Tanmaya Pathak*
Department of Chemistry, Indian Institute of Technology, Kharagpur 721 302, India
tpathak@chem.iitkgp.ernet.in
ReceiVed December 10, 2008
In a departure from the current trend of using metal-catalyzed routes to cyclopropanation, pentosyl and
hexosyl vinyl sulfone-modified carbohydrates having the terminal double bond and a suitably positioned
leaving group are reacted in a stereoselective fashion with a series of nucleophiles to yield a myriad of
cyclopropanes substituted at all three ring carbon atoms.
Introduction
useful synthetic building blocks because of the presence of
“push-pull” effects1d,2r imparted by these functional groups.
Complex chiral cyclopropanes, especially those having stereo-
centers at all three ring carbon atoms, are reported to be of great
interest.3
Chemists have long been fascinated by the cyclopropane
subunit because of its presence in a wide range of natural
products as well as the usefulness of this strained cycloalkane
in other areas of research.1 While unactivated cyclopropanes
have been directly utilized to a limited extent in chemical
synthesis, activated cyclopropanes, such as cyclopropanes
substituted with electron withdrawing or electron donating
groups, have been used extensively as precursors in several
chemical syntheses.1c,2 Moreover, cyclopropanes having donor
and acceptor groups on vicinal carbons have been identified as
Although transition metal-mediated synthesis of cyclopro-
panes has emerged as a general and popular route in recent
times,4 one of the most important advances in cyclopropane
chemistry over the past decade has also taken place in the area
of integrating cyclopropanes and carbohydrates.1c,5 The incor-
poration of cyclopropanes into a carbohydrate provides an
interesting mixture of strained and reactive cyclopropanes
combined with the well-defined stereochemistry inherent in
carbohydrates.1c,5 Although there are several reports on the
synthesis of cyclopropane rings on furanosyl6 and pyranosyl
carbohydrates,7 construction of cylopropanes on acyclic sugars
is virtually unknown. In our search for an efficient nonmetal-
based route for cyclopropanation, we opined that a suitably
† Dedicated to Professor Jyoti Chattopadhyaya on occasion of his 60th
birthday.
(1) (a) Lebel, H.; Marcoux, J.-F.; Molinaro, C.; Charette, A. B. Chem. ReV.
2003, 103, 977. (b) Kulinkovich, O. G. Chem. ReV. 2003, 103, 2597. (c) Yu,
M.; Pagenkopf, B. L. Tetrahedron 2005, 61, 321. (d) von Angerer, S. In
Carbocyclic Three- and Four-membered Ring Compounds. Methods of Organic
Chemistry (Houben-Weyl); de Meijere, A., Ed.; Verlag: New York, 1997; Vol.
E17c, pp 2121-2153.
2710 J. Org. Chem. 2009, 74, 2710–2717
10.1021/jo802709q CCC: $40.75 2009 American Chemical Society
Published on Web 03/09/2009

A DiastereoselectiVe Unique Route to Cyclopropanes
SCHEME 1. General Strategy for the Synthesis of
Cyclopropanes Substituted at All Ring Carbon Atoms
constructed vinyl sulfone group on an open-chain carbohydrate
having a leaving group at the proximity would generate a
chirally pure cyclopropane. Although cyclopropanes were
synthesized from 3-halo-1-alkenyl sulfones three decades back,8d
the strategy stagnated over the years for the nonavailability of
straightforward and general methodologies for the synthesis of
acyclic vinyl sulfones, especially chirally substituted acyclic
vinyl sulfones.8a-c We argued that 1-alkenyl sulfones having
leaving groups at the 4-positions, such as A, may be derived
from carbohydrates. An attack of a nucleophile to such a vinyl
sulfone would generate the negative charge on the sulfone to
generate B and a concomitant attack to the carbon bearing a
leaving group would generate the cyclopropane C (Scheme 1).
The application of this strategy would, however, crucially
depend on the availability of appropriate starting materials.
hexopyranoses through a Ferrier rearrangement. The anomeric
alkoxyl radical fragmentation of these γ-hydroxy sulfones using
the system (diacetoxyiodo)benzene and iodine gave vinyl
sulfones with structures of 1,2-dideoxy-4-O-formyl-2-(phenyl-
sulfonyl)-pent-1-enitol and configurations D-erythro, L-erythro,
and D-threo at the two stereogenic centers.11 Although this
strategy does provide a route to a new class of acyclic vinyl
sulfone-modified carbohydrates, the loss of the one (anomeric)
carbon in the process leading to the formation of five-carbon
systems from hexoses severely restricts its application. We
opined that the best strategy for the synthesis of acyclic vinyl
sulfone-modified carbohydrates would be to design a carbohy-
drate-based route without shortening the chain length.11 This
route would provide access to both five-carbon and six-carbon
acyclic vinyl sulfone-modified carbohydrates depending on the
structure of the starting carbohydrates.
Results and Discussion
There are scant reports on the synthesis of acyclic vinyl
sulfone-modified carbohydrates.9 In the recent past, several
dihydroxylated acyclic vinyl-sulfones, which could be consid-
ered as derivatives of pentoses, have been used in the synthesis
of diverse groups of heterocyclic and carbocyclic compounds;
the synthesis of these vinyl sulfones, however, originated from
noncarbohydrate precursors.9,10 In an attempt to develop a
general strategy for the synthesis of acyclic vinyl sulfone-
modified carbohydrates, Suarez and co-workers reacted the
derivatives of 3-acetyl-D-glycals with sodium benzenesulfinate
in acid medium catalyzed by HgSO4 to afford diastereoisomeric
mixtures of the corresponding 2,3-dideoxy-3-(phenylsulfonyl)-
For the synthesis of the starting material, it was necessary to
incorporate the thiol group as well as other protecting groups
strategically to afford the correct starting material for the
cyclopropanation reaction. Thus, our synthesis of the pentose-
based acyclic vinyl sulfone-modified carbohydrates started from
the easily accessible epoxide 1,12 which was regioselectively
opened at C2 with thiocresol to provide 2. The free hydroxyl
group of 2 was benzyl protected to afford 3 and the furanosyl
ring of 3 was cleaved under acidic conditions. The product thus
generated was reduced to the corresponding diol 4, which was
oxidized to the sulfone 5. Mesylation of 5 and concomitant
elimination of methanesulfonic acid under basic conditions
afforded the required vinyl sulfone 6 in good overall yield
(Scheme 2). For the synthesis of the higher homologue of 6,
the hexofuranosyl epoxide 712 was treated with thiocresol to
afford 8 in a regioselective fashion. Compound 8 was converted
to the vinyl sulfone 12 via intermediates 9-11 in good overall
yield following the route described for 6 (Scheme 2).
Phthalimide reacted with vinyl sulfone 6 in the presence of
NaH to afford the cyclopropane 13 (Table 1; entry 1), which
was easily deprotected to generate the amino methyl cyclopro-
pane 14 (Table 1; entry 1). The nucleophilic oxygen derived
from MeOH/Na and p-methoxybenzyl alcohol (PMBOH)/NaH
added efficiently to 6 to afford the cyclopropanes 15 (Table 1;
entry 2) and 16 (Table 1; entry 3), respectively. Compound 16
was demasked to generate the free alcohol 17 (Table 1; entry
3). NaSMe reacted in a similar fashion to yield the thiomethyl
derivative 18 (Table 1; entry 4). The carbon nucleophile
generated from CH3NO2/NaH also reacted efficiently with 6 to
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J. Org. Chem. Vol. 74, No. 7, 2009 2711

Atta and Pathak
TABLE 1. Cyclopropanes from Pentosyl Acyclic Vinyl Sulfone 6
SCHEME 2. Synthesis of Pentosyl and Hexosyl Acyclic
Vinyl Sulfones
generate the nitro cyclopropane 19 (Table 1; entry 5). Interest-
ingly a nucleobase thymine also efficiently added to 6 in a
Michael fashion but did not undergo (1H NMR) concomitant
cyclization. Therefore, the intermediate still retaining the mesyl
group was treated with NaH to afford the cyclopropane 20
(Table 1; entry 6). On reactions with 6, NaBH4 in MeOH
generated a mixture of products which were converted to a
single compound 21 (Table 1; entry 7) with NaH. The hexosyl
vinyl sulfone 12 also reacted with nucleophiles generated from
phthalimide, NaOMe, p-methoxybenzyl alcohol, NaSMe, BnSH,
thymine, and NaBH4/MeOH to afford cyclopropanes 22-29,
respectively (Table 2; entries 1-6, respectively).
