Molecular complexity from aromatics: Synthesis and photoreaction of endo-tricyclo[5.2.2.02,6]undecane - A stereoselective route to tricyclic framework of protoilludanes

Article abstract of DOI:10.1016/j.bmcl.2005.06.030

A stereoselective route towards protoilludanoids from simple aromatic precursor is described. The methodology involves in situ generation of spiroepoxycyclohexadienone and cycloaddition with cyclopentadiene and photochemical 1,3-acyl shift.

Full text of DOI:10.1016/j.bmcl.2005.06.030

Bioorganic & Medicinal Chemistry Letters 15 (2005) 4367–4369
Molecular complexity from aromatics: Synthesis
and photoreaction of endo-tricyclo[5.2.2.02,6]undecane—
A stereoselective route to tricyclic framework of protoilludanes
Vishwakarma Singh,* Sanjoy Lahiri and Shantanu Pal
Department of Chemistry, Indian Institute of Technology Bombay, Mumbai 400 076, India
Received 19 May 2005; revised 8 June 2005; accepted 9 June 2005
Available online 28 June 2005
Abstract—A stereoselective route towards protoilludanoids from simple aromatic precursor is described. The methodology involves
in situ generation of spiroepoxycyclohexadienone and cycloaddition with cyclopentadiene and photochemical 1,3-acyl shift.
Ó 2005 Elsevier Ltd. All rights reserved.
Protoilludanes are a unique class of naturally occurring
sesquiterpenoids that possess a tricyclic structure com-
posed of a four-membered ring angularly fused to a
cis-hydrindane ring system in a cis:anti:cis fashion. The
fungus Basidiomycetes is a rich source of such secondary
metabolites, and a variety of protoilludanes having a
variety of substitution and functionalisation pattern have
been isolated.1–3 While protoilluden-6-ol 1 is one of the
older members of this family, the melleolides of type 2
(Fig. 1) were isolated recently from the cultured mycelia
Armillariella mellea4a and Armillaria novae-zelandiae.4b
Many of these fungal metabolites and their congeners
exhibit promising biological activities.5 The unusual car-
bocyclic structure coupled with their role in biosynthesis
and the interesting biological properties have generated
renewed interest in the chemistry of protoilludanes.6 Sur-
prisingly, however, only a few methods have been devel-
oped.6,7 Many of these employ a photochemical p2s + p2s
cycloaddition for the creation of cyclobutane ring.
In view of the above and our interest in development of
new methodology employing photochemical reactions
of complex b,c-enones,8 we thought to develop a stereo-
selective route to functionalised protoilludane frame-
work. It was considered that the tricyclic compound of
type 3 having a cis:anti:cis protoilludane network may
be generated in a single stereoselective step from the
endo-annulated tricyclic system 4 containing a b,c-
enone chromophore via a 1,3-acyl shift.9,10 The desired
chromophoric system 4 was thought to be prepared
from the aromatic precursor 5 via its oxidation to the
corresponding spiroepoxycyclohexadienone, cycloaddi-
tion with cyclopentadiene and manipulation of the
resulting adduct (Scheme 1). In this communication,
we report on the synthesis of the tricyclic compound 4
and its photochemical reaction leading to a stereoselec-
tive route to tricyclic framework of protoilludanes.
Towards the above objective, the aldehyde 6 was
prepared from 3,5-dimethyl phenol and subjected to
Figure 1.
Keywords: Cycloaddition; Photochemical 1,3-acyl shift.
*
Corresponding author. Tel.: +91 2225767168; fax: +91
2225723480; e-mail: vks@chem.iitb.ac.in
Scheme 1.
0960-894X/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.06.030

4368
V. Singh et al. / Bioorg. Med. Chem. Lett. 15 (2005) 4367–4369
Scheme 2. Reagents: (i) NaBH4, MeOH–H2O; (ii) NaIO4, CH3CN–H2O, cyclopentadiene (75%).
reduction with sodium borohydride. Though the reduc-
tion proceeded well (TLC), the isolation of the product 5
proved to be difficult. Therefore, the aldehyde 6 was re-
duced and the resulting bis-hydroxymethyl compound 5
was directly subjected to oxidation with sodium metape-
riodate in the presence of cyclopentadiene, following a
procedure developed in our laboratory.11 Usual work-
Scheme 4.
up and chromatography furnished the endo adduct 8
as a result of in situ generation of spiroepoxycyclo-
hexa-2,4-dienone 7 and interception with cyclopentadi-
ene (Scheme 2). The structure of the adduct was
deduced from its spectral data12 and comparison with
other analogous compounds.
to oxa-di-p-methane rearrangement whereas singlet
excitation induces a 1,3-acyl migration.9,10,13 However,
the exact nature of photoreaction depends upon the
structure of the chromophore and the functional groups
in a subtle fashion. Considering the above possibilities, a
solution of the compound 4 was irradiated with a high
pressure mercury vapour lamp (400 W, APP) in a Pyrex
immersion well for half an hour. Chromatography of
the photolysate furnished the tricyclic compound 3
having protoilludane framework as a result of a stereo-
selective 1,3-acyl shift (Scheme 4).
Towards the synthesis of the chromophoric system 4, the
hydroxymethyl group in the adduct 8 was protected as
methyl ether to give 9. Reduction of 9 with zinc in aque-
ous methanol containing ammonium chloride furnished
the keto-alcohol 10 as a mixture of syn–anti isomer (1H
NMR, 300 MHz). The keto-alcohol 10 was then oxidised
with Jones reagent and the resulting b-keto-acid was
decarboxylated to furnish the desired tricyclic compound
4 (Scheme 3), whose structure was clearly revealed from
its spectral data.
The IR spectrum of the photoproduct showed a charac-
teristic absorption band at 1769 cmÀ1 for the cyclobuta-
none carbonyl. 1H NMR (300 MHz) spectrum of 3
exhibited three olefinic signals at d 5.71 (br m, 1H),
5.66 (br m, 1H) and 5.39 (br s, 1H) in addition to other
resonances. The presence of cyclobutanone carbonyl
group in the IR spectrum and three olefinic protons in
After assembly of the tricyclic compound 4 containing a
b,c-enone chromophore, its photochemical reaction in
the excited singlet state was explored. Photochemical
reaction of b,c-enones has stimulated a sustained inter-
est for a long time, which is further enhanced due to
the synthetic potential.9,10 In general, b,c-enones under-
go two unique reactions; that is, triplet excitation leads
1
the H NMR spectrum clearly indicated that a 1,3-acyl
shift had occurred during the irradiation. The above for-
mulation was also supported from the 13C NMR spec-
trum, which exhibited signals at d 205.06, and 131.52,
130.80, 126.16, 125.83 for the carbonyl carbon and
olefinic carbons, respectively. In addition, signals were
observed at d 70.91, 67.61, 59.18, 55.70, 43.51, 43.24,
34.81, 33.63, 23.54, 20.23 for the other carbons.
In summary, we have described an efficient synthesis of
tricyclic compounds of type 4 containing a b,c-enone
chromophore from a simple aromatic precursor and
photoreaction in singlet excited state that provides a
stereoselective entry into functionalised protoilludane
framework in a single step.
Acknowledgments
We are grateful to CSIR New Delhi for continued finan-
cial support and RSIC, IIT Bombay for spectral
facilities.
Scheme 3. Reagents and conditions: (i) NaH, THF, MeI, D, 60%;
(ii) Zn, NH4CI, MeHO–H2O, rt, 54%; (iii) JonesÕ oxidation; (iv) THF–
H2O, D, 40% (for iii and iv).

