Synthesis of ent-crotonadiol and compounds related to it from (+)-larixol

Article abstract of DOI:10.1007/s10600-011-9943-z

A new synthesis of 13E-ent-crotonadiol and its 13Z-isomer from 6α-acetoxy-14,15-bis-norlabd-8(17)-en- 13-one is described. A mixture of methyl esters of 13E- and 13Z-6α-acetoxylabd-8(17),13-dien-15-oic and 13E- and 13Z-6α-hydroxylabd-8(17),13-dien-15-oic acids was formed by its reaction with trimethylphosphonoacetate. Mixtures of 13E- and 13Z-6α-hydroxylabd-8(17),13-dien-15-oic acids were formed by hydrolysis of this mixture. These were separated, methylated, and reduced by LiAlH ₄ to give the pure 13E- and 13Z-crotonadiols in 64 and 16% yields, respectively. The two known syntheses of crotonadiol from (+)-larixol were reproduced. It was shown that they produced only 13E-crotonadiol.

Full text of DOI:10.1007/s10600-011-9943-z

Chemistry of Natural Compounds, Vol. 47, No. 3, July, 2011 [Russian original No. 3, May-June, 2011]
SYNTHESIS OF ent-CROTONADIOL AND COMPOUNDS
RELATED TO IT FROM (+)-LARIXOL
1*
1,2
4
P. F. Vlad, A. Chokyrlan, M. D’Ambrosio,
UDC 547.9+577.1+547.91
1
1
1
1
M. N. Koltsa, A. N. Barba, K. Edu, A. Byryyak,
A. Nikolescu, A. Mari, and K. Deleanu
2,3
4
2,3
A new synthesis of 13E-ent-crotonadiol and its 13Z-isomer from 6ꢀ-acetoxy-14,15-bis-norlabd-8(17)-en-
13-one is described. A mixture of methyl esters of 13E- and 13Z-6ꢀ-acetoxylabd-8(17),13-dien-15-oic and
13E- and 13Z-6ꢀ-hydroxylabd-8(17),13-dien-15-oic acids was formed by its reaction with
trimethylphosphonoacetate. Mixtures of 13E- and 13Z-6ꢀ-hydroxylabd-8(17),13-dien-15-oic acids were
formed by hydrolysis of this mixture. These were separated, methylated, and reduced by LiAlH to give the
4
pure 13E- and 13Z-crotonadiols in 64 and 16% yields, respectively. The two known syntheses of crotonadiol
from (+)-larixol were reproduced. It was shown that they produced only 13E-crotonadiol.
Keywords: crotonadiols, synthesis, larixol, 6ꢀ-acetoxy-14,15-bis-norlabd-8(17)-en-13-one, methyl esters of 13E-
and 13Z-6ꢀ-hydroxy- and 6ꢀ-acetoxylabd-8(17),13-dien-15-oic acids.
25
The labdane diterpenoid labd-8(17),13E-dien-6ꢀ,15-diol (1) {[ꢀ] –28.0° (CHCl )} was isolated from bark of the
D
3
medicinal bush Croton zambesicus Muell. Arg. growing in central and western Africa. The researchers reported [1] the
isolation of a “new labdane diterpenoid” and gave it the common name crotonadiol. C. zambesicus is used by the local
population to treat dysentery, fever, and malaria. Its extracts also exhibit laxative, antimicrobial, and anticonvulsive activity
[2].
The structure, relative configuration, and trans-configuration of the C-13 double bond in 1 were established [1] on
the basis of spectral data. The absolute configuration of diol 1 was not found.
Later Chinese chemists [3] isolated from bark of the larch Larix olgensis Henry var. koreana Nakai a compound
corresponding to the structure of 1 with mp 154°C and [ꢀ] +32.57° (MeOH). They also considered this compound to be
D
“new” and proved its structure and relative stereochemistry on the basis of spectral data and an x-ray crystal structure. The
absolute configuration of diol 1 in this instance also remained unclear. However, it turned out that a compound with the
structure of 1 was described rather long ago [4]. It was synthesized from the natural compound larixol monoacetate (2). An
allylic rearrangement occurred upon its reaction with PCl to form unstable primary chloride 3, which was used without
3
purification in a reaction with KOAc to produce isolarixol diacetate (4) (Scheme 1). This compound was saponified by KOH
in MeOH. The product was chromatographed over a column of SiO to afford crystalline diol 1 in 35% yield, mp 139–140°C.
2
The configuration of the C-13 double bond in the obtained compound and the possible formation of the cis-isomer 5 of 1 were
not discussed [4]. Compound 1 (mp 146–147°C) was also produced in low yield via oxidation of larixol acetate (2) by oxygen
in the presence of heteropolyacids [5]. Both syntheses of diol 1 from larixol acetate (2) confirmed that it, like larixol (6),
belonged to the steric type of labdane diterpenoids. Thus, the absolute configuration of 1 was established.
1) Institute of Chemistry, Academy of Sciences of Moldova, MD-2028, Chisinau, Moldova, fax: 373 22 73 97 75,
e-mail: pavel_f_vlad@yahoo.co.uk; 2) P. Poni Institute of Macromolecular Chemistry, Roumanian Academy of Sciences,
Aleea G. G. Voda, 41, RO-700487, Iasi, Roumania; 3) C. D. Nenitzescu Institute of Organic Chemistry, Roumanian Academy
of Sciences, Splaiul Independentei, 202B, RO-35-98, Bucharest, Roumania; 4) University of Trento, Via Sommarive, 14,
Povo, Italy. Translated from Khimiya Prirodnykh Soedinenii, No. 3, pp. 356–361, May–June, 2011. Original article submitted
January 18, 2011.
