Highly stereoselective synthesis of nerylgeraniol-18-oic acid

Article abstract of DOI:10.1081/SCC-100105135

A stereoselectively total synthesis of nerylgeraniol-18-oic acid from geraniol was described. The key steps were the iodization-rearrangement of 2, 3-epoxy alcohol 4, stereoselective Claisen rearrangement and Horner-Emmons olefination reaction.

Full text of DOI:10.1081/SCC-100105135

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HIGHLY STEREOSELECTIVE SYNTHESIS OF
NERYLGERANIOL-18-OIC ACID
Zuosheng Liu a , Lizeng Peng a , Tao Zhang a & Yulin Li b
a National Laboratory of Applied Organic Chemistry and Institute of Organic Chemistry,
Lanzhou University , Lanzhou, 730000, People's Republic of China
b National Laboratory of Applied Organic Chemistry and Institute of Organic Chemistry,
Lanzhou University , Lanzhou, 730000, People's Republic of China
Published online: 09 Nov 2006.
To cite this article: Zuosheng Liu , Lizeng Peng , Tao Zhang & Yulin Li (2001) HIGHLY STEREOSELECTIVE SYNTHESIS OF
NERYLGERANIOL-18-OIC ACID, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 31:16, 2549-2555, DOI: 10.1081/SCC-100105135
To link to this article: http://dx.doi.org/10.1081/SCC-100105135
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SYNTHETIC COMMUNICATIONS, 31(16), 2549–2555 (2001)
HIGHLY STEREOSELECTIVE SYNTHESIS
OF NERYLGERANIOL-18-OIC ACID
Zuosheng Liu, Lizeng Peng, Tao Zhang, and Yulin Li*
National Laboratory of Applied Organic Chemistry and
Institute of Organic Chemistry, Lanzhou University,
Lanzhou, 730000, People’s Republic of China
ABSTRACT
A stereoselectively total synthesis of nerylgeraniol-18-oic acid
from geraniol was described. The key steps were the iodiza-
tion-rearrangement of 2, 3-epoxy alcohol 4, stereoselective
Claisen rearrangement and Horner-Emmons olefination
reaction.
Nerylgeraniol-18-oic acid (1), a novel nerylgeraniol derivative, was iso-
lated by zdero and co-workers from the aerial part of Heteropappus altaicus1
and cutierrezia espinosae.2 The structure was elucidated by spectroscopic
methods. Herein, we report the first total synthesis of 1 from geraniol (2).
The total synthesis of nerylgeraniol-18-oic (1) is detailed in scheme 1.
Allylic alcohol 3, readily available from geraniol (2) in two steps,3 was treated
by VO(acac)2 and t-BuOOH to give the 2,3-epoxy alcohol 4 in 90% yield.4 By
our method,5 allylic alcohol 5 was obtained in 94% yield with Ph3P, pyridine,
I2 and H2O. On treatment with a large excess of ethyl vinyl ether containing
*Corresponding author. E-mail: liyl@lzu.edu.cn
2549
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

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LIU ET AL.
freshly recrystallized mercuric acetate,6 the allylic alcohol 5 was con-
verted into the corresponding allyl vinyl ether. The allyl vinyl ether was
pyrolysed in a sealed tube at 110ꢀC under Ar for 1 h to obtain the aldehyde
6 in 90% yield.7 The trans : cis isomer ratio, which was determined by GC,
was 93:7.
Scheme 1.
Reagents and conditions: a) ref. 3, two steps, 72%; b) VO(acac)2,
t-BuOOH, C6H6, reflux, 2h, 90%; c) Ph3P, I2, pyridine, Et2O/CH3CN
(5/3), 0ꢀC, 1h, then added 1 eq H2O, 38ꢀC, 6h, 93%; d) 1) Hg(OAc)2, ethyl
vinyl ether, reflux, 24h, 83%; 2) sealed tube, 110ꢀC, 1h, 90%; e) MeMgI,
Et2O, reflux, 2h then 30% H2SO4, 0ꢀC, 1h, 77%; f) NaH, (EtO)2P(O)
CH2CO2Et, DMF, 60ꢀC, 6h, 88%; g) LiHMDS, ꢁ50ꢀC, 30 min., then
aldehyde 6, ꢁ50ꢀC, 16h, 64%; h) KOH, EtOH-H2O, reflux, 2h, 100%.
By Biernacki’s method, treatment methyl cylcopropane ketone 7 with
methylmagnesium iodide, then acidification of the cyclopropylcabinol
derivative gave homoprenyl iodide 8 in 77% yield.8 Alkylation of triethyl

