Synthesis of (2S,1'R,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)-glycine via the stereochemically controlled cyclopropanation of (S)-glyceraldehyde acetonide-derived enones

Article abstract of DOI:10.1016/S0040-4020(00)00677-3

The reaction of ethyl dimethylsulfonium acetate bromide with aromatic enones 5a or 5b derived from (S)-glyceraldehyde acetonide under the action of DBU provides cyclopropanation products in excellent yield and good diastereoselectivity (10/1). High geomet

Full text of DOI:10.1016/S0040-4020(00)00677-3

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 7447–7456
Synthesis of (2S,10R,20R,30R)-2-(20,30-Dicarboxycyclopropyl)-
glycine via the Stereochemically Controlled Cyclopropanation
of (S)-Glyceraldehyde Acetonide-Derived Enones
a
a
b
Dawei Ma,a, Yeyu Cao, Wengen Wu and Yongwen Jiang
*
aState Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, People’s Republic of China
bDepartment of Chemistry, Fudan University, Shanghai 200433, People’s Republic of China
Received 18 May 2000; revised 7 July 2000; accepted 27 July 2000
Abstract—The reaction of ethyl dimethylsulfonium acetate bromide with aromatic enones 5a or 5b derived from (S)-glyceraldehyde
acetonide under the action of DBU provides cyclopropanation products in excellent yield and good diastereoselectivity (10/1). High
geometry-selectivity (Ͼ95/1) can be reached when the reaction is carried out at lower temperature in toluene. The cis-enone 5a gives better
geometry-selectivity than trans-enone 5b. The ylides with amide groups can also be used for cyclopropanation reaction but neither the yields
nor the geometry-selectivity are satisfactory. Based on this reaction a new synthetic protocol for (2S,10R,20R,30R)-2-(20,30-dicarboxycyclo-
propyl)glycine (l-DCG-IV), an isotype-selective agonist of metabotropic glutamate, is developed. ᭧ 2000 Elsevier Science Ltd. All rights
reserved.
Introduction
as discovery of new mGluRs ligands,7 we have reported a
facile synthesis of l-CCG-I using stereochemically
controlled cyclopropanation as a key step (Scheme 1).7a
Herein, we wish to report the total synthesis of l-DCG-IV
by employing the similar strategy.8
As a major neurotransmitter in excitatory synaptic pathways
of the mammalian central nervous system (CNS), l-gluta-
mate plays an important role in many integrative brain
functions.1 In order to have better knowledge of the confor-
mational requirements of l-glutamate for activating each
glutamate receptor subtype, Ohfune and co-workers synthe-
sized four diastereomers of l-2-(carboxycyclopropyl)gly-
cine (l-CCG-I–IV), conformationally restricted analogs in
which a cyclopropyl group fixes the glutamate chain in
either an extended or a folded form.2 Among these
compounds, (2S,10S,20S)-2-(20-carboxycyclopropyl)glycine
(l-CCG-I) could selectively activate the mGluRs with a
similar potency as l-glutamate.1c,2 By further modification
of l-CCG-I, Ohfune found that (2S,10R,20R,30R)-2-(20,30-
dicarboxycyclopropyl)glycine (l-DCG-IV), an analog of
l-CCG-I with a third carboxylic group at 30-position
which is geometrically trans to 20-carboxylic group,3 was
about 10 times more potent than l-CCG-I for activating
group II mGluRs and also possessed better subtype-
selectivity for mGluRs.4 Although this compound was also
found to be a potent agonist for NMDA receptor,5 it has
been widely utilized for investigating the functions of
individual mGluR subtype.6 As a continuing effort to
develop efficient synthesis of mGluR modulators, as well
Results and Discussion
Originally, l-CCG-IV was synthesized from the Garner’s
aldehyde derived from d-serine and the key step was an
intramolecular cyclopropanation.3 Our retrosynthetic analy-
sis of l-DCG-IV is shown in Scheme 1, the key intermediate
6 could be prepared by an intermolecular cyclopropanation
reaction of an enone 5 with a suitable sulfonium ylide. It
was expected that the sulfonium ylide with an electron with-
drawing group would attack the enone 5 in a similar
substrate-induced diastereoselectivity (from si face) as
dimethylsulfoxonium methylide thereby giving the desired
stereochemistry for synthesizing the target molecule. From
the intermediate 6, it would be possible to transform the
acetonide moiety to the a-amino acid moiety by using the
similar method for synthesizing l-CCG-I.7a
Initially, we tried the reaction of ethyl dimethylsulfonium
acetate bromide9 with olefin 5d (R0ˆOMe) to obtain the
desired cyclopropanation product (Eq. (1)). It was found
that this reaction did not occur under various conditions
using different bases and solvents. Recently, Pedregal and
co-workers reported a stereoselective cyclopropanation
Keywords: cyclopropanation; aromatic enones; S-glyceraldehyde.
* Corresponding author. Tel.: ϩ86-21-64163300; fax: ϩ86-21-64166128;
e-mail: madw@pub.sioc.ac.cn
0040–4020/00/$ - see front matter ᭧ 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00677-3

7448
D. Ma et al. / Tetrahedron 56 (2000) 7447–7456
use the more stable amide as a substituent at this position.
ꢀ1†
With these ideas in mind, we undertook the studies of the
cyclopropanation reactions by varying olefins, sulfur ylides,
as well as reaction conditions to get an optimized result. The
results are summarized in Table 1. The reaction of the
aromatic enone 5a with ethyl dimethylsulfonium acetate
bromide worked well to give cyclopropanation products
under the action of DBU in high yield. By column chroma-
tography two fractions were separated. The major fraction
was a mixture of two isomers in a ratio of 10/1 determined
by 1H NMR, which could be recrystallized to deliver a pure
isomer. Its structure was assigned to be (2R,10R,20R030R)-6a
by a single crystal X-ray analysis (Fig. 1). It meant that the
stereochemistry of the three newly created stereogenic
centers is all in correct form for synthesizing l-DCG-IV
as we have expected! This result implied that the sulfur
ylide attacked predominantly the enone 5a from the Re
face as predicted. The minor fraction also contained two
isomers in a ratio of 20/1 and the major isomer was assigned
to be (2R,10R,20R,30S)-9a by its NOESY spectra. As shown
in Fig. 2, marked NOE correlations between 20-H and 30-H
were observed, which indicated that the carboxylate group
and the ketone group are on the same side and trans to the
acetonide group. To check whether any products formed
through the attack of the sulfur ylide from Si face, we
tried to identify the minor isomer in major fraction. After
the mixture was treated with TsOH in methanol (Eq. (2)),
two lactones were separated by column chromatography. By
the NOE analysis as indicated in Fig. 2, the structure of the
lactone 11a could be assigned as (2R,3S,4S,5S), which
implied that the minor isomer 10a should have the
(2R,10S,20S,30S)-configuration. This result manifested that
when the cyclopropane ring formed the diastereoselectivity
was about 10/1.
