Synthesis of enantiomerically pure spiro-cyclopropane derivatives containing multichiral centers

Article abstract of DOI:10.1016/S0957-4166(98)00416-9

A novel chiral source, 5-(R)-[(1R,2S,5R)-(-)-menthyloxy]-3-bromo-2(5H)- furanone (5a), was obtained in 46% yield with d.e.≥98% from the epimeric mixture of 5-(1-menthyloxy)-3-bromo-2(5H)-furanone (Sa+5b) obtained via the bromination of an epimeric mixture

Full text of DOI:10.1016/S0957-4166(98)00416-9

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 4103–4107
Synthesis of enantiomerically pure spiro-cyclopropane derivatives
containing multichiral centers
Hui Huang † and Qinghua Chen ∗
Department of Chemistry, Beijing Normal University, Beijing 100875, P.R. China
Received 10 September 1998; accepted 7 October 1998
Abstract
A novel chiral source, 5-(R)-[(1R,2S,5R)-(−)-menthyloxy]-3-bromo-2(5H)-furanone (5a), was obtained in 46%
yield with d.e.≥98% from the epimeric mixture of 5-(l-menthyloxy)-3-bromo-2(5H)-furanone (5a+5b) obtained
via the bromination of an epimeric mixture of 5-(l-menthyloxy)-2(5H)-furanone (3a+3b) followed by the elimina-
tion of hydrogen bromide. The asymmetric reaction of 5a with a nucleophilic alcohol afforded enantiomerically
pure spiro-cyclopropane derivatives containing four stereogenic centers, 9a–9e, in 50–68% yield with d.e.≥98%.
The enantiomerically pure compounds 9a–9e were identified on the basis of their analytical data and spectroscopic
data, such as [α]D20, UV, IR, 1H NMR, 13C NMR, MS and elementary analysis. The absolute configuration of the
chiral spiro-cyclopropane compound 9a was established by X-ray crystallography. © 1998 Elsevier Science Ltd.
All rights reserved.
Recently, chiral sources obtained from natural chiral auxiliaries, such as (1R,2S,5R)-(−)-menthol
and endo-(−)-borneol, have attracted much attention in the asymmetric synthesis of some biologically
active compounds.1–4 It has been known that the chiral reagent 5-(l-menthyloxy)-2(5H)-furanone be-
haves as a Michael acceptor towards carbon, oxygen, sulfur and nitrogen nucleophiles to give chiral
5-(l-menthyloxy)-4-substituted-butyrolactones.2–4 The 5-(l-menthyloxy)-3,4-dihalo(chloro or bromo)-
2(5H)-furanone reacts readily with nitrogen and sulfur nucleophiles to give the tandem Michael
addition/elimination products, 5-(l-menthyloxy)-4-substituted-3-halo-2-(5H)-furanones.4 We have now
successfully synthesized the novel chiral source, 5-(R)-[(1R,2S,5R)-(−)-menthyloxy)]-3-bromo-2(5H)-
furanone (5a), which was obtained in 46% yield with d.e.≥98% (Scheme 1) from the epimeric mixture
of 5-(l-menthyloxy)-3-bromo-2(5H)-furanone (5a+5b) via the bromination of an epimeric mixture of
5-(l-menthyloxy)-2(5H)-furanone (3a+3b) followed by the elimination of hydrogen bromide.5 After re-
crystallization of the epimeric mixture, the 1H NMR spectrum showed a single epimer 5a: δ5a=5.97 (1H,
s, C5–H5a) ppm, and lost the characteristic shift of 5b: δ5b=5.87 (1H, s, C5–H5b) ppm. Enantiomerically
∗
†
Corresponding author. Fax: (+) 010-62200567; e-mail: qinghuac@bnu.edu.cn
Visiting Scholar, Associate Professor, Department of Chemistry, Tonghua Teacher’s College, Tonghua, 134002, Jilin, P.R.
China.
0957-4166/98/$ - see front matter © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00416-9

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H. Huang, Q. Chen / Tetrahedron: Asymmetry 9 (1998) 4103–4107
Scheme 1. The synthetic route to the chiral source 5a
pure 5a was obtained as pale-yellow needles, m.p. 89–90°C (petroleum ether, 30–60°C). The novel chiral
source, 3-bromo-2(5H)-furanone 5a was identified on the basis of its satisfactory elemental analysis
1
data and spectroscopic data (IR, UV, H NMR, 13C NMR and MS).5 The absolute configuration at the
acetal of 5a was shown to be R by means of an X-ray structure analysis of its asymmetric reaction
product with methanol.6 On the basis of previous work,7 we have accomplished the tandem asymme-
tric double Michael addition/internal nucleophilic substitution of 5-(R)-(l-menthyloxy)-3-bromo-2(5H)-
furanone (5a) with oxygen nucleophiles such as methanol, isopropanol, cyclopentanol, cyclohexanol
and cycloheptanol, in acetonitrile at room temperature, in the presence of potassium carbonate and
tetrabutylammonium bromide as a phase transfer catalyst. The enantiomerically pure compounds, spiro-
cyclopropane bisbutyrolactones 9a–9e with four stereogenic centers were obtained in 50–68% yield
Scheme 2. The synthetic route to 9a–9e