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2551
phosphonate with homoprenyl iodide 8 gave phosphono ester 9 in 88%
yield. The Horner-Emmons reaction of phosphono ester 9 with aldehyde
6 in the presence of LiHMDS9 gave a mixture of ethyl esters 10 in 64%
1
yield (E:Z ¼ 86:14, by H NMR). Hydrolysis of the esters 10 with KOH in
EtOH-H2O gave the nerylgeraniol-18-oic acid (1) in 86% yield and geranyl-
geraniol-18-oic acid (1a) in 14% yield after column chromatography on
silica gel.
EXPERIMENTAL
1H NMR and 13C NMR spectra were recorded on a Bruker AC-80
or Bruker AM-400 spectrometer in CDCl3 solution using TMS as int-
ernal reference. IR spectra were obtained using a FT-170SX spectrophoto-
meter. Mass spectra were measured on a HP 5988 spectrometer
by direct inlet at 70 eV, and signals were given in m/z with relative intensity
(%) in brackets. GC was measured on a HP 5890 spectrometer. Elemental
analyses were determined on a Vario El instrument. All solvents
were freshly purified and dried by standard techniques prior to use. Puri-
fication of products was conducted by flash column chromatography
(FCG) on silica gel (200ꢂ300 mesh) purchased from Qing Dao Marine
Chemical Co.
(E,E)-3, 7-Dimethyl-6, 7-epoxy-8-hydroxy-2, 6-decadien-1-ol acetate
(4)
To a well-stirred suspension of VO(acac)2 (50 mg) and alcohol 3 (7.2 g,
33.96 mmol) in dry benzene (30 mL) was added t-BuOOH (10.98 mL, 3.4 M
in toluene, 37.36 mmol) in dry benzene (30 mL) under Ar atmosphere
at 80ꢀC. After reflux for 2 h, the mixture was extracted with Et2O
(3 Â 50 mL). The organic phases were washed with 10% aq. KOH solution,
saturated NaHCO3 solution, H2O, brine and dried. Evaporation of the
solvent was followed by flash column chromatography (pet. ether: ethyl
acetate 3:1, v/v) to afford the epoxy alcohol 4 (6.95 g, 90%) as a colorless
oil. IR (film): nmax ¼ 3400, 2980, 1732, 1670, 1237, 1028, 967 cmꢁ1; 1H NMR
(80 MHz, CDCl3): d 5.38 (t, 1H, J ¼ 6.7 Hz, CH¼), 4.62 (d, 2H, J ¼ 6.7 Hz,
CH2OAc), 3.66 (d, 1H, J ¼ 12.1 Hz, CHO), 3.56 (d, 1H, J ¼ 12.1 Hz,
CHO), 3.02 (t, 1H, J ¼ 6.2 Hz, epoxy H), 2.12–2.25 (m, 2H, CH2), 2.05
(s, 3H, CH3CO), 1.66–1.77 (m, 2H, CH2), 1.72 (s, 3H, CH3), 1.28 (s,
3H, CH3); Anal. calcd for C12H20O4: C, 63, 15; H, 8.82; found: C, 63.02;
H, 8.79.

