Asymmetric synthesis of both enantiomers of α-methyl-α-methoxyphenylacetic acid from l-(+)-tartaric acid: formal enantioselective synthesis of insect pheromone (-)-frontalin

Article abstract of DOI:10.1016/j.tetasy.2006.07.007

Both antipodes of α-methyl-α-methoxyarylacetic acid derivatives were prepared from a common chiralpool precursor l-(+)-tartaric acid. The key step involves the addition of Grignard reagents to 1,4-diketones derived from tartaric acid. The utility of this

Full text of DOI:10.1016/j.tetasy.2006.07.007

Tetrahedron: Asymmetry 17 (2006) 1979–1984
Asymmetric synthesis of both enantiomers of
a-methyl-a-methoxyphenylacetic acid from L-(+)-tartaric acid:
formal enantioselective synthesis of insect pheromone (ꢀ)-frontalin
Kavirayani R. Prasad,* Appayee Chandrakumar and Pazhamalai Anbarasan
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India
Received 31 May 2006; accepted 6 July 2006
Available online 4 August 2006
Abstract—Both antipodes of a-methyl-a-methoxyarylacetic acid derivatives were prepared from a common chiralpool precursor L-(+)-
tartaric acid. The key step involves the addition of Grignard reagents to 1,4-diketones derived from tartaric acid. The utility of this stra-
tegy was applied in the formal enantioselective synthesis of pine beetle pheromone (ꢀ)-frontalin.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
The construction of chiral building blocks containing a
quaternary center is a continuing synthetic challenge in
organic chemistry.1 Synthesis of these compounds from
chiral pool precursors is of great advantage because of
the low cost and rich source of chirality associated with
the chiral pool compounds. It would be even more reward-
ing to synthesize both antipodes of the chiral quaternary
compounds from a single abundant chiral source, thus
avoiding the use of unnatural sources. As part of our inter-
est in the synthesis of chiral building blocks from tartaric
acid,2 we herein report the synthesis of a-alkyl-a-methoxy-
arylacetic acid derivatives in both enantiomeric forms
starting from single chiral precursor, that is, L-(+)-tartaric
acid. In addition, the utility of this methodology was
applied in the synthesis of pine beetle pheromone
(ꢀ)-frontalin.
We have recently reported the synthesis of a-methoxyaryl-
acetic acids starting from tartaric acid.3 The synthesis
involves the stereoselective reduction of 1,4-diketone, and
elaboration of the 1,4-diol to the a-methoxyarylacetic acid
derivatives (Scheme 1).
In continuation of our efforts in the extension of this stra-
tegy, we envisaged the synthesis of a-methoxyarylacetic
acids containing quaternary centers from C2-symmetric
1,4-diols 4 and 6 containing 1,4-quaternary centers. As
shown in the retrosynthesis (Scheme 2), the synthesis of
both enantiomers of the a-alkyl, a-methoxyarylacetic acid
was envisaged from the corresponding diastereomerically
different diols 4a and 4b and 6a and 6b. It was intended
to perform the addition of alkyl Grignard reagents to the
1,4-diphenyldiketone 2 leading to the C2-symmetric diols
Ar
Ar
Ar
HO
OMe
O
O
steps
OH
OH
O
O
K-Selectride/18-C-6
THF, -78˚C, 87-93%
or
O
O
O
OMe
Ar
Ar
HO
Ar
2
Scheme 1. Asymmetric synthesis of a-methoxyarylacetic acid derivatives.
*
Corresponding author. Tel.: +91 80 22932578; fax: +91 80 23600529; e-mail: prasad@orgchem.iisc.ernet.in
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.07.007

1980
K. R. Prasad et al. / Tetrahedron: Asymmetry 17 (2006) 1979–1984
MeO
Me
Ph
R
N
O
O
O
O
O
O
O
O
O
PhMgBr
RMgX
O
O
O
Ph
R
3a
3b R = Et
N
Me
OMe
R=Me
2
1
RMgX
PhMgBr
Ph
HO
HO
Ph
R
Ph
R
O
O
O
O
Ph
R
Ph
R
O
OH
OH
O
OMe MeO
enantiomers
OH
OH
R
Ph
R
6a-b
4a
R = Me
4b R = Et
Scheme 2. Retrosynthesis for the synthesis of both antipodes of a-alkyl-a-methoxyarylacetic acids.
