Enantioselective syntheses of various chiral multicyclic compounds with quaternary carbon stereocenters by catalytic intramolecular cycloaddition

Article abstract of DOI:10.1021/ja0762083

The intramolecular cycloaddition of 1,n-diene-ynes (n = 4-6), where alkyne and alkene moieties are connected by a 1,1-disubstituted alkene, was examined using a chiral rhodium catalyst, and various types of cycloadducts with quaternary carbon stereocenter

Full text of DOI:10.1021/ja0762083

Published on Web 02/23/2008
Enantioselective Syntheses of Various Chiral Multicyclic
Compounds with Quaternary Carbon Stereocenters by
Catalytic Intramolecular Cycloaddition
Takanori Shibata,* Yu-ki Tahara, Kohei Tamura, and Kohei Endo
Department of Chemistry and Biochemistry, School of AdVanced Science and Engineering,
Waseda UniVersity, Shinjuku, Tokyo, 169-8555, Japan
Received August 17, 2007; E-mail: tshibata@waseda.jp
Abstract: The intramolecular cycloaddition of 1,n-diene-ynes (n ) 4-6), where alkyne and alkene moieties
are connected by a 1,1-disubstituted alkene, was examined using a chiral rhodium catalyst, and various
types of cycloadducts with quaternary carbon stereocenter(s) were obtained in high to excellent enantiomeric
excess. In the case of 1,4-diene-ynes, tricyclic, bicyclic, and spirocyclic compounds were obtained depending
upon the substituents at the 2-position of the 1,4-diene moiety and those at their alkyne termini. On the
other hand, 1,5- and 1,6-diene-ynes gave tricyclic and bicyclic compounds, which included medium-sized
ring systems. The mechanistic considerations for different reaction pathways and the synthetic transformation
of tricyclic products into functionalized spirocyclic compounds are also described. The reaction of enediynes,
where two alkyne moieties are connected by a 1,1-disubstituted alkene, was also examined, and sterically
strained tricyclic compounds with two carbon stereocenters were obtained.
Scheme 1. Conventional Mode of Intramolecular Cycloaddition
Introduction
The transition-metal-catalyzed [2 + 2 + 2] cycloaddition of
C2-unsaturated motifs, such as alkynes and alkenes, is a well-
established protocol for the synthesis of carbo- and heterocyclic
skeletons.1 Depending upon the reaction patterns, it can be
categorized as an intermolecular, semi-intermolecular, or in-
tramolecular reaction. The latter reaction is very attractive
because it gives multicyclic compounds from acyclic substrates
in one pot. The intramolecular [2 + 2 + 2] cycloadditions of
triynes, where two alkyne moieties are connected by a 1,2-
disubstituted alkyne, are most typical, and various transition-
metal complexes have been reported to be efficient catalysts.2
The enantioselective [2 + 2 + 2] cycloaddition of triynes has
also been reported: helically chiral helicene derivatives,3 axially
chiral ortho-diaryl benzenes,4 and planarly chiral metacyclo-
phanes5 have been obtained. The cycloaddition of enediynes
and dienynes, where alkyne and alkene or two alkene moieties
are connected by a 1,2-disubstituted alkyne, has also been
reported.6-8 The reaction of enediynes, where two alkyne
moieties are connected by a 1,2-disubstituted alkene,9 was
reported, and enantioselective variants have recently been
published.10 Compared with these substrates, in which three C2-
unsaturated motifs are in a straight chain (Scheme 1), the
examples of the cycloaddition of dienynes and enediynes,
where the C2-unsaturated motifs are located in a branched
chain, are scarce (Scheme 2). The cycloaddition of these
Scheme 2. New Mode of Intramolecular Cycloaddition
substrates is synthetically intriguing because bridged compounds
with quaternary carbon stereocenters could be obtained.11 When
enediynes are used, the corresponding products would be further
transformed into a more stable skeleton because of the severe
strain of tricyclic compounds, which violates Bredt’s rule.
This article presents the full details of the Rh-catalyzed
enantioselective and intramolecular cycloaddition of 1,n-diene-
ynes (n ) 4-6) and enediynes with branched chains, including
(1) Reviews: (a) Ojima, I.; Tzamarioudaki, M.; Li, Z.; Donovan, R. J. Chem.
ReV. 1996, 96, 635-662. (b) Aubert, C.; Buisine, O.; Malacria, M. Chem.
ReV. 2002, 102, 813-834. (c) Nakamura, I.; Yamamoto, Y. Chem. ReV.
