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Cascade Cyclizations.

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Cascade Cyclizations
F<+&
&
OMe
?Me
I
By H. Martin R. Hoffmann*
Cascade cyclizations, also called tandem, zip, or domino
reactions, are multiple consecutive cyclizations which have
fascinated organic chemists for more than 35 years. Several
reasons account for this interest. Rings are not built up tediously step by step, but convergently in one fell swoop.
Proper induction and termination of the cyclization cascade
provide a major challenge, as does stereocontrol over the
generation of several new chiral centers. To this end, a suitable tether must be constructed, the conformation and
stereoelectronics of which facilitate coupling and ring closure.
Multiple consecutive cyclizations can be triggered by stoichiometric and catalytic amounts of reagents. Biomimetic
cascades of cations which follow the biogenetic isoprene
rule,''] were among the first reactions of this type to be
studied. Thus, many functionalized polyenes containing 1,sdiene units have been cyclized to give higher terpenes."]
Recently, these reactions have been terminated in a novel
way with internal oxygen nucleophiles such as carbonyl, hydroxyl, and /?-ketoester groups. For example, truns,tmnsfarnesylacetone (l),readily available from farnesol, was submitted to the Nishizawa cyclization protocolf3]with mercuric triflate/N,N-dimethylaniline to give sensitive endocyclic enol ether 2, capable of surviving in the presence of the
electrophilic trigger. Demercuration of 2 furnished sclareol
oxide 3,I4]a well known constituent of clary (Salvea sclarea)
which fulfills Ohloffs syntriaxial ruleIS1and is used as a
precursor of ambergris odorants.
0
fi2'
Mn3'
0
.
C0,Me
4
C0,Me
OMe
5
OMe
OMe
Curran et al. and relate to the synthesis of both linear
(9 +12) (AIBN = azobis(isobutyronitri1e) and angular
triquinanes (13 -+14).19]The formation of the less stable
vinyl radical 11 from the more stable tertiary radical 10
7\.[*]
+
H
H
9
H
Bu,Sn'
Bu,SnH
H
10
Bu,SnI
Bu,Sn'
MeNO,,-20 "C
X
11
2: X = HgCl
1
3:X=H
12 hirsutene
65%from 9
n
More conventionally, tandem cyclizations of polyenes
have been initiated with a variety of other electrophiles including protons, bromine cations, Lewis acids,''] sulfenium
ions (from methyl benzenesulfenate PhSOCH, and BF, @I)
and benzeneselenenyl triflate PhSeOTf.[']
In the 1980s radical reactions emerged as efficient processes for carbon-carbon bond formation in the synthesis of
natural products. An oxidative cyclization is the central step
in Snider's synthesis of podocarpic acid."] The reaction is
induced by electrophilic radical 5 , which is generated from
the enol precursor by a one-electron oxidation. Termination
of the cascade is feasible by the oxidation of 6 to cation 7 and
straightforward deprotonation.
Perhaps the best known tandem radical cyclizations terminating in radical rather than ionic fashion were developed by
[*I
Prof. H. M. R. Hoffmann
Institut fur Organische Chemie der Universitat
D-W-3000 Hannover (FRG)
1332
0 VCH
VeriaRsgesellschuft mbH, W-6940 Wernheim, 1992
13
14
B:a= 3:1
might seem surprising at first glance. However, the reaction
is accompanied by loss of a weak acetylenic II bond and
formation of a strong vinylic carbon-carbon bond. Furthermore, termination by hydrogen atom transfer affords a
strong vinylic carbon-hydrogen bond (CH, = CH-H, AHo
= 108 kcalmol-') which compares with A H o = 91 kcal
mol- ' for the bond between hydrogen and a tertiary carbon
atom. Thus, the success of the cyclization may depend on
factors other than those in cationic cyclizations in which the
stability of the cation generated on termination is often critical. It is also obvious that the stereochemistry of the vinylic
bromide 13 ( E or 2 ) is irrelevant to the success of the cascade, since the resulting vinylic radical is linear.
0570-0833i92ilOlO-1332$3.50+ .25/0
Angew. Chem. I n f . Ed. Engl. 1992, 31, No. 10
Recently, the cedrane skeleton 19 was constructed in two
steps from nitroolefin 15 and the y,b-unsaturated aldehyde
16.[’01As in the synthesis of 14 from 13, the key step is the
tandem cyclization 18 --* 19, consisting of consecutive 5-exotrigonal ring closure reactions. Delivery of the hydrogen
atom in the terminating step occurs antiperiplanar to the
face of the double bond, resulting in an equatorial methyl
group. As in the examples above, the two five-membered
rings in 19 must be cis-fused, since a trans-bicyclo[3.3.0]octane substructure would be too strained.
