Enantiospecific total synthesis of (+)-2-pupukeanone

Article abstract of DOI:10.1039/a706321k

The first total synthesis of chiral 2-pupukeanone (+)-4, starting from R-carvone (-)-7 employing a 5-exo-trig radical cyclisation as the key reaction for the construction of the tricyclic isotwistane carbon framework, is described.

Full text of DOI:10.1039/a706321k

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Enantiospecific total synthesis of (؉)-2-pupukeanone
Adusumilli Srikrishna* and Thumkunta Jagadeeswar Reddy
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560012, India
The first total synthesis of chiral 2-pupukeanone (؉)-4,
starting from R-carvone (؊)-7 employing a 5-exo-trig
radical cyclisation as the key reaction for the construction
of the tricyclic isotwistane carbon framework, is described.
oct-5-en-2-one derivatives via intramolecular alkylation,5 R-
carvone was chosen as the starting material for the preparation
of the chiral analogue of 6. The synthetic sequence starting
from R-carvone is depicted in Schemes 2 and 3. To begin with,
carvone 7 was converted into the bicyclo[2.2.2]octenone deriv-
ative 8. Thus, alkylation of R-carvone 7 using LDA and methyl
iodide6 furnished a 3:2 (trans:cis) epimeric mixture of αЈ-
methylcarvone 9, which on treatment with N-bromosuccin-
imide in the presence of sodium acetate and acetic acid in
methylene chloride generated the allyl bromide 10, in 60%
yield.7,8 Intramolecular alkylation of the allyl bromide 10 using
potassium tert-butoxide in tert-butyl alcohol and THF gener-
ated the bicyclo[2.2.2]octenone derivative 8, in 60% yield. Gen-
eration of the enolate using LDA followed by alkylation with
dimethylallyl bromide transformed the bicyclic enone 8 into the
alkylated product 11, [α]D24 Ϫ304.1 (c 1.71, CHCl3). Regioselec-
tive conversion of the trisubstituted olefin in 11 into the corre-
sponding bromohydrin (NBS–H2O–THF)7 furnished the rad-
ical precursor 12, [α]D25 Ϫ254.9 (c 1.22, CHCl3), which was found
to contain predominantly one epimer. The key radical cyclis-
ation was carried out by refluxing a 0.02  benzene solution of
the bromohydrin 12 and 1.1 equiv. tri-n-butyltin hydride in the
presence of a catalytic amount of azobisisobutyronitrile
(AIBN) to furnish a 2.5:1 mixture of the isotwistanes 13 and
14† in near quantitative yield, which were separated by silica
gel column chromatography. After constructing the isotwistane
framework, attention was turned to the degradation of the C-8
methylene group. Thus, ozonolysis of the exo-methylene moiety
in 13 and 14 followed by dehydration of the tertiary alcohol
furnished the enedione 15.‡ In the final stage, the remaining two
tasks, namely regioselective reductive deoxygenation of the C-8
ketone and hydrogenation of the olefin were addressed (Scheme
3). Thus, modified Wolff–Kishner reduction of the enedione 15
The nudibranch Phyllidia varicosa Lamarck, 1801 secretes, as a
part of its defense mechanism, two volatile substances with dis-
tinctive odours, which are lethal to fish and crustaceans. In 1975
and 1979, Scheuer and co-workers reported the isolation of
these compounds, 9- and 2-isocyanopupukeananes (1 and 2)
from this nudibranch, and also from its prey, a sponge, Hymen-
iacidon sp. The structures of these tricyclic marine sesquiter-
penes 1 and 2, containing a novel tricyclo[4.3.1.03,7]decane