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LIU ET AL.
(E)-3, 7-Dimethyl-6-hydroxy-2, 7-decadien-1-ol acetate (5)
To a stirred solution of epoxy alcohol 4 (6.95 g, 30.48 mmol) in dry
Et2O-CH3CN (5:3, 56 mL) was added sequentially of Ph3P (24 g, 91.4 mmol),
pyridine (9.85 mL, 121.9 mmol) and I2 (11.61 g, 45.7 mmol) at 0ꢀC. After
being stirred for 2 h at 0ꢀC, H2O (0.55 mL, 30.48 mmol) was added into
the system. The reaction mixture was refluxed for 6 h at 38ꢀC, then 20%
Na2S2O3 (aq) (5 mL) and saturated NaHCO3 solu tion (5 mL) were added
to quench the reaction and organic layers were extracted with ether
(3 Â 50 mL). The combined ether extracts were washed with 5% HCl
(4 Â 10 mL), saturated NaHCO3 (10 mL), H2O, brine and dried. Evaporation
of the solvent was followed by flash column chromatography (pet. ether: ethyl
acetate 6:1, v/v) to afford allylic alcohol 5 (6.0 g, 93%) as a colorless oil.
IR (film): nmax ¼ 3472, 3074, 2942, 2861, 1727, 1671, 1650, 1296, 1024, 953,
900 cmꢁ1; EIMS (m/z): 213(0.1%, M þ1), 185 (0.1), 152 (1.4), 134 (5), 119 (8),
1
84 (38), 67 (38), 43 (100), 41 (38); H NMR (80 MHz, CDCl3): d 5.36 (1H,
t, J ¼ 7.0 Hz, CH¼), 4.93, 4.84 (2H, s, CH2¼), 4.57 (2H, d, J ¼ 7.0 Hz,
CH2OAc), 4.04 (1H, t, J ¼ 5.6 Hz, CHO), 2.12–2.02 (2H, m, CH2),
2.04 (3H, s, CH3CO), 1.68–1.62 (2H, m, CH2), 1.72 (3H, s, CH3), 1.75
(3H, s, CH3); Anal. calcd for C14H20O3: C, 67.89; H, 9.54; found: C, 67.76;
H, 9.47.
(E,E)-4, 8-Dimethyl-10-acetoxyl-4, 8-octadienal (6)
To a solution of alcohol 5 (4.93g, 23.25 mmol) in ethyl vinyl ether
(27 mL) was added Hg(OAc)2 (3g, freshly recrystallized from anhydrous
EtOH). The mixture was refluxed for 24 h. The reaction mixture was extracted
with Et2O (3 Â 50 mL). The organic phases were washed by H2O, brine and
dried. Evaporation of the solvent was followed by flash column chromato-
graphy (pet. ether: ethyl acetate 15:1, v/v) to afford the vinyl ether (4.6 g, 83%)
as a colorless oil. The vinyl ether (3.28 g, 13.78 mmol) was heated in sealed tube
under Ar atmosphere at 110ꢀC for 1 h. The crude product was purified by flash
column chromatography (pet. ether: ethyl acetate 8:1, v/v) to afford the alde-
hyde 6 (2.95 g, 90%) as a colorless oil. IR: (film): nmax ¼ 2928, 2858, 2721,
1736, 1445, 1377, 1234, 1023, 954 cmꢁ1. EIMS (m/z): 196 (0.2%, M-43), 178
(1), 163(1.2), 134 (4), 119 (5), 93(21), 67 (19), 55 (26), 43(100).
1H NMR
(80 MHz, CDCl3): d 9.77 (t, 1H, J ¼ 1.6 Hz, CHO), 5.35 (t, 1H, J ¼ 6.8 Hz,
CH¼), 5.14 (t, 1H, J ¼ 6.4 Hz, CH¼), 4.60 (d, 2H, J ¼ 6.8 Hz, CH2OAc),
2.25–2.54 (m, 4H, 2CH2), 2.07 (s, 3H, CH3CO), 1.95–2.14 (m, 2H, CH2),
1.71 (s, 3H, CH3), 1.63(s, 3H, CH 3); Anal. calcd for C14H22O3: C, 70.56; H,
9.30; found: C, 70.35; H, 9.26.

