Total synthesis of (±)-1,13-herbertenediol, (±)-α-herbertenol and (±)-β-herbertenol

Article abstract of DOI:10.1016/S0040-4039(02)02734-X

Total synthesis of α-herbertenol, β-herbertenol and 1,13-herbertenediol, employing a Claisen rearrangement and ring-closing metathesis as key reactions for the generation of the cyclopentane containing vicinal quaternary carbons, has been described.

Full text of DOI:10.1016/S0040-4039(02)02734-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 1027–1030
Total synthesis of ( )-1,13-herbertenediol, ( )-a-herbertenol
and ( )-b-herbertenol
A. Srikrishna* and G. Satyanarayana
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India
Received 22 October 2002; accepted 29 November 2002
Abstract—Total synthesis of a-herbertenol, b-herbertenol and 1,13-herbertenediol, employing a Claisen rearrangement and
ring-closing metathesis as key reactions for the generation of the cyclopentane containing vicinal quaternary carbons, has been
described. © 2003 Elsevier Science Ltd. All rights reserved.
Herbertanes are a small group of sesquiterpenes, which
are considered as chemical markers for the liverworts
belonging to the genus Herbertus.1a Isolation of the first
members of the herbertane group herbertene 1a, a-her-
bertenol 1b, b-herbertenol 1c, herbertenediol 1d, her-
bertenal 1e and herbertenolide 2a from Herberta adunca
was reported earlier by Matsuo and co-workers.1b Sub-
sequently,1c Rycroft et al. reported the isolation of the
aldehyde 1f and the ester 1g from Herbertus aduncus.
Recently,1a Asakawa and co-workers reported the isola-
tion of seven new members of this group, herbertenelac-
tol 2b, 1,13-herbertenediol 3, 1,14-herbertenediol 4,
1,15-herbertenediol 5, herbertenones A and B 6a,b and
12-methoxyherbertenediol 7 along with dimeric herber-
tanes, mastigophorenes A–C, from the Japanese liver-
wort Herberta sakuraii. The phenolic herbertanes, e.g.
1b–d and the dimers mastigophorenes have been shown
to possess interesting biological properties such as
growth inhibiting activity, antifungal, antilipid peroxi-
dation and neurotropic activities.1,2 The sesquiterpenes
cuparanes and herbertanes are interesting synthetic
targets owing to the presence of a sterically crowded
1-aryl-1,2,2-trimethylcyclopentane moiety, and the
difficulty associated with the construction of vicinal
quaternary carbon atoms on a cyclopentane ring.
Until recently, unlike the parent hydrocarbon, the phe-
nolic herbertanes have received very little attention
from synthetic chemists despite their interesting biologi-
cal properties.3,4 Since its isolation, there is only one
report on the synthesis of 1,13-herbertenediol 3 by
Fukuyama et al., via an intramolecular Heck reaction.4
Recently,3h we have reported the synthesis of 1,14-her-
bertenediol 4. Now we have developed a new strategy
for the total synthesis of 1,13-herbertenediol 3, a-her-
bertenol 1b and b-herbertenol 1c employing a Claisen
* Corresponding author. Fax: 91-80-3600683; 3600529; e-mail: ask@orgchem.iisc.ernet.in
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02734-X

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A. Srikrishna, G. Satyanarayana / Tetrahedron Letters 44 (2003) 1027–1030
rearrangement and ring closing metathesis (RCM) as
key reactions.
dimethylpent-4-enal6 10 in the presence of lithium fur-
nished the benzyl alcohols 12a,b, which on oxidation
with pyridinium chlorochromate (PCC) and silica gel in
methylene chloride furnished the ketones 13a,b. Since
the conventional Wittig as well as Horner–Wadsworth–
Emmons reactions failed due to steric crowding, a
vinylation and transposition was adopted for the con-
version of the ketones 13a,b into the allyl alcohols 8a,b.
