Silicon-initiated carbonylative carbotricyclization and [2+2+2+1] cycloaddition of enediynes catalyzed by rhodium complexes

Article abstract of DOI:10.1021/ja054221m

The reaction of dodec-11-ene-1,6-diynes or their heteroatom congeners with a hydrosilane catalyzed by Rh(acac)(CO)₂ at ambient temperature and pressure of CO gives the corresponding fused 5-7-5 tricyclic products, 5-oxo-1,3a,4,5,7,9-hexahydro-3

Full text of DOI:10.1021/ja054221m

Published on Web 11/23/2005
Silicon-Initiated Carbonylative Carbotricyclization and
[2+2+2+1] Cycloaddition of Enediynes Catalyzed by Rhodium
Complexes
Bibia Bennacer, Masaki Fujiwara, Seung-Yub Lee, and Iwao Ojima*
Contribution from the Department of Chemistry, State UniVersity of New York at Stony Brook,
Stony Brook, New York 11794-3400
Received June 26, 2005; E-mail: iojima@notes.cc.sunysb.edu
Abstract: The reaction of dodec-11-ene-1,6-diynes or their heteroatom congeners with a hydrosilane
catalyzed by Rh(acac)(CO)2 at ambient temperature and pressure of CO gives the corresponding fused
5-7-5 tricyclic products, 5-oxo-1,3a,4,5,7,9-hexahydro-3H-cyclopenta[e]azulenes or their heteroatom
congeners, in excellent yields through a unique silicon-initiated cascade carbonylative carbotricyclization
(CO-SiCaT) process. It has also been found that the 5-7-5 fused tricyclic products can be obtained from
the same type of enediynes and CO through a novel intramolecular [2+2+2+1] cycloaddition process.
The characteristics of these two tricyclization processes and the fundamental differences in their reaction
mechanisms are discussed. This novel higher-order cycloaddition reaction has also been successfully applied
to the tricyclization of undeca-5,10-diyn-1-als, affording the corresponding 5-7-5 fused-ring products bearing
a seven-membered lactone moiety. Related [2+2+2] tricyclizations of enediyne and diynal substrates are
also discussed. These newly discovered reactions can construct multiple bonds all at once, converting
linear starting materials to polycyclic compounds in a single step. Thus, these new processes provide
innovative routes to functionalized polycyclic compounds that are useful for the syntheses of natural and
unnatural products.
Introduction
in their structures, these polycyclization reactions warrant
extensive studies. In fact, various polycyclization processes have
It would be ideal if the synthesis of complex target molecules
could be achieved quickly, quantitatively, and selectively by a
simple operation from readily available starting materials.1The
transition-metal-catalyzed carbocyclization2 and cycloaddition3,4
reactions are among the synthetically most useful processes for
rapidly increasing molecular complexity. Many of these pro-
cesses are symmetry forbidden and impossible or difficult to
realize in the absence of proper catalysts. Among various metals,
nickel, ruthenium, cobalt, rhodium, and palladium catalysts have
been commonly used to promote these two processes.5-7
Because many bioactive compounds8 include fused-ring systems
been employed for the construction of natural and unnatural
fused-ring systems that can be further elaborated into specific
targets. For instance, in the last two decades, considerable
advances have been made in the development of higher-order
cycloaddition reactions such as [4+3],9 [5+2],10 [6+2],11
[4+2+2],12 and [5+2+1]13 processes. Thus, transition-metal-
catalyzed carbocyclization and higher-order cycloaddition reac-
tions14 provide powerful methods for the construction of
complex polycyclic systems.2c,15-16
(7) (a) Ojima, I.; Clos, N.; Donovan, R. J.; Ingallina, P. Organometallics 1990,
9, 3127-3133. (b) Tanke, R.; Crabtree, R. H. J. Am. Chem. Soc. 1990,
112, 7984-7989.
(8) (a) Vollhardt, K. P. C. Angew. Chem., Int. Ed. Engl. 1984, 23, 539-556.
(b) Cruciani, P.; Aubert, C.; Malacria, M. J. Org. Chem. 1995, 60, 2664-
2665 and references therein.
(9) (a) Harmata, M.; Kahraman, M.; Adenu, G.; Barnes, C. L. Heterocycles
2004, 62, 583-618. (b) Xiong, H.; Huang, J.; Ghosh, S. K.; Hsung, R. P.
J. Am. Chem. Soc. 2003, 125, 12694-12695. (c) Harmata, M.; Schreiner,
P. R. Org. Lett. 2001, 3, 3663-3665. (d) Lee, J. C.; Cha, J. K. Tetrahedron
2000, 56, 10175-10184.
(10) (a) Wender, P. A.; Takahashi, H.; Witulski, B. J. Am. Chem. Soc. 1995,
117, 4720-4721. (b) Wender, P. A.; Rieck, H.; Fuji, M. J. Am. Chem.
Soc. 1998, 120, 10976-10977. (c) Wender, P. A.; Sperandio, D. J. Org.
Chem. 1998, 63, 4164-4165. (d) Wender, P. A.; Barzilay, C. M.; Dyckman,
A. J. J. Am. Chem. Soc. 2001, 123, 179-180. (e) Wender, P. A.; Perdersen,
T. M.; Scanio, M. J. C. J. Am. Chem. Soc. 2002, 124, 15154-15155.
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(1) (a) Wender, P. A.; Handy, S. T.; Wright, D. L. Chem. Ind. 1997, 3, 765-
769 and references therein. (b) Hudlicky, T.; Natchus, M. G. In Organic
Synthesis: Theory and Applications; Hudlicky, T., Ed.; JAI Press:
Greenwich, CT, 1993; Vol. 2, pp 1-26. (c) Wender, P. A. Chem. ReV.
1996, 96, 1-2.
(2) For recent reviews on metal-catalyzed carbocyclization, see: (a) Grotjahn,
D. B. In Comprehensive Organometallic Chemistry II; Hegedus, L. S., Ed.;
Pergamon/Elsevier Science: Kidlington, U.K., 1995; Vol. 12; pp 703, 741.
(b) Lautens, M.; Klute, W.; Tam, W. Chem. Rev. 1996, 96, 49-92. (c)
Ojima, I.; Tzamarioudaki, M.; Li, Z.; Donovan, R. J. Chem. ReV. 1996,
96, 635-662.
(3) AdVances in Cycloaddition; JAI Press: Greenwich, CT, 1994; Vol. 1-3.
(b) Dell, C. P. Contemp. Org. Synth. 1997, 4, 87-117. (c) Dell, C. P. J.
Chem. Soc., Perkin Trans. 1 1998, 3873-3905.
(4) For examples of metal-catalyzed cycloadditions, see: (a) Schore, N. E.
Chem. ReV. 1988, 88, 1081-1119. (b) Fru¨hauf, H.-W. Chem. ReV. 1997,
97, 523-596. (c) Rigby, J. H. Acc. Chem. Res. 1993, 26, 579-585.
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1 1988, 6, 1357-1364.
(6) Negishi, E.; Harring, L. S.; Owczarczyk, Z.; Mohamud, M. M.; Ay, M.
