Stereoselective synthesis of highly substituted cyclopentenones through [4+1] annulations of trialkylsilyl vinyl ketenes with α-benzotriazolyl organolithium compounds

Article abstract of DOI:10.1002/anie.200501579

Closing the ring: Highly functionalized cyclopentenones are prepared by the reaction of readily available metalated benzotriazole derivatives with trialkylsilyl vinyl ketenes (see scheme; Z = heteroatom substituent). Dienolate intermediates are generated

Full text of DOI:10.1002/anie.200501579

Angewandte
Chemie
Annulation
intermediates which are trapped in situ in [2+2] cycloaddi-
tions. Silyl substituents have the ability to suppress the usual
propensity of vinyl ketenes to undergo dimerization and
DOI: 10.1002/anie.200501579
[
2+2] cycloaddition reactions, thus opening up new oppor-
Stereoselective Synthesis of Highly Substituted
Cyclopentenones through [4+1] Annulations of
Trialkylsilyl Vinyl Ketenes with a-Benzotriazolyl
Organolithium Compounds**
tunities for useful synthetic transformations. For example,
TAS vinyl ketenes participate as electron-rich diene compo-
nents in Diels–Alder and hetero-Diels–Alder reactions lead-
ing to cyclohexenones, phenols, and oxygen and nitrogen
[
11]
heterocycles.
In the case of reactions with carbenoid
reagents, addition initially furnishes dienolate intermediates,
which are believed to undergo ionization and subsequent
Christopher P. Davie and Rick L. Danheiser*
4p electrocyclization to generate cyclopentenone rings (see
Cyclopentenones serve as valuable synthetic building blocks
and are themselves key features in the structure of a number
below). TAS vinyl ketenes are readily available through
several routes, including the photochemical Wolff rearrange-
ment of a’-silyl-a’-diazo-a,b-unsaturated ketones used for the
[
1]
of prostaglandins and other bioactive natural products.
Popular strategies for the construction of this important ring
system include the intramolecular aldol reaction, the Nazarov
[
11a]
preparation of 1a–c in this study.
The goal of the current investigation was to extend the
scope of this [4+1] annulation strategy to include the
synthesis of cyclopentenones with a much broader range of
substituents at the C5 position. A variety of carbenoid
reagents were screened with the aim of identifying new
classes of molecules that are competent in the desired
transformation and are more readily available than the
diazo compounds, sulfur ylides, and stable carbenes previ-
[
2]
[3]
cyclization, the Rautenstrauch rearrangement, and the
[
4,5]
Pauson–Khand reaction.
Only a few general [4+1] routes
to five-membered carbocycles have been reported to date,
one example being the method we developed based on anion-
[
6,7]
accelerated vinylcyclopropane rearrangements.
Recently,
[
8]
[9]
studies by us and others have led to several new [4+1]
approaches to the synthesis of the 2-cyclopentenone ring
system. Herein, we report a new variant of our stereo-
controlled [4+1] annulation strategy that provides especially
efficient access to highly substituted and functionalized
cyclopentenones.
[
8]
ously employed. Among the several classes of compounds
examined to date, a-benzotriazolyl organolithium compounds
of type 3 were best able to meet our requirements (Scheme 2).
Extensive research by Katritzky and co-workers over the past
two decades has demonstrated the utility of N-substituted
benzotriazoles as valuable intermediates for organic syn-
As outlined in Scheme 1, our [4+1] annulation strategy is
based on the reaction of nucleophilic species with leaving
groups (“carbenoid reagents”) with trialkylsilyl vinyl ketenes
[
12]
thesis. Benzotriazoles of type 2 bearing a wide range of
Scheme 1. Strategy for [4+1] annulation. L=leaving group.
Scheme 2. Preparation of a-benzotriazolyl organolithium compounds.
Benzotriazoles 2b and 2d–f are commercially available, and the details
for the preparation of 2a, 2c, and 2g–i are given in the Supporting
Information.
[
8]
(
“TAS vinyl ketenes”). The utility of vinyl ketenes as
versatile intermediates in organic synthesis is now well
[
10]
established.
However, vinyl ketenes are rarely isolable
species and in most applications are generated as transient
substituents are either commercially available or readily
prepared in one or two steps from inexpensive starting
materials and undergo metalation with n-butyllithium at
À788C to provide access to a-benzotriazolyl organolithium
derivatives of type 3. The ability of benzotriazole to function
as a leaving group is also well documented and has been
exploited by Katritzky and co-workers in the context of
[
*] C. P. Davie, Prof. R. L. Danheiser
Massachusetts Institute of Technology
Department of Chemistry
Cambridge, Massachusetts 02139 (USA)
Fax: (+1)617-252-1504
E-mail: danheisr@mit.edu
[
12]
numerous useful synthetic transformations.