H. Huang, Q. Chen / Tetrahedron: Asymmetry 9 (1998) 4103–4107
4105
with d.e.≥98% by the tandem asymmetric reaction under the mild conditions indicated in Scheme 2.
The spiro-cyclopropane bisbutyrolactones 9a–9e were identified on the basis of their analytical data and
spectroscopic data.8 The absolute configuration of the chiral spiro-cyclopropane bisbutyrolactone 9a was
established by X-ray crystallography6 and by spectroscopic analysis. The presence of two 5-menthyloxy-
2(5H)-furanone moieties was deduced from the 1H NMR spectrum, which showed two signals at δ: 5.64
1
(1H, s, H-50), 5.66 (1H, s, H-5) assignable to the acetal protons. In addition, the H NMR spectrum
showed two signals at δ: 2.98 (1H, s, H-4), 3.42 (1H, s, H-40), in which the absence of coupling constants
between the vicinal protons H-4/H-5 and H-40/H-50 established a trans relationship. The presence of an
IR band at 3078 cm−1 was assignable to a C–H stretching in a cyclopropane ring and the signal at δ
38.47 (C-4) ppm of the 13C NMR spectrum was also in agreement with the presence of a cyclopropane
ring. On the basis of these data, the proposed structure of spiro-cyclopropane bisbutyrolactone 9a was
consistent with the stereochemistry of the molecule of 9a by its X-ray structure analysis. The ORTEP
drawing and the crystal packing of the molecule of 9a are shown in Figs. 1 and 2, respectively. The
absolute configuration of (1R,2S,5R)-(−)-menthyloxy was unchanged during the asymmetric reaction
process. Accordingly, the absolute configuration of 9a was established and the configuration of the new
stereogenic centers established as 3(S), 4(S), 30(R), 40(R).
Figure 1. The ORTEP drawing of the molecule of 9a
The behavior of 5-(R)-[(1R,2S,5R)-(−)-menthyloxy]-3-bromo-2(5H)-furanone (5a) could be explained
on the basis of a reaction mechanism of the racemic 5-methoxy-3-bromo-2(5H)-furanone,7 such that the
chiral 3-bromo furanone 5a reacts readily with nucleophiles to give the Michael adduct 6. When an anion,
such as a carbanion, is used as a nucleophile, the carbanionic intermediate of type 7, in the absence of

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H. Huang, Q. Chen / Tetrahedron: Asymmetry 9 (1998) 4103–4107
Figure 2. The crystal packing of the molecule of 9a
a proton donor, adds to a second molecule of bromofuranone 5a to give a new anionic intermediate, the
enolate anion 8. This intermediate, at room temperature, suffers an internal nucleophilic substitution of
the halogen to yield the optically active spiro-cyclopropane bisbutyrolactones 9a–9e. At present, we have
also studied the asymmetric reaction of chiral 3-halo-2(5H)-furanone with different series of nucleophilic
reagents such as carbon, oxygen, nitrogen and sulfur nucleophiles. Application of this synthetic strategy
to the new optically active spiro-cyclopropane derivatives in asymmetric synthesis is currently under
investigation.
Acknowledgements
We are grateful to the National Natural Science Foundation of China for supporting this research work.
References
1. Seyden-Penne, J. Chiral Auxiliaries and Ligands in Asymmetric Synthesis; John Wiley: New York, 1995; p. 43.
2. (a) Van Oeveren, A.; Jansen, J. F. G. A.; Feringa, B. L. J. Org. Chem. 1994, 59, 5999; (b) Pelter, A.; Ward, R. S.; Jones,
D. M.; Maddocks, P. Tetrahedron: Asymmetry 1992, 3, 239.
3. (a) Feringa, B. L.; de Lange, B.; Jong, C. J. Org. Chem. 1989, 54, 2471; (b) Feringa, B. L.; de Jons, J. C. Bull. Soc. Chim.
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4. (a) Chen, Q.; Geng, Z.; Huang, B.; Cao, P. Youji Huaxue (Organic Chemistry, in Chinese) 1991, 11, 494; (b) Chen, Q.;
Zou, C. Youji Huaxue (Organic Chemistry, in Chinese) 1994, 14, 1; (c) Chen, Q.; Huang, B. Chinese Science Bulletin (in
Chinese) 1994, 39, 2154; (d) Chen, Q.; Geng, Z. Acta Chimica Sinica (in Chinese) 1993, 51, 622; (e) Chen, Q.; Geng, Z.;
Huang, B. Tetrahedron: Asymmetry 1995, 6, 401; (f) Cui, J.; Du, B.; Chen, Q. Science in China (series B) 1998, 41, 65.
5. 5a: 0.73 g, (46%), m.p. 89–90°C; [α]D20=−121.1 (c 1.82, CHCl3); C14H21O3Br, calcd: C, 53.01; H, 6.67; found: C, 52.93;
H, 6.85); UV λmax (95% EtOH): 251.0 (log ε 3.6) nm; IR (KBr, cm−1): 2910, 2850 (CH), 1761 (C_O), 1612 (C_C),
1
1152 (COC, Vas), 925 (COC, Vs); H NMR (200 MHz, CDCl3) δH: 0.80 (3H, d, J=7.2 Hz, 3H-12), 0.86 (3H, d, J=6.8
Hz, 3H-14), 0.95 (3H, d, J=6.8 Hz, 3H-15), 1.10 (2H, m, 2H-10), 1.40 (2H, m, 2H-9), 1.67 (2H, m, 2H-7), 2.10 (3H, m,
H-8, H-11, H-13), 3.25 (1H, bt, J=10.8, 10.8, 4.6 Hz, H-6), 5.90 (1H, S, H-5), 7.20 (1H, s, H-4) ppm; 13C NMR (45 MHz,

