Diastereoselective intramolecular temporary silicon-tethered rhodium-catalyzed [4+2+2] cycloisomerization reactions: Regiospecific incorporation of substituted 1,3-butadienes

Article abstract of DOI:10.1021/ja046030+

Transition metal-catalyzed carbocyclization reactions represent powerful methods for the construction of complex polycyclic systems. We have developed a regiospecific and diastereoselective intramolecular temporary silicon-tethered rhodium-catalyzed [4+2+

Full text of DOI:10.1021/ja046030+

Published on Web 08/21/2004
Diastereoselective Intramolecular Temporary Silicon-Tethered
Rhodium-Catalyzed [4+2+2] Cycloisomerization Reactions: Regiospecific
Incorporation of Substituted 1,3-Butadienes
P. Andrew Evans* and Erich W. Baum
Department of Chemistry, Indiana UniVersity, Bloomington, Indiana 47405
Received July 3, 2004; E-mail: paevans@indiana.edu
We recently reported the intermolecular rhodium-catalyzed
[4+2+2] carbocyclization for a series of heteroatom-tethered
1,6-enynes with 1,3-butadiene to afford eight-membered rings.1-4
Additional studies aimed at broadening the scope of this reaction
demonstrated that substituted dienes either were unreactive or
afforded mixtures of regioisomers.5 Hence, we envisioned that
tethering the diene to the 1,6-enyne, thereby rendering the process
intramolecular, would circumvent problems associated with low
reactivity and poor regioselectivity. Herein, we now describe the
development of a regiospecific and diastereoselective intramolecular
temporary silicon-tethered (TST) rhodium-catalyzed [4+2+2]
cycloisomerization reaction of 1,6-enynes (E)- and (Z)-1 for the
construction of tricyclic octanoids 2a and 3a, respectively
(Scheme 1).
(where X ) NTs, R ) H)11 using the reaction conditions success-
fully employed for the intermolecular reaction, led to the formation
of a complex reaction mixture (entry 1),1 as did the rhodium-N-
heterocyclic carbene catalyst (entry 2).12 It is well-established that
the counterion of the silver salt additive is often highly significant
in modifying the properties of the active catalytic species to thereby
facilitate the requisite carbocyclization reaction. Interestingly, the
hexafluoroantimonate counterion proved optimum in this regard,
which is orthogonal to the trend observed for the intermolecular
reaction (entry 3).1 To further improve the efficiency and obviate
the necessity for an in situ modification of the precatalyst, we
elected to examine the Wender catalyst ([(COD)Rh(Np)]SbF6).13
Although this catalyst initially afforded only modest improvement
(entry 4), the efficiency could be dramatically improved using the
more coordinating solvent, acetonitrile (entry 5).
Scheme 1
Table 1. Optimization of the Temporary Silicon-Tethered
Rhodium-Catalyzed [4+2+2] Cycloisomerization Reaction
(Scheme 1; (Z)-1 Where X ) NTs, R ) H)a
dsd
3a/3b
yielde
(%)
c
entry
catalystb
additive
solvent
1
2
3
4
5
RhCl(PPh3)3
RhCl(IMes)(COD)
“
[(COD)Rh(Np)]SbF6
[(COD)Rh(Np)]SbF6
AgOTf
PhMe
“
“
“
0
0
18
30
60
“
AgSbF6
-
g19:1
g19:1
g19:1
-
MeCN
a All reactions were carried out on a 0.25 mmol reaction scale at 110 °C
(0.08 M). b 20 mol %. c 2 equiv of AgX relative to the metal. d Diastereo-
selectivity (ds) was determined by 400 MHz NMR on the crude reaction
mixtures. e Isolated yields.
