An efficient, one-pot synthesis of fosfomycin dialkyl esters from (R)-2-tosyloxypropanal

Article abstract of DOI:10.3987/com-07-s(w)45

(R)-2-Tosyloxypropanal (4) was prepared from D-mannitol in a 7-step sequence (51% overall yield). Addition of dialkyl phosphonates to 4 in the presence of titanium isopropoxide and the subsequent treatment with DBU stereoselectively afforded, in one-pot, fosfomycin dimethyl (5a) and dibenzyl (5b) esters both in 58% isolated yield.

Full text of DOI:10.3987/com-07-s(w)45

HETEROCYCLES, Vol. 74, 2007
983
HETEROCYCLES, Vol. 74, 2007, pp. 983 - 989. © The Japan Institute of Heterocyclic Chemistry
Received, 28th August, 2007, Accepted, 19th October, 2007, Published online, 23rd October, 2007. COM-07-S(W)45
AN EFFICIENT, ONE-POT SYNTHESIS OF FOSFOMYCIN DIALKYL
ESTERS FROM (R)-2-TOSYLOXYPROPANAL
Tadashi Hanaya,* Yuichi Nakamura, and Hiroshi Yamamoto1
Department of Chemistry, Faculty of Science, Okayama University,
Tsushima-naka,
Okayama
700-8530,
Japan.
E-mail:
hanaya@cc.okayama-u.ac.jp
Abstract – (R)-2-Tosyloxypropanal (4) was prepared from D-mannitol in a 7-step
sequence (51% overall yield). Addition of dialkyl phosphonates to 4 in the
presence of titanium isopropoxide and the subsequent treatment with DBU
stereoselectively afforded, in one-pot, fosfomycin dimethyl (5a) and dibenzyl (5b)
esters both in 58% isolated yield.
INTRODUCTION
(1R,2S)-1,2-Epoxypropylphosphonic acid (fosfomycin) (1) is a clinically used antibiotic which was
originally isolated from the fermentation broth of Streptomyces fradiae2 and Pseudomonas syringae.3
Fosfomycin is present on the pharmaceutical market as the disodium,4 calcium,5 and
tris(hydroxymethyl)ammonium salts.6 Several synthetic methods for optically active fosfomycin
derivatives have been reported as exemplified by catalytic epoxidation of (Z)-1-propenylphosphonates
and the following optical resolution7 and bromohydroxylation of (Z)-1-propenylphosphonates having a
chiral auxiliary and the following ring closure.8
H
H
Me
P(OH)
O
2
O
1
Another synthetic method has also become available by the stereoselective addition of phosphonates (or
phosphites) to (S)-2-hydroxypropanal derivatives (2),9-11 but the conversion of the resulting
α-hydroxyphosphonates (3) into fosfomycin derivatives (5) requires multi-step procedures (deprotection,
tosylation of α-hydroxy group, and ring closure) (Scheme 1). Meanwhile, we have found that
1,2-epoxyphosphonates are readily obtained by the reaction of α-tosyloxyketones with dimethyl
phosphonate in the presence of DBU12 in the course of our studies involving stereoselective C-P bond
introduction onto carbohydrates.13 This procedure is perceived suitable for preparation of fosfomycin
derivatives, because the addition of phosphonates and the ring closure would proceed in tandem. We
This paper is dedicated to Professor Dr. Ekkehard Winterfeldt on the occasion of his 75th birthday.

984
HETEROCYCLES, Vol. 74, 2007
now describe herein a novel, efficient synthesis of fosfomycin derivatives (5) based on the stereoselective
addition of dialkyl phosphonates to the appropriate precursor (R)-2-tosyloxypropanal (4).
