Stereocontrolled synthesis of (±)-α-pinguisene and (±)-pinguisenol

Article abstract of DOI:10.1039/a705600a

Total synthesis of (±)-α-pinguisene 1 and (±)-pinguisenol 2, employing an orthoester Claisen rearrangement and an intramolecular diazo ketone cyclopropanation reaction for the stereospecific construction of vicinal quaternary carbon atoms, is described.

Full text of DOI:10.1039/a705600a

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Stereocontrolled synthesis of ( )-á-pinguisene and ( )-pinguisenol
Adusumilli Srikrishna* and Dange Vijaykumar
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560012, India
Total synthesis of ( )-á-pinguisene 1 and ( )-pinguisenol 2,
employing an orthoester Claisen rearrangement and an
intramolecular diazo ketone cyclopropanation reaction for
the stereospecific construction of vicinal quaternary car-
bon atoms, is described.
R
Me
O
O
Me
Me
E
(a), (b)
(e), (f)
(h)
O
CO2Et
5 R = H
6 R = Me
7 E = CO2Et
3 E = CH2OH
The sesquiterpenes α-pinguisene 1 and pinguisenol 2 were iso-
lated from the liverworts, Porella vernicosa and its complex (P.
macroloba and P. gracillima) which show some interesting bio-
logical activities, such as allergenic contact dermatitis, anti-
cancer, antimicrobial and antifeedant activities, along with
several other pinguisanes.1 The interesting carbon skeleton,
1,2,6,7-tetramethylbicyclo[4.3.0]nonane, incorporating two
vicinal quaternary centres and four methyl groups attached to
four contiguous carbon atoms in an all-cis fashion, makes the
pinguisanes challenging synthetic targets.2 Recently Schinzer
and co-workers have reported the first total synthesis of
α-pinguisene and pinguisenol based on propargylsilane-
terminated cyclisation of an enone.2 Herein, we report a
stereocontrolled synthesis of 1 and 2 starting from Hagemann’s
ester via the allyl alcohol 3 and the bicyclic ketone 4.
(c), (d)
O
O
O
OR
O
O
O
N2
10
8 R = Et
9 R = H
(2:3)
(g)
O
O
O
O
O
O
R
11
12 R = Me
13 R = H
HO
10
2
9
11
1
3
O
Scheme 1 Reagents conditions: (a) NaH, MeI, Ϫ50 ЊC, 95%; (b)
(CH2OH)2, toluene-p-sulfonic acid (p-TSA), C6H6, 48 h; 52%; (c)
LiAlH4, Et2O, Ϫ70 ЊC, 97%; (d) MeC(OEt)3, EtCO2H (cat.), 180 ЊC, 48
h, 75%; (e) 10% NaOH, MeOH, 4 h, reflux, 92%; (f) (COCl)2, C6H6,
room temp., 2 h; CH2N2, Et2O, 0 ЊC, 2 h; (g) Cu, CuSO4, cyclohexane,
reflux, 3 h; 33% from 9; (h) Li, liq. NH3; MeI (excess), 45 min, 84%
8
4
6
7
5
4
α-pinguisene 1
pinguisenol 2
the diazo ketone 10, obtained from the acid 9 via the acid chlor-
ide, in refluxing cyclohexane furnished, stereospecifically, a 3:2
mixture of the tricyclic keto ketal 11. Reductive cleavage of the
cyclopropane ring using lithium in liquid ammonia followed by
alkylation of the intermediate enolate with methyl iodide was
attempted for the introduction of the fourth methyl group to
generate the keto ketal 12. However, the alkylation step was
unsuccessful and only the keto ketal 13 was obtained. Hence, it
was decided to introduce the methyl group at an early stage and
diazoethane was opted for in the place of diazomethane.
Thus, hydrolysis of the ketal moiety in 8 followed by ester
hydrolysis furnished the keto acid 14, which was transformed
into diazo ketone 15. Copper–copper sulfate catalysed3 intra-
molecular cyclopropanation of the diazo ketone 15 followed by
chromatography on silica gel furnished the tricyclic ketones 16
and 17 in a 3:2 ratio. The sec-methyl group was assigned as
equatorial in the major compound 16, which was further con-
firmed by the equilibration of the minor isomer 17 into the
thermodynamically more stable major isomer 16. Simultaneous
reductive cleavage of the cyclopropane ring and reduction of
the ketone in the six-membered ring (thereby differentiating the
two ketone functionalities as well as avoiding the equilibration
of the C-2 sec-methyl)4 was achieved using lithium in liquid
ammonia to stereoselectively transform the diketone 16 into the
keto alcohol 18. It is interesting to note the generation of the
required stereochemistry at C-7 which may be the consequence
of base catalysed equilibration during work-up. Modified
Wolff–Kishner reduction of the keto alcohol 18 followed by
O
O
OH
3
The synthetic sequence starting from Hagemann’s ester 5 is
depicted in Schemes 1 and 2. The two quaternary carbon
centres were stereoselectively created using a combination of
Claisen rearrangement and intramolecular diazo ketone cyclo-
propanation reactions. The requisite starting material, allyl
alcohol 3, for the projected Claisen rearrangement was
obtained from Hagemann’s ester. Thus, generation of the
dienolate of 5 and low temperature alkylation furnished the γ-
methylated product 6. Simultaneous protection of the ketone
and isomerisation of the olefin in 6 was achieved using the
standard ketalisation conditions to generate the α,β-
unsaturated ester 7, which on reduction with lithium alumin-
ium hydride furnished the allyl alcohol 3. The first quaternary
carbon was created using an orthoester variant of the Claisen
rearrangement. Thus, thermal activation of the allyl alcohol 3
and triethyl orthoacetate in the presence of a catalytic amount
of propionic acid furnished the ene ester 8, which on hydrolysis
with methanolic sodium hydroxide yielded the ene acid 9. The
formation of two isomers in the Claisen rearrangement has
no significance as they can be equilibrated at a later stage.
Anhydrous copper sulfate–copper3 catalysed decomposition of
J. Chem. Soc., Perkin Trans. 1, 1997
3295

