Angularly fused triquinanes from linear substrates through trimethylenemethane diyl [2 + 3] cycloaddition reaction

Article abstract of DOI:10.1021/ol100907t

Angularly fused triquinanes were synthesized from linear dienes and phenyl(propynyl)iodonium salt through trimethylenemethane (TMM) diyl mediated [2 + 3] cycloaddition reaction. TMM diyl intermediates were obtained from alkylidene carbenes generated from reactions of alkynyliodonium salts with nucleophiles.

Full text of DOI:10.1021/ol100907t

ORGANIC
LETTERS
2010
Vol. 12, No. 11
2672-2674
Angularly Fused Triquinanes from Linear
Substrates through Trimethylenemethane
Diyl [2 + 3] Cycloaddition Reaction
Hee-Yoon Lee,* Yongsik Jung, Yeokwon Yoon, Byung Gyu Kim, and
Yeonjoon Kim
Department of Chemistry, Korea AdVanced Institute of Science & Technology (KAIST),
Daejeon 305-701, Korea
leehy@kaist.ac.kr
Received April 20, 2010
ABSTRACT
Angularly fused triquinanes were synthesized from linear dienes and phenyl(propynyl)iodonium salt through trimethylenemethane (TMM) diyl
mediated [2 + 3] cycloaddition reaction. TMM diyl intermediates were obtained from alkylidene carbenes generated from reactions of
alkynyliodonium salts with nucleophiles.
Cycloaddition reactions of trimethylenemethanes (TMMs)1
provide a powerful tool for the synthesis of cyclopentanoids.
The reactions proceed with good selectivity and have been
applied to the total synthesis of structurally or biologically
interesting compounds, especially the polyquinane natural
products.2 However, direct cycloaddition reactions of TMMs
to form angularly fused triquinanes have not been reported yet,
presumably because of the difficulty in the preparation of the
appropriate precursors.3,4 Recently, we reported new synthetic
methodologies to generate TMM diyls from linear substrates
through alkylidene carbenes,5 and these new synthetic meth-
odologies allow the easy preparation of linearly fused triquinanes.
This alkylidene carbene route to TMM diyls can be extended
to the construction of angularly fused triquinanes by simply
altering the connectivity of the olefin that undergoes the
intramolecular cyclopropanation reaction with the alkylidene
carbene (Scheme 1). Formation of the angularly fused triquinanes
Scheme 1
.
Synthetic Pathways to Triquinanes from Alkylidene
Carbene
(1) Yamago, S.; Nakamura, E. Org. React. 2002, 61, 1–217.
(2) Mehta, G. S. Chem. ReV. 1997, 97, 671–719.
should be less complicated than linearly fused triquinanes in
the possible isomeric products as the reaction can produce only
a single stereo- and regioisomeric triquinane product, whereas
the linearly fused triquinane formation can produce stereo- as
well as regioisomeric products.
(3) Little, R. D. Chem. ReV. 1996, 96, 93–114
.
(4) Adam, W.; Finzel, R. J. Am. Chem. Soc. 1992, 114, 4563–4568
.
(5) (a) Lee, H. Y.; Kim, Y. J. Am. Chem. Soc. 2003, 125, 10156–10157.
(b) Lee, H. Y.; Kim, W. Y.; Lee, S. Tetrahedron Lett. 2007, 48, 1407–
1410. (c) Lee, H. Y.; Yoon, Y.; Lim, Y. H.; Lee, Y. Tetrahedron Lett.
2008, 49, 5693–5696.
10.1021/ol100907t  2010 American Chemical Society
Published on Web 05/10/2010