To establish the stereochemistry of the carbon bearing the
sulfone group, a representative compound 18 was subjected to
NOE experiments. The cis relationship between the H-2 and
tuted and optically pure cyclopropanes without using metal
catalysts. Depending on the nucleophiles used, the end product
is a wide range of R-substituted cyclopropanols having func-
tional groups at all three ring carbon atoms. These compounds
also belong to a special class of long-sought but difficult-to-
obtain cyclopropanes attached to vicinal donor (-OR) and
acceptor (-SO2Ar) groups.14 It should be noted that during the
past decade serious attempts have been made by several groups
to synthesize cyclopropanes functionalized with sulfones.2r,15
Our expedient and general strategy enriches the arsenal available
to synthetic organic chemists interested in this class of com-
pounds. Research is in progress to expand the scope of this
1
H-3 in compound 18 was deduced from the H NMR param-
eters. The NOE interactions between H-2/H-3 as well as between
H-4/H-5 confirm that H-3 and the sulfonyl group are in a cis
relationship and the sulfonyl group is in a trans relationship
with (C3-C4) and (C2-OBn) (Figure 1).13 In the H NMR
1
spectra of all cyclopropanes, the H-3 protons appeared within
a specific range (δ 2.25-2.50). Possibly the steric interactions
between the bulky ArO2S, R, and OR groups (Scheme 1)
determine the diastereoselectivity of ring formation. Compounds
15 and 23 were desulfonylated by using 6% Na-Hg to afford
a mixture of isomers 30 and 32, respectively, in moderate yields
(Table 3) whereas 18 and 26 were resistant to desulfonylation
under similar reaction conditions. Compounds 18 and 26,
however, were desulfonylated in moderate yields with LAH to
afford 31 and 33, respectively (Table 3).
In conclusion, we have described an alternative and powerful
general strategy for the synthesis of a new class of polysubsti-
(13) Garci´ıa Ruano, J. L.; Alonso de Diego, S. A.; Rosario, M. M.; Torrente,
E.; Mart´ın, C. A. M. Org. Lett. 2004, 6, 4945.
FIGURE 1. NOE interactions of compound 18.
2712 J. Org. Chem. Vol. 74, No. 7, 2009

A DiastereoselectiVe Unique Route to Cyclopropanes
TABLE 2. Cyclopropanes from Hexosyl Acyclic Vinyl Sulfone 12
TABLE 3. Desulfonylation of Selected Compounds
of NaHCO3, and the product was extracted with EtOAc (3 × 10
mL). The combined organic layer was dried over anhyd Na2SO4
then filtered, and the filtrate was concentrated under reduced
pressure. The residue was purified over silica gel to afford the
sulfide 2 (4.69 g, 83%). Yellow oil, [R]24 -1.2 (c 0.15, CHCl3);
D
1H NMR (400 MHz, CDCl3) δ 2.33 (s, 3H), 2.55 (d, 1H, J ) 8
Hz), 3.38 (s, 3H), 3.54-3.55 (m, 1H), 3.63-3.73 (m, 2H),
3.96-4.00 (m, 1H), 4.17-4.21 (m, 1H), 4.61 (q, 2H, J ) 12 Hz),
4.96 (s, 1H), 7.12 (d, 2H, J ) 8 Hz), 7.27-7.38 (m, 7H); 13C NMR
(100 MHz, CDCl3) δ 21.0, 55.2, 58.2, 70.4 (CH2), 73.5 (CH2), 77.7,
84.1, 108.6, 127.7, 127.8, 128.4, 129.9, 130.3, 131.1, 137.3, 137.8;
HRMS [ES+, (M + Na)+] for C20H24O4SNa obsd 383.1275, calcd
383.1293.
3-Benzyloxy-5-methoxy-2-(benzyloxymethyl)-4-[(4-methylphe-
nyl)sulfanyl]tetrahydrofuran, 3. Compound 2 (5.58 g, 15.50
mmol) was stirred at 0 °C with NaH (0.90 g, 18.60 mmol) and
BnBr (2.40 mL, 20.15 mmol) in DMF (50 mL). The mixture was
stirred at room temprature under N2. After 5-6 h, the reaction
mixture was poured into an aq saturated solution of NH4Cl and
the product was extracted with EtOAc (3 × 10 mL). The combined
organic layer was dried over anhyd Na2SO4 then filtered, and the
filtrate was concentrated under reduced pressure to afford a residue.
methodology by using these donor-acceptor cyclopropanes as
novel synthons for further transformations.
Experimental Section
The residue was purified over silica gel to afford 3 (5.96 g, 71%).
General Methods. See the Supporting Information.
1
Yellow oil, [R]24 +25.9 (c 0.10, CHCl3); H NMR (400 MHz,
D
5-Methoxy-2-(benzyloxymethyl)-4-[(4-methylphenyl)sulfa-
nyl]tetrahydrofuran-3-ol, 2. To a well-stirred solution of the
epoxide 1 (3.70 g, 15.68 mmol) in DMF (40 mL) was added
thiocresol (9.73 g, 78.4 mmol) and NaOMe (2.54 g, 47.04 mmol).
The mixture was heated at 90-100 °C with stirring under N2. After
4-5 h, the reaction mixture was poured into an aq saturated solution
CDCl3) δ 2.40 (s, 3H), 3.44 (s, 3H), 3.61-3.69 (m, 2H), 3.71-3.72
(m, 1H), 3.88-3.91 (m, 1H), 4.31-4.35 (m, 1H), 4.42 (d, 1H, J )
12 Hz), 4.59-4.66 (m, 3H), 5.0 (s, 1H), 7.17 (d, 2H, J ) 8 Hz),
7.24-7.26 (m, 2H), 7.33-7.43 (m, 10H); 13C NMR (100 MHz,
CDCl3): δ 21.1, 55.2, 56.6, 69.7 (CH2), 72.1 (CH2), 73.4 (CH2),
81.9, 83.7, 109.2, 127.6, 127.7, 127.8, 127.9, 128.1,128.2, 128.3,
129.9, 130.7, 131.2, 137.2, 137.6, 138.0; HRMS [ES+, (M + Na)+]
for C27H30O4SNa obsd 473.1762, calcd 473.1762.
(2R,3R,4R)-3,5-Dibenzyloxy-2-[(4-methylphenyl)sulfanyl]pen-
tane-1,4-diol, 4. Compound 3 (5 g, 11.11 mmol) was added to
75% aq trifloroacetic acid and the mixture was stirred at room
temprature for 5-6 h. The reaction mixture was partitioned between
EtOAc and an aq saturated solution of NaHCO3.The separated
organic layer was washed with water, followed by brine. The
combined organic layer was dried over anhyd Na2SO4 and
concentrated in vacuuo. The residue was dissolved in EtOH (40
mL), and sodium borohydride (1.68 g, 44.44 mmol) was added at
0 °C. After being stirred for 3 h at room temperature, the reaction
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1990, 9, 3133. (e) Fedorynski, M.; Dybowska, A.; Jonczyk, A. Synthesis 1988,
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Chem., Int. Ed. 2003, 42, 828.
J. Org. Chem. Vol. 74, No. 7, 2009 2713

Atta and Pathak
mixture was concentrated under reduced pressure to afford a residue.