HP(=O)(OR) or
2
OR'
OR' O
P(OR)
OR' O
P(OR)
TMSP(OR)
2
H
+
2
Me
2
Me
Me
Lewis acid
O
OH
OH
2 (R' = protecting groups)
(1S)-3
(1R)-3
present study
O
OTs
H
H
HP(=O)(OR)
H
P(OR)
H
2
2
H
+
Me
P(OR)
O
Me
Me
2
O
O
DBU
O
4
5
6
Scheme 1
RESULTS AND DISCUSSION
The key intermediate (4) was prepared from D-mannitol in 7 steps according to the reported
procedures14–16 with some modifications in a much improved overall yield (51%) (Scheme 2). Namely,
acetalization of D-mannnitol with 2,2-dimethoxypropane, followed by hydrolysis with aqueous acetic
acid, afforded 3,4-O-isopropylidene-D-mannitol (7). This was converted into the 1,6-dideoxy compound
(8) by tosylation of the primary hydroxy groups and the subsequent reduction with lithium aluminum
hydride. Tosylation of 8, followed by hydrolysis with aqueous trifluoroacetic acid (TFA), afforded
1,6-dideoxy-2,5-di-O-tosyl-D-mannitol (9). Oxidative cleavage of 9 with sodium periodate provided
(R)-tosyloxypropanal (3-deoxy-2-O-tosyl-D-glyceraldehyde) (4).
CH
3
HO
HO
HO
HO
HO
O
1) Me C(OMe)
TsOH, rt, 5 h
91%
2
2
HO
O
1) TsCl, Py
0 °C, 4 h
O
OH
OH
OH
O
2) LiAlH , THF
rt, 8 h
84% (2 steps)
2) 70% AcOH aq
40 °C, 2 h
84%
4
OH
OH
OH
CH
3
D-mannitol
7
8
CH
3
1) TsCl, TEA
Py, rt, 4 h
98%
TsO
HO
CHO
OTs
NaIO
4
OH
MeOH-H O
2
CH
2) 60% TFA aq
50 °C, 2 h
83%
3
OTs
97%
CH
3
9
4
Scheme 2

HETEROCYCLES, Vol. 74, 2007
985
Conversion of 4 with dialkyl phosphonates to fosfomycin derivatives (5a,b) was then examined (Scheme
3) and the results are summarized in Table 1. Compound (4) was treated with dimethyl phosphonate
(1.5 equiv) in the presence of DBU (2.0 equiv) in THF at 20 °C for 2 h (Entry 1). Under these
conditions, addition of the phosphonate and epoxidation of the resulting intermediate (10) proceeded
simultaneously to afford the cis-epoxyphosphonate (5a) and its trans-isomer (6a), in a ratio of 41:59,
which were separable by column chromatography. The similar treatment of 4 at a lower temperature (–5
or –40 °C) to give 10, followed by raising the temperature to 20 °C to afford 5a and 6a, resulted in a
slight increase in the ratio of the desired 5a (Entries 2,3). As for the solvent, use of dichloromethane
showed a better selectivity for production of 5a in comparison with THF and acetonitrile (Entries 2,4,5).
By employing the same conditions as Entry 5, the reaction of 4 with dibenzyl phosphonate gave the
cis-epoxide (5b) and the trans-isomer (6b) in a similar yield and ratio (Entry 6).
