Synthesis of a key intermediate for the total synthesis of pseudopteroxazole

Article abstract of DOI:10.1016/j.tet.2010.01.054

A facile synthesis of a key intermediate for the total synthesis of anti-mycobacterial compound pseudopteroxazole is described employing an intramolecular Diels-Alder cyclization and an iodine-mediated oxidative aromatization step.

Full text of DOI:10.1016/j.tet.2010.01.054

Tetrahedron 66 (2010) 1997–2004
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of a key intermediate for the total synthesis of pseudopteroxazole
*
J.S. Yadav , E. Vijaya Bhasker, P. Srihari
Organic Division-I, Indian Institute of Chemical Technology, Hyderabad 500607, Andhra Pradesh, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A facile synthesis of a key intermediate for the total synthesis of anti-mycobacterial compound pseu-
dopteroxazole is described employing an intramolecular Diels–Alder cyclization and an iodine-mediated
oxidative aromatization step.
Received 30 September 2009
Received in revised form 13 January 2010
Accepted 14 January 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Available online 20 January 2010
1. Introduction
structural assignment and first total synthesis was accomplished,
while in Harmata’s7 group a chiral benzothiazine was utilized for
Marine organisms continue to be a tremendous source of nat-
ural products exhibiting significant biological properties.1 Pseu-
dopteroxazole2 and pseudopterosins A and E,3 the diterpene class
of compounds, isolated from marine soft coral pseudopterogorgia
elisabethae are recent examples, which share a common backbone
skeleton (Fig. 1) and yet display diverse biological activities. Pseu-
dopteroxazole showed inhibitory activity against Mycobacterium
tuberculosis H37Rv,2 whereas pseudopterosins were found to dis-
play potent anti-inflammatory and analgesic activities.3
the total synthesis.
In our long-term programme toward the total synthesis of
biologically active natural products,8 we have recently accomplished
the total synthesis of terpene-based natural products artemisinin
and erogorgiane.9 Herein, we wish to report the synthesis of a key
intermediate for the total synthesis of pseudopteroxazole.
2. Results and discussion
Our retrosynthetic approach for these compounds relied on
a common intermediate 4 with the required tricyclic backbone,
which could be obtained by an intramolecular Diels–Alder cycli-
zation reaction (IMDA) of compound 5 followed by an iodine-me-
diated oxidative aromatization (Scheme 1). IMDA precursor 5 could
be obtained by conversion of ketone 6 to the corresponding silyl
enol ether followed by coupling with Weinreb amide 27. Iodo ke-
O
N
7
10
5
11
H
3
1
Pseudopteroxazole 1
tone 6 was realized from b-keto ester 7 in five steps. Keto ester 7
OH
OH
O
OH
O
HO
OH
HO
O
O
was synthesized in three steps from diol 8, which in turn was
obtained by stereoselective manipulation of commercially available
(S)-(ꢀ)-citronellal 9.
OH
OH
H
H
Accordingly, our journey started with the racemic synthesis of
key intermediate 4 (starting from (ꢁ)-citronellal) and was followed
by an enantiopure synthesis following similar strategy as de-
lineated below.
Pseudopterosin E 3
Pseudopterosin A 2
Figure 1.
Ring cyclization of (S)-(ꢀ)-citronellal was achieved by an ene
reaction with ZnBr2 following a known procedure10 to yield 10 and
10a as the major products. Since the facial selectivity of hydro-
boration is directed by the neighboring chiral hydroxyl group, it
was necessary for us to invert the stereochemistry of the hydroxyl
group in compound 10 to get the desired diastereomer. Thus,
compound 10 was transformed to the required product 10a using
modified Mitsunobu inversion conditions.11 Hydroboration of 10a
using BH3$DMS followed by oxidative hydrolysis afforded mixture
of inseparable diastereomers 8 and 8a in 8:2 ratio.12 At this stage,
The presence of four chiral centers without any adjacent func-
tional groups makes this class of compounds a synthetic challenge.
While there are several synthetic efforts from various groups on
pseudopterosins,4,5 only two groups have been found to be engaged
in the total synthesis of pseudopteroxazole. In Corey’s group6 the
* Corresponding author. Tel.: þ91 40 27193030; fax: þ91 40 27160512.
E-mail address: yadavpub@iict.res.in (J.S. Yadav).
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.01.054

1998
J.S. Yadav et al. / Tetrahedron 66 (2010) 1997–2004
the required stereochemistry at C3 was installed. Selective primary
alcohol protection with TBSCl in presence of NaH afforded easily
separable (column chromatography) diastereomers 11 and 11a. The
required major diastereomer 11 was oxidized with PCC to get the
ketone 12 (Scheme 2).
CO2Me
CO2Me
b
a
c
*
*
12
OH
O
H
H
OTBS
OTBS
7
13
O
Me
CO2Me
CO2Me
OTBS
OTBS
OMe
O
N
d
e
*
OMe
OTBS
OMs
1 or 2
or 3
H
H
H
OTBS
H
H
15
14
16
O
O
O
4
5
g
O
I
O
O
f
H
H
OMe
OTBS
OH
H
H
H
18
17
OTBS
6
7
Scheme 3. Synthesis of keto-alcohol 18. Reagents and conditions: (a) LDA, NCCO2Me,
THF, ꢀ78 ꢂC, 1.5 h, 87% (9:1 mixture). (b) NaBH4, MeOH, 0 ꢂC, 0.5 h, 88%. (c) MsCl,
pyridine (10 equiv), cat. DMAP, CH2Cl2, 0 ꢂC to rt, 6 h, 94%. (d) NaOMe, MeOH, rt, 2 h,
96%. (e) LiHMDS, (MeO)MeNH.HCl, THF, ꢀ10 ꢂC to rt 3 h, 86%. (f) MeMgI, Et2O, THF,
ꢀ10 ꢂC, rt, 30 min 92%. (g) TBAF, THF, 0 ꢂC to rt 1 h, 90%.
CHO
(S)-(-)-Citronellal 9
OH
OH
8
Scheme 1. Retrosynthesis.
OH
OH
O
O
a
b
+
H
H
H
H
a
S(+)-Carvone 19
20
21
21a
CHO
+
isomers
+
OH
10a
OH
H
H
Separable diastereomers
O
10
9
b
OH
OH
d
e
c
+
H
H
H
OH
OH
OTBS
*
23
d
c
10a
+
OH
OH
22
22a
OH
OH
H
5:3
H
Inseparable
diastereomers
8
8a
O
O
OTf
f
e
+
+
H
OH
OTBS
H
H
OH
O
OTBS
H
OH
*
OH
H
H
OTBS
OTBS
24
18
Inseparable
diastereomers
18a
12
11
11a
Inseparable
Scheme 2. Synthesis of 12. Reagents and conditions: (a) ZnBr2, benzene, 5–10 ꢂC,
10 min 70%. 10 (94%), 10a 4%þother isomers 2% (b) (i).Ph3P, DIAD, 4-NO2–C6H4COOH,
benzene, 0 ꢂC to rt, 3 h, 84%. (ii). NaOMe, MeOH, rt 30 min 97%. (c) BH3$DMS, THF, 4 h,
ꢂC to rt 94%. (d) NaH, TBSCl, THF, 0 ꢂC to rt 2 h, 92%. (e) PCC, NaOAc, DCM, 30 min 0 ꢂ
to rt 94%.
diastereomers
Scheme 4. Synthesis of keto-alcohol from (S)-(þ)-carvone. Reagents and conditions:
(a) K-Selectride, THF, ꢀ78 ꢂC, 1 h, NaOH, 30% H2O2, 87%. (b) LiAlH4, THF, ꢀ78 ꢂC, 5 min
88% for, 7% for. (c) ((ꢀ)-ipc)2BH, THF, 0 ꢂC to rt 16 h, 98%. (d) NaH, TBSCl, THF, 0 ꢂC to rt,
2 h, 90%. (ii) PCC, NaOAc, DCM, 0 ꢂC to rt, 1 h, 90%. (e) LDA, N-phenyltriflimide, THF,
ꢀ78 ꢂC, 2 h, 0 ꢂC, 3 h, then rt 12 h, 92%. (f) Ethylvinyl ether, LiCl, Pd(PPh3)4, 3 N HCl,
92%.
0
C
Deprotonation of the ketone 12 on treatment with LDA followed
by reaction with methyl cyanoformate yielded -keto ester 7 as an
b
inseparable diastereomeric mixture. As the newly generated chiral
center was not a requisite in future steps, we proceeded further
with the mixture of diastereomers. The keto functionality in 7 was
reduced with NaBH4 to yield 13, which was mesylated with mesyl
chloride and DMAP in pyridine. Attempts to get the a,b-unsaturated
ester 15 by known procedures with DBU, t-BuOK or NaH yielded
The enantiopure alcohol 18 obtained from (S)-(ꢀ)-citronellal
was converted to iodide 6 via its tosyl ester followed by treatment
with NaI in acetone under reflux conditions. The methyl ketone
functionality in 6 was converted to the corresponding TBS enol
ether 25 by treating with TBSOTf in the presence of triethylamine.
Having, thus-installed the requisite diene, it was necessary to in-
troduce an appropriate dienophile to set the stage for the envis-
aged intramolecular Diels–Alder cyclization reaction. Toward this,
iodide 6 was lithiated with tert-butyllithium16 and the resulting
carbanion was quenched with Weinreb amide 27 to get IMDA
mixtures of inseparable regioisomers. Fortunately, the reaction
with NaOMe was clean to produce the desired
a,b-unsaturated
ester 15 exclusively in 94% yield.13 Ester 15 was converted to
Weinreb amide 17 by treatment with Weinreb salt14 in the pres-
ence of LiHMDS and then treated with methyl magnesium iodide to
yield ketone 17. The ketone 17 on desilylation with TBAF afforded
alcohol 18 (Scheme 3). Simultaneously, compound 18 was also
synthesized in seven steps starting from (S)-(þ)-carvone 19 as
a diastereomeric mixture in our laboratory (Scheme 4). However,
since we could not succeed in separating the diastereomers15 at any
stage after the hydroboration reaction, we had to alter our strategy
and thus proceeded with (S)-(ꢀ)-citronellal.