CHCl3); 1H NMR (400 MHz, CDCl3) δ 2.33 (s, 3H), 3.35 (s, 3H),
3.55-3.59 (m, 1H), 3.64-3.67 (m, 2H), 3.80-3.84 (m, 1H),
4.03-4.05 (m, 1H), 4.27-4.34 (m, 2H), 4.46-4.54 (m, 3H), 4.72
(q, 2H, J ) 12 Hz), 4.91 (s, 1H), 7.09 (d, 2H, J ) 8 Hz), 7.15-7.16
(m, 2H), 7.22-7.35 (m, 15H); 13C NMR (100 MHz, CDCl3) δ 21.1,
55.1, 56.6, 70.3 (CH2), 71.8 (CH2), 73.1 (CH2), 73.4 (CH2), 77.9,
83.5, 83.6, 108.9, 127.4, 127.5 (2 × C), 127.6, 127.8, 127.9, 128.1,
128.2, 128.3, 129.9, 130.9, 131.2, 137.2, 137.8, 138.3, 138.6; HRMS
[ES+, (M + Na)+] for C35H38O5SNa obsd 593.2339, calcd 593.2338.
(2R,3R,4R)-3,5,6-Tribenzyloxy-2-[(4-methylphenyl)sulfanyl]-
hexane-1,4-diol, 10. Compound 9 (3.40 g, 5.97 mmol) was
converted to 10 (1.90 g, 57%) following the procedure described
for the preparation of 4. Semisolid, [R]24D -32.0 (c 0.11, CHCl3);
1H NMR (400 MHz, CDCl3) δ 2.07-2.19 (m, 1H), 2.31 (s, 3H),
3.12 (d, 1H, J ) 5.6 Hz), 3.51-3.54 (m, 1H), 3.63-3.67 (m, 1H),
3.77-3.85 (m, 4H), 3.96-3.98 (m, 1H), 4.29-4.33 (m, 1H),
4.48-4.62 (m, 5H), 4.70 (d, 1H, J ) 11.6 Hz), 7.06 (d, 2H, J ) 8
Hz), 7.22-7.32 (m, 17H); 13C NMR (100 MHz, CDCl3) δ 21.0,
54.3, 62.9 (CH2), 69.9 (CH2), 72.0 (CH2), 72.9 (CH2), 73.5 (CH2),
77.9, 78.3, 127.6, 127.7, 127.8, 127.9, 128.0, 128.3, 128.4, 129.8,
131.6, 132.2, 137.2, 137.8, 137.9, 138.2; HRMS [ES+, (M + Na)+]
for C34H38O5SNa obsd 581.2337, calcd 581.2338.
The residue was purified over silica gel to afford 4 (2.77 g, 58%).
1
Brown solid, mp 70 °C, [R]24 +10.5 (c 0.10, CHCl3); H NMR
D
(400 MHz, CDCl3) δ 1.92-2.18 (m, 2H), 2.31 (s, 3H), 3.55-3.58
(m, 1H), 3.66-3.83 (m, 4H), 3.89 (d, 1H, J ) 8 Hz), 4.18-4.21
(m, 1H), 4.50-4.61 (m, 4H), 7.08 (d, 2H, J ) 8 Hz), 7.24-7.38
(m, 12H); 13C NMR (100 MHz, CDCl3) δ 21.0, 54.6, 62.8 (CH2),
70.7, 70.9 (CH2), 73.4 (CH2), 73.9 (CH2), 78.1, 127.8, 127.9, 128
(2 × C), 128.4, 128.5, 129.8, 131.9, 132.2, 137.1, 137.7, 137.9;
HRMS [ES+, (M + Na)+] for C26H30O4SNa obsd 461.1749, calcd
461.1763.
(2R,3R,4R)-3,5-Dibenzyloxy-2-[(4-methylphenyl)sulfonyl]pen-
tane-1,4-diol, 5. To a well-stirred solution of sulfide 4 (3.70 g,
8.44 mmol) in dry MeOH (40 mL) was added magnesium
monoperoxyphthalate hexahydrate (12.52 g, 25.32 mmol), and the
mixture was stirred at room temperature under N2. After 6 h, MeOH
was evaporated to dryness under reduced pressure, and the residue
was dissolved in an aq saturated solution of NaHCO3. The aqueous
part was washed with EtOAc (3 × 10 mL). The combined organic
layer was dried over anhyd Na2SO4 and concentrated under reduced
pressure to afford a residue. The residue was purified over silica
gel to afford sulfone 5 (3.61 g, 91%). Brown gum, [R]24D +81.3 (c
0 0.17, CHCl3); 1H NMR (400 MHz, CDCl3) δ 2.40 (s, 3H),
2.80-2.97 (m, 2H), 3.58-3.65 (m, 2H), 3.72-3.75 (m, 1H), 3.95
(dd, 1H, J ) 4.4, 12.4 Hz), 4.08-4.18 (m, 3H), 4.36 (d, 1H, J )
11.2 Hz), 4.45 (q, 2H, J ) 6.4 Hz), 4.53 (d, 1H, J ) 11.6 Hz),
7.04-7.06 (m, 2H), 7.21 (d, 2H, J ) 8 Hz), 7.26-7.37 (m, 8H),
7.73 (d, 2H, J ) 8.4 Hz); 13C NMR (100 MHz, CDCl3) δ 21.6,
59.1 (CH2), 68.4, 70.4 (CH2), 70.7, 73.5 (CH2), 73.5, 76.5, 127.8,
128.0, 127.9, 128.1, 128.3, 128.5, 128.8, 129.6, 136.7, 137.3, 137.8,
144.7; HRMS [ES+, (M + H)+] for C26H31O6S obsd 471.1844, calcd
471.1841.
(2R,3R)-1,3-Dibenzyloxy-4-[(4-methylphenyl)sulfonyl]pent-4-
en-2-yl Methanesulfonate, 6. To a well-stirred solution of sulfone
5 (2.63 g, 5.60 mmol) in pyridine (15 mL) was added methane-
sulfonyl chloride (1.7 mL, 22.40 mmol) in pyridine (10 mL)
dropwise at 0 °C under N2. After completion of the addition, the
reaction mixture was kept at +4 °C. After 24 h (TLC), the reaction
mixture was poured into an aq saturated solution of NaHCO3 and
the product was extracted with EtOAc (3 × 10 mL). The combined
organic layer was dried over anhyd Na2SO4 and concentrated under
reduced pressure to afford a residue. The residue was purified over
silica gel to afford the vinyl sulfone 6 (2.43 g, 82%). Yellow oil,
[R]24D -43.2 (c 0.04, CHCl3); 1H NMR (400 MHz, CDCl3) δ 2.44
(s, 3H), 2.97 (s, 3H), 3.72-3.81 (m, 2H), 4.05 (d, 1H, J ) 11.6
Hz), 4.19 (d, 1H, J ) 11.6 Hz), 4.42-4.54 (m, 3H), 5.19 (br s,
1H), 6.21 (s, 1H), 6.67 (s, 1H), 6.99 (d, 2H, J ) 5.2 Hz), 7.22-7.36
(m, 10H), 7.77 (d, 2H, J ) 7.6 Hz); 13C NMR (100 MHz, CDCl3)
δ 21.6, 38.1, 67.3 (CH2), 71.8 (CH2), 73.2 (CH2), 75.2, 81.3, 127.6,
127.7, 127.8, 127.9, 128.2, 128.3, 128.4 (CH2), 128.7, 129.9, 135.1,
136.3, 137.4, 145.0, 147.5; HRMS [ES+, (M + Na)+] for
C27H30O7S2Na obsd 553.1332, calcd 553.1331.
(2R,3R,4R)-3,5,6-Tribenzyloxy-2-[(4-methylphenyl)sulfonyl]-
hexane-1,4-diol, 11. Compound 10 (4.00 g, 7.17 mmol) was
converted to 11 (3.89 g, 92%) following the procedure described
for the preparation of 5. Semisolid, [R]24D -13.4 (c 0.10, CHCl3);
1H NMR (400 MHz, CDCl3) δ 2.37 (s, 3H), 2.95 (br s, 1H), 3.46
(d, 1H, J ) 6 Hz), 3.56-3.60 (m, 1H), 3.67-3.73 (m, 2H),
3.78-3.82 (m, 1H), 3.96-3.98 (m, 1H), 4.07-4.10 (m, 1H),
4.11-4.16 (m, 1H), 4.24-4.26 (m, 1H), 4.41-4.59 (m, 5H), 4.66
(d, 1H, J ) 11.6 Hz), 7.05-7.07 (m, 2H), 7.15 (d, 2H, J ) 8 Hz,),
7.21-7.36 (m, 13H), 7.66 (d, 2H, J ) 8.4 Hz); 13C NMR (100
MHz, CDCl3) δ 21.5, 59.0 (CH2), 68.5, 69.8 (CH2), 72.2, 72.3
(CH2), 72.8 (CH2), 73.5 (CH2), 77.4, 78.1, 127.5, 127.7, 127.8,
127.9, 128.1, 128.4, 129.5, 136.9, 137.5, 137.8, 138.0, 144.4; HRMS
[ES+, (M + H)+] for C34H39O7S obsd 591.2416, calcd 591.2417.
