Synthesis of β2-homophenylalanine derivatives by Negishi cross-coupling reactions

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Tetrahedron 64 (2008) 3701e3712

www.elsevier.com/locate/tet

Synthesis of b²-homophenylalanine derivatives by Negishi

cross-coupling reactions

,y

*

Hannah E. Bartrum, Harry Adams, Lorenzo Caggiano , Richard F.W. Jackson

*

Department of Chemistry, Dainton Building, The University of Shefﬁeld, Brook Hill, Shefﬁeld S3 7HF, UK

Received 6 December 2007; received in revised form 21 January 2008; accepted 7 February 2008

Available online 9 February 2008

Abstract

Three approaches to the synthesis of b²-homophenylalanine derivatives using Negishi cross-coupling reaction are reported. In the ﬁrst two

approaches, two protected a-iodomethyl-b-amino esters are each converted into the corresponding organozinc iodides, which then undergo

Pd-catalysed cross-coupling with aromatic halides to give b²-homophenylalanine derivatives, and the X-ray crystal structure of one product

is reported. Alternatively, Negishi cross-coupling of the zinc reagent derived from N-benzyl 3-iodomethyl azetidin-2-one and aryl halides

gave 3-benzylazetidin-2-ones, masked b²-homophenylalanine derivatives. The X-ray crystal structure of 1-benzyl-3-[(p-toluenesulfonyloxy)-

methyl]-azetidin-2-one conﬁrms the structural assignment.

1

1. Introduction

R

1

2

CO₂H

3

2

CO₂H

H₂N

R

The synthesis of amino acids continues to receive much in-

terest due to their presence in compounds of biological impor-

tance. b-Amino acids are less abundant in nature than a-amino

acids, although they are an important class of compound

present in various natural products.^1e4Peptides containing

b-amino acid residues form stable secondary structures and

are more resistant to enzymatic metabolism than their a-amino

acid counterparts.^2,3,5e9In addition, b-amino acids display

interesting pharmacological properties and are useful synthetic

precursors to b-lactams.^1,10b-Amino acids can be grouped

according to the position of the side-chain, as summarised

by Seebach as b²-, b³- and b^2,3-amino acid^2,3(Fig. 1).

R

β³-homo-amino

β

^2,3-homo-amino

acid

β²-homo-amino

acid

Figure 1. b-Homo-amino acids.

the conversion of a-amino acids into b²-amino acids, and

routes to b²-amino acids are in general less well-developed

than those to b³-amino acids. Previously, in the context of

the synthesis of b³-amino acids, we reported that alkyl iodides

obtained from a selectively reduced ^L-aspartic acid derivative

underwent Pd-catalysed cross-coupling with aryl iodides and

acid chlorides to give b³-substituted amino acid deriva-

tives.^15,16We now wish to report the application of organozinc

chemistry¹⁷to the synthesis of racemic b²-substituted amino

acid derivatives.

Synthetic methods for the preparation of b-amino acids

have been comprehensively reviewed.^2e4,11e14While the

synthesis of b³-amino acids by homologation of a-amino acids

is well established, there is no simple equivalent process for

2. Results and discussion

* Corresponding authors. Tel.: þ44 114 222 9464; fax: þ44 114 222 9303.

E-mail address: r.f.w.jackson@shef.ac.uk (R.F.W. Jackson).

We considered that the required b²-substituted amino acid

framework 1 could be prepared by the conjugate addition

of a protected amine 2 to readily available methyl

y

Present address: Department of Pharmacy and Pharmacology, University

of Bath, Bath BA2 7AY, UK.

doi:10.1016/j.tet.2008.02.024

3702

H.E. Bartrum et al. / Tetrahedron 64 (2008) 3701e3712

Table 1

Synthesis of b²-homophenylalanine derivatives 10 and 11

(2-hydroxymethyl)propenoate 4 (Scheme 1). Conversion of

the hydroxymethyl group into the corresponding alkyl iodide

derivative 3 would afford the precursor for the Negishi

cross-coupling reaction.

Ar

X

Product

Yield (%)

Product

Yield^a(%)

Ph

I

10a

10b

10c

10d

10e

10f

72

62

11a

11b

11c

11d

11e

11f

75 (78)^b

76

89

Br

I

CO₂Me

I

4-MeOeC₆H₄

4-O₂NeC₆H₄

3-O₂NeC₆H₄

4-HOeC₆H₄

3-HOeC₆H₄

a

77

CO₂Me

OH

PGHN

I

24 (45)^c

20 (43)^c

40

60

54

I

3

1

I

62

I

50

CO₂Me

OH

Refers to products obtained after column chromatography.

Undistilled DMF used directly.

Excess zinc removed before cross-coupling, see Section 4.1.3.

b

c

NH₂

+

PG

2

4

Scheme 1. Strategy for b²-substituted amino acid synthesis.

Superior yields were obtained in the Negishi cross-coupling

reaction of the zinc reagent derived from sulfonyl-protected

nitrogen series 9 compared to the corresponding Boc-protected

amino acid derivatives 8 (Table 1). Protonation of the organo-

zinc iodide is a competing reaction pathway and results in the

formation of protected b²-homoalanine, which was isolated in

instances of low yields.

Cross-coupling of the zinc reagent derived from the tosyl-

derivative 9 with both PhI and PhBr to give 11a was equally

effective (Table 1), whereas the reaction of the zinc reagent

derived from the Boc-derivative 8 was somewhat less efﬁcient

with PhBr than with PhI. This is reminiscent of the behaviour

of relatively unreactive a-amino acid-derived organozinc re-

agents, which react with aryl bromides in lower yield than

they do with the corresponding aryl iodides.²³

Methyl (2-hydroxymethyl)propenoate 4 was synthesised

from trimethyl phosphonoacetate and formaldehyde, following

the procedure for the synthesis of the analogous ethyl ester.¹⁸

Conjugate addition of benzylamine to 4 in methanol gave the

corresponding amino alcohol 5 in good yield (Scheme 2).^19,20

Selective protection of the secondary amine was performed

using Boc₂O in basic aqueous solution to afford the protected

amino alcohol 6 in 85% isolated yield. As an alternative, con-

jugate addition of tosyl-protected benzylamine to ester 4 gave

the protected amino alcohol 7 directly (55%). Treatment of

each of the amino alcohols 6 and 7 with iodine, PPh₃and im-

idazole²¹gave the corresponding alkyl iodides 8 and 9 in good

yields after puriﬁcation by column chromatography (Scheme

2).

The crystal structure of the coupled product 11a was

obtained (Fig. 2), which showed that one ortho-proton of the

newly introduced phenyl group is located directly above the

aromatic ring of the N-benzyl substituent. This conformational

effect also appears to persist to some extent in solution, as evi-

denced by the chemical shift of the same ortho-protons in each

of the coupled products 11aef. Although the bulk sample of

adduct 11a was racemic, the crystal was homochiral indicating

that the compound crystallised as a conglomerate.

CO₂Me

OH

Bn

CO₂Me

OH

BnNH₂

MeOH

N

H

4

5, 91%

K₂CO₃

Boc₂O

H

N

MeCN

NaHCO₃

dioxane/H₂O

(to 6)

(to 7)

Bn

Ts

Bn

CO₂Me

I

Bn

CO₂Me

I₂/PPh₃

N

R

N

PG

imidazole

CH₂Cl₂

OH

8, PG = Boc, 73%

9, PG = Ts, 85%

6, PG = Boc, 85%

7, PG = Ts, 55%

Scheme 2. Synthesis of b²-iodomethyl amino acid derivatives 8 and 9.

The alkyl iodides 8 and 9 were each converted into the cor-

responding organozinc iodides using zinc activated with cata-

lytic I₂in DMF.²²Palladium-catalysed cross-coupling of each

of the zinc reagents with aromatic halides using Pd₂(dba)₃/

P(o-tol)₃, gave b²-homophenylalanine derivatives in moderate

to good yields over two steps from the starting alkyl iodides

(Scheme 3, Table 1).

Bn

CO₂Me

I

Bn

CO₂Me

Ar

1. Zn*

N

PG

N

PG

2. ArX, DMF

Pd₂(dba)₃

P(o-tol)₃

8, PG = Boc

9, PG = Ts

10a-f, PG = Boc

11a-f, PG = Ts

Scheme 3. Synthesis of b²-homophenylalanine derivatives.

Figure 2. Coupled Product 11a, showing the proton at C(22).

H.E. Bartrum et al. / Tetrahedron 64 (2008) 3701e3712

3703

The poor yields of the nitrophenyl derivatives 10c and 10d,

obtained by reaction of zinc reagent derived from the alkyl io-

dide 8, are due to competing reduction of the NO₂group of the

product by excess zinc used in the reaction. Removal of the

excess zinc prior to the Negishi coupling reaction gave signif-

icantly improved yields.

Previous studies had shown that unprotected phenols can be

tolerated in the Negishi reaction,²⁴and this proved to the case

here also. Better yields were obtained in the cross-coupling of

the zinc reagent derived from the sulfonyl-protected iodide 9

with both 3- and 4-iodophenol compared with the Boc-ana-

logue 8, which once more testiﬁes to the greater reactivity

of the zinc reagent derived from the sulfonyl-protected iodide

9. Since the reaction tolerates the presence of an unprotected

phenol, we also investigated the effect of residual water in

the solvent. DMF used in these coupling reactions was nor-

beneﬁt of simplicity. The synthesis of the required hydroxy-

methyl b-lactam precursor 14 by heating a solution of benzyl-

amine (4 equiv) and ethyl (2-hydroxymethyl)propenoate

(1 equiv) in dry methanol had been reported.^19,20Unfortu-

nately, in our hands, use of the same reaction conditions

with the methyl ester 4, did not give any of the desired b-lac-

tam 14, but instead a mixture of product 5 already isolated, to-

gether with the 2:1 adduct 15. The structure of this latter

compound was unambiguously determined by X-ray crystal-

lography (Scheme 5, Fig. 3).

CO₂Me

BnHN

OH

5, 30%

CO₂Me

OH

BnNH₂

MeOH, reflux, 16h

BnN

OH

O

+

4

˚

mally distilled from CaH₂and stored over 4 A molecular

14, 0%

CONHBn

sieves. However, when the reaction was conducted using

DMF as supplied, the product was obtained in 78% isolated

yield. This preliminary result demonstrates that DMF may

not need to be rigorously dried prior to use in the cross-coup-

ling reaction.

BnHN

OH

15, 44%

Scheme 5. Attempted direct formation of b-lactam 14.

Removal of the benzyl group from adduct 10a was per-

formed using PdCl₂under an atmosphere of H₂, following

a procedure previously reported for a similarly protected

amine.²⁵In the event, partial removal of the Boc-protecting

group also occurred, possibly due to in situ generation of

HCl. This observation demonstrates the potential for removal

of both nitrogen protecting groups in one synthetic step. How-

ever, for ease of isolation and puriﬁcation the crude reaction

mixture was treated with Boc₂O to give the Boc-protected

b²-homophenylalanine derivative 12 (82%). Although use of

the sulfonamide group gave good yields of highly crystalline

products in the Negishi cross-coupling reaction, cleavage of

the sulfonyl protecting group can require harsh reaction condi-

tions that may result in decomposition. Pleasingly, however,

treatment of adduct 11a with Mg/MeOH, previously used for

the deprotection of sulfonyl aziridines²⁶and applied to piper-

idines,²⁷cleaved the sulfonamide group to give the protected

b²-homophenylalanine derivative 13 (88%) (Scheme 4).

