Synthesis of (±)-ar-macrocarpene

Article abstract of DOI:10.1080/00397910701470727

An efficient first synthesis of the sesquiterpene ar-macrocarpene, an irregular sesquiterpene isolated from Cupressus macrocarpa foliage, starting from 3-methylcyclohexenone has been described, which confirmed the structures of macrocarpenes. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910701470727

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Synthesis of (±)‐ar‐Macrocarpene
A. Srikrishna a & B. Beeraiah a
a Department of Organic Chemistry, Indian Institute of Science, Bangalore,
India
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To cite this article: A. Srikrishna & B. Beeraiah (2007): Synthesis of (±)‐ar‐Macrocarpene, Synthetic
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Synthetic Communicationsw, 37: 2855–2860, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701470727
Synthesis of (+)-ar-Macrocarpene
A. Srikrishna and B. Beeraiah
Department of Organic Chemistry, Indian Institute of Science, Bangalore,
India
Abstract: An efficient first synthesis of the sesquiterpene ar-macrocarpene, an
irregular sesquiterpene isolated from Cupressus macrocarpa foliage, starting from
3-methylcyclohexenone has been described, which confirmed the structures of
macrocarpenes.
Keywords: cuparenes, macrocarpenes, sesquiterpenes, terpene synthesis
Cupressus macrocarpa Hartw. ex Gord. (Moneterey cypress) is a large and
picturesque tree and is the best known and most widely planted conifer in
California. A number of sesquiterpenes were ubiquitous in C. macrocarpa
foliage, such as a-cubebene, b-funebrene, caryophyllene, germacrenes, and
cedrol. Recently, Cool has reported the isolation of a number of new sesqui-
terpenes from C. macrocarpa foliage;[1] of particular interest are the five
irregular sesquiterpenes containing unprecedented carbon framework,
named macrocarpenes. Four of them are dienes 1–4 and one is aromatic 5,
which is referred as ar-macrocarpene. Structures of all the macrocarpenes
1–5 were established from their spectral data and their conversion into a
single saturated compound by hydrogenation. The absolute configuration of
ar-macrocarpene 5 has been assigned tentatively, on the basis of the optical
rotation and correlation with the related natural products in the literature.
The aromatic sesquiterpene cuparene 6, containing a 1-(aryl)-1,2,2-trimethyl-
cyclopentane carbon framework, has been known for the past five decades[2]
and has been present in a variety of essential oils. Cuparenoids also attracted
significant attention from synthetic chemists and a large number of methods
Received in India January 19, 2007
Address correspondence to A. Srikrishna, Department of Organic Chemistry, Indian
Institute of Science, Bangalore 560012, India. E-mail: ask@orgchem.iisc.ernet.in
2855

2856
A. Srikrishna and B. Beeraiah
have been developed for the construction of the aryltrimethylcyclopentane
carbon framework of cuparenoids.[3,4] Cool reported that S-cuparene 6 is
also present in C. macrocarpa as a minor constituent.[1] Structures of a macro-
carpenes 1–5 are very close to cuparene 6 (i.e., presence of a six-membered
ring in place of a five-membered ring by incorporation of the methyl carbon
on benzylic carbon of cuparene into the ring). In continuation of our
interest in the synthesis of cuparenoid natural products,[4] and because macro-
carpenes 1–6 have an unprecedented sesquiterpene carbon framework, we
contemplated confirming the structures by synthesis of ar-macrocarpene 5,
which is the subject of this communication.
To confirm the structures of macrocarpenes, a rapid synthesis of ar-
macrocarpene has been undertaken. The synthetic sequence starting from
3-methylcyclohexenone[5] 7 is depicted in Scheme 1. Conjugate addition of
methylmagnesium iodide in the presence of copper iodide transformed the
enone 7 into 3,3-dimethylcyclohexanone 8 in 87% yield. Reaction of the
cyclohexanone 8 with 4-methylphenylmagnesium bromide at ice temperature
Scheme 1. (a) MeMgI, CuI, Et2O; (b) 4-MeC6H4MgBr, THF; (c) POCl3, py, CH2Cl2;
(d) H2, 10% Pd-C, hexane; (e) Li, liq. NH3, THF.

