Preparation of chiral cyclopropanes with a carbohydrate fragment from levoglucosenone

Article abstract of DOI:10.1016/j.tetasy.2007.08.013

Levoglucosenone (a chiral α,β-unsaturated ketone derivative of cellulose) underwent stereoselective cyclopropanation with sulfonium ylides to form chiral trisubstituted cyclopropanes annulated with the carbohydrate moiety in high yields.

Full text of DOI:10.1016/j.tetasy.2007.08.013

Tetrahedron: Asymmetry 18 (2007) 1986–1989
Preparation of chiral cyclopropanes with a carbohydrate
fragment from levoglucosenone
Alexander V. Samet,* Anatolly M. Shestopalov, Dmitriy N. Lutov,
Lyudmila A. Rodinovskaya, Alexander A. Shestopalov and Victor V. Semenov
N.D. Zelinsky Institute of Organic Chemistry RAS, Leninsky Pr., 47 Moscow, 119991, Russia
Received 25 July 2007; accepted 13 August 2007
Abstract—Levoglucosenone (a chiral a,b-unsaturated ketone derivative of cellulose) underwent stereoselective cyclopropanation with
sulfonium ylides to form chiral trisubstituted cyclopropanes annulated with the carbohydrate moiety in high yields.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
Hexo
8
O
Hendo
O
O
Functionalized chiral cyclopropanes are of major interest
both as key fragments of several biologically active natural
and synthetic products1,2 and as intermediates in organic
synthesis.3 They are usually prepared either by asymmetric
cyclopropanation of achiral olefins in the presence of chiral
catalysts,4 or by direct cyclopropanation of chiral olefins.1,5
1
2
O
6
Et3N
+
R2S+CH2COR' Br-
H
H
4
EtOH
O
O
3
2
H
R'OC
1
3
Scheme 1.
Levoglucosenone 1 [(1S,5R)-6,8-dioxabicyclo[3.2.1]oct-2-
ene-4-one], an unsaturated ketone prepared by acid-
catalyzed pyrolysis of cellulose, was previously used as a
substrate in the stereoselective Michael addition of nucleo-
philes and cycloaddition to the C@C bond on the side
opposite to the 1,6-anhydro bridge.6–9 Therefore, we
envisaged that 1 could be a suitable template for the
preparation of chiral cyclopropanes using such well-
recognized cyclopropanation agents as sulfur ylides.10,11
Table 1. Preparation of compounds 3a–i
Sulfonium
R2S
R0
Product 3
Yield
salt 2
2a
2b
2c
2d
Me2S
(CH2)4S
Me2S
Ph
4-ClC6H4
4-BrC6H4
4-MeOC6H4
3a
3b
3c
3d
80
82
84
92
(CH2)4S
2. Results and discussion
2e
Me2S
Me2S
3e
71
S
We discovered that sulfonium ylides (generated in situ
from the corresponding salts 2 and Et3N) react stereoselec-
tively with the double bond of levoglucosenone to afford
cyclopropanes 3 in good yields11,12 (Scheme 1, Table 1).
Me
2f
3f
69
N
N
O
2g
2h
2i
Me2S
(CH2)4S
Me2S
Cyclopropyl
1-Adamantyl
OEt
3g
3h
3i
74
95
79
78
*
Corresponding
sametav@server.ioc.ac.ru
author.
Tel.:
+7
495
7161418;
e-mail:
Present address: Department of Chemistry, Duke University, Durham,
NC 27708-0346, USA.
2j
(CH2)4S
OEt
3i
0957-4166/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.08.013

A. V. Samet et al. / Tetrahedron: Asymmetry 18 (2007) 1986–1989
1987
The reaction proceeds with the stereospecific formation of
three new asymmetric centers, two of which originate from
the levoglucosenone molecule (C-2 and C-4) and another
one from the sulfonium ylide (C-3). The configurations of
the C-2 and C-4 atoms are assigned assuming that the
cyclopropanation of 1 (analogously to the other similar
reactions previously described in the literature6–9) occurs
on the less sterically hindered side, that is on the side oppo-
site to the 1,6-anhydro bridge. This assumption is
confirmed by the values of the coupling constants
1
J1,2 = 1.3–1.5 Hz in the H NMR spectrum of 3 (products
of the addition to the more sterically hindered side are rare
and have substantially larger J values7,9). The other cou-
pling constants values J2,3 ꢀ J3,4 = 4.0–4.3 Hz, J2,4 = 7.7–
7.8 Hz imply that the H-3 atom is in the trans-position to
H-2 and H-4, considering that cis-constants in cyclopro-
panes are larger than trans. The assigned C-3 configuration
is in a good agreement with the fact that the reactions of
carbonyl-stabilized sulfonium ylides with a,b-unsaturated
carbonyl compounds tend to yield cyclopropanes with
trans-located carbonyl substituents.13 Additional evidence
for the stereochemistry of 3a–i comes from X-ray diffrac-
tion analysis of derivative 4 (see below).
