Discrimination of carbonyl groups of meso-α-diketones with Horner-Wadsworth-Emmons reagent of chiral binaphthyl esters

Article abstract of DOI:10.1016/j.tet.2007.10.006

Asymmetric Horner-Wadsworth-Emmons reactions of selected meso-α-dicarbonyl compounds with chiral phosphonate reagents, which possessed axially dissymmetric 1,1′-bi-2- or 8-naphthol at the carboxylate moiety as a chiral auxiliary, were examined. The reacti

Full text of DOI:10.1016/j.tet.2007.10.006

Tetrahedron 63 (2007) 12712–12719
Discrimination of carbonyl groups of meso-a-diketones with
Horner–Wadsworth–Emmons reagent of chiral binaphthyl esters
Daiki Monguchi,a Yoshihisa Ohta,b Tatsuya Yoshiuchi,b Toshiyuki Watanabe,b Takumi Furuta,a,
*
Kiyoshi Tanaka! and Kaoru Fujic
aSchool of Pharmaceutical Sciences, University of Shizuoka, Shizuoka 422-8526, Japan
bInstitute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011, Japan
cFaculty of Pharmaceutical Sciences, Hiroshima International University, Kure, Hiroshima 737-0112, Japan
Received 11 August 2007; revised 28 September 2007; accepted 1 October 2007
Available online 5 October 2007
Abstract—Asymmetric Horner–Wadsworth–Emmons reactions of selected meso-a-dicarbonyl compounds with chiral phosphonate
reagents, which possessed axially dissymmetric 1,10-bi-2- or 8-naphthol at the carboxylate moiety as a chiral auxiliary, were examined.
The reactions proceeded smoothly with good chemical yields as well as with high diastereoselectivities. Z-olefins were preferentially formed,
and it was found that the free hydroxy group at the 20- or 80-position on the naphthalene ring plays a crucial role in the high diastereoselectivity,
probably due to a complex-induced proximity effect. Mechanistic considerations are also described.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
a marked degree of intermolecular differentiation between
enantiotopic ketones of meso-a-dicarbonyl compounds
using chiral phosphonate reagent (S)-1, which yielded an
optically active enone with 98% ee,10 while the anion of
(S)-2 exhibited an excellent discrimination ability between
the p-faces of enones (Fig. 1).11,12
Wittig and related reactions such as the Horner–Wadsworth–
Emmons (HWE)1 reaction have become versatile synthetic
transformation involving carbon–carbon bond formation.
Their mechanisms and stereochemical courses as well as
the refined reaction conditions have been extensively inves-
tigated.2,3 These types of reactions are often used as crucial
connective steps in natural product synthesis. Although reac-
tions to carbonyl compounds play key roles in synthetic
transformations, including asymmetric synthesis, the olefins
themselves are generally not chiral. Hence, progress toward
developing direct asymmetric reactions using Wittig-style
olefinations had been rather slow before the last two decade.3
Meanwhile, substantial progress has been made toward di-
rectly and effectively preparing non-racemic olefins from
different types of ketonic precursors.4,5 Because the asym-
metric synthesis of optically active organic compounds
from meso-precursors has attracted much attention from
the standpoint of asymmetric desymmetrization, various bi-
ological6 and chemical methods7 have been reported with
respect to this categorical approach. However, compared to
transformations by biocatalysts, only scattered examples
involving carbon–carbon bond formation based on desym-
metrization of meso-compounds have appeared in the litera-
ture.8 Wittig-type reactions have also been scarcely applied
for such asymmetric desymmetrization.9 We have reported
With these successful results in hand, we then considered an
alternative type of reagent, which does not possess a chiral
auxiliary at the phosphonate moiety, but can maintain the
ability of asymmetric induction with the same type of meso-
a-diketones. Thus, two optically active phosphonate re-
agents, (R)-3 and (S)-5, were selected based on the following
reasons.
First, it is already known that axially chiral binaphthol deriva-
tives, including 8,80-binols, are effective for asymmetric
induction,13 and the equivalency of the 2- and 20- or 8- and
80-hydroxy groups due to C2 symmetry causes no formation
of diastereomers in their derivatization. Second, both enan-
tiomers of the reagent are easily prepared, and the chiral
auxiliary is easily recovered after the reaction. Third,
O
O
O
O
O
O
P
P
CH2CO2Me
CH2CH=CH2
* Corresponding author. E-mail: furuta@u-shizuoka-ken.ac.jp
This paper is dedicated to the late Professor Kiyoshi Tanaka, who passed
away on December 8, 2004.
(S)-1
(S)-2
!
Figure 1.
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.10.006

D. Monguchi et al. / Tetrahedron 63 (2007) 12712–12719
12713
The HWE reaction of meso-a-diketone 10, which was
derived from commercially available 5-norbornene-2,3-di-
carboxylic anhydride, with (R)-3, was initially examined us-
ing the same reaction conditions as previously described,10
except the 2.5 equiv of NaH used (Table 1). The reactions
proceeded smoothly with a good chemical yield to give
four possible diastereomers 11a, 12a, 13a, and 14a in a ratio
of 89.5:1.5:1.2:7.8, respectively (Table 1, entry 1). Thus, this
reaction produced a significantly high diastereoselectivity,
and the observed diastereomeric excesses for the Z- and
E-adducts were 97% and 73%, respectively. Interestingly,
the Z/E ratio of the adducts, which was determined by
careful inspection of the 1H NMR spectra as well as HPLC
analysis, was 91:9, which suggests a kinetically controlled
reaction.2g
OCOCH2P(O)(OEt)2
OH
OCOCH2P(O)(OEt)2
OAc
(R)-3
(S)-4
OCOCH2P(O)(OMe)2
OCOCH2P(O)(OMe)2
HO
AcO
(S)-5
(S)-6
Figure 2.
