A ring-rearrangement metathesis approach toward the synthesis of cyclopenta- and cyclohexa[c]indene systems

Article abstract of DOI:10.1021/ol048650l

(Chemical Equation Presented) A highly efficient synthesis of angularly fused tricyclic enones, cyclopenta- and cyclohexa[c]indene skeletons, has been achieved by the tether-directed ring-rearrangement metathesis sequence starting with readily accessible

Full text of DOI:10.1021/ol048650l

ORGANIC
LETTERS
2004
Vol. 6, No. 21
3719-3722
A Ring-Rearrangement Metathesis
Approach toward the Synthesis of
Cyclopenta- and Cyclohexa[c]indene
Systems
Jeremy Holtsclaw and Masato Koreeda*
Department of Chemistry, UniVersity of Michigan, Ann Arbor, Michigan 48109-1055
koreeda@umich.edu
Received July 14, 2004
ABSTRACT
A highly efficient synthesis of angularly fused tricyclic enones, cyclopenta- and cyclohexa[c]indene skeletons, has been achieved by the
tether-directed ring-rearrangement metathesis sequence starting with readily accessible norbornene derivatives bearing allyl and homoallyl
groups at the bridging carbon.
The ubiquitous presence of nonlinear tricyclic cyclopenta-
(i) and cyclohexa[c]indene (ii) skeletons and their equivalents
in numerous complex natural products and pharmacologically
significant molecules has stimulated considerable interest in
the efficient construction of such systems.1 In conjunction
with our program directed at the synthesis of the oral
contraceptive desogestrel (1)2 and the alkaloid magellanine
(2),3 we had an opportunity to explore a new approach toward
these angularly fused tricyclic skeletons. It should also be
noted that the tricyclic ketone 3, prepared by chemical
degradation of vitamin D2 followed by further functional
group manipulations, has recently been used in the synthesis
of side-chain-locked vitamin D analogues.4
(1) See, e.g.: (a) Tinao-Wooldridge, L. V.; Moeller, K. D.; Hidson, C.
M. J. Org. Chem. 1994, 59, 2381-2389. (b) Kocovsky, P.; Dunn, V.;
Gogoll, A.; Langer, V. J. Org. Chem. 1999, 64, 101-119 and references
therein.
(2) Review: Teutsch, G.; Philibert, D. Hum. Reprod. 1994, 9, 12-31.
For synthesis, see: (a) van den Broek, A. J.; van Bokhoven, C.; Hobbelen,
P. M. J.; Leemhuis, J. Recl. TraV. Chim. Pays-Bas 1975, 94, 35-39. (b)
van den Heuvel, M. J.; van Bokhoven, C. W.; de Jongh, H. P.; Zeelen, F.
J. Recl. TraV. Chim. Pays-Bas 1988, 107, 331-334. (c) Corey, E. J.; Huang,
A. X. J. Am. Chem. Soc. 1999, 121, 710-714. (d) Hu, Q.-Y.; Rege, P. D.;
Corey, E. J. J. Am. Chem. Soc. 2004, 126, 5984-5986.
(3) For the synthesis of magellanine alkaloids, see: (a) Hirst, G. C.;
Johnson, T. O.; Overman, L. E. J. Am. Chem. Soc. 1993, 115, 2992-2993.
(b) Paquette, L. A.; Friedrich, D.; Pinard, E.; Williams, J. P.; St. Laurent,
D. R.; Roden, B. A. J. Am. Chem. Soc. 1993, 115, 4377-4378. (c) Williams,
J. P.; St. Laurent, D. R.; Friedrich, D.; Pinard, E.; Roden, B. A.; Paquette,
L. A. J. Am. Chem. Soc. 1994, 116, 4689-4696. (d) Yen, C.-F.; Liao, C.-
C. Angew. Chem., Int. Ed. 2002, 41, 4090-4093. (e) Ishizaki, M.; Niimi,
Y.; Hoshino, O. Tetrahedron Lett. 2003, 44, 6029-6031.
