The enantioselective total synthesis of (-)-myltaylenol

Article abstract of DOI:10.1039/a703164e

Using an intramolecular Diels-Alder cycloaddition followed by an oxidative rupture of the connective unit as the key step, the unusual carbon framework of (-)-myltaylenol was established.

Full text of DOI:10.1039/a703164e

View Article Online / Journal Homepage / Table of Contents for this issue
The enantioselective total synthesis of (2)-myltaylenol
Sven Doye, Torsten Hotopp and Ekkehard Winterfeldt*
Institute of Organic Chemistry, University of Hannover, Schneiderberg 1b, 30167 Hannover, Germany
Using an intramolecular Diels–Alder cycloaddition followed
by an oxidative rupture of the connective unit as the key
step, the unusual carbon framework of (2)-myltaylenol was
established.
highly selective alkylation of this unsaturated ketone with
thiophenylmethyl iodide followed by a Wolff–Kishner reduc-
tion to prepare the cyclopentenol 5. To generate the correspond-
ing cyclopentadiene, the tosylate 7 was formed and treated with
potassium tert-butoxide in THF at 65 °C. Subsequent Pummerer
rearrangement followed by a borohydride reduction gave rise to
the primary alcohol 8, which after treatment with ethene-
sulfonyl chloride was ready for the intramolecular cycloaddi-
tion. For this process and the accompanying oxidative ring
fission of the sulfonate we had decided on the Metz protocol.5
This worked nicely as far as the intramolecular cycloaddition
was concerned. The oxidation employing 2-methoxy-
4,4,5,5-tetramethyl-1,3,2-dioxaborolane, however, which had
been successfully applied by Metz and his colleagues in various
instances, failed. Since the electrophilic attack has to take place
next to a quarternary carbon atom we came to the conclusion
that steric hindrance may be the cause for this failure. We thus
treated the carbanion of 9, generated using BusLi, with
molecular oxygen and were pleased to note the clear formation
of hydroxy ketone 10. As the yield under various conditions,
however, barely exceeded 40% we investigated the relationship
between the amount of BusLi used and the yield under standard
reaction conditions and noticed that a large surplus of the
deprotonating species (10–11 equiv.) reliably gave a 65% yield
of the hydroxy ketone. With this piece of information at hand
one may speculate about the formation of sec-butyl hydro-
peroxide and its possible role as an oxidant. We hesitate,
however, to discuss the mechanism of this useful process at this
stage of our investigation.
In 1985 Matsuo1 and his colleagues reported the isolation of the
unusual sesquiterpenoid alcohol (2)-myltaylenol 1 from the
liverwort Mylia taylorii. The compound is characterized by a
novel polycyclic terpenoid framework containing three consec-
utive quartenary carbon atoms and although Srikrishna2 and his
group in 1994 briefly described a remarkable biomimetic
transformation, which finally gave rise to the corresponding
racemic desoxy compound starting from cyclogeraniol, no
enantioselective approach to this type of molecule has been
reported.
As retrosynthetic planning disclosed an intramolecular
Diels–Alder cycloaddition employing cyclopentadiene 2 to be a
potential key step and since we had in recent years gained some
experience with dienes of this type, the enantioselective
preparation of this compound was considered our first target.
For hydrindane derivatives of this structure the pure enantio-
mers of the Hajos–Wiechert ketone had been shown in our
group to be an ideal starting material3 and as the monoalkylated
derivative 3 is well described in the literature4 we employed the
OTHP
9 steps
10 steps
Without collecting further information about this oxidation
we converted the keto group into the corresponding olefin 11 in
a Shapiro reaction. Since it was hoped that a very bulky
protecting group on the primary alcohol would change it into a
large inert moiety, thus rendering the subsequent borane
addition/oxidation sequence highly regioselective, triiso-
propylsilyl triflate in the presence of triethylamine was used as
O
HO
O
SO2
1
2
3
Scheme 1
OR
OR
i
iii
87%
3
81%
O
i, ii
iii
2
SPh
SPh
99%
73%
HO
6 R = H
7 R = Ts
4 R = THP
5 R = H
O
iv 99%
ii 100%
SO2
O
9
10
v–viii 72%
iv, v
88%
ix
81%
ix, x
85%
vii, viii
49%
1
Pri3SiO
RO
11 R = H
12 R = SiPri3
O
13
vi 99%
O
OH
SO2
2
8
Scheme 3 Reagents and conditions: i, toluene, 111 °C, 20 h; ii, Pd/C, H2,
THF, room temp., 16 h; iii, BusLi, O2, THF–HMPA (7:1), 278 °C, 3 h; iv,
TsN2H3, TsOH, EtOH, MS 3 Å, 78 °C, 2 h; v, BuLi, THF, 75 °C, 50 min;
vi, Pri3SiOTf, NEt3, THF, 278 °C, 2 h; vii, BH3·THF, THF, 0 °C, 24 h, then
NaOH, H2O2, EtOH, 50 °C, 3 h; viii, DMSO, (COCl)2,NEt3, CH2Cl2,
260 °C; ix, Ph3PMeBr, KOBut, benzene, room temp., 48 h; x, Bu4NF, THF,
room temp., 18 h
Scheme 2 Reagents and conditions: i, KOBut, THF, 0 °C, then PhSCH2I,
THF, 278 °C, 30 min; ii, HCl·EtOH, room temp., 16 h; iii, KOH, N2H4,
diglycol, 200 °C, 4 h; iv, TsCl, DMAP, CH2Cl2, room temp., 16 h; v,
KOBut, THF, 65 °C, 3.5 h; vi, NaIO4, MeOH, 0 °C ? room temp., 16 h; vii,
Ac2O, 100 °C, 62 h; viii, KOH, MeOH, room temp., 2 h, then NaBH4, 0 °C,
30 min; ix, ClSO2CHNCH2, EtNPri2, CH2Cl2, 215 °C, 1.5 h
Chem. Commun., 1997
1491