(2R,3R,4R)-5-[(4-Methylphenyl)sulfonyl]-1,2,4-tribenzyloxy-
hex-5-en-3-yl Methanesulfonate, 12. Compound 11 (3.50 g, 5.93
mmol) was converted to 12 (3.09 g, 80%) following the procedure
described for the preparation of 6. Colorless oil, [R]24 -23.8 (c
D
0.10,CHCl3); 1H NMR (400 MHz, CDCl3) δ 2.40 (s, 3H), 2.94 (s,
3H), 3.56-3.60 (m, 1H), 3.81 (d, 1H, J ) 10 Hz), 4.02 (d, 2H, J
) 10.8 Hz), 4.14 (d, 1H, J ) 11.6 Hz), 4.41-4.51 (m, 3H), 4.64
(q, 2H, J ) 5.2 Hz), 5.24 (d, 1H, J ) 5.2 Hz), 6.16 (s, 1H), 6.59
(s, 1H), 6.98 (d, 2H, J ) 6 Hz), 7.24-7.34 (m, 15H), 7.74 (d, 2H,
J ) 8 Hz); 13C NMR (100 MHz, CDCl3) δ 21.6, 38.6, 69.7 (CH2),
71.6 (CH2), 72.2 (CH2), 73.2 (CH2), 74.9, 76.4, 81.6, 127.6, 127.7,
127.8, 127.9, 128.1, 128.2, 128.3, 128.4, 128.6, 128.7 (CH2), 128.9,
129.9, 135.2, 136.4, 137.7, 138.1, 144.9, 148.1; HRMS [ES+, (M
+ Na)+] for C35H38O8S2Na obsd 673.1909, calcd 673.1906.
2-{[(1S,2R,3S)-2-Benzyloxy-3-(benzyloxymethyl)-1-(4-methyl-
phenylsulfonyl)cyclopropyl]methyl}-1H-isoindole-1,3(2H)-di-
one, 13. To a well-stirred solution of phthalimide (0.39 g, 2.66
mmol) and NaH (0.09 g, 1.90 mmol) in DMF (10 mL) was added
6 (0.20 g, 0.38 mmol) and the mixture was stirred at 50 °C under
N2. After 8 h, the reaction mixture was poured into an aq saturated
solution of NH4Cl and the product was extracted with EtOAc (3 ×
10 mL). The combined organic layer was dried over anhyd Na2SO4
then filtered, and the filtrate was concentrated under reduced
pressure to afford a residue. The residue was purified over silica
gel to afford 13 (0.13 g, 58%). Colorless oil, [R]26D +40.8 (c 0.22,
CHCl3); 1H NMR (400 MHz, CDCl3) δ 2.21 (s, 3H), 2.59 (q, 1H,
J ) 8, 14.4 Hz), 3.85-3.93 (m, 2H), 4.20-4.24 (m, 1H), 4.32 (d,
1H, J ) 8 Hz), 4.39 (d, 1H, J ) 15.2 Hz), 4.61 (q, 2H, J ) 12,
26.4 Hz), 4.79 (q, 2H, J ) 11.6, 26.4 Hz), 6.99 (d, 2H, J ) 8 Hz),
7.27-7.37 (m, 10H), 7.59 (d, 2H, J ) 8 Hz), 7.63-7.68 (m, 4H);
13C NMR (100 MHz, CDCl3) δ 21.5, 27.8, 32.4 (CH2), 43.7, 61.1,
63.6 (CH2), 73.1 (CH2), 74.0 (CH2), 123.1, 127.6, 127.8, 127.9,
127.9, 128.1, 128.4, 128.5, 129.5, 131.9, 133.8, 136.4, 136.9, 138.2,
2-(1,2-Dibenzyloxyethyl)-5-methoxy-4-[(4-methylphenyl)sul-
fanyl]tetrahydrofuran-3-ol, 8. Compound 7 (5.70 g, 16.01 mmol)
was converted to 8 (6.13 g, 80%) following the procedure described
for the preparation of 2. Yellow oil, [R]24 -9.9 (c 0.12, CHCl3);
D
1H NMR (400 MHz, CDCl3) δ 2.32 (s, 3H), 3.07 (d, 1H, J ) 4.8
Hz), 3.34 (s, 3H), 3.54-3.55 (m, 1H), 3.63-3.66 (m, 1H),
3.75-3.83 (m, 2H), 4.05 (t, 1H, J ) 5.6 Hz), 4.21-4.25 (m, 1H),
4.53 (d, 1H, J ) 12 Hz), 4.61 (d, 1H, J ) 12 Hz), 4.67-4.74 (m,
2H), 4.89 (d, 1H, J ) 1.6 Hz), 7.10 (d, 2H, J ) 8 Hz), 7.27-7.37
(m, 12H); 13C NMR (100 MHz, CDCl3) δ 21.1, 55.2, 57.9, 70.5
(CH2), 72.9 (CH2), 73.7 (CH2), 76.2, 78.1, 84.5, 108.7, 127.6, 127.7,
127.8, 127.9, 128.4, 128.5, 129.9, 130.9, 136.9, 137.7, 138.4; HRMS
[ES+, (M + Na)+] for C28H32O5SNa obsd 503.1866, calcd 503.1868.
2-(1,2-Dibenzyloxyethyl)-5-methoxy-3-benzyloxy-4-[(4-methyl-
phenyl)sulfanyl]tetrahydrofuran, 9. Compound 8 (6.90 g, 14.38
mmol) was converted to 9 (6.96 g, 85%) following the procedure
described for the preparation of 3. Yellow oil, [R]24D +45.9 (c 0.14,
2714 J. Org. Chem. Vol. 74, No. 7, 2009

A DiastereoselectiVe Unique Route to Cyclopropanes
144.1, 167.4; HRMS [ES+, (M + Na)+] for C34H31NO6SNa obsd
604.1768, calcd 604.1770.
poured into an aq saturated solution of NaHCO3 and then extracted
with DCM (3 × 10 mL). The combined organic layer was dried
over anhyd Na2SO4 then filtered, and the filtrate was concentrated
under reduced pressure to afford a residue. The residue was purified
over silica gel to afford 17 (0.05 g, 74%). Colorless oil, [R]26D +4.5
1-{(1S,2R,3S)-2-Benzyloxy-3-(benzyloxymethyl)-1-[(4-methyl-
phenyl)sulfonyl]cyclopropyl}methanamine, 14. A solution of
compound 13 (0.04 g, 0.069 mmol) and hydrazine hydrate (0.15
mL) in EtOH (15 mL) was heated under reflux. After 6 h, EtOH
was evaporated to dryness under reduced pressure to afford a
residue. The residue was purified over silica gel to afford 14 (0.021
g, 70%). Colorless oil, [R]26D +7.7 (c 0.09, CHCl3); 1H NMR (400
MHz, CDCl3) δ 2.41 (q, 1H, J ) 8, 15.2 Hz), 2.44 (s, 3H), 3.01
(d, 1H, J ) 16 Hz), 3.10 (d, 1H, J ) 16 Hz), 3.63-3.67 (m, 1H),
3.71-3.76 (m, 1H), 4.12 (d, 1H, J ) 8 Hz), 4.36-4.43 (m, 2H),
4.44-4.50 (m, 2H), 7.20-7.23 (m, 4H), 7.26-7.34 (m, 8H), 7.76
(d, 2H, J ) 8 Hz); 13C NMR (100 MHz, CDCl3) δ 21.6, 26.9, 36.7
(CH2), 50.0, 62.0, 63.3 (CH2), 72.8 (CH2), 73.9 (CH2), 127.5, 127.7,
127.8, 128.2, 128.3, 128.5, 128.6, 129.9, 135.4, 136.3, 137.6, 144.7;
HRMS [ES+, (M + H)+] for C26H30NO4S obsd 452.1891, calcd
452.1896.