17
cyclization precursor 5. Treatment with TiCl4 afforded thermo-
dynamically preferred enone 26 as a light yellow solid (mp 172–
174 ꢂC) whose 1H NMR spectrum (singlet at 5.97 ppm (proton on
C10) and doublet at 3.24 ppm (proton on C12)) was consistent
with olefin migration after cycloaddition. Enone 26 was oxida-
tively aromatized with I2 in the presence of methanol18 to give 4,
which possesses most of the attributes of the shared core of the
pseudopterosins (Scheme 5).

J.S. Yadav et al. / Tetrahedron 66 (2010) 1997–2004
1999
4. Experimental section
4.1. General information
O
I
O
OTBS
c
b
a
H
H
H
H
OH
I
All the reagents employed were obtained commercially from
M/s. Aldrich and used without further purifications unless other-
wise stated. For anhydrous reactions, solvents were dried fol-
lowing known literature and removal of solvent was performed
under reduced pressure using a rotary evaporator. All reactions
requiring anhydrous conditions were carried out in oven-dried
glassware under a nitrogen atmosphere. Optical rotations were
measured using Perkin–Elmer model no.343 digital polarimeter
using a 1 mL cell with a 1 dm path length. The 1H NMR spectra
were recorded at 300 or 400 MHz, and the 13C NMR spectra were
recorded at 75 MHz/100 MHz at ambient temperature. Chemical
shifts of the 1H NMR spectra are expressed in parts per million
relative to the solvent residual signal 7.26 in CDCl3 or to tetra-
25
6
18
OTBS
O
OMe
O
d
e
H
H
O
O
5
26
4
OH
O
f
Me
N
O
H
OMe 27
28
Scheme 5. Synthesis of tricyclic core intermediate 4. Reagents and conditions: (a)
(i)TsCl, TEA, DMAP, DCM, 0 ꢂC to rt 8 h, 94%. (ii) NaI, acetone, reflux, 12 h, 88%. (b) TEA,
TBSOTf, DMAP, DCM, 0 ꢂC, 20 min. 91%. (c)t.BuLi, then, Et2O–hexane, ꢀ78 ꢂC, 15 min.
(d)TiCl4, Mol. sieves 4 Å, ꢀ78 ꢂC to rt. DCM, 6 h, 78% (overall yield for two steps c and
d). (e) I2 (6 equiv), MeOH, reflux, 2 h, 82%. (f) BBr3, ꢀ20 ꢂC to rt, DCM, 4 h, 80%.
methylsilane (
d
¼0.00). Chemical shifts of the 13C NMR spectra are
expressed in parts per million relative to the solvent signal 77.00
in CDCl3 unless otherwise noted. Mass spectra were recorded on
LCQ-Ion trap mass spectrometer (Thermo Finnigan, San Jose, USA)
for ESI and Q-TOF mass spectrometer (Q STARXL Hybrid, Applied
biosystems, USA) for HRMS. One or more of the following methods
were used for visualization: UV absorption by fluorescence
quenching; iodine staining; anisaldehyde stain (ethanol (135 mL)/
H2SO4 (5 mL)/AcOH (1.5 mL)/p-anisaldehyde 3.7 mL). Column
chromatography was performed using 60–120 mesh silica gel.
Ethyl acetate and hexane were the common eluents used unless
specified.
The racemic version of compound 4 was recrystallized in EtOH
to get colorless needles and suitable for X-ray crystallography,
which clearly showed the desired relative stereochemistry at C3,
C4, and C7 (Fig. 2).19 Unfortunately, attempts to grow crystals
from enantiopure compound 4 did not succeed.20 Thus, we have
accomplished the synthesis of a key intermediate 4 for the total
synthesis of pseudopteroxazole. Further treatment of methyl
ether 4 with BBr3 in DCM yielded compound 28, a known in-
termediate for the total synthesis of the aglycone of pseu-
dopterosins A and E.4b,5a
4.1.1. (1S,2R,5S)-5-Methyl-2-(prop-1-en-2-yl)cyclohexanol
10. To
a stirred solution of (S)-(ꢀ)-citronellal (9 g, 58.4 mmol) in anhy-
drous benzene (150 mL) was added catalytic amount of ZnBr2
(1.3 g, 5.8 mmol) at w10 ꢂC. After stirring at w10 ꢂC for 10 min, the
precipitated ZnBr2 was filtered off and washed with Et2O/hexane
(1:1, 150 mL). After concentrating the solvent, the residue was
dissolved in water and extracted with Et2O (3ꢃ100 mL). The com-
bined organic layer was washed with brine, dried over anhydrous
Na2SO4 and concentrated under reduced pressure. The crude resi-
due was purified by column chromatography on silica gel (100–
200 mesh, 5% EtOAc/hexane) to afford pure 10 (6.3 g, 70%) followed
by 10a (450 mg, 5%) as colorless oils. Rf¼0.35 and 0.3 (5% EtOAc/
25
hexane), respectively. [
a
]
D
þ10.9 (c 1.0, CHCl3); IR (neat) nmax: 3419,
2922, 2865, 1644, 1451, 1374, 1051, 1027, 888, 547 cmꢀ1
(300 MHz, CDCl3):
;
1H NMR
d
4.94–4.83 (m, 2H), 3.46 (td, J¼4.3, 10.4 Hz, 1H),
2.04 (dm, J¼12.2 Hz, 1H), 1.99–1.83 (m, 2H), 1.79–1.62 (m, 2H), 1.71
(s, 3H), 1.60–1.42 (m, 1H), 1.41–1.24 (m, 1H), 1.07–0.85 (m, 2H), 0.95
(d, J¼6.4 Hz, 3H); 13C NMR (75 MHz, CDCl3):
d 146.5, 112.7, 70.2,
54.0, 42.6, 34.2, 31.3, 29.5, 22.1, 19.1; Mass (ESI-MS) m/z: 155 (100,
[MþH]þ); HRMS (ESI): calcd for C10H19O (MþH)þ, 155.1430; found
155.1437.
4.1.2. (1R,2R,5S)-5-Methyl-2-(prop-1-en-2-yl)cyclohexyl-4-nitro-
benzoate. To a stirred solution of iso-pulegol 10 (6.0 g, 38.9 mmol),
triphenylphosphine (20.4 g, 77.9 mmol), and p-nitrobenzoic acid
(13.0 g, 77.9 mmol) in benzene (40 mL) was added dropwise dii-
sopropylazodicarboxylate (15.7 g, 77.9 mmol) at 0 ꢂC. The clear
yellow reaction mixture was stirred at room temperature for 3 h.
After filtration and washing, solvent was removed under reduced
pressure to furnish a residue, which was purified by column
chromatography on silica gel (60–120 mesh, hexane) to afford pure
Figure 2. X-ray crystal structure of rac-4.
3. Conclusions
In conclusion, we have described the synthesis of a key in-
termediate for the total synthesis of pseudopteroxazole and pseu-
dopterosins A and E. Our approach relies on an IMDA reaction
followed by an iodine-mediated oxidative aromatization reaction,
with a Mitsunobu inversion and a hydroxyl-directed hydroboration
being employed to establish the required stereochemistry. Further
studies toward the total synthesis of pseudopteroxazoles are cur-
rently being investigated.
benzoate (9.9 g, 84%) as a yellowish solid. Rf¼0.5 (Hexane). Mp 93–
25
95 ꢂC. [
a]
ꢀ52 (c 2.0, CHCl3); IR (neat) nmax: 2926, 2863, 1721,
D
1602, 1520, 1345, 1277, 1108, 1006, 925, 714 cmꢀ1
(300 MHz, CDCl3):
8.27 (d, J¼8.8 Hz, 2H), 8.16 (d, J¼8.8 Hz, 2H),
5.53 (s, 1H), 4.73 (s, 1H), 4.68 (s, 1H), 2.16–2.05 (m, 2H), 1.99–1.66
;
1H NMR
d

2000
J.S. Yadav et al. / Tetrahedron 66 (2010) 1997–2004
(m, 4H), 1.77 (s, 3H), 1.40–1.24 (m, 1H), 1.20–1.02 (m, 1H), 0.94 (d,
1463, 1390, 1254, 1073, 838, 777, 670 cmꢀ1
CDCl3):
;
1H NMR (300 MHz,
4.07 (br s, 1H), 3.66 (dd, J¼10.0, 2.2 Hz, 2H), 3.53 (dd,
J¼6.6 Hz, 3H); 13C NMR (75 MHz, CDCl3):
d
163.7, 150.3, 145.7, 136.2,
d
130.5 (2C), 123.4 (2C), 111.0, 72.2, 46.8, 39.1, 34.4, 26.9, 25.2, 22.3,
22.0; Mass (ESI-MS) m/z: 304 (100, [MþH]þ); HRMS (ESI): calcd for
C17H21O4NNa (MþNa)þ, 326.1368; found 326.1357.
J¼10.2, 6.2 Hz, 1H), 1.95–1.38 (m, 6H), 1.22–0.82 (m, 3H), 0.95 (d,
J¼6.9 Hz, 3H), 0.91 (s, 9H), 0.86 (d, J¼6.4 Hz, 3H), 0.08 (s, 6H); 13C
NMR (75 MHz, CDCl3):
d 66.1, 65.9, 46.6, 41.8, 38.2, 35.4, 26.1, 25.8,
25.5, 22.4, 18.2, 16.0, ꢀ5.6; Mass (ESI-MS) m/z: 287 (100, [MþH]þ);
HRMS (ESI): calcd for C16H35O2Si (MþH)þ, 287.2401; found
287.2400.
4.1.3. (1R,2R,5S)-5-Methyl-2-(prop-1-en-2-yl)cyclohexanol
10a. Solid benzoate (9.2 g, 30.3 mmol) obtained above was added
to a solution of a freshly prepared MeONa in MeOH [prepared from
sodium (2.1 g, 91.0 mmol) and MeOH (100 mL)] at room tempera-
ture and the resulting solution was stirred at room temperature.