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N2
copper (1.9 g, 29.9 mmol) and anhydrous CuSO4 (480 mg, 3
mmol) was added to a magnetically stirred solution of the diazo
ketone 15 in 100 ml of anhydrous cyclohexane under a blanket
of nitrogen and refluxed for 1.5 h. After the completion of
the reaction, the solids were filtered off and the solvent was
evaporated under reduced pressure. Purification of the residue
on a silica gel column using ethyl acetate and hexane
(1:20 → 1:5) as eluent furnished the two diketones 16 (180
mg, 14.2% from the acid 14) and 17 (122 mg, 9.7% from the acid
14). For the diketone 16: νmax(neat)/cmϪ1 1715; δH(400 MHz,
CDCl3) 0.84 (1 H, dd, J 5 and 1†) and 1.39 (1 H, d, J 5) [H-2],
0.97 (3 H, d, J 6.5, sec-Me), 0.98 (3 H, s) and 1.34 (3 H, s)
[2 × tert-Me], 1.99 (1 H, d, J 17.5) and 2.07 (1 H, d, J 17.5)
[H-5], 2.23 (1 H, q, J 6.5, H-7), 1.60–1.72 (1 H, m) and 2.28–
2.48 (3 H, m) [H-9 and 10]; δC(22.5 MHz, CDCl3) 213.3, 210.8,
52.0, 46.4, 45.0, 42.8, 40.7, 38.2, 27.0, 25.1, 16.6, 10.2, 8.7; m/z
206 (Mϩ, 20%), 135 (20), 121 (10), 107 (20), 69 (100) (HRMS:
found Mϩ, 206.1316. C13H18O2 requires M, 206.1307). For the
diketone 17: νmax(neat)/cmϪ1 1715; δH(400 MHz, CDCl3) 0.72 (1
H, d, J 5) and 1.19 (1 H, d, J 5) [H-2], 1.03 (3 H, d, J 7.5, sec-
Me), 1.18 (3 H, s) and 1.31 (3 H, s) [2 × tert-Me], 1.97 (1 H, d,
J 18) and 2.02 (1 H, d, J 18) [H-5], 1.64 (1 H, dd, J 13.5, 7,
H-10eq), 2.37 (1 H, q, J 7.5, H-7), 2.45 (1 H, ddd, J 13.5, 13.5
and 5.5, H-10ax), 2.25 (1 H, dd, J 14 and 5.5, H-9eq), 2.57 (1 H,
ddd, J 14, 13.5 and 7, H-9ax); δC(22.5 MHz, CDCl3) 213.7 (2C),
54.7, 43.9, 43.2, 39.2, 38.2, 35.9, 25.3, 23.3, 22.9, 13.5, 10.6; m/z
206 (Mϩ, 26%), 135 (18), 121 (10), 107 (20), 69 (100) (HRMS:
found Mϩ, 206.1310. C13H18O2 requires M, 206.1307).
O
OH
O
Me
(a), (b)
(c)
8
O
O
14
15
(d)
O
O
HO
(f)
+
O
O
O
(3:2)
(e)
18
16
17
(g)
HO
O
(i)
(h)
(±)-1,2
19
4
Scheme 2 Reagents conditions: (a) 3 M HCl, THF, 2 h, 98%; (b) 10%
NaOH, MeOH, reflux, 4 h, 90%; (c) (COCl)2, C6H6, room temp., 2 h;
MeCHN2, Et2O, 0 ЊC, 2 h; (d) Cu, CuSO4, cyclohexane, reflux, 1.5 h;
24% from 14; (e) K2CO3, MeOH, room temp., 48 h, 86%; (f) Li, liq.
NH3, THF, 67%; (g) NH2NH2, diethylene glycol, (CH2OH)2, 180 ЊC,
2 h; Na, 4 h; (h) PCC, CH2Cl2, 2 h; 68% from 18; (i) ref. 2
† J Values are given in Hz.
pyridinium chlorochromate (PCC) oxidation of the resulting
alcohol 19 furnished the bicyclic ketone 4, which exhibited
spectral data (IR, 400 MHz H NMR, 13C NMR and mass)
1
Acknowledgements
identical to that of the authentic sample. Since Schinzer and co-
workers2 have transformed the ketone 4 into pinguisenol (by
addition of vinyl Grignard reagent) and α-pinguisene (via Pd