2004, 104, 2127-2198. (d) Yamamoto, Y. Curr. Org. Chem. 2005, 9, 503-
519. (e) Kotha, S.; Brahmachary, E.; Lahiri, K. Eur. J. Org. Chem. 2005,
4741-4767. (f) Chopade, P. R.; Louie, J. AdV. Synth. Catal. 2006, 348,
2307-2327.
9
10.1021/ja0762083 CCC: $40.75 © 2008 American Chemical Society
J. AM. CHEM. SOC. 2008, 130, 3451-3457
3451

A R T I C L E S
Shibata et al.
Table 1. Reaction Conditions for 1,4-Diene-ynes
mechanistic considerations and synthetic transformation of the
products.12
Results and Discussion
Reaction of 1,4-Diene-ynes. In a previous communication,12
we examined various 1,4-diene-ynes using a chiral Rh catalyst
at 60 °C in 1,2-dichloroethane (DCE). For example, the reaction
of dienyne 1a with a substituent at the 2-position of the 1,4-
diene moiety gave expected tricyclic compound 2a with two
quaternary carbon stereocenters in almost perfect enantioselec-
tivity (Table 1, entry 1).13 On the other hand, dienyne 1b with
no substituent at that position gave unexpected bicyclic com-
pound 3b with a quaternary carbon stereocenter at the ring-
fused position, also with excellent enantiomeric excess (entry
2).14 To facilitate the reaction, the same reactions were examined
using 1,5-cyclooctadiene (COD)-free Rh catalyst, which was
prepared from [Rh(cod)2]BF4 and (S)-tolBINAP, and pretreated
with hydrogen gas to exclude COD before use (entries 3 and
4). Dienynes 1a and 1b were completely consumed at room
temperature within 24 h, and comparable yield and enantiose-
entry
R
dienyne
temp/
°
C
time/h
yield/%
ee/%b
1
Me
H
Me
H
1a
1b
1a
1b
60
60
rt
48
12
24
24
81 (2a)
91 (3b)
88 (2a)
92 (3b)
>99
99
>99
>99
2
3a
4a
rt
a The catalyst was used after exclusion of COD. b The enantiomeric
excess was determined by HPLC analysis using a Daicel chiral column
(OJ-H for 2a and 3b).
lectivity were achieved. We chose these reaction conditions for
further investigation (henceforth, the catalyst, which was
prepared using the procedure mentioned above, is referred to
as “chiral Rh cat.”).
(2) Rh: (a) Grigg, R.; Scott, R.; Stevenson, P. J. Chem. Soc., Perkin Trans. 1
1988, 1357-1364. (b) Ojima, I.; Vu, A. T.; McCullagh, J. V.; Kinoshita,
A. J. Am. Chem. Soc. 1999, 121, 3230-3231. (c) Witulski, B.; Alayrac,
C. Angew. Chem., Int. Ed. 2002, 41, 3281-3284. (d) Kinoshita, H.;
Shinokubo, H.; Oshima, K. J. Am. Chem. Soc. 2003, 125, 7784-7785. Ni:
(e) Bhatarah, P.; Smith, E. H. J. Chem. Soc., Perkin Trans. 1 1992, 2163-
2168. Pd: (f) Negishi, E.; Harring, L. S.; Owczarczyk, Z.; Mohamud, M.
M.; Ay, M. Tetrahedron Lett. 1992, 33, 3253-3256. (g) Yamamoto, Y.;
Nagata, A.; Arikawa, Y.; Tatsumi, K.; Itoh, K. Organometallics 2000, 19,
2403-2405. (h) Yamamoto, Y.; Nagata, A.; Nagata, H.; Ando, Y.; Arikawa,
Y.; Tatsumi, K.; Itoh, K. Chem.-Eur. J. 2003, 9, 2469-2483. (i) Pla-
Quintana, A.; Roglans, A.; Torrent, A. Organometallics 2004, 23, 2762-
2767. Ru: (j) Peters, J.-U.; Blechert, S. Chem. Commun. 1997, 1983-
1984. (k) Hoven, G. B.; Efskind, J.; Rømming, C.; Undheim, K. J. Org.
Chem. 2002, 67, 2459-2463. (l) Yamamoto, Y.; Arakawa, T.; Ogawa, R.;
Itoh, K. J. Am. Chem. Soc. 2003, 125, 12143-12160. Co: (m) Stara´,
I. G.; Stary´, I.; Kolla´rovicˇ, A.; Teply´, F.; Sˇaman, D.; Tichy´, M. J. Org.
Chem. 1998, 63, 4046-4050. (n) Son, S. U.; Paik, S.-J.; Lee, S. I.; Chung,
Y. K. J. Chem. Soc., Perkin Trans. 1 2000, 141-143. (o) Sugihara, T.;
Wakabayashi, A.; Nagai, Y.; Takao, H.; Imagawa, H.; Nishizawa, M. Chem.
