Convenient efficient synthesis of TAK-779, a nonpeptide CCR5 antagonist: Development of preparation of various ammonium salts using trialkylphosphite and N-halogenosuccinimide

Article abstract of DOI:10.1016/S0040-4020(00)01093-0

A convenient and efficient synthesis of TAK-779 (1a), a nonpeptide CCR5 antagonist, has been achieved. The new methylation of tertiary amine (2) using trimethyl phosphite and N-chlorosuccinimide, followed by the addition of HCl led to ammonium chloride (1a) in 89% isolated yield without requiring a chromatographic method. By this preparation, ammonium methanesulfonate (1e) could be obtained in 75% isolated yield.

Full text of DOI:10.1016/S0040-4020(00)01093-0

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 1525±1529
Convenient ef®cient synthesis of TAK-779, a nonpeptide CCR5
antagonist: development of preparation of various ammonium
salts using trialkylphosphite and N-halogenosuccinimide
Tomomi Ikemoto,p Atsuko Nishiguchi, Hiroyuki Mitsudera, Mitsuhiro Wakimasu and
Kiminori Tomimatsu
Chemical Development Laboratories, Takeda Chemical Industries Ltd., 2-17-85 Jusohonmachi, Yodogawa-ku, Osaka 532-8686, Japan
Received 10 October 2000; accepted 17 November 2000
AbstractÐA convenient and ef®cient synthesis of TAK-779 (1a), a nonpeptide CCR5 antagonist, has been achieved. The new methylation
of tertiary amine (2) using trimethyl phosphite and N-chlorosuccinimide, followed by the addition of HCl led to ammonium chloride (1a) in
89% isolated yield without requiring a chromatographic method. By this preparation, ammonium methanesulfonate (1e) could be obtained in
75% isolated yield. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
exchange with resin from ammonium iodide (1b) prepared
by the methylation of tertiary amine (2) with methyl iodide
to ammonium chloride. However, the previous approach
suffered from a tedious chromatographic method for the
anion-exchange. Hence, an ef®cient preparation of 1a on
large scale was required to support clinical evaluation. In
this paper, we report a highy ef®cient synthesis of 1a using
commercially available materials.
N,N-Dimethyl-N-[4-[[[2-(4-methylphenyl)-6,7-dihydro-5H-
benzocyclohepten-8-yl]carbonyl]amino]benzyl]tetrahydro-
2H-pyran-4-aminium chloride (TAK-779,1a)1 was found as
a small molecule nonpeptide CCR5 antagonist (Fig. 1). This
compound inhibited macrophage-tropic HIV-1 infection of
phytochemagglutinin (PHA)-activated peripheral blood
mononuclear cells (PBMCs), and should be a strong candi-
date for the therapy of HIV-1 infected individuals. The key
step is the reaction to form the ammonium moiety, because
TAK-779 has an ammonium salt with a chloride anion. The
key reaction of the original synthesis employed an anion-
2. Results and discussion
The synthesis of tertiary amine (2) is depicted in Scheme 1.
The carboxylic acid (5) could be synthesized by the reported
procedure1b±d via b-ketoester (7). However, it was dif®cult
to separate the desired hydroxy-ester (8) and hydroxy-
hydroxymethyl derivatives (9). To solve this problem, we
have developed an alternative synthesis of carboxylic acid
(5) via the aldehyde (4),2 not b-ketoester (7). Although
many preparations of cyclic a,b-unsaturatedaldehydes
using the reduction of a-dialkoxymethyl cyclohexa-
nones,2a±c followed by dehydration with acid have been
reported, there was only one example using cyclohepta-
none.2a According to the general method,2a the dimethoxy-
methylation of 3 with carbenium ion prepared from methyl
orthoformate, BF3±OEt2, and i-Pr2NEt at 2708C in dichloro-
methane as a solvent (entry 1) afforded b-keto-dimethoxy-
methyl deievative (10a), as shown in Table 1. To avoid the
hazardous solvent and conditions for large-scale prepara-
tion, optimization of the dialkoxymethylation was exam-
ined. As a result, the reaction of 3 and 6 equiv. carbenium
ion prepared from methyl orthoformate afforded at 08C in
THF a good yield of the target (10a). Subsequently, the
reduction of 10a with NaBH4 and the dehydration by
Figure 1.
