Pd-Catalyzed Asymmetric Hydroalkylation of 1,3-Dienes: Access to Unnatural α-Amino Acid Derivatives Containing Vicinal Quaternary and Tertiary Stereogenic Centers

Article abstract of DOI:10.1021/acs.orglett.9b04341

Pd-phosphinooxazoline (Pd-PHOX)-catalyzed asymmetric hydroalkylation of 1,3-dienes with azlactones was successfully developed for the first time, affording various enantioenriched α-quaternary α-amino acid derivatives bearing contiguous quaternary and tertiary stereogenic centers in good yields with exclusive regioselectivity and excellent stereoselective control (up to 92% yield, >20:1 dr, and >99% ee). The scale-up catalytic asymmetric hydroalkylation was performed well without loss of reactivity and stereoselectivities, which exhibited great potential application. The synthetic utility of the current methodology was demonstrated through product transformations to access other biologically important compounds such as chiral β-amino alcohol and α-quaternary cyclic α-amino acid derivatives.

Full text of DOI:10.1021/acs.orglett.9b04341

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Pd-Catalyzed Asymmetric Hydroalkylation of 1,3-Dienes: Access to
Unnatural α‑Amino Acid Derivatives Containing Vicinal Quaternary
and Tertiary Stereogenic Centers
Zongpeng Zhang,† Fan Xiao,† Hui-Min Wu,† Xiu-Qin Dong,*,† and Chun-Jiang Wang*,†,‡
†Engineering Research Center of Organosilicon Compounds & Materials, Ministry of Education, College of Chemistry and
Molecular Sciences, Wuhan University, Wuhan 430072, China
‡State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Shanghai 230021, China
S
* Supporting Information
ABSTRACT: Pd-phosphinooxazoline (Pd-PHOX)-catalyzed
asymmetric hydroalkylation of 1,3-dienes with azlactones was
successfully developed for the first time, affording various
enantioenriched α-quaternary α-amino acid derivatives bearing
contiguous quaternary and tertiary stereogenic centers in good
yields with exclusive regioselectivity and excellent stereo-
selective control (up to 92% yield, >20:1 dr, and >99% ee).
The scale-up catalytic asymmetric hydroalkylation was
performed well without loss of reactivity and stereoselectiv-
ities, which exhibited great potential application. The synthetic utility of the current methodology was demonstrated through
product transformations to access other biologically important compounds such as chiral β-amino alcohol and α-quaternary
cyclic α-amino acid derivatives.
ptically active unnatural α-quaternary α-amino acids (α-
AAs) and derivatives have captured great attention,
conjugated 1,3-dienes have become attractive synthons in
asymmetric hydrofunctionalization,12 which is initiated by a
migratory insertion of in situ-generated transition-metal
hydride (M-H) to deliver an electrophilic π-allyl metal
intermediate followed by a nucleophilic attack. However,
asymmetric hydroalkylation of 1,3-dienes with carbon-based
nucleophiles is rarely explored, especially for the construction
of multiple stereogenic centers.13 To the best of our
knowledge, there is only one racemic example on the
hydroalkylation of 1,3-dienes with azlactones, that is,
(CDC)−Rh-catalyzed hydroalkylation of 1,3-dienes with
azlactones developed by Meek and coworkers to generate
α,α-disubstituted allylic amino acid products containing vicinal
tertiary and quaternary stereocenters in good yields with high
diastereoselectivities (Scheme 1, top).14 Most recently,
Malcolmson and coworkers reported a pioneering asymmetric
addition of carbon-based nucleophiles to 1,3-dienes catalyzed
by a Pd-phosphinooxazoline (Pd-PHOX) complex with high
enantioselectivities.12f,g However, only moderate diastereose-
lectivity was observed with the examined prochiral nucleo-
philes. Encouraged by these achievements and in continuation
of our efforts on asymmetric synthesis of unnatural α-AAs,15
we herein reported the first Pd-catalyzed asymmetric hydro-
alkylation of 1,3-dienes with various prochiral azlactones,
which led to a wide range of chiral α-quaternary α-amino acid
derivatives containing vicinal quaternary and tertiary stereo-
O
which could be attributed to their advantages as versatile
building blocks for the synthesis of unnatural peptides, and
they play an important role in medicinal chemistry.1 In
addition, they have been identified as prevalent substructures
in a large number of other chiral molecules with biological
activities.2 The remarkable importance of chiral unnatural
quaternary α-amino acids has caused an increasing interest to
develop efficient methodologies for the asymmetric con-
struction of these valuable compounds. However, the
preparation of chiral α-quaternary α-amino acid and
derivatives, especially α-quaternary α-amino acid containing
vicinal tertiary and quaternary stereocenters, has been one of
the major and challenging targets in the field of asymmetric
catalytic synthesis.