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9
17756
J. AM. CHEM. SOC. 2005, 127, 17756-17767
10.1021/ja054221m CCC: $30.25 © 2005 American Chemical Society

Carbotricyclization Reactions of Enediynes
A R T I C L E S
Scheme 1
Scheme 3
Scheme 4
Scheme 2
1,6-diynes 5. The reaction of the enediynes 5 with PhMe2SiH
in the presence of a rhodium catalyst under ambient pressure
of CO afforded, to our surprise, fused 5-7-5 ring products 6
incorporating a CO molecule, and our preliminary study was
communicated.22 This novel silicon-initiated cascade carbony-
lative carbotricyclization (CO-SiCaT) of enediynes promoted
by rhodium catalysts provides a powerful method for the rapid
construction of functionalized fused 5-7-5 ring systems (Scheme
3).
During our studies on the scope and limitation of the CO-
SiCaT reaction, we serendipitously found that the reaction of
1-substituted dodec-11-ene-1,6-diyne 7 catalyzed by [Rh(COD)-
Cl]2 in the absence of a hydrosilane gave carbonylative
tricyclization product 8 in good to excellent yields (Scheme 4).
This observation turned out to be the first example of a
[2+2+2+1] cycloaddition reaction, and preliminary results were
communicated.23
Although these two processes, i.e., CO-SiCaT and
[2+2+2+1] cycloaddition, lead to the formation of the same
type of products, these reactions proceed through fundamentally
different mechanisms.22,23 We describe here a full account of
our study on the novel Rh-catalyzed CO-SiCaT and intramo-
lecular [2+2+2+1] cycloaddition processes of enediynes,
involving CO as the single carbon component.
In the course of our investigation into the development of
silicon-initiated cyclization processes, intramolecular silylformyl-
ation,7a silylcyclocarbonylation (SiCCa),17,18 silylcarbocycliza-
tion (SiCaC),18,19 silylcarbobicyclization (SiCaB),18d,e and si-
lylcarbotricyclization (SiCaT)18c,d have been discovered. In 1996,
we reported a stereospecific cascade SiCaC reaction20 of dodec-
6-ene-1,11-diynes (Scheme 1). In this reaction, although in-
tramolecular carbometalation of the vinylsilane moiety of
intermediate A1 with the [Rh]-vinyl moiety to form the third
ring was conceptually possible, the third cyclization did not take
place. Thus, a simple reductive elimination preferentially
occurred to give the corresponding bis(cyclopentyl) 2.
In the case of alkatriynes 3, however, silylcarbotricyclization
(SiCaT) took place to give the fused tricyclic compounds 4a
and 4b in good to excellent yields (Scheme 2).21 Reactions
catalyzed by rhodium carbonyl clusters showed high selectivity
to 4a.
Results and Discussion
Silicon-Initiated Carbonylative Carbotricyclization (CO-
SiCaT) of Enediynes. The scope of the CO-SiCaT reaction
has been investigated systematically by looking at the key
elements and reaction variables involved in this process. The
enediyne 5a was used as the substrate for this study (Scheme
5). Results are summarized in Table 1. Reaction of enediyne
5a with PhMe2SiH (2.0 equiv) catalyzed by Rh(acac)(CO)2 (1
mol %) in toluene under ambient pressure of CO at 70 °C for
1 h gave cyclopenta[e]azulene 6a and bis(cyclopentylidene) 9
as major products and aldehyde 10 as a minor product in 70%
overall isolated yield (6a/9/10 ) 36:43:21) (entry 1). The
reaction under higher CO pressure (10 atm) disfavored the
formation of 9 (entry 2). Addition of P(OPh)3 completely
suppressed the formation of 10 (entry 3), and the use of PPh3
as the additive substantially favored the formation of 10 and
reduced the yield of 6a (entry 4). The use of THF as the solvent
As a part of our studies on the silicon-initiated cascade
carbometalations, we looked at the reaction of dodec-11-ene-
(14) For recent reviews, see: (a) Lautens, M.; Klute, W.; Tam, W. Chem. ReV.
1996, 96, 49-92. (b) Hegedus, L. S. Coord. Chem. ReV. 1998, 168, 149-
175. (c) Haughton, L.; Williams, J. M. J. J. Chem. Soc., Perkin Trans. 1
1999, 2645-2658.
(15) Wender, P. A.; Miller, B. A. Org. Synth.: Theory Appl. 1993, 2, 27-66.
(16) Aubert, C.; Buisine, O.; Malacria, M. Chem. ReV. 2002, 102, 813-834.
(17) (a) Ojima, I.; Donovan, R. J.; Eguchi, M.; Shay, W. R.; Ingallina, P.; Korda,
A.; Zeng, Q. Tetrahedron 1993, 49, 5431-5444. (b) Ojima, I.; Vidal, E.;
Tzamarioudaki, M.; Matsuda, I. J. Am. Chem. Soc. 1995, 117, 6797-6798.
(c) Ojima, I.; Li, Z.; Donovan, R. J.; Ingallina, P. Inorg. Chim. Acta 1998,
270, 279-284. (d) Matsuda, I.; Fukuta, Y.; Tsuchihashi, T.; Nagashima,
H.; Itoh, K. Organometallics 1997, 16, 4327-4345.
(18) (a) Ojima, I.; Donovan, R. J.; Shay, W. R. J. Am. Chem. Soc. 1992, 114,
4, 6580-6582. (b) Ojima, I.; Tzamarioudaki, M.; Tsai, C.-Y. J. Am. Chem.
Soc. 1994, 116, 3643-3644. (c) Ojima, I.; Fracchiolla, D. A.; Donovan,
R. J.; Banerji, P. J. Org. Chem. 1994, 59, 7594-7595. (d) Ojima, I.; Kass,
D. F.; Zhu, J. Organometallics 1996, 15, 5191-5195. (e) Ojima, I.; Zhu,
J.; Vidal, E. S.; Kass, D. F. J. Am. Chem. Soc. 1998, 120, 6690-6697.
(19) Ojima, I.; Vu, A. T.; McCullagh, J. V.; Moralee, A. C.; Fujiwara, M.;
Hoang, T. H. J. Am. Chem. Soc. 2002, 124, 9164-9174.
(20) Ojima, I.; McCullagh, J. V.; Shay, W. R. J. Organomet. Chem. 1996, 521,
421-423.
(21) Ojima, I.; Vu, A. T.; McCullagh, J.; Kinoshita, A. J. Am. Chem. Soc. 1999,
121, 3230-3231.
(22) Ojima, I.; Lee, S.-Y. J. Am. Chem. Soc. 2000, 122, 2385-2386.
(23) (a) Bennacer, B.; Fujiwara, M.; Ojima, I. Org. Lett. 2004, 6, 3589-3591.
(b) Bennacer, B.; Ojima, I. Abstracts of Papers, 227th ACS National
Meeting, Anaheim, CA, March 28-April 1, 2004; American Chemical
Society: Washington, DC, 2004; ORGN-076.
9
J. AM. CHEM. SOC. VOL. 127, NO. 50, 2005 17757

A R T I C L E S
Scheme 5
Bennacer et al.
information for the mechanism of this unique reaction. Although
the mechanism of this novel carbocyclization process is
proposed and discussed later in the text (see Scheme 6), the
formations of 9 and 10 should involve a bimolecular process at
the final reductive elimination step, whereas that of 6a should
not; i.e., the formation of 6a is a unimolecular process.
