Preparation of syn -Tertiary homoallylic alcohols utilizing allenyltitanocenes generated by reductive titanation of γ- Trimethylsilylpropargylic carbonates

Article abstract of DOI:10.1021/ol100395n

Figure presented syn-Tertiary homoallylic alcohols were obtained by the reaction of α-silylallenyltitanocenes generated by the reductive titanation of γ-silylpropargylic carbonates with Cp₂Ti[P(OEt) ₃]₂ with ketones and fo

Full text of DOI:10.1021/ol100395n

ORGANIC
LETTERS
2010
Vol. 12, No. 9
1968-1971
Preparation of syn-Tertiary Homoallylic
Alcohols Utilizing Allenyltitanocenes
Generated by Reductive Titanation of
γ-Trimethylsilylpropargylic Carbonates
Yasutaka Yatsumonji, Takenori Sugita, Akira Tsubouchi, and Takeshi Takeda*
Department of Applied Chemistry, Graduate School of Engineering, Tokyo UniVersity
of Agriculture and Technology, Koganei, Tokyo 184-8588, Japan
takeda-t@cc.tuat.ac.jp
Received February 16, 2010
ABSTRACT
syn-Tertiary homoallylic alcohols were obtained by the reaction of r-silylallenyltitanocenes generated by the reductive titanation of
γ-silylpropargylic carbonates with Cp2Ti[P(OEt)3]2 with ketones and following desilylation and partial hydrogenation. High diastereoselectivity
was observed when aromatic and r,ꢀ-unsaturated ketones were employed.
Recently, much attention has been paid to the stereocon-
trolled construction of adjacent stereogenic centers. Addition
of allylmetal species to ketones, therefore, has been exten-
sively studied as a useful tool for the stereoselective
preparation of anti-homoallylic alcohols bearing a quaternary
center.1 We have studied the reaction of allyltitanocenes
generated by the reductive titanation of allylic sulfides or
related allylic substrates with a titanocene(II) species with
ketones. With this protocol, anti-tertiary homoallylic alcohols
were obtained with unprecedentedly high diastereoselectivity
even when sterically less congested methyl ethyl ketone and
methyl vinyl ketone were employed.2 In contrast to the
preparation of anti-tertiary homoallylic alcohols, there are
only a few reports on the diastereoselective preparation of
syn-counterparts.3-5 Knochel et al., for example, have
recently achieved a highly diastereoselective preparation of
syn-tertiary homoallylic alcohols by the reaction of ꢀ-silyl
substituted crotylzinc reagents with acetophenone derivatives
and subsequent desilylation.3 Our recent results on the three-
component coupling of thioacetals, alkynyl sulfones, and
carbonyl compounds6 prompted us to develop a new route
to syn-tertiary homoallylic alcohols 1 utilizing γ-silylprop-
argyl carbonates 2 as starting materials (Scheme 1). Our new
approach consists of the reaction of R-silylallenyltitanocenes
3, generated by the reductive titanation of 2 with the
(1) (a) Denmark, S. E.; Almstead, N. G. In Modern Carbonyl Chemistry;
Otera, J., Ed.; Wiley-VCH: Weinheim, 2000; Chapter 10. (b) Chemler, S. R.;
Roush, W. R. In Modern Carbonyl Chemistry; Otera, J., Ed.; Wiley-VCH:
Weinheim, 2000; Chapter 11. (c) Risch, N.; Arend, M. In StereoselectiVe
Synthesis, Methods of Organic Chemistry (Houben-Weyl); Helmchen, G.,
Hoffmann, R., Mulzer, J., Schaumann, E., Eds.; Thieme: Stuttgart, 1996;
Vol. 3, pp 1357-1602. (d) Szymoniak, J.; Mo¨ıse, C. In Titanium and
Zirconium in Organic Synthesis; Marek, I., Ed.; Wiley-VCH: Weinheim,
2002; Chapter 13. (e) Dunet, G.; Mayer, P.; Knochel, P. Org. Lett. 2008,
9, 117–120. (f) Ren, H.; Dunet, G.; Mayer, P.; Knochel, P. J. Am. Chem.
Soc. 2007, 129, 5376–5377. (g) Li, S. W.; Batey, R. A. Chem. Commun.
2004, 1382–1383. (h) Yasuda, M.; Hirata, K.; Nishino, M.; Yamamoto,
A.; Baba, A. J. Am. Chem. Soc. 2002, 124, 13442–13447. (i) Thadani, A. N.;
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Yamahata, T.; Tani, K. Organometallics 1997, 16, 4788–4795. (k) Yama-
moto, Y.; Yatagai, H.; Naruta, Y.; Maruyama, K. J. Am. Chem. Soc. 1980,
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(2) Yatsumonji, Y.; Nishimura, T.; Tsubouchi, A.; Noguchi, K.; Takeda,
T. Chem.sEur. J. 2009, 15, 2680–2686.
(3) Helm, M. D.; Mayer, P.; Knochel, P. Chem. Commun. 2008, 1916–
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2004, 126, 8910–8911
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10.1021/ol100395n  2010 American Chemical Society
Published on Web 03/31/2010