Azlactones have been extensively explored and emerged as
important kinds of valuable synthons for the construction of
chiral quaternary α-amino acids in the past decades.3 Various
synthetic strategies have been developed4−11 such as
asymmetric alkylations,4 conjugate additions,5 Mannich-type
reactions,6 cycloadditions,7 and allylic alkylations.8−10 Among
them, transition-metal-catalyzed allylic alkylations of azlactones
have proven to be powerful synthetic methodologies which are
mainly involved allylic alcohols, activated derivatives,8 and
allenes9 as π-allyl fragment sources, and also most recently in
elegant work documented by Gong and coworkers with 1,4-
dienes via C−H activation strategy.10 Since Takahashi reported
the first example of catalytic intermolecular diene hydro-
alkylation promoted by a Pd catalyst in early 1970s,11
Received: December 3, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b04341
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 1. Synthesis of Quaternary α-Amino Acid
Derivatives Containing Vicinal Tertiary and Quaternary
Stereocenters via Hydroalkylation of 1,3-Dienes with
Azlactones
Table 1. Initial Test and Reaction Optimization
b
c
d
entry
ligand
base
NEt3
NEt3
NEt3
NEt3
NEt3
NEt3
NEt3
yield (%)
dr
ee (%)
1
2
3
4
5
6
7
8
9
L1
L2
L3
L4
L5
L6
L7
L7
L7
L7
56
60
89
46
46
67
70
43
50
92
3.8:1
3.5:1
3.8:1
4:1
48
47
37
84
96
94
95
94
95
95
genic centers in good yields with exclusive regioselectivity, high
diastereoselectivities, and excellent enantioselectivities
(Scheme 1, bottom).
6:1
Initially, we investigated the asymmetric induction of
commercially available chiral ligands in the Pd-catalyzed
hydroalkylation with alanine derived azlactone 1a and 1-
phenylbutadiene 2a as the model substrates in the presence of
5 mol % of [Pd(allyl)Cl]2, NEt3, and AgBF4 in CH2Cl2 at
room temperature. As shown in Table 1, some axially chiral
bisphosphine ligands such as (S)-BINAP L1, (S)-H8−BINAP
L2, and (S)-Segphos L3 provided the desired hydroalkylation
product 3a in moderate to good yields with exclusive
regioselectivity albeit with poor stereoselectivities (56−89%
yields, 3.5:1−3.8:1 dr, 37−48% ee, Table 1, entries 1−3). The
planar chiral P,N-ligands L4 and L5 provided the correspond-
ing product 3a in acceptable yields with moderate diaster-
eoselectivities and good to excellent enantioselectivities, and
chiral ligand L5 containing a tert-butyl group with steric
hindrance displayed higher efficiency (4:1−6:1 dr, 84−96% ee,
Table 1, entries 4 and 5). Then, two other P,N-ligands L6 and
L7 containing tert-butyl groups were then applied; promising
stereocontrol results were obtained to give product 3a in
moderate yields with excellent diastereoselectivities and
enantioselectivities, and ligand L7 with two trifluoromethyl
groups on the phenyl ring proved to be the best choice (67−
70% yields, 10:1−12:1 dr, 94−95% ee, Table 1, entries 6 and
7). Subsequently, other organic bases, including N,N-
diisopropylethylamine (DIPEA) and 1,4-diazabicyclo[2.2.2]-
octane (DABCO), were examined in this asymmetric trans-
formation. Although the diastereoselectivities were improved,
unsatisfactory reactivities were detected with reduced yields
(43−50% yields, 14:1 dr, 94−95% ee, Table 1, entries 8 and
9). Fortunately, when Brønsted acid HBF4·Et2O was added,
the yield was greatly improved to 92% with maintained
stereoselectivity control, which could be ascribed to accelerat-
ing the formation of key Pd-π-allyl species12g (Table 1, entry
10).