©
0009-3130/11/4703-0397 2011 Springer Science+Business Media, Inc.
397

OH
16
13
14
11
20
5
17
7
1
OAc
CH OH
CH OH
2
R
2
9
15
c
a
b
1
3
OH
(-)-1
OAc
OAc
OH
(+)-1
OAc
19 18
3, 7
2
4
3: R = Cl; 7: R = Br
e
CH OH
2
OAc
OH
d
OH
OH
OAc
5
6
8
a. PCl or PBr , Et O, r.t., 12 h; b. KOAc, DMF, r.t., 12 h, 39%; c. KOH, EtOH, reflux, 2 h, 98%; d. AcCl, DMA, 5ꢄC, 12 h, 93%;
3
3
2
e. PdCl 4(CH CN) , THF, Ar, r.t., 12 h, 86%
2
3
2
Scheme 1
It became necessary for us to prepare crotonadiol 1 and its isomer 5 with the cis-configuration at C-13 during synthetic
studies of labdane diterpenoids. Because the extract of C. zambesicus contains a small amount of crotonadiol (+)-1, its isolation
was problematical. Therefore, we decided to synthesize (+)-1 and 5 from the available labdane diterpenoid larixol (6).
The reaction of tertiary allyl alcohols with PBr and subsequent substitution of the Br atom in allyl bromides by an
3
acetoxy group is known to form a mixture of the trans- and cis-isomers of primary allyl acetates with the trans-isomers
predominating [6].
Considering these results, we studied the reaction of larixol monoacetate (2) with PBr . Product 7 turned out to be
3
unstable. It decomposed during chromatography over a column of SiO . Therefore, it was used in the next reaction step with
2
KOAc without purification. Chromatography of the product over a column of SiO isolated isolarixol diacetate (4) in 39%
2
yield (Scheme 1). Its structure and stereochemistry were proved on the basis of spectral data and the production of crotonadiol
[(+)-1] upon saponification by KOH in MeOH.
The PMR spectrum of 4 contained resonances for the C(16) methyl at 1.71 ppm; olefinic proton C(14)-H, 5.32;
hydroxymethylene C(15)-H , 4.60; and acetate, 2.06. The presence of an AcOCH CH=C(CH )-CH fragment with the
2
2
3
2
13
E-configuration of the double bond was also confirmed by C NMR spectra (ꢁ 21.9, 170.1, 61.4, 118.3, 142.6, and 22.4 ppm).
13
Resonances of C atoms in C NMR spectra were assigned based on HSQC-correlation experiments. The relative
configuration of 1 was derived on the basis of NOESY correlations between the following atoms: Me(19)ꢂH-C(6) ꢂMe(20);
H-C(6) ꢂH -C(7) ꢂH -C(17); H-C(9) ꢂH-C(5) ꢂH -C(17); and H -C(11) ꢂH -C(17) ꢂH -C(12).
ꢃ
ꢀ
a
a
b
b
The physicochemical and spectral data for crotonadiol [(+)-1] agreed with the literature [3, 4]. The 13Z-isomer 5 of
(+)-1 was not produced. Therefore, we studied the reaction of larixol diacetate (8) with the palladium chloride complex of
acetonitrile PdCl ·(CH CN) . The reaction with it of tertiary allyl alcohol acetates is known to isomerize them into primary
2
3
2
allyl alcohol acetates [7, 8]. Larixol diacetate (8) was produced via acetylation of larixol (6) by acetylchloride in dimethylaniline
(DMA) [9]. The reaction of 8 with PdCl ·(CH CN) formed in high yield (86%) isolarixol diacetate (4). Its cis-isomer 5 in
2
3
2
this instance also was not produced. Therefore, the Wittig–Horner reaction of 6ꢀ-acetoxy-14,15-bis-norlabd-8(17)-en-13-one
(9) with trimethylphosphonoacetate (Scheme 2) was studied next. Acetoxyketone 9 was prepared via oxidation of larixol
acetate (2) by CrO in acetic acid [10] and by KMnO in CH Cl in the presence of a phase-transfer catalyst [11, 12].
3
4
2
2
The Wittig–Horner reaction of 9 gave according to TLC a mixture of two products in ~1:3 ratio. These were separated
by chromatography over a column of SiO . Although each of these two fractions gave a single spot on TLC under various
2
conditions, NMR spectroscopy indicated that each of these fractions was heterogeneous and contained a mixture of two
stereoisomeric compounds. The less polar fraction consisted according to the spectral data of a mixture of 13E- and
13Z-acetoxyesters 10 and 11 in an 8:2 ratio. The more polar fraction was a mixture of stereoisomeric 13E- and 13Z-hydroxyesters
12 and 13 in a 7:2 ratio. The formation of 12 and 13 indicated that 9 was partially saponified under the Wittig–Horner reaction
conditions, giving hydroxyketone 14, which then reacted with phosphonoacetate to give a mixture of 12 and 13.