(isotwistane) framework and an isonitrile functionality, were
elucidated based on degradative and single crystal X-ray dif-
fraction studies.1 The presence of an unusual carbon frame-
work, with two quaternary carbon atoms and an isopropyl
group in a thermodynamically unfavourable endo position
made isocyanopupukeananes 1 and 2, and the corresponding
ketones 9- and 2-pupukeanones (3 and 4) interesting and chal-
X
X
9
Y
Y
10
2
7
6
4
1 X = NC; Y = H
2 X = H; Y = NC
3 X = O; Y = H2
4 X = H2; Y = O
lenging synthetic targets, and several approaches have been
reported for the synthesis of racemic pupukeananes.2,3 Recently,
we reported a short approach to ( )-2-pupukeanone employing
a tandem intermolecular addition of tri-n-butyltin radical to a
terminal acetylene followed by a 5-exo-trig vinyl radical cyclis-
ation as the key strategy.4 In continuation, herein we report the
first enantiospecific total synthesis of chiral 2-pupukeanone
[(ϩ)-4] starting from the readily available monoterpene,
R-carvone [(Ϫ)-7], employing a 5-exo-trig radical cyclisation as
the key reaction.
† All the compounds exhibited spectral data including HRMS consist-
ent with their structures. Selected spectral data (J values given in Hz)
for the isotwistane 13 (contains a small amount of a rearranged prod-
uct): mp 106–108 ЊC, [α]D27 ϩ49.0 (c 1.0, CHCl3); νmax(neat)/cmϪ1 3480,
3050, 1715, 1640, 1370, 1215, 1160, 885; δH(200 MHz, CDCl3) 4.97 and
4.87 (each 1 H, br s; C᎐CH2), 2.25–2.50 (2 H, m), 2.27 (2 H, br s, H-9),
᎐
1.85–2.05 (2 H, m), 1.26–1.56 (3 H, m), 1.203 and 1.16 [each 3 H, s;
HO᎐C(CH3)2], 1.09 and 0.98 (each 3 H, s; 2 × tertiary-CH3); δC(22.5
MHz, CDCl3) 221.3 (s, C᎐O), 143.1 (s, C᎐CH2), 110.6 (t, C᎐CH2), 72.0
᎐
᎐
᎐
As depicted in Scheme 1, it was anticipated that the radical
(s, C᎐OH), 57.9 (d), 55.2 (2 C, s and t), 43.6 (s), 42.2 (d), 40.3, 39.6, 39.1,
28.1 (q), 26.6 (q), 19.5 (q), 18.8 (q). For the isotwistane 14: mp 80–
82 ЊC; [α]D25 ϩ18.0 (c 1.67, CHCl3); νmax(neat)/cmϪ1 3500, 1710, 1650,
1360, 1130, 1020, 930, 885; δH(90 MHz, CDCl3) 4.91 and 4.78 (each 1
O
O
O
O
H, q, J 2; C᎐CH2), 1.35–2.65 (9 H, m), 1.25 and 1.12 [each 3 H, s;
᎐
HO᎐C(CH3)2], 1.09 and 0.93 (each 3 H, s; 2 × tertiary CH3); δC(22.5
Me
Br
MHz, CDCl3) 221.9 (C᎐O), 143.8 (C-8), 110.1 (C᎐CH2), 71.4 (C᎐OH),
᎐
᎐
57.6, 54.7, 50.6, 43.0, 41.0, 40.4, 36.2, 31.7, 30.4, 28.7, 23.3, 19.5.
‡ For the compound 15: [α]D26 ϩ82.4 (c 3.12, CHCl3); νmax(neat)/cmϪ1
1730, 1710, 1395, 1370, 1295, 1225, 1180, 1160, 1095, 1040, 1005, 980,
825; δH(200 MHz, CDCl3) 3.26 (1 H, dd, J 9, 5.5, H-6), 2.56 (1 H, d, J
5.5, H-7), 2.51 (1 H, half AB q, J 16, H-4a), 2.26 (2 H, close AB, H-9),
2.12 (1 H, d with str., J 16.0, H-4b), 2.03 (1 H, dd, J 13.5, 9, H-10exo),
1.63 and 1.57 (each 3 H, s; 2 × olefinic CH3), 1.42 (1 H, d, J 13.5, H-
10endo), 1.19 and 1.071 (each 3 H, s; 2 × tertiary CH3); δC(22.5 MHz,
5
6
Scheme 1
cyclisation of a bromide, e.g. 5, would generate the pupukean-
ane framework, whereas kinetic alkylation of the bicyclic enone
6 would provide the requisite precursor for the bromide 5. As
10-bromocarvone is known to produce 1-methylbicyclo[2.2.2]-
CDCl3) 217.6 (s, C᎐O), 211.7 (s, C᎐O), 136.1 (s), 124.6 (s), 62.2 (d), 54.9
᎐
᎐
(s), 47.9 (t), 44.9 (s), 42.2 (t), 40.1 (d), 39.1 (t), 21.0 (q), 20.6 (q), 19.4 (q),
19.2 (q).
J. Chem. Soc., Perkin Trans. 1, 1997
3293

