A stereospecific approach to cis-anti-cis triquinanes

Article abstract of DOI:10.1081/SCC-120018772

A methodology for the synthesis of compounds containing the cis-anti fused triquinane system has been developed starting from tricyclo[5.2.1.0^2.6]deca-4,8-dien-3-(exo)ol 6 involving Ireland ester Claisen rearrangement and intramolecular diazo ketone cyclopropanation reactions as key steps.

Full text of DOI:10.1081/SCC-120018772

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A Stereospecific Approach to cis-anti-cis Triquinanes
A. Srikrishna a , T. Jagadeeshwar Reddy a , N. Palani b & K. K. Balasubramanian b
a Department of Organic Chemistry , Indian Institute of Science , Bangalore, India
b Department of Chemistry , Indian Institute of Technology , Chennai, India
Published online: 16 Aug 2006.
To cite this article: A. Srikrishna , T. Jagadeeshwar Reddy , N. Palani & K. K. Balasubramanian (2003) A Stereospecific
Approach to cis-anti-cis Triquinanes, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 33:9, 1537-1544, DOI: 10.1081/SCC-120018772
To link to this article: http://dx.doi.org/10.1081/SCC-120018772
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 9, pp. 1537–1544, 2003
A Stereospecific Approach to
cis-anti-cis Triquinanes
1
2
A. Srikrishna,1, T. Jagadeeshwar Reddy, N. Palani,
*
and K. K. Balasubramanian2,
*
1Department of Organic Chemistry,
Indian Institute of Science, Bangalore, India
2Department of Chemistry,
Indian Institute of Technology, Chennai, India
ABSTRACT
A methodology forthe synthesis of compounds containing the
cis-anti-cis fused triquinane system has been developed starting
from tricyclo[5.2.1.02,6]deca-4,8-dien-3-(exo)ol 6 involving Ireland
ester Claisen rearrangement and intramolecular diazo ketone
cyclopropanation reactions as key steps.
Key Words: Triquinanes; Ireland-Claisen rearrangement; Intra-
molecular cyclopropanation; Regiospecific cyclopropane reductive
cleavage.
*Correspondence: A. Srikrishna, Department of Organic Chemistry, Indian
Institute of Science, Bangalore 560012, India; E-mail: ask@orgchem.iisc.ernet.in
K. K. Bolasubramanian, Department of Chemistry, Indian Institute of
Technology, Chennai, India.
1537
DOI: 10.1081/SCC-120018772
Copyright & 2003 by Marcel Dekker, Inc.
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1538
Srikrishna et al.
Among the two linearly fused triquinanes 1 and 2, the cis, anti, cis-
isomer 2 constitute an important class of biologically active natural prod-
ucts such as hirsutic acid 3, coriolin 4, capnellenetriol 5, etc. In the past
two decades numerous methodologies, both as general methodology as
well as target oriented approaches were developed for the construction of
the triquinane system 2.[1] The tricyclo[5.2.1.02,6]deca-4,8-dien-3-(exo)ol[2]
6 and the corresponding ketone are sterically biased systems, and their
facile retro-Diels Alder cleavage made them very useful stereochemically
differentiated masked cyclopentadienol synthons. Lipase mediated
kinetic resolution[3] of the alcohol 6 into its enantiomers increased
its potential further. However, its use as a masked diquinane via the
cleavage of the norbornene double bond was less explored.
We have envisaged that stereocontrolled cyclopentannulation on the
exo-face of the cyclopentene of the tricyclic dienol 6 followed by oxida-
tive cleavage of the norbornene double bond, may be an attractive and
expedient stereocontrolled route to the cis, anti, cis-triquinane.
For stereocontrolled cyclopentannulation of the readily available[2] allyl
alcohol 6, we have conceived a methodology involving a combination
of Claisen rearrangement and intramolecular diazo ketone cyclopropana-
tion reactions. Herein we describe our results.
An Ireland ester Claisen rearrangement[4] was chosen forthe conver-
sion of the alcohol 6 into the acid 8. Thus, treatment of the allyl alcohol 6
with acetic anhydride and sodium acetate furnished the acetate 7.
Reaction of the acetate 7 with lithium diisopropylamide (LDA) and
tert-butyldimethylsilyl chloride in THF, followed by thermolysis of the
resultant enol TBDMS ether generated the g,d-unsaturated acid[5] 8 in a
stereospecific manner. The structure of the tricyclic acid 8 was established
from its spectral data and stereochemistry of the acetic acid side chain
was assigned based on the well established[6] stereospecificity of the
Claisen rearrangement. For the cyclopentannulation via an intramolecu-
[7]
lardiazo ketone cyclopropanation eraction,
the acid 8 was converted
into the diazo ketone 10. Consequently, reaction of the acid 8 with an
excess of oxalyl chloride in benzene at room temperature generated the
acid chloride 9, which on treatment with an excess of ethereal diazo-
methane furnished the diazo ketone 10 (ꢀmax 2080 and 1640 cmꢀ1).
Anhydrous copper sulfate catalyzed decomposition of the diazo ketone
10 in refluxing (with two 100 W tungsten lamps) cyclohexane furnished
the pentacyclic ketone 11 via stereospecific insertion of the resulting
ketocarbenoid. The structure of the ketone 11 was established from its
spectral data (see experimental section). Regioselective reductive cleav-
age[8] of the cyclopropane ring employing lithium in liquid ammonia
reduction conditions transformed the pentacyclic ketone 11 into the