Scheme 1.
reaction of enones with ethyl (dimethylsulfuranylidene)-
acetate (EDSA) generated in situ by treatment of ethyl
dimethylsulfonium acetate bromide with DBU,10 which
stimulated us to employ the similar strategy to build our
desired cyclopropane ring. As shown in Schemes 1 and 2,
we planned to use aromatic ketones 5 (R0ˆPh) to obtain the
corresponding cyclopropanation product 6. It was expected
that in this case the ketone moiety could be converted into a
carboxylate group by Baeyer–Villiger oxidation to give
ester 7. In the course of synthesizing l-DCG-VI, another
factor we had to consider was that if the COR substituent
of 6 was an ester group, lactonization would occur spon-
taneously to give 8 when its acetonide moiety was subjected
to deprotection under the acidic condition. This lactoniza-
tion would obviously cause major problems for further
transformations. To solve this problem, it was intended to
ꢀ2†
As shown in Table 1, either the trans-olefin 5b or the cis-
olefin 5a could provide 6a as the major diastereomer and the
geometry of the olefins only influenced slightly the ratio of
two mixtures (compare entries 1 and 2), which indicated that
the same intermediate probably formed during the course of
each reaction. A lower reaction temperature inhibited the
Scheme 2.

D. Ma et al. / Tetrahedron 56 (2000) 7447–7456
7449
Table 1. Cyclopropylation of enones 5 with sulfonium ylides. Reaction condition: enone 5 (1 mmol), sulfonium salt (1 mmol), DBU (1 mmol), solvent (1 mL)
Entry
Enone 5
R
Solvent
Temperature (ЊC)
Time (h)
Products (yield (%)a
R0
Geometry
Z (5a)
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OMe
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Benzene
CH3CN
CHCl3
0
0
3
3
4
6
6
10
1
1
1
3
6a (87)b
6a (73)b
6a (95)b
6a (74)b
6a (96)b
9a (7)
9a (10)
9a (4)
9a (10)
9a (1)
9a (0.5)
9a (14)
9a (14)
9a (21)
9a (11)
9a (5)
E (5b)
Z (5a)
E (5b)
Z (5a)
Z (5a)
Z (5a)
E (5b)
E (5b)
Z (5a)
Z (5a)
E (5b)
E (5b)
Ϫ20
Ϫ20
Ϫ40
Ϫ78
25
25
25
Ϫ20
Ϫ40
0
6a (95)b
6a (73)b
6a (80)b
6a (74)b
6a (78)b
6a (73)b
6b (72)b
6c (52)
9
10
11
12
13
8
3
10
Toluene
Toluene
9b (9)
9c (8)
OC(CH3)3
0
14
15
16
Ph
Ph
Ph
E (5b)
E (5b)
E (5b)
Toluene
Toluene
Toluene
0
0
10
10
10
6d (53)
6e (34)
6e (0)
9d (9)
9e (25)
9e (0)
Ϫ20
17
18
19
20
21
22
Ph
Ph
Ph
CH3
E (5b)
E (5b)
E (5b)
NEt2
NEt2
NEt2
OEt
OEt
Me
Toluene
CH3CN
CHCl3
Toluene
CH3CN
Toluene
0
0
Ϫ78
0
25
0
10
10
15
3
10
10
–
–
6f (21)
6f (37)
6g (45)
6h (25)
6i (34)
9f (18)c
9f (13)d
9g (18)
9h (12)f
9i (38)g
E (5c)
EϩZ (5e)e
EϩZ (5aϩ5b)
Ph
a Isolated yield.
b Containing inseparable 10% (2S,10S,20S030S)-isomer.
c Compound 12 was isolated in 17% yield.
d Compound 12 was isolated in 13% yield.
e R0COvCN.
formation of 9a thereby enhancing the geometry-selectivity
of this reaction. For example, when the reaction of 5a with
EDSA was carried out below Ϫ40ЊC, it gave exclusively 6a
and its (2R,10S,20S,30S)-isomer 10a. However, the ratio of
6a to 10a did not change in a wide temperature range
(entries 2, 3, 5 and 6), which indicated that the attack of
the EDSA to the olefin from si face or re face was indepen-
dent on the reaction temperature. Among the solvents tested,
toluene was found to be the best one for either reaction yield
or geometry-selectivity (compare entries 3, 10 and 11).
Besides the EDSA, the ylides with amide substituents could
also react with enone 5b to afford the corresponding cyclo-
propanation products. In these cases, neither the reaction
yields nor geometry-selectivity were as good as those of
EDSA. However, better diastereoselectivity could be
obtained. When the reaction was carried out in toluene,
only two isomers were isolated as determined by 1H
NMR. The structure of each product was assigned by
1
comparing its H NMR spectrum with that of 6a or 9a.
For example, the obvious similarity of the chemical shifts
of protons in cyclopropane ring between 6c–6f and 6a indi-
cated that they all had (2R,10R,20R030R)-configuration. This
conclusion was further supported by their reactions under
acidic conditions. Treatment of 6c–6f with hydrochloride in
methanol gave the same product 8a. While similarity in the
1H NMR spectra between 9c–9f and 9a demonstrated that
they all had (2R,10R,20R,30S)-configuration. When the reac-
tion was run in the polar solvents, another isomer 12 was
Figure 1. X-Ray structure of 6a.

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D. Ma et al. / Tetrahedron 56 (2000) 7447–7456
Figure 2. NOE correlations of compounds 9a, 9f, 8a, 11a and 12.
also isolated and its structure was assigned by the NOE
experiments. This isomer might result from the isomeriza-
tion of 9f because we found that the treatment of 9f with
DBU in chloroform for 6 h could provide a mixture of 9f
and 12 (Eq. (3)). This result was consistent with that of the
Pedregal’s report.10 As mentioned before, lowering the reac-
tion would be of benefit for either the reaction yield or the
geometry-selectivity. However, when these sulfonium salts
with amide substituents were used at the lower temperature,
it was found that the reaction in toluene did not take place at
all due to their poor solubility (entries 16 and 17). Although
the reaction of 5b with the diethylamine-derived ylide could
occur at Ϫ78ЊC in chloroform, either the reaction yield or
the geometry-selectivity was still found unsatisfactory
(entry 19). Thus, these results led us to prepare the desired
6f indirectly when we processed the total synthesis of
l-CCG-IV (as indicated in Scheme 4). In addition, it was
found that the methyl ketone 5c did not give as satisfactory
result as that of the phenyl ketone 5b (entry 20).
