Highly diastereoselective addition of allyltitanocenes to α-chiral ketones

Article abstract of DOI:10.1016/j.tetlet.2012.05.085

The addition of allyltitanium reagents, generated by the desulfurizative titanation of allylic sulfides with the titanocene(II) reagent Cp ₂Ti-1-butene, to α-chiral ketones produced tertiary homoallylic alcohols bearing three adjacent chiral ce

Full text of DOI:10.1016/j.tetlet.2012.05.085

Tetrahedron Letters 53 (2012) 3930–3933
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Highly diastereoselective addition of allyltitanocenes to a-chiral ketones
⇑
Takeshi Takeda , Satoshi Yoshida, Takuya Nishimura, Akira Tsubouchi
Department of Applied Chemistry, Graduate School of Engineering, Tokyo University of Agriculture and Technology, Koganei, Tokyo 184-8588, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The addition of allyltitanium reagents, generated by the desulfurizative titanation of allylic sulfides with
Received 18 April 2012
Revised 12 May 2012
Accepted 18 May 2012
Available online 24 May 2012
the titanocene(II) reagent Cp2Tiꢀ1-butene, to
a-chiral ketones produced tertiary homoallylic alcohols
bearing three adjacent chiral centers with high diastereoselectivity.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Allylation
Allylic sulfides
Chiral ketones
Diastereoselectivity
Homoallylic alchols
Stereoselective construction of acyclic systems bearing multi-
chiral centers by allylation of carbonyl compounds is of crucial
importance in organic synthesis.1 For the construction of three
contiguous stereogenic centers, the addition of allylmetals to
interest from a synthetic point of view. Then we have studied the
reaction between various allyltitanocenes 1 and non-heteroatom
substituted
a-chiral ketones 2 and found that a variety of tert-
homoallylic alcohols 3 were produced with extremely high diaste-
reoselectivity using acyclic as well as cyclic ketones (Scheme 1).
Cinnamyl phenyl sulfide (4a) was treated with the titano-
cene(II) reagent 5 at ꢀ78 to 0 °C to produce the cinnamyltitano-
cene 1a. Although the reaction of 1a with 3-methylpentan-2-one
(2a) at ꢀ78 °C gave an almost 1:1 mixture of two diastereomers
(Table 1, entry 1), similar reaction of 1a with 3-phenylbutan-2-
one (2b) proceeded with perfect diastereoselectivity (entry 2).
The stereochemistry of the resulting homoallylic alcohol 3b is
identical with that obtained by the reaction of cinnamylzinc re-
agent with 2b reported by Knochel.4 Cyclohexanones 2cꢀe also re-
acted with 1a to afford the homoallylic alcohols 3cꢀe with good to
complete diastereoselectivity (entries 3ꢀ5). It was reported that
the reaction of cinnamylzinc reagent with 2d gave 3d in modest
a
-chiral aldehydes has been extensively studied.2 A challenging
task in this field is stereocontrolled construction of consecutive
stereogenic centers involving a tetrasubstituted carbon in acyclic
aliphatic systems by reaction of allylmetals with
However, only a few reactions of allylmetals with
a
a
-chiral ketones.
-alkoxy, hydro-
xyl or b-carbamoyl ketones, in which the coordination of oxygen to
the metal plays an important role to control the stereochemistry,
have been studied.3 Knochel and co-workers reported the highly
diastereoselective reaction of cinnamylzinc reagents with a variety
of a
-chiral ketones including non-heteroatom substituted ones.4 A
similar reaction of allylzinc other than cinnamylzinc reagents,
however, has not appeared yet.
We have studied the preparation of the allyltitanium species by
the desulfurizative titanation of allylic sulfides with the titano-
cene(II)ꢀ1-butene complex and their reaction with unsymmetrical
ketones.5 Our previous approach to the construction of tert-homo-
allylic alcohols bearing three adjacent stereocenters utilized the
reaction of allyltitanocenes bearing a d-chiral carbon.6 In this
study, we observed that a chiral allyltitanocene reacted with an
yield due to the competitive deprotonation of
a-benzylic proton
of 2d.4 In contrast, 3d was produced in good yield by the reaction
of cinnamyltitanocene 1a (entry 4). The result would be attribut-
able to the low basicity of allyltitanocenes, and hence the reaction
of (ꢀ)-menthone (2e) proceeded without epimerization (entry 5).
What is of interest is that the reactions of aralkyl group substi-
tuted allyltitanocene 1b, generated by the desulfurizative titana-
a-chiral ketone to produce a tert-homoallylic alcohol bearing four
chiral centers with good diastereoselectivity. In light of the fact
tion of branched sulfide 4b, and crotyltitanocene 1c with a-chiral
that there is no report on the highly diastereoselective addition
of aliphatic allylmetals to non-heteroatom substituted a-chiral ke-
tones, the diastereoselectivity observed in the above study is of
ketones 2 took place with much higher diastereoselectivity (Tables
2 and 3); perfect diastereoselectivity was observed in these reac-
tions with the exception that the reaction using 2a gave the homo-
allylic alcohols 3f and 3k with reasonable diastereoselectivity.
The stereochemistry of the tert-homoallylic alcohols 3b and 3c
was assigned by comparison of their NMR spectral data with those
⇑
Corresponding author. Tel./fax: +81 42 388 7034.
E-mail address: takeda-t@cc.tuat.ac.jp (T. Takeda).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.05.085