398

CO CH
2
3
CO H
2
c
d
d
1
5
12
13
10 + 11
R
R
(8 : 2)
OH
15
O
CO H
2
CO CH
2
3
10, 12
b
a
R
9, 14
c
12 + 13
(7 : 2)
OH
16
11, 13
9, 10, 11:R = OAc; 12, 13, 14: R = OH
a. NaOCH , (CH O) P(O)CH CO CH , C H , reflux, 2 h, 23% 10/11 and 76% 12/13; b. KOH, EtOH, reflux, 1 h, 77% and 79% 15, 19%
3
3
2
2
2
3
6 6
and 22 16; c. TMSCHN (2M), THF, MeOH, r.t., 0.5 h, 97% 12 and 98% 13; d. LiAlH , Et O, Ar, 0ꢄC, 3 h, 86% (+)-1 and 80% 5
2
4
2
Scheme 2
High-resolution mass spectra of acetoxyesters 10 and 11 did not show peaks for the molecular ions. They did have
+
strong peaks with m/z 316 [M – 60] that were formed upon cleavage from them of acetic acid. Such fragmentation provided
evidence of an acetoxy group in 10 and 11 and confirmed their structures. The PMR spectrum of the predominant isomer 10
13
contained resonances of methyl Me(16) at 2.13 ppm; methoxyl, 3.67; H-C(6), 5.01, and H-C(14), 5.62. The C NMR
spectrum of 10 showed resonances for C atoms of a triply substituted double bond at 160.7 ppm [C(13)] and 115.2 [C(14)];
a carboxyl, 167.3 [C(15)]; and methyl, 18.9 [C(16)]. These chemical shifts indicated that the C(13) double bond had the
trans-configuration. These data together confirmed the structure of 10. The PMR spectrum of the minor isomer 11 exhibited
13
a resonance for the C(16) methyl at 1.87 ppm. It appeared at 25.3 ppm in the C NMR spectrum, indicating that the C-13
double bond had the Z-configuration.
–1
IR spectra of 12 and 13 contained bands characteristic of hydroxyl at 3519, 3430, 1154, and 1160 cm and of ester
at 1735, 1265, and 1240. The molecular formula C H O for 12 and 13 was established on the basis of high-resolution mass
21 34
3
spectral data, according to which molecular ions with m/z 334.2507 and 334.2502 appeared in mass spectra of 12 and 13.
13
PMR and C NMR spectra of 12 and 13 were similar to those of 10 and 11 and confirmed their structures.
Because the mixtures of esters 10/11 and 12/13 could not be separated, they were saponified separately by alcoholic
base (Scheme 2). Mixtures of the same stereoisomeric hydroxyacids 15 and 16 were produced in both instances. These were
separated by chromatography over columns of SiO .
2
–1
IR spectra of 15 and 16 contained absorption bands characteristic of hydroxyls at 3452, 3406, 1163, and 1066 cm ;
carbonyl, 1712 and 1694; and exomethylene, 1644, 1648, 893, and 897. The molecular formula C H O for hydroxyacids
20 32
3
+
13E-15 and 13Z-16 were established by high-resolution mass spectral data. Peaks for molecular ions [M] appeared at m/z
13
320.2349 and 320.2356. PMR and C NMR spectra of 15 and 16 confirmed their structures.
Separate methylation of hydroxyacids 13E-15 and 13Z-16 by trimethylsilyldiazomethane (TMSCHN ) produced in
2
almost quantitative yield the pure hydroxyesters 13E-12 and 13Z-13. Reduction of them by LiAlH produced in high yield
4
crotonadiols (+)-1 and 5, respectively (Scheme 2). Their structures were confirmed by spectral data.
The literature contains contradictory information about crotonadiol (1). It has been described as a liquid with
[ꢀ] –28° (CHCl ) [1] and as a crystalline compound with mp 154°C and [ꢀ] +32.57° (MeOH) [3]. Haeuser [4], in discussing
D
3
D
his results, noted that larixol acetate (2) isomerized with PBr but used PCl in the Experimental part [4]. This same researcher
3
3
gave the following properties for (+)-1: mp 139–140°C and [ꢀ] +36.3° (EtOH). Others [5] also described (+)-1 as a crystalline
D
compound with mp 146–147°C.
Keeping in mind the physicochemical and spectral properties of (+)-1 and (–)-1, it can be concluded that the crotonadiol
obtained in one instance [1] was an ent-labdane series diterpenoid and its structure and absolute configuration were given by
(–)-1. It is difficult to explain why (–)-1 is a liquid whereas its isomer has such a high melting point. The physicochemical
properties of isomers, with the exception of the specific rotation, are known to coincide. Thus, the analysis of the physicochemical
and spectral data for crotonadiol (+)-1 and its isomer 5 indicated that both these compounds were normal labdane diterpenoids.
399

EXPERIMENTAL
Melting points were determined in a capillary on a Buchi B-540 instrument. Specific rotation was recorded in CHCl
3
on a JASCO DIP-181 polarimeter. IR spectra were recorded on a PYE UNICAM SP3-200S spectrophotometer; PMR and
13
C NMR spectra, on Bruker AM 400 and Bruker Avance DRX 400 spectrometers (both 400.13 and 100.61 MHz) from 2–3%
solutions in CDCl with TMS internal standard. High-resolution mass spectra were measured in a KRATOS MS spectrometer.
3
Reaction mixtures were worked up by extracting with Et O, washing the extract with H O until neutral, drying over Na SO ,
2
2
2
4
filtering, and vacuum distilling solvent. TLC used Silica gel 60 F (Merck) or RP-18 F (Merck) plates with detection by
254
254
Ce(SO ) solution in aqueous H SO (2 N) with subsequent heating at 80°C for 5 min. Column chromatography used silica
4 2
2
4
gel grade 70–230 ꢅm (Merck).