Consequently, reaction of the ketones 13a,b with vinyl-
magnesium bromide furnished the allylic alcohols
14a,b. Oxidative transposition (PCC-silica gel) of the
allyl alcohols 14a,b followed by regioselective reduction
of the resultant aldehydes 15a,b with sodium borohy-
dride in methanol generated the alcohols 8a,b. An ortho
ester variant of the Claisen rearrangement7 with triethyl
orthoacetate and a catalytic amount of propionic acid
It was envisioned (Scheme 1) that Claisen rearrange-
ment of the allyl alcohol 8 followed by a ring-closing
metathesis (RCM) reaction would generate the
cyclopentene 9 containing two quaternary carbon
atoms, which could be transformed into herbertanes.5
Coupling of a suitably substituted aromatic bromide
with 2,2-dimethylpent-4-enal 10 could be adopted for
the generation of the allyl alcohol 8.
The synthetic sequence starting from 2-bromo-4-methyl-
anisole 11a and 4-bromo-2-methylanisole 11b is
depicted in Scheme 2. Thus, a sonically accelerated
Barbier reaction of the bromides 11a,b and 2,2-
Scheme 1.
Scheme 2. Reagents, conditions and yields: (a) Li, THF, ))), 45 min, 72 and 79%; (b) PCC, silica gel, CH2Cl2, 2 h, 91 and 89%;
(c) CH2ꢀCHMgBr, THF, 4 h, 78 and 80%; (d) PCC, silica gel, CH2Cl2, 24 h, 84 and 76%; (e) NaBH4, MeOH, 0–5°C, 89 and 81%;
(f) MeC(OEt)3, EtCOOH, sealed tube, 180°C, 36 and 48 h, 30 and 45%; (g) PhCHꢀRuCl2(PCy3)2 (5 mol%), CH2Cl2, rt, 6 and 10
h, 88 and 94%; (h) H2, 10%Pd/C, EtOH, 6 h, 99 and 99%; (i) LAH, Et2O, 0–5°C, 1 h, 94 and 96%; (j) PCC, silica gel, CH2Cl2,
0.5 h, 86 and 84%; (k) (Ph3P)3RhCl, C6H6, sealed tube, 120°C, 24 h, 80 and 66%; (l) BBr3, CH2Cl2, −40°C to rt, 1.5 h, 95 and
89%.

A. Srikrishna, G. Satyanarayana / Tetrahedron Letters 44 (2003) 1027–1030
1029
in a sealed tube transformed the allyl alcohols 8a,b into
the esters 16a,b, thus creating the vicinal quaternary
carbon atoms. RCM reactions8 of the dienes 16a,b with
5 mol% of Grubbs’ catalyst [PhCHꢀRuCl2(PCy3)2] in
methylene chloride generated the cyclopentenes† 17a,b
in a very efficient manner, which on hydrogenation
with 10% palladium over carbon as the catalyst fur-
nished the homoherbertane esters 18a,b. A reduction–
oxidation protocol transformed the esters 18a,b into the
aldehydes† 19a,b. Wilkinson’s catalyst mediated decar-
bonylation of the aldehydes 19a,b followed by demethy-
lation of the resultant ethers 20a,b with boron
tribromide furnished a-herbertenol 1b and b-her-
bertenol 1c, mp 81°C (lit.1b 80–81°C), respectively,
24 and reductive work-up furnished a 5:4 mixture of the
aldehyde† 22 and the ketone 25, which were separated
by silica gel column chromatography. Grignard reac-
tion transformed the ketone 25 back into the alcohol
23. Oxidation9 of the aldehyde 22 with sodium
chlorite10 followed by esterification with diazomethane
furnished the ester 26. Boron tribromide mediated
demethylation transformed the ester 26 into the
lactone4† 27. Finally, reduction of the lactone 27 with
lithium aluminium hydride furnished 1,13-herbertene-
1
diol 3, which exhibited H and 13C NMR spectral data
identical to that of the natural compound.1a
In conclusion, we have developed a methodology for
the synthesis of a- and b-herbertenols 1b,c and 1,13-
herbertenediol 3. Conversion of a-herbertenol 1b into
herbertenediol 1d and the dimeric herbertanes
mastigophorenes has already been established.2,3 Cur-
rently, we are investigating the extension of this
methodology for other oxidised herbertenes such as
1e–g and 7.