Accordingly, the formation of 6a should be favored at higher
dilution, and those of 9 and 10 should be disfavored. In addition,
a stoichiometric amount of the hydrosilane should not be
necessary for the formation of 6a because this product does
not incorporate the hydrosilane component. This indicates that
only a substoichiometric amount of hydrosilane would be
sufficient for this reaction to proceed, and such a condition
should suppress the formations of 9 and 10. Thus, we carried
out the reaction with a substoichiometric amount of hydrosilane,
and indeed, our analysis and prediction was proven correct.
Thus, the reaction with 0.5 equiv of PhMe2SiH at high dilution
conditions (0.015 M) gives 6a exclusively in high overall yield
(entries 7, 10, and 11). The reaction with 0.1 equiv of the
hydrosilane is 100% selective to the formation of 6a but does
not give complete conversion in 96 h (entry 8). In the absence
of PhMe2SiH, no reaction takes place after 96 h, recovering
at a lower temperature (22 °C) gave better product selectivity
for 6a (entry 5). Then, the reaction at a lower concentration
(0.015 M) dramatically increased the product selectivity, yield-
ing 6a as the sole product (entry 6).
The observed remarkable dilution effects on the product
selectivity appear to be, in part, attributed to the concentration
of CO in solution relative to those of the catalyst and
hydrosilane; i.e., the relative concentration of CO is higher in
dilute solution if the amounts of the catalyst and hydrosilane
are kept constant. Also, this observation provides crucial
Table 1. CO-SiCaT of Endiyne 5aa
product
ratio
R3SiH
concn
(M)
temp
C)
CO
time
(h)
yield
(%)b
entry
catalyst
(equiv)
solvent
(
°
(atm)
6a
9
10
1
2
Rh(acac)(CO)2
Rh(acac)(CO)2
Rh(acac)(CO)2
Rh(acac)(CO)2
Rh(acac)(CO)2
Rh(acac)(CO)2
Rh(acac)(CO)2
Rh(acac)(CO)2
Rh(acac)(CO)2
Rh4(CO)12
[Rh(CO)2Cl]2
Rh(acac)(CO)2
Rh(acac)(CO)2
Rh(acac)(CO)2
Rh(acac)(CO)2
PhMe2SiH (2.0)
PhMe2SiH (2.0)
PhMe2SiH (1.0)
PhMe2SiH (1.0)
PhMe2SiH (1.0)
PhMe2SiH (1.0)
PhMe2SiH (0.5)
PhMe2SiH (0.1)
PhMe2SiH (0.0)
PhMe2SiH (0.5)
PhMe2SiH (0.5)
PhMe2SiH (0.5)
(EtO)3SiH (0.5)
Et3SiH (0.5)
toluene
toluene
toluene
toluene
THF
THF
THF
THF
THF
THF
THF
THF
0.2
0.2
0.2
0.2
70
60
50
50
22
22
22
22
22
22
22
22
22
22
22
1
10
1
1
1
1
1
1
1
1
1
1
1
1
1
1
10
10
10
12
24
30
96
96
17
23
96
96
96
96
70
55
62
52
65
82
92
33
0
78
80
42
34
12
0
36
55
65
10
70
100
100
100
0
43
9
35
32
15
0
0
0
0
8
0
0
0
10
0
21
36
0
58
15
0
0
0
0
0
3c
4d
5
0.2
6
7
8
9
10
11
12
13
14
15
0.15
0.015
0.015
0.015
0.015
0.015
0.015
0.015
0.015
0.015
92
100
100
100
90
0
0
0
0
THF
THF
THF
t-BuMe2SiH (0.5)
0
0
a Reaction was run with enediyne (0.25-0.5 mmol scale), hydrosilane, and Rh catalyst (1 mol %) in the solvent under CO. b Isolated yields. c P(OPh)3
(3 equiv to catalyst) was added as a ligand. d PPh3 (3 equiv to catalyst) was added as a ligand.
Scheme 6
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17758 J. AM. CHEM. SOC. VOL. 127, NO. 50, 2005

Carbotricyclization Reactions of Enediynes
A R T I C L E S
Table 2. CO-SiCaT of Enediynes 5a
enediyne 5a (entry 9). Thus, PhMe2SiH is proven necessary
for this reaction to occur, although no silyl group is incorporated
into product 6a. The best result is achieved by using 0.5 equiv
of PhMe2SiH at 0.015 M concentration, giving 6a as the single
product in 92% isolated yield (entry 7).
As for the catalyst, Rh(acac)(CO)2, Rh4(CO)12, and [Rh-
(CO)2Cl]2 show similar efficacy. For hydrosilanes in this
process, the reactions with Ph2MeSiH and (EtO)3SiH give 6a
exclusively, although the reactions using (EtO)3SiH are slower
than those with PhMe2SiH. Trialkylsilanes behave differently;
that is, the reaction with Et3SiH gives a 9:1 mixture of 6a and
9-TES in low conversion, and that with t-BuMe2SiH does not
give any conversion after 96 h. Accordingly, PhMe2SiH is the
best hydrosilane, so far, for this process.
As described above, the optimal reaction conditions for the
CO-SiCaT reaction include the use of Rh(acac)(CO)2, 0.5 equiv
of PhMe2SiH at 0.015 M concentration in THF at room
temperature, and ambient pressure of CO. To examine the scope
and limitations of this reaction for functional group tolerance,
a variety of substrates containing ether, ester, hydroxyl, and
sulfonamide groups have been subjected to the optimal condi-
tions for the CO-SiCaT process. Results are summarized in
Table 2.
As Table 2 shows, these functional groups and heteroatoms
are well tolerated in this reaction to give the corresponding fused
5-7-5 tricyclic compounds 6 in good to excellent isolated yields.
The reaction of 5d gives 6d that contains two fused pyrrolidine
moieties in 85% isolated yield (entry 4), and the reaction of 5b
that contains dipropargyl ether as well as propargyl allyl ether
moieties is sluggish to give 6b in 50% yield after 48 h (entry
2). However, the reactions of unsymmetrical substrates bearing
a malonate group as well as a dipropargyl ether or a sulfonamide
moiety give the corresponding 5-7-5 products (6c,e,f) in
excellent yields (entries 3, 5, and 6). In the case of 5g, bearing
a tert-butyl carbamate group, the reaction requires 40 °C to give
6g in high yield (entry 7). The substrates 5g-l derived from
5a, bearing ethers, hydroxyl groups, and ketals, are also well
tolerated in this reaction, which give the corresponding 6h-l
in good to high yields (entries 8-12).
A. Mechansim of the CO-SiCaT Reaction. The most
plausible mechanism for this novel carbonylative carbotricy-
clization, which can accommodate all observed results, is
illustrated in Scheme 6. The reaction begins with the insertion
of the terminal alkyne moiety into the Si-[Rh] bond of the
hydrosilane-Rh oxidative adduct.22 Carbocyclization then oc-
curs to give (Z)-dienyl[Rh](H) intermediate A6. Because of the
steric hindrance between the vinylsilane and the vinyl-[Rh]
moieties, A6 isomerizes to C6 via B6 through the “Ojima-
Crabtree mechanism”.7 Subsequent carbocyclization to D6,
followed by reductive elimination, should give 9. The CO
insertion to D6 gives acyl-[Rh](H) intermediate E6. Reductive
elimination of E6 should yield aldehyde 10. Carbocyclization
of E6 gives tricyclic intermediate F6 that has the silicon and
the [Rh] moieties in syn positions. Subsequent â-silyl elimin-
ation18e,21 should take place to afford the fused 5-7-5 tricyclic
product 6 and to regenerate the active catalyst species, R3Si-
[Rh](H). The proposed mechanism can nicely accommodate the
observed three products under nonoptimized conditions, dilution
a All reactions were run with 0.25 mmol of enediyne under CO (1 atm)
using 1 mol % of Rh(acac)(CO)2 in 17 mL of THF at 22 °C unless otherwise
noted. b Isolated yields are based on an average of two runs. c Reaction was
run at 40 °C.