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Stereospecific Approach to cis-anti-cis Triquinanes
1539
Scheme 1. (a) Ac2O, anhydrous AcONa, RT, 24 h, 80%; (b) LDA, ꢀ78ꢁC,
TBDMSCl, reflux, 3 h, 60%; (c) (COCl)2, C6H6, RT, 3 h; (d) CH2N2, Et2O,
0ꢁC ! RT, 2 h; (e) Anhydrous CuSO4, c–C6H12, W-lamp, reflux, 6 h, 50%
(from the acid 8); (f) i. Li, liq NH3, ꢀ33ꢁC, 20 min; ii. PCC, silica gel, 2 h, 91%.
tetracyclic ketone 12. On the otherhand ozonolytic cleavage of the nor-
bornene double bond in 11 followed by reductive work up with dimethyl
sulfide generated the keto-dialdehyde 13, whose structure was established
from its spectral data in particular the presence of two aldehyde signals

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1540
Srikrishna et al.
1
at ꢁ 9.88 and 9.83 in the H NMR spectrum and three carbonyl carbon
resonances at ꢁ 213.8, 202.9, and 201.0 in the 13C NMR spectrum.[9]
Acetalization of the dialdehyde 13 with pyridinium p-toluenesulfonate
(PPTS) in methanol furnished the bis-acetal 14. The compounds 12–14
are ideally suitable for further elaboration into a variety of cis, anti, cis-
triquinanes.
In conclusion, we have developed a convenient methodology, based
on Ireland ester Claisen rearrangement and intramolecular diazo ketone
cyclopropanation reactions, for the conversion of dicyclopentadiene into
useful precursors for the generation of cis, anti, cis-triquinanes. The ready
availability of the alcohol 6 and the acetate 7 in optically active form,
via enzymatic kinetic resolution, enhances the synthetic potential of the
present methodology.
EXPERIMENTAL SECTION
2-(endo-Tricyclo[5.2.1.02,6]deca-4,8-diene-
3-(exo)-yl)acetic Acid (8)
A solution of the acetate 7 (1 g, 5.36 mmol) in dry THF (5 mL) was
added to LDA (10.7 mmol, prepared in situ from diisopropylamine and
n-BuLi) in THF (10 mL) at ꢀ78ꢁC and stirred at the same temperature
for0.5 h. TBDMSCl (0.8 g, 5.36 mmol) in dyr THF (5 mL) was added,
stirred for 0.5 h at ꢀ78ꢁC, and allowed to warm to room temperature.
TLC analysis showed the formation of the enol silyl ether. The mixture
was then refluxed for 3 h. It was cooled and aqueous sodium hydroxide
(2 g in 5 mL water) was added. The mixture was stirred at room tempera-
ture for 0.5 h and then extracted with hexane (5 mL) to remove the

