Ketone super silyl enol ethers in sequential reactions: Diastereoselective generation of tertiary carbinols in one pot

Article abstract of DOI:10.1021/ja7102586

Ketone super silyl enol ethers are shown to be excellent nucleophiles in the Mukaiyama aldol reaction as well as in sequential one-pot diastereoselective reactions. High yields and diastereoselectivities are obtained with a variety of silyl enol ether/ald

Full text of DOI:10.1021/ja7102586

Published on Web 01/15/2008
Ketone Super Silyl Enol Ethers in Sequential Reactions: Diastereoselective
Generation of Tertiary Carbinols in One Pot
Matthew B. Boxer,† Matsujiro Akakura,‡ and Hisashi Yamamoto*,†
Department of Chemistry, The UniVersity of Chicago, 5735 South Ellis AVenue, Chicago, Illinois 60637, and
Department of Chemistry, Aichi UniVersity of Education, Igaya-cho, Kariya 448-8542, Japan
Received November 12, 2007; E-mail: yamamoto@uchicago.edu
Scheme 1. Highly Diastereoselective Mukaiyama Aldol Reactions
Generation of tertiary carbinols in a diastereoselective manner
remains an important synthetic task in organic chemistry.1 While
the design of catalytic enantioselective reactions is garnering the
majority of recent attention, broadly applicable, catalytic, diaste-
reoselective reactions remain a significant objective. This is
particularly true for compounds with nearby stereocenters where
frequent use of expensive external chiral sources is not ideal.
Continuing our research efforts with the tris(trimethylsilyl)silyl
(TTMSS or super silyl group) and its sequential aldol (SA)
reactions,2 which were shown to proceed with unprecedented
reactivity and diastereoselectivity, we initially explored the use of
ketone derived silyl enol ethers for the simple aldol reaction. Starting
with the acetone-derived super silyl enol ether 1, we looked at the
diastereoselective aldol reaction with chiral aldehydes 2 and 4
(Scheme 1). The reaction proceeded giving ketones 3 and 5 in high
yield with high Felkin selectivity even in the case of 2-methyl-
butyraldehyde, showcasing this enol ether’s ability to differentiate
methyl and ethyl groups.3 The super silyl enol ether of cyclohex-
anone (6) was reacted with iso-butyraldehyde giving 7 in high yield
with unprecedented high anti selectivity for this type of Mukaiyama
aldol reaction. This is in stark contrast to the TBS- and TMS-enol
ethers of cyclohexanone, which have been reported to give little to
no selectivity in aldol reactions with a variety of catalysts.4
Pleased with these initial aldol results, we wondered if these
reagents could be used for SA-reactions such as subsequent addition
of organometallics, that is, Grignards, in a one-pot SA-Grignard
protocol to generate tertiary carbinols. While a plethora of literature
reports and in-depth studies exist regarding the diastereoselectivity
of additions to â-oxygenated aldehydes,5 significantly fewer reports
can be found for the corresponding simple â-oxygenated ketones
(aside from hydrogenation/reduction reactions).6 The majority of
these reports involve a â-hydroxy ketone and are proposed to
undergo cyclic, six-membered transition states involving a Lewis
acid catalyst or the metal from the organometallic species. While
there is a report concerning syn selectivity for the methyl and butyl
addition to â-TBSoxy protected ketones,6c sparse examples exist
for this type of diastereoselective reaction. This may be due to two
main factors: (1) ketones are typically less selective and less
reactive than aldehydes in many stereoselective reactions, and (2)
stereoselectivity induced by â-chirality is often lower than that
induced by R-chirality. We hoped that the superior diastereoselec-
tivity imposed by the super silyl group would also allow for a
successful sequential reactions of in situ formed â-super siloxy
ketones.
excellent diastereoselectivity giving the anti product as the major
diastereomer.7,8 This observed sense of stereoinduction results from
nucleophilic attack on the opposite π-face of the carbonyl to our
previously reported SA-Grignard reactions utilizing the acetaldehyde
super silyl enol ether.2c The proposed reason for this distinction
was investigated with DFT calculations and will be discussed
subsequently.
