Asymmetric total synthesis of (R)-α-cuparenone, (S)-cuparene and formal synthesis of (R)-β-cuparenone through Meinwald rearrangement and ring closing metathesis (RCM) reaction

Article abstract of DOI:10.1016/j.tet.2016.12.072

Asymmetric synthesis of enantiopure cuparenoid sesquiterpenes (R)-α-cuparenone, (S)-cuparene and a formal synthesis of (R)-β-cuparenone was presented in this article. Meinwald rearrangement of an enantiopure trisubstituted 2,3-epoxy alcohol derivative was

Full text of DOI:10.1016/j.tet.2016.12.072

Accepted Manuscript
Asymmetric total synthesis of (R)-α-cuparenone, (S)-cuparene and formal synthesis
of (R)-β-cuparenone through Meinwald rearrangement and ring closing metathesis
(RCM) reaction
Rajan Kumar, Joydev Halder, Samik Nanda
PII:
S0040-4020(16)31378-3
10.1016/j.tet.2016.12.072
TET 28364
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 14 November 2016
Revised Date: 28 December 2016
Accepted Date: 29 December 2016
Please cite this article as: Kumar R, Halder J, Nanda S, Asymmetric total synthesis of (R)-α-cuparenone,
(S)-cuparene and formal synthesis of (R)-β-cuparenone through Meinwald rearrangement and ring
closing metathesis (RCM) reaction, Tetrahedron (2017), doi: 10.1016/j.tet.2016.12.072.
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ACCEPTED MANUSCRIPT
Asymmetric total synthesis of (R)-α-cuparenone, (S)-cuparene and formal synthesis of
(R)-β-cuparenone through Meinwald rearrangement and ring closing metathesis (RCM)
reaction
Rajan Kumar, Joydev Halder and Samik Nanda*
O
O
Meinwald
rearrangement
Me
H
O
ROC
OPg
p-Tol
OPg
p-Tol
p-Tol
p-Tol
(R)-β-cuparenone
p-Tol
(R)-α-cuparenone
R = H; Pg = TBDPS
(S)-cuparene

ACCEPTED MANUSCRIPT
Asymmetric total synthesis of (R)-α-cuparenone, (S)-cuparene and formal synthesis of (R)-
β-cuparenone through Meinwald rearrangement and ring closing metathesis (RCM)
reaction
Rajan Kumar, Joydev Halder and Samik Nanda*
Department of Chemistry, Indian Institute of Technology Kharagpur, Kharagpur, 721302, India
Tel: +91-3222-283328; Fax: +91-3222-282252.
snanda@chem.iitkgp.ernet.in
Abstract: Asymmetric synthesis of enantiopure cuparenoid sesquiterpenes (R)-α-cuparenone,
(S)-cuparene and a formal synthesis of (R)-β-cuparenone was presented in this article. Meinwald
rearrangement of an enantiopure trisubstituted 2,3-epoxy alcohol derivative was the key reaction
employed to construct the quaternary streocenter in the target molecules. Ring closing metathesis
(RCM) reaction was explored in the final stage of synthesis to access the cyclopentane core of
the natural products.
Introduction
A family of sesquiterpenes known as cuparenoids containing the hypothetical cuparane skeleton
has been isolated from various natural sources. α and β-Cuparenones (1 and 2) are
cyclopentanoid sesquiterpenes isolated from the essential oil of leaves from Thuja orientallis
(Commonly known as “Morpankhi”, Family- Cupressaceae) by Sukhdeb and coworkers in
1964.1 Thuja orientalis is an evergreen, monoecious tree or shrub growing to 10-60 feet tall.
Their leaves contain essential oils (consist of several terpenoids as an essential components) used
to treat fungal infections, cancer, moles and parasitic worms. In addition Thuja orientalis is used
internally in the treatment of coughs, hemorrhages, excessive menstruation, bronchitis, asthma,
skin infections, mumps, bacterial dysentery, arthritic pains and premature blandness. Later on
both the sesquiterpenes (R-enantiomer) was isolated from the liverworts Mania fragrans in 1976
by Benesova et al.2 Whereas cuparene (3) the deoxygenated product of the α/β-cuparenone,
3
another sesquiterpene was isolated by Erdtman et al in 1958 and no significant biological
activity was reported so far for the molecule (Fig-1).
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O
O
Me
Me
Me
Me
Me
Me
Me
Me
Me
Cuparene skeleton
Me
Me
Me
1
R-(-)-α-cuparenone ( )
R-(+)- -cuparenone (2)
β
S-(-)-Cuparene (3)
Figure 1: Structure of cuparenones and cuparene
Presence of two contiguous quaternary carbon (one being stereogenic) in the above molecules
make them valuable synthetic targets. Though numerous synthetic reports were documented in
4-6
the literature for the total synthesis of the above sesquiterpenoids,
the presence of two
adjacent quaternary carbon atoms in the cuparenoid skeleton often poses a dreadful synthetic
challenge. In the quest for relatively unexplored synthetic strategies for cuparenoids, herein we
wish to report the asymmetric synthesis of α/β-cuparenones and (S)-cuparene from a common
intermediate. We envision that Meinwald rearrangement 7 of an enantiopure epoxide will lead to
the stereogenic quaternary carbon present in the target molecules and was never attempted
before.
Our proposed retrosynthesis was outlined in Scheme 1, (S)-cuparene was thought to be
synthesized from (R)-α-cuparenone through reductive deoxygenation method. RCM (ring
closing metathesis) reaction was planned at the final stage of the synthesis to construct the
cyclopentane core of the target molecules. Meinwald rearrangement of enantiopure epoxide was
envisioned as a crucial disconnection to construct the quaternary sterocenters in the target
molecules. The enantiopure epoxides was planned to be synthesized by Sharpless asymmetric
epoxidation reaction of suitable allylic alcohol. The allylic alcohol was synthesized by
employing an aldol reaction of 4-methylbenzyl cyanide with acetaldehyde (Scheme 1).
The proposed synthetic strategy was very flexible and can be regarded as enantiodivergent also
as both the enantiomer of all the target molecules can be accessed from the intermediate obtained
2

