A new method for the synthesis of β-amino acid derivatives and β- lactams. Reaction of N-alkoxycarbonyl-1-methoxyamines with esters

DOI: 10.1021/jo990821q

Source and publish data:

Journal of Organic Chemistry p. 7511 - 7514 (1999)

Update date:2022-08-02

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Authors:

Kise, Naoki

Ueda, Nasuo

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Article abstract of DOI:10.1021/jo990821q

The reaction of N-alkoxycarbonyl-1-methoxyamines with esters is an alternative to the reaction of imines with esters for the synthesis of β- amino acid derivatives. In this reaction, N-alkoxycarbonyl-1-methoxyamines corresponding to unstable imines can also be employed. Although anti adducts were obtained preferentially in the absence of Ti complexes, the diastereoselectivity of this reaction was reversed by the addition of Ti(OPr- i)₄. The obtained adducts were transformed to the corresponding β-lactams.

Full text of DOI:10.1021/jo990821q

J . Org. Chem. 1999, 64, 7511-7514

7511

A New Meth od for th e Syn th esis of â-Am in o Acid Der iva tives a n d

â-La cta m s. Rea ction of N-Alk oxyca r bon yl-1-m eth oxya m in es w ith

Ester s

Naoki Kise* and Nasuo Ueda

Department of Biotechnology, Faculty of Engineering, Tottori University, Tottori 680-0945, J apan

Received May 19, 1999

The reaction of N-alkoxycarbonyl-1-methoxyamines with esters is an alternative to the reaction of

imines with esters for the synthesis of â-amino acid derivatives. In this reaction, N-alkoxycarbonyl-

1-methoxyamines corresponding to unstable imines can also be employed. Although anti adducts

were obtained preferentially in the absence of Ti complexes, the diastereoselectivity of this reaction

was reversed by the addition of Ti(OPr-i)₄. The obtained adducts were transformed to the

corresponding â-lactams.

Sch em e 1

In tr od u ction

Reaction of imines with ester enolates or ketene acetals

is a potential method for the synthesis of â-amino acid

derivatives, which are important precursors for â-lactam

synthesis (Scheme 1).^1,2However, readily enolizable

imines (R¹) benzyl, allyl) or imines susceptible to

â-elimination (R¹) â-alkoxyethyl)³cannot be employed

for these reactions. We have reported a new synthetic

method from N-alkoxycarbonyl-1-methoxyamines 1 and

esters 2 to â-amino acid derivatives 3 (Scheme 2).⁴The

key steps of this method are simultaneous in situ

generation of an ester enolate and an N-alkoxycarbon-

ylimine and subsequent addition of the former to the

later. This method provides a novel route to â-amino

acids starting from amines. Herein we report full details

of our study on this reaction. It is noted that N-alkoxy-

carbonyl-1-methoxyamines corresponding to unstable

imines (R¹) benzyl, allyl, and â-alkoxyethyl) can be

employed for this reaction. The diastereoselectivity of this

reaction was also studied in the absence and the presence

of Ti complexes. The reversal of the diastereoselectivity

was observed by the addition of Ti(OPr-i)₄.

Sch em e 2

or 2b (R³) H) was carried out by adding a THF solution

of 1 and 2 to a solution of LDA at -70 °C and raising the

temperature to 0 °C. The results are depicted in Table

1. Methyl acetate (2a ) gave a poor result due to self-

condensation of the acetate (run 1), while tert-butyl

acetate (2b) gave a satisfactory result (run 2). When TiCl-

(OPr-i)₃was added to the reaction mixture, the reaction

proceeded at -70 °C and afforded a good result even with

2a (run 3). In addition, 1b-e (R¹) allyl, benzyl, and

â-alkoxyethyl) corresponding to unstable imines also gave

the adducts 3c-g in good yields (runs 4-8).

Resu lts a n d Discu ssion

Rea ction w ith Alk yl Aceta tes. N-Alkoxycarbonyl-

1-methoxyamines

1 were prepared from N-alkoxy-

carbonyamines⁵or R-amino acids⁶by anodic oxidation in

methanol. The reaction of 1a (R¹) Me) with acetate 2a

(1) For reviews, see: (a) Hart, D. J .; Ha, D.-C. Chem. Rev. 1989,

89, 1447. (b) Brown, M. J . Heterocycles 1989, 29, 2225. (c) van der

Steen, F. H.; van Koten, G. Tetrahedron 1991, 47, 7503.

(2) For recent reports, see: (a) Cainelli, G.; Panunzio, M.; Bandini,

E.; Martelli, G.; Spunta, G. Tetrahedron 1996, 52, 1685. (b) Cozzi, P.