T. Takeda et al. / Tetrahedron Letters 53 (2012) 3930–3933
3931
Table 2
Reaction of 5-phenyl-2-pentenyltitanocene 1b with a-chiral ketones 2
R1
O
5
Cp2Ti
Entry
1
2
Product 3
Yielda (%)
drb
R1
SPh
or
Ph
SPh
4
2a
76
67:33c
3f
Ph
OH
R2
R4
R2
R1
*
2
3
2b
2c
72
73
>99:1c
R3
Ph
2
R1
Ph
TiCp2SPh
SPh
*
R4
OH
3g
R3
*
OH
1
Ph
3
Single isomer
Single isomer
OH
3h
Ph
Ph
SPh
Ph
SPh
4b
4
5
2d
2e
80
78
4a
4c (E:Z = 88:12)
OH
3i
Ph
O
O
O
Ph
Single isomer
2a
2d
2b
2c
OH
3j
O
O
a
b
c
Ph
Isolated yield.
Determined by NMR analysis.
Determined by GC analysis.
2e
Scheme 1. Diastereoselective addition of allyltitanocenes 1 to
a-chiral ketones 2.
Table 3
Reaction of crotyltitanocene 1c with
a-chiral ketones 2
Entry
1
2
Product 3
Yielda (%)
drb
Table 1
Reaction of cinnamyltitanocene 1a with
a
-chiral ketones 2
69:31c
Entry
1
2
Product 3
Yielda (%)
drb
2a
74
72
3k
3l
OH
Ph
2a
77
56:44c
2
3
2b
2c
Single isomer
Single isomer
Ph
3a
3b
OH
Ph
OH
2
3
2b
2c
74
85
Single isomer
85:15c
Ph
62
79
OH
OH
3m
3n
Ph
Ph
4
5
2d
2e
Single isomer
Single isomer
OH
OH
3c
Ph Ph
4
5
2d
2e
74
79
Single isomer
Single isomer
66
OH
Ph
3d
3e
OH
3o
a
b
c
Isolated yield.
Determined by NMR analysis.
Determined by GC analysis.
OH
a
b
c
Isolated yield.
Determined by NMR analysis.
Determined by GC analysis.
temperature/18 h).7 The stereochemistry of 3e, 3f, 3h, 3jꢀo was
deduced from the assignment described above.
The stereochemical pathway of the reaction is rationalized by
the six-membered chair-like transition states. Considering our pre-
reported.4 The molecular structures of 3d and 3i were determined
by X-ray analysis.7 The stereochemistry of 3g was also confirmed
by X-ray analysis after transformation into 4-methyl-3-
phenethyl-5-phenylhexa-1,4-diol (6) by hydroboration (9-BBN/
THF/room temperature/6 h)-oxidation (3 M NaOH/H2O2/room
vious observation that the reaction of
c-substituted allyltitanoc-
enes with methyl ketones having a group larger than isopropyl
proceeds with complete anti-selectivity,5 it is reasonable to assume
that the relative configuration between C (
a) and C (b) of both
major and minor products 3 and 30 is anti (Scheme 2). The anti