After 30 min, water was added and the reaction mixture was
extracted with Et2O (3ꢃ100 mL). The combined organic layer was
washed with brine, dried over anhydrous Na2SO4 and concentrated
under reduced pressure. The crude residue was purified by chro-
matography on silica gel (60–120 mesh, 5% EtOAc/hexane) to afford
4.1.6. (2R,5S)-2-((R)-1-(tert-Butyldimethylsilyloxy)propan-2-yl)-5-
methylcyclohexanone 12. To a stirred suspension of PCC (10.3 g,
48 mmol), NaOAc (7.9 g, 96.5 mmol) in anhydrous CH2Cl2 (100 mL)
at w10 ꢂC, was added alcohol 11 (4.6 g, 16.0 mmol) in CH2Cl2
(50 mL) and stirred for 30 min. To the resulting mixture was added
silica gel (w20 g), solvent was removed under reduced pressure
and purified on a short path column of silica gel (60–120 mesh, 4%
pure neo-isopulegol 10a (4.55 g, 97%) as a colorless oil. Rf¼0.4 (5%
EtOAc/hexane) to afford pure ketone 12 (4.3 g, 94%) as a colorless
25
25
EtOAc/hexane). [
a]
ꢀ22.2 (c 2.0, CHCl3); IR (neat) nmax: 3411, 2925,
oil. Rf¼0.5 (10% EtOAc/hexane). [
a
]
þ20.0 (c 2.0, CHCl3); IR (neat)
D
D
2862, 1639, 1451, 1374, 1045, 1025, 881, 547 cmꢀ1
;
1H NMR
nmax: 2954, 2859, 1710, 1463, 1364, 1253, 1090, 1041, 839, 776,
(300 MHz, CDCl3): 4.94 (s, 1H), 4.78 (s, 1H), 4.02–3.96 (m, 1H),
d
668 cmꢀ1 1H NMR (300 MHz, CDCl3):
;
d
3.52–3.36 (m, 2H), 2.51–
2.02–1.92 (m, 2H), 1.88–1.63 (m, 3H), 1.78 (s, 3H), 1.60–1.40 (m, 2H),
2.20 (m, 3H), 2.08–1.74 (m, 4H), 1.46–1.23 (m, 2H), 1.02 (d, J¼6.2 Hz,
1.19–1.06 (m, 1H), 1.03–0.85 (m, 1H), 0.88 (d, J¼6.4 Hz, 3H); 13C
3H), 0.87 (s, 9H), 0.80 (d, J¼6.9 Hz, 3H), 0.03 (s, 3H), 0.02 (s, 3H); 13C
NMR (75 MHz, CDCl3):
d
147.2,111.2, 66.2, 48.3, 40.8, 34.7, 25.7, 23.8,
NMR (75 MHz, CDCl3): d 212.3, 65.8, 50.7, 49.7, 35.2, 33.9, 33.1, 26.8,
22.7, 22.1; Mass (ESI-MS) m/z: 155 (100, [MþH]þ); HRMS (ESI):
25.8, 22.3, 18.2, 12.7, ꢀ5.41, ꢀ5.48; Mass (ESI MS) m/z: 285 (100,
[MþH]þ); HRMS (ESI): calcd for C16H33O2Si (MþH)þ, 285.2244;
found 285.2248.
calcd for C10H19O (MþH)þ, 155.1430; found 155.1434.
4.1.4. (1R,2R,5S)-2-((R)-1-Hydroxypropan-2-yl)-5-methylcyclohex-
anol 8. To a stirred solution of (ꢀ)-neo-isopulegol 10a (3.8 g,
20.7 mmol) in anhydrous THF was added BH3$DMS (1.58 g,
20.7 mmol) dropwise over a period of 15 min. After complete ad-
dition, the reaction was stirred at 0 ꢂC for 3 h and at room tem-
perature for 4 h. The reaction was cooled to 0 ꢂC and basified with
3 N NaOH (15 mL). After 5 min, H2O2 (5.6 mL, 30% aq solution) was
added slowly (exothermic) and the reaction mixture was stirred at
room temperature. After 3 h, water was added and extracted with
EtOAc (4ꢃ100 mL). The combined organic layer was washed with
brine, dried over anhydrous Na2SO4 and concentrated under re-
duced pressure. The crude residue was purified by column chro-
matography on silica gel (230–400 mesh, 50% EtOAc/hexane) to
afford partially separated diastereomers 8 and 8a (4.0 g, 94%) as
4.1.7. (3R,6S)-Methyl-3-((R)-1-(tert-butyldimethylsilyloxy)propan-2-
yl)-6-methyl-2-oxocyclohexanecarboxylate 7. To a stirred solution of
diisopropylamine (4.0 mL, 28.2 mmol) in anhydrous THF (40 mL)
was added n-BuLi (13.2 mL, 1.6 M solution in hexane, 21.1 mmol) at
ꢀ10 ꢂC and stirred for 20 min at same temperature. To the resulting
mixture at ꢀ78 ꢂC was added a solution of ketone 12 (4 g,
14.0 mmol) in anhydrous THF (40 mL). After 30 min, was added
methyl cyanoformate (1.25 g, 14.7 mmol) at ꢀ78 ꢂC and stirred for
30 min. The reaction mixture was quenched with aq saturated
NH4Cl (30 mL) and extracted with Et2O (3ꢃ75 mL). The combined
organic layer was washed with brine, dried over anhydrous Na2SO4
and concentrated under reduced pressure. The residue was purified
by column chromatography on silica gel (100–120 mesh, 5% EtOAc/
hexane) to afford pure keto ester 7 (4.2 g, 87%) as a colorless oil.
Rf¼0.45 (10% EtOAc/hexane). IR (neat) nmax: 2954, 2931, 2858, 1749,
a colorless highly viscous oil. Rf¼0.4 (40% EtOAc/hexane).
25
Data for major product (8): Highly viscous oil. [
a]
ꢀ6.2 (c 1.0,
D
CHCl3); IR (neat) nmax: 3314, 2919, 1612, 1454, 1373, 1249, 1035, 969,
1710, 1464, 1357, 1254, 1095, 840, 776, 668 cmꢀ1
;
1H NMR
839 cmꢀ1; 1H NMR (300 MHz, CDCl3):
d
4.07 (s, 1H), 3.84 (br s, 2H,
(300 MHz, CDCl3): 3.74 (s, 3H), 3.53–3.31 (m, 2H), 3.04 (d,
d
2OH), 3.61 (dd, J¼10.9, 2.8 Hz, 1H), 3.48 (dd, J¼10.9, 5.6 Hz, 1H),
1.87–1.36 (m, 6H), 1.25–0.87 (m, 3H), 0.96 (d, J¼7.2 Hz, 3H), 0.84 (d,
J¼12.0 Hz, 1H), 2.58–2.47 (m, 1H), 2.32–2.15 (m, 2H), 2.08–1.89 (m,
2H), 1.53–1.35 (m, 2H), 1.01 (d, J¼6.4 Hz, 3H), 0.86 (s, 9H), 0.79 (d,
J¼6.9 Hz, 3H), 0.014 (s, 3H), 0.004 (s, 3H); 13C NMR (75 MHz,
J¼6.2 Hz, 3H); 13C NMR (75 MHz, CDCl3):
d 66.1, 64.5, 45.9, 42.1,
38.0, 35.3, 26.0, 25.4, 22.3, 15.8; Mass (ESI-MS) m/z: 195 (MþþNa);
HRMS (ESI): calcd for C10H20O2Na (MþNa)þ, 195.1360; found
195.1365.
CDCl3): d 206.8, 170.3, 65.5, 51.8, 49.7, 37.3, 33.1, 32.8, 26.2, 25.8,
21.0, 18.2, 12.5, ꢀ5.4, ꢀ5.5; Mass (ESI-MS) m/z: 343 (100, [MþH]þ);
HRMS (ESI): calcd for C18H35O4Si (MþH)þ, 343.2299; found
343.2297.
4.1.5. (1R,2R,5S)-2-((R)-1-(tert-Butyldimethylsilyloxy)propan-2-yl)-
5-methylcyclohexanol 11. To a well-stirred suspension of freshly
activated NaH (880 mg, 22.0 mmol, 60% dispersion in mineral oil)
in anhydrous THF (100 mL), was added a solution of mixture of
diastereomers 8 and 8a (3.6 g, 20.9 mmol) in THF (30 mL) slowly at
0 ꢂC. After 30 min, added TBSCl (3.15 g, 24.4 mmol) in anhydrous
THF (30 mL) at 0 ꢂC and then mixture was allowed to warm up to
room temperature. After 2 h, the reaction was quenched with ice
flakes and extracted with Et2O (3ꢃ100 mL). The combined organic
layer was washed with brine, dried over anhydrous Na2SO4 and
concentrated under reduced pressure. The crude residue was pu-
rified by column chromatography on silica gel (100–200 mesh, 8%
EtOAc/hexane) to afford pure compound 11 (5.0 g, 83.7%) followed
4.1.8. (3R,6S)-Methyl-3-((R)-1-(tert-butyldimethylsilyloxy)propan-2-
yl)-2-hydroxy-6-methylcyclohexanecarboxylate 13. To a stirred so-
lution of keto ester 7 (3.6 g, 10.5 mmol) in MeOH (100 mL) was
added NaBH4 (400 mg, 10.5 mmol) portion wise at 0 ꢂC. After
30 min, solvent was removed under reduced pressure and to this
was added aq saturated NH4Cl (20 mL), and extracted with EtOAc
(3ꢃ75 mL). The combined organic layer was washed with brine,
dried over anhydrous Na2SO4 and concentrated under reduced
pressure. The residue was purified by column chromatography on
silica gel (60–120 mesh, 10% EtOAc/hexane) to afford pure alcohol
13 (3.18 g, 88%) as a colorless crystalline solid. Rf¼0.5 (10% EtOAc/
hexane). Mp 48–50 ꢂC. IR (neat) nmax: 3517, 2953, 2930, 2858, 1715,
by 11a (495 mg, 8.3%) as colorless oils. Rf¼0.5 and 0.4 (20% EtOAc/
1463, 1254, 1200, 1090, 838, 775, 669 cmꢀ1
;
1H NMR (300 MHz,
25
hexane). [
a
]
ꢀ9.3 (c 1.0, CHCl3); IR (neat) nmax: 3442, 2926, 2860,
CDCl3): 4.19 (s, 1H), 3.68 (s, 3H), 3.63–3.49 (m, 2H), 3.41 (d,
d
D

J.S. Yadav et al. / Tetrahedron 66 (2010) 1997–2004
2001
J¼2.2 Hz, 1H), 2.12–2.00 (m, 2H), 1.82–1.43 (m, 4H), 1.25–1.09 (m,
2H), 0.94–0.85 (m, 15H), 0.04 (s, 3H), 0.034 (s, 3H); 13C NMR
(75 MHz, CDCl3): 175.3, 68.0, 66.5, 55.3, 51.4, 45.4, 37.4, 34.4, 27.8,
1463, 1409, 1371, 1253, 1092, 988, 841, 776, 669 cmꢀ1
(300 MHz, CDCl3):
3.25 (s, 3H), 2.67–2.52 (m,1H), 2.48–2.37 (m,1H),1.94–1.63 (m, 3H),
;
1H NMR
d
5.89 (s, 1H), 3.65 (s, 3H), 3.56–3.42 (m, 2H),
d
25.7, 23.9, 20.6, 18.1, 15.8, ꢀ5.66, ꢀ5.63; Mass (ESI-MS) m/z: 345
(100, [MþH]þ); HRMS (ESI): m/z calcd for C18H37O4Si (MþH)þ,
345.2456; found 345.2459.
