Synthesis of the naturally occurring [3.3.3]propellane (±)-modhephene featuring a photocycloaddition-reductive fragmentation diquinane construction

Article abstract of DOI:10.1039/a704260d

Modhephene has been synthesized in 11 steps and 21% overall yield from cyclopentadiene, by a stereoselective route that features a photocycloaddition-fragmentation sequence for the construction of the diquinane core.

Full text of DOI:10.1039/a704260d

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Synthesis of the naturally occurring [3.3.3]propellane (±)-modhephene
featuring a photocycloaddition–reductive fragmentation diquinane
construction
Curt A. Dvorak and Viresh H. Rawal†
Department of Chemistry, The University of Chicago, Chicago, IL 60637 and Department of Chemistry, The Ohio State
University, Columbus, OH 43210, USA
Modhephene has been synthesized in 11 steps and 21%
overall yield from cyclopentadiene, by a stereoselective route
that features a photocycloaddition–fragmentation sequence
for the construction of the diquinane core.
light provided oxetane 10 (89%), which possesses the con-
nectivity required for a diquinane. Initially a three step sequence
was used to convert oxetane 10 to a diquinane. Treatment of 10
with Pri
NMgI gave alcohol 11, which on oxidation with
2
pyridinium dichromate (PDC) gave keto alkene 12 in good
overall yield. Reductive fragmentation of 12 afforded the
expected diquinane, 6, in 80% yield.
The fascinating realm of the polyquinane sesquiterpenes,
1
recently reviewed, has stimulated the development of new
methodologies for the construction of fused five-membered
rings. Previously we reported a route to di- and tri-quinanes that
takes advantage of the connectivity gained when acylnorbornyl
derivatives, obtained via the Diels–Alder reaction, are subjected
The hidden diquinane unit was also liberated by a novel,
direct fragmentation of the strained oxetane precursor, which
shortened the sequence by one step (Scheme 4). Treatment of
oxetane 10 with LDBB (2.0 equiv.), the radical anion of 4,4A-di-
2
8
to the Paterno–B u¨ chi reaction (Scheme 1). This expeditious
3
tert-butylbiphenyl, in the presence of Et Al (2.1 equiv.)
assembly of a [3.3.0]bicyclic array is well suited for the
synthesis of many members of the polyquinane class of natural
products. We have completed concise, high-yielding syntheses
of natural products having linear2d and angular triquinane
frameworks using the photocycloaddition–fragmentation se-
quence. We report here a concise synthesis of naturally
promoted the simultaneous scission of the oxetane C–O bond
and the back-bond of the norbornane skeleton, affording
diquinane moiety 13 in 86% yield. The resulting allylic alcohol
9
2b,e
was then oxidized to enone 6 under standard conditions.
In preparation for closure of the final propellane ring, a
suitable radical precursor was introduced a to the carbonyl
group of 6 (Scheme 5). Selenation of the kinetic enolate of 6
afforded the desired phenyl selenide in 61% yield, provided
inverse quenching conditions were employed. The bridgehead
radical derived from 14 was expected to undergo 5-exo-trig
cyclization onto the butenyl side-chain, concurrently setting the
3
occurring propellane, modhephene 1, further extending the
utility of our general strategy.
The propellane skeleton, the three contiguous quaternary
centers, and the angular methyl group combine to make
modhephene an attractive synthetic challenge, one taken on by
4
4m
several research groups. We have examined two routes to
angular methyl group stereochemistry. Subjection of selenide
modhephene, outlined retrosynthetically in Scheme 2. Appeal-
ing at first was a route that took advantage of enone 3, a late-
stage intermediate in our isocomene synthesis, wherein the
methyl group stereochemistry was controlled through a Diels–
Alder reaction.2 While it was possible to form the third ring
14 to standard radical conditions gave an excellent yield of the
propellane (95%), albeit with a disappointing 2:1 ratio of
inseparable diastereomers. This ratio was increased to a useful
6:1 level (69%) by carrying out the cyclization in toluene at
b,e
10
3
278 °C using Et B–air to initiate the radical chain.
by an alkylative cyclization of the terminal iodide derived from
5
3,
the resulting enone 2 could not be converted to mod-
radical cyclization
2h,l
hephene. An alternate route to the propellane framework of
modhephene hinged on formation of the ring containing the
angular methyl group, potentially by a radical cyclization. The
Me
Me
Me
Me
Me
O
A
B
6
requisite diquinane precursor 6 was expected to be readily
available through the photocycloaddition–reductive fragmenta-
tion sequence.
Diquinane 6 was prepared in high overall yield as described
in Scheme 3. Norbornene 8, obtained from cyclopentadiene and
Me
O
Me
Me
alkylation
2
modhephene 1
5
methyl acrylate (H
2
O, room temp., 100%), was alkylated
O
O
H
H
selectively on the exo face with 4-bromobut-1-ene using LDA
in THF with 1,3-dimethyl-3,4,5,6-tetrahydropyrimidin-
2
(1H)-one (DMPU). The resulting ester 7 was converted into
methyl ketone 9 by a one-pot modification of Corey’s
procedure, affording the Paterno–B u¨ chi precursor in 94% yield
Me
Me
Me
7
OMOM
for the two steps. Irradiation of ketone 9 with Corex-filtered
3
6
fragmentation
O
Me
H
H
R
R
O
O
OMe
O
OMe
O
Me
Me
R
4
7
Scheme 1
Scheme 2
Chem. Commun., 1997
2381