O
O
H P(OR)
OTs
OTs O
P(OR)
H
H
P(OR)
H
H
2
2
+
H
Me
P(OR)
O
Me
2
2
O
O
Me
Me
condition 1
condition 2
O
OH
R = Me 5a
R = Bn 5b
6a
6b
4
10
Scheme 3
Table 1. Reaction of (R)-tosyloxypropanal (4) with dialkyl phosphonates in the presence of DBU a
——————————————————————————————————————————————
Entry
Phosphonates Solvents Conditions 1
Conditions 2
Yields (%)b Ratio of 5:6 c
——————————————————————————————————————————————
1
2
R = Me
Me
Me
Me
Me
Bn
THF
DBU, 20 °C, 2 h
DBU, –5 °C, 2 h
DBU, –40 °C, 10 h
DBU, –5 °C, 2 h
DBU, –5 °C, 2 h
DBU, –5 °C, 2 h
Ti(OiPr)4, 20 °C, 2 h
Ti(OiPr)4, –5 °C, 10 h DBU, 20 °C, 3 h
Ti(OiPr)4, 20 °C, 2 h
DBU, 20 °C, 3 h
Ti(OiPr)4, –5 °C, 10 h DBU, 20 °C, 3 h
–
84
91
74
80
82
86
66
69
62
66
41:59
46:54
50:50
43:57
57:43
55:45
78:22
84:16
76:24
88:12
THF
20 °C, 2 h
20 °C, 2 h
20 °C, 2 h
20 °C, 2 h
20 °C, 2 h
DBU, 20 °C, 3 h
3
THF
4
MeCN
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
5
6
7
Me
Me
Bn
8
9
10
Bn
——————————————————————————————————————————————
i
a
All reactions were carried out by use of 1.5 equiv of phosphonate, 2.0 equiv of DBU, and 1.2 equiv of Ti(O Pr)4
(for Entries 7–10). b Total yield of 5a (5b) and 6a (6b) purified by column chromatography. c The ratios were
1
determined by H (in particular, H-1 and H-3 signals) and 31P NMR for the diasteromeric mixture before
separation.

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HETEROCYCLES, Vol. 74, 2007
In an effort to enhance the diastereoselectivity for production of the (1R)-10, the precursor for the desired
epoxide (5), we examined the use of Lewis acids as a chelating agent to promote the addition of
phosphonates. Thus, treatment of 4 with dimethyl phosphonate in the presence of titanium isopropoxide
(1.2 equiv) in dichloromethane at 20 °C for 2 h gave the α-hydroxyphosphonate intermediate (10), which
was then treated with DBU (2.0 equiv) to afford 5a and 6a in a ratio of 78:22 (Entry 7). The
predominant production of 5a can be perceived as the result of the preferential approach of the
phosphonate to a cyclic, titanium-chelated intermediate from the less hindered re-face (the opposite side
of the methyl group). In contrast, the use of magnesium bromide as a Lewis acid yielded only a trace
amount of products. The similar experiment at –5 °C using titanium isopropoxide gave rise more
preferentially to the desired 5a in a ratio of 84:16 (Entry 8), whereas almost no phosphonate addition took
place at a further lower temperature (–20 °C). The reaction of 4 with dibenzyl phosphonate under these
conditions revealed similar results with those of dimethyl phosphonate (Entries 9,10); the desired
cis-epoxide (5b) was obtained in the highest diastereoselectivity (88:12) (Entry 10). Dibenzyl ester (5b)
is readily converted into fosfomycin (1) by hydrogenolysis according to the reported procedure.11
The present work thus demonstrates an efficient synthesis of fosfomycin derivatives from
(R)-2-tosyloxypropanal with reasonably good diastereoselectivity. This synthetic procedure is highly
useful because the addition of a phosphonate and the formation of epoxide can be carried out by a one-pot
procedure without isolation of the intermediates.
EXPERIMENTAL
All reactions were monitored by TLC (Merck silica gel 60F, 0.25 mm) with an appropriate solvent system
[(A) 1:3, (B) 1:2, (C) 1:1 AcOEt–hexane, and (D) AcOEt]. Column chromatography was performed
with Daiso Silica Gel IR-60/210w. Components were detected by exposing the plates to UV light
and/or spraying them with 20% sulfuric acid–ethanol (with subsequent heating). Optical rotations were
measured with a Jasco P-1020 polarimeter in CHCl3. The NMR spectra were measured in CDCl3 with
1
13
31
Varian Unity Inova AS600 (600 MHz for H, 151 MHz for C) and Mercury 300 (121 MHz for P)
spectrometer at 23 °C. Chemical shifts are reported as δ values relative to CHCl3 (7.26 ppm as an
internal standard for 1H), CDCl3 (77.0 ppm as internal standard for 13C), and 85% phosphoric acid (0 ppm
as an external standard for 31P).