A general approach toward these skeletons (see Scheme
1) is predicated upon using the tethered-alkene-directed ring-
Scheme 1. Retrosynthetic Analysis of Tricyclic Compounds 4
(n ) 1 or 2)
10.1021/ol048650l CCC: $27.50
© 2004 American Chemical Society
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opening metathesis (ROM) of norbornene ring CdC bond
followed by the ring-closing olefin metathesis (RCM)5
involving the enone CdC double bond starting from the
achiral bicyclic enone 5. Enone 5 in turn was envisaged to
be stereoselectively derived from readily accessible bicyclic
ketone 66 (see Scheme 1). Cyclopenta[c]indene derivative
(4; n ) 1) is foreseen as a pivotal intermediate toward
desogestrel (1) and others.
Scheme 2. ROC/RCM Reactions of Norbornene Derivativesa
Prior to the investigation of this directed metathesis
rendition, a more direct ROM-RCM approach to access
hydrindane compounds was first examined by supplanting
an allylic or homoallylic group in enone 5 with an alkyl
group (8a and 8b, Scheme 2). Despite the extensive literature
associated with the olefin metathesis of norbornenes,5e,7,8 the
steric hindrance of the juxtaposing syn-alkyl group at the
norbornene bridge carbon was considered to be insurmount-
able for the sizable ruthenium-based olefin metathesis
catalysts to overcome. Moreover, an issue that needed to be
contemplated, in the event the catalyst’s approach from the
exo-face is inhibitive, concerned the possibility of the
approach of the catalyst to the norbornene CdC bond from
the endo-face.
In an effort to ascertain these facets of the reaction, enone
8 was prepared from 7, which involved the initial stereo-
selective cuprate addition to the enone 7. All attempts to
achieve the ROM-RCM reaction from 8 with Grubbs’s
catalyst A or B resulted in the recovery of 8. With the use
of the more robust Hoveyda catalyst C, under forcing
conditions, conversion to the dimer of 8 (as a single
stereoisomer) involving the enone CdC bond was observed,
suggesting that the presence of the syn-methyl group at the
bridging carbon presents too much of a steric encumbrance
for the metathesis reaction to take place with these ruthenium
catalysts in this system. It is also interesting to note that the
catalyst’s approach from the endo-face of the norbornene
a Reagents and conditions: (a) Ph3PdCHC(dO)CH3, benzene,
reflux. (b) MeLi, CuCN, TMSCl, THF, -78 °C (95%). (c) (i) LDA,
THF then TMSCl; (ii) Me2N+dCH2I-, CH2Cl2; (iii) MeI, THF;
(iv) aq NaHCO3, CH2Cl2 (61% yield for four steps).9 (d) (i) LDA,
THF; EtCHO; (ii) MsCl, pyridine; (iii) Et3N, ether (70% yield for
three steps). (e) (Ph3PCuH)6, benzene (95%).10 (f) (i) LDA, THF;
MeCHO; (ii) MsCl, pyridine; (iii) Et3N, ether (77% yield for three
steps). (g) catalyst A (1 mol %), CH2Cl2, room temperature. (h)
Me3SO+I-, NaH, DMSO (88%). (i) Catalyst B (10 mol %), CH2Cl2,
room temperature.
apparently does not seem to be readily feasible with these
ruthenium catalysts. To further gain insight into the steric
requirement for the syn group attached to the bridging
carbon, two other norbornene derivatives 10 and 12 were
prepared. While enone 10 underwent a smooth ROM-RCM
process to cleanly produce hydrindane 11 (as an E/Z
mixture), the formation of the corresponding hydrindane 13
from cyclopropane enone 12 was observed to be much more
slower and less efficient. These results further provided
evidence that the metathesis reactions with the ruthenium
catalysts could not effectively proceed when an alkyl group
is placed on the bridging carbon syn to the norbornene Cd
C bond.7,8 Additionally, ruthenium-methylidene complexes
are known to be inefficient initiators for olefin metathesis
reactions.11 Therefore, the enone unit attached to the nor-
bornene skeleton was designed to have a â-substituent. Thus,
to minimize the formation of the methylidene complexes, a
â-substituted enone was incorporated as an essential struc-
(4) Varela, C.; Nilsson, K.; Torneiro, M.; Mourin˜o, A. HelV. Chim. Acta
2002, 85, 3251-3261.
(5) (a) Handbook of Metathesis; Grubbs, R. H., Ed.; Wiley-VCH:
Weinheim, Germany, 2003; Vols. 1-3. For recent reviews, see: (b)
Fu¨rstner, A. Angew. Chem., Int. Ed. 2000, 39, 3012-3043. (c) Trnka, T.
