Cyclic hydroxamates, especially multiply substituted [1,2]oxazinan-3-ones

937

Cyclic hydroxamates, especially multiply

substituted [1,2]oxazinan-3-ones

Saul Wolfe, Marie-Claire Wilson, Ming-Huei Cheng, Gennady V. Shustov, and

Christiana I. Akuche

Abstract: Routes to putative N-acyl-D-ala-D-ala surrogates, beginning with the conversion of 4-, 5-, and 6-membered lac-

tones into 5-, 6-, and 7-membered cyclic hydroxamates, are reported. The key step of the synthesis is trimethylaluminium-

promoted cyclization of an ω-aminooxyester. The 7-membered cyclic hydroxamate crystallizes in a chair conformation.

Extension of the reaction sequence to homoserine or homoserine lactone leads to cyclocanaline and N-acylated cyclo-

canalines. The 4-phenylacetamido derivative of cyclocanaline crystallizes in a boat conformation. The attachment of a

2-carboxypropyl substituent to the ring nitrogen of a 4-acylaminocyclocanaline has been effected, prior to cyclization,

by coupling of the acyclic aminooxyester precursor to the triflate of benzyl lactate or, after cyclization, by coupling to

tert-butyl α-bromopropionate in the presence of potassium fluoride – alumina, followed by removal of the protecting

group in each case. A six-membered homolog of the antibiotic lactivicin has been synthesized by the reaction of 4-

phenylacetamidocyclocanaline with benzyl 2-oxoglutarate in the presence of carbodiimide, followed by hydrogenolysis.

Starting with methyl 2,4-dibromo-2,4-dideoxy-^L-erythronate, which is available in two steps from L-ascorbic acid, these

reaction sequences have been applied to the stereospecific synthesis of a ^D-alanine derivative whose nitrogen atom is

enclosed within a 3,4-disubstituted [1,2]oxazinan-3-one.

Key words: ^D-ala-D-ala surrogate, cyclocanaline, homolactivicin, peptidoglycan, trimethylaluminium.

Résumé : On a développé des nouvelles voies permettant de préparer des produits de substitutions potentiels de la N-

acyl-^D-ala-D-ala; elles débutent par la conversion des lactones à 4-, 5- et 6-chaînons en hydroxamates cycliques à 5-, 6-

et 7-chaînons. L’étape clé de la synthèse est une cyclisation catalysée par le triméthylaluminium d’un ω-aminooxyester.

L’hydroxamate cyclique à sept chaînons cristallise dans une conformation chaise. L’extension de la séquence de réac-

tion à l’homosérine ou à la lactone de l’homosérine conduit à la formation de la cyclocanaline et à des cyclocanalines

N-acétylées. Le dérivé 4-phénylacétamido de la cyclocanaline cristallise dans la conformation bateau. On a effectué la

fixation d’un substituant 2-carboxycyclopropyle sur l’azote du cycle d’une 4-acylaminocyclocanaline avant la cyclisa-

tion, par le couplage du précurseur aminooxyester acyclique au triflate du lactate de benzyle, ou après la cyclisation,

par couplage à l’α-bromopropionate de t-butyle en présence de fluorure de potassium et d’alumine, suivi dans chaque

cas de l’enlèvement du groupe protecteur. On a réalisé la synthèse d’un homologue à six chaînons de l’antibiotique

lactivicine par réaction de la 4-phénylacétamidocyclocanaline avec du 2-oxoglutarate de benzyle en présence de carbo-

diimide, suivie d’une hydrogénolyse. Utilisant comme produit de départ le 2,4-dibromo-2,4-didésoxy-^L-érythronate de

méthyle qui est disponible en deux étapes à partir de l’acide ^L-ascorbique, on a applique cette séquence de réactions à

la synthèse stéréospécifique d’un dérivé ^D-alanine dont l’atome d’azote est inclus dans une [1,2]oxazinan-3-one disubs-

tituée dans les positions 3 et 4.

Mots clés : substitut de ^D-ala-D-ala, cyclocanaline, homolactivicine, peptidoglycane, triméthylaluminium.

[Traduit par la Rédaction] Wolfe et al. 960

Introduction

C4 of 1 and the attachment of a 2-carboxypropyl substituent

onto the ring nitrogen of the resulting cyclocanaline deriva-

tive 4 (3) would lead to 5, a novel but conformationally flexi-

ble surrogate of 3.

There is precedent for the proposal of 5 as a synthetic tar-

get in the structure of the natural product lactivicin (6),

which exhibits affinity to penicillin-recognizing enzymes

(4), and in the claim that homolactivicins (7) have antibacte-

rial activity (5). However, as a caveat, it was known at the

We have recently given theoretical and experimental rea-

sons for our belief that the six-membered cyclic hydroxamate

1 can function as a β-lactam surrogate (1). Since penicillin

(2), the quintessential β-lactam compound, is itself a

conformationally constrained surrogate of N-acyl-^D-ala-D-ala

(3) (the peptide terminus of the growing bacterial cell wall

peptidoglycan (2)), the introduction of an acylamino group at

Received 19 November 2002. Published on the NRC Research Press Web site at http://canjchem.nrc.ca on 15 August 2003.

S. Wolfe,¹M.-C. Wilson, M.-H. Cheng, G.V. Shustov, and C.I. Akuche. Department of Chemistry, Simon Fraser University,

Burnaby, BC V5A 1S6, Canada.

¹Corresponding author (e-mail: swolfe@sfu.ca).

Can. J. Chem. 81: 937–960 (2003)

doi: 10.1139/V03-122

938

Can. J. Chem. Vol. 81, 2003

Results and discussion

Although earlier workers (7) had found cyclization of

unsubstituted γ-halohydroxamic acids (11, R = H, X = halo-

gen) to lead mainly to the 5-membered 1-hydroxypyrrolidin-

2-one (12) and not to the 6-membered 1, we observed that

only the 6-membered ring is produced in the cyclization of

13, R = H or Me (1). However, in the latter case (R = Me),

the N-acylated product 13, formed by coupling of the tert-

butyl ester of N-hydroxyalanine to 14, was accompanied by

the O-acylated product.

beginning of the present work that cycloserine derivatives

such as 8 are inactive (6).