[
**] We thank the National Institutes of Health (GM 28273) and Merck
Research Laboratories for generous financial support.
The reaction of the benzotriazolyl carbamate 2a with TAS
vinyl ketene 1a was examined to investigate the feasibility of
the proposed [4+1] annulation (Scheme 3). Benzotriazole 2a
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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5867

Communications
tion of an alkoxy moiety and a vinyl or alkynyl group
entries 3 and 4). Each of these reactions was observed to
(
proceed with a preference for the formation of the cyclo-
pentenone with the heteroatom substituent at C5 trans to the
substituent at C4. This preference is particularly high with
3
small R groups, such as hydrogen or alkynyl moieties. The
Scheme 3. Demonstration of the feasibility of the [4+1] annulation.
Bn=benzyl.
latter case is synthetically significant, as the products of such
reactions (e.g., 7a) undergo hydrogenation (Scheme 4) to
furnish 5-alkyl-substituted cyclopentenones that cannot be
produced directly under such mild conditions or with such
high stereoselectivity (see below).
was prepared in 70% overall yield as previously described by
[
13]
Katritzky and co-workers
through protection of benzyl-
amine as its tert-butyloxycarbonyl (Boc) derivative and
reaction of the crude carbamate with one equivalent of
benzotriazole and one equivalent of paraformaldehyde in the
presence of catalytic para-toluenesulfonic acid (toluene,
reflux). Metalation of 2a with nBuLi produced the expected
organolithium species, which was found to add smoothly to
vinyl ketene 1a at À788C in the desired fashion. Upon
warming to room temperature, the resulting dienolate
intermediate lost the benzotriazole moiety and cyclopente-
none 4a formed in good yield and with greater than 96%
selectivity for the trans-substituted isomer.
Tables 1 and 2 delineate the scope of the [4+1] annulation.
In some cases, the desired cyclopentenone begins to appear at
low temperature during the addition of the organolithium
reagent, and formation of the five-membered-ring product is
completed simply by warming to room temperature (Table 1).
This protocol proved effective for annulations that involve
carbenoid reagents with strong electron-donor substituents
such as amine derivatives (entries 1 and 2) and the combina-
Scheme 4. Preparation of 5-alkyl-substituted cyclopentenones.
Attempted annulation with a-benzotriazolyllithium
reagents 3d–i under similar conditions did not lead to the
desired cyclopentenones. Control experiments that employed
benzotriazole 3d confirmed that addition to TAS vinyl ketene
1a proceeds smoothly at À788C in the expected manner, but
cyclization of the resulting dienolate intermediate does not
then occur. We therefore turned to the use of Lewis acids to
promote the crucial ionization of the benzotriazole group
required for five-membered-ring formation. Extensive
screening studies identified ZnBr as particularly effective
2
[
14]
for the desired transformation.
Although no reaction is
observed upon addition of one equivalent of
ZnBr2 to the dienolate solution, efficient
cyclization takes place when two or more
equivalents of the Lewis acid are added at
À788C and the reaction mixture is allowed
to warm to room temperature. Under these
conditions, the desired [4+1] annulation can
be achieved with a variety of carbenoid
reagents that bear a single heteroatom sub-
stituent such as SPh or OMe (Table 2).
Cyclopentenone formation is even observed
with the aryl-substituted benzotriazole 3g,
although in this case elevated temperatures
are required to complete the cyclization.
A notable feature of these [4+1] annu-
lations is the high level of stereoselectivity
observed in most of the reactions. Control
experiments established that the stereo-
chemical outcome of these [4+1] annula-
tions is not a consequence of thermodynamic
control. Specifically, equilibration experi-
ments yielded mixtures of trans- and cis-
substituted cyclopentenones with ratios sig-
nificantly different from those obtained in
[
a]
Table 1: [4+1] Cyclopentenone annulations.
[
b]
Entry
1
Ketene
Carbenoid
reagent
Product
Yield [%]
[
c]
(trans/cis)
1a
3a
3a
4a
5a
73 (ꢀ96:4)
67 (ꢀ99:1)
2
1b
[
d]
3
1a
1a
3b
3c
6a,b
70 (76:24)
54 (97:3)
4
7a
[
15]
the annulation. Thus, it appears likely that
the stereochemical course of the [4+1]
[
a] Only the major diastereomer is shown for cases in which d.r. ꢀ96:4; Bt=benzotriazolyl. [b] Yields of
1
annulation reflects
a
mechanism-based
isolated product purified by column chromatography. [c] Ratios determined by H NMR spectroscopic
analysis. [d] 6a: R =OEt, R =–CH=CH ; 6b: R =–CH=CH , R =OEt.