(1S,2R,3S)-2-Benzyloxy-3-(benzyloxymethyl)-1-[(methoxy)meth-
yl]cyclopropyl 4-Methylphenyl Sulfone, 15. To a well-stirred
solution of 6 (0.20 g, 0.38 mmol) in dry MeOH (10 mL) was added
NaOMe (0.12 g, 2.28 mmol) and the mixture was stirred at ambient
temperature under N2. After 5-6 h, MeOH was evaporated to
dryness under reduced pressure and the residue was dissolved in
an aq saturated solution of NH4Cl. The product was extracted with
EtOAc (3 × 10 mL). The combined organic layer was dried over
anhyd Na2SO4 then filtered, and the filtrate was concentrated under
reduced pressure to afford a residue. A solution of the residue in
DMF (10 mL) was treated with NaH (0.04 g, 0.76 mmol) for 1 h.
Then the reaction mixture was poured into an aq saturated solution
of NaHCO3 and the product was extracted with EtOAc (3 × 10
mL). The combined organic layer was dried over anhyd Na2SO4
and concentrated under reduced pressure to afford a residue. The
1
(c 0.21, CHCl3); H NMR (400 MHz, CDCl3) δ 2.37 (q, 1H, J )
8, 16.0 Hz), 2.43 (s, 3H), 3.01-3.04 (m, 1H), 3.70-3.79 (m, 2H),
3.84-3.89 (m, 1H), 4.14-4.19 (m, 1H), 4.28 (d, 1H, J ) 7.6 Hz),
4.36-4.42 (m, 2H), 4.51 (s, 2H), 7.09-7.11 (m, 2H), 7.26-7.37
(m, 10H), 7.81 (d, 2H, J ) 8 Hz); 13C NMR (100 MHz, CDCl3) δ
21.6, 27.3, 50.0, 56.4 (CH2), 62.7, 63.2 (CH2), 72.6 (CH2), 74.2
(CH2), 127.4, 127.8, 128.1, 128.2, 128.3, 128.5, 128.9, 129.6, 135.7,
136.1, 137.1, 144.6; HRMS [ES+, (M + Na)+] for C26H28O5SNa
obsd 475.1522, calcd 475.1555.
(1R,2R,3S)-2-Benzyloxy-3-(benzyloxymethyl)-1-[(methylsul-
fanyl)methyl]cyclopropyl 4-Methylphenyl Sulfone, 18. To a well-
stirred solution of 6 (0.36 g, 0.68 mmol) in dry DMF (10 mL) was
added NaSMe (0.33 g, 4.76 mmol) and the mixture was stirred at
ambient temperature under N2. After 1 h, the reaction mixture was
poured into an aq saturated solution of NaHCO3 and the product
was extracted with EtOAc (3 × 10 mL). The combined organic
layer was dried over anhyd Na2SO4 and concentrated under reduced
pressure to afford a residue. The residue was purified over silica
gel to afford 18 (0.19 g, 58%). Yellow oil, [R]26 +17.4 (c 0.08,
D
1
CHCl3); H NMR (400 MHz, CDCl3) δ 1.97 (s, 3H), 2.40-2.44
(m, 1H), 2.46 (s, 3H), 2.76 (d, 1H, J ) 14.4 Hz), 2.97 (d, 1H, J )
14.4 Hz), 3.61-3.65 (m, 1H), 3.83-3.87 (m, 1H), 4.24 (d, 1H, J
) 8 Hz), 4.48-4.56 (m, 2H), 4.63 (s, 2H), 7.26-7.38 (m, 12H),
7.81 (d, 2H, J ) 8 Hz); 13C NMR (100 MHz, CDCl3) δ 17.8, 21.7,
27.9, 28.8 (CH2), 47.8, 62.2, 63.4 (CH2), 72.8 (CH2), 73.9 (CH2),
127.5, 127.6, 127.8, 128.1, 128.3, 128.5, 128.9, 129.6, 135.6, 136.6,
137.9, 144.7; HRMS [ES+, (M + Na)+] for C27H30O4S2Na obsd
505.1480, calcd 505.1483.
residue was purified over silica gel to afford 15 (0.10 g, 57%).
(1R,2R,3S)-2-Benzyloxy-3-(benzyloxymethyl)-1-(2-nitroethyl)-
cyclopropyl 4-Methylphenyl Sulfone, 19. To a well-stirred solution
of nitromethane (0.22 mL, 4.18 mmol) and NaH (0.09 g, 1.90
mmol) in DMF (10 mL) was added 6 (0.20 g, 0.38 mmol) and the
mixture was stirred at ambient temperature under N2. After 3 h,
the reaction mixture was poured into an aq saturated solution of
NH4Cl and the product was extracted with EtOAc (3 × 10 mL).
The combined organic layer was dried over anhyd Na2SO4 then
filtered, and the filtrate was concentrated under reduced pressure
to afford a residue. The residue was purified over silica gel to afford
19 (0.09 g, 47%). Colorless oil, [R]24D -75.0 (c 0.04, CHCl3); 1H
NMR (400 MHz, CDCl3) δ 2.29-2.42 (m, 3H), 2.46 (s, 3H), 3.47
(t, 1H, J ) 10.4 Hz), 3.67-3.71 (m, 1H), 4.10 (d, 1H, J ) 7.6
Hz), 4.38-4.48 (m, 4H), 4.71- 4.85 (m, 2H), 7.22 (br s, 2H),
7.31-7.36 (m, 10H), 7.73 (d, 2H, J ) 7.6 Hz); 13C NMR (100
MHz, CDCl3) δ 21.0, 21.7, 27.1, 45.6, 61.4, 63.0 (CH2), 72.5 (CH2),
73.1 (CH2), 74.1 (CH2), 127.7, 127.9, 128.5, 128.6, 128.7, 130.2,
134.5, 136.0, 137.4, 145.4; HRMS [ES+, (M + Na)+] for
C27H29NO6SNa obsd 518.1616, calcd 518.1613.
1-{[(1S,2R,3S)-2-Benzyloxy-3-(benzyloxymethyl)-1-(4-methyl-
phenylsulfonyl)cyclopropyl]methyl}-5-methylpyrimidine-
2,4(1H,3H)-dione, 20. To a well-stirred solution of thymine (0.42
g, 3.36 mmol) and TMG (0.30 mL, 2.40 mmol) in DMF (10 mL)
was added 6 (0.25 g, 0.48 mmol) and the mixture was stirred at
ambient temperature under N2. After 5 h, the reaction mixture was
diluted with EtOAc (30 mL) and the undissolved solid was filtered
off. The filtrate was washed with an aq saturated solution of
NaHCO3 and the aqueous phase was extracted with EtOAc (3 ×
10 mL). The combined organic layer was dried over anhyd Na2SO4
then filtered, and the filtrate was concentrated under reduced
pressure. A solution of the crude material in DMF (10 mL) was
treated with NaH (0.05 g, 0.96 mmol) for 1 h. Then the reaction
mixture was poured into an aq saturated solution of NaHCO3 and
the product was extracted with EtOAc (3 × 10 mL). The combined
organic layer was dried over anhyd Na2SO4 and concentrated under
reduced pressure to afford a residue. The residue was purified over
1
Colorless oil, [R]24 +21.2 (c 0.03, CHCl3); H NMR (400 MHz,
D
CDCl3) δ 2.35 (m, 1H), 2.44 (s, 3H), 3.09 (s, 3H), 3.59-3.63 (m,
2H), 3.71-3.75 (m, 1H), 3.85 (d, 1H, J ) 11.6 Hz), 4.22 (d, 1H,
J ) 7.6 Hz), 4.43-4.58 (m, 4H), 7.26-7.38 (m, 12H), 7.74 (d,
2H, J ) 8 Hz); 13C NMR (100 MHz, CDCl3) δ 21.7, 27.8, 48.3,
58.5, 62.1, 63.3 (CH2), 66.2 (CH2), 72.6 (CH2), 73.9 (CH2), 127.6
(2 × C), 127.9, 128.1, 128.3, 128.5, 128.8, 129.3, 136.7, 136.8,
138.1, 144.2; HRMS [ES+, (M + Na)+] for C27H30O5SNa obsd
489.1712, calcd 489.1712.