Commun. 2002, 576-577. (p) Teply´, F.; Stara´, I. G.; Stary´, I.; Kolla´rovicˇ,
A.; Sˇaman, D.; Vyskocˇil, Sˇ.; Fiedler, P. J. Org. Chem. 2003, 68, 5193-
5197. Mo: (q) Nishida, M.; Shiga, H.; Mori, M. J. Org. Chem. 1998, 63,
8606-8608. Fe: (r) Saino, N.; Kogure, D.; Okamoto, S. Org. Lett. 2005,
7, 3065-3067. (s) Saino, N.; Kogure, D.; Kase, K.; Okamoto, S. J.
Organomet. Chem. 2006, 691, 3129-3136.
Mechanistic Study. The proposed mechanism for different
products depending upon the substituents at the 1,4-diene moiety
of dienynes is depicted in Scheme 3. Oxidative coupling of the
metal complex to the 1,6-enyne moiety of dienyne gives
metallacyclopentene A as a common intermediate.15 Steric
repulsion between R2 and the bulky chiral ligand (Ln) on the
metal probably controls the direction of intramolecular olefin
insertion: when R2 is not a hydrogen atom, olefin moiety inserts
in a direction where R2 is distant from the metal center to give
metallacycle B, and subsequent reductive elimination gives
tricyclic compound 2. On the other hand, when R2 is a hydrogen
atom, the olefin inserts in another direction to give metallacycle
C. Subsequent â-hydrogen elimination and reductive elimination
give bicyclic compound 3 with a methyl group at the ring-fusion
carbon atom.
To elucidate the mechanism mentioned above, we examined
the cycloaddition of deuterated 1,4-diene-yne 1b-D under the
same reaction conditions (eq 1): bicyclic product 3b-D, which
has two deuterated vinylic protons and a monodeuterated methyl
group, was obtained, and almost perfect incorporation of the
deuteriums was ascertained. These results strongly support the
notion that this mechanism includes â-hydrogen elimination and
completely exclude the possibility that it includes the intramo-
lecular [4 + 2] cycloaddition of 1,3-diene-yne along with
carbon-carbon double bond isomerizations.16
(3) Stara´, I. G.; Stary´, I.; Kolla´rovicˇ, A.; Teply´, F.; Vyskocˇil, Sˇ.; Sˇaman, D.
Tetrahedron Lett. 1999, 40, 1993-1996.
(4) Shibata, T.; Tsuchikama, K.; Otsuka, M. Tetrahedron: Asymmetry 2006,
17, 614-619.
(5) Tanaka, K.; Sagae, H.; Toyoda, K.; Noguchi, K.; Hirano, M. J. Am. Chem.
Soc. 2007, 129, 1522-1523.
(6) Carbonylative carbocyclization of enediynes was already reported: (a)
Ojima, I.; Lee, S.-Y. J. Am. Chem. Soc. 2000, 122, 2385-2386. (b)
Bennacer, B.; Fujiwara, M.; Lee, S.-Y.; Ojima, I. J. Am. Chem. Soc. 2005,
127, 17756-17767.
(7) (a) Montgomery, J.; Seo, J. Tetrahedron 1998, 54, 1131-1144. (b)
Slowinski, F.; Aubert, C.; Malacria, M. Tetrahedron Lett. 1999, 40, 5849-
5852. (c) Slowinski, F.; Aubert, C.; Malacria, M. AdV. Synth. Catal. 2001,
343, 64-67. (d) Slowinski, F.; Aubert, C.; Malacria, M. J. Org. Chem.
2003, 68, 378-386.
(8) Tanaka, D.; Sato, Y.; Mori, M. J. Am. Chem. Soc. 2007, 129, 7730-7731.
(9) Yamamoto, Y.; Kuwabara, S.; Ando, Y.; Nagata, H.; Nishiyama, H.; Itoh,
K. J. Org. Chem. 2004, 69, 6697-6705.
(10) (a) Shibata, T.; Kurokawa, H.; Kanda, K. J. Org. Chem. 2007, 72, 6521-
6525. (b) Tanaka, K.; Nishida, G.; Sagae, H.; Hirano, M. Synlett 2007,
1426-1430.
(11) Quaternary Stereocenters: Challenges and Solutions for Organic Synthesis;
Christoffers, J., Baro, A., Eds.; Wiley-VCH: Weinheim, Germany, 2005.