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well as the stereocontrolled formation of the propellane
skeleton.
i, ii
iii
This work was supported financially by the National
Institutes of Health (R01-GM-45624) and The University of
Chicago. Pfizer and Merck are thanked for additional financial
support in the form faculty awards to V. H. R.
O
OMe
O
Me
O
Me
10
8
9
iv
O
H
Footnote and References
vi
v
†
5
Present address: Department of Chemistry, The University of Chicago,
735 S. Ellis Avenue, Chicago, IL 60637, USA.
O
Me
HO
1
G. Metha and A. Srikrishna, Chem. Rev., 1997, 97, 671.
6
12
Scheme 3 Reagents and conditions: i, LDA, THF, DMPU, 4-bromobut-
-ene; ii, MeS(O)CH Li, THF; Zn, aq. NaOH, PhCH (94% overall); iii, hn,
PhH, corex filters (89%); iv, Pr NMgI (2.6 equiv.) in THF (1.0 m), room
11
2 (a) V. H. Rawal and C. Dufour, J. Am. Chem. Soc., 1994, 116, 2613; (b)
V. H. Rawal, C. Dufour and A. Eschbach, J. Chem. Soc., Chem.
Commun., 1994, 1797; (c) V. H. Rawal, C. Dufour and S. Iwasa,
Tetrahedron Lett., 1995, 36, 19; (d) V. H. Rawal, A. Fabre and S. Iwasa,
Tetrahedron Lett., 1995, 36, 6851; (e) V. H. Rawal, A. Eschbach,
C. Dufour and S. Iwasa, Pure Appl. Chem., 1996, 37, 675; (f) C. Dufour,
S. Iwasa, A. Fabre and V. H. Rawal, Tetrahedron Lett., 1996, 37,
1
2
3
i
2
temp., 1.5 days (87%); v, PDC (2.9 equiv.), DMF, room temp., 1 day (91%);
vi, LDBB (3 equiv.) in THF (0.1 m), 278 °C (80%)
7
867.
3
Isolation: L. H. Zalkow, R. N. Harris, III and D. Van Derveer, J. Chem.
Soc., Chem. Commun., 1978, 420; F. Bohlmann, C. Zdero, R.
Bohlmann, R. M. King and H. Robinson, Phytochemistry, 1980, 19,
HO
H
i
ii
6
5
79.
4
Syntheses: (a) M. Karpf and A. S. Dreiding, Tetrahedron Lett., 1980,
21, 4569; Helv. Chim. Acta, 1981, 64, 1123; (b) A. B. Smith, III and
P. J. Jerris, J. Am. Chem. Soc., 1981, 103, 194; J. Org. Chem., 1982, 47,
O
Me
Me
10
13
1
845; (c) H. Schostarez and L. A. Paquette, J. Am. Chem. Soc., 1981,
Scheme 4 Reagents and conditions: i, LDBB, THF, Et
warm to room temp., 12 h (86%); ii PDC, DMF, room temp., 16 h (91%)
3
Al, 278 °C, 4 h,
1
03, 722; Tetrahedron, 1981, 37, 4431; (d) W. Oppolzer and
F. Marazza, Helv. Chim. Acta, 1981, 64, 1575; W. Oppolzer and
K. Battig, Helv. Chim. Acta, 1981, 64, 2489; (e) P. A. Wender and
G. B. Dreyer, J. Am. Chem. Soc., 1982, 104, 5805; (f) J. Wrobel,
K. Takahashi, V. Honkan, G. Lannoye, J. M. Cook and S. H. Bertz,
J. Org. Chem., 1983, 48, 139; (g) Y. Tobe, S. Yamashita, T. Yamashita,
K. Kakiuchi and Y. Odaira, J. Chem. Soc., Chem. Commun., 1984,
Me
O
O
O
H
SePh
i
ii
1
4
1
259; (h) D. Wilkening and B. P. Mundy, Tetrahedron Lett., 1984, 25,
619; B. P. Mundy, D. Wilkening and K. B. Lipkowitz, J. Org. Chem.,
985, 50, 5727; (i) G. Metha and D. Subrahmanyam, J. Chem. Soc.,
Me
Me
Me
Chem. Commun., 1985, 768; G. Metha and D. Subrahmanyam, J. Chem.
Soc., Perkin Trans. 1, 1991, 395; (j) E. A. Marsh, S. K. Math and
C. J. Flann, Tetrahedron Lett., 1988, 29, 2147; Tetrahedron, 1989, 45,
4950; (k) L. Fitjer, A. Kanschik and M. Majewski, Tetrahedron Lett.,