To avoid this problem in the general case Z ≠ H, we ex-

amined the sequence 15 → 16 → 17, in which ring closure

proceeds by N2—C3 bond formation. Previous workers had

reported (8) that this strategy produces cyclocanaline in 35%

yield by the action of ethanolic KOH on canaline ethyl ester

and N-benzoyl cyclocanaline in 75% yield upon treatment of

N-benzoyl canaline ethyl ester with methanolic NaOH. We

have now found trimethylaluminium (9) cyclization of

aminooxy esters to be a general reaction for the production

of cyclic hydroxamates of increasing complexity. The work

proceeded in five stages.

In this paper we describe a reaction sequence leading

from lactone precursors to cyclic hydroxamates and the ap-

plication of this sequence to the synthesis of biologically in-

active ^D-cyclocanaline, to non-stereospecific syntheses of

biologically inactive 5 and 7, and to a stereospecific ap-

proach to the more general structure 9.

Crystal structures of the parent 7-membered cyclic

hydroxamate [1,2]oxazepan-3-one and phenylacetylcyclo-

canaline 10 are also reported.

5-, 6-, 7-, And 8-membered cyclic hydroxamates from

4-, 5-, 6-, and 7-membered lactone precursors

In the first stage, with γ-butyrolactone as the prototype

Wolfe et al.

939

Scheme 1. Reagents and conditions: (i) 45% HBr–HOAc, 75 °C; (ii) MeOH; (iii) FtOH, Et₃N, MeCN, reflux; (iv) MeNHNH₂, CH₂Cl₂;

(v) AlMe₃, THF.

(Scheme 1), a four-step synthesis of the parent 5-, 6-, 7-, and

8-membered cyclic hydroxamates from 4-, 5-, 6-, and 7-

membered lactones was developed, consisting of conversion

to ω-bromo methyl esters, displacement of bromine with

N-hydroxyphthalimide, removal of the phthalimido (Ft) pro-

tecting group with methylhydrazine, and cyclization.

2 equiv in tetrahydrofuran or toluene and at room tempera-

ture or reflux temperature, the yield of 21 was 65–79%.

Following these exploratory experiments, the 5-, 7-, and

8-membered cyclic hydroxamates were prepared, as summa-

rized in Table 1. The EI mass spectra all showed, in addition

to the molecular ion, the peak at [M – 32]. In the case of the

8-membered ring, [1,2]oxazocan-3-one, after numerous un-

successful experiments, cyclization of the aminooxy ester

was performed by dropwise treatment of 4 equiv of a

0.18 mol/L solution of trimethylaluminium in heptane

(4.96 mL) and toluene (50 mL) with 50 mL of a 0.4% solu-

tion of the ester in toluene, followed by stirring at room tem-

perature for six days. After addition of water and

concentration to near dryness, the gelatinous residue was dis-

solved in 1:4 dichloromethane:tetrahydrofuran, filtered

through Celite, and evaporated. Preparative layer chromatog-

raphy yielded three bands, one of which contained 84 mg of

material. The GC of this material contained several peaks, one

of which, comprising 2% of the total, gave an EI-MS with

peaks at m/z 129, corresponding to the molecular ion, and 97,

corresponding to loss of H₂NO. In Yamamoto’s trimethyl-

aluminium-promoted lactam synthesis (14), the 8-membered

ring was obtained in 7% yield, which was increased to 43%

using triethylgallium.

The 7-membered ring [1,2]oxazepan-3-one crystallized as

colourless plates, mp 84.5–85.8 °C, and its crystal structure

was determined. The compound crystallizes in the P2₁/a

space group and is centrosymmetric with four molecules,

consisting of two hydrogen-bonded dimers, in the unit cell.

Figure 1 shows several views of the crystal structure. As

seen in the centre of this figure, the dimer is held together

by linear NH···O=C hydrogen bonds; this causes the two

monomeric units to be offset with respect to each other, un-

like the structure drawn at the bottom. The monomeric struc-

ture is a chair.

Heating of butyrolactone at 75 °C with a 45% solution of

hydrogen bromide in acetic acid, followed by addition of

methanol, gave methyl γ-bromobutyrate (18) in 86% yield

(10). A protected aminooxy group was introduced by dis-

placement of bromine with N-hydroxysuccinimide (11) or N-

hydroxyphthalimide (12). Both products were crystalline,

with mp 69–71.5 and 79–81 °C, respectively, but the yield of

methyl γ-phthalimidooxybutyrate (20) was 78%, and the

yield of methyl γ-succinimidooxybutyrate could not be in-

creased above 28%. Removal of the succinimido protecting

group required a 12 h treatment with 4 equiv of hydrazine

hydrate in methanol at room temperature to give 20 in 45%

yield (12). In contrast, 19 gave a quantitative yield of 20

with 1.5 equiv of methylhydrazine in dichloromethane for

1.5 h at –10 to 0 °C (13). The methyl ester was stable to

these conditions. The cyclization of 20 was achieved initially

using the basic conditions reported by Khomutov et al. (8).

Refluxing with potassium hydroxide in methanol for 2 h,

followed by stirring at room temperature overnight, pro-

duced 21 in 24% yield. The ¹H NMR spectrum showed

peaks at 8.89 (1H, br s, NH), 4.03 (2H, t, 6.5 Hz, CH₂O),

2.52 (2H, t, 7.2 Hz, COCH₂), and 2.10 (2H, quintet, 6.9 Hz,

COCH₂CH₂) ppm. The ¹³C NMR spectrum showed peaks at

172.93, 69.04, 27.42, and 21.55 ppm. Infrared absorptions at

3403 and 1667 cm^–1were assigned to the N-H and carbonyl

groups. The CI mass spectrum showed an [M + 1] peak at

m/z 102. The EI mass spectrum showed, in addition to the

molecular ion, a peak at [M – 32], corresponding to loss of

H₂NO (22). Trimethylaluminium gave better results. With

940

Can. J. Chem. Vol. 81, 2003

Table 1. Conversion of lactones into cyclic hydroxamates.

n

Yield (%)

1

2

3

4

56

86

87

95

21^a

78

74

99

50

45

79

82^b

trace^c

quantitative

97

98

^aThis reaction was found to proceed via methyl acrylate. The compound was therefore prepared more conve-

niently by addition of N-hydroxyphthalimide to methyl acrylate in refluxing methanol containing triethylamine.

