Control of up to five stereocenters in a cascade reaction: Synthesis of highly functionalized five-membered rings

Article abstract of DOI:10.1021/ja801488z

Mukaiyama-Aldol and Prins reactions have been identified as highly efficient methods in C-C bond formation since they were discovered several decades ago. Since both reactions gave the same common intermediate, oxocarbonium, we intend to combine the two reactions into a domino process, which means the formation of multiple C-C bonds and stereogenic centers in one pot without isolation of any intermediates. We envisage that the domino reactions involving the Mukaiyama-Aldol reaction of silyl enol ether and acetal treated with Lewis acid (TiBr₄) will produce an oxonium intermediate which upon trapping by an alkene functionality in an intramolecular Prins cyclization will generate the cyclopentyl ring system. Copyright

Full text of DOI:10.1021/ja801488z

Published on Web 05/20/2008
Control of up to Five Stereocenters in a Cascade Reaction: Synthesis of
Highly Functionalized Five-Membered Rings
Hao Li and Teck-Peng Loh*
DiVision of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences,
Nanyang Technological UniVersity, Singapore 637616
Received February 27, 2008; E-mail: teckpeng@ntu.edu.sg
Scheme 1. Our Proposed Hypothesis
Discovery of an efficient method to construct complex molecules
with multiple stereogenic centers in excellent regio-, diastereo-, and
enantioselectivity has been an important goal for both academic
and industrial researchers.1 In particular, asymmetric domino and
cascade reactions which allow the formation of multiple C-C bonds
and many stereogenic centers in a one-pot manner are useful for
the synthesis of natural products and synthetic building blocks.
These processes are usually cleaner as they generate less waste by
minimizing isolation of intermediates in the multistep synthesis of
complex molecular targets.2,3 Accordingly, much effort has been
focused on the development of new stereoselective cascade reac-
tions, including the recent reports by Enders et al.4 on an elegant
asymmetric domino reaction for the construction of cyclohexane
derivatives in excellent stereoselectivities. However, the develop-
ment of a highly stereoselective domino reaction for the synthesis
of cyclopentane derivatives remains difficult.5,6
Table 1. MAP Reactions with Monosubstituted Acetal (Z)-8a
Here we report the development of a highly regio-, diastereo-,
and enantioselective domino Mukaiyama-Aldol-Prins (MAP)
reaction for the synthesis of a highly substituted cyclopentyl system.
This cascade reaction provides a powerful means to create a highly
functionalized five-membered ring system in good to excellent
yields with the generation of up to five new stereogenic centers in
excellent regio- and diastereoselectivies with complete enantiose-
lectivities.7 In addition, variation of the substrates and simple
manipulation of the products will allow the construction of diverse
polyfunctionalized cyclopentane derivatives, which can serve as
building blocks for the synthesis of complex molecules.
WeenvisagethatthedominoreactionsinvolvingtheMukaiyama-Aldol
reaction of silyl enol ether 1 with acetal 2 will produce an
oxocarbenium intermediate 4,8 which upon trapping by an alkene
functionality in an intramolecular Prins cyclization fashion9,10may
generate the cyclopentyl ring system 5 (Scheme 1).
entry
R1
R2
R3b
yieldc (%)
drd
1
2
3
4
CH3
CH3CH2
CH3
CH3CH2
Et
Et
Et
Et
90
91
86
80
(87:13)
81
85
93
>99:1
>99:1
>99:1
>99:1
-(CH2)3-
CH3, Br
(Z/E ) 85:15)e
CH3
CH3CH2
5
6
7
8
CH3
CH3CH2
CH2OBn
CH2OBn
CH2OBn
CH2OBn
>99:1
>99:1
>99:1
>99:1
-(CH2)3-
-(CH2)2-
90
a Mukaiyama-Aldol-Prins reactions were run with 2 equiv of TiBr4,
1 equiv of acetal, and 1.2 equiv of silyl enol ether under N2 atmosphere.
b Monosubstituted acetals (Z)-8 were prepared by Wittig reactions. MAP
reaction cannot proceed using monosubstituted acetal (E)-8. c Isolated
yield. d Diastereomeric ratios were based on 1H and 13C NMR analyses.
e MAP reaction proceeds smoothly with (Z)- or (E)-silyl enol ether.
excellent diastereoselectivity (Table 1, entry 4). The E/Z isomers
(85/15) of the silyl enol ether which cannot be separated were
retained in the product. This reaction further expanded the scope
of this method. The MAP domino process can also proceed
smoothly with -CH2OBn-substituted acetal to afford the products
