Chiral auxiliary based reductive alkylation of α, α-diallkyl β-phosphonyl esters

Article abstract of DOI:10.1002/jccs.201200508

Acyclic α, α-disubstituted β-phosphonyl esters containing chiral alcoholic auxiliaries were efficiently prepared and evaluated for the lithium naphthalenide-mediated asymmetric reductive alkylation. Among which, the best diastereoselectivity was received fromthe substrates bearing a (-)-phenylmenthyl group in leading to alkylated esters with up to 83:17 dr. The diastereoselectivity is proven to be controlled by the π-facial differentiation created by the chiral ester as well as the geometry of tetrasubstituted enolates generated by the reductive cleavage of C-P bond.

Full text of DOI:10.1002/jccs.201200508

JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
Article
Chiral Auxiliary Based Reductive Alkylation of a,a-Diallkyl b-Phosphonyl Esters
Jr-Sheng Bau,a I-Chia Chen,b Zhen-Xing Yanga and Jia-Liang Zhua,*
aDepartment of Chemistry, National Dong-Hwa University, Hualien 974, Taiwan, R.O.C.
bDepartment of Cosmetic Applications and Management, Cardinal Tien College of Healthcare and Management, Taipei,
Taiwan, R.O.C.
(Received: Sept. 22, 2012; Accepted: Nov. 27, 2012; Published Online: Jan. 17, 2013; DOI: 10.1002/jccs.201200508)
Acyclic a,a-disubstituted b-phosphonyl esters containing chiral alcoholic auxiliaries were efficiently
prepared and evaluated for the lithium naphthalenide-mediated asymmetric reductive alkylation. Among
which, the best diastereoselectivity was received from the substrates bearing a (-)-phenylmenthyl group in
leading to alkylated esters with up to 83:17 dr. The diastereoselectivity is proven to be controlled by the
p-facial differentiation created by the chiral ester as well as the geometry of tetrasubstituted enolates gen-
erated by the reductive cleavage of C-P bond.
Keywords: b-Phosphonyl esters; Chiral auxiliary; Diastereoselectivity; Reductive alkylation; Lith-
ium naphthalenide.
INTRODUCTION
The stereocontrolled construction of quaternary car-
proach for the asymmetric formation of quaternary carbon
centers by the reductive alkylation of chiral bicyclic thio-
glycolate lactams.6 This method was based on the stereo-
specific generation of tetrasubstituted enolates through
the lithium butyldiphenylide (LiDBB)-induced reductive
cleavage of C-S bond, with the geometry of the resulting
enolates (E/Z) being strictly defined by the constrained
S-C-C-O dihedral angle as well as relative locations of two
pre-introduced alkyl groups. The diastereofacial selectivity
of the subsequent alkylation was then controlled by the lib-
erated chiral auxiliary to lead to the products with high
diastereomeric excesses (Scheme I). In addition to this, a
related strategy of using chiral amide auxiliaries to control
the diastereoselectivity of the Birch reductive alkylation
was addressed by Schultz’s group.7 To our knowledge,
there are no other methodologies on the asymmetric reduc-
tive alkylation have been reported.
bon centers represents a formidable challenge in organic
synthesis. One approach to this problem is by the asymmet-
ric alkylation of tetrasubstituted enolates generated by the
a-deprotonation of chiral carbonyl derivatives1 including
chiral lactams,2a,2b amides,2c esters,2d-f imides,2g-i and en-
amines.2j Although the same goal can nowadays be at-
tended by enantioselective catalytic methods,3 the chiral
auxiliary-based alkylation still boasts practical aspects.
Apart from a pre-introduced alkyl group, the chiral precur-
sors employed for asymmetric alkylation usually carry an-
other appendage on their pro-chiral a-carbons, sometimes
constituting cyclic enolates2b and/or containing the chelat-
ing functionalities.2h,2j This should make the arbitrary in-
troduction of three out of four substituents to quaternary
carbon centers to be difficult. In some cases, the precursors
were not stable under basic deprotonation conditions to un-
dergo elimination into ketenes.4 These, as we see, may limit
the generality of the existing protocols.
Gleason´s approach for asymmetric cre-
ation of quaternary carbons
Scheme I
The reductive alkylation operation has offered an at-
tractive option for creating quaternary carbon centers.5 The
documented procedures often involve the cleavage of a
functionality such as -CN, -SO2R, -Br etc. from a carbon
centre by electron donating species, followed by trapping
the resulting carboanions or enolates with alkylating agents.
Many systems for the reductive alkylation were developed,
but only a few were designed to create chiral quaternary
carbons. In 2002, Gleason et al. reported an elegant ap-
Our previous study demonstrated that the cyclic b-
phosphonyl esters derived from the Diels-Alder reaction of
triethyl 2-phosphono-2-alkenoates underwent the facile
dephosphonylation by treating with lithium naphthalenide
* Corresponding author. Tel.: +886-3-8633583; Fax: +886-3-8633570; E-mail: jlzhu@mail.ndhu.edu.tw
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Bau et al.
(LN) in THF at -30 ºC, and the resulting enolates could be
trapped in situ by alkyl halides to thus permit the installa-
tion of various alkyl groups to the a carbon of the car-
boxylate moiety. (Scheme II).8 During the investigation,
we also observed that LN was superior to LiDBB in leading
to the higher conversion. In light of these results, we were
interested in applying the protocol to the acyclic chiral
b-phosphonyl esters for exploring the asymmetric con-
struction of quaternary carbon centers. Our design resided
on generating tetrasubstitued enolates via the reductive
cleavage of the phosphonyl group from a,a-dialkyl b-
phosphonyl esters, and using a chiral auxiliary on the car-
boxylate moiety to control the facial selectivity of the al-
kylation. Given with the success, this method would pro-
vide a new entry to forming all-carbon quaternary centers
with the regiocontrolled introduction of alkyl groups in a
stereoselective manner.
Scheme III Preparation of a,a-dialkyl b-phosphonyl
ester
phonyl ester system. Decreasing the temperature of the
LN-treatment to -60 ºC gave an improved diastereoselec-
tivity (dr = 62:38).11 On this basis, it was further noted that
the introduction of hexamethylphosphoramide (HMAP) to
the reaction mixture after dephosphonylation improved the
yield and ratio slightly (78%, dr = 66:34). More impor-
tantly, the addition of HMPA could eliminate the formation
of the protonated by-product, which was difficult to be sep-
arated from 3a by chromatographic purification. The reac-
tions of 2b-d under the same conditions produced 3b-d in
Scheme II
RESULTS AND DISCUSSION
Four enantiomerically pure alcohols including (-)-
phenylmenthol,2f (-)-menthol,9 (-)-borneol and (1R,2S)-
trans-2-phenyl-1-cyclohexanol were chosen as the chiral
auxiliaries for our investigation. With these alcohols, we
first prepared the substrates bearing methyl and n-propyl
groups for screening the auxiliaries and reaction condi-
tions. The synthesis began with the trans-esterification of
triethyl phosphonoacetate with the corresponding chiral al-
cohols (R*OH) in the presence of 4-dimethyl aminopyri-
dine (DMAP)10 to yield the phosphonoacetates 1a-d in
good yields (Scheme III). The successive alkylation by
iodopropane and iodomethane in the presence of t-BuO-K+
afforded the precursors 2a-d. The NMR analysis revealed
that they all existed as diastereomeric mixtures.
Table 1. Reductive alkylation of 2a-d
O
O
O
Et
LN (5 eq), THF, 30 min
then EtI (6 eq), 4 h
P(OEt)2
*RO
n-Pr
*RO
n-Pr
Me
Me
2a-d
3a-d
Substrate Reagents and conditions Product Yield[a] dr[b]
2a
2a
2a
LN/-30 ºC/30 min/then
EtI/-30 ºC to rt/4 h
LN/-60 ºC/30 min/then
EtI/-60 ºC to rt/4 h
LN/-60 ºC/30 min/then
EtI/HMPA (5 eq)/-60 ºC
to rt/4 h
3a
3a
3a
77
73
78
59:41
62:38
66:34
2b
2c
2d
LN/-60 ºC/30 min/then
EtI/HMPA (5 eq)/-60 ºC
to rt/4 h
LN/-60 ºC/30 min/then
EtI/HMPA (5 eq)/-60 ºC
to rt/4 h
LN/-60 ºC/30 min/then
EtI/HMPA (5 eq)/-60 ºC
to rt/4 h
3b
3c
3d
80
85
54
57:43
51:49
53:47
With the requisite substrates in hand, we investigated
their reductive alkylation by using iodoethane as the al-
kylating reagent. As outlined in Table 1, the attempt of our
previously developed reaction conditions (Scheme II)8 to
2a led to the formation of 3a in 77% yield but almost with-
out any stereoselectivity (dr = 59:41). Despite of this, the
good yield of 3a implied that the reductive alkylation con-
ditions should be compatible with the acyclic b-phos-
[a] Isolated yield. [b] Diastereomeric ratio was determined by
integration of 400 MHz NMR spectrum.
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Asymmetric Reductive Alkylation of b-Phosphonyl Esters
trimethylsilyl chloride in order to determine the partition
between the E- and Z-enolates.12 However, the effort was
not successful due to the instability of the resulting silyl
enol ethers. To determine the true reason (B or C), we then
synthesized substrates 2e13 and 2f13 following the same se-
quence in Scheme III and applied them to the reaction.
The reaction of 2e (dr = 57:43) with CH3I offered 3a
as a 50:50 diastereomeric mixture (Scheme V).13 As com-
pared with the dr of 3a given in Table 1 (66:34), this result
indicates that the decreased size differentiation between the
pre-installed alkyl groups (n-Pr/Et vs. n-Pr/Me) could
cause the reduced diastereoselectivity. Since the geometry
of the enolates (E/Z) is virtually controlled by the steric dif-
ferentiation of the alkyl groups, it is thus reasonable to pro-
pose that the model C should be responsible for the forma-
tion of the minor diastereomer. To unambiguously prove
this, we further conducted the reductive alkylation on 2f re-
spectively with 1-iodopentane and 1-iodohexane. The re-
actions afforded 3e and 3f in the same diastereomeric ratio
(66:34).13 The quaternary carbon centres of their major iso-
mers were proven to be in the S-form14,15 in consistency
with the A-like transition state (E-geometry/front ap-
proach). Within B-like pathway, the bulkier alkylating re-
agent would definitely experience the larger steric hin-
drance when approaching to the enolate. Because the dia-
stereoselectivity in these two cases was independent to the
sizes of the alkylating reagents (n-C6H13I > n-C5H11I), the
possibility of the B-like model can therefore be precluded.
poorer dr´s than 3a, suggesting that the (-)-phenylmenthyl
group was the most effective among the tested auxiliaries.