1
2
1
2
kinetic preference for the observed products.
2
2
5
868
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Angewandte
Chemie
[
a]
Table 2: Lewis acid promoted [4+1] cyclopentenone annulations.
leaving-group departure. An alter-
native pathway involves ionization
to produce oxidopentadienylic
[
16]
cation 20,
which should then
undergo rapid conrotatory 4p-elec-
[
17]
trocyclic closure to generate the
[
18]
[
b]
[c]
cyclopentenone product. Finally,
the involvement of cyclopropanone
intermediates of type 19 cannot be
excluded, particularly in view of the
finding that simple silyl ketenes
react with diazomethane and tri-
methylsilyldiazomethane to form
mono- and bis(silyl)cyclopropa-
Entry
Ketene
1a
Carbenoid
reagent
Product
Yield [%] (trans/cis)
69–74 (98:2)
75 (98:2)
1
2
3
4
3d
3d
3e
3e
3 f
9a
10a
11a
12a
13a,b
1b
[
19]
nones.
The stereochemical outcome of
the [4+1] annulations that we inves-
1a
68–82 (ꢀ99:1)
67–70 (ꢀ99:1)
85 (74:26)
[
8]
tigated previously is consistent
with a mechanism that involves
stereospecific conrotatory electro-
cyclic closure of a 2-oxidopentadie-
nylic cation. In those prior cases, we
suggested that ionization of the
dienolate intermediate occurs to
generate a cation in which the
single C1 substituent is cis to the
oxy anion to minimize nonbonded
interactions. A similar mechanism
can account for the reactions
reported herein, provided that one
assumes that ionization leads to the
isomer of intermediate 20 shown in
Scheme 5 because of an associative
interaction between the heteroatom
Z and the metal (M = Zn or Li) in
1c
[
d]
5
6
7
8
1a
[
e]
1a
1a
1a
3g
3h
3i
14a
34 (ꢀ99:1)
65 (77:23)
64 (97:3)
[f]
15a,b
16a
1
8 and/or 20. Alternatively, if cycli-
zation of 18 involves a concerted
process, then the stereochemical
outcome could reflect a preference
for the mode of conrotation from 18
that rotates the leaving group anti
[
a] Only the major diastereomer is shown for cases in which d.r.ꢀ97:3. [b] Yields of isolated product
1
purified by column chromatography. [c] Ratios determined by H NMR spectroscopic analysis. [d] 13a:
R =Cb, R =H; 13b: R =H, R =Cb. [e] Reaction mixture was allowed to warm to RTover 10 h and then
heated at reflux for an additional 4 h. [f] 15a: R =OPh, R =CH ; 15b: R =CH , R =OPh.
Cb=
1
2
1
2
1
2
1
2
3
3
Scheme 5 outlines several alter-
native pathways to account for the
mechanism of the [4+1] annulation.
Addition of the carbenoid reagent to
the vinyl ketene is predicted to be
highly stereoselective because of the
shielding effect of the bulky trialkyl-
silyl group and should result in the
formation of the Z-enolate 18.
Direct formation of the five-mem-
bered-ring product could then result
from a concerted process in which
ring closure is concomitant with Scheme 5. Possible mechanistic pathways for the [4+1] annulation. M=metal center, L=ligand.
Angew. Chem. Int. Ed. 2005, 44, 5867 –5870
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Communications
to the incipient s bond and which proceeds via the transition
state in which the donor heteroatom occupies an “outside”
position (“torquoselectivity”).
[7] For other recent examples, see: C. Spino, H. Rezaei, K. Dupont-
Gaudet, F. BØlanger, J. Am. Chem. Soc. 2004, 126, 9926, and
references therein.
[
20]
[
8] a) J. L. Loebach, D. M. Bennett, R. L. Danheiser, J. Am. Chem.
Soc. 1998, 120, 9690; b) A. M. Dalton, Y. Zhang, C. P. Davie,
R. L. Danheiser, Org. Lett. 2002, 4, 2465; c) for the extension of
this strategy to include reactions of nucleophilic carbenes, see:
J. H. Rigby, Z. Wang, Org. Lett. 2003, 5, 263.
The vinyl silane moiety incorporated in the [4+1]
annulation products provides a useful handle for further
synthetic transformations. Of particular interest to us was
their conversion into vinyl halides, as a number of naturally
occurring 2-halocyclopentenones have recently been found to
[9] For examples, see: a) M. Murakami, K. Itami, Y. Ito, J. Am.
