Stereoselective carbon-carbon bond forming reactions between various chiral alkyl aryl carbinols and triethyl methanetricarboxylate by oxidation-reduction condensation using alkyl diphenylphosphinites

Article abstract of DOI:10.1246/cl.2005.1676

Oxidation-reduction condensation reactions between alkyl diphenylphosphinites derived from chiral alkyl aryl carbinols and triethyl methanetricarboxylate proceeded smoothly to afford the corresponding condensation products in good yields with inversion of stereochemistries. Copyright

Full text of DOI:10.1246/cl.2005.1676

1676
Chemistry Letters Vol.34, No.12 (2005)
Stereoselective Carbon–Carbon Bond Forming Reactions
between Various Chiral Alkyl Aryl Carbinols and Triethyl Methanetricarboxylate
by Oxidation–Reduction Condensation Using Alkyl Diphenylphosphinites
Teruaki Mukaiyama,ꢀy;yy Yuzo Nagata,y;yy and Kazuhiro Ikegaiy;yy
yCenter for Basic Research, The Kitasato Institute, 6-15-5 (TCI), Toshima, Kita-ku, Tokyo 114-0003
yyKitasato Institute for Life Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641
(Received September 29, 2005; CL-051247)
Oxidation–reduction condensation reactions between alkyl
diphenylphosphinites derived from chiral alkyl aryl carbinols
and triethyl methanetricarboxylate proceeded smoothly to afford
the corresponding condensation products in good yields with
inversion of stereochemistries.
Table 1. Screening of carbon nucleophilesa
DBBQ
+
H Nu
Ph OPPh
rac-1a
H-Nu
2
CHCl
Ph
Nu
3
0 °C, 3 h
(pK ) Yield/% Entry H-Nu
CO Et
rac-2a
b
b
Entry
1
(pK ) Yield/%
a
a
CN
2
(12.0)
45
4
(13.3)
(−)
ND
To develop carbon–carbon bond forming reactions by con-
trolling the absolute stereochemistry is a fundamental challenge
in synthetic organic chemistry. Bimolecular nucleophilic substi-
tution (SN2) reactions using carbon nucleophiles and chiral sec-
ondary alcohols as alkylating agents are simple and effective
methods to construct inverted chiral tertiary stereogenic cen-
ters.1 Recently, Tsunoda et al. reported C-alkylation of active
methylene compounds with primary and secondary alcohols us-
ing phosphorane reagents such as cyanomethylenetrimethyl-
phosphorane (CMMP).2 It was also reported from our laboratory
that C-alkylation of (phenylsulfonyl)acetonitrile proceeded
smoothly under mild and neutral conditions by oxidation–reduc-
tion condensation using alkyl diphenylphosphinites and 2,6-di-
tert-butyl-1,4-benzoquinone (DBBQ).3 When chiral secondary
alkyl diphenylphosphinite 1h derived from (R)-4-phenyl-2-buta-
nol was employed in the above condensation, the corresponding
