Formal total synthesis of (±)-herbertenediol and (±)-mastigophorenes A and B

Article abstract of DOI:10.1016/S0040-4039(01)01109-1

A simple and straightforward formal total synthesis of the sesquiterpene herbertenediol and its dimers mastigophorenes A and B, starting from vanillin, is described.

Full text of DOI:10.1016/S0040-4039(01)01109-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 5781–5782
Formal total synthesis of ( )-herbertenediol and
( )-mastigophorenes A and B
A. Srikrishna* and M. Srinivasa Rao
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India
Received 8 May 2001; accepted 21 June 2001
Abstract—A simple and straightforward formal total synthesis of the sesquiterpene herbertenediol and its dimers mastigophorenes
A and B, starting from vanillin, is described. © 2001 Elsevier Science Ltd. All rights reserved.
The dimeric sesquiterpene phenols mastigophorenes A
tion of our interest in the synthesis of natural products
containing multiple contiguous quaternary carbon
atoms,7 we herein describe a simple and straightforward
formal total synthesis of racemic herbertenediol and
mastigophorenes A and B starting from vanillin.
and B 1 and 2, isolated1 along with their isomers
mastigophorenes
B
and
C
from the liverwort
Mastigophora diclados, were shown to stimulate nerve
growth. On the other hand, the logical monomeric
precursor of mastigophorenes, herbertenediol 3,
isolated2 along with other herbertenes from the liver-
wort Herberta adunca, was recently found to exhibit a
potent anti-lipid peroxidation activity.3 The interesting
structure and associated biological activities make
mastigophorenes and herbertenediol intriguing syn-
thetic targets of current interest. The first synthesis of
herbertenediol 3 was accomplished2b,3 via hydroxyla-
tion of the sesquiterpene a-herbertenol 4, whereas
recently Mukherjee and co-workers reported4 the syn-
thesis of ( )-herbertenediol 3 from a tetralone deriva-
tive. The first synthesis of mastigophorenes A and B 1
and 2 was achieved5 in 1999 via the phenolic coupling
of natural herbertenediol 3. Almost at the same time,6
Meyers and Degnan reported an enantioselective syn-
thesis of herbertenediol (−)-3 and its conversion to
mastigophorenes A and B (−)-1 and (−)-2. In continua-
The differential nature of the two ortho substituted
oxygen functionalities in vanillin 5 was exploited for the
introduction of a side chain at the C-5 position via a
Claisen rearrangement. The synthetic sequence starting
from the phenol 6, obtained by Clemmensen’s reduc-
tion of vanillin 5, is depicted in Scheme 1. Thus,
allylation of the hydroxy group in 6 generated the allyl
ether 7. Thermal activation of the allyl ether 7 at 180°C
furnished the ortho Claisen product 8, which on ether-
ification with dimethyl sulfate and sodium hydroxide
generated the dimethoxy compound 9. Ozonolytic
cleavage of the allyl group in 9, followed by further
oxidation of the resultant aldehyde 10 and esterification
furnished the ester 11 in 94% overall yield. Alkylation
of the ester 11 with LDA and methyl iodide generated
the ester 12, which on further alkylation with LDA,
Me Me
OH
X
Me
Me
Me
Me Me
MeMe
HO OHHO OH
Me
Me
Mastigophorene A 1
Mastigophorene B 2
Me
Me Me
Me
X = OH Herbertenediol 3
X = H α-Herbertenol 4
Me
MeMe
MeMe
HO OHHO OH
* Corresponding author. Fax: 91-80-3600683; e-mail: ask@orgchem.iisc.ernet.in
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01109-1