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A R T I C L E S
Scheme 7
Bennacer et al.
Scheme 8
Scheme 9
achieved by simply blocking the facile â-hydride elimination
with the appropriate introduction of a heteroatom or gem
disubstitution in the cyclohexyl moiety of enediyne 11. Ac-
cordingly, further studies along this line are actively underway
in these laboratories.
effects, and the fact that only substoichiometric hydrosilane is
needed to yield 6.24
Next, we investigated the reaction of enediyne 11 in which
the alkene group is a part of a cyclic system (Scheme 7). If the
reaction proceeds via CO-SiCaT, fused 5-7-6-5 tetracyclic
product 12 should be formed. However, the reaction of 11 under
the standard CO-SiCaT conditions did not give 12 but afforded
tricyclic product 13 in 63% isolated yield. As Scheme 7
illustrates, the result indicates that after the second carbocy-
clization, forming intermediate A7, â-hydride elimination took
place exclusively in intermediate B7 over CO insertion to form
the corresponding acyl-[Rh] intermediate. This type of facile
â-hydride elimination in the cyclohexyl-containing enyne 15
was previously observed in the SiCaC of a propargyl(cyclo-
hexyl)malonate, wherein the â-hydride elimination was much
faster than the reductive elimination to give 16 (Scheme 8).19
The yield of 13 was improved to 79% when 2 equiv of PhMe2-
SiH to 11 were used. The reactions under different conditions,
i.e., (i) at higher temperatures (up to 70 °C), (ii) at higher CO
pressures (10-30 atm), (iii) use of Rh4(CO)12 as the catalyst,
(iv) use of other hydrosilanes (Ph2MeSiH, Et3SiH), or (v)
addition of P(OPh)3, did not improve the yield of 13 but rather
decreased the yield or slowed the reaction (under higher CO
pressures). It should be noted that 13 was formed as a single
stereoisomer (the stereochemistry was unambiguously deter-
mined based on NOE; i.e., 14 was not formed, which is
consistent with the proposed mechanism in Scheme 6). This
result shows a limitation of the CO-SiCaT process in the
substrate type. However, the same result strongly suggests that
the formation of the fused 5-7-6-5 tetracyclic product could be
B. Attempted CO-SiCaT of Enediyne 7a. We also
investigated the reaction of an enediyne 7a, which bears a
2-butynyl group instead of a propargyl group at one terminal,
to examine the effect of this terminal methyl group on the
reactivity and mode of the reaction. To our surprise, the
attempted CO-SiCaT reaction of 7a resulted in the formation
of SiCaT products 17a and 18a without CO insertion (Scheme
9). Results are listed in Table 3. The reaction of 7a under the
standard CO-SiCaT conditions for 24 h did not give any
product, and enediyne 7a was recovered (entry 1). However,
when the reaction using 0.3 equiv of PhMe2SiH was run at 70
°C in toluene for 3 h, SiCaT21 product 17a was obtained in
96% yield (entry 3). The reaction using 0.1 equiv of the
hydrosilane for 24 h gave a 1:1 mixture of 17a and 18a in 90%
yield (entry 4). The use of higher CO pressure (25 atm)
suppressed the reaction (entry 5). No reaction took place even
after 72 h in the absence of the hydrosilane (entry 6), which
clearly indicates that the hydrosilane is necessary for the reaction
to occur. The reaction using Rh4(CO)12 as the catalyst gave a
2:1 mixture of 17a and 18a in only 50% yield (entry 2).
C. Mechanism of the SiCaT Reaction of Enediyne 7a. The
proposed mechanism for the formation of SiCaT products 17a
and 18a is shown in Scheme 10. The reaction begins in the
same manner as that of CO-SiCaT (Scheme 6) to form
intermediate A10 after the first silylcarbocyclization. However,
because of the methyl substituent, the Z f E isomerization does
not occur, which makes a sharp contrast with the CO-SiCaT
mechanism (Scheme 6). Because the silyl group and the [M]-
(H) moiety (M ) Rh) is very close, a σ-bond metathesis takes
place to form metalacycle intermediate B10, liberating a hy-
drosilane. There are two possible ways that the olefin moiety
(24) (a) Koga, Y.; Kobayashi, T.; Narasaka, K. Chem. Lett. 1998, 249-250.
(b) Jeong, N.; Lee, S.; Sung, B. K. Organometallics 1998, 17, 3642-3644.
(c) Jeong, N.; Sung, B. K.; Choi, Y. K. J. Am. Chem. Soc. 2000, 122,
6771-6772. (d) Kobayashi, T.; Koga, Y.; Narasaka, K. J. Organomet.
Chem. 2001, 624, 73-87.
9
17760 J. AM. CHEM. SOC. VOL. 127, NO. 50, 2005

Carbotricyclization Reactions of Enediynes
A R T I C L E S
Table 3. SiCaT Reaction of Enediyne 7a
product ratiob
PhMe2SiH
temp
C)
CO
time
(h)
yield
(%)
entry
catalyst
(equiv)
solvent
(
°
(atm)
17a
18a
1
2
3
4
5
6
Rh(acac)(CO)2
Rh4(CO)12
Rh(acac)(CO)2
Rh(acac)(CO)2
Rh(acac)(CO)2
Rh(acac)(CO)2
1.0
1.0
0.3
0.1
0.3
THF
22
70
70
70
70
70
1
1
1
1
25
1
24
3
3
24
24
72
no reaction
toluene
toluene
toluene
toluene
toluene
50
96
90
67
100
50
34
0
50
low conversion
no reaction
none
Scheme 10
Table 4. Intramolecular [2+2+2+1] Cycloaddition of Enediyne 7a with CO
yield (%)a
catalyst
(mol %)
additive
(equiv)
concn
temp
C)
CO
time
entry
solvent
(M)
(
°
(atm)
(h)
8
17
1
2
3
4
5
6
7
8
9
Rh(acac)(CO)2 (5)
Rh(acac)(CO)2 (5)
[Rh(COD)Cl]2 (5)
[Rh(COD)Cl]2 (5)
[Rh(COD)Cl]2 (5)
[Rh(COD)Cl]2 (5)
[Rh(COD)Cl]2 (5)
[Rh(COD)Cl]2 (5)
[Rh(COD)Cl]2 (5)
[Rh(COD)Cl]2 (5)
[Rh(COD)Cl]2 (5)
[Rh(COD)Cl]2 (5)
[Rh(COD)Cl]2 (5)
[Rh(CO)2Cl]2 (5)
Co2(CO)8 (5)
PhMe2SiH (0.3)
none
PhMe2SiH (0.5)
none
none
none
none
none
none
none
none
none
none
none
mol sieves
none
none
toluene
toluene
toluene
toluene
DMF
EtOH
dioxane
CHCl3
Cl(CH2)2Cl
Cl(CH2)2Cl
toluene
Cl(CH2)2Cl
Cl(CH2)2Cl
Cl(CH2)2Cl
Cl(CH2)2Cl
toluene
0.015
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
70
50
70
50
50
50
50
50
50
50
50
50
50
50
65
90
90
1
1
1
1
1
1
1
1
1
1
1
4
25
1
1
1
1
3
24
24
24
24
24
24
20
20
13
16
48
48
24
13
16
16
0
49
0
77
0
0
56
41
77
88
80
66
38
64
0
96
20
70
15
38
21
25
55
15
<4
9
30
46
19
58
27
80
10b
11b
12b
13b
14b
15b
16b
17b
Rh(PPh3)3Cl (5)
Rh4(CO)12 (5)
19
0
toluene
a Isolated yields. b CO was bubbled into the solution.