alkylated product was formed in a good yield with complete ster-
eo-inversion. However, the above combination using (phenyl-
sulfonyl)acetonitrile and DBBQ was less effective when benzyl-
ic phosphinites derived from alkyl aryl carbinols such as 1a was
employed owing to their high reactivities which caused unde-
sired side reactions3 (see Table 1, Entry 1). Then, the use of alkyl
aryl carbinols in C-alkylation was continuously studied. We
would like here to report stereoselective C–C bond formation
from chiral alkyl aryl carbinols via oxidation–reduction conden-
sation between alkyl diphenylphosphinites and triethyl methane-
tricarboxylate (TEMT) using dialkyl azodicarboxylates.
In the first place, C-alkylation of various carbon nucleo-
philes with racemic phosphinite 1a and DBBQ was examined
in order to find a suitable reagent (Table 1). In spite of their sim-
ilar pKa values, (phenylsulfonyl)acetonitrile gave the desired
product only in 45% yield (Entry 1), and the result of using ma-
lononitirile and bis(phenylsulfonyl)methane were also unsatis-
factory (Entries 2 and 3). At the same time, the use of diethyl
malonate and the corresponding methine derivative did not
afford the desired product either, which was probably due to
their low acidities (Entries 4 and 5). Based on the above results,
the use of triethyl methanetricarboxylate (pKa 7.5 in DMSO)
was then tried and the C-alkylated product was afforded in
60% yield (Entry 6).
SO Ph
2
CO Et
2
CN
CO Et
2
Me
2
3
(11.1)
(12.2)
27
5
ND
60
CN
CO Et
2
SO Ph
CO Et
2
2
ND
6 EtO C
(7.5)
2
SO Ph
CO Et
2
2
aThe reactions were carried out by using rac-1a (1.0 equiv.),
DBBQ (1.2 equiv.), and nucleophiles (1.2 equiv.). pKa values
in DMSO.
b
Table 2. Optimization of reaction conditionsa
HC(CO2Et)3
Oxidant
Ph
C(CO2Et)3
(S)-2a
Ph OPPh2
(R)-1a (99%ee)
CHCl3
Temp, 3 h
Entry
Oxidant
Temp/ꢁC Yield/% Ee/%
1
2
3
1,4-Benzoquinone
DMBQ
DBBQ
0
0
0
ND
36
60
—
97
97
4
5
6
7
DEAD
DIAD
DTBAD
ADDP
0
0
0
0
72
67
72
ND
97
97
96
—
8
9
10
DEAD
DIAD
DTBAD
ꢂ63
ꢂ63
ꢂ63
73
69
74
98
97
97
aThe reactions were carried out by using 1a (1.0 equiv.),
oxidant (1.2 equiv.), and TEMT (1.2 equiv.).
R
R'O2C N N CO2R'
O
O
R
DEAD (R′ = Et)
DIAD (R′ = i-Pr)
DTBAD (R′ = t-Bu)
DMBQ (R = Me)
DBBQ (R = t-Bu)
phosphinite (R)-1a (99% ee) and TEMT was tried (see Table 2).
When 1,4-benzoquinone derivatives were employed, the yield
of 2a was significantly influenced by the substituents located
at 2- and 6-positions of 1,4-benzoquinone (Entries 1–3) and the
Next, optimization of the reaction conditions of using chiral
Copyright Ó 2005 The Chemical Society of Japan