To address the absolute stereochemistry of 3a (dr = 66:34),
we further converted it into the known optically active acid
4. As shown in Scheme IV, treatment of 3a with LiAlH4
yielded the alcohol intermediate plus the quantitative re-
covery of the chiral auxiliary. The subsequent Jones oxida-
tion of the resulting alcohol produced acid 4 in 66% yield
over two steps. The comparison of the specific optical rota-
20
tion of synthesized 4 with the literature date {lit. [a]D
=
+16.4, EtOH, ee% = 98%}6b established the R-configura-
tion of the quaternary carbon centre of the major isomer of
3a.
Scheme IV
The major R-isomer should be derived from the tran-
sition model A in Figure 1. In which, the electrophilic at-
tack occurs from the front side of the lithium enolate with
the back side being blocked by the 1-methyl-1-phenyl-
ethyl appendage. Meanwhile, the enolateadopts the more
stable E-configuration with the bulkier auxiliary and pro-
pyl group being trans to each other. In theory, there are two
pathways possibly responsible for the generation of the mi-
nor S-isomer. One involves the approach of the alkylating
agent from the more hindered face of the E-enolate (B). In-
evitably, this model would be strongly disfavored by the
steric interaction between the alkylating agent and the aux-
iliary. Besides, the minor isomer can also be formed through
the addition from the less hindered face of the enolate in a
Z-geometry (C), which, as we thought, was more likely to
account for the formation of the minor isomer. To verify
this, we initially attempted to trap the enolates of 2a by
Scheme V
OLi
O
n-Pr
Ph
O
n-Pr
*RO
Me
Et
Realizing that the alkyl groups should have sufficient
size differentiation for the stereocontrol, we subsequently
prepared substrates 2g and 2h containing the benzyl/cyclo-
hexyl and methyl groups. Two separable diastereomers
were obtained for 2g (2g-1 and 2g-2).16 Respective subjec-
tion of them to the reductive alkylation with EtI yielded
product 3g in almost identical dr´s13 majoring in the R-
form17,18 (from A-like pathway) (R/S = 83:17 and 81:19)
Me
Et
A
I
R-isomer (major)
OLi
OLi
Ph
O
n-Pr
n-Pr
Me
n-Pr
O
or
O
*RO
Me
Ph
I
Et
Et
Me
Et
I
S-isomer (minor)
B
C
Fig. 1. Proposed stereomodels for alkylation.
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(Scheme VI). Herein, the absolute stereochemistry of the
starting substrates was nearly inconsequential to the dia-
stereoselectivity of the alkylation. We therefore assume
that the formation of the enolates from the C-P bond cleav-
age might occur through an intermediary carboanion rather
than in a concerted mechanism that is proposed for the thio-
glycolate lactams (Scheme I).6 Finally, the reaction of 2h
with EtI also proceeded smoothly to give 3h in 82:18 dr
(R/S).13,17,18
(q) or multiplet (m). Coupling constants (J) are reported in Hertz
(Hz). The resonances of infrared (IR) spectra are reported in wave
numbers (cm-1). High resolution mass spectra (HRMS) were de-
termined in electron impact (EI) mode and by magnetic sector an-
alyzer. Specific optical rotations were measured in a polarimeter
with sodium light (589.6 nm).
Preparation of 1a-d
(1R,2S,5R)-5-Methyl-2-(2-phenylpropan-2-yl)cyclohex-
yl 2-(diethoxyphosphoryl)-acetate (1a)
Typical procedure for trans-esterification: To a solution of
(-)-phenylmenthol (950 mg, 4.09 mmol) in dry toluene (15 mL),
triethyl phosphonoacetate (2.48 mL, 12.3 mmol) and 4-dimethyl
aminopyridine (151.4 mg, 1.23 mmol) were successively added.
The mixture was stirred in an oil bath at 115 ºC for 2 days, then
cooled to rt and concentrated under reduced pressure. The residue
was subjected to chromatographic purification on silica gel (hex-
ane-EtOAc: hexane-EtOAc, 8:1, 5:1, 3:1) to afford 1.64 g of 1a
(98%) as a colorless oil. IR (neat) 3087, 3056, 2956, 1730, 1600,
1271, 1025, 972, 840 cm-1; 1H NMR (400 MHz, CDCl3) d 7.30-
7.24 (m, 4H), 7.18-7.07 (m, 1H), 4.83 (ddd, J = 10.7, 10.6, 4.4 Hz,
1H), 4.15-3.96 (m, 4H), 2.37 (dd, J = 21.2, 14.4 Hz, 1H), 2.08 (dd,
J = 21.2, 14.4 Hz, 1H), 2.06-2.00 (m, 1H), 1.84 (tm, J = 15.2 Hz,
2H), 1.67 (dm, J = 10.1 Hz, 1H), 1.52-1.39 (m, 1H), 1.34-1.24 (m,
9H), 1.20 (s, 3H), 1.18-1.11 (m, 1H), 1.02-0.89 (m, 2H), 0.87 (d, J
= 6.5 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 165.0 (d, JC-P = 5.9
Hz), 151.7, 127.9, 125.3, 125.1, 75.0, 62.3 (d, JC-P = 5.9 Hz), 50.2,
41.3, 39.4, 34.4, 33.7 (d, JC-P = 132.9 Hz), 31.2, 29.2, 26.2, 23.1,
21.7, 16.2 (d, JC-P = 6.3 Hz); HRMS-EI m/z [M]+ calcd for
Scheme VI
In summary, we have demonstrated that the acyclic
b-phosphonyl esters underwent the reductive alkylation as
facilely as previously reported cyclic precursors.8 Among
the auxiliaries examined, (-)-phenylmenthyl group was
shown to be optimal in inducing the facial selectivity for
the alkylation. Under this premise, the stereoselection is
also related to the geometry of the enolate intermediates.
The employed alcohol auxiliary was recoverable by a sim-
ple reduction. As such, a new method for the asymmetric
and regiocontrolled formation of quaternary carbon centres
has been innovated.
C22H35O5P 410.2222, found 410.2230. [a]20 = +14.0 (c = 1.1,
D
CHCl3).
(1R,2S,5R)-(Diethoxy-phosphoryl)-acetic acid 2-isopro-
pyl-5-methyl-cyclohexyl ester (1b)
EXPERIMENTAL
The typical procedure of preparing 1a was followed by us-
ing triethyl phosphonoacetate (2.91 mL, 14.4 mmol), (1R,2S,5R)-
(-)-menthol (750 mg, 4.8 mmol) and DMAP (177.7 mg, 1.44
mmol) as the reagents. The chromatographic purification (silica
gel, hexane-EtOAc, 8:1, 5:1, 3:1) afforded 1.50 g of 1b (94%) as a
colorless oil, plus 28 mg of recovered phosphonoacetate. IR
(neat) 2956, 1730, 1272, 1027 cm-1; 1H NMR (400 MHz, CDCl3)
d 4.73 (ddd, J = 10.9, 10.9, 4.4 Hz, 1H), 4.24-4.10 (m, 4H), 2.94
(d, J = 21.7 Hz, 2H), 2.06-1.92 (m, 2H), 1.68 (dm, J = 12.8 Hz,
2H), 1.54-1.35 (m 2H), 1.35 (t, J = 7.08 Hz, 6H), 1.12-0.94 (m,
3H), 0.90 (d, J = 6.6 Hz, 3H), 0.89 (d, J = 7.0 Hz, 3H), 0.76 (d, J =
6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 165.1 (d, JC-P = 6.1
Hz), 75.3, 62.3 (d, JC-P = 4.7 Hz), 62.3 (d, JC-P = 4.9 Hz), 46.7,
40.5, 34.4 (d, JC-P = 133.4 Hz), 34.0, 31.2, 25.6, 23.0, 21.8, 20.6,
16.2 (d, JC-P = 6.2 Hz), 15.8; HRMS-EI m/z [M]+ calcd for
General remarks
All of reagents were purchased from commercial suppliers
and used without further purification. All of reactions were per-
formed under an atmosphere of nitrogen except otherwise noted.
