Asymmetric synthesis of 3,4-dihydroxyglutamic acids via enantioselective reduction of cyclic meso-imide

Article abstract of DOI:10.1016/j.tet.2004.06.109

Stereoselective synthesis of (3S,4S)- and (3R,4R)-series of 3,4-dihydroxyglutamic acids was investigated. The key reaction in this synthesis is asymmetric reduction of meso-imide derived from meso-tartaric acid. Lewis acid-promoted cyanation of the obtained optically active lactam via the acyliminium intermediate followed by standard deprotection procedure afforded the desired 3,4-dihydroxyglutamic acids. Graphical abstract

Full text of DOI:10.1016/j.tet.2004.06.109

Tetrahedron 60 (2004) 8089–8092
Asymmetric synthesis of 3,4-dihydroxyglutamic acids via
enantioselective reduction of cyclic meso-imide
*
Makoto Oba, Shinichi Koguchi and Kozaburo Nishiyama
*
Department of Material Science and Technology, Tokai University, 317 Nishino, Numazu, Shizuoka 410-0395, Japan
Received 14 April 2004; revised 17 June 2004; accepted 24 June 2004
Available online 21 July 2004
Abstract—Stereoselective synthesis of (3S,4S)- and (3R,4R)-series of 3,4-dihydroxyglutamic acids was investigated. The key reaction in
this synthesis is asymmetric reduction of meso-imide derived from meso-tartaric acid. Lewis acid-promoted cyanation of the obtained
optically active lactam via the acyliminium intermediate followed by standard deprotection procedure afforded the desired 3,4-
dihydroxyglutamic acids.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
imide derived from meso-tartaric acid. Such synthetic
operation on the meso-imide can establish the absolute
stereochemistry at three contiguous centers in a single step.
Much attention is being paid to the synthesis of non-
proteinogenic as well as unusual amino acids of natural
occurrence. 3,4-Dihydroxyglutamic acid is a natural
glutamic acid derivative, which was isolated from the
seeds of Lepidum sativum and the leaves of Rheum
rhaponticum about 50 years ago.1 However, nothing is
known concerning the stereochemistry of the three con-
secutive chiral centers. Recently, two groups reported the
stereoselective synthesis of (2S,3S,4S)- and (2S,3S,4R)-3,4-
dihydroxyglutamic acid,2,3 and the former compound was
found to be a selective agonist of mGluR1. However, the
methods require multistep synthesis from the commercially
available compound and lack applicability to other dia-
stereomers. Therefore, a simple and general approach to all
stereoisomers of 3,4-dihydroxyglutamic acid must be
explored.
There are some reports on the enantioselective reduction of
cyclic meso-imide.5–8 Among them, optically active oxa-
borolidines mainly derived from L-amino acid have been
widely used as a catalyst for borane reduction.5 On the other
hand, chiral BINAL-H is also recognized as an effective
reducing agent for enantioselective desymmetrization of
meso-imide;6 however, reduction of meso-imide derived
from meso-tartaric acid by the BINAL-H complex is not
reported. In this paper, we examined the asymmetric
synthesis of 3,4-dihydroxyglutamic acids via enantio-
selective reduction of cyclic meso-imide prepared from
meso-tartaric acid with BINAL-H because both (S)-(K)-
and (R)-(C)-binaphthol are commercially available.
We have previously reported a concise stereoselective
synthesis of (2S,3S,4R)-, (2R,3S,4R)-, (2S,3R,4S)-, and
(2R,3R,4S)-3,4-dihydroxyglutamic acid starting from L- or
D-tartaric acid.4 In order to obtain the corresponding
(3S,4S)- and (3R,4R)-isomers, there are at least two ways
including enantioselective symmetry breaking of meso-
tartaric acid or utilization of a chiral starting material.
Taking advantage of our previous work in this area, we
planned to investigate enantioselective reduction of meso-
2. Results and discussion
Scheme 1 shows the synthetic course of (3R,4R)-series of
3,4-dihydroxyglutamic acids. First of all, the enantio-
selective reduction of cyclic meso-imide 1, derived from
meso-tartaric acid, was carried out with 3 equiv. of
(R)-BINAL-H reagent prepared in situ by mixing lithium
aluminum hydride with equimolar amounts of (R)-(C)-
binaphthol and ethanol in tetrahydrofuran.9 The enantio-
meric excess was assessed by HPLC analysis to be 83% ee
using a chiral stationary column after conversion of the
initially formed hydroxylactam into triacetoxylactam 2.