propanation is through the Michael addition and the subse-
quent elimination–cyclization.11 If the Michael addition
was the fast step and the elimination–cyclization was the
slow step, the geometry of the reaction products would be
controlled by the stability of intermediates A or B which
was formed through TS-1 and TS-2, respectively. It is
obviously that the intermediate A is the more stable one
because in the intermediate B two bulky groups are crowded
at one side.11 Thus, in this case the compound 9 should be
the major product. This is not in agreement with the above
experimental results. However, if the elimination–cycliza-
tion was the fast step and the Michael addition was the slow
step, the stereochemistry of the cyclopropanation products
would depend on the ratio of intermediates C and D which
benefit from electrostatic attraction, and was formed
through transition states TS3 and TS4, respectively.11
Because of the bigger steric hindrance between acetonide
group and the COR group in the intermediate D, this inter-
mediate is not so stable in comparison with the intermediate
C. Thus, in this case 6 should be the major product, which
agreed with the above experimental results. Therefore it
was concluded that the predominant formation of
(2R,10R,20R030R)-isomer was due to the fact that the
Michael addition step was the rate-determining step in the
present reaction.
ꢀ3†
Based on the above investigations, we started the total
synthesis of l-CCG-IV according to the reaction sequence
as outlined in Scheme 4. (S)-Glyceraldehyde acetonide 4,
could be prepared in large scale according to the known
procedure,12 and was reacted with the ketone ylide 3a
derived from 2-bromoacetophenone to afford olefins 5a
and 5b in a ratio of 1/1. Since it has been found that both
5a and 5b could react with EDSA to give 6a as the major
product, the Wittig reaction products 5a and 5b were not
separated and were directly used for next step. The reaction
of the mixture of 5a and 5b with EDSA at Ϫ40ЊC worked
well to produce 6a in about 80% yield after simple
recrystallization. Compound 6a was then hydrolyzed with
10% NaOH to transfer the ester to the corresponding acid,
which was further coupled with diethylamine under the
Although the reaction of ethyl dimethylsulfonium acetate
bromide with the a,b-unsaturated ester 5d failed to give
the corresponding cyclopropanation products, the a,b-
unsaturated nitrile 5e under the similar condition provided
us the desired cyclopropanes 6h and 9h in moderate yield
(entry 21). In addition, the sulfonium yield derived from
acetone also worked for this reaction and gave diketone
cyclopropanes 6i and 9i (entry 22). It is notable in these
two cases no other diastereomers were detected, which is
similar with the cases when the ylides with amide
substituents were used (entries 14–19)
A possible mechanism for the present reaction is discussed
in Scheme 3. It is known that the mechanism of ylide cyclo-

D. Ma et al. / Tetrahedron 56 (2000) 7447–7456
7451
Scheme 3.
action of DCC to provide the amide 6f. Now it was neces-
sary to transform the ketone moiety into the corresponding
ester by the Baeyer–Villiger oxidation.13 Many conditions
were checked to directly oxidize 6f and it was found that
these reactions were complicated partly because the
acetonide group was unstable under the acidic conditions.
Thus, the protecting group for diol had to be changed.
Accordingly, the acetonide group of 6f was removed
under the action of hydrochloride/methanol and the
resultant diol was reprotected with the acetyl group to
yield the diacetate 13. Treatment of 13 with trifluoro-
peracetic acid14 that was in situ prepared by mixing 95%
hydrogen peroxide and trifuoroacetic anhydride afforded the
Baeyer–Villiger oxidation product 14 in 83% yield. It is
notable this reaction did not work at all if hydrogen peroxide
at lower concentration (such as 80% H2O2) was used. Next,
the ester 14 was treated with potassium carbonate in metha-
nol to remove the two acetal protecting groups and trans-
form the phenyl ester to the corresponding potassium salt.
The generated salt was then reacted with iodomethane to
provide diol 15. Unlike the synthesis of l-CCG-I,7a the
primary hydroxy group of the diol 15 could be selectively
protected with TBDMS group without difficulty. After the
alcohol 16 was obtained, it was expected to be possible to
convert the free hydroxy group into the amino group
according to the similar reaction sequence for synthesizing
l-CCG-I.7a Unfortunately, although the alcohol 16 could be
transformed into the mesylate 20 by reacted it with
methanesulfonic chloride carefully, it was found that the
reaction of 20 with sodium azide in DMF gave the lacto-
nization product 21 as a sole product (Scheme 5). In fact it
was found that the mesylate 20 could spontaneously convert
into 21 even in DMF without any base assistance. Other
amination methods such as direct reaction of 20 with amines
or ammonia gave similar results. Fortunately, after some
experimentation, we found that the Mistunobu’s procedure
worked well for our desired transformation.15 Thus, reacting
the alcohol 16 with DPPA under the action of DEAD and

7452
D. Ma et al. / Tetrahedron 56 (2000) 7447–7456
Scheme 4.
Scheme 5.
triphenylphosphine at room temperature for 24 h produced
the azide 17 in 75% yield. Finally, the azide 17 was
converted to the corresponding amine by the hydrogenation
catalyzed by Pd/C, which was trapped in situ with di-tert-
butyl dicarbonate to provide 18 in 84% yield.7a After the
deprotection with TBAF/HOAc, the resultant alcohol was
subjected to the Jones oxidation to afford the acid 19.
Heating a mixture of 19 in 6N HCl at 100ЊC for 24 h
removed all the protecting groups to give the crude
l-DCG-IV as hydrochloride salt, which was purified
by ion-exchange column (Dowex-50 W×4) to furnish
l-DCG-IV as its ammonium salt. Its spectral data were
the same as those reported.3
Experimental
(R)-3-(2,2-Dimethyl-[1,3]dioxolan-4-yl)-1-phenyl-prop-
2Z-en-1-one 5a and (R)-3-(2,2-dimethyl-[1,3]dioxolan-4-
yl)-1-phenyl-prop-2E-en-1-one 5b. To a solution of (S)-
glyceraldehyde acetonide 4 (6.4 g, 49 mmol) in methanol
(20 mL) was added ylide 3a (20.6 g, 54.1 mmol) at 0ЊC.
After it was stirred for 10 h with cooling by ice-water, the
solvent was evaporated by rotavapor and the residual oil
was chromatographed (1/10 ethyl acetate/petroleum ether
as eluent) to give 5a (5.5 g, 48%) and 5b (5.7 g, 50%).
