Enantiospecific synthesis and confirmation of the relative and absolute stereostructure of 11-hydroxyguaiadienes

Article abstract of DOI:10.1016/j.tetasy.2010.11.018

Enantiospecific total synthesis of two epimeric sesquiterpenes 11-hydroxyguaiadienes has been accomplished starting from the readily available monoterpene (R)-limonene, which confirmed the structure and absolute configuration of the natural products.

Full text of DOI:10.1016/j.tetasy.2010.11.018

Tetrahedron: Asymmetry 21 (2010) 2830–2833
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Enantiospecific synthesis and confirmation of the relative and absolute
stereostructure of 11-hydroxyguaiadienes
⇑
Adusumilli Srikrishna , Vijendra H. Pardeshi, Konda Mahesh
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Enantiospecific total synthesis of two epimeric sesquiterpenes 11-hydroxyguaiadienes has been accom-
plished starting from the readily available monoterpene (R)-limonene, which confirmed the structure and
absolute configuration of the natural products.
Received 11 October 2010
Accepted 22 November 2010
Available online 20 December 2010
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
1a along with clavukerin A from limonene oxide, employing an
8-endo trig radical cyclization and intramolecular aldol condensa-
Guaianes constitute
a
large group among various bicy-
tion as the key steps. However, the authors reported4b that the spe-
cific rotation of the synthetic sample did not match the value
reported2 for the natural product 1a, resulting in ambiguity over
its structure. In continuation of our interest in the synthesis of nat-
ural products5 starting from the readily available monoterpene (R)-
limonene 5, and in order to solve the ambiguity regarding the
structures of 11-hydroxyguaiadienes 1a and 1b, and also to estab-
lish their absolute configuration, the synthesis of both hydroxy-
guaiadienes 1a and 1b was undertaken.
clo[5.3.0]decane containing sesquiterpenes and are present in
plant, liverwort as well as marine sources.1 Hydroxyguaianes are
interesting oxygenated sesquiterpene natural products isolated
from plant and marine sources. In 1977, Bohlmann et al. reported2
the isolation of 11-hydroxyguaiadiene 1a from the roots of
Parthenium hysterophorus along with guaiadiene 2 and pseudoguai-
anolides 3 and 4. The structure of 11-hydroxyguaiadiene 1a was
established on the basis of the spectroscopic data, in particular,
analysis of europium induced shifts in the 1H NMR spectrum. In
2000, Nkunya et al. during their phytochemical analysis of the root
bark of Lettowianthus stellatus Diels (Annonaceae), a plant which
grows in the coastal rainforests of Kenya and Tanzania, reported3
the isolation of the epimeric 11-hydroxyguaiadiene 1b along with
several known sesquiterepenes and aporphinoid alkaloids. The
structure of 11-hydroxyguaiadiene 1b was deduced on the basis
of detailed 1 and 2D NMR studies (IR, HRMS, 1H and 13C NMR,
homonuclear COSY, HMQC, and HMBC experiments).
2. Results and discussion
It was thought (Scheme 1) that the synthesis of the isomeric
hydroxyguaiadienes 1a and 1b could be achieved by starting from
the C-6 epimeric hydroxy ketones 6a and 6b, whose synthesis from
(R)-limonene 5 was recently accomplished in our laboratory, enro-
ute to aciphyllenes,5f by employing a type II carbonyl ene reaction6
of aldehyde 7 as the key step.
OH
HO
H
H
H
H
H
H
H
H
O
O
AcO
O
OH
OH
O
O
1a
2
3
4
1b
There has been no report on the synthesis of 11-hydroxyguai-
adiene 1b and only one report4a on the synthesis of 11-hydroxy-
guaiadiene 1a. In 1996, Lee and Yoon reported the synthesis of
The synthetic sequences are depicted in Schemes 2–4. The
synthesis of the key intermediate hydroxyketones 6a and 6b has
been carried out employing the methodology developed in our lab-
oratory.5f Thus, a four step conversion of (R)-limonene 5 generated
the bromide 8, which on coupling with ethyl acetoacetate gener-
ated ketoester 9. The keto ester 9 was then transformed into
⇑
Corresponding author. Tel.: +91 8022 932 215; fax: +91 80 23600529.
