Stereocontrolled alkylative construction of quaternary carbon centers

Article abstract of DOI:10.1021/ja806021y

Protocols for the stereodefined formation of α,α-disubstituted enolates of pseudoephedrine amides are presented followed by the implementation of these in diastereoselective alkylation reactions. Direct alkylation of α,α-disubstituted pseudoephedrine amide substrates is demonstrated to be both efficient and diastereoselective across a range of substrates, as exemplified by alkylation of the diastereomeric pseudoephedrine α-methylbutyramides, where both substrates are found to undergo stereospecific replacement of the α-C-H bond with α-C-alkyl, with retention of stereochemistry. This is shown to arise by sequential stereospecific enolization and alkylation reactions, with the alkyl halide attacking a common π-face of the E- and Z-enolates, proposed to be opposite the pseudoephedrine alkoxide side chain. Pseudoephedrine α-phenylbutyramides are found to undergo highly stereoselective but not stereospecific α-alkylation reactions, which evidence suggests is due to facile enolate isomerization. Also, we show that α,α-disubstituted pseudoephedrine amide enolates can be generated in a highly stereocontrolled fashion by conjugate addition of an alkyllithium reagent to the s-cis-conformer of an α-alkyl-α,β-unsaturated pseudoephedrine amide, providing α,α-disubstituted enolate substrates that undergo alkylation in the same sense as those formed by direct deprotonation. Methods are presented to transform the α-quaternary pseudoephedrine amide products into optically active carboxylic acids, ketones, primary alcohols, and aldehydes. Copyright

Full text of DOI:10.1021/ja806021y

Published on Web 09/13/2008
Stereocontrolled Alkylative Construction of Quaternary Carbon Centers
David A. Kummer, William J. Chain, Marvin R. Morales, Olga Quiroga, and Andrew G. Myers*
Department of Chemistry and Chemical Biology, HarVard UniVersity, Cambridge, Massachusetts 02138
Received July 31, 2008; E-mail: myers@chemistry.harvard.edu
Here we describe practical methods for the stereocontrolled
construction of quaternary carbon centers using pseudoephedrine
as a chiral auxiliary.1-3 Protocols for the stereodefined formation
of R,R-disubstituted enolates of pseudoephedrine amides are
presented followed by the implementation of these in diastereose-
lective alkylation reactions.
Equations 1 and 2 illustrate the finding that the diastereomeric
R-methylbutyramides 1 and 2 undergo stereospecific enolization with
lithium diisopropylamide (LDA) in the presence of lithium chloride
at 0 °C to form Z- and E-enolates, respectively, as inferred from 1H
NMR analysis of the corresponding cyclic siloxane derivatives [formed
upon trapping at -40 °C with dichlorodiisopropylsilane in the presence
of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU)].4
These observations can be rationalized within the framework of prior
Figure 1. Proposed pretransition state assemblies leading to favored (Z)
and disfavored (E) geometric enolate isomers by sequential deprotonations
analyses of pseudoephedrine amide alkylation reactions, extended here
to enolate formation.1c-f We propose that in the favored pretransition
state assemblies the alkoxide side chain and base are positioned on
opposite faces of the incipient enolate, with the R-C-H bond aligned
for deprotonation (see Figure 1, which illustrates the proposal for the
specific case of substrate 1).
of pseudoephedrine amide 1. Lithium is depicted in yellow.
tion for the otherwise puzzling observation that the diastereose-
lectivity of benzylation of 1 is higher at lower conversion (19:1 at
65% conversion versus 9.9:1 at full conversion): the small amount
of E-enolate that is formed during the deprotonation of amide 1 is
alkylated more slowly, and with opposite diastereoselectivity
relative to the Z-enolate. This consideration further suggested that
more highly diastereoselective reactions might be achieved simply
by using a slight excess of enolate, with the electrophile as a limiting
reagent. This proposal was borne out by experiment (Chart 1). Using
excess enolate (1.25 equiv), the diastereoselectivity of benzylation
of amide 1 increased, to 19:1, with no diminution in yield (93%,
now based on the electrophile, first entry, Chart 1). The other entries
of Chart 1 reveal that a number of different electrophiles react
efficiently and diastereoselectively with various R,R-disubstituted
enolates of pseudoephedrine amides, including unactivated alkyl
halides such as isobutyl iodide.6
An interesting feature of the enolization-alkylation reactions of
R,R-disubstituted pseudoephedrine amides emerged when we
investigated the R-phenylbutyramides 3 and 4 as substrates, using
an excess of benzyl bromide as the electrophile (2 equiv). Both
substrates afforded an identical mixture of the two possible
alkylation products (19:1 dr), in 91% yield (eqs 5 and 6), which
suggests that the E- and Z-R-phenyl-R-ethyl enolate intermediates
might interconvert under the reaction conditions. This proposal was
supported by enolate trapping experiments with dichlorodiisopro-
Alkylation of enolates derived from amides 1 and 2 at -40 °C,
initially examined using an excess of the electrophile benzyl
bromide (2 equiv), was also stereospecific; replacement of the
R-C-H bond with R-C-benzyl proceeded with net retention of
stereochemistry in each case (eqs 3 and 4). Together, the experi-
mental results summarized in eqs 1-4 reveal that Z- and E-R-
methyl-R-ethyl disubstituted pseudoephedrine amide enolates are
alkylated preferentially from a common diastereoface. The sense
of alkylation is the same as that observed in the alkylation of
R-monosubstituted pseudoephedrine amides and is rationalized
similarly: the electrophile is proposed to approach the enolate π-face
opposite the alkoxide side chain.1c-f,5 Significantly, benzylation
of the Z-enolate (derived from 1) is both more diastereoselective
and more rapid than benzylation of the E-enolate (derived from
2). The rate ratio is >4, based upon the kinetics of product formation
(see Supporting Information (SI)). This finding suggests an explana-
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J. AM. CHEM. SOC. 2008, 130, 13231–13233 13231