Figure 1. X-ray structure of 4.
The keto-ester 3i can undergo further transformations.
Thus, heating it in methanolic NaOH affords the acid 3j,
while refluxing 3i in methanolic HCl affects both the ester-
and the keto-groups and results in the formation of ketal 4
(Scheme 2). Similar ketals were formed by the addition of
MeOH to levoglucosenone 1.18
In all cases, cyclopropanes 3 are isolated as single isomers,
and no signals of other stereoisomers are found in NMR
spectra of the reaction mixtures. The crystalline products
3a–i do not require any further purification, which is in
contrast to the previously studied reactions of the sulfo-
nium ylides with other unsaturated 6-membered cyclic ke-
tones.13–15 Most likely, the rigid bicyclic structure of 1
causes a significant energy difference between the corre-
sponding transition states, thus limiting the possible diaste-
reomeric products to only one isomer. Interestingly, very
high stereoselectivity was previously observed for the
cyclopropanation of some chiral bicyclic cyclopent-2-enon-
es as well.16,17 It is noteworthy that the yields and selectiv-
ities of the reactions are little affected by the nature of the
R2S substituents in the sulfonium ylides (cf. preparation of
3i from the salt of dimethylsulfide 2i and the salt of tetra-
hydrothiophene 2j, Table 1).
The structure of compound 4 was supported by X-ray dif-
fraction analysis (Fig. 1), thus providing additional proof
for the assignment of the stereocenters in keto-ester 3i
and its analogues 3a–h,j.
Taking into account the lability of the carbohydrate moi-
ety,19,20 compounds 3 can serve as starting reagents for
the preparation of the highly derivatized chiral cyclopro-
panes. Such an investigation is currently underway.
3. Experimental
3.1. General
O
O
NMR spectra were recorded on a Bruker-DRX500 spec-
O
O
1
trometer (500.13 MHz for H, 125.75 MHz for 13C). Opti-
MeOH
HCl
OMe
OMe
H
H
cal rotations were measured on a Jasco-340 polarimeter.
X-ray diffraction study was performed by Professor V. S.
Sergienko at the N. S. Kurnakov Institute of General
and Inorganic Chemistry (Moscow). Crystallographic data
for the structure in this paper have been deposited with the
Cambridge Crystallographic Data Center as supplemen-
tary publication number CCDC 653502. Copies of the data
can be obtained free of charge on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK [fax: +44(0)-1223-
336033 or e-mail: deposit@ccdc.cam.ac.uk].
H
H
O
H
H
MeOOC
EtOOC
3i
4
1) NaOH, MeOH
2) HCl
O
O
H
H
O
H
3.2. Synthetic procedures
HOOC
3j
3.2.1. Sulfonium salts 2a–j (general procedure). A mixture
of the corresponding bromide21 (10 mmol) and Me2S or
Scheme 2.

1988
A. V. Samet et al. / Tetrahedron: Asymmetry 18 (2007) 1986–1989
tetrahydrothiophene (12 mmol) in acetone (5 ml) was kept
at 0 ꢁC for 24 h, after which the resulting precipitate was
filtered off and washed with acetone (2 ml). The product
was used without further purification. Yields: 85–95%.
