Stereoselective Construction of Acyclic Carbon Chains by a One-Pot Coupling Process Based on Alkenyloxazoline-Titanium Complexes

Article abstract of DOI:10.1002/anie.200352769

A versatile organometallic intermediate, an alkenyloxazoline-titanium complex, has been developed that enables one-pot multicomponent diastereoselective and asymmetric coupling processes to be achieved in a remarkably efficient manner (see scheme).

Full text of DOI:10.1002/anie.200352769

Communications
asymmetric synthesis.[1] Complexation of organic compounds
having this group with transition metals may lead to the
development of unique synthetic transformations,[2] but an
olefin complex such as the one in Scheme 1 (M = metal)[3] has
not been investigated. We report here that titanation of
alkenyloxazolines proceeds nicely to give novel olefin–tita-
nium complexes (Scheme 1,M = Ti(OiPr)2),which subse-
quently allow for a diastereoselective multicomponent cou-
pling process and an asymmetric coupling reaction.
Scheme 1. Generation of the olefin–metal complex.
Treatment of alkenyloxazoline 2[4] with a titanium(ii)
alkoxide reagent 1 formed from Ti(OiPr)4 with two equiv-
alents of iPrMgCl,[5] generates olefin complex 3,[6] which
underwent a coupling reaction with 1-octyne (4) to give
titanacycle 6 (R = C6H13; Scheme 2). Intermediates 3 and 6
were identified by deuteriolysis.[7] The carbon–titanium bond
a to the oxazoline (rather than the vinyl–titanium bond) of 6
selectively reacted with the octanal to give,after hydrolytic
Asymmetric Synthesis
Stereoselective Construction of Acyclic
Carbon Chains by a One-Pot Coupling
Process Based on Alkenyloxazoline–
TitaniumComplexes**
Kazuhisa Mitsui, Takayuki Sato, Hirokazu Urabe,*
and Fumie Sato*
Oxazoline is known as a versatile functional group in
organic synthesis for the activation of substrates and for
[*] K. Mitsui, T. Sato, Prof. H. Urabe
Department of Biological Information
Graduate School of Bioscience and Biotechnology
Tokyo Institute of Technology
4259 Nagatsuta-cho, Midori-ku, Yokohama
Kanagawa 226-8501 (Japan)
Fax: (+81)45-924-5826
Scheme 2. Four-component coupling process.
E-mail: hurabe@bio.titech.ac.jp
Prof. F. Sato
work-up,a single regioisomer 8 having exclusively an E-
olefinic bond. Surprisingly,the crude reaction mixture con-
tained this adduct 8 together with a very small amount of one
of the four possible diastereoisomers (d.r. = 96:4) arising from
the three consecutive stereogenic centers. Compound 8 could
be readily separated from this minor isomer[8] by flash
chromatography on silica gel to give a pure sample in 66%
yield. The stereochemistry of 8 was determined (as depicted)
by derivatization.[7] A stereochemical course from 2 to 8 is
proposed in the Supporting Information.[7] Analogously,the
sequential treatment of 2 with silylacetylene 5 and nonanal
Department of Biomolecular Engineering
Graduate School of Bioscience and Biotechnology
Tokyo Institute of Technology
4259 Nagatsuta-cho, Midori-ku, Yokohama
Kanagawa 226-8501 (Japan)
Fax: (+81)45-924-5826
E-mail: fsato@bio.titech.ac.jp
[**] We thank the Japan Society for the Promotion of Science and Kurata
Foundation (to H.U.) for financial support and Professor Munetaka
Akita of this institute for the X-ray crystallographic analysis.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
490
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DOI: 10.1002/anie.200352769
Angew. Chem. Int. Ed. 2004, 43, 490 –492