Among the simple alcohols such as methanol, 2-propanol,
2-methyl-2-propanol, and butanol tested as the additive,
Keywords: Asymmetric synthesis; 3,4-Dihydroxyglutamic acid; meso-
Imide; Desymmetrization.
* Corresponding authors. Tel.: C81-55-968-1111; fax: C81-55-968-1155;
e-mail: makoto@wing.ncc.u-tokai.ac.jp
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.06.109

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M. Oba et al. / Tetrahedron 60 (2004) 8089–8092
Scheme 1. (i) (R)-BINAL-H (EtOH), K78 8C; (ii) Ac2O in pyridine, 61% (2 steps); (iii) BF3–OEt2, Me3SiCN, toluene, 87%; (iv) AcCl, EtOH; (v)
Me2C(OMe)2, p-toluenesulfonic acid, acetone, 36 and 60% yields for 4a and 4b, respectively (2 steps); (vi) Ce(NH4)2(NO3)6, acetonitrile–H2O; (vii) 6 M HCl,
reflux, 16 h, then Dowex 50W-X8, 75% (2 steps); (viii) as in vi; (ix) 1 M HCl, reflux, 3 h, then Dowex 50W-X8, 38% (2 steps).
ethanol afforded the best enantioselectivity. By comparing
the sign of the specific rotation of the 3,4-dihydroxy-
glutamic acid 5a formed from the triacetate 2 with that of
known 3,4-dihydroxyglutamic acid, the (2S,3S,4S)-isomer,2
the absolute configuration of the triacetate 2 was presumed
as depicted in Scheme 1. The triacetate 2 was obtained as a
single diastereomer and the stereochemical outcome
suggests that the preferred trajectory of the (R)-BINAL-H
reagent would be from the least hindered face of the
carbonyl group attached to the S center of the cyclic meso-
imide. Matsuki and co-workers reported that (R)-BINAL-H
would attack the carbonyl carbon adjacent to the R center of
the bicyclic meso-imide.6 At the present stage, we cannot
pinpoint the origin of enantioselective discrimination of
the two enantiotopic imide carbonyl groups; however, the
interaction of an acetoxy group with the (R)-BINAL-H
reagent may be responsible for the observed reversal of the
enantioselectivity.
with boron trifluoride etherate (1.5 equiv.) at room tem-
perature for 1 h, cyanolactam 3 was obtained in 87% yield
as a 38:62 mixture of syn and anti adducts. The
stereochemistry of the cyanolactam 3 was determined by
comparison of the J4,5 values, 5 and 1 Hz for the syn and anti
adducts, respectively,10 and was finally confirmed by
transformation to 3,4-dihydroxyglutamic acid 5. Several
investigations were made on the diastereoselective
cyanation; however, there was no improvement in
diastereoselectivity.
Separation of the diastereomers was carried out after
conversion of the diacetate 3 to the corresponding acetonide
4 because the diastereomeric mixture of 3 could not be
separated by column chromatography. The cyanolactams
4a and 4b were isolated in 36 and 60% yields, respectively,
and were independently treated with ammonium cerium
(IV) nitrate followed by acidic hydrolysis to give novel
(2R,3R,4R)- and (2S,3R,4R)-3,4-dihydroxyglutamic acid 5a
and 5b in 75 and 38% yields, respectively. The transform-
ation of the anti adduct 4b to 5b needed to be performed
with care. The final acidic hydrolysis should be performed
The obtained triacetoxylactam 2 was then subjected to
cyanation reaction. When a solution of triacetate 2 and
trimethylsilyl cyanide (1.5 equiv.) in toluene was treated
Scheme 2. (i) (S)-BINAL-H (EtOH), K78 8C; (ii) Ac2O in pyridine, 68% (2 steps); (iii) BF3–OEt2, Me3SiCN, toluene, quant.; (iv) AcCl, EtOH;
(v) Me2C(OMe)2, p-toluenesulfonic acid, acetone, 26 and 46% yields for 8a and 8b, respectively (2 steps); (vi) Ce(NH4)2(NO3)6, acetonitrile–H2O; (vii) 6 M
HCl, reflux, 16 h, then Dowex 50W-X8, 80% (2 steps); (viii) as in vi; (ix) 1 M HCl, reflux, 3 h, then Dowex 50W-X8, 63% (2 steps).