Tetrahydrofurane was freshly distilled from sodium-benzophe-
none, and dimethyl sulfoxide was freshly distilled from calcium
hydride before use. TLC analysis was carried out on glass-backed
silica gel plates, and visualized by UV light, ethanolic solution of
vanillin (5%), iodine or aqueous KMnO4 solution (10%). The
products were purified by flash chromatography using silica gel
(70-230 mesh). NMR spectra were recorded on 400 MHz spec-
trometers using deuteriochloroform (CDCl3) as solvents. Chemi-
cal shifts measurements are reported in delta (d) units. Splitting
patterns are described as singlet (s), doublet (d), triplet (t), quartet
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Asymmetric Reductive Alkylation of b-Phosphonyl Esters
C16H31O5P 334.1909, found 334.1913. [a]20 = -47.3 (c = 1.1,
an ice bath. The ice bath was then removed and stirring was con-
tinued for 20 minutes followed by the addition of iodopropane
(0.17 mL, 1.74 mmol). The mixture was heated at 50 ºC for 50
min, cooled to rt and diluted with ethyl acetate (180 mL). The so-
lution was successively washed with saturated aqueous NH4Cl
solution (45 mL), water (45 mL ´ 2) and brine (45 mL) and con-
centrated in vacuo. The residue was purified by flash chromatog-
raphy (silica gel, hexane-EtOAc, 7:1, 5:1, 3:1) to give 552.3 mg
of mono-alkylated phosphonate plus 22.3 mg of recovered 1a. Po-
tassium tert-butoxide (564.7 mg, 4.88 mmol) was added to a
stirred solution of the freshly prepared mono-alkylated phospho-
nate (552.3 mg, 1.22 mmol) in dry DMSO (8.3 mL) pre-cooled at
0 ºC in an ice bath. The ice bath was then removed and stirring
was continued for 15 minutes followed by the addition of iodo-
methane (0.31 mL, 4.88 mmol). The reaction mixture was heated
at 65 ºC for 4 hours, then cooled to rt and diluted with ethyl ace-
tate (180 mL). The solution was successively washed with NH4Cl
solution (45 mL), water (45 mL ´2) and brine (45 mL) and con-
centrated in vacuo. The residue was purified by flash chromatog-
raphy (silica gel, hexane-EtOAc, 6:1, 5:1, 3:1) to furnish 560.4
mg of 2a as a mixture of two diastereomers (57/43) (85%, over
two steps). IR (neat) 3100, 2961, 1794, 1249, 1052, 1026 cm-1; 1H
NMR (400 MHz, CDCl3) major: d 7.32-7.26 (m, 4H), 7.19-7.11
(m, 1H), 4.98-4.85 (m, 1H), 4.22-4.08 (m, 4H), 2.09-1.88 (m,
3H), 1.71- 1.56 (m, 1H), 1.56-1.41 (m, 2H), 1.40 (s, 3H), 1.37-
1.29 (m, 9H), 1.28-1.13 (m, 3H), 1.25 (d, J = 17.4 Hz, 3H), 1.02-
0.85 (m, 5H), 0.84 (d, J = 4.1 Hz, 3H), 0.79-0.64 (m, 1H); minor: d
7.32-7.26 (m, 4H), 7.19-7.11 (m, 1H), 4.98-4.85 (m, 1H), 4.22-
4.08 (m, 4H), 2.09-1.88 (m, 3H), 1.71- 1.56 (m, 1H), 1.56-1.41
(m, 2H), 1.39 (s, 3H), 1.37-1.29 (m, 9H), 1.17 (d, J = 17.4 Hz,
3H), 1.28-1.13 (m, 3H), 1.02-0.85 (m, 5H), 0.82 (d, J = 4.1 Hz,
3H), 0.79-0.64 (m, 1H); 13C NMR (100 MHz, CDCl3) major: d
171.3 (d, JC-P = 3.5 Hz), 150.5, 128.0, 125.7, 125.3, 77.0, 62.6 (d,
JC-P = 7.0 Hz), 62.6 (d, JC-P = 7.0 Hz), 50.4, 48.6 (d, JC-P = 136.0
Hz), 41.4, 40.4, 36.3 (d, JC-P = 4.1 Hz), 34.4, 31.4, 30.8, 27.5,
23.1, 21.8, 17.7 (d, JC-P = 11.6 Hz), 17.1 (d, JC-P = 4.4 Hz), 16.5 (d,
D
CHCl3).
(1S,2R,4S)-1,7,7-Trimethylbicyclo[2.2.1]heptan-2-yl
2-(diethoxyphosphoryl)-acetate (1c)
The typical procedure of preparing 1a was followed by us-
ing triethyl phosphonoacetate (9.84 mL, 48.6 mmol), (-)-borneol
(2.5 g, 16.2 mmol) and DMAP (600 mg, 4.86 mmol) as the re-
agents. The chromatographic purification (silica gel, hexane-
EtOAc: 10:1, 6:1, 3:1) afforded 1c as pale yellow oil (4.85 g,
93%) plus 91 mg of recovered phosphonoacetate. IR (neat) 2955,
1735, 1279, 1115, 1023 cm-1; 1H NMR (400 MHz, CDCl3) d 4.92
(dm, J = 9.9 Hz, 1H), 4.24-4.10 (m, 4H), 2.97 (d, J = 21.5Hz, 2H),
2.34 (ddd, J = 18.7, 9.8, 3.9 Hz, 1H), 1.98 (ddd, J = 12.6, 9.0, 3.9
Hz, 1H), 1.80-1.70 (m, 2H), 1.67 (t, J = 4.5 Hz, 1H), 1.34 (t, J =
7.2 Hz, 6H), 1.26-1.21 (m, 1H), 1.01 (ddd, J = 23.5, 11.2, 4.0 Hz,
1H), 0.89 (s, 3H), 0.86 (s, 3H), 0.84 (s, 3H); 13C NMR (100 MHz,
CDCl3) d 165.9 (d, JC-P = 6.5 Hz), 81.2, 62.4 (d, JC-P = 6.1 Hz),
48.8, 47.8, 44.7, 36.4, 34.5 (d, JC-P = 133.5 Hz), 27.9, 26.9, 19.6,
18.7 16.5 (d, JC-P = 6.2 Hz), 13.3; HRMS-EI m/z [M]+ calcd for
C16H29O5P 332.1753, found 332.1760. [a]20D = -18.1 (c = 0.62,
95% EtOH).
(1R,2S)-2-Phenylcyclohexyl 2-(diethoxyphosphoryl)-
acetate (1d)
The typical procedure of preparing 1a was followed by us-
ing triethyl phosphonoacetate (3.27 mL, 16.17 mmol), (1R,2S)-
trans-2-phenyl-1-cyclohexanol (950 mg, 5.39 mmol) and DMAP
(199.54 mg, 1.62 mmol) as the reagents. The chromatographic
purification (silica gel, hexane-EtOAc, 8:1, 5:1, 3:1) yielded 1.76
g of 1d (96.8%) and 47.3 mg of recovered phosphonoacetate. IR
(neat) 3100, 1732, 1647, 1550, 1269, 1028, 968, 758 cm-1; 1H
NMR (400 MHz, CDCl3) d 7.26-7.21 (m, 2H), 7.21-7.10 (m, 3H),
5.02 (ddd, J = 10.1, 10.0, 5.1 Hz, 1H), 4.10-3.88 (m, 4H), 2.79-
2.57 (m, 3H), 2.23-2.09 (m, 1H), 1.95-1.80 (m, 2H), 1.76 (m, 1H),
1.58-1.49 (m, 1H), 1.49-1.40 (m, 2H), 1.36-1.30 (m, 1H), 1.26 (t,
J = 7.0 Hz, 3H), 1.22 (t, J = 7.9 Hz, 3H); 13C NMR (100 MHz,
CDCl3) d 165.1 (d, JC-P = 6.1 Hz), 142.9, 128.3, 127.4, 126.4,
77.1, 62.5 (d, JC-P = 6.3 Hz), 62.4 (d, JC-P = 6.2 Hz), 49.4, 34.2 (d,
JC-P = 134.1 Hz), 34.2, 32.0, 25.7, 24.7, 16.3 (d, JC-P = 6.0 Hz);
HRMS-EI m/z [M]+ calcd for C18H27O5P 354.1596, found
354.1587. [a]20D = -17.0 (c = 1.05, CHCl3).
JC-P = 6.0 Hz), 16.5 (d, JC-P = 6.0), 14.2; minor: d 171.0 (d, JC-P
=
3.5 Hz), 150.9, 128.0, 125.6, 125.3, 76.3, 62.6 (d, JC-P = 7.0 Hz),
62.5 (d, JC-P = 7.0 Hz), 49.9, 48.6 (d, JC-P = 129.8 Hz), 41.3, 40.1,
35.9 (d, JC-P = 4.1 Hz), 34.4, 31.3, 29.1, 27.2, 24.9, 21.8, 17.9 (d,
JC-P = 11.6 Hz), 16.5 (d, JC-P = 6.0), 16.4 (d, JC-P = 7.2 Hz), 16.1 (d,
JC-P = 4.4 Hz), 14.5; HRMS-EI m/z [M]+ calcd for C26H43O5P
466.2848, found 466.2857.
Preparation of 2a-h
(1R,2S,5R)-2-(Diethoxy-phosphoryl)-2-methyl-pentanoic
acid 5-methyl-2-(1-methyl-1-phenyl-ethyl)-cyclohexyl
ester (2a)
(1R,2S,5R)-2-(Diethoxy-phosphoryl)-2-methyl-pentanoic
acid 2-isopropyl-5-methyl-cyclohexyl ester (2b)
From 1b, the typical procedure of preparing 2a was fol-
lowed by using iodopropane and iodomethane as the alkylating
Typical procedure for dialkylation: Potassium tert-but-
oxide (201.2 mg, 1.74 mmol) was added to a stirred solution of 1a
(600 mg, 1.46 mmol) in dry DMSO (1.4 mL) pre-cooled at 0 ºC in
J. Chin. Chem. Soc. 2013, 60, 531-541
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535

Article
Bau et al.
