Regioselective cyclization of alpha,omega-alkynoic acids catalysed by TpRu complexes: synthesis of endocyclic enol lactones [Tp = hydrotris(pyrazolyl)borate].

Article abstract of DOI:10.1039/b106647c

The sigma-enynyl complex [TpRu(C(Ph)=C(Ph)C identical to CPh)(P-MeiPr2)] efficiently catalyses the regioselective cyclization of alpha,omega-alkynoic acids to yield endocyclic enol lactones having ring size up to 12 atoms.

Full text of DOI:10.1039/b106647c

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Regioselective cyclization of a,w-alkynoic acids catalysed by TpRu
complexes: synthesis of endocyclic enol lactones [Tp =
hydrotris(pyrazolyl)borate]†
Manuel Jiménez-Tenorio,a M. Carmen Puerta,a Pedro Valerga,*a F. Javier Moreno-Dorado,b
Francisco M. Guerrab and Guillermo M. Massanetb
a Departamento de Ciencia de Materiales e Ingeniería Metalúrgica y Química Inorgánica, Facultad de
Ciencias, Universidad de Cádiz, Apartado 40, 11510 Puerto Real, Cádiz, Spain.
E-mail: pedro.valerga@uca.es; Fax: 34 956 016288; Tel: 34 956 016340
b Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Cádiz, Apartado 40, 11510
Puerto Real, Cádiz, Spain. Fax: 34 956 016288; Tel: 34 956 016374
Received (in Cambridge, UK) 24th July 2001, Accepted 27th September 2001
First published as an Advance Article on the web 25th October 2001
The s-enynyl complex [TpRu{C(Ph)NC(Ph)C·CPh}(P-
MeiPr2)] efficiently catalyses the regioselective cyclization of
a,w-alkynoic acids to yield endocyclic enol lactones having
ring size up to 12 atoms.
lactones were isolated by solvent removal followed by pre-
parative HPLC. In the case of larger lactone rings, the catalyst
load and reaction time were increased to 10% and 24 h
respectively, diluting the substrate concentration to ca. 0.05 M
in order to prevent the formation of linear oligomers. As shown
in Table 1, endocyclic enol lactones were the only product
generated when catalyst 1 was used. So far, our catalyst has
proven to be able to cyclize ring systems of up to 12 atoms. This
constitutes an efficient method for the synthesis of macrocyclic
enol lactones, with the potential ability for accessing even larger
cyclic systems. In these cases, the cyclization is not ster-
eoselective, and mixtures of the endocyclic Z- and E-enol
lactones are obtained (entry 4).§ The complex [TpRuH(PPh3)2]
(2)14 can also cyclize alkynoic acids to enol lactones (Table 1,
entries 5–8). However, with pentynoic acid the only exception,
the cyclization is not regioselective, and mixtures of endocyclic
(anti-Markovnikov) and exocyclic (Markovnikov) enol lac-
tones are obtained. Detailed studies carried out on rhodium and
iridium complexes, supported by X-ray crystal structure
determinations of some iridium model catalytic intermediates,11
have led to a mechanistic proposal for the catalytic cyclization
of alkynoic acids leading to exocyclic enol lactones.10,11 Based
upon these observations, we can propose in our case a similar
catalytic cycle to account for the formation of exocyclic enol
lactones (Scheme 1, pathway A). Compound 2 dissociates one
PPh3 molecule followed by insertion of the alkynoic acid into
the Ru–H bond. The resulting alkenyl complex releases
alkenoic acid (10-undecenoic acid has been isolated from runs
Enol lactones are present in a number of biologically active
natural products. Whereas some compounds contain the
exocyclic enol lactone substructure,1 other natural products
contain an endocyclic enol lactone ring, e.g. eresmofarfugin A,2
and all products containing the isocoumarin ring system.3,4
Endocyclic enol lactones are useful intermediates in the
synthesis of more complex natural products such as the alkaloid
(2)-aspidospermidine.5 The cyclization of a,w-acetylenic acid
precursor represents one effective synthetic approach to enol
lactone systems.6 Silver salts and mercuric salts have been used
as catalysts, but their utility suffers from limited scope, drastic
conditions and poor selectivity.7 Transition metal complexes
have shown to catalyse efficiently the cyclization of a,w-
alkynoic acids to give enol lactones of 5- and 6-member rings,
with variable degree of regio- and stereoselectivity depending
upon the catalyst used and the particular alkynoic acid [eqn.
(1)].8–11
(1)
In the case of terminal alkynoic acids (R = H), the metal-
catalysed cyclization reaction yields exclusively exocyclic enol
lactones. This can be interpreted in terms of the regioselective
Markovnikov addition of the carboxylic acid to the terminal
alkyne.12 Alternatively the anti-Markovnikov addition would
produce the corresponding endocyclic enol lactone. However,
anti-Markovnikov addition products have never been observed
to any significant extent, hence the use of this synthetic route for
the general preparation of enol lactones seems to be very
limited. We have recently reported the s-enynyl complexes
Table 1 Catalysed cyclization of alkynoic acids to enol lactones
Product
Total
[TpRu{PhCNC(R)C·CPh}(PMeiPr2}] [R
= Ph, H; Tp =
Entry
Catalyst
n
ratio a+b
yield (%)
hydrotris(pyrazolyl)borate(12)] and their ability to catalyse the
dimerisation and even cross-coupling of alkynes.13 We have
now found that [TpRu{PhCNC(Ph)C·CPh)(PMeiPr2}] (1) ca-
1
2
3
4
5
6
7
8
1
1
1
1
2
2
2
2
1
2
3
7
1
2
3
7
0+100
0+100
0+100
0+100b
0+100
47+53
32+68
13+87c
97
95
45a
84
98
95
50a
79
talyses
the
regioselective
cyclization
of
HOOCCH2(CH2)nC·CH (n = 1, 2, 3, 7) to the corresponding
endocyclic enol lactones. Results are shown in Table 1 (entries
1–4).‡ The cyclization takes place smoothly in refluxing
toluene in 6 h, and 2% catalyst load. Analytical samples of the
a The remaining yield corresponds to 7-oxoheptanoic acid. b As a mixture of
Z/E isomers in the ratio 51+49. c As a mixture of Z/E isomers in the ratio
41+59.
† Electronic supplementary information available: selected spectral data for
enol lactone derivatives. See http://www.rsc.suppdata/cc/b1/b106647c/
2324
Chem. Commun., 2001, 2324–2325
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b106647c