Scheme 1
Table 1. Preparation of Homopropargylic Alcohols 6 Utilizing
Propargylic Carbonate 2aa
titanocene(II) reagent Cp2Ti[P(OEt)3]2 4, with ketones 5
followed by desilylation and partial hydrogenation of the
triple bond of the resulting δ-silylhomopropargylic alco-
hols 6.
We first examined the regio- and diastereoselectivity of
the addition of organotitanium species 3 to various carbonyl
compounds 5 (Table 1). The treatment of allenyltitanium
species 3a generated from the propargyl carbonate 2a with
hydrocinnamaldehyde (5a) at 0 °C for 2 h regioselectively
gave the homopropargyl alcohol 6a as an almost 1:1 mixture
of the diastereomers (entry 1). A similar reaction using the
aralkyl methyl ketone 5b produced the homopropargyl
alcohol 6b with moderate diastereoselectivity (entry 2). It is
of interest that high syn-stereoselectivity was observed in
the reaction of R,ꢀ-unsaturated ketone 5c (entry 3). The same
tendency of diastereoselectivity was also seen in the reactions
of cyclic ketones 5f and g (entries 6 and 7). Similarly to the
R,ꢀ-unsaturated ketones, the reactions of acetophenones 5i-l
produced the homopropargylic alcohols 6i-l with high syn-
selectivity. The diastereoselectivity of these reactions was
found to be dependent on the substituent on the aromatic
ring; the syn-homopropargyl alcohol 6l was obtained with
high diastereoselectivity (95%), whereas the reaction of the
acetophenone bearing an electron-withdrawing trifluoro-
methyl group gave the alcohol 6j with lower selectivity
(entries 10 and 12).
Several propargylic carbonates 2b-d having an R-sub-
stituent other than a methyl group were also subjected to
the titanocene(II)-promoted reaction with unsaturated ketones
(Table 2). Over 85% diastereoselectivity in favor of the
formation of syn-homopropargylic alcohols was achieved in
these reactions.
The syn-tertiary homopropargylic alcohols 6, separated
from the anti-isomers, were successfully transformed into
homoallylic alcohols 1 by the desilylation with tetrabuty-
lammonium fluoride and subsequent hydrogenation using a
Lindlar’s catalyst (Table 3).
a Carried out using 2 (1.2 equiv) and 4 (1.8 equiv). b Isolated yield
based on 5 used. c Determined by GLC analysis. d Carried out using 4 (1.5
equiv) and 5 (2 equiv). e Based on 2 used. f Ratio of diastereomers.
Supporting Information). The syn-configuration of 6c was
unambiguously confirmed by X-ray single-crystal struc-
tural analysis after transformation into its pivalate. The
configuration of propargylic alcohols 6f,7i,2p2 was deter-
mined at the stage of homoallylic alcohols 1 by compari-
son with the authentic anti-tertiary homoallylic alcohols.
The stereochemistry of the homopropargylic alcohols
6 was determined as follows (details are provided in the
(7) Seebach, D.; Widler, L. HelV. Chim. Acta 1982, 65, 1972–1981.
Org. Lett., Vol. 12, No. 9, 2010
1969