6
14
15
iii, iv
Me
Me
Me
1
988, 29, 5525; L. Fitjer, M. Majewski and A. Kanschik, Tetrahedron
v
Lett., 1988, 29, 1263; (l) C. P. Jasperse and D. P. Curran, J. Am. Chem.
Soc., 1990, 112, 5601; (m) C. Sha, T. Jean and D. Wang, Tetrahedron
Lett., 1990, 31, 3745; (n) G. A. Kraus and J. Shi, J. Org. Chem., 1990,
55, 5423; J. Org. Chem., 1991, 56, 4147; (o) S. C. Suri, Tetrahedron
Lett., 1993, 34, 8321; (p) T. Uyehara, T. Murayama, K. Sakai, M. Ueno
and T. Sato, Tetrahedron Lett., 1996, 37, 7295; (q) H. Lee, D. Kim and
S. Kim, Chem. Commun., 1996, 1539.
Me
Me
Me
Me
modhephene 1
16
Scheme 5 Reagents and conditions: i, LDA, THF, 278 °C to room temp.;
PhSeCl, 278 °C, inverse quench (61%); ii, Bu SnH, AIBN, PhH, reflux
2:1, 95%) (6:1 at 278 °C); iii, Me CuLiCN, THF, Et O·BF
iv, Ph PNCH , THF (85% overall), MPLC separation; v, TsOH (cat.),
CH Cl , 3 h ( ~ 100%)
5
6
The details of this alkylation will be reported in a full paper.
General reviews on radical chemistry: D. P. Curran, Synthesis, 1988,
3
(
2
2
3
;
4
17; 489; D. P. Curran, in Comprehesnive Organic Synthesis, ed. B. M.
Trost and I. Fleming, Pergamon Press, Oxford, 1991; vol. 4, pp. 715–
77; pp. 779–899; B. Giese, B. Kopping, T. G o¨ bel, J. Dickhut,
3
2
2
2
7
G. Thoma, K. J. Kulicke and F. Trach, Org. React., 1996, 48, 301.
E. J. Corey and M. Chaykovsky, J. Am. Chem. Soc., 1965, 87, 1345;
J. S. Swenton, D. K. Anderson, D. K. Jackson and L. Narasimhan,
J. Org. Chem., 1981, 46, 4825; K. Ishizumi, N. Ohashi and N. Tanno,
J. Org. Chem., 1987, 52, 4477.
For an extensive investigation of the reductive fragmentation of simple
oxetanes, see B. Mudryk and T. Cohen, J. Org. Chem., 1989, 54, 5657;
J. Org. Chem., 1991, 56, 5760; For epoxide fragmentations, see:
B. Mudryk and T. Cohen, Org. Synth., 1993, 72, 173 and references
cited therein.
7
8
The final two carbons were appended as previously des-
cribed. Introduction of the geminal dimethyl unit to the hindered
enone 15 requires a Lewis acid to assist the 1,4-addition of the
4
b,l
higher order cuprate.
Wittig olefination of the keto group
with triphenylphosphonium methylide4d put in place the final
carbon. The major diastereomer from the radical cyclization
was separated at this stage by MPLC and then treated with a
catalytic amount of TsOH, which isomerized the double bond to
the endocyclic position, affording modhephene 1. The minor
diastereomer was similarly converted to epimodhephene.
The modhephene synthesis described here was accomplished
in 11 steps from cyclopentadiene, with an overall yield of 21%,
the highest to date. The synthesis illustrates the direct
fragmentation of the cage-like oxetane 10 to diquinane 13 as
9 An extensive study has been carried out on the scope of this direct
oxetane fragmentation, and the results have been submitted for
publication.
1
0 K. Nozaki, K. Oshima and K. Utimoto, J. Am. Chem. Soc., 1987, 109,
2
547; Tetrahedron Lett., 1988, 29, 6125; 6127.
Received in Corvallis, OR, USA, 16th June 1997; 7/04260D
2382
Chem. Commun., 1997