M. Oba et al. / Tetrahedron 60 (2004) 8089–8092
8091
in refluxing 1 M HCl for 3 h. Refluxing in 6 M HCl
overnight as in the synthesis of 5a resulted in undesirable
epimerization at the a-position.
hydroxylactam. To a solution of the hydroxylactam in
pyridine (60 mL) was added acetic anhydride (1.83 g,
18.0 mmol), and the reaction mixture was stirred at room
temperature overnight. After evaporation of the solvent, the
residue was extracted with ethyl acetate. The organic layer
was washed successively with 1 M HCl and saturated
aqueous NaHCO3, dried over MgSO4, and evaporated. The
crude product was purified by column chromatography on
silica gel (hexane–ethyl acetateZ50:50) to give the title
compound 2 (690 mg, 61%) as an oil. 1H NMR (DMSO-d6)
d 1.91 (s, 3H), 1.97 (s, 3H), 2.07 (s, 3H), 3.70 (s, 3H), 4.20
(d, JZ15 Hz, 1H), 4.49 (d, JZ15 Hz, 1H), 5.45 (d, JZ
7 Hz, 1H), 5.50 (dd, JZ7, 5 Hz, 1H), 6.11 (d, JZ5 Hz, 1H),
6.87 (d, JZ9 Hz, 2H), 7.15 (d, JZ9 Hz, 2 H). 13C NMR
(CDCl3) d 19.89, 20.08, 20.21, 43.03, 54.99, 64.78, 67.12,
79.49, 113.97, 126.97, 129.58, 159.21, 167.81, 168.87,
169.19, 169.52. HRMS (EI, 30 eV) m/z 379.1279 (MC,
calcd for C18H21NO8 379.1267).
3,4-Dihydroxyglutamic acids in another enantiomeric
series, the (3S,4S)-isomers, were synthesized from a chiral
triacetoxylactam 6 prepared by reduction of the meso-imide
1 with (S)-BINAL-H. The results are summarized in
Scheme 2. Using the same procedure for the preparation
of the corresponding (3R,4R)-isomers, the known
(2S,3S,4S)-3,4-dihydroxyglutamic acid (9a)2 and novel
(2R,3S,4S)-isomer (9b) were obtained in good yields.
In conclusion, asymmetric synthesis of (3S,4S)- and
(3R,4R)-series of 3,4-dihydroxyglutamic acids using
enantioselective desymmetrization of meso-imide derived
from meso-tartaric acid was achieved. Lewis acid-promoted
cyanation of the obtained optically active lactam via the
acyliminium intermediate followed by standard deprotec-
tion procedure afforded the 3,4-dihydroxyglutamic acids.
Coupled with the results obtained in our previous work,4 the
present study provides a facile and versatile protocol for
accessing all eight stereoisomers of 3,4-dihydroxyglutamic
acids.
3.1.3. (3R,4R)-3,4-Diacetoxy-5-cyano-1-(4-methoxyben-
zyl)-2-pyrrolidinone (3). To a solution of acetoxylactam
2 (3.03 g, 8.0 mmol) and trimethylsilyl cyanide (1.19 g,
12.0 mmol) in toluene (80 mL) was added a solution of
boron trifluoride etherate (2.27 g, 12.0 mmol) in toluene
(8 mL) at room temperature. After it was stirred for 1 h, the
reaction mixture was quenched with saturated aqueous
Na2CO3 and extracted with ethyl acetate. The organic layer
was dried over MgSO4 and concentrated in vacuo. The
crude product was purified by column chromatography on
silica gel (hexane–ethyl acetateZ50:50) to give the title
compound 3 (2.60 g, 87%) as a 62:38 mixture of
diastereomers. HRMS (EI, 30 eV) m/z 346.1186 (MC,
3. Experimental
3.1. General
1H and 13C NMR spectra were recorded at 400 and
100 MHz, respectively. All chemical shifts are reported as
d values (ppm) relative to residual chloroform (dH 7.26),
residual DMSO (dH 2.50), dioxane (dH 3.53 and dc 66.5), or
the central peak of CDCl3 (dc 77.0). High-resolution mass
spectra (HRMS) were determined using perfluorokerosene
as an internal standard. Optical rotations were measured on
a HORIBA SEPA-200 polarimeter. Enantiomeric excess
was determined on an HPLC system (monitored at 254 nm)
equipped with a chiral column (CHIRALPAK AS-H) using
a mixture of hexane and ethanol (50:50) as an eluent.