Keywords: trialkylphosphite; N-halogenosuccinimide; alkylation; TAK-
779.
Corresponding author. Tel.: 16-6300-6840; fax: 16-6300-6251;
e-mail: ikemoto_tomomi@takeda.co.jp
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)01093-0

1526
T. Ikemoto et al. / Tetrahedron 57 (2001) 1525±1529
Scheme 1. Reagents and conditions: (i) NaOMe, (MeO)2CO; (ii) NaBH4, MeOH; (iii) MsCl, Et3N, then DBU; (iv) 2N NaOH; (v) CH(OR3)3, BF3±OEt2, i-
Pr2Net, THF, 2108C; (vi) NaBH4, then 6N HCl, 658C; (vii) NaClO2, H2O2, toluene±aq. NaH2PO4 (pHˆ2); (viii) (COCl)2, cat. DMF, THF; (ix) 11, Et3N.
Table 1. Reaction of 3 with CH(OR3)3, BF3±OEt2 and i-Pr2NEt
Entry
R
Carbenium ion (equiv.)
Solvent
Conditions
Ratio by HPLCa
3
10
1
2
3
4
5
6
Me
Me
Me
Me
Et
2
2
6
4
2
6
CH2Cl2
Toluene
THF
CH(OMe)3
CH2Cl2
THF
2708C, 2 h!08C, 3 h
08C, 3 h
08C, 4 h
14
88
12
60
13
40
10a; 86
10a; 12
10a; 88
10a; 40
10b; 87
10b; 60
08C, 2 h
2308C, 2 h!rt, 4.5 h
Et
08C, 5 h!rt, 1 h
a Determined at 254 nm.
conc. HCl could lead to 4. Oxidation of 4 with NaClO2
proceeded quantitatively to give 5 (overall isolated yield
was 55% from 3) in toluene±phosphoric acid buffer
(pHˆ1) at 508C with addition of H2O2 as scavenger of
HOCl.3 On the other hand, the Vielsmeier reaction
(POCl3/DMF) of the reductant prepared from 3 with
NaBH4 afforded low yield (,15%) of 4.2d,e The reaction
of acid-chloride prepared by the treatment of the carboxylic
acid (5) with a DMF catalytic oxalyl chloride, and 4-[N-
methyl-N-(tetrahydropyran-4-yl)aminomethyl]aniline (11)
gave 2 in 82% yield.
other is a method where by the ammonium cation having an
other anion (Y2) instead of chloride prepared from a tertiary
amine and alkylation reagents exchanged to ammonium
chloride, as shown in Fig. 2 (Eqs. (1) and (2)). Although
the anion-exchange by resin was popular, it was dif®cult as
the equilibrium lies so far to the right by this protocol. On
the other hand, alkylation of a tertiary amine with alkyl oxy-
acid ester (RSA), followed by the treatment with HCl
smoothly resulted in ammonium chloride, for example,
dialkylcarbonate,4e alkyl salitylate,4f and trialkyl phosphate
(Fig. 2 (Eqs. (3) and (4)).5 To attain our goal, we have
attempted a convenient synthesis of ammonium chloride
by chemical reaction. The reactions of 2 using methyl sali-
tylate or trimethyl phosphate were examined, since this
process was the ®nal stage and the reaction using dimethyl-
carbonate required a high-pressure condition. Methylation
of 2 with methyl salitylate was not entirely successful, but
the reaction of 2 and trimethyl phosphate at 1008C for 6 h,
followed the treatment with HCl/IPE led to a mixture of the
desired ammonium chloride (1a) in 47% yield and benzyl
chloride (12). In the latter reaction, the HPLC data showed
that the resultant prepared from the reaction of a tertiary
amine and trimethyl phosphate led to 12 by HCl. From
these results, this reaction mechanism was thought to be
as shown in Scheme 2, that is, the tertiary amine attacked
®rstly the phosphorus atom, followed by the transformation
to yield ammonium compound (1c) and oxyphosphate (13),
Generally, there have been two kinds of procedures for
ammonium chloride prepared from a tertiary amine.4,5 One
is the direct preparation by the reactions of a tertiary amine
with alkylchloride4a±d that requires unusual equipment. The
Figure 2.