13E-6ꢀ-Acetoxy-15-bromolabda-8(17),13-diene (7). A solution of larixol acetate (2, 200 mg, 0.58 mmol) in a
mixture of anhydrous Et O (2 mL) and Py (0.06 mL) was cooled in an ice bath, treated with a solution of PBr (0.06 mL,
2
3
0.58 mmol) in Et O (0.23 mL), and stirred at –6°C for 1 h and overnight at room temperature. The usual work up gave
2
unstable bromide 7 (248 mg) that was used without further purification in further reactions.
13E-6ꢀ,15-Diacetoxylabda-8(17),13-diene (4). A solution of bromide 7 (200 mg, 0.49 mmol) in DMF (3 mL) was
treated with KOAc (96 mg, 0.98 mmol) and stirred overnight. The usual work up gave a product (210 mg) that was
chromatographed over a column of SiO (21 g) with elution by hexane:EtOAc (4:1). Yield 74 mg (39%) of liquid diacetate 4.
2
–1
IR spectrum (CCl , , cm ): 3083, 2928, 1737, 1647, 1443, 1366, 1239, 1023, 969, 894.
4
PMR spectrum (ꢁ, ppm, J/Hz): 0.76 (3H, s, CH -20), 0.89 (3H, s, CH -19), 1.03 (3H, s, CH -18), 1.71 (3H, s,
3
3
3
CH -16), 1.00-2.22 (12H, m), 2.04 (1H, m, H -7), 2.06 (3H, s, MeO), 2.07 (3H, s, MeO), 2.70 (1H, dd, J = 4.0, 12.0, H -7),
3
ꢀ
ꢃ
4.60 (2H, d, J = 7.2, H -15), 4.64 (1H, d, J = 0.8, H -17), 4.95 (1H, d, J = 0.8, H -17), 5.05 (1H, td, J = 5.2, 11.2, H-6), 5.32
2
(1H, td, J = 1.2, 7.2, H-14).
13
b
a
C NMR spectrum (ꢁ, ppm): 16.1 (C-20), 16.5 (C-16), 19.0 (C-2), 21.0 (COCH ), 21.8 (C-11), 21.9 (COCH ), 22.4
3
3
(C-19), 33.5 (C-4), 36.1 (C-18), 38.3 (C-12), 39.2 (C-1), 39.6 (C-10), 43.5 (C-3), 44.2 (C-7), 55.3 (C-9), 57.6 (C-5), 61.4
(C-15), 73.3 (C-6), 109.3 (C-17), 118.3 (C-14), 142.6 (C-13), 144.2 (C-8), 170.1 (COCH ), 171.1 (COCH ).
3
3
13E-Labda-8(17),13-dien-6ꢀ,15-diol; [(+)-1] (crotonadiol). A solution of allyl diacetate 4 (50 mg, 0.13 mmol) in
EtOH (2 mL) was treated with a solution of KOH (36 mg, 0.65 mmol) in EtOH (1 mL) and refluxed for 2 h. The usual work
up and vacuum distillation of solvent gave a solid (62 mg) that was chromatographed over a column of SiO (6 g) with
2
16
elution by hexane:EtOAc (7:3) to afford crystalline crotonadiol (38.0 mg, 98%), mp 145–146°C (EtOH), [ꢀ] +25.2°
D
–1
(c 0.01). IR spectrum (film, , cm ): 3465, 2953, 1645, 1466, 1387, 1210, 1016, 942, 895, 859.
PMR spectrum (ꢁ, ppm, J/Hz): 0.68 (3H, s, CH -20), 0.99 (3H, s, CH -19), 1.09 (1H, d, J = 10.7, H-5), 1.15 (3H, s,
3
3
CH -18), 1.59 (1H, br.d, J = 10.0, H-9), 1.65 (3H, br.s, CH -16), 1.82 (1H, br.ddd, J = 6.5, 10.0, 14.0, H -12), 2.02 [1H, br.dd,
3
3
a
J = 12.2, 10.7, H -C(7)], 2.15 [br.ddd, J = 14.0, 10.0, 4.0, H -12], 1.00–1.63 (8H, m), 2.66 (dd, J = 4.9, 12.2, H -7), 3.81 (1H,
ꢀ
b
ꢃ
ddd, J = 4.9, 10.7, 10.7, H-6), 4.14 (2H, d, J = 6.9, H -15), 4.57 (1H, dd, J = 1.4, H -17), 4.88 (1H, dd, J = 1.4, H -17), 5.37
2
b
a
(1H, tdq, J = 1.3, 1.3, 6.9, H-14).
13
C NMR spectrum (ꢁ, ppm): 16.1 (C-20), 16.4 (C-16), 19.2 (C-2), 22.1 (C-11), 22.4 (C-19), 33.9 (C-4), 36.6 (C-18),
38.4 (C-12), 39.3 (C-1), 39.4 (C-10), 43.7 (C-3), 49.1 (C-7), 55.5 (C-9), 59.4 (C-15), 60.5 (C-5), 71.7 (C-6), 108.2 (C-17),
123.2 (C-14), 140.3 (C-13), 145.5 (C-8).