E-mail address: askiisc@gmail.com (A. Srikrishna).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.11.018

A. Srikrishna et al. / Tetrahedron: Asymmetry 21 (2010) 2830–2833
2831
H
H
H
H
H
H
6
CHO
O
OH
O
O
1a β-Me
1b α-Me
6a β-Me
6b α-Me
OH
7
5
Scheme 1.
H
H
H
a-d
e
f-h
CO2Et
H
5
CHO
H
Br
CH3
O
O
7
8
9
O
i
H
H
H
H
H
j
OH
OH
OH
+
6b
6a
O
O
10
O
( 3 : 4 )
Scheme 2. Reagents: (a) O3/O2, CH2Cl2–MeOH; Me2S; (b) piperidine, AcOH, C6H6; (c) NaBH4, MeOH; (d) PBr3, py, Et2O; (e) MeCOCH2COOEt, K2CO3, acetone; (f) (CH2OH)2, p-
TSA, C6H6; (g) LAH, Et2O; (h) IBX, DMSO; (i) BF3ꢂEt2O, CH2Cl2; (j) H2, (Ph3P)3RhCl, EtOAc.
H
H
H
H
H
H
a
c
b
91%
6a
87%
93%
OH
O
O
11a
12a
1a
Scheme 3. Reagents: (a) MsCl, Et3N, CH2Cl2, rt, 6 h; (b) RhCl3ꢂH2O, EtOH; (c) MeMgCl, THF.
H
H
H
H
H
H
a
c
b
92%
6b
85%
93%
OH
O
O
11b
12b
1b
Scheme 4. Reagents: (a) MsCl, Et3N, CH2Cl2, rt, 6 h; (b) RhCl3ꢂH2O, EtOH; (c) MeMgCl, THF.
aldehyde 7 in three steps. A boron trifluoride diethyl etherate med-
iated type II carbonyl ene reaction of aldehyde 7 generated hydro-
xy ketone 10 in a stereoselective manner. Hydrogenation of the
exomethylene group in 10 using Wilkinson catalyst generated a
mixture of hydroxy ketones 6a and 6b. The stereochemistries of
the secondary methyl group as well as the other stereogenic cen-
ters in 6a and 6b were confirmed by single crystal X-ray diffraction
analysis5f of the minor isomer 6b.
ethanol for 24 h furnished dienone 12a in 91% yield. A shift in the
carbonyl absorption band to 1661 cmꢀ1 due to the dienone in the
IR spectrum and in the 1H NMR spectrum, the absence of signals
due to the diallylic methylene, and presence of a downfield singlet
at d 7.34 due to the b-olefinic proton of the dienone established the
structure of the bicyclic dienone 12a, which was further confirmed
by the 14 lines in the 13C NMR spectrum. The regioselective Grig-
nard reaction of the enone with methylmagnesium chloride fur-
It was seen that it required three steps for the conversion of
hydroxyketones 6a,b into 11-hydroxyguaiadienes 1a,b, via dehy-
dration, isomerisation of the resultant olefin, and nucleophilic
addition of the fifteenth carbon. Firstly, the sequence was carried
out with the major hydroxy ketone 6a to generate hydroxyguaiadi-
ene 1a. The reaction of the b-hydroxy ketone 6a with an excess of
methanesulphonyl chloride and triethylamine in anhydrous meth-
ylene chloride at rt furnished enone 11a in 87% yield. After explor-
ing various reagents (acidic as well as basic) for the isomerisation
of the double bond in the bicyclic dienone 11a, rhodium chloride7
was found to be suitable. Thus, refluxing a solution of the bicyclic
enone 11a with a catalytic amount of rhodium chloride hydrate in
nished the 6b,7a-11-hydroxyguaiadiene 1a in 93% yield, whose
structure was established from its spectroscopic data. Comparison
of the 1H and 13C NMR spectra of the sample obtained herein in
deuterochloroform with those reported4a by Lee and Yoon, for their
synthetic sample, revealed that both were identical. Moreover, the
1H NMR spectrum of the compound obtained in the present study
in a 1:1 mixture of deuterochloroform and hexadeuterobenzene
was found to be identical to that reported by Bohlmann et al.