G.; Simone, B. D.; Umani-Ronchi, A. Tetrahedron Lett. 1996, 37, 1691.

Tetrahedron 1996, 52, 2573; J . Org. Chem. 1996, 61, 8293. (d) Shankar,

B. B.; Kirkup, M. P.; McCombie, S. W.; Clader, J . W.; Ganguly, A. K.

Tetrahedron Lett. 1996, 37, 4095. (e) Baldoli, C.; Buttero, P. D.;

Lincandro, E.; Papagni, A. Tetrahedron 1996, 52, 4849. (f) Cainelli,

G.; Giacomini, D.; Galletti, P. Synthesis 1997, 886.

The reaction of 1f,⁷prepared from L-threonine, with

tert-butyl acetate (2b) afforded anti adduct preferentially

(Scheme 3). The yield and stereoselectivity of 3h slightly

increased in the presence of TiCl(OPr-i)₃. The stereo-

chemistry of the adduct 3h was determined by H NMR

(3) The reaction of imines derived from 3-benzyloxypropanal has

been reported with boron enolates: Iimori, T.; Ishida, Y.; Shibasaki,

M. Tetrahedron Lett. 1986, 27, 2153.

(4) Some parts of this study have been reported in preliminary

communications: (a) Shono, T.; Kise, N.; Sanda, F.; Ohi, S.; Tsubata,

K. Tetrahedron Lett. 1988, 29, 231. (b) Shono, T.; Kise, N.; Sanda, F.;

Ohi, S.; Yoshioka, K. Tetrahedron Lett. 1989, 30, 1253.

(5) Shono, T.; Hamaguchi, H.; Matsumura, Y. J . Am. Chem. Soc.

1975, 97, 4264.

(6) Horikawa, H.; Iwasaki, T.; Matsumoto, K.; Miyoshi, M. J . Org.

Chem. 1978, 43, 335.

(7) Renaud, P.; Seebach, D. Angew. Chem., Int. Ed. Engl. 1986, 25,

843.

Published on Web 09/03/1999

7512 J . Org. Chem., Vol. 64, No. 20, 1999

Kise and Ueda

Ta ble 1. Rea ction s of 1a -e w ith Alk yl Aceta tes 2a ,b

% yield of 3a

run

R¹

R²

R⁴

additive

1a Me

1b allyl

1c allyl

Me 2a Me none^b

<10

F igu r e 1. Nonchelation models.

Me 2b t-Bu none^b

Me 2a Me TiCl(OPr-i)₃3a

Me 2a Me TiCl(OPr-i)₃3c

t-Bu 2a Me TiCl(OPr-i)₃3d

1d benzyl

Me 2b t-Bu none^b

Me 2a Me TiCl(OPr-i)₃3f

1e TBDMSO- Me 2a Me TiCl(OPr-i)₃3g

CH₂CH₂

Isolated yields. -70 °C f 0 °C. ^c-70 °C.

Sch em e 3

F igu r e 2. Closed transition states.

the size of R¹increased (Me f i-Pr f t-Bu). Larger R³

(Et f i-Pr) and R⁴(Me f i-Pr) also raised the anti

selectivity (runs 8 and 10), while larger R²(Me f t-Bu)

lowered the selectivity to some extent (run 16). Although

the addition of TiCl₄had little effect on the yield and

diastereoselectivity of 3 (run 2), the addition of TiCl(OPr-

i)₃slightly increased the anti selectivity in most cases.

On the contrary, syn selectivity was observed in the

presence of Ti(OPr-i)₄(Table 3). As in the above results,

increasing bulk of R¹(Me f i-Pr f t-Bu) increased the

syn selectivity (runs 1-3). However, larger R²(Me f

t-Bu), R³(Et f i-Pr), and R⁴(Me f i-Pr) groups decreased

the syn selectivity (runs 4, 5, and 8).

Tr a n sition Sta te Hyp oth eses. The present reactions

proceed through the nucleophilic addition of ester eno-

lates to N-alkoxycarbonylimines. It is known that esters

form lithiated E-enolates predominantly by treatment

with LDA⁹and Li enolates are transformed to Ti enolates

by the addition of TiCl(OPr-i)₃.¹⁰Although the geometry

of the N-alkoxycarbonylimines could not be confirmed,

it is likely that E-forms are more favorable than Z-forms.