1.38–1.17 (m, 2H), 0.99 (d, J¼6.9 Hz, 3H), 0.88 (s, 9H), 0.81 (d,
J¼6.9 Hz, 3H), 0.03 (s, 6H); 13C NMR (75 MHz, CDCl3):
d 171.4, 139.8,
134.1, 65.8, 60.8, 39.6, 37.0, 33.5, 31.4, 31.0, 25.8, 22.9,19.4,18.2,12.8,
ꢀ5.41, ꢀ5.46; Mass (ESI-MS) m/z: 356 (100, [MþH]þ); HRMS (ESI):
calcd for C19H38NO3Si (MþH)þ, 356.2615; found 356.2614.
4.1.9. (3R,6S)-Methyl-3-((R)-1-(tert-butyldimethylsilyloxy)propan-2-
yl)-6-methyl-2-(methylsulfonyloxy)cyclohexanecarboxylate
14. To
a solution of alcohol 13 (2.8 g, 8.1 mmol) and pyridine (6.4 g,
81.4 mmol) in anhydrous CH2Cl2 (50 mL) at w5 ꢂC was added
methanesulphonylchloride (2.8 g, 24.4 mmol), catalytic amount of
DMAP (100 mg, 10 mol %) and allowed to stir at room temperature.
After 6 h, the reaction mixture was quenched with aq saturated
NaHCO3 (20 mL) and extracted with CH2Cl2 (3ꢃ50 mL). The com-
bined organic layer was washed with brine, dried over anhydrous
Na2SO4 and concentrated under reduced pressure. The residue was
purified by column chromatography on silica gel (60–120 mesh,
10% EtOAc/hexane) to afford the pure mesyl-ester 14 (3.2 g, 94%) as
a colorless oil. Rf¼0.5 (10% EtOAc/hexane). IR (neat) nmax: 2953,
2857, 1740, 1463, 1340, 1253, 1174, 1092, 1021, 901, 838, 777,
4.1.12. 1-((3S,6S)-3-((R)-1-(tert-Butyldimethylsilyloxy)propan-2-yl)-
6-methylcyclohex-1-enyl)ethanone 17. To a solution of the Weinreb
amide 16 (1.2 g, 3.4 mmol) in THF (30 mL) at ꢀ20 ꢂC was added
MeMgI (10.1 mL, 1.0 M solution in THF, 10.1 mmol) over 10 min. The
resulting solution was allowed to warm to room temperature and
stirred for 30 min. The reaction mixture was quenched with aq
saturated NH4Cl solution diluted with water (25 mL), and then
extracted with Et2O (3ꢃ50 mL). The combined organic layer was
washed with brine, dried over anhydrous Na2SO4 and concentrated
under reduced pressure. The residue was purified by column
chromatography on silica gel (60–120 mesh, 4% EtOAc/hexane) to
afford pure ketone 17 (960 mg, 92%) as a colorless oil. Rf¼0.5 (5%
25
539 cmꢀ1; 1H NMR (300 MHz, CDCl3):
d
5.35 (s, 1H), 3.81 (dd, J¼3.9,
EtOAc/hexane). [
a
]
D
ꢀ48.8 (c 1.0, CHCl3); IR (neat) nmax: 2954,
10.3 Hz, 1H), 3.68 (s, 3H), 3.46 (dd, J¼3.2, 10.3 Hz, 1H), 3.03 (s, 3H),
2.16–1.97 (m, 2H), 1.83 (dq, J¼3.4, 13.4 Hz, 1H), 1.74–1.49 (m, 3H),
1.36 (qd, J¼3.6, 12.6 Hz, 1H), 1.10–0.97 (m, 1H), 0.93 (d, J¼6.8 Hz,
3H), 0.91–0.85 (m,12H), 0.05 (s, 3H), 0.03 (s, 3H); 13C NMR (75 MHz,
2931, 2859, 1670, 1630, 1466, 1387, 1363, 1251, 1094, 840, 776,
669 cmꢀ1; 1H NMR (300 MHz, CDCl3):
d
6.72 (d, J¼3.2 Hz,1H), 3.59–
3.48 (m, 2H), 2.77–2.63 (m, 1H), 2.52–2.41 (m, 1H), 2.28 (s, 3H),
1.84–1.59 (m, 3H), 1.41–1.24 (m, 2H), 1.00 (d, J¼6.8 Hz, 3H), 0.90 (s,
9H), 0.84 (d, J¼6.9 Hz, 3H), 0.05 (s, 6H); 13C NMR (75 MHz, CDCl3):
CDCl3): d 172.6, 80.3, 65.1, 54.6, 51.7, 41.9, 39.0, 35.3, 33.6, 27.3, 25.8,
23.0, 20.0, 18.2, 15.3, ꢀ5.6, ꢀ5.7; Mass (ESI-MS) m/z: 423 (100,
[MþH]þ); HRMS (ESI): calcd for C19H39O6SSi (MþH)þ, 423.2231;
found 423.2230.
d 199.8,145.2,144.2, 65.8, 39.9, 36.8, 29.3, 27.8, 26.0, 25.8, 20.3, 20.0,
18.2, 13.7, ꢀ5.44, ꢀ5.47; Mass (ESI-MS) m/z: 311 (100, [MþH]þ);
HRMS (ESI): calcd for C18H35O2Si (MþH)þ, 311.2401; found
311.2403.
4.1.10. (3R,6S)-Methyl-3-((R)-1-(tert-butyldimethylsilyloxy)propan-
2-yl)-6-methylcyclohex-1-enecarboxylate 15. To a stirred solution of
mesyl-ester 14 (2.5 g, 5.9 mmol) in MeOH (50 mL) was added
NaOMe (950 mg, 17.7 mmol) at 0 ꢂC and stirred at room tempera-
ture for 2 h. Solvent was removed under reduced pressure, and the
residue was quenched with aq saturated NH4Cl, diluted with water
and extracted with Et2O (3ꢃ50 mL). The combined organic layer
was washed with brine, dried over anhydrous Na2SO4 and con-
centrated under reduced pressure. The residue was purified by
column chromatography on silica gel (60–120 mesh, 3% EtOAc/
4.1.13. 1-((3S,6S)-3-((R)-1-Hydroxypropan-2-yl)-6-methylcyclohex-
1-enyl)ethanone 18. To a stirred solution of ketone 17 (870 mg,
2.8 mmol) in THF (15 mL) at 0 ꢂC was added TBAF (7 mL, 1.0 M so-
lution in THF, 7.0 mmol) over 10 min. After stirring at room tem-
perature for 1 h, the mixture was poured in to saturated NH4Cl
(20 mL) and extracted with Et2O (3ꢃ60 mL). The combined organic
layer was washed with brine, dried over anhydrous Na2SO4 and
concentrated under reduced pressure. The residue was purified by
column chromatography on silica gel (60–120 mesh, 30% EtOAc/
hexane) to afford pure
a colorless oil. Rf¼0.6 (5% EtOAc/hexane). [
IR (neat) nmax: 2953, 2859, 1717, 1639, 1465, 1250, 1092, 840, 775,
669 cmꢀ1; 1H NMR (300 MHz, CDCl3):
6.82–6.76 (m, 1H), 3.72 (s,
a
,
b
-unsaturated ester 15 (1.85 g, 95.8%) as
hexane) to afford the pure alcohol 18 (490 mg, 90%) as a colorless
25
25
a
]
D
ꢀ20.3 (c 1.0, CHCl3);
oil. Rf¼0.4 (30% EtOAc/hexane). [
a
]
ꢀ53.0 (c 1.0, CHCl3); IR (neat)
D
nmax: 3415, 2930, 2873, 1663, 1458, 1387, 1361, 1247, 1033, 942, 880,
d
605 cmꢀ1; 1H NMR (300 MHz, CDCl3):
d
6.71 (d, J¼2.8 Hz,1H), 3.70–
3H), 3.50 (d, J¼6.2 Hz, 2H), 2.66–2.52 (m, 1H), 2.43–2.31 (m, 1H),
3.53 (m, 2H), 2.79–2.62 (m, 1H), 2.54–2.42 (m, 1H), 2.29 (s, 3H), 2.10
(br s, –OH, 1H), 1.91–1.63 (m, 3H), 1.44–1.25 (m, 2H), 1.00 (d,
J¼6.8 Hz, 3H), 0.89 (d, J¼7.0 Hz, 3H); 13C NMR (75 MHz, CDCl3):
1.89–1.55 (m, 3H), 1.40–1.21 (m, 2H), 1.05 (d, J¼6.9 Hz, 3H), 0.87 (s,
9H), 0.82 (s, 3H), 0.028 (s, 6H); 13C NMR (75 MHz, CDCl3):
d 168.2,
143.2, 135.6, 65.8, 51.3, 39.8, 36.9, 29.9, 29.0, 25.8, 20.9, 20.2, 18.2,
13.6, ꢀ5.45, ꢀ5.47; Mass (ESI-MS) m/z: 327 (100, [MþH]þ); HRMS
(ESI): calcd for C18H35O3Si (MþH)þ, 327.2350; found 327.2351.
d 200.0, 145.4, 143.5, 65.7, 39.9, 37.0, 29.4, 27.9, 26.0, 20.6, 20.0, 13.6;
Mass (ESI-MS) m/z: 197 (100, [MþH]þ); HRMS (ESI): calcd for
C12H21O2 (MþH)þ, 197.1536; found 197.1535.