Figure 3. Product 15 arising from 1,2- and 1,4- addition of benzylamine to 4.

Using a procedure previously reported for the cyclisation of

a very similar substrate,²⁸treatment of the amino alcohol 5

with ^tBuMgCl in THF gave the b-lactam 14 (67%). The phys-

ical and spectroscopic data for the b-lactam 14 differed from

that previously reported,²⁰notably in the IR stretching fre-

quency of the carbonyl group (we observed 1729 cm^ꢀ1, com-

pared with the reported value of 1710 cm^{ꢀ1 20}

and in the

)

physical state of the compound. The identity of our material

was conﬁrmed by conversion into the crystalline tosylate 16

whose structure was determined by X-ray crystallography

(Fig. 4). The iodo b-lactam 17 was obtained either by treat-

ment of the hydroxymethyl b-lactam 14 with iodine and

PPh₃(76%), or by treatment of the tosylate 16 with NaI

(89%) (Scheme 6).

Conversion of the iodo b-lactam 17 into the corresponding

zinc reagent proceeded smoothly, and subsequent Pd(0)-cata-

lysed cross-coupling with aromatic halides gave the expected

3-benzylazetidin-3-ones 18aef (Scheme 7, Table 2). 3-Methyl

azetidin-2-one, resulting from protonation of the organozinc

iodide intermediate, was also recovered from these reactions.

Although Negishi reactions of organozinc reagents derived

from azetidines have been reported,²⁹the results reported

herein appear to be the ﬁrst examples of an organozinc halide

derived from a b-lactam undergoing a Negishi reaction.

1. PdCl₂, H₂

Bn

CO₂Me

Ph

MeOH

CO₂Me

Ph

N

Boc

BocNH

2. Boc₂O, NEt₃

CH₂Cl₂

10a

12, 82%

Bn

CO₂Me

Ph

Mg/MeOH

CO₂Me

Ph

N

Ts

BnNH

11a

13, 88%

Scheme 4. Deprotection of coupled products.

An alternative protecting group strategy was also investi-

gated, in which the b²-amino acid derivative was masked as

a b-lactam derivative. This approach offered the potential

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H.E. Bartrum et al. / Tetrahedron 64 (2008) 3701e3712

4. Experimental

4.1. General experimental

All reagents used were purchased from commercial sources

and used without further puriﬁcation. All moisture/air sensi-

tive reactions were conducted under a positive pressure of ni-

trogen in ﬂame dried or oven dried glassware. Water is

demineralised water and all solvents used were HPLC grade

or distilled. Petroleum ether refers to the fraction which boils

in the range 40e60 ^ꢁC. Dry DMF was distilled from calcium

˚

hydride and stored over 4 A molecular sieves.

Nuclear magnetic resonance (NMR) spectra were recorded

on a Bruker DRX-500 NMR spectrometer at room temperature

or at the stated temperature. Chemical shifts were measured

relative to residual solvent and are expressed in parts per mil-

lion (d). Coupling constants (J) are given in hertz and the mea-

sured values are rounded to the nearest 0.1 Hz and are not

rationalised. High-resolution mass spectra were recorded using

a MicroMass LCT operating in electrospray (ES) mode or Kra-

tos MS 25 or MS 80 for electro impact (EI). Chemical analy-

ses were performed using a Perkin Elmer 2400 CHN elemental

analyser. Infra-red spectra were recorded on a Perkin Elmer

Paragon 100 FTIR spectrophotometer (n_maxin cm^ꢀ1) as thin

ﬁlms using NaCl plates. Melting points were determined using

a Linkam HFS91 heating stage, used in conjunction with

a TC92 controller and are uncorrected.

Figure 4. b-Lactam 16.

OH

CO₂Me

OH

^tBuMgCl

THF

BnHN

BnN

O

5

14, 67%

I₂, PPh₃

Imidazole

CH₂Cl₂

TsCl, NEt₃

DMAP, Me₃NH⁺Cl^-

CH₂Cl₂

I

OTs

NaI

acetone

BnN

O

17, 76% from 14

89% from 16

16, 73%

Thin layer chromatography (TLC) was performed on pre-

coated plates (0.2 mm, Merck DC-alufolien Kieselgel 60

Scheme 6. Synthesis of the iodo b-lactam 17.

F₂₅₄) and compounds were visualised by UV light (254 nm),

ninhydrin solution (5% in MeOH) or KMnO₄. Column chro-

matography was performed using silica gel 60 from BDH

Lab or Davisil Fluorochem.

I

Ar

1. Zn*

BnN

17

2. ArX, DMF

O

4.1.1. Iodination procedure

Pd₂(dba)₃(2.5 mol. %)

P(o-tol)₃(10 mol. %)

18a-f

A solution of the alcohol (10.5 mmol) in dry CH₂Cl₂

(20 mL) was added dropwise by syringe over 5 min to a stirred

solution of triphenylphosphine (2.90 g, 11.07 mmol), imid-

azole (0.75 g, 11.07 mmol) and iodine (2.81 g, 11.07 mmol)

in dry CH₂Cl₂(30 mL) under nitrogen at room temperature.

The reaction continued until TLC analysis indicated complete

consumption of starting material. The precipitate was removed

by ﬁltration and the ﬁltrate was washed with aqueous sodium

thiosulfate solution (2ꢂ30 mL, 1 M) and brine, dried (MgSO₄)

and evaporated under reduced pressure to afford the crude

product, which was puriﬁed by silica gel column

chromatography.

Scheme 7. Synthesis of 3-benzylazetidin-2-ones.

Table 2

Synthesis of 3-benzylazetidin-2-ones 18

Entry

Ar

X

Product

Yield^a(%)

1

2

3

4

5

6

7

a

Ph

I

18a

18b

18c

18d

18e

18f

72

68

65

44

47

56

52

Br

I

4-MeOeC₆H₄

4-O₂NeC₆H₄

3-O₂NeC₆H₄

4-HOeC₆H₄

3-HOeC₆H₄

I

Refers to products obtained after column chromatography.

4.1.2. Cross-coupling reaction: procedure A (one-pot)

Zinc dust (195 mg, 3.0 mmol, 6.0 equiv) was placed in

a dry 25 mL round bottom ﬂask, with sidearm, containing

a rugby ball shaped magnetic stirrer. The ﬂask was ﬂushed

with nitrogen and dry DMF (0.2 mL) added under nitrogen

via syringe followed by catalytic iodine (40 mg, 0.15 mmol,

0.3 equiv). Effervescence was observed and the DMF changed

from colourless to yellow and back again. A solution of the ap-

propriate alkyl iodide (0.5 mmol) was dissolved in DMF

3. Conclusions

In this paper, we have shown that racemic b²-substituted

amino acid derivatives 10, 11 and 18 can be prepared from

a readily available b-amino ester precursor, making use of

the Negishi cross-coupling with aromatic halides, including

unprotected iodophenols.

H.E. Bartrum et al. / Tetrahedron 64 (2008) 3701e3712

3705

(0.3 mL) under nitrogen and transferred to the activated zinc

suspension via syringe. The solution was stirred at room tem-

perature and the insertion proceeded with a noticeable exo-

therm. When the solution had cooled Pd₂(dba)₃(11.0 mg,

0.0125 mmol, 2.5 mol %), P(o-tol)₃(15 mg, 0.05 mmol,

10 mol %) and the aryl iodide (1.3 equiv relative to the alkyl

iodide) were added to the ﬂask and the reaction mixture was

left at room temperature overnight. The crude reaction mixture

was applied directly to a silica gel chromatography column to

afford the puriﬁed cross-coupled product.

CHCH_AH_BN), 3.71 (3H, s, CO₂CH₃), 3.78e3.79 (2H, m,

NHCH₂Ph), 3.96 (1H, dd, J 10.9 and 3.8, CH_AH_BOH), 4.02

(1H, dd, J 10.9 and 5.3, CH_AH_BOH) and 7.22e7.33 (5H, m,

Ar); d_C(126 MHz, CDCl₃) 45.8, 49.7, 51.9, 53.9, 64.7,

127.3, 127.6, 128.2, 128.4, 128.5, 138.9 and 173.5; m/z (EI)

223 (M^þ, 2%) and 91 (C₆H^þ₇, 100). Found M^þ223.1208.

C₁₂H₁₇NO₃requires 223.1208.

4.1.3.3. Methyl 2-{[N-benzyl-(tert-butoxycarbonyl)-amino]-

methyl}-3-hydroxy-propanoate 6. Using conditions originally

reported for a vicinal amino alcohol,³¹a solution of NaHCO₃

(1.13 g, 13.4 mmol) in H₂O (20 mL) was added to a stirred so-

lution of amino alcohol 5 (2.99 g, 13.4 mmol) in dioxane

(40 mL) at room temperature. After 10 min Boc₂O (2.95 g,

13.4 mmol) was added and the pH monitored and adjusted

to pH 10 as necessary with the addition of NaHCO₃. After

18 h the reaction mixture was concentrated under reduced

pressure and EtOAc and H₂O were added. The organic layer

was separated, washed with brine (30 mL), dried (Na₂SO₄)

and the solvent removed under reduced pressure to give, with-

out the need for further puriﬁcation, the Boc-benzyl protected

amino alcohol 6 (3.64 g, 85%) as a colourless oil. R_f0.35 (pet-

rol/EtOAc, 1:1); n_max(ﬁlm)/cm^ꢀ13445 br, 2976, 1732 and

1694. At 22 ^ꢁC the ¹H NMR of this compound showed signif-

icant rotameric behaviour. Upon heating to 61 ^ꢁC most peaks

sharpened, but the signals for CH and CHCH_AH_BN remained

hidden due to broadening. Their presence was noted by the

baseline integrals (1H between 2.5e3.5 and 1H between 3.4e

4.0); d_H(500 MHz, CDCl₃, 61 ^ꢁC) 1.48 (9H, s, C(CH₃)₃), 2.77

(1H, br s, OH), 3.51 (1H, dd, J 14.6 and 5.9, CHCH_AH_BN),

3.70 (3H, s, CO₂CH₃), 3.74 (1H, dd, J 11.7 and 4.9,

CH_AH_BOH), 3.85 (1H, dd, J 11.7 and 4.9, CH_AH_BOH), 4.45

(2H, s, NCH₂Ph) and 7.22e7.35 (5H, m, Ar); d_C(126 MHz,

CDCl₃, 22 ^ꢁC) 28.3, 44.2, 44.8, 45.9, 46.6, 50.4, 51.4, 51.9,

59.8, 81.0, 127.2, 127.4, 127.7, 128.0, 128.6, 137.9, 157.0 and

173.2. Upon heating rotameric peaks coalesced to give the ex-

pected number of signals; d_C(126 MHz, CDCl₃, 61 ^ꢁC) 28.2,

44.7, 46.5, 51.3, 51.6, 60.2, 80.6, 127.2, 128.0, 128.5, 137.9,

156.5 and 173.2; m/z (ES) 346 (MNa^þ, 98%) and 323 (M^þ,

100). Found MNa^þ346.1646. C₁₇H₂₅NO₅Na requires

346.1630.

