Pd(0)-Catalyzed Chemo-, Diastereo-, and Enantioselective α-Quaternary Alkylation of Branched Aldehydes

Article abstract of DOI:10.1021/acscatal.0c02861

Quaternary carbon stereocenters are ubiquitous in a wide variety of organic compounds and drug molecules. Highly enantioselective construction of such quaternary carbon centers poses a singular challenge due to the steric repulsion between the four different carbon substituents. Herein, we report a novel strategy to control the enantioselective construction of chiral α-quaternary aldehydes from racemic α-branched aldehydes. Distinct from the established chiral α-quaternary aldehyde synthesis, this project employed a chiral π-allyl-Pd complex neighboring the enolate to determine both the enantio- and diastereoselectivity. The synthetic utility of the products has been highlighted by a series of derivatizations, and the potential of this method has been extended to the synthesis of chiral α-quaternary ketones. Furthermore, this reaction exemplifies the themes of step and atom economy, in addition to the principles of diversity-oriented synthesis.

Full text of DOI:10.1021/acscatal.0c02861

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Article
Pd(0)-catalyzed Chemo-, Diastereo- and Enantioselective
#-Quaternary Alkylation of Branched Aldehydes
Barry M. Trost, Zhijun Zuo, Youliang Wang, and Johnathan E. Schultz
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.0c02861 • Publication Date (Web): 24 Jul 2020
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Pd(0)-catalyzed
Chemo-,
Diastereo-
and
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Enantioselective α-Quaternary Alkylation of
Branched Aldehydes
Barry M. Trost,a* Zhijun Zuo,a‡ Youliang Wang,b‡ and Johnathan E. Schultzc
a Department of Chemistry, Stanford University, Stanford, California 94305-5080, United States
b School of Chemistry, Xi'an Jiaotong University, Xi’an 710049, P. R. China
c Chemical Process Development, Bristol Myers Squibb, New Brunswick, NJ 08901, United States
KEYWORDS: Asymmetric catalysis; Palladium; Quaternary center; Aldehyde; Enolate
ABSTRACT: Quaternary carbon stereocenters are ubiquitous in a wide variety of organic
compounds and drug molecules. Highly enantioselective construction of such quaternary carbon
centers poses a singular challenge due to the steric repulsion between the four different carbon
substituents. Herein, we report a novel strategy to control the enantioselective construction of
chiral α-quaternary aldehydes from racemic α-branched aldehydes. Distinct from the established
chiral α-quaternary aldehydes synthesis, this project employed a chiral π-ally-Pd complex
neighboring to the enolate to determine both the enantio- and diastereoselectivity. The synthetic
utility of the products has been highlighted by a series of derivatizations and the potential of this
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method extended to the synthesis of chiral α-quaternary ketones. Furthermore, this reaction
exemplifies the themes of step and atom economy, in addition to the principles of diversity-
oriented synthesis.
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INTRODUCTION
Construction of quaternary carbon stereocenters remains a very challenging but important
endeavor for modern synthetic chemistry due to its prevalence in numerous natural products and
pharmaceuticals.1 Although synthetic chemists have made tremendous progress in developing
novel methodologies to form quaternary carbon centers, this still remains a daunting challenge for
access to many areas of chemical space.2 From the synthetic perspective, it is important to
introduce transformable functionalities into the structure of a synthetic intermediate for further
modification, instead of merely preparing an optical pure quaternary carbon centers. Among
various functionalities, the formyl group plays a vital role in organic syntheses.3 Additionally,
aldehydes bearing all-carbon α-quaternary centers constitute a vital structural motif in a great
number of biologically active natural products. For other synthetic targets, a formyl group bearing
an α-quaternary center conveniently serves an intermediate for further transformation (Figure 1).4
Figure 1. Representative bioactive and natural products containing α-quaternary aldehydes or converting from
α-quaternary aldehydes.
