Syntheses of (R)- and (S)-3-methylheptanoic acids

Article abstract of DOI:10.1002/cjoc.201400861

Starting from chiral methyl molecules 3 and 4, both derived from (R)-4-methyl-δ-valerolactone, we have accomplished the synthesis of (R) and (S)-3-methylheptanoic acids. Our methods are amendable to the syntheses of a wide variety of chiral 3-methyl alkanoic acids. Both enantiomers of 3-methylheptanoic acid have been synthesized from chiral methyl molecules which were derived from (R)-4-methyl-δ-valerolactone (5). A wide variety of chiral 3-methyl alkanoic acids can also be synthesized by the methods described herein.

Full text of DOI:10.1002/cjoc.201400861

FULL PAPER
DOI: 10.1002/cjoc.201400861
Syntheses of (R)- and (S)-3-Methylheptanoic Acids
Shunji Zhang, Yong Shi,* and Weisheng Tian*
CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, Shanghai 200032, China
Starting from chiral methyl molecules 3 and 4, both derived from (R)-4-methyl-δ-valerolactone, we have ac-
complished the synthesis of (R) and (S)-3-methylheptanoic acids. Our methods are amendable to the syntheses of a
wide variety of chiral 3-methyl alkanoic acids.
Keywords pheromones, chiral pool, natural products, total synthesis, (R)-4-methyl-δ-valerolactone
Introduction
citronellol made the search of its alternatives appealing.
Herein, we reported the syntheses of (S)-1 and (R)-2
from two new chiral pool molecules we recently devel-
oped.
Optically active 3-methyl substituted carboxylic ac-
ids are an important class of structural units in natural
products and building blocks in organic synthesis,
therefore, have received significant attention from re-
search community and resulted in a variety of successful
strategies. For instance, as illustrated in Figure 1,
(S)-3-methylheptanoic acid (1) is a synthetic unit used
in the syntheses of PGI2 (prostacyclin I2) analogues such
as pimilprost and ronoprost, while its enantiomer,
(R)-3-methylheptanoic acid (2) is a constituent of the
abdominal sex-attracting secretion of male Kheper ni-
groaeneus dung beetle.[1] Both 1 and 2 have been syn-
thesized for many times.[1b,2]
Experimental
Methyl (S)-4-methyloctanoate (6)
At ambient temperature, under argon, to a solution of
methyl (R)-5-bromo-4-methylpentanoate (3, 2.03 g, 10
mmol) and N-methylpyrrolidinone (NMP, 3.8 mL, 40
mmol) in anhydous THF (25 mL) was added Li2CuCl4
(1.5 mol•L－1 in THF, 0.66 mL, 1 mmol), then n-PrMgBr
(freshly prepared by refluxing n-PrBr with Mg in THF,
24 mmol, 20 mL) dropwise. Stirring was continued for 4
h and the reaction mixture was quenched with an aque-
ous NH4Cl solution. After decantation, the aqueous lay-
er was extracted with ether and the combined organic
layers were washed with brine, dried over Na2SO4, fil-
tered, and concentrated under reduced pressure. Purifi-
cation by flash column chromatography on silica gel
(PE/EA: 200/1 then 100/1) gave 6 (1.51 g, 8.8 mmol,
O
O
R
S
HO
OH
2
( )-3-methylheptanoic acid (1)
S
(R)-3-methylheptanoic acid ( )
O
CO2Me
O
CO2Me
1
90%) as colorless oil. [α]2D4 ＋1.1 (c 1.14, CHCl3); H
H
H
O
HO
NMR (CDCl3, 300 MHz) δ: 3.67 (s, 3H), 2.33－2.30 (m,
2H), 1.73－1.08 (m, 9H), 0.91－0.86 (m, 6H); 13C
NMR (CDCl3, 75 MHz) δ: 174.6, 51.4, 40.6, 36.3, 32.4,
31.9, 31.9, 29.2, 22.9, 19.3, 14.1; IR (KBr) ν: 2959,
2930, 2874, 2862, 1744, 1460, 1437, 1380, 1261, 1172,
1111, 1020, 807 cm−1; ESIMS m/z: 173 ([M＋H]＋), 195
([M＋Na]＋); HRMS calcd for C10H20O2172.1463, found
172.1463.