(12) A preliminary communication: Shibata, T.; Tahara, Y. J. Am. Chem. Soc.
2006, 128, 11766-11767.
(13) The absolute configuration of phenyl-substituted tricyclic compound 2 (R
) Ph) was already determined by X-ray measurements (ref 12). That of
2a (R ) Me) could be speculatively assigned because the first metallacycle
formation step, where chirality is generated, is common (A in Scheme 3).
(14) Compound 3b was already obtained in enantioselective [2 + 2 + 2]
cycloaddition of 1,6-enyne and acetylene (ref 14a), and its absolute
configuration was speculatively assigned by the comparison of that of a
related compound in a related reaction (ref 14b): (a) Shibata, T.; Arai, Y.;
Tahara, Y. Org. Lett. 2005, 7, 4955-4957. (b) Evans, P. A.; Lai, K. W.;
Sawyer, J. R. J. Am. Chem. Soc. 2005, 127, 12466-12467.
(15) Bicyclic metallacyclopentene is a common intermediate to the present
reaction and intramolecular Pauson-Khand-type reaction of enynes.
Actually, the absolute configuration of the asymmetric carbon atom at the
ring-fusion carbon atom is the same when Rh-(S)-BINAP derivative
catalysts were used: (a) Jeong, N.; Sung, B. K.; Choi, Y. K. J. Am. Chem.
Soc. 2000, 122, 6771-6772. (b) Shibata, T.; Toshida, N.; Takagi, K. J.
Org. Chem. 2002, 68, 7446-7450.
9
3452 J. AM. CHEM. SOC. VOL. 130, NO. 11, 2008

Syntheses of Various Chiral Multicyclic Compounds
A R T I C L E S
Scheme 3. Proposed Mechanism for the Different Pathways Dependent upon the Substituents
Scheme 4. Proposed Mechanism for the Construction of a
Spirocyclic System
On the basis of the proposed mechanism described above,
we hypothesized that the introduction of bulkier substituents to
the alkyne terminus could realize the selective formation of
spirocyclic compounds and examined the cycloaddition of 1,4-
diene-ynes 1d-f with 4-, 3-, and 2-substituted phenyl groups,
respectively (Table 2).18 In the case of dienyne 1d with a
4-methylphenyl group, the results were almost the same as those
with 1c (entry 1). When dienyne 1e with a 3-methylphenyl group
was used, the formation of spirocyclic compound drastically
decreased (entry 2). In contrast, dienyne 1f with a 2-methylphe-
nyl group gave spirocyclic compound 4f as the sole detectable
product, albeit in low yield (entry 3).
We further examined several 1,4-diene-ynes with an ortho-
substituted aryl group at their alkyne termini (Table 3).18 When
a 2-biphenyl group was introduced, spirocyclic compound 4g
was selectively formed in good yield (entry 1). 1-Naphthyl and
9-phenanthryl groups also gave good results, and the corre-
sponding spirocyclic compounds 4h and 4i were obtained in
excellent enantiomeric excess (entries 2 and 3). Dienyne 1j
with a phenyl group at the olefinic moiety was also a good
substrate (entry 4).19 Nitrogen-tethered dienyne 1k was also
transformed into the corresponding product 4k in acceptable
yield (entry 5).
Synthesis of Chiral Spirocyclic Compounds. In the screen-
ing of various 1,4-diene-ynes, with oxygen-tethered dienyne 1c,
which has a phenyl group at its alkyne terminus, unexpected
spirocyclic compound 4c was obtained as a minor product, albeit
with excellent enantiomeric excess, along with tricyclic product
2c (eq 2).
Cycloaddition of 1,5-Diene-ynes. We next examined 1,5-
diene-yne in place of 1,4-diene-yne. Initially, 1,5-diene-ynes
with no substituent at the 2-position of 1,5-diene moiety were
used under the same reaction conditions (Table 4).18 From
nitrogen-tethered 1,5-diene-yne 5a, achiral tricyclic product 6a
and chiral bicyclic product 7a with excellent enantiomeric excess
were obtained (entry 1). 1,5-Diene-yne 5b with no substituent
at the alkyne terminus also gave a mixture of achiral compound
6b and chiral bicyclic product 7b, which has a 5,7-fused ring
system (entry 2). In the case of 1,5-diene-yne 5c with a phenyl
group at its alkyne terminus, achiral tricyclic compound was
obtained almost exclusively (entry 3). Carbon- and oxygen-
tethered 1,5-diene-ynes 5d and 5e were also transformed into
two products, and the enantiomeric excess of bicyclic com-
pounds 7d and 7e exceeded 99% (entries 4 and 5).