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after Meinwald rearrangement of the enantiopure epoxide. The intermediate 8 (Scheme 2)
containing the required all carbon quaternary stereocenter can be regarded as pseudo symmetric
(having pseudo σv in its structure; -CH2OTBDPS and –CHO/COMe functional group are
regarded as enantiotopic and interconvertable to each other by standard FGI). The origin of
divergency from intermediate 8, made the overall synthetic strategy very reliable and flexible as
both the enantiomer of the target compounds can be accessed by following same sequence of
reactions.
O
OH
Reductive
FGI
deoxygenation
1. RCM
O
p-Tol
2. Hydrogenation
OEt
p-Tol
p-Tol
p-Tol
(S)-Cuparene
(R)- -cuparenone (1)
α
FGI
O
OH
O
RCM
1,4-addition
ROC
p-Tol
OTBDPS
p-Tol
p-Tol
p-Tol
R = H for 1
Meinwald
2
rearrangement
R = Me for
(R)- -cuparenone (2)
β
Me
H
Me
H
CN
SAE
RCM: Ring closing metathesis
SAE: Sharpless Asymmetric Epoxidation
FGI: Functional group interconversion
Pg = TBDPS
O
OPg
OH
p-Tol
p-Tol
FGI here without affecting other side
will lead one enantiomeric target
ROC
FGI here without affecting other side
will lead one enantiomeric target
OTBDPS
p-Tol
Pseudo σv
The origin of enantiodivergency in the oveerall synthetic pathway
Scheme 1: Retrosynthetic analysis of cuparenones through exploration of Meinwald
rearrangement and RCM reaction.
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Present work:
Synthesis of (R)-α-cuparenone and (S)-cuparene: The synthesis was initiated from 4-
methylbenzyl cyanide, which on aldol reaction with Me-CHO in presence of K2CO3 afforded E-
acrylonitrile (4) as a major product in 90% yield.8 The E-geometry was confirmed by 2D-
NOESY analysis as shown in Scheme 2. Compound 4 upon reduction with DIBAL-H followed
by acid hydrolysis and further NaBH4 reduction afforded E-allylic alcohol (5) as a major product
in 85% yield. The E-geometry in compound 5 was also reconfirmed with the help of NMR
9,10b
analysis (2D-NOESY). Sharpless asymmetric epoxidation
of 5 with D-DET afforded
enantiopure epoxide 6 in 82% yield. The free hydroxyl group in 6 was then protected as its
TBDPS ether by treatment with TBDPS-Cl and imidazole to afford compound 7 in 90% yield.
Lewis acid promoted semipinacol type rearrangement of epoxides through 3,2-migration
(referred as Meinwald rearrangement) induced by epoxide ring opening was widely used in the
field of natural product synthesis.10 Suitably substituted 2,3-epoxy alcohol derivative can
undergo 1,2 or 2,3 (even 3,2) migration in a stereoselective fashion to lead quaternary
stereocenters in presence of Lewis acids. A schematic diagram for such migration was outlined
in Figure 2.
Figure 2: Lewis acid mediated Meinwald rearrangement of enantiopure epoxide 7.
As envisioned in Figure 2, Meinwald rearrangement of compound 7 was then attempted with a
series of Lewis acids as presented in Table 1.
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Table 1: Meinwald rearrangement of enantiopure 7 with different Lewis acids.
Entry
Lewis acid used
Reaction condition
(temp, solvent, time)
-78°C, DCM, 1h
-78°C, DCM, 1h
-78°C, DCM, 1h
-78°C, DCM, 1h
-78°C, DCM, 1h
-78°C, toluene, 1h
-78°C, DCM, 1h
-78°C, toluene, 1h
-78°C, DCM, 1h
-78°C, DCM, 1h
Product distribution (yield%) a
1
BF3:OEt2
MgBr2
Only 8 (30%)
NR
2
3
Hg(OCOCF3)2
Et2AlCl
Me3Al
Only 8 (40%)
Only 8 (55%)
Only 8 (50%)
Only 8 (40%)
Only 8 (40%)
Only 8 (38%)
Only 8 (32%)
Only 8 (95%)
4
5
6
Me3Al
7
Et3Al
8
Et3Al
Ti(OiPr)4
9
10
MAD
a : Isolated yield after purification; NR: No reaction; DCM: dichloromethane
From Table 1 it was observed that use of MAD (methyl aluminum bis(4-methyl-2,6-di-tert-
butylphenoxide) as Lewis acid afforded the best result in which the desired aldehyde 8 was
obtained in 95% yield as a sole product (3,2 migration as the major product due to stability of
generated carbocation type intermediate). Wittig olefination of aldehyde 8 with Ph3P=CH2
(generated from Ph3P+MeI- and LHMDS) furnished olefin 9 in 90% yield. Removal of TBDPS
functionality in compound 9 by TBAF followed by Dess-Martin periodinane (DMP) 11 oxidation
afforded aldehyde 10 in 88% yield (two steps). The aldehyde 10 was next converted to acid 11
by adopting a two stage protocol.12 In first step Wittig reaction with Ph3P=CHOMe (generated
from Ph3P+CH2OMeCl- and n-butyl lithium at -15 °C) followed by acidic hydrolysis yielded its
13
higher homologue aldehyde, which on Pinnick oxidation in second step afforded acid 11 in
60% yield (in two steps). Esterification of acid 11 with EtOH and SOCl2 afforded ester 12 in
80% yield. Installation of the gem-dimethyl group was accomplished by treating compound 12
with LDA and excess MeI 14 to furnish compound 13 in 75% yield (brsm). LiAlH4 reduction of
13 followed by Dess-Martin periodinane (DMP) oxidation afforded aldehyde 14 in 85% yield.
Treatment of CH2=CHMgBr with aldehyde 14 at -78°C furnished RCM precursor 15 in 90%
15
yield as diastereomeric mixture. Finally RCM reaction of 15 in presence of G-I catalyst in
5

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refluxing DCM followed by Dess-Martin periodinane (DMP) oxidation furnished
cyclopentenone 16 in 85% yield. Hydrogenation with Pd-C/H2 afforded (R)-α-cuparenone in
almost quantitative yield (Scheme 2; overall yield = 9.4% from 4-mehylbenzyl cyanide).
Reductive deoxygenation of (R)-α-cuparenone under Huang-Minlon condition (hydrazine
hydrate, hydrazine dihydrochloride and KOH) 16 furnished (S)-cuparene (3) in 80% yield (overall
yield = 7.5% from 4-methylbenzyl cyanide). The analytical data of our synthesized compounds
(1H-NMR, 13C-NMR, HRMS and [α]D) matches perfectly with those of reported values. The
ORTEP presentation (CCDC 1502182) of α-cuparenone was also presented in Figure-3.
Figure-3: ORTEP presentation of compound 1 (drawn at 30% probability).
6

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Scheme 2: Asymmetric synthesis of (R)-α-cuparenone and (S)-cuparene.
7

