Triquinanes from linear alkylidene carbenes via trimethylenemethane diyls

Article abstract of DOI:10.1021/ja036263l

The intramolecular [2+3] cycloaddition reaction of the trimethylenemethane diyl generated from the intramolecular cyclopropanation reaction of alkylidene carbene produced linearly fused triquinanes regio- and stereoselectively. The current tandem cycloaddition reaction was applied to a 14-step total synthesis of hirsutene from methallyl alcohol. Copyright

Full text of DOI:10.1021/ja036263l

Published on Web 07/31/2003
Triquinanes from Linear Alkylidene Carbenes via Trimethylenemethane Diyls
Hee-Yoon Lee* and Yeonjoon Kim
Center for Molecular Design & Synthesis, School of Molecular Science (BK21) and Department of Chemistry,
Korea AdVanced Institute of Science & Technology, Daejon, 305-701, Korea
Received May 21, 2003; E-mail: leehy@kaist.ac.kr
Carbenes are useful intermediates in organic synthesis.1 While
alkylidene carbene2 has been used for the C-H insertion reaction,3
it has been much less used for the cyclopropanation reaction4
presumably due to the instability of the products from the
intramolecular cyclopropanation reaction.5 This was well exempli-
fied in Koebrich’s reports6 in which the intramolecular cyclopro-
panation reaction of the 2-methyl-1-hexa-1,5-dienylidene carbene
system formed the reactive bicyclo[3.1.0]hex-1-ene system that
underwent subsequent transformation to form various dimeric
products. The mechanism and reactive intermediates of the forma-
tion of dimeric products were thoroughly studied by Berson,7 and
one of the reactive intermediates was the trimethylenemethane
(TMM).8 TMM diyls, its metallo-analogues, and its zwitterionic
analogues are well known to undergo a [2+3] cycloaddition reaction
with olefins to form cyclopentane rings.9 As the [2+3] cycloaddition
reaction of TMM diyls has been applied to the total synthesis of
various polycyclic natural products,10 we were intrigued by a
possibility of utilizing alkylidene carbene as a source of TMM diyl
that would undergo a [2+3] cycloaddition reaction or radical
reactions because carbenes have rarely been used as sources for
diradicals.5b
products from the [2+3] cycloaddition reaction of TMM diyls but
also produce compounds through other reaction pathways such as
the ene reaction or [2+2] cycloaddition reaction of 3. The reaction
was believed to proceed through the alkylidene carbene and the
subsequently formed TMM diradical intermediates. Along the way,
one existing CdC bond was cleaved, and four new C-C bonds
were formed with four contiguous stereocenters. Although 4 could
form regioisomeric products, only a single regioisomeric product
was observed, and complete stereoselectivity for the cis-anti isomer
was also observed. The complete stereoselectivity in the current
cycloaddition reaction was presumed to be due to a severe 1,3-
allylic interaction of the hydroxymethyl substituent of the TMM
diradical intermediate with the tethered alkyl chain during the
cycloaddition reaction.13
With the successful transformation of 1 into 5, we examined
the cyclization reaction with substrates having various substitution
patterns on the terminal olefin (Table 1). The reaction preserved
the stereochemistry of the olefins during the [2+3] cycloaddition
reaction14 and was not affected much by the electronic environment
of the olefins as most substrates produced tricyclic compounds in
similar yields except entry 7.
Herein, we report a tandem cycloaddition reaction of alkylidene
carbenes of linear substrates into tricyclic compounds through
sequential formation of alkylidiene carbenes and the TMM diradical
intermediates as shown in Scheme 1. We selected epoxyaziridinyl
imines as the source of alkylidene carbenes11c among several
popular sources for alkylidene carbenes11 because the reaction
conditions for generation of alkylidene carbenes from epoxyaziri-
dinyl imines were deemed most suitable for the transformation of
the initially formed methylenecyclopropane intermediates into the
TMM diradicals before other reaction pathways could prevail.12
Table 1.
1
2
3
entry
product
R
R
R
yield (%)
Scheme 1
1
2
3
4
5
6
7
5
Ph
Ph
CO2Et
H
Me
H
H
H
H
H
H
H
H
H
H
68
54
49
52
50
52
35
22a
22b
22c
22d
22e
22f
H
H
H
H
Me
H
The efficiency of this tandem reaction was demonstrated by
application of the current methodology to a total synthesis of
hirsutene.15 The tricyclic precursor (6) for hirsutene could be
assembled from the linear epoxyaziridinylimine (7), which, in turn,
could be prepared through the Wittig reaction of a known aldehyde
(8)16 and a phosphonium salt containing an allylic alcohol moiety
(9) (Figure 1).