A proposed reaction mechanism for the formation of a
spirocyclic system is shown in Scheme 4: when an intramo-
lecular olefin insertion occurs between the metal center and sp2
carbon atom (a), tricyclic compound 2c is obtained via tricyclic
intermediate B. In contrast, when such an insertion occurs
between the metal center and sp3 carbon atom (b), tricyclic
metallacycle E would be obtained, and subsequent â-hydrogen
elimination and reductive elimination would give spirocyclic
compound 4c. In general, insertion into the metal center-sp2
carbon atom proceeds more readily than that into a metal center-
sp3 carbon atom;17 however, steric repulsion between phenyl
and methyl groups could induce the latter in the present reaction.
Next, we examined the cycloaddition of 1,5-diene-ynes, which
possess a methyl group at the 2-position of the 1,5-diene moiety
(Table 5). Both nitrogen- and oxygen-tethered dienynes gave
(16) Enantioselective intramolecular [4 + 2] cycloaddition of 1,3-diene-ynes:
(a) O’Mahony, D. J. R.; Belanger, D. B.; Livinghouse, T. Synlett 1998,
443-445. (b) Gilbertson, S. R.; Hoge, G. S.; Genov, D. G. J. Org. Chem.
1998, 63, 10077-10080. (c) Shibata, T.; Takasaku, K.; Takesue, Y.; Hirata,
N.; Takagi, K. Synlett 2002, 1681-1682.
(17) Shibata, T.; Koga, Y.; Narasaka, K. Bull. Chem. Soc. Jpn. 1995, 68, 911-
919.
(18) The absolute configuration of the chiral multicyclic products could be
speculatively assigned because they were probably formed via the common
metallacyclopentene intermediate (A).
(19) The substituent at the 2-position of 1,4-diene moiety is apparently important
for the induction of the steric repulsion; 1,4-diene-yne with no substituent
gave no spirocyclic compound. See ref 12.
9
J. AM. CHEM. SOC. VOL. 130, NO. 11, 2008 3453

A R T I C L E S
Shibata et al.
Table 2. Effect of Substituents at the Alkyne Terminus
entry
Me
dienyne
time/h
yield of 2/%
ee of 2/%a
yield of 4/%
ee of 4/%a
1
2
3
4-
3-
2-
1d
1e
1f
24
3
24
51 (2d)
60 (2e)
<2 (2f)
98
93
29 (4d)
<5 (4e)
38 (4f)
97
92
a The enantiomeric excess was determined by HPLC analysis using a Daicel chiral column (AD-H for 2d and 2e, OJ-H for 4d, and OD-H for 4f).
Table 3. Enantioselective Synthesis of Spirocyclic Compounds
oxygen-tethered dienynes predominantly provided chiral
tricyclic compounds with excellent enantiomeric excess (entries
3 and 4).
Cycloaddition of 1,6-Diene-ynes. To investigate the effect
of the length of the carbon chain between two alkene moieties
on the ratio of the cycloadducts, we further examined 1,6-diene-
ynes (Table 7).18 Nitrogen-tethered 1,6-diene-yne 9a was
entry
Z
R1
R2
dienyne
yield/%
ee/%b
completely consumed under the same reaction conditions as
those mentioned above to afford tricyclic compound 10a
predominantly with excellent enantiomeric excess, and only a
trace amount of bicyclic compound 11a with a 5,8-fused ring
system could be detected (entry 1). In the case of 1,6-diene-
yne 9b and oxygen-tethered 1,6-diene-yne 9c with a phenyl
group at their alkyne termini, tricyclic compounds 10b and 10c
with two carbon stereocenters were predominant products, and
bicyclic products 11b and 11c were nonisolable minor products
(entries 2 and 3).
1
2
3
O
O
O
O
2-PhC6H4
Me
Me
Me
Ph
1g
1h
1i
1j
1k
80 (4g)
82 (4h)
72 (4i)
78 (4j)
44 (4k)
96
97
99
93
92
1-naphthyl
9-phenanthryl
1-naphthyl
1-naphthyl
4
5a
NTs
Me
a The reaction was examined at 60 °C. b The enantiomeric excess was
determined by HPLC analysis using a Daicel chiral column (OD-H for 4g,
OJ-H for 4h, IA for 4i and 4j, and AD-H for 4k).
tricyclic compounds, which were achiral (entries 1-3). In
contrast to the case of 1,4-diene-ynes with a substituent at the
diene moiety (Table 3), the reaction of oxygen-tethered dienynes
5g and 5h with phenyl and naphthyl groups, respectively, gave
no spirocyclic compounds (entries 2 and 3).