4a and 4b, while, the addition of PhMgBr to diketones 3a
and 3b leads to the other C2-symmetric diastereomer 6a
and 6b.
[a]D = +52 (c 1, CHCl3). The enantiomeric purity of acid
11b was found to be >95% as determined by the 1H
NMR of the corresponding menthyl ester within detectable
limits.8 Performing the same transformations on the diaste-
reomeric alcohol 6a afforded the enantiomer of ent-11a
[a]D = +38 (c 1, MeOH) (Scheme 4).9
1,4-Diones 2, 3a, and 3b were synthesized by the addition
of Grignard reagents to the bis-Weinreb amide 1 of tartaric
acid.4 Under the conditions previously optimized by us5 for
the nucleophilic addition reactions to diketones 2 and 3,
addition of methylmagnesium bromide and ethylmagne-
sium bromide to ketone 2 resulted in the formation of dia-
stereomeric alcohols 4a and 5a in 84:16 and 4b and 5b in
75:25 ratios, respectively. While ether solvents favored
higher diastereoselectivity in the addition of MeMgBr to
diketone 2, non-ether solvents, such as dichloromethane,
were found to be better for the addition of EtMgBr. The
diastereomeric alcohols 4a and 5a were separable by col-
umn chromatography, while alcohols 4b and 5b were insep-
arable and were isolated as their corresponding methyl
ethers. To synthesize the other C2-symmetric diastereomers
6a and 6b, addition of PhMgBr to alkyl diketones 3a and
3b was envisaged. Addition of PhMgBr to diketone 3a pro-
ceeded with high diastereoselectivity leading to alcohols
5a:6a in 5:95 ratio, while addition to diketone 3b led to
alcohols 5b:6b in 25:75 ratio (Table 1, Scheme 3).
To demonstrate the synthetic utility of this methodology,
the synthesis of pine beetle pheromone (ꢀ)-frontalin 1610
was undertaken. The pheromone frontalin 16 is an aggre-
gation pheromone produced by Dendroctonus brevicomis,
the western pine beetle, which is a significant pest in the
timber regions of the west coast of North America. It
was anticipated to synthesize quaternary alcohol 15, a
key intermediate in the synthesis of frontalin from the
C2-symmetric tertiary alcohol 13, which in turn can be
obtained by the addition of MeMgBr to diketone 12. Dike-
tone 1211 was prepared by the addition of 4-pentenylmag-
nesium bromide to the bis-Weinreb amide 1 derived from
tartaric acid (Scheme 5).
Thus, the addition of 4-pentenylmagnesium bromide to
bis-Weinreb amide 1 derived from L-(+)-tartaric acid re-
sulted in diketone 12 in 96% yield. The reaction of diketone
12 with MeMgBr in the presence of MgBr2ÆOEt2 in dichlo-
romethane afforded C2-symmetric alcohol 13 in 74% yield,
along with 20% of C1-symmetric isomer. Tertiary alcohol
13 was protected as its benzyl ether, which without further
purification was treated with FeCl3Æ6H2O to yield diol 14 in
40% yield for two steps. Cleavage of the 1,2-diol unit in 14
to the corresponding aldehyde was effected with Pb(OAc)4
and the resultant aldehyde was reduced with NaBH4 to
yield alcohol 15 [a]D = ꢀ4.1 (c 1.1, CHCl3); lit.12
Protection of alcohols 4a and 4b as their methyl ethers 7a
and 7b was performed under standard conditions using
NaH/MeI in DMF. Deprotection of the acetonide6 was
achieved to yield diols 8a and 8b, which underwent smooth
reaction with Pb(OAc)4 to afford the aldehydes, which were
oxidized to the corresponding acids 11a [a]D = ꢀ39 (c 1,
MeOH) {lit.7a [a]D = ꢀ26 (c 1, MeOH) lit.7b [a]D = +37.6
(c 8.8, MeOH) for 97% ee of the enantiomer} and 11b
Table 1. Addition of RMgX to 1,4-diketones 2, 3a, and 3b derived from tartaric acid
S. no.
Ketone
RMgX
Solvent
Temperature (ꢁC)
dr (4:5:6)
Yield (%)
1
2
3
4
2
MeMgBr
EtMgBr
PhMgBr
PhMgBr
Ether
DCM
THF
THF
0
0
84
75
0
16
25
5
0
0
95
75
76a
72b
81a
71b
2
3a
3b
ꢀ78
ꢀ78
0
25
a Isolated yield of the major diastereomer.
b Isolated as the corresponding dimethyl ether.

