Regio- and Stereoselective Synthesis of Fully Substituted Silyl Enol Ethers of Ketones and Aldehydes in Acyclic Systems

Article abstract of DOI:10.1002/anie.201909089

The regio- and stereoselective preparation of fully substituted and stereodefined silyl enol ethers of ketones and aldehydes through an allyl-Brook rearrangement is reported. This fast and efficient method proceeds from a mixture of E and Z isomers of easily accessible starting materials.

Full text of DOI:10.1002/anie.201909089

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Accepted Article
Title: Regio- and Stereoselective Synthesis of Fully Substituted Silyl
Enol Ethers of Ketones and Aldehydes in Acyclic Systems
Authors: Ilan Marek
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Angewandte Chemie International Edition
COMMUNICATION
Regio- and Stereoselective Synthesis of Fully Substituted Silyl
Enol Ethers of Ketones and Aldehydes in Acyclic Systems
Peter-Yong Wang,[a][b] Guillaume Duret,[a][b] and Ilan Marek[a]*
Dedicated to Professor Yitzhak Apeloig on the occasion of his 75th birthday
Abstract: The regio- and stereoselective preparation of fully
substituted and stereodefined silyl enol ethers of ketone and
aldehyde are reported through an allyl-Brook rearrangement. This
fast and efficient strategy proceeds from a mixture of E and Z-
isomers of easily accessible starting materials.
rearrangement (Scheme 1, path d).[15] Although these methods
provided the desired stereodefined enolates of ketones, they
intrinsically present some limitations. For instance, the
stereochemistry of the enolate resulting from the reaction of
methyllithium to ketene depends on the steric bulk between the
two substituents on the ketene (R2 versus Me). The
transformation proceeding through the carbamoyl transfer is
restricted to the formation of ’-alkoxy-substituted enolate and
finally, the Michael addition followed by the Brook
rearrangement proceeds only for reactive electrophiles (R2-X).
Even more difficult is the stereodefined preparation of acyclic
fully-substituted enolate of aldehydes (3, Scheme 1) which is still
in its complete infancy.[16] As we have been involved in the last
few years in the design of new strategies allowing the
preparation of stereodefined -disubstituted enolates as a new
source of quaternary carbon stereocenters, we report herein a
unified approach for the regio-and stereoselective preparation of
fully substituted silyl enol ether of ketones and aldehydes.
Enolate derivatives are important key intermediates in organic
synthesis, widely used in the stereoselective formation of
carbon-carbon bonds.[1] Most of the conventional methods for
their preparation rely on the selective formation of kinetic
enolates by deprotonation of
-substituted carbonyl
compounds.[2] However, the generation of fully-substituted
enolates 1-3, or enolate equivalent, in acyclic systems is a more
complex task and has been the focus of few independent
studies.[3] Any solution allowing for the preparation of
geometrically defined -disubstituted enolates 1-3 would, by
addition of the appropriate electrophile, not only empower the
aldol reaction but also provide an efficient and straightforward
access to the synthesis of a large family of products possessing
quaternary carbon stereocenters.[4] From the reductive ring-
opening of diastereoisomerically pure bicyclic lactams[5] to the
stereospecific enolization of acyclic -alkylbutyramides,[6] or
conjugated addition[7] through the double stereodifferentiation
deprotonation of enantiomerically enriched -branched esters,[8]
the formation of stereodefined fully substituted enolates of
amides and esters 1 have been achieved with a great efficiency.
In this context, we have reported the carbometalation reaction of
ynamides[9] followed by a stereo-retentive oxidation reaction[10]
providing the expected fully-substituted enolate of amides 1 as a
single isomer where the stereochemistry of the enolate was
predetermined during the regio- and stereoselective
carbometalation step.[11] Although few additional studies were
reported,[12] one could safely consider that the stereoselective
formation of acyclic -disubstituted enolates of amides and
esters (1) doesn’t represent anymore a major synthetic problem.
