Diversity-oriented stereoselective synthesis of β,γ-disubstituted tert-homoallylic alcohols

Article abstract of DOI:10.1021/acs.orglett.5b00084

The successive treatment of β-(trimethylsilyl)allyl phenyl sulfides with titanocene(II)-1-butene complex and ketones produced tertiary γ-(trimethylsilyl)homoallylic alcohols with good anti-selectivity, which reacted with a variety of organic halides in th

Full text of DOI:10.1021/acs.orglett.5b00084

Letter
pubs.acs.org/OrgLett
Diversity-Oriented Stereoselective Synthesis of β,γ-Disubstituted tert-
Homoallylic Alcohols
Takeshi Takeda,* Sota Amarume, Ippei Sekioka, and Akira Tsubouchi
Department of Applied Chemistry, Graduate School of Engineering, Tokyo University of Agriculture and Technology, Koganei,
Tokyo 184-8588, Japan
S
* Supporting Information
ABSTRACT: The successive treatment of β-(trimethylsilyl)-
allyl phenyl sulfides with titanocene(II)-1-butene complex and
ketones produced tertiary γ-(trimethylsilyl)homoallylic alco-
hols with good anti-selectivity, which reacted with a variety of
organic halides in the presence of copper(I) tert-butoxide to
afford the cross-coupling products, γ-substituted homoallylic
alcohols.
iastereoselective allylation of carbonyl compounds with
allylmetal species is a useful process for the stereo-
Scheme 1. Diversity-Oriented Synthesis of γ-Substituted
Homoallylic Alcohols
D
selective construction of acyclic systems and frequently
employed for the synthesis of natural products.1 The
application of this process, however, sometimes encounters
obstacles such as appropriate organometallic reagents are not
easily available.
Recently, we have disclosed the highly diastereoselective
preparation of tert-homoallylic alcohols bearing two or three
stereogenic centers by the addition of allyltitanocenes to
ketones.2 The γ-substituted E-allyltitanocenes are readily
prepared by the desulfurizative titanation of α- or γ-
monosubstituted allylic sulfides with titanocene(II)-1-butene
complex with complete stereo- and regioselectivity.2a While the
addition of allylmetals to ketones generally exhibits rather
limited diastereoselectivity compared with their addition to
aldehydes, the organotitanium species thus formed react with
ketones to produce tert-homoallylic alcohols with unexpectedly
high anti-selectivity. Aside from the chemistry of allyltitano-
cenes, we have continuously studied the preparation of alkenyl
and arylcopper(I) species by the silicon migration of silyl-
group-containing copper(I) alkoxides3 or copper(I) enolates.4
The organocopper(I) species thus formed are highly reactive
toward organic halides, including allylic, benzylic, and alkyl
halides.
All these results of organotitanium and silicon chemistry
prompted us to investigate the highly diastereoselective
preparation of γ-substituted homoallylic alcohols 1. The process
consists of the reaction of β-(trimethylsilyl)allyltitanium
reagents 2, generated by the reductive titanation of β-
(trimethylsilyl)allyl phenyl sulfides 3, with ketones 4 and the
copper(I) tert-butoxide-promoted reaction of the resulting γ-
(trimethylsilyl)homoallylic alcohols 5 with organic halides 6
(Scheme 1). This process enables us to prepare tert-homoallylic
alcohols bearing a variety of substituents at the β-position from
the same starting materials. The similar diversity-oriented
synthesis of δ-substituted homoallylic alcohols by the titanoene-
(II)-promoted reaction of α-(benzyldimethylsilyl)allyl phenyl
sulfides with ketones and the following cross-coupling with
organic halides has been reported by us.5
The treatment of β-(trimethylsilyl)crotyl phenyl sulfide 3a
with a titanocene(II)-1-butene complex in cyclopentyl methyl
ether (CPME)−THF at 0 °C for 2 h generated the
allyltitanium species 2, which then reacted with acetophenone
4a at −40 °C for 18 h to produce the γ-(trimethylsilyl)homo-
allylic alcohol 5a with 90% anti selectivity in 69% yield.6 The
result indicates that the desulfurizative titanation of 3a
generated the Z-allyltitanium species 2a, which reacted with
4a through the well-established six-membered chairlike
transition state. Knochel and co-workers reported the stereo-
selective formation of syn-5a by the zinc promoted reaction of
β-(trimethylsilyl)crotyl chloride with 4a through the formation
of an E-allylzinc reagent.7 It is of great interest that the
stereochemical outcome of our reaction is completely different
from that of their reaction.
