Synthesis of the racemate and both enantiomers of massoilactone

Article abstract of DOI:10.1271/bbb.67.2210

A simple and efficient synthesis of (±)-massoilactone (1) as a key substance for the butter and milk flavor was accomplished from n-hexanal in only a few steps. Application of its racemic synthesis enabled natural (R)-(-)-and unnatural (S)-(+)-massoilacto

Full text of DOI:10.1271/bbb.67.2210

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Synthesis of the Racemate and Both Enantiomers of
Massoilactone
Masashi ISHIKAWAa, Masayasu AMAIKEa, Masamichi ITOHa, Yasuhiro WARITAa & Takeshi
KITAHARAb
a Technical Research Center, T. Hasegawa Co., Ltd.335 Kariyado, Nakahara-ku, Kawasaki
211-0022, Japan
b Department of Applied Biological Chemistry, Graduate School of Agricultural and Life
Sciences, The University of Tokyo1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan
Published online: 22 May 2014.
To cite this article: Masashi ISHIKAWA, Masayasu AMAIKE, Masamichi ITOH, Yasuhiro WARITA & Takeshi KITAHARA (2003)
Synthesis of the Racemate and Both Enantiomers of Massoilactone, Bioscience, Biotechnology, and Biochemistry, 67:10,
2210-2214, DOI: 10.1271/bbb.67.2210
To link to this article: http://dx.doi.org/10.1271/bbb.67.2210
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Biosci. Biotechnol. Biochem., 67 (10), 2210–2214, 2003
Synthesis of the Racemate and Both Enantiomers of Massoilactone
Masashi ISHIKAWA,1 Masayasu AMAIKE,1 Masamichi ITOH,1 Yasuhiro WARITA,1,õ
2
and Takeshi KITAHARA
1Technical Research Center, T. Hasegawa Co., Ltd., 335 Kariyado, Nakahara-ku, Kawasaki 211-0022, Japan
2Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences,
The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan
Received May 22, 2003; Accepted June 30, 2003
A simple and e‹cient synthesis of (})-massoilactone
(1) as a key substance for the butter and milk ‰avor was
accomplished from n-hexanal in only a few steps. Appli-
Fig. 1. Structures of the Racemate and Both Enantiomers of
cation of its racemic synthesis enabled natural (R)-(|)-
Massoilactone.
and unnatural (S)-({)-massoilactone (1a, 1b) to be
synthesized by starting from commercially available
(R)-({)-1,2-epoxyheptane (5).
Results and Discussion
Key words: massoilactone;
(R)-({)-1,2-epoxyhep-
Synthesis of (})-massoilactone (1)
tane; Mitsunobu inversion; ‰avor
Our synthetic plan for 1 was based on using eco-
nomical raw materials and employing a short-step
industrial procedure. We therefore selected n-hex-
anal for the C-6 unit, allyl chloride for the C-3 unit
and NaCN for the C-1 unit as the raw materials.
(})-1-Nonen-4-ol (2), which was easily prepared by
Grignard reaction of n-hexanal with allyl magnesium
chloride29) in THF, was used as the starting material.
Epoxidation30) of homoallylic alcohol 2 was achieved
with 40z AcOOH in the presence of NaOAc in tol-
uene to give (})-epoxy alcohol 3 in a good yield.
In 1937, Abe1) ˆrst found (|)-massoilactone (1a)
from the bark oil of Cryptocarya massoia which
grows wild in New Guinea and has been traditionally
used for many centuries as a constituent of native
medicines. (|)-Massoilactone (1a) was later isolated
as a defense substance from two species of formicine
ants of the genus Camponotus collected in Western
Australia,2) and as a ‰avor substance from cane
molasses3) and tuberose ‰owers.4) This lactone 1a has
also been shown to occur in Hierochloe odorata and
Hierochloe australis, both being commonly used in
vodka production.5) Its structure was conˆrmed to be
1 by the synthesis of its racemate,6,7) and the absolute
conˆguration of natural 1a was determined as (R)-
form by the unambiguous synthesis of its unnatural
(S)-isomer 1b.8) Many reports on the synthesis of the
racemate (1)9–14) and both enantiomers (1a and 1b)
have been published. The literature shows that vari-
ous asymmetric syntheses of both 1a and 1b utilized
optically active starting materials15–26) and optical
resolution of the diastereomeric derivatives.27,28)
Since the industrial use of massoilactone, which is
very useful as a butter and milk ‰avor, has recently
been increasing, substantial eŠort has been devoted
to its synthesis. We now describe an e‹cient and
industrial synthesis of 1 starting from n-hexanal, and
an asymmetric synthesis of 1a and 1b starting from
commercially available (R)-({)-1,2-epoxyheptane
(5)20,21) that applies the synthetic method for 1.