View Article Online
nished a 1.3:1 mixture of 2-pupukeanone 4 and its C-5 exo
epimer 17, which exhibited a 400 MHz NMR spectrum identi-
cal to that reported.3b In contrast, ozonolytic cleavage of the
enone 16 furnished the dione 18, [α]D25 27.0 (c 2.0, CHCl3), which
exhibited spectral data identical to that of an authentic3c,4
racemic sample. The racemic dione 18 has been converted into
2-pupukeanone stereoselectively by Chang and co-workers.3c
Even though the present sequence generates the enantiomer of
the natural series, the ready availability of S-carvone makes the
present strategy applicable for the synthesis of the natural enan-
tiomer also.
O
O
O
O
(a)
(b)
(c)
95%
60%
60%
Br
Me
(–)-7
9
10
8
90% (d)
O
O
O
O
O
(f)
(e)
(g),(h)
88%
98%
60%
Acknowledgements
H
Br
1
OH
OH
We thank Professor Chang for providing the copies of the H
and 13C NMR spectra of the dione 18 and 2-pupukeanone; SIF
and IPC for recording the high resolution NMR spectra; DST
for the financial support and UGC for the award of a research
fellowship to T. J. R.
15
13 α-H
14 β-H
12
11
Scheme 2 Reagents and conditions: (a) LDA, THF, Ϫ10 ЊC → rt,
MeI, 9 h; (b) NaOAc, AcOH, NBS, CH2Cl2, 0 ЊC → rt, 6 h; (c)
KϩϪOBut, THF, 0 ЊC → rt, 3 h; (d) LDA, THF, HMPA, (CH3)2-
C᎐CH᎐CH2Br, Ϫ90 ЊC → rt,
8 h; (e) NBS (1.1 equiv.), H2O,
References
᎐
THF, Ϫ10 ЊC → rt, 24 h; (f) AIBN, Bun SnH, C6H6, reflux, 5 h; (g)
3
1 (a) B. J. Burreson, P. J. Scheuer, J. Finer and J. Clardy, J. Am. Chem.
Soc., 1975, 97, 4763; (b) M. R. Hagadone, B. J. Burreson, P. J. Scheuer,
J. S. Finer and J. Clardy, Helv. Chim. Acta, 1979, 62, 2484.
2 (a) E. J. Corey, M. Behforouz and M. Ishiguro, J. Am. Chem. Soc.,
1979, 101, 1608; (b) H. Yamamoto and H. L. Sham, J. Am. Chem.
Soc., 1979, 101, 1609; (c) G. A. Schiesher and J. D. White, J. Org.
Chem., 1980, 45, 1864; (d) S. L. Hsieh, C. T. Chiu and N.-C. Chang,
J. Org. Chem., 1989, 54, 3820. For the synthesis of chiral analogue of
9-pupukeanone, see: A. Srikrishna, P. Hemamalini and G. V. R.
Sharma, J. Org, Chem., 1993, 58, 2509.
(i) O3–O2, MeOH, CH2Cl2, Ϫ90 ЊC; (ii) Me2S, Ϫ90 ЊC → rt, 8 h; (h)
TsOH, C6H6, reflux, 8 h (rt = room temp.)
O
O
O
O
O
(a)
(b)
+
90%
75%
H
H
3 (a) E. J. Corey and M. Ishiguro, Tetrahedron Lett., 1979, 2745;
(b) G. Frater and J. Wenger, Helv. Chem. Acta, 1984, 67, 1702;
(c) N.-C. Chang and C.-K. Chang, J. Org. Chem., 1996, 61, 4967;
(d) K. Kaliappan and G. S. R. Subba Rao, Tetrahedron Lett., 1997,
38, 2185.
15
16
4
17
O
(d)
(c)
80%
4 A. Srikrishna, D. Vijaykumar and G. V. R. Sharma, Tetrahedron Lett.,
1997, 38, 2003.
5 A. Srikrishna, G. V. R. Sharma, S. Danieldoss and P. Hemamalini,
J. Chem. Soc., Perkin Trans. 1, 1996, 1305.
6 J.-P. Gesson, J.-C. Jacquesy and B. Renoux, Tetrahedron, 1989, 45,
5853.
7 J. Rodriguez and J.-P. Dulcere, Synthesis, 1993, 1177.
8 In addition, varying amounts (15–20%) of easily separable 2,6-
dimethyl-5-(2-acetoxy-1-bromoisopropyl)cyclohexenone, resulting
from the trapping of the intermediate carbonium ion, was also
obtained.
O
18
Scheme 3 Reagents and conditions: (a) (i) NH2NH2ؒH2O, HOCH2-
CH2OH, diethylene glycol, 180 ЊC, 2 h; (ii) Na, diethylene glycol,
180 ЊC, 4 h; (b) PtO2, H2, EtOH, 2 d; (c) (i) O3–O2, MeOH, CH2Cl2,
Ϫ90 ЊC; (ii) Me2S, Ϫ90 ЊC → rt, 8 h; (d) reference 3c
furnished the enone 16 in 90% yield,§ via regioselective reduc-
tion of the C-8 ketone, leaving the sterically more crowded C-2
ketone intact. Catalytic hydrogenation3b–d of the enone 16 fur-
§ For the compound 16: [α]D26 ϩ101.8 (c 2.26, CHCl3); νmax(neat)/cmϪ1
1725, 1710, 1450, 1370, 1100, 1015, 995; δH(200 MHz, CDCl3) 2.92 (1
H, dd, J 8.5, 3.4, H-6), 2.34 (1 H, d, J 16.5), 1.5–2.1 (8 H, m), 1.63 and
1.53 [each 3 H, s; C᎐C(CH3)2], 1.19 and 0.90 (each 3 H, s; 2 × tertiary
᎐
Paper 7/06321K
Received 29th August 1997
Accepted 19th September 1997
CH3); δC(22.5 MHz, CDCl3) 222.5 (s, C᎐O), 137.5 (s), 122.7 (s), 53.8 (s),
᎐
45.5 (d, C-6), 42.6 (t, C-4), 42.3 (s), 40.7 (d), 38.4 (t), 32.8 (t), 20.8
(2 C, t and q), 20.5 (q), 18.7 (q), 17.1 (q).
3294
J. Chem. Soc., Perkin Trans. 1, 1997