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Synthesis of (R)-β-cuparenone: The synthesis of another target terpenoid was accomplished as
depicted in Scheme 3. The synthetic journey began with aldehyde 8 (Scheme 2), addition of
MeLi followed by DMP oxidation afforded the ketone 17 in 81% yield. Attempted olefination
with standard protocol such as Wittig, Tebbe and Peterson reaction failed miserably with
substrate 17. Direct methylenation (transfer of -CH2 group) of compound 17 was carried out with
CH2Cl2 in presence of Mg and TiCl4 by following Yan’s protocol 17 to furnish olefin 18 in 60%
yield. The rest of the synthetic steps were almost similar as depicted in Scheme 2 for the
synthesis of (R)-α-cuparenone. Ring closing metathesis reaction of 21 with G-I catalyst in
refluxing DCM followed by DMP oxidation furnished cyclopentenone 22. The synthesis of (R)-
5g
β-cuparenone from 22 was reported elsewhere
hence the formal synthesis of the target
molecule was achieved.
Scheme 3: Synthesis of (R)-β-cuparenone
In conclusion we have described an efficient asymmetric synthesis of cuparenoid sesquiterpenes
α/β-cuparenones and cuparene. Lewis acid mediated Meinwald rearrangement of an enantiopure
epoxy compound was the key reaction employed to generate the quaternary stereocenter in the
target molecules. The enantiopure epoxide was synthesized by employing Sharpless asymmetric
epoxidation reaction. Finally late stage ring closing metathesis (RCM) reaction was used to
construct the cyclopentane core of the target molecules.
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Acknowledgements: Financial support from IIT-Kharagpur is gratefully acknowledged (Grant:
SGIRG). We are also thankful to DST-India (IRPHA) for Departmental NMR facilities. The
authors RK and JH are thankful to UGC-India for providing research fellowship.
Experimental Section
Materials and methods: All oxygen and/or moisture-sensitive reactions were carried out under
N2 atmosphere in glassware that had been flame-dried under vacuum (ca. 0.5 Torr) and purged
with N2 prior to use. Unless otherwise stated, materials were obtained from commercial suppliers
and used without further purification. THF, diethyl ether were distilled from sodium
benzophenone ketyl. Dichloromethane (DCM), hexane were distilled from calcium hydride.
Reactions were monitored by thin-layer chromatography (TLC) carried out on 0.25 mm silica gel
plates with UV light, ethanolic anisaldehyde, and phosphomolybdic acid/heat as developing
agents. Silica gel 100-200 mesh was used for column chromatography. Yields refer to
chromatographically and spectroscopically homogeneous materials unless otherwise stated.
°
NMR spectra were recorded on 600, 400 & 200 MHz spectrometers at 25 C in CDCl3 using
TMS as the internal standard. Chemical shifts are shown in δ, 13C NMR spectra were recorded
with a complete proton decoupling environment. The chemical shift value is listed as δΗ and δC
for 1H and 13C, respectively. Coupling constants (J) are reported in hertz (Hz) and the resonance
multiplicity abbreviations used are s, singlet; d, doublet; dd, doublet of doublets; t, triplet; q,
quartet; m, multiplet; comp, overlapping multiplets of magnetically non-equivalent protons.
Mass spectrometric analysis was performed in the CRF, IIT-Kharagpur (TOF analyzer). Optical
rotations were measured on a digital polarimeter.
(E)-2-p-tolylbut-2-enenitrile (4):
To a stirred solution of p-xylyl cyanide (5.0 g, 38.2 mmol) in MeOH (50 mL) were added K2CO3
(5.3 g, 38.2 mmol) and acetaldehyde (2.15 mL, 38.2 mmol) sequentially at room temperature,
and the reaction mixture was stirred at 65 °C for 2 h. TLC analysis indicated the disappearance
of the starting material after that reaction mixture was filtrated and the solvent was evaporated
under reduced pressure. The residue was purified by silica gel column chromatography
(EtOAc/hexane, 1:5) to afford the compound 4 (5.4 g) as a colorless oil in 90% yield.
Rf = 0.6 (EtOAc/ hexane, 1:5).
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1H NMR (400 MHz, CDCl3), δH: 7.41 (d, 2H, J = 8.4 Hz), 7.19 (d, 2H, J = 8.4 Hz), 6.84 (q, 1H,
J = 7.2 Hz), 2.36 (s, 3H), 2.19 (d, 3H, J = 7.2 Hz).
13C NMR (100 MHz, CDCl3), δc: 140.9, 139.0, 130.6, 129.8, 129.7, 125.5, 117.0, 21.3, 17.9.
HRMS (ESI) for C11H12N [M + H]+, calculated: 158.0969; found: 158.0972.
(E)-2-p-tolylbut-2-en-1-ol (5):
To a solution of 4 (12.6 g, 80.1 mmol) in dry hexane (200 mL) at -30 °C was added DIBAL-H
(1.5 M toluene solution, 54 mL) over 20 min. After 2 h at 0 °C, the reaction mixture was
quenched with dropwise addition of ice cold 3 N H2SO4 (54 mL) at 0 °C. The resulting solution
was stirred at 0 °C for 0.5 h. The organic layer was separated, and the aqueous phase was
extracted with EtOAc. The combined organic layer was washed with saturated NaHCO3 and
dried, filtered, and concentrated in vacuo. The residue in MeOH (200 mL) was treated with
NaBH4 (3.0 g, 80.0 mmol) at 0 °C for 30 min. TLC analysis indicated the disappearance of the
starting material and the reaction was quenched with dropwise addition of saturated ammonium
chloride solution. MeOH was evaporated under reduced pressure, the content of the flask was
then extracted with EtOAc, and the organic layer was washed with water and brine. The organic
layer was dried (MgSO4) and evaporated to afford the crude alcohol. Purification of the crude
product by silica gel chromatography (EtOAc/hexane, 1:8) afforded compound 5 (11.0 g) as a
colorless oil in 85% yield.
Rf = 0.3 (EtOAc/ hexane, 1:8).
1H NMR (600 MHz, CDCl3), δH: 7.21 (d, 2H, J = 7.8 Hz), 7.15 (d, 2H, J = 7.8 Hz), 5.83 (q, 1H,
J = 6.6 Hz), 4.32 (s, 2H), 2.39 (s, 3H), 1.67 (d, 3H, J = 6.6 Hz).
13C NMR (100 MHz, CDCl3), δc: 140.9, 136.8, 135.2, 129.2, 128.7, 123.3, 68.3, 21.3, 14.5.
HRMS (ESI) for C11H15O [M + H]+, calculated: 163.1123; found: 163.1128.
((2R,3R)-3-methyl-2-p-tolyloxiran-2-yl)methanol (6):
Diethyl D-(-)-tartrate (1.26 mL, 7.4 mmol) and titanium tetraisopropoxide (1.69 mL, 5.7 mmol)
were added sequentially to a mixture of powdered activated 4 Å molecular sieves (4.5 g) and
10