1
5a: pale yellow oil; H NMR (300 MHz, CDCl3) d 7.93
(d, Jˆ7.9 Hz, 2H), 7.54 (t, Jˆ7.8 Hz, 1H), 7.45 (t,
Jˆ7.8 Hz, 2H), 6.97 (dd, Jˆ11.5, 1.5 Hz, 1H), 6.49 (dd,
Jˆ11.6, 6.6 Hz, 1H), 5.37 (m, 1H), 4.53 (dd, Jˆ8.4,
7.2 Hz, 1H), 3.69 (dd, Jˆ8.3, 6.8 Hz, 1H), 1.48 (s, 3H),
1.39 (s, 3H); MS m/z 232 (Mϩ); HRMS found m/z
232.1091 (Mϩ), C14H16O3 requires 232.1096. 5b: pale
yellow oil; 1H NMR (300 MHz, CDCl3) d 7.93 (d,
Jˆ7.9 Hz, 2H), 7.55 (t, Jˆ7.8 Hz, 1H), 7.48 (t, Jˆ7.8 Hz,
2H), 7.18 (dd, Jˆ15.3, 1.1 Hz, 1H), 6.99 (dd, Jˆ15.3,
In conclusion, we have developed a stereochemically
controlled reaction for synthesizing the enantiopure 1,2,3-
trisubstituted cyclopropane. Its efficiency was demonstrated
by the total synthesis of l-DCG-IV using this reaction. It is
obviously that the present method would be useful for
synthesizing other important 1,2,3-trisubstituted cyclo-
propane derivatives.16

D. Ma et al. / Tetrahedron 56 (2000) 7447–7456
7453
5.3 Hz, 1H), 4.79 (m, 1H), 4.23 (dd, Jˆ8.2, 6.6 Hz, 1H),
3.72 (dd, Jˆ8.3, 7.3 Hz, 1H), 1.48 (s, 3H), 1.38 (s, 3H); MS
m/z 232 (Mϩ); HRMS found m/z 232.1093 (Mϩ), C14H16O3
requires 232.1096.
9H); MS m/z 347 (MϩϩHϩ). HRMS found m/z 346.1769
(Mϩ), C20H26O5 requires 346.1778.
(1R,2R,3R)-2-Benzoyl-3-[(R)-(2,2-dimethyl-[1,3]dioxolan-
4-yl)]-cyclopropanecarboxylic acid, morpholino amide
6d. [a]1D7ˆϪ42.8 (c 0.25, CHCl3); IR (neat) 3059, 1720,
General procedure for cyclopropanation reaction
;
1667 cmϪ1 1H NMR (300 MHz, CDCl3) d 8.04 (d,
Jˆ8.1 Hz, 2H), 7.59 (t, Jˆ8.0 Hz, 1H), 7.49 (t, Jˆ8.0 Hz,
2H), 4.08 (dd, Jˆ7.9, 6.0 Hz, 1H), 4.00 (m, 1H), 3.89–3.70
(m, 6H), 3.60 (m, 2H), 3.48 (t, Jˆ4.8 Hz, 1H), 3.35 (m, 1H),
2.59 (dd, Jˆ9.2, 4.5 Hz, 1H), 2.22 (ddd, Jˆ9.4, 9.2, 5.3 Hz,
1H), 1.43 (s, 3H), 1.30 (s, 3H); MS m/z 360 (MϩϩHϩ);
HRMS found m/z 359.1728 (Mϩ), C20H25NO5 requires
359.1733.
The enone 5a (9.48 mmol) and a suitable sulfonium salt
(10.5 mmol) was dissolved in toluene (8 mL). The resulting
solution was cooled with ice-water and DBU (1.57 mL,
10.5 mmol) was added in a dropwise manner. The resultant
mixture was stirred at indicated temperature (Table 1) until
TLC showed disappearance of the enone, and then ethyl
acetate (40 mL) was added to dilute the solution. After the
organic layer was separated, it was washed with water and
brine, and dried over Na2SO4. The solvent was evaporated
and the residual oil was chromatographed (1/4–1/2 ethyl
acetate/petroleum ether as eluent) to afford the correspond-
ing cyclopropanation products.
(1S,2R,3R)-2-Benzoyl-3-[(R)-(2,2-dimethyl-[1,3]dioxolan-
4-yl)]-cyclopropanecarboxylic acid, morpholino amide
9d. [a]1D7ˆϩ51 (c 1.9, CHCl3); IR (neat) 3063, 1724,
;
1663 cmϪ1 1H NMR (300 MHz, CDCl3) d 8.01 (d,
Jˆ8.0 Hz, 2H), 7.61 (t, Jˆ7.9 Hz, 1H), 7.50 (t, Jˆ8.0 Hz,
2H), 4.01 (m, 1H), 3.89–3.53 (m, 10H), 3.39 (dd, Jˆ9.5,
5.1 Hz, 1H), 2.88 (t, Jˆ5.4 Hz, 1H), 2.15 (m, 1H), 1.48 (s,
3H), 1.33 (s, 3H); MS m/z 360 (MϩϩHϩ); HRMS found m/z
359.1731 (Mϩ), C20H25NO5 requires 359.1733.
(1R,2R,3R)-2-Benzoyl-3-[(R)-(2,2-dimethyl-[1,3]dioxolan-
4-yl)]-cyclopropanecarboxylic acid, ethyl ester 6a. mp
78.2ЊC; [a]1D4ˆϪ31.3 (c 1.35, CHCl3); IR (neat) 3053,
1
1721, 1665 cmϪ1; H NMR (300 MHz, CDCl3) d 7.97 (d,
Jˆ8.4 Hz, 2H), 7.59 (dd, Jˆ8.4, 8.0 Hz, 1H), 7.49 (t,
Jˆ8.3 Hz, 2H), 4.32 (dt, Jˆ9.3, 6.4 Hz, 1H), 4.20 (q,
Jˆ7.3 Hz, 2H), 3.73 (dd, Jˆ8.0, 6.3 Hz, 1H), 3.24
(dd, Jˆ5.6, 4.7 Hz, 1H), 2.59 (dd, Jˆ9.3, 4.7 Hz, 1H),
2.20 (ddd, Jˆ9.4, 9.4, 5.9 Hz, 1H), 1.44 (s, 3H), 1.33
(s, 3H), 1.29 (t, Jˆ7.3 Hz, 3H); MS m/z 319 (MϩϩHϩ);
HRMS found m/z 318.1489 (Mϩ), C18H22O5 requires
318.1467.
(1R,2R,3R)-2-Benzoyl-3-[(R)-(2,2-dimethyl-[1,3]dioxolan-
4-yl)]-cyclopropanecarboxylic acid, diethyl amide 6f.