inserts into the [M]-C bonds of B10, generating 5-7-5 tricyclic
metallacycle C10 or 5-7-6 tricyclic metallacycle D10. Reductive
elimination of C10 or D10 yields fused 5-6-5 tricyclic diene-
[M] complex E10. When there is sufficient hydrosilane in the
system, E10 reacts with the hydrosilane to form 17a and
regenerate the active catalyst species R3Si[Rh](H), and aroma-
tization via dehydrogenation competes to give 18a, generating
dihydro-[M] species. Then, the [M](H)2 species reacts with a
hydrosilane to liberate molecular hydrogen and regenerate the
active species R3Si[Rh](H).
The proposed mechanism accommodates the results listed in
Table 4 very well and explains why CO-SiCaT did not take
place for enediyne 7a. However, it looks possible that an
apparent CO-SiCaT product can be obtained from intermediate
C10 via CO insertion, whereas intermediate D10 would undergo
facile reductive elimination. The fact that no CO incorporation
took place in this reaction may suggest that this reaction
proceeds through D10 rather than through C10.
Intramolecular [2+2+2+1] Cycloaddition of Enediynes
with CO. A possible intermediacy of metallacycle C10 encour-
aged us to explore hitherto an unknown intramolecular
[2+2+2+1] cycloaddition route to fused 5-7-5 tricyclic systems.
The formation of metallacycles such as B10 from 1,6-diynes is
a rather common reaction pathway in carbocyclizations.2 Ac-
cordingly, we set out to search for reaction conditions and
variables, which might promote the novel intramolecular
[2+2+2+1] cycloaddition of enediyne 7 with carbon monoxide.
Gratifyingly, we quickly found that the desired fused 5-7-5
tricyclic product 8 was formed through the novel [2+2+2+1]
cycloaddition in the absence of hydrosilane, although the
reaction was accompanied by intramolecular [2+2+2] cycload-
dition product 17 (Scheme 11). Thus, we immediately carried
9
J. AM. CHEM. SOC. VOL. 127, NO. 50, 2005 17761

A R T I C L E S
Scheme 11
Bennacer et al.
catalyst than Rh(PPh3)3Cl, although the efficacy was consider-
ably lower than that of [Rh(COD)Cl]2.
A. Scope of the Enediyne Substrates for the [2+2+2+1]
Cycloaddition Process. Next, a variety of 1-substituted dodec-
11-ene-1,6-diynes were employed to examine the scope of this
reaction, especially for its functional group tolerance. Various
enediynes 7 containing ether, sulfonamide, carbamate, ester, and
ketal groups were examined. In addition, enediynes 7 bearing
a methyl, phenyl, or TMS as the substituent of the terminal
acetylene moiety were employed as well. Results are sum-
marized in Table 5. These functional groups and heteroatoms
are generally well tolerated in this process, affording the
corresponding 8b-n in good to excellent yields. For the
substrates 7d (entry 4), 7h (entry 8), 7i-l (entries 9-12), and
7n (entry 14), [2+2+2+1] adducts 8d, 8h, 8i-l, and 8n are
the exclusive products, respectively. The reactions of 7e-g
having a p-toluenesulfonamide moiety gave 8e-g as predomi-
nant products accompanied by 17e-g as minor products (entries
5-7), and the reaction of 7h bearing a t-Boc-amino moiety
afforded 8h exclusively (entry 8). The reaction of 8m (R )
Ph) gave a ca. 2:1 mixture of 8m (major) and 17m (minor),
and that of 7n (R ) TMS) yielded 8n as the sole product.
Although Cl(CH2)2Cl is the preferred solvent in most cases, the
use of toluene gave better selectivity in some cases. For example,
the reaction of 7j in Cl(CH2)2Cl gave 8j in 75% isolated yield,
but the yield of 8j was improved to 91% (86% isolated yield)
when the solvent was changed to toluene (entry 10). A more
drastic solvent effect was observed in the reaction of 7m. The
reaction in Cl(CH2)2Cl gave 8m in only 27% yield (17m: 61%
yield), and the same reaction in toluene reversed the product
selectivity, affording 8m and 17m in 56% and 28% isolated
yields, respectively (entry 13). Apparently, the use of toluene
in these cases favored the CO insertion process.
out optimization of this new higher-order cycloaddition process.
Results are summarized in Table 4.
As Table 4 shows, the attempted CO-SiCaT reaction of 7
in the presence of PhMe2SiH catalyzed by Rh(acac)(CO)2 or
[Rh(COD)Cl]2 (entries 1 and 3) failed to give 8 but yielded the
5-6-5 fused-ring product 17 exclusively in 70% and 96% isolated
yields, respectively. Under the same conditions but without
hydrosilane (entries 2 and 4), 8 was formed in 49% yield using
Rh(acac)(CO)2 as the catalyst and in 77% yield when [Rh-
(COD)Cl]2 was used as the catalyst. These sharply contrasting
results in the presence and absence of hydrosilane clearly
indicate that the CO-SiCaT and intramolecular [2+2+2+1]
cycloaddition processes are fundamentally different, although
the same type of product is formed. Because [Rh(COD)Cl]2 was
a better catalyst than Rh(acac)(CO)2, we used this catalyst for
further optimization. We examined [Rh(COD)Cl]2 as a poten-
tially efficient catalyst for this novel [2+2+2+1] cycloaddition
with CO because it has been shown that [Rh(COD)Cl]2 is an
efficient catalyst for the catalytic Pauson-Khand reactions of
enynes.24 We looked at the possible effects of concentration by
employing 0.015, 0.1, and 0.4 M concentrations and found that
0.1 M was the best substrate concentration, and either lower or
higher concentrations decreased the yield and product selectivity
of 8. As for the solvent for this reaction, DMF and EtOH (entries
7 and 8) yielded only 17. The use of dioxane and chloroform
gave a mixture of 8 and 17 (entries 5 and 6). Other solvents
such as THF, dimethoxyethane, and dibutyl ether were also
examined at different temperatures, but the product selectivity
for 8 was more or less in the same range. Accordingly, toluene
(entry 4) and dichloroethane (entry 9) gave, so far, the best yield
and selectivity for 8 (92% yield and 77% selectivity). However,
we found that the bubbling of CO gas into the reaction mixture
dramatically increased the selectivity for the formation of 8;
i.e., the reaction gave 8 in 88% isolated yield with less than
4% of the side product 17 (entry 10). This protocol was also
effective for the reaction in toluene, giving 8 in 80% isolated
yield accompanied by a small amount of 17 (9%). Interestingly,
the reactions at higher CO pressures disfavored the formation
of carbonylative product 8 (entries 12 and 13). Next, we
screened other catalysts for this reaction. The reaction using
Co2(CO)8 in the presence of molecular sieves (entry 22) or Rh4-
(CO)12 (entry 24) as the catalyst yielded 17 exclusively. Also,
the reaction catalyzed by Co2(CO)8-P(OPh)3 or [Ir(COD)Cl]2
gave only 17. Other catalysts, [Rh(dppp)(CO)Cl]2, [Cp*RhCl2]2,
[Rh(COD)2]SbF6, and Rh(PPh3)3Cl/AgSbF6, strongly favored
the formation of 17 accompanied by a minute amount of 8. The
use of [Rh(CO)2Cl]2 (entry 14) and Rh(PPh3)3Cl (entry 16) gave
a mixture of 8 and 17; however, [Rh(CO)2Cl]2 was a much better
When a 3-pyridinyl group was introduced to the 1 position,
no reaction took place and the starting material 7o was recovered
intact. No reaction occurred with substrate 7q, either. A free
hydroxyl group in the substrate 7p was not tolerated in this
reaction, resulting in very messy mixtures without a trace of
8p or 17p. Accordingly, these enediyne substrates set a
limitation in the scope of the Rh-catalyzed [2+2+2+1] cy-
cloaddition process. However, it should be noted that 7o did
undergo the SiCaT reaction (see Scheme 10) to give 17o in
88% isolated yield, as shown in Scheme 12.