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dichloromethane (100 mL) at 0 °C with stirring. The reaction mixture was cooled to -20 °C, tert-
butyl hydroperoxide (2.7 M in dichloromethane, 54.8 mL, 148.2 mmol) was added dropwise
over 0.2 h, and the resulting mixture was stirred at -20 °C for 1 h. Compound 5 (9.2 g, 57 mmol)
dissolved in dichloromethane (55 mL) was then added dropwise over 0.2 h. After stirring for 15
h at -20 °C, the reaction mixture was poured into a freshly prepared ferrous sulfate solution (33 g
.
of FeSO4 7H2O and 11 g of citric acid in 100 mL of H2O) at -20 °C and stirred for 1 h. The
organic layer was separated, and the aqueous layer was extracted with Et2O. The combined
organic layer was concentrated in vacuo. To the residue in Et2O (200 mL) was added 30% NaOH
(10 mL), and the resultant mixture was stirred at 0 °C for 1 h. The two phases were then
separated, and the aqueous phase was extracted twice with Et2O. The combined organic phases
were washed with brine and dried over MgSO4. The organic solution was filtered and then
concentrated in vacuo. Purification of the crude product by silica gel chromatography
(EtOAc/hexane, 1:5) afforded compound 6 (8.3 g) in 82% yield as a colorless oil.
Rf = 0.2 (EtOAc/ hexane, 1:5).
[α]D28 = +40.2 (c =1.1, CHCl3).
1H NMR (400 MHz, CDCl3), δH: 7.23 (d, 2H, J = 8.2 Hz), 7.19 (d, 2H, J = 8.2 Hz), 3.97–3.91
(m, 2H), 3.51 (t, 1H, J = 5.6 Hz), 2.36 (s, 3H), 1.05 (d, 3H, J = 5.2 Hz).
13C NMR (100 MHz, CDCl3), δc: 137.7, 132.8, 129.2, 127.0, 66.1, 64.8, 57.0, 21.3, 14.2.
HRMS (ESI) for C11H14O2Na [M + Na]+, calculated: 201.0892; found: 201.0899.
Tert-butyl(((2R,3R)-3-methyl-2-p-tolyloxiran-2-yl)methoxy)diphenylsilane (7):
To a stirred solution of epoxide 6 (8.0 g, 44.9 mmol) in dry DCM (150 mL) were added
imidazole (6.1 g, 89.8 mmol), tert-butyl(chloro)diphenylsilane (14.0 ml, 53.9 mmol) and a
catalytic amount of DMAP sequentially at 0 °C, and the reaction mixture was stirred at room
temperature for 2 h. After that time water was added to the reaction mixture, the organic layer
was separated, and the aqueous layer was extracted with DCM. The combined organic layer was
washed with brine, dried over anhydrous MgSO4, and concentrated in vacuo. The residue was
then purified by silica gel column chromatography (EtOAc/hexane, 1:30) to afford the
compound 7 (16.8 g) in 90% yield as a colorless oil (at room temperature).
11

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Rf = 0.4 (EtOAc/ hexane, 1:30).
[α]D28 = +30.8 (c =1.5, CHCl3).
1H NMR (400 MHz, CDCl3), δH: 7.65–7.62 (m, 4H), 7.44–7.39 (m, 6H), 7.21 (d, 2H, J = 8.0
Hz), 7.13 (d, 2H, J = 8.0 Hz), 3.98–3.94 (m, 2H), 3.45–3.44 (m, 1H), 2.34 (s, 3H), 1.03 (d, 3H,
J = 5.2 Hz), 1.02 (s, 9H).
13C NMR (100 MHz, CDCl3), δc: 137.1, 135.7, 135.5, 133.5, 133.4, 133.1, 129.6, 128.6, 127.7,
127.6, 127.4, 67.0, 65.8, 56.8, 26.7, 21.1, 19.3, 14.4.
HRMS (ESI) for C27H32O2SiNa [M + Na]+, calculated: 439.2070; found: 439.2078.
(R)-3-(tert-butyldiphenylsilyloxy)-2-methyl-2-p-tolylpropanal (8):
To a solution of 7 (9.0 g, 21.6 mmol) in dichloromethane (100 mL) was added methyl aluminum
bis(4-methyl-2,6-di-tert-butylphenoxide) (0.4 M in toluene, 108 mL) at -78 °C. After being
stirred at -78 °C for 1 h, the reaction mixture was poured into a solution of cold 2 N HCl (210
mL). The organic layer was separated, and the aqueous layer was extracted with
dichloromethane. The combined organic layer was washed with brine, dried over anhydrous
MgSO4 and concentrated in vacuo. The residue was then purified by silica gel column
chromatography (EtOAc/hexane, 1:40) to afford the compound 8 (8.54 g) as a colorless oil in
95% yield.
Rf = 0.3 (EtOAc/ hexane, 1:40).
[α]D28 = +24.6 (c =0.6, CHCl3).
1H NMR (400 MHz, CDCl3), δH: 9.67 (s, 1H), 7.62–7.57 (m, 4H), 7.42–7.36 (m, 6H), 7.16–7.15
(m, 2H), 7.12–7.10 (m, 2H), 4.25–4.20 (m, 1H), 3.92–3.87 (m, 1H), 2.35 (s, 3H), 1.62 (s, 3H),
1.02 (s, 9H).
13C NMR (100 MHz, CDCl3), δc: 202.1, 137.1, 135.7, 135.6, 135.3, 133.0, 129.8, 129.7, 129.4,
127.7, 127.7, 127.1, 67.8, 55.8, 26.7, 21.0 19.3, 17.6.
HRMS (ESI) for C27H33O2Si [M + H]+, calculated: 417.2250; found: 417.2255.
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(R)-tert-butyl(2-methyl-2-p-tolylbut-3-enyloxy)diphenylsilane (9):
To a suspension of methyltriphenylphosphonium iodide (649 mg, 1.60 mmol) in dry THF (5 mL)
was added LiHMDS (1.0 M solution in THF, 1.60 mL) at 0 ºC. The yellow mixture was stirred at
0 ºC for 15 min. A solution of the aldehyde 8 (334 mg, 0.80 mmol) in 2 mL of THF was added to
the reaction mixture. The yellow suspension was stirred at room temperature for further 8 h.
After that the reaction was quenched with addition of water, and the layers were separated and
extracted with 25 mL of ether, washed with brine. The organic solution was then dried over
anhydrous MgSO4, and concentrated under vacuum. The crude residue was purified by flash
column chromatography (EtOAc/hexane, 1:100) to afford compound 9 (299 mg) in 90% yield as
a colorless oil.
Rf = 0.6 (EtOAc/ hexane, 1:100).
[α]D28 = +20.2 (c =0.8, CHCl3).
1H NMR (400 MHz, CDCl3), δH: 7.64–7.60 (m, 4H), 7.59–7.50 (m, 2H), 7.47–7.30 (m, 4H),
7.27 (d, 2H, J = 8.4 Hz), 7.16 (d, 2H, J = 8.4 Hz), 6.20 (dd, 1H, J = 10.8, 17.6 Hz), 5.21 (d, 1H,
J = 10.8 Hz), 5.13 (d, 1H, J = 18.0 Hz), 3.86 (d, 1H, J = 9.8 Hz), 3.82 (d, 1H, J = 9.8 Hz), 2.38
(s, 3H), 1.52 (s, 3H), 1.06 (s, 9H).
13C NMR (100 MHz, CDCl3), δc: 144.6, 142.4, 135.7, 135.7, 135.5, 133.6, 129.5, 129.5, 128.6,
127.6, 127.6, 127.2, 113.2, 71.3, 46.5, 26.8, 22.6, 21.0, 19.4.
HRMS (ESI) for C28H35OSi [M + H]+, calculated: 415.2457; found: 415.2462.
(R)-2-methyl-2-p-tolylbut-3-enal (10):
To an ice-cooled solution of compound 9 (4.0 g, 9.6 mmol) in dry THF (20.0 mL) was added a 1
M solution of TBAF (15.0 mL, 15.0 mmol). The reaction mixture was stirred at room
temperature for 12 h. After that the reaction was quenched with addition of water, THF was
removed under vacuum. The content of the flask was then extracted with EtOAc, and the organic
layer was washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo to afford
the crude product. The crude alcohol was used for next step without further purification.
13