T. Ikemoto et al. / Tetrahedron 57 (2001) 1525±1529
1527
a-branch and a succinimide anion attacked the methyl
carbon of 14a (Scheme 3). Therefore, we thought that the
addition of tertiary amine (2) having stronger basicity gener-
ally than a succinimide anion in this reaction might allow a
tertiary amine (2) to initially attack the methyl group of the
intermediate. As a consequence, the reaction might produce
an ammonium compound with succinimide aninon (1d),
followed by the treatment with HCl to give the desired
ammonium chloride 1a. As shown in Table 2, methylation
of 2 with trimethyl phosphite and N-chlorosuccinimide
(NCS) showed good results in most of the solvents. In
particular, the reaction of 2, NCS (3 equiv.), trimethyl phos-
phite (3 equiv.), and trimethyl phosphate as a solvent at
808C for 6 h, followed by the addition of HCl/IPE proceeded
to give 1a in 89% isolated yield without a chromatographic
method. Moreover, the treatment with methanesulfonic acid
gave an ammonium product having a methanesulfonic anion
(1e) in 75% isolated yield, after methylation of 2 was carried
out. In this connection, trimethyl phosphite (3 equiv.) could
not entirely react with 2 in AcOBut without NCS. Further-
more, 1-methyl-1,3-benzimidazole was also prepared from
1,3-benzimidazole in 27% yield using this methylation.
Scheme 2.
In conclusion, a convenient ef®cient synthesis of 1a has
been achieved. The carboxylic acid (5) was prepared by
dimethoxymethylation of 3, followed by reduction, dehy-
dration, and oxidation. Ammonium chloride (1a) has been
obtained in good yield by a new methylation of tertiary
amine (2) using trimethyl phosphite and NCS.
Scheme 3.
since 2 has the activated benzyl moiety. Subsequently, the
treatment of these compounds with HCl might produce both
1a and 12. Namely, it is predictable that the reaction might
quantitatively give 1a if the tertiary amine could ®rstly
attack the methyl group of the reagent.6 In the known
Michaelis±Arbuzov reaction,7 nucleophilic attack of phos-
phines with an alkyl halide produced an increase in the
coordination number to four, and the formation of a phos-
phonium species led to merely the formation of a tetraco-
odinate phosphorous(V) species if one of the ligands
attached to the phosphorous is an alkoxy group which can
undergo facile alkyl±oxygen cleavage. N-Halogenosuccini-
mide instead of alkyl halide also reacted rapidly with
tertiary phosphites to give N-(dialkylphosphonyl)succini-
mide passed through a trialkylhalogenophosphonium suc-
cinimide salt (14).8 In the case of trimethyl phosphite, the
reaction yielded both the Michaelis±Arbuzov type product
and N-methylsuccinimide,8e because a trimethylhalogen-
ophosphonium succinimide salt (14a) does not have an
3. Experimental
3.1. General
Melting points were recorded on a BuÈchi B-540 micro melt-
ing apparatus and were uncorrected. IR spectra were
recorded on a Horiba FT-210 spectrophotometer. H NMR
1
spectra was recorded on a Bruker DPX-300 spectrometer
using tetramethylsilane as an internal standard. HPLC
was performed on a YMC-Pack ODS-A302 column
(6i.d.£150 mm) with 0.05 M KH2PO4 aqueous solution±
MeCN (2:8, 3:7, 4:6, and 7:3) at 258C. Detection was
affected with a Shimadzu SPD-10A spectrophotometric
detector at 254 nm. Elemental analysis was carried out by
Takeda Analytical Research Laboratories Ltd.