for the natural product. The synthetic hydroxyguaiadiene 1a
also had a specific rotation {½a D26
¼ ꢀ34:7 (c 1.0, CHCl3)} value
ꢁ
comparable to that reported for the natural product {lit.2
½
a 2D4
ꢁ
¼
þ34:0 (c 2.5, CHCl3)} but with an opposite sign, thus establishing

2832
A. Srikrishna et al. / Tetrahedron: Asymmetry 21 (2010) 2830–2833
the absolute configuration of the natural hydroxyguaiadiene 1a as
(6S,7S).
IR (neat): m
max/cmꢀ1 2956, 2922, 2874, 2856, 1661 (C@O), 1623,
1434, 1382, 1356, 1260, 1219; 1H NMR (400 MHz, CDCl3+CCl4): d
7.34 (1H, s, H-20), 3.16 (1H, br s, H-70), 2.65-2.25 (2H, m), 2.38
(3H, s, CH3C@O), 2.20–1.70 (4H, m), 1.89 (3H, s, olefinic-CH3),
1.70–1.50 (3H, m), 0.76 (3H, d, J 6.9 Hz, sec-CH3); 13C NMR
(100 MHz, CDCl3+CCl4): d 199.9 (C, C@O), 148.1 (C), 140.0 (C),
134.7 (C), 134.6 (CH, C-20), 51.6 (CH, C-70), 38.6 (CH2), 34.5 (CH2),
34.3 (CH, C-60), 26.8 (CH2), 25.9 (CH3, CH3C@O), 23.0 (CH2), 15.2
(CH3), 13.7 (CH3); HRMS: m/z calcd for C14H20ONa (M+Na):
227.1412, found: 227.1417.
After successfully accomplishing the synthesis of 6b,7a-isomer
1a, synthesis of the diastereomeric 11-hydroxyguaiadiene 1b was
also carried out in a similar manner. Thus, reaction of the b-hydro-
xy ketone 6b with an excess of methanesulphonyl chloride and tri-
ethylamine in methylene chloride at rt furnished the enone 11b in
85% yield. Isomerisation of the double bond in the enone 11b with
rhodium chloride hydrate in ethanol furnished the dienone 12b in
92% yield. Regioselective Grignard reaction of the enone 12b with
methylmagnesium chloride in anhydrous THF furnished (6R,7S)-
11-hydroxyguaiadiene 1b in 93% yield, whose structure was
established from its spectral data. It was further confirmed by
comparing the 1H and 13C NMR spectra of the synthetic material
1b, recorded in hexadeuterobenzene, with those of the natural
compound reported3 by Nkunya et al. The optical rotation of the
4.2. 2-[(6S,7S)-6,10-Dimethylbicyclo[5.3.0]deca-1(10),2-dien-3-
yl]propan-2-ol 1a
To a cold (0 °C), magnetically stirred solution of the dienone 12a
(10 mg, 0.05 mmol) in anhydrous THF (0.5 mL) was added methyl-
magnesium chloride (3.0 M in THF, 0.25 mL, 0.75 mmol) and
stirred for 4 h at rt. The reaction was quenched with aq NH4Cl
(3 mL) and extracted with ether (3 ꢃ 3 mL). The combined organic
extract was washed with brine (5 mL) and dried (Na2SO4). Evapo-
ration of the solvent and purification of the residue on a silica gel
column using ethyl acetate–hexane (1:19) as eluent furnished
synthetic hydroxyguaiadiene 1b, ½a D26
¼ ꢀ55:1 (c 1.1, CHCl3), was
ꢁ
found to be identical to that of the natural product 1b including
the sign of rotation, {lit.3
establishing the absolute configuration of the natural product 1b
½
a 2D1
ꢁ
¼ ꢀ55:0 (c 0.25, CHCl3)}, thereby
as (6R,7S).