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Stereospecific Approach to cis-anti-cis Triquinanes
1541
non-acidic components. The aqueous layerwas acidified with dilute
hydrochloric acid to pH 2.0 and extracted with ether (3 Â 10 mL). The
combined ether extract was washed with brine and dried (Na2SO4).
Evaporation of the solvent and purification of the residue by flash
column chromatography furnished the acid 8 (605 mg, 60%). IR
1
(CCl4): ꢀmax/cmꢀ1 3600–3300, 1705, 1630. H NMR (400 MHz, CDCl3):
ꢁ 11.5 (1H, brs, COOH), 5.97 (1H, dd, J ¼ 6 and 2.8 Hz), 5.88 (1H, dd,
J ¼ 6 and 2.8 Hz), 5.52 (1H, d, J ¼ 5.8 Hz), 5.40 (1H, d, J ¼ 5.8 Hz), 3.25
(1H, brs), 2.98 (1H, brs), 2.70 (1H, brs), 2.40–2.20 (4H, m), 1.50 (1H,
m), 1.20 (1H, m). 13C NMR (100.5 MHz, CDCl3): ꢁ 179.2 (s), 135.5 (d),
134.7 (d), 133.0 (d), 132.7 (d), 54.5 (d), 50.1 (t), 48.9 (d), 45.8 (d), 44.7 (d),
43.7 (d), 40.7 (t). HRMS: m/z Calcd. forC 12H14O2 190.0994; Found
190.1014.
Pentacyclo[8.2.1.02,9.03,5.04,8]tridec-11-en-6-one (11)
To a magnetically stirred solution of the acid 8 (310 mg, 1.76 mmol) in
dry benzene (2.4 mL) was slowly added oxalyl chloride (1.5 mL,
17.5 mmol) and the reaction mixture was stirred for 3 h at RT.
Evaporation of benzene and the excess oxalyl chloride under reduced
pressure furnished the acid chloride 9, which was taken in dry ether
(10 mL) and added dropwise to a cold magnetically stirred ethereal solu-
tion of diazomethane (60 mL, prepared from 5 g of N-nitroso-N-methyl-
urea and 40 mL of 60% aq. KOH solution). The reaction mixture was
slowly warmed up to RT, stirred for 2 h, and the excess diazomethane and
ether were carefully evaporated on a hot water bath. Purification by rapid
filtration through a silica gel column using ethyl acetate–hexane (1:5) as
eluent furnished the diazo ketone 10 (320 mg) as yellow oil. [IR (neat):
ꢀ
max 3040, 2080, 1640 cmꢀ1]. To a magnetically stirred, refluxing (by keep-
ing two 100 W tungsten lamps nearthe flask) suspension of anhydrous
copper sulfate (1.2 g) in 400 mL dry cyclohexane was added dropwise, a
solution of the diazo ketone 10 (320 mg) in cyclohexane (25 mL) overa
period of 2 h and refluxed for 4 h. The reaction mixture was then cooled
and copper sulfate was filtered off using a sintered funnel. Evaporation of
the solvent and purification of the residue on a silica gel column using
ethyl acetate–hexane (1:20 to 1:5) as eluent furnished the pentacyclic
ketone 11 (140 mg) as yellow oil (50% overall yield from the acid 8). IR
1
(neat): ꢀmax/cmꢀ1 3040, 1720. H NMR (300 MHz, CDCl3): ꢁ 6.19 (1H,
dd, J ¼ 5.4 and 2.7 Hz), 6.11 (1H, dd, J ¼ 5.7 and 2.7 Hz), 3.00–2.80 (3H,
m), 2.65–2.50 (2H, m), 2.45 (1H, q, J ¼ 5.1 Hz), 2.17 (1H, dd, J ¼ 6.3 and
3.9 Hz), 2.05–1.95 (1H, m), 1.63 (1H, dd, J ¼ 9.9 and 5.7 Hz), 1.56 (1H, dd,