^bThe 7-membered ring ([1,2]oxazepan-3-one) crystallized as colourless plates; mp 84.5–85.8 °C, and its X-

ray structure was determined.

^cSee text.

Scheme 2.

formation with O1 and C4 at the apices and an equatorial

acylamino substituent.

Cyclocanaline and N-acylcyclocanalines

In the second stage, with trimethylaluminium-promoted

cyclization of an ω-aminooxyester established as a viable re-

action, syntheses of cyclocanaline and N-acylated cyclocana-

lines from homoserine (23) or homoserine lactone (24) were

undertaken, as shown in Scheme 2, via 26, the mesylate of

the N-acylated methyl ester 25. The conversion of 26 to 27

proceeded in 64% yield with R₁= tert-butoxy, using N-

hydroxyphthalimide and DBU in dimethylformamide, and in

84% yield with R₁= benzyl, using N-hydroxyphthalimide

and triethylamine in acetonitrile. In both cases the removal

of the phthalimido group and the subsequent cyclization of

28 to 29 proceeded without incident. Deprotection of 29,

R₁= t-BuO, to the trifluoroacetic acid salt of cyclocanaline

took place in 98% yield, and this salt was converted to 29,

R₁= PhOCH₂.

The phenylacetyl derivative 10 crystallized as colourless

plates, mp 164–165 °C, of acceptable quality for an X-ray

structure determination. The compound crystallizes in the

P2₁/a space group and is centrosymmetric with four mole-

cules (two enantiomeric pairs) in the unit cell. Figure 2

shows one of these pairs. The oxazinone ring has a boat con-

The reaction sequences just described were carried out

from racemic homoserine, from commercially available S-

homoserine lactone, and from R-methionine, which is readily

converted to R-homoserine lactone (15). ^D-Cyclocanaline was

inactive at a concentration of 125 µg/mL against a panel of

gram-positive, gram-negative, and β-lactam-producing organ-

isms.

N2-alkylation of cyclic hydroxamates

In the third stage we examined the attachment of a

substituent to the ring nitrogen of a cyclic hydroxamate. The

initial experiments were performed under Mitsunobu condi-

tions (16), using tert-butoxycarbonyl-protected R-cycloserine

(30) and ethyl S-lactate (31). With tetrahydrofuran as the sol-

vent, these experiments yielded a mixture of two products

1

whose H NMR spectra featured methyl doublets at 1.53 and

1.58 ppm and methine quartets at 4.80 and 4.96 ppm. The CI

mass spectrum showed an [M + 1] peak at m/z 303 and a

prominent peak at 247 corresponding to loss of C₄H₈. The

mixture is assigned structure 32, formed by nonstereospecific

Wolfe et al.

941

Fig. 1. Crystal structure of [1,2]oxazepan-3-one.

attachment of the carboxypropyl chain to the ring nitrogen.

Loss of stereochemical integrity has been seen previously

(17) in Mitsunobu reactions of α-hydroxyesters.

Following these experiments with the five-membered cy-

clic hydroxamate, the Mitsunobu coupling of 21 with ethyl

S-lactate was examined. In this case, because of the insolu-

bility of the oxazinone in tetrahydrofuran, dichloromethane

was employed as the solvent (18) to yield two isomeric ad-

ducts. The major adduct, isolated in 51% yield, is assigned

the N-alkylated structure 33 on the basis of an [M + 1] peak

at 202 in the CI-MS and the presence of a methine quartet at

1

5.03 ppm in the H NMR spectrum. The minor adduct, iso-

lated in 7% yield, is assigned the O-alkylated structure 34 on

the basis of a downfield shift of the methine quartet to

942

Can. J. Chem. Vol. 81, 2003

Scheme 3.

5.20 ppm. O-Alkylation is a known reaction of N-acylated

hydroxylamines (19).

negative, and β-lactam-producing organisms, are shown in

Figs. 3 and 4.

The loss of stereochemical integrity in the attachment of

the carboxypropyl moiety to the ring nitrogen in the case of

tert-butoxycarbonyl R-cycloserine and the competing O-

alkylation in the reaction of the oxazinone suggested that the

introduction of a carboxypropyl substituent be performed

prior to cyclization, i.e., 20 → 35. However, 20 was

unreactive under Mitsunobu conditions.

It was then discovered (Scheme 3) that 35 could be syn-

thesized in 74% yield by alkylation of the amino group of 20

with the triflate of benzyl S-lactate. This alkylation reaction

is reported to proceed with inversion of configuration (20), a

finding confirmed in the present work (vide infra).

The cyclization of 35 using trimethylaluminium pro-

ceeded in 84% yield to give the benzyl ester 36, which was

successfully deprotected by hydrogenolysis to the acid 37.

For the synthesis of homolactivicin (7, R = PhCH₂)

(Scheme 5), racemic 10, benzyl 2-oxoglutarate, and dicyclo-

hexylcarbodiimide were stirred for three days in acetonitrile

to give the diastereomeric products 41a (31%) and 41b

(21%). Hydrogenolysis of a 1:1 mixture of 41a and 41b

gave a homolactivicin, mp 150–152 °C, as a mixture of iso-

mers, which was inactive at a concentration of 32 µg/mL

against a panel of Gram-positive, Gram-negative, and β-

lactam-producing organisms.