3.1.1. 2-(4-Methylphenyl)-6,7-dihydro-5H-benzocyclo-
hepten-8-carboxylic acid (5). To a solution of methyl
Table 2. Methylation of 2 with P(OMe)3 and NCS
Entry
P(OMe)3 (equiv.)
NCS (equiv.)
Solvent
Conditions
Ratio by HPLCa
Yield (%)b
2
1a
1
2
3
4
5
6
7
3
3
10
3
3
3
3
10
3
3
i-PrOH
Re¯uxed, 6 h
Re¯uxed, 6 h
Re¯uxed, 6 h
808C, 3 h
Re¯uxed, 11 h
808C, 13 h
808C, 6 h
62
17
13
41
8
38
83
87
59
92
88
99
Toluene
THF
DMF
n-BuOAc
Diglyme
OvP(OMe)3
71
30
78
80
89
3
3
3
3
12
1
a Determined at 254 nm.
b Isolated yield of 1a.

1528
T. Ikemoto et al. / Tetrahedron 57 (2001) 1525±1529
orthoformate (25.5 ml, 240 mmol) and THF (80 ml) at
2108C, BF3±OEt2 (36.2 ml, 288 mmol) was dropped, and
stirred for 0.5 h at 08C. A solution of 3 (10.0 g, 40 mmol)
and THF (20 ml), and i-Pr2NEt (61.6 ml, 360 mmol) were
added to the reaction mixture, and stirred for 5 h under the
same conditions. Water (100 ml) was added to the reaction
mixture, and extracted with AcOEt (100 ml). After that
concentrated in vacuo IPE (100 ml) and silica-gel (20 g)
were added and stirred for 15 min. Silica-gel was removed
by ®ltration, and concentrated in vacuo to give a brown oil
(10a). An analytically pure sample of 10a was obtained by
chromatography on silica-gel with n-hexane/AcOEt (8:1) as
a brown oil: 1H NMR (CDCl3): d 1.67±1.75 (2H, m), 2.07±
2.13 (2H, m), 2.38 (3H, s), 2.96±2.99 (2H, m), 3.12±3.17
(1H, m), 3.40 (6H, s), 4.90 (1H, d, Jˆ6.8 Hz), 7.22±7.26
(3H, m), 7.50 (2H, d, Jˆ8.1 Hz), 7.59 (1H, dd, Jˆ7.9,
2.0 Hz), 7.83 (1H, d, Jˆ2.0 Hz).
was added. After Et3N (62.0 ml, 446 mmol) was added to
a suspension of 11 (23.2 g, 79 mmol) and THF (200 ml)
and stirred for 0.5 h at room temperature, a solution of
acid chloride was dropped to the whole at 20±308C with
ice-bathing and stirred for 1 h under the same conditions.
Water (200 ml) was added to the reaction mixture, which
was separated and extracted with AcOEt (200 ml). The
organic solution was washed with 10% citric acid aqueous
solution (100 ml£2), 5% NaHCO3 aqueous solution
(100 ml£2), and sat. NaCl aqueous solution (100 ml), and
concentrated in vacuo. After the concentrate was solved by
AcOEt (370 ml) under re¯uxing condition, the solution was
cooled to room temperature, stirred for 1 h at room tempera-
ture, and stirred for 1 h at 58C. The solid was collected by
®ltration, washed with cooled AcOEt (60 ml). The colorless
crystalline solid was dried at 408C in vacuo to give 2 (28.3 g,
yield 82%). Mp 162±1638C. Anal. Calcd for C32H36N2O2:
C, 79.96; H, 7.55; N, 5.83%. Found: C, 79.87; H, 7.50; N,
1
NaBH4 (4.5 g, 120 mmol) was added to a solution of 10a
and EtOH (180 ml) at room temperature, and stirred for 1 h.