In contrast, the diastereoselectivity (19% de for Z-adduct)
of the reaction with (S)-4 was considerably decreased com-
pared to the HWE reaction with (R)-3 under the same reac-
tion conditions (Table 1, entry 2). The reaction with (S)-4
gave a mixture of four diastereomers 11b, 12b, 13b, and
14b in a ratio of 48.1:32.7:6.7:12.5, respectively, but a com-
parable Z/E ratio (81:19) was again observed. These results
strongly suggest that the prominent role of the 20-hydroxy
group14 is for the high degree of induction of the diastereo-
selectivity.
separation and purification of the adducts by chromato-
graphic methods are possible without employing chiral
stationary phases. Finally, in addition to the asymmetric in-
duction brought about by an effective chiral environment
due to the axial chirality of the binaphthyl, the intramolecu-
lar hydroxy group of these reagents may lead to a complex-
induced proximity effect (CIPE).14 Herein, we report our
results of the diastereoselective differentiation of the meso-
a-diketones using readily available optically active phospho-
nate reagents (R)-3, (S)-5, and related reagents (Fig. 2).
The E/Z stereochemistry of the products was mainly deduced
by comparing the chemical shift of the olefinic protons in their
1H NMR spectra10 and by comparing the chemical transfor-
mation to the known compound.
2. Results and discussion
Chiral phosphonate reagents (R)-3 and (S)-5 were prepared
by condensation of the corresponding optically active 1,10-
bi-2-naphthol (R)-7 or 1,10-bi-8-naphthol (S)-9 with diethyl-
or dimethylphosphonoacetic acid, respectively. The optical
purity of these reagents was verified by HPLC analysis on
a chiral column. In order to compare the diastereoselectivity
observed in the HWE reactions, the corresponding acetates
(S)-4 and (S)-6 were also prepared in a similar manner
from the monoacetate15 of (S)-1,10-bi-2-naphthol (S)-8 and
acetylation of (S)-5, respectively (Scheme 1).
Thus, the stereostructure of the major Z-diastereomer 11a
obtained in the reaction with (R)-3 was confirmed by a chem-
ical transformation through an ester exchange reaction to the
methyl ester 15,16 whose absolute structure has already been
established,10 and identified using HPLC analysis in the
chiral stationary phase. Additionally, the stereostructure of
major E-diastereomer 14a obtained in the same reaction
with (R)-3 was determined by a similar ester exchange reac-
tion (Table 1, entry 1). The stereostructures of the adducts
obtained in the reaction with (S)-4 were also elucidated in
a similar way to that described above (Table 1, entry 2).
By these stereochemical outcomes of the products, it has
been clearly shown that reagent (R)-3 preferentially discrim-
inates the opposite carbonyls of substrate 10, which leads to
Z- and E-adducts, 11a and 14a, respectively.17
OH
OH
(EtO)2POCH2CO2H
WSC, DMAP, CH2Cl2
68%
(R)-3
(R)-7
Another aspect of this symmetric HWE reaction worth
noting is that the anions of (S)-110 and (R)-3, which have
opposite chiralities, both afford major products with iden-
tical absolute structures in the bicyclo systems. This indi-
cates that the same sense of chiral auxiliary could be used
to produce opposite enantiomers by altering the structure
of the reagents.
(EtO)2POCH2CO2H
OH
OAc
(S)-4
WSC, DMAP, CH2Cl2
93%
(S)-8
OH
Ac2O
(MeO)2POCH2CO2H
WSC, DMAP, CH2Cl2
25%
Next, the asymmetric HWE reaction of 10 with the anions of
(S)-5 and (S)-6 was carried out. In the reaction with the anion
of (S)-5, Z-diastereomer 11c was obtained as the major prod-
uct (Table 1, entry 3). This also indicates that the reaction
with (S)-5 is also kinetically controlled. The ee value of
15, which was derived from the ester exchange reaction of
(S)-6
(S)-5
HO
pyridine
quant.
(S)-9
Scheme 1.

Table 1. Asymmetric HWE reaction with chiral phosphonate reagents
O
H
O
H
O
O
MeOC
H
O
O
O
MeOC
O
O
O
ROC
ROC
H
O
O
reagent
O
NaH
MeOC
ROC
H
O
H
O
+
+
+
+
+
+
NaH
THF
O
O
O
MeOH
COMe
COR
H
H
ent-15
12
15
ent-16
11
13
16
14
Entry
Substrate
Reagent
R
Product ratio
(11:12:13:14)
Z/E ratio
de (%)
Combined yield
of isomers (%)
Methyl ester (ee%)
Z
E
Z
E
O
MeOC
O
MeOC
O
O
H
11a:12a:13a:14a
(89.5:1.5:1.2:7.8)
OTBDPS
OTBDPS
1
O
(R)-3
(S)-4
91/9
97
19
73
30
88
69
OTBDPS
OTBDPS
O
OTBDPS
OTBDPS
OH
H
15
ent-16
51% ee
10
80% ee
11b:12b:13b:14b
(48.1:32.7:6.7:12.5)
2
10
81/19
15 14% ee
ent-16 15% ee
OAc
11c:12c:13c:14ca
(85.8:8.7:4.5:1.0)
3
4
10
10
(S)-5
(S)-6
—
—
>90c
—
70
86
15 90% ee
—
HO
11d—14db
>64c
>66c
15 64% ee
ent-16 66% ee
AcO
O
O
MeOC
O
O
H
11e:12e:13e:14e
(24.8:9.2:45.2:20.8)
5
(R)-3
34/66
46
37
69
O
OH
COMe
H
18
19
O
17
46% ee
37% ee
a
The detailed correlation of each isomers (8.7:4.5:1.0) to 12c–14c has yet to be assigned, except for the major product 11c that corresponds to 85.8.