Angewandte
Chemie
afforded the adduct 9 in good yield. In place of the simple
hydrolysis,deuteriolysis or iodinolysis of the remaining vinyl–
titanium bond in the intermediate 7 (R = SiMe3) gave
deuterium-labeled and iodinated products 10 and 11,respec-
tively. Thus,the four-component coupling of the unsaturated
oxazoline,acetylene,aldehyde,and an electrophile proceeded
in one pot with nearly complete regio-,olefinic stereo-,and
diastereoselectivities to give an acyclic carbon chain of the
defined structure.[9] This and the following transformations
were made possible by the collaboration of the aforemen-
tioned feature of oxazolines and the behavior of the
olefin–metal complex.
Scheme 3. Stereochemistry of the starting alkenyloxazoline.
More results regarding the transformation of Scheme 2
are summarized in Table 1. The combination of oxazoline 2,
acetylene 4 or 5,and a variety of aldehydes always showed
able than the Z isomers,and hence the former are,syntheti-
cally,the substrates of choice.
Oxazoline is a potential chiral auxiliary,[1] so we next
pursued the possibility of an asym-
metric coupling reaction between
Table 1: Diastereoselective coupling reaction of oxazolines, acetylenes, and aldehydes according to
the oxazoline–titanium complex
and acetylene (Table 2). Oxazo-
lines 25–27[4] (R = Et, tBu,and iPr
groups,respectively) were used in
the reaction (entries 1–3) to eval-
uate the chiral induction by the
oxazoline substituent R. Of these
substrates,oxazoline 27 (R = iPr)
prepared from (S)-valinol showed
the most satisfactory result
(entry 3). High chiral induction of
92:8–96:4 was uniformly observed
with the valinol-derived oxazolines
27–30 to give coupling products
34–38 in good yields (entries 4–
8).[14] The stereochemistry of the
products 31 and 33 was unambigu-
ously determined as depicted by
derivatization to a known com-
pound.[7] Optically active allylsi-
lane 38[11] was easily prepared
Scheme 2.
Entry
Oxazoline
Acetylene
R2
Aldehyde
R3
Product
R1
Yield [%][a]
d.r.[b]
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
Ph
Ph
Ph
2
2
2
2
2
C6H13
C6H13
C6H13
SiMe3
SiMe3
SiMe3
SiMe3
SiMe3
SiMe3
4
4
4
5
5
5
5
5
5
C8H17
(E)-C5H11CH CH
Ph
C8H17
iPr
8
15
16
9
17
18
20
21
8
66
54
68
73
72
70
62
60
48
96:4
88:12
92:8
93:7
90:10
95:5
96:4
95:5
89:11
=
À
2
Ph
p-ClC6H4
12
13
14
C8H17
C8H17
C8H17
[c]
1-C10H7
SiMe3
[a] Yield of the isolated pure major isomer after chromatographic separation on silica gel.
[b] Diastereoselectivity of a crude sample. Two stereoisomers were detected in the crude reaction
mixture. [c] 1-Naphthyl.
Table 2: Asymmetric induction in the coupling of chiral oxazolines and acetylenes.
high diastereoselectivities (entries 1–6). The
structure of product 18 (entry 6) was also
confirmed by X-ray crystallographic analy-
sis.[7,10] The aryl-substituted vinyloxazolines
12 and 13 also participated in the reaction
(entries 7 and 8). Entry 9 illustrates the
diastereoselective preparation of function-
alized allylsilane 21[11] from (silylvinyl)oxa-
zoline 14.[12]
Entry
Oxazoline
R1
Acetylene
Product
R
R2
Yield [%][a]
d.r.[b]
1
2
3
4
5
6
7
8
Et
Ph
Ph
Ph
Ph
p-ClC6H4
p-ClC6H4
1-C10H7
25
26
27
27
28
28
29
30
C6H13
C6H13
C6H13
SiMe3
C6H13
SiMe3
SiMe3
SiMe3
4
4
4
5
4
5
5
5
31
32
33
34
35
36
37
38
65
52
72
73
67
74
54
63
75:25[b,c]
92:8[d]
93:7[b]
92:8[b,d]
96:4[d]
94:6[d]
95:5[d]
95:5[d]
While all reactions described above
started with E-alkenyloxazolines, Z-alkeny-
loxazolines such as 22[13] in Scheme 3 gave
the same product 9 previously obtained
from the E-oxazoline 2 (see Scheme 2).
Rapid isomerization of the initially formed
olefin complex 23 to less sterically con-
gested 3 via the azatitanacyclopentene 24
should account for this phenomenon. The
E-olefinic oxazolines are more readily avail-
tBu
iPr
iPr
iPr
iPr
iPr
iPr
[e]
SiMe3
[a] Yield of isolated product. [b] Enantioselectivity of the carboxylic acid produced after hydrolysis of the
oxazoline. [c] In practice, the antipode of 25 was used. [d] Diastereoselectivity of a crude sample. [e] 1-
Naphthyl.
Angew. Chem. Int. Ed. 2004, 43, 490 –492
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Communications
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The oxazoline moiety of the above products should be
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8641. However,in these cases,the notion of diastereoselective