OH
Ronoprost
OH
Pimilprost, SM-10902
OH
Figure 1 The structures of (S)- and (R)-3-methylheptanoic acid.
Typical synthetic methods required the use of chiral
auxiliaries and/or sensitive organometallic reagents at
low temperatures, hence, although efficient, were of
limited value for large-scale production. Although Chiu
and co-workers from Pfizer have developed a practical
approach for chiral 1 by functional group manipulation
of optically active citronellol,[2j] the expensiveness of
(S)-4-Methyl-1,1-diphenyloctan-1-ol (7)
To a suspension of Mg (322 mg, 13.4 mmol) in THF
(15 mL) was added a solution of bromobenzene (1.4 mL,
13.3 mmol) in THF (5 mL) dropwise, at ambient tem-
*
E-mail: shiong81@sioc.ac.cn; wstian@sioc.ac.cn
Received December 16, 2014; accepted March 25, 2015; published online May 5, 2015.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201400861 or from the author.
674
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Chin. J. Chem. 2015, 33, 674—678

Syntheses of (R)- and (S)-3-Methylheptanoic Acids
perature, under argon. The mixture was allowed to stir
for 30 min, then added a solution of 6 (990 mg, 5.76
mmol) in THF (5 mL), and stirred for 6 h before being
J＝14.7, 5.1 Hz, 1H), 2.01－1.90 (m, 1H), 1.38－1.17
(m, 6H), 0.97 (d, J＝6.6 Hz, 3H), 0.89 (t, J＝6.6 Hz,
3H); IR (KBr) ν: 2960, 2875, 2671, 1710, 1460, 1413,
1382, 1289, 937, 714 cm−1; ESIMS m/z: 143.0 ([M－
H]－).
quenched with 1.2 mol•L－ HCl. The mixture was ex-
1
tracted with EtOAc for three times and the combined
organic layers were washed with saturated aqueous
NaHCO3 solution and brine, then dried over Na2SO4
and concentrated in vacuo. Flash column chromatogra-
phy on silica gel (PE/EA: 200/1) provided 7 (1.43 g, 4.8
mmol, 84%) as colorless oil. [α]2D4 ＋3.8 (c 1.39,
CHCl3); 1H NMR (CDCl3, 300 MHz) δ: 7.43－7.19 (m,
10H), 2.37－2.18 (m, 2H), 2.13(s, 1H), 1.44－1.06 (m,
9H), 0.88－0.84 (m, 6H); IR (KBr) ν: 3480, 3062, 3026,
2956, 2928, 1494, 1448, 1378, 699 cm−1; EIMS (70 eV)
m/z (%): 183 ([Ph2COH]＋, 100), 278 ([M－H2O]＋, 1).
Anal. calcd for C21H28O: C 85.05, H 9.52; found 85.25,
H 9.50.