Table 2. Preparation of Homopropargylic Alcohols 6 Utilizing Propargylic Carbonates 2b-d Having an R-Substituent Other Than Methyl Groupa
a Carried out using 2 (1.2 equiv) and 4 (1.8 equiv). b Isolated yield based on 5 used. c Determined by GLC analysis.
The syn-stereochemistry of the homopropargylic alcohol
Table 3. Transformation of Homopropargylic Alcohols 6 into
Homoallylic Alcohols 1
6g was determined after transformation to 6f. The ho-
mopropargylic alcohol 6j was transformed into the lactone
by hydroboration/oxidation of the corresponding homoallyl
alcohol 1c and further oxidation of the resulting diol with
PCC.2 The X-ray analysis of the lactone clearly supported
the syn-stereochemistry of 6j. Alternatively, the stereo-
chemistry of the homopropargylic alcohol 6d was deter-
mined by its transformation to the stereochemically well-
defined2,3-dimethyl-4-pentene-1,2-diol.8Thestereochemistry
of other homopropargylic alcohols 6e,h,k,l-o was esti-
mated to be syn in analogy with other homopropargylic
alcohols.
The reaction of allenylmetals with carbonyl compounds
has been well studied.9 Although highly diastereoselective
addition of the allenylmetals to ketones has not appeared,
various diastereoselective reactions with aldehydes have
been reported. Yamamoto and co-workers reported that the
allenyltitaniums, generated by the lithiation of alkynes
followed by transmetalation with Ti(OiPr)4, react with
aldehydes to produce anti-secondary homopropargylic al-
cohols with high diastereoselectivity.10 The similar prefer-
ential formation of anti-homopropargylic alcohols was
observed in the reaction of allenyltitaniums, generated by
the treatment of propargyl substrates with a titanium reagent
prepared from Ti(OiPr)4 and iPrMgBr, with aldehydes.11 The
stereoselectivity is rationalized by the reaction pathway
involving a six-membered-ring transition state. These reac-
(8) Chen, Y.; Eltepu, L.; Wentworth, P., Jr. Tetrahedron Lett. 2004,
45, 8285–8288.
´
(9) For recent examples, see: (a) Justicia, J.; Sancho-Sanz, I.; Alvarez-
Manzaneda, E.; Oltra, J. E.; Cuerva, J. M. AdV. Synth. Catal. 2009, 351,
2295–2300. (b) Yanagisawa, A.; Suzuki, T.; Koide, T.; Okitsu, S.; Arai, T.
Chem. Asian J 2008, 3, 1793–1800, and references cited therein.
(10) Furuta, K.; Ishiguro, M.; Haruta, R.; Ikeda, N.; Yamamoto, H. Bull.
Chem. Soc. Jpn. 1984, 57, 2768–2776.
a Isolated yield.
(11) Nakagawa, T.; Kasatkin, A.; Sato, F. Tetrahedron Lett. 1995, 36,
3207–3210.
1970
Org. Lett., Vol. 12, No. 9, 2010

tions, however, cannot be applied to ketones, and hence, the
diastereoselectivity of the formation of tertiary homoprop-
argylic alcohols using allenytitanium reagents has remained
obscure.
In contrast to the preferential formation of anti-secondary
homopropargylic alcohols described above, high syn-
selectivity was observed in the reaction of allenyltitanocenes
3 with aromatic and R,ꢀ-unsaturated ketones. Although,
without further study on the reaction mechanism, it is difficult
to rationalize all the stereochemical results of the present
reaction, high syn-selectivity would be explained by assuming
the stereochemical pathway involving noncyclic transition
sates.
results described here clearly show that our approach using
the allenyltitanocene species and unsaturated ketones is
extremely useful for the stereoselective preparation of syn-
tertiary homoallylic alcohols. Further study on the origin of
high syn-selectivity observed in the reaction of allenyltita-
niums with unsaturated ketones is currently underway.
Acknowledgment. This work was supported by a Grant-
in-Aid for Scientific Research (No. 21350026) from the
Ministry of Education, Culture, Sports, Science and Technol-
ogy, Japan.
Supporting Information Available: Experimental pro-
cedures and characterization data of all products. This
material is available free of charge via the Internet at
http://pubs.acs.org.
In conclusion, we have developed a new method for the
preparation of syn-tertiary homoallylic alcohols utilizing
allenyltitanium species generated by the reductive titanation
of propargylic carbonates with the titanocene(II) reagent. The
OL100395N
Org. Lett., Vol. 12, No. 9, 2010
1971