[a]1D4ˆϪ62.7 (c 2.3, CHCl3); IR (neat): 1672, 1633 cmϪ1
;
1H NMR (300 MHz, CDCl3) d 8.01 (d, Jˆ7.8 Hz, 2H), 7.59
(t, Jˆ8.0 Hz, 1H), 7.43 (t, Jˆ7.9 Hz, 2H), 4.05 (dd, Jˆ7.8,
6.0 Hz, 1H), 3.93 (m, 1H), 3.73–3.53 (m, 3H), 3.46 (t,
Jˆ5.1 Hz, 1H), 3.31 (dt, Jˆ14.6, 7.3 Hz, 1H), 3.17 (dt,
Jˆ14.4, 7.1 Hz, 1H), 2.58 (dd, Jˆ9.4, 4.5 Hz, 1H), 2.18
(ddd, Jˆ9.5, 9.4, 5.5 Hz, 1H), 1.40 (s, 3H), 1.27 (s, 3H),
1.23 (t, Jˆ7.3 Hz, 3H), 1.10 (t, Jˆ7.3 Hz, 3H); MS m/z 346
(MϩϩHϩ); HRMS found m/z 345.1940 (Mϩ), C20H27NO4
requires 345.1949.
(1S,2R,3R)-2-Benzoyl-3-[(R)-(2,2-dimethyl-[1,3]dioxolan-
4-yl)]-cyclopropanecarboxylic acid, ethyl ester 9a.
[a]1D7ˆϩ74 (c 0.25, CHCl3); IR (neat) 3053, 1721,
;
1665 cmϪ1 1H NMR (300 MHz, CDCl3) d 8.04 (t,
Jˆ8.0 Hz, 2H), 7.56 (t, Jˆ7.9 Hz, 1H), 7.48 (d, Jˆ8.0 Hz,
2H), 4.22 (m, 2H), 3.99 (q, Jˆ7.1 Hz, 2H), 3.76 (dt, Jˆ9.0,
4.8 Hz, 1H), 2.92 (dd, Jˆ9.1, 6.2 Hz, 1H), 2.45–2.34 (m,
2H), 1.41 (s, 3H), 1.34 (s, 3H), 1.04 (t, Jˆ7.1 Hz, 3H); MS
m/z 319 (MϩϩHϩ); HRMS found m/z 318.1489 (Mϩ),
C18H22O5 requires 318.1467.
(1S,2R,3R)-2-Benzoyl-3-[(R)-(2,2-dimethyl-[1,3]dioxolan-
4-yl)]-cyclopropanecarboxylic acid, diethyl amide 9f.
[a]1D7ˆϩ69.8 (c 1.0, CHCl3); IR (neat): 1672, 1633 cmϪ1
;
1H NMR (300 MHz, CDCl3) d 8.02 (d, Jˆ7.8 Hz, 2H), 7.57
(t, Jˆ8.0 Hz, 1H), 7.47 (t, Jˆ7.9 Hz, 2H), 4.01 (m, 1H),
3.70 (dd, Jˆ8.1, 5.9 Hz, 1H), 3.64–3.31 (m, 6H), 2.88 (t,
Jˆ5.3 Hz, 1H), 2.19 (ddd, Jˆ9.5, 9.4, 5.7 Hz, 1H), 1.41 (s,
3H), 1.29 (s, 3H), 1.25 (t, Jˆ7.3 Hz, 3H), 1.10 (t, Jˆ7.3 Hz,
3H); MS m/z 346 (MϩϩHϩ); HRMS found m/z 345.1940
(Mϩ), C20H27NO4 requires 345.1949.
(1R,2R,3R)-2-Benzoyl-3-[(R)-(2,2-dimethyl-[1,3]dioxolan-
4-yl)]-cyclopropanecarboxylic acid, tert-butyl ester 6c.
[a]1D4ˆϪ15.6 (c 0.5, CHCl3); IR (neat) 3061, 1718,
;
1670 cmϪ1 1H NMR (300 MHz, CDCl3) d 8.00 (d,
Jˆ8.1 Hz, 2H), 7.61 (t, Jˆ8.0 Hz, 1H), 7.49 (t, Jˆ8.1 Hz,
2H), 4.23 (dt, Jˆ9.3, 6.1 Hz, 1H), 4.12 (dd, Jˆ8.0, 6.0 Hz,
1H), 3.69 (t, Jˆ7.7 Hz, 1H), 3.21 (t, Jˆ5.3 Hz, 1H), 2.53
(dd, Jˆ9.5, 4.7 Hz, 1H), 2.15 (ddd, Jˆ9.5, 9.3, 5.5 Hz, 1H)
1.50 (s, 9H), 1.45 (s, 3H), 1.31 (s, 3H); MS m/z 347
(MϩϩHϩ). HRMS found m/z 346.1771 (Mϩ), C20H26O5
requires 346.1778.
(1S,2S,3R)-2-Benzoyl-3-[(R)-(2,2-dimethyl-[1,3]dioxolan-
4-yl)]-cyclopropanecarboxylic acid, diethyl amide 12.
[a]1D7ˆϪ5.1 (c 1.0, CHCl3); IR (neat): 1672, 1633 cmϪ1
;
1H NMR (300 MHz, CDCl3) d 8.02 (d, Jˆ7.8 Hz, 2H),
7.53 (t, Jˆ8.0 Hz, 1H), 7.44 (t, Jˆ7.9 Hz, 2H), 4.23 (m,
1H), 4.17 (dd, Jˆ8.0, 6.2 Hz, 1H), 3.78 (dd, Jˆ7.9,
6.6 Hz, 1H), 3.54–3.38 (m, 2H), 3.24–3.06 (m 2H), 3.01
(dd, Jˆ9.0, 5.9 Hz, 1H), 2.49 (dd, Jˆ6.1, 5.9 Hz, 1H), 2.34
(dd, Jˆ8.9, 6.3 Hz, 1H), 1.43 (s, 3H), 1.35 (s, 3H), 1.12 (t,
Jˆ7.3 Hz, 3H), 0.96 (t, Jˆ7.3 Hz, 3H); MS m/z 346
(MϩϩHϩ); HRMS found m/z 345.1940 (Mϩ), C20H27NO4
requires 345.1949.
(1S,2R,3R)-2-Benzoyl-3-[(R)-(2,2-dimethyl-[1,3]dioxolan-
4-yl)]-cyclopropanecarboxylic acid, tert-butyl ester 9c.