ACCEPTED MANUSCRIPT
NaHCO3 (3.84 g, 40.57 mmol) was added to the solution of alcohol (1.45 g, 8.33 mmol) in 50
mL of DCM at 0 ºC, after that Dess-Martin periodinane (5.0 g, 11.18 mmol) was added to
reaction mixture at the same temperature, and the reaction mixture was gradually warmed to the
room temperature during 2 h. After completion of the reaction it was diluted with 60 mL of
DCM. The organic part was then successively washed with 40 mL of saturated sodium
thiosulfate solution, 40 mL of 5% NaHCO3 and then with 60 mL of brine solution. The organic
layer was then dried over anhydrous MgSO4 and evaporated in vacuo to furnish the crude
aldehyde. The aldehyde was subsequently purified through silica gel chromatography to afford
compound 10 (1.47 g) as a colorless oil in 88% yield (for two step).
Rf = 0.6 (EtOAc/ hexane, 1:20).
[α]D25 = +58.1 (c =1.1, CHCl3).
1H NMR (400 MHz, CDCl3), δH: 9.58 (s, 1H), 7.22 (d, 2H, J = 7.8 Hz), 7.16 (d, 2H, J = 7.8 Hz),
6.23 (dd, 1H, J = 10.8, 17.6 Hz), 5.42 (d, 1H, J = 10.8 Hz), 5.19 (d, 1H, J = 17.6 Hz), 2.37 (s,
3H), 1.55 (s, 3H).
13C NMR (100 MHz, CDCl3), δc: 199.4, 138.5, 137.2, 136.9, 129.6, 127.3, 117.1, 57.5, 20.9,
20.1.
HRMS (ESI) for C12H15O [M + H]+, calculated: 175.1123; found: 175.1129.
(R)-3-methyl-3-p-tolylpent-4-enoic acid (11):
The homologation of aldehyde 10 to acid 11 was performed through a two step sequence as
followed without isolating any intermediate.
Step1: To a suspension (methoxymethyl)triphenylphosphonium chloride (5.5 g, 16.1 mmol) in
dry THF (50 mL) was added n-butyllithium (1.6M, 10 ml, 16 mmol) at -15 ºC. After stirring for
5 min, a solution of the aldehyde 10 (418 mg, 2.4 mmol) in dry THF (8 ml) was added to the
reaction mixture at the same temperature, and was stirred for 2 h at 0 ºC. After that the reaction
solution was quenched with addition of water, and the layers were separated and extracted with
250 mL of ether. The organic solution was washed with brine and dried over anhydrous MgSO4
and concentrated in vacuo. The crude enolether was then taken in THF (10 mL) and stirred with
14

ACCEPTED MANUSCRIPT
1M HCl (10 mL) at room temperature for 1 h. Then the reaction mixture was diluted with ether
and the layers were separated. The organic layer was washed with aqueous NaHCO3 followed by
brine and dried over anhydrous MgSO4 and concentrated in vacuo.
Step 2: To a solution of homologated aldehyde (316 mg, 1.7 mmol) in tBuOH (8 ML) was added
2.0 M solution of 2-methylbut-2-ene (10.1 mL, 20.4 mmol) in THF, and the resulting solution
was stirred at room temperature for 10 min. Freshly prepared solution of NaClO2 (923 mg, 10.2
mmol) and NaH2PO4 (612 mg, 5.1 mmol) in water (8 mL) was added and the reaction mixture
was stirred for further 2 h. After that time the reaction mixture was diluted with the addition of
(20 mL) of water and extracted with EtOAc. The organic layer was then washed with brine and
dried over anhydrous MgSO4. The organic solution was then concentrated in vacuo to furnish the
crude product, which was immediately purified through silica gel chromatography
(EtOAc/hexane, 1:1) to afford acid 11 (295 mg) as a colorless oil in 60% yield (for two step).
Rf = 0.1 (EtOAc/ hexane, 1:1).
[α]D25 = -5.2(c =1.1, CHCl3).
1H NMR (400 MHz, CDCl3), δH: 7.20 (d, 2H, J = 7.8 Hz), 7.13 (d, 2H, J = 7.8 Hz), 6.14 (dd,
1H, J = 10.8, 17.6 Hz), 5.14 (d, 1H, J = 10.8 Hz), 5.08 (d, 1H, J = 17.6 Hz), 2.80 (s, 2H), 2.33
(s, 3H), 1.55 (s, 3H).
13C NMR (100 MHz, CDCl3), δc: 177.1, 145.4, 143.0, 136.0, 129.1, 126.2, 112.6, 45.5, 43.0,
25.6, 21.0.
HRMS (ESI) for C13H17O2 [M + H]+, calculated: 205.1228; found: 205.1234.
(R)-ethyl 3-methyl-3-p-tolylpent-4-enoate (12):
To a solution of acid 11 (500 mg, 2.4 mmol) in DCM (2.0 mL) was added thionyl chloride (0.23
mL, 3.2 mmol). The mixture was stirred then for 2 h at room temperature, after that dry ethanol
(24 mL) was added and the mixture was stirred for 4 h. The solvent was then evaporated under
vacuum. The Purification of the crude product by silica gel chromatography (EtOAc/hexane, 1:5)
afforded ester 12 (446 mg) as a colorless oil in 80% yield.
Rf = 0.6 (EtOAc/ hexane, 1:5).
15