4.1.11. (3R,6S)-3-((R)-1-(tert-Butyldimethylsilyloxy)propan-2-yl)-N-
methyoxy-N,6-dimethylcyclohex-1-enecarboxamide 16. To a solu-
tion of unsaturated ester 15 (1.5 g, 4.6 mmol) and Me(OMe)NH$HCl
(670 mg, 6.9 mmol) in anhydrous THF (30 mL) at ꢀ10 ꢂC was added
LiHMDS (13.8 mL, 1.0 M in THF, 13.8 mmol) dropwise over 15 min.
After stirring further 15 min at ꢀ10 ꢂC, the mixture was warmed to
room temperature and stirred for 2 h. The reaction mixture was
quenched with aq saturated NH4Cl and extracted with Et2O
(3ꢃ50 mL). The combined organic layer was washed with brine,
dried over anhydrous Na2SO4 and concentrated under reduced
pressure. The residue was purified by column chromatography on
silica gel (60–120 mesh, 30% EtOAc/hexane) to afford pure Weinreb
4.1.14. 1-((3S,6S)-3-((R)-1-Iodopropan-2-yl)-6-methylcyclohex-1-
enyl)ethanone 6. To a stirred solution of alcohol 18 (430 mg,
2.2 mmol) and Et3N (0.66 g, 6.6 mmol) in anhydrous CH2Cl2
(15 mL), was added p-TsCl followed by DMAP (40 mg, 10 mol %) at
0 ꢂC and the resulting mixture was allowed for stirring at room
temperature for 8 h. The mixture was poured in to saturated
NaHCO3 (20 mL) and extracted with CH2Cl2 (3ꢃ50 mL). The com-
bined organic layer were washed with brine, dried over anhydrous
Na2SO4 and concentrated under reduced pressure. The residue was
purified by column chromatography on silica gel (60–120 mesh,
10% EtOAc/hexane) to afford pure tosyl-ester (720 mg, 94%) as
25
a colorless oil. Rf¼0.5 (10% EtOAc/hexane). [
a
]
ꢀ18.0 (c 1.0, CHCl3);
D
amide 16 (1.4 g, 85.9%) as a colorless oil. Rf¼0.3 (20% EtOAc/hex-
IR (neat) nmax: 3417, 2969, 1708, 1495, 1456, 1358, 1176, 1124, 1035,
1007, 816, 684, 565 cmꢀ1 1H NMR (300 MHz, CDCl3):
7.79 (d,
25
ane). [
a]
ꢀ13.1 (c 1.0, CHCl3); IR (neat) nmax: 2930, 2856, 1653,
;
d
D

2002
J.S. Yadav et al. / Tetrahedron 66 (2010) 1997–2004
J¼8.3 Hz, 2H), 7.36 (d, J¼7.9 Hz, 2H), 6.53 (d, J¼2.8 Hz, 1H), 3.96 (d,
J¼6.0 Hz, 2H), 2.72–2.58 (m, 1H), 2.46 (s, 3H), 2.43–2.33 (m, 1H),
2.23 (s, 3H), 2.03–1.89 (m, 1H), 1.76–1.50 (m, 2H), 1.32–1.18 (m, 2H),
0.97 (d, J¼7.0 Hz, 3H), 0.88 (d, J¼7.1 Hz, 3H); 13C NMR (75 MHz,
(s, 1H), 4.24 (s, 1H) 2.61 (dd, J¼4.9, 15.3 Hz, 1H), 2.51–2.06 (m, 4H),
2.03 (s, 3H), 2.01 (s, 3H of tert-butyl propargyl ketone), 1.89–1.62
(m, 2H), 1.38–1.23 (m, 2H), 1.19 (s, 9H of tert-butyl propargyl ke-
tone), 1.05 (d, J¼6.8 Hz, 3H), 0.95 (s, 9H), 0.91 (d, J¼6.6 Hz, 3H), 0.17
CDCl3):
d
199.7, 146.1, 144.8, 141.1, 132.8, 129.8 (2C), 127.8 (2C), 72.6,
(s, 3H), 0.15 (s, 3H); 13C NMR (75 MHz, CDCl3):
d 192.2, 188.1, 157.0,
36.9, 36.6, 29.0, 27.8, 26.1, 21.6, 20.5, 19.9, 13.5; Mass (ESI-MS) m/z:
351 (100, [MþH]þ); HRMS (ESI): calcd for C19H27O4S (MþH)þ,
351.1625; found 351.1623.
A suspension of tosyl-ester (700 mg, 2 mmol) and NaI (2.4 g,
15.9 mmol) in acetone (30 mL) was heated to reflux for 12 h. The
solvent was removed under reduced pressure, and the residue was
diluted with water and then extracted with Et2O (2ꢃ40 mL). The
combined organic layer were washed with brine, dried over an-
hydrous Na2SO4 and concentrated under reduced pressure. The
residue was purified by column chromatography on neutral alu-
141.1, 127.8, 91.3, 90.2, 89.7, 81.6, 80.4, 50.1, 39.4, 34.2, 30.1, 29.0,
25.9, 25.7, 21.8, 20.4, 16.7, 3.9, ꢀ4.5, ꢀ4.6; Mass (ESI-MS) m/z: 361,
[MþH]þ; HRMS (ESI): calcd for C22H37O2Si (MþH)þ, 361.2563;
found 361.2565.
4.1.17. (6S,6aR,9S)-3,6,9-Trimethyl-6,6a,7,8,9,9a-hexahydro-3aH-
phenalene-1,4(3a1H,5H)-dione 26. To a stirred solution of com-
pound 5 (250 mg) and molecular sieves (4 Å, 2 g) in CH2Cl2 (10 mL)
at ꢀ78 ꢂC, was added TiCl4 (0.1 mL, 1.0 M solution in CH2Cl2) slowly
with syringe. The resulting mixture was stirred at ꢀ78 ꢂC for 10 min
and allowed to warm to room temperature. After stirring for 6 h,
the reaction mixture was poured in to saturated NaHCO3 (10 mL),
diluted with water and extracted with CH2Cl2 (3ꢃ30 mL). The
combined organic layer was washed with brine, dried over anhy-
drous Na2SO4 and concentrated under reduced pressure. The resi-
due was purified by column chromatography on silica gel
(60–120 mesh, 10% EtOAc/hexane) to afford pure diketone 26
mina (3% EtOAc/hexane) to afford pure iodide 6 (540 mg, 88%) as
25
a colorless oil. Rf¼0.6 (5% EtOAc/hexane). [
a]
ꢀ42.0 (c 1.2, CHCl3);
D
IR (neat) nmax: 2929, 1667, 1627, 1454, 1355, 1245, 1197, 600 cmꢀ1
;
1H NMR (300 MHz, CDCl3):
d
6.62 (d, J¼3.2 Hz, 1H), 3.31–3.21 (m,
2H), 2.76–2.62 (m, 1H), 2.51–2.41 (m, 1H), 2.30 (s, 3H),1.84–1.64 (m,
3H), 1.40–1.27 (m, 2H), 1.00 [d, J¼6.8 Hz, 6H, (two doublets merged
with a common ‘J’ value)]; 13C NMR (75 MHz, CDCl3):
d 199.7, 146.0,
141.5, 39.6, 39.1, 29.1, 27.8, 26.2, 20.1, 19.9, 17.5, 14.4; Mass (ESI MS)
m/z: 329 (80, [MþNa]þ); HRMS (ESI): calcd for C12H19ONaI
(MþNa)þ, 329.0378; found 329.0384.
(114 mg, 78% overall yield for two steps) as a pale yellowish solid
25
(tiny granules). Rf¼0.4 (20% EtOAc/hexane). Mp 172–174 ꢂC. [
a]
D
þ30.5 (c 1.0, CHCl3); IR (neat) nmax: 2932, 2217, 1707, 1650, 1446,
1372, 1213, 1105, 874, 613, 528 cmꢀ1 1H NMR (300 MHz, CDCl3):
;
4.1.15. tert-Butyl(1-((3S,6S)-3-((R)-1-iodopropan-2-yl)-6-methyl-
cyclohex-1-enyl)vinyloxy)dimethylsilane 25. To a stirred solution of
iodide 6 (400 mg, 1.3 mmol) and Et3N (390 mg, 3.9 mmol) in an-
hydrous CH2Cl2 (15 mL) at 0 ꢂC was added TBSOTf (410 mg,
1.6 mmol) slowly over a period of 10 min followed by catalytic
amount of DMAP (w30 mg). After stirring at 0 ꢂC for 15 min, the
reaction mixture was poured into ice water and extracted with
CH2Cl2 (2ꢃ30 mL). The combined organic layer was washed with
brine, dried over anhydrous Na2SO4 and concentrated under re-
duced pressure. The residue was purified by column chromatog-
d
5.97 (s, 1H), 3.24 (d, J¼5.4 Hz, 1H), 2.94–2.78 (m, 1H), 2.71–2.55
(m, 1H), 2.51–2.02 (m, 3H), 1.94 (s, 3H), 1.92–1.54 (m, 4H), 1.46–1.19
(m, 2H), 1.05 (d, J¼4.7 Hz, 3H), 0.87 (d, J¼6.8 Hz, 3H); 13C NMR
(75 MHz, CDCl3):
d 208.5, 198.8, 158.0, 128.5, 56.5, 49.6, 45.2, 42.5,
40.6, 30.8, 27.1, 26.6, 24.4, 20.3, 19.9, 12.8; Mass (ESI-MS) m/z: 269
(MþþNa); HRMS (ESI): calcd for C16H22O2Na (MþNa)þ, 269.1517;
found 269.1529.