3,4-O-Isopropylidene-D-mannitol (7).14
The following modification of the literature procedures14 was made. To a suspension of D-mannitol
(1.80 g, 9.88 mol) in 2,2,-dimethoxypropane (20.0 mL, 165 mmol) was added p-toluenesulfonic acid
monohydrate (120 mg, 0.63 mmol). The mixture was stirred at rt for 5 h, neutralized with triethylamine,
and evaporated in vacuo. The residue was dissolved in CHCl3, washed with water, dried (Na2SO4), and
evaporated in vacuo.
The residue was recrystallized from hexane to give
1,2:3,4:5,6-tri-O-isopropylidene-D-mannitol (2.71g, 91%) as colorless needles: mp 69–70 °C (lit.,14 mp
69 °C, 75% yield by using acetone-H2SO4), Rf = 0.60 (A).
The triacetonide (2.71 g, 8.96 mmol) was dissolved in 70% aqueous acetic acid (30 mL) and stirred at
40 °C for 2 h. The mixture was co-evaporated with toluene in vacuo and the residue was crystallized

HETEROCYCLES, Vol. 74, 2007
987
with acetone to give 7 (1.67 g, 84%) as colorless needles: mp 88–89 °C (lit.,14 mp 90 °C, 78% yield), Rf =
0.13 (D).
1,6-Dideoxy-3,4-O-isopropylidene-D-mannitol (8).15
Modification of the literature procedures14,15 was made as follows. To a solution of 7 (445 mg, 2.00
mmol) in dry pyridine (6.0 mL) was added, with stirring, tosyl chloride (860 mg, 4.51 mmol) at –5 °C.
The mixture was stirred at 0 °C for 4 h, diluted with a small amount of cold water, and concentrated in
vacuo. The residue was dissolved in CHCl3, washed with water, dried (Na2SO4), and evaporated in
vacuo to give 3,4-O-isopropylidene-1,6-di-O-tosyl-D-mannitol (1.05 g) as a pale yellow syrup (lit.,14 mp
86 °C) ; Rf = 0.52 (C).
The crude ditosylate was dissolved in dry THF (10 mL) and then lithium aluminum hydride (180 mg,
4.72 mmol) was added in several portions at 0 °C under argon. The mixture was stirred at rt for 8 h and
then a small amount of water was added. The mixture was diluted with ethyl acetate (20 mL) and
filtered through Celite. The filtrate was evaporated in vacuo and the residue was purified by column
chromatography with 1:2 AcOEt-hexane to give 8 (320 mg, 84% from 7) as colorless needles (from
AcOEt-hexane): mp 91–92 °C (lit.,15 mp 85–88 °C, 50% yield from 7); Rf = 0.40 (C); 1H NMR17 δ = 1.37
(6H, d, J1,2 = J5,6 = 6.1 Hz, H3-1,6), 1.37 (6H, s, Me2C), 3.25 (2H, br s, HO-2,5), 3.63 (2H, m, H-3,4),
13
3.78 (2H, qdd, J2,3 = J4,5 = 5.6, J2,4 = J3,5 = 1.5 Hz, H-2,5); C NMR δ = 20.46 (C-1,6), 26.85 (CMe2),
69.28 (C-2,5), 84.03 (C-3,4), 108.74 (CMe2).
1,6-Dideoxy-2,5-di-O-tosyl-D-mannitol (9).16
Compound (9) was prepared from 8 via 1,6-dideoxy-3,4-O-isopropylidene-2,5-di-O-tosyl-D-mannitol by
using the literature procedures.15,16
3,4-O-Isopropylidene-2,5-di-O-tosylate: Colorless needles (98% yield), mp 91–92 °C (from
AcOEt-hexane) (lit.,15 85% yield, mp 90–91 °C); Rf = 0.55 (A).