The synthesis of 19 also testifies to the synthetic versatility
of the nitro group in reactions of three fundamental mechanistic types, namely, pericyclic, ionic, and free radical. Nitroolefin 15 is the Diels-Alder adduct of isoprene and nitroethylene. The nitro group not only activates the dienophile,
but also controls regioselectivity (“para”). Nitroalcohol 17 is
formed in an ionic nitroaldol reaction (Henry reaction). Finally, since the nitro group is attached to a tertiary carbon in
17, it serves as a convenient leaving group in the generation
of the tertiary radical
thus demonstrating excellent
overall eficiency in the use of this one functional group.
Me,Sn,
Me3SnC1, NaF3H3CN,
0
111.
21
22
stereoisomers i2:11
MeO, ,OMe
CAN, MeOH
54 %
23
radical 24 (rather than Me’) and trimethylstannylium ion 25.
Even if the double cyclization had been successful with
Bu,SnH instead of Me,SnH, any differentiation of alkyl
groups during the oxidation step would have been lost!
+.
Me3SnCH2R
Me,SnCH,R
RCH2’
+
Me,Sn+
25
24
cANl
RCHO
I
15
17
A monocyclization reaction was applied in the synthesis of
the lignan antibiotic burseran (31).[”] Starting from 1,6diene 26, Hanessian and LLger prepared tetrahydrofuran 27,
Bu,SnH, AIBN,
caH,A
b
52 %
Ar
Me,SnCI, NaBH,CN,
27 (2:l cqhrans)
26
1. cro,
H
r.”.“,,, n
o
::E
H
H
19
20
Hanessian and Legerr”] have recently cyclized a series of
dienes and trienes with trimethyltin hydride Me,SnH rather
than Bu,SnH. Me,SnH is sterically less encumbered and
therefore probably more reactive than Bu,SnH. It has been
generated conveniently in situ, from Me,SnCl and
NaBH,CN, which is superior to the more reactive LiAlH, as
a hydride donor. The (trimethylstanny1)methyl group in the
cyclization product 22 does not lead the synthesis into a
cul-de-sac, since this group can be converted into a masked
aldehyde by a novel oxidative destannylation. The oxidation
probably involves single-electron transfer (SET) from stannane to (NH,),Ce(NO,), (CAN) to produce a (trimethylstanny1)methyl radical cation which disproportionates reversibly to the most stable radical, namely, the primary
Angrw,. Chrm.
hi.
Ed. Engl. 1992, 3 f , No. 10
AI
Ar
CAN, MeOH
(slowaddition)
68%
0
.29 ( 1 9 1 trons/cis)
28 (21)
Li
b
71%
0 VCH Verlagsgesellschafi mbH, W-6940 Weinheim, 1992
ArMe0
OMc
M
e
O
Me0
q
0
OMe
31
0570-0833/92/1020-1333$3.50+.25/0
1333
substituted in the 3 and 4 positions with typically the cis
isomer predominating. Since tetrahydrofurans such as 27
and related five-membered heterocycles are usually difficult
to obtain with substituents in the 3 and 4 positions, the
radical route is very useful. Oxidation of 27 with CAN gave
the aldehyde 28, without attack of the electron-rich aromatic
moiety or alteration of the ratio of isomers (2: 1) of 27. Further steps furnished (+)-burseran (31), which was also obtained enantiomerically pure when the racemic mixture was
resolved at an earlier stage in the synthesis (DBU = l &
diazabicyclo[5.4.0]undec-7-ene).
The stereochemical outcome of cyclization cascades such
as 9 +12, 13 +14 is dictated by the stereochemistry of the
central five-membered ring which serves as a platform for
the construction of two new rings. For example, for steric
reasons radical 10 has little option but form cis-anti-cis-fused
hirsutene 12 (cf. also 21 -+ 22). In contrast, not only the
conformation must be decided but also the choice between a
C-C double bond and a C-C triple bond must be made in the
reactions of the radicals generated from functionalized 1,5enyne 32, which has recently been shown to enter into radical-mediated, sequential 5-exo-trigonal, 6-endo-digonal cyclizations. The 6-endo-digonal closure is unusual in itself and
requires heating to 100 “C. The overall reaction 32 33
34 is a cycloisomerization, that is, the radical chain is
driven by iodine atom transfer. Interestingly, the cascade has
--f
+
32
0, Icat.)
toluene, 1~
100~C
33,32%
34, 2.4%
also been terminated by hydrogen atom transfer (with catalytic amounts of cobaloxime and NaBH,) under milder conditions, that is at 50°C. The tricyclic compound 33 arises
from an “abnormal” boat transition state with transoid
pseudo-axial substituents, whereas formation of compact
dioxatriquinane 34 requires a cisoid chair transition state.