[a]1D7ˆϪ14.2 (c 0.5, CHCl3); IR (neat) 3053, 1721,
;
1665 cmϪ1 1H NMR (300 MHz, CDCl3) d 8.06 (d,
Jˆ8.2 Hz, 2H), 7.54 (t, Jˆ8.1 Hz, 1H), 7.46 (t, Jˆ8.1 Hz,
2H), 4.19 (m, 2H), 3.78 (m, 1H), 2.83 (dd, Jˆ9.6, 6.6 Hz,
1H), 2.39–2.28 (m, 2H), 1.41 (s, 3H), 1.35 (s, 3H), 1.19 (s,
(1R,2R,3R)-2-Benzoyl-3-[(R)-(2,2-dimethyl-[1,3]dioxolan-

7454
D. Ma et al. / Tetrahedron 56 (2000) 7447–7456
4-yl)]-cyclopropanenitrile 6h. [a]2D0ˆϩ8.6 (c 1.03,
(1R,2R,3R)-2-Benzoyl-3-[(R)-1,2-diacetoxyethyl]-cyclo-
propanecarboxylic acid, diethyl amide 13. A mixture of
6f (1.9 g, 5.6 mmol) in MeOH (30 mL) and 10% aqueous
HCl (10 mL) was stirred overnight. After the solution was
concentrated, the residue was diluted with methylene
chloride (70 mL), and washed by aqueous NaHCO3. The
organic layer was dried over Na2SO4, and concentrated to
dryness to give 1.6 g of crude diol as an oil, which was
dissolved in CH2Cl2 (10 mL). To this stirring solution was
added DMAP (10 mg, 0.08 mmol), triethylamine
(2.17 mL), and Ac2O (1.48 mL, 15.9 mmol) with cooling
by ice-water. After stirring was continued for 1 h at the
same temperature, the solution was diluted with methylene
chloride (50 mL), washed with aqueous NH4Cl, and dried
over Na2SO4. The crude product was purified by chromato-
graphy eluting with ethyl acetate/petroleum ether (1/2) to
afford 13 (1.72 g, 79%) as an oil. [a]1D8ˆϪ78.2 (c 0.55,
CHCl3); IR (neat): 2251, 1675, 1637 cmϪ1 1H NMR
;
(300 MHz, CDCl3) d 4.30–4.10 (m, 4H), 3.69 (dd, Jˆ7.7,
6.0 Hz, 1H), 2.21 (d, Jˆ8.5 Hz, 2H), 1.99 (dd, Jˆ14.2,
7.6 Hz, 1H), 1.46 (s, 3H), 1.29 (s, 3H). 1.27 (t, Jˆ7.6 Hz,
3H); MS m/z 238 (MϩϪHϩ); Anal. Calcd for C12H17NO4: C,
60.24, H, 7.16, N, 5.85, found: C, 60.45, H, 7.14, N, 5.74.
(1S,2R,3R)-2-Benzoyl-3-[(R)-(2,2-dimethyl-[1,3]dioxolan-
4-yl)]-cyclopropanenitrile 9h. [a]2D0ˆϪ23.4 (c 0.89,
CHCl3); IR (neat): 2255, 1674, 1637 cmϪ1 1H NMR
;
(300 MHz, CDCl3) d 4.30–4.09 (m, 4H), 3.65 (dd, Jˆ7.6,
5.4 Hz, 1H), 2.19 (d, Jˆ8.3 Hz, 2H), 1.98 (t, Jˆ7.6 Hz, 1H),
1.36 (s, 3H), 1.28 (s, 3H), 1.27 (t, Jˆ7.2 Hz, 3H); MS m/z
238 (MϩϪHϩ); Anal. Calcd for C12H17NO4: C, 60.24, H,
7.16, N, 5.85, found: C, 60.19, H, 7.26, N, 5.56.
1
(1R,2R,3R)-2-Benzoyl-3-[(R)-(2,2-dimethyl-[1,3]dioxolan-
4-yl)]-cyclopropyl methyl ketone 6i. [a]2D0ˆϩ114 (c 1.11,
CHCl3); IR (neat) 1746, 1674 cmϪ1; H NMR (300 MHz,
CDCl3) d 8.02 (d, Jˆ8.5 Hz, 2H), 7.55 (t, Jˆ8.4 Hz, 1H),
7.47 (t, Jˆ8.4 Hz, 2H), 5.00 (dt, Jˆ9.5, 4.7 Hz, 1H), 4.31
(dd, Jˆ11.9, 3.8 Hz, 1H), 4.14 (dd, Jˆ11.9, 5.0 Hz, 1H),
3.62–3.49 (m, 3H), 3.30 (dt, Jˆ14.6, 7.2 Hz, 1H), 3.20 (dt,
Jˆ14.4, 7.1 Hz, 1H), 2.56 (dd, Jˆ9.2, 4.5 Hz, 1H), 2.31 (m,
1H), 2.00 (s, 3H), 1.92 (s, 3H), 1.22 (t, Jˆ7.2 Hz, 3H), 1.07
(t, Jˆ7.2 Hz, 3H); MS m/z 389 (Mϩ); HRMS found m/z
389.1814 (Mϩ), C21H27NO6 requires 389.1838.
CHCl3); IR (neat): 1695, 1670, 1630 cmϪ1 1H NMR
;
(300 MHz, CDCl3) d 7.97 (d, Jˆ8.4 Hz, 2H), 7.60 (dd,
Jˆ8.4, 8.0 Hz, 1H), 7.47 (t, Jˆ8.3 Hz, 2H), 4.16 (m, 2H),
3.70 (m, 1H), 3.39 (t, Jˆ4.8 Hz, 1H), 2.87 (dd, Jˆ9.3,
4.7 Hz, 1H), 2.43 (s, 3H), 2.32 (dt, Jˆ9.2, 5.2 Hz, 1H),
1.48 (s, 3H), 1.29 (s, 3H); MS m/z 273 (MϩϪMe); Anal.
Calcd for C17H20O4: C, 70.81, H, 6.99, found: C, 70.82, H,
7.01.
(1R,2R,3R)-2-[(R)-1,2-Diacetoxyethyl]-3-diethylcarbamoyl-
cyclopropane-carboxylic acid, phenyl ester 14. To a
solution of (CF3CO)2O (1.2 mL, 8.5 mmol) in methylene
chloride (1 mL) was added 95% H2O2 (0.35 mL,
8.4 mmol) at 0ЊC. After the mixture was stirred for
10 min, a suspension solution of 13 (440 mg, 1.13 mmol)
and Na2HPO4 (600 mg, 4.2 mmol) in CH2Cl2 (5 mL) was
added. The resultant solution was stirred at room tempera-
ture overnight and then refluxed for 0.5 h. The cooled
solution was diluted with CH2Cl2 (50 mL), washed by satu-
rated aqueous NaHCO3, and dried over Na2SO4. After
removal of solvent, the residual oil was chromatographed
eluting with ethyl acetate/petroleum ether (1/2) to afford 14
(380 mg, 83%) as a pale yellow oil. [a]1D4ˆϪ32.8 (c 2.8,
(1S,2R,3R)-2-Benzoyl-3-[(R)-(2,2-dimethyl-[1,3]dioxolan-
4-yl)]-cyclopropyl methyl ketone 9i. [a]1D7ˆϪ97 (c 1.0,
CHCl3); IR (neat): 1698, 1670, 1630 cmϪ1 1H NMR
;
(300 MHz, CDCl3) d 7.98 (d, Jˆ8.0 Hz, 2H), 7.59 (t,
Jˆ7.9 Hz, 1H), 7.48 (t, Jˆ8.0 Hz, 2H), 4.05 (m, 1H), 3.71
(dd, Jˆ8.1, 6.1 Hz, 1H), 3.07 (dd, Jˆ8.2, 6.3 Hz, 1H), 3.32
(dd, Jˆ8.6, 4.8 Hz, 1H), 3.08 (t, Jˆ5.1 Hz, 1H), 2.40 (s,
3H), 2.18 (dt, Jˆ9.4, 5.5 Hz, 1H), 1.42 (s, 3H), 1.31 (s,
3H); MS m/z 273 (MϩϪMe); Anal. Calcd for C17H20O4:
C, 70.81, H, 6.99, found: C, 70.55, H, 6.99.