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1542Srikrishna et al.
J ¼ 9.9 and 4.5 Hz), 1.40 (1H, d, J ¼ 8.1 Hz), 1.22 (1H, d, J ¼ 8.4 Hz).
13C NMR (22.5 MHz, CDCl3): ꢁ 214.1 (s, C¼O), 134.9 (d), 132.1 (d),
57.1 (d), 52.4 (t), 49.9 (t), 47.6 (d), 46.8 (2 C, d), 38.5 (d), 37.7 (d), 36.2
(d), 32.9 (d). Mass: m/z 186 (Mþ, 7%), 121 (53), 91 (30), 78 (100). HRMS:
m/z Calcd. forC 13H14O 186.1045; Found 186.1052.
Tetracyclo[8.2.1.02,9.03,7]tridec-11-en-5-one (12)
To a solution of lithium (7 mg, 1 mmol) in 15 mL of freshly distilled
ammonia (overNaNH 2) was added dropwise a solution of the pentacyclic
ketone 11 (20 mg, 0.11 mmol) in 0.5 mL of dry THF. The reaction mixture
was stirred for 20 min and then quenched with solid ammonium chloride.
Ammonia was evaporated, the reaction mixture was diluted with water
and extracted with ether (3 Â 2 mL). The etherextract was washed with
brine and dried (Na2SO4). The solvent was evaporated and the residue
was taken in 0.5 mL of CH2Cl2, added to a suspension of PCC (32 mg,
0.15 mmol) and silica gel (15 mg) in 1 mL of CH2Cl2 and magnetically
stirred for 2 h. The reaction mixture was filtered through a small silica
gel column. Evaporation of the solvent and purification of the residue over
a silica gel column using ethyl acetate–hexane (1:20) as eluent furnished
the ketone 12 (18.3 mg, 91%) as oil. IR (neat): ꢀmax/cmꢀ1 1730. 1H NMR
(300 MHz, CDCl3): ꢁ 6.20 (2H, brs), 2.95–2.75 (3H, m), 2.75–2.60 (1H,
m), 2.55–2.00 (5H, m), 1.95 (1H, dd, J ¼ 19.0 and 5.9 Hz), 1.55–1.35 (4H,
m). 13C NMR (75 MHz, CDCl3): ꢁ 221.2, 136.6, 136.2, 54.4, 52.9, 47.7, 46.7,
46.2, 45.1, 44.6, 44.1, 43.0, 34.5. Mass: m/z 188 (Mþ, 7%), 123 (20), 66 (100).
9,11-bis(Dimethoxymethyl)tricyclo-
[6.3.0.02,4.03,7]undecan-5-one (14)
Through a cold (ꢀ90ꢁC) solution of the compound 11 (30 mg,
0.16 mmol) in methanol (0.1 mL) and CH2Cl2 (3 mL) containing
NaHCO3 (ꢂ10 mg) was passed a stream of pre-cooled ozone in oxygen
gas until the reaction mixture turned to blue in color. The excess ozone
was flushed off by passing oxygen gas. Dimethyl sulfide (0.13 mL,
1.78 mmol) was added to the reaction mixture, which was warm up to
RT and stirred for 8 h. Then the reaction mixture was diluted with
CH2Cl2 (5 mL) washed with brine and dried (Na2SO4). Evaporation of
the solvent furnished 5-oxotricyclo[6.3.0.02,4.03,7]undecane-9,11-dialde-
hyde (13). [IR (neat): ꢀmax/cmꢀ1 2720, 1710. 1H NMR (300 MHz,
CDCl3): ꢁ 9.88 (1H, s), 9.83 (1H, d, J ¼ 2.7 Hz), 3.00–2.40 (8H, m),

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Stereospecific Approach to cis-anti-cis Triquinanes
1543
2.05–1.20 (4H, m). 13C NMR (75 MHz, CDCl3): ꢁ 213.8, 202.9, 201.0,
61.3, 55.7, 51.7, 48.0, 44.7, 39.1, 37.2, 35.7, 31.7, 25.9]. To a solution of
the dialdehyde 13 (25 mg, 0.115 mmol) in 0.5 mL of dry methanol was
added 5 mg of PPTS and the reaction mixture was stirred at RT for
24 h. Then it was diluted with CH2Cl2 (5 mL), washed with brine, and
dried (Na2SO4). Evaporation of the solvent and purification of the residue
on a silica gel column using ethyl acetate–hexane (1:50) as eluent furnished
the diacetal 14 (20 mg, 56%). IR (neat): ꢀmax/cmꢀ1 1715, 1125, 1060.
1H NMR (90 MHz, CDCl3): ꢁ 4.5 (1H, d, J ¼ 9 Hz), 4.4 (1H, d,
J ¼ 9 Hz), 3.40–3.30 (12H, 4 Â s, 4 Â OCH3), 3.10–1.30 (12H, series of
m). 13C NMR (75 MHz, CDCl3): ꢁ 105.5, 105.3, 59.5, 58.8, 53.5, 53.0,
52.6, 51.4, 49.2, 45.6, 45.1, 42.2, 38.4, 38.2, 37.5, 36.3 (carbonyl carbon
not seen). Mass: m/z 310 (Mþ, 15%), 248 (35), 247 (35), 233 (28), 165 (30),
91 (45), 75 (100). HRMS: m/z Calcd. forC 17H26O5 310.1780;
Found 310.1775.
ACKNOWLEDGMENTS
We thank the Head, R.S.I.C., I.I.T., Madras for NMR and mass
spectra of some of the compounds. N.P. is grateful to Prof. T. R.
Govindachari and Dr. S. Narasimhan, Centre for Agrochemical
Research, SPIC Science Foundation, Madras for their encouragement.
T.J.R is grateful to the University Grants Commission, New Delhi for the
award of a research fellowship.
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Received in the UK April 4, 2002