C O M M U N I C A T I O N S
Chart 1. Quaternary Carbon Centers Formed by
Enolization-Alkylation of Pseudoephedrine Amidesa,b,c
a Isolated yields. b For activating alkyl groups (allyl, benzyl) alkyl
bromides were used and for nonactivating groups (ethyl, isobutyl) alkyl
iodides were used. c Alkylation was conducted at -20 °C.
with methyllithium, at -78 °C in the presence of lithium chloride)
and captured as stable di-iso-propylsiloxane derivatives.4 1H NMR
spectroscopic analysis of the latter established that in both cases
addition had occurred almost exclusively by conjugate addition to the
s-cis rotamer of the R,ꢀ-unsaturated amide.
pylsilane (eq 7). If the working model described above applies to
the alkylation of R-phenylbutyramides 3 and 4, then the more
reactive enolate is the E-isomer, with the R-phenyl substituent cis
to the N-methyl group (note that this is also the thermodynamically
preferred isomer; see eq 7 and additional data in the SI).
As with R,R-disubstituted enolates formed by direct deprotonation,
Z- and E-enolates formed by conjugate addition are alkylated from a
common diastereoface, affording major products that are diastereoi-
someric (see eqs 10 and 11). The alkylation reaction of eq 11 was
notably slow (66% yield after 18 h at 0 °C), which is perhaps not
surprising, given that the E-enolate intermediate (with the N-methyl
group cis to the R-tert-butylmethyl group) is sterically hindered (see
models of Figure 2). Interestingly, this was also one of the most poorly
selective alkylation reactions we have identified, perhaps because the
alkoxide side chain and the tert-butyl group are oriented on opposite
π-faces of the enolate (see Figure 2). That the alkylation occurred at
all underscores the point that (pseudoephedrine) amide enolates are
remarkably reactive. As the examples presented in Chart 2 make
evident, the conjugate addition-alkylation protocol is viable for the
construction of a variety of differently substituted quaternary carbon
centers, although the yields of conjugate addition-alkylation products
are somewhat reduced when primary alkyllithium reagents are used
as nucleophiles in the conjugate addition, as a consequence of
competitive 1,2-addition to the amide.8
An alternative method for the stereocontrolled generation of R,R-
disubstituted pseudoephedrine amide enolates as alkylation substrates
was also developed, following the precedent of Badia et al. for the
formation of R-monosubstituted pseudoephedrine amide enolates by
conjugate addition.1g,h Equations 8 and 9 depict transformations
producing the Z and E geometric isomers, respectively, of R-n-butyl-
R-tert-butylmethyl pseudoephedrine amide enolates, generated by the
conjugate addition of an appropriate organolithium reagent to an
R-alkyl-R,ꢀ-unsaturated pseudoephedrine amide (monodeprotonated,
Figure 2. Proposed models of the E-enolate derived from R,ꢀ-unsaturated
pseudoephedrine amide 6. Lithium is depicted in yellow.
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C O M M U N I C A T I O N S
