Methods of Non-a-Amino Acid Synthesis, 2nd Edition

41

2

Cyclic Precursors

The preparation of acyclic molecules from cyclic precursors is a well-known strat-

egy.

1

The ability to control relative stereochemistry and regiochemistry in the

reactions of cyclic molecules is important since cleavage of that ring transfers that

stereochemistry or regiochemistry to the acyclic product.

2

Several methods will be

described in this chapter that allow the synthesis of amino acids, particularly substi-

tuted amino acids, from various cyclic precursors.

2.1 FROM LACTAMS OR IMIDES

2.1.1 FRom β-lactams

As rst noted in Chapter 1, Section 1.5.1, the hydrolysis of lactams is a convenient

source of amino acids. This transformation is, of course, illustrative of the conver-

sion of a cyclic precursor to an acyclic amino acid. β-Lactams (2-azetidinone deriva-

tives) are an interesting class of compounds in their own right, and hydrolysis leads

to 3-aminopropanoic acid derivatives (β-alanine derivatives). The basic hydrolysis

of a β-lactam such as 4-ethyl-2-azetidinone (1) gave 3-aminopentanoic acid (2),

3

for example. It is therefore appropriate to briey discuss the synthesis of β-lactams.

N

H

2

NC

O

2

H

H O

Ba(OH)

2

• 8 H

2

O

50°C, 10 h

12

93%

A common method for preparing β-lactams is a thermal [2+2]-cycloaddition

4

of

an isocyanate with an alkene. Chlorosulfonyl isocyanate (CSI, O=C=N–SO

2

Cl) is a

common synthetic precursor, and in one example it reacted with 2-methyl-2-butene

to give 3, which was hydrolyzed with HCl to give 2,3-dimethyl-3-aminobutanoic

acid, 4.

5

A similar reaction with 2,3-dimethyl-2-butene gave 2,2,3-trimethyl-3-ami-

nobutanoic acid; 2-methyl-2-pentene gave 2,2-dimethyl-3-aminopentanoic acid; and

2,4,4-trimethyl-1-pentene gave 3,5,5-trimethyl-3-aminohexanoic acid.

5

A variation

1

For example, see Smith, M.B. Organic Synthesis, 3rd ed. Wavefunction, Inc./Elsevier, Irvine, CA/

London, England, 2010, pp. 563–564.

2

For example, see Smith, M.B. Organic Synthesis, 3rd ed. Wavefunction, Inc./Elsevier, Irvine, CA/

London, England, 2010, pp. 551–564.

3

Haug, Th.; Lohse, F.; Metzger, K.; Batzer, H. Helv. Chim. Acta 1968, 51, 2069.

4

See (a) Smith, M.B. Organic Synthesis, 3rd ed. Wavefunction, Inc./Elsevier, Irvine, CA/London,

England, 2010, pp. 1076–1097; (b) Smith, M.B. March’s Advanced Organic Chemistry, 7th ed. John

Wiley & Sons, Hoboken, NJ, 2013, pp. 1040–1051.

5

Graf, R. J. L. Ann. Chem. 1963, 661, 111.

42

Methods of Non-α-Amino Acid Synthesis, Second Edition

of this reaction removed the N-chlorosulfonyl group from the β-lactam by treatment

with thiophenol and pyridine.

6

CNO SO

2

Cl

Me

Me

Me

N

H

2

NC

O

2

H

Me

Me

Me

Me

Me

Me

ClO

2

S

O

34

HCl

CH

2

Cl

2

There are many examples of this type of cycloaddition-hydrolysis route to amino

acids. Reaction of CSI with allenes leads to alkylidene β-lactams.

7

Hydrolysis fol-

lowed by hydrogenation leads to the corresponding amino acid. Allene 5, for example,

reacted with CSI to give 6. Treatment with HCl gave 2-(1-amino-2-methylethyl)-4-

methylpent-2-enoic acid (7), and catalytic hydrogenation of the alkenyl unit gave

a quantitative yield of 3-amino-3-methyl-2-(2-methylpropyl)-butanoic acid, 8.

7

It

is clear that this methodology provides a route to both unsaturated and saturated

β-amino acids. Several 2-alkyl-3-methyl-3-aminobutanoic acid derivatives were pre-

pared by this method, and other allenes can be used in reactions with CSI.

7,8

C

N

SO

2

Cl

O

NH

2

CO

2

H

NH

2

CO

2

H

EtOH, 50 psi

3 h

56 7

8

67%

quant.

quant.

CSI

HCl

H

2

. PtO

2

Just as allenes can be condensed with isocyanates, other dienes also react, eventu-

ally leading to alkenyl amino acids. The condensation of chlorosulfonyl isocyanate

(CSI) and 1,3-pentadiene is an example that gave 9.

9

Removal of the sulfonyl group

and hydrolysis gave methyl 3-aminohex-4-enoate (10), a synthetic intermediate for

the preparation of daunosamine.

9

Similar reaction with 1,3-butadiene and N-benzyl

isocyanate led to 3-aminopent-4-enoic acid (23% overall yield).

10

N

HO

2

CN

H

2

HO

1.ClO

2

SN=C=O

2.Na

2

SO

3

–78°C +5°C

HCl, MeOH

RT, 2h

910

72%

quant.

6

Moriconi, E.J.; Kelly, J.F. Tetrahedron Lett. 1968, 1435.

7

Moriconi, E.J.; Kelly, J.F. J. Org. Chem. 1968, 33, 3036.

8

See Graf, R. J. L. Ann. Chem. 1963, 661, 111.

9

(a) Hauser, F.M.; Rhee, R.P. J. Org. Chem. 1981, 46, 227; (b) Moriconi, E.J.; Meyer, W.C. J. Org.

Chem. 1971, 36, 2841; (c) Hauser, F.M.; Rhee, R.P.; Ellenberger, S.R. J. Org.Chem. 1984, 49, 2236.

10

Arbuzov, B.A.; Zobova, N.N. Dokl. Akad. Nauk. SSSR 1966, 170, 1317 (Engl. 993).