in high yields and excellent diastereoselectivities. On the basis of
X-ray analysis of a product (see Supporting Information), the
relative configuration of the five-membered rings system was
determined.
Of mechanistic interest is that no reaction was observed when
the E isomer of the acetal was used in this reaction. On the basis
of this information and the stereochemistries observed in the
products, a plausible mechanism for the formation of the five-
membered ring products was proposed as shown in Scheme 2. We
believe that the steric repulsion between bulky OTIPS and R3 in
the E isomer disfavored pathway B.
In our initial studies, we reacted the monosubstituted acetal
(Scheme 1, R1 ) Me, R5 ) Et) with silyl enol ether (Scheme 1,
R2,3 ) Me, R4 ) TMS) in the presence of titanium tetrabromide.
Unfortunately, the desired domino process did not take place. Only
the Mukaiyama-Aldol reaction product 6 was obtained (Scheme
1). Next, we replaced the labile trimethyl silyl group with more
robust silicon protecting groups, such as a triisopropylsilyl (TIPS)
group. To our delight, the desired product 9 was obtained in very
high yield with excellent diastereoselectivity (Table 1, entry 1).
Using different silyl enol ethers (Table 1, entries 2 and 3), the
domino process proceeded in the same manner to give the desired
products in high yields with excellent diastereoselectivities. In all
cases, a single isomer was obtained, and three new bonds and four
new stereocenters were generated from this highly efficient cy-
clization process.
A noteworthy point in this study is the intriguing bromosubsti-
tuted silyl enol ether. In this case, five new chiral centers were
formed contiguously in a one-pot reaction in high yield and
Besides the acyclic acetal, we also looked into the cyclic acetal
version (Scheme 3). Treatment of the TIPS silyl enol ether with
9
7194 J. AM. CHEM. SOC. 2008, 130, 7194–7195
10.1021/ja801488z CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2. Mechanism of Five-Membered Ring System Formation
Scheme 4. Determination of Absolute Stereochemistry of Major
Products
Scheme 3. MAP Reactions Using Cyclic Acetal
In conclusion, we have developed a highly stereoselective
domino reaction, accomplished with easily accessible starting
materials. The novelty of this domino reaction is the ability to
construct five-membered ring systems with up to five new chiral
centers in a one-pot manner in high yields with excellent
diastereo- and enantioselectivities. This new methodology
provides a simple and practical method for the synthesis of
polyfunctional cyclopentane building blocks.
Table 2. MAP Reactions in Asymmetric Version for
Five-Membered Ringsa,b
Acknowledgment. We gratefully acknowledge the Nanyang
Technological University and Singapore Ministry of Education
Research Fund Tier 2 (No. T206B1221) for the financial support
of this research, and Dr. Y.-X. Li and Dr. K. F. Mok for X-ray
support.
entry
R1
R2
yield (%)
dr
1
2
3
4
CH3
CH3
93
94
90
80
90:10
89:11
92:8
CH3CH2
-(CH2)3-
CH3CH2
-(CH2)3-
Supporting Information Available: Additional experimental pro-
cedures, chromatograms, cif file of crystallographic data, and spectral
data. This material is available free of charge via the Internet at http://
pubs.acs.org.
CH3Br
(Z/E ) 85:15)
99:1
(90:10)
a Chiral pure cyclic acetals (Z) were prepared using (2R,3R)-(-)-
butanediol. b M: Major; N: Minor.
References
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These encouraging results set the stage for carrying out asym-
metric version of this methodology. Inspired by our research work
on an intermolecular polyene cyclization initiated by a chiral
acetal,11 we decided to introduce an asymmetric element by using
chiral pure cyclic acetal. In all cases, the cyclization reaction using
cyclic monosubstituted acetal provided the desired products in high
yields and excellent stereoselectivities (Table 2).
The absolute stereochemistry of the minor isomer was
determined by X-ray crystallography analysis (see Supporting
Information), while the relative configuration of the major isomer
is assumed to be the same as the racemic product as shown in
Table 1. We manage to confirm the absolute configuration of
the major isomer as (1S, 3R,5R) after a series of synthetic
manipulations (Scheme 4).12
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J. AM. CHEM. SOC. VOL. 130, NO. 23, 2008 7195