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At present, only limited types of catalytic asymmetric reactions are known to facilitate the
formation of α-quaternary aldehydes from readily available α-branched aldehydes. With the recent
advancement of organocatalysis,5 some elegant methods have been disclosed for the direct
enantioselective α-allylation or α-alkylation of aldehydes to prepare quaternary stereocenters by
means of an SN2 mechanism,6 or an SN1 mechanism with stabilized carbocations.7 A chiral amine
was employed as the catalyst to form the chiral enamine intermediate, which could efficiently
prevent the aldol-dimerization pathway and also enable chiral induction for nucleophilic attack. In
2018, our group demonstrated a versatile enantioselective stereodivergent process to access acyclic
α-quaternary aldehydes using Zn-ProPhenol catalysis (Scheme 1a, top).8 The geometrically pure
Zn-enolate intermediate could undergo the Mannich reaction to afford synthetically useful α-
quaternary β-amino-aldehydes with excellent enantio- and diastereoselectivity. The transition-
metal-catalyzed α-allylation is another emerging strategy to construct quaternary carbon centers
(Scheme 1a, middle).9 The groups of List9b and Gong9e have successfully carried out the reaction
by synergistic catalysis using a π-allyl-Pd-TRIP ion pair complex with achiral amine in excellent
selectivities. In 2016, the Evans group reported an unprecedented example where an aldehyde,
activated by strong base, was able to react with a chiral π-allyl-rhodium intermediate to synthesize
enantioenriched α-quaternary aldehydes.9d Despite the success for construction of chiral
quaternary stereocenters, the established methods to control the enantioselectivity are limited to
above two major approaches, thus limiting the types of products. Thus, from the synthetic point of
view, the development of mechanistically new strategies to control the enantioselective synthesis
of α-quaternary aldehydes is still highly
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Scheme 1. The existing asymmetric catalytic strategies for the construction of α-quaternary aldehydes and our
new design for construction α-quaternary aldehydes through Pd-catalyzed alkylation reaction.
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desirable. In conjunction with our long-standing interest in the π-allyl palladium controlled
asymmetric reaction.10 We envisioned that a neighboring π-allyl palladium motif, installed at the
α-position of an aldehyde, might dominate the enantio- and diastereoselective induction for the
construction of a quaternary carbon center (Scheme 1a, bottom). In this context, we disclose a
novel Pd-catalyzed enantio- and diastereoselective α-quaternary alkylation of α-branched
aldehydes to synthesize complex cyclic compounds (Scheme 1b). We devised the bifunctional
substrate 1 which incorporated both an allyl carbonate and an α-formyl methine moiety. We
proposed that the reaction proceeded through the zwitterionic Pd-complex intermediate I,
generated in situ by the ionization of the allyl carbonate followed by the base-assisted
deprotonation. The stereoselective enolization of intermediate I would lead to the key intermediate
II, which then reacted with prochiral π-system coupling partners to deliver the cyclic adducts
bearing an α-quaternary carbon center along with one or two additional contiguous stereocenters,
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which is the first report of generating such structural elements. From another perspective, we are
disclosing a highly diastereo- and enantioselective approach for hetero- and carbocyclic five-
membered ring systems analogous to what the Diels-Alder reactions succeeded for the six
membered rings, where the high efficiency and selectivities are enabled by the high conformational
control of the diene and dienophile.11 The importance of the Diels-Alder reactions for six
membered ring systems foreshadowed the substantial applications of analogous reactions to make
five membered rings. However, additional challenges arise from the fact that: 1) unlike direct
installing the chiral porckets on the heteroatom of enolate or the electrophiles, whether the
neighboring π-allyl palladium motif could give the appropriate asymmetric induction for this
transformation, 2) the intermediate I is prone to undergo the aldol condensation and other potential
undesired pathways,12 3) an examination of the structural requirements of this process involving
an enolate with no control of the enolate olefin geometry would lead to a prediction of poor
stereocontrol.