ACCEPTED MANUSCRIPT
[α]D28 = -16.2(c =1.1, CHCl3).
1H NMR (400 MHz, CDCl3), δH: 7.21 (d, 2H, J = 8.2 Hz), 7.11 (d, 2H, J = 8.2 Hz), 6.14 (dd,
1H, J = 10.8, 17.2 Hz), 5.16–5.04 (m, 2H), 4.00 (q, 2H, J = 7.2 Hz), 2.77 (d, 1H, J = 3.0 Hz),
2.75 (d, 1H, J = 3.0 Hz), 2.34 (s, 3H), 1.54 (s, 3H) 1.11 (t, 3H, J = 7.2 Hz).
13C NMR (50MHz, CDCl3), δc: 171.4, 145.8, 143.2, 135.8, 128.9, 126.3, 112.2, 60.1, 45.9, 43.2,
25.6, 21.0, 14.2.
HRMS (ESI) for C15H21O2 [M + H]+, calculated: 233.1541; found: 233.1550.
(R)-ethyl 2,2,3-trimethyl-3-p-tolylpent-4-enoate (13):
Under N2 atmosphere, LDA (lithium diisopropylamide, 2.5 M in THF, 10 mL) was slowly
dropped to a stirred solution of 12 (1.8 g, 7.7 mmol) in THF (50 mL) at -78 °C. The resulting
mixture was stirred at -78 °C for 1 h, and then MeI (2.6 mL, 39.5 mmol) was added. The reaction
solution was then stirred for 8 h, and the reaction was quenched by the addition of a saturated
aqueous solution of NH4Cl. The solution was then extracted with 80 mL of EtOAc. The
combined organic phases were washed with brine, dried over MgSO4 and evaporated. The
residue was then purified through silica gel chromatography (EtOAc/hexane, 1:60) to furnish
compound 13 (1.5 g) as a colorless oil in 75% yield.
Rf = 0.3 (EtOAc/ hexane, 1:60).
[α]D28 = -71.6 (c =1.2, CHCl3).
1H NMR (400 MHz, CDCl3), δH: 7.22 (d, 2H, J = 8.4 Hz), 7.08 (d, 2H, J = 8.4 Hz), 6.80 (dd,
1H, J = 11.0, 17.4 Hz), 5.17 (dd, 1H, J = 1.2, 11.0 Hz), 5.03 (dd, 1H, J = 1.2, 17.4 Hz), 3.99 (q,
2H, J = 7.2 Hz), 2.32 (s, 3H), 1.54 (s, 3H), 1.14 (t, 3H, J = 7.2 Hz), 1.12 (s, 6H).
13C NMR (100MHz, CDCl3), δc: 176.8, 143.7, 141.7, 135.8, 128.4, 128.1, 114.0, 60.4, 49.3,
48.4, 22.5, 21.4, 21.0, 14.1.
HRMS (ESI) for C17H25O2 [M + H]+, calculated: 261.1854; found: 261.1862.
(R)-2,2,3-trimethyl-3-p-tolylpent-4-enal (14):
16

ACCEPTED MANUSCRIPT
To a solution of LAH (114 mg, 3.0 mmol,) in dry THF (9 mL) was added a solution of ester 13
(1.0 g, 3.84 mmol) in dry THF (6 mL) at 0 ºC. The reaction was then stirred at the same
temperature for 4 h. TLC analysis indicated the disappearance of the starting material and the
reaction was slowly quenched with dropwise addition of saturated sodium sulfate solution. The
precipitate was then filtered off, and the filtrate was concentrated in vacuo. The crude alcohol
was then used for next step without further purification.
According to the experimental procedure of compound 10, the crude alcohol was then converted
into aldehyde 14 (706 mg) by DMP oxidation in 85% yield (for two step) as a colorless oil.
Rf = 0.4 (EtOAc/ hexane, 1:20).
[α]D25 = -44.2 (c =1.1, CHCl3).
1H NMR (400 MHz, CDCl3), δH: 9.59 (s, 1H), 7.19 (d, 2H, J = 8.0 Hz), 7.10 (d, 2H, J = 8.0 Hz),
6.58 (dd, 1H, J = 11.0, 17.4 Hz), 5.25 (d, 1H, J = 11.0 Hz), 5.10 (d, 1H, J = 17.4 Hz), 2.31 (s,
3H), 1.53 (s, 3H), 1.01 (s, 6H).
13C NMR (50MHz, CDCl3), δc: 207.0, 142.4, 140.8, 136.1, 128.5, 128.2, 115.1, 50.9, 47.7, 20.9,
20.8, 18.9, 18.8.
HRMS (ESI) for C15H21O [M + H]+, calculated: 217.1592; found: 217.1598.
(R)-4,4,5-trimethyl-5-p-tolylhepta-1,6-dien-3-ol (15):
Aldehyde 14 (1.7 g, 7.9 mmol) was taken in 16 mL of anhydrous THF. Solution of
vinylmagnesium bromide (1.0 M in THF, 8.8 mL, 8.8 mmol) was added to it at -78 ºC. The
reaction mixture was then kept at the same temperature for 2 h, after that time saturated NH4Cl
solution was added to it. The solution was then extracted with EtOAc, and the organic layer was
washed with water and brine. The organic layer was dried (MgSO4) and evaporated to afford the
crude alcohol. Purification of the crude product by silica gel chromatography (EtOAc/hexane,
1:20) afforded an inseparable mixture of diastereomeric compound 15 (1.73 g) in 90% yield as a
colorless oil.
Rf = 0.2 (EtOAc/ hexane, 1:20).
17

ACCEPTED MANUSCRIPT
1H NMR (400 MHz, CDCl3), δH: 7.37–7.31 (m, 1H), 7.29–7.26 (m, 1H), 7.10–7.09 (m, 2H),
6.98–6.90 (m, 1H), 5.89–5.80 (m, 1H), 5.18–5.02 (m, 4H), 4.18–4.11 (m, 1H), 2.31 (s, 3H), 1.00
(s, 3H), 0.76 (s, 3H), 0.71(s, 3H).
13C NMR (50 MHz, CDCl3), δc: 146.0, 145.2, 142.8, 138.8, 138.4, 135.6, 135.5, 128.6, 128.6,
128.3, 116.2, 115.8, 113.2, 77.2, 76.5, 49.3, 48.7, 43.9, 43.6, 22.9, 22.6, 21.8, 20.9, 17.8, 17.3.
(R)-4,5,5-trimethyl-4-p-tolylcyclopent-2-enone (16):
Alcohol 15 (2.3 g, 9.4 mmol) was taken in anhydrous degassed DCM (800 mL). A catalytic
amount (5 mol%) of 1st generation Grubbs’ catalyst was then added to it and the solution was
stirred at reflux for 4 h. The reaction mixture was then cooled to room temperature and solution
was evaporated under reduced pressure. The content of the flask was then passed through a short
silica gel bed to furnish the diastereomeric cyclic alcohol (1.9 g), which was pure enough to use
in the next reaction without any further purification.
NaHCO3 (3.6 g, 43.6 mmol) was added to the solution of alcohol (1.9 g, 8.8 mmol) in 50 mL of
DCM at 0 ºC, after that Dess-Martin periodinane (4.8 g, 11.3 mmol) was added to reaction
mixture at the same temperature, and the reaction mixture was gradually warmed to the room
temperature during 2h. After completion of the reaction it was diluted with 250 mL of DCM. The
organic part was then successively washed with 80 mL of saturated sodium thiosulfate solution,
80 mL of 5% NaHCO3 and then with 60 mL of brine solution. The organic layer was then dried
over anhydrous MgSO4 and evaporated in vacuo. The residue was then purified by silica gel
chromatography (EtOAc/hexane, 1:20) to afford cyclic ketone 16 (1.71 g) as a colorless oil in
85% yield (for two step).
Rf = 0.4 (EtOAc/ hexane, 1:20).
[α]D28 = -32.6 (c =0.5, CH3COCH3).
1H NMR (400 MHz, CDCl3), δH: 7.74 (d, 1H, J = 6.0 Hz), 7.14 (d, 2H, J = 8.0 Hz), 7.06 (d, 2H,
J = 8.0 Hz), 6.22 (d, 1H, J = 6.0 Hz), 2.33 (s, 3H), 1.45 (s, 3H), 1.18 (s, 3H), 0.58 (s, 3H).
13C NMR (100MHz, CDCl3), δc: 215.1, 169.1, 140.5, 136.6, 129.4, 129.2, 126.9, 54.7, 51.8,
26.6, 26.0, 21.1, 20.2.
18