6N HCl aqueous solution (40 ml, 240 mmol) was added to
the reaction mixture with ice-bathing, and stirred for 1 h at
658C. The organic solvent was distilled, and extracted with
AcOEt (180 ml). The AcOEt extract was washed with sat.
NaCl aqueous solution (90 ml), and concentrated in vacuo
to give crude 4 (14.6 g) as a light-brown solid. An analyti-
cally pure sample of 4 was obtained by chromatography
on silica-gel with n-hexane/AcOEt (2:1) as a white solid:
1H NMR (CDCl3): d 1.99±2.07 (2H, m), 2.40 (3H, s), 2.62
(2H, t, Jˆ5.8 Hz), 2.94 (2H, t, Jˆ5.3 Hz), 7.23±7.31
(4H, m), 7.47±7.51 (3H, m), 7.59 (1H, d, Jˆ1.8 Hz), 9.59
(1H, s).
5.67. H NMR (CDCl3): d 1.67±1.79 (4H, m), 2.15±2.19
(2H, m), 2.29 (3H, s), 2.41 (3H, s), 2.66±2.75 (3H, m),
2.87±2.91 (2H, m), 3.34±3.43 (2H, m), 3.59 (2H, s),
4.03±4.08 (2H, m), 7.23±7.34 (4H, m), 7.42±7.59 (7H,
m), 7.70 (1H, s). IR (KBr, cm21): 3300, 1655, 1550.
3.1.3. N,N-Dimethyl-N-[4-[[[2-(4-methylphenyl)-6,7-di-
hydro-5H-benzocyclohepten-8-yl]carbonyl]amino]benzyl]-
tetrahydro-2H-pyran-4-aminium chloride (TAK-779,1a).
Trimethyl phosphite (0.37 ml, 3.1 mmol) was added to a
solution of 2 (0.50 g, 3.1 mmol), NCS (0.42 g, 1.0 mmol),
and trimethyl phophate (5 ml) with ice-bathing, and stirred
for 6 h at 808C. After cooled to rt, 1.8N HCl/IPE (3 ml) and
acetone (0.5 ml) were added, and stirred overnight at room
temperature. The solid was collected by ®ltration, washed
with acetone±AcOEt (1:3, 4 ml). The colorless crystalline
solid was dried at 408C in vacuo to give 1a (0.49 g, yield
89%). Mp 222±2238C (decomp.). Anal. Calcd for
C33H39N2O2Cl: C, 74.62; H, 7.40; N, 5.27; Cl, 6.67%.
30 w/w% H2O2 solution (5.4 ml, 48 mmol) and NaClO2
(7.2 g, 80 mmol) in water (15 ml) were added to a suspen-
sion of crude 4 (described above), 2 mol/l NaH2PO4
aqueous solution (40 ml, 88 mmol, adjusted to pH2 with
conc. HCl), and toluene±MeOH (2:1, 240 ml). The whole
was stirred for 1 h at 508C, and cooling to room temperature,
10 w/w%Na2S2O3 aqueous solution (40 ml) was added to
the reaction mixture. 1N KOH aqueous solution (88 ml) was
added to the organic solution, and the organic solvent was
distilled. The remaining solution was washed with IPE
(50 ml£2), adjusted to pH1 with 6N HCl aqueous solution,
and extracted with AcOEt (100 ml). The AcOEt extract was
washed with sat. NaCl aqueous solution (50 ml), and
concentrated in vacuo. The residue was triturated with
IPA±water (1:1, 30 ml), collected by ®ltration. The color-
less crystalline solid was dried at 408C in vacuo to give 5
(6.1 g, yield 55% from 3). Mp. 186±1888C. Anal. Calcd for
C19H18O2: C, 81.99; H, 6.52%. Found: C, 81.91; H, 6.52.).
