Improved synthetic method for preparing spiro α-chloroepoxides

Article abstract of DOI:10.1016/S0040-4039(02)00302-7

A new synthetic method via α-chloroolefine derivatives for preparing epimers of spiro α-chloroepoxides (2-chloro-oxyrane derivatives), which are useful key intermediates for the synthesis of branched-chain functionalized compounds, is developed as an alternative to previous methods requiring dichloromethyllithium.

Full text of DOI:10.1016/S0040-4039(02)00302-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 3087–3090
Improved synthetic method for preparing spiro a-chloroepoxides
Ken-ichi Sato,* Takao Sekiguchi, Tetsuya Hozumi, Toshiya Yamazaki and Shoji Akai
Laboratory of Organic Chemistry, Faculty of Engineering, Kanagawa University, 3-27-1, Rokkakubashi, Kanagawa-ku,
Yokohama 221-8686, Japan
Received 19 December 2001; revised 7 February 2002; accepted 8 February 2002
Abstract—A new synthetic method via a-chloroolefine derivatives for preparing epimers of spiro a-chloroepoxides (2-chloro-
oxyrane derivatives), which are useful key intermediates for the synthesis of branched-chain functionalized compounds, is
developed as an alternative to previous methods requiring dichloromethyllithium. © 2002 Elsevier Science Ltd. All rights reserved.
In previous papers,1 one author reported a facile, effec-
tive and simple reagent, dichloromethyllithium, for syn-
thesizing various functionalized branched-chain sugars
to be used as ‘chirons’2 via 2,2-dichloroethanol and
spiro a-chloroepoxy derivatives. However, this method
is not totally efficient for the synthesis of functionalized
branched-chain sugars having the required configura-
tion at the branching carbon atom other than
a-hydroxyaldehyde derivatives,1a,1c because the configu-
rations of the products depend on the stereoselectivity
of the reaction between the carbonyl compounds and
dichloromethyllithium, which attacks from the less hin-
dered side.3 In order to develop a procedure for con-
structing functionalized branched-chains, we have
conducted experiments to obtain the epimers of spiro
a-chloroepoxides which are not synthesized by previous
methods.
One author has reported methods for synthesizing both
epimers of unsubstituted spiro epoxides from the same
carbohydrate carbonyl compounds and the stereoselec-
tivities attained in the reaction of carbonyl compounds
with various nucleophiles.3 The results show that the
configurations of the oxygen of the products of the
reactions between carbohydrate carbonyl compounds
with general nucleophiles and the corresponding prod-
ucts derived from carbohydrate exo olefine compounds
with peracid are complementary. Considering the above
results, we adopted a synthetic route via chloroolefine
to obtain the epimers of spiro a-chloroepoxides instead
of those synthesized in the reaction of a carbonyl
compound with dichloromethyllithium.
In 1978, Miyano et al. reported4
chloromethyltriphenylphosphonium iodide,5 which can
a
reagent,
less hindered side
R1
R1
R2
R1
R2
O
CHO
Nu
Nu
m-CPBA
(CH2Cl)2
less hindered side
R2
Cl
Cl
R1
hindered side
O
Epimer
Epimer
R2
R1
R2
R1
R2
R1
R2
Nu
CHO
CHCl2
OH
Nu
DBU
DMSO
hindered side
Cl
O
Scheme 1.
Keywords: carbonyl compounds; carbohydrates; Wittig reactions; epoxidation.
* Corresponding author. Fax: +81 45 413 9770; e-mail: satouk01@kanagawa-u.ac.jp
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00302-7

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K. Sato et al. / Tetrahedron Letters 43 (2002) 3087–3090
be utilized for the conversion of aldehydes and ketones
into chloroolefins. We designed chloroolefins which
could be easily converted into chloroepoxides using
organic peracid via the same stereochemical course as
reported6 (Scheme 1). In this work, we selected carbo-
hydrate carbonyl compounds as the substrates in order
to easily confirm the stereochemistry.