+
Mass spectrum (EI, 70 eV, m/z, I , %): 306.2558 0.0022, [M] , C H O ; calcd 306.2559.
rel
20 34 2
6ꢀ,13-Diacetoxylabda-8(17),14-diene (8). A cooled (5°C) solution of 6 (250 mg, 0.82 mmol) in DMA (8 mL) was
treated dropwise with AcCl (3.22 g, 2.92 mL, 49 mmol) over 50 min at the same temperature. The mixture was stirred
overnight at room temperature. The usual work up gave a solid (315 mg) that was purified by chromatography over a column
of SiO (31 g) with elution by hexane:EtOAc (4:1) to afford crystalline 8 (296 mg, 93%) [11, 13], mp 116–117°C (EtOH) (lit.
2
–1
mp 115–116.5°C [11], 114–116.5°C [13]). IR spectrum (CCl , , cm ): 3091, 2938, 1726, 1644, 1443, 1365, 1240, 1117,
4
1021, 969, 914, 865.
PMR spectrum (ꢁ, ppm, J/Hz): 0.75 (3H, s, CH -20), 0.89 (3H, s, CH -19), 1.03 (3H, s, CH -18), 1.54 (3H, s,
3
3
3
CH -16), 1.06–1.75 (12H, m), 2.02 (1H, m, H -7), 2.03 (3H, s, COCH ), 2.05 (3H, s, COCH ), 2.70 (1H, dd, J = 6.0, 12.0,
3
ꢀ
3
3
H -7), 4.64 (1H, s, H -17), 4.94 (1H, s, H -17), 5.04 (1H, td, J = 5.2, 11.0, H-6), 5.13 (1H, d, J = 11.0, H-C15), 5.14 (1H, d,
ꢃ
b
a
J = 17.4, H-15), 5.97 (1H, dd, J = 11.0, 17.4, H-14).
400

13
C NMR spectrum (ꢁ, ppm): 16.0 (C-20), 17.7 (C-2), 19.1 (C-11), 21.9 (COCH ), 22.2 (COCH ), 22.4 (C-19), 23.6
3
3
(C-16), 33.5 (C-4), 36.2 (C-18), 39.0 (C-1), 39.2 (C-12), 39.8 (C-10), 43.5 (C-3), 44.2 (C-7), 56.3 (C-9), 57.6 (C-5), 73.2
(C-6), 83.3 (C-13), 109.4 (C-17), 113.2 (C-15), 14.18 (C-14), 144.3 (C-8), 169.9 (COCH ), 170.1 (COCH ).
3
3
13E-6ꢀ,15-Diacetoxylabda-8(17),13-dene (4). A solution of 8 (250 mg, 0.64 mmol) in anhydrous THF (7 mL)
under Ar was treated with PdCl (CH CN) (6.3 mg, 0.024 mmol), The mixture was stirred overnight at room temperature.
2
3
2
The usual work up gave a solid (287 mg) that was chromatographed over a column of SiO (28 g) with elution by hexane:EtOAc
2
13
(4:1) to afford 4 (215 mg, 86%). The PMR and C NMR spectra of this compound were identical with those reported earlier.
13E-Labda-8(17),13-dien-6ꢀ,15-diol [(+)-1] (crotonadiol). A solution of 4 (200 mg, 0.51 mmol) in EtOH (6 mL)
was treated with a solution of KOH (143 mg, 2.55 mmol) in EtOH (4 mL) and refluxed for 2 h. The usual work up gave a solid
(168 mg) that was chromatographed over a column of SiO (10 g) with elution by hexane:EtOAc (7:3) to afford crystalline
2
16
13
crotonadiol (151.0 mg, 96%), mp 145-146°C (EtOH), [ꢀ] +23.4° (c 0.007). The PMR and C NMR spectra of this compound
D
agreed with those obtained by us earlier.
Methyl Esters of 13E- and 13Z-6ꢀ-Acetoxylabda-8(17),13-dien-15-oic Acids 10 and 11 and 13E- and 13Z-6ꢀ-
Hydroxylabda-8(17),13-dien-15-oic Acids 12 and 13. A solution of sodium methoxide that was produced by the reaction of
metallic Na (8.6 mg, 0.358 g·atom) with MeOH (2.2 mL) was added dropwise to a refluxing solution of
trimethylphosphonoacetate (680.0 mg, 3.74 mmol) and acetoxyketone 9 (400.0 mg, 1.25 mmol) in anhydrous benzene
(29.0 mL). The resulting mixture was refluxed for 2 h. The usual work up gave a solid (469 mg) that was chromatographed
over a column of SiO (45 g) with elution by hexane:EtOAc (95:5) to afford a mixture of liquid acetoxyesters 10 and 11
2
–1
(108.0 mg, 23%, E–Z ratio 8:2). IR spectrum (CCl , , cm ): 3106, 3079, 2979, 2872, 1745, 1664, 1443, 1373, 1246, 1157,
1032, 973, 901, 893. Mass spectrum (EI, 70 eV, m/z, I , %): 316.24000 0.0010, [M – 60] , C H O ; calcd 316.2402.