The product ratio has yet to be determined.
Evaluated from the ee values of 15 and ent-16.
b
c

D. Monguchi et al. / Tetrahedron 63 (2007) 12712–12719
12715
a mixture of the products, was 90% ee. On the other hand,
the same reaction with the anion of (S)-6 resulted in the for-
mation of both Z- and E-olefins with moderate diastereo-
selectivity (Table 1, entry 4). The direct ester exchange
reaction of the reaction mixture afforded 15 and ent-16 in
64% ee and 66% ee, respectively. These results also indicate
the important role of the 80-hydroxy group14 for a high
degree of stereoselectivity.
employed as the substrate (Fig. 3b). Assuming these factors,
two TSs, TS-A and TS-B in which a ketonic carbonyl coor-
dination to a metal cation is considered, are conceptualized,
the former leads to 11a and the latter to 14a through
simultaneous eliminations. Inspection of the stereomodels
indicates that TS-B suffers from an unfavorable steric inter-
action between the substrate and one of the OEt groups of the
reagent. Thus, the observed E/Z ratio can be explained by
virtue of this interaction in the TS.
The HWE reaction of an alternate a-diketone 1718 with re-
agent (R)-3 gave the mixture of 11e–14e in 69% yield with
lower Z/E ratio and diastereoselectivity than those of 10
(Table 1, entry 5). Thus, the Z/E ratio was 34:66 and the dia-
stereoselectivity for Z- and E-adducts was 46% de and 37%
de, respectively. In order to elucidate the stereochemical re-
lationship among these adducts 11e–14e, the transformation
to methyl esters 18 and 19 and the following HPLC analyses
using the chiral stationary phase were carried out. Conse-
quently, it was found that preferentially formed methyl ester
18 from major Z-adduct 11e is identical to that17 obtained
from the asymmetric HWE reaction of 17 with (S)-1. Unlike
the reaction of 10, the anion of (R)-3 discriminated the same
carbonyl groups of 17 to give 18 and 19 as the two major
diastereomers (Table 1, entry 5).
The formation of minor adducts 12a and 13a could result
from an unfavorable endo-attack by a reagent. The following
two factors, nucleophilic attack of an E-enolate and/or re-
action from re-face of a reagent, could also be considered
to explain the formation of 12a and 13a.
In contrast to the reaction with a type 3 reagent, the reaction
of a type 4 reagent seems to differ. Here, for simplification,
the mechanistic explanation using reagent (R)-4 in lieu of
Side view
Top view
(a)
(b)
+
M
+
AcO
M
OAc
O
HO
O
C
O
P
C
O
H
OEt
OEt
OEt
O
H
P
OEt
Si
3'
It is likely that the HWE reaction described above is
governed by kinetically controlled factors; thus, the stereo-
chemical outcomes of the reactions can be explained by con-
sidering a transition state (TS) involving a chelated reagent.
The presence of a hydroxy group attached to the additional
naphthalene ring renders a more rigid chelate formation
due to the tridentate type complex with a metal cation, while
the axially dissymmetric binaphthyl topology dictates the
orientation of the approach to the electrophile from the
less hindered side, si-face of the anion of (R)-3 (Fig. 3a). It
is reasonable that the preferential direction of approach of
a nucleophile occurs from the exo-direction when 10 is
H
Re
Re
For Z-isomer
TS-C
+
M
OAc
H
O
R*OC
O
P
O
C
O
EtO
EtO
O
O
O
OTBDPS
OTBDPS
ROH2C
12b
major
CH2OR
R = TBDPS
TS-D
+
M
AcO
(a)
(b)
+
O
O
O
C
O
P
M
Nu-
OEt
OEt
O
R*OC
O
O
O
C
O
P
O
OTBDPS
OTBDPS
OEt
OEt
O
H
3'
H
O
Nu-
Si
CH2OTBDPS
CH2OTBDPS
O
CH2OR
11b
H
Nu-
CH2OR
minor
R* = (R)-2'-acetoxy-binaphthyl
For E-isomer
TS-E
+
TS-A
M
+
O
C
O
P
M
O
ROC
R
O
O
OEt
OEt
OAc
O
O
O
O
C
O
O
OTBDPS
OTBDPS
O
H
EtO
EtO
P
H
OTBDPS
OTBDPS
O
CH2OTBDPS
COR*
11a
O
CH2OTBDPS
CH2OR
CH2OR
13b
major
+
TS-B
M
O
+
O
TS-F
O
C
O
P
ROC
AcO
M
O
OEt
R
O
R*OC
OEt
O
O
C
O
P
H
O
O
OEt
OEt
H
O
O
H
OTBDPS
OTBDPS
O
OTBDPS
OTBDPS
3'
TBDPSOH2C
14a
CH2OTBDPS
ROH2C
14b
CH2OR
R = (R)-2'-hydroxy-binaphthyl
minor
Figure 3.
Figure 4.