Subsequent cyanation31) of 3 with NaCN AcOH in
W
EtOH aq. aŠorded (})-dihydroxy cyanide 4 as the
sole product in a quantitative yield. Finally, the reac-
tion of 4 with 1.2 equivalent of conc. HCl under gen-
tle re‰ux proceeded smoothly to give the desired
(})-massoilactone (1) in a 67z yield. Thus, a simple
and industrially suitable synthesis of 1 was estab-
lished in a 46z overall yield with only four steps
from n-hexanal.
Synthesis of (R)-(|)- and (S)-({)-massoilactone
(1a and 1b)
The same procedure as that described for 1
was applied to the synthesis of both enantiomers 1a
and 1b from (R)-({)-1-nonen-4-ol (2a).24) Grignard
reaction of (R)-({)-1,2-epoxyheptane (5)20,21) with
vinylmagnesium chloride in the presence of CuI gave
(R)-homoallylic alcohol 2a in an 86z yield.
Mitsunobu inversion32) of 2a was employed to obtain
corresponding enantiomer (S)-2b. Treatment of 2a,
using 3,5-dinitrobenzoic acid as a nucleophile,
õ
ä
To whom correspondence should be addressed. Fax: {81-44-434-5257; E-mail: Yasuhiro Warita—t-hasegawa.co.jp

Synthesis of ({)- and (|)-Massoilactone
2211
Scheme 1. Synthesis of the Racemate and Both Enantiomers of Massoilactone.
Reagents: (a) 40z AcOOH, N aOAc; (b) N aCN , AcOH; (c) conc. HCl; (d) vinylmagnesium chloride, CuI; (e) PP,h3,5-dinitroben-
3
zoic acid, diethyl azodicarboxylate; (f) KOH, MeOH.
aŠorded (S)-2b in a 79z yield upon transesteriˆca-
tion of the resulting 3,5-dinitrobenzoate. The optical
purity of starting material 5 and resulting 2a and 2b
were respectively evaluated to be 94.1z e.e., 93.8z
e.e. and 93.5z e.e. by a GLC analysis using a chiral
GLC column33) with cyclodextrin derivatives.
Similarly, epoxidation of both homoallylic alcohols
2a and 2b with 40z AcOOH gave diastereomeric
mixtures of epoxy alcohols 3a and 3b in 68z and
LA400 spectrometer, the peak for CDCl3 (at d 77.0)
being used as the internal standard. MS spectra were
obtained with a Hitachi M-80B spectrometer at
70 eV, and optical rotation values were measured
with a Horiba SEPA-2000 polarimeter. GLC ana-
lyses were performed by a Hewlett-Packard 5890 gas
chromatograph with a 0.25 mm i.d.~50 m capillary
column coated with a mixture of heptakis-(2,6-di-O-
methyl-3-O-pentyl)-b-CD, octakis-(2,6-di-O-methyl-
3-tri‰uoroacetyl)-g-CD and OV-1701 (2:1:7) (column
73z yields, which were then cyanated with NaCN
W
AcOH to aŠord crude dihydroxy cyanides 4a and 4b.
Finally, 4a and 4b were each hydrolyzed with conc.
HCl under re‰ux to give the desired (R)-(|)-mas-
soilactone (1a) and (S)-({)-massoilactone (1b) in
65z and 68z yields from 3a and 3b, respectively.
