Amino Acid Schiff Base Bearing Benzophenone Imine As a Platform for Highly Congested Unnatural α-Amino Acid Synthesis

for Highly Congested Unnatural α ‑Amino Acid Synthesis

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Amino Acid Schiﬀ Base Bearing Benzophenone Imine As a Platform

Yohei Matsumoto, Jun Sawamura, Yumi Murata, Takashi Nishikata,* Ryo Yazaki,*

and Takashi Ohshima*

Cite This: https://dx.doi.org/10.1021/jacs.0c02707

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ABSTRACT: Unnatural α-amino acids are invaluable building blocks in synthetic organic chemistry and could upgrade the function

of peptides. We developed a new mode for catalytic activation of amino acid Schiﬀ bases, serving as a platform for highly congested

unnatural α-amino acid synthesis. The redox active copper catalyst enabled eﬃcient cross-coupling to construct contiguous

tetrasubstituted carbon centers. The broad functional group compatibility highlights the mildness of the present catalysis. Notably,

we achieved successive β-functionalization and oxidation of amino acid Schiﬀ bases to aﬀord dehydroalanine derivatives bearing

tetrasubstituted carbon. A three-component cross-coupling reaction of an amino acid Schiﬀ base, alkyl bromides, and styrene

derivatives demonstrated the high utility of the present method. The diastereoselective reaction was also achieved using menthol

derivatives as a chiral auxiliary, delivering enantiomerically enriched α-amino acid bearing α,β-continuous tetrasubstituted carbon.

The synthesized highly congested unnatural α-amino acid could be derivatized and incorporated into peptide synthesis.

INTRODUCTION

Scheme 1. Amino Acid Schiﬀ Bases for Unnatural α-Amino

Acid Synthesis

■

Unnatural α-amino acids are invaluable building blocks in

synthetic organic chemistry and could upgrade the function of

peptides, which are widely used as pharmaceuticals and

biological materials. The establishment of an eﬃcient method

for synthesizing unnatural α-amino acids, for which artiﬁcial

synthesis is essential, is one of the most urgent research topics.

Of the unnatural α-amino acids, synthetic methods of α,α-

disubstituted-α-amino acid (α-tetrasubstituted α-amino acids),

which can control lipophilicity, conformation stability, and

peptidase degradation, have been reported. Meanwhile,

synthetic methods of more hindered unnatural α-amino acid

bearing α,β-continuous tetrasubstituted carbon, which have

potential for upgrading these characteristics, is fairly rare

because eﬃcient and general methodologies to overcome

extreme steric hindrance have not been established (Scheme

A).

Amino acid Schiﬀ bases (I, II), which were developed by

O’Donnell, are one of the most important starting materials for

Received: March 9, 2020

the synthesis of various natural and unnatural α-amino acids

(

Scheme 1). For example, an enolate nucleophile III can be

easily generated under phase-transfer catalytic conditions,

allowing for subsequent coupling with alkyl halides IV via

XXXX American Chemical Society

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e⁻(ionic) reactions (Scheme 1A). This method can be

Table 1. Optimization of the Reaction Conditions

applied to synthesize various α-mono- and disubstituted α-

amino acids V from a glycinate Schiﬀ base bearing

benzophenone imine I or an amino acid Schiﬀ base bearing

aldimine II, respectively. The applicability of alkylating

reagents, however, has been limited to primary and small

secondary alkyl halides, and incorporation of highly congested

tertiary alkyl groups has not been achieved due to the nature of

the nucleophilic substitution reaction.

We thus focused on the use of an α-monosubstituted amino

acid Schiﬀ base bearing benzophenone imine VI, which is

generally introduced to the glycinate. The Schiﬀ base VI could

generate an azaallyl radical species VII via a single electron

transfer process, in which the formed radical species would be

further stabilized by a captodative eﬀect (Scheme 1B). We

hypothesized that this radical species VII would be

preferentially generated with the assistance of redox active

Cu(II) catalyst (Cu activation: Cu to Cu ). The formed

radical species VII would couple with tertiary alkyl radical IX

generated from tertiary alkyl bromide VIII and Cu(I) catalyst

in proximity to the VII (Cu activation: Cu to Cu ), aﬀording

extremely congested α-amino acid bearing contiguous

tetrasubstituted carbon centers X.