On the other hand, and despite all these efforts, the
stereoselective formation of fully-substituted enolates of ketones
2 is still challenging as one needs to control the regio- and
stereoselectivity of the enolization process (Scheme 1, path a).
Attractive solutions to this problem were reported through either
the in-situ generation and trapping of ketene intermediates
(Scheme 1, path b),[13] via a combined metalation – addition of a
carbonyl and carbamoyl transfer (Scheme 1, path c),[14] or
R1
R1
R1
(RO)R2N
[M]
Alkyl
H
R2
R2
R2
O
=
[M]
O
[M]
O
1
2
3
R1 ≠ R2
alkyl
R1 ≠ R2
[M] = metal, SiR3
=
alkyl
R1 ≠ R2
[M] = metal, SiR3
= alkyl
[M] = metal, SiR3
Path a: Enolate of ketone. Regioselectivity and stereoselectivity?
O-[M]
O-[M]
O-[M]
O-[M]
O
R2
R1
R1
R3
+
R1
R3
?
R3
R1
R3
+
+
R1
R2
R2
R2 R3
R2
Path b: Seebach's approach
tBu
tBu
O
OLi
OLi
Me
MeLi
THF, -78 °C
MeLi
THF, -78 °C to rt
R2
R2
R2
O
O
R2
Me
tBu
Me
tBu
Me
•
O
Me
Path c: Metalation - nucleophilic addition - carbamoyl transfer approach
R1
R1
OCb
[M]-O
R1
Carbamoyl
transfer
Nucleophilic carbonyl
addition
R1
R3
O
NiPr2 Metalation
OCb
R3
OCb
R2
R2
R3
H
R2
O
[M]
R2
O-[M]
O
OCb
Path d: Tsubouchi - Takeda’s approach
Michael
addition
R1Cu•tBuOCu
R3
R3
R3
O
[1,3]-Brook
rearrangement
R2-X
R1
R3
SiPh3
R1
OSiPh3
R1
OSiPh3
OCu
SiPh3
R2
Cu
Scheme 1. Various strategies for the synthesis of fully substituted enolates
through a Michael-addition followed by
a
sp2-type Brook
Based on the pioneering work of Kuwajima,[17] we hypothesized
that stereodefined fully substituted silyl enol ether of ketone 2
should be obtained through the addition of a catalytic amount of
base to -hydroxy alkenyl silane 4. The resulting alcoholate 5
[a]
[b]
Dr. G. Duret, Mr. P.-Y. Wang, Prof. Dr. Ilan Marek
Schulich Faculty of Chemistry
Technion – Israel Institute of Technology
Technion City, 3200009 Haifa. Israel
E-mail: chilanm@technion.ac.il
Equal contributors
should
promote
an
intramolecular
allylmetal-Brook
rearrangement[18] to lead to the chelated silyl ether 6. The
starting material 4 would then protonate 6 to give the expected
stereodefined silyl enol ether 2 and regenerate 5 to further
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201909089
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COMMUNICATION
continue the catalytic cycle (Scheme 2). The final
stereochemistry of 2 depending on the existence of the
intramolecular chelation in 6. Conceptually very simple, this
flexible and convenient approach should provide an answer to
the formation of polysubstituted silyl enol ether of ketones 2.[19]
It should be noted that the preparation of all starting -hydroxy
alkenyl silanes 4 is easy and straightforward (see Supporting
Information).[20]
R3Si
OH
R3
alkyl
R2
4
Base (catalytic)
O-[M]
R3Si
R3Si
O
R3
alkyl
R2
R3
alkyl
R2
5
2
R3Si
R3Si
OH
O
[M]
R3
alkyl
R3
alkyl
R2
4
R2
6
Scheme 2. Proposed catalytic cycle for the preparation of stereodefined fully
substituted silyl enol ether of ketones
However, and to our surprise, the experimental conditions
originally reported for the Brook rearrangement[17] didn’t provide
the expected products in decent yields, particularly that our
ultimate goal was to have a one-pot procedure allowing access
to all possible stereoisomers, and we had to reoptimize the
conditions for this transformation on our model substrate 4a (R1
= R2 = R3 = Me, see Supporting Information for all details and
optimization). Following this optimization, we found that when -
hydroxy alkenyl silane 4a was treated with 0.3 equivalent of t-
BuOLi in THF at -20 °C, the silyl enol ether 2a was obtained in
74% yield in 10 to 30 min with an excellent 02:98 E/Z ratio (2a,
Scheme 3). At the outset, a scale-up experiment established our