5782
A. Srikrishna, M. S. Rao / Tetrahedron Letters 42 (2001) 5781–5782
OR
X
OMe
Me
OH
X
O
X
MeO
MeO
MeO
MeO
COOMe
a
b-d
e,f
Me
8. R = H; X = CH2
9. R = Me; X = CH2
10. R = Me, X = O
11. X = H
12. X = Me
Me
5. X = CHO
6. X = Me
7
g
OMe
OMe
OMe
Me
CHO
Me
CHO
Me
COOMe
j
h,i
MeO
MeO
MeO
Me
O
Me
Me
14
13
15
k
OMe
OMe
OMe
O
O
O
MeO
MeO
MeO
Me
Me
Me
m
n
Me
Me
17
Me
l
Me
(+)-1-3
--
Me
Me
Me
16
18
Scheme 1. Reagents, conditions and yields: (a) K2CO3, Me2CꢀO, CH2ꢀCHCH2Br, reflux, 8 h, 92%; (b) sealed tube, 180°C, 15 h,
67%; (c) 10% aq. NaOH, Me2SO4, 87%; (d) O3/O2, CH2Cl2–MeOH, −70°C; Me2S, rt, 3 h; (e) 2.5 M Jones reagent, Me2CꢀO,
0°C“rt, 1 h; MeOH, H2SO4, 6 h; 94% from 9; (f) LDA, THF, MeI, −70°C“rt, 4 h, 88%; (g) LDA, THF, HMPA,
CH2ꢀCHCH2Br, −70°C“rt, 4 h, 74%; (h) LiAlH4, Et2O, 1.5 h; (i) PCC, CH2Cl2, rt, 2 h; 87% from 13; (j) PdCl2, CuCl, DMF,
H2O, O2, rt, 16 h, 77%; (k) 2 M KOH in MeOH, THF, rt, 5 h, 92%; (l) NaH (excess), THF, DMF, MeI, rt, 8 h, 76%; (m) 10%
Pd-C, H2, EtOH, rt, 1 atm., 1 h, 95%; (n) Refs. 4 and 6.
HMPT and allyl bromide furnished the key intermedi-
bertenediol 3, which is converted6 into mastigophorenes
A and B 1 and 2, the present sequence constitutes a
formal total synthesis of these natural products.
ate pentenoate 13.† A two-step conversion of the ester
group into an aldehyde transformed the ester 13 into
.
the aldehyde 14. Oxidation of the terminal olefin in the
pentenal 14 under Wacker conditions8 (PdCl2, CuCl,
DMF, H2O, O2) followed by intramolecular aldol con-
densation of the resultant keto-aldehyde 15 furnished
the cyclopentenone 16† in 71% overall yield. Dimethyla-
tion using sodium hydride and methyl iodide followed
by catalytic hydrogenation of the resultant enone 17
transformed the cyclopentenone 16 into cyclopentanone
18 in 72% yield, which exhibited spectral data identical
to those of an authentic sample.4 Since the cyclopen-
tanone 18 has already been transformed4 into her-
Acknowledgements
We thank Professor D. Mukherjee for providing copies
of the spectra of 18.
References
1. Fukuyama, Y.; Asakawa, Y. J. Chem. Soc., Perkin Trans.
1 1991, 2737.
2. (a) Matsuo, A.; Yuki, S.; Nakayama, M. Chem. Lett.
1983, 1041; (b) Matsuo, A.; Yuki, S.; Nakayama, M. J.
Chem. Soc., Perkin Trans. 1 1986, 701.
3. Fukuyama, Y.; Kiriyama, Y.; Kodama, M. Tetrahedron
Lett. 1996, 37, 1261.
4. Gupta, P. D.; Pal, A.; Roy, A.; Mukherjee, D. Tetrahedron
Lett. 2000, 41, 7563.
5. Bringmann, G.; Pabst, T.; Rycroft, D. S.; Connolly, J. D.
Tetrahedron Lett. 1999, 40, 483.
6. Degnan, A. P.; Meyers, A. I. J. Am. Chem. Soc. 1999, 121,
2762.
7. Srikrishna, A.; Vijaykumar, D. J. Chem. Soc., Perkin
Trans. 1 1999, 1265 and references cited therein.
8. Tsuji, J. Synthesis 1984, 369.
† All compounds exhibited spectral data consistent with their struc-
tures. Yields (unoptimised) refer to isolated and chromatographi-
cally pure compounds. Selected spectral data for the pentenoate 13:
IR (neat): wmax/cm−1 1735, 1640, 1587, 917. 1H NMR (300 MHz,
CDCl3+CCl4): l 6.59 (1H, s), 6.54 (1H, s), 5.60–5.35 (1H, m), 4.97
(1H, d, J 18 Hz), 4.95 (1H, d, J 7.5 Hz), 3.80 (3H, s), 3.71 (3H, s),
3.61 (3H, s), 2.30–2.00 (2H, m), 2.29 (3H, s), 1.39 (3H, s). 13C NMR
(75 MHz, CDCl3+CCl4): l 176.4, 152.0, 144.3, 136.9, 134.3, 131.9,
118.9, 117.8, 112.4, 59.8, 55.5, 51.4, 47.2, 42.3, 23.4, 21.6. For the
1
cyclopentenone 16: IR (neat): wmax/cm−1 1714. H NMR (300 MHz,
CDCl3+CCl4): l 7.79 (1H, d, J 6 Hz), 6.59 (1H, s), 6.50 (1H, s), 6.09
(1H, d, J 6 Hz), 3.80 (3H, s), 3.73 (3H, s), 2.66 and 2.53 (2H, 2×d,
J 18.3 Hz), 2.55 (3H, s), 1.53 (3H, s). 13C NMR (75 MHz,
CDCl3+CCl4): l 209.8 (C), 170.7 (CH), 152.4 (C), 145.2 (C), 138.0
(C), 132.6 (C), 130.6 (CH), 119.1 (CH), 112.5 (CH), 60.3 (CH3),
55.6 (CH3), 50.9 (CH2), 47.2 (C), 28.3 (CH3), 21.5 (CH3).