Synthesis of (+)-ar-Macrocarpene
2857
generated the tertiary alcohol 9 in 96% yield. Dehydration of the tertiary
alcohol 9 with phosphorousoxy chloride and pyridine in methylene chloride
generated a 3 : 1 mixture of the olefines 10 in 94% yield, which on catalytic
hydrogenation in hexane with 10% palladium on charcoal as the catalyst
generated quantitatively (+)-ar-macrocarpene 5. Alternatively, the tertiary
alcohol 9 on reaction with lithium in liquid ammonia directly generated
(+)-ar-macrocarpene 5 in 81% yield. Synthetic ar-macrocarpene (+)-5
1
exhibited H and 13C NMR spectral data (in C6D6) identical to that reported
for the natural product.
In conclusion, we have accomplished a rapid and efficient synthesis of ar-
macrocarpene (+)-5 starting from 3-methylcyclohexenone 7 in four steps
with an overall yield of 79%. The present sequence confirms the structures
of macrocarpenes 1–5.
EXPERIMENTAL
IR spectra were recorded on Jasco FTIR 410 spectrophotometer. 1H
(300 MHz) and 13C (75 MHz) NMR spectra were recorded on JNM l-300
spectrometer. A 1:1 mixture of CDCl3 and CCl4 was used as solvent for
preparing the NMR samples. The chemical shifts (d ppm) and coupling
constants (Hz) are reported in the standard fashion with reference to either
1
internal tetramethylsilane (for H) 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 using a Micromass
Q-TOF micromass spectrometer using electrospray ionization.
3,3-Dimethylcyclohexanone 8
To a cold (2308C) magnetically stirred solution of CuI (8.66 g, 45.5 mmol) in
dry ether (10 ml), a solution of methylmagnesium iodide [prepared from Mg
(3.3 g, 136.4 mmol) and MeI (8.5 ml, 136.4 mmol) in ether (17 ml)] was
added, and the reaction mixture was stirred for 15 min at the same tempera-
ture. The resultant yellow solution was added to a solution of the enone 7
(1.0 g, 9.1 mmol) in dry ether (3 ml) at 2308C over a period of 15 min.
The reaction mixture was stirred at the same temperature for 1 h and then at
rt for 1 h. It was quenched with saturated aq. NH4Cl (10 ml) and extracted
with ether (3 ꢀ 5 ml). The combined organic layer was washed with brine
(10 ml) and dried (Na2SO4). Evaporation of the solvent and purification of
the residue over a silica-gel column using methylene chloride–hexane
(1:10) as eluent furnished the cyclohexanone 8 as a colorless oil (995 mg,
87%). IR (neat): nmax/cm21 1712. 1H NMR (300 MHz, CDCl3 þ CCl4):
d 2.19 (2H, t, J 6.9 Hz, H-6), 2.07 (2H, s, H-2), 1.90–1.75 (2H, m),