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2553
Ethyl 2-(Diethylphosphono)-6-methyl-5-heptaenoate (9)
To a stirred suspension of NaH (80%, 920 mg, 30 mmol) in anhydrous
DMF (20 mL) was added dropwise a solution of ethyl (diethylphosphono)-
acetate (4.45 mL, 22 mmol) in DMF (10 mL). The mixture was stirred at
room temperature for 2 h and a solution of iodide 8 (4.2 g, 20 mmol) was
added. The resulting solution was stirred at 60ꢀC for 6 h and partitioned
between Et2O (20 mL) and H2O (10 mL). The reaction mixture was
extracted with Et2O (3 Â 50 mL). The organic phases were washed with
H2O, brine and dried. Evaporation of the solvent was followed by flash
column chromatography (pet. ether: ethyl acetate 3:1, v/v) to afford the
phosphono ester 9 (5.44 g, 88%) as a colorless oil. IR (film): nmax ¼ 2983,
2935, 1734, 1445, 1258, 1031, 969 cmꢁ1; EIMS m/z: 306 (10%, M), 261 (12),
224 (100), 197 (82), 169 (31), 152 (84), 123 (44), 109 (32), 81 (51), 67 (29), 55
1
(52), 41 (91); H NMR (80 MHz, CDCl3): d 5.01 (1H, t, J ¼ 7.2 Hz, CH¼),
3.93–4.30 (6H, m, 3CH2), 2.70–3.10 (1H, m, CH), 1.90–2.16 (4H, m, 2CH2),
1.64 (3H, s, CH3), 1.54 (3H, s, CH3), 1.16–1.38 (9H, m, 3CH3); Anal. calcd
for C14H27O5P: C, 54.89; H, 8.88; found: C, 54.79; H, 8.85.
(E,E,E)-1-Acetoxy-11-carboethoxy-3,7,15-trimethyl-hexa-deca-2,
6,10-tetraene (10)
To a stirred solution of hexamethyldisilazane (0.912 mL, 1.44 mmol) in
anhydrous DME(25 mL) was added dropwise n-BuLi (2.34 mL, 1.55 M,
3.63 mmol) at ꢁ50ꢀC over 5 min. After being stirred for an additional
30 min at that temperature, a solution of phosphonate 9 (1.016 g,
3.32 mmol) in DME(15 mL) was added dropwise via syringer. After 45 min
at ꢁ50ꢀC, a solution of aldehyde 6 (720 mg, 3.025 mmol) in DME(10 mL) was
added. The resulting mixture was stirred at –50ꢀC for 16 h, the saturated
NH4Cl(10 mL) was added to quench the reaction. The mixture was extracted
with Et2O(3 Â 50 mL), the organic phases were washed with H2O, brine and
dried. Evaporation of the solvent was followed by flash column chromato-
graphy (pet. ether: ethyl acetate 8:1, v/v) to give the mixture of E and Z
isomers of ester 10 (760 mg, 64%) as a colorless oil. IR(film): nmax ¼ 2971,
2928, 2859, 1740, 1712, 1651, 1446, 1374, 1233, 1025, 955 cmꢁ1; EIMS m/z:
290 (0.1%, M), 330 (0.1, M-AcOH), 300 (0.9), 272 (1), 232 (3), 212 (5), 189 (2),
161 (4), 138 (5), 107 (10), 93(20), 67 (19), 43(100);
1H NMR (400 MHz,
CDCl3): d 6.72(1H, t, J ¼ 7.4 Hz, trans CH¼), 5.90 (1H, t, J ¼ 7.3Hz, cis
CH¼), 5.33 (1H, t, J ¼ 7.0 Hz, CH¼), 5.13(1H, t, J ¼ 7.0 Hz, CH¼), 4.58
(2H, d, J ¼ 7.0 Hz, CH2OAc), 4.18 (2H, q, J ¼ 7.2 Hz, CH2O), 2.23–2.32 (4H,
m, 2CH2), 2.03–2.13 (8H, m, 4CH2), 2.04 (3H, s, CH3CO), 1.70 (3H, s, CH3),