reagents (dr = 50:50, 75% over two steps). IR (neat) 2978, 2958,
1725, 1250, 1054, 1028 cm-1; 1H NMR (400 MHz, CDCl3) major:
d 4.65 (td, J = 10.9, 4.3 Hz, 1H), 4.15-4.00 (m, 4H), 2.06-1.87 (m,
3H), 1.62 (dm, J = 12.0 Hz, 2H), 1.69-1.55 (m, 1H), 1.47-1.30 (m,
3H), 1.37 (d, J = 4.8 Hz, 3H), 1.29-1.21 (m, 6H), 1.14-0.90 (m,
3H), 0.90-0.80 (m, 10H), 0.68 (d, J = 3.7 Hz, 3H); minor: d 4.61
(td, J = 10.9, 4.3 Hz, 1H), 4.15-4.00 (m, 4H), 2.06-1.87 (m, 3H),
1.62 (dm, J = 12.0 Hz, 2H), 1.69-1.55 (m, 1H),1.47-1.30 (m, 3H),
1.33 (d, J = 4.8 Hz, 3H), 1.29-1.21 (m, 6H), 1.14-0.90 (m, 3H),
0.90-0.80 (m, 10H), 0.67 (d, J = 3.7 Hz, 3H); 13C NMR (100 MHz,
CDCl3) major: d 171.1 (d, JC-P = 1.8 Hz), 75.4, 62.5 (d, JC-P = 7.0
Hz), 62.4 (d, JC-P = 7.0 Hz), 48.3 (d, JC-P = 133.2 Hz), 46.9, 40.5,
36.0 (d, JC-P = 4.2 Hz), 34.2, 31.3, 25.6, 22.9, 21.9, 20.8, 17.6 (d,
JC-P = 13.0 Hz), 17.0 (d, JC-P = 4.6 Hz), 16.4 (d, JC-P = 3.8 Hz), 16.4
(d, JC-P = 5.5 Hz), 15.6, 14.1; minor: d 171.0 (d, JC-P = 1.8 Hz),
reagents (dr = 65:35, 73% over two steps). IR (neat) 3086, 3029,
2961, 1723, 1272, 1054, 1024 cm-1; 1H NMR (400 MHz, CDCl3)
major: d 7.19-7.03 (m, 5H), 4.96 (td, J = 10.4, 4.3Hz, 1H), 4.07-
3.85 (m, 4H), 2.68-2.56 (m, 1H), 2.09-2.00 (m, 1H), 1.90-1.80 (m,
1H), 1.80-1.50 (m, 3H), 1.48-1.23 (m, 5H), 1.23-1.14 (m, 6H),
1.06 (d, J = 16.8 Hz, 3H), 0.95-0.67(m, 1H), 0.59 (t, J = 7.2 Hz,
3H),0.41-0.30 (m, 1H); minor: d 7.19-7.03 (m, 5H), 4.93 (td, J =
10.4, 4.3 Hz, 1H), 4.07-3.85 (m, 4H), 2.68-2.56 (m, 1H), 2.16-
2.09 (m, 1H), 1.90-1.80 (m, 1H), 1.80-1.50 (m, 3H), 1.48-1.23 (m,
5H), 1.23-1.14 (m, 6H), 1.12 (d, J = 16.8 Hz, 3H), 0.95-0.67 (m,
1H), 0.42 (t, J = 7.2 Hz, 3H), 0.19-0.04 (m, 1H); 13C NMR (100
MHz, CDCl3) major: d 170.6(d, JC-P = 3.4 Hz), 143.1, 128.2,
127.5, 126.3, 76.7, 62.5 (d, JC-P = 6.1Hz), 62.4 (d, JC-P = 6.2 Hz),
49.7, 48.2 (d, JC-P = 133.5 Hz), 35.9 (d, JC-P = 4.3 Hz), 34.1, 31.9,
25.7, 24.6, 16.9, 16.7 (d, JC-P = 4.7 Hz), 16.4, 16.3 (d, JC-P = 3.4
Hz), 14.2; minor: d 170.7 (d, JC-P = 3.4 Hz), 143.2, 128.3, 127.3,
126.4, 77.0, 62.4 (d, JC-P = 6.2Hz), 62.3 (d, JC-P = 6.1 Hz), 49.6,
48.3 (d, JC-P = 133.5 Hz), 35.5 (d, JC-P = 4.3 Hz), 34.5, 31.8, 25.8,
24.6, 16.9 (d, JC-P = 4.7 Hz), 16.8, 16.5 (d, JC-P = 3.4 Hz),16.3,
14.3; HRMS-EI m/z [M]+ calcd for C26H43O5P 410.2222, found
410.2231.
75.2, 62.6 (d, JC-P = 7.0 Hz), 62.5 (d, JC-P = 7.0 Hz), 48.6 (d, JC-P
=
133.2 Hz), 46.9, 40.4, 35.8 (d, JC-P = 4.2 Hz), 34.2, 31.3, 25.2,
22.8, 22.0, 20.9, 17.7 (d, JC-P = 13.0 Hz), 17.1 (d, JC-P = 4.6 Hz),
16.4 (d, JC-P = 3.8 Hz), 16.4 (d, JC-P = 5.5 Hz), 15.6, 14.3; HRMS-
EI m/z [M]+ calcd for C20H39O5P 390.2535, found 390.2533.
(1S,2R,4S)-2-(Diethoxy-phosphoryl)-2-methyl-pentanoic
acid 1,7,7-trimethyl-bicyclo[2.2.1]hept-2-yl ester (2c)
From 1c, the typical procedure of preparing 2a was fol-
lowed by using iodopropane and iodomethane as the alkylating
reagents (dr = 51:49, 76% over two steps). IR (neat) 2959, 2974,
1729, 1250, 1053, 1025 cm-1; 1H NMR (400 MHz, CDCl3) major:
d 4.90-4.77 (m, 1H), 4.20-4.05 (m, 4H), 2.38-2.27 (m, 1H), 2.14-
1.95 (m, 2H), 1.80-1.60 (m, 3H), 1.45 (m, 2H), 1.40-1.35 (m, 2H),
1.34-1.25 (m, 7H), 1.23-1.08 (m, 2H), 1.03-0.94 (m, 1H), 0.94-
0.79 (m, 12H); minor: d 4.90-4.77 (m, 1H), 4.20-4.05 (m, 4H),
2.38-2.27 (m, 1H), 2.14-1.95 (m, 2H), 1.80-1.60 (m, 3H), 1.45 (m,
2H), 1.40-1.35 (m, 2H), 1.34-1.25 (m, 7H), 1.23-1.08 (m, 2H),
1.03-0.94 (m, 1H), 0.94-0.79 (m, 12H); 13C NMR (100 MHz,
CDCl3) major: d 171.7 (d, JC-P = 2.3 Hz), 81.1, 62.7 (d, JC-P = 3.2
Hz), 62.6 (d, JC-P = 3.7 Hz), 48.7, 48.5 (d, JC-P = 132.1 Hz), 47.7,
44.9, 36.4, 35.7 (d, JC-P = 3.8 Hz), 27.9, 27.1, 19.6, 18.8, 17.7 (d,
JC-P = 3.8 Hz), 16.9 (d, JC-P = 4.0 Hz), 16.5 (d, JC-P = 5.3 Hz), 16.5
(d, JC-P = 5.3 Hz), 14.3, 13.4; minor: d 171.8 (d, JC-P = 2.3 Hz),
81.0, 62.5 (d, JC-P = 3.2 Hz), 62.4 (d, JC-P = 3.7 Hz), 48.9, 48.4 (d,
JC-P = 132.1 Hz), 47.7, 44.9, 36.6, 35.8 (d, JC-P = 3.8 Hz), 28.0,
27.1, 19.6, 18.8, 17.8 (d, JC-P = 3.8 Hz), 17.0 (d, JC-P = 4.0 Hz),
16.5 (d, JC-P = 5.3 Hz), 16.5 (d, JC-P = 5.3 Hz),14.4, 13.3; HRMS-
EI m/z [M]+ calcd for C20H37O5P 388.2379, found 388.2371.
(1R,2S)-2-(Diethoxy-phosphoryl)-2-methyl-pentanoic
acid 2-phenyl-cyclohexyl ester (2d)
(1R,2S,5R)-2-(Diethoxy-phosphoryl)-2-ethyl-pentanoic
acid 5-methyl-2-(1-methyl-1-phenyl-ethyl)-cyclohexyl
ester (2e)
2e was similarly prepared as 2a from 1a. Sequential alkyla-
tions, first with iodopropane then with iodoethane, afforded 2e as
a 57:43 diastereomeric mixture after chromatographic purifica-
tion (silica gel, hexane-EtOAc, 9:1, 7:1, 5:1) (82% over two
steps). IR (neat) 3107, 3057, 2963, 1718, 1246, 1220, 1053, 1027
1
cm-1; H NMR (400 MHz, CDCl3) major: d 7.25-7.19 (m, 4H),
7.14-7.04 (m, 1H), 4.94-4.82 (m, 1H), 4.15-4.03 (m, 4H), 2.22-
1.84 (m, 3H), 1.83-1.54 (m, 3H), 1.52-1.38 (m, 2H), 1.37-1.23 (m,
9H), 1.34 (s, 3H), 1.21 (s, 3H), 0.96-0.81 (m, 8H), 0.79 (d, J = 6.4
Hz, 3H), 0.76-0.64 (m, 1H); minor: d 7.25-7.19 (m, 4H), 7.14-
7.04 (m, 1H), 4.94-4.82 (m, 1H), 4.15-4.03(m, 4H), 2.22-1.84 (m,
3H), 1.83-1.54 (m, 3H), 1.52-1.38 (m, 2H), 1.37-1.23 (m, 9H),
1.32 (s, 3H), 1.20 (s, 3H), 0.96-0.81 (m, 8H), 0.79 (d, J = 6.4 Hz,
3H), 0.76-0.64 (m, 1H); 13C NMR (100 MHz, CDCl3) major: d
170.9 (d, JC-P = 2.3 Hz), 150.6, 128.0, 125.6, 125.3, 76.7, 62.2 (d,
JC-P = 7.7 Hz), 62.1 (d, JC-P = 7.7Hz), 53.0 (d, JC-P = 131.9 Hz),
50.2, 41.4, 40.2, 34.4, 33.1 (d, JC-P = 3.4 Hz), 31.3, 30.0, 27.5,
24.7 (d, JC-P = 3.2 Hz), 23.9, 21.7, 18.0, 16.4 (d, JC-P = 5.9 Hz),
16.4 (d, JC-P = 5.9 Hz), 14.6, 9.4 (d, JC-P = 2.6 Hz); minor: d 170.9
(d, JC-P = 2.3 Hz), 150.7, 128.0, 125.6, 125.2, 76.6, 62.2 (d, JC-P
=
7.7 Hz), 62.1 (d, JC-P = 7.7Hz), 52.9 (d, JC-P = 131.9 Hz), 50.1,
41.3, 40.2, 34.4, 33.3 (d, JC-P = 3.4 Hz), 31.3, 29.5, 27.4, 24.4,
24.1 (d, JC-P = 3.2 Hz), 21.7, 17.9, 16.4 (d, JC-P = 5.9 Hz), 16.4 (d,
From 1d, the typical procedure of preparing 2a was fol-
lowed by using iodopropane and iodomethane as the alkylating
536
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J. Chin. Chem. Soc. 2013, 60, 531-541

JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
Asymmetric Reductive Alkylation of b-Phosphonyl Esters
JC-P = 5.9 Hz), 14.7, 9.4 (d, JC-P = 2.6 Hz); HRMS-EI m/z [M]+
calcd for C27H45O5P 480.3005 found 480.3011.