Stage 5: Chiral synthesis of 2,4,5-trisubstituted

[1,2]oxazinan-3-ones

As summarized in Scheme 6, calcium ^L-threonate (42),

prepared in 95% yield by hydrogen peroxide oxidation of ^L-

ascorbic acid (21), was converted in 90% yield to methyl

2,4-dibromo-2,4-dideoxy-^L-erythronate (43) by the proce-

dure of Bock et al. (22). Methoxymethylation using dimeth-

oxymethane and boron trifluoride, followed by reaction with

sodium azide in dimethylformamide, gave the protected

azido threonate 44 in 68% yield over the two steps. Hydro-

genolysis in the presence of di-tert-butyl carbonate yielded

the protected threonate methyl ester 45 (74%), and the intro-

duction of the aminooxy function by an N-hydroxy-

phthalimide-methylhydrazine sequence produced 46 in 46%

yield from 45. Reaction of 46 with the triflate of benzyl ^L-

lactate gave a single N-hydroxyalanine product, assigned the

R-configuration 47, in 66% yield. The cyclizations of 46 and

47 to 48 and 49 were achieved in 90% and 63% yield, re-

spectively.

N2- and N′-functionalized [1,2]oxazinan-3-ones

Alkylation of 28, R₁= PhCH₂, R₂= Me, with the triflate

of benzyl S-lactate afforded 38 in 29% yield as a 1:1 mixture

of diastereomers. Cyclization with trimethylaluminium pro-

duced one of the isomers of 39 in 36% yield.

More effectively in this case (Scheme 4), treatment of 10

with tert-butyl S-α-bromopropionate in the presence of po-

tassium fluoride – alumina produced the diastereomeric

products 40a (26%) and 40b (31%). Deprotection with

trifluoroacetic acid gave 5a, mp 58–60 °C, from 40a and 5b,

1

mp 189–190 °C, from 40b. The H NMR spectra of these

compounds, neither of which was active at a concentration

of 32 ␮g/mL against a panel of Gram-positive, Gram-

Wolfe et al.

943

Fig. 2. Crystal structure of phenylacetylcyclocanaline.

Scheme 4.

Scheme 5.

Experimental

Scheme 7 summarizes the conversion of 49 to 52, which

has the R-configuration in the alanine side chain, the R--

configuration at C4, and the S-configuration at C5. This

compound exhibited weak activity vs. Micrococcus luteus

(Table 2).

Nuclear magnetic resonance spectra were recorded on

Bruker 100SY (¹H at 100 MHz) and Bruker AMX-400 (¹H

at 400 MHz and ¹³C at 100 MHz) spectrometers. Chemical

shifts are denoted in δ units (ppm) relative to the solvent and

converted to the TMS scale using δ (CHCl₃) = 7.27 ppm for

944

Can. J. Chem. Vol. 81, 2003

1

Fig. 3. H NMR spectrum of 5a in CD₃OD.

1

Fig. 4. H NMR spectrum of 5b in CD₃OD.

1

the H spectra and δ (CDCl₃) = 77.23 ppm for the ¹³C spec-

direct inlet electron impact (EI) measurements or chemical

ionization (CI) measurements, were recorded on a Hewlett-

Packard 5985 GC–MS–IS system. Elemental analyses were

tra. Infrared spectra were recorded on a PerkinElmer 599B

spectrometer. Low-resolution mass spectra, determined as

Wolfe et al.

945

Scheme 6. Reagents and conditions: (i) 50% H₂O₂, CaCO₃; (ii) 30% HBr–HOAc, room temperature (RT), then MeOH, reflux;

(iii) CH₂(OMe)₂, BF₃·Et₂O; (iv) NaN₃, DMF; (v) H₂, Pd–C, (BOC)₂O, EtOAc; (vi) FtOH, DBU, DMF; (vii) MeNHNH₂, CH₂Cl₂;

(viii) S-CF₃SO₂OCHMeCO₂Bn, 2,6-lutidine, CH₂Cl₂.

Table 2. Zones of inhibition vs. M. luteus.

Compound

Weight (µg)

Moles (µM)

Zone size (mm)

Ratio (mm/µM)

DACG^a

DL-cyclocanaline

37

52

3.01 × 10^–2

3.05

3.44

2.31

1.86

39

58

48

23

38

32

1300

11

14

10

20

10

600

400

600

400

1.24

26

^aDesacetoxycephalosporin G.

performed on a Carlo Erba model 1106 elemental analyzer.

Melting points (mp) were obtained on a Fisher-Johns appa-

ratus and are uncorrected. Preparative layer chromatography

(PLC) was carried out on precoated Merck Silica Gel 60 F-

254 plates with aluminium backing. Spots were observed

under short-wavelength ultraviolet light and were visualized

with a solution of 1% ceric sulfate or 2% molybdic acid in

10% sulfuric acid. Flash column chromatography was car-

ried out on Merck Silica Gel 60 (230–400 Mesh).

(75 mL) was heated for 4 h at 75 °C, cooled to room

temperature, treated with methanol (150 mL), and stirred

overnight. Evaporation of the solvent gave a dark oil, which

was dissolved in ethyl acetate (150 mL) and washed succes-

sively with saturated sodium bicarbonate (2 × 150 mL) and

saturated sodium chloride (150 mL), dried over anhydrous

magnesium sulfate, and evaporated to yield a clear oil

1

(48.8 g, 86%). IR (neat) (cm^–1): 1738. H NMR (CDCl₃) δ:

3.68 (3H, s, OCH₃), 3.44 (2H, t, 6.4 Hz, CH₂γ), 2.51 (2H, t,

7.2 Hz, CH₂α), 2.17 (2H, quintet, 6.8 Hz, CH₂β). ¹³C NMR

(CDCl₃) δ: 172.96, 51.70, 32.66, 32.19, 27.70. CI-MS (m/z):

181 ([M + 1]), 183 ([M + 3]). Calcd. for C₅H₉O₂Br:

C 33.17, H 5.02; found: C 32.62, H 4.85.