The synthesis started from a known compound (10) obtained
from the reaction of the dianion of methallyl alcohol with THP-
ether of bromoethanol17 after the protecting group exchange
(Scheme 2). The primary hydroxyl group was converted to
triphenylphosphonium bromide (11) through standard activation
When a solution of 1 in toluene was heated at 110 °C until all
of the starting material disappeared, a single major product 5 was
isolated. The observation of a single major product formation was
quite gratifying because the reaction could yield not only isomeric
9
10156
J. AM. CHEM. SOC. 2003, 125, 10156-10157
10.1021/ja036263l CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
Acknowledgment. This work was supported by the Center for
Molecular Design and Synthesis (CMDS-KOSEF) at KAIST. We
thank Ms. Suyoung Ryou for her help with preparation of the
manuscript.
Supporting Information Available: Synthetic schemes for the
substrates, experimental details, and spectral data for cyclization
products and synthetic intermediates (PDF). This material is available
free of charge via the Internet at http://pubs.acs.org.
References
Figure 1. Synthetic analysis of DL-hirsutene.
(1) (a) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern catalytic methods for
organic synthesis with diazo compounds: from cyclopropanes to ylides.
Wiley: New York, 1998. (b) Charette, A. B.; Beauchemin, A. In Organic
Reactions; Overman, L. E., Ed.; John Wiley & Sons: New York, 2001;
Vol. 57, p 1.
(2) (a) McKey, C. In Carbenes; Moss, R. A., Jones, H., Eds.; Wiley-
Interscience: New York, 1975; Vol. 2. (b) Stang, P. J. Chem. ReV. 1978,
78, 383. (c) Kirmse, W. Angew. Chem., Int. Ed. Engl. 1997, 36, 1164.
(3) (a) Taber, D. F.; Neubert, T. D.; Rheingold, A. L. J. Am. Chem. Soc.
2002, 124, 12416. (b) Feldman, K. S.; Saunders, J. C.; Wrbleski, M. L.
J. Org. Chem. 2002, 67, 7096 and references therein.
(4) Sasaki, A.; Aoyama, T.; Shioiri, T. Tetrahedron 1999, 55, 3687.
(5) (a) Lee, H. Y.; Lee, Y. H. Synlett 2001, 1656. (b) Feldman, K. S.; Mareska,
D. A. J. Org. Chem. 1999, 64, 5650.
(6) (a) Koebrich, G.; Heinemann, H. Chem. Commun. 1969, 493. (b) Koebrich,
G.; Baumann, M. Angew. Chem., Int. Ed. Engl. 1972, 11, 52.
(7) (a) Salinaro, R. F.; Berson, J. A. J. Am. Chem. Soc. 1982, 104, 2228. (b)
Rule, M.; Salinaro, R. F.; Pratt, D. R.; Berson, J. A. J. Am. Chem. Soc.
1982, 104, 2223.
followed by the substitution reaction sequence. Wittig reaction of
the ylide of 11 with 8 and deprotection of TBDPS group afforded
trienyl alcohol (12). This alcohol was transformed into epoxyaziri-
dinylimine (7) through a three-step sequence of selective epoxi-
dation of the allylic alcohol,18 oxidation of the epoxy alcohol by
Dess-Martin periodinane,19 and condensation with N-amino-2-
phenylaziridine.20 The epoxyaziridinylimine (7) was heated in
refluxing toluene to produce the triquinane alcohol (6), which was
converted into hirsutene in a four-step sequence; the TMSCl assisted
1,4-addition21 of the methyl group to the corresponding unsaturated
aldehyde followed by dehydration of the corresponding alcohol
using Grieco’s protocol.22 Hirsutene was also obtained directly from
6 through the NiCl2(dppf)-catalyzed allylic alkylation reaction23 of
TMS-ether of 6.23a,24
(8) (a) Berson, J. A. Acc. Chem. Res. 1978, 11, 446. (b) Lazzara, M. G.;
Harrison, J. J.; Rule, M.; Hilinski, E. F.; Berson, J. A. J. Am. Chem. Soc.
1982, 104, 2233.
Scheme 2 a
(9) (a) Yamago, S.; Nakamura, E. In Organic Reactions; Overman, L. E.,
Ed.; John Wiley & Sons: New York, 2002; Vol. 61, p 1. (b) Little, R. D.
Chem. ReV. 1986, 86, 875. (c) Little, R. D.; Brown, L. M.; Masjedizadeh,
M. R. J. Am. Chem. Soc. 1992, 114, 3071. (d) Nakamura, E.; Yamago, S.
Acc. Chem. Res. 2002, 35, 867. (e) Trost, B. M. Angew. Chem. 1986, 98,
1. (f) Chan, D. M. T. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 5, Chapter 3.2.
(g) Binger, P.; Buch, H. M. Top. Curr. Chem. 1987, 135, 77.
