Stereoselective Multicomponent Reactions Using Zincate Nucleophiles: β-Dicarbonyl Synthesis and Functionalization

Article abstract of DOI:10.1021/acs.orglett.6b02320

A general strategy for conjugate addition-C-acylation that enables the synthesis of enantioenriched β-dicarbonyl compounds is described. A novel method for derivatizing these adducts by stereo- and site-selective zinc-catalyzed addition of alkyllithium reagents is also reported. These reactions can be performed in tandem to achieve an enantio- and diastereoselective four-component coupling. The in situ generation of weakly basic lithium zincate species is central to the success of all three transformations.

Full text of DOI:10.1021/acs.orglett.6b02320

Letter
pubs.acs.org/OrgLett
Stereoselective Multicomponent Reactions Using Zincate
Nucleophiles: β‑Dicarbonyl Synthesis and Functionalization
Stephen K. Murphy,† Mingshuo Zeng,† and Seth B. Herzon*,†,‡
†Department of Chemistry, Yale University, New Haven, Connecticut 06520, United States
‡Department of Pharmacology, Yale School of Medicine, New Haven, Connecticut 06520, United States
S
* Supporting Information
ABSTRACT: A general strategy for conjugate addition−C-
acylation that enables the synthesis of enantioenriched β-
dicarbonyl compounds is described. A novel method for
derivatizing these adducts by stereo- and site-selective zinc-
catalyzed addition of alkyllithium reagents is also reported.
These reactions can be performed in tandem to achieve an enantio- and diastereoselective four-component coupling. The in situ
generation of weakly basic lithium zincate species is central to the success of all three transformations.
ulticomponent reactions rapidly increase molecular
enolates with regiocontrol is a noteworthy element of this
Mcomplexity, allowing improvements in synthetic effi- strategy. However, the related sequence involving 1,4-addition
ciency.1 The conjugate addition of an organometallic reagent to
an enone followed by trapping of the resulting enolate with an
and enolate C-acylation is conspicuously underdeveloped
(Figure 1A, bottom).2b,3 As noted in a review, “...conjugate
addition−enolate acylation reactions are very substrate depend-
ent. With certain substrates, O-acylation competes or even
predominates despite the use of conditions conducive to
reaction at carbon.”2b Competitive proton transfer from the β-
dicarbonyl product to the enolate can also occur, which leads to
C,O-diacylated and nonacylated products.2b,3c Consequently,
reliable methods for β-diketone synthesis by a three-component
coupling strategy have been elusive, and enantioselective
variants are unknown.4
aldehyde (the Noyori three-component coupling, Figure 1A,
top) exemplifies the power of such transformations to affect
strategic fragment couplings.2 The ability to access ketone
Herein, we report the first general strategy for affecting
enantio- and diastereoselective 1,4-addition−C-acylation reac-
tions (Figure 1B). Key to its success is the use of in situ
generated zincate enolates that are highly nucleophilic at
carbon but weakly basic.5 This reaction yields C-acylated
products irrespective of the nucleophile, enone, or acylating
reagent employed. Furthermore, we have leveraged the power
of this sequence to develop a four-component coupling that
sets three contiguous stereocenters with absolute and relative
stereocontrol (Figure 1C). This transformation combines 1,4-
addition−C-acylation with a novel 1,2-addition of zincates to β-
diketones. As shown, the latter transformation can also be
performed independently using zinc catalysis.
To control the absolute stereochemistry of 1,4-addition, we
employed Feringa’s phosphoramidite-based method, which is
among the most general and reliable for stereoselective 1,4-
addition of organozinc reagents to enones.4a,6 As shown in
Scheme 1, direct trapping of the resulting methylzinc enolate
with acetyl chloride was inefficient and provided the C-, O-, and
diacylated products 2a−4a in 11−36% yields.7,8 We hypothe-
sized that this methylzinc enolate could be activated by the
Figure 1. (A) Tandem conjugate addition−acylation is highly
substrate dependent. (B) Strategy for tandem conjugate addition−
acylation exploiting the activation of zinc enolates with organolithium
reagents. (C) Four-component coupling to establish three contiguous
stereocenters in a single flask.
Received: August 8, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02320
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Organic Letters
Letter
a
Scheme 1. Reactivity of Alkylzinc Enolates and Lithium
Dialkylzincate Enolates
Scheme 2. Scope of the 1,4-Addition−Acylation Sequence
addition of a second nucleophile to form an ate complex in situ.