The anti selectivity can be explained by considering

closed transition states (boat and chair forms) in which

the nitrogen atom of the N-alkoxycarbonylimine coordi-

nates the lithium or titanium metal of the enolate as

shown in Figure 2. Boat form A is more favorable than

chair form B due to the R¹-R³and R¹-OR⁴steric

interactions in B. Therefore, large R¹, R³, and R⁴groups

increased the anti selectivity. On the other hand, it is

reported that Ti ate complexes are formed from Li

enolates and Ti(OPr-i)₄.¹⁰The syn selectivity in the

presence of Ti(OPr-i)₄might be elucidated by open

transition states depicted in Figure 3, in which transition

state C is more likely than D due to the steric repulsion

between R¹and R³groups in D. This hypothesis is

consistent with the result that large R¹groups increased

the syn selectivity; however, it cannot explain the fact

that large R³groups decreased the syn selectivity.

Tr a n sfor m a tion of Ad d u cts to â-La cta m s. The

obtained adducts 3 were transformed to the correspond-

Sch em e 4

spectral analysis of γ-lactone 4 derived from 3h (Scheme

4). The isomer showing a larger NOE between 4-H and

5-CH₃was assigned to be trans-4. The anti selectivity

can be explained by nonchelation control (dipolar model

or Felkin-Anh model)⁸in the addition of the ester

enolate to the N-alkoxycarbonylimine generated from 1f

(Figure 1).

Rea ction w ith Alk yl Bu tyr a tes a n d Meth yl Iso-

va ler a te. Next, we examined the reactions of 1 with

butyrates and isovalerates 2c-e in the absence and

presence of Ti complexes (Tables 2 and 3). The diaste-

reoselectivities were determined by H NMR analysis.

The stereoconfigurations of the adducts were confirmed

by their transformation to â-lactams (vide infra). In the

absence of Ti complexes, the reactions of 1 with 2c-e

gave anti isomers of adducts 3 preferentially in all the

cases (Table 2). The stereoselectivity was influenced by

the R¹-R⁴groups in reactants 1 and 2. According to runs

1, 4, and 6 in Table 2, the anti selectivity increased as

(9) (a) Ireland, R. E.; Mueller, R. H.; Willard, A. K. J . Am. Chem.

Soc. 1976, 98, 2868. (b) Heathcock, C. H. Asymmetric Synthesis;

Morrison, J . D., Ed.; Academic Press: New York, 1984; Vol. III, pp

123-124.

(10) (a) Reetz, M. T.; Peter, R. Tetrahedron Lett. 1981, 22, 4691. (b)

Reetz, M. T. Organotitanium Reagents in Organic Synthesis; Springer-

Verlag: Berlin, 1986; pp 148-174.

(8) For a review of the chelation and nonchelation control additions,

see: Reetz, M. T. Angew. Chem., Int. Ed. Engl. 1984, 23, 556.

Synthesis of â-Amino Acid Derivatives and â-Lactams

J . Org. Chem., Vol. 64, No. 20, 1999 7513

Ta ble 2. Rea ction s of 1 w ith Alk yl Bu tyr a te 2c,e a n d Meth yl Isova ler a te 2d

% yield of 3^a

run

R¹

R²

R³

i-Pr

R⁴

additive

none^c

anti:syn^b

i-Pr

t-Bu

i-Pr

70:30

67:33

75:25

67:33

70:30

85:15

55:45

78:22

72:28

80:20

67:33

75:25

70:30

75:25

65:35

60:40

67:33

63:37^e

75:25^e

TiCl₄

TiCl(OPr-i)₃

none^c

TiCl(OPr-i)₃

none^c

t-Bu

i-Pr

benzyl

TiCl(OPr-i)₃

none^c

TiCl(OPr-i)₃

none^c

TiCl(OPr-i)₃

none^c

TiCl(OPr-i)₃

none^c

TBDMSOCH₂CH₂

i-Pr

TiCl(OPr-i)₃

none^c

allyl

i-Pr

none^c

TBDPSOCH₂CH₂

none^c

Isolated yields. Determined by ¹H NMR analysis. ^c-70 °C f 0 °C. -70 °C. ^eDetermined by ¹H NMR analysis of decarbamated

amines.

Ta ble 3. Rea ction s of 1 w ith 2 in th e P r esen ce of Ti(OP r -i)₄

%yield of 3^a

run

R¹

R²

R³

i-Pr

R⁴

anti:syn^b

i-Pr

t-Bu

i-Pr

t-Bu

i-Pr

8:92

33:67

5:95

33:67

18:82

35:65

33:67

25:75

35:65

40:60^c

benzyl

TBDMSOCH₂CH₂

i-Pr

allyl

TBDPSOCH₂CH₂

Isolated yields. Determined by ¹H NMR analysis. ^cDetermined by ¹H NMR analysis of decarbamated amines.