(10) (a) Little, R. D. In Studies in Natural Products Chemistry; Atta-ur-Rahman,
Ed.; Elsevier Health Science: Amsterdam, 2000; Vol. 22, p 195. (b) Little,
R. D. Chem. ReV. 1996, 96, 93. (c) Allan, A. K.; Carroll, G. L.; Little, R.
D. Eur. J. Org. Chem. 1998, 1, 1.
(11) (a) Shioiri, T.; Aoyama, T. J. Synth. Org. Chem. Jpn. 1996, 54, 918. (b)
Wolinsky, J.; Clark, G. W.; Thorstenson, P. C. J. Org. Chem. 1976, 41,
745. (c) Kim, S.; Cho, C. M. Tetrahedron Lett. 1994, 35, 8405. (d)
Kunishima, M.; Hioki, K.; Tani, S.; Kato, A. Tetrahedron Lett. 1994, 35,
7253. (e) Ochiai, M.; Kunishima, M.; Nagao, Y.; Fuji, K.; Shiro, M.;
Fujita, E. J. Am. Chem. Soc. 1986, 108, 8281. (f) Zhdankin, V. V.; Stang,
P. J. Tetrahedron 1998, 54, 10927. (g) Gilbert, J. C.; Giamalva, D. H.;
Weerasooriya, U. J. Org. Chem. 1983, 48, 5251.
(12) (a) Platz, M. S.; Berson, J. A. J. Am. Chem. Soc. 1976, 98, 6743. (b)
Duncan, C. D.; Corwin, L. R.; Davis, J. H.; Berson, J. A. J. Am. Chem.
Soc. 1980, 102, 2350.
(13) Little, R. D. Chem. ReV. 1986, 86, 875.
(14) Little, R. D.; Muller, G. W. J. Am. Chem. Soc. 1979, 101, 7129.
(15) Banwell, M. G.; Edwards, A. J.; Harfoot, G. J.; Jolliffe, K. A. J. Chem.
Soc., Perkin Trans. 1 2002, 2439 and references therein.
(16) Little, R. D.; Higby, R. G.; Moeller, K. D. J. Org. Chem. 1983, 48, 3139.
(17) Lipshutz, B. H.; Sharma, S.; Dimock, S. H.; Behling, J. R. Synthesis 1992,
191.
(18) Sharpless, K. B.; Michaelson, R. C. J. Am. Chem. Soc. 1973, 95, 6136.
(19) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
(20) Mueller, P. K.; Joos, R.; Felix, D.; Schreiber, J.; Wintner, C.; Eschenmoser,
A. Org. Synth. 1976, 55, 114.
a Reaction conditions: (a) 2.5 equiv of n-BuLi, TMEDA, Et2O-THF,
Br(CH2)2OTHP, 45%; (b) TBDPSCl, imidazole, CH2Cl2; (c) p-TsOH,
MeOH, 89% for two steps; (d) MsCl, Et3N, CH2Cl2; (e) LiBr, acetone,
reflux, 90% for two steps; (f) PPh3, NaHCO3, CH3CN, reflux, 79%; (g)
n-BuLi, THF, 8; (h) TBAF, THF, 75% for two steps; (i) VO(acac)2,
t-BuOOH, benzene, 84%; (j) Dess-Martin periodinane, CH2Cl2; (k)
H2NNCH2CHPh, MeOH, 80% for two steps; (l) toluene, reflux, 57%; (m)
(i) TPAP-NMO/CH2Cl2, 81%; (ii) Me2CuLi, TMSCl/Et2O-THF, HCl,
NaBH4/MeOH 93%; (iii) o-NO2PhSeCN-n-Bu3P/THF, H2O2/THF, 81%;
(n) (i) TMSCl, Et3N, THF, 84%; (ii) MeMgBr, NiCl2(dppf), benzene, reflux,
83% (hirsutene:13 ) 4:1).
(21) Mattsuzawa, S.; Horiguchi, Y.; Nakamura, E.; Kuwajima, I. Tetrahedron
1989, 45, 349.
(22) Grieco, P. A.; Gilman, S.; Nishizawa, M. J. Org. Chem. 1976, 41, 1485.
(23) (a) Cossy, J.; Belotti, D.; Pete, J. P. Tetrahedron Lett. 1987, 28, 4547. (b)
Chuit, C.; Felkin, H.; Frajerman, C.; Roussi, G.; Swierczewski, G. Chem.
Commun. 1968, 604. (c) Hayashi, T.; Konishi, M.; Yokota, K.-I.; Kumada,
M. Chem. Commun. 1981, 313.
In summary, a tandem reaction sequence starting from alkylidene
carbenes of linear substrates to form triquinane compounds was
developed and was successfully applied to a total synthesis of
hirsutene.
(24) The minor product obtained as a mixture with hirsutene was tentatively
assigned as the regio-isomeric compound 13.
JA036263L
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J. AM. CHEM. SOC. VOL. 125, NO. 34, 2003 10157