Stereoselective total syntheses of (±)-1,14-herbertenediol and (±)-tochuinyl acetate and facile total syntheses of (±)-α-herbertenol, (±)-β-herbertenol and (±)-1,4-cuparenediol

Article abstract of DOI:10.1016/S0040-4039(02)02674-6

Stereoselective total syntheses of (±)-1,14-herbertenediol (7) and (±)-tochuinyl acetate (10) and facile total syntheses of (±)-α-herbertenol (2), (±)-β-herbertenol (3) and (±)-1,4-cuparenediol (8) have been successfully accomplished involving intramolecu

Full text of DOI:10.1016/S0040-4039(02)02674-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 737–740
Stereoselective total syntheses of ( )-1,14-herbertenediol and
( )-tochuinyl acetate and facile total syntheses of
( )-a-herbertenol, ( )-b-herbertenol and ( )-1,4-cuparenediol
Tapas Paul, Ashutosh Pal, Pranab Dutta Gupta and Debabrata Mukherjee*
Department of Organic Chemistry, Indian Association for the Cultivation of Science, Kolkata 700 032, India
Received 18 October 2002; accepted 22 November 2002
Abstract—Stereoselective total syntheses of ( )-1,14-herbertenediol (7) and ( )-tochuinyl acetate (10) and facile total syntheses of
( )-a-herbertenol (2), ( )-b-herbertenol (3) and ( )-1,4-cuparenediol (8) have been successfully accomplished involving intramolec-
ular cyclisation of 3-aryl-3-methyl-6-bromohexanoates and in situ methylation of the resulting cyclopentanecarboxylates as the key
reactions. © 2003 Elsevier Science Ltd. All rights reserved.
Herbertanes and cuparanes possessing sterically
crowded cyclopentane moieties belong to an expanding
family of sesquiterpenes and have become popular syn-
thetic targets in recent years as some members exhibit
interesting biological activities. The isolation of the first
members of the herbertane family herbertene (1), a-her-
bertenol (2), b-herbertenol (3), herbertenediol (4), and
herbertenolide (5) (Fig. 1) from the liverwort Herberta
adunca was reported1 earlier by Matsuo and co-work-
ers. Recently, Asakawa and co-workers reported2,3 the
isolation of seven new herbertanes and two new
cuparanes from Japanese liverworts. Many of the
sesquiterpenes isolated from liverworts, particularly the
sesquiterpene phenols, show a wide spectrum of biolog-
ical properties which include1,4 potent antifungal, neu-
rotrophic and anti-lipid peroxidation activities.
1,14-Herbertenediol (7),2 1,4-cuparenediol (8)3 and
cuparene-1,4-quinone (9)3 (Fig. 1) are a few examples
of recently isolated sesquiterpenes from liverworts with
novel structural features. The total synthesis of natu-
rally occurring sesquiterpenes containing the 1-aryl-
1,2,2-trimethylcyclopentane ring system has been an
active area of research in recent times and current
interest5 in phenolic sesquiterpenes is reflected in the
Figure 1.
Keywords: terpenes; phenols; conjugate addition; cyclisation; alkylation.
* Corresponding author. Fax (91)-33-473-2805; e-mail: ocdm@mahendra.iacs.res.in
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02674-6

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T. Paul et al. / Tetrahedron Letters 44 (2003) 737–740
number of diverse synthetic approaches to these com-
pounds. The synthesis of these sesquiterpenes is associ-
ated with the difficulty of the generation of the two
adjacent quaternary carbon atoms at C-1 and C-2 on
the cyclopentane ring and an appropriately substituted,
often highly substituted, aromatic ring at C-1. We have
recently developed a very useful and convenient general
method for the synthesis of herbertane and cuparane
sesquiterpenes from easily accessible 3,3-disubstituted-
6-bromohexanoates, employing an intramolecular
anionic cyclisation strategy to generate the vicinally
substituted cyclopentanes related to the natural prod-
ucts. We envisaged that intramolecular cyclisation of
3-aryl-3-methyl-6-bromohexanoates in the presence of
base and in situ methylation of the resulting cyclopen-
tanecarboxylates from the less hindered face would
generate stereoselectively, in one step, 1,1,2,2-tetra-
substitutedcyclopentanes related to naturally occurring
herbertanes and cuparanes as shown in Scheme 1.
Based on this approach, we have successfully accom-
plished a new total synthesis of the bioactive phenolic
herbertanes 2 and 3 and the first total synthesis of the
cuparane sesquiterpenes 8 and 9. Highly stereoselective
total syntheses of 1,14-herbertenediol (7), via 11-epi-
herbertenolide (6), and the cuparane-type sesquiterpene
tochuinyl acetate (10),6 a marine natural product, have
also been achieved during the present studies. The
sesquiterpenes 7 and 10 possess two vicinal stereogenic
quaternary carbon atoms on a cyclopentane ring and
have recently attracted the attention7 of many synthetic
chemists.