4
+
rel
21 32 2
PMR spectrum of 10 (ꢁ, ppm, J/Hz): 0.72 (3H, s, CH -20), 0.85 (3H, s, CH -19), 0.99 (3H, s, CH -18), 1.40 (1H, d,
3
3
3
J = 11.4, H-5), 1.61 (1H, br.d, J = 11.6, H-9), 1.00-1.70 (8H, m), 1.96 (1H, m, H -12), 2.00 (1H, m, H -7), 2.02 (3H, s, MeO),
a
ꢀ
2.13 (3H, d, J = 1.3, CH -16), 2.28 (1H, m, H -12), 2.67 (1H, dd, J = 5.2, 12.1, H -7), 3.67 (3H, s, MeO), 4.59 (1H, ddd,
3
b
ꢃ
J = 1.4, H -17), 4.94 (1H, ddd, J = 1.4, H -17), 5.01 (1H, ddd, J = 5.1, 11.0, 11.0, H-6), 5.62 (1H, m, H-14).
b
a
13
C NMR spectrum (ꢁ, ppm): 16.0 (C-20), 18.9 (C-16), 19.0 (C-2), 21.7 (COCH ), 21.9 (C-11), 22.5 (C-19), 33.5
3
(C-4), 36.1 (C-18), 39.1 (C-1), 39.6 (C-10), 39.7 (C-12), 43.4 (C-3), 44.1 (C-7), 50.8 (CO CH ), 55.2 (C-9), 57.5 (C-5), 73.2
2
3
(C-6), 109.4 (C-17), 115.2 (C-14), 143.9 (C-8), 160.7 (C-13), 167.3 (COCH ), 170.1 (CO CH ).
3
2
3
PMR spectrum of 11 (ꢁ, ppm, J/Hz): 0.72 (3H, s, CH -20), 0.85 (3H, s, CH -19), 0.99 (3H, s, CH -18), 1.43 (1H, d,
3
3
3
J = 10.9, H-5), 1.69 (1H, br.d, H-9), 1.10-1.75 (8H, m), 2.02 (3H, s, MeO), 1.87 (3H, d, J = 1.3, CH -16), 2.00 (1H, m, H -7),
3
ꢀ
2.55 (2H, m, H -12), 2.68 (1H, dd, J = 5.2, 12.1, H -7), 3.64 (3H, s, MeO), 4.77 (1H, ddd, J = 1.4, H -17), 4.96 (1H, ddd,
2
ꢃ
b
J = 1.4, H -17), 5.02 (1H, ddd, J = 5.2, 11.0, 11.0, H-6), 5.62 (1H, m, H-14).
a
13
C NMR spectrum (ꢁ, ppm): 16.0 (C-20), 19.1 (C-2), 21.7 (COCH ), 21.9 (C-11), 22.5 (C-19), 25.3 (C-16), 32.7
3
(C-12), 33.5 (C-4), 36.1 (C-18), 38.9 (C-1), 39.8 (C-10), 43.4 (C-3), 44.2 (C-7), 50.8 (CO CH ), 56.2 (C-9), 57.5 (C-5), 73.4
2
3
(C-6), 109.4 (C-17), 144.1 (C-8), 115.8 (C-14), 160.7 (C-13), 166.7 (CO CH ), 170.2 (COCH ).
2
3
3
The same solvent mixture eluted from the column mixtures of liquid hydroxyesters 12 and 13 (320.0 mg, 76%,
E–Z ratio 7:2). Their spetral data are given below.
13E-6ꢀ-Hydroxylabda-8(17),13-dien-15-oicAcid (15) and 13Z-6ꢀ-Hydroxylabda-8(17),13-dien-15-oicAcid (16).
A. A solution of the mixture of 10 and 11 (80.0 mg, 0.21 mmol) in EtOH (20 mL) was treated with a solution of KOH
(95.0 mg, 1.69 mmol) in EtOH (3.0 mL). The resulting mixture was refluxed for 1 h. The usual work up gave a solid (72 mg)
that was chromatographed over a column of SiO (7 g) with elution by hexane:EtOAc (85:15) to afford crystalline 15
2
25
–1
(54.0 mg, 79%), mp 134–135°C (hexane:EtOAc 4:1), [ꢀ] +50.1° (c 0.35). IR spectrum (CCl , , cm ): 3406, 3089, 2931,
D
4
2857, 1694, 1644, 1444, 1381, 1252, 1163, 1052, 1012, 978, 893.
PMR spectrum (ꢁ, ppm, J/Hz): 0.68 (3H, s, CH -20), 0.99 (3H, s, CH -19), 1.15 (3H, s, CH -18), 1.09 (1H, d,
3
3
3
J = 11.0, H-5), 1.59 (1H, br.d, J = 11.0, H-9), 1.99 (1H, dddd, J = 1.0, 6.0, 10.0, 14.0, H -12), 2.03 (1H, br.dd, J = 1.4, 11.0,
a
12.0, H -7), 1.01-1.70 (8H, m), 2.15 (3H, d, J = 1.2, CH -16), 2.32 (1H, dddd, J = 1.0, 4.0, 10.0, 14.0, H -12), 2.67 (1H, dd,
ꢀ
3
b
J = 5.0, 12.0, H -7), 3.82 (1H, ddd, J = 5.0, 11.0, 11.0, H-6), 4.56 (1H, ddd, J = 1.4, H -17), 4.91 (1H, ddd, J = 1.4, H -17), 5.66
ꢃ
(1H, br.s, H-14).
13
b
a
C NMR spectrum (ꢁ, ppm): 16.1 (C-20), 19.1 (C-2), 19.2 (C-16), 21.8 (C-11), 22.4 (C-19), 33.9 (C-4), 36.6 (C-18),
39.3 (C-1), 3.94 (C-10), 40.0 (C-12), 43.7 (C-3), 49.1 (C-7), 55.4 (C-9), 60.5 (C-5), 71.7 (C-6), 108.3 (C-17), 114.9 (C-14),
145.2 (C-8), 163.6 (C-13), 171.5 (CO H).