3.2.7. (1S,2R,3S,4S,6R)-3-(2-Thienoyl)-7,9-dioxatricyclo-
1
[4.2.1.02,4]-nonane-5-one 3e. Mp 146–147 ꢁC (EtOH). H
NMR (acetone-d6): 2.25–2.35 (m, 2H, H-2 and H-4); 3.57
(t, J = 4.1 Hz, 1H, H-3); 3.87 (dd, J = 7.2, 4.8 Hz, 1H,
H-8exo); 4.16 (d, J = 7.2 Hz, 1H, H-8endo); 4.99 (s, 1H,
H-6); 5.10 (br d, J = 4.8 Hz, 1H, H-1); 7.30 (dd, J = 5.0,
3.8 Hz, 1H); 8.00 (d, J = 5.0 Hz, 1H); 8.20 (d, J = 3.8 Hz,
1H). 13C NMR (DMSO-d6): 24.2, 26.5, 29.2, 68.1, 70.6,
99.0, 129.2, 134.7, 136.2, 143.3, 187.9, 194.7. Anal. Calcd
for C12H10O4S: C, 57.59; H, 4.03; S, 12.81. Found: C,
57.67; H, 3.80; S, 13.00.
3.2.2. Reaction of levoglucosenone with sulfonium ylides
(general procedure). To a suspension of levoglucosenone
1 (0.50 g, 4 mmol) and sulfonium salt 2 (4 mmol) in EtOH
(5 ml), Et3N (0.44 g, 4.4 mmol, 10% molar excess) was
added, and the resulting solution kept at 35–40 ꢁC for
3 h. Then the reaction mixture was concentrated to ca. 1/
2 of the initial volume, diluted with water (10 ml), and
extracted with CHCl3 (3 · 5 ml). The organic solvent was
evaporated to dryness, the residue triturated with 3 ml
MeOH (ether is used for 3g), and the resulting crystalline
product filtered off and dried. For the preparation of 3f,
25% molar excess of Et3N was used, and the reaction mix-
ture kept at 50–60 ꢁC for 5 h.
3.2.8. (1S,2S,3S,4S,6R)-3-(5-Methylfurazane-4-yl)carbonyl-
7,9-dioxatricyclo[4.2.1.02,4]nonane-5-one 3f. Mp 152–
24
1
154 ꢁC (MeOH). ½aꢁD ¼ ꢂ4:8 (c 1.0, DMSO). H NMR
(DMSO-d6): 2.42 (m, 2H, H-2 and H-4); 2.52 (s, 3H);
3.60 (t, J = 4.0 Hz, 1H, H-3); 3.80 (dd, J = 7.2, 4.7 Hz,
1H, H-8exo); 4.12 (d, J = 7.2 Hz, 1H, H-8endo); 5.07 (br
d, J = 4.7 Hz, 1H, H-1); 5.14 (s, 1H, H-6). Anal. Calcd
for C11H10N2O5: C, 52.80; H, 4.03; N, 11.20. Found: C,
53.18; H, 3.84; N, 11.36.
3.2.3.
(1S,2S,3S,4S,6R)-3-Benzoyl-7,9-dioxatricyclo-
[4.2.1.02,4]-nonane-5-one 3a. Mp 119–120 ꢁC (EtOH).
22
1
½aꢁD ¼ ꢂ55:1 (c 1.0, CHCl3). H NMR (acetone-d6): 2.27
(ddd, J = 7.8, 4.1, 1.5 Hz, 1H, H-2); 2.36 (dd, J = 7.8,
4.1 Hz, 1H, H-4); 3.63 (t, J = 4.1 Hz, 1H, H-3); 3.88 (dd,
J = 7.1, 4.7 Hz, 1H, H-8exo); 4.17 (d, J = 7.1 Hz, 1H, H-
8endo); 4.98 (s, 1H, H-6); 5.11 (br d, J = 4.7 Hz, 1H, H-
1); 7.56 (t, J = 8.1 Hz, 2H); 7.67 (t, J = 8.1 Hz, 1H); 8.10
(d, J = 8.1 Hz, 2H). 13C NMR (DMSO-d6): 25.4, 27.2,
30.1, 69.1, 71.7, 100.1, 129.2, 129.8, 134.7, 137.4, 195.6,
196.0. Anal. Calcd for C14H12O4: C, 68.85; H, 4.95. Found:
C, 69.06; H, 4.83.
3.2.9.
(1S,2S,3S,4S,6R)-3-(Cyclopropyl)carbonyl-7,9-di-
oxatricyclo[4.2.1.02,4]nonane-5-one 3g. Mp 85–86 ꢁC (Et2O).