12716
D. Monguchi et al. / Tetrahedron 63 (2007) 12712–12719
(S)-4 is tentatively considered. Thus, tridentate chelation is
impossible for acetate 4. Hence, deviation from the rigid
form causes comparative space for the re-face approach to
the electrophile (Fig. 4a and b). Consequently, two TSs
based on an exo-attack of the reagents, TS-C and TS-D,
might be considered for the formation of the Z-olefin
(Fig. 4). Comparison of these TS models suggests that the
repulsive interaction between the substrate and 30-H of the
reagent in TS-D dictates that Z-11b is the minor product.
As for E-adducts, the same type of steric interaction for
aforementioned TS-B exists in both TS-E and TS-F, and
this might be why E-adducts are minor products. Further-
more, the additional repulsive interaction depicted in TS-F
makes E-14b a less favorable. We now return to the reaction
with (S)-4 (Table 1, entry 2). The proportion of the products,
11b, 12b, 13b, and 14b (48.1:32.7:6.7:12.5), can be
explained in agreement with these considerations.
4.2. HPLC analysis of derivatives 3, 4, 11a–14e, 15,
16, 18, and 19
HPLC analyses were performed using a solvent system of
hexane/2-PrOH at the flow rates indicated below, and each
peak was detected at 254 nm. Either silica or chiral column
with the following solvent ratio for 2-PrOH in hexane was
used. Chiralpak AD, 20%, 1.0 mL/min for (R)-3 and (S)-4;
Shim-pack PREP SIL(H), 1.0%, 0.5 mL/min for 11a–14a,
11b–14b, and 11e–14e; Chemco ORB, 1.0%, 1.0 mL/min
for 11c–14c; Backbond DNBPG (covalent) chiral, 1.0%,
1.0 mL/min for 15; Chiralpak AS (Daicel Chemical Ind.
LTD) 0.5%, 0.5 mL/min for 16; Chiralpak AS, 3.0%,
1.0 mL/min for 18; Chiralcel OJ (Daicel Chemical Ind.
LTD) 1.0%, 0.5 mL/min for 19.
4.3. 20-Hydroxy-1,10-binaphthyl diethoxyphosphono-
acetate ((R)-3), 20-acetoxy-1,10-binaphthyl diethoxy-
phosphonoacetate ((S)-4), and 80-hydroxy-1,10-
binaphthyl dimethoxyphosphonoacetate ((S)-5)
It is plausible that the moderate Z/E selectivity as well as dia-
stereoselectivity observed in the asymmetric HWE reaction
of 17 with (R)-3 might be attributable to the structural
feature of the a-diketone, where bulky endo-substituents
do not exist. Consequently, a considerable degree of endo-
approach of the nucleophile would be realized.
Preparation of 20-hydroxy binaphthyl diethoxyphosphono-
acetate reagents (R)-3 is typical. Diethyl phosphonoacetic
acid (1.9 mL, 9.8 mmol), DMAP (120 mg, 1.0 mmol,
10 mol %), and WSC (2.8 g, 14.7 mmol, 1.5 equiv) at 0 ꢀC
were added, dropwise, to a stirred solution of (R)-bi-2-naph-
thol (3.1 g, 10.8 mmol, 1.1 equiv) in CH2Cl2 (20 mL). The
mixture was stirred for 12 h at room temperature. The re-
action mixture was poured into a cold saturated NH4Cl
solution and extracted with EtOAc. The organic layer was
washed with brine, dried, and evaporated to give a residue,
which was purified by flash column chromatography with
EtOAc/hexane (4:1) to afford (R)-(+)-20-hydroxy-1,10-
binaphthyl diethoxyphosphonoacetate (3) in 68% yield.
(S)-(+)-20-Acetoxy-1,10-binaphthyl diethoxyphosphonoace-
tate (4) and (S)-(+)-80-hydroxy-1,10-binaphthyl dimethoxy-
phosphonoacetate (5) were similarly prepared in 93% and
25% yields, respectively.
3. Conclusions
In conclusion, the present study indicates that the optically
active phosphonate reagents of 3 or 5 type with C2-symmet-
rical element are not only versatile but also complementary
to the HWE reagent of the 1 type and asymmetric desymmet-
rization of a-diketones with s-symmetry. The reactions in
this study provide a fascinating methodology to create opti-
cally active molecules. The optically active binaphthol mole-
cules function as efficient chiral inducers by their axial
chirality as well as neighboring-group participation of the
free hydroxy group in these diastereoselective HWE reac-
tions. Because both enantiomers of 3 or 5 are easily prepared
in optically pure form and the auxiliary can be recovered by
hydrolytic cleavage or ester exchange reactions of the
adducts, the diastereoselective HWE reaction outlined above
may be exploited immediately for the practical synthesis of
a wide range of interesting non-racemic compounds, such as
intermediates of natural products.19
4.3.1. Compound (R)-3. Mp 146–147 ꢀC; colorless powder
(from hexane/EtOAc); [a]2D0 +46.4 (c 1.08, CHCl3, >99%
1
ee); H NMR d 1.17 (t, 3H, J¼7.0), 1.24 (t, 3H, J¼7.0),
2.83 (d, 2H, J¼21.4), 3.91 (q, 2H, J¼7.0), 4.01 (q, 2H, J¼
7.0), 7.02 (d, 1H, J¼8.1), 7.19–7.54 (m, 7H), 7.83–8.09
(m, 4H); 13C NMR d 15.9, 16.0, 32.5, 34.9, 62.7, 62.8,
62.9, 113.9, 118.6, 121.5, 123.5, 123.6, 124.7, 126.0,
126.4, 126.7, 127.4, 128.0, 128.3, 129.0, 130.3, 130.6,
132.4, 133.6, 133.7, 147.7, 152.2, 165.3, 165.4; 31P NMR
d 18.89 (from 85% H3PO4); IR (CHCl3) 1760, 1620, 1600,
1260, 1220 cmꢁ1; MS (m/z) 464 (M+); HRMS (m/z) calcd
for C26H25O6P (M+): 464.1389; found: 464.1402. Anal.
