Regio- and diastereoselective reductive coupling of vinylepoxides catalyzed by titanocene chloride

Article abstract of DOI:10.1021/ol052849w

The Ti(III)-catalyzed reaction of a series of vinylepoxides leads, with regio- and E-diastereoselectivity control, to good-to-excellent yields of the corresponding homocoupling products. This homocoupling reaction, which involves a new C-C bond-forming method, takes place via a S_N2′ process between an allyltitanium species and the starting vinylepoxide. The process can be used for the rapid and efficient formation of highly valuable intermediates for organic synthesis, as well as new interesting homologues of natural products.

Full text of DOI:10.1021/ol052849w

ORGANIC
LETTERS
2
006
Vol. 8, No. 4
69-672
Regio- and Diastereoselective Reductive
Coupling of Vinylepoxides Catalyzed by
Titanocene Chloride
6
Alejandro F. Barrero,* Jos e´ F. Qu ´ı lez del Moral, Elena M. S a´ nchez, and
Jes u´ s F. Arteaga
Department of Organic Chemistry, Institute of Biotechnology, UniVersity of Granada,
AVda. FuentenueVa, 18071 Granada, Spain
afbarre@goliat.ugr.es
Received November 24, 2005
ABSTRACT
The Ti(III)-catalyzed reaction of a series of vinylepoxides leads, with regio- and E-diastereoselectivity control, to good-to-excellent yields of the
corresponding homocoupling products. This homocoupling reaction, which involves a new C C bond-forming method, takes place via a S
−
N
2′
process between an allyltitanium species and the starting vinylepoxide. The process can be used for the rapid and efficient formation of
highly valuable intermediates for organic synthesis, as well as new interesting homologues of natural products.
The structural unit 2,7-dimethylocta-2,6-diene is included in
a number of terpenoids belonging to the families of triter-
penes and carotenes. In this context, 2,7-dimethylocta-2,6-
On the basis of the reductive coupling of terpenic allylic
halides catalyzed by Cp TiCl, which leads, with high yields
2
5
1
and selectivities, to the corresponding R,R′ coupling products
via allyltitanium species (Scheme 2, pathway a), we surmised
that structures such as 1 could be efficiently prepared via
dien-1,8-diol (1) has been widely used as a central building
block for the synthesis of squalene-derived polyethers with
potent cytotoxic activities, such as teurilene, glabrescol,
6a-c
the Cp TiCl-mediated homolytic opening of vinyloxiranes
2
2
thyrsiferol, venustratiol, longilene peroxide, etc. (Scheme 1).
(Scheme 1). Thus, the exposure of vinyloxiranes to catalytic
(
1) Dictionary of Terpenoids; Connolly, J. D., Hill, R. A., Eds.; Chapman
Hall: London, U.K., 1991; Vol. 2, p 1405.
2) (a) Hashimoto, M.; Kan, T.; Nozaki, K.; Yanagiya, M.; Shirahama,
&
Scheme 1
(
H.; Matsumoto, T. J. Org. Chem. 1990, 55, 5088-5107. (b) Hashimoto,
M.; Harigaya, H.; Yanagiya, M.; Shirahama, H. J. Org. Chem. 1991, 56,
2
1
2
229-2311. (c) Morimoto, Y.; Iwai, T.; Kinoshita, T. J. Am. Chem. Soc.
999, 121, 6792-6797. (d) Morimoto, Y.; Kinoshita, T.; Iwai, T. Chirality
002, 14, 578-586. (e) Morimoto, Y.; Iwai, T.; Nishikawa, Y.; Kinoshita,
T. Tetrahedron: Asymmetry 2002, 13, 2641-2647. (f) McDonald, F. E.;
Wei, X. Org. Lett. 2002, 4, 593-595.
(3) (a) Brossas, J.; Pinazzi, C. P.; Clouet, F. J. Polym. Sci., Part A:
Polym. Chem. 1973, 11, 1517-1529. (b) Watanabe, S.; Suga, K.; Watanabe,
T. Chem. Ind. 1970, 1145.
To date, low yields of 1 have been prepared as a mixture
(
4) Lindel, T.; Franck, B. Tetrahedron Lett. 1995, 36, 9465-9468.
3
of stereoisomers via isoprene dimerization or, at 30% overall
(5) Barrero, A. F.; Herrador, M. M.; Qu ´ı lez del Moral, J. F.; Arteaga,
4
yields, in four steps from tiglic acid using Franck’s protocol.
P.; Arteaga, J. F.; Piedra, M.; S a´ nchez, E. Org. Lett. 2005, 7, 2301-2304.
1
0.1021/ol052849w CCC: $33.50
© 2006 American Chemical Society
Published on Web 01/17/2006