Herein, we report the first successful application of a TMM
diyl [2 + 3] cycloaddition reaction to the synthesis of
angularly fused triquinanes. Among the three strategies we
have reported for the formation of alkylidene carbenes, the
epoxyaziridinyl imine route was tested first as this route
offers neutral reaction conditions and showed the highest
efficiency among the three routes for the formation of linearly
fused triquinanes (Scheme 2).5a
5a was obtained in 40% yield8 along with the unanticipated
regioisomeric product 6 as the minor product in 16% yield
without forming rearranged alkyne product (Scheme 3).
Scheme 3. Reaction of Propynyliodonium Salt with Dienylated
Malonate Anion and Detailed Mechanistic Pathway
Scheme 2. Reactions of Epoxyaziridine Imines
When the epoxyaziridinyl imine 1a was heated at 110 °C,
the desired angularly fused triquinane product 2a was observed
though the yield was low. When the ester group of 1a was
replaced by a methoxymethyl group, alkyne 3b was obtained
as the major product with desired product 2b as the minor
product. Formation of the rearranged alkyne product was
unexpected since rearrangement of an alkyl group of the
alkylidene carbene is much slower than hydrogen migration.6
This result indicated that the intramolelcular cyclopropanation
reaction onto the exocyclic olefin was not facile enough to
compete with carbene rearrangement and retarded the formation
of 2b. Real disappointment came from the fact that the
substrates with methyl or hydrogen on the olefin (1c and 1d)
produced the rearranged alkyne products without desired
angularly fused triquinane products in detectable quantity. This
result was not only synthetically inadequate but also quite
surprising as the reactivity of the TMM diyl cycloaddition
reaction has not been affected by the substitution pattern of the
olefin counterpart except for the regioselectivity of the cycload-
dition reaction.7
The reaction starts with addition of the anion of 4a to the
propynyliodonium salt to form the alkylidene carbene A.
Intramolecular cyclopropanation of A produces strained alky-
lidene cyclopropane B that breaks the cyclopropane ring to form
TMM diyl. While [2 + 3] cycloaddition reaction of the TMM
diyl with olefin could proceed via either C or D, the cyclopen-
tane ring of C appears to be sterically less encumbered with
the tether and the olefin than that of D and provides bias for 5a
as the major product. Though an unanticipated minor product
was produced along with the desired product, the overall
efficiency for the cascade reaction improved dramatically. With
this successful result, we examined the cycloaddition reaction
of substrates with various substitution patterns, and the results
are summarized in Table 1.
All of the substrates in the table produced only the angularly
fused triquinanes 5 with no sign of the formation of products
analogous to 6. It was only the phenyl substituent on the olefin
that produced the regioisomeric products. This exception is
presumed to be due to the steric interaction of the cyclopentene
ring of C with the phenyl group of the olefin that reduces the
preference of C over D in the cycloaddition reaction. The stepwise
nature of the cycloaddition reaction might have contributed to the
formation of 6 as the diradical intermediate formed from the first
Since the inefficiency of the cascade reaction to form
angularly fused triquinane product appeared to be mainly due
to the competing carbene rearrangement to form an alkyne,
lower reaction temperatures were thought to suppress the
carbene rearrangement and to improve the yield of the desired
products. As the alkynyl iodonium salt route to alkylidene
carbene has been used to produce linearly fused triquinanes
successfully at ambient temperature,5c they were explored next.
When the anion of malonate 4a was treated with propynyli-
odonium salt, the desired angularly fused triquinane product
(6) Knorr, R. Chem. ReV. 2004, 104, 3795–3849.
(7) Masjedizadeh, M. R.; Dannecker-Doering, I.; Little, R. D. J. Org.
Chem. 1990, 55, 2742–2752.
(8) Starting material 4a was not completely consumed, and the yield of
5a was 45% based on the recovered starting material.
Org. Lett., Vol. 12, No. 11, 2010
2673