4-Methoxyphenyl (S)-3-methylheptanoate (9)
A solution of 4-methoxyphenol (24 mg, 0.19 mmol),
1 (23 mg, 0.16 mmol), DCC (48 mg, 0.23 mmol) and
DMAP (11 mg, 0.1 mmol) was stirred at ambient tem-
perature for 10 h and filtered. The filtrate was washed
with aqueous KOH solution, water, aqueous HOAc so-
lution and water, dried over Na2SO4, and concentrated
in vacuo. Flash column chromatography on silica gel
afforded 9 (33 mg, 83% yield, 91.0% ee). HPLC (chiral)
Chiralpakic AD-H (4.6 cm×250 cm) at 23 ℃, λ＝220
nm, hexane/2-propanol 90/10, retention times 7.48 min
(S), 7.87 min (R) at 0.70 mL/min flow rate. [α]2D2 −2.1
1
(S)-(4-Methyloct-1-ene-1,1-diyl)dibenzene (8)
(c 0.95, CHCl3); HNMR (CDCl3, 300 MHz) δ: 7.01－
Compound 7 (2.865 g, 9.7 mmol) was treated with
TMSCl (0.55 mL, 4.3 mmol) in CH2Cl2 (100 mL) at
ambient temperature for 6 h. The reaction mixture was
concentrated and purified on silica gel (eluted with pen-
tane) to give 8 (2.76 g, 9.7 mmol, 99%) as colorless liq-
6.88 (m, 4H), 3.81 (s, 3H), 2.54 (dd, J＝14.7, 6.0 Hz,
1H), 2.34 (dd, J＝14.7, 8.1 Hz, 1H), 2.14－2.03 (m,
1H), 1.46－1.24 (m, 6H), 1.04 (d, J＝6.9 Hz, 3H), 0.92
(t, J＝6.6 Hz, 3H); 13C NMR (CDCl3, 75 MHz) δ: 172.2,
157.1, 144.2, 122.3, 114.4, 55.6, 41.8, 36.4, 30.5, 29.1,
22.8, 19.7, 14.0; IR (KBr) ν: 2959, 2932, 2874, 2860,
1758, 1507, 1467, 1443, 1380, 1298, 1249, 1197, 1147,
1103, 1036, 838 cm−1; ESIMS m/z: 251.2 ([M＋H]＋),
273.2 ([M＋Na]＋); HRMS-ESI [M＋H]＋ calcd for
C15H23O3 251.1642; found 251.1637.
1
uid. [α]2D3 ＋21.6 (c 1.79, CHCl3); H NMR (CDCl3,
300 MHz) δ: 7.38－7.15 (m, 10H), 6.11 (t, J＝7.5 Hz,
1H), 2.17－1.90 (m, 2H), 1.35－1.05 (m, 7H), 0.89－
0.84 (m, 6H); IR (KBr) ν: 3081, 3058, 3024, 2957, 2927,
2872, 2859, 1599, 1495, 1459, 1444, 1377, 769, 758,
700 cm−1; EIMS m/z (%): 193 ([Ph2CCHCH2]＋, 100),
278 (M＋, 16). Anal. calcd for C21H26: C 90.59, H 9.41;
found C 90.76, H 9.47.
(R)-5-(Methoxymethoxy)-4-methylpentanal (10)
Ester 4 (1.05 g, 5.5 mmol) in anhydrous ether (70
mL) was treated with LiAlH4 (209 mg, 5.5 mmol) at 0
℃for 5 h. The reaction mixture was quenched with
Na2SO4•10H2O, filtered and washed with ether. The
filtrate was concentrated and subjected to flash column
chromatography on silica gel (PE/EA: 5/1) to provide
(R)-5-(methoxymethoxy)-4-methylpentan-1-ol (860 mg,
5.3 mmol, 96%) as colorless oil. [α]2D3 ＋4.4 (c 1.02,
(S)-3-Methylheptanoic acid (1)
Method 1: To a solution of 8 (301 mg, 1.08 mmol) in
tert-butanol (70 mL) was added a solution of NaIO4
(1.38 g, 6.4 mmol) and KMnO4 (57 mg, 0.36 mmol) in
water (200 mL). The pH value of the reaction solution
was adjusted with 5% aqueous K2CO3 solution to 8－9
and the mixture was allowed to stir at ambient tempera-
1
CHCl3); HNMR (CDCl3, 300 MHz) δ: 4.61 (s, 2H),
ture for 6 h and acidified to pH 1－2 with 1.2 mol•L－
3.64 (t, J＝6.6 Hz, 2H), 3.41－3.29 (m, 5H), 1.80－
1.44 (m, 4H), 1.25－1.13 (m, 1H), 0.94 (d, J＝6.9 Hz,
3H); IR (KBr) ν: 3415, 2936, 2880, 2827, 2772, 1465,
1388, 1216, 1151, 1112, 1048, 963, 921 cm−1; ESIMS
m/z: 163.2 ([M＋H]＋). Anal. calcd for C8H18O3: C
59.23, H 11.18; found C 59.45, H 11.37.
