Expedient construction of multiple stereogenic centers in an acyclic system via the addition of aldehydes, ketones, and chiral imines to an enyne-titanium alkoxide complex

Full text of DOI:10.1021/ja001334r

7138
J. Am. Chem. Soc. 2000, 122, 7138-7139
Scheme 1. Stereoselective and -specific Addition of
Enyne-Titanium Complex to Aldehyde
Expedient Construction of Multiple Stereogenic
Centers in an Acyclic System via the Addition of
Aldehydes, Ketones, and Chiral Imines to an
Enyne-Titanium Alkoxide Complex
Takashi Hamada, Ryo Mizojiri, Hirokazu Urabe, and
Fumie Sato*
Department of Biomolecular Engineering
Tokyo Institute of Technology, 4259 Nagatsuta-cho
Midori-ku, Yokohama, Kanagawa 226-8501, Japan
ReceiVed April 17, 2000
Stereoselective construction of an array of several stereogenic
centers in one flask should constitute an important method in
organic synthesis,1 especially when this process could be per-
formed in an asymmetric fashion. Herein we describe a regio-
and stereoselective addition reaction of aldehydes, ketones, or
imines to one or both of the two carbon-titanium bonds of a
conjugated enyne-titanium alkoxide complex 1 (eq 1),2-4 which
creates up to three new consecutive stereo-defined carbon centers
as formulated in 1 f 2. The product 2 has allenic axial chirality,
the synthetic utility of which has become more and more
appreciated recently,5 as well as sp3 chirality due to the substit-
uents on the carbon chain.
i-PrMgCl in situ,6 to generate the enyne-titanium complex 5
(Scheme 1), as evidenced by the protonolysis and deuteriolysis
of the complex that cleanly afforded the stereo-defined diene 6
(exclusively Z,Z-isomer). The addition of the enyne complex 5
to benzaldehyde (0.7 equiv) proceeded in a quite different fashion
from a simple (η2-1-silyl-1-alkyne)Ti(O-i-Pr)2 complex reported
previously by us.6b Thus, the reaction proceeded at the remote
olefinic carbon to give the allenyl alcohol 7 as a mixture of only
two diastereoisomers out of the four possible ones. The other
carbon-titanium bond in 5 not participating in the aldehyde
addition was identified by deuteriolysis to give 7-d1 with high
deuterium incorporation on the allene carbon. Oxidation of 7
afforded the ketone 8 virtually as a single isomer, which shows
that the diastereoisomers of 7 as alcohol epimers. This was further
confirmed by deoxygenation of the hydroxy group to give known
allene 97 as a single isomer,8 which established the relative
stereochemistry of the allene moiety and the methyl group in 7.
The same reaction starting from the isomeric (E)-enyne 10 (>99%
E) afforded exclusively a different set of products as shown by
the sequence 10 f 11 f 12, or 11 f 13 f 14, or 13 to the
known allene 157 (Scheme 1). Thus, the stereochemical integrity
of the olefinic portion of the starting enynes was completely
transmitted to the series of products, which allows the stereo-
specific and selective preparation of allene derivatives from the
enynes. This reaction has broad applicability with respect to both
enynes and aldehydes (or ketones), which is shown in Supporting
Information.8
In place of the simple hydrolytic workup mentioned above,
further reaction of the intermediate adduct with an aldehyde or a
ketone should broaden the utility of this method. When the
titanium complex 5 was first treated with acetone8 and then with
benzaldehyde or heptanal, a single adduct 16 or 17 was obtained
(Scheme 2). Diol 16 crystallized from toluene to give large prisms,
X-ray crystallography of which unambiguously determined the
structure of 16. Alternatively, complex 5 was intercepted first
with benzaldehyde and then with pivalaldehyde9 to give a 58:42
mixture of two diols 18, the ratio of which paralleled the mixture
of adduct 7 obtained by the simple hydrolysis (61:39, Scheme
1), suggesting that the reaction with pivalaldehyde proceeds with
excellent stereoselectivity. This hypothesis was verified by the
selective deoxygenation of the benzylic hydroxy group of 18,
which resulted in the formation of the corresponding tert-butyl
carbinol as a single isomer.8 The structure of 18 was deduced
based on 16. The same sequence from (E)-enyne 10, acetone,
(Z)-Enyne 4 (99.5% Z) was treated with (η2-propene)Ti(O-i-
Pr)2 (3) (1.25 equiv), readily prepared from Ti(O-i-Pr)4 and
(1) Although there are numerous methods available for the stereoselective
construction of two stereogenic centers, those for more than three in an
asymmetric fashion are less common. Carruthers, W. Cycloaddition Reactions
in Organic Synthesis; Pergamon Press: Oxford, 1990. Trost, B. M.; Fleming,
I., Eds. ComprehensiVe Organic Synthesis; Pergamon Press: Oxford, 1991;
Vol. 5. Bunce, R. A. Tetrahedron 1995, 51, 13103-13159. Parsons, P. J.;
Penkett, C. S.; Shell, A. J. Chem. ReV. 1996, 96, 195-206. Tietze, L. F. Chem.