formation of TMM diyls obtainable from the substrates that possess
an alkynyl iodonium salt in the same molecule (Scheme 4).
Table 1. Angularly Fused Triquinanes from Iodonium Salt and
Malonate Anions
Scheme 4. From Linear Substrate to Angularly Fused Triquinane
4
X
R1
R2
R3
5
yield (%)
4b
4c
4d
4e
4f
C(COOEt)2
C(COOEt)2
C(COOEt)2
C(OMe)2
C(S(CH2)3S)
O
H
Me
H
H
H
H
Me
H
H
H
H
H
5b
5c
5d
5e
5f
33
38
34
28
34
0
Me
Me
Me
Me
H
When the alkynyl iodonium salt prepared from the reaction of
dieneyne 7 with 8 was treated with phenylsulfinate anion or
thiophenoxide, the desired angularly fused triquinanes 9 were
obtained along with substituted alkynes 10. The formation of
alkynes 10 occurred through the rearrangement of the correspond-
ing alkylidene carbenes.12 If the formation of 10 was from the
corresponding alkylidene carbene, a carbon nucleophile would form
an alkylidene carbene that will not rearrange easily. When cyanide
anion that has not been reported as a nucleophile for alkynyl
iodonium salts13 was treated with the alkynyl iodonium salt in the
hope that the rearrangement of the corresponding alkylidene
carbene would not occur, result similar to that with the heteroatom
nucleophiles was observed as the reaction produced the angularly
fused triquinane product 9b as well as the alkyne product 10b.
In summary, we have demonstrated for the first time that
the angularly fused triquinanes can be synthesized through
TMM-mediated [2 + 3] cycloaddition reaction using tandem
cycloaddition reaction of alkylidene carbene generated from
alkynyl iodonium salts through TMM diyls. The new synthetic
methodology can readily be applied to the total synthesis of
various angularly fused triquinane natural products.2
4g
4h
H
Ph
H
H
5g
5h
O
0
bond formation between TMM diyl and the olefin is stabilized by
the phenyl group and this radical intermediate survives long enough
to react with either end of the allylic radical.9 The moderate yield
of the tandem cycloaddition reaction to angularly fused triquinane
seems to reflect the ring strain during the cycloaddition reaction.
Though the yields of angularly fused triquinanes appeared moder-
ate, the synthetic strategy is useful for the synthesis of natural
products as there were no other products in significant amount and
relatively good per step efficiency of the multistep reaction
sequence (70% per step).
Results in the Scheme 3 and Table 1 show that the tandem
cycloaddition reaction for the formation of angularly fused
triquinanes appeared to be quite general regardless of the
substitution pattern of the olefin (4c, 4d), whereas the cycload-
dition reaction to form linearly fused triquinanes was sensitive
to the substitution pattern as the cis-olefins and exo-olefins did
not undergo cycloaddition reaction.5a On the contrary, substrates
that contain relatively acidic protons (4g, 4h) did not produce
the desired products. This result might reflects the strain
associated with cyclization,10 since the substrates for the linear
triquinane formation produced the desired linearly fused
triquinanes, though the yields were low.5b
Acknowledgment. This research was supported by Basic
Science Research Program through the National Research
Foundation of Korea (NRF) funded by the Ministry of Educa-
tion, Science and Technology (KRF-2008-314-C00198).
Note Added after ASAP Publication. Scheme 3 was
incorrect in the version published ASAP May 10, 2010; the
correct version reposted May 12, 2010.
While the alkynyliodonium route to TMM diyls provides a
convergent pathway to triquinanes, only the propynyliodonium
salt can be used as the electrophile to form alkylidene carbenes
because of the facile rearrangement of the acetylenic iodonium
salt to an alkyne or C-H insertion reactions of the carbene
intermediates that would be derived from other substituted
alkynes.11 To expand the substrate scope, we next examined the
Supporting Information Available: Synthetic schemes
for the substrates, experimental details, and spectral data for
cyclization products. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL100907T
(9) Siemionko, R. K.; Berson, R. A. J. Am. Chem. Soc. 1980, 102, 3870–
3882.
(11) (a) Tykwinski, R. R.; Stang, P. J.; Persky, N. E. Tetrahedron Lett.
1994, 35, 23–26. (b) Ochiai, M.; Kunishima, M.; Nagao, Y.; Fuji, K.; Shiro,
M.; Fujita, E. J. Am. Chem. Soc. 1986, 108, 8281–8283.
(12) (a) Ochiai, M.; Kunishima, M.; Tani, S.; Nagao, Y. J. Am. Chem.
Soc. 1991, 113, 3135–3142. (b) Zhdankin, V. V.; Stang, P. J. Tetrahedron
1998, 54, 10927–10966.
(10) Examples of reactivity differences due to different substitution
patterns of the olefin in the cyclopropanation reaction: (a) Mori, K.
Tetrahedron: Asymmetry 2007, 18, 838. (b) Uchida, T.; Katsuki, T. Synthesis
2006, 1715. Different cycloaddition mode of Pauson-Khand reaction to
form angularly fused triquinanes: (c) Knudsen, M. J.; Schore, N. E. J. Org.
Chem. 1984, 49, 5025. (d) Ishizaki, M.; Iwahara, K.; Niimi, Y.; Satoh, H.;
Hoshino, O. Tetrahedron 2001, 51, 2729.
(13) Ochiai, M.; Kunishima, M.; Fuji, K.; Nagao, Y. J. Org. Chem. 1988,
53, 6144–6145.
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