was described from L-(+)-tartaric acid. Key steps include
K. R. Prasad et al. / Tetrahedron: Asymmetry 17 (2006) 1979–1984
1981
Ph
O
O
RMgX
O
O
Ph
Ph
R
Ph
Ph
R
Ph
Ph
R
Ph
2
O
O
O
O
O
O
OH
OH
OH
OH
OH
OH
R
R
R
R
O
O
4
5
O
O
6
PhMgBr
a
b
R = Me, R = Et
R
3a
3b
R = Me
R = Et
Scheme 3. Addition of Grignard reagents to 1,4-diketones derived from tartaric acid.
Ph
Ph
Ph
R
R
Ph
R
R
R
R
O
O
O
O
O
O
O
MeO
MeO
OMe
OMe
OH
OH
HO
HO
NaH/MeI
DMF, rt, 1h
NaH/MeI
DMF, rt, 1h
O
Ph
7a
Ph
R
Ph
R
Ph
4a
9a
R = Me, 98%
7b R = Et, 97%
R = Me, 71%
9b R = Et, 72%
6a
R = Me
6b R = Et
R = Me
4b R = Et
FeCl3.6H2O
DCM, rt, 30 min
FeCl3.6H2O
DCM, rt, 30 min
Ph
Ph
R
Ph
R
R
Ph
R
Ph R
i) Pb(OAc)4, benzene
rt,1.5 h
HO
HO
O
OH
OH
O
OMe
analogous
8 to11
MeO
MeO
OMe
OMe
ii) NaClO2, NaH2PO4
MeO
OH
OH
ent-11a
tBuOH-H2O,
1.5 h
c-hexene
11a
11b
95%
93%
, 95%
R
Ph
10a
R = Me, 79%
8a
R = Me, 79%
8b R = Et, 93%
Scheme 4. Synthesis of both enantiomers of a-alkyl-a-methoxyaryl acetic acids.
HO Me
BnO Me
OH
the stereoselective addition of Grignard reagents to 1,4-
diketones derived from tartaric acid. Application of these
building blocks containing a quaternary carbon center
was illustrated in the synthesis of pine beetle pheromone
frontalin.
O
O
O
3
O
3
frontalin 16
HO Me
15
13
Me
OMe
O
N
N
O
O
O
O
O
3
O
4. Experimental
3
O
12
MeO
Me
4.1. General procedures
1
Scheme 5. Retrosynthesis for the synthesis of (ꢀ)-frontalin.
Column chromatography was performed on silica gel,
Acme grade 100–200 mesh. TLC plates were visualized
either with UV, in an iodine chamber, or with phospho-
molybdic acid spray, unless noted otherwise. Unless
stated otherwise, all reagents were purchased from
commercial sources and used without additional purifica-
tion. THF was freshly distilled over Na-benzophenone
ketyl. Melting points were uncorrected. Unless stated
otherwise, all the reactions were performed under inert
atmosphere. Compounds 2, 3a,b were prepared according
to the literature procedure.4b Preparation of 1,4-diols 4a,b
and 6a,b was achieved according to the procedure
reported.5
[a]D = ꢀ3.6 (c 1, CHCl3) in 90% yield for two steps
(Scheme 6). Conversion of 15 to frontalin is known in
the literature12 using Wacker oxidation and deprotection
of the benzyl group. Thus the present sequence constitutes
a formal synthesis of (ꢀ)-frontalin.
3. Conclusion
In conclusion, an enantioselective approach to both enan-
tiomers of a-alkyl-a-methoxyarylacetic acid derivatives

1982
K. R. Prasad et al. / Tetrahedron: Asymmetry 17 (2006) 1979–1984
Me
OMe
O
N
N
HO Me
O
O
O
O
MgBr
MeMgBr, MgBr2.OEt2
O
O
3
−
DCM, 78˚ C, 3.5 h
THF, 0 °C, 1 h, 94%
O
O
3
74%
Me OH
O
MeO
Me
13
12
1
BnO Me
HO
i) Pb(OAc)4
BnO Me
i) NaH, DMF
O
ref. 12
benzene, rt, 1.5 h
ii) NaBH4/MeOH
0 ºC, 1 h
BnCl, rt, 4 h
ii) FeCl3. 6H2O
DCM, rt, 4 h
3
O
HO
OH
frontalin 16
3
15
Me OBn
90% for two steps
40% for two steps
14
Scheme 6. Stereoselective synthesis of (ꢀ)-frontalin.