9: Colorless needles (83%), mp 87–88 °C (from ether) (lit.,16 82% yield, mp 84.5–85.5 °C); Rf = 0.20 (B).
(R)-2-Tosyloxypropanal (3-deoxy-2-O-tosyl-D-glyceraldehyde) (4).16
The following modification of the literature procedures16 was made. To a solution of 9 (147 mg, 0.321
mmol) in methanol (3.0 mL) was added dropwise a solution of sodium periodate (89.0 mg, 0.416 mmol)
in water (3.0 mL) at 0–5 °C. The mixture was stirred at rt for 1 h and the most of methanol was distilled
off in vacuo. The residue was diluted with water and then extracted with ether three times. The
combined organic layer was washed with water, dried (Na2SO4), and evaporated in vacuo. The residue
was purified by column chromatography with 1:2 AcOEt-hexane to give 4 [142 mg, 97% yield (lit.,16
86%)] as a colorless syrup: Rf = 0.20 (B).
Dimethyl (1R,2S)-1,2-epoxypropylphosphonate (5a) and its (1S,2S)-epimer (6a).
Procedures for Entry 5 in Table 1. To a solution of 4 (114 mg, 0.499 mmol) in dry CH2Cl2 (2.0 mL)
were added dimethyl phosphonate (0.070 mL, 0.76 mmol) and then DBU (0.150 mL, 1.00 mmol) at
–5 °C under argon. The mixture was stirred at the same temperature for 3 h and then at 20 °C for 2 h,
and evaporated in vacuo. The residue was dissolved in CHCl3, washed with water, dried (Na2SO4), and

988
HETEROCYCLES, Vol. 74, 2007
evaporated in vacuo. The residue was separated by column chromatography with 1:1 AcOEt-hexane to
give 5a (38.9 mg, 47%) and 6a (29.1 mg, 35%).
5a: Colorless syrup; Rf = 0.35 (D); [α]D +3.28° (c 2.02) [lit.,9 [α]D +5.50° (MeOH)]; H NMR17 δ =
1.57 (3H, dd, J2,3 = 5.4, J3,P = 1.0 Hz, H3-3), 2.95 (1H, dd, J1,P = 27.6, J1,2 = 4.4 Hz, H-1), 3.28 (1H, dqd,
J2,P = 6.4 Hz, H-2), 3.81, 3.83 [3H each, 2d, JPOMe = 10.9 Hz, P(OMe)2]; 13C NMR δ = 14.08 (C-3), 49.40
30
21
1
1
2
2
31
(d, J1,P = 205.0 Hz, C-1), 52.79, 53.21 [2d, JC,P = 6.3 Hz, P(OMe)2], 53.31 (d, J2,P = 1.7 Hz, C-2); P
NMR δ = 22.00.
6a: Colorless syrup; Rf = 0.28 (D); [α]D30 –18.3° (c 2.44); 1H NMR δ = 1.39 (3H, dd, J2,3 = 5.1, J3,P = 1.7
Hz, H3-3), 2.77 (1H, dd, J1,P = 31.0, J1,2 = 2.7 Hz, H-1), 3.29 (1H, dqd, J2,P = 5.4 Hz, H-2), 3.80, 3.81 [3H
each, 2d, JPOMe = 10.7 Hz, P(OMe)2]; 13C NMR δ = 17.44 (C-3), 50.68 (d, 1J1,P = 203.4 Hz, C-1), 52.86 (d,
2J2,P = 1.7 Hz, C-2), 53.13, 53.55 [2d, 2JC,P = 6.3 Hz, P(OMe)2]; 31P NMR δ = 21.18.