Noyori’s finding that the lithium enolate of cyclohexanone
undergoes C-acylation after activation with dimethylzinc
provided an important precedent.5a Indeed, a dramatic increase
in reactivity and regioselectivity was observed when methyl-
lithium (1.05 equiv) was added immediately before the
acylating reagent.9 The resulting lithium dimethylzincate
enolate was rapidly C-acylated at −78 °C to provide the 1,3-
dicarbonyl 2a in 80% isolated yield. The O-acylated and
1
diacylated products 3a and 4a were not detected by H NMR
or GC−MS analysis.
This three-component coupling is general and provides
access to an array of stereochemically defined 1,3-diketones
(Scheme 2). In all cases examined, exclusive C-acylation was
observed irrespective of the organozinc reagent, enone, or acid
chloride employed. Furthermore, all products were generated in
>90% ee, and only the trans diastereomers were formed,
although the products 2a−g,n,o exist partially as their enol
tautomers. In agreement with Feringa’s report on the 1,4-
addition of organozinc reagents to enones,4a the absolute
configuration of 2j was established to be 2S,3S on the basis of
single-crystal X-ray analysis.10 Unhindered or electron-deficient
aliphatic acid chlorides underwent acylation rapidly at −78 °C
(2a−d), while warming to 0 °C was necessary when more
hindered electrophiles, such as isobutyryl chloride (2g), were
employed. Sterically and electronically diverse aroyl chlorides
were excellent substrates for this reaction. Although certain
aroyl chlorides displayed reactivity in the absence of
methyllithium, the yields and selectivities were diminished in
those instances.11 Esters (2q), anisoles (2p), benzyl ethers
(2d), aryl chlorides (2o), ortho-substitution (2n and 2o), and
proximal quaternary centers (2m) were all compatible with this
sequence. Furthermore, the method is applicable to medium-
sized enones such as 2-cyclohepten-1-one and 2-cycloocten-1-
one (products 2k and 2l). In contrast to analogous reactions
with organocopper reagents,3 >20:1 C-selectivity was main-
tained with a variety of β-substituents (2a−c,h−j).
The scope of this reaction includes a range of carbonyl
electrophiles (Table 1). Chloroformates, cyanoformates,13
anhydrides, and benzoyl fluorides provided the corresponding
addition−acylation products in 48−73% yields (entries 1−4). It
is noteworthy that chloroformates and anhydrides typically
provide O-acylated products when reacted with a variety of
metalloenolates,2b,14,15 and in the absence of activation,
monoalkylzinc enolates were completely unreactive toward
chloroformates and cyanoformates (entries 1 and 2). The
reaction was readily performed on a 21 mmol scale using
Mander’s reagent as the electrophile (entry 2).
a
General conditions: R2Zn (1.05 equiv), Cu(OTf)2 (2 mol %), L* (4
mol %), Et2O, −30 to 0 °C, 0.5−5 h, then CH3Li (1.05 equiv), −78
°C, 1−5 min, then acid chloride (1.2 equiv), −78 to 0 °C, 15 min−3 h.
In general, isolated yields were 5−15% lower than NMR yields due to
decomposition of diketones on silica gel. This phenomenon has been
noted by others.12 Instances where the isolated yields and NMR yields
b
differed by >20% are denoted with an asterisk. Average of two runs.
Table 1. Scope of the Carbonyl Electrophile in the
Asymmetric Conjugate Addition−Acylation
a b
,
with CH3Li
without CH3Li
no.
electrophile
yield (%)
48
C:O
yield (%)
C:O
c
d
d
f
1
2
3
4
2r
2s
2h
2h
R′OCOCl
>20:1
>20:1
7.3:1
11:1
<1
<1
25
30
e
(CH3O)COCN
(C6H5CO)2O
C6H5COF
72
73
65
1:1.7
11:1
f
a
Acylations performed in the absence of CH3Li were conducted at 22
b
c
°C for 2 h. Each product is formed in 96% ee. R′ = (R)-menthyl.
d
e
Determined by GC−MS analysis. 21 mmol scale. Isolated after C-
f
methylation. NMR yields.
example, ketoester 2s undergoes diastereoselective C-alkylation
on treatment with iodomethane and sodium tert-butoxide
(Scheme 3, eq 1). Based on our finding that zincate enolates are
nonbasic nucleophiles useful in β-dicarbonyl synthesis, we
The β-dicarbonyl compounds accessed in this study can be
converted to other stereochemically complex products. For
B
DOI: 10.1021/acs.orglett.6b02320
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Organic Letters
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addition to the aryl ketone in preference to the dialkyl ketone
and the selectivity improved when bulkier substrates were
employed (6f−h).