Methyl γ-bromobutyrate (18)

A solution of γ-butyrolactone (25 mL, 28.0 g, 0.325 mol)

in a 45% solution of hydrogen bromide in acetic acid

946

Can. J. Chem. Vol. 81, 2003

Scheme 7. Reagents and conditions: (i) TFA, anisole; (ii) PhCH₂COCl, Et₃N, CH₂Cl₂; (iii) H₂, 5% Pd–C, EtOAc.

was refluxed for 3 h, then cooled and filtered. The precipi-

Methyl γ-succinimidooxybutyrate

tate was washed with water and recrystallized from ethanol

to give 0.180 g (15%) of the product, identical to the prod-

uct of Method A.

Method A

Methyl γ-bromobutyrate (0.5 g, 2.9 mmol) was added

dropwise to a solution of N-hydroxysuccinimide (0.308 g,

2.6 mmol) and triethylamine (0.38 mL, 0.276 g, 2.6 mmol)

in tetrahydrofuran (20 mL). The reaction mixture was stirred

for 4 h at room temperature and then filtered. The filtrate

was evaporated under reduced pressure to give crystals

(47 mg, 10%); mp 69–71.5 °C. IR (KBr) (cm^–1): 1727,

Method D

A solution of methyl γ-bromobutyrate (1.01 g, 5.5 mmol),

N-hydroxysuccinimide (0.584 g, 5.5 mmol), and triethyl-

amine (0.77 mL, 0.559 g, 5.5 mmol) in dimethylformamide

(11 mL) was stirred at room temperature for 24 h, then

poured into water (80 mL) and extracted with ethyl acetate

(2 × 60 mL). This extract was washed successively with wa-

ter (2 × 100 mL) and saturated sodium chloride (100 mL),

dried over anhydrous magnesium sulfate, and evaporated to

give a solid, which was crystallized from ethanol to yield

0.175 g (15%) of the product, identical to the product of

Method A.

1

1710. H NMR (CDCl₃) δ: 4.15 (2H, t, 6.1 Hz, CH₂γ), 3.69

(3H, s, OCH₃), 2.70 (4H, s, succinimido ring), 2.60 (2H, t,

7.3 Hz, CH₂α), 2.03 (2H, t, t, 7.3 Hz, 6.8 Hz, CH₂β). ¹³C

NMR (CDCl₃) δ: 173.35, 171.10, 76.18, 51.67, 29.87, 25.44,

23.41. CI-MS (m/z): 216 ([M + 1]). Calcd. for C₉H₁₃NO₅: C

50.22, H 6.10, N 6.51; found: C 50.24, H 6.14, N 6.52.

Method B

A solution of methyl γ-bromobutyrate (1.01 g, 5.5 mmol),

N-hydroxysuccinimide (0.576 g, 5.5 mmol), and sodium

methoxide (0.282 g, 5.5 mmol) in dimethylformamide

(11 mL) was heated at 100 °C for 6 h. The solvent was then

removed under reduced pressure, and the residue was dis-

solved in ethyl acetate (100 mL) and washed successively

with water (2 × 100 mL) and saturated sodium chloride

(100 mL), dried over anhydrous magnesium sulfate, and

evaporated to give a solid, which was crystallized from etha-

nol to yield 0.331 g (28%) of product, identical to the prod-

uct of Method A.

Methyl γ-phthalimidooxybutyrate (19)

A

mixture of methyl γ-bromobutyrate (14.7 g,

81.5 mmol), N-hydroxyphthalimide (13.3 g, 81.5 mmol),

and triethylamine (22.7 mL, 16.5 g, 0.163 mol) in aceto-

nitrile (110 mL) was refluxed for 3 h. The insoluble solid

was removed by filtration, and the filtrate was evaporated.

The residue was diluted with ethyl acetate (100 mL), and

this solution was washed successively with water (3 ×

100 mL) and saturated sodium chloride (100 mL), dried over

anhydrous magnesium sulfate, and evaporated. The solid

was recrystallized from hot ethanol to give 16.8 g (78%); mp

79–81 °C. IR (KBr) (cm^–1): 1735, 1727. H NMR (CDCl₃)

1

Method C

δ: 7.79 (4H, m, phthalimido ring), 4.26 (2H, t, 6.1 Hz,

CH₂γ), 3.70 (3H, s, OCH₃), 2.66 (2H, t, 7.3 Hz, CH₂α), 2.09

(2H, quintet, 6.7 Hz, CH₂β). ¹³C NMR (CDCl₃) δ: 174.50,

163.63, 134.43, 128.94, 123.48, 78.20, 51.50, 33.85, 25.14.

A solution of methyl γ-bromobutyrate (1.01 g, 5.5 mmol),

N-hydroxysuccinimide (0.587 g, 5.5 mmol), and triethyl-

amine (1.54 mL, 1.12 g, 11.1 mmol) in acetonitrile (10 mL)

Wolfe et al.

947

CI-MS (m/z): 264 ([M + 1]). Calcd. for C₁₃H₁₃NO₅: C

59.30, H 4.99, N 5.32; found: C 59.17, H 4.97, N 5.49.

chromatography on silica gel using ethyl acetate as the

eluent to yield an oil (18 mg, 24%), identical to the product

of Method A.

Methyl γ-aminooxybutyrate (20)

Method C

Method A

A

solution of methyl γ-aminooxybutyrate (3.03 g,

A solution of methyl γ-phthalimidooxybutyrate (2.75 g,

10.45 mmol) in dichloromethane (50 mL) was cooled to

–10 °C and treated dropwise, with stirring, with methyl-

hydrazine (0.83 mL, 0.72 g, 15.7 mmol). Stirring was con-

tinued for 1.5 h at –10 to 0 °C, and the mixture was then

filtered. The filtrate was concentrated, and the residue, in

ethyl acetate (50 mL), was washed with 1:1 saturated so-

dium chloride:saturated sodium bicarbonate (22 mL). The

aqueous layer was washed with ethyl acetate (50 mL), and

the combined organic extracts were dried over anhydrous

magnesium sulfate and evaporated to give a yellow oil

(1.39 g, 100%). IR (neat) (cm^–1): 3322, 1734. ¹H NMR

(CDCl₃) δ: 5.25 (2H, br s, NH₂), 3.68 (2H, t, 6.2 Hz, CH₂γ),

3.68 (3H, s, OCH₃), 2.38 (2H, t, 7.3 Hz, CH₂α), 1.92 (2H,

quintet, 6.7 Hz, CH₂β). ¹³C NMR (CDCl₃) δ: 173.95, 74.78,

51.58, 30.71, 23.65. CI-MS (m/z): 134 ([M + 1]). Calcd. for

C₅H₁₁NO₃: C 45.09, H 8.34, N 10.52; found: C 45.02,

H 8.36, N 10.49.