H. Huang, Q. Chen / Tetrahedron: Asymmetry 9 (1998) 4103–4107
4107
CDCl3) δC: 15.58 (C-15), 20.78 (C-14), 22.09 (C-12), 25.31 (C-13), 22.94 (C-10), 31.34 (C-8), 34.01 (C-9), 40.16 (C-7),
47.57 (C-11), 79.24 (C-6), 99.69 (C-5), 117.51 (C-4), 147.49 (C-3), 165.98 (C-2); m/z: 316 (M+, 18), 301 (M+−CH3, 18),
288 (M+−C2H4, 16), 73 (C2HO3+·, 100).
6. The stereochemistry of 9a has been determined by a single crystal X-ray analysis. Crystal data: C29H45O7Br, Mr=585.56,
orthorhombic system, P212121 space group, a=9.748(4) Å, b=12.537(5) Å, c=25.851(9) Å, V=3.159 Å3, Z=4, Dx=1.231
g cm−3, µ=13.41 cm−1, F(000)=1240. Monochromated Mo-Kα diffraction, λ=0.71073 Å, R=0.0475, Rw=0.0609, 3830
independent points, 865 perceivable points of I≥3σ(I).
7. Farina, F.; Maestro, M. C.; Martin, M. R.; Martin, M. V.; Sanchez, F.; Soria, M. L. Tetrahedron 1986, 42(13), 3715.
8. 5-(R)-(l-Menthyloxy)-3-bromo-butyrolacto-[3,4,100,200]-spiro[4.2]-[cyclopropane-300,30]-40-methoxy-50-(R)-(l-menthyl-
oxy)-butyrolactone 9a: 0.29 g (50%); white crystals, m.p. 156–158°C (petroleum ether, 30–60°C); [α]D20=−108.4 (c
1.02, CHCl3); C29H45O7Br, calcd: C, 59.58; H, 7.75; found: C, 59.72; H, 8.07; UV: (λmax, CHCl3): 241.8 (log ε 0.70) nm;
IR (KBr, cm−1): 3077.8 (cyclopropane C–H), 1789.7 (C_O), 1123.4 (COC, Vas), 920.6 (COC, Vs); 1H NMR (200 MHz,
CDCl3) δH: 0.66 (3H, d, J=7.2 Hz, 3H-120), 0.70 (3H, d, J=6.8 Hz, 3H-140), 0.72 (3H, d, J=6.8 Hz, 3H-150), 0.79 (3H,
d, J=7.2 Hz, 3H-12), 0.84 (3H, d, J=6.8 Hz, 3H-14), 0.89 (3H, d, J=6.8 Hz, 3H-15), 1.09–1.45 (6H, m, 2H-10, 2H-100,
H-9e, H-9e0), 1.49–1.69 (6H, m, 2H-7, 2H-70, H-9a, H-9a0), 1.89–2.17 (6H, m, H-8, H-80, H-11, H-110, H-13, H-130),
2.98 (1H, s, H-4), 3.28 (3H, s, H-160), 3.42 (1H, s, H-40), 3.59 (2H, m, H-6, H-60), 5.64 (1H, s, H-50), 5.66 (1H, s, H-5)
ppm; 13C NMR (45 MHz, CDCl3) δC: 15.57 (C-150), 15.61 (C-15), 20.72 (C-140), 20.81 (C-14), 22.09 (C-120), 22.19
(C-12), 22.81 (C-100), 23.11 (C-10), 24.79 (C-130), 25.40 (C-13), 31.27 (C-80), 31.32 (C-8), 34.05 (C-30), 34.07 (C-90),
34.15 (C-9), 38.47 (C-4), 38.50 (C-3), 39.11 (C-70), 40.02 (C-7), 47.34 (C-110), 47.43 (C-11), 57.42 (C-160), 76.78 (C-6),
78.38 (C-60), 82.48 (C-40), 97.23 (C-50), 99.26 (C-5), 167.76 (C-20), 168.74 (C-2); m/z: 584 (M+, 15), 540 [(M−C3H8)+,
15] 454 [(M−C10H10)+, 15 ] 83 (C4H3O2+, 100), 43 (C3H7+, 96), 41 (C3H5+, 53).