Calcd for C26H25O6P: C, 67.24; H, 5.43. Found: C, 67.45;
H, 5.40.
4. Experimental
4.1. General
Melting points are uncorrected. Nuclear magnetic resonance
(NMR) spectra were taken at 200 MHz in CDCl3 with chem-
ical shifts being reported as d ppm from tetramethylsilane as
an internal standard and couplings are expressed in hertz. In-
fra-red (IR) spectra were measured in CHCl3 solution. THF
was distilled from benzophenone ketyl and dichloromethane
was from calcium hydride. Unless otherwise noted, all reac-
tions were run under an argon atmosphere. All extractive
organic solutions were dried over anhydrous MgSO4. Flash
column chromatography was carried out with Silica Gel 60
(spherical, 150–325 mesh), and Silica Gel 60 F254 plates
(Merck) were used for preparative TLC (prep. TLC).
4.3.2. Compound (S)-4. Colorless oil; [a]2D0 +4.6 (c 1.32,
1
CHCl3, >99% ee); H NMR d 1.19 (t, 3H, J¼7.0), 1.21 (t,
3H, J¼7.0), 1.84 (s, 3H), 2.77 (q, 1H, J¼14.5), 2.88 (q, 1H,
J¼14.5), 3.90–4.12 (m, 4H), 7.13–7.50 (m, 8H), 7.91–8.02
(m, 4H); 13C NMR d 15.6, 15.7, 20.0, 31.9, 34.5, 62.2,
62.3, 62.4, 77.0, 121.1, 121.7, 122.8, 123.0, 125.5, 125.6,
125.9, 126.5, 126.6, 127.8, 129.4, 129.5, 131.3, 131.4,
133.0, 133.1, 146.3, 146.6, 164.2, 164.3, 169.4; 31P NMR
d 19.45 (from 85% H3PO4); IR (CHCl3) 1760, 1260, 1200,

D. Monguchi et al. / Tetrahedron 63 (2007) 12712–12719
12717
1100 cmꢁ1; MS (m/z) 506 (M+); HRMS (m/z) calcd for
C28H27O7P (M+): 506.1494; found: 506.1476. Anal. Calcd
for C28H27O7P: C, 66.40; H, 5.37. Found: C, 65.95; H, 5.44.
146.0, 147.9, 152.0, 165.4, 202.3; IR (CHCl3) 1760, 1740,
1660, 1620, 1220, 1110 cmꢁ1; MS (m/z) 971 (M+). Anal.
Calcd for C63H62O6Si2$1/2H2O: C, 77.19; H, 6.48. Found:
C, 76.99; H, 6.61.
4.3.3. Compound (S)-5. Yellow powder; [a]2D2 +171.4
(c 0.50, CHCl3, >99% ee); 1H NMR d 1.43 (dd, 1H, J¼14.2,
33.7), 1.85 (dd, 1H, J¼14.2, 33.7), 3.57 (q, 6H, J¼11.2),
6.81–8.04 (m, 12H); IR (CHCl3) 1755, 1265, 1225, 1209,
1105, 1057, 1038 cmꢁ1; FABMS (m/z) 437 (M+H)+. Anal.
Calcd for C24H21O6P$1/4H2O: C, 65.38; H, 4.81. Found:
C, 65.34; H, 4.95.
1
4.5.2. Compound 12a. Colorless oil; H NMR d 0.79 (s,
9H), 0.87 (s, 9H), 1.80 (br s, 2H), 2.39–2.62 (m, 2H), 2.75
(br s, 1H), 3.19 (m, 1H), 3.34 (m, 3H), 3.87 (dd, 1H, J¼
4.9, 10.3), 5.32 (br s, 1H), 5.51 (s, 1H), 7.05–8.15 (m,
32H); IR (CHCl3) 1740, 1660, 1620, 1600, 1110,
1060 cmꢁ1; MS (m/z) 971 (M+).
1
4.4. 80-Acetoxy-1,10-binaphthyl dimethoxyphosphono-
acetate ((S)-6)
4.5.3. Compound 13a. Colorless oil; H NMR d 0.79 (s,
9H), 1.02 (s, 9H), 1.08 (d, 1H, J¼11.0), 1.38 (d, 1H, J¼
11.0), 2.07 (m, 1H), 2.50 (m, 1H), 2.56 (br d, 1H, J¼3.5),
3.14 (t, 1H, J¼10.8), 3.32 (t, 1H, J¼10.8), 3.56 (dd, 1H,
J¼4.1, 10.7), 4.18 (dd, 1H, J¼4.9, 10.6), 4.95 (br s, 1H),
6.13 (s, 1H), 6.72–8.00 (m, 32H); IR (CHCl3) 1735, 1625,
1600, 1115, 1055 cmꢁ1; MS (m/z) 971 (M+).