1
which exhibited H and 13C NMR spectral data identi-
cal to those reported in the literature.1b,3
For the synthesis of 1,13-herbertenediol 3, degradation
of the homoherbertene ester 18a was explored (Scheme
3). Thus, reaction of the ester 18a with an excess of
phenyllithium followed by dehydration of the resultant
tertiary alcohol with phosphorus oxychloride furnished
the olefin 21. However, attempted ozonolysis of 21
failed to generate the requisite aldehyde 22, as the
electron rich aromatic ring in 21 is preferentially
cleaved prior to the olefin under the conditions
employed. On the other hand, reaction of the ester 18a
with an excess of methylmagnesium iodide followed by
dehydration of the resultant tertiary alcohol 23 with
phosphorus oxychloride furnished a regioisomeric mix-
ture of the olefin 24. Ozonolysis of the olefinic mixture
Acknowledgements
We thank Professor Y. Asakawa for providing a copy
of the 1H NMR spectrum of the diol 3, and the
C.S.I.R., New Delhi for the award of a research fellow-
ship to G.S.
† All the compounds exhibited spectral data consistent with their structures. Yields (unoptimised) refer to isolated and chromatographically pure
compounds. Spectral data for the cyclopentene ester 17a: IR (neat): wmax/cm−1 1732. 1H NMR (300 MHz, CDCl3+CCl4): l 6.97 (1H, s), 6.89
(1H, d, J 8.4 Hz), 6.66 (1H, d, J 8.4 Hz), 6.17 (1H, d, J 6 Hz), 5.76 (1H, d, J 6 Hz), 3.83 (2H, q, J 6.9 Hz), 3.77 (3H, s), 3.70 and 2.31 (2H,
2×d, J 14.4 Hz), 2.35 and 2.15 (2H, 2×d, J 15.6 Hz), 2.24 (3H, s), 1.26 (3H, s), 0.96 (3H, t, J 6.9 Hz), 0.54 (3H, s). 13C NMR (75 MHz,
CDCl3+CCl4): l 172.2 (C), 156.3 (C), 139.3 (CH), 130.6 (C), 130.4 (CH), 128.7 (C), 127.7 (2 C, CH), 110.8 (CH), 59.2 (CH2), 59.0 (C), 54.8
(CH3), 49.0 (CH2), 45.3 (C), 40.5 (CH2), 28.8 (CH3), 25.3 (CH3), 20.9 (CH3), 14.2 (CH3). For the cyclopentene ester 17b: IR (neat): wmax/cm−1
1738. 1H NMR (300 MHz, CDCl3+CCl4): l 6.97 (1H, d, J 7.8 Hz), 6.95 (1H, s), 6.64 (1H, d, J 8.4 Hz), 6.26 (1H, d, J 5.4 Hz), 5.83 (1H, d,
J 5.4 Hz), 3.87 (2H, q, J 6.9 Hz), 3.78 (3H, s), 3.00 and 2.44 (2H, 2×d, J 14.7 Hz), 2.29 and 2.13 (2H, 2×d, J 16.8 Hz), 2.17 (3H, s), 1.13 (3H,
s), 1.02 (3H, t, J 6.9 Hz), 0.44 (3H, s). 13C NMR (75 MHz, CDCl3+CCl4): l 171.2 (C), 156.1 (C), 138.8 (CH), 133.9 (C), 129.1 (2 C, C), 125.4
(C), 124.8 (CH), 109.0 (CH), 59.5 (CH2), 57.6 (C), 54.9 (CH3), 47.3 (CH2), 45.8 (C), 41.3 (CH2), 28.0 (CH3), 23.7 (CH3), 16.8 (CH3), 14.3 (CH3).