Received: January 9, 2015
© XXXX American Chemical Society
A
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Letter
a
We believe that the difference between the stereochemical
courses of two reactions could be explained by the difference in
bulkiness between the divalent zinc and tetravalent titanium.
To rationalize the stereoselective formation of Z-allyltitano-
cenes, the two major conformations for both the Z- and E-
allylmetals bearing a trimethylsilyl group at the β-position
should be considered (Scheme 2). The stereoselective
Table 1. Preparation of γ-Silyl Homoallylic Alcohols 5
Scheme 2. Major Conformations of Allyltitanocenes 1
formation of Z-allylzinc species is assumed to be attributable
to the unfavorable steric interaction between the γ-substituent
and the β-silyl group in the conformations A and B. Due to the
sterically less bulky zinc moiety, the 1,3-allylic strain between
the γ-substituent and the zinc moiety in conformation C and
the steric constraint between the silyl group and the zinc
moiety in conformation D are negligible, and hence the E-
allylzinc reagent is relatively more stable than its Z-isomer. In
the case of the formation of allyltitanocene 1, in contrast, the
repulsions between the sterically demanding titanocene moiety
and other groups in the conformations other than A are more
serious than the strain caused by the crowding of the γ- and the
β-substituents in conformation A. As a result, the Z-
allyltitanocene is preferentially produced.
Under the same reaction conditions, the allylation of several
carbonyl compounds 4 with β-(trimethylsilyl)allyl sulfides 3
was performed and a variety of γ-silyl homoallylic alcohols 5
were obtained with anti-selectivity (Table 1). The diaster-
eoselectivity was high enough even when the sterically less
demanding ketones, such as ethyl methyl ketone 4c, were
employed (entry 7). The reaction using benzaldehyde 4d also
gave the anti-secondary homoallylic alcohol 5h with high
diastereoselectivity (entry 8).
a
Conditions: (1) β-silylallyl sulfide 3 (1.25 equiv), Cp2Ti(II) (2.5
equiv), 0 °C for 2 h; (2) ketone 4 (1 equiv), −40 °C for 18 h.
b
c
Isolated yield based on ketone 4 used. Determined by NMR analysis.
The key step of the previously reported copper(I)-mediated
cross-couplings is the transmetalation of pentacoordinated
silicates with copper(I) salt to form organocopper species.
Indeed the reaction of the fluoride ion coordinated,
pentacoordinated silicates, generated by the treatment of
alkenylbenzyldimethylsilanes with tetrabutylammonium fluo-
ride, with copper(I) iodide produced alkenylcopper(I)
species.5b The geometry of γ-silyl alcohols 5 would allow the
formation of five-membered pentacoordinated cyclic silicates 7
(Scheme 3). Therefore, the treatment of these alcohols 5 with
copper(I) tert-butoxide is expected to afford the alkenylcopper-
(I) species 8 through the Si−C bond cleavage. The
organometallic compounds 8 thus formed would then react
with organic halides 6 to produce the cross-coupling products
1.
Scheme 3. Copper(I)-promoted Cross-coupling of γ-Silyl
Homoallylic Alcohols 5
In keeping with this notion, the homoallylic alcohol 5a was
successively treated with copper(I) tert-butoxide and allyl
chloride 6a in DMF at 0 °C for 1 h and then at 25 °C for 18 h
B
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to produce the trimethylsilyl ether 9a. The γ-substituted
homoallylic alcohol 1a was obtained in 84% yield by the
hydrolysis of crude silyl ether 9a with water/tetrabutylammo-
nium fluoride (TBAF) (entry 1, Table 2). The similar allylation
also took place using methallyl chloride 6b (entries 2, 6, and 9).
Benzyl bromide and methyl iodide were also reactive toward
the organocopper intermediates (entries 3 and 7). It is of
special note that the reaction using alkyl halides having a β-
hydrogen such as ethyl iodide (entries 4, 8, and 10), butyl
iodide (entry 11), and even the alkyl iodide bearing an acidic
hydrogen (entry 5) produced the cross-coupling products in
good yields. In all these reactions, the configuration of
homoallylic alcohols was virtually completely retained.