Stereochemical models for the 1,2-addition of zincates to
diketones are depicted in Scheme 5. Given the high levels of
Scheme 3. C-Alkylation and Nucleophilic Addition
Scheme 5. Stereochemical Models for 1,2-Additions to
Ketones with Zincate Nucleophiles
a
Yield over two steps (conjugate addition−acylation and C-alkylation).
stereoselectivity obtained when either cyclic or acyclic
substrates are used, we suggest that the β-diketones chelate
to a lithium cation leading to a rigid transition state.18 In the
case of acyclic substrates, syn-pentane interactions force the
alkyl backbone of the molecule into an extended conformation
that increases the steric demand around the dialkyl ketone.
Thus, addition occurs to the aryl ketone from the face opposite
the α-substituent. The regioselectivity is reversed for cyclic
substrates. In these instances, the substituents on the dialkyl
ketone are constrained by the ring, rendering that carbonyl
more accessible. Furthermore, nucleophilic addition to the aryl
ketone would generate syn-pentane interactions between the β-
alkyl substituent and either the aryl group or incoming
nucleophile. Accordingly, equatorial attack of the zincate on
the cyclohexanone occurs to produce the observed stereo-
isomer.
considered that trialkylzincates might be ideal nucleophiles for
1,2-addition to enolizable β-dicarbonyls. Existing methods for
the 1,2-addition of organometallic reagents to β-diketones
employ stoichiometric amounts of cerium trichloride or excess
Grignard reagents with heating.16 By comparison, we found
that the addition could be carried out efficiently using
substoichiometric amounts of ZnCl2 (10 mol %) and 1.25
equiv of methyllithium (Scheme 3, eq 2). We believe that
methyllithium reacts rapidly with the zinc salt leading to in situ
formation of the triorganozincate.17 In the absence of zinc
chloride, 1,2-addition products are formed in only 25% yield as
mixtures of regioisomers and diastereomers. Treating 2h with
preformed LiZn(CH3)3 led to the β-hydroxy ketone 6a in 98%
yield as a single isomer, supporting the intermediacy of a
triorganozincate in the zinc-catalyzed process.
This zinc-catalyzed 1,2-addition is applicable to a variety of
enolizable cyclic and acyclic β-diketones (Scheme 4). Using the
Finally, we discovered that this method can be modified to
affect a one-flask asymmetric four-component coupling
(Scheme 6). By increasing the amount of methyllithium used
Scheme 4. Scope of ZnCl2-Catalyzed Addition of
Methyllithium to β-Diketones
Scheme 6. Four-Component Coupling Reactions
a
Methylmagnesium bromide used instead of methyllithium.
to activate the zinc enolate from 1.05 to 2.05 equiv, the β-
hydroxy ketone 6a was obtained in 54% yield as a single
detectable diastereomer and in 96% ee. The yield was improved
to 61% when methylmagnesium bromide was used as the
activator and products 6i,j were synthesized using alternative
acid chlorides and organolithium reagents. This four-
component coupling forges three C−C bonds and sets three
contiguous stereocenters.
In summary, we have developed a general method for the
stereoselective addition of organozinc reagents to α,β-
unsaturated ketones followed by high-yielding acylation of the
resulting enolates. This fundamental sequence provides stereo-
and regiocontrolled access to 1,3-dicarbonyl products and
products derived from conjugate addition−C-acylation, the
cyclic dialkyl ketone substituent undergoes addition in
preference to the aryl ketone (>20:1 regioselectivity). The
high stereo- and regioselectivity are maintained for substrates
with varying steric bulk at the β-position (6a−c). While yields
were excellent for electron-neutral and electron-rich β-
diketones (6a−d), substrates with electron-withdrawing
substituents provided low yields of product (30%, 6e),
potentially due to competitive proton transfer. Distinct
regioselectivity was observed when acyclic β-diketones were
employed. In these instances, the zincate underwent selective
C
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Organic Letters
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(6) For a complementary approach to enantioselective addition of
organozinc reagents to enones, see: Degrado, S. J.; Mizutani, H.;
Hoveyda, A. H. J. Am. Chem. Soc. 2001, 123, 755.
closes a long-standing gap in the methodological literature. The
products are useful precursors to other complex products via
site- and stereoselective C-alkylation or zinc-catalyzed alkyla-
tion. Key to the success of these strategies was the use of
zincate nucleophiles which undergo chemo-, regio-, and
diastereoselective addition reactions while avoiding competitive
proton transfers from acidic 1,3-dicarbonyl functional groups.