2858
A. Srikrishna and B. Beeraiah
1.60–1.48 (2H, m), 0.94 (6H, s, 2 ꢀ tert-CH3). 13C NMR (75 MHz,
CDCl3 þ CCl4): d 210.3 (C, C55O), 54.9 (CH2, C-2), 40.7 (CH2), 38.1
(CH2), 35.9 (C, C-3), 28.6 (2C, CH3, 2 ꢀ CH3), 22.5 (CH2, C-5). HRMS:
m/z calcd. for C8H15O (M þ H): 127.1123; found: 127.1125.
1-(4-Methylphenyl)-3,3-dimethylcyclohexan-1-ol 9
To an ice-cold magnetically stirred solution of the cyclohexanone 8 (200 mg,
1.59 mmol) in ether (3 ml), a solution of 4-methylphenylmagnesium bromide
[prepared from 4-bromotoluene (0.9 ml, 7.95 mmol) and Mg (309 mg,
12.7 mmol) in ether (5 ml)] was added and stirred for 30 min at the same temp-
erature. The reaction was quenched with saturated aq. NH4Cl (5 ml) and
extracted with ether (3 ꢀ 5 ml). The combined organic layer was washed
with brine (5 ml) and dried (Na2SO4). Evaporation of the solvent and purifi-
cation of the residue on a silica-gel column using ethyl acetate–hexane (1:20)
as eluent furnished the alcohol 9 as a colorless oil (333 mg, 96%). IR (neat):
1
nmax/cm21 3556, 3456, 1512, 814. H NMR (300 MHz, CDCl3 þ CCl4): d
7.31 (2H, d, J 8.1 Hz) and 7.07 (2H, d, J 8.1 Hz) [Ar-H], 2.30 (3H, s, Ar-
CH3), 2.00–1.15 (9H, m), 1.16 (3H, s) and 0.86 (3H, s) [2 ꢀ tert-CH3]. 13C
NMR (75 MHz, CDCl3 þ CCl4): d 147.3 (C), 135.8 (C), 128.8 (2C, CH),
124.5 (2C, CH), 74.2 (C, C-OH), 51.2 (CH2, C-2), 39.2 (CH2), 38.9 (CH2),
34.3 (CH3), 31.3 (C, C-3), 27.5 (CH3), 21.0 (CH3), 19.0 (CH2). HRMS: m/z
calcd. for C15H22ONa (M þ Na): 241.1568; found: 241.1576.
1-(4-Methylphenyl)-3,3-dimethylcyclohexene and
1-(4-Methylphenyl)-5,5-dimethylcyclohexenes 10
To a magnetically stirred ice-cold solution of the alcohol 9 (21 mg, 0.1 mmol) in
methylene chloride (3 ml), pyridine (0.12 ml, 1.5 mmol) and POCl3 (0.14 ml,
1.5 mmol) were added sequentially and stirred at the same temperature for
1 h. The reaction was quenched with water (5 ml) and extracted with
methylene chloride (3 ꢀ 3 ml). The combined organic layer was washed with
3 N HCl (3 ml) and brine (3 ml) and dried (Na2SO4). Evaporation of the
solvent and purification of the residue over a silica-gel column using hexane
as eluent furnished a ꢀ3:1 mixture of cyclohexenes 10 (18 mg, 94%) as
colorless oil. IR (neat): nmax/cm1 3024, 810. 1H NMR (300 MHz,
CDCl3 þ CCl4): (3:1 mixture of regioisomers) d 7.56 (2H, d, J 7.8 Hz) and
7.39 (2H, d, J 7.8 Hz) [Ar-H], 6.33 and 6.09 (1H, brs, C55CH), 2.65 (3H, s,
Ar-CH3), 2.70–2.50 (2H, m), 2.50–2.45 (1H, m), 2.15–2.06 and 1.84–1.79
(1H, m), 1.73 (2H, t, J 6.6 Hz), 1.32 and 1.39 (6H, s, 2 ꢀ tert-CH3). 13C
NMR (75 MHz, CDCl3 þ CCl4): (3 : 1 mixture of regioisomers) d 140.0 and
139.7 (C, C55CH), 135.9 (C, Ar-C), 135.5 (C, Ar-C), 122.3 and 134.2 (CH,
C55CH), 128.8 (2C, CH, 2 ꢀ Ar-CH), 125.1 (2C, CH, 2 ꢀ Ar-CH), 41.5