3932
T. Takeda et al. / Tetrahedron Letters 53 (2012) 3930–3933
located at the equatorial position in transition states 8 and 80.
Me
RL
The preferential formation of major diastereomer 3 via the transi-
tion state 8 would be due to the destabilization of transition state
80 by steric repulsion between the substituents of allyltitanocene
(R1) and cyclohexanone (R2).
In conclusion, it has been shown that the reaction of allyltita-
nocenes with both cyclic and acyclic a-chiral ketones is a versatile
R
RS
α
H
Ti
O
RL β'
β
R
Me OH
3
RS
SPh
major
H
(α,β'-syn-α,β-anti)
7
and straightforward method for the preparation of tert-homoallylic
alcohols bearing three consecutive stereogenic centers with high
diastereoselectivity.9 The low basicity of allyltitanocenes enables
their use for the allylation of ketones possessing acidic hydrogens
such as 2-phenylcyclohexanone.
Further study on the construction of acyclic systems with mul-
tistereogenic centers using allyltitanium reagents is currently
underway.
O
RL
+
R
TiCp2SPh
Me
1
RS
2
Me
R
Acknowledgment
RS
Ti
α
R
H
RL
β'
β
O
This work was supported by Grant-in-Aid for Scientific Re-
search (No. 21350026) from the Ministry of Education, Culture,
Sports, Science and Technology, Japan
RS
SPh
Me OH
3'
H
minor
(α,β'-anti-α,β-anti)
RL
7'
Supplementary data
Scheme 2. Stereochemical pathway of the reaction of allyltitanocenes
acyclic ketones 2a,b.
1 with
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.
2012.05.085.
selectivity is interpreted based on the argument that the addition
proceeds via the formation of transition states 7 and 70 in which
the larger substituent attached to the carbonyl group occupies an
equatorial position. The isomers 3 and 30 are attributed to the rel-
References and notes
1. (a) Stereoselective Synthesis, Methods of Organic Chemistry (Houben-Weyl), E21
ed.; Helmchen, G., Hoffmann, R., Mulzer, J., Schaumann, E., Eds.; Thieme:
Stuttgart, 1996; Vol. 3.; (b) Chemler, S. R.; Roush, W. R. In Otera, J., Ed.; Modern
Carbonyl Chemistry; Wiley-VCH: Weinheim, 2000. Chapter 10; (c) Denmark, S.
E.; Almstead, N. G. In Otera, J., Ed.; Modern Carbonyl Chemistry; Wiley-VCH:
Weinheim, 2000. Chapter 11; (d) Sato, F.; Urabe, H.; Okamoto, S. Chem. Rev.
2000, 100, 2835; (e) Szymoniak, J.; Moise, C. In Marek, I., Ed.; Titanium and
Zirconiums in Organic Synthesis; Wiley-VCH: Weinheim, 2002. Chapter 13.
2. For selected examples, see: (a) Hoffmann, R. W.; Zeib, H. J.; Landner, W.; Tabche,
S. Chem. Ber. 1982, 115, 2357; (b) Keck, G. E.; Boden, E. P. Tetrahedron Lett. 1984,
25, 1879; (c) Keck, G. E.; Abbott, D. E. Tetrahedron Lett. 1984, 25, 1883; (d)
Yamamoto, Y.; Yatagai, H.; Ishihara, Y.; Maeda, N.; Maruyama, K. Tetrahedron
1984, 40, 2239; (e) Yamamoto, Y.; Komatsu, T.; Maruyama, K. J. Organomet.
Chem. 1985, 285, 31; (f) Roush, W. R.; Adam, M. A.; Harris, D. J. J. Org. Chem. 1985,
50, 2000; (g) Hoffmann, R. W.; Weidmann, U. Chem. Ber. 1985, 118, 3966; (h)
Coxon, J. M.; van Eyk, S. J.; Steel, P. J. Tetrahedron Lett. 1985, 26, 6121; (i) Roush,
W. R.; Halterman, R. L. J. Am. Chem. Soc. 1986, 108, 294; (j) Brown, H. C.; Bhat, K.
S.; Randad, R. S. J. Org. Chem. 1987, 52, 3701; (k) Garcia, J.; Kim, B. M.;
Masamune, S. J. Org. Chem. 1987, 52, 4831; (l) Collins, S.; Dean, W. P.; Ward, D. G.
Organometallics 1988, 7, 2289; (m) Mulzer, J.; Schulze, T.; Strecker, A.; Denzer,
W. J. Org. Chem. 1988, 53, 4098; (n) Brown, H. C.; Bhat, K.; Randad, R. S. J. Org.