4.1.3. Cross-coupling reaction: procedure B (two-pot)

As procedure A except once the reaction had cooled after

zinc insertion, the solution was removed via syringe to a

separate ﬂask to which were added Pd₂(dba)₃(11.0 mg,

0.0125 mmol, 2.5 mol %), P(o-tol)₃(15 mg, 0.05 mmol,

10 mol %) and the aryl iodide (1.3 equiv relative to the alkyl

iodide). The reaction mixture was left at room temperature

overnight and the crude reaction mixture was applied directly

to a silica gel chromatography column to afford the puriﬁed

cross-coupled product.

4.1.3.1. Methyl 2-(hydroxymethyl)propenoate 4. Following

a previously reported procedure for the ethyl ester,¹⁸a satu-

rated aqueous solution of K₂CO₃(6.63 g, 48 mmol) was

slowly added (30 min) to a rapidly stirred solution of trimethyl

phosphonoacetate (5.46 g, 30 mmol) and formaldehyde (37%

w/w solution, 10 mL, 117 mmol) at room temperature, which

produced an exotherm. After the addition the reaction mixture

was stirred at room temperature for a further 1 h before being

quenched with H₂O (30 mL). The aqueous phase was ex-

tracted with CH₂Cl₂(3ꢂ30 mL) and the organic fractions

combined, washed with brine (2ꢂ30 mL), dried (MgSO₄)

and evaporated under reduced pressure. Puriﬁcation by silica

gel column chromatography (petrol/EtOAc, gradient from

20e100% EtOAc) gave the ester 4 (1.9 g, 55%) as a colourless

oil. R_f0.6 (EtOAc); (Found: C, 51.6; H, 7.3. C₅H₈O₃requires

C, 51.7; H, 6.9); n_max(ﬁlm)/cm^ꢀ13410 br, 1715 and 1636; d_H

(500 MHz, CDCl₃) 2.99 (1H, t, J 6.3, CH₂OH), 3.73 (3H, s,

CO₂CH₃), 4.27 (2H, d, J 6.2, CH₂OH), 5.81 (1H, d, J 2.4,

H_AH_B]C) and 6.21 (1H, d, J 2.4, H_AH_B]C); d_C(126 MHz,

CDCl₃) 52.2, 62.4, 126.0, 139.7, 167.1; m/z (EI) found: M^þ,

116.0474. C₅H₈O₃requires M^þ116.0473, 117 (16%, MH^þ),

116 (50, M^þ), 99 (100, M^þꢀOH). Spectroscopic data consis-

tent with that previously reported.³⁰

4.1.3.4. Methyl 2-{[N-benzyl-(tert-butoxycarbonyl)-amino]-

methyl}-3-iodo-propanoate 8. Following the iodination proce-

dure, alcohol 6 (3.39 g, 10.5 mmol) gave, after puriﬁcation by

silica gel column chromatography (petrol/EtOAc, gradient

from petrol to 80% EtOAc), the alkyl iodide 8 (3.30 g, 73%)

as a colourless oil. R_f0.75 (petrol/EtOAc, 1:1); n_max(ﬁlm)/

cm^ꢀ12977, 1740 and 1698; d_H(500 MHz, CDCl₃, 61 ^ꢁC) 1.49

(9H, s, C(CH₃)₃), 3.13e3.20 (1H, m, CHCH₂I), 3.25e3.37

(2H, m, CHCH₂I), 3.40e3.52 (2H, m, CHCH₂N), 3.74 (3H,

s, CO₂CH₃), 4.45 (1H, d, J 15.6, NCH_AH_BPh), 4.53 (1H, d,

J 15.6, NCH_AH_BPh) and 7.23e7.36 (5H, m, Ar); d_C

(126 MHz, CDCl₃, 22 ^ꢁC) 0.0, 0.79, 25.9, 26.6, 26.7, 42.9,

45.2, 45.6, 46.9, 47.6, 48.9, 49.8, 50.1, 50.3, 50.5, 78.7, 125.4,

125.5, 125.6, 125.7, 126.0, 126.7, 126.8, 127.4, 136.2, 153.9,

154.1 and 170.5. More signals than expected in ¹³C NMR due

4.1.3.2. Methyl 2-[(N-benzyl-amino)-methyl]-3-hydroxy-propan-

oate 5. By minor modiﬁcation of the literature procedure,¹⁸

benzylamine (1.1 mL, 10 mmol) was added to a solution of

the ester 4 (1.0 g, 8.6 mmol) in MeOH (HPLC grade, but

not dried, 20 mL). The reaction mixture was stirred at room

temperature for 16 h before being concentrated under reduced

pressure to give, without the need for puriﬁcation, the amino

alcohol product 5 (1.75 g, 91% yield) as a colourless oil. R_f

0.1 (EtOAc); n_max(ﬁlm)/cm^ꢀ13324 br, 2952 and 1732; d_H

(500 MHz, CDCl₃) 2.68e2.73 (1H, m, CH), 2.91 (1H, dd,

J 12.1 and 4.4, CHCH_AH_BN), 3.16 (1H, dd, J 12.1 and 5.7,

3706

H.E. Bartrum et al. / Tetrahedron 64 (2008) 3701e3712

to presence of rotamers; m/z (ES) 456 (MNa^þ, 55%), 334

(MH^þꢀCO₂(CH₃)₃, 97) and 268 (100). Found MNa^þ

456.0656. C₁₇H₂₄INO₄Na requires 456.0648.

(ﬁlm)/cm^ꢀ12977, 1738 (C]O), 1694, 1521 and 1347 s; d_H

(500 MHz, CDCl₃, 61 ^ꢁC) 1.50 (9H, s, C(CH₃)₃), 2.78e2.90

(1H, m, CHCH_AH_BAr), 2.99 (1H, dd, J 13.8 and 9.4,

CHCH_AH_BAr), 3.07e3.19 (1H, m, CH), 3.42e3.52 (2H, m,

CHCH₂N), 3.60 (3H, s, CO₂CH₃), 4.38 (1H, d, J 15.6,

NCH_AH_BPh), 4.51 (1H, d, J 15.5, NCH_AH_BPh), 6.99e7.62

(7H, m, Ar) and 8.11e8.14 (2H, m, Ar); d_C(126 MHz,

CDCl₃, 22 ^ꢁC) 28.4, 35.9, 46.0, 46.6, 48.7, 49.3, 50.8, 51.8,

51.9, 80.5, 123.7, 127.2, 127.4, 127.8, 128.0, 128.6, 129.6,

138.1, 146.5, 146.7, 155.7 and 173.9. More signals than ex-

pected in ¹³C NMR due to presence of rotamers; m/z (ES)

451 (MNa^þ, 5%), 329 (MH^þꢀC₅H₈O₂, 100). Found MNa^þ

451.1850. C₂₃H₂₈N₂O₆Na requires 451.1845.

4.1.3.5. Methyl 2-{[N-benzyl-(tert-butoxycarbonyl)-amino]-

methyl}-3-phenylpropanoate 10a. Following procedure A, al-

kyl iodide 8 (217 mg, 0.5 mmol) and iodobenzene (0.86 mL,

0.65 mmol) gave, after puriﬁcation by silica gel column chro-

matography (petrol/EtOAc, gradient from petrol to 50%

EtOAc), the b²-amino acid derivative 10a (138 mg, 72%) as

a pale orange oil. R_f0.7 (petrol/EtOAc, 1:1); n_max(ﬁlm)/

cm^ꢀ12977, 1738 and 1697; d_H(500 MHz, CDCl₃, 61 ^ꢁC)

1.48 (9H, s, C(CH₃)₃), 2.63e2.84 (1H, m, CHCH_AH_BPh), 2.91

(1H, dd, J 13.8 and 8.8, CHCH_AH_BPh), 3.07e3.18 (1H, m,

CH), 3.41e3.52 (2H, m, CHCH₂N), 3.60 (3H, s, CO₂CH₃),

4.35 (1H, d, J 15.5, NCH_AH_BPh), 4.46e4.60 (1H, m,

NCH_AH_BPh) and 7.11e7.35 (10H, m, Ar); d_C(126 MHz,

CDCl₃, 22 ^ꢁC) 27.7, 28.0, 28.4, 36.2, 36.5, 46.4, 47.0, 48.3,

49.1, 50.5, 51.5, 51.8, 80.2, 126.5, 127.2, 127.5, 127.9, 128.1,

128.5, 128.7, 129.1, 138.0, 138.5, 138.7, 155.8 and 174.8.

More signals than expected in ¹³C NMR due to presence of ro-

tamers; m/z (ES) 384 (MH^þ, 77%) and 328 (MH^þꢀC₄H₉,

100). Found MH^þ384.2170. C₂₃H₃₀NO₄requires 384.2175.

In addition, following procedure A, alkyl iodide 8 (217 mg,

0.5 mmol) and bromobenzene (68.5 mg, 0.65 mmol) gave,

after puriﬁcation as previously described, the b²-amino acid

derivative 10a (119 mg, 62%) as a pale orange oil, spectro-

scopically consistent with that previously reported herein.

Following procedure B, alkyl iodide 8 (217 mg, 0.5 mmol)

and 1-iodo-4-nitro benzene (162 mg, 0.65 mmol) gave, after

puriﬁcation as previously described, the b²-amino acid deriva-

tive 10c (96 mg, 45% yield) as a pale orange oil, spectroscop-

ically consistent with that previously reported herein.

4.1.3.8. Methyl 2-{[N-benzyl-(tert-butoxycarbonyl)-amino]-

methyl}-3-(m-nitrophenyl)-propanoate 10d. Following proce-

dure A, alkyl iodide 8 (217 mg, 0.5 mmol) and 1-iodo-3-nitro

benzene (162 mg, 0.65 mmol) gave, after puriﬁcation by silica

gel column chromatography (petrol/EtOAc, gradient from pet-

rol to 100% EtOAc), the b²-amino acid derivative 10d (42 mg,

20%) as a pale orange oil. R_f0.30 (petrol/EtOAc, 3:2); n_max

(ﬁlm)/cm^ꢀ13931, 1737, 1695, 1531 and 1352 s; d_H(500 MHz,

CDCl₃, 61 ^ꢁC) 1.50 (9H, s, C(CH₃)₃), 2.80e2.92 (1H, m,

CHCH_AH_BAr), 3.00 (1H, dd, J 13.8 and 9.5, CHCH_AH_BAr),

3.07e3.18 (1H, m, CH), 3.44e3.54 (2H, m, CHCH₂N), 3.61

(3H, s, CO₂CH₃), 4.40 (1H, d, J 15.5, NCH_AH_BPh), 4.52

(1H, d, J 15.4, NCH_AH_BPh), 7.03e7.67 (7H, m, Ar), 7.97e

7.99 (1H, m, Ar) and 8.06e8.09 (1H, m, Ar); d_C(126 MHz,

CDCl₃, 22 ^ꢁC) 28.4, 35.7, 46.3, 46.8, 48.6, 49.2, 50.7, 51.7,

51.9, 80.5, 121.7, 123.6, 127.2, 127.4, 127.8, 128.6, 129.4,

135.1, 138.1, 140.8, 148.3, 155.7 and 173.9. More signals than

expected in ¹³C NMR due to presence of rotamers; m/z (ES)

451 (MNa^þ, 13%), 429 (MH^þ, 2) and 329 (MH^þꢀC₅H₈O₂,

100). Found MH^þ429.2044. C₂₃H₂₉N₂O₆requires 429.2026.