Recently, Watson’s

group reported elegant copper catalyzed alkylation of nitro-

Conditions: 1a (0.1 mmol), 2a (0.2 mmol), K CO (1.0 equiv), and

alkanes. A wide variety of nitroalkanes and α-bromocarbonyl

compounds could be used under mild conditions. Con-

struction of contiguous tetrasubstituted carbon, however, is

very limited. Here, we report that an α-amino acid Schiﬀ base

is a key platform for the synthesis of highly congested

unnatural α-amino acids.

tert-butylbenzene (0.5 mL). Yields were determined by H NMR

analysis. 5 mol % of the (CuOTf) ·benzene complex was used.

by the internal basis of the Cu(II) acetate complex. Other

Cu(I) catalysts aﬀorded product 3aa in low chemical yield. In

addition, other redox active metals, iron and nickel, did not

catalyze the reaction at all.

RESULTS AND DISCUSSION

We selected alkyl bromide 2a as a cross-coupling partner to

construct contiguous tetrasubstituted carbon centers.

■

Having identiﬁed the optimal conditions, we evaluated the

scope of the amino acid synthesis (Table 2). The present

catalysis can be run on a gram scale and product 3aa was

isolated in 1.74 g (79% yield). It is noteworthy that bulky tert-

butyl ester substrate could be applicable (3aa′). Various phenyl

glycine derivatives were applicable, including electron-with-

drawing and -donating substituents (Me, OMe, Cl, Ph) (3ba-

3ea). The use of meta-substituted aryl groups (3fa, 3ga)

produced no detrimental eﬀects. An acceptable yield was

obtained when a highly hindered ortho-substituted phenyl

substrate was used under the optimized reaction conditions

1,12

Initially we compared the reactivity of a general amino acid-

derived Schiﬀ base bearing aldimine and one bearing

benzophenone imine using a Cu(OAc) /phenanthroline

complex (Scheme 2). Although the aldimine substrate did

not provide the desired product, benzophenone imine

substrate 1a provided the product in 66% yield.

Scheme 2. Initial Trial Using Amino Acid Schiﬀ Bases

Bearing Aldimine and Benzophenone Imine

(

3ha). A naphthyl group was applicable to the present catalysis

3ia). Product 3ja was isolated in 35% yield using an α-thienyl

substrate. Azlactone was also converted to a α-amino acid

derivative bearing contiguous tetrasubstituted carbon centers,

although regioisomers were observed in a 4.2/1 ratio (3ka).

We next performed the reaction using various alkyl bromides

. Cyclic scaﬀolds, cyclohexane, cyclopentane, and cyclobutane

were incorporated into amino acid derivatives (3aa−3ad). The

reaction of benzyl ester proceeded without any detrimental

eﬀects (3ae). The aniline functionality survived under the

optimized conditions and product 3af was isolated in 76%

yield as a diastereomixture. Other functionalities, such as alkyl

chloride, aryl iodide, and alkyl bromide, could be used under

slightly modiﬁed reaction conditions (3ag, 3ah, and 3aj). The

longer acyclic alkyl chain at the α-position of alkyl bromide 2

decreased the chemical yields due to steric hindrance (3ah−

3aj). Although the chemical yield was moderate when using a

protecting group-free primary hydroxy group (3ak), a tertiary

hydroxy group provided the product in high yield (3al).

Chemoselective α-alkylation of 1 was achieved in the presence

This initial trial prompted us to further optimize the reaction

condition using benzophenone imine. As shown in Table 1,

various bidentate ligands were evaluated. A survey of

phenanthroline derivatives revealed that bathophenanthroline

(

L5) was the optimal ligand, aﬀording product 3aa in 86%

yield. 2,2′-Bipyridyl ligands (L8 and L9) provided product 3aa

in slightly lower yield than L1.