JC-P = 134.1 Hz), 41.4, 40.4 (d, JC-P = 4.2 Hz), 40.4, 34.3, 31.2,
30.9, 27.5, 23.1, 21.6, 16.5 (d, JC-P = 5.2 Hz), 16.5 (d, JC-P = 5.2
Hz), 16.5 (d, JC-P = 5.2 Hz); HRMS-EI m/z [M]+ calcd for
C30H43O5P 514.2848, found 514.2847. 2g-2: IR (neat) 3087,
(1R,2S,5R)-2-(Diethoxy-phosphoryl)-2-methyl-butyric
acid 5-methyl-2-(1-methyl-1-phenyl-ethyl)-cyclohexyl
ester (2f)
1
3061, 1715, 1249, 1050 cm-1; H NMR (400 MHz, CDCl3): d
2f was similarly prepared as 2a from 1a. Sequential alkyla-
tions, first with iodoethane then with iodomethane, afforded 2f as
a 56:44 diastereomeric mixture after chromatographic purifica-
tion (silica gel, hexane-EtOAc, 8:1, 5:1, 3:1) (66% over two
steps). IR (neat) 3145, 3088, 3057, 1718, 1250, 1049, 1027 cm-1;
1H NMR (400 MHz, CDCl3) major: d 7.29-7.22 (m, 4H), 7.17-
7.08(m, 1H), 4.89 (td, J = 10.6, 4.3 Hz, 1H), 4.20-4.05 (m, 4H),
2.23-1.89 (m, 3H), 1.77-1.62 (m, 1H), 1.54-1.35 (m, 2H), 1.39 (s,
3H), 1.35-1.27 (m, 8H), 1.27-1.12 (m, 2H), 1.24 (d, J = 13.5 Hz,
3H), 1.03- 0.86 (m, 2H), 0.89 (t, J = 7.4 Hz, 3H), 0.82 (t, J = 5.0
Hz, 3H), 0.79-0.65 (m, 1H); minor: d 7.29-7.22 (m, 4H), 7.17-
7.08 (m, 1H), 4.92 (td, J = 10.6, 4.3 Hz, 1H), 4.20-4.05 (m, 4H),
2.23-1.89 (m, 3H), 1.77-1.62 (m, 1H), 1.54-1.35 (m, 2H), 1.36 (s,
3H), 1.35-1.27 (m, 8H), 1.27-1.12 (m, 2H), 1.16 (d, J = 17.2 Hz,
3H), 1.03- 0.86 (m, 2H), 0.88 (t, J = 7.4 Hz, 3H), 0.82 (t, J = 5.0
Hz, 3H), 0.79-0.65 (m, 1H); 13C NMR (100 MHz, CDCl3) major:
d 171.3 (d, JC-P = 3.1 Hz), 150.7, 128.0, 125.7, 125.3, 77.0, 62.6
(d, JC-P = 5.4 Hz), 62.6 (d, JC-P = 6.3 Hz), 50.3, 48.9 (d, JC-P = 131.6
Hz), 41.5, 40.3, 34.5, 31.3, 30.3, 27.5, 27.3 (d, JC-P = 4.8 Hz),
23.6, 21.8, 16.5 (d, JC-P = 2.7 Hz), 16.5, 16.4 (d, JC-P = 4.7 Hz), 8.9
(d, JC-P = 11.9 Hz); minor: d 170.9 (d, JC-P = 3.1 Hz), 150.9, 128.1,
125.6, 125.3, 76.4, 62.6 (d, J = 5.4 Hz), 62.4 (d, JC-P = 6.3 Hz),
49.9, 48.9 (d, JC-P = 135.7 Hz), 41.4, 40.2, 34.5, 31.3, 29.1, 27.3,
26.8 (d, JC-P = 4.8 Hz), 25.0, 21.8, 16.5, 16.5 (d, JC-P = 2.7 Hz),
15.6 (d, JC-P = 4.7 Hz), 9.1 (d, JC-P = 11.9 Hz); HRMS-EI m/z [M]+
calcd for C25H41O5P 452.2692, found 452.2697.
7.24-7.11 (m, 7H), 7.09 (m, 3H), 4.87 (td, J = 4.2 Hz, 1H), 4.24-
4.15 (m, 4H), 3.65 (dd, J = 13.1, 7.6 Hz, 1H), 2.80 (dd, J = 13.2,
8.8 Hz, 1H), 2.07-1.96 (m, 1H), 1.86 (td, J = 11.2, 3.1 Hz, 1H),
1.52-1.45 (m, 1H), 1.40-1.31 (m, 8H), 1.28-1.23 (m, 1H), 1.12 (d,
J = 13.4 Hz, 3H), 1.00 (s, 3H), 0.97-0.87 (m, 2H), 0.84 (d, J = 6.4
Hz, 3H), 0.78 (s, 3H); 13C NMR (100 MHz, CDCl3): d 170.2 (d,
JC-P = 4.1 Hz), 151.0, 136.2 (d, JC-P = 16.0 Hz), 131.1, 128.2,
128.0, 126.9, 125.4, 125.0, 76.6, 63.1 (d, JC-P = 7.1 Hz), 63.1 (d,
JC-P = 7.1 Hz), 50.1 (d, JC-P = 128.2 Hz), 49.9, 41.2, 40.0, 38.8 (d,
JC-P = 3.7 Hz), 34.5, 31.3, 28.7, 27.2, 24.3, 21.8, 16.5 (d, JC-P = 5.5
Hz), 16.5 (d, JC-P = 5.5 Hz), 15.5 (d, JC-P = 5.5 Hz); HRMS-EI m/z
[M]+ calcd for C30H43O5P 514.2848, found 514.2856.
(1R,2S,5R)-2-Cyclohexyl-2-(diethoxy-phosphoryl)-
propionic acid 5-methyl-2-(1-methyl-1-phenyl-ethyl)-
cyclohexyl ester (2h)
2h was similarly prepared as 2a from 1a. Sequential alkyla-
tions, first with cyclohexyl iodide then with iodoethane, afforded
2h as a 55:45 diastereomeric mixture after chromatographic puri-
fication (silica gel, hexane-EtOAc, 10:1, 7:1, 5:1, 3:1) (86% over
two steps). IR (neat) 3087, 3057, 1718, 1244, 1049 cm-1; 1H NMR
(400 MHz, CDCl3): d 7.30-7.25 (m, 4H), 7.20-7.11 (m, 1H), 4.88
(td, J = 10.2, 3.8 Hz, 1H), 4.23-4.03 (m, 4H), 2.35-2.20 (m, 1H),
2.12 (td, J = 11.9, 2.3 HZ, 1H), 2.05-1.88 (m, 2H), 1.80-1.70 (m,
2H), 1.69-1.65 (m, 1H), 1.45 (s, 3H), 1.40-1.20 (m, 17H), 1.15 (d,
J = 17.6 Hz, 3H), 1.07-0.86 (m, 3H), 0.84 (t, J = 6.4 Hz, 3H),
0.79-0.62 (m, 1H);minor: d 7.30-7.25 (m, 4H), 7.20-7.11 (m, 1H),
4.89 (td, J = 10.4, 3.8 Hz, 1H), 4.23-4.03 (m, 4H), 2.35-2.20 (m,
1H), 2.12 (td, J = 11.9, 2.3 HZ, 1H), 2.05-1.88 (m, 2H), 1.80-1.70
(m, 2H), 1.69-1.65 (m, 1H), 1.45 (s, 3H), 1.40-1.20 (m, 17H),
1.15 (d, J = 17.6 Hz, 3H), 1.07-0.86 (m, 3H), 0.84 (t, J = 6.4 Hz,
3H), 0.79-0.62 (m, 1H); 13C NMR (100 MHz, CDCl3) major: d
171.6 (d, JC-P = 3.9 Hz), 150.7, 128.0, 125.7, 125.3, 76.8, 62.4 (d,
JC-P = 7.2 Hz), 62.3 (d, JC-P = 7.2 Hz), 53.6 (d, JC-P = 133.9 Hz),
50.6, 41.6 (d, JC-P = 3.4 Hz), 41.2, 40.4, 34.5, 31.4, 31.3, 28.5,
(1R,2S,5R)-2-(Diethoxy-phosphoryl)-2-methyl-3-phenyl
propionic acid 5-methyl-2-(1-methyl-1-phenyl-ethyl)-
cyclohexyl ester (2g)
2g was similarly prepared as 2a from 1a. Sequential alkyla-
tions, first with benzyl bromide then with iodomethane, afforded
2g as two seperable diastereomers (2g-1, 80%; 2g-2, 20%) after
chromatographic purification (silica gel, hexane-EtOAc, 8:1, 5:1,
3:1, 2:1). 2g-1: IR (neat) 3087, 3061, 1718, 1249, 1050 cm-1; 1H
NMR (400 MHz, CDCl3): d 7.27-7.09 (m, 10H), 4.80 (td, J = 4.2
Hz, 1H), 4.28-4.16 (m, 4H), 3.52 (dd, J = 13.2, 9.7 Hz, 1H), 2.92
(dd, J = 13.2, 8.6 Hz, 1H), 1.82-1.71 (m, 2H), 1.43-1.30 (m, 14H),
1.28 (s, 3H), 1.20-1.13 (m, 1H), 0.90-0.79 (m, 1H), 0.76 (d, J =
6.4 Hz, 3H), 0.6 (qd, J = 12.8, 3.1 Hz, 1H), 0.49 (q, J = 11.7 Hz,
1H); 13C NMR (100 MHz, CDCl3): d 170.6 (d, JC-P = 3.0 Hz),
150.5, 135.7 (d, JC-P = 15.0 Hz), 130.9, 128.0, 126.9, 125.8, 125.3,
77.2, 63.1 (d, JC-P = 7.0 Hz), 62.8 (d, JC-P = 7.0 Hz), 50.3, 49.6 (d,
27.9 (d, JC-P = 14.0 Hz), 26.7, 26.6, 26.1, 22.3, 21.8, 16.5 (d, JC-P
=
5.4 Hz), 16.5, 16.4 (d, JC-P = 3.2 Hz), 12.3 (d, JC-P = 3.3 Hz); mi-
nor: d 171.5 (d, JC-P = 3.9 Hz), 150.9, 128.0, 125.6, 125.3, 77.5,
62.5 (d, JC-P = 7.2 Hz), 62.4 (d, JC-P = 7.2 Hz), 53.6 (d, JC-P = 129.2
Hz), 49.9, 42.2 (d, JC-P = 3.4 Hz), 41.0, 40.2, 34.4, 31.5, 29.7, 28.7
(d, JC-P = 14.0 Hz), 27.8, 27.4, 26.3, 26.2, 24.2, 21.7, 16.5 (d, JC-P
= 5.3 Hz), 16.4, 16.4 (d, JC-P = 3.4 Hz), 11.7 (d, JC-P = 3.3 Hz);
HRMS-EI m/z [M]+ calcd for C29H47O5P 506.3161, found
J. Chin. Chem. Soc. 2013, 60, 531-541
© 2013 The Chemical Society Located in Taipei & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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537

Article
Bau et al.