We further examined the reaction of 1,5-diene-ynes with aryl
groups at the 2-position of the 1,5-diene moiety (Table 6).18
When dienyne 5i with a phenyl group was submitted to the
same reaction conditions, chiral tricyclic compound 8i was
obtained with excellent enantiomeric excess as a minor product
along with achiral tricyclic compound 6i (entry 1). 2-Methyl-
phenyl group changed the formation ratio of two products:
chiral tricyclic compound 8j was given as a major product (entry
2). In the case of bulkier 2-biphenyl group, nitrogen- and
In contrast, when an oxygen atom was introduced into the
carbon chain between two alkene moieties, bicyclic compound
Table 4. Cycloaddition of 1,5-Diene-ynes with No Substituent at the 2-Position of 1,5-Diene Moiety
entry
Z
R
dienyne
time/h
total yield/%
6/7
ee of 7/%b
1
2
3
4
5
NTs
NTs
NTs
C(CO2Bn)2
O
Me
H
Ph
H
5a
5b
5c
5d
5e
12
2
24
48
3
>99 (6a + 7a)
89 (6b + 7b)
95 (6c)
89 (6d + 7d)
61 (6e + 7e)
2:1
>99
1:1
>20:1a
1:1a
99
>99
>99
Me
2:1a
a The ratio of 6/7 was determined by 1H NMR. b The enantiomeric excess was determined by HPLC analysis using a Daicel chiral column (AD-H for 7a,
7b, 7d, and 7e).
9
3454 J. AM. CHEM. SOC. VOL. 130, NO. 11, 2008

Syntheses of Various Chiral Multicyclic Compounds
A R T I C L E S
Table 5. Cycloaddition of 1,5-Diene-ynes with a Methyl Group at
the 2-Position of 1,5-Diene Moiety
arrangement of the metal center and the â-hydrogen, and thus
the spirocyclic compound would not be obtained from E′ in
the case of 1,5- and 1,6-diene-ynes. When R2 is a bulky group,
olefin moiety inserts in another direction because of the steric
repulsion between R2 and the ligand (Ln), and chiral compounds
8 with different tricyclic skeleton are obtained.
Synthetic Application of Tricyclic Compounds. Some of
the obtained tricyclic products were subjected to oxidative
cleavage of the carbon-carbon double bond using ozonolysis
along with reductive treatment: tricyclic compound 2a was
readily transformed into 2-azaspiro[4.4]nonane 12a with two
quaternary stereocenters (eq 4).20 Also, from tricyclic com-
pounds 10a and 10e, which have a seven-membered ring and/
or an oxygen atom among the ring atoms, the corresponding
spirocyclic compounds 13a and 13e were obtained, respectively
(eq 5).21
entry
Z
R
dienyne
time/h
yield/%
1
NTs
O
O
Me
Ph
5f
5g
5h
3
3
24
88 (6f)
82 (6g)
47 (6h)
2
3a
1-naphthyl
a The reaction was examined at 60 °C, but dienyne 5h was not completely
consumed.
11d with a 5,8-fused ring system was obtained (eq 3). Also in
this case, a substituent at the 2-position of the diene moiety
suppressed the formation of bicyclic compound 11e, and chiral
tricyclic compound 10e was the sole detectable product.
Consideration of the Reaction Mechanism of 1,5- and 1,6-
Diene-ynes. The proposed reaction mechanism of 1,5- and 1,6-
diene-ynes is shown in Scheme 5. Bicyclic products 7 and 11
are certainly derived from metallacycle C′, which is formed by
olefin insertion between the metal center and sp2 carbon atom
(a) in metallacyclopentene A′. In contrast, two mechanisms
should be considered as the reaction pathway to the formation
of tricyclic products 6 and 10. The pathway via metallacycle
B′ is more reasonable; however, the formation of tricyclic
product 6h from oxygen-tethered dienyne 5h with a bulky aryl
group at its alkyne terminus should be derived from metallacycle
E′ because spirocyclic products were formed from oxygen-
tethered 1,4-diene-ynes with a naphthyl group via metallacycle
E (Scheme 4). The different ring systems could cause different
A chiral spirocyclic structure is found in many natural
products and biologically active compounds,22 and its rigid
framework acts as an effective chiral ligand.23 While various
Table 6. Cycloaddition of 1,5-Diene-ynes with Aryl Groups at the 2-Position of 1,5-Diene Moiety
entry
Z
R
dienyne
time/h
total yield/%
6/8a
ee of 8/%b
1
2
3
4
NTs
NTs
NTs
O
Ph
5i
0.5
1
2
95 (6i + 8i)
98 (6j + 8j)
78 (6k + 8k)
75 (6l + 8l)
1.5:1
1:2
1:13
1:13
>99
99
99
2-MeC6H4
2-PhC6H4
2-PhC6H4
5j
5k
5l
2
99
1
a The ratio of 6/8 was determined by H NMR. b The enantiomeric excess was determined by HPLC analysis using a Daicel chiral column (IB for 8i,
OD-H for 8j, and AD-H for 8k and 8l).