Since the seminal work of Nishiyama6 and Stork7 on the use of
“temporary silicon tethers” (TST) in free radical cyclization
reactions, this strategy has been employed extensively in target
directed synthesis.8 The most attractive features of the TST strategy
are (i) the reactive components are generally easily tethered, (ii)
the tethers provide intramolecularity, which render the processes
regiospecific and stereoselective, and (iii) the tethers incorporate
latent functionality that can be further manipulated. Despite the
multitude of transformations that have successfully employed a
temporary silicon tether, there remains a paucity of metal-catalyzed
carbocyclization reactions employing this strategy.9 Nonetheless,
we anticipated that application of the TST approach to the rhodium-
catalyzed [4+2+2] carbocyclization reaction would provide rapid
entry into various polycyclic octanoid derivatives having latent
functionality necessary for further synthetic manipulation. More-
over, the inability to incorporate carbon tethers in the intermolecular
reaction manifold prompted the reexamination of this tether in the
context of the present reaction, Viz. intramolecularity of the
π-components. Hence, it was expected that the competing ene-
cycloisomerization observed in the intermolecular reaction with
carbon-tethered 1,6-enynes would be minimized.10
Table 2 summarizes the scope of the intramolecular rhodium-
catalyzed [4+2+2] cycloisomerization reaction. This study dem-
onstrated that nitrogen and oxygen tethers could be utilized (entries
1-8); however, the sulfone tethers (where X ) SO2), which were
utilized in the intermolecular reaction, proved unsuitable for this
particular transformation. Interestingly, not only were the carbon-
tethered enynes effective substrates, but they proved to be the most
efficient tethers examined (entries 9-12). This reaction also
proceeds efficiently with 1,3-disubstituted dienes, thereby circum-
venting the regiochemical problems associated with the intermo-
lecular version (entries 2, 4, 6, etc.).5 The ability to vary the olefin
geometry results in complementary diastereoinduction, in which
the (E)- and (Z)-olefins are stereospecifically incorporated, to afford
the tricyclic octanoids 2a and 3a with excellent selectivity (entries
1-12). Furthermore, the (E)-isomers are superior substrates in terms
of efficiency in the cycloisomerization, as compared to their (Z)-
counterparts (entries 1/2 vs 3/4, etc.). OVerall, this method
represents one of the most Versatile cycloisomerization reactions
deVeloped to date.
Preliminary studies tested the validity of this hypothesis, as
outlined in Table 1. Attempted cycloisomerization of enyne (Z)-1
The stereospecificity with respect to the olefin geometry is in
agreement with the model outlined in Figure 1. Initial complexation
9
11150
J. AM. CHEM. SOC. 2004, 126, 11150-11151
10.1021/ja046030+ CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Scope of the Regio- and Diastereoselective TST
Rhodium-Catalyzed [4+2+2] Cycloisomerization with Various
Carbon- and Heteroatom-Tethered 1,6-Enynesa
Pharmaceuticals for the CreatiVity in Organic Chemistry Award
(P.A.E.). Roche Pharmaceuticals is kindly acknowledged for an
Excellence in Chemistry Award (E.W.B.).
1,6-enyne 1
Supporting Information Available: Experimental procedures,
X-ray crystallographic analysis of 2a and 3a (where X ) NTs, R )
Me), and spectral data for (E)- and (Z)-1, 2a, and 3a. This material is
available free of charge via the Internet at http://pubs.acs.org.
entry
X
E/Z
R
dsb,c
yield (%)d
1
2
3
4
5
6
7
8
9
NTs
“
“
“
O
“
“
“
E
“
Z
“
E
“
Z
“
E
“
Z
“
H
Me
H
Me
H
Me
H
Me
H
2a
“
3a
“
2a
“
3a
“
2a
“
3a
“
g19:1
g19:1
g19:1
g19:1
g19:1
g19:1
g19:1
g19:1
g19:1
g19:1
g19:1
g19:1
75
85
60
71
73
85
39
44
86
88
71
74
References
(1) (a) Evans, P. A.; Robinson, J. E.; Baum, E. W.; Fazal, A. N. J. Am. Chem.
Soc. 2002, 124, 8782. (b) Evans, P. A.; Robinson, J. E.; Baum, E. W.;
Fazal, A. N. J. Am. Chem. Soc. 2003, 125, 14648.
(2) For another example of a rhodium-catalyzed [4+2+2] carbocyclization
reaction, see: Gilbertson, S. R.; DeBoef, B. J. Am. Chem. Soc. 2002,
124, 8784.
(3) For related metal-catalyzed [4+2+2] carbocyclization reactions, see: (a)
Greco, A.; Carbonaro, A.; Dall’Asta, G. J. Org. Chem. 1970, 35, 271. (b)
Carbonaro, A.; Cambisi, F.; Dall’Asta, G. J. Org. Chem. 1971, 36, 1443.
(c) Lyons, J. E.; Myers, H. K.; Schneider, A. Ann. N.Y. Acad. Sci. 1980,
333, 273. (d) Lautens, M.; Tam, W.; Lautens, J. C.; Edwards, L. G.;
Crudden, C. M.; Smith, A. C. J. Am. Chem. Soc. 1995, 117, 6863. (e)
Varela, J. A.; Castedo, L.; Saa´, C. Org. Lett. 2003, 5, 2841.
(4) For examples of other rhodium-catalyzed carbocyclization reactions leading
to eight-membered rings, see: (a) [6+2]: Wender, P. A.; Correa, A. G.;
Sato, Y.; Sun, R. J. Am. Chem. Soc. 2000, 122, 7815. (b) [5+2+1]:
Wender, P. A.; Gamber, G. G.; Hubbard, R. D.; Zhang, L. J. Am. Chem.
Soc. 2002, 124, 2876.