Chem. 1989, 54, 1570; (o) Martin, S. F.; Li, W. J. Org. Chem. 1989, 54, 6129; (p)
Hoffmann, R. W.; Brinkmann, H.; Frenking, G. Chem. Ber. 1990, 123, 2387; (q)
Roush, W. R.; Grover, P. T. Tetrahedron Lett. 1990, 31, 7567; (r) Batey, R. A.;
Thadani, A. N.; Smil, D. V.; Lough, A. J. Synthesis 2000, 990; (s) Thadani, A. N.;
Batey, R. A. Tetrahedron Lett. 2003, 44, 8051; (t) Rauniyar, V.; Hall, D. G. Angew.
Chem., Int. Ed. 2006, 45, 2426; (u) Tanaka, K.; Fujimori, Y.; Saikawa, Y.; Nakata,
M. J. Org. Chem. 2008, 73, 6292; (v) Vogt, M.; Ceylan, S.; Kirschning, A.
Tetrahedron 2010, 66, 6450; (w) Kim, H.; Ho, S.; Leighton, J. L. J. Am. Chem. Soc.
2011, 133, 6517; (x) Sancho-Sanz, I.; Miguel, D.; Millán, A.; Estévez, R. E.; Oller-
López, J. L.; Álvarez-Manzaneda, E.; Robles, R.; Cuerva, J. M.; Justicia, J. J. Org.
Chem. 2011, 76, 732.
ative configuration between C (a
) and C (b0). The preferential for-
mation of major diastereomer 3 is well explained on the basis of
the Felkin-Anh conformational model of the transition state 7
which is more stable than 70 destabilized by RL–R and RL–H inter-
actions. Diastereoselectivity of the reaction of
a-chiral aldehydes
with (E)-lithium and boron enolates has been explained in a simi-
lar manner.8
The stereochemical outcome of the addition of allyltitanocenes
1 to cyclohexanones 2cꢀe is also explained by the six-membered
cyclic transition states similar to the reaction of cinnamylzinc re-
agents4 (Scheme 3). The
a-carbon bearing the
a
substituent is
R1
R2
R2
O
Ti
R1
OH
SPh
R2
H
8
3
O
R1
TiCp2SPh +
1
2
3. (a) Sato, K.; Kira, M.; Sakurai, H. J. Am. Chem. Soc. 1989, 111, 6429; (b) Taniguchi,
M.; Oshima, K.; Utimoto, K. Bull. Chem. Soc. Jpn. 1995, 68, 645; (c) Kumar, S.;
Kaur, P.; Mittal, A.; Singh, P. Tetrahedron 2006, 62, 4018; (d) Babu, S. A.; Yasuda,
M.; Baba, A. J. Org. Chem. 2007, 72, 10264.
4. Dunet, G.; Mayer, P.; Knochel, P. Org. Lett. 2008, 10, 117.
5. Yatsumonji, Y.; Nishimura, T.; Tsubouchi, A.; Noguchi, K.; Takeda, T. Chem. Eur. J.
2009, 15, 2680.
R1
R2
Ti
O
R1
6. Takeda, T.; Nishimura, T.; Yatsumonji, Y.; Noguchi, K.; Tsubouchi, A. Chem. Eur. J.
2010, 16, 4729.
7. CCDC 86577 (3d), 866578 (3i), and 870056 (6) contain supplementary
crystallographic data for this paper. Also see the Supplementary data for details.
8. Roush, W. R. J. Org. Chem. 1991, 56, 4151.
9. Typical procedure: Preparation of 3-methyl-2,4-diphenylhex-5-en-3-ol (3b): To a
THF (12 mL) suspension of Cp2TiCl2 (996 mg, 4.0 mmol) was added a 1.54 M
hexane solution of BuLi (5.2 mL, 8.0 mmol) at ꢀ78 °C under argon. After 1 h, a
THF (8 mL) solution of 4a (453 mg, 2.0 mmol) was added dropwise over 5 min to
OH
SPh
R2
H
8'
3'
Scheme 3. Stereochemical pathway of the reaction of allyltitanocenes
cyclohexanones 2c–e.
1 with

T. Takeda et al. / Tetrahedron Letters 53 (2012) 3930–3933
3933
the mixture and stirring was continued for 15 min at the same temperature and
then at 0 °C for 45 min. After stirring the reaction mixture at ꢀ78 °C for 30 min,
a THF (4 mL) solution of 2b (356 mg, 2.4 mmol) was added dropwise over
10 min, and the reaction mixture was further stirred for 18 h. The reaction was
quenched by addition of 1 M NaOH, and insoluble materials were filtered off
through Celite and washed with ether. The organic materials were extracted
with ether and dried over Na2SO4. After removal of the solvent, the residue was
purified by PTLC (hexane/AcOEt = 9:1, v/v) to give 3b (394 mg, 74%).