(3.0 equiv.) and n-BuLi (1.5 mol/L in hexane, 2.8
equiv.) in THF at −18°C gave the corresponding a-
chloroolefin derivatives 5–8 (E, Z mixture) in good
yields. The results are shown in Table 1. All the prod-
ucts consist of E and Z diastereomer mixtures, of which
only 5 was isolated and identified. The compounds 5 (E
and Z) were purified with preparative TLC (hexane–
ethyl acetate=3:1, v/v) to separate each isomer. Both
the E and Z diastereomers were oxidized with m-
chloroperbenzoic acid (mCPBA) (5.0 equiv.) in 1,2-
dichloroethane at 70°C. Both compound 5 (E: more
polar) and 5 (Z: less polar) gave the corresponding
unstable spiro a-chloroepoxide 9 (S) and 9 (R) in 65
and 75% yields, respectively, in almost the same reac-
tion time. The configuration of each product 5 (E), 5
(Z), 9 (S), 9 (R) at 3 and 3%-C was confirmed by NMR
(NOESY). Additionally, the configuration of com-
As substrates, 1,2:5,6-di-O-isopropyden-a-
ofranose-3-ulose (1),7,8 methyl 4,6-O-benzyliden-2-O-
methyl-a-
-ribo-hexopyranosid-3-ulose (2),9 methyl
4,6-O-benzyliden-2-deoxy-a- -erythro-hexopyranosid-
3-ulose (3),10,11 methyl 4,6-O-benzyliden-3-O-methyl-a-
D-ribo-hex-
D
D
D
-arabino-hexopyranosid-2-ulose (4)12 were prepared
by Swern oxidation8,13 of the corresponding hydroxy
derivatives in almost quantitative yields. The reaction
of 1–4 with chloromethyltriphenylphosphonium iodide
Table 1. Synthesis of a-chloroolefin derivatives from uloses
Ph3P+CH2Cl I -
n-BuLi
R1
R1
R2
O
THF, -18 oC
R2
Cl
Yield
(Diastereomer Ratio*)
Ulose
α-Chloroolefin
less polar : more polar
O
O
O
O
O
O
79%
(1 : 1)
O
O
Cl
O
O
O
1
5E, Z
O
O
Ph
Ph
O
O
O
O
83%
(1 : 1)
O
Cl
MeO
MeO
OMe
OMe
6 (E, Z mixture)
2
O
O
Ph
Ph
Ph
Ph
O
O
O
O
83%
(1 : 1)
O
Cl
OMe
OMe
3
7 (E, Z mixture)
O
O
O
O
O
O
MeO
MeO
80%
(2 : 1)
O
OMe
8 (E, Z mixture)
OMe
Cl
4
*Determined by NMR spectrum and TLC (Silica gel 60 F254, Merck;
Hexane / EtOAc 1 : 1 - 3 : 1).

K. Sato et al. / Tetrahedron Letters 43 (2002) 3087–3090
3089
pounds 9 (S) and 9 (R) at 3-C was supported by
converting them into the known unsubstituted spiro
epoxides by reduction of chlorine with n-Bu3SnH,
AIBN in toluene at 100°C.14 Under these oxidation
conditions, there was no difference in reactivity between
the (E) and (Z) isomers; therefore, the (E) and (Z)
mixtures were used without isolation. The structures of
10–12 were confirmed by converting them into the
known unsubstituted spiro epoxides15–17 in a similar
manner to that mentioned above. Compounds 9–12 are
more unstable than the corresponding 3-C epimer. The
results are summarized in Table 2. These results show
that oxygen attacks from the less hindered side to give
the corresponding spiro a-chloroepoxide in moderate
yields. Thus, we were able to establish a new synthetic
procedure for synthesizing epimeric spiro a-chloroepox-
ides complementary to our previously described
method.
at 80°C as a model nucleophilic reaction to show the
relative reactivities. The results are summarized in
Table 3. The epimers of 13 and 14 are not detected in
the polar degradation remains. The reaction time and
yields were almost the same for both epimers at 3-C of
9 and 10. The structures of a-azidoaldehyde com-
pounds 13 and 14 were confirmed by comparison of
their physical constants with compounds prepared from
the 3-C epimers of the corresponding spiro a-chloroe-
poxides.1 NMR data for 13, 14 and their epimers are
summarized in Ref. 18. It is noteworthy that 13 and 14
could not be synthesized by the previously described
methods. According to our previous work, other nucle-
ophiles such as H− and AcO− may react in a similar
manner to that reported.1
In conclusion, we have elaborated the methods for
synthesizing various functionalized branched-chain
compounds having the desired configuration at the
branching carbon.