Table 7. Cycloaddition of 1,6-Diene-ynes
entry
Z
R
dienyne
time/h
total yield/%
10/11a
ee of 10/%b
1
2
3
NTs
NTs
O
Me
Ph
Ph
9a
9b
9c
24
24
3
93 (10a + 11a)
91 (10b + 11b)
63 (10c + 11c)
13:1
14:1
>20:1
>99
95
89
1
a The ratio of 10/11 was determined by H NMR. b The enantiomeric excess was determined by HPLC analysis using a Daicel chiral column (OJ-H for
10a, and AD-H for 10b and 10c).
9
J. AM. CHEM. SOC. VOL. 130, NO. 11, 2008 3455

A R T I C L E S
Shibata et al.
Scheme 5. Possible Explanation for the Cycloaddition of 1,n-Diene-ynes (n ) 5, 6)
Table 8. Enantioselective Intramolecular Cycloaddition of
Enediynes
methods for the synthesis of chiral spirocyclic compounds have
been reported, there are a few transition-metal-catalyzed enan-
tioselective approaches. Overman and co-workers reported a
pioneering work on the enantioselective intramolecular Mizo-
roki-Heck reaction using a chiral Pd catalyst.24 This was
followed by Zr-catalyzed diene cyclization25 and tandem olefin
metathesis.26 Mikami and co-workers reported a highly enan-
tioselective method using the intramolecular ene-type cyclization
of enynes.27 On the other hand, we recently disclosed an
enantioselective [2 + 2 + 2] cycloaddition of diynes and alkenes
for the synthesis of spirocyclic compounds.28 Therefore, the
above protocol provides a new cycloaddition-based approach
for the generation of a spirocyclic system.
Cycloaddition of Enediynes. Finally, we examined the
cycloaddition of enediynes, where two alkyne moieties are
connected by a 1,1-disubstituted alkene tether (Table 8). When
oxygen-tethered symmetrical enediyne 14a with methyl groups
at its alkyne termini was subjected to the reaction using the
same Rh catalyst, tricyclic compound 15a with two chiral carbon
atoms and an exo-methylene moiety were obtained in good yield
entry
Z
R
enediyne
temp/
°
C
time/h
yield/%
ee/%b
1
O
NTs
NTs
Me
Me
H
14a
14b
14c
rt
60
40
6
6
24
78 (15a)
87 (15b)
74 (15c)
99
93
88
2
3a
a The volume of solvent is ten times as much as that in other entries.
b The enantiomeric excess was determined by HPLC analysis using a Daicel
chiral column (OD-H for 15a, and IA for 15b and 15c).
and excellent enantiomeric excess (entry 1). Nitrogen-tethered
symmetrical enediyne 14b was also transformed into the
corresponding tricyclic diene 15b at an elevated reaction
temperature (entry 2). Under the same conditions, however, the
reaction of nitrogen-tethered unsymmetrical enediyne 14c, which
has substituted and unsubstituted alkyne termini, gave a complex
mixture. Under diluted conditions, which would prevent the
intermolecular reaction of the unsubstituted alkyne terminus,
tricyclic product 15c was isolated in good yield (entry 3).
A proposed mechanism for the cycloaddition of enediynes
14 is shown in Scheme 6. In a manner similar to the reaction
of dienynes, oxidative coupling of the metal complex to 1,6-
enyne moieties gave metallacyclopentene H with a chiral center
at the ring-fusion carbon atom. Then, the alkyne moiety inserted
into the bond between the metal center and the sp3 carbon atom,
probably because insertion into the metal-sp2 carbon bond is
highly strained because of the linearity of the alkyne moiety.
The resulting tricyclic intermediate I has a carbon-carbon
double bond at the bridgehead position and would undergo
double-bond isomerization to release the severe strain. At this
(20) The stereospecific transformation was ascertained by the enantiomeric
excess of 12a, and its absolute configuration was speculatively determined
by that of chiral tricyclic compound 2a.