4.2. General procedure for the preparation of 4,5-bis-
(1-methoxy-1-phenylalkyl)-2,2-dimethyl-1,3-dioxolanes
7a and 7b, and 9a and 9b
(m, 2H), 1.57–1.44 (m, 2H), 1.08 (s, 6H), 0.72 (t, 6H,
J = 7.2 Hz); 13C NMR (75 MHz, CDCl3): d 141.6, 127.9,
127.6, 126.9, 109.2, 83.2, 81.8, 50.5, 27.6, 24.9, 8.3; HRMS
for C25H34O4+Na calcd 421.2355; found 421.2356.
In an oven dried two-neck round-bottom flask equipped
with a magnetic stir bar, guard tube and a stopper was
placed
4.2.4. (4R,5R)-4,5-Bis((R)-1-methoxy-1-phenylpropyl)-2,2-
dimethyl-1,3-dioxolane 9b. Colorless oil, yield 72%;
[a]D = ꢀ32.5 (c 1.2, CHCl3); IR (neat): 2935, 1493, 1446,
a,a0,2,2-dialkyl-a,a0-diphenyl-1,3-dioxolane-4,5-
dimethanol 4a or 4b, 6a or 6b (0.5 mmol). This was dis-
solved in 2 mL of DMF. It was cooled to 0 ꢁC and NaH
(0.076 g, 2 mmol, 60% suspension in oil) was introduced
portionwise. The reaction mixture was stirred for 1 h at
the same temperature and CH3I (0.2 mL, 3.2 mmol) was
added dropwise. The reaction mixture was slowly warmed
up to room temperature over the course of 1 h. After the
reaction was complete (monitored by TLC), it was cau-
tiously quenched with saturated solution of NH4Cl and ex-
tracted with diethyl ether (3 · 10 mL). The combined ether
extract was washed with brine (30 mL), dried over Na2SO4,
filtered, and concentrated. Silica gel chromatography of the
residue yielded 4,5-bis(1-methoxy-1-phenylalkyl)-2,2-di-
methyl-1,3-dioxolanes 7 and 9.
1
1219, 1082, 887, 702 cmꢀ1; H NMR (300 MHz, CDCl3):
d 7.41–7.19 (m, 10H), 4.03 (s, 2H), 3.20 (s, 6H), 2.29–2.16
(m, 2H), 2.03–1.89 (m, 2H), 0.89 (t, 6H, J = 7.2 Hz), 0.80
(s, 6H); 13C NMR (75 MHz, CDCl3): d 141.0, 128.7,
127.2, 126.7, 107.7, 81.6, 79.5, 50.4, 27.3, 26.2, 7.4; HRMS
for C25H34O4+Na calcd 421.2355; found 421.2334.
4.2.5. General procedure for the preparation of 1,4-dime-
thoxy-1,4-diphenyl-1,4-dialkylbutane-2,3-diol. In a single-
neck round-bottom flask equipped with a magnetic stirrer
bar and a guard tube was placed a solution of 4,5-bis-
(1-methoxy-1-phenylalkyl)-2,2-dimethyl-1,3-dioxolane
7
and 9 (0.4 mmol) in CH2Cl2 (5 mL). FeCl3Æ6H2O (0.38 g,
1.4 mmol) was introduced into the flask at room tempera-
ture. The resulting yellow colored suspension was stirred
for 30 min and after the reaction was complete (monitored
by TLC), it was quenched by the addition of saturated
solution of NaHCO3. The aqueous layer was extracted
with diethyl ether (3 · 10 mL), and the combined organic
layers were washed with brine, dried over Na2SO4, and
concentrated. Silica gel column chromatography of the
residue afforded 1,4-dimethoxy-1,4-diphenyl-1,4-dialkyl-
butane-2,3-diol (8 and 10).
4.2.1.