Con clu sion

The reaction of N-alkoxycarbonyl-1-methoxyamines 1

with esters 2 is a useful method for the synthesis of

â-amino acid derivatives and â-lactams. By this method,

N-alkoxycarbonyl-1-methoxyamines corresponding to un-

stable imines (R¹) benzyl, allyl, and â-alkoxyethyl) can

also be employed. The reactions in the absence of Ti

complexes or in the presence of TiCl(OPr-i)₃gave anti

adducts preferentially. On the other hand, syn selectivity

was observed when the reaction was carried out in the

presence of Ti(OPr-i)₄.

F igu r e 3. Open transition states.

ing â-lactams 5 by deprotection of carbamate group and

subsequent cyclization (Table 4). The stereochemistry of

each diastereomer of 3 was confirmed by ¹H NMR

spectral analysis of â-lactam 5. The coupling constants

between 3-H and 4-H were 5-6 Hz for cis-5 and 2-2.5

Hz for trans-5.^1,2c

Exp er im en ta l Section

Gen er a l Meth od s. IR spectra were recorded with a Shi-

madzu FTIR-8100 infrared spectrometer. ¹H and ¹³C NMR

spectra were measured with a J EOL GX-270 spectrometer

with tetramethylsilane (TMS) as an internal standard. Column

7514 J . Org. Chem., Vol. 64, No. 20, 1999

Ta ble 4. Tr a n sfor m a tion of 3 to â-La cta m s 5

Kise and Ueda

from the corresponding N-alkoxycarbonyamines by anodic

oxidation in methanol⁵except for 1d and 1f ⁷which were

synthesized from N-methoxycarbonyl-R-amino acids.⁶

Gen er a l P r oced u r e for th e Rea ction of 1 a n d 2. A

mixture of 1 (2 mmol) and ester 2 (2.2 mmol) in THF (3 mL)

was added to a solution of LDA (4.5 mmol) in THF-hexane (6

mL) at -70 °C. After stirring for 15 min, an additive (2.2 mmol)

was added to the mixture. The mixture was stirred for 1-6 h

at the temperature described in Tables 1 and 2 until almost

all of 1 was consumed (checked by TLC). The mixture was

diluted with 1 M HCl (20 mL) and extracted with CH₂Cl₂(3 ×

10 mL). The product 3 was isolated by column chromatography

on silica gel (hexane-ethyl acetate).

Deca r ba m a tion of 3 was accomplished by usual methods,

that is, the treatment with HBr/AcOH for methylcarbamates

and with TFA for tert-butoxycarbamates. The obtained amines

were subjected to cyclization without purification.

P r ep a r a tion of â-La cta m s 5. A solution of decarbamated

3 (1 mmol) in THF (3 mL) was added to a solution of LDA (1.5

mmol) in THF-hexane (5 mL) at 0 °C. The mixture was stirred

for 2-8 h at this temperature until almost all of the starting

â-amino ester was consumed (checked by TLC). The mixture

was diluted with 1 M NH₄Cl (20 mL) and extracted with CH₂-

Cl₂(3 × 10 mL). The product 5 was isolated by column

chromatography on silica gel (hexane-ethyl acetate).

%yield of 5^a

run

R¹

R²

R³

anti-3i

syn-3i

anti-3j

syn-3j

i-Pr

trans-5a 76

cis-5a

trans-5b 68

cis-5b 42

trans-5c 64

cis-5c 48

anti-3k t-Bu

syn-3k

anti-3l

syn-3l

anti-3n benzyl

syn-3n benzyl

anti-3q allyl

syn-3q

anti-3r

syn-3r

anti-3s

syn-3s

t-Bu

i-Pr

i-Pr trans-5d 84

i-Pr cis-5d 46

trans-5e 67

cis-5e

trans-5f

cis-5f

t-Bu Et

allyl

TBDPSOCH₂CH₂t-Bu Et

trans-5g 82

cis-5g 58

TBDPSOCH₂CH₂t-Bu i-Pr trans-5h 84

TBDPSOCH₂CH₂t-Bu i-Pr cis-5h 60

Isolated yields.

Su p p or tin g In for m a tion Ava ila ble: Compound charac-

terrization data. This material is available free of charge via

the Internet at http://pubs.acs.org.

chromatography was performed on silica gel 60 (Merck).

Tetrahydrofuran was distilled from benzophenone ketyl.

N-Alk oxyca r bon yl-1-m et h oxya m in es 1 were prepared

J O990821Q

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Article Doi

A new method for the synthesis of β-amino acid derivatives and β- lactams. Reaction of N-alkoxycarbonyl-1-methoxyamines with esters

DOI: 10.1021/jo990821q

Source and publish data:

Authors:

Article abstract of DOI:10.1021/jo990821q

Full text of DOI:10.1021/jo990821q

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