Pyridine (17 mg, 0.22 mmol, 1.0 equiv), acetyl chloride
(18.8 mL, 0.26 mmol, 1.2 equiv) at 0 ꢀC were added, drop-
wise, to a stirred solution of (S)-5 (100 mg, 0.22 mmol,
1.0 equiv) in CH2Cl2 (5 mL). The mixture was stirred for
2 h at room temperature. The reaction mixture was poured
into a cold saturated NH4Cl solution and extracted with
EtOAc. The organic layer was washed with brine, dried,
and evaporated to give a residue, which was purified by flash
chromatography with EtOAc/hexane (2:3) to afford (S)-
(+)-80-acetoxy-1,10-binaphthyl dimethoxyphosphonoacetate
(6) (107 mg) in quantitative yield.
1
4.5.4. Compound 14a. Colorless oil; H NMR d 0.81 (s,
9H), 0.99 (s, 9H), 1.44 (d, 1H, J¼10.6), 1.76 (d, 1H, J¼
10.6), 2.41–2.62 (m, 2H), 3.02 (br d, 1H, J¼2.2), 3.29 (t,
1H, J¼7.4), 3.30 (t, 1H, J¼9.2), 3.53 (br d, 1H, J¼2.2),
3.59 (dd, 1H, J¼5.5, 10.9), 4.06 (dd, 1H, J¼4.1, 10.9),
4.89 (br s, 1H), 6.13 (s, 1H), 6.96–7.98 (m, 32H); IR
(CHCl3) 1735, 1620, 1600, 1115, 1080 cmꢁ1; MS (m/z)
971 (M+).
4.4.1. Compound (S)-6. Yellow powder; [a]2D2 +228.7 (c
0.60, CHCl3, >99% ee); 1H NMR d 0.90 (s, 3H), 1.35 (dd,
1H, J¼6.9, 14.2), 1.75 (dd, 1H, J¼6.9, 14.2), 3.58 (q, 6H, J¼
11.2), 7.05–7.93 (m, 12H); IR (CH3Cl) 1757, 1368, 1265,
1225, 1202, 1103, 1057, 1037, 775, 737 cmꢁ1; FABMS
(m/z) 479 (M+H)+.
1
4.5.5. Compound 11b. Colorless oil; H NMR d 0.87 (s,
3H), 0.97 (s, 3H), 1.70 (d, 1H, J¼13.0), 1.77 (d, 1H, J¼
13.0), 1.80 (s, 3H), 2.40–2.59 (m, 2H), 2.68 (br s, 1H),
3.20 (br s, 1H), 3.45 (d, 1H, J¼7.3), 3.49 (d, 1H, J¼10.2),
3.55 (d, 1H, J¼10.2), 3.95 (dd, 1H, J¼4.9, 11.2), 5.77 (s,
1H), 7.17 (d, 1H, J¼7.8), 7.23–7.61 (m, 26H), 7.86 (d, 1H,
J¼9.1), 7.89 (d, 1H, J¼8.1), 7.93 (d, 1H, J¼8.8), 7.95 (d,
1H, J¼8.1), 8.05 (d, 1H, J¼9.1); 13C NMR d 18.8, 19.0,
20.4, 26.3, 26.5, 26.7, 33.8, 35.7, 41.9, 42.6, 45.9, 53.0,
62.0, 62.1, 120.7, 122.0, 122.3, 123.0, 123.5, 125.7, 126.2,
126.3, 126.5, 126.7, 126.8, 127.7, 127.8, 127.9, 128.0,
128.2, 128.4, 129.6, 129.7, 131.6, 131.7, 133.4, 133.5,
133.6, 133.9, 135.5, 135.6, 135.7, 141.7, 145.9, 146.9,
147.0, 164.5, 169.9, 202.3; IR (CHCl3) 1750, 1730, 1650,
1590, 1190, 1110 cmꢁ1. Anal. Calcd for C65H64O7Si2: C,
77.04; H, 6.37. Found: C, 76.60; H, 6.53.
4.5. HWE reaction of 10 with the anion of chiral
phosphonate reagent. General procedure
The HWE reaction of a-diketone 10 with the anion of (R)-3
is typical. Compound (R)-3 (49 mg, 0.11 mmol, 1.0 equiv)
at ꢁ78 ꢀC was added, dropwise, to a stirred solution of
NaH (10 mg, 0.26 mmol, 2.5 equiv) in THF (3 mL). After
stirring for 10 min at 0 ꢀC, the reaction mixture was cooled
to ꢁ78 ꢀC. A solution of a-diketone 10 (28 mg, 0.04 mmol)
in THF (1 mL) was added, and the mixture was stirred for
2 h at the same temperature. The reaction mixture was
poured into a cold saturated NH4Cl solution and extracted
with EtOAc. The organic layer was washed with brine, dried,
and evaporated to give a residue, which was subjected to
flash column chromatography with EtOAc/hexane (1:5) to
afford a mixture of diastereomers 11a–14a (90 mg, 88%
yield) in a ratio of 89.5:1.5:1.2:7.8. Prep. TLC of the mixture
gave pure samples.