ReV. 1996, 96, 115-136.
(2) For review on group 4 metal-acetylene and -olefin complexes, see:
Buchwald, S. L.; Nielsen, R. B. Chem. ReV. 1988, 88, 1047-1058. Negishi,
E.; Takahashi, T. Acc. Chem. Res. 1994, 27, 124-130. Ohff, A.; Pulst, S.;
Lefeber, C.; Peulecke, N.; Arndt, P.; Burlakov, V. V.; Rosenthal, U. Synlett
1996, 111-118. Negishi, E.; Takahashi, T. Bull. Chem. Soc. Jpn. 1998, 71,
755-769.
(3) A few group 4 metal-conjugated enyne complexes were reported, but
their unique synthetic utility has not been pursued. Stepnicka, P.; Gyepes, R.;
C´ısarova´, I.; Hora´cek, M.; Kubista, J.; Mach, K. Organometallics 1999, 18,
4869-4880. Takahashi, T.; Xi, Z.; Nishihara, Y.; Huo, S.; Kasai, K.; Aoyagi,
K.; Denisov, V.; Negishi, E. Tetrahedron 1997, 53, 9123-9134.
(4) Cf. group 4 metal-acetylene complexes are known to add to aldehydes,
ketones, or imines, but the reaction stops at the stage of mono-addition (see
literature cited in references 2, 6, and 10). For the double addition to group
4 metal-olefin or -diene complexes, see: Thorn, M. G.; Hill, J. E.; Waratuke,
S. A.; Johnson, E. S.; Fanwick, P. E.; Rothwell, I. P. J. Am. Chem. Soc. 1997,
119, 8630-8641. Yasuda, H.; Tatsumi, K.; Nakamura, A. Acc. Chem. Res.
1985, 18, 120-126.
(5) Wender, P. A.; Glorius, F.; Husfeld, C. O.; Langkopf, E.; Love, J. A.
J. Am. Chem. Soc. 1999, 121, 5348-5349. Brummond, K. M.; Wan, H.; Kent,
J. L. J. Org. Chem. 1998, 63, 6535-6545. Urabe, H.; Takeda, T.; Hideura,
D.; Sato, F. J. Am. Chem. Soc. 1997, 119, 11295-11305. Jin, J.; Weinreb, S.
M. J. Am. Chem. Soc. 1997, 119, 5773-5784. Shepard, M. S.; Carreira, E.
M. J. Am. Chem. Soc. 1997, 119, 2597-2605. Ha, J. D.; Lee, D.; Cha, J. K.
J. Org. Chem. 1997, 62, 4550-4551. Marshall, J. A.; Wolf, M. A.; Wallace,
E. M. J. Org. Chem. 1997, 62, 367-371. Yoshida, Y.; Okamoto, S.; Sato, F.
J. Org. Chem. 1996, 61, 7826-7831 and references therein. For stereospecific,
electrophlic addition to silylallenes, see: Fleming, I.; Dunogue´s, J.; Smithers,
R. In Organic Reactions; Kende, A. S., Ed.; Wiley: New York, 1989; Vol.
37, pp 57-575. Masse, C. E.; Panek, J. S. Chem. ReV. 1995, 95, 1293-1316.
Fleming, I.; Barbero, A.; Walter, D. Chem. ReV. 1997, 97, 2063-2192.
Marshall, J. A.; Maxson, K. J. Org. Chem. 2000, 65, 630-633. The allenes
used in these reports were prepared through the SN2′ displacement of propargyl
alcohol derivatives. Thus, the conversion of eq 1 should provide a different
way to make such allenes.
(6) (a) Sato, F.; Urabe, H.; Okamoto, S. Pure Appl. Chem. 1999, 71, 1511-
1519. (b) Harada, K.; Urabe, H.; Sato, F. Tetrahedron Lett. 1995, 36, 3203-
3206.
(7) Myers, A. G.; Zheng, B. J. Am. Chem. Soc. 1996, 118, 4492-4493.
(8) See Supporting Information.
(9) Pivalaldehyde was chosen as the second aldehyde in order to discrimi-
nate between the two hydroxy groups in 18 for structural determination.