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RESULTS AND DISCUSSION
With the above questions in mind, we first probed the racemic reactions by reacting nitroolefin 1a
●
with bifunctional allyl carbonate 2a in the presence of Pd2(dba)3 CHCl3 and triisopropyl phosphite
L1 in THF at 60 °C (see Table 1). The desired cyclic adduct 3aa bearing a quaternary carbon
center could be isolated in 83% yield, albeit with poor diastereoselectivity (entry 1). With the
racemic reaction established, we turned our efforts to realizing the enantioselective transformation
by applying chiral phosphorous ligands. A chiral diamidophosphite ligand L2 showed excellent
reactivity and diastereoselectivity with promising enantioselectivity (entry 2). Toluene and 1,4-
dioxane did not give better results (entry 3-4). Interestingly, increasing the steric bulk about the
ligand backbone led to a distinct improvement in enantioselectivity but with an erosion of
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diastereoselectivity (entry 5-6). Use of the phosphoramidite ligand (Feringa ligand) L5 led to poor
reactivity (entry 7). When the reaction was conducted in other solvents at lower temperature, DME
was found to be ideal in terms of reactivity and selectivity (entry 8-10). Both the
diastereoselectivity and enantioselectivity were slightly increased when the reaction was
performed at 35 °C (entry 11). Surprisingly, the reaction was completely shut down at room
temperature (entry 12). Extending the methyl group at the α-position of aldehyde to an ethyl group
had a beneficial effect on diastereoselectivity, which is presumably conducive to the geometrically
more controlled enolization of intermediate II (entry 13). Gratifyingly, after briefly screening
various solvents, the desired product 3ab was isolated in 89% yield with excellent
diastereoselectivity and enantioselectivity (12:1 dr and 99:1 er) in the presence of 1,4-dioxane
(entry 14-16). Interestingly, the cyclohexane diamidophosphite L2 also gave excellent results
under this reaction condition (entry 17).
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Table 1. Optimization of reaction condition
Entrya ligand
R
Solvent
THF
T (°C) Yield Erb
Drc
2:1
1
2
L1
L2
Me
Me
60
60
83%
/
THF
90% 85.5:14.5 10:1
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L2
L2
L3
L4
L5
L4
L4
L4
L4
L4
L4
L4
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L4
L2
Me
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Me
Me
Me
Me
Me
Me
Me
Me
Et
Dioxane
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35
rt
85% 84.5:15.5 6:1
4
Toluene
THF
89% 85:15
71% 86:14
7:1
8:1
5
6
THF
85% 91.5:8.5 5:1
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THF
21%
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5:1
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THF
82% 92:8
9
2-Me-THF
DME
86% 92.5:7.5 7:1
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88% 94:6
85% 95:5
<10% /
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DME
DME
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72% 93:7
13:1
Et
THF
65% 98.5:1.5 12:1
Et
Toluene
Dioxane
Dioxane
68% 99:1
89% 99:1
90% 97:3
14:1
12:1
13:1
Et
Et
aReactions were performed on a 0.10 mmol scale for 12 h. bEnantiomeric ratio (er) determined using chiral HPLC. cDiastereomeric
ratio (dr) determined by crude 1H NMR.
With the optimized conditions in hand, we proceeded to evaluate the generality of this reaction by
screening various kinds of π-system coupling partners (Scheme 2). By reacting with α-branched
aldehydes 2a or 2b, the nitrostyrenes with various steric and electronic properties behaved very
well to afford the desired products with good yield (60-90%), excellent enantioselectivities (up to
99.5:0.5 er) and moderate to excellent diastereoselectivities (up to 19:1 dr). With respect to the
aromatic ring in the nitroolefin, a series of substituents such as methoxy (1c), methylthio (1d),
methyl (1e) and methylenedioxy (1f) groups at para- or ortho-positions were well tolerated and
gave the anticipated products in excellent results. It is worth noting that, the nitroolefin 1e, bearing
a sterically congested group, proceeded smoothly in the reaction. Moreover, substrates containing
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medicinally relevant heteroaromatics (1h-j) could also undergo the cycloaddition efficiently with
good results. Notably, the nitroolefin is not limited to aromatic substituted ones. Benzophenone
imine substituted nitroethylene 1k and conjugated 1,3-nitrodienes 1l also proved to be feasible,
thus yielding synthetically useful cyclopentane structures. Moreover, a general and representative
aliphatic nitroolefin 1m could also participate in this transformation to give the anticipated product
3ma with 2.4:1 dr and 99.5:0.5 er. To our surprise, the nitrostyrenes with electron-withdrawing
groups (4-chloro or 4-CF3) on the phenyl ring did not give the desired products at all.13
Scheme 2. Scope with respect to π-system coupling partners
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The coupling partners of this reaction are not limited to nitroolefins. Other types of electron-
deficient π-systems such as Meldrum’s acid alkylidene 1n, azlactone 1o, pyrone 1p and coumarin
1q were demonstrated to be applicable and gave the corresponding cyclic adducts in 69-91% yields
and excellent diastereo- and enantioselectivities (up to 19:1 dr and 97.5:2.5 er). Upon treating 3qb
with 1N NaOH under mild condition, the highly functionalized cyclopentane carboxylic acid 4
could be obtained in quantitative yield. Ts-imine 1r served as an excellent partner in this reaction
thereby extending the method to access biologically important substituted pyrrolidines. The
absolute configuration was assigned by comparison to optical rotation of known compound 3rb.14
Notably, tetrahydrofuran bearing two vicinal tetra-substituted stereogenic centers, which would be
challenging to synthesize by conventional chemical strategies, could be easily accessed in good
diseteroselectivity and promising enantioselectivity. Much to our delight, the azadiene 1t prefered
the [4+3] type cycloaddition pathway,15 leading to the entropically disfavored medium-sized
benzofuro[3,2-b]azepines with a quaternary carbon center in excellent result.