(1S,2R,3S)-2-Benzyloxy-1-{[(4-methoxybenzyl)oxy]methyl}-3-
(benzyloxymethyl)cyclopropyl 4-Methylphenyl Sulfone, 16. To
a well-stirred solution of p-methoxybenzyl alcohol (0.50 mL, 3.99
mmol) and NaH (0.14 g, 2.85 mmol) in DMF (10 mL) was added
6 (0.30 g, 0.57 mmol) and the mixture was stirred at ambient
temperature under N2. After 6 h, the reaction mixture was poured
into an aq saturated solution of NH4Cl and the product was extracted
with EtOAc (3 × 10 mL). The combined organic layer was
dried over anhyd Na2SO4 tehn filtered, and the filtrate was
concentrated under reduced pressure to afford a residue. The residue
was purified over silica gel to afford 16 (0.19 g, 58%). Colorless
1
oil, [R]26 +44.8 (c 0.25, CHCl3); H NMR (400 MHz, CDCl3) δ
D
2.35-2.39 (m, 1H), 2.41 (s, 3H), 3.55-3.60 (m, 1H), 3.66 (d, 1H,
J ) 12 Hz), 3.73-3.77 (m, 1H), 3.80 (s, 3H), 3.94 (d, 1H, J )
11.6 Hz), 4.16-4.25 (m, 3H), 4.41-4.58 (m, 4H), 6.75 (d, 2H, J
) 8.4 Hz), 6.92 (d, 2H, J ) 8.4 Hz), 7.18-7.38 (m, 12H), 7.70 (d,
2H, J ) 8 Hz); 13C NMR (100 MHz, CDCl3) δ 21.6, 27.9, 48.3,
55.3, 62.2, 63.5 (CH2), 63.6 (CH2), 72.6 (2 × CH2), 73.9 (CH2),
113.5, 127.6, 127.6, 127.9, 128.1, 128.3, 128.5, 128.8, 129.1, 129.3,
129.5, 136.6, 136.9, 138.2, 144.1, 159.1; HRMS [ES+, (M + Na)+]
for C34H36O6SNa obsd 595.2135, calcd 595.2130.
{(1S,2R,3S)-2-Benzyloxy-3-(benzyloxymethyl)-1-[(4-ethylphe-
nyl)sulfonyl]cyclopropyl}methanol, 17. Compound 16 (0.09 g,
0.158 mmol) and DDQ (0.04 g, 0.19 mmol) were added to a well-
stirred mixture of DCM-H2O (20:1) and the mixture was stirred at
ambient temperature. After 16-18 h, the reaction mixture was
J. Org. Chem. Vol. 74, No. 7, 2009 2715

Atta and Pathak
1
silica gel to afford 20 (0.126 g, 48%). White gum, [R]26D +13.0 (c
Colorless oil, [R]26 +56.7 (c 0.10, CHCl3); H NMR (400 MHz,
D
1
0.2, CHCl3); H NMR (400 MHz, CDCl3) δ 1.67 (s, 3H), 2.40 (s,
CDCl3) δ 2.33(m, 1H), 2.38 (s, 3H), 3.66-3.70 (m, 2H), 3.75-3.80
(m, 5H), 3.93 (d, 1H, J ) 11.6 Hz), 4.14 (d, 1H, J ) 8.4 Hz),
4.19-4.24 (m, 3H), 4.50-4.59 (m, 5H), 6.69 (d, 2H, J ) 8.4 Hz),
6.88 (d, 2H, J ) 8.4 Hz), 6.97 (d, 2H, J ) 6 Hz), 7.12 (d, 2H, J
) 8 Hz), 7.16-7.34 (m, 13H), 7.71(d, 2H, J ) 8 Hz); 13C NMR
(100 MHz, CDCl3) δ 21.6, 30.3, 47.9, 55.2, 61.3, 63.9 (CH2), 71.6
(CH2), 72.6 (CH2), 73.1 (CH2), 73.5 (CH2), 73.7, 74.1 (CH2), 113.5,
127.1, 127.5, 127.6, 127.7, 127.8, 127.9, 128.1, 128.4, 128.5, 128.9,
129.2, 129.3, 129.5, 136.7, 137.1, 138.3, 138.6, 143.8, 159.2; HRMS
[ES+, (M + Na)+] for C42H44O7SNa obsd 715.2705, calcd 715.2693.
{(1S,2S,3R)-2-(1,2-Dibenzyloxyethyl)-3-benzyloxy-1-[(4-
methylphenyl)sulfonyl]cyclopropyl}methanol, 25. Compound 24
(0.09 g, 0.13 mmol) was converted to 25 (0.05 g, 71%) following
the procedure described for the preparation of 17. Colorless oil,
[R]26D +20.5 (c 0.11, CHCl3); 1H NMR (400 MHz, CDCl3) δ 2.30
(q, 1H, J ) 8.8, 10.0 Hz), 2.40 (s, 3H), 3.05 (d, 1H, J ) 9.2 Hz),
3.62-3.66 (m, 1H), 3.74-3.77 (m, 1H), 3.79-3.84 (m, 1H), 3.91
(d, 1H, J ) 13.6 Hz), 3.99-4.01 (m, 1H), 4.22 (d, 1H, J ) 11.2
Hz), 4.28 (d, 1H, J ) 8.4 Hz), 4.48 (d, 1H, J ) 11.2 Hz), 4.54-4.61
(m, 3H), 4.66 (d, 1H, J ) 11.2 Hz), 6.91 (d, 2H, J ) 6.4 Hz),
7.18-7.37 (m, 15H), 7.79 (d, 2H, J ) 8.4 Hz); 13C NMR (100
MHz, CDCl3) δ 21.6, 29.9, 49.3, 56.8 (CH2), 61.8, 70.5 (CH2),
71.2 (CH2), 72.6, 73.3 (CH2), 74.3 (CH2), 127.2, 127.5, 127.6, 127.7,
128.0, 128.1 (2 × C), 128.4, 128.5, 128.8, 129.6, 135.5, 136.4,
137.5, 137.9, 144.6; HRMS [ES+, (M + Na)+] for C34H36O6SNa
obsd 595.2102, calcd 595.2130.
3H), 2.46 (q, 1H, J ) 7.2, 15.0 Hz), 3.56-3.63 (m, 1H), 3.67-3.71
(m, 1H), 3.92 (d, 1H, J ) 15.6 Hz), 4.35 (d, 1H, J ) 7.6 Hz),
4.41-4.48 (m, 2H), 4.59-4.65 (m, 3H), 7.21 (d, 2H, J ) 6.4 Hz),
7.26-7.42 (m, 11H), 7.71 (d, 2H, J ) 8.4 Hz), 8.57 (s, 1H); 13C
NMR (100 MHz, CDCl3) δ 12.3, 21.7, 28.0, 40.2 (CH2), 45.6, 61.1,
62.6 (CH2), 73.1 (CH2), 74.2 (CH2), 110.4, 127.7, 127.9, 128.1,
128.4, 128.5, 128.6, 128.8, 129.9, 135.4, 135.9, 137.4, 139.6, 145.3,
151.2, 163.7; HRMS [ES+, (M + H)+] for C31H33N2O6S obsd
561.2056, calcd 561.2059.