1
calcd for C17H18N2O6 346.1165). Major isomer: H NMR
(CDCl3) d 2.02 (s, 3H), 2.17 (s, 3H), 3.80 (s, 3H), 3.98 (d,
JZ15 Hz, 1H), 4.07 (d, JZ1 Hz, 1H), 5.12 (d, JZ15 Hz,
1H), 5.61 (dd, JZ6, 1 Hz, 1H), 5.63 (d, JZ6 Hz, 1H), 6.98
(d, JZ9 Hz, 2H), 7.19 (d, JZ9 Hz, 2H). Minor isomer: 1H
NMR (CDCl3) d 2.17 (s, 3H), 2.34 (s, 3H), 3.80 (s, 3H), 4.43
(d, JZ15 Hz, 1H), 4.30 (d, JZ5 Hz, 1H), 5.19 (d, JZ
15 Hz, 1H), 5.42 (d, JZ5 Hz, 1H), 5.53 (dd, JZ5, 5 Hz,
1H), 6.98 (d, JZ9 Hz, 2H), 7.19 (d, JZ9 Hz, 2H).
3.1.1. (3R*,4S*)-3,4-Diacetoxy-1-(4-methoxybenzyl)-2,5-
pyrrolidinedione (1). According to the procedure for the
preparation of the corresponding N-benzyl derivative
reported by Hiemstra and co-workers,5 the title compound
1 was obtained as colorless needles (hexane–chloroform),
3.1.4. (3R,4R,5S)-3,4-O-Isopropylidene-5-cyano-1-(4-
methoxybenzyl)-2-pyrrolidinone (4a) and (3R,4R,5R)-
3,4-O-isopropylidene-5-cyano-1-(4-methoxybenzyl)-2-
pyrrolidinone (4b). To a solution of cyanolactam 3 (3.42 g,
9.87 mmol) in ethanol (86 mL) was added acetyl chloride
(2.02 g, 25.8 mmol), and the solution was stirred at 50 8C
for 2.5 h. After evaporation of the solvent, the residue was
dissolved in acetone (86 mL). To the solution was added
2,2-dimethoxypropane (4.47 g, 43.0 mmol) and p-toluene-
sulfonic acid (440 mg, 2.55 mmol), and the solution was
stirred at 30 8C for 2 h. After removal of the solvent, the
crude product was purified by column chromatography on
silica gel (hexane–ethyl acetateZ50:50) to give the title
compound 4b (1.80 g, 60%) as an oil, which solidified upon
standing. Colorless powder (hexane–chloroform), mp 94–
95 8C. 1H NMR (CDCl3) d 1.33 (s, 3H), 1.35 (s, 3H), 3.78 (s,
3H), 3.91 (d, JZ15 Hz, 1H), 4.12 (s, 1H), 4.85 (s, 2H), 5.10
(d, JZ15 Hz, 1H), 6.87 (d, JZ9 Hz, 2H), 7.17 (d, JZ9 Hz,
2H). 13C NMR (CDCl3) d 25.75, 26.84, 44.79, 51.24, 55.18,
74.81, 76.76, 113.92, 114.42, 114.93, 125.01, 139.88,
1
mp 102–103 8C. H NMR (CDCl3) d 2.11 (s, 6H), 3.77 (s,
3H), 4.66 (s, 2H), 5.53 (s, 2H), 6.83 (d, JZ9 Hz, 2H), 7.31
(d, JZ9 Hz, 2H). 13C NMR (CDCl3) d 19.95, 42.37, 55.23,
65.96, 114.08, 126.75, 130.49, 159.57, 168.99, 170.89.
HRMS (EI, 70 eV) m/z 335.0970 (MC, calcd for
C16H17NO7 335.1005).