4.1.18. (3S,3aR,6S)-7-Methoxy-3,6,9-trimethyl-2,3,3a,4,5,6-hexahy-
drophenalen-1-one 4. To
a solution of diketone 26 (30 mg,
raphy on neutral alumina (Hexane) to afford the pure compound 25
0.12 mmol) in MeOH (10 mL) was added iodine granules (177 mg,
0.70 mmol) at room temperature. The resulting dark brown solu-
tion was heated to 60 ꢂC and stirred for 2 h. After removing the
solvent under reduced pressure, residue was dissolved in CHCl3
(15 mL), stirred along with saturated hypo solution (15 mL) for
30 min and the layer were separated. The aqueous layer was
extracted with CHCl3 (2ꢃ10 mL). The combined organic layer was
washed with brine, dried on anhydrous Na2SO4 and concentrated
under reduced pressure. The residue was purified by column
chromatography on silica gel (100–200 mesh, 8% EtOAc/hexane) to
25
(500 mg, 91%) as a colorless oil. Rf¼0.7 (Hexane). [
a
]
ꢀ42.1 (c 1.0,
D
CHCl3); IR (neat) nmax: 2955, 2930, 2858, 1593, 1462, 1274, 1194,
1009, 838, 780, 691 cmꢀ1 1H NMR (300 MHz, CDCl3):
;
d
6.01 (d,
J¼3.4 Hz, 1H), 4.37 (s, 1H), 4.25 (s, 1H), 3.34–3.19 (m, 2H), 2.51–2.37
(m, 1H), 2.26–2.15 (m, 1H), 1.84–1.63 (m, 2H), 1.59–1.48 (m, 1H),
1.42–1.29 (m, 2H), 1.07 (d, J¼7.0 Hz, 3H), 1.00 (d, J¼6.6 Hz, 3H), 0.96
(s, 9H), 0.17 (s, 3H), 0.15 (s, 3H); 13C NMR (75 MHz, CDCl3):
d 156.7,
140.8, 127.1, 91.3, 39.2, 39.1, 29.3, 28.7, 25.8, 25.6, 20.7, 20.3, 18.1,
16.0, ꢀ4.5, ꢀ4.6; Mass (ESI-MS) m/z: 443 (60, [MþNa]þ); HRMS
(ESI): calcd for C18H33INaOSi (MþNa)þ, 443.1243; found 443.1250.
afford the pure aromatized compound 4 (25.8 mg, 82%) as a white
25
solid. Rf¼0.4 (10% EtOAc/hexane). Mp 106–108 ꢂC. [
a
]
D
þ54.9 (c 1.0,
4.1.16. (S)-6-((1R,4S)-3-(1-(tert-Butyldimethylsilyloxy)vinyl)-4-
methylcyclohex-2-enyl)hept-2-yn-4-one 5. To a well-stirred solu-
tion of compound 25 (250 mg, 0.59 mmol) and Weinreb amide 27
(90 mg, 0.71 mmol) dissolved in anhydrous Et2O/hexane (1:1,
10 mL) at ꢀ78 ꢂC was added t-BuLi (0.93 mL, 1.6 M solution in
pentane, 1.5 mmol) dropwise with syringe. After stirring for further
15 min at the same temperature, the reaction mixture was
quenched with aq saturated NH4Cl (10 mL), diluted with water and
extracted with Et2O (3ꢃ30 mL). The combined organic layer was
washed with brine, dried over anhydrous Na2SO4 and concentrated
under reduced pressure. The residue was purified through short
path column chromatography using neutral alumina (5% EtOAc/
hexane) to afford the inseparable mixture of Diels–Alder precursor
5 (quantitative yield) and tert-butyl propargyl ketone (byproduct)
as a colorless oil. Rf¼0.3 (5% EtOAc/hexane). The above mixture as
such was used for the next step without further purification. IR
(neat) nmax: 2951, 2244, 1706, 1521, 1481, 1410, 1270, 1012, 836,
CHCl3); IR (neat) nmax: 2924, 2859, 1740, 1668, 1584, 1560, 1457,
1320, 1262, 1153, 1098, 1025, 841, 800, 545 cmꢀ1
;
1H NMR
(300 MHz, CDCl3): 6.60 (s,1H), 3.86 (s, 3H), 3.27–3.12 (m,1H), 2.64
d
(s, 3H), 2.61 (dd, J¼3.7, 16.8 Hz,1H), 2.37–2.11 (m, 4H), 1.85–1.68 (m,
1H), 1.45–1.03 (m, 2H), 1.19 (d, J¼6.6 Hz, 3H), 1.12 (d, J¼6.6 Hz, 3H);
13C NMR (75 MHz, CDCl3):
d 199.5, 160.2, 147.0, 141.0, 128.0, 124.0,
112.3, 55.1, 48.8, 44.3, 35.1, 31.3, 27.8, 27.1, 23.9, 22.8, 19.5; Mass
(ESI-MS) m/z: 259 (100, [MþH]þ); HRMS (ESI): calcd for
C17H22O2Na (MþNa)þ, 281.1517; found 281.1530.
4.1.19. (3S,3aR,6S)-7-Hydroxy-3,6,9-trimethyl-2,3,3a,4,5,6-hexahy-
drophenalen-1-one 28. To a stirred solution of compound 4 (12 mg,
0.046 mmol) in anhydrous CH2Cl2 (3 mL) was added BBr3 (0.14 mL,
1.0 M solution in CH2Cl2, 0.14 mmol) with syringe at ꢀ20 ꢂC. The
resulting solution was allowed to warm to room temperature and
then stirred for 1 h. After quenching the reaction mixture with
saturated NaHCO3, extracted with CH2Cl2 (3ꢃ5 mL), combined or-
ganic layer were washed with brine and dried over anhydrous
715 cmꢀ1; 1H NMR (300 MHz, CDCl3):
d
5.96 (d, J¼2.2 Hz, 1H), 4.36

J.S. Yadav et al. / Tetrahedron 66 (2010) 1997–2004
2003
Na2SO4. After removing the solvent under reduced pressure, the
crude product obtained was purified by column chromatography
on silica gel (100–200 mesh, 12% EtOAc/hexane) to afford the pure
1645, 1452, 1373, 1049, 887 cmꢀ1; 1H NMR (300 MHz, CDCl3):
d
4.70
(s, 2H), 3.18 (td, J¼10.5, 3.7 Hz, 1H), 2.08–1.94 (m, 2H), 1.84–1.67 (m,
2H), 1.74 (s, 3H), 1.59 (s, 1H), 1.38–1.08 (m, 4H), 1.06 (d, J¼6.3 Hz,
phenol 28 (9 mg, 80%) as a colorless crystalline solid. Mp 168–
3H); 13C NMR (75 MHz, CDCl3):
d 149.6, 108.7, 76.5, 44.3, 40.7, 40.1,
25
170 ꢂC. [
a
]
D
þ62.4 (c 0.5, CHCl3); IR (neat) nmax: 3421, 3110, 2932,
33.4, 31.2, 21.0, 18.5; Mass (EI-MS) m/z: 154 (15%, Mþ).
2854, 1712, 1632, 1577, 1450, 1320, 1255, 1169, 1093, 801 cmꢀ1
;
1H
NMR (300 MHz, CDCl3): 6.52 (s, 1H), 5.38 (br s, –OH, 1H), 3.24–
d
4.1.23. (1S,2S,5S)-5-((R)-1-Hydroxypropan-2-yl)-2-methylcyclohex-
3.09 (m, 1H), 2.61 (dd, J¼4.0, 17.2 Hz, 1H), 2.57 (s, 3H), 2.39–2.13 (m,
4H), 1.87–1.70 (m, 1H), 1.26 (d, J¼6.8 Hz, 3H), 1.47–1.05 (m, 2H), 1.12
anol 22, 22a. To a stirred solution of (ꢀ)-
a-pinene (18.2 mL,
114 mmol) in THF (100 mL) at 0 ꢂC was added BH3$DMS complex
(5.4 mL, 57.3 mmol) over 5 min. After 1 h alkene 21 (8.84 g,
57.3 mmol) in THF (50 mL) was added via syringe over 10 min and
the reaction was allowed to warm to room temperature. After 3 h,
10% aq NaOH (22 mL) and H2O2 (19 mL, 30% aq solution) were
added sequentially and then stirred for 16 h. The reaction mixture
was diluted with water (50 mL) and chloroform (100 mL). The
phases were separated and the aqueous phase was extracted with
chloroform (3ꢃ200 mL). The combined organic layer was washed
with brine, dried over Na2SO4, concentrated in vacuo and purified
by column chromatography (silica gel, diethyl ether) to give a 5:2
mixture of diols 22 and 22a (9.63 g, 55.9 mmol, 98%) as a colorless
viscous oil. Partial separation of the diastereomers was achieved by
column chromatography on silica (230–400 mesh, using a 3:1:1
mixture of diethyl ether, THF, and hexane). The enriched samples
(d, J¼6.4 Hz, 3H); 13C NMR (150.0 MHz, CDCl3):
d 199.6, 157.2, 148.3,
141.1, 125.7, 124.3, 117.4, 48.7, 44.4, 35.0, 31.4, 27.9, 27.1, 23.4, 22.5.
19.4; Mass (ESI-MS) m/z: 245 (100, [MþH]þ); HRMS (ESI): calcd for
C16H21O2 (MþH)þ, 245.1536; found 245.1539.