To a solution of oxalyl chloride (8 mL, 93 mmol) in
CH2Cl2 (230 mL) cooled at −78 ℃ was added drop-
wise a solution of dimethylsulfoxide (DMSO 13.5 mL,
190 mmol) in CH2Cl2 (20 mL). After 30 min, a solution
of (R)-5-(methoxymethoxy)-4-methylpentan-1-ol (10.0
g, 62 mmol) in CH2Cl2 (30 mL) was added. The reac-
tion mixture was then stirred for 60 min at −78 ℃ and
triethylamine (43 mL, 300 mmol) was added in one por-
tion. After 10 min at −78 ℃, the mixture was allowed
to warm to room temperature, stirred for 3 h, and
quenched with a saturated aqueous solution of NH4Cl.
The mixture was extracted with CH2Cl2 and the com-
1
HCl. The mixture was extracted with EtOAc for three
times and the combined organic layers were washed
with water and brine, dried over Na2SO4, and concen-
trated in vacuo. Flash column chromatography on silica
gel (PE/EA: 100/1) provided 1 (131 mg, 0.91 mmol,
84%) as colorless liquid.
Method 2: A solution of 8 (176 mg, 0.63 mml) in
EtOAc (10 mL) was treated with ozone for 30 min at 0
℃ and 30% H2O2 (10 mL) and 1.2 mol•L－ HCl (10
1
mL) for 8 h at ambient temperature. The mixture was
extracted with ether for three times and the combined
organic layers were washed with water and brine, dried
over Na2SO4, and concentrated in vacuo. Flash column
chromatography on silica gel (PE/EA: 100/1) provided
1 (83 mg, 0.58 mmol, 91%) as colorless liquid. [α]D25
1
−4.6 (c 1.05, CHCl3); H NMR (CDCl3, 300 MHz) δ:
10.48 (s, 1H), 2.36 (dd, J＝15.0, 6.0 Hz, 1H), 2.14 (dd,
Chin. J. Chem. 2015, 33, 674—678
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675

Zhang, Shi & Tian
FULL PAPER
bined organic extracts were washed with water and
brine. The organic layer was dried over MgSO4, filtered,
and concentrated under reduced pressure. Distillation of
the residue under reduced pressure afforded aldehyde 10
(7.98 g, 50 mmol, 81%, 75 ℃/1 mm Hg) as a colorless
1467, 1380, 1256, 1039, 982, 798, 667 cm−1; ESIMS
m/z: 139.1 ([M＋Na]＋).
(R)-2-Methylhexyl 4-methylbenzenesulfonate (13)
Alcohol 12 (2.01 g, 17.4 mmol) was treated with
TsCl (4.24 g, 22.2 mmol) in dry pyridine (20 mL) at
ambient temperature for 36 h. The mixture was poured
into cold diluted aqueous HCl solution and extracted
with ether for three times. The combined organic layers
were washed with a saturated aqueous CuSO4 solution,
water, a saturated aqueous NaHCO3 solution, and brine,
dried over Na2SO4 and filtered. The filtrate was concen-
trated and purified via flash column chromatography on
silica gel (PE/EA: 100/1) to furnish 13 (4.32 g, 16 mmol,
1
oil. [α]2D4 ＋2.9 (c 1.42, CHCl3); HNMR (CDCl3, 300
MHz) δ: 9.76 (t, J＝1.8 Hz, 1H), 4.59 (s, 2H), 3.36－
3.34 (m, 5H), 2.53－2.38 (m, 2H), 1.85－1.69 (m, 2H),
1.54－1.41 (m, 1H), 0.93 (d, J＝6.9 Hz, 3H); IR (KBr)
ν: 3448, 2955, 2933, 2877, 1715, 1460, 1389, 1229,
1188, 1125, 1049, 987, 924 cm ; ESIMS m/z: 178.2
([M＋H2O]＋). Anal. calcd for C8H16O3: C 59.97, H
10.07; found C 59.95, H 9.93.
