Literature Seminar
M2 Horigome
2018. 11. 15.

〈Topic〉
Stereoselective Synthesis ofα,α-Disubstituted-α-amino Acids

Contents
1. Introduction of α,α-Disubstituted amino acids

2. Synthesis of chiral α,α-disubstituted α-amino acids
3. Introduction of quaternary α-aryl amino acids
4. Enantioselective introduction of an aryl substituent at the α-carbon
5. Summary2

α,α-Disubstituted amino acids

3Phenytoin

α,α-Disubstituted amino acids

Characteristics of α, α-di-substituted amino acids(1) Chemical stability.
(2) Increase in lipid solubility.
(3) Restriction on side chain conformation.
(4) Restriction of the conformation of the peptide containing it.
(5) Stabilization of the peptide containing it in vivo.

4

Application of α,α-Disubstituted amino acids

5AibAc6c

Aip

The higher the helicity is, the higher
the antibacterial activity is.
M. L. McLaughlin et. al., J. Med. Chem., 39, 3603

They use a helical structure to bring
functional groups closer together.

P. Scrimin et. al., J. Am. Chem. Soc., 121, 6948

Chiral α,α-disubstituted amino acids

6

Chiral α,α-disubstituted α-amino acids
are contained in various physiologically
active natural products.

The direction of the helical structure of
the peptide can be controlled by using
Chiral α,α-disubstituted α-amino acids.

Synthesis of achiral α,α-disubstituted amino acids

7

Strecker methods & Bucherer-Bergs methods

Strecker methods

Bucherer-Bergs methods

8Synthesis of chiral α,α-disubstituted α-amino acids : Enzymatic procedures

The synthesis of racemic butylethylglycine (Beg) from butyl ethyl ketone by
Strecker synthesis and subsequent resolution using pig liver estearase.
The unreacted enantiomerically pure (S)-amino ester was recovered in
31% yield.

Imawaka, N. et. al. Helv. Chim. Acta, 2000, 83, 2823.

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Self-regeneration of stereocentres

Yee, N. K. et al. Tetrahedron Asymmetry 2003, 14, 3495.

The principle of ‘self-regeneration of stereocentres’『in which the stereogenic centre of a chiral molecule generates atemporary centre of chirality, which in turn is used to introduce
diastereoselectively a new ligand at the original stereogenic centre』
has been applied to the synthesis of various acyclic quaternaryamino acids.

Self-regeneration of stereocentres

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via oxazolidinones

Perciaccante, R. et.al. Org. Biomol. Chem. 2003, 1, 2853

via tetrahydropyrimidinones(Asparagine, Asparagic acid)

Konopelski, J. P. et. al. J. Org. Chem. 1999, 64, 7885

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Memory of chirality

Memory of chirality is a phenomenon that occurs in processes where
an initial stereogenic centre is destroyed during the generation of thecorresponding reactive intermediate, but this intermediate is able to‘remember’ the configuration of its precursor to transfer the chirality
to the final compound without using any external chiral source.
Fuji, K. et. al. Angew. Chem., Int. Ed. 2000, 39, 2155.

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Memory of chirality

Steric hinderance
Base can approach H only when
H and Boc are anti parallel.
And alkylation reagent
approaches from opposite side.

Base & alkylation reagent
Chelate effectThe yield is low without MOM.
MOM is bringing the base closeto H by chelating effect.
This promotes the base comingfrom the opposite side of Boc.
When the Bn part is small, the rotation barrier of C-N in E is small, and epimerization occurs.
Fuji, K. et. al. Angew. Chem., Int. Ed. 2000, 39, 2155.

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Alkylation under phase-transfer conditions

Maruoka, K. et. al. Angew. Chem., Int. Ed. 2005, 44, 1549.

Suitable chiral catalysts to perform the synthesis of the asymmetric synthesis of α,αdisubstituted α-amino acids under phase-transfer conditions have been described.

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Alkylation under phase-transfer conditions

R-H =,Q+ =16Alkylation under phase-transfer conditions

R-H =,

Q+ =Addition of nucleophiles to the C≡N bond

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The catalytic enantioselective Strecker reaction is an attractive methodology for the synthesisof α,α-disubstituted α-amino acids.

Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 10012

Addition of nucleophiles to the C≡N bond

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The catalytic enantioselective Strecker reaction is an attractive
methodology for the synthesis of α,α-disubstituted α-amino acids.

N. Kato, M. Suzuki, M. Kanai, and M. Shibasaki, Tetrahedron Lett., 45, 3153.

Addition of nucleophiles to the C≡N bond

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Proposed catalytic cycle

Lack of reactivity using only
HCN is important from themechanistic point of view,that is, the pre-catalyst 6
cannot be directly converted
to the active catalyst 3.
N. Kato, M. Suzuki, M. Kanai, and M. Shibasaki, Tetrahedron Lett., 45, 3153.