1H NMR (CDCl3): d 2.07±2.13 (2H, m), 2.39 (3H, s),
2.67±2.71 (2H, m), 2.86±2.89 (2H, m), 7.20±7.26 (4H,
m), 7.43±7.55 (3H, m), 7.91 (1H, s). IR (KBr, cm21):
2923, 1671.
1
Found: C, 74.37; H, 7.32; N, 5.23; Cl, 6.53.). H NMR
(DMSO-d6): d 1.85±2.18 (6H, m), 2.34 (3H, s), 2.64 (2H,
m), 2.78 (8H, m), 3.35 (2H, m), 3.50±3.75 (1H, m), 4.04±
4.07 (2H, m), 4.46 (2H, s), 7.26±7.88 (12H, m), 10.22 (1H,
s). IR (KBr, cm21): 1652, 1521.
3.1.4. N,N-Dimethyl-N-[4-[[[2-(4-methylphenyl)-6,7-di-
hydro-5H-benzocyclohepten-8-yl]carbonyl]amino]benzyl]-
tetrahydro-2H-pyran-4-aminium methanesulfonate (1e).
Trimethyl phosphite (0.50 ml, 4.2 mmol) was added to a
solution of 2 (1.00 g, 2.1 mmol), NCS (0.56 g, 4.2 mmol),
and trimethyl phosphate (4 ml) with ice-bathing, and stirred
for 4 h at 808C. After being cooled to room temperature,
MeSO3H (0.27 ml, 4.2 mmol), IPE (7 ml), and acetone
(5 ml) were added, and stirred overnight at room tempera-
ture. The solid was collected by ®ltration, washed with
acetone±AcOEt (1:4, 5 ml). The colorless crystalline solid
was dried at 408C in vacuo to give 1e (0.90 g, yield
75%). Mp 217±2198C (decomp.). Anal Calcd for
C34H42N2O5S: C, 69.12; H, 7.17; N, 4.74; S, 5.43%.
Found: C, 69.14; H, 7.19; N, 4.82; S, 5.41. 1H NMR
(CDCl3): d 1.75±2.20 (6H, m), 2.32 (3H, s), 2.34 (3H, s),
2.64 (2H, m), 2.75±3.00 (8H, m), 3.30±3.45 (2H, m), 3.50±
3.75 (1H, m), 4.00±4.25 (2H, m), 4.47 (2H, s), 7.25±7.90
(12H, m), 10.30 (1H, s). IR (KBr, cm21): 1654, 1529, 1517,
1317, 1193, 1180, 1039.
3.1.2. N-[4-[N-Methyl-N-4-(tetrahydropyranyl)amino-
methyl]phenyl]-2-(4-methylphenyl)-6,7-dihydro-5H-benzo-
cyclohepten-8-carboxamide (2). Oxalyl chloride (12.6 ml,
144 mmol) was dropped to a solution of 5 (20.0 g,
72 mmol), DMF (0.4 ml) and THF (200 ml) at 20±308C,
and stirred for 2 h at room temperature. The reaction
mixture was concentrated in vacuo, and THF (200 ml)

T. Ikemoto et al. / Tetrahedron 57 (2001) 1525±1529
1529
USP 4,891,440. (b) Hoffman, F. W.; Tuan, T.; James, C. O.
WO 9,817,750. (c) Kikuchi, K.; Nakahama, T.; Sato, F. JP
10,158,224. (d) Sato, A.; Hamano, K.; Wakui, T. JP
10,182,565. (e) Mori, S.; Ida, K.; Ue, M. JP 63,284,148.
(f) Kametani, T.; Kigasawa, K.; Sugahara, H.; Hiiragi, M.;
Hayasaka, T.; Iwata, T.; Ishimaru, H. Chem. Pharm. Bull.
1967, 15, 613.
Acknowledgements
The authors thank Drs Taiichi Okada, Mitsuru Shiraishi, Mrs
Yoshio Aramaki, and Masaki Seto for helpful discussions.