confidence in the robustness of the current method as 2a could
be prepared on a 2g scale. The opposite stereoisomer 2b could
equally be prepared with similar selectivity by changing the
nature of the two substituents R2 and R3 (R1 = Me, R2 = Et, R3 =
H). The nature of the silyl group doesn’t influence the reaction as
similar yields and E:Z ratios were found for dimethylphenylsilyl
tert-butyldimethylsilyl, triethylsilyl, or trimethylsilyl groups
respectively (2c-2f, Scheme 3). It should be noted that in the
latter case (2f), the silyl enol ether decomposes upon purification
by column chromatography. Either the E or the Z-isomers of
structurally similar silyl enol ethers with different R1 alkyl groups
(2i and 2j, 2n and 2o) could be easily prepared underlining the
power of the proposed strategy. All E:Z ratios were determined
by GC analysis and the stereochemistry of the two isomers 2i
and 2j was unambiguously determined by NOESY experiments
(see Supplementary Information).
Scheme 3. Scope for the formation of stereodefined fully substituted ketone
silyl enol ether 2
Interestingly, the alkyl group R1 could be secondary (2m,
Scheme 3), showing that this proposed approach allows the
formation of a stereo- and regioselective enolate derivative as
single isomer that would be inaccessible through classical
deprotonation of ,’-branched disubstituted ketone. Even more
appealing is the formation of stereodefined fully substituted silyl
enol ethers in the presence of acidic protons (2n-2q, Scheme 3,).
In the latter case (2q), a lower catalytic amount of base needs to
be employed (10 mol%) for a longer period of time (7 h) to reach
good yields. As illustrative example, stereodefined fully
substituted silyl enol ether 2r possessing an allylic stereocenter
was prepared without racemization. Finally, we were delighted
that the desired silyl enol ethers could be directly prepared in a
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10.1002/anie.201909089
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COMMUNICATION
one-pot procedure from either simple acylsilanes or ,-
unsaturated ketones (Scheme 4). Based on calculated
isodesmic reaction (Scheme 4, path a), 5 is slightly more basic
that tBuOH and therefore should be able to undergo the Li-allyl
Brook rearrangement before being in-situ hydrolyzed by tBuOH
into the desired silyl enol ether 2. Using this simple one-pot
procedure several fully substituted silyl enol ethers 2 were
obtained with very high E:Z isomeric ratios by simply adding an
alkyllithium to the acylsilane followed by addition of tBuOH
(Scheme 4, path b).
ether 2 (Scheme 2) and simple enones can be used as starting
materials.
Having successfully demonstrated that we could prepare
stereodefined polysubstituted silyl enol ethers of ketones in
acyclic systems by a Li allyl-Brook rearrangement, we wondered
if the same strategy could lead to the preparation of their
aldehyde analogs. While being very interesting building blocks
for subsequent transformations,[22] the lack of stability as well as
the difficulties to control the stereoselectivity make them
challenging to prepare.[16] Using our optimized conditions on 7a,
the expected stereodefined fully substituted silyl enol ether of
aldehyde 8a was obtained in only 37% yield, still with an
outstanding 02:98 E:Z ratio, along the formation of 9a in almost
20% and unidentified side products (Scheme 5). After extensive
optimization of the experimental conditions (See supporting
information for all details), we found that the best condition for
the reaction to proceed was to treat 7a with 2 equiv. of tBuOCu
with DMPU (5% in volume) in THF at -20 °C. In this condition, 8a
was obtained in 89% as almost a single isomer with less than
5% of 9a.