(4R,5R)-4,5-Bis((S)-1-methoxy-1-phenylethyl)-2,2-
dimethyl-1,3-dioxolane 7a. Colorless oil, yield 97%;
[a]D = +25.7 (c 0.7, CHCl3); IR (neat): 3086, 2981, 1494,
1
1445, 1240, 1160, 1076, 868 cmꢀ1; H NMR (300 MHz,
CDCl3): d 7.17–7.06 (m, 10H), 4.31 (s, 2H), 3.01 (s, 6H),
1.44 (s, 6H), 1.38 (s, 6H); 13C NMR (75 MHz, CDCl3): d
141.7, 127.9, 126.8, 111.7, 85.0, 50.0, 28.0, 19.5; HRMS
for C23H30O4+Na calcd 393.2042; found 393.2054.
4.2.2.
(4R,5R)-4,5-Bis((R)-1-methoxy-1-phenylethyl)-2,2-
dimethyl-1,3-dioxolane 9a. Colorless oil, yield 98%;
[a]D = ꢀ80 (c 0.5, CHCl3); IR (neat): 2983, 1445, 1376,
4.2.6. (2S,3R,4R,5S)-2,5-Dimethoxy-2,5-diphenylhexane-
3,4-diol 8a. White solid, yield 79%; mp 104.6–105.6 ꢁC;
[a]D = +70 (c 0.5, CHCl3); IR (neat): 3492, 2941, 1494,
1241, 1164, 1103, 1074, 863, 776 cmꢀ1
;
1H NMR
1
(300 MHz, CDCl3): d 7.32–7.22 (m, 10H), 4.18 (s, 2H),
3.05 (s, 6H), 1.32 (s, 6H), 1.26 (s, 6H); 13C NMR
(75 MHz, CDCl3): d 141.6, 128.0, 127.8, 127.2, 111.6,
85.5, 80.4, 50.3, 28.0, 19.4; HRMS for C23H30O4+Na calcd
393.2042; found 393.2045.
1445, 1372, 1163, 1073, 763 cmꢀ1; H NMR (300 MHz,
CDCl3): d 7.25–7.06 (m, 10H), 3.62 (d, 2H, J = 3.6 Hz),
3.47 (d, 2H, J = 3.6 Hz), 3.20 (s, 6H), 1.55 (s, 6H); 13C
NMR (75 MHz, CDCl3): d 142.4, 128.1, 126.8, 126.2,
83.2, 74.8, 51.1, 19.5. Anal. Calcd for C, 72.70; H, 7.93.
Found C, 72.79; H, 8.00.
4.2.3. (4R,5R)-4,5-Bis((S)-1-methoxy-1-phenylpropyl)-2,2-
dimethyl-1,3-dioxolane 7b. Colorless oil, yield 71%;
[a]D = ꢀ38 (c 0.5, CHCl3); IR (neat): 2981, 1446, 1377,
4.2.7. (2R,3R,4R,5R)-2,5-Dimethoxy-2,5-diphenylhexane-
3,4-diol 10a. Viscous mass, yield 79%; [a]D = ꢀ48 (c 0.5,
CHCl3); IR (neat): 3463, 2936, 1558, 1541, 1457, 1373,
1242, 1213, 1079 cmꢀ1 1H NMR (300 MHz, CDCl3): d
;
7.32–7.21 (m, 10H), 4.33 (s, 2H), 3.24 (s, 6H), 1.83–1.71
1159, 1103, 1071, 761, 700 cmꢀ1 1H NMR (300 MHz,
;

K. R. Prasad et al. / Tetrahedron: Asymmetry 17 (2006) 1979–1984
1983
CDCl3): d 7.19–7.04 (m, 10H), 3.51 (d, 2H, J = 3.9 Hz),
3.03 (d, 2H, J = 3.9 Hz), 2.94 (s, 6H), 1.54 (s, 6H); 13C
NMR (75 MHz, CDCl3): d 140.9, 128.1, 127.2, 127.1,
82.1, 74.5, 50.0, 16.1; HRMS for C20H26O4+Na calcd
353.1729; found 353.1738.
NMR (300 MHz, CDCl3): d 7.48–7.30 (m, 5H), 3.20 (s,
3H), 2.56–2.44 (m, 1H), 2.23–2.10 (m, 1H), 0.94 (t, 6H,
J = 7.2 Hz); 13C NMR (75 MHz, CDCl3): d 174.5, 137.9,
128.6, 128.5, 126.5, 84.5, 51.0, 25.0, 7.4.