We describe here the results of our initial experiments with
the coupling reaction of vinyloxiranes when treated with
catalytic Cp TiCl. Two works on the subject have already
2
Scheme 2
been published: thus, Yadav et al. used an excess of Ti(III)
to reduce internal vinylepoxides to the corresponding allylic
alcohols, to convert terminal vinylepoxides into conjugate
dienes and to synthesize butadienyl alcohols via the deoxy-
1
0
genation of epoxyallylic alcohols.
We started our study by making commercial vinyloxirane
react with 0.2 equiv of Cp TiCl and Mn in excess (8 equiv)
4
2
2
in the presence of 4 and 7 equiv of TMSCl and collidine,
respectively.
Under these conditions, the reaction took place rapidly
and after 10 min a 66% yield of γ,γ′ coupling product 5
together with minor quantities of the γ,R′ regioisomer 6 were
obtained (Table 1, entry 1). The reaction also proved to be
completely diastereoselective, with only E isomers being
obtained.
Table 1. Homocoupling Processes of Vinylepoxides in the
Presence of Catalytic Cp
2
TiCl
Ti(III) in the presence of an excess of TMSCl/collidine (a
combination previously reported to regenerate starting Ti(IV)
species from titanium alcoxides)6d would afford the corre-
sponding â-titanoxy radical I, which would then evolve
toward an allyltitanium species II (an intermediate similar
to that postulated for allylic halides). The latter, acting as a
soft nucleophile, would finally add to a second molecule of
Cp2TiCl2/
sub-
Mn
c
time
yield ratio
(%) γ,γ′:γ,R′
entry strate (equiv) (M) (min) producta
1
2
3
4
5
6
7
8
9
0
4
2
2
2
7
11
2
2
2
2
0.2/8
0.2/8
0.2/8
0.2/8
0.2/8
0.2/8
0.2/8
0.2/8
0.2/8
0.01/8
0.01/4
0.01/8
0.2/8
0.1
0.1
0.1
0.1
0.1
0.1
1
10 5 + 6
10 1 + 3
60 1 + 3
17 1 + 3
15 8 + 9 + 10 75
15 8 + 9 + 10 72
88
92
52
93
3:1
6:1
5:1
5.5:1
1:0
1:0
6:1
6:1
5:1
5:1
5:1
1:0
2:1
b
c
N
the starting vinyloxirane via a S 2′ process (Scheme 2,
pathway b).
Nucleophilic addition to vinylepoxides has been quite
extensively studied, and it transpires that the outcome of the
reaction depends on the degree of hardness of the nucleo-
10 1 + 3
87
90
91
89
92
0.01 10 1 + 3
0.05 70 1 + 3
0.1
0.1
0.1
0.1
d
7
phile. Within this context, palladium complexes have been
1
50 1 + 3
50 1 + 3
50 8 + 9 + 10 75
15 13 + 14 88
reported to promote coupling reactions between vinyloxiranes
11
12
2
11
12
and nucleophiles to give excellent yields of predominantly
8
13
S
N
2′ products. Recently, the copper-catalyzed enantiose-
lective conjugate addition of trialkylaluminum reagents to
a
In most cases, the different isomers obtained in each homocoupling
vinylepoxides using chiral phosphorus-based ligands has been
process were isolated either by column chromatography on AgNO3 (15%)/
b
reported.9
Si gel or by HPLC. For details, see Supporting Information. Reaction
c
carried out at 0 °C. Reaction carried out using 10 mmol of substrate.
d
Reaction carried out in the presence of 20 equiv of acrylonytrile.
(6) The methodology for the homolytic opening of oxyranes using
stoichiometric Ti(III) was initially established by: (a) RajanBabu, T. V.;
Nugent, W. A. J. Am. Chem. Soc. 1994, 116, 986-997. For catalytic
protocols, see: (b) Gans a¨ uer, A.; Bluhm, H.; Pierobon, M. J. Am. Chem.
Soc. 1998, 120, 12849-12859. (c) Gans a¨ uer, A.; Lauterbach, T.; Narayan,
S. Angew. Chem., Int. Ed. 2003, 42, 5556-5573. (d) Justicia, J. J.; Rosales,
A.; Oller-L o´ pez, J. L.; Valdivia, M. V.; Ha ¨ı dour, A.; Oltra, J. E.; Barrero,
A. F.; C a´ rdenas, D. J.; Cuerva, J. M. Chem.-Eur. J. 2004, 10, 1778-
Having efficiently achieved the homocoupling of the
vinyloxirane 4, we subjected 1,2-epoxyisoprene, 2, to the
same experimental conditions to prepare the valuable syn-
thetic intermediate 1. The hoped-for conversion took place
efficiently, with a 76% yield of 1 being obtained as a result
of a γ,γ′ coupling process (entry 2). An additional 16% of
the γ,R′ isomer 3 was isolated. Like that with vinyloxirane,
the reaction was completely diastereoselective toward E
olefins. An increase in the regioselectivity of the process
was also noted. No higher regioselectivity was obtained when
the reaction was carried out at 0 °C; instead, a decrease in
the reaction rate was observed (entry 3).
1
788.
(
7) (a) Rao, A. S.; Paknikar, S. K.; Kirtane, J. G. Tetrahedron 1983, 39,
2
2
323-2367. (b) Restorp, P.; Somfai, P. Chem. Commun. 2004, 18, 2086-
087.
(8) (a) Tsuji, J. In Palladium Reagents and Catalysts; Wiley: Chichester,
U.K., 1995. (b) Godleski, S. A. In ComprehensiVe Organic Synthesis; Trost,
B. M., Fleming, I., Eds.; Pergamon: Oxford, U.K., 1991; Vol. 4, pp 585-
6
61. For some recent examples, see: (c) Nanayakkara, P.; Alper, H. J.
Org. Chem. 2004, 69, 4686-4691. (d) Casta n˜ o, A. M.; M e´ ndez, M.; Ruano,
M.; Echavarren, A. J. Org. Chem. 2001, 66, 589-593. (e) Trost, B. M.;
Bunt, R. C.; Lemoine, R. C.; Calkins, T. L. J. Am. Chem. Soc. 2000, 122,
5
968-5976. (f) Trost, B. M.; Ceschi, M. A.; K o¨ nig, B. Angew. Chem., Int.
Ed. Engl. 1997, 36, 1486-1489. (g) White, J. D.; Jensen, M. S. J. Am.
Chem. Soc. 1995, 117, 6224-6233.
(10) (a) Yadav, J. S.; Shekharam, T.; Srinivas, D. Tetrahedron Lett. 1992,
33, 7973-7976. (b) Yadav, J. S.; Shekharam, T.; Gadgil, V. R. J. Chem.
Soc., Chem. Commun. 1990, 11, 843-844.
(9) Equey, O.; Alexakis, A. Tetrahedron: Asymmetry 2004, 15, 1531-
1
536.
670
Org. Lett., Vol. 8, No. 4, 2006