506.3271.
4H), 0.88 (s, 3H), 0.81 (t, J = 7.3 Hz, 3H), 0.72 (d, J = 6.9 Hz, 3H);
minor: d 4.61 (td, J = 10.9, 1.2 Hz, 1H), 2.03-1.95 (m, 1H), 1.95-
1.85 (m, 1H), 1.73-1.54 (m, 4H), 1.53-1.24 (m, 5H), 1.23-0.09 (m,
1H), 1.08 (s, 3H), 1.06-0.91 (m, 2H), 0.90 (s, 3H), 0.89-0.84 (m,
4H), 0.88 (s, 3H), 0.81 (t, J = 7.3 Hz, 3H), 0.72 (d, J = 6.9Hz, 3H);
13C NMR (100 MHz, CDCl3) major: d 177.0, 73.8, 47.0, 46.4,
41.4, 40.8, 34.3, 32.0, 31.4, 25.9, 23.0, 22.1, 20.9, 20.5, 17.9,
15.8, 14.7, 8.9; minor: d 176.9, 73.8, 47.0, 46.5, 41.7, 40.8, 34.3,
32.2, 31.4, 25.8, 23.0, 22.1, 20.9, 20.3, 18.0, 15.7, 14.6, 8.9;
HRMS-EI m/z [M]+ calcd for C18H34O2 282.2559, found
282.2549.
Reductive alkylation of 2a-h
(1R,2S,5R)-2-Ethyl-2-methyl-pentanoic acid 5-methyl-
2-(1-methyl-1-phenyl-ethyl)-cyclohexyl ester (3a)
Typical procedure for reductive alkylation. Under a nitro-
gen atmosphere, a 0.336 M solution of lithium naphthalenide
o
(LN) (2.5 mL, 0.84 mmol) in THF pre-cooled to -60 C was
quickly added by syringe to a solution of 2a (77 mg, 0.165 mmol)
in anhydrous THF (0.7 mL) at -60 oC. The resulting dark-green
mixture was stirred at -60 oC for 30 min, then iodoethane (0.08
mL, 0.99 mmol) and HMPA (0.145 mL, 0.83 mmol) were succes-
sively added, and stirring was continued at -60 oC for 30 min and
rt for 4 hours. The mixture was then quenched with water (10 mL)
and extrated with EtOAc (80 mL ´ 2). The combined organic ex-
tracts were washed with water (20 mL) and brine (20 mL), dried
over Na2SO4, filtered and concentrated. Flash chromatography
(silica gel, hexane-EtOAc, 100:0, 300:1, 100:1) afforded 3a (46
mg, 78%) as a mixture of two diastereomers (dr = 66:34). IR
(neat) 3012, 2959, 1717, 1229, 1146 cm-1; 1H NMR (400 MHz,
CDCl3) major: d 7.33-7.24 (m, 4H), 7.20-7.12 (m, 1H), 4.87 (td, J
= 10.6, 4.2 Hz, 1H), 2.05- 1.92 (m, 2H), 1.60-1.40 (m, 5H), 1.37
(s, 3H), 1.35-1.26 (m, 3H), 1.25 (s, 3H), 1.22-1.13 (m, 1H), 1.05-
0.87 (m, 3H), 0.99 (s, 3H), 0.90 (t, J = 7.1 Hz, 3 H), 0.86 (d, J = 6.5
Hz, 3H), 0.81 (t, J = 7.2 Hz, 3H); minor: d 7.33-7.24 (m, 4H),
7.20-7.12 (m, 1H), 4.87 (td, J = 10.6, 4.2 Hz, 1H), 2.05-1.92 (m,
2H), 1.60-1.40 (m, 5H), 1.37 (s, 3H), 1.35-1.26 (m, 3H), 1.25 (s,
3H), 1.22-1.13 (m, 1H), 1.05-0.87 (m, 3H), 1.00 (s, 3H), 0.90 (t, J
= 7.1 Hz, 3 H), 0.86 (d, J = 6.5 Hz, 3H), 0.81 (t, J = 7.2 Hz, 3H);
13C NMR (100 MHz, CDCl3) major: d 177.1, 151.0, 128.1, 125.7,
125.3, 75.2, 50.1, 46.0, 41.9, 40.4, 40.3, 34.6, 31.5, 31.4, 29.6,
27.4, 24.5, 21.9, 20.7, 17.8, 14.8, 8.9; minor: d 177.1, 151.0,
128.1, 125.7, 125.3, 75.2, 50.1, 46.0, 41.9, 40.8, 40.3, 34.6, 31.4,
31.0, 29.7, 27.4, 24.3, 21.9, 20.7, 17.7, 14.6, 9.0; HRMS-EI m/z
[M]+ calcd for C24H38O2 358.2872, found 358.2931.
(1S,2R,4S)-2-Ethyl-2-methyl-pentanoic acid 1,7,7-tri-
methyl-bicyclo[2.2.1]hept-2-yl ester (3c)
Starting from 2c, the typical procedure for preparing 3a
was followed by using iodoethane as the alkylating reagent. After
chromatographic purification (silica gel, hexane-EtOAc, 100:0,
300:1, 100:1, 70:1), 3c was obtained in 85% yield (dr = 51:49). IR
(neat) 2958, 2937, 1727, 1221, 1152 cm-1; 1H NMR (400 MHz,
CDCl3) major: d 4.80 (t, J = 2.7 Hz, 1H), 2.41-2.30 (m, 1H), 1.93
(dd, J = 9.0, 4.1 Hz, 1H), 1.79-1.70 (m, 1H), 1.70-1.64 (m, 2H),
1.63-1.56 (m, 1H), 1.50-1.26 (m, 4H), 1.23-1.14 (m, 2H), 1.10 (s,
3H), 0.92-0.84 (m, 5H), 0.90 (s, 3H), 0.87 (s, 3H), 0.84-0.80 (m,
5H); minor: d 4.82 (t, J = 2.7 Hz, 1H), 2.41-2.30 (m, 1H), 1.96
(dd, J = 9.1, 4.1 Hz, 1H), 1.79-1.70 (m, 1H), 1.70-1.64 (m, 2H),
1.63-1.56 (m, 1H), 1.50-1.26 (m, 4H), 1.23-1.14 (m, 2H), 1.10 (s,
3H), 0.92-0.84 (m, 5H), 0.90 (s, 3H), 0.87 (s, 3H), 0.84-0.80 (m,
5H); 13C NMR (100 MHz, CDCl3) major: d 177.6, 79.5, 48.7,
47.7, 46.4, 45.0, 41.5, 37.1, 32.1, 28.1, 27.3, 20.6, 19.7, 18.9,
18.0, 14.7, 13.5, 8.9; minor d 177.6, 79.5, 48.7, 47.7, 46.4, 45.0,
41.7, 37.0, 32.2, 28.1, 27.3, 20.6, 19.7, 18.9, 18.0, 14.6, 13.4, 8.9;
HRMS-EI m/z [M]+ calcd for C18H32O2 280.2402, found
280.2398.
(1R,2S)-2-Ethyl-2-methyl-pentanoic acid 2-phenyl-
cyclohexyl ester (3d)
In the same procedure and by using iodomethane as the
alkylting reagent, 3a was also synthesized from 2e in 83% yield
as a 50:50 diastereomeric mixture.
Starting from 2d, the typical procedure for preparing 3a
was followed by using iodoethane as the alkylating reagent. After
chromatographic purification (silica gel, hexane-EtOAc, 100:0,
300:1, 100:1, 70:1), 3d was obtained in 54% yield (dr = 53:47). IR
(neat) 3063, 3029, 2960, 1722, 1221, 1156 cm-1; 1H NMR (400
MHz, CDCl3) major: d 7.25-7.11 (m, 5H), 4.96 (td, J = 9.5, 4.3
Hz, 1H), 2.67 (td, J = 11.7, 3.8 Hz, 1H), 2.13 (dm, J = 12.1 Hz,
1H), 1.92 (dm, J = 13.1 Hz, 1H), 1.88-1.73 (m, 2H), 1.63-1.42 (m,
3H), 1.42-1.28 (m, 3H), 1.27-0.89 (m, 4H), 0.85 (s, 3H), 0.60 (t, J
= 7.0 Hz, 3H), 0.55 (t, J = 7.4 Hz, 3H); minor: d 7.25-7.11 (m,
5H), 4.93 (td, J = 9.5, 4.3 Hz, 1H), 2.67 (td, J = 11.7, 3.8 Hz, 1H),
2.13 (dm, J = 12.1 Hz, 1H), 1.93 (dm, J = 13.1 Hz, 1H), 1.88-1.73
(m, 2H), 1.63-1.42 (m, 3H), 1.42-1.28 (m, 3H), 1.27-0.89 (m,
(1R,2S,5R)-2-Ethyl-2-methyl-pentanoic acid 2-isopro-
pyl-5-methyl-cyclohexyl ester (3b)
Starting from 2b, the typical procedure for preparing 3a
was followed by using iodoethane as the alkylating reagent. After
chromatographic purification (silica gel, hexane-EtOAc, 100:0,
300:1, 100:1), 3b was obtained in 80% yield (dr = 57:43). IR
(neat) 2958, 1724, 1220, 1145 cm-1; 1H NMR (400 MHz, CDCl3)
major: d 4.62 (td, J = 10.9, 1.2 Hz, 1H), 2.03-1.95 (m, 1H), 1.95-
1.85 (m, 1H), 1.73-1.54 (m, 4H), 1.53-1.24 (m, 5H), 1.23-0.09 (m,
1H), 1.07 (s, 3H), 1.06-0.91 (m, 2H), 0.90 (s, 3H), 0.89-0.84 (m,
538
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J. Chin. Chem. Soc. 2013, 60, 531-541

JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
Asymmetric Reductive Alkylation of b-Phosphonyl Esters
4H), 0.84 (s, 3H), 0.73 (t, J = 7.0 Hz, 3H), 0.36 (t, J = 7.4 Hz, 3H);
13C NMR (100 MHz, CDCl3) major: d 176.6, 143.5, 128.3, 127.5,
126.3, 75.7, 49.9, 46.1, 41.5, 34.3, 32.6, 32.1, 25.9, 24.7, 20.2,
17.4, 14.7, 8.5; minor: d 176.6, 143.5, 128.3, 127.6, 126.3, 75.8,
49.9, 46.2, 41.6, 34.1, 32.6, 32.0, 25.9, 24.7, 20.1, 17.5, 14.7, 8.3;
HRMS-EI m/z [M]+ calcd for C20H30O2 302.2246, found 302.2256.