C(CO2Et)2
10
11
12
“
“
“
Me
H
Me
a All reactions (0.25 mmol) were carried using 20 mol % [(COD)-
Rh(Np)]SbF6 in MeCN at 110 °C (0.08 M). b Diastereoselectivity (ds) was
determined by 400 MHz NMR on the crude reaction mixtures. c The relative
configuration of 2a and 3a (where X ) NTs, R ) Me) was proven by
1
X-ray crystallography and related by analogy to the H NMR of the other
tethers. d Isolated yields.
(5) Treatment of the 1,6-enyne i with piperylene iia gave no reaction, whereas
isoprene iib afforded the cycloadducts iii/iv in 60% yield, as a 1:1 mixture
of regioisomers.
(6) Nishiyama, H.; Kitajima, T.; Matsumoto, M.; Itoh, K. J. Org. Chem. 1984,
49, 2298.
(7) Stork, G.; Kahn, M. J. Am. Chem. Soc. 1985, 107, 500.
(8) For recent reviews on TST strategies, see: (a) White, J. D.; Carter, R. G.
In Science of Synthesis: Houben-Weyl Methods of Molecular Transforma-
tions; Fleming, I., Ed.; Georg Thieme Verlag: New York, 2001; Vol. 4,
pp 371-412. (b) Skrydstrup, M. In Science of Synthesis: Houben-Weyl
Methods of Molecular Transformations; Fleming, I., Ed.; Georg Thieme
Verlag: New York, 2001; Vol. 4, pp 439-530 and pertinent references
therein.
(9) For examples of metal-mediated and metal-catalyzed TST carbocyclization
reactions, see: (a) Kagoshima, H.; Hayashi, M.; Yukihiko, H.; Saigo, K.
Organometallics 1996, 15, 5439. (b) Brummond, K. M.; Sill, P. C.;
Rickards, B.; Geib, S. J. Tetrahedron Lett. 2002, 43, 3735 and references
therein.
(10) For an example of an ene-cycloisomerization and the consequence of olefin
geometry, see: Cao, P.; Wang, B.; Zhang, X. J. Am. Chem. Soc. 2000,
122, 6490.
(11) The 1,6-enyne (Z)-1 (where X ) NTs, R ) H) was prepared using the
three-step protocol outlined below. Mitsunobu coupling of the allylic
alcohol 5 with the propargyl sulfonamide 4 furnished the allylic sulfona-
mide 6. The tert-butyldimethylsilyl ether 6 was deprotected, and the
primary alcohol coupled with the diene 7 to afford (Z)-1 in 87% overall
yield (3 steps).
Figure 1. Proposed transition structures for the observed diastereoselectivity
in the [4+2+2] with 1,6-enynes (E)- and (Z)-1.
and subsequent isomerization of the (E)- and (Z)-enynes 1 presum-
ably result in the formation of the requisite metallacyclopentenes.
The diastereoselectivity observed in the resulting intramolecular
rhodium-catalyzed [4+2+2] cycloisomerization is consistent with
the identical orientation of the diene in both cases. This preference
can be attributed to a nonbonding interaction between one of the
isopropyl groups on silicon and the C-2 proton on the 1,3-butadiene
derivative.14
In conclusion, we have developed a regiospecific and diastereo-
selective intramolecular temporary silicon-tethered rhodium-
catalyzed [4+2+2] cycloisomerization reaction of a tethered enyne
for the construction of tricyclic eight-membered heterocycles and
carbocycles. This methodology also allows (E)- and (Z)-olefins to
be utilized in a stereospecific manner. The ability to incorporate
either alkene geometry is particularly significant, since related
carbocyclization reactions are often limited in this respect. Finally,
the ability to utilize carbon-tethered 1,6-enynes and to regiospe-
cifically incorporate substituted 1,3-butadiene derivatives provides
exciting opportunities for future applications toward the total
synthesis of cyclooctanoid-containing diterpenes.
(12) This catalyst provided a general solution to the problem of diastereose-
lectivity in the intermolecular [4+2+2] carbocyclization of 3-substituted
sulfonamide 1,6-enynes and 1,3-butadiene. Evans, P. A.; Fazal, A. N.;
Baum, E. W. Manuscript in preparation.
(13) Wender, P. A.; Williams, T. J. Angew. Chem., Int. Ed. 2002, 41, 4550.
(14) (a) Sieburth, S. M.; Fensterbank, L. J. Org. Chem. 1992, 57, 5279. (b)
Evans, P. A.; Cui, J.; Buffone, G. P. Angew. Chem., Int. Ed. 2003, 42,
1734.
Acknowledgment. We sincerely thank the National Science
Foundation (CHE-0316689) for generous financial support. We also
thank Johnson and Johnson for a Focused GiVing Award and Pfizer
JA046030+
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