catalysed coupling of the enol triflate with vinyltrialkyl-
stanane), the present sequence constitutes a formal synthesis of
1 and 2. Currently, we are investigating the extension of this
methodology for the chiral synthesis of 1 and 2.
We thank Professor Schinzer for copies of the IR, 400 MHz 1H
NMR, 13C NMR and mass spectra of authentic 4, and C. S. I. R.,
New Delhi for financial support.
References
1 Y. Asakawa, M. Toyota and T. Aratani, Tetrahedron Lett., 1976, 3619;
Y. Asakawa, M. Toyota and T. Takemoto, Phytochemistry, 1978, 17,
457 and references cited therein.
Experimental
2 So far there is only one approach reported for α-pinguisene 1 and
pinguisenol 2, see: D. Schinzer, K. Ringe, P. G. Jones and D. Döring,
Tetrahedron Lett., 1995, 36, 4051; D. Schinzer and K. Ringe,
Tetrahedron, 1996, 52, 7475. The authors referred to α-pinguisene as
β-pinguisene. For the synthesis of pinguisone and its derivatives see,
S. Bernasconi, P. Gariboldi, G. Jommi, S. Montanari and M. Sisti,
J. Chem. Soc., Perkin Trans. 1, 1981, 2394; T. Uyehara, Y. Kabasawa
and T. Kato, Bull. Chem. Soc. Jpn., 1986, 59, 2521; R. Baker, D. L.
Selwood, C. J. Swain, N. M. H. Webster and J. Hirshfield, J. Chem.
Soc., Perkin Trans. 1, 1988, 471 and references cited therein.
3 J. E. McMurry and L. C. Blaszczak, J. Org. Chem., 1974, 39, 2217.
4 It is worth noting that as per the molecular mechanics calculations,
unlike in the diketone 16, in 1,2,6,7-tetramethylbicyclo[4.3.0]nonan-
3,8-diones the 1β,2α,6β,7α-isomer is more stable than the
1β,2β,6β,7β-isomer.
3á,6â,7â- and 3á,6â,7á-Trimethyltricyclo[4.4.0.01,3]decane-4,8-
diones (16 and 17)
To a magnetically stirred solution of the acid (1.2 g, 6.12 mmol)
in dry benzene (6 ml) was added oxalyl chloride (2.6 ml, 30.6
mmol). The reaction mixture was stirred for 2 h at room
temperature, concentrated under reduced pressure to afford the
acid chloride and then was used without further purification.
To an ice-cold magnetically stirred solution of ethereal diazo-
ethane (0.12 mol in 125 ml of diethyl ether, prepared from N-
nitrosoethylurea) was added, dropwise, a solution of the acid
chloride obtained above in anhydrous diethyl ether (5 ml) and
the resulting solution was stirred for 2 h at ice temperature. The
excess diazoethane and diethyl ether were removed by careful
evaporation on a water bath and the residue was rapidly filtered
through a short silica gel column using 1:5 ethyl acetate and
hexane as eluent, to furnish the diazo ketone 15 as a yellow oil.
[νmax(neat)/cmϪ1 3095, 2100, 1710, 1640, 900]. A mixture of
Paper 7/05600A
Received 1st August 1997
Accepted 18th September 1997
3296
J. Chem. Soc., Perkin Trans. 1, 1997