3.1.2. (3R,4S)-3,4,5-Triacetoxy-1-(4-methoxybenzyl)-2-
pyrrolidinone (2). To a solution of (3R*,4S*)-3,4-diace-
toxy-1-(4-methoxybenzyl)-2,5-pyrrolidinedione (1, 1.00 g,
3.00 mmol) in THF (90 mL) was added a solution of
(R)-BINAL-H (EtOH) (9.00 mmol) in THF (25 mL) at
K78 8C under an argon atmosphere. After it was stirred for
17 h, the reaction mixture was quenched with 1 M HCl
and extracted with ethyl acetate. The organic layer was
dried over MgSO4 and evaporated to dryness to give a

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M. Oba et al. / Tetrahedron 60 (2004) 8089–8092
159.73, 169.69. HRMS (EI, 70 eV) m/z 302.1224 (MC,
calcd for C16H18N2O4 302.1266).
3.1.7. (2S,3S,4S)-3,4-Dihydroxyglutamic acid (9a).
According to the procedure for the preparation of compound
5a, deprotection and hydrolysis of cyanolactam 8a (532 mg,
1.76 mmol) gave the title compound 9a (195 mg, 63%) as a
white powder, [a]D25ZK0.5 (c 1.0, H2O) (lit.2 [a]2D8ZK0.8
(c 1.0, H2O)). The physical and spectral data of compound
9a are identical with those of the compound 5a.
Further elution with a mixture of hexane and ethyl acetate
(50:50) gave the corresponding (3R,4R,5S)-isomer 4a
(1.09 g, 36%) as a pale yellow oil, which solidified upon
standing. Colorless needles (hexane–chloroform), mp 174–
175 8C. 1H NMR (CDCl3) d 1.42 (s, 3H), 1.52 (s, 3H), 3.78
(s, 3H), 3.95 (d, JZ14 Hz, 1H), 4.30 (d, JZ4 Hz, 1H), 4.70
(d, JZ5 Hz, 1H), 4.77 (dd, JZ5, 4 Hz, 1H), 5.18 (d, JZ
14 Hz, 1H), 6.86 (d, JZ8 Hz, 2H), 7.22 (d, JZ8 Hz, 2H).
13C NMR (CDCl3) d 25.79, 26.72, 44.89, 51.38, 55.19,
71.15, 76.90, 112.95, 114.06, 114.46, 125.63, 130.22,
159.76, 169.08. HRMS (EI, 70 eV) m/z 302.1273 (MC,
calcd for C16H18N2O4 302.1266).
3.1.8. (2R,3S,4S)-3,4-Dihydroxyglutamic acid (9b).
According to the procedure for the preparation of compound
5b, deprotection and hydrolysis of cyanolactam 8b (958 mg,
3.17 mmol) gave the title compound 9b (454 mg, 80%) as a
white powder, [a]2D5ZC2.0 (c 1.0, H2O). The physical and
spectral data of compound 9b are identical with those of
compound 5b.
3.1.5. (2R,3R,4R)-3,4-Dihydroxyglutamic acid (5a). To a
suspension of cyanolactam 4a (302 mg, 1.00 mmol) and
diammonium cerium (IV) nitrate (1.09 g, 2.00 mmol) in
acetonitrile (15 mL) was added water (3 mL) at room
temperature, and the resulting mixture was stirred for 4 h.
The reaction mixture was then diluted with ethyl acetate,
washed with water, and dried over MgSO4. After removal of
the solvent, the residue was hydrolyzed in refluxing 6 M
HCl (20 mL) for 16 h. The cooled aqueous solution was
washed with chloroform and concentrated to dryness. The
residue was submitted to ion exchange column chroma-
tography on Dowex 50W-X8 to furnish the title compound
5a (128 mg, 75%) as a colorless powder (EtOH–H2O), mp
155–160 8C (dec). [a]2D5ZC0.7 (c 1.0, H2O). 1H NMR
(D2O) d 3.63 (d, JZ0.4 Hz, 1H), 4.09 (d, JZ3.5 Hz, 1H),
4.49 (dd, JZ3.5, 0.4 Hz, 1H). 13C NMR (D2O) d 56.96,
71.20, 76.21, 173.91, 178.33. HRMS (EI, 70 eV) m/z
135.0559 [(MKCO2)C, calcd for C4H9NO4 135.0532).
MS (FAB) m/z 180 (MHC).