Chart 2. Quaternary Carbon Centers Formed by Conjugate
Addition-Alkylation of R,ꢀ-Unsaturated Pseudoephedrine
Amidesa,b,c,d
Acknowledgment. Dedicated to Prof. E. J. Corey on the
occasion of his 80th birthday. We thank the NSF (CHE-0749566),
the NIH/NIGMS (GM007598-30), the Harvard College Research
Program, Pfizer Inc., Amgen, and Merck & Co., Inc. for financial
support of this research. We thank Dr. Richard Staples for X-ray
crystallographic analyses and Stephan Zuend for helpful discussions.
Supporting Information Available: Rate data, stereochemical
assignments, detailed experimental procedures, and characterization data
for all new compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
References
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a Isolated yields. b Methyl iodide was used for introduction of an
R-methyl group; otherwise, alkyl bromides were used as electrophiles.
c Alkylation was conducted at 0 °C. d Excess phenyllithium (2.25 equiv)
was used in lieu of deprotonation with methyllithium.
We have explored a number of useful transformations of
pseudoephedrine amides bearing R-quaternary carbon centers.
Among these, alkaline hydrolysis to form carboxylic acids has
proven to be both general and high yielding (eq 12 and SI).1a,e In
preliminary studies, we have also shown that methyl ketones can
be formed, using an excess of methyllithium in the presence of
HMPA (eq 13), and that primary alcohols can be formed by
reduction with lithium amidotrihydroborate (eq 14).9 Most recently,
(3) For a recent method to construct quaternary carbon centers employing a chiral
catalyst and an extensive summary of the recent literature in this area, see:
Doyle, A. G.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2007, 46, 3701.
(4) Myers, A. G.; Widdowson, K. L.; Kukkola, P. J. J. Am. Chem. Soc. 1992,
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(5) Alkylation reactions of R,R-disubstituted pseudoephedrine amide enolates were
somewhat less diastereoselective and proceeded more slowly when conducted
in the absence of either lithium chloride or DMPU (or both).
(6) In reactions with limiting electrophile, excess base (LDA) should not be
used, for many electrophiles are destroyed with any excess base (benzyl
bromide forms a mixture of 1-bromo-1,2-diphenylethane and stilbene, for
example).7
(7) (a) Klunder, A. J. H.; Lange, J. H. M.; Zwanenburg, B. Tetrahedron Lett.
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of methyllithium (2.25 equiv) to pseudoephedrine methacrylamide in the
presence of lithium chloride at-78 °C in THF followed by alkylation with
benzyl bromide (2 equiv) in the presence of DMPU (2.5 equiv) at-40 °C
provided the quaternary product depicted in eq 3 in 53% yield (19:1 dr).
(9) (a) Myers, A. G.; Yang, B. H.; Kopecky, D. J. Tetrahedron Lett. 1996, 37,
3623. (b) See ref 1g,h for an alternative reduction method.
(10) Chain, W. J.; Myers, A. G. Org. Lett. 2007, 9, 355.
we have discovered that the oxazolium triflate derivatives developed
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