These synthetic 1a and 1b enantiomers were com-
pletely identical with racemic massoilactone (1) in
their IR and NMR spectral properties, while the
optical purity values for 1a and 1b were shown to be
93.4z e.e. and 93.0z e.e. by a GLC analysis.33) As
reported,28) natural 1a was found to have a fresher
and stronger milk-butter-coconut-like ‰avor than
unnatural 1b. In summary, an e‹cient synthesis of
both enantiomers 1a and 1b was achieved in 38z
and 34z respective overall yields in only 4–5 steps
from 5.
temp., 709C to 1609C, programmed at 0.79C min;
W
carrier gas, He at 0.9 ml min). Column chro-
W
matography was carried out on Merck Kieselgel 60
Art 7734.
(})-1-Nonen-4-ol (2). To a stirred mixture of Mg
turnings (26.7 g, 1.1 g atom) in dry THF (100 ml) was
added a small portion (20 ml) of a solution of n-hex-
anal (100.0 g, 1.0 mol) and allyl chloride (91.8 g,
1.2 mol) in dry THF (400 ml). After the reaction had
begun at 459C, the remaining solution was added
dropwise over 2 hr at 309C under ice-cooling, and
stirring was continued for 1 hr at room temperature.
The reaction mixture was slowly poured into cooled
2.0 M HCl aq. (600 g) and then extracted with tol-
uene. The organic layer was successively washed with
Na2CO3 aq. and brine, dried over MgSO4 and con-
centrated in vacuo. The residue was distilled to give
134.0 g (94z) of 2. Bp: 64–659C at 0.5 kPa. IR nmax
(ˆlm) cm|1: 3358 (brm, OH), 1641 (m, CH2CH-).
NMR dH (400 MHz, CDCl3): 0.90 (3H, t, J6.8 Hz,
9-CH3), 1.20–1.50 (9H, m, 5-, 6-, 7-, 8-CH2 and
OH), 2.10–2.32 (2H, m, 3-CH2), 3.62–3.66 (1H, m,
4-CH), 5.13 and 5.14 (total 2H, each dd, J15.6,
12.0, 1.2 Hz, 1-CH2), 5.70–5.90 (1H, m, 2-CH).
NMR dC (100 MHz, CDCl3): 14.04, 22.64, 25.36,
31.88, 36.82, 41.97, 70.73, 118.04, 134.95. HRMS
Experimental
(R)-({)-1,2-Epoxyheptane was purchased from
Japan Energy Corporation, all other chemicals being
of technical grade and commercially available. All
boiling point (bp) data are uncorrected. Melting
point (mp) data were measured with a Buchi B-545
instrument and are uncorrected. IR spectra were
1
measured with a Jasco IR-5000 spectrometer. H-
NMR spectra were recorded at 400 MHz by a Jeol
JNM-LA400 spectrometer, the peak for TMS (at
d 0.00) being used as the internal standard. 13C-NMR
spectra were recorded at 100 MHz by a Jeol JNM-
m z (M{): calcd. for C H O, 142.1358; found,
W
142.1350.
9
18

2212
M. ISHIKAWA et al.
(4R)-1-Nonen-4-ol (2a). To a stirred mixture of
(})-1,2-Epoxynonan-4-ol (3). To a stirred mixture
of 2 (71.0 g, 0.50 mol)and sodium acetate (14.2 g,
0.17 mol)in toluene (250 ml)was added dropwise
40z AcOOH (114.0 g, 0.60 mol)over 2 hr at 40 9C.
After being stirred for 6 hr at 459C, the mixture was
washed with brine. The organic layer was separated,
successively washed with FeSO4 aq., Na2 CO3 aq. and
brine, dried over MgSO4 and concentrated in vacuo.
The residue was distilled to give 3 (59.2 g, 75z) . Bp:
82–839C at 0.53 kPa. IR nmax (ˆlm)cm |1: 3423 (brm,
OH), 1258, 843 (m, epoxy). NMR dH (400 MHz,
CDCl3 ) : 0.89 (3H, t,J6.6 Hz, 9-CH3), 1.25–2.10
(11H, m, 3-, 5-, 6-, 7-, 8-CH2 and OH), 2.51 and 2.62
(total 1H, each dd, J4.9, 2.7 Hz, 1-CH), 2.79 and
2.83 (total 1H, each dd, J4.9, 4.3 Hz, 1-CH),
3.00–3.20 (1H, m, 2-CH), 3.78–3.95 (1H, m, 4-CH).