(1R,2S,5R)-2-Ethyl-2-methyl-heptanoic acid 5-methyl-
2-(1-methyl-1-phenyl-ethyl)-cyclohexyl ester (3e)
(1R,2S,5R)-2-Benzyl-2-methyl-butyric acid 5-methyl-2-
(1-methyl-1-phenyl-ethyl)-cyclohexyl ester (3g)
Starting from 2g-1, the typical procedure for preparing 3a
was followed by using iodoetane as the alkylating reagent. After
chromatographic purification (silica gel, hexane-EtOAc, 100:0,
150:1, 100:1), 3g was obtained in 85% yield (dr = 83:17). IR
(neat) 3086, 3060, 2964, 1714, 1601, 1218, 1170 cm-1; 1H NMR
(400 MHz, CDCl3) major: d 7.31-7.12 (m, 10H), 4.88 (td, J =
10.6, 4.2 Hz, 1H), 3.00 (d, J = 13.2 Hz, 1H), 2.61 (d, J = 13.2 Hz,
1H), 2.04-1.92 (m, 2H), 1.70-1.59 (m, 1H), 1.58-1.35 (m, 4H),
1.14 (s, 3H), 1.09 (s, 3H), 0.99-0.92 (m, 2H), 0.94 (s, 3H), 0.91-
0.84 (m, 6H), 0.81-0.71 (m, 1H); minor: d 7.31-7.12 (m, 10H),
4.88 (td, J = 10.6, 4.2 Hz, 1H), 2.77 (d, J = 13.2 Hz, 1H), 2.69 (d, J
= 13.2 Hz, 1H), 2.04-1.92 (m, 2H), 1.70-1.59 (m, 1H), 1.58-1.35
(m, 4H), 1.33 (s, 3H), 1.23 (s, 3H), 0.99-0.92 (m, 2H), 0.96 (s,
3H), 0.91-0.84 (m, 6H), 0.81-0.71 (m, 1H); 13C NMR (100 MHz,
CDCl3) major: d 176.5, 151.2, 138.1, 130.8, 128.0, 127.9, 126.3,
125.5, 125.2, 75.6, 50.0, 47.6, 44.1, 41.9, 40.1, 34.6, 32.6, 31.4,
28.8, 27.3, 24.7, 21.9, 19.9, 9.1; minor: d 176.6, 151.2, 137.8,
130.8, 128.1, 127.8, 126.3, 125.6, 125.3, 75.4, 49.9, 47.2, 44.2,
41.8, 40.2, 34.6, 31.3, 30.9, 28.8, 27.3, 25.2, 21.8, 20.5, 9.3;
HRMS-EI m/z [M]+ calcd for C28H38O2 406.2872, found 406.2872.
3g was similarly prepared from 2g-2 in 74% yield with
81:19 dr.
Starting from 2f, the typical procedure for preparing 3a was
followed by using 1-iodo-pentane as the alkylating reagent. After
chromatographic purification (silica gel, hexane-EtOAc, 100:0,
300:1, 100:1, 70:1), 3e was obtained in 72% yield (dr = 66:34). IR
(neat) 3088, 3022, 2957, 1717, 1236, 1145 cm-1; 1H NMR (400
MHz, CDCl3) major: d 7.34-7.27 (m, 4H), 7.20-7.12 (m, 1H),
4.86 (td, J = 10.5, 4.2 Hz, 1H), 2.02-1.92 (m, 2H), 1.68-1.57 (m,
1H), 1.55-1.34 (m, 5H), 1.36 (s, 3H), 1.34-1.12 (m, 7H), 1.26 (s,
3H), 0.99 (s, 3H), 0.97-0.70 (m, 12H); minor: 7.34-7.27 (m, 4H),
7.20-7.12 (m, 1H), 4.85 (td, J = 10.6, 4.1 Hz, 1H), 2.02-1.92 (m,
2H), 1.68-1.57 (m, 1H), 1.55-1.34 (m, 5H), 1.36 (s, 3H), 1.34-
1.12 (m, 7H), 1.26 (s, 3H), 0.98 (s, 3H), 0.97-0.70 (m, 12H); 13
C
NMR (100 MHz, CDCl3) major: d 177.1, 151.0, 128.0, 125.7,
125.3, 75.2, 50.1, 46.0, 41.9, 40.3, 38.6, 34.6, 32.3, 31.3, 30.1,
29.8, 27.5, 24.2, 24.1, 22.6, 21.8, 20.7, 14.0, 9.0; minor: d 177.1,
151.0, 128.0, 125.7, 125.3, 75.2, 50.1, 46.0, 41.9, 40.3, 38.1, 34.6,
32.5, 31.5, 31.3, 29.6, 27.5, 24.4, 24.2, 22.6, 21.8, 20.6, 14.0, 8.9;
HRMS-EI m/z [M]+ calcd for C26H42O2 386.3185, found 386.3271.
(1R,2S,5R)-2-Ethyl-2-methyl-octanoic acid 5-methyl-2-
(1-methyl-1-phenyl-ethyl)-cyclohexyl ester (3f)
(1R,2S,5R)-2-Cyclohexyl-2-methyl-butyric acid 5-
methyl-2-(1-methyl-1-phenyl-ethyl)-cyclohexyl ester
(3h)
Starting from 2h, the typical procedure for preparing 3a
was followed by using iodoethane as the alkylating reagent. After
chromatographic purification (silica gel, hexane-EtOAc, 100:0,
150:1, 100:1, 70:1), 3h was obtained in 83% yield (dr = 82:18). IR
(neat) 3088, 3057, 2927, 1716, 1226, 1140 cm-1; 1H NMR (400
MHz, CDCl3) major: d 7.34-7.26 (m, 4H), 7.20-7.12 (m, 1H),
4.84 (td, J = 10.5, 4.0 Hz, 1H), 2.11-1.92 (m, 2H), 1.82-1.71 (m,
2H), 1.70-1.59 (m, 3H), 1.58-1.39 (m, 5H), 1.38 (s, 3H), 1.33-
1.18 (m, 3H), 1.24 (s, 3H), 1.17-1.03 (m, 2H), 1.02-0.89 (m, 3H),
0.92 (s, 3H), 0.88-0.73 (m, 1H), 0.85 (d, J = 6.4 Hz, 3H), 0.80 (t, J
= 7.5 Hz, 3H); minor: d 7.34-7.26 (m, 4H), 7.20-7.12 (m, 1H),
4.84 (td, J = 10.5, 4.0 Hz, 1H), 2.11-1.92 (m, 2H), 1.82-1.71 (m,
2H), 1.70-1.59 (m, 3H), 1.58-1.39 (m, 5H), 1.39 (s, 3H), 1.33-
1.18 (m, 3H), 1.24 (s, 3H), 1.17-1.03 (m, 2H), 1.02-0.89 (m, 3H),
0.92 (s, 3H), 0.88-0.73 (m, 1H), 0.85 (d, J = 6.4 Hz, 3H), 0.80 (t, J
= 7.5 Hz, 3H); 13C NMR (100 MHz, CDCl3) major: d 176.8,
151.1, 128.0, 125.6, 125.2, 75.6, 50.1, 49.6, 44.2, 41.8, 40.3, 34.6,
31.4, 29.8, 29.8, 29.0, 27.5, 26.9, 26.9, 26.9, 26.8, 24.1, 21.9,
16.4, 9.1; minor: d 176.8, 151.0, 128.0, 125.6, 125.2, 75.7, 50.2,
49.6, 44.6, 41.9, 40.3, 34.6, 31.4, 30.2, 29.3, 28.6, 27.6, 27.0,
Starting from 2f, the typical procedure for preparing 3a was
followed by using 1-iodo-hexane as the alkylating reagent. After
chromatographic purification (silica gel, hexane-EtOAc, 100:0,
150:1, 100:1), 3f was obtained in 74% yield (dr = 66:34). IR
(neat) 3088, 3057, 2956, 1717, 1241, 1144 cm-1; 1H NMR (400
MHz, CDCl3) major: d 7.32-7.26 (m, 4H), 7.19-7.12 (m, 1H),
4.86 (td, J = 10.6, 4.2 Hz, 1H), 2.23-1.92 (m, 2H), 1.68-1.56 (m,
1H), 1.55-1.35 (m, 5H), 1.36 (s, 3H), 1.34-1.19 (m, 9H), 1.25 (s,
3H), 0.99 (s, 3H), 0.98-0.90 (m, 2H), 0.90-0.71 (m, 10H); minor:
d 7.32-7.26 (m, 4H), 7.19-7.12 (m, 1H), 4.86 (td, J = 10.6, 4.2 Hz,
1H), 2.23-1.92 (m, 2H), 1.68-1.56 (m, 1H), 1.55-1.35 (m, 5H),
1.36 (s, 3H), 1.34-1.19 (m, 9H), 1.25 (s, 3H), 0.99 (s, 3H), 0.98-
0.90 (m, 2H), 0.90-0.71(m, 10H); 13C NMR (100 MHz, CDCl3)
major: d 177.1, 151.0, 128.0, 125.7, 125.3, 75.2, 50.1, 46.0, 41.9,
40.3, 38.6, 34.6, 31.8, 31.3, 31.0, 29.8, 29.8, 27.5, 24.4, 24.1,
22.6, 21.8, 20.7, 14.1, 9.0; minor: d 177.1, 151.0, 128.0, 125.7,
125.3, 75.2, 50.1, 46.0, 41.9, 40.3, 38.2, 34.6, 31.8, 31.4, 31.3,
30.0, 29.6, 27.5, 24.5, 24.4, 22.6, 21.8, 20.6, 14.1, 8.9; HRMS-EI
m/z [M]+ calcd for C27H44O2 400.3341, found 400.3341.