4.2.13. Preparation of (4R,5R)-4,5-bis(hex-5-enoyl)-2,2-
dimethyl-1,3-dioxolane 12. In an oven dried two neck
50 mL round-bottom flask equipped with a magnetic stir
bar and an argon inlet was placed the bis-Weinreb amide
1 (0.5 g, 1.8 mmol) dissolved in 6 mL of THF. This was
cooled to 0 ꢁC and a THF solution of 4-pentenylmagne-
sium bromide (7 mL of 1 M solution in THF, 7 mmol)
was added dropwise under an argon atmosphere. The reac-
tion was stirred for 1 h, quenched with satd NH4Cl (10 mL)
and extracted with ether (2 · 10 mL). The combined organ-
ic layers were washed with brine and dried over Na2SO4.
The residue obtained after the evaporation of solvent was
purified by column chromatography to yield 12 in 96%
(0.51 g) as a colorless oil. [a]D = +11.6 (c 1.2, CHCl3); IR
(neat): 2937, 1725, 1455, 1375, 1259, 1153, 995, 914,
4.2.8.
(2S,3R,4R,5S)-3,6-Dimethoxy-3,6-diphenyloctane-
4,5-diol 8b. Viscous mass, yield 93%; [a]D = ꢀ16.3 (c
0.8, CHCl3); IR (neat): 3467, 2974, 1446, 1155, 1055, 758,
700 cmꢀ1; H NMR (300 MHz, CDCl3): d 7.29–7.07 (m,
1
10H), 3.82 (d, 2H, J = 1.8 Hz), 3.56 (d, 2H, J = 1.8 Hz),
3.54 (s, 6H), 2.49–2.31 (m, 2H), 1.68–1.56 (m, 2H), 0.53
(t, 6H, J = 7.2 Hz); 13C NMR (75 MHz, CDCl3): d 141.6,
128.0, 126.6, 126.2, 84.6, 75.9, 52.8, 25.3, 7.7; HRMS for
C22H30O4+Na calcd 381.2042; found 381.2029.
4.2.9. General procedure for the preparation of 2-methoxy-2-
phenylalkanoic acid. To a solution of diol 8a or 10a or 10b
(0.21 mmol) in 2 mL of benzene at room temperature was
added Pb(OAc)4 (0.23 g, 0.52 mmol) under argon atmo-
sphere. The reaction mixture was stirred for 1.5 h at the
same temperature and filtered through a short pad of Cel-
ite. The Celite pad was washed with ether (15 mL) and the
ether layers were combined. After removal of the solvent,
the crude residue of the aldehyde was subjected to oxida-
tion without further purification.
1
860 cmꢀ1; H NMR (300 MHz, CDCl3): d 5.77 (ddt, 2H,
J = 17.1, 10.2, 6.6 Hz), 5.06–4.96 (m, 4H), 4.55 (s, 2H),
2.75–2.56 (m, 4H), 2.12–2.05 (m, 4H), 1.77–1.67 (m, 4H),
1.42 (s, 6H); 13C NMR (75 MHz, CDCl3): d 208.4, 137.8,
115.3, 112.4, 81.4, 38.2, 32.9, 26.1, 22.1; HRMS for
C17H26O4+Na calcd 317.1729; found 317.1742.
A solution of the crude aldehyde (obtained above) dis-
solved in cyclohexene (1.2 mL) and tert-BuOH (12 mL)
was added to a solution of NaClO2 (0.15 g, 1.7 mmol)
and NaH2PO4 (0.20 g, 1.7 mmol) in water (6 mL). The
resultant solution was stirred for 3.5 h at room tempera-
ture. It was extracted with ethyl acetate (3 · 10 mL) and
the combined extracts were dried over Na2SO4, filtered,
and concentrated to yield the acid. An analytically pure
sample was obtained by NaHCO3 extraction of an organic
layer of the crude acid and acidification of the bicarbonate
layer and extraction with ethylacetate.