NMR dC (100 MHz, CDCl3): 14.03, 22.62, 25.20,
31.80, 37.54, 39.03, 39.75, 46.61, 46.87, 50.24,
CuI (0.95 g, 5.0 mmol)and a solution of ( R)-({)-5
(5.7 g, 50 mmol)in dry THF (50 ml)was added drop-
wise a solution of vinylmagnesium chloride in THF
(1.38 M, 43.5 ml, 60 mmol)over 1 hr at |509C, stir-
ring being continued for 0.5 hr at 09C. The mixture
was poured into NH4Cl aq. and extracted with ether.
The extract was washed with brine, dried over MgSO4
and concentrated in vacuo. The residue by SiO2
(150 g)chromatography, eluting with n-hexane-ethyl
acetate (95:5), gave 2a (6.1 g, 86z) . a[ ]2D0 {7.96 (c
1.080, EtOH). Its IR and NMR spectra were identical
with those of racemate 2. HRMS m z (M{) : calcd.
W
for C9H18 O, 142.1358; found, 142.1349. The enan-
tiomeric purity of resulting 2a was found to be 93.8z
e.e. by a GLC analysis: tR 73.64 min [96.9z, 2a], tR
74.73 min [3.1z, 2b].
(4S)-1-Nonen-4-ol (2b). To a stirred solution of
Ph3P (10.5 g, 40 mmol), 3,5-dinitrobenzoic acid
(8.5 g, 40 mmol)and 2a (5.7 g, 40 mmol)in dry THF
(150 ml)was added dropwise a 40 z solution of
diethyl azodicarboxylate in toluene (17.4 g, 40 mmol)
over 30 min at room temperature. After being stirred
for 16 hr at room temperature, the mixture was
concentrated in vacuo. The residue by SiO2 (130 g)
chromatography, eluting with n-hexane-ethyl acetate
(25:1), gave (4S)-benzoate (11.2 g, 83z)as light
yellow crystals. Mp: 37.5–38.09C. [a]2D0 |9.43 (c
1.123, EtOH). IR nmax (KBr)cm |1: 1716 (s, CO),
1631 (m, CH2CH-), 1546, 1346 (s, N-O). NMR dH
(400 MHz, CDCl3): 0.87–0.90 (3H, t, J6.6 Hz,
9-CH3 ), 1.30–1.42 (6H, m, 6-, 7- and 8-CH2),
1.74–1.80 (3H, m, 5-CH2), 2.50–2.55 (2H, m,
3-CH2 ), 5.10 and 5.14 (total 2H, each dd, J17.2,
10.4, 1.2 Hz, 1-CH2 ), 5.28–5.30 (1H, m, 4-CH),
5.77–5.85 (1H, m, 2-H), 9.14 (2H, s, aromatic), 9.22
(1H, s, aromatic). NMR dC (100 MHz, CDCl3):
13.98, 14.13, 22.51, 22.68, 25.07, 31.57, 33.62,
38.67, 76.78, 118.47, 122.27, 129.40, 133.10, 134.44,
148.72, 162.19. To a stirred and ice-cooled solution
of (4S)-benzoate (11.0 g, 33 mmol) in THF (120 ml)
was added dropwise a mixture of 1 M KOH aq.
(36 ml)and MeOH (70 ml.) Stirring was continued
for 2 hr at room temperature, and then the mixture
was extracted with ether. The ethereal layer was
washed with brine, dried over MgSO4 and concen-
trated in vacuo. The residue by SiO2 (50 g)chro-
matography, eluting with n-hexane-ethyl acetate
(20:1), gave 2b (4.4 g, 95z) . a[]2D0 |8.74 (c 1.075,
EtOH). Its IR and NMR spectra were identical with
50.65, 69.33, 70.58. HRMS m z (M{) : calcd. for
W
C9H18O2, 158.1307; found, 158.1330.
(4R)-1,2-Epoxynonan-4-ol (3a). In the same
manner as that described for the preparation of 3, 2a
(5.7 g, 40 mmol)was treated with 40 z AcOOH
(9.1 g, 48 mmol)and sodium acetate (1.1 g, 13 mmol)
in toluene (20 ml). The residue by SiO2 (50 g)chro-
matography, eluting with n-hexane-ethyl acetate
(20:1), gave 3a as unseparable diastereomers (4.3 g,
68z) . [a]2D0 |9.87 (c 1.215, EtOH). Its IR and NMR
spectra were identical with those of racemate 3.
