New total synthesis of (±)-herbertene, (±)-β-herbertenol and (±)-herbertenediol

Article abstract of DOI:10.1016/S0040-4039(00)01298-3

The total syntheses of the herbertane sesquiterpenes (±)-herbertene (1), (±)-β-herbertenol (2) and (±)-herbertenediol (5) have been successfully accomplished involving copper-catalysed conjugate addition of Grignard reagents to unsaturated compounds and α

Full text of DOI:10.1016/S0040-4039(00)01298-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 7563–7566
New total synthesis of ( )-herbertene, ( )-b-herbertenol and
( )-herbertenediol
Pranab Dutta Gupta, Ashutosh Pal, Arnab Roy and Debabrata Mukherjee*
Department of Organic Chemistry, Indian Association for the Cultivation of Science, Calcutta 700 032, India
Received 5 June 2000; accepted 28 July 2000
Abstract
The total syntheses of the herbertane sesquiterpenes ( )-herbertene (1), ( )-b-herbertenol (2) and
( )-herbertenediol (5) have been successfully accomplished involving copper-catalysed conjugate addition
of Grignard reagents to unsaturated compounds and a,a-dimethylation of primary esters as key reactions.
© 2000 Elsevier Science Ltd. All rights reserved.
Keywords: terpenes; phenols; Grignard reagents; alkylation; cyclopentanones.
From the liverwort Herberta adunca, Matsuo and co-workers1 isolated several biologically
active sesquiterpene phenols, e.g. 2–5, together with the parent hydrocarbon (−)-herbertene (1).
The sesquiterpene phenols 2–5 possess significant antifungal properties and recently, Fukuyama
et al. have found2 that herbertenediol (5) exhibits potent anti-lipid peroxidation activity. The
total syntheses of the herbertane sesquiterpenes present interesting problems in view of the
difficulty associated with the construction of the vicinal quaternary centres on the five-membered
ring. In connection with our studies on conjugate addition of Grignard reagents to unsaturated
cyano-esters and unsaturated dinitriles, we have accomplished the total syntheses of the
sesquiterpenes ( )-herbertene (1),3 ( )-b-herbertenol (2)4 and ( )-herbertenediol (5)2 involving
copper-catalysed conjugate addition of appropriate Grignard reagents to the unsaturated
compounds 7a, 7b and 15, respectively, as key steps (Fig. 1).
Figure 1.
* Corresponding author. Fax: 91-33-4732805; e-mail: ocdm@mahendra.iacs.res.in
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01298-3

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The acetophenones 6a and 6b were condensed with ethyl cyanoacetate to provide the
unsaturated cyano-esters 7a and 7b in 79 and 74% yields, respectively. Conjugate addition of
to 7a in the presence of CuBr·S(CH3)2 afforded 8a6 (62%) as a diastereoiso-
5
meric mixture, which on hydrolysis, decarboxylation and esterification furnished the methyl
ester 9a in 75% yield (Scheme 1). The cyano-ester 7b was similarly converted into the methyl
ester 9b in 45% overall yield. Alkylation of 9a with MeI at −78°C using LDA (1 equiv.) as the
base provided the monomethyl ester 10a as a diastereoisomeric mixture in 94% yield. The ester
10a was alkylated with MeI at 0°C in the presence of LDA (1.7 equiv.) and HMPA (2 equiv.)
to give the dimethyl ester 11a7 (89%). a,a-Dimethylation of the ester 9b was similarly carried out
to provide 11b7 (84%). The conversion of 9a into 11a could also be accomplished in 82% yield
in a one pot process employing a sequential methylation without isolating the monomethyl ester
10a. Deacetalisation of 11a followed by oxidation of the resulting aldehyde with Jones reagent
and esterification with CH2N2 furnished the diester 12a in 75% overall yield. The ester 11b was
similarly converted into the diester 12b (75%). Dieckmann cyclisation of the diesters 12a and 12b
followed by decarbomethoxylation of the resulting crude b-keto-esters afforded the cyclopen-
tanones 13a7 and 13b7 in 74 and 72% yields, respectively. Huang–Minlon reduction8 of 13a
furnished ( )-herbertene (1)7 (81%). Huang–Minlon reduction of 13b followed by demethylation
with BBr3 afforded ( )-b-herbertenol (2)7 (72%), mp 83–84°C. The spectral data of 1 and 2
agreed very well with those reported in the literature.
Scheme 1. 6a–13a: R=H; 6b–13b: R=OMe. Reagents and conditions: i, CH2(CN)CO2Et, NH4OAc, AcOH, C6H6,
reflux; ii,
, CuBr·Me2S, THF, Et2O, −5 to 25°C; iii, KOH, HOCH2CH2OH, H2O, reflux; AcOH, 0°C; iv,
CH2N2, Et2O, 0°C; v, LDA (1 equiv.), THF, −20°C; MeI, HMPA, −78°C; vi, LDA (1.7 equiv.), HMPA (2 equiv.),
THF, 0°C; MeI, 0°C; vii, AcOH–H2O (4:1), 25 to 60°C; Jones reagent, Me2CO, 0 to 20°C, CH2N2; viii, t-BuOK,
C6H6, reflux, then H3O+; DMSO, NaCl, 155°C; ix, N2H4, N2H4·2HCl, (HOCH2CH2)2O, 125°C; KOH, 210°C; x,
BBr3, CH2Cl2, 0 to 25°C.
The synthesis of herbertenediol (5) is outlined in Scheme 2. The tetralone 149 was condensed
with malononitrile to provide the unsaturated dinitrile 15, mp 122–123°C in near quantitative
yield. Conjugate addition of MeMgI to 15 in the presence of CuI afforded 16 (88%), mp
136–137°C, which on hydrolysis, decarboxylation, and esterification furnished the methyl ester
17 in 80% yield. a,a-Dimethylation of 17 as described for 11a afforded the ester 18 (85%).