(1R,2R,3S)-2-Benzyloxy-3-(benzyloxymethyl)-1-methylcyclo-
propyl 4-Methylphenyl Sulfone, 21. To a well-stirred solution of
6 (0.10 g, 0.187 mmol) in dry MeOH (10 mL) was added NaBH4
(0.07 g, 1.87 mmol) and the mixture was stirred at ambient
temperature under N2. After 1 h, MeOH was evaporated to dryness
under reduced pressure, and the residue was dissolved in an aq
saturated solution of NaHCO3 and the product was extracted with
EtOAc (3 × 10 mL). The combined organic layer was dried over
anhyd Na2SO4 and concentrated under reduced pressure to afford
a residue. A solution of the crude material in DMF (10 mL) was
treated with NaH (0.02 g, 0.37 mmol) for 1 h. Then the reaction
mixture was poured into an aq saturated solution of NaHCO3 and
the product was extracted with EtOAc (3 × 10 mL). The combined
organic layer was dried over anhyd Na2SO4 and concentrated under
reduced pressure to afford a residue. The residue was purified over
silica gel to afford 21 (0.04 g, 50%). Colorless oil, [R]27D +63.8 (c
0.08, CHCl3); 1H NMR (400 MHz, CDCl3) δ 1.31 (s, 3H), 2.28 (q,
1H, J ) 14 Hz), 2.43 (s, 3H), 3.44-3.54 (m, 1H), 3.62-3.71 (m,
1H), 4.15 (d, 1H, J ) 16 Hz), 4.34-4.51 (m, 4H), 7.14-7.19 (m,
2H), 7.26-7.36 (m, 10H), 7.75 (d, 2H, J ) 16.4 Hz); 13C NMR
(100 MHz, CDCl3) δ 7.2, 21.7, 26.2, 43.7, 60.6, 63.4 (CH2), 72.5
(CH2), 73.8 (CH2), 127.4, 127.5, 127.9, 128.1, 128.3, 128.5, 128.7,
129.7, 135.3, 136.7, 138.1, 144.3; HRMS [ES+, (M + Na)+] for
C26H28O4SNa calcd 459.1582, obsd 459.1606.
(1R,2S,3R)-2-(1,2-Dibenzyloxyethyl)-3-benzyloxy-1-[(methyl-
sulfanyl)methyl]cyclopropyl 4-Methylphenyl Sulfone, 26. Com-
pound 12 (0.30 g, 0.46 mmol) was converted to 26 (0.16 g, 56%)
following the procedure described for the preparation of 18.
1
Colorless oil, [R]24 +15.3 (c 0.04, CHCl3); H NMR (400 MHz,
D
CDCl3) δ 1.94 (s, 3H), 2.37 (t, 1H, J ) 8.8 Hz), 2.46 (s, 3H),
2.75-2.83 (m, 2H), 3.65-3.70 (m, 2H), 3.78-3.81 (m, 1H), 4.21
(d, 1H, J ) 8.8 Hz), 4.37 (d, 1H, J ) 11.2 Hz), 4.57-4.65 (m,
4H), 4.80 (d, 1H, J ) 11.6 Hz), 7.02-7.04 (m, 2H), 7.20-7.37
(m, 15H), 7.85 (d, 2H, J ) 8.4 Hz); 13C NMR (100 MHz, CDCl3)
δ 17.9, 21.7, 29.0 (CH2), 31.1, 47.3, 61.2, 71.4 (CH2), 72.1 (CH2),
73.0, 73.4 (CH2), 74.4 (CH2), 127.3, 127.6, 127.7, 128.0, 128.4,
128.5, 128.9, 129.5, 135.7, 136.8, 138.1, 138.4, 144.4; HRMS [ES+,
(M + Na)+] for C35H38O5S2Na obsd 625.2031, calcd 625.2058.
(1R,2S,3R)-2-(1,2-Dibenzyloxyethyl)-3-benzyloxy-1-[(benzyl-
sulfanyl)methyl]cyclopropyl 4-Methylphenyl Sulfone, 27. To a
well-stirred solution of benzylthiol (0.20 mL, 1.53 mmol) and TMG
(0.10 mL, 0.918 mmol) in DMF (10 mL) was added 12 (0.10 g,
0.153 mmol) and the mixture was stirred at ambient temperature
under N2. After 3 h, the reaction mixture was poured into an aq
saturated solution of NH4Cl and the product was extracted with
EtOAc (3 × 10 mL). The combined organic layer was dried over
anhyd Na2SO4 then filtered, and the filtrate was concentrated under
reduced pressure to afford a residue. The residue was purified over
silica gel to afford 27 (0.05 g, 49%). Colorless oil, [R]26D +63.3 (c
0.05, CHCl3); 1H NMR (400 MHz, CDCl3) δ 2.29-2.34 (m, 1H),
2.43 (s, 3H), 2.64 (d, 1H, J ) 13.6 Hz), 2.81 (d, 1H, J ) 14 Hz),
3.51 (s, 3H), 3.58-3.62 (m, 1H), 3.71 (d, 1H, J ) 10.4 Hz), 4.15-
4.21 (m, 2H), 4.51-4.60 (m, 4H), 4.68 (d, 1H, J ) 11.6 Hz), 6.94
(d, 2H, J ) 7.2 Hz), 7.07 (br s, 2H), 7.15-7.33 (m, 18H), 7.76 (d,
2H, J ) 7.6 Hz); 13C NMR (100 MHz, CDCl3) δ 21.7, 25.9 (CH2),
31.2, 38.2 (CH2), 46.8, 61.2, 71.5 (CH2), 71.9 (CH2), 73.2, 73.3
(CH2), 74.3 (CH2), 126.9, 127.2, 127.4, 127.6, 127.8, 127.9, 128.0,
128.3 (2 × C), 128.4, 128.7, 128.9, 129.4, 135.4, 136.7, 137.7,
138.1, 138.3, 144.2; HRMS [ES+, (M + Na)+] for C41H42O5S2Na
obsd 701.2372, calcd 701.2371.
2-{[(1S,2S,3R)-2-(1,2-Dibenzyloxyethyl)-3-benzyloxy-1-(4-meth-
ylphenylsulfonyl)cyclopropyl]methyl}-1H-isoindole-1,3(2H)-di-
one, 22. Compound 12 (0.40 g, 0.61 mmol) was converted to 22
(0.22 g, 52%) following the procedure described for the preparation
1
of 13. Colorless oil, [R]26 +52.3 (c 0.11, CHCl3); H NMR (400
D
MHz, CDCl3) δ 2.31 (s, 3H), 2.49 (q, 1H, J ) 8.8, 10.4 Hz),
3.67-3.71 (m, 1H), 3.82-3.85 (m, 1H), 3.94-4.01 (m, 2H), 4.32
(d, 1H, J ) 8.8 Hz), 4.43 (d, 1H, J ) 14.8 Hz), 4.52 (d, 1H, J )
11.2 Hz), 4.61 (q, 2H, J ) 12.4 Hz), 4.72-4.80 (m, 2H), 5.08 (d,
1H, J ) 11.6 Hz), 7.02 (d, 2H, J ) 8 Hz), 7.24-7.38 (m, 15H),
7.65-7.67 (m, 4H), 7.70-7.72 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ 21.6, 29.3, 31.4 (CH2), 42.9, 61.7, 71.2 (CH2), 71.7 (CH2),
72.4, 73.4 (CH2), 74.2 (CH2), 123.1, 127.4, 127.7, 127.8, 127.9,
127.9, 128.1, 128.2, 128.4, 128.5, 129.5, 132.1, 133.8, 136.1, 137.2,
138.1, 138.2, 144.1, 167.5; HRMS [ES+, (M + Na)+] for
C42H39NO7SNa obsd 724.2348, calcd 724.2345.
(1S,2S,3R)-2-(1,2-Dibenzyloxyethyl)-3-benzyloxy-1-(methoxy-
methyl)cyclopropyl 4-Methylphenyl Sulfone, 23. Compound 12
(0.20 g, 0.30 mmol) was converted to 23 (0.08 g, 46%) following
the procedure described for the preparation of 15. Colorless oil,
[R]24D +48.9 (c 0.21, CHCl3); 1H NMR (400 MHz, CDCl3) δ 2.29
(t, 1H, J ) 9.2 Hz), 2.43 (s, 3H), 3.08 (s, 3H), 3.62-3.72 (m, 3H),
3.75-3.83 (m, 2H), 4.13 (d, 1H, J ) 8.4 Hz), 4.28 (d, 1H, J )
11.2 Hz), 4.47 (d, 1H, J ) 11.6), 4.54-4.63 (m, 4H), 7.04-7.07
(m, 2H), 7.20-7.38 (m, 15H), 7.77 (d, 2H, J ) 8 Hz); 13C NMR
(100 MHz, CDCl3) δ 21.6, 30.2, 47.9, 58.5, 61.2, 66.1 (CH2), 71.6
(CH2), 72.6 (CH2), 73.4 (CH2), 73.5, 74.0 (CH2), 127.2, 127.5,
127.6, 127.8, 127.9, 128.0, 128.3, 128.4, 128.9, 129.2, 136.6, 136.8,
138.2, 138.5, 143.9; HRMS [ES+, (M + Na)+] for C35H38O6SNa
obsd 609.2282, calcd 609.2287.