23
½aꢁD ¼ þ37:3 (c 1.0, CHCl3). 1H NMR (DMSO-d6):
0.9-1.0 (m, 4H); 2.09 (m, 2H, H-2 and H-4); 2.34 (m, 1H);
3.04 (t, J = 4.1 Hz, 1H, H-3); 3.75 (dd, J = 7.1, 4.7 Hz, 1H,
H-8exo); 4.03 (d, J = 7.1 Hz, 1H, H-8endo); 5.03 (br d,
J = 4.7 Hz, 1H, H-1); 5.06 (s, 1H, H-6). Anal. Calcd for
C11H12O4: C, 63.45; H, 5.81. Found: C, 63.23; H, 5.99.
3.2.10.
(1S,2S,3S,4S,6R)-3-(1-Adamantoyl)-7,9-dioxatri-
cyclo[4.2.1.02,4]-nonane-5-one 3h. Mp 124–125 ꢁC (EtOH).
23
3.2.4. (1S,2S,3S,4S,6R)-3-(4-Chlorobenzoyl)-7,9-dioxatricy-
clo[4.2.1.02,4]-nonane-5-one 3b. Mp 110–111 ꢁC (EtOH).
1
½aꢁD ¼ ꢂ13:3 (c 1.0, CHCl3). H NMR (DMSO-d6): 1.71,
1.83, 2.01 (m, 17H, CH-adamantyl, H-2, H-4); 3.09
(t, J = 4.3 Hz, 1H, H-3); 3.76 (dd, J = 7.4, 4.9 Hz, 1H,
H-8exo); 4.03 (d, J = 7.4 Hz, 1H, H-8endo); 4.99 (br d,
J = 4.9 Hz, 1H, H-1); 5.04 (s, 1H, H-6). Calcd for
C18H22O4: C, 71.50; H, 7.33. Found: C, 71.29; H, 7.56.
22
1
½aꢁD ¼ ꢂ69:8 (c 1.0, CHCl3). H NMR (DMSO-d6): 2.27
(m, 2H, H-2, H-4); 3.65 (t, J = 4.3 Hz, 1H, H-3); 3.79
(dd, J = 7.4, 4.9 Hz, 1H, H-8exo); 4.09 (d, J = 7.4 Hz,
1H, H-8endo); 5.11 (m, 2H, H-1, H-6); 7.64 (d,
J = 8.6 Hz, 2H); 8.04 (d, J = 8.6 Hz, 2H). Anal. Calcd
for C14H11ClO4: C, 60.34; H, 3.98. Found: C, 60.08; H,
4.13.
3.2.11. Ethyl (1S,2R,3S,4S,6R)-5-oxo-7,9-dioxatricyclo-
3i. Mp
[4.2.1.02,4]nonane-3-carboxylate
135–136 ꢁC
23
1
(EtOH). ½aꢁD ¼ ꢂ24:2 (c 1.0, CHCl3). H NMR (DMSO-
d6): 1.21 (t, J = 7.1 Hz, 3H); 2.11 (dd, J = 7.9, 4.1 Hz,
1H, H-4); 2.19 (ddd, J = 7.9, 4.1, 1.3 Hz, 1H, H-2); 2.43
(t, J = 4.1 Hz, 1H, H-3); 3.75 (dd, J = 7.1, 4.8 Hz, 1H,
H-8exo); 4.07 (d, J = 7.1 Hz, 1H, H-8endo); 4.12 (q,
J = 7.1, 2H); 5.02 (br d, J = 4.8 Hz, 1H, H-1); 5.03 (s,
1H, H-6). Anal. Calcd for C10H12O5: C, 56.60; H, 5.70.
Found: C, 56.65; H, 5.84.
3.2.5. (1S,2S,3S,4S,6R)-3-(4-Bromobenzoyl)-7,9-dioxatricy-
clo[4.2.1.02,4]-nonane-5-one 3c. Mp 152–153 ꢁC (EtOH).