10:1
12:1
14:1
14:1
12:1
DIPEA
DABCO
NEt3
e
10
a
All reactions were carried on with 0.15 mmol 1a, 0.1 mmol 2a, base
(3 equiv), and AgBF4 (12 mol %) in 2 mL of DCM, 18−24 h.
b
c
d
1
Isolated yield. dr was determined by the crude H NMR. ee was
e
determined by HPLC analysis. With 10 mol % of HBF4·Et2O as the
additive.
Pd-L7 complex, a series of alkyl substituents with different
steric hindrances at the C4 position of azlactones was first
explored, which showed good compatibility in this reaction
system. The azlactones with methyl (1a), ethyl (1b), benzyl
(1c), iso-butyl (1d), and allyl (1e) group underwent the
reactions smoothly to afford the desired products (3a−3e) in
good yields with exclusive regioselectivity and good to
excellent diastereoselectivities and enantioselectivities (75−
92% yields, 10:1 to >20:1 dr, 93 to >99% ee, Table 2, entries
1−5). Remarkably, valine derived azlactone (1f) with sterically
bulky iso-propyl group worked well in this transformation,
which is a challenging substrate in the bismetallic catalytic
system (entry 6).13 In addition, the substrates with different
substituted groups at the C2 position were further investigated.
We found that the electric properties and positions of the
substituents on the aryl ring have little influence on the
reactivities and stereoselectivities. The substrates containing
electron-rich (1g−1h, 1k) or electron-deficient (1i−1j, 1l−
1m) substituents on the phenyl ring at different positions have
proved to be good reaction partners, affording the correspond-
ing products (3g−3m) with excellent results (75−90% yields,
10:1−19:1 dr and 94−98% ee, Table 2, entries 7−13). In
addition, azlactones (1n−1o) with phenyl group at the C4
position were also tested, and the desired products (3n−3o)
were obtained in good yields and excellent enantioselectivities,
Having established the optimized reaction conditions, we
explored the substrate scope generality of this Pd-catalyzed
asymmetric hydroalkylation of 1-phenylbutadiene 2a with a
variety of azlactones. As shown in Table 2, with the performed
B
DOI: 10.1021/acs.orglett.9b04341
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a
Table 2. Substrate Scope of Azlactones
Table 3. Substrate Scope of 1,3-Dienes
b
c
d
entry
1
R
R′
3
yield (%)
dr
ee (%)
Me
Et
Bn
iBu
allyl
iPr
Ph
Ph
Ph
Ph
Ph
Ph
3a
3b
3c
3d
3e
3f
92
85
82
80
75
54
89
90
87
80
78
86
75
70
85
12:1
>20:1
10:1
>20:1
10:1
>20:1
15:1
13:1
19:1
19:1
10:1
19:1
95
>99
95
93
99
97
96
98
95
95
95
95
94
95
87
e
2
f
3
f
4
f
5
f
6
7
8
Me
Me
Me
Me
Me
Me
Me
Ph
p-MeC6H4
p-MeOC6H4
p-FC6H4
p-ClC6H4
m-MeC6H4
m-FC6H4
o-FC6H4
Me
3g
3h
3i
3j
3k
3l
3m
3n
3o
e
9
10
11
12
e
13
15:1
4.3:1
1.2:1
f
14
f
15
Ph
Ph
a
All reactions were carried on with 0.15 mmol 1, 0.1 mmol 2a, Pd-L7
catalyst (10 mol %), NEt3 (3 equiv), and HBF4·Et2O (10 mol %) in 2
b
c
mL of DCM, 18−24 h. Isolated yield. dr was determined by crude
d
e
1H NMR. ee was determined by HPLC analysis. DABCO was used
f
a
as the base. Ee was determined after alcoholysis with K2CO3/MeOH
All reactions were carried on with 0.15 mmol 1a, 0.1 mmol 2, Pd-L7
catalyst (10 mol %), NEt3 (3 equiv), and HBF4·Et2O (10 mol %) in 2
mL of DCM, 18−24 h. Yield is isolated yield. dr was determined by
to facilitate HPLC analysis.