Chemistry Letters Vol.34, No.12 (2005)
1677
Table 3. Condensation reactions using various chiral alcoholsa
used. These triester products 2 can be transformed to the corre-
sponding chiral 3-aryl-3-alkyl propanoic acids by the reported
saponification–decarboxylation procedure.1e–1g
HC(CO Et)
2
3
ClPPh
Et N, DMAP
3
2
Ph P
2
O
C(CO Et)
OH
Alk
Oxidant
2
3
General procedures are as follows. (1) Preparation of phos-
phinites 1a–1h: To a stirred solution of an alcohol (10 mmol) and
4-(dimethylamino)pyridine (3 mmol) in anhydrous THF (20 mL)
were added successively triethylamine (12 mmol) and chlorodi-
phenylphosphine (11 mmol) at 0 ꢁC (the reaction was carried out
at ꢂ78 ꢁC only in the case of 1d). After stiring at 0 ꢁC (ꢂ78 ꢁC
for 1d) for 1 h, the white slurry was concentrated in vacuo at rt,
and the residue was then diluted with hexane–ethyl acetate
(100 mL, v/v = 8/1). Insoluble triethylamine salts were filtered
off through an alumina–celite bed. After concentration, the
corresponding phosphinite was obtained as analytically pure
form. (2) Oxidation–reduction condensation between 1a–1h
and TEMT: At ꢂ63 ꢁC, to a solution of 1 (0.5 mmol) and TEMT
(0.6 mmol) in 2 mL of anhydrous THF was added dropwise a
2 M toluene solution of a dialkyl azodicarboxylate (0.6 mmol).
After 3 h, the mixture was allowed to warm to rt and then
concentrated in vacuo. The residue was dissolved in diethyl
ether, washed with 4 M NaOH and brine, dried over Na2SO4,
filtered, and evaporated under reduced pressure. The crude was
purified by preparative TLC on silica gel (eluent, hexane/
EtOAc) to yield the desired triester-product 2a–2h.
Alk
Ar
Alk
Ar
THF
CHCl
Ar
3
−63 °C, 3 h
0 °C
1b−1h
2b−2h
Tricarboxylate 2
Oxidant Yield/% Ee/%
Phosphinite1
Yield/%
b
Alcohol
Ee/%
93
DEAD
DIAD
DTBAD
79
81
80
88
88
88
(R)-
2b
OH
(S)
1b (93)
1c (95)
Me
DEAD
DIAD
DTBAD
58
56
59
75
75
75
(R)-
2c
OH
(S)
77
Cl
DEAD
DIAD
DTBAD
87
89
89
38
42
49
(R)-
2d
OH
(S)
81
99
1d (91)
MeO
OH
DEAD
1e (quant.) DIAD
DTBAD
71
63
56
96
96
96
(R)-
2e
(S)
DEAD
1f (quant.) DIAD
DTBAD
78
57
48
97
79
73
(R)-
2f
OH
99
81
99
(S)
(S)
OH
DEAD
1g (quant.) DIAD
DTBAD
54
56
62
81
81
81
It is noted that an efficient method for C–C bond formation
using chiral alkyl aryl carbinols as chiral alkylating agents
was developed by oxidation–reduction condensation using alkyl
diphenylphosphinites. The new combination of phosphinites,
dialkyl azodicarboxylates and TEMT worked effectively to pro-
duce the desired triesters 2 in good yields with a highly inverted
fashion.
(R)-
2g
DEAD
1h (95)
8
13
99 (S)-
2h
99
OH
(R)
DTBAD
aThe reactions were carried out by using 1b–1h (1.0 equiv.),
oxidant (1.2 equiv.), and TEMT (1.2 equiv.). Ee values were
determined by chiral HPLC analysis.
b
This study was supported in part by the Grant of the 21st
Century COE Program from the Ministry of Education, Culture,
Sports, Science and Technology (MEXT), Japan.
reaction with DBBQ afforded 2a in 60% yield with 97% ee. Af-
ter screening various oxidants, it was found that diethyl azodi-
carboxylate (DEAD), diisopropyl azodicarboxylate (DIAD),
and di-tert-butyl azodicarboxylate (DTBAD) gave the desired
product in 67–72% yields with 96–97% ees (Entries 4–6),
whereas 1,10-(azodicarbonyl)dipiperidine (ADDP) did not afford
the desired product at all (Entry 7). When the reaction was car-
ried out by using DEAD at ꢂ63 ꢁC, the inverted (S)-2a was ob-
tained in 73% yield with 98% ee.
With the optimal reaction conditions in hand, the scope of
the reaction was investigated by using various chiral alkyl aryl
carbinols (Table 3). First, chiral alcohols were transformed into
the corresponding phosphinites in excellent yields according to
the previously reported procedure of using chlorodiphenylphos-
phine.4 Subsequent condensation reactions were then carried out
by using dialkyl azodicarboxylates under the above-mentioned
conditions (CHCl3, ꢂ63 ꢁC) and the corresponding triester-
products 2 were successfully afforded in good yields with com-
plete or almost complete inversion of stereochemistries when
benzylic diphenylphosphinites 1b, 1c, and 1e–1g were em-
ployed. Significant loss of enantiomeric excess was observed
in the alkylation using phosphinite 1d bearing a para-methoxy
moiety because the reaction proceeded via SN1 and SN2 path-
ways competitively. C-Alkylation of TEMT with the unreactive
non-benzylic phosphinite 1h gave the desired product 2h in poor
yields.1f Interestingly, bulkiness of the ester moieties of azo-
oxidants affected inversion ratios only when 1e and 1f were
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Published on the web (Advance View) November 19, 2005; DOI 10.1246/cl.2005.1676