B. Mechanism of Intramolecular [2+2+2+1] Cycloaddi-
tion. A proposed mechanism of the novel intramolecular
[2+2+2+1] cycloaddition reaction is illustrated in Scheme 13.
This reaction is believed to proceed through a series of
metallacycles. The proposed mechanism includes (i) selective
9
17762 J. AM. CHEM. SOC. VOL. 127, NO. 50, 2005

Carbotricyclization Reactions of Enediynes
A R T I C L E S
Table 5. Rh-Catalyzed Intramolecular [2+2+2+1] Cycloaddition of Enediynes 7 with CO
a All reactions were run with 50-100 mg of enediyne (C ) 0.1 M) and 5 mol % of [Rh(COD)Cl]2 under CO (1 atm). b 1H NMR yields using mesitylene
as the internal standard. c Isolated yields based on an average of two runs. d Reaction was run with 2.5 mol % of [Rh(COD)Cl]2.
coordination of the diyne moiety of enediyne 7 to the active
Rh-catalyst species, forming metallacycle A13 ([2+2+M]); (ii)
insertion of the olefin moiety of 7 into the Rh-C bond to form
5-7-5 fused tricyclic rhodacycle B13 ([2+2+2+M]); (iii) coor-
dination of CO to the [Rh] metal followed by migratory insertion
of CO into the Rh-C bond to form 5-8-5 rhodacycle C13 or
D13 ([2+2+2+1+M]); and (iv) reductive elimination to form
[2+2+2+1] cycloadduct 8 and regenerate the active Rh-catalyst
species. Reductive elimination from the 5-7-5 rhodacycle B13,
prior to the CO insertion, gives [2+2+2] cycloadduct 17.
C. Characteristics of the CO-SiCaT and [2+2+2+1]
Cycloaddition Reactions. As discussed above, we have dis-
9
J. AM. CHEM. SOC. VOL. 127, NO. 50, 2005 17763

A R T I C L E S
Scheme 12
Bennacer et al.
Scheme 14
Scheme 13. Proposed Mechanism of Intramolecular [2+2+2+1]
Cycloaddition
catalyst system than [Rh(COD)Cl]2 in toluene (toluene is the
best solvent for this catalyst). In the absence of PhMe2SiH,
otherwise under the same conditions, no reaction took place at
all and 5a was recovered intact (entries 2 and 4). Thus, it is
very clear that the CO-SiCaT reaction requires the hydrosilane.
Also, it should be pointed out that the CO-SiCaT reaction
proceeds smoothly at ambient temperature. In sharp contrast,
the [2+2+2+1] cycloaddition of 5a requires a much higher
concentration (0.1 M) and 50 °C to proceed. Also, the reaction
gives a mixture of 6a (major) and 17a(H) (minor) (entries 6
and 7). A marked difference in the catalytic activity and
selectivity was observed between [Rh(COD)Cl]2 and Rh(acac)-
(CO)2; i.e., the reaction catalyzed by Rh(acac)(CO)2 needed 90
°C to proceed and resulted in the exclusive formation of 17a-
(H) with no trace of 6a (entry 5).
Scheme 15 summarizes the differences and complementary
nature of the CO-SiCaT and [2+2+2+1] cycloaddition reac-
tions. It is confirmed that the mechanisms of these two reactions
are fundamentally different. The CO-SiCaT reaction takes place
only with 1-terminal free enediynes 5 through silicon-initiative
cascade carbocyclization processes. On the other hand, the
[2+2+2+1] cycloaddition reaction proceeds with 1-substituted
and unsubstituted enediynes 7a and 5 through sequential
metallacycle formations.
The fact that only fairly good product selectivity was observed
for this enediyne substrate under the standard conditions for
the [2+2+2+1] cycloaddition reaction suggests that the ene-
diynes bearing a free acetylene moiety are not good substrates
for this reaction because the reactions with 1-methyl enediyne
7a gave much better results (see Table 6, entry 1). In fact, the
reactions of two other 1-terminus free enediynes, 5b and 5d,
showed the same tendency (Scheme 16). The reaction of 5b
under the standard [2+2+2+1] cycloaddition conditions pro-
ceeded slowly to give 6b in 51% isolated yield after 3 days at
50 °C. The CO-SiCaC reaction of 5b gave 6b in 91% isolated
yield after 24 h at 22 °C (see Table 2, entry 2). In a similar
manner, the [2+2+2+1] cycloaddition of 5d afforded 6d in
52% isolated yield after 24 h at 50 °C, and the CO-SiCaT
reaction of 5d gave 6d in 84% isolated yield after 24 h at 22
°C (see Table 2, entry 4).
covered two different reactions that give fused 5-7-5 tricyclic
products, incorporating carbon monoxide. Although these two
reactions yield the same type of products, the mechanisms of
these reactions are fundamentally different; i.e., the CO-SiCaT
reaction proceeds through sequential carbocyclizations (Scheme
6), and the [2+2+2+1] cycloaddition reaction involves se-
quential metallacycle formations (Scheme 13). We have shown
above a number of compelling cases in which two reaction
conditions gave markedly different outcomes. However, those
differences were observed for the reactions of enediynes 7
bearing a substituent at the terminal acetylene moiety, wherein
the CO-SiCaT reaction did not take place and in most cases
the SiCaT reaction occurred to afford the corresponding fused
5-6-5 tricyclic products 17 and/or 18. Accordingly, a natural
question arises; i.e., what will happen when enediynes do not
have a substituent at the terminal acetylene moiety for which
the CO-SiCaT has taken place? To answer this question and
to confirm the fundamental difference between the CO-SiCaT
and [2+2+2+1] reactions, we looked at the reactions of
enediyne 5a under the optimized reaction conditions of these
two processes (Scheme 14). Results are summarized in Table
6.