We then examined a series of copper salts. Both cationic

Cu(II) triﬂate and Cu(II) halides were ineﬀective in the

present reaction. In contrast, Cu(II) acetate, which can

function as a Lewis acid/Brønsted base cooperative catalyst,

was optimal, indicating that activation of 1a would be achieved

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Table 2. Substrate Scope of α -Alkylation

Conditions: 1a (0.1 mmol), 2a (0.2 mmol), K CO (1.0 equiv), and tert-butylbenzene (0.5 mL). Isolated yields were shown. Diastereomeric ratios

were determined by H NMR analysis of the crude reaction mixture. Regioisomer ratio of C4/C2 of azlactone = 4.2/1. Reaction time was 72 h.

Reaction time was 48 h. 1a (0.1 mmol), 2r (0.2 mmol), KO Bu (2.0 equiv), and DMA (1.0 mL).

of potentially reactive activated oleﬁn (3am). Malonate-

derived alkyl bromide provided product 3an in 37% yield.

Ketone and amide could be used instead of an ester of 2 (3ao,

Scheme 3. Chemoselective Cross-Coupling Using Alanine

Schiﬀ Base

ap). A 2-azetidinone scaﬀold bearing contiguous tetrasub-

stituted carbon could be constructed, aﬀording product 3aq in

1% yield as a diastereomixture. Remarkably, the unactivated

alkyl halide, tert-butyl iodide, aﬀorded the product 3ar in 47%

yield under slightly modiﬁed reaction conditions.

Alanine-derived Schiﬀ base 1l was applicable to the present

catalysis and product 3la was isolated in 44% yield under

slightly modiﬁed reaction conditions (Scheme 3, condition A).

The moderate yield was due to the competitive formation of β-

alkyl dehydroalanine product 4a. Thus, we next focused on

the synthesis of 4a as the major product and found that

simpliﬁed reaction conditions (Cu(OAc) /AgOAc) produced

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a in 81% yield with an exclusive E-isomer formation (Scheme

Table 3. Substrate Scope of Chemoselective Alkylation

, condition B), demonstrating chemoselective synthesis of α-

alkylation product 3 and β-alkylation product 4 by modifying

the reaction conditions.

The scope of α- and β-alkylations was next evaluated using

aliphatic substituted amino acids (Table 3). A series of

aliphatic substituted amino acids was used under the condition

A, providing α-alkylation products (3la-3oa), although the

chemical yields were moderate. Under condition B, we

observed wide functional group tolerance similar to that

shown in Table 2 (aniline, alkyl halides, aryl iodide, and

hydroxy group). Various cyclic and acyclic alkyl chains were

incorporated (4a−4m). Alkyl bromide bearing diester, ketone,

amide, and 2-azetidinone could be used (4n−4q). For the β-

alkylation, α-bromo nitroalkane provided product 4r in 15%

yield. It is noteworthy that tetrasubstituted oleﬁns bearing a

quaternary carbon, whose formation from the saturated

starting material is particularly challenging, were constructed

(

4s and 4t), highlighting that our strategy can also be used to

construct sterically congested oleﬁns.

The eﬃciency of the present chemoselective catalysis was

demonstrated by a three-component cross-coupling reaction

(Scheme 4). Styrene was eﬃciently incorporated into the

product and 6 was isolated in 71% yield as the exclusive

regioisomer. Various alkyl bromides and styrene derivatives

could be incorporated, demonstrating that the present method

is highly useful for synthesizing a diverse set of unnatural α-

amino acid derivatives bearing tetrasubstituted carbons at the

α- and δ-positions. To the best of our knowledge, no catalytic

difunctionalization of alkene by two diﬀerent tetrasubstituted

carbons have been reported.

Finally, we focused on the synthesis of enantioenriched α-

amino acid bearing α,β-continuous tetrasubstituted carbon.

Although catalytic enantioselective variant using chiral ligand

was found to be diﬃcult at this stage, modiﬁed (−)-menthol

derivatives as chiral auxiliary turned out to be eﬀective to

synthesis chiral products (Scheme 5).