M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18-29. (d) Schrock, R. R. In
Carbene Chemistry; Bertrand, G., Ed.; Marcel Dekker: New York, 2002;
pp 205-230. (e) Grubbs, R. H.; Trnka, T. M.; Sanford, M. S. In Current
Methods in Inorganic Chemistry; Kurokawa, H., Yamamoto, A., Eds.;
Elsevier: Amsterdam, 2003; Vol. 3, pp 187-231. (f) Arjona, O.; Csa´ky¨,
A. G.; Plumet, J. Eur. J. Org. Chem. 2003, 611-622. (g) Connon, S. J.;
Blechert, S. Angew. Chem., Int. Ed. 2003, 42, 1900-1923. (h) Schrock, R.
R.; Hoveyda, A. H. Angew. Chem., Int. Ed. 2003, 42, 4592-4633. (i)
Hoveyda, A. H.; Gillingham, D. G.; Van Veldhuizen, J. J.; Kataoka, O.;
Garber, S. B.; Kingsbury, J. S.; Harrity, J. P. A. Org. Biomol. Chem. 2004,
2, 8-23. (j) Deiters, A.; Martin, S. F. Chem. ReV. 2004, 104, 2199-2238.
(k) McReynolds, M. D.; Dougherty, J. M.; Hanson, P. R. Chem. ReV. 2004,
104, 2239-2258.
(6) Gassman, P. G.; Pape, P. G. J. Org. Chem. 1964, 29, 160-163.
(7) (a) Feast, W. J.; Gibson, V. C.; Ivin, K. J.; Kenwright, A. M.;
Khosravi, E. J. Mol. Catal. 1994, 90, 87-99. (b) North, M. In Ring Opening
Metathesis Polymerization and Related Chemistry; Khosravi, E., Szymanska-
Buzar, T., Eds.; Kluwer Academic Publishers: Dordrecht, The Netherlands,
2002; pp 157-166 and references cited therein.
(8) For some recent, select examples of the RCM reaction of norbornene
compounds, see: (a) Schneider, M. F.; Lucas, N.; Velder, J.; Blechert, S.
Angew. Chem., Int. Ed. Engl. 1997, 36, 257-259. (b) Stragies, R.; Blechert,
S. Synlett 1998, 169-170. (c) Hagiwara, H.; Katsumi, T.; Endou, S.; Hoshi,
T.; Suzuki, T. Tetrahedron 2002, 58, 6651-6654. (d) Tsang, W. C. P.;
Jernelius, J. A.; Cortez, G. A.; Weatherhead, G. S.; Schrock, R. R.; Hoveyda,
A. H. J. Am. Chem. Soc. 2003, 125, 2591-2596.
(9) Danishefsky, S.; Kitahara, T.; McKee, R.; Schuda, P. F. J. Am. Chem.
Soc. 1976, 98, 6715-6717.
(10) Mahoney, W. S.; Brestensky, D. M.; Stryker, J. M. J. Am. Chem.
Soc. 1988, 110, 291-293.
(11) (a) Sanford, M. S.; Love, J. A.; Grubbs, R. H. J. Am. Chem. Soc.
2001, 123, 6543-6554. (b) Hong, S. H.; Day, M. W.; Grubbs, R. H. J.
Am. Chem. Soc. 2004, 126, 7414-7415.
3720
Org. Lett., Vol. 6, No. 21, 2004

tural feature in the system. Taken together, these consider-
ations culminated in the formulation of the syn-alkenyl chain-
directed ring-rearrangement metathesis approach shown in
Scheme 1.12,13
Table 1. Metathesis Reactions of Homoallyl-Tethered
Trieneone 15
The homoallyl-tethered enone 15 was readily accessible
from norbornen-7-one (6) in four steps in 60% overall yield
(Scheme 3). In contrast, allyl analogue 20 was not obtainable
Scheme 3. Synthesis of Alkene-Tethered Metathesis Precursors
15 and 20
15
catalysta solvent temp time % yield 21:22
15a : R ) Me
15a : R ) Me
15a : R ) Me
15a : R ) Me
15b: R ) i-Pr
15c: R ) Ph
15c: R ) Ph
15c: R ) Ph
15c: R ) Ph
15c: R ) Ph
B
B
A
A
B
B
B
C
C
A
CH2Cl2 23 °C 14 h
benzene 23 °C 14 h
CH2Cl2 23 °C 14 h
benzene 23 °C 24 h
CD2Cl2 23 °C 3 h
>90b
>90b
22:78
42:58
>90b >99:1
62b >98:2
>98c >99:1
CD2Cl2 23 °C 0.5 h >98c
CD2Cl2 40 °C 17 h
>98c
CD2Cl2 23 °C 0.5 h >98c
CD2Cl2 40 °C 17 h
>98c
81:19
81:19
80:20
86:14
CD2Cl2 23 °C 0.5 h >98c >99:1
a Performed with 5 mol % catalyst. b Isolated yield (as a mixture of 21
1
and 22). c Yield estimated by H NMR spectroscopy.