Procedures for Entry 8 in Table 1. To a solution of 4 (114 mg, 0.499 mmol) in dry CH2Cl2 (2.0 mL)
was added titanium isopropoxide (0.180 mL, 0.608 mmol) at –5 °C under argon. The mixture was
stirred at the same temperature for 40 min and then dimethyl phosphonate (0.070 mL, 0.76 mmol) was
added. After stirring at –5 °C for 10 h, DBU (0.150 mL, 1.00 mmol) was added and the mixture was
stirred at 20 °C for 3 h. Then, water (0.5 mL) was added and the resulting precipitate was filtered off
through Celite. The filtrate was diluted with water and extracted with CHCl3. The combined organic
layer was dried (Na2SO4) and evaporated in vacuo. The residue was separated by column
chromatography to give 5a (48.2 mg, 58%) and 6a (9.2 mg, 11%).
Dibenzyl (1R,2S)-1,2-epoxypropylphosphonate (5b) and its (1S,2S)-epimer (6b).
Procedures for Entry 10 in Table 1. The same procedures described above for Entry 8 were employed.
Thus, compound (4) (114 mg, 0.499 mmol) was treated with dibenzyl phosphonate (0.170 mL, 0.77
mmol) to give 5b (92.6 mg, 58%) and 6b (12.7 mg, 8%), after separation by column chromatography
with 1:2 AcOEt-hexane.
23
20
1
5b: Colorless syrup; Rf = 0.40 (C); [α]D +5.04° (c 1.67) [lit.,11 [α]D +4.4° (CDCl3)]; H NMR17 δ =
1.56 (3H, d, J2,3 = 5.6 Hz, H3-3), 2.95 (1H, dd, J1,P = 28.1, J1,2 = 4.4 Hz, H-1), 3.24 (1H, dqd, J2,P = 6.4 Hz,
2
H-2), 5.03, 5.09 [1H each, 2dd, 2JCH2 = 11.7, JPOCH = 8.3 Hz, POCH2], 5.10, 5.13 [1H each, 2dd, JCH2
=
11 7, JPOCH = 8.8 Hz, POCH2], 7.32–7.38 (10H, m, Ph); 13C NMR δ = 14.11 (C-3), 50.13 (d, 1J1,P = 204.4
2
2
Hz, C-1), 53.67 (d, J2,P = 1.7 Hz, C-2), 67.76, 68.15 [2d, JC,P = 6.3 Hz, POCH2], 128.03, 128.09 [2s,
Ph(o)], 128.55, 128.60 [2s, Ph(p)], 128.60, 128.61 [2s, Ph(m)], 135.81, 135.89* [2d, JC,P = 5.8, 6.3* Hz,
3
Ph(ipso)]; 31P NMR δ = 22.56.
6b: Colorless syrup; Rf = 0.33 (C); [α]D –11.3° (c 2.27); 1H NMR δ = 1.28 (3H, d, J2,3 = 5.1, J3,P = 1.8
23
Hz, H3-3), 2.71 (1H, dd, J1,P = 31.5, J1,2 = 2.5 Hz, H-1), 3.23 (1H, quintd, J2,P = 5.1 Hz, H-2), 5.04, 5.08
2
2
[1H each, 2dd, JCH2 = 11.7, JPOCH = 7.8 Hz, POCH2], 5.045, 5.09 [1H each, 2dd, JCH2 = 11.7, JPOCH
=
13
1
8.8 Hz, POCH2], 7.32–7.38 (10H, m, Ph); C NMR δ = 14.16 (C-3), 51.38 (d, J1,P = 202.1 Hz, C-1),
2
2
53.04 (d, J2,P = 1.2 Hz, C-2), 68.15, 68.31 [2d, JC,P = 6.3 Hz, POCH2], 128.01, 128.09 [2s, Ph(o)],
128.55, 128.62 [2s, Ph(p)], 128.60, 128.62 [2s, Ph(m)], 135.72, 135.86* [2d, JC,P = 6.3, 5.6* Hz,
3
Ph(ipso)]; 31P NMR δ = 19.89.