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To further expand the generality of this process, α-branched aldehydes with other substituents
were subjected to the reaction (Scheme 3). Attaching an alkene functionality to the methyl chain
proceeded without an erosion of stereoselectivity or reactivity. To our surprise, the terminal alkyne
group was tolerated in this transformation and led to synthetically important 1,5-enyne unit16 with
excellent enantioselectivity and moderate diastereoselectivity. Delightfully, the preliminary result
showed that α-branched ketone 2e was also an effective in this transformation and gave the
corresponding α-quaternary ketone adduct 3ae in excellent yield and enantioselectivity, albeit with
diminished, but synthetically useful diastereoselectivity.
Scheme 3. Scope with respect to α-branched aldehydes and preliminary result for α-branched ketone
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To showcase the synthetic potential of our protocol for scaled applications, the millimole reaction
was conducted with reduced loadings of the catalyst and the ligand by increasing the reaction
concentration to 0.25 M. The levels of diastereomeric and enantiomeric enrichment at 1.0 mol %
of Pd2(dba)3•CHCl3 remained unchanged (Scheme 4, middle). In order to demonstrate the utility
of our method for generating interesting and useful chiral building blocks, a number of selective
transformations were carried out. Ozonolysis of 3ab smoothly provided the cyclopentenenone 5,
formed through the elimination of HNO2 and decarboxylation. Seyferth-Gilbert homologation of
the aldehyde furnished alkyne 6 efficiently in 83% yield.17 The adduct 3ab could also be applied
to the Wittig reaction to give chiral 1,4-diene 7. To our surprise, the structurally complex bridged
ring systems 8 could be accessed through the base-assisted Michael addition and intramolecular
aldol reaction. In addition, the bicyclo[2.2.1] nitrone 9 could be obtained in near quantitative yield
upon treating 3ab in the reducing condition.18 Pinnick oxidation of aldehyde 3ab provides an
efficient route to the α-quaternary carboxylic acid 10 with good yield.19 It should be notable that
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these transformations open an efficient and unique avenue to access polyfunctionalized
cycloadducts, which are difficult or even impossible to obtain by other strategies.