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complexes could be used for diastereoselective transformations
as described in the text,but their generation and the subsequent
reactions appear to be retarded because of the enhanced steric
hindrance around the olefin portion. Indeed,few examples of
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useful for further transformations.[1] For example,hydrolysis
of 34 with dilute aqueous acid effected concomitant desilyl-
ation (Scheme 4) to give a 3-aryl-4-pentenoic acid 39,which is
a known precursor for the synthesis of neurokinin receptor
antagonists.[15]
M. D. Rausch, J.Am.Chem.Soc.
1983, 105,416 – 426; J. M.
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Scheme 4. Synthetic application.
In conclusion,the novel alkenyloxazoline–titanium com-
plexes proved to be a versatile template for diastereoselective
and asymmetric coupling reactions. Further investigation on
the utility of these functionalized olefin–titanium complexes
and the synthetic application of the products obtained here is
in progress.
[10] CCDC-218515 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/conts/retrieving.html (or from the Cam-
bridge Crystallographic Data Centre,12 Union Road,Cam-
bridge CB21EZ,UK; fax: ( + 44)1223-336-033; or deposit@
ccdc.cam.ac.uk).
[11] For reviews,see: T. K. Sarkar in Science of Synthesis, Vol.4 ,
Organometallic Compounds of As, Sb, Bi and Si (Ed.: I.
Received: September 2,2003 [Z52769]
Fleming),Georg Thieme,Stuttgart,
2002,pp. 837 – 925; I.
Fleming,A. Barbero,D. Walter, Chem.Rev. 1997, 97,2063 –
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Synthesis 1990,1101 – 1111.
Keywords: asymmetric synthesis · C-C coupling ·
diastereoselectivity · metallacycles · oxazolines
.
[12] When the aryl or silyl substituent of vinyloxazolines is replaced
with an alkyl group,the desired coupling product was not
formed. For silicon-assisted stabilization of olefin–titanium
alkoxide complexes,see R. Mizojiri,H. Urabe,F. Sato,
Tetrahedron Lett. 1999, 40,2557 – 2560; R. Mizojiri,H. Urabe,
F. Sato, J.Org.Chem. 2000, 65,6217 – 6222.
[13] The pure Z isomer was prepared by the treatment of the
(phenylethynyl)oxazoline with 1 followed by hydrolysis. The
generation and utility of the intermediate alkynyloxazoline–
titanium alkoxide complex will be reported in due course.
[14] The further addition of benzaldehyde to the intermediate
titanacyclopentene generated according to entry 4 in Table 2
afforded most likely an 82:13:5 mixture of three isomeric
products in 67% yield,which nearly appears to be the sum of the
observations of Tables 1 and 2.
[1] For reviews,see: a) K. A. Lutomski,A. I. Meyers in Asymmetric
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[2] Aryloxazoline–transition metal complexes have found useful
applications; see ref. [1b] and A. R. Pape,K. P. Kaliappan,E. P.
Kündig, Chem.Rev. 2000, 100,2917 – 2940.
[3] The olefin complex could be depicted by a few limiting
structures involving 24,but all of these are represented by the
general form of the metallacyclopropane shown in Scheme 1.
[4] For their preparation,see: M. C. Elliott,E. Kruiswijk, J.Chem.
Soc.Perkin Trans.1 1999,3157 – 3166.
[15] N.-Y. Shih,M. Albanese,J. C. Anthes,N. I. Carruthers,C. A.
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Seidl,S.-C. Wong,J. J. Piwinski, Bioorg.Med.Chem.Lett. 2002,
12,141 – 145.
[5] F. Sato,H. Urabe in Titanium and Zirconium in Organic
Synthesis (Ed.: I. Marek),Wiley-VCH,Weinheim,
pp. 319 – 354; F. Sato,S. Okamoto, Adv.Synth.Catal.
2002,
2001,
343,759 – 784; J. J. Eisch, J. Organomet.Chem. 2001, 617–618,
148 – 157; F. Sato,H. Urabe,S. Okamoto, Chem.Rev. 2000, 100,
2835 – 2886; O. G. Kulinkovich,A. de Meijere, Chem.Rev. 2000,
100,2789 – 2834.
[6] For reviews on olefin complexes of Group 4 metals,see: ref. [5];
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[7] For details,see the Supporting Information.
[8] The stereochemistry of the minor isomer has not been deter-
mined.
[9] Multicomponent coupling of the ethylene—Group 4 metal
complex,acetylene,and aldehyde (or ketone) was reported:
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492
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Angew. Chem. Int. Ed. 2004, 43, 490 –492