Quaternary α-aryl amino acids

20

α-aryl amino acids and their derivatives are valuable precursors to bioactive molecules.

fidarestat

Enantioselective introduction of an aryl substituent at the α-carbon

21

Biography
2015-present: Professor of Chemistry, University of Bristol
2001-2015: Professor of Organic Chemistry, University of Manchester
2000-2001: Reader in Chemistry, University of Manchester
1994-2000: Lecturer in Chemistry, University of Manchester1992-1994: Royal Society Western European Research Fellow and Post-doc with Prof Marc Julia
at the École Normale Supérieure, Paris on transition metal catalysed reactions ofsulfones, and carbenoid chemistry
1989-1992: PhD at University of Cambridge with Dr Stuart Warren on asymmetric synthesis
using phosphine oxide chemistry
1986-1989: BA (Natural Sciences) at Churchill College, University of Cambridge
1968: Born: Kampala, Uganda

Enantioselective introduction of an aryl substituent at the α-carbon

An amino acid (A) is converted diastereoselectively into an imidazolidinone (B)carrying a pendent urea function. Treatment with base forms an enolate (C) in
which the aromatic substituent (Ar) of the urea migrates to the rear face of theimidazolidone, directed by the bulky tert-butyl group, as indicated by the red dottedarrows. Hydrolysis of the product (D) provides the quaternary α-aryl amino acid (E).

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Clayden rearrangement

Heteroatom-promoted lateral lithiationis the site-selective replacement of abenzylic hydrogen atom for lithium forthe purpose of further functionalization.

The origin of Clayden rearrangement

MeHN

By replacing the final methylation with anaqueous quench, the rearranged product3a was obtained in a satisfying 89% yield.

Clayden, J. et. al., J. Am. Chem. Soc. 129, 7488 (2007).

Substrate scope of clayden rearrangement

This method could be applied to electron rich Ar.

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Asymmetric clayden rearrangement

DMPU was added to increase
the reactivity of the resultingorganolithium.

Stereochemically retentive rearrangement.

Evidence that clayden rearrangement is occurring via intramolecular manner

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Application of clayden rearrangement to asymmetric α-arylation of amino acids

O・Stereochemically invertive rearrangement.
・This method is applied to urea derivatives derived
from L-phenylalanine, L-valine and L-methionine.

Kawabata, T. et. al. J. Am. Chem. Soc. 135, 13294 (2013).

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Application of clayden rearrangement to asymmetric α-arylation of amino acids

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It is deprotonated when the proton faces in a sterically empty direction.
Then, the anion reacts with the aromatic ring immediately and the stereochemistry reverses.

When the Bn part is small, the rotation barrier is small, and epimerization occurs.

Expansion of substrate scope of asymmetric α-arylation of amino acids

29

・This method can be applied to urea derivatives derived
from amino acids which have small side chain.
・However, The doubly N‐methylated hydantoin product 6
proved extremely resistant to hydrolysis to the corresponding
quaternary N‐methylated amino acid.
Clayden, J. et. al., Angew.Chem.Int. Ed. 54, 8961 (2015) .

Expansion of substrate scope of asymmetric α-arylation of amino acids

So they modified the substrates 3 with the aim of rearranging
their N‐unsubstituted analogues 7.
Singly N‐methylated hydantoin product 9 is easily hydrolyzed tothe corresponding quaternary N‐methylated amino acid.

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Expansion of substrate scope of asymmetric α-arylation of amino acids

31

TMSCl0 eq.
1 eq.
2 eq.
3 eq.

Expansion of substrate scope of asymmetric α-arylation of amino acids

The most stable conformation
Rearrangement of the more hindered leucine was less clean(and all attempted rearrangements of valine- or phenylglycinederived ureas failed), suggesting that leucine lies at the limit of
the methodÏs tolerance to steric hindrance.

Some substrates (generally
those with acidic protons
in the β position) failed torearrange cleanly.

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Enantioselective introduction of an aryl substituent at the α-carbon

An amino acid (A) is converted diastereoselectively into an imidazolidinone (B)carrying a pendent urea function. Treatment with base forms an enolate (C) inwhich the aromatic substituent (Ar) of the urea migrates to the rear face of theimidazolidone, directed by the bulky tert-butyl group, as indicated by the red dottedarrows. Hydrolysis of the product (D) provides the quaternary α-aryl amino acid (E).

33

Self-regeneration of stereocentres

The principle of ‘self-regeneration of stereocentres’『in which the stereogenic centre of a chiral molecule generates a
temporary centre of chirality, which in turn is used to introduce
diastereoselectively a new ligand at the original stereogenic centre』
has been applied to the synthesis of various acyclic quaternaryamino acids.

34

Self-regeneration of stereocentres＆Clayden rearrangement

35

Self-regeneration of stereocentres
Stereoselective introductionof alkyl group to α-positionof amino acid.

Clayden rearrangement+
Intramolecular reaction using urea
allows transposition of aryl.

Synthesis imidazolidinone intermediate

36Synthesis imidazolidinone intermediate cis-337

Synthesis imidazolidinone intermediate cis-338

Scope of the imidazolidinone arylation: amino acids and migrating groups

39Clayden’s Quaternary amino acid synthesis

・It avoids the use of valuable transition metals.
・It enables arylation with electron-rich, electron-poor and heterocyclic substituents.
・Either enantiomer of the product can be formed from a single amino acid precursor.
・The method is practical and scalable, and provides the opportunity to produce
α-arylated quaternary amino acids in multi-gram quantities.

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Summary41