4.5.6. Compound 12b. Colorless oil; 1H NMR d 0.78 (s, 9H),
0.84 (s, 9H), 1.77 (d, 1H), 1.83 (s, 3H), 1.90 (d, 1H), 2.38–2.56
(m, 2H), 2.71 (br s, 1H), 3.22 (br s, 1H), 3.33 (dd, 1H, J¼6.7,
11.1), 3.36 (br d, 2H, J¼6.7), 3.83 (dd, 1H, J¼4.9, 10.2), 5.63
(s, 1H), 7.10–7.54 (m, 27H), 7.84 (d, 1H, J¼8.9), 7.86 (d, 1H,
J¼8.1), 7.93 (d, 1H, J¼8.8), 7.97 (d, 1H, J¼7.6), 8.06 (d, 1H,
J¼9.2); 13C NMR d 18.7, 20.5, 26.5, 35.6, 41.9, 42.5, 46.2,
53.1, 61.8, 62.1, 120.6, 122.0, 122.3, 123.1, 123.4, 125.8,
126.3, 126.4, 126.6, 126.7, 126.8, 127.7, 128.1, 128.2,
129.7, 131.6, 131.8, 133.3, 133.4, 133.5, 133.8, 135.4,
135.5, 135.6, 146.4, 146.9, 164.1, 169.8, 202.1; IR (CHCl3)
1750, 1735, 1655, 1590, 1190, 1105, 1080 cmꢁ1; MS (m/z)
1013 (M+). Anal. Calcd for C65H64O7Si2: C, 77.04; H, 6.37.
Found: C, 76.57; H, 6.47.
1
4.5.1. Compound 11a. Colorless oil; H NMR d 0.88 (s,
9H), 0.95 (s, 9H), 1.77 (br s, 2H), 2.36–2.61 (m, 2H), 2.72
(br s, 1H), 3.16 (br s, 1H), 3.39 (d, 2H, J¼7.0), 3.41 (dd,
1H, J¼7.0, 10.2), 3.93 (dd, 1H, J¼5.0, 10.2), 5.27 (br s,
1H), 5.45 (s, 1H), 7.01–8.15 (m, 32H); 13C NMR d 18.7,
18.9, 26.5, 26.6, 35.6, 41.7, 42.7, 43.0, 45.7, 52.3, 52.9,
61.7, 61.9, 62.0, 114.0, 118.4, 119.9, 122.1, 123.0, 123.5,
124.8, 125.9, 126.3, 126.7, 127.3, 127.6, 127.7, 127.8,
127.9, 128.0, 128.4, 129.0, 129.7, 130.3, 130.9, 132.4,
132.9, 133.2, 133.4, 133.6, 133.7, 135.3, 135.5, 135.6,
1
4.5.7. Compound 14b. Colorless oil; H NMR d 0.75 (s,
9H), 1.01 (s, 1H), 1.30 (d, 1H, J¼9.4), 1.40 (d, 1H,

12718
D. Monguchi et al. / Tetrahedron 63 (2007) 12712–12719
J¼9.4), 1.99 (m, 1H), 2.53 (m, 1H), 2.60 (br d, 1H, J¼3.8),
3.01 (br d, 1H, J¼3.8), 3.13 (t, 1H, J¼9.5), 3.32 (t, 1H,
J¼9.5), 3.38 (m, 1H), 4.09 (m, 1H), 6.18 (s, 1H), 6.83–
7.52 (m, 26H), 7.57–7.64 (m, 3H), 7.82–7.95 (m, 3H).
113.0, 114.0, 118.2, 118.3, 121.7, 123.1, 123.8, 124.5,
125.8, 126.5, 126.9, 127.6, 128.1, 128.4, 129.1, 130.5,
130.9, 132.4, 133.6, 134.7, 134.8, 141.6, 147.9, 151.9,
152.1, 152.2, 165.3, 202.4; IR (CHCl3) 1750, 1730, 1620,
1600, 1515, 1510, 1170, 1150 cmꢁ1; MS (m/z) 432 (M+);
HRMS (m/z) calcd for C29H20O4 (M+): 432.1362; found:
432.1363. Anal. Calcd for C29H20O4: C, 80.54; H, 4.66.
Found: C, 80.28; H, 4.77.
4.5.8. Compound 11c. Yellow oil; 1H NMR d 0.95 (s, 9H),
1.07 (s, 9H), 1.25–1.55 (m, 1H), 2.04 (s, 1H), 2.23–2.55
(m, 1H), 2.58 (br s, 1H), 2.85 (br s, 1H), 3.31 (m, 2H),
3.83 (m, 1H), 4.17 (m, 1H), 4.77 (s, 1H), 5.25 (s, 1H), 6.75–
7.65 (m, 32H); IR (CHCl3) 2961, 2932, 2859, 1732, 1427,
4.7. General procedure for ester exchange of the HWE
adducts to methyl esters
1373, 1265, 1250, 1233, 1217, 1211, 1190, 1111 cmꢁ1
.
4.6. HWE reaction of 17 with the anion of (R)-3
The ester exchange reaction of Wittig adduct 13e to the
methyl ester 19 is typical. Wittig adduct 13e (321 mg,
0.74 mmol) in MeOH (2 mL) at room temperature was
added to a solution of NaH (60 mg, 1.50 mmol, 2.0 equiv)
in MeOH (12 mL). After stirring for 1 h, the reaction mix-
ture was poured into a cold saturated NH4Cl solution and
extracted with EtOAc. The organic layer was washed with
brine, dried, and evaporated to give a residue, which was pu-
rified by flash column chromatography with EtOAc/hexane
(1:5) to afford 19 (59 mg) in 47% yield.
Compound (R)-3 (254 mg, 0.55 mmol, 1.0 equiv) at ꢁ78 ꢀC
was added, dropwise, to a stirred solution of NaH (55 mg,
1.38 mmol, 2.5 equiv) in THF (15 mL). After stirring for
10 min at 0 ꢀC, the reaction mixture was cooled to
ꢁ78 ꢀC. A solution of a-diketone 17 (67 mg, 0.55 mmol)
in THF (2 mL) was added, and the mixture was stirred for
2 h at the same temperature. The reaction mixture was added
to H2O and extracted with EtOAc. The organic layer was
washed with saturated NaHCO3 solution, brine, dried, and
evaporated to give a residue, which was subjected to flash
column chromatography with EtOAc/hexane (1:3) to afford
a mixture of diastereomers 11e–14e (163.2 mg, 69% yield).