－
1
1
92%) as colorless oil.[1b] [α]D22 −2.7 (c 1.67, CHCl3); H
(R)-6-(Methoxymethoxy)-5-methylhex-1-ene (11)
To a suspension of methyltriphenylphosponium io-
NMR (CDCl3, 300 Mz) δ: 7.79 (d, J＝8.4 Hz, 2H), 7.35
(d, J＝7.8 Hz, 2H), 3.87 (dd, J＝9.3, 5.7 Hz, 1H), 3.80
(dd, J＝9.0, 6.6 Hz, 1H), 2.45 (s, 3H), 1.82－1.71 (m,
1H), 1.36－1.04 (m, 6H), 0.87 (d, J＝6.9 Hz, 3H), 0.85
(d, J＝7.2 Hz, 3H); IR (KBr) ν: 2961, 2932, 1599, 1362,
1189, 1178, 1098, 966, 832, 814, 792, 667, 556 cm−1;
ESIMS m/z: 293.0 ([M＋Na]＋); HRMS-ESI [M＋Na]＋
calcd for C14H22O3S: 293.1182, found 293.1169.
dide (27.0 g, 66.8 mmol) in dry THF (160 mL) at 0 ℃
under argon was added n-BuLi (24 mL of 2.5 mol•L－
1
solution in hexanes, 60 mmol). The mixture was stirred
for 20 min, and a solution of the aldehyde (7.92 g, 50
mmol) in THF (20 mL) was added over 30 min. The
resulting reaction mixture was stirred for 5 h, quenched
by addition of aqueous ammonium chloride, and the
mixture was diluted with ether. The phases were sepa-
rated, and the aqueous phase extracted with ether twice.
The organic phases were washed with brine, dried over
sodium sulfate, and concentrated in vacuo. The residue
was purified via flash column chromatography on silica
gel (PE/EA: 200/1) to afford alkene 11 (6.738 g, 43
mmol, 86%) as colorless oil. [α]2D3 ＋0.3 (c 1.37,
CHCl3); 1H NMR (CDCl3, 300 MHz) δ: 5.89－5.75 (m,
1H), 5.06－4.93 (m, 2H), 4.62 (s, 2H), 3.43－3.30 (m,
5H), 2.20－1.99 (m, 2H), 1.81－1.70 (m, 1H), 1.60－
1.49 (m, 1H), 1.29－1.17 (m, 1H), 0.95 (d, J＝9.2 Hz,
3H); 13CNMR (CDCl3, 300 MHz) δ: 139.0, 114.3, 96.6,
73.1, 55.1, 32.9, 32.8, 31.2, 17.0; IR (KBr) ν: 3079,
2930, 2884, 2824, 2770, 1642, 1465, 1441, 1387, 1217,
1153, 1112, 1049, 918 cm−1; EIMS m/z (%): 97
([M−MeOMe]＋, 4). Anal. calcd for C9H118O2: C 68.31,
H 11.47; found C 68.11, H 11.44.
(R)-3-Methylheptanenitrile (14)
A solution of 13 (3.704 g, 13.7 mmol) and NaCN
(818 mg, 16.7 mmol) in dry DMSO (20 mL) was stirred
at 30 ℃ under argon for 36 h, then diluted with water
and extracted with ether for three times. The combined
organic layers were washed with water, a saturated
aqueous NaHCO3 solution and brine, dried over Na2SO4,
filtered, and concentrated in vacuo. The residue was
purified via flash column chromatography on silica gel
(PE/EA: 80/1) to afford nitrile 14 (1.69 g, 13.5 mmol,
1
99%) as colorless oil. [α]2D3 −3.1 (c 0.85, CHCl3); H
NMR (CDCl3, 300 MHz) δ: 2.33 (dd, J＝16.5, 5.7 Hz,
1H), 2.24 (dd, J＝16.5, 6.9 Hz, 1H), 1.90－1.77 (m,
1H), 1.48－1.28 (m, 6H), 1.06 (d, J＝6.6 Hz, 3H), 0.90
(t, J＝6.9 Hz, 3H); 13C NMR (CDCl3, 75 MHz) δ: 118.9,
35.6, 30.4, 29.0, 24.5, 22.6, 19.5, 14.0; IR (KBr) ν: 2962,
931, 2875, 2861, 2248, 1463, 1427, 1384, 1348 cm−1;
EIMS m/z (%): 110 ([M−Me]＋, 11), 124 ([M−H]＋, 2);
HRMS-EI [M−Me] ＋ calcd for C7H12N: 110.0970,
found 110.0972.