11-hydroxyguaiadiene 1a (10 mg, 93%) as colorless oil. ½a D26
¼
ꢁ
3. Conclusion
ꢀ34:7 (c 1.0, CHCl3); {lit.2
½
a 2D4
ꢁ
¼ þ34:0 (c 2.5, CHCl3)}; IR (neat):
m
max/cmꢀ1 3376 (OH), 2965, 2924, 2871, 2855, 1606, 1462, 1377,
The enantioselective total synthesis of both the isomers of 11-
hydroxyguaiadienes 1a and 1b has been accomplished. The present
sequence, in addition to the complete stereostructure, has also
established the absolute configuration of the natural products.
1250, 1159, 942; 1H NMR [400 MHz, (1:1) CDCl3+C6D6]: d 6.43
(1H, s, H-20), 3.16 (1H, br s, H-70), 2.35 (1H, dd, J 16.9 and
7.7 Hz), 2.25 (1H, dd, J 8.8 and 1.3 Hz), 2.14 (1H, ddd, J 11.2, 8.4
and 2.8 Hz), 2.05–1.80 (2H, m), 1.75 (3H, s, olefinic-CH3), 1.70–
1.40 (2H, m), 1.45–1.25 (2H, m), 1.28 (6H, s, H-1 and 3), 1.00–
0.80 (1H, m), 0.83 (3H, d, J 6.8 Hz, sec-CH3); 1H NMR (400 MHz,
CDCl3): d 6.40 (1H, s, H-20), 3.15 (1H, br s, H-70), 2.45 (1H, br dd, J
17.0 and 10.1 Hz), 2.40–2.20 (2H, m), 2.19 (1H, ddd, J 11.5, 8.7
and 2.9 Hz), 2.05–1.80 (3H, m), 1.75 (3H, s, olefinic-CH3), 1.65–
1.20 (3H, m), 1.36 (6H, s, 2 ꢃ tert-CH3), 0.78 (3H, d, J 6.8 Hz, sec-
CH3); 13C NMR (100 MHz, CDCl3): d 147.8 (C), 138.0 (C), 134.2
(C), 117.7 (CH, C-20), 74.4 (C, C-2), 50.9 (CH, C-70), 37.9 (CH2),
35.8 (CH2), 34.8 (CH, C-60), 29.1 (CH3), 28.9 (CH3), 26.9 (CH2),
25.5 (CH2), 14.6 (CH3), 14.5 (CH3); HRMS: m/z calcd for C15H23
(MꢀOH): 203.1800, found: 203.1800.
4. Experimental
IR spectra were recorded on a Jasco FTIR 410 and Perkin Elmer
FTIR spectrum BX and GX spectrophotometers. 1H (400 MHz) and
13C (100 MHz) NMR spectra were recorded on a Brucker Avance
400 spectrometer. The chemical shifts (d ppm) and coupling con-
stants (Hz) are reported in the standard fashion with reference to
either internal tetramethylsilane (for 1H) or the central line
(77.0 ppm) of CDCl3 (for 13C). In the 13C NMR spectra, the nature
of the carbons (C, CH, CH2, or CH3) was determined by recording
the DEPT-135 spectra, and is given in parentheses. High resolution
mass spectra were recorded on a Micromass Q-TOF micro mass
spectrometer using electron spray ionization mode. Optical rota-
tions were measured using a Jasco DIP-370 and Jasco P-1020 pola-
4.3. 1-[(6R,7S)-6,10-Dimethylbicyclo[5.3.0]deca-1(10),2-dien-3-
yl]ethanone 12b
rimeters and [a] .