J. Chin. Chem. Soc. 2013, 60, 531-541
© 2013 The Chemical Society Located in Taipei & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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539

Article
Bau et al.
26.9, 26.9, 26.7, 23.8, 21.9, 16.4, 9.3; HRMS-EI m/z [M]+ calcd
for C27H42O2 398.3185, found 398.3227.
2002, 43, 8121. (i) Abe, T.; Suzuki, T.; Sekiguchi, K.;
Hosokawa, S.; Kobayashi, S. Tetrahedron Lett. 2003, 44,
9303. (j) Tomioka, K.; Ando, K.; Takemasa, Y.; Koga, K. J.
Am. Chem. Soc. 1984, 106, 2718, and references cited there-
in.
(+)-2-Ethyl-2-methyl-pentanoic acid (4) prepared from 3a
(dr = 66:34). A stirred suspension of LiAlH4 (131.9 mg, 3.3
mmol) in THF (19 mL) pre-cooled at 0 ºC was added with a solu-
tion of 3a (197.4 mg, 0.55 mmol) in THF (2 mL). The mixture was
continued to stir at rt for 3 h, cooled to 0 ºC, slowly quenched with
5% NaOH aqueous solution (5 mL) and extracted with ether (90
mL ´2). The organic layers were combined and washed with wa-
ter (40 mL ´ 2) and brine (40 mL). After concentration, the resi-
due was subjected to chromatographic purification (silica gel,
hexane-EtOAc, 40:1, 20:1, 15:1) to give the alcohol intermediate
(57.4 mg, 80%). To a stirred solution of alcohol (29.1 mg, 0.223
mmol) in acetone (3 mL) at 0 ºC was dropwise added with 0.375
mL (1.01 mmol) of Jones reagent19 (2.68 M, prepared from 5.34 g
of CrO3, 4.6 mL of conc. H2SO4 and 20 mL of H2O). The mixture
was stirred at 0 ºC for 1 h, diluted with CH2Cl2 (70 mL) and suc-
cessively washed with water (30 mL) and brine (30 mL). After
concentration, the crude residue was purified by chromatography
(silica gel, hexane-EtOAc, 9:1, 4:1) to afford 26.6 mg of 4 (82.5%,
66% over two steps). 1H NMR (400 MHz, CDCl3): d 9.76 (br s,
1H), 1.75-1.56 (m, 2H), 1.54-1.37 (m, 2H), 1.36-1.18 (m, 2H),
3. For reviews, see: (a) Noyori, R. Asymmetric Catalysis in Or-
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Mann, A. Angew. Chem. Int. Ed. 2001, 40, 4591-4597.
4. Esteban, J.; Costa, A. M.; Gómez, À.; Vilarrasa, J. Org. Lett.
2008, 10, 65, and the references cited in 2a.
5. For examples, see: (a) Coates, R. M.; Shah, S. K.; Mason, R.
W. J. Am. Chem. Soc. 1982, 104, 2198. (b) Yu, J.; Cho, H. S.;
Chandrasekhar, S.; Falck, J. R. Tetrahedron Lett. 1994, 35,
5437. (c) Shia, K. S.; Chang, N. Y.; Yip, J.; Liu, H. J. Tetra-
hedron Lett. 1997, 38, 7713. (d) Wu, J. D.; Shia, K. S.; Liu,
H. J. Tetrahedon Lett. 2001, 42, 4207. (e) Evans, P. A.; Ken-
nedy, L. J. Tetrahedon Lett. 2001, 42, 7015. (f) Wolckenhauer,
S. A.; Rychnovsky, S. D. Org. Lett. 2004, 6, 2745. (g) Raubo,
P.; Beer, M. S.; Hunt, P. A. Huscroft, I. T.; London, C.;
Stanton, J. A.; Kulagowski, J. J. Bioorg. Med. Chem. Lett.
2006, 16, 1255. (h) Ko, Y. J.; Zhu, J. L. Synthesis 2007, 3659.
(i) Shibatomi, K.; Futatsugi, K.; Kobayashi, F.; Iwasa, S.;
Yamamoto, H. J. Am. Chem. Soc. 2010, 132, 5625. (j) Wu, Y.
K.; Ly, T. W. Shia, K. S. Curr. Org. Synth. 2010, 78.
6. Manthorpe, J. M.; Gleason, J. L. Angew. Chem. Int. Ed.
2002, 41, 2338-2341. (b) Arpin, A.; Manthorpe, J. M.;
Gleason, J. L. Org. Lett. 2006, 8, 1359.
1.12 (s, 3H), 0.90 (t, J = 7.0 Hz, 3H), 0.87 (t, J = 7.1 Hz, 3H); 13
C
NMR (100 MHz, CDCl3): d 184.3, 46.2, 41.1, 31.7, 20.4, 17.8,
14.6, 8.8; [a]D20 = +4.3 (EtOH). {lit.18 [a]D22 = +16.4, (EtOH )}.
7. Schultz, A. G. Chem. Commun. 1999, 1263.
ACKNOWLEDGEMENTS
8. Liao, C. C.; Zhu, J. L. J. Org. Chem. 2009, 74, 7873.
9. Emura, T.; Esaki, T.; Tachibana, K.; Shimizu, M. J. Org.
Chem. 2006, 71, 8559.
We are grateful to the National Science Council of
Taiwan R.O.C. for financial support (99-2113-M-259-001-
MY2).
10. Hatakeyama, S.; Satoh, K.; Sakurai, K.; Takano, S. Tetrahe-
dron Lett. 1987, 28, 2713.
11. Further decreased temperatures merely gave poorer conver-
sion of 3a in the same dr. Besides, the use of less than 6 equiv
of EtI (e.g. 4 equiv) and/or 5 equiv of LN (e.g. 3 equiv) re-
sulted in inconsistent yields of 3a.
REFERENCES
1. For leading reviews, see: (a) Fuji, K. Chem. Rev. 1993, 93,
2037. (b) Groaning, M. D.; Meyers, A. I. Tetrahedron 2000,
56, 9843. (c) Denissova, I.; Barriault, L. Tetrahedron 2003,
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12. Manthorpe, J. M.; Gleason, J. L. J. Am. Chem. Soc. 2001,
123, 2091.
2. For examples, see: (a) Boeckman, R. K.; Boehmler, D. J.;
Musselman, R. A. Org. Lett. 2001, 3, 3777. (b) Degnan, A.
P.; Meyers, A. I. J. Am. Chem. Soc. 1999, 121, 2762. (c)
Kummer, D. A.; Chain, W. J.; Morales, M. R.; Quiroga, O.;
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Kunisch, F.; Hobert, K.; Welzel, P. Tetrahedron Lett. 1985,
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Quiroga, M. L. J. Org. Chem. 1995, 60, 7934. (f) Jones, M.
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(g) Kobayashi, S.; Hosokawa, S.; Sekiguchi, K.; Enemoto,
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13. Diastereomeric ratio was determined by integration of 400
MHz NMR.
14. Similarly to 3a, the S-configuration of the quaternary carbon
centres of the major isomers of 3e and 3f was confirmed by
converting them into the known optically active acids. The
yield of 2-ethyl-2-methyl-heptanoic acid prepared from 3e
was 74% over two steps. The specific optical rotation was
determined as [a]D = -1.57 (CHCl3). {lit.15 [a]D = -4.8,
(CHCl3) (ee% = 96%)}. The yield of 2-ethyl-2-methyl-
octanoic acid prepared from 3f was 71% over two steps. The
20
25
20
specific optical rotation was determined as [a]D = -1.32
540
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CHEMICAL SOCIETY
Asymmetric Reductive Alkylation of b-Phosphonyl Esters
(EtOH). {lit.15 [a]D25 = -4.0, (EtOH) (ee% = 98%)}.
15. Leuser, H.; Perrone, S.; Liron, F.; Kneisel, F. F.; Knochel, P.
Angew. Chem. Int. Ed. 2005, 44, 4627.
-7.4, (CH2Cl2 ) (ee% = 86%)}. The yield of 2-cyclohexyl-2-
methyl-butyric acid derived from 3h was 69% over two
20
steps. The specific optical rotation was determined as [a]D
16. The absolute configurations of 2g-1 and 2g-2 remain to be
determined.
= +12.6 (benzene). {lit.18 [a]D22 = +21.1, (benzene )}
18. see: (a) Cram, D. J.; Langemann, A.; Allinger, J.; Kopecky,
K. R. J. Am. Chem. Soc. 1959, 81, 5740. (b) Ruano, J. L. G.;
Martín-Castro, A. M.; Tato, F.; Torrente, E.; Poveda, A. M.
Chem. Eur. J. 2010, 16, 6317.
17. Similarly to 3a, the R-configuration of the quaternary carbon
centres of the major isomers of 3g and 3h was confirmed by
converting them into the known optically active acids. The
yield of 2-benzyl-2-methyl-pentanoic acid prepared from
3g-1 was 95% over two steps. The specific optical rotation
19. Nagamitsu, T.; Sunazuka, T.; Tanaka, H.; Omura, S.;
Sprengeler, P. A. Smith III, A. B. J. Am. Chem. Soc. 1996,
118, 3584.
was determined as [a]D = -5.6 (CH2Cl2). {lit.6b [a]D
=
20
25
J. Chin. Chem. Soc. 2013, 60, 531-541
© 2013 The Chemical Society Located in Taipei & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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