For the aldehyde 19a: IR (neat): wmax/cm−1 2732, 1717. 1H NMR (300 MHz, CDCl3+CCl4): l 9.26 (1H, brs), 7.02 (1H, s), 6.96 (1H, d, J 8.4
Hz), 6.70 (1H, d, J 8.4 Hz), 3.72 (3H, s), 3.68 (1H, dd, J 15.0 and 2.7 Hz), 2.65–2.50 (1H, m), 2.28 (3H, s), 2.21 (1H, dd, J 15.0 and 2.1 Hz),
1.95–1.70 (3H, m), 1.60–1.49 (2H, m), 1.09 (3H, s), 0.67 (3H, s). 13C NMR (75 MHz, CDCl3+CCl4): l 204.0 (CH), 156.0 (C), 130.8 (C), 130.3
(CH), 129.2 (C), 128.3 (CH), 111.2 (CH), 54.7 (CH3), 52.5 (C), 48.0 (CH2), 45.7 (C), 40.7 (CH2), 37.6 (CH2), 26.3 (CH3), 25.8 (CH3), 21.1 (CH3),
1
20.9 (CH2). For the aldehyde 19b: IR (neat): wmax/cm−1 2733, 1716. H NMR (300 MHz, CDCl3+CCl4): l 9.21 (1H, brs), 7.03 (1H, s), 7.03 (1H,
d, J 9.3 Hz), 6.68 (1H, d, J 9.3 Hz), 3.80 (3H, s), 2.96 (1H, d, J 15.6 Hz), 2.53–2.40 (1H, m), 2.33 (1H, dd, J 15.6 and 3.0 Hz), 2.19 (3H, s),
1.95–1.75 (3H, m), 1.65–1.50 (2H, m), 1.07 (3H, s), 0.57 (3H, s). 13C NMR (75 MHz, CDCl3+CCl4): l 202.8 (CH), 156.2 (C), 134.7 (C), 129.9
(2 C, C and CH), 125.9 (CH), 109.2 (CH), 55.0 (CH3), 51.5 (C), 48.9 (CH2), 45.4 (C), 39.3 (CH2), 33.9 (CH2), 26.1 (CH3), 24.4 (CH3), 20.0
(CH2), 16.9 (CH3). For the aldehyde 22: IR (neat): wmax/cm−1 2710, 1725. 1H NMR (300 MHz, CDCl3+CCl4): l 9.54 (1H, s), 7.04 (1H, s), 7.02
(1H, d, J 7.8 Hz), 6.75 (1H, d, J 7.8 Hz), 3.72 (3H, s), 2.60–2.40 (1H, m), 2.32 (3H, s), 2.17–2.00 (1H, m), 1.91–1.50 (4H, m), 1.16 (3H, s), 0.67
(3H, s). 13C NMR (75 MHz, CDCl3+CCl4): l 200.2 (CH), 155.2 (C), 130.0 (CH), 129.5 (C), 128.8 (CH), 127.9 (C), 111.5 (CH), 64.5 (C), 55.2
(CH3), 44.7 (C), 40.5 (CH2), 30.9 (CH2), 28.5 (CH3), 24.0 (CH3), 21.1 (CH3), 19.7 (CH2). For the lactone 27: IR (neat): wmax/cm−1 1798, 1796.
1H NMR (300 MHz, CDCl3+CCl4): l 7.04 (1H, d, J 8.4 Hz), 6.96 (1H, s), 6.94 (1H, d, J 8.4 Hz), 2.36 (3H, s), 2.40–1.64 (6H, m), 1.03 (3H,
s), 0.92 (3H, s). 13C NMR (75 MHz, CDCl3+CCl4): l 179.4 (C), 151.7 (C), 132.5 (C), 129.3 (C), 128.9 (CH), 125.6 (CH), 110.1 (CH), 60.1 (C),
47.6 (C), 38.7 (CH2), 34.7 (CH2), 25.4 (CH3), 23.6 (CH3), 21.5 (CH3), 21.0 (CH2).

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A. Srikrishna, G. Satyanarayana / Tetrahedron Letters 44 (2003) 1027–1030
Scheme 3. Reagents, conditions and yields: (a) MeMgI, Et2O, 4 h, 83%; (b) POCl3, py, 0.5 h, 68%; (c) i. O3/O2, MeOH–CH2Cl2
(1:4), −70°C; ii. Me2S, rt, 3 h, 70%; (d) i. NaClO2, NaH2PO4, t-BuOH, cyclohexene, H2O, 3 h; ii. CH2N2, Et2O, 0°C, 20 min; 66%;
(e) BBr3, CH2Cl2, −40°C to rt, 40 min, 65%; (f) LAH, THF, 0–5°C, 1 h, 95%.
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