V. Singh et al. / Bioorg. Med. Chem. Lett. 15 (2005) 4367–4369
4369
12. Data for compound 8, IR: 3443, 1730 cmÀ1
.
1H NMR
References and notes
(300 MHz, CDCl3–CCl4) d: 5.68 (m, 1H, olefinic proton),
5.42 (m, 1H, olefinic proton), 4.29 (part of an AB system,
JAB = 11.7 Hz, 1H, CH2OH), 4.04 (part of an AB system,
JAB = 11.7 Hz, 1H, CH2OH), 3.29 (m of d, J = 9 Hz, 1H,
methine H), 3.09 (d, J = 2.1 Hz, 1H, methine proton), 2.95
(part of an AB system, JAB = 6 Hz, 1H, CH2O–), and 2.85
(part of an AB system, JAB = 6 Hz, 1H, CH2O–), 2.67 (m,
1H), 2.54–2.4 (m, 1H), 2.09 (m of d, J = 17.1 Hz, 1H,
methylene H), 1.8 (s, 3H, CH3), 1.34 (s, 1H), 1.13 (s, 3H,
CH3). 13C NMR (75 MHz, CDCl3–CCl4) d: 205.32 (CO),
137.20, 134.20, 133.36, 129.16 (olefinic carbons), 57.61,
49.74, 37.01 (methylene carbons), 58.55, 49.92, 42.67
(methine carbons), 18.44, 12.18 (methyl carbons), 44.04
and 37.01 (quaternary carbons). The above assignment
was made on the basis of DEPT spectrum. Mass (m/z): 246
(M+).
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Data for compound 4: IR: 1734 cmÀ1
.
1H NMR
(300 MHz, CDCl3) d: 5.65 (m, 1H, olefinic proton), 5.41
(m, 1H, olefinic proton), 3.99 (part of an AB system,
JAB = 11.1 Hz, 1H, CH2OMe), 3.89 (part of an AB
system, JAB = 11.1 Hz, 1H, CH2OMe), 3.25 (s, 3H,
OMe), 3.22 (m merged with singlet due to OMe, 1H,
methine H), 2.97 (d, J = 2.3 Hz, 1H, methine H), 2.4
(merged m, 2H), 2.15–2.10 (m, 1H, methine H), 1.98 (s,
2H, methylene H), 1.78 (s, 3H, vinylic CH3) and 1.32 (s,
3H, CH3). 13C NMR (75 MHz, CDCl3) d: 213 (CO),
135.03, 134.72, 133.03, 129.43 (olefinic carbon), 67.21,
60.26, 57.44, 49.75, 47.76, 46.65, 42.70, 36.54, 19.86 and
18.37 for methine, methylene, quaternary and methyl
carbons. Mass (m/z): 217 [M+À(OMe)].
Data for compound 3: mp 70–71 °C; IR mmax: 1769 cmÀ1
.
1H NMR (CDCl3–CCl4) d: 5.71 (br m, 1H, olefinic
proton), 5.66 (br m, 1H, olefinic proton), 5.39 (br s, 1H,
olefinic proton), 3.68 (part of an AB pattern,
JAB = 10.2 Hz, 1H, CH2OMe) and 3.45 (part of an AB
pattern, JAB = 10.2 Hz, 1H, CH2OMe), 3.29 (s, 3H, OMe),
3.21 (s, 1H), 3.16 (s, 1H), 2.47–2.32 (m, 3H), 2.19 (m, 1H),
1.70 (s, 3H, vinylic CH3), 1.27 (s, 3H, CH3). 13C NMR
(75 MHz, CDCl3–CCl4) d: 205.06 and 131.52, 130.80,
126.16, 125.83 (carbonyl carbon and olefinic carbons),
70.91, 67.61, 59.18, 55.70, 43.51, 43.24, 34.81, 33.63, 23.54,
20.23..
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11. Singh, V.; Prathap, S. Synlett 1994, 542.