The integration of 1H NMR indicated the Z/E ratio of these
products in a ratio of 34:66. Further purification of these ad-
duct was performed by prep. TLC to give Z- (11e, 12e) and
E-isomers (13e, 14e) in 65 mg (27%) and 95 mg (40%), re-
spectively. According to the general procedure (see Section
4.7), both Z- and E-isomers converted to the corresponding
methyl esters 18 and 19, respectively. The ee values of 18
and 19 were measured by HPLC analysis on chiral stationary
phase to give 46% ee and 37% ee, respectively. Because no
Z- to E-isomerization occurred on 18, these ee values are
equal to the de values of Z- (11e, 12e) and E-adducts (13e,
14e). By using both the de values and Z/E ratio of the
adducts, the product ratio of 11e, 12e, 13e, and 14e was
calculated to give 24.8:9.2:45.2:20.8 as shown in Table 1.
4.7.1. Compound 18. Colorless oil; [a]2D0 ꢁ142.5 (c 0.87,
1
CHCl3, 46% ee); H NMR d 2.17 (d, 1H, J¼9.5), 2.39 (dt,
1H, J¼9.5, 1.8), 3.21 (br s, 1H), 3.50 (br s, 1H), 3.81 (s,
3H), 5.94 (s, 1H), 6.31 (dd, 1H, J¼3.3, 5.4), 6.60 (dd, 1H, J¼
2.9, 5.4); IR (CHCl3) 1740, 1735, 1720, 1700, 1680, 1670,
1655 cmꢁ1; MS (m/z) 178 (M+); HRMS (m/z) calcd for
C10H10O3 (M+): 178.0630; found: 178.0631. Anal. Calcd
for C10H10O3: C, 67.41; H, 5.66. Found: C, 67.51; H, 5.73.
4.7.2. Compound 19. Colorless oil; [a]2D0 ꢁ14.1 (c 0.52,
1
CHCl3, 37% ee); H NMR d 2.05 (d, 1H, J¼9.8), 2.43 (dt,
1H, J¼1.8, 9.8), 3.22 (br s, 1H), 3.78 (s, 3H), 4.59 (br s,
1H), 6.29 (dd, 1H, J¼3.0, 6.4), 6.33 (s, 1H), 6.57 (dd, 1H,
J¼3.0, 5.5); IR (CHCl3) 1745, 1720, 1340, 1200 cmꢁ1
;
MS (m/z) 178 (M+); HRMS (m/z) calcd for C10H10O3
(M+): 178.0630; found: 178.0650. Anal. Calcd for
C10H10O3: C, 67.41; H, 5.66. Found: C, 67.50; H, 5.69.
4.6.1. Compound 11e. Orange oil; 1H NMR d 2.08 (d, 1H,
J¼9.5), 2.34 (dt, 1H, J¼1.8, 9.5), 3.18 (br s, 1H), 3.35 (br
s, 1H), 5.35 (br s, 1H), 5.62 (s, 1H), 6.27 (dd, 1H, J¼2.9,
5.4), 6.50 (q, 1H, J¼2.9), 7.06 (dd, 1H, J¼1.1, 8.3), 7.19–
7.38 (m, 6H), 7.51 (dt, 1H, J¼1.1, 8.1), 7.85 (dd, 1H,
J¼8.9, 20.4), 7.86 (d, 1H, J¼8.9), 7.99 (d, 1H, J¼8.1),
8.12 (d, 1H, J¼8.9); 13C NMR d 47.4, 49.1, 54.9, 112.3,
114.0, 116.7, 118.4, 122.0, 123.0, 123.5, 124.8, 125.8,
126.3, 126.7, 127.3, 127.9, 128.0, 128.4, 129.0, 130.3,
130.9, 132.4, 133.5, 133.7, 134.2, 141.7, 144.8, 147.9,
148.2, 152.0, 165.3, 200.7; IR (CHCl3) 1760, 1740, 1665,
1620, 1600, 1510, 1200, 1170, 1150 cmꢁ1; MS (m/z) 432
(M+); HRMS (m/z) calcd for C29H20O4 (M+): 432.1362;
found: 432.1373. Anal. Calcd for C29H20O4: C, 80.54; H,
4.66. Found: C, 80.02; H, 4.70.
Acknowledgements
We thank Prof. Takeo Kawabata and Prof. Kazunori
Tsubaki, Institute for Chemical Research, Kyoto University
for their valuable discussions, and Dr. Valluru Krishna
Reddy for reading this manuscript.
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16. Among the ester exchange reaction (Table 1, entries 1 and 2),
the decrease of the optical purity of the methyl esters 15 and
ent-16 was observed. Namely, the ee value of 15 decreased to
80% from 97% de; at the same time, that of ent-16 dropped
down to 51% from 73% de of the original value. This appear-
ance of racemization might be originated form the isomeriza-
tion between the E- and Z-isomers of the adducts 11–14
and/or methyl esters 15–ent-16 during ester exchange reaction.
This consideration has been experimentally supported by the
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at 254 nm to give the (E)-16 without any loss of optical purity.
See Ref. 10. On the other hand, no isomerization of Z-methyl
ester 18 to E-methyl ester 19 occurred at all. See Ref. 17.
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€
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