A survey of

(−)-menthol derivatives revealed that 1-naphthyl substituted

menthol derivative 1δ aﬀorded the product in high yield with

high diastereoselectivity under slightly modiﬁed reaction

conditions. Noteworthy is that the product 3δa could be

easily puriﬁed by conventional column choreography to aﬀord

enantiomerically pure compounds. The substrate scope of

diastereoselective reaction was described in Scheme 6. Several

cyclic motifs could be incorporated at β-position with high

diastereoselectivities (3δb-3δe). Both ketone and amide

derived-alkyl bromides also exhibited high diastereoselectiv-

ities.

Selective deprotection of product 3aa was achieved under

mildly acidic conditions, aﬀording amino ester 7 in 86% yield

(

Scheme 7a). Treatment with HCl under heated conditions

delivered the protecting group-free amino acid 8 in 89% yield

Scheme 7b). The amide bond formation of 7 proceeded to

aﬀord the dipeptide 9 in high yield using Fmoc-Gly-Cl

Condition A: 1 (0.1 mmol), 2 (0.2 mmol), Cu(OAc) (10 mol %),

L5 (10 mol %), K CO (1.0 equiv), AgOAc (1.2 equiv), and tert-

butylbenzene (0.5 mL). 100 °C, 24 h. Condition B: 1 (0.1 mmol), 2

(0.2 mmol), Cu(OAc) (10 mol %), AgOAc (3.0 equiv), and tert-

(

Scheme 7c). Hydrogenation and deprotection of 4a

butylbenzene (0.5 mL). 110 °C, 48 h. Isolated yields were shown.

proceeded simultaneously using palladium on carbon under

Reaction temperature was 130 °C.

hydrogen atmosphere, delivering γ-tetrasubstituted amino ester

0 (Scheme 7d).

As control experiments, each component was omitted from

product 3aa was observed at room temperature, presumably

the standard reaction conditions (Scheme 8). No product was

observed in the absence of copper salt (entry 2). Low chemical

yield was also observed without ligand (entry 3). The addition

of base was essential for high yield (entry 4). Trace amount of

due to the relatively low acidity of α-proton of 1 (pK in

DMSO 21.2).

We further performed mechanistic studies (Scheme 9). In

the absence of alkyl bromide 2a, treatment of Schiﬀ base 2l

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Scheme 4. Three-Components Cross-Coupling

Scheme 6. Diastereoselective Reaction Using Chiral

Auxiliary

Conditions: 1 (0.3 mmol), 2 (1.2 mmol), Cu(OAc) (10 mol %), L5

Conditions: 1 (0.1 mmol), 2 (0.12 mmol), 5 (0.20 mmol), K CO₃

(

10 mol %), KO Bu (4.0 equiv), and THF (3.0 mL), room

temperature, 6 h. Isolated yields were shown.

(

1.0 equiv), and tert-butylbenzene (0.5 mL). Isolated yields were

shown

Scheme 7. Transformation of the Products

Scheme 5. Diastereoselective Reaction Using Chiral

Auxiliary

Conditions: 1 (0.1 mmol), 2 (0.4 mmol), Cu(OAc) (10 mol %), L5

(10 mol %), KO Bu (4.0 equiv), and THF (1.0 mL), room

temperature, 6 h.

with a stoichiometric amount of Cu(I) complex did not

provide the homocoupling dimer 11. In contrast, homocou-

pling dimer 11 was observed in 32% yield using a Cu(II)

complex, indicating that radical species would be generated

22−24

with a Cu(II) complex (Scheme 9a).