References
5. (a) Cheymol, J.; Chabrier, P.; Selim, M.; Leduc, P. C. R. Hebd
Seances. Acad. Sci. 1959, 249, 2573. (b) Liguori, A.; Sindona,
G.; Uccella, N. Tetrahedron 1984, 40, 1901. (c) Chiacchio, U.;
Liguori, A.; Romeo, G.; Sindona, G.; Uccella, N. Heterocycles
1993, 36, 799.
1. (a) Baba, M.; Nishimura, O.; Kanzaki, N.; Okamoto, M.;
Sawada, H.; Iizawa, Y.; Shiraishi, M.; Aramaki, Y.; Okonogi,
K.; Ogawa, Y.; Meguro, K.; Fujino, M. Proc. Natl. Acad. Sci.
USA 1999, 96, 5698. (b) Kanzaki, N.; Shiraishi, M.; Iizawa,
Y.; Baba, M.; Nishimura, O.; Fujino, M. Drugs Future 2000,
25, 252. (c) Shiraishi, M.; Aramaki, Y.; Seto, M.; Imoto, H.;
Nishikawa, Y.; Kanzaki, N.; Okamoto, M.; Sawada, H.; Nishi-
mura, O.; Baba, M.; Fujino, M. J. Med. Chem. 2000, 43, 2049.
(d) Ikemoto, T.; Ito, T.; Hashimoto, H.; Kawarasaki, T.; Nishi-
guchi, A.; Mitsudera, H.; Wakimasu, M.; Tomimatsu, K. Org.
Process. Res. Dev. 2001 (in press). (e) The synthesis of 1a also
was reported using the reaction of benzylchloride and a
tertiary amine; see Ref. 1b±d.
6. (a) Baddiley, J.; Clark, M. V.; Michalski, J. J.; Todd, R. A.
J. Chem. Soc. 1949, 815. (b) Clark, M. V.; Todd, R. A.
J. Chem. Soc. 1950, 2023, 2030. (c) Ikemoto, T.; Haze, A.;
Hatano, H.; Kitamoto, Y.; Ishida, M.; Nara, K. Chem. Pharm.
Bull. 1995, 43, 210.
7. (a) Edmundson, S. R. In The Chemistry of Organophos-
phorous Compounds, Hartley, R. F., Ed.; Wiley: New York,
1996; Vol. 4, pp 55±68. (b) Arbusov, A. B. Zn. Russ. Fiz.
Khim. Obshch. 1906, 38, 687. (c) Michaelis, A.; Kaehne, R.
Ber. Dtsch. Chem. Ges. 1898, 31, 1048.
2. (a) Dasgupta, R.; Ghatak, R. U. Tetrahedron Lett. 1985, 26,
1581. (b) Samanta, S. S.; Ghosh, C. S.; De, A. J. Chem. Soc.
Perkin Trans. 1 1997, 3637. (c) Mock, L. W.; Tsou, H.-R.
J. Org. Chem. 1981, 46, 2557. (d) Reddy, P. M.; Rao,
S. K. G. Synthesis 1980, 815. (e) Reddy, P. M.; Rao, S. K. G.
J. Org. Chem. 1981, 46, 5371. (f) Myrboh, B.; Ila, H.;
Junjappa, H. J. Org. Chem. 1983, 48, 2557.
8. (a) Tsolis, K. A.; McEwen, E. W.; WanderWert, A. Tetra-
hedron Lett. 1964, 5, 3217. (b) Bose, K. A.; Lai, B. Tetra-
hedron Lett. 1973, 14, 3973. (c) Mukaiyama, T.; Obata, T.;
Mitsunobu, O. Bull. Chem. Soc. Jpn 1965, 1088, 1091. (d)
Desmarchelier, M. J.; Fukuto, R. T. J. Org. Chem. 1972, 37,
4218. (e) Scharf, J. D. J. Org. Chem. 1974, 39, 923.
3. Dalcanale, E.; Montanari, F. J. Org. Chem. 1986, 51, 567.
4. (a) Nagatsu, Y.; Nagamoto, A., Harada, K.; Mukouyama, H.