2
+
Mass spectrum (EI, 70 eV, m/z, I , %): 320.2349 0.0017, [M] , C H O ; calcd 320.2351.
rel
20 32 3
401

22
Next the same solvent mixture eluted liquid hydroxyacid 16 (13.0 mg, 19%), [ꢀ] +20.8° (c 0.25). IR spectrum
D
–1
(film, , cm ): 3452, 3089, 2931, 2857, 1712, 1648, 1453, 1390, 1066, 897, 758.
PMR spectrum (ꢁ, ppm, J/Hz): 0.67 (3H, s, CH -20), 0.99 (3H, s, CH -19), 1.15 (3H, s, CH -18), 1.11 (1H, d,
3
3
3
J = 11.0, H-5), 1.67 (1H, m, H-9), 1.91 (3H, d, J = 1.3, CH -16), 2.04 (1H, br.dd, J = 1.4, 11.0, 12.0, H -7), 1.00-1.70 (8H, m),
3
ꢀ
2.64–2.50 (2H, m, H -12), 2.67 (1H, dd, J = 5.0, 12.0, H -7), 3.82 (1H, ddd, J = 5.0, 11.0, 11.0, H-6), 4.72 (1H, ddd, J = 1.4,
2
ꢃ
H -17), 4.91 (1H, ddd, J = 1.4, H -17), 5.66 (1H, br.s, H-14).
b
a
13
C NMR spectrum (ꢁ, ppm): 16.1 (C-20), 19.1 (C-2), 22.4 (C-19), 22.7 (C-11), 25.7 (C-16), 32.9 (C-12), 33.9 (C-4),
36.6 (C-18), 39.2 (C-1), 39.5 (C-10), 43.7 (C-3), 49.1 (C-7), 56.3 (C-9), 60.5 (C-5), 71.7 (C-6), 108.3 (C-17), 115.5 (C-14),
145.3 (C-8), 163.9 (C-13), 171.0 (CO H).
2
+
Mass spectrum (EI, 70 eV, m/z, I , %): 320.2356 0.0016, [M] , C H O ; calcd 320.2351.
rel
20 32 3
B. A solution of the mixture of hydroxyacids 12 and 13 (290.0 mg, 0.87 mmol) in EtOH (9.0 mL) was treated with a
solution of KOH (392.0 mg, 6.99 mmol) in EtOH (11.0 mL). The resulting mixture was refluxed for 1 h. The usual work up
gave a solid (282.0 mg) that was chromatographed over a column of SiO (28 g) with elution by hexane:EtOAc (85:15) to
2
13
afford crystalline 15 (214.0 mg, 77%) and 16 (60.0 mg, 22%). The PMR and C NMR spectra of 15 and 16 agreed with those
obtained above.
Methyl Ester of 13E-6ꢀ-Hydroxylabda-8(17),13-dien-15-oic Acid (12). A solution of 15 (200.0 mg, 0.63 mmol)
in THF (2.7 mL) was stirred, treated with a solution of TMSCHN (2.0 M in hexane, 1.3 mL), and stirred for 30 min. The
2
solvent was vacuum distilled. The product (226.0 mg) was chromatographed over a column of SiO (22 g) with elution by
2
25
hexane:EtOAc (9:1) to afford liquid 12 (202.0 mg, 97%), [ꢀ] +54.5° (c 0.30). Mass spectrum (EI, 70 eV, m/z, I , %):
D
rel
+
334.2507 0.0018, [M] , C H O ; calcd 334.2508.
21 34
3
PMR spectrum (ꢁ, ppm, J/Hz): 0.68 (3H, s, CH -20), 0.99 (3H, s, CH -19), 1.08 (1H, d, J = 11.0, H-5), 1.15 (3H, s,
3
3
CH -18), 1.58 (1H, br.d, J = 11.0, H-9), 1.00–1.70 (8H, m), 1.96 (1H, dddd, J = 1.0, 4.0, 10.0, 14.0, H -12), 2.02 (br.dd,
3
a
J = 1.0, 11.0, 12.0, H -7), 2.14 (3H, d, J = 1.4, CH -16), 2.28 (1H, dddd, J = 1.0, 6.0, 10.0, 14.0, H -12), 2.66 (1H, dd, J = 5.0,
ꢀ
3
b
11.0, 11.0, H -7), 3.67 (3H, s, MeO), 3.82 (1H, br.ddd, J = 5.0, 11.0, 11.0, H-6), 4.55 (1H, ddd, J = 1.4, H -17), 4.90 (1H, ddd,
ꢃ
b
J = 1.4, H -17), 5.62 (1H, m, H-14).
a
13
C NMR spectrum (ꢁ, ppm); 16.1 (C-20), 18.9 (C-16), 19.1 (C-2), 21.8 (C-11), 22.4 (C-19), 33.9 (C-4), 36.6 (C-18),
39.3 (C-1), 39.4 (C-10), 39.8 (C-12), 43.7 (C-3), 49.1 (C-7), 50.8 (CO CH ), 55.3 (C-9), 60.5 (C-5), 71.7 (C-6), 108.3 (C-17),
2
3
115.1 (C-14), 145.2 (C-8), 160.8 (C-13), 167.3 (CO CH ).
2
3
Methyl Ester of 13Z-6ꢀ-Hydroxylabda-8(17),13-dien-15-oic Acid (13). A solution of 16 (120.0 mg, 0.38 mmol)
in THF (1.6 mL) was stirred, treated with a solution of TMSCHN (2.0 M in hexane, 0.76 mL), and stirred for 30 min. The
2
solvent was vacuum distilled. The product (127.0 mg) was chromatographed over a column of SiO (12 g) with elution by
2
21
–1
hexane:EtOAc (9:1) to afford liquid 13 (122.0 mg, 98%), [ꢀ] +63.0° (c 0.94). IR spectrum (film, , cm ): 3430, 2930,
1735, 1647, 1438, 1265, 1160, 1021, 896. Mass spectrum (EI, 70 eV, m/z, I , %): 334.2502 0.0025, [M] , C H O ; calcd
D
+
rel
21 34 3
334.2508.