A stereocontrolled total synthesis of tochuinyl acetate
(10) was initially undertaken. The marine sesquiterpene
10 was isolated6 from the dendronotid nudibranch
Tochuina tetraquetra and also from its feed, the soft
coral Gersemia rubiformis. As mentioned before, the
presence of a sterically congested cyclopentane ring
with two vicinal stereogenic quaternary centres makes
the acetate 10 an interesting synthetic target. The first
synthesis of ( )-10 was accomplished by Ishibashi et al.8
using a thiochromane approach, and later Taber and
co-workers9 synthesised ( )-10 involving rhodium
catalysed intramolecular CꢀH insertion of a diazo
ketone as a key step. Very recently, Srikrishna and
co-workers7 achieved the synthesis of ( )-10, employing
a ring-closing metathesis reaction based methodology.
Scheme 1.
Scheme 2. Reagents and conditions: (i)
, CuBr·Me2S, THF, Et2O, 0–20°C; (ii) KOH, HOCH2CH2OH, H2O,
reflux, AcOH, 0°C; (iii) CH2N2, Et2O, 0°C; (iv) AcOH–H2O (4:1), 25–60°C; (v) NaBH4, MeOH, 0–25°C; (vi) PBr3, C6H6, 0–70°C;
(vii) LDA (1.2 equiv.), THF, HMPA (1.5 equiv.), −70°C; (viii) LDA (1.6 equiv.), HMPA (2 equiv.), THF, 0°C, MeI, 0°C; (ix)
LAH, THF, reflux; (x) Ac2O, C5H5N, 25°C.

T. Paul et al. / Tetrahedron Letters 44 (2003) 737–740
739
Our synthesis of ( )-tochuinyl acetate 10 is outlined in
Scheme 2. The first quaternary carbon atom was cre-
ated through conjugate addition to the unsaturated
cyanoester 11. Thus, conjugate addition of 3,3-ethylene-
dioxypropylmagnesium bromide10 to the unsaturated
cyanoester 11 in the presence of CuBr·S(CH3)2 pro-
vided 1211 (58%) which on hydrolysis, decarboxylation
and esterification afforded the ester 13 in 75% yield.
Deacetalisation of 13 followed by reduction of the
resulting aldehyde 14 with NaBH4 afforded the primary
alcohol 15 (83%) which was treated with PBr3 to give
the bromoester 16 in 74% yield. The bromoester 16 was
converted into the cyclopentanecarboxylate 1712 (85%)
in a one pot process involving an intramolecular cycli-
sation of 16 by treatment with LDA (1.2 equiv.) in
THF and HMPA at −70°C followed by alkylation with
MeI at 0°C in the presence of LDA (1.6 equiv.) and
HMPA (2 equiv.), without isolating the initial cyclised
product 17a. The second quaternary carbon atom was
thus generated very efficiently and in a stereoselective
manner, highlighting the potential of the present
method. The high stereoselectivity observed in the
transformation of 16 into 17 is due to methylation
taking place from the less hindered side7 of the interme-
diate enolate of the ester 17a. In the 1H NMR spectrum
of 17, the ester methyl signal appeared at l 3.25 ppm,
indicating shielding of the methoxycarbonyl group by
the vicinal cis aryl group. The stereostructure 17 of the
ester, as shown in Scheme 2, was further confirmed by
conversion of 17, which is suitably functionalised into
( )-tochuinyl acetate (10). Thus, reduction of 17 with
LiAlH4 followed by acetylation of the resulting alcohol
18 furnished ( )-10 in 72% overall yield. The spectral
data of synthetic 10 were identical with those of the
natural product.
We have further explored the possibility of application
of the present method to the total synthesis of the
sesquiterpene phenols a-herbertenol (2), b-herbertenol
(3), herbertenediol (7), and cuparenediol (8) which were
isolated from liverworts. The present synthesis of the
phenolic sesquiterpenes is outlined in Scheme 3 The
acetophenones 19a, 19b and 19c13 were condensed with
ethyl cyanoacetate to provide the unsaturated cyano-
esters 20a (75%), 20b (73%) and 20c (75%), respectively.