10.1021/ja001334r CCC: $19.00 © 2000 American Chemical Society
Published on Web 07/08/2000

Communications to the Editor
J. Am. Chem. Soc., Vol. 122, No. 29, 2000 7139
Table 1. Asymmetric Construction of Three Stereogenic Centers
Scheme 2. Sequential Stereospecific and -selective Addition
of Two Carbonyl Compounds
enyne
entry R1
imine
R2
yield
El+
El
product (%) dsa
1
2
3
4
5
Me
10 Et
23 H+
23 Me2CdO Me2C(OH)-
H
24
25
29
30
31
67 95:5
45 93:7
67 92:8
53 93:7
53 97:3
C6H13 26 Et
Me
Me
23 H+
H
H
H
10 Me 27 H+
10 i-Bu 28 H+
a This value most likely reflects the degree of asymmetric induction.
react with 23, allenylamine 24 was produced as a 95:5 mixture
of two isomers unaccompanied with the remaining six possible
isomers. The relative and absolute stereochemistry of the major
allenylamine 24 was determined by derivatization and correlation
to known compounds,8 which also revealed that the selectivity
of 95:5 in this case most likely stems from the asymmetric
induction step (i.e., the relative stereochemistry between the
phenethylamine part and the remainder of the molecule) rather
than the alignment of substituents on the allene chain. More
examples, including the carbonyl addition of the intermediate
titanium species, are summarized in Table 1, which shows that
diastereoselectivities up to 97:3 for the three newly created chiral
centers could be achieved by this method.
Scheme 3. Addition of Enyne-Titanium Complex to Imines
The above transformations appear to be very practical, because
(i) the stereo-defined conjugated enynes are readily accessible
by the Sonogashira coupling reaction,12 (ii) the optically active
imines are derived from inexpensive phenylethylamine in one step,
and (iii) the reagents, the titanium alkoxide and Grignard reagent,
are available at low cost. A preliminary rationalization of
stereochemical course of these reactions is presented in Supporting
Information; however essential information on the structures of
the reacting intermediates as well as the stereo- and regiochemical
patterns of the organotitanium reactions is so far not available.13
and an aldehyde afforded virtually a single product 19 or 20,
which proved to be isomeric to 16 or 17, respectively. The
structure of 19 was unambiguously assigned by correlation to 16
of the established structure.8 These results demonstrated that the
tandem addition of aldehydes or ketones to both the carbon-
titanium bonds in 1 serves for the construction of three stereogenic
centers in an acyclic system.
As far as the coupling partners are concerned, imines impart
more advantages to this reaction as regards the selectivity and
asymmetric synthesis (Scheme 3). The acetylene complex 11
reacted with an achiral imine 21 to afford an allenylamine 22
virtually as a single isomer.10 This is in marked contrast to the
aforementioned aldehyde addition, which usually gave rise to the
formation of a mixture of two isomeric alcohols. The structure
assigned to 22 was verified by the comparison with authentic
samples.8 It should be noted that the relative stereochemistry of
the allene moiety and the methyl group in 22 is different from
that of the corresponding aldehyde adduct 13 obtained from the
same E-enyne (Scheme 1), suggesting a different stereochemical
approach between aldehydes and imines to the enyne-titanium
complex. Gratifyingly, extension of this reaction to an asymmetric
version starting with N-(R-phenylethyl)imines11 such as 23 turned
out to be quite promising. When the complex 11 was allowed to
Acknowledgment. We thank the Ministry of Education, Science,
Sports and Culture (Japan) for financial support and Prof. Munetaka Akita
of this institute for X-ray crystallography.
Supporting Information Available: Addendum to Scheme 1, typical
procedures and characterization data for starting materials and products,
and rationalization of the stereochemical outcome of the reaction (PDF).
This material is available free of charge via the Internet at http://pubs.acs.org.
JA001334R
(11) Juaristi, E.; Leo´n-Romo, J. L.; Reyes, A.; Escalante, J. Tetrahedron:
Asymmetry 1999, 10, 2441-2495. Bloch, R. Chem. ReV. 1998, 98, 1407-
1438. Enders, D.; Reinhold: U. Tetrahedron: Asymmetry 1997, 8, 1895-
1946. Gao, Y.; Sato, F. J. Org. Chem. 1995, 60, 8136-8137.
(12) Sonogashira, K. In ComprehensiVe Organic Synthesis; Trost, B. M.;
Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 3, pp 521-549.
(13) For the reactions of organotitanium compounds, see: Reetz, M. T.
Organotitanium Reagents in Organic Synthesis; Springer-Verlag: Berlin, 1986.
Ferreri, C.; Palumbo, G.; Caputo, R. In ComprehensiVe Organic Synthesis;
Trost, B. M.; Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 1, pp
139-172. Reetz, M. T. In Organometallics in Synthesis; Schlosser, M., Ed.;
Wiley: Chichester, 1994; pp 195-282.
(10) The addition to imines must be carried out in ether-THF (1:1) rather
than ether (cf. Schemes 1 and 2); otherwise, a mixture of allenylamine and
undesired dienylamine is produced. Unfortunately, (Z)-enyne complex 5
behaved like a simple acetylene-titanium complex to furnish only dienyl-
amines. For the reaction of the simple acetylene complexes with imines, see:
Gao, Y.; Harada, K.; Sato, F. Tetrahedron Lett. 1995, 36, 5913-5916.