the tricyclic cyclohexa[c]indene system 21.8d Interestingly,
Grubbs’s catalyst A was most selective in this reaction, as
it quantitatively converted enone 15 (R ) Me) into tricyclic
enone 21 virtually without contamination by the spiro
cycloheptenone 22 at 23 °C (14 h) in CH2Cl2. Cyclohep-
tenone 22 could be isomerized to tricyclic enone 21 in the
presence of catalyst B, but the reverse isomerization (i.e.,
21 f 22) was not observed, presumably manifesting the
unfavorable thermodynamic energies of 22 due to the
conjugated cycloheptenone17 in addition to the severely
strained norbornene structure.18
The metathesis reactions of allyl analogue 20 proved to
be somewhat problematic. Table 2 describes the results based
on the 1H NMR analysis of the products from the metathesis
reactions of trienone 20 under a variety of conditions. The
metathesis reactions of 20 proceeded relatively quickly,
particularly with catalyst B, with virtually no starting enone
left. However, unlike the case of homoallyl analogue 15,
the formation of the spiro cyclohexenone product 24
persisted, presumably reflecting the relative stability of the
six-membered conjugated ketone. The most favorable ratio
of 2.4:1 between the two products 23 and 24 was observed
when 20b (R ) i-Pr) was treated with catalyst B in CD2Cl2
at 23 °C for 1 h. Although this nominally corresponds to a
71% yield of the desired tricyclic enone 23, the major
difficulty encountered was that products 23 and 24 exhibited
a Reagents and conditions: (a) CH2dCHCH2CH2MgBr/CuBr‚
DMS, LiCl, TMSCl, THF, -78 °C. (b) (i) LDA, THF; R-CHO;
(ii) MsCl, pyridine; (iii) Et3N. (c) LDA, THF, -78 °C; allyl
bromide. (d) LiAlH4, THF (92%). (e) DCC‚MeI (99%).16 (f) t-BuLi,
-78 °C, pentane/ether; trans-RCHdCHCHO. (g) TPAP, NMO,
CH2Cl2, room temperature.
by a similar route, as conjugate allyl additions to enone 7
could not be realized. The problem was circumvented by
the use of an epimeric mixture of ester 1614 which was in
turn available in three steps in overall 61% yield from ketone
6 ((i) Ph3P+CH2OCH3‚Cl-/KOtBu/ether, 0 °C; (ii) HClO4,
H2O/ether; (iii) I2/KOH, MeOH15). Allylation of 16 provided
cleanly syn-allyl ester 17, which was further transformed into
trienone 20 in four steps (Scheme 3).
The results of the metathesis reactions of homoallyl-
tethered trienone 15 using ruthenium-based reagents A-C
are presented in Table 1. All of these catalysts were highly
effective initiators of the metathesis reactions of 15, thus
making the metathesis approach a highly efficient route to
(12) Randl, S.; Blechert, S. In Handbook of Metathesis; Grubbs, R. H.,
Ed.; Wiley-VCH: Weinheim, Germany, 2003; Vol. 2, pp 151-175.
(13) A relayed RCM strategy is similar in its concept to what is described
in this report but differs in that, in the former approach, the tether used
does not end up in the product. See, for example: Wang, X.; Bowman, E.
J.; Bowman, B. J.; Porco, J. A. Angew. Chem., Int. Ed. 2004, 43, 3601-
3605 and references therein.
(16) Scheffold, R.; Saladin, E. Angew. Chem., Int. Ed. Engl. 1972, 11,
229-231.
