Highly diastereoselective preparation of aldol products using new functionalized allylic aluminum reagents

Article abstract of DOI:10.1021/ol403692k

Chloro-substituted triethylsilyl enol ethers derived from cyclohexanone and related ketones are converted with aluminum powder in the presence of indium trichloride to functionalized allylic aluminum reagents which represent a new type of synthetic equiva

Full text of DOI:10.1021/ol403692k

Letter
pubs.acs.org/OrgLett
Highly Diastereoselective Preparation of Aldol Products Using New
Functionalized Allylic Aluminum Reagents
Zhi-Liang Shen,† Zhihua Peng,† Chun-Ming Yang,† Julian Helberg,† Peter Mayer,† Ilan Marek,‡
and Paul Knochel*,†
†Department Chemie, Ludwig-Maximilians-Universitat Munchen, Butenandtstr. 5-13, 81377 Munchen, Germany
̈
̈
̈
‡The Mallat Family Laboratory of Organic Chemistry, Schulich Faculty of Chemistry and Lise Meitner-Minerva Center for
Computational Quantum Chemistry, Technion-Israel Institute of Technology, Technion City, Haifa 32000, Israel
S
* Supporting Information
ABSTRACT: Chloro-substituted triethylsilyl enol ethers
derived from cyclohexanone and related ketones are converted
with aluminum powder in the presence of indium trichloride
to functionalized allylic aluminum reagents which represent a
new type of synthetic equivalent of metal enolates. These
allylic organometallics undergo highly diastereoselective
additions to aldehydes and methyl aryl ketones, giving aldol
products with a β-quaternary center.
corresponding allylic chloride of type 2 and represent a new
type of d2 enolate synthetic equivalents (A).7 They underwent
highly diastereoselective additions to aldehydes or ketones,
leading in the last case to aldol products of type 3 bearing a β-
quaternary carbon center.8
The required chlorotriethylsilyl enol ethers 2a−c were
prepared in two steps from the corresponding ketones 4a−c
(Scheme 2). In the first step, the triethylsilyl enol ethers 5a−c
he aldol functional unit has a central position in organic
Tchemistry since this structural unit is found in numerous
natural products.1 Substituted aldol derivatives bearing
quaternary centers are sensitive organic molecules due to
retro-aldol decomposition pathways.
Extensive research efforts have been made to prepare such
molecules in a stereoselective manner.2 Aluminum organo-
metallic chemistry has received in recent years renewed
attention.3 Recently, we have shown that functionalized allylic
aluminum reagents bearing electron-attracting groups in
position 2 such as a cyano or an ester group undergo highly
diastereoselective additions to aldehydes and aryl methyl
ketones.4−6 Herein, we report the preparation of new
functionalized allylic aluminum reagents of type 1 bearing a
triethylsilyloxy substituent in position 2 and their diastereo-
selective additions to carbonyl derivatives (Scheme 1). These
organometallic reagents were readily prepared from the
Scheme 2. Preparation of Allylic Chlorides 2a−c Bearing
Silyl Enol Ether Functional Unit
Scheme 1. Preparation of Allylic Aluminum Reagents 1a−c
and Their Additions to Aldehydes and Methyl Ketones
were obtained by the reaction of Et3SiCl (1.2 equiv), NaI (1.2
equiv), and Et3N (1.2 equiv) in CH3CN (25 °C, 12 h) with the
corresponding ketones 4a−c in 78−90% yields.9 The allylic
chlorination of 5a−c proceeds best using NCS (1.0 equiv) in
CH2Cl2 (reflux, 0.5 h), leading to the allylic chlorides 2a−c in
40−69% yields.10 These allylic chlorides can be stored at −70
°C for several months without decomposition. Using aluminum
powder (3 equiv) in the presence of 5 mol % of InCl311 in THF
according to the method of Takai, the silyl enol ethers 2a−c
were converted into the corresponding allylic aluminum
Received: December 20, 2013
Published: January 30, 2014
© 2014 American Chemical Society
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dx.doi.org/10.1021/ol403692k | Org. Lett. 2014, 16, 956−959