References and notes
1. Virtanen, A. I.; Ettala, T. Soumen Kemistilehti 1956, B29,
107–108.
2. Dauban, P.; De Saint-Fuscien, C.; Dodd, R. H. Tetrahedron
1999, 55, 7589–7600. Dauban, P.; De Saint-Fuscien, C.;
Acher, F.; Prezeau, L.; Brabet, I.; Pin, J.-P.; Dodd, R. H.
Bioorg. Med. Chem. Lett. 2000, 10, 129–133.
3. Langlois, N. Tetrahedron Lett. 1999, 40, 8801–8803.
4. Oba, M.; Koguchi, S.; Nishiyama, K. Tetrahedron Lett. 2001,
42, 5901–5902. Oba, M.; Koguchi, S.; Nishiyama, K.
Tetrahedron 2002, 58, 9359–9363.
5. Shimizu, M.; Nishigaki, Y.; Wakabayashi, A. Tetrahedron
Lett. 1999, 40, 8873–8876. Romagnoli, R.; Roos, E. C.;
Hiemstra, H.; Moolenaar, M. J.; Speckamp, W. N. Tetrahedron
Lett. 1994, 35, 1087–1090. Ostendorf, M.; Romagnoli, R.;
Pereiro, I. C.; Roos, E. C.; Moolenaar, M. J.; Speckamp,
W. N.; Hiemstra, H. Tetrahedron: Asymmetry 1997, 8,
1773–1789. Dixon, R. A.; Jones, S. Tetrahedron: Asymmetry
2002, 13, 1115–1119.
3.1.6. (2S,3R,4R)-3,4-Dihydroxyglutamic acid (5b). To a
suspension of cyanolactam 4b (1.69 g, 5.60 mmol) and
diammonium cerium (IV) nitrate (9.21 g, 16.8 mmol) in
acetonitrile (56 mL) was added water (11 mL) at room
temperature, and the resulting mixture was stirred for 4 h.
The reaction mixture was then diluted with ethyl acetate,
washed with water, and dried over MgSO4. Evaporation of
the solvent gave deprotected cyanolactam (418 mg, 41%).
The obtained crude cyanolactam (93.2 mg, 0.511 mmol)
was hydrolyzed in refluxing 1 M HCl (30 mL) for 3 h. The
cooled aqueous solution was washed with chloroform and
concentrated to dryness. The residue was submitted to ion
exchange column chromatography on Dowex 50W-X8 to
furnish the title compound 5b (82.6 mg, 92%) as a colorless
powder (EtOH–H2O), mp 170–180 8C (dec). [a]2D5ZK1.6
(c 1.0, H2O). 1H NMR (D2O) d 3.77 (d, JZ4.4 Hz, 1H), 3.87
(d, JZ3.7 Hz, 1H), 4.13 (dd, JZ4.4, 3.7 Hz, 1H). 13C NMR
(D2O) d 56.96, 71.20, 72.82, 171.58, 177.46. HRMS (EI,
70 eV) m/z 135.0519 [(MKCO2)C, calcd for C4H9NO4
135.0532). MS (FAB) m/z 180 (MHC).
6. Matsuki, K.; Inoue, H.; Ishida, A.; Takeda, M.; Nakagawa, M.;
Hino, T. Heterocycles 1993, 36, 937–940. Matsuki, K.; Inoue,
H.; Ishida, A.; Takeda, M.; Nakagawa, M.; Hino, T. Chem.
Pharm. Bull. 1994, 42, 9–18.
7. Miller, S. A.; Chamberlin, A. R. J. Org. Chem. 1989, 54,
2502–2504. Miller, S. A.; Chamberlin, A. R. J. Am. Chem.
Soc. 1990, 112, 8100–8112.
8. Kang, J.; Lee, J. W.; Kim, J. I.; Pyun, C. Tetrahedron Lett.
1995, 36, 4265–4268.
9. Noyori, R.; Tomino, I.; Tanimoto, Y. J. Am. Chem. Soc. 1979,
101, 3129–3131. Noyori, R.; Tomino, I.; Tanimoto, Y.;
Nishizawa, M. J. Am. Chem. Soc. 1984, 106, 6709–6716.
10. In a similar system, the value of J4,5 of the syn adduct is larger
than that of the anti isomer. See Ref. 7.