After analyzing these preliminary results, it seemed
reasonable to anticipate that higher regioselectivities could
be reached by increasing the degree of substitution of the
carbons attached to the oxirane ring. Pleasingly, the coupling
of epoxides 7, methyl (12R,13R + 12S,13S)-12,13-epoxy-
trans-communate (6:4 ratio), was found to be completely
regioselective, leading to a 75% yield of diols 8 (12R,12′R),
diastereomers) (entry 13). There was also a decrease in the
regioselectivity of the homocoupling process compared to
the results found with acyclic epoxides. The formation of
13 is of additional interest because its oxidation leads
satisfactorily to ketones 16 and 17 (1:1), which have been
used as the starting substrate in the search of liquid crystals
1
2
(Scheme 5).
9
(12R,12′S), and 10 (12S,12′S) (entry 5, Scheme 3). Only
Scheme 5
Scheme 3a
These results are in agreement with the mechanisms
proposed in pathway (b) of Scheme 2. This proposal involves
1
13
either an η -allyltitanium species (II), which would be
added to the starting oxirane via a S 2′ process, or a
N
dimerization of the intermediate allylic radical (I). The
following experimental data were taken into account to
decide between the two possible pathways. Changes in the
concentration of the starting material, 2, do not affect the
outcome of the reaction to any significant degree (entries 7
and 8). Furthermore, when 2 is treated with Ti(III) in the
presence of the radical trap acrylonitrile, no additional
products were detected (entry 9).
Additionally, the reductions of vinylepoxides reported by
Yadav et al. can also be attributed to the participation of
allyltitanium intermediates. All of the above seems to indicate
that the allyltitanium species is likely to be the intermediate
involved in these coupling processes, although a dimerization
of the intermediate allylic radical I should not be ruled out.
Thus, a catalytic cycle justifying the regeneration of the
Ti(III) reagent is shown in Scheme 6.
a
Together with 1, 5, and 13, the corresponding γ,R′ regioisomers
3
, 6, and 14 were also obtained (cf. Table 1 for proportions).
E olefins were obtained. Similar results were obtained when
epoxides 11, methyl (12R,13S + 12S,13R)-12,13-epoxy-cis-
communate (57:43 ratio), were made to react under identical
conditions, with a 72% yield of diols 8-10 being isolated
entry 6). Diols 8-10 were made to converge easily to the
same diketone, 15, by oxidation with Dess-Martin perio-
dinane at a yield of 71% (Scheme 4). Compounds 8-10 and
(
1
5 can be considered analogues of natural onoceranes with
potential bioactivity.
11
Bearing in mind that an increase in the degree of
substitution on the oxirane favors the existence of the species
IIb (possessing E stereochemistry), a type V intermediate,
involving an intermolecular association between the allyl-
titanium species and the starting vinylepoxide (Scheme 7),
may well account for the observed γ,γ′ regioselectivity and
Scheme 4
1
E,E diastereoselectivity. In V, the substituent R must adopt
an axial orientation to allow the proposed chairlike geometry,
which explains satisfactorily the complete diastereoselectivity
toward E olefins that we found. Furthermore, the similarity
of the results obtained with the diastereomeric 12,13-epoxides
7
or 11 (entries 5 and 6) supports the existence of this
intermediate.
When the reaction was made with cyclic vinylepoxide 12,
diol 13 was obtained as major compound (as a mixture of
(
12) Hoffmann, R. W.; Brandl, T.; Kirsch, P.; Harmas, K. Synlett 2001,
9
60-963.
1
(
13) Existence of η -allyltitanium species in equillibrium has been
(11) Orhan, I.; Terzioglu, S.; Sener, B. Planta Med. 2003, 69, 265-
postulated previously: Kasatkin, A.; Nakagawa, T.; Okamoto, S.; Sato, F.
2
67.
J. Am. Chem. Soc. 1995, 117, 3881-3882.
Org. Lett., Vol. 8, No. 4, 2006
671