(14) (a) Bly, R. K.; Bly, R. S. J. Org. Chem. 1963, 28, 3165-3172. (b)
Sauers, R. R.; Hawthorne, R. M. J. Org. Chem. 1964, 29, 21685-1687.
(c) Bernaert, E.; Anteunis, M.; De Waele, R. Bull. Soc. Chem. Belg. 1973,
82, 795-802.
(15) Yamada, S.; Morizono, D.; Yamamoto, K. Tetrahedron Lett. 1992,
33, 4329-4332.
(17) Heap, N.; Whitham, G. H. J. Chem. Soc. B 1966, 164-170.
(18) Strain energy of norbornene is estimated to be 100 kJ/mol. (a)
Lebedev, B.; Smirnova, N.; Kiparisova, Y.; Makovetsky, K. Makromol.
Chem. 1992, 193, 1399-1411. (b) North, M. In AdVances in Strained and
Interesting Organic Molecules; Halton, B., Ed.; JAI Press: Stamford, CN,
2000; Vol. 8, pp 145-185.
Org. Lett., Vol. 6, No. 21, 2004
3721

Table 2. 1H NMR Analysis of the Products from the
Metathesis Reactions of Allyl-Tethered Trieneone 20
Scheme 4. Synthesis of Tricyclic Enone 23
20
catalysta solvent
temp
time
20:23:24
20a : R ) Me
20a : R ) Me
20a : R ) Me
20a : R ) Me
20a : R ) Me
20a : R ) Me
20b: R ) i-Pr
20b: R ) i-Pr
20b: R ) i-Pr
20c: R ) Ph
20c: R ) Ph
A
A
B
B
B
B
B
B
B
B
B
CD2Cl2 23 °C 0.5 h
CD2Cl2 40 °C 3 h
CD2Cl2 23 °C 0.5 h
CD2Cl2 40 °C 3 h
7.9:0.1:1
2.3:0.1:1
1.1:1.1:1
0:1:1
1.1:1:1.4
0:1:1.4
0:2.4:1
0:2.3:1
0:1.9:1
0:1.9:1
C6D6
C6D6
23 °C 1 h
45 °C 3 h
its use toward the synthesis of desogestrel (1) is currently
under investigation.
CD2Cl2 23 °C 1 h
CD2Cl2 23 °C 17 h
CD2Cl2 40 °C 39 h
CD2Cl2 23 °C 2 h
In summary, we have developed an efficient route toward
functionalized angularly fused tricycles, cyclopenta- and
cyclohexa[c]indenes, by the use of the directed ROM-RCM
reactions starting from readily available norbornen-7-one (6)
via allyl- and homoallyl-tethered norbornene derivatives in
30% (nine steps) and 61% overall yields (six steps),
respectively.
This ring-rearrangement strategy relies on an initial
ruthenium-alkylidene species generated on the syn-alkenyl
tether that can then be directed to activate the norbornene
CdC bond, an otherwise unreactive site with syn-alkyl
substitution. Following the highly favorable ROM of the
norbornene CdC bond, the ensuing RCM of the resulting
ruthenium species with the CdC bond of the enone or allylic
alcohol completes the molecular rearrangement and affords
the cyclopenta- or cyclohexa[c]indene system.
C6D6
23 °C 2 h
0.1:1.9:1
a Performed with 5 mol % catalyst.
identical chromatographic behaviors and that enone 23 could
not be obtained in pure form. In addition, attempts at
isomerizing cyclohexenone 24 to tricyclic enone 23 in the
presence of metathesis catalyst B or C proved to be
unsuccessful.
In an effort to circumvent the problem, it was found that
the treatment of allylic alcohol compound 19 in CH2Cl2 at
room temperature in the presence of catalyst B resulted in
the formation of predominantly the two diastereomeric
tricyclic allylic alcohols 25 and 26 (Scheme 4). Moreover,
the extent of formation of allylic alcohol 27 was less than
10% isolated yield. Although these two tricyclic allylic
alcohols could be separated by chromatography, the diaster-
eomeric mixture of products thus obtained was directly
oxidized to the desired tricyclic enone 23 using the product
from 19 with R as either i-Pr or Ph.
Supporting Information Available: Spectroscopic data
of all new compounds and experimental procedures. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Tricyclic enone 23 has proved to be an efficient dienophile
in the stereo- and regioselective Diels-Alder reactions, and
OL048650L
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Org. Lett., Vol. 6, No. 21, 2004