PMR spectrum (400 MHz, ꢁ, ppm, J/Hz): 0.68 (3H, s, CH -20), 0.99 (3H, s, CH -19), 1.11 (1H, d, J = 11.0, H-5), 1.15
3
3
(3H, s, CH -18), 1.68 (1H, m, H-9), 1.00–1.70 (8H, m), 1.87 (3H, d, J = 1.4, CH -16), 2.04 (1H, br.dd, J = 1.0, 11.0, 12.0,
3
3
H -7), 2.48–2.62 (2H, m, H -12), 2.68 (1H, dd, J = 5.0, 12.0, H -7), 3.65 (3H, s, MeO), 3.82 (1H, br.ddd, J = 5.0, 11.0, 11.0,
ꢀ
2
ꢃ
H-6), 4.74 (1H, ddd, J = 1.4, H -17), 4.93 (1H, ddd, J = 1.4, H -17), 5.62 (1H, m, H-14).
b
a
13
C NMR spectrum (ꢁ, ppm): 16.1 (C-20), 19.1 (C-2), 21.8 (C-11), 22.4 (C-19), 25.3 (C-16), 32.8 (C-12), 33.9 (C-4),
36.6 (C-18), 39.3 (C-1), 39.4 (C-10), 43.7 (C-3), 49.1 (C-7), 50.8 (CO CH ), 56.3 (C-9), 60.5 (C-5), 71.7 (C-6), 108.3 (C-17),
2
3
115.8 (C-14), 145.2 (C-8), 160.8 (C-13), 166.7 (CO CH ).
2
3
13E-Labda-8(17),13-dien-6ꢀ,15-diol [(+)-1] (crotonadiol). A solution of LiAlH (23.0 mg, 0.6 mmol) in dry Et O
4
2
(3.0 mL) under Ar at 0°C was stirred, treated dropwise with a solution of 12 (192.0 mg, 0.58 mmol) in anhydrous Et O
2
(7.0 mL), stirred at the same temperature for 3 h, and worked up. Distillation of solvent gave a solid (175.0 mg) that was
chromatographed over a column of SiO (10 g) with elution by hexane:EtOAc (7:3) to afford crystalline (+)-1 (151.0 mg,
2
16
86%), mp 144–145°C (EtOH), [ꢀ] +19.3° (c 0.012).
D
13
The PMR and C NMR spectra of this compound were identical to those obtained above.
13Z-Labda-8(17),13-dien-6ꢀ,15-diol (5). A solution of LiAlH (16.0 mg, 0.41 mmol) in dry Et O (3.0 mL) under
4
2
Ar at 0°C was stirred, treated dropwise with a solution of 13 (133.0 mg, 0.39 mmol) in anhydrous Et O (4.0 mL), stirred at the
2
same temperature for 3 h, and worked up. Distillation of solvent gave a solid (119.0 mg) that was chromatographed over a
402

16
column of SiO (8 g) with elution by hexane:EtOAc (7:3) to afford diol 5 (97.0 mg, 80%), liquid, [ꢀ] +41.35° (c 0.014).
2
D
–1
IR spectrum (CHCl , , cm ): 3360, 2920, 1638, 1440, 1372, 1215, 1043, 888, 870, 756.
3
PMR spectrum (400 MHz, ꢁ, ppm, J/Hz): 0.72 (3H, s, CH -20), 1.01 (3H, s, CH -19), 1.17 (3H, s, CH -18), 1.13 (1H,
3
3
3
d, J = 10.4, H-5), 1.55 (1H, br.d, J = 10.0, H-9), 1.00-1.67 (8H, m), 1.69 (3H, br.s, CH -16), 2.07 (1H, t, J = 10.4, 12.0, H -7),
3
ꢀ
2.28–2.38 (2H, m, H -12), 2.68 (1H, dd, J = 4.8, 12.0, H -7), 3.70 (2H, t, J = 6.0, H -15), 3.84 (1H, ddd, J = 4.8, 10.4, 10.4,
2
ꢃ
2
H-6), 4.56 (1H, s, H -17), 4.90 (1H, s, H -17), 5.27 (1H, t, J = 6.0, H-14).
b
a
13
C NMR spectrum (ꢁ, ppm): 16.0 (C-20), 19.1 (C-2), 22.8 (C-11), 22.4 (C-19), 23.3 (C-16), 33.9 (C-4), 35.3 (C-12),
36.7 (C-18), 39.5 (C-1), 39.4 (C-10), 43.8 (C-3), 49.0 (C-7), 56.7 (C-9), 60.5 (C-15), 60.6 (C-5), 71.6 (C-6), 109.2 (C-17),
128.7 (C-14), 130.7 (C-13), 145.6 (C-8).
+
Mass spectrum (EI, 70 eV, m/z, I , %): 306.2557 0.0021, [M] , C H O ; calcd 306.2559.
rel
20 34 2
ACKNOWLEDGMENT
The authors from P. Poni Institute are grateful for support by Project No. 264115 (STREAM), which is an integral
part of European Project FP7-REGPOT-2010-1.
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