Scheme 6
Scheme 7
2
In summary, the reduction of vinyloxiranes with Cp TiCl
resulted in good-to-excellent yields of homocoupling prod-
ucts and good control of the regio- and diastereoselectivity
of the process was maintained in most cases. This is a
completely novel carbon-carbon bond-forming reaction
compatible with a number of functional groups. The process
leads to the rapid, efficient formation of highly-functionalized
intermediates for the synthesis of organic compounds such
as 1 and 13 or new hybrids of natural products such as
homoonoceranes.
The satisfactory results obtained when 2, 7, and 11 were
used as substrates for coupling prompted us to test the
feasibility of achieving this process while lowering the
Acknowledgment. This research was supported by the
Spanish Ministry of Science and Technology. Project BQU
002-03211. Thanks go to our colleague Dr. J. Trout for
revising our English text.
2
2 2
quantities of Cp TiCl and Mn used. In the case of 2, when
the quantity of titanium was reduced 20 times, only a slight
decrease of the reaction rate was noted but yields remained
similar (entry 10). Comparable results were found when the
quantity of Mn was reduced by half (entry 11). Similarly,
Supporting Information Available: Experimental pro-
1
cedures and spectroscopic data of new compounds and H
1
3
and C NMR spectra of 1, 3, 5-10, 12, 13, and 15-17.
This material is available free of charge via the Internet at
http://pubs.acs.org.
2
when epoxides 11 were treated with 0.01 equiv of Cp TiCl
and 8 equiv of Mn, 75% of the corresponding γ,γ′ coupling
products was obtained (entry 12). We believe that the
repetition of results when the quantity of reagents is notably
reduced increases the potential interest of this protocol.
OL052849W
672
Org. Lett., Vol. 8, No. 4, 2006