ACCEPTED MANUSCRIPT
HRMS (ESI) for C15H19O [M + H]+, calculated: 215.1436; found: 215.1440.
(R)-2,2,3-trimethyl-3-p-tolylcyclopentanone (1):
A stirred solution of cyclopentenone 16 (100 mg, 0.47 mmol) and 50 mg of 10% Pd/C in 4 mL
of ethyl acetate was stirred under hydrogen atmosphere (3 atm, in a Parr hydrogenation
apparatus) for 3 h. The solution was then filtered through a short pad of silica gel and the
solution was concentrated in vacuo. The residue was then purified by silica gel column
chromatography (EtOAc/hexane, 1:10) to afford cuparenone 1 (96.5 mg) in 95% yield as a solid.
Rf = 0.5 (EtOAc/ hexane, 1:10).
[α]D25 = -160.2 (c =0.4, CHCl3).
1H NMR (400 MHz, CDCl3), δH: 7.29 (d, 2H, J = 8.0 Hz), 7.17 (d, 2H, J = 8.0 Hz), 2.70–2.60
(m, 1H), 2.58–2.41 (m, 2H), 2.38 (s, 3 H), 1.95–1.89 (m, 1H), 1.27 (s, 3 H), 1.20 (s, 3 H), 0.62
(s, 3 H).
13C NMR (100 MHz, CDCl3), δc: 222.6, 141.9, 135.8, 128.9, 126.4, 53.2, 48.3, 33.8, 29.7, 25.3,
22.1, 20.8, 18.4.
HRMS (ESI) for C15H21O [M + H]+, calculated: 217.1592; found: 217.1599.
(S)-1-methyl-4-(1,2,2-trimethylcyclopentyl)benzene (3):
A mixture of the ketone 1 (480 mg, 2.2 mmol), hydrazine hydrate (7.0 mL, 99%), hydrazine
dihydrochloride (1.9 g) and diethylene glycol (20 mL) was heated to 125 °C in an inert
atmosphere and kept at that temperature for 2 h. The reaction mixture was then cooled to 80 °C
and solid pellets of potassium hydroxide (3.2 g) were added. The temperature was gradually
raised to 210 °C by distilling off low boiling materials. The reaction mixture was maintained at
210-220 °C for further 3 h. The reaction solution was then cooled, poured into water (30 mL),
and extracted with ether (3 x 60 mL). The distillate containing the low boiling materials was also
diluted with water (25 mL) and extracted with ether (3 x 40 mL). The combined ethereal extract
was washed with cold dilute hydrochloric acid (30 mL, 3N), water (2 x 50 mL). The organic
extract was then dried over MgSO4 and the filtrate was concentrated in vacuo. The residue was
19

ACCEPTED MANUSCRIPT
then purified by silica gel column chromatography (EtOAc/hexane, 1:100) to afford (S)-cuparene
3 (356 mg) as a colorless oil, in 80% yield.
Rf = 0.7 (EtOAc/ hexane, 1:100).
[α]D28 = -60.5 (c =0.4, CHCl3).
1H NMR (400 MHz, CDCl3), δH: 7.25 (d, 2H, J = 8.0 Hz), 7.09 (d, 2H, J = 8.0 Hz), 2.51–2.48
(m, 1H), 2.32 (s, 3H), 1.81–1.79 (m, 2H), 1.77–1.70 (m, 2H), 1.58–1.54 (m, 1H), 1.26 (s, 3H),
1.06 (s, 3H), 0.56 (s, 3H).
13C NMR (100 MHz, CDCl3), δc: 144.5, 134.7, 128.1, 126.9, 50.2, 44.1, 39.7, 36.8, 26.4, 24.3,
24.2, 20.8, 19.7.
HRMS (ESI) for C15H23 [M + H]+, calculated: 203.1800; found: 203.1807.
(R)-4-(tert-butyldiphenylsilyloxy)-3-methyl-3-p-tolylbutan-2-one (17):
Aldehyde 8 (2.2 g, 5.2 mmol) was taken in 16 mL of anhydrous diethylether. Solution of
methyllithium (3.0 M in diethoxymethane, 1.9 mL, 5.72 mmol) was added to it at 0 ºC. The
reaction mixture was kept at the same temperature for 2 h, after that time saturated NH4Cl
solution was added to it. The solution was then extracted with EtOAc, and the organic layer was
washed with water and brine. The organic layer was dried (MgSO4) and evaporated to afford the
crude alcohol this alcohol was used for next step without further purification.
NaHCO3 (1.9 g, 22.85 mmol) was added to the solution of alcohol (1.97 g, 4.6 mmol) in 22 mL
of DCM at 0 ºC, after that Dess-Martin periodinane (2.5 g, 5.9 mmol) was added to reaction
mixture at the same temperature. The reaction mixture was gradually warmed to the room
temperature during 2 h. After completion of the reaction it was diluted with 150 mL of DCM.
The organic part was then successively washed with 40 mL of saturated sodium thiosulfate
solution, 40 mL of 5% NaHCO3 and then with 30 mL of brine solution. The organic layer was
then dried over anhydrous MgSO4 and evaporated in vacuo. Purification by flash column
chromatography (EtOAc/hexane, 1:15) afforded ketone 17 (1.82 g) as a colorless oil in 81%
yield (for two step).
Rf = 0.4 (EtOAc/ hexane, 1:15).
20

ACCEPTED MANUSCRIPT
[α]D28 = +28.5 (c = 0.4, CHCl3).
1H NMR (400 MHz, CDCl3), δH: 7.65–7.62 (m, 2H), 7.51–7.50 (m, 2H), 7.48–7.40 (m, 4H),
7.39–7.31 (m, 2H), 7.13 (d, 2H, J = 8.0 Hz), 7.06 (d, 2H, J = 8.0 Hz), 4.22 (d, 1H, J = 10.0 Hz),
3.89 (d, 1H, J = 10.0 Hz), 2.34 (s, 3H), 2.00 (s, 3H), 1.61 (s, 3H) 1.01 (s, 9H).
13C NMR (100 MHz, CDCl3), δc: 209.9, 137.9, 136.7, 135.6, 135.6, 133.3, 133.1, 129.6, 129.5,
129.3, 127.6, 127.5, 126.4, 68.9, 57.5, 26.7, 26.2, 20.9, 20.4, 19.3
HRMS (ESI) for C28H35O2Si [M + H]+, calculated: 431.2406; found: 431.2430.
(R)-tert-butyl(2,3-dimethyl-2-p-tolylbut-3-enyloxy)diphenylsilane (18):
To a suspension consisting of Mg (192 mg, 8 mmol), TiCl4 (379 mg, 0.21 mL, 2 mmol), and
DCM (4 mL) was added a solution of ketone 17 (430.65 mg, 1 mmol) in DCM (3 mL) and THF
(2 mL) at 0°C. After being stirred for 30 min at 0 ºC, the resulting green-black mixture was
stirred for an additional 1 h at room temperature. The reaction mixture was cooled to 0 ºC and
saturated potassium carbonate solution (10 mL) was added and the mixture was diluted with
ether (20 mL). The organic layer was separated and washed with brine. The organic extract was
then dried over MgSO4, and the filtrate was evaporated in vacuo. Purification by flash column
chromatography (EtOAc/hexane, 1:80) afforded compound 18 (258 mg) as a colorless oil in 60%
yield.
Rf = 0.6 (EtOAc/ hexane, 1:80).
[α]D25 = -10.5 (c =1.8, CHCl3).
1H NMR (400 MHz, CDCl3), δH: 7.57–7.55 (m, 2H), 7.46–7.40 (m, 2H), 7.39–7.29 (m, 6H), 7.14
(d, 2H, J = 8.2 Hz), 7.07 (d, 2H, J = 8.2 Hz), 4.95–4.91 (m, 2H), 3.87 (d, 1H, J = 9.4 Hz), 3.83
(d, 1H, J = 9.4 Hz), 2.32 (s, 3H), 1.57 (s, 3H), 1.50 (s, 3H) 1.01 (s, 9H).
13C NMR (100 MHz, CDCl3), δc: 149.4, 142.0, 135.7, 135.3, 133.7, 133.6, 129.5, 129.4, 128.6,
127.5, 127.4, 127.0, 125.5, 111.0, 70.4, 49.0, 26.8, 22.9, 20.9, 20.5, 19.3.
HRMS (ESI) for C29H37OSi [M + H]+, calculated: 429.2613; found: 429.2619.
21