22.8 mmol) in tetrahydrofuran (40 mL) was cooled to 0 °C,

and a 2.0 mol/L solution of trimethylaluminium in hexanes

(22.8 mL, 45.6 mmol) was added in portions. The reaction

mixture was allowed to warm to room temperature with stir-

ring during 2 h and quenched with acetone (15mL) with stir-

ring for 30 min and then by slow addition of water (50 mL).

Most of the solvent was removed under reduced pressure,

and 1:4 dichloromethane:tetrahydrofuran (300 mL) was

added. Filtration through Celite and evaporation of the fil-

trate gave an oil (1.51 g, 65%), identical to the product of

Method A.

Methyl β-bromopropionate

A solution of β-propiolactone (2 mL, 2.29 g, 30.8 mmol)

in 30% hydrogen bromide in acetic acid (10 mL) was stirred

at room temperature for 20 h. Then methanol (20 mL) was

added, and stirring was continued for an additional 15 h.

Evaporation of the solvent gave a dark oil, which was dis-

solved in ethyl acetate (50 mL) and washed successively

with saturated sodium bicarbonate (2 × 50 mL) and satu-

rated sodium chloride (50 mL), dried over anhydrous mag-

nesium sulfate, and evaporated to yield a clear oil (2.88 g,

56%). IR (neat) (cm^–1): 1742. ¹H NMR (CDCl₃) δ: 3.77

(3H, s, OCH₃), 3.62 (2H, t, 6.8 Hz, CH₂β), 2.96 (2H, t,

6.8 Hz, CH₂α). CI-MS (m/z): 167 ([M + 1]), 169 ([M + 3]).

Method B

Hydrazine hydrate (0.07 mL, 74.6 mg, 1.49 mmol) was

added, with stirring, to a solution of methyl γ-succinimido-

oxybutyrate (80 mg, 0.37 mmol) in methanol (3 mL).

Stirring was continued at room temperature for 12 h, and the

solvent was then removed. The solid residue was triturated

with ethyl acetate (2 × 8 mL, 1 × 4 mL), and the ethyl ace-

tate was evaporated to give the product as an oil (22.3 mg,

45%), identical with the product of Method A.

Methyl β-phthalimidooxypropionate

Method A

[1,2]Oxazinan-3-one (21)

A solution of N-hydroxyphthalimide (18.1 g, 0.111 mol)

and triethylamine (15.5 mL, 11.3 g, 0.111 mol) in methanol

(100 mL) was stirred at room temperature for 10 min.

Methyl acrylate (10 mL, 9.56 g, 0.111 mol) was added

dropwise, and the solution was heated to reflux for 18 h and

then cooled to room temperature. The solvent was removed

under reduced pressure and the residue was dissolved in

ethyl acetate (150 mL) and washed successively with water

(50 mL), saturated sodium bicarbonate (5 × 50 mL), water

(50 mL), 5% citric acid (50 mL), water (50 mL), and satu-

rated sodium chloride (50 mL), dried over anhydrous mag-

nesium sulfate, and evaporated. The solid residue was

recrystallizated from hot ethanol to give white crystals,

Method A

A

solution of methyl γ-aminooxybutyrate (0.51 g,

3.75 mmol) in toluene (37.5 mL) was treated with a

2.0 mol/L solution of trimethylaluminium in hexanes

(3.75 mL, 7.5 mmol). The resulting mixture was refluxed for

2 h, cooled to room temperature, and poured onto a mixture

of 5% hydrochloric acid and ice. The aqueous layer was ex-

tracted with chloroform and the organic layer was evapo-

rated to dryness. The residue was purified by flash

chromatography on silica gel, using 7:1 ethyl acetate:hex-

anes as the eluent, to yield a colourless oil (0.30 g, 79%). IR

(CH₂Cl₂) (cm^–1): 3403, 1667. H NMR (CDCl₃) δ: 8.89 (1H,

1

5.88 g (21%). IR (KBr) (cm^–1): 1745, 1727, 1657. H NMR

br s, NH), 4.03 (2H, t, 6.5 Hz, CH₂O), 2.52 (2H, t, 7.2 Hz,

COCH₂), 2.10 (2H, quintet, 6.9 Hz, COCH₂CH₂). ¹³C NMR

(CDCl₃) δ: 172.93, 69.04, 27.42, 21.55. CI-MS (m/z): 102

([M + 1]). Anal. calcd. for C₄H₇NO₂·0.1H₂O: C 46.68,

H 6.97, N 13.61; found: C 46.73, H 7.01, N 13.21.

(CDCl₃) δ: 7.81 (4H, m, phthalimido ring), 4.51 (2H, t,

6.5 Hz, CH₂␤), 3.71 (3H, s, OCH₃), 2.85 (2H, t, 6.5 Hz, CH₂

α). ¹³C NMR (CDCl₃) δ: 170.58, 163.44, 134.53, 128.90,

123.58, 73.40, 51.95, 33.65. CI-MS (m/z): 250 ([M + 1]).

Calcd. for C₁₂H₁₁N₁O₅: C 57.82, H 4.46, N 5.62; found: C

57.70, H 4.50, N 5.46.