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Oxidation of 18 with CrO3 gave the keto-ester 19, mp 99–100°C, in 74% yield. Baeyer–Villiger
reaction of 19 provided the lactone 20 (82%), mp 105–106°C. Alkaline hydrolysis of 20 followed
by treatment with Me2SO4 and esterification with CH2N2 gave the diester 21 (82%). Dieckmann
cyclisation of 21 and subsequent decarbomethoxylation of the resulting b-keto-ester furnished
the ketone 227 (73%), mp 70–71°C. Huang–Minlon reduction8 of 22 followed by demethylation
with BBr3 afforded ( )-herbertenediol (5)7 (70%) whose spectral data were identical to those of
the natural product.
Scheme 2. Reagents and conditions: i, CH2(CN)2, NH4OAc, AcOH, C6H6, reflux; ii, MeMgI, CuI, Et2O, THF, 25°C
then reflux; iii, KOH, HOCH2CH2OH, H2O, reflux, then H3O+; heat (190°C); iv, CH2N2, Et2O, 0°C; v, LDA (1
equiv.), THF, −20°C; MeI, HMPA, −78°C; vi, LDA (1.7 equiv.), HMPA (2 equiv.), THF, 0°C; MeI, 0°C; vii, CrO3,
AcOH–H2O (4:1), 10 to 25°C; viii, MCPBA, CH2Cl2, CF3CO2H, 0–25°C; ix, aq. NaOH, MeOH, reflux; then Me2SO4,
50–55°C, H3O+; x, t-BuOK, C6H6, reflux, H3O+; DMSO, NaCl, 155°C; xi, N2H4, N2H4·2HCl, (HOCH2CH2)2O,
125°C; KOH, 210°C; xii, BBr3, CH2Cl2, −78 to 0°C.
Acknowledgements
We are grateful to the CSIR, New Delhi, for financial support (Grant No. 01(1534)/98/EMR-
II). One of us (P. D. G.) thanks the CSIR for a fellowship.
References
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2. Fukuyama, Y.; Kiriyama, Y.; Kodama, M. Tetrahedron Lett. 1996, 37, 1261–1264.