ACCEPTED MANUSCRIPT
(R)-2,3-dimethyl-2-p-tolylbut-3-en-1-ol (19):
To an ice-cooled solution of compound 18 (100 mg, 0.23 mmol) in dry THF (1.0 mL) was added
a 1 M solution of TBAF (0.3 mL, 0.3 mmol). The reaction mixture was stirred at room
temperature for 12 h. After that time the reaction was quenched with addition of water. The
content of the flask was then extracted with EtOAc, and the organic layer was washed with brine,
dried over anhydrous MgSO4 and concentrated in vacuo. Purification by flash column
chromatography (EtOAc/hexane, 1:5) afforded compound 19 (38.5 mg) in 88% yield as a
colorless oil.
Rf = 0.4 (EtOAc/ hexane, 1:5).
[α]D25 = +40.4 (c =1.2, CHCl3).
1H NMR (600 MHz, CDCl3), δH: 7.19–7.14 (m, 4H), 5.08 (s, 1H), 4.98 (s, 1H), 3.89 (d, 1H, J =
10.5 Hz), 3.84 (d, 1H, J = 10.5 Hz), 2.34 (s, 3H), 1.58 (s, 3H) 1.24 (s, 3H).
13C NMR (150 MHz, CDCl3), δc: 148.9, 141.1, 135.9, 129.1, 126.7, 112.0, 69.1, 49.1, 22.8, 20.9,
20.3.
HRMS (ESI) for C13H19O [M + H]+, calculated: 191.1436; found: 191.1440.
(R)-3,4-dimethyl-3-p-tolylpent-4-enal (20):
NaHCO3 (384 mg, 4.57 mmol) was added to the solution of alcohol (175 mg, 0.92 mmol) in 5
mL of DCM at 0 ºC, after that Dess-Martin periodinane (500 mg, 1.18 mmol) was added to
reaction mixture at the same temperature, and the reaction mixture was gradually warmed to the
room temperature during 2 h. After completion of the reaction it was diluted with 30 mL of
DCM. The organic part was then successively washed with 8 mL of saturated sodium thiosulfate
solution, 8 mL of 5% NaHCO3 and then with 6 mL of brine solution. The organic layer was then
dried over anhydrous MgSO4 and evaporated in vacuo to furnish the aldehyde.
The crude aldehyde was then used for next step without further purification. In next step
according to the experimental procedure for homologation, as described in the experimental part
of compound 11, crude aldehyde (159 mg, 0.84 mmol), was converted into homologated
aldehyde 20 (121 mg) as a colorless oil in 65% yield (overall yield for two step).
22

ACCEPTED MANUSCRIPT
Rf = 0.5 (EtOAc/ hexane, 1:10).
[α]D25 = +55.1 (c =1.5, CHCl3).
1H NMR (400 MHz, CDCl3), δH: 9.56 (s, 1H), 7.25–7.08 (m, 4H), 5.02–5.01 (m, 2H), 2.80 (s,
2H), 2.38 (s, 3H) 1.62 (s, 6H).
13C NMR (100 MHz, CDCl3), δc: 203.6, 149.9, 142.4, 136.2, 129.2, 126.1, 111.7, 52.2, 45.3,
26.0, 21.0, 20.0.
HRMS (ESI) for C14H19O [M + H]+, calculated: 203.1436; found: 203.1442.
(R)-5,6-dimethyl-5-p-tolylhepta-1,6-dien-3-ol (21):
Compound 20 (500 mg, 2.5 mmol) was then converted to its corresponding alcohol 21 (496 mg)
as a colorless oil in 86% yield in a similar way as described for the synthesis of compound 15.
Rf = 0.4 (EtOAc/ hexane, 1:10).
1H NMR (400 MHz, CDCl3), δH: 7.19–7.10 (m, 4H), 5.90–5.84 (m, 1H), 5.17 (dd, 1H, J = 5.8,
17.0 Hz), 5.08–5.01 (m, 3H), 4.18 (s, 1H), 2.32 (s, 3H), 2.19–2.14 (m, 2H), 1.56 (s, 3H), 1.49
(s, 3H).
13C NMR (100 MHz, CDCl3), δc: 152.8, 151.3, 144.1, 143.9, 142.2, 142.0, 135.8, 135.6, 129.3,
129.1, 126.5, 126.3, 113.7, 113.6, 111.3, 70.6, 70.6, 46.5, 46.4, 46.3, 45.8, 26.1, 25.7, 21.0, 20.6,
20.3.
(R)-3,4-dimethyl-4-p-tolylcyclopent-2-enone (22):
Alcohol 21 (400 mg, 1.73 mmol) was then converted to cyclic ketone 22 (285 mg) as a colorless
oil in 82% yield in similar way as described for the synthesis of compound 16.
Rf = 0.2 (EtOAc/ hexane, 1:5).
[α]D25 = +210 (c =0.4, CHCl3).
1H NMR (400 MHz, CDCl3), δH: 7.14–7.09 (m, 4H), 6.02 (s, 1H), 2.65 (d, 1H, J = 18.8 Hz),
2.53 (d, 1H, J = 18.8 Hz), 2.32 (s, 3H), 1.82 (s, 3H), 1.62 (s, 3H).
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13C NMR (100 MHz, CDCl3), δc: 208.8, 184.9, 141.3, 136.4, 130.3, 129.5, 125.7, 54.5, 50.0,
23.8, 21.0, 15.1.
HRMS (ESI) for C14H17O [M + H]+, calculated: 201.1279; found: 201.1284.
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