HRMS m z (M{) : calcd. for CH O , 158.1307;
W
found, 158.1322.
9
18
2
(4S)-1,2-Epoxynonan-4-ol (3b). In the same man-
ner as that just described, 2b (4.3 g, 30 mmol)gave
3b (3.5 g, 74z) . [a]2D0 {8.57 (c 1.065, EtOH). Its IR
and NMR spectra were identical with those of 3 and
3a. HRMS m z (M{) : calcd. for CH O , 158.1307;
W
found, 158.1319.
9
18
2
(})-3,5-Dihydroxydecanenitrile (4). To a solution
of 95z NaCN (17.0 g, 0.33 mol)in water (60 ml)was
added a solution of 3 (47.4 g, 0.30 mol) in 95 z
EtOH (60 ml). To this mixture was added dropwise
AcOH (20.0 g, 0.33 mol) over 1 hr at 35 9C under
water-cooling, and stirring was continued for 4 hr at
609C. The mixture was diluted with water and ex-
tracted with CH2 Cl2. The extract was washed with
brine, dried over MgSO4 and concentrated in vacuo
to give crude 4 (56.0 g, q.y.). IR nmax (ˆlm)cm |1
:
3406 (brm, OH), 2253 (m, CN). NMR dH (400 MHz,
CDCl3 ): 0.88–0.90 (3H, m, 9-CH3), 1.24–1.82 (10H,
m, 4-, 6-, 7-, 8- and 9-CH2), 2.51–2.60 (2H, dd, J
16.0, 5.8 Hz , 2-CH2 ), 3.85–4.30 (2H, m, 3-CH and
5-CH).
those of racemate 2. HRMS m z (M{) : calcd. for
W
C9H18 O, 142.1358; found, 142.1372. The enantio-
meric purity of resulting 2b was found to be 93.6z
e.e. by a GLC analysis: tR 73.64 min [3.2z, 2a], tR
74.73 min [96.8z, 2b].
(})-Massoilactone (1). A mixture of 4 (46.3 g,
0.25 mol)and conc. HCl (46 g)was heated at 90–

Synthesis of ({)- and (|)-Massoilactone
2213
and identiˆcation of (|)-2-deceno-5-lactone (mas-
soialactone). Agric. Biol. Chem., 32, 1306–1309
(1968).
959C for 3 hr. The cooled mixture was diluted with
water and extracted with toluene. The extract was
successively washed with Na2CO3 aq. and brine,
dried over MgSO4 and concentrated in vacuo. The
residue was distilled to give 1 (28.2 g, 67z). Bp:
111–1129C at 0.5 kPa. IR nmax (ˆlm) cm|1: 1724 (s, C
O), 1252 (s, C„O). NMR dH (400 MHz, CDCl3):
0.90 (3H, t, J6.9 Hz, 10-CH3), 1.28–1.78 (8H, m,
6-, 7-, 8 and 9-CH2), 2.31–2.36 (2H, m, 4-CH2),
4.40–4.45 (1H, m, 5-CH), 6.02 (1H, dt, J10.0,
2.0 Hz, 3-CH2), 6.88 (1H, ddd, J10.0, 3.6, 3.6 Hz,
2-CH2 ). NMR dC (100 MHz, CDCl3): 13.99, 22.51,
24.50, 29.41, 31.54, 34.85, 78.04, 121.45, 145.06,
164.63. These NMR data are in good accord with
4) Kaiser, R., and Lamparsky, D., Das lacton der 5-
hydroxy-cis-2, cis-7-decadiensaeure und weitere lac-
tone aus dem absolue der blueten von polianthes
tuberosa L. Tetrahedron Lett., 20, 1659–1660 (1976).
5) Bernreuther, A., Lander, V., HuŠer, M., and Schrei-
er, P., Enantioselective analysis of dec-2-en-5-olide
(massoilactone) from natural sources by multidimen-
sional capillary gas chromatography. Flavour Fragr.
J., 5, 71–73 (1990).
6) Crombie, L., Amides of vegetable origin. Part V.