(R)-2-Methylhexan-1-ol (12)
The alkene 11 (140 mg, 0.89 mmol), 5% Pd/C (29
mg), and MeOH (10 mL) were combined, and the reac-
tion vessel was evacuated and back-filled with hydrogen
(1 atm). The reaction mixture was stirred under hydro-
gen for 12 h and then filtered over a plug of silica gel
topped with Celite (MeOH eluent). To the filtrate was
added concentrated HCl (0.1 mL) and the resulting so-
lution was heated to reflux for 3 h and cooled. After
being neutrilized with saturated NaHCO3, washed with
brine, the organic layer was dried over Na2SO4 and
concentrated in vacuo to afford 12 (85 mg, 0.73 mmol,
83%) as colorless oil.[3] [α]D22 ＋10.8 (c 1.73, CHCl3);
1HNMR (CDCl3, 300Mz) δ: 3.50 (dd, J＝15.9, 5.7 Hz,
1H), 3.42 (dd, J＝10.2, 6.6 Hz, 1H), 1.66－1.58 (m,
1H), 1.46－1.06 (m, 6H), 0.92 (d, J＝6.9 Hz, 3H), 0.90
(d, J＝6.9 Hz, 3H); IR (KBr) ν: 3300, 2959, 2929, 2875,
(R)-3-Methylheptanoic acid (2)
A solution of nitrile 14 (199 mg, 1.6 mmol) in
H2SO4/H2O (6 mL/6 mL) was stirred at reflux for 6 h
and cooled and diluted with water (50 mL). The mixture
was extracted with ether for three times and the com-
bined organic layers were washed with water and brine,
dried over Na2SO4, filtered, and concentrated in vacuo.
Purification via flash column chromatography on silica
gel (PE/EA: 100/1) afforded acid 2 (209 mg, 1.45 mmol,
91%) as a colorless oil. [α]2D3 ＋4.3 (c 1.39, CHCl3); 1H
NMR (CDCl3, 300 MHz) δ: 9.94 (br s, 1H), 2.36 (dd,
J＝15.0, 6.0 Hz, 1H), 2.14 (dd, J＝15.0, 8.1 Hz, 1H),
2.10－1.90 (m, 1H), 1.38－1.16 (m, 6H), 0.97 (d, J＝
676
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Chin. J. Chem. 2015, 33, 674—678

Syntheses of (R)- and (S)-3-Methylheptanoic Acids
6.9 Hz, 3H), 0.89 (t, J＝6.3 Hz, 3H); IR (KBr) ν: 2962,
2932, 2878, 1710, 1466, 1412, 1381, 1300, 1229, 939,
812 cm−1; ESIMS m/z: 167.2 ([M＋Na]＋).
Scheme 1 Retrosynthetic analysis of 1 and 2
O
O
S
R
OH
HO
4-Methoxyphenyl (R)-3-methylheptanoate (15)
2
1
CN substitution
A solution of 4-methoxyphenol (204 mg, 1.65 mmol),
2 (167 mg, 1.16 mmol), DCC (410 mg, 2.0 mmol) and
DMAP (83 mg, 0.7 mmol) was stirred at ambient tem-
perature for 10 h and filtered. The filtrate was washed
with aqueous KOH solution, water, aqueous HOAc so-
lution and water, dried over Na2SO4, and concentrated
in vacuo. Flash column chromatography on silica gel
afforded 15 (263 mg, 1.05 mmol, 91% yield, 95.6% ee).