Synthesis of (+)-ar-Macrocarpene
2859
and 37.0 (CH2), 34.9 and 27.6 (CH2), 29.4 and 32.3 (C, CMe2), 28.5 and 30.2
(2C, CH3, 2 ꢀ tert-CH3), 23.8 and 20.2 (CH2), 21.1 (CH3, Ar-CH3).
1,1-Dimethyl-3-(4-methylphenyl)cyclohexane (ar-Macrocarpene 5)
To a solution of the mixture of cyclohexenes 10 (17 mg, 0.09 mmol) in hexane
(2 ml), 10% Pd/C (10 mg) was added and stirred at rt in an atmosphere of
hydrogen created by evacuative displacement of air (balloon) for 7 h. The
reaction mixture was filtered through a small column of silica gel using
methylene chloride. Evaporation of the solvent and purification of the
residue over a silica-gel column using hexane as eluent furnished ar-macro-
carpene (+)-5 as a colorless oil (17 mg, 100%).
Alternative Procedure
To magnetically stirred, freshly distilled (over sodium) ammonia (50 ml) in a
two-necked flask equipped with Dewar condenser, freshly cut lithium (35 mg,
5.0 mmol) was added followed by a solution of the alcohol 9 (72 mg,
0.33 mmol) in anhydrous THF (3 ml). The resulting blue solution was
stirred at 2338C for 20 min and then quenched with NH4Cl (solid). After
evaporation of ammonia, the residue was taken in water (5 ml) and
extracted with ether (3 ꢀ 5 ml). The combined organic layer was washed
with brine and dried (Na2SO4). Evaporation of the solvent and purification
of the residue over a silica-gel column using hexane as eluent furnished ar-
macrocarpene (+)-5 (54 mg, 81%) as a colorless oil. IR (neat): nmax/cm21
1
1514, 810. H NMR (300 MHz, C6D6): d 6.87 (4H, s, Ar-H), 2.33 (1H, tt, J
12.3 and 3.6 Hz, H-3), 1.89 (3H, s, Ar-CH3), 1.54 (1H, m), 1.30–0.74 (7H,
m), 0.64 (3H, s) and 0.62 (3H, s) [2 ꢀ tert-CH3]. 1H NMR (300 MHz,
CDCl3 þ CCl4): d 7.04 (4H, s, Ar-H), 2.63 (1H, tt, J 12.3 and 6.6 Hz, H-3),
2.30 (3H, s, Ar-CH3), 1.90–1.79 (1H, m), 1.70–1.10 (7H, m), 0.99 (3H, s)
and 0.94 (3H, s) [2 ꢀ tert-CH3]. 13C NMR (75 MHz, C6D6): d 145.0
(C, Ar-C), 135.3 (C, Ar-C), 129.3 (CH, 2 ꢀ Ar-CH), 127.2 (CH, 2 ꢀ Ar-
CH), 48.0 (CH2), 40.0 (CH), 39.2 (CH2), 34.6 (CH2), 33.7 (CH3, Ar-CH3),
31.3 (C, CMe2), 30.2 (CH2), 24.7 (CH3), 21.1 (CH2), 21.0 (CH3). 13C NMR
(75 MHz, CDCl3 þ CCl4): d 144.7 (C), 135.0 (C), 129.0 (2C, CH), 126.8
(2C, CH), 47.8 (CH2), 39.7 (CH), 39.1 (CH2), 34.3 (CH2), 33.7 (CH3), 31.4
(C, C-1), 24.8 (CH3), 22.9 (CH2), 21.1 (CH3).
ACKNOWLEDGMENT
We thank the Council of Scientific and Industrial Research, New Delhi, for the
research fellowship to B. B.

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A. Srikrishna and B. Beeraiah
REFERENCES
1. Cool, L. G. Phytochemistry 2005, 66, 249.
2. Enzell, C.; Erdtman, H. Tetrahedron 1958, 4, 361.
3. Kulkarni, M. G.; Davawala, S. I.; Shinde, M. P.; Dhondge, A. P.; Borhade, A. S.;
Chavhan, S. W.; Gaikwad, D. D. Tetrahedron Lett. 2006, 47, 3027, and references
cited therein.
4. (a) Srikrishna, A.; Ravikumar, P. C. Tetrahedron Lett. 2005, 46, 6105;
(b) Srikrishna, A.; Lakshmi, B. V. Tetrahedron Lett. 2005, 46, 7029;
(c) Srikrishna, A.; Lakshmi, B. V.; Ravikumar, P. C. Tetrahedron Lett. 2005, 47,
1277; (d) Srikrishna, A.; Ravikumar, P. C. Tetrahedron 2006, 62, 9393.
5. Furniss, B. S.; Hannaford, A. J.; Smith, P. W. G.; Tatchell, A. R. Vogel’s Textbook
of Practical Organic Chemistry, 5th edn.; Longman: Essex, 1989; p. 1098.