Chem. Soc. 1999, 121, 4130; b) S. V. Gagnier, R. C. Larock, J.
Am. Chem. Soc. 2003, 125, 4804.
10] G. B. Dudley, K. S. Takaki, D. D. Cha, R. L. Danheiser, Org.
Lett. 2000, 2, 3407, and references therein.
[
1]
exhibit potent antitumor activity. In addition, the utility of 2-
haloenones in a variety of transition-metal-catalyzed coupling
reactions is well documented. With these ends in mind, we
investigated the transformations outlined in Scheme 6 to lay
[
[
11] a) J. L. Loebach, D. M. Bennett, R. L.
Danheiser, J. Org. Chem. 1998, 63, 8380;
b) D. M. Bennett, I. Okamoto, R. L.
Danheiser, Org. Lett. 1999, 1, 641.
[
12] Reviews: a) A. R. Katritzky, X. Lan, J. Z.
Yang, O. V. Denisko, Chem. Rev. 1998,
9
8, 409; b) A. R. Katritzky, K. Manju,
S. K. Singh, N. K. Meher, Tetrahedron
005, 61, 2555.
2
[
[
13] A. R. Katritzky, Z. Luo, Y. Fang, P. J.
Steel, J. Org. Chem. 2001, 66, 2858.
14] Other Lewis acids that promote the
desired reaction in good yield include
BF ·OEt , AlCl , Cu(OTf) , TiCl , and
3
2
3
2
4
SnCl4.
[
15] For example, exposure of 9a to KOtBu in
THF (RT, 19 h) afforded a 91:9 mixture
of 9a and the corresponding cis isomer,
and similar reaction of 11a produced a
Scheme 6. Useful synthetic transformations of [4+1] annulation products. AIBN=azobisisobutyronitrile.
6
2:38 mixture of trans- and cis-substi-
tuted cyclopentenones; exposure of 12a to methanesulfonic acid
MeOH, RT, 32 h) afforded a 70:30 mixture of trans/cis isomers.
the groundwork for future applications of this annulation
methodology. Conversion of a-silyl cyclopentenone annula-
tion products 11a and 12a into iodoenone 22 proceeded
smoothly by using a modification of the method of Alimar-
(
[
16] Depending on the reaction conditions, this intermediate may be
a free zwitterionic species or could still be associated with the
metal center.
[
21]
danov and Negishi. Reduction of 22 with nBu SnH then
3
afforded 23, and Sonogashira coupling proceeded smoothly to
furnish 24 with no detectable epimerization or double-bond
migration in either case.
Further studies are underway aimed at the development
of asymmetric variants of the annulation reaction and its
application in the synthesis of natural products.
[17] Pentadienyl cation electrocyclic ring closures are involved in the
mechanism of the Nazarov cyclization; for reviews, see: refer-
ence [2a] and S. E. Denmark in Comprehensive Organic Syn-
thesis, Vol. 5 (Eds.: B. M. Trost, I. Fleming), Pergamon, Oxford,
1991, p. 751.
[
18] For the formation of cyclopentenones through the base-induced
cyclization of a’-chloro-b’,g’-unsaturated ketone enolate and
enamine derivatives, see: J. Mathew, J. Org. Chem. 1991, 56, 713.
Although it was proposed that these cyclizations proceed by an
Received: May 10, 2005
Published online: August 5, 2005
“intramolecular abnormal S 2’” mechanism, we believe these
N
reactions more likely involve the cyclization of an oxidopenta-
dienylic cation analogous to 20. For a related transformation
which involves a benzotriazolyl moiety in place of chloride as the
leaving group, see: A. R. Katritzky, G. Zhang, J. Jiang, J. Org.
Chem. 1995, 60, 7605.
Keywords: annulation · azoles · cyclopentenones ·
electrocyclic reactions · ketenes
.
[
[
19] G. S. Zaitseva, I. F. Lutsenko, A. V. Kisin, Yu. I. Baukov, J.
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[
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gold(i)-catalyzed variant, see: X. Shi, D. J. Gorin, F. D. Toste, J.
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[
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[
21] A. Alimardanov, E.-i. Negishi, Tetrahedron Lett. 1999, 40, 3839.
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6] R. L. Danheiser, J. J. Bronson, K. Okano, J. Am. Chem. Soc.
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5
870
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Angew. Chem. Int. Ed. 2005, 44, 5867 –5870