Scheme 4. One-pot synthesis of silyl enol ether 2a from acylsilanes or ,-
unsaturated ketones.
Scheme 5. Scope for the formation of stereodefined fully substituted silyl enol
ether of aldehyde 8
Alternatively, fully substituted silyl enol ethers 2 could be
similarly in-situ prepared with high isomeric ratios from -
unsaturated ketones by successive addition of PhMe2SiLi[21]
derivative and tBuOH (Scheme 4, path c). Although yields are
lower due to the addition of PhMe2SiLi to enones, this
transformation underline that the stereochemistry of the initial
enone has no effect on the stereochemistry of the final silyl enol
We applied this new optimized condition to several -hydroxy
alkenyl silanes 7a-f, and we were delighted to obtain the
corresponding silyl enol ethers of aldehydes 8a-f in good yields
and excellent E/Z selectivity (Scheme 5). Here again, both
stereoisomers could be independently prepared by simply
changing the nature of the R1 and R2 groups (see formation of
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10.1002/anie.201909089
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COMMUNICATION
Scheme 6. Representative examples of stereodefined silyl enol ethers of
ketones and aldehydes in stereoselective synthesis
8a and 8b, Scheme 5). We could perform the reaction on both
isomers independently as well as on a 1:1 mixture of the starting
materials (4 and 7). In all cases, the same products (2 and 8
respectively) were obtained with similar stereochemistries and
yields. This stereoconvergent reaction could easily be
rationalized by an equilibration of the configurationally labile
carbanion 6 (Scheme 2) into a chelated species, controlling the
final stereochemistry of the Brook-products.
In conclusion, we have described a fast and efficient reaction
sequence allowing the preparation of a wide range of fully
substituted stereodefined silyl enol ethers of ketones and
aldehydes with excellent E:Z ratios from easily accessible
starting materials through
a
postulated allylmetal Brook
rearrangement. Efforts to exploit this new approach in
asymmetric catalysis for the creation of quaternary carbon
stereocenters will be reported in due course.
To illustrate the potential of these diversely polysubstituted silyl
enol ethers in stereoselective synthesis, an aldol reaction has
been performed on the two independent isomers 2a and 2b.
When methyllithium in dimethoxyethane was added to 2a at
room temperature, the lithium enolate was formed without losing
the initial stereochemistry.[23] Then, the subsequent addition of
scandium triflate in DCM and naphthaldehyde at low
temperature afforded the aldol 10a in 70% yield with an
excellent 95:05 diastereoselectivity (Scheme 6).[24] Alternatively,
when the same transformation was performed on 2b, the
opposite diastereoisomer 10b was formed with similar
selectivities. In the case of silyl enol ether of aldehydes 8a and
8b, the direct Mukaiyama aldol transformation has been tested
with benzaldehyde dimethyl acetal and provide 11a in 82% yield
with a diastereoisomeric ratio of 91:09 and 11b in similar
selectivity from 8a and 8b respectively.[25] These representative
examples illustrate the power of the preparation of stereodefined
silyl enol ether of ketones and aldehydes through the formation
of quaternary carbon stereocenters in acyclic systems via the
classical aldol-type chemistry.
Acknowledgements
This research was supported by the Israel Science Foundation
administrated by the Israel Academy of Sciences and
Humanities (330/17).
Keywords: hydroxy silane • silyl enol ether • Brook
rearrangement • stereochemistry • migration
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10.1002/anie.201909089
Angewandte Chemie International Edition
COMMUNICATION
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COMMUNICATION
The regio- and stereoselective
preparation of fully substituted and
stereodefined silyl enol ethers of
ketone and aldehyde are reported
through an allyl-Brook rearrangement.
This fast and efficient strategy
proceeds from a mixture of E and Z-
isomers of easily accessible starting
materials
P.-Y. Wang, G. Duret and I. Marek*
Page No. – Page No.
Regio- and Stereoselective Synthesis of
Fully Substituted Silyl Enol Ethers of
Ketones and Aldehydes in Acyclic Systems
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