Stereochemistry of conjugated dienes. Synthesis of
(})-massoialactone. J. Chem. Soc., 1007–1025, 2535
(1955).
those reported in ref. 8. HRMS m z (M{): calcd. for
W
C10H16 O2, 168.1150; found, 168.1162.
7) Abe, S., and Sato, K., Studies on synthesis of massoi-
lactone and its homologues. Part II. Synthesis of
nonyn-1-ol-4-carboxylic acid-1-lactone (massoi-lac-
tone). Bull. Chem. Soc. Japan, 29, 88–90 (1956).
8) Mori, K., Absolute conˆguration of (|)-massoilac-
tone as conˆrmed by a synthesis of (S)-({)-isomer.
Agric. Biol. Chem., 40, 1617–1619 (1976).
(R)-(|)-Massoilactone (1a). In the same manner
as that described for the preparation of 1, 3a (1.6 g,
10 mmol) was treated with 95z NaCN (0.64 g,
13 mmol) and AcOH (0.75 g, 13 mmol) in EtOH aq.
(5.2 ml) to give crude 4a (1.7 g). 4a (1.6 g) was then
treated with conc. HCl (1.6 g) to give 1a (1.0 g, 65z
from 3a). [a]2D0 |117.3 (c 1.045, CHCl3 ); ref. 26 [a]D28
|109.7 (c 3.9, CHCl3). Its IR and NMR spectra were
9) Nobuhara, A., Syntheses of unsaturated lactones.
Part I. Some lactones of 5-substituted-5-hydroxy-2-
enoic acids as a synthetic butter or butter cake ‰avor.
Agric. Biol. Chem., 32, 1016–1020 (1968).
identical with those of racemate 1. HRMS m z (M{):
10) Carlson, R. M., Oyler, A. R., and Peterson, J. R.,
Synthesis of substituted 5,6-dihydro-2H-pyran-2-
ones. Propiolic acid dianion as a reactive three-
carbon nucleophile. J. Org. Chem., 40, 1610–1616
(1975).
W
calcd. for C10H16 O2, 168.1150; found, 168.1142. The
enantiomeric purity of resulting 1a was found to be
93.4z e.e. by a GLC analysis: tR 117.90 min [3.3z,
1b], tR 118.96 min [96.7z, 1a].
11) Fehr, C., Galindo, J., and OhloŠ, G., Novel ap-
proach to the synthesis of 6-substituted 5,6-dihydro-
2(2H )-pyranones. Helv. Chim. Acta, 64, 1247–1256
(1981).
(S)-({)-massoilactone (1b). In the same manner as
that just described, 3b (3.5 g, 22 mmol) gave 1b
(2.5 g, 68z). [a]2D0 {109.0 (c 1.125, CHCl3 ); ref. 23
[a]2D8 {110.5 (c 2.4, CHCl3 ). Its IR and NMR spectra
12) Bacardit, R., and Moreno-manas, M., A very simple
synthesis of natural saturated d-substituted d-lac-
tones. The pheromone of uespa orientalis. Chem.
Lett., 5–6 (1982).
were identical with those of 1 and 1a. HRMS m z
W
(M{): calcd. for C10H16 O2, 168.1150; found,
168.1152. The enantiomeric purity of resulting 1b
was found to be 93.0z e.e. by a GLC analysis: tR
117.90 min [96.5z, 1b], tR 118.96 min [3.5z, 1a].
13) Yoshida, T., and Saito, S., A new method for synthe-
sis of a,b-unsaturated d-lactones via Michael addition
using methyl (phenylsulˆnyl) acetate. Chem. Lett.,
1587–1590 (1982).
14) Pohmakotr, M., and Jarupan, P., A new synthesis of
a,b-unsaturated g- and d-lactones via intramolecular
acylation of a-sulˆnyl carbanion. Tetrahedron Lett.,
26, 2253–2256 (1985).
Acknowledgments
We are most grateful to Emeritus Professors M.
Matsui and K. Mori of The University of Tokyo for
their continuing encouragement. Our thanks are also
due to Dr. T. Yanai and Mr. S. Tamogami of T.
Hasegawa Co., Ltd., for the MS and GLC analyses.
15) Midland, M. M., Tramontano, A., Kazubski, A.,
Graham, R. S., Tsai, D. J. S., and Cardin, D. B.,
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