HPLC (chiral) Chiralpakic AD-H (4.6 cm×250 cm) at
23 ℃, λ＝220 nm, hexane/2-propanol 90/10, retention
times 7.39 min (S), 7.95 min (R) at 0.70 mL/min flow
Wittig;
hydrogenation
Barbier-wieland
degradation
alkylation
MOMO
OMe
O
Br
OMe
O
R
R
3
4
R
Ref. 4
Ref. 4
MOMOM, H2SO4
O
HBr, MeOH
O
5
1
rate. [α]2D2 ＋2.5 (c 1.99, CHCl3); HNMR (CDCl3, 300
Scheme 2 Synthesis of (S)-methylheptanoic acid (1)
MHz) δ: 7.01－6.88 (m, 4H), 3.81 (s, 3H), 2.54 (dd,
J＝14.7, 6.3 Hz, 1H), 2.34 (dd, J＝14.7, 7.8 Hz, 1H),
2.14－2.07 (m, 1H), 1.46－1.24 (m, 6H), 1.04 (d, J＝
6.3 Hz, 3H), 0.92 (t, J＝6.6 Hz, 3H); 13CNMR (CDCl3,
75 MHz) δ: 172.1, 157.2, 144.3, 122.3, 114.5, 55.6, 41.8,
36.4, 30.5, 29.1, 22.8, 19.8, 14.1; IR (KBr) ν: 2959,
2931, 2874, 2860, 1758, 1507, 1467, 1443, 1380, 1298,
1249, 1197, 1146, 1103, 1036, 838 cm−1; ESIMS m/z:
251.2 ([M＋H]＋), 273.1 ([M＋Na]＋); HRMS-ESI [M＋
H]＋ calcd for C15H23O3: 251.1642, found 251.1652.
a
b
OMe
3
O
6
Ph
c
Ph
Ph
Ph
OH
8
7
1
O
O
d
e
S
O
9
(ee 91.0%)
Results and Discussion
Reagents and conditions: (a) n-PrMgBr, Li2CuCl4, NMP, THF, r.t., 4 h,
90%; (b) PhMgBr, THF, r.t., 6 h, 84%; (c) TMSCl, CH2Cl2, r.t., 6 h, 99%;
(d) NaIO4, KMnO4, t-BuOH-H2O, pH 8－9, r.t., 6 h, 84% or O3, EtOAc, 0
In our synthetic plan, as depicted in Scheme 1, both
(S)- and (R)-3-methylheptanoic acids would obtain their
chiral methyl groups from (R)-4-methyl-δ-valerolactone
5, a compound which we obtained from pilot production
of pregnenolone and could be conveniently transformed
into bromoester 3 and MOM-protected hydroxyl ester
4.[4] An alkylation at the left side and a one-carbon con-
traction via Barbier-Wieland degradation[5] at the right
side of bromoester 3 would give 1, while two one-car-
bon expansions, by a CN substitution and a hydrolysis
at the left side and by a Wittig reaction and hydrogena-
tion at the right side, of hydroxylester 4 would provide 2.
All the reactions are routine and scalable.
℃, 30 min, then 30% H2O2, 1.2 mol•L－ HCl, r.t., 8 h, 91%; (e)
1
4-methoxyphenol, DCC, DMAP, CH2Cl2, r.t., 10 h, 83%, 91.0% ee.
(91.0% ee) was obtained by its derivative 9.
The synthesis of the (R)-enantiomer 2 from ester 4 is
shown in Scheme 3. Starting from the right side, reduc-
tion with LiAlH4 followed by Swern oxidation, allowed
to convert ester 4 into aldehyde 10, which underwent
Wittig olefination smoothly to provide alkene 11 in high
yield. Hydrogenation of the double bond and removal of
the MOM ether in 11 gave alcohol 12 whose newly ex-
posed hydroxyl was employed to expand one carbon.
From 12, a three-step sequence involving sulfonylation
(TsCl in pyridine), cyano substitution (NaCN in DMSO)
and hydrolysis of nitrile (reflux in sulfuric acid/water)
gave the desired (R)-methylheptanoic acid 2 over three
steps in 83% yield. The enantiomer excess of 2 was
measured by its derivative 15 to be 95.6%.