Organic Letters
Letter
reagents 1 in ca. 70% yield for 1a,b and ca. 50% yield for 1c as
determined by GC analysis of hydrolyzed reaction aliquots
(Scheme 1).
The treatment of various aldehydes and methyl ketones (0.5
equiv) with these allylic aluminum reagents 1a−c at −78 °C
produced the expected aldol adducts of type 3 in 64−90%
yields and high diastereoselectivities in favor of the syn
diastereomer (Table 1).12 The stereochemistry of products 3
Scheme 3. Conversion of Alcohol 3a to β-Hydroxy Ketone 7
by Desilylation and Diastereoselective Preparation of 1,3-
Diol 8 Bearing Three Contiguous Stereogenic Centers
Starting from β-Hydroxy Ketone 7
Table 1. Diastereoselective Preparation of Homoallylic
Alcohols 3 Using Allylic Aluminum Reagents 1a−c
Figure 1. Proposed transition state for the diastereoselective additions
of 1a−c to aldehydes and methyl ketones.
17
Zn(BH4)2 as reducing agents gave satisfactory diastereo-
selectivities via chelation control. Interestingly, the opposite
diastereomer anti,syn-1,3-diol 8 was predominantly obtained by
18
using Me4NBH(OAc)3 as reductive reagent. The stereo-
chemistry of the two diastereomers of product 8 was
determined by comparison with the already reported NMR
data of similar 1,3-diol compounds.19
To functionalize the alcohols of type 3 further, we have used
the method developed by Myers involving a Shi epoxidation of
the silyl enol ether followed by a reductive opening of the
epoxide by BH3·THF,20 as shown in Scheme 4. Protection of
the alcohol 3a with Et3SiOTf resulted in the formation of disilyl
compound 9 (86% yield).21 A subsequent Shi epoxidation of 9
with oxone in the presence of chiral ketone B22 produced the
intermediate epoxide 10, which was in situ opened with BH3·
THF according to Myers’ procedure, leading to the selectively
protected triol 11 in 81% yield. The use of cyclohexanone as a
catalyst instead of Shi’s chiral ketone B produced the same
product 11 but in 66−70% yield. After desilylation of product
11 with TBAF, triol 12 with four contiguous chiral centers was
formed in 90% yield. The stereochemistry of triol 12 was
ambiguously determined by X-ray diffraction analysis. This
further confirmed the stereochemistry of the previous aldol
product 3a as being the syn diastereomer (Figure 2). By
applying the same sequence to the lactone 3d obtained
previously (Table 1, entry 4), we have prepared the selectively
protected disilyloxy lactone 13 bearing four contiguous
stereogenic centers in 68% yield as a single diastereomer
(Scheme 5).
a
b
All reactions were carried out on a 2 mmol scale. With 0.5 equiv of
c
d
electrophiles. Yield of isolated, analytically pure product. Diastereo-
selectivities were determined by H NMR spectroscopy.
1
was established by treating the aldol product 3a with HF·Py in
THF (−20 to 0 °C, 2 h). This afforded the β-hydroxy ketone 7
in 72% yield as only one diastereoisomer (Scheme 3).
Comparison of the H and 13C NMR data of ketone 7 with
1
the literature indicated that the diastereomer produced was the
syn isomer.13 The syn selectivity of the addition reaction can be
rationalized by the proposed transition state shown in Figure
1.14
The diastereoselective reduction of aldol product 7 was
examined in some detail (Scheme 3), and the use of L-
selectride15 (THF, −78 °C) provided syn,syn-1,3-diol 8 as
major diastereomer (90% yield, dr = 98:2) with three
contiguous chiral centers. Also, the use of DIBAL-H16 and
In summary, we have reported a new approach to aldol
products bearing a β-quaternary center with high diastereo-
selectivities using novel functionalized allylic aluminum
reagents bearing a silyloxy substituent in position 2. Extension
of this reaction is currently underway in our laboratory.
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Organic Letters
Letter
Scheme 4. Diastereoselective Preparation of Triol 12 with
Four Contiguous Chiral Centers Starting from Aldol
Product 3a
ACKNOWLEDGMENTS
■
We thank the German−Israel Project Cooperation (DIP) for
financial support. We also thank BASF SE (Ludwigshafen),
W.C. Heraeus GmbH (Hanau), and Rockwood Lithium GmbH
(Hochst) for the gift of chemicals.
̈
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AUTHOR INFORMATION
Corresponding Author
■
*E-mail: paul.knochel@cup.uni-muenchen.de.
Notes
The authors declare no competing financial interest.
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