Finally, we examined the reaction of 9 (R), 9 (S), and
10 (R,S mixture) with NaN3 and 15-crown-5 in DMSO
Table 2. Oxidation of a-chloroolefin with mCPBA
less hindered side
R1
R1
O
m-CPBA
(CH2Cl)2
70 oC
R2
Cl
R2
Cl
hindered side
α-Chloroolefin
Spiro α-Chloroepoxide
Yield
O
O
O
O
O
O
O
9S: 65% from 5E
9R: 76% from 5Z
O
O
Cl
Cl
O
O
*
*
5(E, Z)
9(S, R)
O
O
Ph
Ph
O
O
O
O
O
10 (R, S mixture): 69%
from 6 (E, Z mixture)
Cl
Cl
MeO
MeO
OMe
OMe
6 (E, Z mixture)
10 (R, S mixture)
O
O
O
Ph
Ph
O
O
O
O
11 (R, S mixture): 79%
from 7 (E, Z mixture)
Cl
7 (E, Z mixture)
Cl
OMe
OMe
11 (R, S mixture)
O
Ph
O
Ph
O
O
O
O
O
MeO
MeO
12 (R, S mixture): 75%
from 8 (E, Z mixture)
OMe
OMe
Cl
Cl
8 (E, Z mixture)
12 (R, S mixture)

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K. Sato et al. / Tetrahedron Letters 43 (2002) 3087–3090
−
Table 3. Nucleophilic reaction of spiro a-chloroepoxides with N3
NaN3
15-Crown-5
R1
R1
R2
CHO
N3
O
DMSO
80 oC
R2
Cl
α-Chloroolefin
Spiro α-Chloroepoxide
Yield
O
O
O
O
O
O
CHO
66% from 9(R)
65% from 9(S)
O
O
O
Cl
O
N
3O
9(R, S)
13
O
O
O
Ph
Ph
O
O
O
O
OHC
MeO
52%
Cl
MeO
OMe
N3
14
OMe
10 (R, S mixture)
17. Sato, K.; Yoshimura, J. Bull. Chem. Soc. Jpn. 1978, 51,
2116–2121.
References
18. The physical data of a-azidoaldehyde compounds 13, 14
and epimers of 13, 14.
1. (a) Sato, K.; Suzuki, K.; Ueda, M.; Kajihara, Y.; Hori, H.
Bull. Chem. Soc. Jpn. 1997, 70, 225–230; (b) Sato, K.;
Yamamoto, Y.; Hori, H. Tetrahedron Lett. 1996, 37,
2799–2800; (c) Sato, K.; Suzuki, K.; Hashimoto, Y. Chem.
Lett. 1995, 83–84; (d) Sato, K.; Suzuki, K.; Ueda, M.;
Katayama, M.; Kajihara, Y. Chem. Lett. 1991, 1469–1471.
2. Hanessian, S. Total Synthesis of Natural Products: The
‘Chiron’ Approach; Pergamon Press: Oxford, 1983.
3. Yoshimura, J.; Sato, K. J. Synth. Org. Chem. Jpn. (Yuki
Gousei Kagaku Kyoukaishi ) 1982, 40, 415–426.
4. Miyano, S.; Izumi, Y.; Hashimoto, H. J. Chem. Soc., Chem.
Commun. 1978, 446–447.
5. Appel, R.; Morbach, W. Synthesis 1977, 699–700.
6. Funabashi, M.; Sato, H.; Yoshimura, J. Bull. Chem. Soc.
Jpn. 1976, 49, 788–790.
7. Yoshimura, J.; Sato, K.; Hashimoto, H. Chem. Lett. 1977,
1327–1330.
8. Baker, D. C.; Horton, D.; Tindall, C. G., Jr. Carbohydr.
Res. 1972, 24, 192–197.
9. Sato, K.; Yoshimura, J. Bull. Chem. Soc. Jpn. 1978, 51,
2116–2121.
10. Rosenthal, A.; Catsoulacos, P. Can. J. Chem. 1968, 46,
2868–2872.
11. Klemer, A.; Rodemeyer, G. Chem. Ber. 1974, 107, 2612–
2614.