4.1.20. N-Methoxy-N-methylbut-2-ynamide 27. To a well-stirred
solution of 2-butynoic acid (3 g, 35.6 mmol) and Weinreb salt in
CH2Cl2 (10 mL) was added Et3N (3.60 g, 35.6 mmol) followed by
CBr4 (11.84 g, 35.6 mmol) at room temperature and allowed for
stirring for 5 min. To the resulting solution was added TPP (9.36 g,
35.6 mmol) in CH2Cl2 (60 mL) slowly at w10 ꢂC and stirred at room
temperature for 30 min. After removing the solvent, to the residue
was added 1:2 of EtOAc/hexane and filtered off. The combined or-
ganic layer was washed with brine and dried over anhydrous
Na2SO4. After removing the solvent under reduced pressure, the
crude product was purified by column chromatography on silica gel
(60–120 mesh, 30% EtOAc/hexane) to afford the pure product 27
(4.0 g, 90%) as a colorless viscous oil. Rf¼0.3 (30% EtOAc/hexane). IR
(neat) nmax: 2977, 2936, 2242, 1706, 1635, 1427, 1385, 1256, 1206,
were then recrystallized from ether/petrol. After
a two re-
crystallizations 22 was attained as a semisolid contaminated with
w18% of 22a, while 22a was partially crystallized out as colorless
needles. Data for mixture of diastereomers: IR (neat) nmax: 3314,
2919, 1454, 1373, 1249, 1035, 839 cmꢀ1; 1H NMR (300 MHz, CDCl3):
979, 723, 583 cmꢀ1; 1H NMR (200 MHz, CDCl3):
d
3.76 (s, 3H), 3.21
155.1, 85.6, 71.9,
d 3.61–3.43 (m, 2H), 3.18–3.06 (m, 1H), 1.96–1.80 (m, 3H, 2OH),
(br s, 3H), 2.04 (s, 3H); 13C NMR (75 MHz, CDCl3):
d
1.78–1.70 (m, 1H), 1.65–1.41 (m, 3H), 1.33–0.94 (m, 4H), 1.01 (d,
J¼6.4 Hz, 3H), 0.93–0.87 (m, 3H); Mass (ESI-MS) m/z: 195
(MþNa)þ; HRMS (ESI): calcd for C10H20O2Na (MþNa)þ, 195.1360;
found 195.1365.
61.8, 32.1, 3.8; Mass (ESI-MS) m/z: 128 (100, [MþH]þ). HRMS (ESI):
calcd for C6H10NO2 (MþH)þ, 128.0714; found 128.0719.
4.1.21. (2S,5S)-2-Methyl-5-(prop-1-en-2-yl)cyclohexanone
20. To
a stirred solution (S)-(þ)-carvone 19 (5 g, 33.3 mmol) in anhydrous
THF (100 mL) at ꢀ78 ꢂC was added a solution of potassium tri-sec-
butylborohydride (33.3 mL, 1.0 M solution in THF, 33.3 mmol)
dropwise over a period of 20 min. After stirring at ꢀ78 ꢂC for 1 h
and 15 min at room temperature, the resultant solution was
transferred in to an Erlenmeyer flask containing 10% aq NaOH so-
lution. An aq solution of H2O2 (30%, 70.8 mL) was carefully added at
0 ꢂC and the mixture was stirred for 3 h at room temperature. The
aq phase was extracted with EtOAc/hexane (1:1, 2ꢃ100 mL) and
combined layer was washed with aq saturated Na2SO3 (50 mL) and
dried over anhydrous Na2SO4. After removing the solvent under
vacuo, the residue was purified by column chromatography on
silica gel (230–400 mesh, 2% EtOAc/hexane) to afford the pure 20
4.1.24. (1S,2S,5S)-5-((S)-1-(tert-Butyldimethylsilyloxy)propan-2-yl)-
2-methylcyclohexanone 23. To a well-stirred suspension of freshly
activated NaH (976 mg, 24.4 mmol, 60% dispersion in mineral oil) in
anhydrous THF (100 mL), was added a solution of mixture of di-
astereomers (22, 22a) (4 g, 23.2 mmol) in THF (40 mL) at 0 ꢂC. After
30 min TBSCl (3.48 g, 23.2 mmol) in anhydrous THF (4 mL) was
added at 0 ꢂC. After two hours, the reaction was quenched with ice
pieces and extracted with Et2O (3ꢃ100 mL). The combined organic
layer was washed with brine, dried on anhydrous Na2SO4 and
concentrated under reduced pressure. The crude residue was pu-
rified by column chromatography on silica gel (230–400 mesh, 10–
30% Et2O/hexane) to afford the compound diTBS ether (266 mg, 4%)
followed by a mixture of monoTBS ether as inseparable di-
astereomers (6.0 g, 90%) as colorless viscous oils. Rf¼0.8 and 0.3
(30% Et2O/hexane).
(4.46 g, 87%) followed by it’s diastereomer (0.42 g, 9%) as colorless
25
liquids. [
a
]
ꢀ11.2 (c 1.2, CHCl3); IR (neat) nmax: 2924, 2860, 1640,
D
1450, 1370, 1027, 887 cmꢀ1; 1H NMR (300 MHz, CDCl3):
d
4.75–4.68
Data for monoTBS ether: IR (neat) nmax: 3440, 2928, 1464, 1262,
(m, 2H), 2.45–1.86 (m, 6H), 1.73(s, 3H), 1.67–1.23 (m, 2H), 1.00 (d,
1076, 840, 772 cmꢀ1 1H NMR (300 MHz, CDCl3):
; d 3.87–3.81 (m,
J¼6.4 Hz, 3H); 13C NMR (75 MHz, CDCl3):
d
212.3, 147.3, 109.3, 46.7,
1H), 3.60–3.52 (m, 1H), 3.41 (dd, 1H), 1.90–1.58 (m, 4H), 1.54–1.19
(m, 4H), 1.17–0.80 (m, 2H), 0.95 (d, 3H), 0.89 (s, 9H), 0.87–0.83 (m,
46.5, 44.4, 34.6, 30.4, 20.1, 14.0; Mass (EI-MS) m/z: 152 (Mþ, 14%).
3H), 0.03 (s, 6H); 13C NMR (75 MHz, CDCl3):
d 71.0, 70.9, 66.4,
4.1.22. (1S,2S,5S)-2-Methyl-5-(prop-1-en-2-yl)cyclohexanol 21. To
a stirred suspension of LiAlH4 (2.28 g, 60.0 mmol) in THF (50 mL) at
ꢀ78 ꢂC was added a solution of (ꢀ)-dihydrocarvone 20 (3.5 g,
23.0 mml) in THF (50 mL) over 10 min. After a further 5 min the
reaction was quenched with aq saturated Na2SO4 (10 mL) and
allowed to warm to room temperature. The resultant solid was
filtered through sintered funnel and washed with EtOAc/hexane
(1:9, 200 mL). After concentrating the solvent the residue was
purified by column chromatography on silica gel (100–200 mesh,
4% EtOAc/hexane) to yield alcohol 21a (250 mg, 7%) as a colorless
66.2, 40.1, 37.9, 36.3, 36.0, 32.0, 31.8, 30.1, 28.2, 28.1, 28.0, 25.9,
25.6, 18.3, 13.5, 13.2, ꢀ5.4; Mass (ESI MS) m/z: 287 (100, [MþH]þ);
HRMS (ESI): calcd for C16H35O2Si (MþH)þ, 287.2401; found
287.2409.
To a solution of monoTBS ether mixture (3.2 g, 11.2 mmol) in
CH2Cl2 (100 mL) was added NaOAc (5.5 g, 67.1 mmol) in one por-
tion followed by pyridinium chlorochromate (7.2 g, 33.5 mmol)
portion wise at w5 ꢂC and allowed to warm to room temperature.
After 1 h, the solvent was concentrated to 1/3 of its volume under
reduced pressure and adsorbed on silica gel. Purification by column
chromatography using silica gel (230–400 mesh, 5% Et2O/hexane)
afforded the inseparable mixture of ketones 23 (2.86 g, 90%) as
oil, and alcohol 21 as a colorless oil (3.12 g, 88%). Rf¼0.4 (5% EtOAc/
25
hexane). [
a
]
ꢀ26.2 (c 1.0, CHCl3); IR (neat) nmax: 3345, 2924, 2857,
D

2004
J.S. Yadav et al. / Tetrahedron 66 (2010) 1997–2004
a colorless oil. Rf¼0.6 (10% Et2O/hexane). IR (neat) nmax: 2954, 2929,
1712, 1458, 1250, 1092, 841, 779 cmꢀ1 1H NMR (300 MHz, CDCl3):
Supplementary data
;
d
3.56–3.42 (m, 2H), 2.40–2.05 (m, 4H), 1.93–1.78 (m, 2H), 1.69–1.22
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tet.2010.01.054.
(m, 3H), 1.01 (d, J¼6.4 Hz, 3H), 0.93–0.84 (m, 12H), 0.03 (s, 6H); 13C
NMR (75 MHz, CDCl3): d 213.2, 213.1, 65.7, 46.2, 44.8, 44.4, 41.7, 41.6,
40.1, 35.0, 29.6, 27.6, 25.8, 18.1, 14.2, 13.2, 13.1, ꢀ5.5; Mass (ESI MS)
m/z: 285 (100, [MþH]þ); HRMS (ESI): calcd for C16H33O2Si (MþH)þ,
285.2244; found 285.2246.
References and notes
1. (a) Blunt, J. W.; Copp, B. R.; Munro, M. H. G.; Northcote, P. T.; Prinsep, M. R. Nat.
Prod. Rep. 2005, 22, 15–61 and previous reviews in this series; (b) Hill, R. A.
Annu. Rep. Prog. Chem., Sect. B 2005, 101, 124–136; (c) Faulkner, D. J. Nat. Prod.
Rep. 1999, 16, 155–198 and previous reviews in this series.
2. Rodriguez, A. D.; Ramirez, C.; Rodriguez, I. I.; Gonzalez, E. Org. Lett. 1999, 1, 527–
530.
3. (a) Look, S. A.; Fenical, W.; Matsumoto, G. K.; Clardy, J. J. Org. Chem.1986, 51, 5140–
5145; (b) Fenical, W. J. Nat. Prod. 1987, 50, 1001–1008; (c) Look, S. A.; Fenical, W.;
Jacobs, R. S.; Clardy. J. Proc. Natl. Acad. Sci. U.S.A. 1986, 83, 6238–6240.
4. (a) Broka, C. A.; Chan, S.; Peterson, B. J. Org. Chem. 1988, 53, 1584–1586;
For other total synthesis see; (b) Corey, E. J.; Carpino, P. J. Am. Chem. Soc.