1
crude H NMR, and ee was determined by HPLC analysis.
albeit with moderate diastereoselectivities (70−85% yields,
1.2:1−4.3:1 dr and 87−95% ee, Table 2, entries 14 and 15).
Promoted by these experimental results, we then evaluated
various 1,3-dienes for further substrate scope study. A wide
range of diversified 1,3-dienes was well-tolerated. To facilitate
HPLC analysis of ee values, the corresponding products were
subsequently alcoholyzed to deliver quaternary α-amino acid
derivatives containing adjacent tertiary and quaternary stereo-
centers in good yields with exclusive regioselectivity and good
to excellent stereoselectivities (50−90% yields, 4:1 to >20:1 dr,
86−97% ee). Various aryl substituted 1,3-dienes bearing
electron-donating or electron-withdrawing groups worked
well in this transformation (Table 3, entries 1−9). In addition,
we also examined the position of substituted group on the
phenyl ring, whether it is at the ortho-, meta-, or para-position;
these reactions were performed smoothly to provide the
desired products in good yields with excellent stereo-
selectivities. Moreover, the heteroaromatic substrate (E)-2-
(buta-1,3-dien-1-yl)furan (2j) was suitable to work in this
reaction system, affording the expected product (4j) with 86%
yield, 14:1 dr, and 97% ee (Table 3, entry 10). To be noted,
the alkyl substrates (E)-buta-1,3-dien-1-ylcyclohexane (2k)
and (E)-hexa-3,5-dien-1-ylbenzene (2l) also facilitated the
reactions with 1,3-oxazol-5(4H)-one (1a) efficiently, which led
to the corresponding products (4k and 4l) with good to
excellent results (55−78% yields, 4:1−5:1 dr, 86−93% ee,
Table 3, entries 11 and 12). The methyl (E)-penta-2,4-
dienoate 2m, the functionalized 1,3-diene bearing electron-
withdrawing ester group, was also tolerated in this Pd-catalyzed
asymmetric hydroalkylation, and the desired product 4m was
obtained with good yield, high diastereoselectivity and
excellent enantioselectivity (82% yield, > 20:1 dr, 87% ee,
Table 3, entry 13).
To demonstrate the synthetic utility of the current
methodology, a scale-up asymmetric catalytic hydroalkylation
reaction between azlactone 1a and 1-phenylbutadiene 2a was
performed under the standard conditions, and 3a was readily
obtained in comparable yields without loss of enantioselectiv-
ity, as shown in Scheme 2 (top). The enantioenriched
hydroalkylation product obtained herein can be converted
into synthetically useful chiral compounds in a facile manner.
Scheme 2. Scale-up and Synthetic Transformations
C
DOI: 10.1021/acs.orglett.9b04341
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Synthesis and Introduction into Naturally Occurring Peptides and
For example, reduction of 3a with NaBH4 furnished β-amino
alcohol derivative 5 in nearly quantitative yield without
decrease of enantioselectivity.16 In addition, the hydro-
alkylation/alcoholysis product 3e containing two vinyl groups
was readily converted to α-quaternary cyclic α-amino acid
derivative 6 in 70% yield and without loss of stereoselectivity
via intramolecular ring closing metathesis,17 which is a
synthetically useful building block in medicinal chemistry18
(Scheme 2, bottom).
In summary, we successfully developed the first Pd-catalyzed
asymmetric hydroalkylation of 1,3-dienes with azlactones. A
series of chiral α-quaternary α-amino acid derivatives bearing
vicinal tertiary and quaternary stereogenic centers was
obtained in good yields, exclusive regioselectivity, and good
to excellent stereoselective control. This protocol can be
proceeded well in scale-up version, and the desired products
were easily converted to other important molecules such as
chiral β-amino alcohol and α-quaternary cyclic α-amino acid
derivative. Further investigations on detailed mechanism of the
current Pd-catalyzed asymmetric hydroalkylation are in
progress in our lab.