As Table 6 shows, the CO-SiCaT reaction of 5a was carried
out with PhMe2SiH (0.5 equiv) at ambient temperature and
pressure of CO in THF or toluene in high dilution (0.015 M)
for 24 h using Rh(acac)(CO)2 or [Rh(COD)Cl]2 as the catalyst
(entries 1 and 3), whereas the [2+2+2+1] reaction of 5a was
performed at 50 °C and ambient pressure of CO in toluene or
dichloroethane at 0.1 M concentration for 24 h using [Rh(COD)-
Cl]2 as the catalyst (entries 6 and 7). The CO-SiCaT reaction
of 5a gave 6a as the exclusive product without any trace of
17a(H) (entries 1 and 3), and Rh(acac)(CO)2 in THF is a better
Rh-Catalyzed Tricyclizations of Related Substrates. We
also investigated the extension of the CO-SiCaT and [2+2+2+1]
cycloaddition reactions of enediynes to related substrates, i.e.,
allenediyne 19 and diynals 21a,b. The attempted [2+2+2+1]
cycloaddition of allenediyne 19 catalyzed by [Rh(COD)Cl]2
under the standard conditions afforded the fused 5-6-6 tricyclic
product 20 exclusively in 97% isolated yield (>98% yield by
1H NMR) through [2+2+2] cycloaddition (Scheme 17). To the
best of our knowledge, this presents the first example of
9
17764 J. AM. CHEM. SOC. VOL. 127, NO. 50, 2005

Carbotricyclization Reactions of Enediynes
A R T I C L E S
Table 6. Comparison between the CO-SiCaT and [2+2+2+1] Cycloaddition Reactions
yield (%)a
catalyst
(mol %)
silane
concn
(M)
temp
C)
entry
(equiv)
solvent
(
°
6a
17a(H)
1
2
3
4
5
6
7
Rh(acac)(CO)2 (1)
Rh(acac)(CO)2 (1)
[Rh(COD)Cl]2 (5)
[Rh(COD)Cl]2 (5)
Rh(acac)(CO)2 (1)
[Rh(COD)Cl]2 (5)
[Rh(COD)Cl]2 (5)
PhMe2SiH (0.5)
none
PhMe2SiH (0.5)
none
none
none
THF
THF
0.015
0.015
0.015
0.015
0.1
rt
rt
rt
rt
90
50
50
92
0
no reaction
toluene
toluene
toluene
toluene
Cl(CH2)2Cl
72
0
no reaction
0
66
73
47
30
16
0.1
0.1
none
a Isolated yields.
Scheme 15
Scheme 16
Scheme 17
A. Reactions of Diynals under CO-SiCaT and [2+2+2+1]
Cycloaddition Conditions. The reaction of undeca-5,10-diyn-
1-al (21a) catalyzed by Rh(acac)(CO)2 (1 mol %) under the
CO-SiCaT conditions with PhMe2SiH (1 equiv) at high dilution
(0.015 M) in THF at 50 °C for 24 h failed to give any CO-
SiCaT or SiCaT product but gave the corresponding bicycliza-
tion product 22 in 45% isolated yield. The formation of 22, as
the sole product, was improved to 81% isolated yield at a higher
concentration (0.1 M) in toluene (Scheme 18). When the same
reaction was run in toluene, otherwise under the same conditions,
a mixture of 22 (36%) and deoxygenated bicyclization product
intramolecular [2+2+2] cycloaddition of allenediyne, and
further studies on this novel reaction are actively underway in
these laboratories.
9
J. AM. CHEM. SOC. VOL. 127, NO. 50, 2005 17765

A R T I C L E S
Scheme 18
Bennacer et al.
Scheme 20
Scheme 21
Scheme 19
The preferential formations of 25b and 26b indicate that the
two endo-double-bond system is substantially more favorable
than the two exo-double-bond system. In fact, the tricyclization
reaction of 21a, which does not have a methyl substituent at
the terminal acetylene moiety, at 60 °C for 68 h gave fused
5-7-5 tricyclic lactone 25a (major) and 26a (minor); i.e., the
kinetic product 24a was not isolated at all in this reaction
(Scheme 21).
The overall results on the reactions of diynals 21 show that
the intramolecular tricyclization involving diyne and aldehyde
components is ready to occur by the catalysis of [Rh(COD)-
Cl]2, and the novel [2+2+2+1] cycloaddition of diynal with
CO was achieved for the first time. However, the [2+2+2+1]
cycloaddition and [2+2+2] cycloaddition processes are compet-
ing. Thus, further optimization of the [2+2+2+1] cycloaddition
process is necessary for this reaction to be synthetically useful.
Nevertheless, it is worth mentioning that unique fused 5-7-5
tricyclic lactones 25 can be obtained in fairly good isolated
yields even at this discovery stage. Further studies on this novel
higher-order cycloaddition reaction are actively underway in
these laboratories.
In summary, we reported here the full account of the novel
silicon-initiated carbonylative carbotricyclization (CO-SiCaT)
as well as higher-order [2+2+2+1] cycloaddition reactions of
enediynes with CO catalyzed by rhodium complexes. The most
plausible mechanisms for these two reactions, which are
fundamentally different from each other, were proposed and
discussed. Another mechanism for the formation of fused 5-6-5
tricyclic products from 1-substituted enediynes under CO-
SiCaT conditions was proposed. The scope and limitations of
these unique processes were described. These newly discovered
reactions allow us to construct multiple bonds all at once,
converting linear starting materials to polycyclic compounds
in one single step. Thus, these new processes have high synthetic
potential to provide innovative routes to appropriately func-
tionalized polycyclic intermediates for the syntheses of natural
and unnatural products of medicinal and/or biological interests.
23 (48%) was isolated (Scheme 18). The use of higher CO
pressure (20 atm) only slowed the reaction, forming 22, in
toluene.
Because the diynal 21a did not seem to be suitable for the
CO-SiCaT reaction, we examined the [2+2+2+1] cycload-
dition conditions. The metal-catalyzed cycloaddition of an
aldehyde to diynes has not been extensively studied. Thus, only
a few successful examples have been reported for the intermo-
lecular [2+2+2] cycloadditions of 1,7-diynes (no free terminal
acetylene moieties) with aldehydes catalyzed by Ni(COD)2-
PR3 (R ) Bu or Cy). However, no intramolecular version has
been reported to date.25 The reaction of dodeca-5,10-diyn-1-al
(21b) was carried out with [Rh(COD)Cl]2 (5 mol %) at 50 °C
and ambient pressure of CO in toluene (0.1 M) for 24 h. The
reaction gave the corresponding [2+2+2+1] cycloaddition
products 24b and 25b (65% combined yield) as well as an
interesting acetylbis(cyclopentenyl) 26b (33%) in nearly quan-
titative overall yield (Scheme 19). On monitoring the reaction,
it was found that fused 5-7-5 tricyclic lactone 24b was the
kinetic product. Thus, only 24b and 26b were formed in the
early stage of the reaction. The clean and complete isomerization
of 24b-25b was observed by leaving a mixture of 24b and
25b in CDCl3 in an NMR tube at ambient temperature for two
weeks. The formation of acetylbis(cyclopentenyl) 26b can be
readily explained by assuming the intermediacy of [2+2+2]
cycloadduct A20, which underwent an electrocyclic ring opening
of the central pyrane moiety to form the bicyclic dienone
structure of 26b (Scheme 20).