This strategy is applicable to a wide range of enones,
organozinc reagents, and carboxylic acid derivatives, and the
use of these methods in multistep synthesis is currently
ongoing.
(7) Related alkylzinc enolates have been trapped intermolecularly by
aldehydes, oxycarbenium ions, allylic electrophiles, and silylating
agents, see: (a) Naasz, R.; Arnold, L. A.; Pineschi, M.; Keller, E.;
Feringa, B. L. J. Am. Chem. Soc. 1999, 121, 1104. (b) Alexakis, A.;
Trevitt, G. P.; Bernardinelli, G. J. Am. Chem. Soc. 2001, 123, 4358.
(c) Knopff, O.; Alexakis, A. Org. Lett. 2002, 4, 3835. (d) Dijk, E. W.;
Panella, L.; Pinho, P.; Naasz, R.; Meetsma, A.; Minnaard, A. J.; Feringa,
B. L. Tetrahedron 2004, 60, 9687. For intramolecular reactions, see:
(e) Agapiou, K.; Cauble, D. F.; Krische, M. J. J. Am. Chem. Soc. 2004,
126, 4528.
(8) Acylation of the zinc enolate derived from ethyl tert-butyl ketone
with benzoyl chloride has been reported to occur in 65% yield, see:
Hansen, M. M.; Bartlett, P. A.; Heathcock, C. H. Organometallics 1987,
6, 2069. The rhodium-catalyzed acylation of zinc enolates with aroyl
chlorides has also been reported, see: Sato, K.; Yamazoe, S.;
Yamamoto, R.; Ohata, S.; Tarui, A.; Omote, M.; Kumadaki, I.;
Ando, A. Org. Lett. 2008, 10, 2405.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b02320.
Experimental procedures and characterization data
(PDF)
(9) Other organometallic reagents, such as methylmagnesium
bromide, n-butyllithium, phenyllithium, and vinyllithium, can be
used to promote C-acylation.
(10) The data for 2j has been deposited to the CCDC (ref no.
CCDC 1503495).
AUTHOR INFORMATION
■
(11) See the Supporting Information for comparisons.
(12) Bartlett, S. L.; Beaudry, C. M. J. Org. Chem. 2011, 76, 9852.
(13) During the preparation of this manuscript, a related procedure
for the conjugate addition of dimethylzinc to 2-cyclohexen-1-one and
acylation with Mander’s reagent was employed in the asymmetric total
synthesis of amphilectane and serrulatane natural products, see: Yu, X.;
Su, F.; Liu, C.; Yuan, H.; Zhao, S.; Zhou, Z.; Quan, T.; Luo, T. J. Am.
Chem. Soc. 2016, 138, 6261.
(14) May, T. L.; Dabrowski, J. A.; Hoveyda, A. H. J. Am. Chem. Soc.
2011, 133, 736.
(15) Vuagnoux-d’Augustin, M. V.; Alexakis, A. Tetrahedron Lett.
2007, 48, 7408.
(16) (a) Bartoli, G.; Marcantoni, E.; Petrini, M. Angew. Chem., Int. Ed.
Engl. 1993, 32, 1061. (b) Yuan, R.; Zhao, D.; Zhang, L.-Y.; Pan, X.;
Yang, Y.; Wang, P.; Li, H.-F.; Da, C.-S. Org. Biomol. Chem. 2016, 14,
724. (c) Leighton and co-workers developed a method for the
enantioselective allylation of diketones using a chiral allylsilane
reagent, see: Chalifoux, W.; Reznik, S. K.; Leighton, J. L. Nature
2012, 487, 86.
(17) Hatano, M.; Suzuki, S.; Ishihara, K. J. Am. Chem. Soc. 2006, 128,
9998.
(18) Lower yields were obtained when the reaction was conducted in
tetrahydrofuran, perhaps due to interfere with the formation of
chelated intermediates.
Corresponding Author
*E-mail: seth.herzon@yale.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from Yale University, the National Institute
of General Medical Sciences (R01GM090000), and the
National Sciences and Engineering Research Council of Canada
(postdoctoral fellowship to S.K.M.) is gratefully acknowledged.
We thank Dr. Brandon Mercado for X-ray crystallographic
analysis.
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D
DOI: 10.1021/acs.orglett.6b02320
Org. Lett. XXXX, XXX, XXX−XXX