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b04341.
(4) (a) Trost, B. M.; Czabaniuk, L. C. Benzylic Phosphates as
Electrophiles in the Palladium-Catalyzed Asymmetric Benzylation of
Azlactones. J. Am. Chem. Soc. 2012, 134, 5778−5781. (b) Trost, B.
M.; Czabaniuk, L. C. Palladium-Catalyzed Asymmetric Benzylation of
Azlactones. Chem. - Eur. J. 2013, 19, 15210−15218. (c) Uraguchi, D.;
Asai, Y.; Seto, Y.; Ooi, T. Asymmetric Synthesis of α,α-Disubstituted
α-Amino Acids via Enantioselective Alkylation of Azlactones under
Biphasic Conditions Using P-Spiro Chiral Tetraaminophosphonium
Salts as a Phase-Transfer Catalyst. Synlett 2009, 2009, 658−660.
(d) Uraguchi, D.; Asai, Y.; Ooi, T. Site-Directed Asymmetric
Quaternization of a Peptide Backbone at a C-Terminal Azlactone.
Angew. Chem., Int. Ed. 2009, 48, 733−737.
General procedures, synthetic transformations, proposed
catalytic cycle, references, and NMR and HPLC spectra
(PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: xiuqindong@whu.edu.cn.
*E-mail: cjwang@whu.edu.cn.
ORCID
Xiu-Qin Dong: 0000-0002-5045-1198
(5) (a) Cabrera, S.; Reyes, E.; Aleman, J.; Milelli, A.; Kobbelgaard,
S.; Jørgensen, K. A. Organocatalytic Asymmetric Synthesis of α,α-
Disubstituted α-Amino Acids and Derivatives. J. Am. Chem. Soc. 2008,
130, 12031−12037. (b) Uraguchi, D.; Ueki, Y.; Ooi, T. Chiral
Organic Ion Pair Catalysts Assembled Through a Hydrogen-Bonding
Network. Science 2009, 326, 120−123. (c) Hayashi, Y.; Obi, K.; Ohta,
Y.; Okamura, D.; Ishikawa, H. Diphenylprolinol Silyl Ether as a
Catalyst in an Enantioselective, Catalytic Michael Reaction for the
Formation of α,α-Disubstituted α-Amino Acid Derivatives. Chem. -
Asian J. 2009, 4, 246−249. (d) Balaguer, A. N.; Companyo, X.;
Calvet, T.; Font-Bardía, M.; Moyano, A.; Rios, R. Highly Regio- and
Diastereoselective Oxazol-5-one Addition to Nitrostyrenes. Eur. J.
Org. Chem. 2009, 2009, 199−203. (e) Jiang, H.; Paixao, M. W.;
Monge, D.; Jørgensen, K. A. Acyl Phosphonates: Good Hydrogen
Bond Acceptors and Ester/Amide Equivalents in Asymmetric
Organocatalysis. J. Am. Chem. Soc. 2010, 132, 2775−2783. (f) Liu,
Q.; Qiao, B.; Chin, K. F.; Tan, C.-H.; Jiang, Z. Asymmetric Michael
Addition of 5H-Oxazol-4-ones to Vinyl Sulfones: Stereoselective
Synthesis of Monofluorinated Analogs of 2-Tertiary Hydroxyl-3-
Methyl-Substituted Carboxylic Acid Derivatives. Adv. Synth. Catal.
2014, 356, 3777−3783. (g) Uraguchi, D.; Ueki, Y.; Sugiyama, A.; Ooi,
T. Highly stereoselective Michael addition of azlactones to electron-
deficient triple bonds under P-spiro chiral iminophosphorane
catalysis: importance of protonation pathway. Chem. Sci. 2013, 4,
Chun-Jiang Wang: 0000-0003-3629-6889
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support from the National Natural
Science Foundation of China (Grants 21525207 and
21772147), the Wuhan Morning Light Plan of Youth Science
and Technology (Grant 2017050300307), and the Funda-
mental Research Funds for Central Universities (Grant
2042018kf0202). The Program of Introducing Talents of
Discipline to Universities of China (111 Project) is also
appreciated.
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