Scheme 2. SA-Grignard Reaction to Generate Distinct
Diastereomers
Using a simple one-pot SA-reaction protocol, 1 underwent the
aldol reaction with 4 initiated by 0.1 mol % of HNTf2, and phenyl
magnesium bromide was subsequently added dropwise at -78 °C
(Scheme 2). The product 8 was formed with good yield and
Realizing that by simple substrate choice distinct diastereomers
could be generated, 10 was formed with high selectivity by simply
† The University of Chicago.
‡ Aichi University of Education.
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10.1021/ja7102586 CCC: $40.75 © 2008 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3. 4-Component SA-A-Grignard Reactions
Table 1. SA-Grignard Reaction
in moderate yield with high diastereoselectivity. The same protocol
was used with 12 as the second silyl enol ether and phenylmag-
nesium bromide was finally added to give 26 in moderate yield
and selectivity.
DFT calculations at the B3LYP/6-311+G(d,p)//B3LYP/6-31G-
(d) level were done to address the aforementioned diastereoselec-
tivities.11 Where we had previously observed syn selectivity (SA-
Grignard reaction with â-super siloxy aldehydes), we are now seeing
anti selectivity (SA-Grignard reaction with â-super siloxy ketones).
The calculations assigned a reactant weak complex (RWC) as the
relative zero point. The transition state (TS) energy was then
calculated as well as the product energy. The vinyl Grignard dimer
was used in the calculations due to classic experiments12 as well
as in new calculations showing its likelihood as the reactive
species.13 This was done for both syn and anti reaction courses.
The calculations showed that the vinyl Grignard addition to the
â-super siloxy aldehyde favored the syn pathway by 0.3 kcal/mol
in the TS leading to the experimentally observed syn isomer (Figure
1). Calculations for the â-super siloxy methyl ketone showed a
switching to the super silyl enol ether of acetophenone (9) and
sequentially adding methyl Grignard (Scheme 2). Intrigued by the
possibility of accessing stereodefined isomers with similarly sized
substituents at the quaternary carbon, we used 9 and added p-F-
phenyl Grignard obtaining the expected anti isomer 11 in good yield
and selectivity (Scheme 2).7 Using the super silyl enol ether of
4′-F-acetophenone (12) and adding phenyl Grignard did indeed give
the expected diastereomer 13 in similar yield and selectivity. These
examples clearly indicate the control of the transition state exhibited
by the super siloxy substituent in these open-chain â-super siloxy
ketones as well as the ability to generate the desired diastereomers
by the simple choice of silyl enol ether and Grignard.
The generality of this one-pot reaction was shown by the success
of a variety of super silyl enol ethers, aldehydes, and Grignard
reagents (Table 1). The cyclohexanone super silyl enol ether 6 was
used, followed by the addition of the methyl Grignard to give 15,
containing three contiguous stereocenters with the selectivity of
the Grignard addition dictated by the stereocenter at the R-position
of the ketone.7 Use of vinyl Grignards worked well giving products
16, 17, and 18 with good diastereoselectivity.7 The use of the propyl
Grignard succeeded in this reaction giving products 19 and 20.
Importantly, formation of 17 and 20 showcases the super silyl
groups powerful control of diastereoselection by first differentiating
methyl and ethyl groups to give large excess of the Felkin isomer
and by second stereoselectively controlling the Grignard addition
via its presence in the â-position. Use of benzylmagesium chloride
gave the lowest selectivity producing 21 with a moderate 78/22
ratio.9 A variety of aryl Grignards worked very well in this reaction
producing bisaryl tertiary carbinols 22 and 23 with good selectivity.
Product 22, containing the valuable pyridine moiety was generated
by in situ preparation of the heteroaryl Grignard formed by
Knochel’s powerful iPrMgCl 2,6-dibromopyridine exchange reac-
tion.10
Figure 1. Structures of optimized transition states (TS). Calculated energies
(kcal/mol) determined via stationary-point calculations of reactant weak
complex (RWC), TS and product in vinyl Grignard addition to â-super
siloxy aldehyde. Yellow ) Si, gray ) C, white ) H, red ) O, green ) Cl,
purple ) Mg; blue bond indicates forming C-C bond in TS.