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3. Abad, A.; Agullo, C.; Cunat, A. C.; Perni, R. H. J. Org. Chem. 1999, 64, 1741–1744 and references therein.
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6. Satisfactory spectroscopic and microanalytical data were obtained for all new compounds.
1
7. Selected spectral data for: 11a: H NMR (CDCl3, 300 MHz) l 1.04 (s, 3H), 1.14 (s, 3H), 1.38 (s, 3H), 1.22–1.75
(m, 3H), 2.33 (s, 3H), 2.32–2.45 (m, 1H), 3.50 (s, 3H), 3.82–3.97 (m, 4H), 4.84 (t, 1H, J=4.6 Hz), 6.98–7.16 (m,
4H); 13C NMR (CDCl3, 75 MHz) l 21.24, 21.71, 21.77, 22.11, 28.80, 29.26, 45.43, 49.79, 51.16, 64.70, 64.84,
1
104.95, 125.43, 126.66, 127.13, 129.15, 136.57, 142.50, 177.18. 11b: H NMR (CDCl3, 300 MHz) l 1.03 (s, 3H),
1.12 (s, 3H), 1.36 (s, 3H), 1.24–1.73 (m, 3H), 2.19 (s, 3H), 2.26–2.39 (m, 1H), 3.51 (s, 3H), 3.80 (s, 3H), 3.80–3.94
(m, 4H), 4.84 (t, 1H, J=4.7 Hz), 6.72 (d, 1H, J=8.4 Hz), 7.00 (d, 1H, J=2.5 Hz), 7.01 (dd, 1H, J=8.4, 2.5 Hz);
13C NMR (CDCl3, 75 MHz) l 16.44, 21.29, 21.77, 22.11, 28.84, 29.24, 44.86, 49.84, 51.13, 55.09, 64.66, 64.81,
1
104.96, 108.63, 124.83, 126.64, 130.75, 134.00, 155.80, 177.29. 13a: H NMR (CDCl3, 300 MHz) l 0.62 (s, 3H),
1.19 (s, 3H), 1.26 (s, 3H), 1.88–1.96 (m, 1H), 2.37 (s, 3H), 2.35–2.74 (m, 3H), 7.05–7.25 (m, 4H); 13C NMR
(CDCl3, 75 MHz) l 18.45, 21.70, 22.07, 25.31, 29.58, 33.69, 48.48, 53.14, 123.52, 126.95, 127.18, 128.01, 137.54,
1
144.91, 222.44. 13b: H NMR (CDCl3, 300 MHz) l 0.62 (s, 3H), 1.16 (s, 3H), 1.24 (s, 3H), 1.86–1.92 (m, 1H),
2.24 (s, 3H), 2.38–2.70 (m, 3H), 3.83 (s, 3H), 6.80 (d, 1H, J=9 Hz), 7.15–7.18 (m, 2H); 13C NMR (CDCl3, 75
MHz) l 16.50, 18.32, 22.08, 25.32, 29.72, 33.70, 47.88, 53.18, 55.16, 109.40, 124.63, 125.90, 128.84, 136.44, 156.06,
1
222.67. 1: H NMR (CDCl3, 300 MHz) l 0.56 (s, 3H), 1.07 (s, 3H), 1.26 (s, 3H), 1.51–1.83 (m, 5H), 2.34 (s, 3H),
2.45–2.54 (m, 1H), 6.98–7.20 (m, 4H); 13C NMR (CDCl3, 75 MHz) l 19.70, 21.78, 24.29, 24.41, 26.48, 36.76,
1
39.75, 44.19, 50.45, 124.09, 126.05, 127.32, 127.81, 136.71, 147.53. 2: H NMR (CDCl3, 300 MHz) l 0.56 (s, 3H),
1.04 (s, 3H), 1.23 (s, 3H), 1.52–1.80 (m, 5H), 2.24 (s, 3H), 2.40–2.48 (m, 1H), 4.74 (bs, 1H), 6.68 (d, 1H, J=8.4
Hz), 7.05 (dd, 1H, J=8.4, 2.3 Hz), 7.09 (d, 1H, J=2.3 Hz); 13C NMR (CDCl3, 75 MHz) l 16.13, 19.69, 24.25,
1
24.50, 26.49, 36.92, 39.70, 44.17, 49.91, 113.92, 122.29, 125.61, 129.69, 139.81, 151.44. 19: H NMR (CDCl3, 300
MHz) l 1.09 (s, 3H), 1.18 (s, 3H), 1.47 (s, 3H), 1.85–1.97 (m, 1H), 2.17–2.26 (m, 1H), 2.39 (s, 3H), 2.53–2.63 (m,
1H), 2.70–2.82 (m, 1H), 3.60 (s, 3H), 3.88 (s, 3H), 6.71 (s, 1H), 6.75 (s, 1H); 13C NMR (CDCl3, 75 MHz) l 22.40,
23.10, 23.77, 26.05, 32.82, 37.16, 42.16, 49.42, 51.59, 55.96, 111.08, 120.97, 121.43, 143.70, 149.47, 159.06, 177.04,
197.72. 22: 1H NMR (CDCl3, 300 MHz) l 0.75 (s, 3H), 1.27 (s, 3H), 1.34 (s, 3H), 2.07–2.16 (m, 1H), 2.32 (s, 3H),
2.39–2.46 (m, 2H), 2.66–2.78 (m, 1H), 3.81 (s, 3H), 3.85 (s, 3H), 6.67 (d, 1H, J=1.5 Hz), 6.76 (d, 1H, J=1.5 Hz);
13C NMR (CDCl3, 75 MHz) l 20.10, 21.66, 22.20, 24.42, 31.70, 34.11, 49.60, 53.60, 55.67, 60.26, 111.78, 120.73,
1
132.34, 138.15, 146.33, 152.99, 223.18. 5: H NMR (CDCl3, 300 MHz) l 0.76 (s, 3H), 1.18 (s, 3H), 1.41 (s, 3H),
1.49–1.79 (m, 5H), 2.22 (s, 3H), 2.55–2.66 (m, 1H), 5.11 (bs, 1H), 5.37 (s, 1H), 6.56 (s, 1H), 6.68 (s, 1H); 13C
NMR (CDCl3, 75 MHz) l 20.26, 21.14, 22.80, 25.40, 26.83, 39.20, 40.92, 44.82, 51.09, 113.39, 121.87, 128.25,
133.45, 140.94, 143.32.
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