(21) The transformation without racemization was ascertained by NMR analyses
of 13a and 13e, where only single diastereomers were detected, and their
absolute configurations were speculatively determined by that of chiral
tricyclic compounds 10a and 10e.
(22) A recent review of spirocyclic compounds in nature and the synthesis of
spirocyclic structure: Pradhan, R.; Patra, M.; Behera, A. K.; Mishra, B.
K.; Behera, R. K. Tetrahedron 2006, 62, 779-828 and references therein.
(23) (a) Kato, T.; Marubayashi, K.; Takizawa, S.; Sasai, H. Tetrahedron:
Asymmetry 2004, 15, 3693-3697 and references therein. (b) Xie, J.-H.;
Zhu, S.-F.; Fu, Y.; Hu, A.-G.; Zhou, Q.-L. Pure Appl. Chem. 2005, 77,
2121-2132. (c) Guo, Z.; Guan, X.; Chen, Z. Tetrahedron: Asymmetry
2006, 17, 468-473.
(24) (a) Ashimori, A.; Overman, L. E. J. Org. Chem. 1992, 57, 4571-4572.
(b) Ashimori, A.; Bachand, B.; Overman, L. E.; Poon, D. J. J. Am. Chem.
Soc. 1998, 120, 6477-6487.
(25) Yamaura, Y.; Hyakutake, M.; Mori, M. J. Am. Chem. Soc. 1997, 119,
7615-7616.
(26) Teng, X.; Cefalo, D. R.; Schrock, R. R.; Hoveyda, A. H. J. Am. Chem.
Soc. 2002, 124, 10779-10784.
(27) (a) Hatano, M.; Mikami, K. J. Am. Chem. Soc. 2003, 125, 4704-4705. (b)
Mikami, K.; Yusa, Y.; Hatano, M.; Wakabayashi, K.; Aikawa, K. Chem.
Commun. 2004, 98-99.
(28) Tsuchikama, K.; Kuwata, Y.; Shibata, T. J. Am. Chem. Soc. 2006, 128,
13686-13687.
9
3456 J. AM. CHEM. SOC. VOL. 130, NO. 11, 2008

Syntheses of Various Chiral Multicyclic Compounds
A R T I C L E S
Scheme 6. Proposed Mechanism for the Generation of the
exo-Methylene Moiety
three types of multicyclic compounds were obtained: (1)
sterically strained tricyclic compounds, which include bicyclo-
[2.2.1]heptene, bicyclo[2.2.2]octene, bicyclo[3.2.1]octane, and
bicyclo[3.2.2]nonene skeletons, (2) bicyclic compounds with a
methyl group at the ring-fusion carbon atom, and (3) spirocyclic
compounds. In the case of enediynes with two 1,6-enyne
moieties, tricyclo[6.3.1.01,8]dodecenes with two stereocenters
at the ring-fusion carbon atoms were obtained. All of these
products had quaternary carbon stereocenter(s), and their
enantiomeric excess was high to excellent. Therefore, the present
protocol provides a new family of chiral multicyclic compounds
with quaternary carbon stereocenter(s). Further transformations
of the functionalized spirocyclic compounds into synthetically
useful intermediates are under investigation.
step, the second carbon stereocenter was generated (J), and
subsequent reductive elimination gave tricyclic compound 15
with an exo-methylene moiety.
Acknowledgment. We thank Prof. Masaharu Nakamura
(Kyoto University, Japan) and Prof. Kazunori Koide (University
of Pittsburgh) for their helpful advice for the preparation of
2-methylenepent-4-en-1-ol, which was derived into 1,4-diene-
ynes. This research was supported by a Grant-in-Aid for
Scientific Research from the Ministry of Education, Culture,
Sports, Science and Technology, Japan.
Conclusions
We have comprehensively studied the Rh-catalyzed enanti-
oselective intramolecular cycloaddition of diene-ynes and ene-
diynes, where alkyne and alkene or two alkyne moieties are
connected by a 1,1-disubstituted alkene tether. In the case of
1,n-diene-ynes (n ) 4-6), the choice of the substituent at the
2-position of the 1,n-diene moiety and that at the alkyne terminus
determined the direction and position of intramolecular alkene
insertion into the bicyclic metallacyclopentene intermediate, and
Supporting Information Available: Spectral data for all new
compounds and CIF file of 6a. This material is available free
of charge via the Internet at http://pubs.acs.org.
JA0762083
9
J. AM. CHEM. SOC. VOL. 130, NO. 11, 2008 3457