Method B

Potassium hydroxide (0.042 g, 0.75 mmol) in methanol

(4 mL) was added to a solution of methyl γ-aminooxy-

butyrate (0.10 g, 0.75 mmol) in methanol (10 mL), and the

mixture was refluxed for 2 h, cooled to room temperature,

stirred overnight, neutralized with 5% hydrochloric acid, and

evaporated. The residue was purified by preparative layer

Method B

A

mixture of methyl β-bromopropionate (0.50 g,

2.99 mmol), N-hydroxyphthalimide (0.49 g, 2.99 mmol),

and triethylamine (0.64 mL, 0.45 g, 4.49 mmol) in aceto-

nitrile (7 mL) was refluxed for 3 h, cooled, and filtered. The

948

Can. J. Chem. Vol. 81, 2003

filtrate was evaporated under reduced pressure, and the resi-

due was dissolved in ethyl acetate (20 mL). This solution

was washed successively with water (3 × 20 mL) and satu-

rated sodium chloride (20 mL), dried over anhydrous mag-

nesium sulfate, and evaporated. Recrystallization from hot

ethanol gave 48.9 mg (6%) of white crystals, identical to the

product of Method A.

and triethylamine (8.6 mL, 6.24 g, 61.5 mmol) in aceto-

nitrile (40 mL) was refluxed for 3 h, cooled, and filtered.

The filtrate was evaporated under reduced pressure, and the

residue was dissolved in ethyl acetate (75 mL). This solution

was washed successively with water (3 × 75 mL) and satu-

rated sodium chloride (75 mL), dried over anhydrous mag-

nesium sulfate, and evaporated. Recrystallization from hot

ethanol gave 6.33 g (74%) of product. IR (KBr) (cm^–1):

1

1727, 1710. H NMR (CDCl₃) δ: 7.81 (4H, m, phthalimido

Methyl β-aminooxypropionate

ring), 4.21 (2H, t, 6.1 Hz, CH₂δ), 3.68 (3H, s, OCH₃), 2.43

(2H, t, 7.1 Hz, CH₂α), 1.86 (4H, m, CH₂βCH₂γ). ¹³C NMR

(CDCl₃) δ: 173.74, 163.60, 134.45, 128.93, 123.49, 77.88,

51.55, 33.45, 27.51, 21.11. CI-MS (m/z): 278 ([M + 1]).

Calcd. for C₁₄H₁₅NO₅: C 60.63, H 5.46, N 5.05; found:

C 60.54, H 5.43, N 5.06.

A solution of methyl β-phthalimidooxypropionate (1.5 g,

6.02 mmol) in dichloromethane (50 mL) was cooled to –10 °C

and methylhydrazine (0.5 mL, 0.433 g, 9.03 mmol) was

added dropwise with stirring. Stirring was continued for

1.5 h at –10 to 0 °C. The mixture was then filtered, and the

filtrate was concentrated. The residue was dissolved in ethyl

acetate (30 mL), and this solution was washed with 1:1 satu-

rated sodium chloride:saturated sodium bicarbonate (8 mL).

The aqueous layer was washed with ethyl acetate (30 mL),

and the combined organic layers were dried over anhydrous

magnesium sulfate and evaporated. Purification by short col-

umn chromatography on silica gel, using a gradient solvent

system (hexanes to ethyl acetate) gave 0.359 g (50%) of an

Methyl δ-aminooxypentanoate

A solution of methyl δ-phthalimidooxypentanoate (2.01 g,

72.4 mmol) in dichloromethane (50 mL) was cooled to –10 °C,

and methylhydrazine (0.58 mL, 0.50 g, 10.8 mmol) was

added dropwise with stirring. Stirring was continued for

1.5 h, and the mixture was then filtered and the filtrate evap-

orated. The residue was dissolved in ethyl acetate (50 mL),

and this solution was washed with 1:1 saturated sodium

chloride:saturated sodium bicarbonate (30 mL). The aqueous

layer was extracted with ethyl acetate (50 mL), and the com-

bined organic layers were dried over anhydrous magnesium

sulfate and evaporated to give an oil (1.03 g, 97%). IR (neat)

1

oil. H NMR (CDCl₃) δ: 5.85 (2H, s, NH₂), 3.73 (3H, s,

CH₃), 3.26 (2H, t, 6.2 Hz, CH₂β), 2.67 (2H, t, 6.2 Hz,

CH₂α). CI-MS (m/z): 120 ([M + 1]).

Isoxazolidin-3-one

A solution of methyl β-aminooxypropionate (0.251 g,

2.10 mmol) in tetrahydrofuran (25 mL) was cooled to 0 °C

and a 2.0 mol/L solution of trimethylaluminium in hexanes

(2.1 mL, 4.20 mmol) was added in portions. The reaction

mixture was allowed to warm to room temperature with stir-

ring during 4 h and then by slow addition of water (2 mL)

with stirring for 30 min. Most of the solvent was removed

under reduced pressure, and chloroform (300 mL) was

added. Filtration through Celite and evaporation of the fil-

trate gave a colourless oil (83.0 mg, 45%). ¹H NMR

(CDCl₃) δ: 9.21 (1H, br s, NH), 4.41 (2H, t, 8.2 Hz, CH₂β),

2.79 (2H, t, 8.2 Hz, CH₂α). CI-MS (m/z): 88 ([M + 1]).

Calcd. for C₃H₅NO₂: C 41.38, H 5.79, N 16.09; found:

C 40.89, H 5.84, N 15.55.

1

(cm^–1): 3320, 1732. H NMR (CDCl₃) δ: 4.50 (2H, br s,

NH₂), 3.67 (3H, s, OCH₃), 3.66 (2H, t, 6.2 Hz, CH₂δ), 2.34

(2H, t, 7.0 Hz, CH₂α), 1.66 (4H, m, CH₂βCH₂γ). ¹³C NMR

(CDCl₃) δ: 173.97, 75.37, 51.50, 33.76, 27.43, 21.49. CI-MS

(m/z): 148 ([M + 1]).