HETEROCYCLES, Vol. 74, 2007
989
ACKNOWLEDGEMENTS
We are grateful to the SC-NMR Laboratory of Okayama University for the NMR measurements.
REFERENCES AND NOTES
1. Present address: School of Pharmacy, Shujitsu University, Okayama 703-8516, Japan.
2. D. Hendlin, E. O. Stapley, M. Jackson, H. Wallick, A. K. Miller, F. J. Wolf, T. W. Miller, L. Chaiet,
F. M. Kahan, E. L. Foltz, H. B. Woodruff, J. M. Marta, S. Hernandez, and S. Mochales, Science,
1969, 166, 122; B. G. Christensen, W. J. Leanza, T. R. Beattie, A. A. Patchett, B. H. Ariaon, R. E.
Ormond, F. A. Kuehl, G. Albers-Shonberg, and O. Jardetzky, Science, 1969, 166, 123.
3. J. Shoji, T. Kato, H. Hinoo, T. Hattori, K. Hirooka, K. Matsumoto, T. Tanimoto, and E. Kondo, J.
Antibiot., 1986, 39, 1011.
4. S. Inoue, T. Niizato, I. Komiya, Y. Yuda, and Y. Yamada, J. Pharm. Dyn., 1982, 5, 941.
5. ’The Merck Index,’ 14th ed., ed. by M. J. O’Neil, Merck & Co. Inc., Whitehouse Station, NJ, 2006,
p.730.
6. D. Chiarino, D. Della Bella, and V. Ferrari, Eur. Patent, 27597, 1981 (Chem. Abstr., 1981, 95,
115748d).
7. E. J. Glamkowski, G. Gal, R. Purick, A. J. Davidson, and M. Sletzinger, J. Org. Chem., 1970, 35,
3510; N. N. Girotra and N. L. Wendler, Tetrahedron Lett., 1969, 10, 4647.
8. C. Giordano and G. Castaldi, J. Org. Chem., 1989, 54, 1470.
9. T. Oshikawa and M. Yamashita, Jpn. Patent, 07324092, 1995 (Chem. Abstr., 1996, 124, 232132b).
10. F. Hammerschmidt, Liebigs Ann. Chem., 1991, 469.
11. E. Bandini, G. Martelli, G. Spunta, and M. Panunzio, Tetrahedron: Asymmetry, 1995, 6, 2127.
12. T. Hanaya, K. Yasuda, H. Yamamoto, and H. Yamamoto, Bull. Chem. Soc. Jpn., 1993, 66, 2315; T.
Hanaya, H. Yamamoto, H. Kawamoto, M.-A. Armour, A. M. Hogg, and H. Yamamoto, Bull. Chem.
Soc. Jpn., 1992, 65, 2922.
13. T. Hanaya and H. Yamamoto, Trends in Heterocyclic Chemistry, 2003, 9, 1; H. Yamamoto and T.
Hanaya, ’Studies in Natural Products Chemistry,’ ed. by Atta-ur-Rahman, Elsevier, Amsterdam,
1990, Vol. 6, pp. 351–384; T. Hanaya and H. Yamamoto, Yuki Gosei Kagaku Kyokai Shi, 1993, 51,
377.
14. Y. L. Merrer, A. Duréault, C. Greck, D. Micas-Languin, C. Gravier, and J.-C. Depezay,
Heterocycles, 1987, 25, 541.
15. H. B. Kagan, J. C. Fiaud, C. Hoornaert, D. Meyer, and J. C. Poulin, Bull. Soc. Chim. Belg., 1979, 88,
923.
16. T. Sugiyama, T. Murayama, K. Yamashita, and T. Oritani, Biosci. Biotech. Biochem., 1995, 59,
1921.
1
17. The complete parameters for 5a,b and 8 obtained in the present study are shown here, because H
NMR data for these compounds reported in Refs. 9, 11 and 15, respectively, include insufficient
assignments.