View Article Online
the silylating reagent. Although models indicate a remarkable
regional shielding of the cyclopentene 12 the observed
selectivity was less than 1.5:1 in favour of the desired ketone
13.
schen Industrie, and S. Doye is grateful for a Kekule´ scholarship
from this institution.
Footnote and References
As the chromatographic separation of the intermediate pairs
of epimeric secondary alcohols did not pose any problems and
the subsequent Swern oxidation gave a high yield of the
corresponding ketone, we were at this stage ready to use a
Wittig reaction for the introduction of the exocyclic double
bond. This operation as well as the subsequent deprotection
with tetrabutylammonium fluoride proceeded in very high yield
and gave rise to (2)-myltaylenol 1, which by comparison with
authentic spectra kindly provided by Dr Matsuo proved to be the
desired natural compound.
* E-mail: winterfeldt@mbox.oci.uni-hannover.de
1 D. Takaoka, A. Matsuo, J. Kuramoto, M. Nakayama and S. Hayashi,
J. Chem. Soc., Chem. Commun., 1985, 482.
2 A. Srikrishna, C. V. Yelamaggad, K. Krishnan and M. Nethaji, J. Chem.
Soc., Chem. Commun., 1994, 2259.
3 K. Matcheva, M. Beckmann, D. Schomburg and E. Winterfeldt,
Synthesis, 1989, 814.
4 D. J. Crispin, A. E. Vanstone and J. S. Whitehurst, J. Chem. Soc. (C),
1970, 10.
5 P. Metz, M. Fleischer and R. Fro¨hlich, Tetrahedron, 1995, 51, 711.
The kind help provided by Dr Matsuo is highly appreciated.
The work described was supported by the Fonds der Chemi-
Received in Cambridge, UK, 8th May 1997; 7/03164E
1492
Chem. Commun., 1997