Synthesis of 6f from 6a
1
CHCl3); IR (neat) 1746, 1638 cmϪ1; H NMR (300 MHz,
To a solution of 6a (2.4 g, 7.5 mmol) in 95% ethanol
(10 mL) was added NaOH (300 mg, 7.5 mmol). The
mixture was stirred at 0ЊC for 10 h and then ethanol was
removed by rotavapor. The residue was added brine
(10 mL) and NaH2PO4 until pHˆ5, and extracted with
methylene chloride (3×30 mL). After the combined organic
layers were dried over Na2SO4 and concentrated, the
residual oil was chromatographed eluting with 1/1 ethyl
acetate/petroleum ether to provide 2.15 g of acid.
CDCl3) d 7.39 (t, Jˆ8.0 Hz, 2H), 7.25 (t, Jˆ8.0 Hz, 1H),
7.11 (d, Jˆ8.1 Hz, 2H), 4.93 (dt, Jˆ10.0, 4.4 Hz, 1H), 4.41
(dd, Jˆ11.9, 4.2 Hz, 1H), 4.28 (dd, Jˆ11.9, 4.5 Hz, 1H),
3.65–3.51 (m, 2H), 3.30 (dt, Jˆ14.6, 7.2 Hz, 1H), 3.22 (dt,
Jˆ14.4, 7.1 Hz, 1H), 2.81 (t, Jˆ5.1 Hz, 1H), 2.53 (dd,
Jˆ9.9, 4.6 Hz, 1H), 2.20 (ddd, Jˆ9.9, 9.7, 5.6 Hz, 1H),
2.08 (s, 3H), 2.03 (s, 3H), 1.24 (t, Jˆ7.2 Hz, 3H), 1.09 (t,
Jˆ7.2 Hz, 3H); MS m/z 406 (MϩϩHϩ); HRMS found m/z
406.1839 (MϩϩHϩ), C21H28NO7 requires 406.1866.
The above acid (2.1 g, 7.1 mmol) was dissolved in CH2Cl2
(20 mL). To this stirring solution was added HOBt (1.0 g,
7.4 mmol) and HNEt2 (0.92 mL, 8.8 mmol). The mixture
was cooled in ice bath and then a solution of DCC (1.5 g,
7.4 mmol) in CH2Cl2 (5 mL) was added in a dropwise
manner. After the resulting solution was stirred at room
temperature overnight, it was diluted with methylene
chloride (30 mL) and then washed with aqueous NH4Cl,
and dried over Na2SO4. The solvent was removed by rota-
vapor and the residual oil was chromatographed to afford 6f
(1.93 g, 74%). Its 1H NMR spectra was identical with that of
6f prepared by direct cyclopropanation.
(1R,2R,3R)-2-[(R)-1,2-Dihydroxyethyl]-3-diethylcarbamoyl-
cyclopropane-carboxylic acid, methyl ester 15. To a solu-
tion of 14 (440 mg, 1.1 mmol) in anhydrous MeOH (5 mL)
was added K2CO3 (340 mg, 2.5 mmol). The resultant
mixture was stirred at room temperature overnight before
iodomethane (3 mL) was added. The stirring was continued
for 12 h and then the solvent was removed by rotavapor. The
residue was partitioned between methylene chloride
(50 mL) and water (10 mL). The organic layer was washed
with brine, dried over Na2SO4, and concentrated. Column
chromatography of the residual oil afforded 15 (210 mg,

D. Ma et al. / Tetrahedron 56 (2000) 7447–7456
7455
75%) as a pale yellow oil. [a]1D7ˆϩ53.3 (c 1.2, CHCl3); IR
(neat) 1731, 1621 cmϪ1; 1H NMR (300 MHz, CDCl3) d 3.73
(m, 1H), 3.70 (s, 3H), 3.60–3.30 (m, 6H), 2.36 (dd, Jˆ9.1,
5.2 Hz, 1H), 2.29 (t, Jˆ5.3 Hz, 1H), 1.93 (m, 1H) 1.25 (t,
Jˆ7.2 Hz, 3H), 1.11 (t, Jˆ7.2 Hz, 3H); MS m/z 260
(MϩϩHϩ); HRMS found m/z 259.1414 (Mϩ), C12H21NO5
requires 259.1420.
1H), 3.75 (m, 1H), 3.69 (s, 3H), 3.63–3.15 (m, 6H), 2.71
(m, 1H), 2.34 (dd, Jˆ9.6, 4.9 Hz, 1H), 2.03 (m, 1H), 1.48 (s,
9H), 1.26 (t, Jˆ7.1 Hz, 3H), 1.08 (t, Jˆ7.1 Hz, 3H), 0.88 (s,
9H), 0.04 (s, 6H); MS m/z 473 (MϩϩHϩ); HRMS found m/z
472.2942 (Mϩ), C23H44N2O6Si requires 472.2967.
(1R,2R,3R)-2-[(S)-N-tert-Butoxycarbonylglycine]-3-di-
ethyl-carbamoyl-cyclopropanecarboxylic acid, methyl
ester 19. To a solution of 18 (100 mg, 0.21 mmol) in THF
(5 mL) was added tetrabutylammonium fluoride hydrate
(266 mg, 1 mmol) and HOAc (0.1 mL, 1.7 mmol) at 0ЊC.