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LIU ET AL.
1.67 (3H, s, CH3), 1.61 (3H, s, CH3), 1.59 (3H, s, CH3), 1.28 (3H, t, J ¼ 7.2 Hz,
CH3); Anal. calcd for C24H38O4: C, 73.81; H, 9.81; found: C, 73.62; H, 9.85.
Nerylgeraniol-18-oic acid (1)
A mixture of ester 10 (36 mg, 0.092 mmol) and KOH(20 mg,
0.36 mmol) in 3 mL of EtOH-H2O (1:1) was refluxed for 2 h. The solution
was cooled to room temperature, diluted with Et2O (5 mL), acidified with 5%
aq. HCl solution and stirred for 10 min at room temperature. The mixture
was extracted with Et2O (50 mL). The organic layers were washed with H2O,
brine and dried. Evaporation of the solvent was followed by flash column
chromatography (pet. ether: ethyl acetate 3:1, v/v) to give nerylgeraniol-18-
oic acid (1) (25 mg, 86%) and geranylgeraniol-18-oic acid (1a) (4 mg, 14%).
nerylgeraniol-18-oic acid (1): IR (film): nmax ¼ 3347, 2965, 2925, 1686, 1638,
1445, 1276, 991 cmꢁ1; EIMS m/z: 302 (0.2%, M), 287 (0.1), 259 (0.4), 234
(0.3), 219 (1.1), 201(1.1), 189 (2.2), 151 (6), 135 (10), 121 (14), 107 (15), 93 (26),
1
81 (20), 69 (100), 41 (71); H NMR (400 MHz) (CDCl3): d 6.86 (1H, t,
J ¼ 7.0 Hz, CH¼), 5.41(1H, t, J ¼ 7.0 Hz, CH¼), 5.14(2H, t, J ¼ 7.2 Hz,
CH¼), 4.16(2H, d, J ¼ 7.0 Hz, CH2O), 2.27–2.33(4H, m, 2CH2), 2.05–
2.12(8H, m, 4CH2), 1.68(3H, s, CH3), 1.67(3H, s, CH3), 1.62(3H, s, CH3);
1.60 (3H, s, CH3); 13C NMR(100 MHz) (CDCl3): d 172.57, 145.08, 139.32,
133.98, 132.30, 131.29, 124.94, 123.64, 123.55, 59.39, 39.33, 38.36, 27.62,
27.20, 26.80, 26.10, 25.68, 17.62, 16.19, 15.92; Anal. Calcd for C20H32O3:
C, 74.96; H, 10.06; found: C, 74.90; H, 10.02; geranylgeraniol-18-oic acid
(1a): 1H NMR(400 MHz) (CDCl3): d 5.94(1H, t, J ¼ 6.8 Hz, CH¼),
5.41(1H, t, J ¼ 7.0 Hz, CH¼), 5.12(2H, t, J ¼ 7.2 Hz, CH¼), 4.18 (2H, d,
J ¼ 7.0 Hz, CH2O), 2.27–2.33(4H, m, 2CH2), 2.05–2.12(8H, m, 4CH2),
1.69(3H, s, CH3), 1.68 (3H, s, CH3), 1.62(3H, s, CH3), 1.60(3H, s, CH3);
Anal. Calcd for C20H32O3: C, 74.96; H, 10.06; found: C, 74.88; H, 10.11.
ACKNOWLEDGMENT
The project was financially supported by the Nature Science
Foundation of China (200720152).
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3. Unbriet, M.; Sharpless, K.B. J. Am. Chem. Soc. 1977, 99, 5526.
4. Sharpless, K.B.; Michaelson, R.C. J. Am. Chem. Soc. 1973, 95, 6136.
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Received in the USA November 10, 2000

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