Following procedure B, alkyl iodide 8 (217 mg, 0.5 mmol)

and 1-iodo-3-nitro benzene (162 mg, 0.65 mmol) gave, after

puriﬁcation as previously described, the b²-amino acid deriva-

tive 10d (92 mg, 43%) as a pale orange oil, spectroscopically

consistent with that previously reported herein.

4.1.3.6. Methyl 2-{[N-benzyl-(tert-butoxycarbonyl)-amino]-

methyl}-3-(p-methoxyphenyl)-propanoate 10b. Following pro-

cedure A, alkyl iodide 8 (217 mg, 0.5 mmol) and 4-iodoanisole

(152 mg, 0.65 mmol) gave, after puriﬁcation by silica gel col-

umn chromatography (petrol/EtOAc, gradient from petrol to

80% EtOAc), the b²-amino acid derivative 10b (158 mg,

77% yield) as a pale orange oil. R_f0.5 (petrol/EtOAc, 1:1);

n_max(ﬁlm)/cm^ꢀ12976, 1737 and 1695; d_H(500 MHz,

CDCl₃, 61 ^ꢁC) 1.48 (9H, s, C(CH₃)₃), 2.63e2.74 (1H, m,

CHCH_AH_BAr), 2.85 (1H, dd, J 13.9 and 8.8, CHCH_AH_BAr),

3.01e3.17 (1H, m, CH), 3.41e3.44 (2H, m, CHCH₂N), 3.61

(3H, s, CO₂CH₃), 3.80 (3H, s, ArCH₃), 4.34 (1H, d, J 15.5,

NCH_AH_BPh), 4.45e4.60 (1H, m, NCH_AH_BPh), 7.78e7.87

(2H, m, Ar), 7.00e7.09 (2H, m, Ar) and 7.18e7.35 (5H, m,

Ar); d_C(126 MHz, CDCl₃, 22 ^ꢁC) 28.4, 35.4, 46.7, 47.3,

48.4, 49.0, 50.5, 51.7, 55.2, 80.1, 113.9, 127.2, 127.8, 128.5,

129.7, 130.6 and 174.9. More signals than expected in ¹³C

NMR due to presence of rotamers; m/z (ES) 414 (MH^þ,

7%), 413 (M^þ, 23) and 120 (100); m/z (EI) found M^þ

413.2186. C₂₄H₃₁NO₅requires 413.2202.

4.1.3.9. Methyl 2-{[N-benzyl-(tert-butoxycarbonyl)-amino]-

methyl}-3-(p-hydroxyphenyl)-propanoate 10e. Following pro-

cedure A, alkyl iodide 8 (217 mg, 0.5 mmol) and 4-iodophenol

(143 mg, 0.65 mmol) gave, after puriﬁcation by silica gel col-

umn chromatography (petrol/EtOAc, gradient from petrol to

100% EtOAc), the b²-amino acid derivative 10e (80 mg,

40% yield) as a pale orange oil. R_f0.3 (petrol/EtOAc, 1:1);

n_max(ﬁlm)/cm^ꢀ13362br, 2977, 1735 and 1694; d_H(500 MHz,

CDCl₃, 61 ^ꢁC) 1.48 (9H, s, C(CH₃)₃), 2.64e2.72 (1H, m,

CHCH_AH_BAr), 2.83 (1H, dd, J 13.9 and 8.8, CHCH_AH_BAr),

3.02e3.10 (1H, m, CH), 3.40e3.45 (2H, m, CHCH₂N), 3.60

(3H, s, CO₂CH₃), 4.34 (1H, d, J 15.5, NCH_AH_BPh), 4.48e

4.1.3.7. Methyl 2-{[N-benzyl-(tert-butoxycarbonyl)-amino]-

methyl}-3-(p-nitrophenyl)-propanoate 10c. Following proce-

dure A, alkyl iodide 8 (217 mg, 0.5 mmol) and 1-iodo-4-nitro

benzene (162 mg, 0.65 mmol) gave, after puriﬁcation by silica

gel column chromatography (petrol/EtOAc, gradient from pet-

rol to 100% EtOAc), the b²-amino acid derivative 10c (52 mg,

24%) as a pale orange oil; R_f0.30 (petrol/EtOAc, 3:2); n_max

H.E. Bartrum et al. / Tetrahedron 64 (2008) 3701e3712

3707

4.53 (1H, m, NCH_AH_BPh), 4.76 (1H, s, OH), 6.69e6.84 (2H,

m, Ar), 6.99 (2H, d, J 8.4, Ar) and 7.18e7.34 (5H, m, Ar); d_C

(126 MHz, CDCl₃, 22 ^ꢁC) 28.4, 35.7, 46.7, 47.3, 48.4, 49.1,

50.5, 51.6, 51.8, 80.3, 115.3, 178.2, 127.8, 128.5, 129.9, 130.5,

154.3 and 174.9. More signals than expected in ¹³C NMR due

to presence of rotamers; m/z (ES) 422 (MNa^þ, 24%), 400 (M^þ,

4) and 300 (MH^þꢀC₅H₈O₂, 100). Found MH^þ400.2113.

C₂₃H₃₀NO₅requires 400.2124.

155.8 and 174.7; m/z (ES) 316 (MNa^þ, 100%) and 194

(MH^þꢀCO₂(CH₃)₃,

78).

C₁₆H₂₃NO₄Na requires 316.1525.

Found

MNa^þ

316.1510.

4.1.3.12. N-Benzyl-4-methylbenzenesulfonamide. Following

a procedure previously described for the synthesis of N-benz-

yl-4-bromobenzenesulfonamide,³²a solution of p-toluenesul-

fonyl chloride (5.7 g, 30 mmol) in CH₂Cl₂(60 mL) was

added to a stirred solution of benzylamine (3.95 mL,

36 mmol) and triethylamine (2.44 mL, 30 mmol) in CH₂Cl₂

(60 mL) at 0 ^ꢁC. The reaction mixture was warmed to room

temperature and stirred for 16 h. The reaction mixture was

concentrated under reduced pressure and partitioned between

EtOAc and H₂O. The organic extracts were washed succes-

sively with HCl (1 N solution, 3ꢂ200 mL) and brine

(2ꢂ150 mL), dried (Na₂SO₄), evaporated under reduced pres-

sure and the crude solid recrystallised from EtOAc/heptane to

yield N-benzyl-4-methylbenzene-sulfonamide (7.31 g, 91%

yield) as white needles. Mp 112.5e113 ^ꢁC; lit. 111.1 ^ꢁC³³;

(Found: C, 64.2; H, 5.6; N, 5.2; S, 12.3. C₁₄H₁₅NO₂S requires

C, 64.3; H, 5.8; N, 5.4; S, 12.3); m/z (EI) 261 (3%, M^þ), 106

(100%, M^þꢀSO₂Ar), 91 (47%, C₆H₇^þ). Found: M^þ, 261.0832.

C₁₄H₁₅NO₂S requires M^þ261.0824. Spectroscopic data con-

sistent with that previously reported.^33,34

4.1.3.10. Methyl 2-{[N-benzyl-(tert-butoxycarbonyl)-amino]-

methyl}-3-(m-hydroxyphenyl)-propanoate 10f. Following pro-

cedure A, alkyl iodide 8 (217 mg, 0.5 mmol) and 3-iodophenol

(143 mg, 0.65 mmol) gave, after puriﬁcation by silica gel col-

umn chromatography (petrol/EtOAc, gradient from petrol to

100% EtOAc), the b²-amino acid derivative 10f (100 mg,

50% yield) as a pale orange oil. R_f0.35 (petrol/EtOAc, 1:1);

n_max(ﬁlm)/cm^ꢀ13372 br (OH), 2978, 1738 and 1694; d_H

(500 MHz, CDCl₃, 61 ^ꢁC) 1.48 (9H, s, C(CH₃)₃), 2.65e2.71

(1H, m, CHCH_AH_BAr), 2.86 (1H, dd, J 13.9 and 8.6,

CHCH_AH_BAr), 3.07e3.15 (1H, m, CH), 3.41e3.49 (2H, m,

CHCH₂N), 3.61 (3H, s, CO₂CH₃), 4.35 (1H, d, J 15.5,

NCH_AH_BPh), 4.51 (1H, d, J 15.3, NCH_AH_BPh), 5.60 (1H, s,

OH), 6.47e6.91 (3H, m, Ar) and 7.10e7.34 (6H, m, Ar); d_C

(126 MHz, CDCl₃, 22 ^ꢁC) 26.6, 27.0, 34.7, 35.0, 44.9, 45.4,

46.9, 47.8, 49.1, 50.2, 50.5, 79.2, 112.3, 114.5, 119.3, 125.9,

126.4, 127.2, 127.3, 128.3, 136.5, 136.7, 138.8, 154.6, 154.9

and 173.7. More signals than expected in ¹³C NMR due to

presence of rotamers; m/z (ES) 422 (MNa^þ, 3%), 400 (MH^þ,

48) and 300 (MH^þꢀC₅H₈O₂, 100). Found MH^þ400.2104.

C₂₃H₃₀NO₅requires 400.2124.