Homocoupling

dimer 11 was not observed without L5 in the presence of

On the basis of a series of control experiments, we present a

proposed catalytic cycle in Figure 1A. Deprotonative activation

of amino acid Schiﬀ base II would be achieved by Cu(II)

acetate I, which functions as a Lewis acid/Brønsted base

Cu(OAc) . When amino acid Schiﬀ base 2a was treated with

TEMPO under stoichiometric conditions, TEMPO adduct 12

was detected (Scheme 9b). Furthermore, when α-cyclopropyl

substrate 13 was used under the optimized conditions, we

detected ring-opened products 14 along with double alkylated

product 15, which also supported the generation of radical

species (Scheme 9c). While alkyl bromide 2a was not coupled

with TEMPO under Cu(II) complex in the absence of an

amino acid Schiﬀ base, a Cu(I) complex provided TEMPO

adduct 16 in 43% yield (Scheme 9d). These results indicated

that a Cu(I) complex could activate alkyl bromide 2 to aﬀord

radical species. The addition of L5 was also essential for

activating 2a.

25,26

cooperative catalyst, generating enolate intermediate III.

The resonance persistent azaally radical species IV would have

large contribution to further cross-coupling reaction, which

was supported by the homocoupling dimer V formation and a

series of control experiments (Scheme 9a-c). The concom-

itantly generated Cu(I) acetate VI would activate alkyl

bromide VII, providing tertiary alkyl radical species VIII

with the generation of Cu(II) species IX. Finally, the cross-

coupling of two diﬀerent tertiary radicals, IV and VIII

generated in proximity to the copper catalyst would deliver

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Article

Scheme 8. Control Experiments

Conditions: 1 (0.1 mmol), 2 (0.2 mmol) K CO (1.0 equiv), and

tert-butylbenzene (0.5 mL). Yields were determined by H NMR

analysis using 2-methoxynaphthalene as an internal standard.

Scheme 9. Mechanistic Studies Using CuOAc and

Cu(OAc)₂

Figure 1. Postulated catalytic cycle.

In conclusion, we developed a new mode for catalytic

activation of an amino acid Schiﬀ base. The redox active

copper catalyst enabled eﬃcient cross-coupling, leading to

hitherto-inaccessible highly congested unnatural α-amino acid

derivatives. The broad functional group compatibility high-

lights the mildness of the present method. Noteworthy is that

modifying the reaction conditions enabled β-alkylation

followed by oxidation, aﬀording dehydroalanine derivatives

bearing tetrasubstituted carbon. Enantiomerically enrich α-

amino acid synthesis could be also achieved using chiral

auxiliary. The synthesized highly congested unnatural α-amino

acid could be coupled with amino acid to aﬀord the dipeptide.

Studies to further examine the utility of a platform derived

from an α-amino acid Schiﬀ base for other reactions are in

progress in our group.

ASSOCIATED CONTENT

sı Supporting Information

The Supporting Information is available free of charge at

■

Experimental procedures and spectroscopic data for all

new compounds (PDF)

AUTHOR INFORMATION

Corresponding Authors

■

the product X. The salt metathesis reaction of IX with KOAc

would regenerate Cu(II) acetate I. The alternative mechanism

involved Cu(III)/Cu(I) pathway, in which the reductive

elimination of intermediate XIII occurs, cannot be ruled out

Takashi Nishikata − Graduate School of Science and

Engineering, Yamaguchi University, Ube, Yamaguchi 755-8611,

Japan; orcid.org/0000-0002-2659-4826; Email: nisikata@

yamaguchi-u.ac.jp

(Figure 1B).

J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society

Rumsey, S. M.; Benedetti, E.; Nemethy, G.; Scheraga, H. A.

Article

Ryo Yazaki − Graduate School of Pharmaceutical Sciences,

Kyushu University, Maidashi, Higashi-ku, Fukuoka 812-8582,

Japan; orcid.org/0000-0001-9405-1383; Email: yazaki@

phar.kyushu-u.ac.jp

Takashi Ohshima − Graduate School of Pharmaceutical

Sciences, Kyushu University, Maidashi, Higashi-ku, Fukuoka

Sensitivity of polypeptide conformation to geometry. Theoretical

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Balaram, P. Structural Characteristics of α -Helical Peptide Molecules

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12-8582, Japan; orcid.org/0000-0001-9817-6984;

Email: ohshima@phar.kyushu-u.ac.jp

Authors

(f) Toniolo, C.; Benedetti, E. Structures of polypeptides from α -

Yohei Matsumoto − Graduate School of Pharmaceutical

Sciences, Kyushu University, Maidashi, Higashi-ku, Fukuoka

amino acids disubstituted at the α -carbon. Macromolecules 1991 , 24 ,

004 −4009. (g) Tanaka, M. Design and Synthesis of Chiral α , α -

12-8582, Japan

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Oligopeptides. Chem. Pharm. Bull. 2007, 55, 349−358.