Conjugate addition of 3,3-ethylenedioxypropylmagne-
sium bromide to 20a–c in the presence of CuBr·S(CH3)2
afforded 21a (58%), 21b (60%) and 21c (58%) which on
hydrolysis, decarboxylation and esterification furnished
the methyl esters 22a (75%), 22b (77%), and 22c (74%),
respectively. Deacetalisation of 22a followed by reduc-
tion of the resulting aldehyde 23a with NaBH4
Scheme 3. 19a–28a: R1=OMe, R2=H, R3=Me; 19b–28b: R1=H, R2=OMe, R3=Me; 19c–28c: R1=R3=OMe, R2=Me.
Reagents and conditions: (i) CH2C(CN)CO2Et, NH4OAc, AcOH, C6H6, reflux; (ii) , CuBr·Me2S, THF, Et2O,
0–20°C; (iii) KOH, HOCH2CH2OH, H2O, reflux, AcOH, 0°C; (iv) CH2N2, Et2O, 0°C; (v) AcOH–H2O (4:1), 25–60°C; (vi) NaBH4,
MeOH, 0–25°C; (vii) PBr3, C6H6, 0–70°C; (viii) LDA (1.2 equiv.), THF, HMPA (1.5 equiv.), −70°C; (ix) LDA (1.6 equiv.),
HMPA (2 equiv.), THF, 0°C, MeI, 0°C; (x) LAH, THF, reflux; (xi) PCC, NaOAc, CH2Cl2, 25°C; (xii) N2H4, N2H4·2HCl,
(HOCH2CH2)2O, 125°C; KOH, 210°C; (xiii) BBr3, CH2Cl2, −70 to 20°C; (xiv) (NH4)2Ce(NO3)6, MeCN, H2O, 25°C.

740
T. Paul et al. / Tetrahedron Letters 44 (2003) 737–740
afforded the primary alcohol 24a (82%) which was
converted into the bromoester 25a (72%) with PBr3.
The esters 22b and 22c were similarly converted into the
bromoesters 25b (62%) and 25c (62%), respectively. As
described earlier for 17, the transformation of the bro-
moester 25a into the cyclopentanecarboxylate 26a was
accomplished in 83% yield in a one pot process employ-
ing an intramolecular cyclisation of 25a using LDA as
the base followed by in situ methylation of the resulting
product. Intramolecular cyclisation and in situ methyla-
tion of the esters 25b and 25c were similarly carried out
to provide the esters 26b (85%) and 26c (85%), respec-
tively. As expected, very high diastereoselectivity was
References
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1
observed in the above transformations. In the H NMR
spectra of 26a–c, upfield singlets, characteristic14 of the
methyl group cis to the aromatic ring in cuparanes,
were absent but the ester methyl signals appeared at l
3.18, 3.28 and 3.26 ppm, respectively. The upfield shifts
of the ester methyl signals indicated shielding of the
methoxycarbonyl groups by the vicinal cis aryl groups,
establishing the stereochemistry of these intermediates
as shown in Scheme 3.
1992, 57, 436–441.
10. Bu¨chi, G.; Wu¨est, H. J. Org. Chem. 1969, 34, 1122–1123.
11. Satisfactory spectroscopic and microanalytical data were
obtained for all new compounds.
1
12. Selected spectral data for the ester 17: H NMR (CDCl3,
Reduction of the esters 26a-c with LiAlH4 afforded the
primary alcohols 27a12 (88%), 27b (90%) and 27c (85%)
which on oxidation with pyridinium chlorochromate
provided the aldehydes 28a (84%), 28b12 (85%) and 28c
(84%), respectively. Huang–Minlon reduction of 28a
followed by demethylation with BBr3 afforded ( )-a-
herbertenol (2) (71%). Similarly, Huang–Minlon reduc-
tion of 28b and 28c and subsequent demethylation of
the resulting products with BBr3 furnished b-her-
bertenol (3) (71%) and ( )-1,4-cuparenediol (8)12 (70%),
respectively. Oxidation of 8 with ceric ammonium
nitrate afforded ( )-cuparene-1,4-quinone (9)12 in 88%
yield.