1-{[(1S,2S,3R)-2-(1,2-Dibenzyloxyethyl)-3-benzyloxy-1-(4-meth-
ylphenyl sulfonyl)cyclopropyl]methyl}-5-methylpyrimidine-2,4(1H,
3H)-dione, 28. Compound 12 (0.25 g, 0.38 mmol) was converted
to 28 (0.12 g, 46%) following the procedure described for the
preparation of 20. Colorless oil, [R]24D -72.4 (c 0.04, CHCl3); 1H
NMR (400 MHz, CDCl3) δ 1.69 (s, 3H), 2.37 (s, 3H), 2.40-2.42
(1S,2S,3R)-2-(1,2-Dibenzyloxyethyl)-3-benzyloxy-1-{[(4-meth-
oxybenzyl)oxy]methyl}cyclopropyl 4-Methylphenyl Sulfone, 24.
Compound 12 (0.30 g, 0.46 mmol) was converted to 24 (0.18 g,
57%) following the procedure described for the preparation of 16.
2716 J. Org. Chem. Vol. 74, No. 7, 2009

A DiastereoselectiVe Unique Route to Cyclopropanes
(m, 1H), 3.69-3.77 (m, 2H), 3.82-3.87 (m, 1H), 4.02 (d, 1H, J )
16 Hz), 4.34-4.39 (m, 2H), 4.52-4.66 (m, 6H), 7.02-7.04 (m,
2H), 7.15-7.37 (m, 15H), 7.52 (d, 1H, J ) 0.8 Hz), 7.73 (d, 2H,
J ) 8 Hz), 8.40 (br s, 1H); 13C NMR (100 MHz, CDCl3) δ 12.2,
21.6, 31.1, 40.6 (CH2), 45.3, 61.5, 70.9 (CH2), 71.3 (CH2), 72.3,
73.5 (CH2), 73.9 (CH2), 110.2, 127.2, 127.4, 127.8, 127.9 (2 × C),
128.2, 128.5, 128.6, 128.7, 129.7, 134.9, 135.9, 137.7, 139.7, 144.9,
151.0, 163.6; HRMS [ES+, (M + Na)+] for C39H40N2O7SNa obsd
703.2452, calcd 703.2454.
under N2. After 12 h, the reaction mixture was poured into an aq
saturated solution of NH4Cl and the product was extracted with
EtOAc (3 × 10 mL). The combined organic layer was dried over
anhyd Na2SO4 then filtered, and the filtrate was concentrated under
reduced pressure to afford a residue. The residue was purified over
silica gel to afford a mixture of 31 (0.04 g, 58%). Colorless oil; 1H
NMR (400 MHz, CDCl3) δ 1.11-1.31 (m, 4H), 2.15 (s, 3H), 2.18
(s, 3H), 2.43-2.49 (m, 3H), 2.72-2.73 (m, 1H), 3.32-3.35 (m,
1H), 3.51 (t, 1H, J ) 6.4 Hz), 3.58-3.79 (m, 4H), 4.55-4.67 (m,
8H), 7.26-7.39 (m, 20H).
(1R,2S,3R)-2-(1,2-Dibenzyloxyethyl)-3-benzyloxy-1-methylcy-
clopropyl 4-Methylphenyl Sulfone, 29. Compound 12 (0.25 g,
0.38 mmol) was converted to 29 (0.10 g, 48%) following the
Compound 32. Compound 23 (0.06 g, 0.10 mmol) was
converted to a mixture of 32 (0.02 g, 55%) following the procedure
1
procedure described for the preparation of 21. Colorless oil, [R]27
described for the preparation of 30. Colorless oil; H NMR (400
D
+63.0 (c 0.2, CHCl3); 1H NMR (400 MHz, CDCl3) δ 1.32 (s, 3H),
2.21 (t, 1H, J ) 8.8 Hz), 2.42 (s, 3H), 3.56-3.61 (m, 1H),
3.64-3.68 (m, 1H), 3.76 (dd, 1H, J ) 2.4, 10.4 Hz), 4.12 (d, 1H,
J ) 8.4 Hz), 4.23 (d, 1H, J ) 11.6 Hz), 4.47-4.64 (m, 5H),
6.96-6.98 (m, 2H), 7.18-7.38 (m, 15H), 7.76 (d, 2H, J ) 8 Hz);
13C NMR (100 MHz, CDCl3) δ 7.7, 21.6, 28.9, 43.6, 60.1, 71.2
(CH2), 72.4 (CH2), 73.3 (CH2), 73.4, 73.7 (CH2), 127.5, 127.6,
127.7, 128.0, 128.3, 128.4, 128.5, 128.7, 129.6, 135.2, 136.5, 138.2,
138.3, 144.2; HRMS [ES+, (M + Na)+] for C34H36O5SNa obsd
579.2181, calcd 579.2154.
Compound 30. To a solution of 15 (0.15 g, 0.32 mmol) in dry
MeOH (10 mL) were added Na2HPO4 (0.272 g, 1.92 mmol) and
6% Na (Hg) (excess) at 0 °C. The mixture was stirred for 6 h at
room temperature under N2 then filtered through a short silica gel
column. The filtrate was concentrated and the product was purified
over silica gel to afford a mixture of 30 (0.056 g, 56%). Colorless
oil, 1H NMR (400 MHz, CDCl3) δ 1.19-1.22 (m, 1H), 1.27-1.33
(m, 2H), 1.72 (s, 1H), 1.89 (br s, 1H), 3.27 (d, 1H, J ) 6.4 Hz),
3.32 (s, 3H), 3.34 (s, 3H), 3.49-3.77 (m, 8H), 4.49-4.69 (m, 8H),
7.26-7.38 (m, 20H).
MHz, CDCl3) δ 1.03-1.08 (m, 1H), 1.23-1.29 (m, 2H), 1.81 (br
s, 1H), 3.07-3.11 (m, 1H), 3.21-3.24 (m, 1H), 3.33 (s, 3H), 3.34
(s, 3H), 3.35-3.45 (m, 2H), 3.60-3.81 (m, 8H), 4.47-4.76 (m,
12H), 7.23-7.41 (m, 30H).
Compound 33. Compound 26 (0.12 g, 0.20 mmol) was
converted to a mixture of 33 (0.04 g, 42%) following the procedure
1
described for the preparation of 31. Colorless oil; H NMR (400
MHz, CDCl3) δ 1.03-1.09 (m, 2H), 1.13-1.22 (m, 2H), 2.15 (s,
3H), 2.18 (s, 3H), 2.21-2.30 (m, 1H), 2.49-2.53 (m, 2H),
2.81-2.85 (m, 1H), 3.14-3.17 (m, 1H), 3.37-3.40 (m, 1H),
3.58-3.80 (m, 6H), 4.48-4.79 (m, 12H), 7.22-7.40 (m, 30H).
Acknowledgment. T.P. thanks the Department of Science
and Technology (DST), New Delhi for financial support. A.K.A.
thanks CSIR, New Delhi for a fellowship. DST is also thanked
for the creation of the 400 MHz facility.
Supporting Information Available: Experimental proce-
dures, full spectroscopic data of all compounds, and NOE data
for 18. This material is available free of charge via the Internet
at http://pubs.acs.org.
Compound 31. To a well-stirred solution of 18 (0.09 g, 0.19
mmol) in dry THF (10 mL) was added LAH (0.04 g, 0.95 mmol)
at 0 °C under argon, and the mixture was stirred at room temperature
JO802709Q
J. Org. Chem. Vol. 74, No. 7, 2009 2717