4.1.3.13. Methyl 2-{[N-benzyl-(p-tolylsulfonyl)-amino]-methyl}-

3-hydroxy-propanoate 7. Using conditions originally reported

for the Michael addition of a mono-substituted sulfonamide to

an alkyl acrylate,^35,36K₂CO₃(0.69 g, 5 mmol) was added to

a stirred solution of N-benzyl-4-methylbenzenesulfonamide

(1.96 g, 7.5 mmol) and the acrylate 4 (0.58 g, 5 mmol) in

MeCN (25 mL) at room temperature. After three days, the

mixture was ﬁltered through Celite^Ò, washed (3ꢂ25 mL

EtOAc) and concentrated under reduced pressure. Puriﬁcation

by silica gel column chromatography (petrol/EtOAc, gradient

from 20e100% EtOAc) followed by recrystallisation from

petrol/Et₂O gave the alcohol 7 (1.05 g, 55% yield) as white

needles. Mp 75.5e76.0 ^ꢁC. R_f0.6 (EtOAc); (Found: C, 60.3;

H, 6.1; N, 3.6; S, 8.6. C₁₉H₂₃NO₅S requires C, 60.5; H, 6.1;

N, 3.7; S, 8.5); n_max(ﬁlm)/cm^ꢀ13520 br, 1733 and 1337; d_H

(500 MHz, CDCl₃) 2.28 (1H, ddt, J 10.1, 5.0 and 3.5, CH),

2.49 (3H, s, SO₂C₆H₄CH₃), 2.66 (1H, t, J 7.1, CH₂OH),

3.19 (1H, dd, J 15.0 and 5.1, CHCH_AH_BN), 3.64 (3H, s,

CO₂CH₃), 3.72 (1H, dd, J 15.0 and 10.5, CHCH_AH_BN),

4.1.3.11. Methyl 2-{[N-(tert-butoxycarbonyl)-amino]-methyl}-

3-phenyl-propanoate 12. Using conditions reported for a simi-

larly Boc-benzyl protected amine,²⁵PdCl₂(128 mg,

0.72 mmol) was added to a stirred solution of the Boc-benzyl

protected amine 10a (138 mg, 0.36 mmol) in MeOH (2.1 mL)

under a H₂atmosphere for 4 h. The reaction mixture was ﬁl-

tered through Celite^Ò, washed (3ꢂ25 mL MeOH) and concen-

1

trated under reduced pressure. Since analysis of the crude H

NMR suggested partial removal of the Boc group had oc-

curred, along with debenzylation, the crude product was

treated with Boc₂O (88.4 mg, 0.40 mmol, 1.1 equiv) and

Et₃N (0.033 mL, 0.40 mmol, 1.1 equiv) in CH₂Cl₂(10 mL)

for 12 h. The reaction mixture was then washed successively

with a saturated aqueous solution of NaHCO₃(10 mL) and

brine (10 mL), dried (MgSO₄) and evaporated under reduced

pressure. Puriﬁcation by silica gel column chromatography

(petrol/EtOAc, gradient from petrol to 50% EtOAc), gave

the Boc-protected amino ester 12 (87 mg, 82%) as a colourless

oil. R_f0.60 (petrol/EtOAc, 1:1); n_max(ﬁlm)/cm^ꢀ13375, 2977

and 1715 br; d_H(500 MHz, CDCl₃, 61 ^ꢁC) 1.46 (9H, s,

C(CH₃)₃), 2.83 (1H, dd, J 12.8 and 6.0, CHCH_AH_BPh),

2.90e3.07 (2H, m, CHCH_AH_BPh), 3.26e3.35 (1H, m,

CHCH_AH_BN), 3.35e3.45 (1H, m, CHCH_AH_BN), 3.67 (3H,

s, CO₂CH₃), 4.79 (1H, s, NH), 7.15e7.25 (3H, m, Ar) and

7.27e7.31 (2H, m, Ar); d_C(126 MHz, CDCl₃, 22 ^ꢁC) 28.4,

35.9, 41.5, 47.4, 51.8, 79.4, 126.6, 128.5, 128.9, 138.3,

3.76e3.87 (2H, m, CH₂OH), 4.02 (1H, d,

J 14.4,

NCH_AH_BPh), 4.61 (1H, d, J 14.4, NCH_AH_BPh), 7.29 (2H,

dd, J 6.9 and 2.6, Ar), 7.32e7.36 (3H, m, Ar), 7.38 (2H, d,

J 8.0, Ar) and 7.77 (2H, d, J 8.3, Ar); d_C(126 MHz, CDCl₃)

21.8, 46.3, 46.7, 52.2, 54.6, 59.8, 127.5, 128.5, 128.8, 129.0,

130.2, 135.7, 136.1, 144.1 and 172.9; m/z (EI) 378 (MH^þ,

2%) and 91 (C₇H^þ₇, 100). Found MH^þ378.1367.

C₁₉H₂₄NO₅S requires 378.1375.

4.1.3.14. Methyl 2-{[N-benzyl-(p-tolylsulfonyl)-amino]-methyl}-

3-iodo-propanoate 9. Following the iodination procedure, al-

cohol 7 (3.98 g, 10.5 mmol) gave, after puriﬁcation by silica

gel column chromatography (petrol/EtOAc, gradient from

3708

H.E. Bartrum et al. / Tetrahedron 64 (2008) 3701e3712

petrol to 50% EtOAc) and recrystallisation from petrol/Et₂O,

the alkyl iodide 9 (4.35 g, 85%) as white needles. Mp 84.5e

85 ^ꢁC. R_f0.8 (petrol/EtOAc, 1:1); (Found: C, 47.0; H, 4.5;

N, 2.7; I, 26.2; S, 7.0. C₁₉H₂₂INO₄S requires C, 46.8; H,

4.6; N, 2.9; I, 26.2; S, 6.6); n_max(ﬁlm)/cm^ꢀ13030, 1737 and

1342; d_H(500 MHz, CDCl₃) 2.49 (3H, s, SO₂C₆H₄CH₃),

2.88e2.93 (1H, m, CH), 3.18 (1H, dd, J 10.1 and 6.9,

CHCH_AH_BN), 3.26 (1H, dd, J 10.1 and 4.7, CHCH_AH_BN),

3.30e3.40 (2H, m, CH₂I), 3.66 (3H, s, CO₂CH₃), 4.26 (1H,

d, J 14.7, NCH_AH_BPh), 4.40 (1H, d, J 14.7, NCH_AH_BPh),

7.29 (2H, dd, J 6.9 and 2.6, Ar) and 7.28e7.39 (7H, m, Ar);

d_C(126 MHz, CDCl₃) 2.3, 21.3, 47.0, 50.2, 51.2, 52.0,

127.1, 127.9, 128.3, 128.5, 129.6, 135.3, 135.4, 143.5

and 171.4; m/z (ES) 510 (MNa^þ, 17%) and 488 (MH^þ,

100); m/z (EI) found MH^þ488.0374. C₁₉H₂₃INO₄S requires

488.0393.

13.9 and 6.6, CHCH_AH_BAr), 2.84 (1H, dq, J 7.9 and 6.6,

CH), 3.29 (1H, dd, J 14.4 and 6.2, CHCH_AH_BN), 3.33 (1H,

dd, J 14.4 and 7.9, CHCH_AH_BN), 3.47 (3H, s, CO₂CH₃),

3.81 (3H, s, ArOCH₃), 4.21 (1H, d, J 14.9, NCH_AH_BPh),

4.42 (1H, d, J 14.9, NCH_AH_BPh), 6.75e6.80 (2H, m,

Ar), 6.83e6.87 (2H, m, Ar), 7.68 (2H, d, J 8.3, Ar) and

7.21e7.40 (7H, m, Ar); d_C(126 MHz, CDCl₃) 21.6, 35.4,

47.3, 50.2, 51.7, 53.5, 55.2, 113.8, 127.4, 127.9, 128.5,

128.6, 129.2, 129.8, 130.2, 136.1, 136.2, 143.5, 158.2 and

174.2; m/z (EI) 467 (M^þ, 13%) and 91 (C₆H₇^þ, 100). Found

M^þ467.1774. C₂₆H₂₉NO₅S requires 467.1766.

4.1.3.17. Methyl 2-{[N-benzyl-(p-tolylsulfonyl)-amino]-methyl}-

3-(p-nitrophenyl)-propanoate 11c. Following procedure A, al-

kyl iodide 9 (244 mg, 0.5 mmol) and 1-iodo-4-nitro benzene

(162 mg, 0.65 mmol) gave, after puriﬁcation by silica gel col-

umn chromatography (petrol/EtOAc, gradient from petrol to

80% EtOAc) and recrystallisation from petrol/Et₂O, the

b²-amino acid derivative 11c (145 mg, 60%) as a pale orange

solid. Mp 68.5e69 ^ꢁC. R_f0.30 (petrol/EtOAc, 1:1); (Found: C,

62.1; H, 5.4; N, 5.6; S, 6.7. C₂₅H₂₆N₂O₆S requires C, 62.2; H,

5.4; N, 5.8; S, 6.7); n_max(ﬁlm)/cm^ꢀ11735, 1519 and 1345 s;

d_H(500 MHz, CDCl₃) 2.49 (3H, s, SO₂C₆H₄CH₃), 2.74e2.82

(2H, m, CHCH_AH_BAr), 2.87e2.91, (1H, m, CHCH_AH_BAr),

3.27 (1H, dd, J 14.3 and 5.7, CHCH_AH_BN), 3.44 (1H, dd,

J 14.3 and 7.2, CHCH_AH_BN), 3.48 (3H, s, CO₂CH₃), 4.09

(1H, d, J 14.7, NCH_AH_BPh), 4.53 (1H, d, J 14.7, NCH_AH_BPh),

6.98 (2H, d, J 8.7, Ar), 7.31e7.47 (7H, m, Ar), 7.75 (2H, d, J

8.3, Ar) and 8.05 (2H, d, J 8.7, Ar); d_C(126 MHz, CDCl₃)

21.6, 35.5, 46.8, 51.0, 51.1, 54.3, 123.5, 127.4, 128.2, 128.7,

128.9, 129.6, 129.9, 135.7, 136.3, 143.9, 146.5, 146.6 and

173.2; m/z (EI) 483 (MH^þ, 4%) and 91 (C₆H₇^þ, 100). Found

MH^þ483.1594. C₂₅H₂₇N₂O₆S requires 483.1590.

4.1.3.15. Methyl 2-{[N-benzyl-(p-tolylsulfonyl)-amino]-methyl}-

3-phenyl-propanoate 11a. Following procedure A, alkyl io-

dide 9 (244 mg, 0.5 mmol) and iodobenzene (0.86 mL,

0.65 mmol) gave, after puriﬁcation by silica gel column chro-

matography (petrol/EtOAc, gradient from petrol to 50%

EtOAc) and recrystallisation from petrol/Et₂O, the b²-amino

acid derivative 11a (160 mg, 75%) as colourless blocks, which

were analysed by X-ray crystallography. Mp 112e112.5 ^ꢁC. R_f

0.5 (petrol/EtOAc, 1:1); n_max(ﬁlm)/cm^ꢀ13029, 1735 and

1340; d_H(500 MHz, CDCl₃) 2.47 (3H, s, SO₂C₆H₄CH₃),

2.69 (1H, dd, J 13.8 and 6.8, CHCH_AH_BPh), 2.75 (1H, dd,

J 13.8 and 8.6, CHCH_AH_BPh), 2.86e2.93 (1H, m, CH), 3.30

(1H, dd, J 14.4 and 6.2, CHCH_AH_BN), 3.35 (1H, dd, J 14.4

and 7.9, CHCH_AH_BN), 3.47 (3H, s, CO₂CH₃), 4.21 (1H, d,

J 14.9, NCH_AH_BPh), 4.43 (1H, d, J 14.9, NCH_AH_BPh), 6.94

(2H, d, J 6.6, Ar), 7.19e7.35 (10H, m, Ar) and 7.68 (2H, d,

J 8.3, Ar); d_C(126 MHz, CDCl₃) 21.5, 36.2, 47.0, 50.2,

51.6, 53.5, 126.4, 127.3, 127.9, 128.3, 128.5, 128.6, 128.7,

129.7, 136.0, 136.1, 138.1, 143.4 and 174.0; m/z (EI) 438

(MH^þ, 18%), 488 (M^þ, 46) and 406 (M^þꢀMeO, 100). Found

M^þ437.1658. C₂₅H₂₇NO₄S requires 437.1661.