23
1
½aꢁD ¼ ꢂ58:6 (c 1.0, CHCl3). H NMR (acetone-d6): 2.27
(ddd, J = 7.7, 4.1, 1.5 Hz, 1H, H-2); 2.33 (dd, J = 7.7,
4.1 Hz, 1H, H-4); 3.62 (t, J = 4.1 Hz, 1H, H-3); 3.87 (dd,
J = 7.1, 4.9 Hz, 1H, H-8exo); 4.15 (d, J = 7.1 Hz, 1H, H-
8endo); 4.98 (s, 1H, H-6); 5.11 (br d, J = 4.9 Hz, 1H, H-
1); 7.75 (d, J = 8.1 Hz, 2H); 8.04 (d, J = 8.1 Hz, 2H). Anal.
Calcd for C14H11BrO4: C, 52.04; H, 3.43; Br, 24.73. Found:
C, 51.77; H, 3.32; Br, 24.95.
3.2.12. (1S,2R,3S,4S,6R)-5-Oxo-7,9-dioxatricyclo- [4.2.1.02,4]-
nonane-3-carboxylic acid 3j. A solution of 3i (212 mg,
1 mmol) and NaOH (0.10 g, 2.5 mmol) in MeOH (2 ml)
was refluxed for 2 h, neutralized with HCl and evaporated
to dryness. To the residue, water (2 ml) was added, and
the resulting suspension extracted with EtOAc (3 · 3 ml),
and the solvent evaporated to dryness to yield essentially
pure 3j. Yield 147 mg (80%), mp 150–151 ꢁC (EtOH).
3.2.6. (1S,2S,3S,4S,6R)-3-(4-Methoxybenzoyl)-7,9-dioxatri-
3d. Mp
cyclo[4.2.1.02,4]-nonane-5-one
140–141 ꢁC
1
(EtOH). H NMR (DMSO-d6): 2.25 (m, 2H, H-2, H-4);
3.60 (t, J = 4.3 Hz, 1H, H-3); 3.78 (dd, J = 7.8, 4.2 Hz,
1H, H-8exo); 3.88 (s, 3H, CH3); 4.09 (d, J = 7.8 Hz, 1H,
H-8endo); 5.09 (m, 2H, H-1, H-6); 7.11 (d, J = 9.1 Hz,
2H); 8.07 (d, J = 9.1 Hz, 2H). Anal. Calcd for C15H14O5:
C, 65.69; H, 5.14. Found: C, 65.48; H, 5.31.
24
1
½aꢁD ¼ ꢂ30:1 (c 1.0, DMSO). H NMR (DMSO-d6): 2.07
(dd, J = 7.9, 4.0 Hz, 1H, H-4); 2.13 (ddd, J = 7.9, 4.0,
1.4 Hz, 1H, H-2); 2.31 (t, J = 4.0 Hz, 1H, H-3); 3.75 (dd,

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J = 7.1, 4.7 Hz, 1H, H-8exo); 4.06 (d, J = 7.1 Hz, 1H, H-
8endo); 5.01 (m, 2H, H-1 and H-6); 12.84 (br s, 1H,
COOH). Anal. Calcd for C8H8O5: C, 52.18; H, 4.38.
Found: C, 51.95; H, 4.44.
3.2.13. Methyl (1S,2R,3S,4S,6R)-5,5-dimethoxy-7,9-di-
oxatricyclo[4.2.1.02,4]nonane-3-carboxylate 4. To a solu-
tion of 3i (212 mg, 1 mmol) in MeOH (2 ml), three drops
of concd HCl was added, and the solution was refluxed
for 4 h and kept overnight. The resulting crystals of 4 are
filtered off and dried. Yield 124 mg (51%), mp 99–100 ꢁC
(EtOH). 1H NMR (DMSO-d6): 1.40 (br dd, J = 9.0,
4.5 Hz, 1H, H-2); 1.71 (t, J = 4.5 Hz, 1H, H-3); 1.77 (dd,
J = 9.0, 4.5 Hz, 1H, H-4); 3.17 (s, 3H, OMe); 3.20 (s, 3H,
OMe); 3.63 (m, 4H, COOMe and H-8exo); 3.94 (d,
J = 7.0 Hz, 1H, H-8endo); 4.71 (d, J = 4.3 Hz, 1H, H-1);
5.05 (s, 1H, H-6). Anal. Calcd for C11H16O6: C, 54.09; H,
6.60. Found: C, 54.29; H, 6.51.
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Acknowledgment
This research was supported by grant from Chemical Block
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