13: [h]2D5 +92.0 (c 1.0, CHCl3); IR wCHO: 1734 cm−1; wN3: 2120
1
cm−1; H NMR (270 MHz, CDCl3) l 9.60 (1H, s, CHO),
5.90 (1H, d, J1,2=3.6 Hz, H-1), 4.64 (1H, d, H-2), 4.25 (1H,
d, J4,5=8.3 Hz, H-4), 4.16 (1H, dd, J6,6%=10.4 Hz, H-6),
4.07 (1H, ddd, J5,6%=5.0 Hz, H-5), 3.97 (1H, dd, H-6%), 1.61,
1.51, 1.38, 1.35 (12H, each s, CH3×4), NOE (CHO–H-5:
5.2%; CHO–H-2: 2.8%); elem. anal. (C13H19O6N3): calcd
for C, 49.84; H, 6.11; N, 13.41. Found: C, 49.94; H, 5.92;
1
N, 13.12%. 14: IR wCHO: 1728 cm−1; wN3: 2124 cm−1; H
NMR (270 MHz, CDCl3) l 9.90 (1H, s, CHO), 7.65–7.34
(5H, m, Ph), 5.46 (1H, s, Ph–CH), 4.96 (1H, dd, J1,2=4.0
Hz, H-1), 4.37 (1H, dd, J6a,6e=10.6 Hz, H-6e), 4.23 (1H,
dd, J4,5=9.6. Hz, J5,6e=5.0 Hz, J5,6a=10.6 Hz, H-5), 3.86
(1H, d, H-4), 3.79 (1H, d, H-2), 3.73 (1H, dd, H-6a), 3.53,
3.39 (6H, each s, OCH3×2), NOE (no observation); epimer
of 13: [h]2D4 +76.9 (c 1.8, CHCl3); IR wCHO: 1736 cm−1; wN3
:
1
2120 cm−1; H NMR (200 MHz, CDCl3) l 9.67 (1H, s,
CHO), 5.94 (1H, d, J1,2=3.4 Hz, H-1), 4.63 (1H, d, H-2),
4.55 (1H, d, J4,5=8.5 Hz, H-4), 4.23 (1H, ddd, J5,6=3.7
Hz, J5,6%=5.9 Hz, H-5), 4.15 (1H, dd, J6,6%=8.6 Hz, H-6%),
4.04 (1H, dd, H-6), 1.61, 1.38, 1.33, 1.31 (12H, each s,
CH3×4), NOE (CHO–H-4: 10.0%); elem. anal.
(C13H19O6N3): calcd for C, 49.84; H, 6.11; N, 13.41. Found:
C, 50.04; H, 6.31; N, 13.30; epimer of 14: [h]2D7 +44.5 (c 2.0,
CHCl3); IR wCHO: 1732 cm−1; wN3: 2120 cm−1; 1H NMR (200
MHz, CDCl3) l 10.03 (1H, s, CHO), 7.43–7.26 (5H, m, Ph),
5.54 (1H, s, Ph–CH), 4.98 (1H, dd, J1,2=3.7 Hz, H-1), 4.40
(1H, dd, J6a,6e=10.0 Hz, H-6e), 4.22 (1H, ddd, J4,5=10.0
Hz, J5,6e=4.5 Hz, J5,6a=10.0 Hz, H-5), 3.80 (1H, d, H-4),
3.75 (1H, dd, H-6a), 3.54, 3.52 (6H, each s, OCH3×2), 3.51
(1H, d, H-2), NOE (CHO–H-5: 37%); elem. anal.
(C16H19O6N3): calcd for C, 55.01; H, 5.48; N, 12.03. Found:
C, 55.35; H, 5.71; N, 12.33%.
12. Miljkovic, M.; Gligorijevic, M.; Miljkovic, D. J. Org. Chem.
1974, 39, 2118–2121.
13. Huang, H. L.; Omura, K.; Swern, D. J. Org. Chem. 1976,
41, 3329–3331.
14. Funabashi, M.; Sato, H.; Yoshimura, J. Bull. Chem. Soc.
Jpn. 1976, 49, 788–790.
15. Funabashi, M.; Hong, N.; Kodama, H.; Yoshimura, J.
Carbohydr. Res. 1978, 67, 139–145.
16. Sato, K.; Yoshimura, J. Carbohydr. Res. 1979, 73, 75–84.