4.1.3.18. Methyl 2-{[N-benzyl-(p-tolylsulfonyl)-amino]-methyl}-

3-(m-nitrophenyl)-propanoate 11d. Following procedure A, al-

kyl iodide 9 (244 mg, 0.5 mmol) and 1-iodo-3-nitro benzene

(162 mg, 0.65 mmol) gave, after puriﬁcation by silica gel col-

umn chromatography (petrol/EtOAc, gradient from petrol to

80% EtOAc) and recrystallisation from petrol/Et₂O, the

b²-amino acid derivative 11d (130 mg, 54%) as a pale orange

solid. Mp 114.5e116 ^ꢁC. R_f0.30 (petrol/EtOAc, 1:1); n_max

(ﬁlm)/cm^ꢀ11735, 1528 and 1351 s; d_H(500 MHz, CDCl₃)

2.49 (3H, s, SO₂C₆H₄CH₃), 2.68e2.75 (1H, m, CH), 2.80

(1H, dd, J 13.7 and 9.9, CHCH_AH_BAr), 2.90 (1H, dd, J 13.7

and 6.4, CHCH_AH_BAr), 3.28 (1H, dd, J 14.2 and 6.4,

CHCH_AH_BN), 3.45 (1H, dd, J 14.3 and 7.8, CHCH_AH_BN),

3.49 (3H, s, CO₂CH₃), 4.10 (1H, d, J 14.6, NCH_AH_BPh),

4.55 (1H, d, J 14.6, NCH_AH_BPh), 7.23 (1H, d, J 7.7, Ar),

7.35e7.42 (8H, m, Ar), 7.67e7.69 (1H, m, Ar), 7.73e7.77

(2H, m, Ar) and 8.00e8.04 (1H, m, Ar); d_C(126 MHz,

CDCl₃) 21.6, 35.3, 46.9, 50.1, 51.9, 54.3, 121.6, 122.1,

123.3, 123.5, 127.4, 128.4, 128.7, 128.9, 129.2, 129.9, 130.3,

133.1, 135.2, 135.8, 136.1, 140.6, 143.8, 148.2 and 173.2; m/z

(EI) 483 (MH^þ, 8%) and 91 (C₆H₇^þ, 100). Found MH^þ

483.1569. C₂₅H₂₇N₂O₆S requires 483.1590.

In addition, following procedure A, alkyl iodide 9 (244 mg,

0.5 mmol) and bromobenzene (68.5 mg, 0.65 mmol) gave, af-

ter puriﬁcation as previously described, the b²-amino acid de-

rivative 11a (167 mg, 76%) as pale orange needles,

spectroscopically consistent with that previously reported

herein.

4.1.3.16. Methyl 2-{[N-benzyl-(p-tolylsulfonyl)-amino]-methyl}-

3-(p-methoxyphenyl)-propanoate 11b. Following procedure A,

alkyl iodide 9 (244 mg, 0.5 mmol) and 4-iodoanisole (152 mg,

0.65 mmol) gave, after puriﬁcation by silica gel column chro-

matography (petrol/EtOAc, gradient from petrol to 50%

EtOAc) and recrystallisation from heptane/EtOAc, the

b²-amino acid derivative 11b (208 mg, 89%) as a pale grey

solid. Mp 69e70.5 ^ꢁC. R_f0.55 (petrol/EtOAc, 1:1); (Found:

C, 66.8; H, 6.1; N, 2.8; S, 6.6. C₂₆H₂₉NO₅S requires C,

66.8; H, 6.3; N, 3.0; S, 6.9); n_max(ﬁlm)/cm^ꢀ12921, 1735

and 1341; d_H(500 MHz, CDCl₃) 2.47 (3H, s, SO₂C₆H₄CH₃),

2.63 (1H, dd, J 13.9 and 6.7, CHCH_AH_BAr), 2.69 (1H, dd, J

H.E. Bartrum et al. / Tetrahedron 64 (2008) 3701e3712

3709

4.1.3.19. Methyl 2-{[N-benzyl-(p-tolylsulfonyl)-amino]-methyl}-

3-(p-hydroxyphenyl)-propanoate 11e. Following procedure A,

chromatography eluting with EtOAc to give the amine 13

(114 mg, 88% yield) as a colourless oil. R_f0.3 (EtOAc);

n_max(ﬁlm)/cm^ꢀ12949 and 1731; d_H(500 MHz, CDCl₃)

2.80e2.99 (5H, m, NCH₂CHCH₂Ph), 3.68 (3H, s, CO₂CH₃),

3.78 (1H, d, J 13.3, NCH_AH_BPh), 3.83 (1H, d, J 13.3,

NCH_AH_BPh) and 7.17e7.39 (10H, m, Ar); d_C(126 MHz,

CDCl₃) 36.3, 47.9, 50.2, 51.7, 53.7, 126.4, 126.9, 128.1,

128.4, 128.5, 128.7, 128.9, 139.0, 140.3 and 175.3; m/z (EI)

284 (MH^þ, 6%), 283 (M^þ, 12) and 91 (C₆H^þ₇, 100). Found

M^þ283.1574. C₁₈H₂₁NO₂requires 283.1572.

alkyl iodide

9 (244 mg, 0.5 mmol) and 4-iodophenol

(143 mg, 0.65 mmol) gave, after puriﬁcation by silica gel col-

umn chromatography (petrol/EtOAc, gradient from petrol to

70% EtOAc) and recrystallisation from petrol/Et₂O, the

b²-amino acid derivative 11e (141 mg, 62%) as a pale orange

solid. Mp 163.5e164 ^ꢁC. R_f0.40 (petrol/EtOAc, 1:1); (Found:

C, 65.8; H, 5.8; N, 2.7; S, 6.8. C₂₅H₂₇NO₅S requires C, 66.2;

H, 6.0; N, 3.1; S, 7.1); n_max(ﬁlm)/cm^ꢀ13416 br, 1732 and

1338; d_H(500 MHz, CDCl₃) 2.37 (3H, s, SO₂C₆H₄CH₃),

2.51 (1H, dd, J 13.9 and 6.7, CHCH_AH_BAr), 2.56 (1H, dd,

J 13.9 and 8.6, CHCH_AH_BAr), 2.69e2.78 (1H, m, CH), 3.18

(1H, dd, J 12.9 and 4.8, CHCH_AH_BN), 3.22 (1H, dd, J 12.9

and 6.3, CHCH_AH_BN), 3.36 (3H, s, CO₂CH₃), 4.10 (1H, d,

J 14.9, NCH_AH_BPh), 4.31 (1H, d, J 14.9, NCH_AH_BPh), 4.70

(s, 1H, OH), 6.56e6.63 (2H, m, Ar), 6.67e6.71 (2H, m,

Ar), 7.14e7.30 (7H, m, Ar) and 7.58 (2H, d, J 8.3, Ar); d_C

(126 MHz, CDCl₃) 21.6, 35.4, 47.3, 50.1, 51.7, 53.5, 115.2,

127.4, 127.9, 128.6, 128.7, 129.8, 129.9, 130.3, 136.1, 136.2,

143.5, 154.2 and 174.3; m/z (EI) 453 (M^þ, 2%) and 91 (100%,

C₆H^þ₇). Found M^þ453.1629. C₂₅H₂₇NO₅S requires 453.1610.

4.1.3.22. N-Benzyl-2-[(benzyl-amino)-methyl]-3-hydroxy-prop-

anamide 15. Following the procedure reported to afford the

corresponding b-lactam 14,^19,20benzylamine (0.50 mL,

4.55 mmol) was added dropwise to a stirred solution of the ac-

rylate 4 (132 mg, 1.14 mmol) in dry MeOH (0.17 mL) at room

temperature. After 30 min the reaction was heated at reﬂux for

16 h. Removal of the solvent under reduced pressure gave

a crude solid, which was washed with hexane and then recrys-

tallised (EtOAc/heptane) to give the amide 15 (149 mg, 44%)

as colourless plates, which were analysed by X-ray crystallog-

raphy. Mp 95e96.5 ^ꢁC; n_max(ﬁlm)/cm^ꢀ13273, 3061 and

1660; d_H(500 MHz, CD₃OD) 2.65e2.73 (1H, m, CH), 2.78

(1H, dd, J 12.0 and 5.2, CHCH_AH_BN), 2.88 (1H, dd, J 12.0

and 8.2, CHCH_AH_BN), 3.68 (1H, dd, J 10.7 and 6.1,

CH₂NHCH_AH_BPh), 3.72e3.78 (3H, m, CH₂NHCH_AH_BPh

and CHCH₂OH), 4.41 (1H, d, J 15.0, CONHCH_AH_BPh),

4.36 (1H, d, J 15.0, CONHCH_AH_BPh) and 7.20e7.32 (10H,

m, Ar); d_C(126 MHz, CD₃OD) 44.1, 48.4, 49.9, 54.4, 63.4,

128.2, 128.3, 128.6, 129.4, 129.5, 129.6, 139.9, 140.3 and

175.5; m/z (EI) 299 (MH^þ, 9%), 298 (M^þ, 14), 106 (BnNH^þ₂,

87) and 91 (C₆H^þ₇, 100). Found MH^þ299.1774. C₁₈H₂₃N₂O₂

requires 299.1760. The ﬁltrate was concentrated under re-

duced pressure to afford the amino alcohol 5 (76 mg, 30%)

as a pale yellow oil, spectroscopically consistent with that

previously reported herein.

4.1.3.20. Methyl 2-{[N-benzyl-(p-tolylsulfonyl)-amino]-methyl}-

3-(m-hydroxyphenyl)-propanoate 11f. Following procedure A,

alkyl iodide 9 (244 mg, 0.5 mmol) and 3-iodophenol (143 mg,

0.65 mmol) gave, after puriﬁcation by silica gel column chro-

matography (petrol/EtOAc, gradient from petrol to 70%

EtOAc), the b²-amino acid derivative 11f (142 mg, 62%) as

an orange oil. R_f0.30 (petrol/EtOAc, 1:1); n_max(ﬁlm)/cm^ꢀ1

3434 br, 2951 and 1732; d_H(500 MHz, CDCl₃) 2.35 (3H, s,

SO₂C₆H₄CH₃), 2.51 (1H, dd, J 13.8 and 6.7, CHCH_AH_BAr),

2.59 (1H, dd, J 13.9 and 8.6, CHCH_AH_BAr), 2.75e2.82 (1H,

m, CH), 3.17 (1H, dd, J 14.4 and 6.3, CHCH_AH_BN), 3.23

(1H, dd, J 14.4 and 7.8, CHCH_AH_BN), 3.37 (3H, s,

CO₂CH₃), 4.09 (1H, d, J 14.9, NCH_AH_BPh), 4.30 (1H, d,

J 14.9, NCH_AH_BPh), 5.38 (s, 1H, OH), 6.30e6.32 (1H, m,

Ar), 6.39 (1H, d, J 7.7, Ar), 6.59 (1H, ddd, J 8.1, 2.5 and

0.7, Ar), 6.98 (1H, t, J 7.8, Ar), 7.14e7.23 (7H, m, Ar) and

7.56 (2H, d, J 8.3, Ar); d_C(126 MHz, CDCl₃) 21.6, 36.0,

46.9, 50.2, 51.8, 53.6, 113.6, 115.7, 121.0, 127.4, 127.9,

128.6, 128.7, 129.6, 129.8, 136.0, 136.1, 139.9, 143.6, 155.8

and 174.3; m/z (EI) 453 (M^þ, 2%) and 91 (C₆H₇^þ, 100). Found

M^þ453.1606. C₂₅H₂₇NO₅S requires 453.1610.