values are given in units of 10ꢀ1 deg cm2 gꢀ1
D
To a magnetically stirred solution of enone5f 11b (20 mg,
0.10 mmol) in ethanol (1 mL) was added RhCl3ꢂH2O (6 mg) and
refluxed for 24 h. Ethanol was removed under reduced pressure
and the reaction mixture was filtered through a short silica gel col-
umn using CH2Cl2. Evaporation of the solvent and purification of
the residue on a silica gel column using CH2Cl2–hexane (1:19) as
eluent first furnished the unreacted starting material 11b (8 mg).
Further elution of the column using CH2Cl2–hexane (1:9) gave
the conjugated dienone 12b (11 mg, 92%, based on starting mate-
Analytical thin-layer chromatography (TLC) were performed on
glass plates (7.5 ꢃ 2.5 and 7.5 ꢃ 5.0 cm) coated with Acme’s silica
gel G containing 13% calcium sulfate as binder and various combi-
nations of ethyl acetate–hexane and methylene chloride–hexane
were used as eluent. Visualization of spots was accomplished by
exposure to iodine vapor. Acme’s silica gel (100–200 mesh) was
used for column chromatography.
4.1. 1-[(6S,7S)-6,10-Dimethylbicyclo[5.3.0]deca-1(10),
2-dien-3-yl]ethanone 12a
rial consumed) as pale blue oil. ½a D24
¼ ꢀ150:8 (c 1.1, CHCl3); IR
ꢁ
(neat):
m
max/cmꢀ1 2954, 2924, 2870, 1660 (C@O), 1620, 1435,
To a magnetically stirred solution of enone5f 11a (22 mg,
0.11 mmol) in ethanol (1 mL) was added RhCl3ꢂH2O (6 mg) and re-
fluxed for 24 h. Ethanol was then removed under reduced pressure
and the reaction mixture was filtered through a short silica gel col-
umn using CH2Cl2. Evaporation of the solvent and purification of
the residue on a silica gel column using CH2Cl2–hexane (1:19) as
eluent first furnished the unreacted starting material 11a
(11 mg). Further elution of the column with CH2Cl2–hexane (1:9)
gave the conjugated dienone 12a (10 mg, 91%, based on starting
1379, 1353, 1256, 1231, 1021; 1H NMR (400 MHz, CDCl3+CCl4): d
7.33 (1H, s, H-20), 2.64 (1H, dd, J 18.0 and 9.5 Hz), 2.60–2.15 (4H,
m), 2.37 (3H, s, CH3C@O), 2.09 (1H, ddd, J 12.3, 8.1 and 4.2 Hz),
1.88 (3H, s, olefinic-CH3), 1.77 (1H, ddd, J 13.7, 7.5 and 2.8 Hz),
1.65–1.30 (3H, m), 0.97 (3H, d, J 6.6 Hz, sec-CH3); 13C NMR
(100 MHz, CDCl3+CCl4): d 199.7 (C, C@O), 147.6 (C), 139.9 (C),
136.7 (C), 134.9 (CH, C-20), 53.8 (CH, C-70), 38.6 (CH, C-60), 37.4
(CH2), 35.1 (CH2), 29.8 (CH2), 25.7 (CH3, CH3C@O), 23.7 (CH2),
21.5 (CH3), 15.3 (CH3); HRMS: m/z calcd for C14H20ONa (M+Na):
227.1412, found: 227.1413.
material consumed) as pale blue oil. ½a D22
¼ ꢀ103:7 (c 0.7, CHCl3);
ꢁ

A. Srikrishna et al. / Tetrahedron: Asymmetry 21 (2010) 2830–2833
2833
4.4. 2-[(6R,7S)-6,10-Dimethylbicyclo[5.3.0]deca-1(10),2-dien-3-
C-60), 36.7 (CH2), 35.9 (CH2), 29.8 (CH2), 28.9 (CH3) and 28.8 (CH3)
yl]propan-2-ol 1b
[C-1 and 3], 26.4 (CH2), 21.5 (CH3), 14.8 (CH3); HRMS: m/z calcd for
C15H23 (MꢀOH): 203.1800, found: 203.1803.