4.2.14. Preparation of (4R,5R)-4,5-bis((S)-2-hydroxyhept-6-
en-2-yl)-2,2-dimethyl-1,3-dioxolane 13. In an oven dried
two-neck round-bottom flask equipped with a magnetic stir
bar, septa and argon inlet were placed diketone 12 (0.5 g,
1.7 mmol) and MgBr2ÆEt2O (1.3 g, 5 mmol) in 4mL of
DCM. It was stirred for 1 h at ꢀ78 ꢁC, and a solution of
MeMgBr (2.2 mL of 3 M solution in ether, 6.6 mmol)
was introduced dropwise with the aid of a syringe. The
reaction mixture was stirred for further 2.5 h at the same
temperature, and after the reaction was complete (TLC),
it was quenched by the addition of satd NH4Cl. It was then
extracted with ether (2 · 20 mL) and the combined ethereal
layers were washed with brine and dried over Na2SO4. The
residue obtained after evaporation of the solvent was puri-
fied by column chromatography to yield diastereomeric
diol 13 in 74% (0.41 g) as a colorless oil. [a]D = ꢀ5 (c
2.7, CHCl3); IR (neat): 3295, 2981, 1459, 1376, 1240,
4.2.10. (S)-2-Methoxy-2-phenylpropanoic acid 11a. Vis-
cous mass, yield 95% for two steps; [a]D = +38 (c 1,
MeOH); IR (neat): 3693–3065 (br), 2925, 1726, 1495,
1
1455, 1104, 989, 721 cmꢀ1; H NMR (300 MHz, CDCl3):
d 7.49–7.30 (m, 5H), 6.52 (br s, 1H), 3.27 (s, 3H), 1.84 (s,
3H); 13C NMR (75 MHz, CDCl3): d 175.7, 138.9, 128.6,
128.4, 126.2, 81.3, 51.7, 20.7; HRMS for C10H12O3+Na
calcd 203.0684; found 203.0687.
1
1064, 910, 889 cmꢀ1; H NMR (400 MHz, CDCl3): d 5.83
(ddt, 2H, J = 17.0, 10.2, 6.6 Hz), 5.06–4.92 (m, 4H), 3.82
(s, 2H), 3.57–3.60 (br s, 2H), 2.12–2.02 (m, 4H), 1.65–
1.45 (m, 8H), 1.35 (s, 6H), 1.22 (s, 6H); 13C NMR
(100 MHz, CDCl3): d 138.9, 114.5, 107.4, 80.4, 72.0, 40.9,
34.1, 27.2, 22.0, 21.9; HRMS for C19H34O4+Na calcd
349.2355; found 349.2356.
4.2.11. (R)-2-Methoxy-2-phenylpropanoic acid ent-11a.
Viscous mass, yield 95% for two steps; [a]D = ꢀ39 (c 1,
MeOH) {lit.7a [a]D = +37.6 (c 8.8, MeOH) for 97% ee of
the enantiomer lit.7b [a]D = ꢀ26 (c 1, MeOH)}; IR (neat):
3693–3065 (br), 2942, 1719, 1495, 1447, 1144, 1074, 1046,
4.2.15. Preparation of (6S,7R,8R,9S)-6,9-bis(benzyloxy)-
6,9-dimethyltetradeca-1,13-diene-7,8-diol 14. In an oven
dried 25 mL two-neck round-bottom flask equipped with
a guard tube and a stopper was placed a solution of 13
(0.4 g, 1.2 mmol) in 5 mL of DMF. This was cooled to
0 ꢁC and NaH (0.29 g, 7.3 mmol, 60% suspension in min-
eral oil) was added portionwise. The reaction mixture
was stirred for 1 h at room temperature. The mixture was
then cooled to 0 ꢁC and benzyl bromide (0.9 mL,
7.5 mmol) added dropwise. The reaction mixture was
1
721 cmꢀ1; H NMR (300 MHz, CDCl3): d 7.49–7.30 (m,
5H), 6.52 (br s, 1H), 3.27 (s, 3H), 1.84 (s, 3H); 13C NMR
(75 MHz, CDCl3): d 175.8, 138.9, 128.6, 128.4, 126.2,
81.3, 51.7, 20.7; HRMS for C10H12O3+Na calcd
203.0684; found 203.0687.
4.2.12. (S)-2-Methoxy-2-phenylbutanoic acid 11b. Viscous
mass, yield 93% for two steps; [a]D = +52 (c 1, CHCl3); IR
1
(neat): 3222, 2952, 1718, 1448, 1145, 1058, 721 cmꢀ1; H

1984
K. R. Prasad et al. / Tetrahedron: Asymmetry 17 (2006) 1979–1984
warmed up to RT and stirred at room temperature for 3 h.
After the reaction was complete (TLC), it was quenched
with cautious addition of water (5 mL) and extracted with
ether (2 · 20 mL). The combined ether layer was washed
with brine and dried over Na2SO4. The residue obtained
after the evaporation of solvent was used as such for the
next step.