4.1.3.23. 1-Benzyl-3-hydroxymethyl-azetidin-2-one 14. Fol-

lowing a procedure reported for a closely related compound,²⁸

the amino alcohol 5 (1.78 g, 8 mmol) in dry THF (5 mL) was

added dropwise to a stirred solution of tert-butyl magnesium

chloride (24 mL, 24 mmol, 1 M solution in THF) under nitro-

gen. After 3 h the reaction was quenched with saturated aque-

ous NH₄Cl solution, extracted with EtOAc (3ꢂ30 mL) and the

combined organic fractions were washed with brine

(2ꢂ20 mL), dried (Na₂SO₄) and concentrated under reduced

pressure. Puriﬁcation by silica gel column chromatography

(CH₂Cl₂/MeOH, gradient from CH₂Cl₂to 2.5% MeOH)

gave the hydroxymethyl b-lactam 14 (1.02 g, 67% yield) as

a pale yellow oil. R_f0.2 (2.5% MeOH/CH₂Cl₂); n_max(ﬁlm)/

cm^ꢀ13403, 2922 and 1729; d_H(500 MHz, CDCl₃) 3.10 (1H,

dd, J 5.5 and 2.5, CHCH_AH_BN), 3.15 (1H, app t, J 5.4,

CHCH_AH_BN), 3.30 (1H, app qd, J 4.9 and 2.5, CH), 3.75

(1H, dd, J 11.7 and 4.4, CH_AH_BOH), 3.90 (1H, dd, J 11.7

and 4.9, CH_AH_BOH), 4.29 (1H, d, J 15.1, NCH_AH_BPh), 4.33

(1H, d, J 15.1, NCH_AH_BPh) and 7.13e7.29 (5H, m, Ar); d_C

(126 MHz, CDCl₃) 42.0, 45.9, 52.1, 59.3, 127.7, 128.1,

4.1.3.21. Methyl 2-[(N-benzyl-amino)-methyl]-3-phenyl-propa-

noate 13. Using conditions originally reported for the cleav-

age of sulfonyl aziridines²⁶and piperidines,²⁷magnesium

turnings (0.57 g, 22.9 mmol) were added to a stirred suspen-

sion of the sulfonyl-protected b²-amino acid 11a (200 mg,

0.46 mmol) in MeOH (10 mL) at room temperature. The reac-

tion proceeded with a noticeable exotherm. After 1 h, the reac-

tion was quenched (30 mL HCl, 2 M), basiﬁed (aqueous

K₂CO₃) to pH 9 and extracted with EtOAc (3ꢂ30 mL). The

combined organic fractions were washed (2ꢂ20 mL brine),

dried (MgSO₄) and evaporated under reduced pressure and

the crude product puriﬁed by silica gel column

3710

H.E. Bartrum et al. / Tetrahedron 64 (2008) 3701e3712

128.5, 128.6, 128.8, 135.4 and 168.9; m/z (ES) 214 (MNa^þ,

60%) and 192 (MH^þ, 55). Found MH^þ192.1028.

C₁₁H₁₄NO₂requires 192.1025. Spectroscopic data is not con-

sistent with that previously reported.²⁰

(25 mg, 0.16 mmol) was added. Stirring was continued for

a further 24 h before the reaction mixture was diluted with

water (10 mL), extracted with EtOAc (3ꢂ15 mL) and the

combined organic fractions washed with aqueous sodium thio-

sulfate solution (2ꢂ10 mL, 1 M) and brine, dried (MgSO₄)

and concentrated under reduced pressure. Puriﬁcation by silica

gel column chromatography (petrol/EtOAc, gradient from

petrol to 50% EtOAc) gave the alkyl iodide 17 (44 mg,

89%) as a colourless oil, spectroscopically consistent with

that previously reported herein.

4.1.3.24. 1-Benzyl-3-[(p-toluenesulfonyloxy)-methyl]-azetidin-

2-one 16. Using the procedure previously described for tosy-

lation of protected serine,³⁷DMAP (3.8 mg, 0.03 mmol),

Me₃NHCl (6.0 mg, 0.06 mmol) and p-toluenesulfonic acid

(120 mg, 0.63 mmol) were added to a stirred solution of the

hydroxymethyl b-lactam 14 (120 mg, 0.63 mmol) in CH₂Cl₂

(1.1 mL) at 0 ^ꢁC. Triethylamine (88 mL, 0.63 mmol) in

CH₂Cl₂(0.27 mL) was added dropwise to the reaction mixture

and the resulting slurry stirred for 2 h at 0 ^ꢁC. The reaction

mixture was diluted with water (20 mL), extracted with

CH₂Cl₂(3ꢂ15 mL) and the combined organic fractions

washed with brine (2ꢂ10 mL), dried (Na₂SO₄) and evaporated

under reduced pressure. Puriﬁcation by silica gel column chro-

matography (petrol/EtOAc, gradient from petrol to 80%

EtOAc) followed by recrystallisation from EtOAc/heptane

gave the tosylate 16 (159 mg, 73%) as colourless blocks,

which were analysed by X-ray crystallography. Mp 101e

102.5 ^ꢁC. R_f0.4 (EtOAc); (Found: C, 62.9; H, 5.4; N, 3.9; S,

9.0. C₁₈H₁₉NO₄S requires C, 62.6; H, 5.5; N, 4.1; S, 9.3);

n_max(ﬁlm)/cm^ꢀ12923, 1749, 1176 and 1360 s; d_H

(500 MHz, CDCl₃) 2.38 (3H, s, SO₂C₆H₄CH₃), 3.05 (1H,

dd, J 5.9 and 2.5, CHCH_AH_BN), 3.12e3.27 (1H, m,

CHCH_AH_BN), 3.35e3.46 (1H, m, CH), 4.16 (1H, dd, J 10.6

and 6.8, CH_AH_BOTs), 4.20e4.29 (2H, m, CH_AH_BOTs and

NCH_AH_BPh), 4.36 (1H, d, J 15.1, NCH_AH_BPh), 7.08e7.34

(7H, m, Ar) and 8.34 (2H, d, J 8.3, Ar); d_C(126 MHz,

CDCl₃) 21.7, 42.5, 46.1, 49.1, 66.6, 127.9, 128.0, 128.1,

128.9, 129.9, 132.4, 134.9, 145.2 and 165.3; m/z (ES) 368

(MNa^þ, 28%) and 346 (MH^þ, 100). Found MH^þ346.1112.

C₁₈H₂₀NO₄S requires 346.1113.

4.1.3.26. 1,3-Dibenzyl-azetidin-2-one 18a. Following proce-

dure A, alkyl iodide 17 (151 mg, 0.5 mmol) and iodobenzene

(0.86 mL, 0.65 mmol) gave, after puriﬁcation by silica gel col-

umn chromatography (petrol/EtOAc, gradient from petrol to

80% EtOAc) and recrystallisation from heptane/EtOAc, the

b²-amino acid derivative 18a (90 mg, 72%) as pale orange

needles. Mp 49.5e51 ^ꢁC. R_f0.2 (50% EtOAc/petrol); (Found:

C, 81.1; H, 6.9; N, 5.6. C₁₇H₁₇NO requires C, 81.2; H, 6.8; N,

5.6); n_max(ﬁlm)/cm^ꢀ13029 and 1746; d_H(500 MHz, CDCl₃)

2.79 (1H, dd, J 5.7 and 2.4, CHCH_AH_BN), 2.86 (1H, dd, J 14.4

and 8.4, CHCH_AH_BPh), 3.00 (1H, dd, J 14.4 and 4.9,

CHCH_AH_BPh), 3.07 (1H, t, J 5.4, CHCH_AH_BN), 3.38e3.43

(1H, m, CH), 4.10 (1H, d, J 15.2, NCH_AH_BPh), 4.34 (1H, d,

J 15.2, NCH_AH_BPh), 6.91 (2H, dd, J 7.6 and 1.7, Ar) and

7.09e7.21 (8H, m, Ar); d_C(126 MHz, CDCl₃) 34.2, 43.9,

45.7, 50.7, 126.6, 127.6, 127.9, 128.6, 128.8, 129.0, 135.5,

138.1 and 169.7; m/z (ES) 274 (MNa^þ, 6%) and 252 (MH^þ,

100). Found MH^þ252.1392. C₁₇H₁₈NO requires 252.1388.

Following procedure A, alkyl iodide 17 (217 mg, 0.5 mmol)

and bromobenzene (68.5 mg, 0.65 mmol) gave, after puri-

ﬁcation as previously described, the b-lactam 18a (86 mg,

68%) as pale orange needles, spectroscopically consistent

with that previously reported herein.

4.1.3.27. 1-Benzyl-3-(p-methoxybenzyl)-azetidin-2-one 18b.

Following procedure A, alkyl iodide 17 (151 mg, 0.5 mmol)

and 4-iodoanisole (152 mg, 0.65 mmol) gave, after puriﬁca-

tion by silica gel column chromatography (petrol/EtOAc, gra-

dient from petrol to 80% EtOAc), the b²-amino acid derivative

18b (90 mg, 65% yield) as a pale orange oil. R_f0.4 (50%

EtOAc/petrol); n_max(ﬁlm)/cm^ꢀ12910 and 1745; d_H

(500 MHz, CDCl₃) 2.86 (1H, dd, J 5.6 and 2.4, CHCH_AH_BN),

2.92 (1H, dd, J 14.5 and 7.8, CHCH_AH_BAr), 2.99 (1H, dd,

J 14.5 and 5.0, CHCH_AH_BAr), 3.15 (1H, t, J 5.4, CHCH_AH_BN),

3.46 (1H, dtd, J 7.5, 5.0 and 2.4, CH), 3.79 (3H, s, ArOCH₃),

4.14 (1H, d, J 15.2, NCH_AH_BPh), 4.45 (1H, d, J 15.2,

NCH_AH_BPh), 6.73e6.88 (2H, m, Ar), 6.93e7.02 (2H, m,

Ar), 7.06e7.16 (2H, m, Ar) and 7.22e7.26 (3H, m, Ar); d_C

(126 MHz, CDCl₃) 33.2, 43.7, 45.7, 50.9, 55.3, 113.9, 127.5,

127.9, 128.7, 129.8, 130.2, 135.4, 158.4 and 169.8; m/z (ES)

282 (MH^þ, 100%). Found MH^þ282.1502. C₁₈H₂₀NO₂

requires 282.1494.