1989, 111, 5472–5474; (c) McCombie, S. W.; Box, B.; Ganguly, A. K. Tetra-
hedron Lett. 1991, 32, 2087–2090; (d) Buszek, K. R.; Bixby, D. L. Tetrahe-
dron Lett. 1995, 50, 9129–9132; (e) Majdalani, A.; Schmalz, H.-G. Synlett
1997, 1303–1305; (f) Lazerwith, S. E.; Corey, E. J. J. Am. Chem. Soc. 1998,
120, 12777–12782; (g) Lazerwith, S. E.; Johnson, T. W.; Corey, E. J. Org.
Lett. 2000, 2, 2389–2392; (h) Chow, R.; Kocienski, P. J.; Kuhl, A.; LeB-
4.1.25. (3R,6S)-3-((S)-1-(tert-Butyldimethylsilyloxy)propan-2-yl)-6-
methylcyclohex-1-enyl trifluoromethane sulfonate 24. To a stirred
solution of diisopropylamine (1.25 mL, 8.8 mmol) in anhydrous THF
(30 mL) was added n-BuLi (4.6 mL, 1.6 M solution in hexane,
7.4 mmol) at ꢀ10 ꢂC and stirred for 20 min at same temperature. To
the resulting mixture at ꢀ78 ꢂC was added a mixture of ketones 23
(1.4 g, 4.9 mmol) in anhydrous THF (20 mL) dropwise with syringe.
The reaction mixture was stirred at the same temperature for 2 h
and to this was added solid N-phenyltrifluoromethanesulfonimide
(2.63 g, 7.4 mmol) in one portion. The resulting solution was stirred
at 0 ꢂC for 3 h and then at room temperature for 16 h. After re-
moving the solvent under reduced pressure, the crude enoltriflate
was purified by column chromatography on silica gel (230–
400 mesh, 5% Et2O/hexane) to afford the inseparable mixture of
enoltriflate 24 (1.88 g, 92%) as a colorless oil. Rf¼0.4 (5% Et2O/
hexane). IR (neat) nmax: 2958, 2933, 1675, 1416, 1211, 1142, 1096,
razidec, J.-Y.; Muir, K.; Fish, P. J. Chem. Soc., Perkin Trans.
1 2001,
2344–2355; (i) Harrowven, D. C.; Tyte, M. J. Tetrahedron Lett. 2004, 45,
2089–2091.
5. (a) Corey, E. J.; Carpino, P. Tetrahedron Lett. 1990, 31, 3857–3858; (b) Eklund, L.;
Sarvary, I.; Frejd, T. J. Chem. Soc., Perkin Trans. 1 1995, 303–305; (c) Gill, S.;
Kocienski, P.; Kohler, A.; Pontiroli, A.; Qun, L. Chem. Commun. 1996, 1743–1744;
(d) LeBrazidec, J.-Y.; Kocienski, P. J.; Connolly, J. D.; Muir, K. W. J. Chem. Soc.,
Perkin Trans. 1 1998, 2475–2477; (e) Kocienski, P. J.; Pontiroli, A.; Qun, L. J. Chem.
Soc., Perkin Trans. 1 2001, 2356–2366; (f) Zhong, W.; Moya, C.; Jacobs, R. S.;
Little, R. D. J. Org. Chem. 2008, 73, 7011–7016.
6. (a) Johnson, T. W.; Corey, E. J. J. Am. Chem. Soc. 2001, 123, 4475–4479; (b) Da-
vidson, J. P.; Corey, E. J. J. Am. Chem. Soc. 2003, 125, 13486–13489.
7. (a) Harmata, M.; Hong, X.; Barnes, C. L. Org. Lett. 2004, 6, 2201–2203; (b)
Harmata, M.; Hong, X. Org. Lett. 2005, 7, 3581–3583; (c) Harmata, M.; Cai, Z.;
Chen, Y. J. Org. Chem. 2009, 74, 5559–5561.
8. For few recent contributions see (a) Yadav, J. S.; Srihari, P.; Bhasker, E. V.; Reddy,
A. B. Tetrahedron Lett. 2009, 50, 2420–2424; (b) Yadav, J. S.; Reddy, C. S. Org. Lett.
2009, 11, 1705–1708; (c) Yadav, J. S.; Pratap, T. V.; Rajender, V. J. Org. Chem. 2007,
72, 5882–5885; (d) Yadav, J. S.; Chetia, C. Org. Lett. 2005, 9, 4587–4589; (e)
Yadav, J. S.; Srihari, P. Tetrahedron: Asymmetry 2004, 15, 81–89.
9. (a) Yadav, J. S.; Babu, R. S.; Sabitha, G. ARKIVOC 2003, 125–139; (b) Yadav, J. S.;
Babu, R. S.; Sabitha, G. Tetrahedron Lett. 2003, 44, 387–389; (c) Yadav, J. S.;
Basak, A. K.; Srihari, P. Tetrahedron Lett. 2007, 48, 2841–2843.
10. Nakatani, Y.; Kawashima, K. Synthesis 1978, 147–148.
11. Chavan, S. P.; Zubaidha, P. K.; Dhondge, V. D. Tetrahedron 1993, 49, 6429–6436.
12. Gaudin, J.-M. Tetrahedron 2000, 56, 4769–4776.
13. (a) Morgans, D. J.; Feigelson, G. B. J. Am. Chem. Soc. 1983, 105, 5477–5479; (b)
Tokoroyama, T.; Pan, L.-R. Tetrahedron Lett. 1989, 30, 197–200.
14. Waters, S. P.; Tian, Y.; Li, Y. M.; Danishefsky, S. J. J. Am. Chem. Soc. 2005, 127,
13514–13515.
15. These diastereomers were mentioned to be partially separable. See Harrowven,
D. C.; Pascoe, D. D.; Demurtas, D.; Bourne, H. O. Angew. Chem., Int. Ed. 2005, 117,
1247–1248 Complete separation was not achieved (chromatography/re-
crystallization) to proceed further with single diastereomer.
972, 889, 840, 607 cmꢀ1 1H NMR (300 MHz, CDCl3):
; d 5.68–5.60
(m, 1H), 3.54–3.46 (m, 2H), 2.61–2.43 (m, 2H), 2.28–1.94 (m, 1H),
1.89–1.54 (m, 2H), 1.48–1.22 (m, 2H), 1.13 (d, J¼6.6 Hz, 3H), 0.93–
0.81 (m, 12H), 0.04 (s, 6H); 13C NMR (75 MHz, CDCl3):
d 153.4, 153.2,
130.9, 129.9, 122.7, 121.0, 65.8, 65.6, 39.5, 39.3, 33.0, 32.0, 31.7, 25.8,
25.5, 17.8, 18.2, 16.5, 13.0, 12.8, ꢀ5.5; Mass (ESI-MS) m/z: 417 (80,
MþH)þ; HRMS (ESI): calcd for C17H32F3O4SSi (M)þ, 417.1743; found
417.1749.
4.1.26. 1-((3S,6S)-3-(1-Hydroxypropan-2-yl)-6-methylcyclohex-1-
enyl)ethanone 18, 18a. To a well-stirred slurry of enoltriflate (1 g,
2.4 mmol), LiCl (713 mg, 16.8 mmol), and Pd(OAc)2 (54 mg,
10 mol %) in anhydrous THF (30 mL), was added ethylvinyl ketone
(346 mg, 4.8 mmol) at room temperature. The reaction mixture was
heated to reflux for overnight, cooled to 0 ꢂC and treated with 5 M
HCl solution under stirring for 15 min. The resultant solution was
extracted with EtOAc (3ꢃ50 mL) then washed with water, brine
and dried over anhydrous Na2SO4. After removing the solvent un-
der reduced pressure, the residue was purified by column chro-
matography on silica gel (230–400 mesh, 30% EtOAc/hexane) to
furnish the inseparable mixture of keto-alcohol 18 and 18a
(433 mg, 92%) as a colorless oil. Rf¼0.3 (30% EtOAc/hexane). IR
(neat) nmax: 3415, 2930, 2873, 1663, 1458, 1387, 1361, 1247, 1033,
16. Cassidy, M.; Padwa, A. Org. Lett. 2004, 6, 4029–4032.
17. No attempts were made to study the product for prediction of the type of re-
action involved. Based on the following reference we call this reaction as an
intramolecular Diels–Alder cyclization reaction as is catalyzed by Lewis acid.
See Little, R.D.; Masjedizadeh, M. R.; Wallquist, O.; Mc. Loughlin, J.I. Org. React.
1995, 47, 315–551.
942, 880, 605 cmꢀ1 1H NMR (300 MHz, CDCl3):
; d 6.78–6.62 (m,
1H), 3.78–3.53 (m, 2H), 2.87–2.62 (m, 1H), 2.64–2.42 (m, 1H), 2.32
(s, 1H), 2.29 (s, 2H), 2.10 (br s, 1H), 1.92–1.20 (m, 5H), 1.02–0.86 (m,
6H); 13C NMR (75 MHz, CDCl3):
d 200.2, 200.0, 145.4, 145.3, 143.5,
18. Kotnis, A. S. Tetrahedron Lett. 1990, 31, 481–484.
143.2, 65.8, 65.7, 39.9, 37.0, 29.4, 29.3, 27.9, 26.0, 25.9, 20.6, 19.8,
13.6, 13.4.
19. Crystal data: C17H22O2, M¼258.35, monoclinic, space group P21/c, a¼5.
3719(5)Å, b¼16.1920(15)Å, c¼16.3048(15)Å,
b
¼93.661(2)ꢂ, V¼1415.3(2)Å3, Z¼4,
Dcalcd¼1.212 mg mꢀ3
,
T¼294(2)K,
m
¼0.078 mmꢀ1
,
F(000)¼560,
l
¼0.71073 Å.
Data collection yielded 13,378 reflections resulting in 2493 unique, averaged
Acknowledgements
reflection, 2031 with I>2s(I). Full-matrix least-squares refinement led to a final
R¼0.0480, wR¼0.1265, and GOF¼1.020. Intensity data were measured on
Bruker Smart Apex with CCD area detector. CCDC 741295 contains Supple-
mentary crystallographic data for the structure.
The authors thank Dr. K. Ravi Kumar and Dr. B. Sridhar for X-ray
crystallographic analysis. One of us (EVB) thanks CSIR, New Delhi
for financial assistance.
20. Attempts in ethanol, methanol, and combination of hexane/diethyl ether so-
lutions did not yield the required crystal.