114.8, 77.6, 67.3, 63.6, 34.8, 34.2, 22.9, 20.1; HRMS for
C15H22O2+Na calcd 257.1517; found 257.1515.
Acknowledgements
We thank DST, New Delhi, for funding of this project.
A.C.K. and P.A. thank CSIR for a research fellowship.
To a DCM (4 mL) solution of crude product obtained
above was added FeCl3Æ6H2O at room temperature, under
argon atmosphere. The reaction mixture was stirred for 4 h
during which time the reaction was complete (TLC). It was
filtered through a short pad of Celite and the Celite pad
washed with ether (10 mL). To the ether layer, solid NaH-
CO3 and a few drops of water were added and stirred for
10 min, to remove the iron impurities. It was then filtered,
and dried over Na2SO4. Evaporation of the solvent fol-
lowed by column chromatography of the crude residue
afforded 1,2-diol 14 (0.23 g) in 40% yield as a colorless
oil. [a]D = ꢀ12.2 (c 2.7, CHCl3); IR (neat): 3492, 2940,
References
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1413, 1382, 1106, 1056, 910, 734, 696 cmꢀ1 1H NMR
;
(300 MHz, CDCl3): d 7.36–7.21 (m, 10H), 5.74 (ddt, 2H,
J = 17.4, 10.2, 6.6 Hz), 5.03–4.90 (m, 4H), 4.47 (d, 2H,
J = 11.4 Hz), 4.42 (d, 2H, J = 11.4 Hz), 3.88 (d, 2H, J =
5.4 Hz), 3.08 (d, 2H, J = 5.4 Hz), 2.09–1.95 (m 4H), 1.82–
1.20 (m, 8H), 1.30 (s, 6H); 13C NMR (75 MHz, CDCl3):
d 139.2, 138.7, 128.3, 127.3, 114.6, 80.4, 70.7, 63.6, 34.7,
34.2, 22.6, 19.3; HRMS calcd for C33H42O4+Na
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8. Use of both antipodes of acids 11a in the enantiomeric excess
determination of secondary alcohols and amines was
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4.2.16. Preparation of (S)-2-(benzyloxy)-2-methylhept-6-en-
1-ol 15. To a solution of 1,2-diol 15 (0.2 g, 0.4 mmol) in
3 mL of benzene at room temperature was added Pb(OAc)4
(0.38 g, 0.8 mmol) under argon atmosphere. The reaction
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pad of Celite. The Celite pad was washed with DCM
(10 mL). Evaporation of dichloromethane yielded the
crude aldehyde which was dissolved in 2 mL of MeOH.
It was cooled to 0 ꢁC and NaBH4 (30 mg, 0.8 mmol) was
added at the same temperature. The reaction mixture was
stirred for 1 h at 0 ꢁC and was cautiously quenched with
water and extracted with ether (2 · 20 mL). The combined
ether layer was washed with brine and dried over Na2SO4.
Residue obtained after evaporation of the solvent was puri-
fied by column chromatography to yield alcohol 15 (0.18 g,
90%) as a colorless oil. [a]D = ꢀ4.1 (c 1.1, CHCl3); lit.12
[a]D = ꢀ3.6 (c 1, CHCl3); IR (neat): 3442, 2973, 2938,
_
Kowalczyk, R.; Skarzewski, J. Tetrahedron: Asymmetry
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inseparable mixture of diastereomers. Formation of monom-
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dimethyl ether 9b through a SN1 process involving a
carbocation. Further investigations concerning the anomaly
of the reactivity of the diastereomers are underway.
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Tetrahedron: Asymmetry 2005, 15, 3951.
1496, 1380, 1060, 910, 734, 696 cmꢀ1
;
1H NMR
(300 MHz, CDCl3): d 7.36–7.23 (m, 5H), 5.81 (ddt, 1H,
J = 17.1, 10.5, 6.6 Hz), 5.07–4.92 (m, 2H), 4.43 (s, 2H),
3.57 (d, 1H, J = 11.4 Hz), 3.48 (d, 1H, J = 11.4 Hz),
2.12–2.01 (m, 2H), 1.69–1.16 (m, 4H), 1.24 (s, 3H); 13C
NMR (75 MHz, CDCl3): d 139.1, 138.5, 128.4, 127.4,
12. Kang, S.-K.; Rho, S.-H.; Namkoong, E.-Y. Bull. Korean
Chem. Soc. 1995, 16, 191.