4.1.3.25. 1-Benzyl-3-iodomethyl-azetidin-2-one 17. Following

the iodination procedure, hydroxymethyl b-lactam 14

(2.01 g, 10.5 mmol) gave, after puriﬁcation by silica gel col-

umn chromatography (petrol/EtOAc, gradient from petrol to

80% EtOAc), the alkyl iodide 17 (2.40 g, 76%) as a colourless

oil. R_f0.3 (petrol/EtOAc, 1:1); n_max(ﬁlm)/cm^ꢀ12922 and

1748; d_H(500 MHz, CDCl₃) 2.97 (1H, dd, J 2.2 and 5.9,

CHCH_AH_BN), 3.30e3.34 (1H, m, CHCH_AH_BN), 3.35 (1H,

dd, J 10.1 and 1.5, CH_AH_BI), 3.51 (1H, dd, J 10.1 and 3.1,

CH_AH_BI), 3.52e3.55 (1H, m, CH), 4.39 (1H, d, J 14.9,

NCH_AH_BPh), 4.45 (1H, d, J 14.9, NCH_AH_BPh) and 7.27e

7.41 (5H, m, Ar); d_C(126 MHz, CDCl₃) 0.0, 44.9, 45.5, 50.8,

126.7, 127.2, 127.7, 133.9 and 165.5; m/z (ES) 324 (MNa^þ,

27%) and 302 (MH^þ, 100); m/z (EI) Found MH^þ302.0031.

C₁₁H₁₃INO requires 302.0042.

The alkyl iodide 17 was also prepared using a procedure

previously described for a tosylated serine derivative.³⁷So-

dium iodide (50 mg, 0.33 mmol) was added to a stirred solu-

tion of the tosylate 16 (57 mg, 0.165 mmol) in acetone

(2 mL) at room temperature and was stirred in the dark for

24 h, after which time another equivalent of sodium iodide

4.1.3.28. 1-Benzyl-3-(p-nitrobenzyl)-azetidin-2-one 18c. Fol-

lowing procedure A, alkyl iodide 17 (151 mg, 0.5 mmol) and

1-iodo-4-nitro benzene (162 mg, 0.65 mmol) gave, after

H.E. Bartrum et al. / Tetrahedron 64 (2008) 3701e3712

3711

puriﬁcation by silica gel column chromatography (petrol/

EtOAc, gradient from petrol to 100% EtOAc), the b-lactam

18c (65 mg, 44%) as a pale orange oil. R_f0.30 (petrol/EtOAc,

1:1); n_max(ﬁlm)/cm^ꢀ12898, 1746, 1518 and 1346 s; d_H

(500 MHz, CDCl₃) 2.76 (1H, dd, J 5.8 and 2.4, CHCH_AH_BN),

3.01 (1H, dd, J 14.5 and 7.4, CHCH_AH_BAr), 3.07 (1H, dd,

J 14.5 and 5.8, CHCH_AH_BAr), 3.17 (1H, app t, J 5.5,

CHCH_AH_BN), 3.41e3.51 (1H, m, CH), 4.09 (1H, d, J 15.0,

NCH_AH_BPh), 4.35 (1H, d, J 15.0, NCH_AH_BPh), 6.94e6.97

(2H, m, Ar), 7.16e7.20 (3H, m, Ar), 7.28e7.31 (2H, m, Ar)

and 8.02e8.05 (2H, m, Ar); d_C(126 MHz, CDCl₃) 33.9, 43.5,

45.8, 49.7, 123.6, 127.7, 127.9, 128.7, 129.9, 135.1, 145.5,

146.8 and 168.6; m/z (ES) 319 (MNa^þ, 4%) and 297 (MH^þ,

100). Found MH^þ297.1232. C₁₇H₁₇N₂O₃requires 297.1239.

from petrol to 100% EtOAc) and recrystallisation from hep-

tane/EtOAc, the b²-amino acid derivative 18f (70 mg, 52%)

as pale orange needles. Mp 145.5e147.0 ^ꢁC. R_f0.20 (40%

EtOAc/petrol); n_max(ﬁlm)/cm^ꢀ13289 br and 1722; d_H

(500 MHz, CDCl₃) 2.81e2.86 (2H, m, CHCH_AH_BN,

CHCH_AH_BAr), 2.91 (1H, dd, J 14.4 and 5.1, CHCH_AH_BAr),

3.09 (1H, t, J 5.4, CHCH_AH_BN), 3.22e3.59 (1H, m, CH), 4.09

(1H, d, J 15.2, NCH_AH_BPh), 4.36 (1H, d, J 15.2, NCH_AH_BPh),

6.59 (1H, d, J 7.6, Ar), 6.65e6.76 (2H, m, Ar), 6.88e6.95

(3H, m, Ar), 7.04 (1H, t, J 7.8, Ar) and 7.15e7.20 (2H, m,

Ar); d_C(126 MHz, CDCl₃) 33.8, 43.9, 45.9, 50.3, 113.9,

116.1, 121.0, 127.6, 127.9, 128.8, 129.7, 135.1, 139.3, 156.5

and 170.4; m/z (ES) 290 (MNa^þ, 78%) and 268 (MH^þ,

100). Found MH^þ268.1346. C₁₇H₁₈NO₂requires 268.1338.

4.1.3.29. 1-Benzyl-3-(m-nitrobenzyl)-azetidin-2-one 18d. Fol-

lowing procedure A, alkyl iodide 17 (151 mg, 0.5 mmol) and

1-iodo-3-nitro benzene (162 mg, 0.65 mmol) gave, after puri-

ﬁcation by silica gel column chromatography (petrol/EtOAc,

gradient from petrol to 100% EtOAc), the b-lactam 18d

(70 mg, 47%) as a pale orange oil. R_f0.35 (50% EtOAc/pet-

rol); n_max(ﬁlm)/cm^ꢀ12918, 1743, 1527 and 1351 s; d_H

(500 MHz, CDCl₃) 2.80 (1H, dd, J 5.8 and 2.4, CHCH_AH_BN),

3.01 (1H, dd, J 14.6 and 7.8, CHCH_AH_BAr), 3.10 (1H, dd, J

14.6 and 5.6, CHCH_AH_BAr), 3.15e3.23 (1H, m,

CHCH_AH_BN), 3.40e3.55 (1H, m, CH), 4.13 (1H, d, J 15.0,

NCH_AH_BPh), 4.35 (1H, d, J 15.0, NCH_AH_BPh), 6.96e6.98

(2H, m, Ar), 7.18e7.21 (3H, m, Ar), 7.37e7.41 (1H, m,

Ar), 7.52e7.54 (1H, m, Ar) and 8.00e8.03 (2H, m, Ar); d_C

(126 MHz, CDCl₃) 34.3, 44.1, 46.3, 50.4, 122.3, 124.2,

128.2, 128.4, 129.2, 129.9, 135.6, 135.9, 140.4, 148.7 and

169.1; m/z (ES) 297 (MH^þ, 100%). Found MH^þ297.1248.

C₁₇H₁₇N₂O₃requires 297.1239.

5. X-ray crystallography

Crystallographic data were collected and measured on

a Bruker Smart CCD area detector with an Oxford Cryosys-

tems low temperature system at T¼150(2) K.

Crystal data for 11a: C₂₅H₂₇NO₄S, M¼437.54, monoclinic,

˚

a¼17.1018(14),

b¼5.8145(4),

c¼22.6997(17) A,

b¼

3

ꢁ

˚

98.521(5) , U¼2232.3(3) A , space group Cc, Z¼4, m(Mo

Ka)¼0.177 mm^ꢀ1, 19,770 reﬂections collected, 4960 indepen-

dent (R¼0.0443). Final R indices [I>2s(I)] R¼0.0384,

wR₂¼0.0777. R indices (all data) R¼0.0458, wR₂¼0.0815.

Absolute structure parameter ꢀ0.01(6).

Crystal data for 15: C₁₈H₂₂N₂O₂, M¼298.38, monoclinic,

ꢁ

˚

a¼15.2861(19), b¼5.6781(7), c¼18.199(6) A, b¼98.893(8) ,

3

˚

U¼1560.6(3) A , space group P2₁/c, Z¼4, m(Mo Ka)¼

0.083 mm^ꢀ1, 9664 reﬂections collected, 2668 independent

(R¼0.0914). Final

R

indices [I>2s(I)] R¼0.0675,

wR₂¼0.1639. R indices (all data) R¼0.0954, wR₂¼0.1862.

Crystal data for 16: C₁₈H₁₉NO₄S, M¼345.40, monoclinic,

ꢁ

˚

4.1.3.30. 1-Benzyl-3-(p-hydroxybenzyl)-azetidin-2-one 18e.

Following procedure A, alkyl iodide 17 (151 mg, 0.5 mmol)

and 4-iodophenol (143 mg, 0.65 mmol) gave, after puriﬁcation

by silica gel column chromatography (petrol/EtOAc, gradient

from petrol to 100% EtOAc) and recrystallisation from pen-

tane/EtOAc, the b²-amino acid derivative 18e (75 mg, 56%)

as a pale orange solid. Mp 170e171.5 ^ꢁC. R_f0.15 (40%

EtOAc/petrol); n_max(ﬁlm)/cm^ꢀ13262 br, 2922 and 1722; d_H

(500 MHz, CD₃OD) 2.86 (1H, dd, J 14.4 and 5.1, CHCH_A-

H_BAr), 2.89e2.94 (2H, m, CHCH_AH_BAr, CHCH_AH_BN),

3.21 (1H, t, J 5.4, CHCH_AH_BN), 3.39e3.64 (1H, m, CH),

4.09 (1H, d, J 15.3, NCH_AH_BPh), 4.46 (1H, d, J 15.2,

NCH_AH_BPh), 6.69e6.71 (2H, m, Ar), 6.88e6.90 (2H, m,

Ar), 7.08e7.10 (2H, m, Ar) and 7.15e7.20 (3H, m, Ar); d_C

(126 MHz, CD₃OD) 33.6, 44.3, 46.4, 51.6, 116.3, 128.4,

128.7, 129.3, 129.7, 131.6, 136.7, 157.4 and 172.6; m/z (EI)

268 (MH^þ, 5%) and 267 (M^þ, 27). Found M^þ267.1262.

C₁₇H₁₇NO₂requires 267.1259.

a¼18.9157(14), b¼7.7269(6), c¼11.4895(9) A, b¼97.736(8) ,

3

˚

U¼1664.0(2) A , space group P2₁/c, Z¼4, m(Mo Ka)¼

0.216 mm^ꢀ1, 21,270 reﬂections collected, 3887 independent

(R¼0.0651). Final R indices [I>2s(I)] R¼0.0410, wR₂¼

0.0806. R indices (all data) R¼0.0737, wR₂¼0.0988.

Crystallographic data (excluding structure factors) for the

structures in this paper have been deposited with the Cam-

bridge Crystallographic Data Centre as supplementary publi-

cation nos. CCDC 669758e669760, respectively. Copies of

the data can be obtained, free of charge, on application to

CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax:

þ44 (0)1223 336033 or e-mail: deposit@ccdc.cam.ac.uk).

Acknowledgements

We thank the University of Shefﬁeld for the award of an

EPSRC DTA studentship to H.E.B.

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Article Doi

Synthesis of β2-homophenylalanine derivatives by Negishi cross-coupling reactions

DOI: 10.1016/j.tet.2008.02.024

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