As in Scheme 2, the synthesis of (S)-1 started with a
chemoselective Cu(I)-catalyzed alkylation of propyl-
magnesium bromide[6] with bromoester 3 to provide
ester 6 in excellent yield. Then a Barbier-Wieland deg-
radation was employed to remove the extra one carbon
in 6. By reacting with phenylmagnesium bromide, ester
6 was converted into the alcohol 7, which underwent
dehydration effectively in the presence of catalytic
amount of TMSCl in DCM[7] to lead to the diphenyl
alkene 8. Cleavage of the double bond in 8 was
achieved by oxidizing with KMnO4/NaIO4 in t-BuOH-
H2O[8] to provide the desired 1 in 84% yield. Oxidation
of 8 with ozone in EtOAc followed by treatment of the
Conclusions
We have accomplished the synthesis of (S)-3-meth-
ylheptanoic acid 1 from bromoester 3 in four steps with
an overall yield of 68% and the synthesis of (R)-3-meth-
ylheptanoic acid 2 from ester 4 in seven steps with an
overall yield of 46%. Since in the alkylation and
resulting mixture with 30% H2O2/1.2 mol•L－ HCl also
gave 1 in better yield. The optical purity of compound 1
1
Chin. J. Chem. 2015, 33, 674—678
© 2015 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
677

Zhang, Shi & Tian
FULL PAPER
J. Chem. Ecol. 2011, 37, 724.
Scheme 3 Synthesis of (R)-methylheptanoic acid (2)
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(i) Tanaka, T.; Hazato, A.; Bannai, K.; Okamura, N.; Sugiura, S.;
Manabe, K.; Toru, T.; Kurozumi, S.; Suzuki, M.; Kawagishi, T.;
Noyori, R. Tetrahedron 1987, 43, 813; (j) Breitenbach, R.; Chiu, C.
K. F.; Massett, S. S.; Meltz, M.; Murtiashaw, C. W.; Pezzullo, S. L.;
Staigers, T. Tetrahedron: Asymmetry 1996, 7, 435; (k) Norsikian, S.;
Marek, I.; Normant, J.-F. Tetrahedron Lett. 1997, 38, 7523; (l)
Norsikian, S.; Marek, I.; Klein, S.; Poisson, J. F.; Normant, J. F.
Chem. Eur. J. 1999, 5, 2055; (m) Pinheiro, S.; Pedraza, S. F.; Peralta,
M. A.; Teixeira, R. C.; de Farias, F. M. C.; Ferreira, V. F.; Costa, P. R.
R. Tetrahedron: Asymmetry 2002, 13, 2513; (n) Reyes, E.; Vicario, J.
L.; Carrillo, L.; Badía, D.; Uria, U.; Iza, A. J. Org. Chem. 2006, 71,
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[3] Yadav, J. S.; Gayathri, K. U.; Thrimurtulu, N.; Prasad, A. R.
Tetrahedron 2009, 65, 3536.
a, b
c
MOMO
H
MOMO
4
11
O
10
g
d
f
RO
NC
14
12
13
R = H
R = Ts
e
O
h
O
2
O
15
(ee 97.7%)
Reagents and conditions: (a) LiAlH4, Et2O, 0 ℃, 5 h, 96%; (b) DMSO,
(COCl)2, CH2Cl2, −78 ℃, 2.5 h, Et3N, r.t., 3 h, 81%; (c) Ph3PMeI, n-BuLi,
THF, 0 ℃, 20 min, r.t., 5 h, 86%; (d) 5% Pd/C, H2, MeOH, r.t., 12 h; then
HCl, MeOH, reflux, 3 h, 83%; (e) TsCl, pyridine, 0 ℃, 36 h, 92%; (f)
NaCN, DMSO, 30 ℃, 36 h, 99%; (g) H2SO4, H2O, reflux, 6 h, 91%; (e)
4-methoxyphenol, DCC, DMAP, CH2Cl2, r.t., 10 h, 91%, 95.6% ee.
the Wittig olefination steps the length of the carbon
backbone may be easily varied, a wide variety of chiral
3-methyl alkanoic acids (both/either enantiomer) are
presumably accessible. Syntheses of other natural prod-
ucts containing chiral methyl unit are ongoing in this
laboratory.
[4] (a) Tian, W.-S. CN1146457 (A), 1996 [Chem. Abstr. 1998, 128,
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2007, 65, 705.
[5] (a) Wieland, H. Ber. 1912, 45, 484; (b) Barbier, P.; Locquin, R.
Compt. Rend. 1913, 156, 1443.
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© 2015 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2015, 33, 674—678