(25) Tsuda, T.; Kiyoi, T.; Miyane, T.; Saegusa, T. J. Am. Chem. Soc. 1988,
110, 8570-8572.
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17766 J. AM. CHEM. SOC. VOL. 127, NO. 50, 2005

Carbotricyclization Reactions of Enediynes
A R T I C L E S
was bubbled into the solution at room temperature. After 15 min, [Rh-
(COD)Cl]2 (5.3 mg, 0.0108 mmol, 5 mol %) was added under CO and
the resulting mixture was stirred at room temperature for an additional
5 min. Then, the reaction mixture was heated to 50 °C with stirring
and kept for 16 h under CO (ambient pressure, bubbled into the
solution). All volatiles were removed from the reaction mixture under
reduced pressure, and the crude product was purified by flash
chromatography on silica gel (EtOAc/hexanes ) 1:9-3:7) affording
8a as a light yellow oil (92.5% yield by 1H NMR; 93 mg, 88% isolated
We also reported the first examples of intramolecular tricy-
clization of diynals, including the formation of fused 5-7-5
tricyclic lactones through [2+2+2+1] cycloaddition with CO
as one carbon unit. In addition, the first [2+2+2] cycloaddition
of an allenediyne, yielding the corresponding fused 5-6-6
tricyclic product was reported. These novel polycyclization
processes clearly warrant further investigations.
Experimental Section
1
yield) and 17a as a colorless oil (5.5% yield by H NMR; <4 mg,
General Method and Materials. See Supporting Information.
General Procedure for the Catalytic CO-SiCaT Reaction. A
typical procedure is described for the reaction of 4,4,9,9-tetra-
(carbethoxy)dodec-11-ene-1,6-diyne (5a). A reaction vessel equipped
with a stirring bar and a CO inlet was charged with Rh(acac)(CO)2
(0.6 mg, 1 mol %). After purging the reaction vessel with CO, THF
(14.6 mL) was added to dissolve the catalyst. Dimethylphenylsilane
(38 µL, 0.5 equiv) was then added, and the mixture was stirred at 22
°C. After 1 min, a solution of substrate 5a (112 mg, 0.25 mmol) in
THF (2 mL) was added, and the reaction mixture was stirred under
CO (1 atm) for 30 h. All volatiles were removed under reduced pressure.
The crude products were purified by column chromatography on silica
gel using hexanes/EtOAc (5:1) as eluent to give 2,2,8,8-tetra(carbe-
thoxy)-5-oxo-1,3a,4,5,7,9-hexahydro-3H-cyclopenta[e]azulene (6a) as
a colorless oil (109 mg, 92%): TLC (SiO2, hexanes/EtOAc ) 5:1, Rf
) 0.17); 1H NMR (300 MHz, CDCl3) δ 1.24 (t, 6 H, J ) 7.2 Hz), 1.25
(t, 6 H, J ) 7.2 Hz), 1.96 (dd, 1 H, J ) 11.7 Hz/J ) 12.9 Hz), 2.51
(bd, 1 H, J ) 12.9 Hz), 2.72 (m, 3 H), 3.01(m, 1 H), 3.13 (m, 4 H),
3.25 (dd, 1 H, J ) 2.1 Hz/J ) 17.4 Hz), 4.19 (q, 4 H, J ) 7.2 Hz),
4.20 (q, 4 H, J ) 7.2 Hz), 6.03 (s, 1 H); 13C NMR (75 MHz, CDCl3)
δ 13.90 (2C), 13.9 (2C), 37.7, 39.5, 40.5, 41.0, 43.6, 44.7, 57.5, 58.8,
61.7, 61.8, 61.8 (2C), 124.0, 129.4, 150.1, 154.1, 170.4, 170.6, 170.7
(2C), 197.5; IR (neat, cm-1) 2981 (m), 2938 (w), 1731 (s), 1646 (s),
1603 (w), 1465 (w), 1447 (m), 1366 (m), 1288 (s), 1252 (s), 1193 (s),
1159 (s), 1099 (m), 1070 (s), 1018 (m), 861 (w); HRMS (FAB) m/z
calcd for C25H33O9 (M + 1)+ 477.2125, found 477.2124 (∆ ) -0.2
ppm).
<4% isolated yield).
6-Methyl-2,2,8,8-tetra(carbethoxy)-5-oxo-1,3a,4,5,7,9-hexahydro-
3H-cyclopenta[e]azulene (8a): colorless oil; TLC (SiO2, EtOAc/
hexanes ) 1:4, Rf ) 0.30); 1H NMR (400 MHz, CDCl3) δ 1.25 (m, 12
H), 1.90 (s, 3 H), 1.96 (m, 1 H), 2.61-3.20 (m, 10 H), 4.22 (m, 8 H);
13C NMR (100 MHz, CDCl3) δ 14.0, 15.8, 37.4, 39.9, 40.3, 40.9, 42.4,
45.7, 56.9, 59.1, 61.7, 129.7, 130.8, 147.3, 149.5, 170.7, 170.8, 170.9,
171.0, 197.3; IR (neat, cm-1) 2910 (s), 1731 (s), 1644 (s), 1367 (m),
1289 (m), 1068 (m); HRMS (EI) m/z calcd for C26H34O9 (M+) 490.2203,
found 490.2205 (∆ ) 0.4 ppm).
5-Methyl-2,2,7,7-tetra(carbethoxy)-1,3,3a,4,6,8-hexahydro-as-in-
dacene (17a): colorless oil; TLC (SiO2, EtOAc/hexanes ) 1:4, Rf )
1
0.56); H NMR (400 MHz, CDCl3) δ 1.22 (m, 12 H), 1.70 (s, 3 H),
1.82 (m, 1 H), 1.84 (m, 1 H), 2.13 (m, 1 H), 2.60-3.07 (m, 8 H), 4.18
(m, 8 H); 13C NMR (100 MHz, CDCl3) δ 13.9, 14.0, 19.4, 35.9, 36.1,
36.7, 36.8, 39.7, 41.3, 59.4, 59.7, 61.4, 123.5, 128.2, 128.9, 131.1, 171.6,
171.7, 171.9; HRMS (EI) m/z calcd for C25H35O8 (M + H)+ 463.2332,
found 463.2325 (∆ ) -1.5 ppm).
For other reactions and their products, see Supporting Information.
Acknowledgment. This research was supported by grants
from the National Institutes of Health (NIGMS) and the National
Science Foundation. Generous support from Mitsubishi Chemi-
cal Corporation is gratefully acknowledged.
Supporting Information Available: Experimental procedures
and complete characterization data for all new substrates and
products. This material is available free of charge via the Internet
at http://pubs.acs.org.
General Procedure for the [2+2+2+1] Cycloaddition Reaction.
A typical procedure is described for the reaction of enediyne 7a. All
other reactions are run following the same procedure unless otherwise
noted. Enediyne 7a (100 mg, 0.216 mmol) was introduced to a Schlenck
tube, followed by Cl(CH2)2Cl (2.16 mL) under argon, and then CO
JA054221M
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J. AM. CHEM. SOC. VOL. 127, NO. 50, 2005 17767