Table 2. Cross-Coupling of γ-(Trimethylsilyl)homoallylic
a
Alcohols 5 with Allyl, Benzyl, and Alkyl Halides
It is expected that the transmetalation of putative
alkenylcopper intermediates with haloorganopalladium(II)
species, generated by the oxidative addition of C(sp2)−X
electrophiles to palladium(0), results in the formation of
diorganopalladiums, which then afford cross-coupling products
through the reductive elimination process. Indeed, the
copper(I) tert-butoxide-promoted reaction of homoallylic
alcohol 5d with iodotoluene 6h in the presence of tris-
(dibenzylideneacetone)dipalladium(0) produced the arylation
product 1o in 76% yield with complete retention of
configuration (Table 3, entry 4). The cross-coupling of 5
took place with both electron-rich (entries 1 and 5) and
electron-deficient (entries 3 and 6) aryl halides. Notably,
alkenyl halides could be employed as coupling partners (see
Table 3. Cross-Coupling of γ-(Trimethylsilyl)homoallylic
a
Alcohols 5 with Aryl and Alkenyl Halides
a
a
Conditions: (1) homoallylic alcohol 5 (1 equiv), organic halide 6 (3
Conditions: (1) homoallylic alcohol 5 (1 equiv), organic halide 6 (3
equiv), tBuOCu (3 equiv), 0 °C for 1 h then 25 °C for 18 h; (2) TBAF
equiv), tBuOCu (3 equiv), Pd2(dba)3 (15 mol %), 0 °C for 1 h then 25
°C for 18 h; (2) TBAF (3 equiv), 25 °C for 15 h. Isolated yield based
on the alcohol 5 used. Determined by NMR analysis.
b
b
(3 equiv), 25 °C for 15 h. Isolated yield based on the alcohol 5 used.
c
c
Determined by NMR analysis.
C
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benzyldimethylsilyl group containing titanium carbene complexes with
carbonyl compounds and alkynes and the following copper(I)-
promoted cross-coupling of the resulting alkenylbenzyldimethylsilanes
with organic halides was also reported; (c) Takeda, T.; Mori, A.; Fujii,
T.; Tsubouchi, A. Tetrahedron 2014, 70, 5776.
(6) The anti-stereochemistry of 5a was confirmed by comparison
with the reported NMR data.7 The stereochemistry of 5b and 5i was
also assigned by comparison with the NMR data of authentic
homoallylic alcohols2a after the protodesilylation by the treatment with
NaH (2.1 equiv) in HMPA−THF at 25 °C for 18 h.7
(7) Helm, M. D.; Mayer, P.; Knochel, P. Chem. Commun. 2008, 1916.
(8) For selected reviews, see: (a) Tsuji, J. Palladium Reagents and
Catalysts; John Wiley & Sons: Chicheter, 2004; p 338. (b) Denmark, S.
E.; Sweis, R. F. In Metal-Catalyzed Cross-Coupling Reactions; de
Meijere, A., Diederich, F., Eds.; Wiley-VCH: Weinheim, 2004; p 163.
(c) Hiyama, T.; Shirakawa, E. Top. Curr. Chem. 2002, 219, 61.
(d) Chang, W.-T. T.; Smith, R. C.; Regens, C. S.; Bailey, A. D.;
Werner, N. S.; Denmark, S. E. Org. React. 2011, 75, 213. (e) Sore, H.
F.; Galloway, W. R. J. D.; Spring, D. R. Chem. Soc. Rev. 2012, 41, 1845.
For recent examples, see: (f) Denmark, S. E.; Tymonko, S. A. J. Am.
Chem. Soc. 2005, 127, 8004. (g) Zhang, L.; Wu, J. J. Am. Chem. Soc.
2008, 130, 12250. (h) Molander, G. A.; Iannazzo, L. J. Org. Chem.
2011, 76, 9182. (i) Monguchi, Y.; Yanase, T.; Mori, S.; Sajiki, H.
Synthesis 2013, 45, 40.
entry 2). The double bond geometry of alkenyl halides was also
completely retained during the cross-coupling event.
In conclusion, we have developed a diversity-oriented
strategy for the construction of γ-substituted anti-homoallylic
alcohols which consists of the addition of silyl-group-containing
allyltitanocenes to ketones and the copper(I)-mediated cross-
coupling of the resulting γ-silyl homoallylic alcohols. In sharp
contrast with the Hiyama-type cross-couplings, which generally
require the use of rather difficult to handle heteroatom-
functionalized organosilanes,8 the trimethylsilyl group of the
bench-stable γ-silyl homoallylic alcohols can be displaced with a
variety of alkyl, allyl, aryl, and alkenyl groups.
Further study on the diversity-oriented strategy for the
construction of unsaturated systems using silyl-group-contain-
ing organotitanium species is currently underway.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and full characterization of all
compounds. This material is available free of charge via
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: takeda-t@cc.tuat.ac.jp.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by JSPS KAKENHI Grant Number
26410037.
■
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