300 MHz) l 1.31 (s, 3H), 1.40 (s, 3H), 1.56–2.00 (m, 4H),
2.27–2.37 (m, 1H), 2.28 (s, 3H), 2.52–2.60 (m, 1H), 3.25
(s, 3H), 7.05 (d, 2H, J=8.4 Hz), 7.17 (d, 2H, J=8.4 Hz);
13C NMR (CDCl3, 75 MHz) l 20.3, 20.7, 21.1, 24.2, 35.8,
37.9, 50.9, 51.4, 56.6, 126.2, 126.2, 128.3, 128.3, 135.3,
1
143.4, 176.9. For the alcohol 27a: H NMR (CDCl3, 300
MHz) l 1.19 (s, 3H), 1.41 (s, 3H), 1.31–2.48 (m, 7H), 2.27
(s, 3H), 3.12 (bs, 2H), 3.78 (s, 3H), 6.79 (d, 1H, J=8.1
Hz), 7.00 (dd, 1H, J=8.1, 1.9 Hz), 7.08 (d, 1H, J=1.9
Hz); 13C NMR (CDCl3, 75 MHz) l 20.8, 20.9, 21.2, 24.0,
37.1, 41.9, 48.9, 50.3, 55.2, 70.4, 112.0, 127.7, 129.3,
129.8, 135.1, 156.2. For the aldehyde 28b: 1H NMR
(CDCl3, 300 MHz) l 1.24 (s, 3H), 1.29 (s, 3H), 1.52–1.60
(m, 1H), 1.75–2.39 (m, 5H), 2.20 (s, 3H), 3.78 (s, 3H),
6.73 (d, 1H, J=9 Hz), 7.10 (d, 1H, J=9 Hz), 7.11 (s,
1H), 9.03 (s, 1H); 13C NMR (CDCl3, 75 MHz) l 16.4,
16.5, 20.7, 24.6, 33.1, 37.7, 49.7, 55.1, 58.5, 109.4, 124.7,
126.0, 128.9, 135.8, 156.1, 206.4. For 1,4-cuparenediol 8:
1H NMR (CDCl3, 300 MHz) l 0.76 (s, 3H), 1.16 (s, 3H),
1.38 (s, 3H), 1.47–1.77 (m, 5H), 2.15 (s, 3H), 2.49–2.53
(m, 1H), 4.41 (bs, 1H), 4.49 (bs, 1H), 6.46 (s, 1H), 6.74 (s,
1H); 13C NMR (CDCl3, 75 MHz) l 15.1, 20.2, 22.9, 25.4,
26.9, 39.4, 41.1, 44.7, 50.8, 116.2, 119.1, 121.9, 132.0,
146.8, 148.1. For cuparene-1,4-quinone 9: 1H NMR
(CDCl3, 300 MHz) l 0.74 (s, 3H), 1.12 (s, 3H), 1.29 (s,
3H), 1.51–1.76 (m, 5H), 2.01 (d, 3H, J=1.5 Hz), 2.20–
2.29 (m, 1H), 6.51 (q, 1H, J=1.5 Hz), 6.64 (s, 1H); 13C
NMR (CDCl3, 75 MHz) l 14.8, 19.8, 22.9, 25.2, 27.8,
38.5, 41.5, 44.0, 51.3, 133.9, 135.5, 143.6, 155.0, 188.2,
The ester 26a was smoothly converted into the lactone
11-epi-herbertenolide (6) (78%) by treatment with BBr3.
Reduction of 6 with LiAlH4 finally yielded 1,14-her-
bertenediol (7)12 in 91% yield. The identities of our
synthetic compounds 2, 3, 8, 9 and 7 were secured
1
through comparison of H and 13C NMR data with
those of authentic compounds.
In conclusion, we have developed a convenient and
useful general method for the synthesis of herbertane
and cuparane sesquiterpenes based on intramolecular
cyclisation of 3-aryl-3-methyl-6-bromohexanoates and
in situ methylation of the resulting cyclopentanecar-
boxylates. Stereocontrolled total syntheses of ( )-1,14-
herbertenediol and ( )-tochuinyl acetate and facile total
syntheses of ( )-a-herbertenol, ( )-b-herbertenol and
( )-1,4-cuparenediol have been achieved by the applica-
tion of the present method.
1
188.6. For 1,14-herbertenediol 7: H NMR (CDCl3, 300
MHz) l 1.23 (s, 3H), 1.55 (s, 3H), 1.18–1.97 (m, 6H), 2.27
(s, 3H), 2.42–2.47 (m, 1H), 3.26, 3.34 (2×d, 2H, J=11.1
Hz), 6.73 (d, 1H, J=7.8 Hz), 6.91 (dd, 1H, J=7.8, 1.5
Hz), 6.96 (d, 1H, J=1.5 Hz); 13C NMR (CDCl3, 75
MHz) l 20.4, 20.9, 21.1, 23.9, 35.9, 42.3, 48.9, 50.9, 70.7,
117.9, 128.0, 129.2, 129.8, 132.9, 153.1.
Acknowledgements
13. Fuganti, C.; Serra, S. J. Chem. Soc., Perkin Trans. 1
We are grateful to the CSIR, New Delhi, for financial
support (Grant No. 01(1742)/02/EMR-II). One of us
(T.P.) thanks the CSIR for a fellowship.
2000, 3758–3764.
14. Irie, T.; Suzuki, T.; Yasunari, Y.; Kurosawa, E.; Masa-
mune, T. Tetrahedron 1969, 25, 459–468.