Jun Sawamura − Graduate School of Pharmaceutical Sciences,

Kyushu University, Maidashi, Higashi-ku, Fukuoka 812-8582,

Japan

Yumi Murata − Graduate School of Science and Engineering,

Yamaguchi University, Ube, Yamaguchi 755-8611, Japan

(3) Synthetic examples of continuous tetrasubstituted α-amino acid

were reported only as part of substrate generality, see (a) Reeves, J.

T.; Tan, Z.; Herbage, M. A.; Han, Z. S.; Marsini, M. A.; Li, Z.; Li, G.;

Xu, Y.; Fandrick, K. R.; Gonnella, N. C.; Campbell, S.; Ma, S.;

Grínberg, N.; Lee, H.; Lu, B. Z.; Senanayake, C. H. Carbamoyl Anion

Addition to N-Sulfinyl Imines: Highly Diastereoselective Synthesis of

α -Amino Amides. J. Am. Chem. Soc. 2013 , 135 , 5565 −5568. (b) Li,

K.; Wu, Q.; Lan, J.; You, J. Coordinating Activation Strategy for

Complete contact information is available at:

https://pubs.acs.org/10.1021/jacs.0c02707

Notes

C(sp )−H/C(sp )−H Cross-Coupling to Access β -Aromatic α -

Amino Acids. Nat. Commun. 2015, 6, 8404−8412.

4) (a) O ’Donnell, M. J.; Boniece, J. M.; Earp, S. E. The synthesis of

The authors declare no competing ﬁnancial interest.

amino acids by phase-transfer reactions. Tetrahedron Lett. 1978 , 19 ,

641 −2644. (b) O ’Donnell, M. J.; Eckrich, T. M. The synthesis of

ACKNOWLEDGMENTS

■

This work was ﬁnancially supported by JSPS KAKENHI Grant

No. JP15H05846 in Middle Molecular Strategy, JP18H04262

and JP18H04263 in Precisely Designed Catalysts with

Customized Scaﬀolding (R.Y. and T.N.), Grant-in-Aid for

Scientiﬁc Research (B) (No. JP17H03972), Grant-in-Aid for

Scientiﬁc Research (C) (No. JP16K08166), the Naito

Foundation (T.N.), and Platform Project for Supporting

Drug Discovery and Life Science Research (Basis for

Supporting Innovative Drug Discovery and Life Science

Research (BINDS)) from AMED under Grant No.

JP19am0101091. R.Y. thanks Qdai-jump Research Program

and Takeda Science Foundation for ﬁnancial support.

amino acid derivatives by catalytic phase-transfer alkylations.

Tetrahedron Lett. 1978 , 19 , 4625 −4628. (c) O ’Donnell, M. J. The

Enantioselective Synthesis of α -Amino Acids by Phase-Transfer

Catalysis with Achiral Schiff Base Esters. Acc. Chem. Res. 2004 , 37 ,

506 −517. (d) O ’Donnell, M. J. Benzophenone Schiff Bases of Glycine

Derivatives: Versatile Starting Materials for the Synthesis of Amino

Acids and Their Derivatives. Tetrahedron 2019 , 75 , 3667 −3696.

5) (a) Maruoka, K.; Ooi, T. Enantioselective Amino Acid Synthesis

by Chiral Phase-Transfer Catalysis. Chem. Rev. 2003 , 103 , 3013 −

028. (b) Lygo, B.; Andrews, B. I. Asymmetric Phase-Transfer

Catalysis Utilizing Chiral Quaternary Ammonium Salts: Asymmetric

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