Scheme 4. Large-scale preparation of 3ab and its derivatization
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EtO2C
O
Et
Et
Et
NO2
NO2
Me
Me
6
5
Me
7
83% yield
>20:1 dr
89% yield
>20:1 dr
85% yield
>20:1 dr
Bestmann reagent
K2CO3, MeOH, rt
O3, PPh3
DCM, -78 °C
PPh3CHCO2Et
CHCl3, reflux
NO2
Pd2(dba)3
∑
CHCl3 (1.0 mol%)
OHC
Et
OHC
OBoc
L4 (2.0 mol%)
+
1,4-dioxane (0.25 M)
35 °C, 12 h
77% yield, 11:1 dr
Et
Me
NO2
1a
2.2 mmol
2b
2.0 mmol
98.5:1.5 er
Me
3b
DBU
NaClO2, NaH2PO4
2-Methyl-2-butene
tBuOH/H2O, rt
SmI2
MeOH, 0 °C
methyl acrylate
MeCN, rt
O
OH
OH
Me
N
Me
HO2C
Et
Et
H N
Me
Me
HO
HN
2
Me
CO2Me
Et
OH
Me
HO
NO2
Me
HN
N
NO2
O
Me
Nigegladines A
Me
Lycocasuarines A
O
Me
9
92% yield
>20:1 dr
Me
Me
8
10
59% yield
>20:1 dr
72% yield
>20:1 dr
The stereochemical outcome of this transformation can be rationalized by consideration of the
geometry of the π-allyl palladium/enolate intermediate (Scheme 5). A cis relationship between the
enolate oxygen and the π-allyl is likely a result of either two-fold binding to palladium or
electrostatic interactions between the charged moieties of the zwitterionic intermediate.
Additionally, this orientation may minimize ligand interactions with the alkyl side chain and
potentially explains the increase in diastereoselectivity when changing the side chain from a
methyl to ethyl substituent. The extension of chiral information in the ligand allows for translation
to the site of the conjugate addition, favoring addition to the Re face with the bulky aromatic
substituent of the π-acceptor aligned away from the palladium complex. The seeming
stereospecificity in product formation with respect to the substituents on the acceptor gives some
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credence to the idea that the reaction is a concerted cycloaddition; however, the thermodynamic
trans relationship could simply be favored in a step-wise mechanism.
Scheme 5. Plausible stereochemical mode of 3ab
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CONCLUSIONS
In summary, we have disclosed an unprecedented strategy to control the enantioselective
alkylation of α-branched aldehydes to synthesize chiral cyclic α-quaternary aldehydes with one or
two additional contiguous stereocenters. In contrast to the previous strategies, this new strategy
does not rely on the use of external chiral amine, base or chiral electrophiles to construct the α-
quaternary aldehydes, but instead relies on a chiral palladium complex for stereoinduction.
Impressively, the diastereo- and enantioselective event occurs as a Michael addition distal to the
chiral information. This is further emphasized since the in-situ generated π-allyl-Pd species on the
carbon center of enolate has been validated to undergo the chiral induction efficiently in the
construction of quaternary carbon center. An array of synthetically useful and flexible hetero- and
carbocycles were efficiently assembled. Furthermore, elaborations of the available multifunctional
cycloadducts enabled rapid access to a wide range of structural types, which are ubiquitous in
complex molecular targets. Due to its convergency, this reaction exemplifies themes of step and
atom economy.20 Furthermore, the ease of post-synthetic modifications by selective functional
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group interconversions renders this reaction practical for diversity-oriented synthesis, an
increasingly important strategy in drug discovery.21
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ASSOCIATED CONTENT
AUTHOR INFORMATION
Corresponding Author
*bmtrost@stanford.edu
ORCID
Barry M. Trost: orcid.org/0000-0001-7369-9121
Zhijun Zuo: orcid.org/0000-0002-7838-4003
Youliang Wang: orcid.org/0000-0002-2613-3616
Author Contributions
The manuscript was written through contributions of all authors. All authors have given approval
to the final version of the manuscript. ‡Z. Z. and Y. W. contributed equally.
Notes
The authors declare no competing financial interest.
Supporting Information.
Complete experimental procedures, compound characterization, representative NMR spectra. This
material is available free of charge via the Internet at http://pubs.acs.org.
ACKNOWLEDGMENT
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We are grateful to the Tamaki Foundation for financial support. We also thank S. Lynch (Stanford
University) for his help with two-dimensional nuclear magnetic resonance analysis.
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Table of Content
Pd(0)-catalyzed Chemo-, Diastereo- and Enantioselective α-Quaternary Alkylation of
Branched Aldehydes
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Quaternary carbon stereocenters are ubiquitous in a wide variety of organic compounds and drug
molecules. A novel strategy to control the enantioselective construction of chiral α-quaternary
aldehydes from racemic α-branched aldehydes was achieved. The synthetic utility of the products
has been highlighted by a series of derivatizations and the potential of this method extended to the
synthesis of chiral α-quaternary ketones.
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