To a cold (0 °C), magnetically stirred solution of the dienone 12b
(11 mg, 0.05 mmol) in dry THF (0.5 mL) was added methylmagne-
sium chloride (3.0 M in THF, 0.25 mL, 0.75 mmol) and stirred for
3 h at rt. The reaction was then quenched with aq. NH4Cl (3 mL)
and extracted with ether (3 ꢃ 3 mL). The combined organic extract
was washed with brine (5 mL) and dried (Na2SO4). Evaporation of
the solvent and purification of the residue on a silica gel column
using ethyl acetate–hexane (1:19) as eluent furnished 11-hydroxy-
Acknowledgment
We thank the Council of Scientific and Industrial Research, New
Delhi for the award of a research fellowship to V.H.P.
References
guaiadiene 1b (11 mg, 93%) as colorless oil. ½a D26
ꢁ
¼ ꢀ55:1 (c 1.1,
1. Foley, D. A.; Maguire, A. R. Tetrahedron 2010, 66, 1131.
CHCl3); {lit.3
½
a 2D1
ꢁ
¼ ꢀ55:0 (c 0.25, CHCl3)}; IR (neat):
m
max/cmꢀ1
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Phytochemistry 2000, 53, 1067.
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(reported to be in a mixture of CDCl3 and C6D6).
5. (a) Srikrishna, A.; Babu, N. C. Tetrahedron Lett. 2001, 42, 4913; (b) Srikrishna, A.;
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3398 (OH), 2948, 2923, 2868, 2855, 1453, 1373, 1360, 1164,
1
1137, 1023, 945; H NMR (400 MHz, C6D6): d 6.56 (1H, s, H-20),
2.55–2.45 (1H, m), 2.42 (1H, dd, J 16.7 and 9.4), 2.35–2.10 (2H,
m), 2.10–1.95 (2H, m), 1.81 (1H, dddd, J 13.9, 9.9, 5.1 and
2.4 Hz), 1.73 (3H, s, olefinic-CH3), 1.60–1.20 (4H, m), 1.27 (3H, s)
and 1.26 (3H, s) [H-1 and 3], 0.96 (3H, d, J 6.6 Hz, sec-CH3); 1H
NMR (400 MHz, CDCl3): d 6.37 (1H, s, H-20), 2.55–2.40 (1H, m),
2.35–2.10 (2H, m), 2.10–1.95 (2H, m), 1.85–1.70 (1H, m), 1.74
(3H, s, olefinic-CH3), 1.70–1.10 (5H, m), 1.36 (6H, s, H-1 and 3),
0.95 (3H, d, J 6.6 Hz, sec-CH3); 13C NMR (100 MHz, C6D6): d 148.1
(C, C-30), 137.1 (C), 136.9 (C), 118.0 (CH, C-20), 73.7 (C, C-2), 54.1
(CH, C-70), 39.3 (CH, C-60), 36.9 (CH2), 36.2 (CH2), 30.2 (CH2), 29.2
(CH3) and 29.0 (CH3) [C-1 and 3], 26.6 (CH2), 21.7 (CH3), 14.8
13
(CH3); C NMR (100 MHz, CDCl3): d 147.6 (C, C-30), 137.9 (C),
7. Grieco, P. A.; Nishizawa, M.; Marinovic, N.; Ehmann, W. J. J. Am. Chem. Soc. 1976,
98, 7102.
136.4 (C), 117.5 (CH, C-20), 74.3 (C, C-2), 53.7 (CH-70), 38.9 (CH,