The resulting solution was stirred at rt for 4 h and poured
into saturated NaHCO3 solution (10 mL). The mixture was
extracted with methylene chloride three times and the
combined organic layers were washed with water, brine,
dried over anhydrous Na2SO4 and then concentrated. The
crude product was purified by column chromatography on
silica gel (1/3 ethyl acetate/petroleum ether as eluent as
eluent) to provide alcohol (75 mg), which was dissolved
in acetone (7 mL). This resultant solution was cooled with
ice-water and Jones reagent (80 mL) was added. After the
reaction mixture was stirred at the same temperature for 3 h
it was allowed to warm to rt. The reaction was quenched
with 2-propanol and extracted with EtOAc three times. The
combined organic layers were washed with brine, dried over
anhydrous Na2SO4, and then concentrated in vacuo to give
an oily residue. This oil was purified by column chromato-
graphy (1/3 ethyl acetate/petroleum as eluent) to afford 19
(1R,2R,3R)-2-[(R)-1-tert-Butyldimethylsiloxy-2-hydroxy-
ethyl]-3-diethyl-carbamoyl-cyclopropanecarboxylic acid,
methyl ester 16. A solution of 15 (150 mg, 0.58 mmol),
tert-butyldimethylsilyl chloride (104 mg, 0.69 mmol),
DMAP (52 mg, 0.43 mmol), and triethylamine (0.25 mL,
1.8 mmol) in methylene chloride (2 mL) was stirred for
12 h. The solution was partitioned between methylene
chloride (20 mL) and brine (20 mL). After the organic
layer was concentrated, the residual oil was chromato-
graphed (1/3 ethyl acetate/petroleum as eluent) to afford
16 (188 mg, 87%) as a pale yellow oil. [a]1D7ˆϪ48.6 (c
;
0.70, CHCl3); IR (neat) 1733, 1623 cmϪ1 1H NMR
(300 MHz, CDCl3) d 3.69 (s, 3H), 3.64 (d, Jˆ5.5 Hz,
2H), 3.62–3.29 (m, 5H), 2.38 (d, Jˆ7.2 Hz, 2H), 1.95 (m,
1H), 1.24 (t, Jˆ7.1 Hz, 3H), 1.12 (t, Jˆ7.1 Hz, 3H), 0.88 (s,
9H), 0.05 (s, 6H); MS m/z 374 (MϩϩHϩ); HRMS found m/z
373.2280 (Mϩ), C18H35NO5Si requires 373.2284.
(1R,2R,3R)-2-[(S)-1-tert-Butyldimethylsiloxy-2-azido-ethyl]-
3-diethyl-carbamoyl-cyclopropanecarboxylic acid, methyl
ester 17. To a solution of 16 (180 mg, 0.48 mmol) in
anhydrous THF (8 mL) was added triphenylphosphine
(633 mg, 2.4 mmol), diethyl azodicarboxylate (0.93 mL,
2.4 mmol), and diphenylphosphoryl azide (0.50 mL,
2.4 mmol) at Ϫ20ЊC, respectively. After the stirring was
continued for 6 h at the same temperature, the reaction solu-
tion was warmed to room temperature and then stirred over-
night. The solvent was removed via rotavapor and the
residual oil was directly loaded on a silica gel column and
then eluted with 1/5 ethyl acetate/petroleum ether to provide
17 (144 mg, 75%) of as a yellow oil. [a]2D4ˆϪ13.9 (c 1.0,
1
(50 mg, 71%). [a]2D0ˆϩ23.3 (c 0.45, CHCl3); H NMR
(300 MHz, CDCl3) d 5.75 (br d, Jˆ6.9 Hz, 1H), 4.42 (dd,
Jˆ11.0, 7.1 Hz, 1H), 3.74 (s, 3H), 3.51–3.34 (m, 4H), 2.59
(t, Jˆ5.5 Hz, 1H), 2.42 (dd, Jˆ8.5, 6.2 Hz, 1H), 1.83 (m,
1H), 1.43 (s, 9H), 1.23 (t, Jˆ7.2 Hz, 3H), 1.16 (t, Jˆ7.1 Hz,
3H); MS m/z 372 (Mϩ); HRMS found m/z 372.1901 (Mϩ),
C17H28N2O7 requires 372.1897.
l-DCG-IV. A mixture of 19 (50 mg, 0.14 mmol) and 6N
HCl (2 mL) was heated in a sealed tube at 80ЊC for 24 h.
The cooled solution was concentrated to dryness and the
residue was purified with DOWEX-50 W (elution with
1% NH3) to give l-DCG-IV (20 mg, 65%) of as an ammo-
nium salt. [a]D20ˆϪ19.6 (c 0.56, H2O) [lit.3 [a]2D0ˆϪ20.2 (c
0.44, H2O)]; 1H NMR (300 MHz, D2O) d 3.94 (d, Jˆ9.9 Hz,
1H), 2.17 (dd, Jˆ9.5, 4.9 Hz, 1H), 2.05 (t, Jˆ5.6 Hz, 1H),
1.86 (ddd, Jˆ9.9, 9.5, 5.3 Hz, 1H).
CHCl3); IR (neat) 2114, 2004, 1734 cmϪ1 1H NMR
;
(300 MHz, CDCl3) d 3.73 (s, 3H), 3.66 (m, 1H), 3.60–
3.20 (m, 6H), 2.58 (t, Jˆ5.1 Hz, 1H), 2.40 (dd, Jˆ9.6,
4.8 Hz, 1H), 1.97 (m, 1H), 1.28 (t, Jˆ7.1 Hz, 3H), 1.10 (t,
Jˆ7.1 Hz, 3H), 0.89 (s, 9H), 0.08 (s, 6H); MS m/z 399
(MϩϩHϩ); HRMS found m/z 398.2344 (Mϩ),
C18H34N4O4Si requires 398.2349.
(1R,2R,3R)-2-[(S)-1-tert-Butyldimethylsiloxy-2-(tert-bu-
toxycarbonyl)amino-ethyl]-3-diethyl-carbamoyl-cyclo-
propanecarboxylic acid, methyl ester 18. A suspension of
10% Pd/C (20 mg) in ethyl acetate (2 mL) was vigorously
stirred under hydrogen atmosphere until the uptake of
hydrogen ceased. To this was added a mixture of azide 17
(130 mg, 0.30 mmol) and di-tert-butyl dicarbonate (260 mg,
1.16 mmol) in ethyl acetate (1 mL). The resulting solution
was stirred under H2 (1 atm) at rt until disappearance of the
azide as monitored by TLC. The solution was filtered and
the filtrate was concentrated in vacuo to give the crude
product. The crude product was purified by column chro-
matography on silica gel (1/4 ethyl acetate/petroleum ether
as eluent) to give 18 (120 mg, 84%) as a pale yellow oil.
[a]2D2ˆϪ20.8 (c 0.75, CHCl3); IR (neat) 3378, 1714,
Acknowledgements
We thank the Chinese Academy of Sciences, National
Natural Science Foundation of China (grant 29725205),
and Qiu Shi Science & Technologies Foundation for their
financial support.
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