Owing to our past success with the sequential aldol-aldol (SA-
A) reaction,2a we decided to combine this method with our SA-
Grignard reaction for a 4-component SA-A-Grignard protocol
(Scheme 3). The aldol reaction of the acetaldehyde silyl enol ether
was followed by a second aldol reaction with 24, and subsequent
addition of methyl Grignard to give the 4-component product 25
preference for the observed anti isomer formation by 2.6 kcal/mol
in the TS (Figure 2). The major reasons for the dissimilarity in TS
energies for the latter is the presence of significant steric repulsion
between the ketone’s methyl group and â-isopropyl group in the
syn TS. The anti TS does not suffer from this interaction and is
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C O M M U N I C A T I O N S
Pharmaceuticals (ACS, Division of Organic Chemistry Fellowhip)
for funding. Calculations were performed at the Research Center
for Computational Science (RCCS), Okazaki Research Facilities,
National Institutes of Natural Science (NINS). Thanks to Ian Steele
for X-ray analysis and Antoni Jurkiewicz for NMR expertise.
Supporting Information Available: Complete ref 11, experimental
procedures, computational methods, compound characterization and
crystallographic data. This material is available free of charge via the
Internet at http://pubs.acs.org.
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(7) Relative stereochemistry determined by derivatization and X-ray crystal-
lographic analysis (see Supporting Information for details).
(8) The term anti concerns the relationship between the two alcohol groups
when the final incoming nucleophile and alkyl chain containing the
â-supersiloxy moiety are placed in the same plane. This is done as it is
a consistent method with our (and others) previous work with aldehydes
(ref. 2) and conveys the opposite selectivity generated between these
â-supersiloxy carbonyl compounds.
Figure 2. Structures of optimized transition states (TS). Calculated energies
(kcal/mol) determined via stationary point calculations of reactant weak
complex (RWC), TS and product in vinyl Grignard addition to â-super
siloxy ketone. Yellow ) Si, gray ) C, white ) H, red ) O, green ) Cl,
purple ) Mg; blue bond indicates forming C-C bond in TS.
thus largely favored. Both the ketone and aldehyde TSs indicate a
conformational preference that minimizes destabilizing electrostatic
â-C-O and CdO dipole interactions.14 The aldehyde, in which
the methyl group is replaced with a hydrogen, results in the oxygen
being the larger atom (hydrogen vs oxygen in aldehyde and methyl
vs oxygen in ketone) and preferably passes through the TS leading
to the syn isomer. This calculated TS is in accord with our
previously predicted TS for the similarly acid-catalyzed SA-A
reaction.2a A key feature that can be realized from these calculations
is that the super silyl group creates a large umbrella-like structure
under which the rest of the molecule aligns. This umbrella restricts
the conformational freedom of the remaining portion of the
molecule. The stereochemical outcome is then largely determined
by the carbonyl and its substituent’s (methyl for ketone and
hydrogen for aldehyde in this study) interaction with the medium
â-group (isopropyl in this study). This is in contrast to typical open-
chain ketones and aldehydes which have much more freedom of
rotation due to a lack of the umbrella effect. This umbrella effect
is why we believe we see such high selectivities for these â-super
siloxy carbonyl addition reactions.
In conclusion, we have shown the utility of ketone super silyl
enol ethers for SA reactions. These silyl enol ethers were shown
to succeed in simple Mukaiyama aldol reactions with high selectiv-
ity as well as SA-Grignard reactions and 4-component SA-A-
Grignard reactions. With the growing demand for one-pot reactions
capable of generating relatively complex molecular architecture,
we believe the super silyl group is emerging as a key piece for
diastereoselective one-pot SA-reactions.
(9) Relative stereochemistry determined by conversion to the acetonide and
subsequent interrogation of NOE between the benzylic protons and
CH(OH) methine proton.
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Acknowledgment. This Communication is dedicated to E.J.
Corey on occasion of his 80th birthday. Thanks to Novartis
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