According to a CAS online search, both the tricyclic 5 . 5 6
1334
0 VCH
Veriagsgeseilschafl mbH, W-6940 Weinheim, 1992
ring system in 33 and the corresponding 6 . 5 . 6 ring system
are
Synthetic methods based on reactions of radicals have
come of age and are now almost standard procedures for
carbon-carbon bond forrnation.[l4, High chemoselectivity, stereoselectivity, and the possibility of working without
protecting groups as well as taking advantage of umpolung
provide new opportunities for using old compounds. In this
fashion, the “reaction windows” of organic reactions are
defined more clearly. Apart from many obvious and important practical applications and advantages, the intellectual
base of organic chemistry has been broadened and strengthened decisively.
German version: Angew. Chem. 1992,104,1361
[I]A.Eschenmoser, L. Ruzicka, 0.Jeger, D. Arigoni, Helv. Chinz. Acta 1955,
38,1890;G. Stork, A. W. Burgstahler. J. Am. Chen?.Soc. 1955,77,5068.
Cf. R. Bohlmann, Angew. Chem. 1992,104,596;Angew. Chem. lnt. Ed.
Engl. 1992,31;582;C. H. Heathcock, ihid. 1992,104,675 and 1992,31,
665.
121 W. S. Johnson, S. D. Lindell, J. Steele. J. Am. Chern. Soc. 1987,109, 5852.
Cf. Chemtracts: Org. Chem. 1988,1, 32.For a transannular rr-cyclization
terminated by simultaneous formation of a bridgehead cation-bridgehead
olefin see U . Vogt, U. Eggert, A . M. 2. Slawin, D. J. Williams, H. M. R.
Hoffmann, Angew. Chem. 1990,102, 1530;Angew. Chem. I n f . Ed. EngI.
1990,29, 1456;H. M. R.Hoffmann. U. Eggert, Syniett 1991,337.
H. Takenaka, T. Sato, M. Nishizawa, Tetrahedron Lett. 1989,30,2261; M .
Nishizawa, H. Takenaka, H. Nishide, Y. Hayashi. ibid. 1983,24,2581,
and
references therein.
A. S. Gopalan, R. Prieto, B. Mueller. D. Peters, Tetrahedron Lett. 1992,33,
1679.
G. Ohloff Riechstaffe und Geruchuinn. Die molekuiare Well der Diifre,
Springer, Heidelberg, 1990.
S. R. Harring. T. Livinghouse, Tetrahedron Lett. 1989. 30, 1499; S.R.
Harring, T. Livinghouse, J Chem. Soc. Chem. Commun. 1992,502,503.
S. Murata, T. Suzuki, Tetrahedron Lett. 1990,31. 6535, and references
therein.
B. B. Snider, R. Mohan, S. A. Kates, J. Org. Chem. 1985,SO, 3659.
Reviews: C.P.Jasperse, D. P. Curran, T. L. Fevig, Chem. Rev. 1991,91,
1237;W. B. Motherwell, D. Crich, Best Synthetic Methods. Free Radical
Chain Reactions in Organic Synthesis, Academic Press, London, 1991 ;
D. H. R. Barton, The Invention of Chemical Reactions: The Last Five Years
(Tetrahedron 1992,48. 2529).
Y.-J. Chen. W.-Y. Lin, Tetrahedron Lett. 1992,33, 1749. For a review of
aliphatic nitro compounds in organic synthesis, see R. Tamurd, A.
Kamimura, N. Ono, Synthesis 1991,423.
S . Hanessian, R. Leger, J. Am. Chem. Soc. 1992,lf4,3115.
S. Hanessian. R. Lerer,
1992,402.
- Synlerr
.
U. Albrecht, R. Wartchow, H. M. R. Hoffmann, Angew. Chem. 1992,104,
903:Angen,. Chem. Int. Ed. Engl. 1992,St.910.
[I41 The converse also applies: chemoselective C-C bond cleavage in complex.
polyfunctionalized molecules is feasible. For example, the fragmentation
of anomeric carbohydrate alkoxy radicals affords acyclic chiral building
blocks: P. de Armas, C. G. Francisco. E. Suarez, Angew. Chem. 1992.104.
146; Angew Chem. Int. Ed. Engl. 1992,31,112.
[I51 Transition metal (Pd, Zr) mediated zip cyclirations provide a range of
further synthetic possibilities; see for example B. M . Trost, Y. Shi, J Am.
Chem. SOC.1991, 113, 701; B. M. Trost, Science 1991, 254, 1471; E.
Negishi, Pure Appl. Chem. 1992.64,323.
1161 Note added in proof (Sept. 9,1992):The tricyclo[9.3.1.O]pentadecanesystem of the taxanes has been synthesized by a spectacular 12-endo-trig,6rxo-trig cyclization: S. A. Hitchcock, G. Pattenden, Tetrahedron Lett.
1992,33,4843.
0570-0833I92llOlO-1334
3 3.S0+.25/0
Angen. Chem. Int. Ed. Engl. 1992,31,No. 10
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