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tautomerisation. In fact, we have already observed that facile
alkyne to vinylidene rearrangement takes place at the
{[TpRuCl(PMeiPr2)]} moiety furnishing neutral vinylidene
complexes [TpRuNCNCHR(Cl)(PMeiPr2)] (R
=
Ph, But,
SiMe3).13 For catalysts 2, the alkyne to vinylidene rearrange-
ment possibly occurs at a slower rate, similar to that of the attack
of the carboxylate on the p-alkyne, so both pathways A and B
of Scheme 1 might operate simultaneously. Further investiga-
tions are currently in progress in order to expand the
applicability of these catalytic reactions, and in order to find
additional information in support of our proposal for the
reaction sequence in the catalytic cycle.
We thank the M.E.C./M.C.Y.T. of Spain (DGICYT, Projects
PB97-1357, PB97-1360) for financial support, and Johnson
Matthey plc for generous loans of ruthenium trichloride.
Notes and references
‡ General procedure. A round bottom flask fitted with a condenser was
loaded with 0.02 equiv. of the catalyst and dry toluene (5 mL), and the
mixture was heated at 100 °C under argon. Then, 1 equiv. of alkynoic acid
dissolved in dry toluene (2 mL) was added. The reaction mixture was
refluxed for 6 h and then allowed to cool to rt. Cyclohexane (5 mL) was
added and the solvent removed using reduced pressure. In the case of
octynoic and undecynoic acids, the catalyst load and reaction time were
increased to 10% and 24 h respectively, diluting the substrate concentration
to ca. 0.05 M in order to prevent the formation of linear oligomers. The ratio
of the different products present in the crude was established by integration
of the signals in the 1H NMR spectrum. Pure samples of the lactones were
obtained by preparative HPLC.
§ There is evidence for the formation of Z- and E-stereoisomers also in case
of the 8-membered lactone ring, but the E-stereoisomer is strained, and
tends to open up during the purification process yielding 7-oxoheptanoic
acid (Table 1, entry 3).
Scheme 1 Proposed mechanism for the cyclization of alkynoic acids to
exocyclic enol lactones (pathway A) or endocyclic enol lactones (pathway
B) catalysed by the complexes 1 and 2.
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acid molecule, furnishing a coordinatively unsaturated carbox-
ylate complex which seems to be the actual catalytic species. An
alternative pathway must be figured out in order to explain the
regioselective formation of endocyclic enol lactones. Dixneuf
and co-workers have developed ruthenium-based catalysts
which can give either Markovnikov or anti-Markovnikov
addition of acids or other organic substrates to terminal alkynes
in a regioselective fashion.12 The anti-Markovnikov addition
takes place when the terminal carbon atom of the alkyne
becomes electrophilic, this being feasible if a ruthenium–
vinylidene intermediate species is generated at some stage
during the catalytic process.12 Therefore, we assume that in our
case, a fast alkyne to vinylidene rearrangement takes place,
most likely via a concerted 1,2-hydrogen shift (Scheme 1,
pathway B).15 In this fashion, the terminal carbon of the alkyne
becomes electrophilic, and hence the carboxylate group attacks
at this position. Ring closure yields an endocyclic alkenyl
complex. As in pathway A, reaction with another alkynoic acid
molecule releases the enol lactone and regenerates the coor-
dinatively unsaturated carboxylate complex. It appears that the
fast isomerization to vinylidene prior to carboxylate attack is the
key step in the regioselective formation of endocyclic enol
lactones. In the case of catalyst 1, the presence of highly basic
phosphine PMeiPr2 prompts the fast alkyne to vinylidene
8
T. Wakabayashi, Y. Ishii, K. Ishikawa and M. Hidai, Angew. Chem.,
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Valerga, Organometallics, 2000, 19, 1333.
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Valerga, Inorg. Chim. Acta, 1997, 259, 77.
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Chem. Commun., 2001, 2324–2325
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