[1,2]Oxazepin-3-one

A solution of methyl δ-aminooxypentanoate (96.6 mg,

0.656 mmol) in tetrahydrofuran (3 mL) was cooled to 0 °C,

and a 2.0 mol/L solution of trimethylaluminium in hexanes

(0.68 mL, 1.36 mmol) was added dropwise. The resulting

solution was allowed to warm to room temperature and was

stirred for 5.5 h. Acetone (0.8 mL) was added, and after

20 min, water (2 mL) was added dropwise. Most of the sol-

vent was removed under reduced pressure; 1:4 dichloro-

methane:tetrahydrofuran (50 mL) was added, and the

mixture was filtered through Celite. Evaporation of the fil-

trate gave a white solid, which was recrystallized from hot

ethyl acetate (61.7 mg, 82%); mp 84.5–85.8 °C. IR (KBr)

Methyl δ-bromopentanoate

A solution of δ-valerolactone (5.0 mL, 5.39 g, 53.8 mmol)

in 30% hydrogen bromide in acetic acid (15 mL) was heated

at 75 °C for 5 h, cooled to room temperature, and methanol

(20 mL) was added. The mixture was stirred overnight, and

the solvent was evaporated to give a dark oil, which was dis-

solved in ethyl acetate (50 mL) and washed successively

with saturated sodium bicarbonate (2 × 50 mL) and satu-

rated sodium chloride (50 mL), dried over anhydrous mag-

nesium sulfate, and evaporated to yield a clear oil (9.16 g,

87%). IR (neat) (cm^–1): 1737. ¹H NMR (CDCl₃) δ: 3.67

(3H, s, OCH₃), 3.41 (2H, t, 6.4 Hz, CH₂δ), 2.35 (2H, t,

1

(cm^–1): 3419, 1642. H NMR (CDCl₃) δ: 8.27 (1H, br s,

NH), 4.07 (2H, m, CH₂δ), 2.63 (2H, m, CH₂α), 1.91 (2H, m,

CH₂γ), 1.81 (2H, m, CH₂β). ¹³C NMR (CDCl₃) δ: 179.36,

78.37, 35.79, 30.94, 21.85. CI-MS (m/z): 116 ([M + 1]).

Calcd. for C₅H₉NO₂: C 52.15, H 7.89, N 12.17; found:

C 52.12, H 7.91, N 12.18.

7.3 Hz, CH₂α), 1.90 (2H, m, CH₂γ), 1.79 (2H, m, CH₂β). ¹³

C

Methyl ε-bromohexanoate

NMR (CDCl₃) δ: 173.55, 51.58, 33.00, 31.97, 23.47. CI-MS

(m/z): 195 ([M + 1]), 197 ([M + 3]).

A solution of ε-caprolactone (5.2 mL, 5.36 g, 46.9 mmol)

in 30% hydrogen bromide in acetic acid (12.5 mL) was

heated for 6 h at 75 °C, cooled to room temperature, treated

with methanol (20 mL), and stirred overnight. Evaporation

of the solvent gave a dark oil, which was dissolved in ethyl

acetate (50 mL) and washed successively with saturated so-

Methyl δ-phthalimidooxypentanoate

A

mixture of methyl δ-bromopentanoate (6.01 g,

30.8 mmol), N-hydroxyphthalimide (5.03 g, 30.8 mmol),

Wolfe et al.

949

dium bicarbonate (2 × 50 mL) and saturated sodium chloride

(50 mL), dried over anhydrous magnesium sulfate, and evap-

orated to yield a clear oil (9.31 g, 95%). H NMR (CDCl₃) δ:

3.67 (3H, s, OCH₃), 3.40 (2H, t, 6.8 Hz, CH₂ε), 2.33 (2H, t,

7.5 Hz, CH₂α), 1.87 (2H, m, CH₂δ), 1.66 (2H, m, CH₂β), 1.47

(2H, m, CH₂γ). CI-MS (m/z): 209 ([M + 1]), 211 ([M + 3]).

filtration and washed with cold ethanol to yield 0.384 g

(81%); mp 117–119 °C. CI-MS (m/z): 102 ([M + 1]). Calcd.

for C₄H₈NO₂Br: C 26.40, H 4.44, N 7.70; found: C 26.35,

H 4.25, N 7.51.

1

α-Amino-γ-bromobutyric acid hydrobromide

A suspension of α-amino-γ-butyrolactone hydrobromide

(97 mg, 0.53 mmol) in 45% hydrogen bromide in acetic acid

(3 mL) was stirred for 4 h at 75 °C, cooled to room tempera-

ture, and concentrated under reduced pressure to give a

white solid (140 mg, 100%), which was used in the next step

without further purification. IR (KBr) (cm^–1): 3451, 1720. ¹H

NMR (D₂O) δ: 4.10 (1H, t, 6.8 Hz, CHα), 3.59 (2H, t,

7.0 Hz, CH₂γ), 2.50 (1H, m, CHβ), 2.38 (1H, m, CHβ).

Methyl ε-phthalimidooxyhexanoate

A

mixture of methyl ε-bromohexanoate (6.44 g,

30.8 mmol), N-hydroxyphthalimide (5.02 g, 30.8 mmol),

and triethylamine (8.6 mL, 6.24 g, 61.5 mmol) in aceto-

nitrile (40 mL) was refluxed for 3 h, cooled, and filtered.

The filtrate was concentrated and the residue diluted with

ethyl acetate (50 mL). This solution was washed succes-

sively with water (3 × 50 mL) and saturated sodium chloride

(50 mL), dried over anhydrous magnesium sulfate, and evap-

orated. Recrystallization from hot ethanol gave 8.89 g

BOC-α-amino-γ-bromobutyric acid

α-Amino-γ-bromobutyric acid hydrobromide (130 mg,

0.50 mmol) was dissolved in 50% aqueous acetone

(1.8 mL), triethylamine (0.14 mL, 0.102 g, 1.0 mmol) and

BOC-ON (141 mg, 0.55 mmol) were added, and the solution

was stirred for 3 h at room temperature. The solvent was

then removed under reduced pressure, and the residue was

dissolved in water (3 mL), washed with ethyl acetate

(3 mL), acidified to pH 3 with 5% citric acid, and again ex-

tracted with ethyl acetate (3 × 3 mL). The latter extracts

were combined, washed successively with water (2 × 3 mL)

and saturated sodium chloride (3 mL), dried over anhydrous

magnesium sulfate, and evaporated to give 29.5 mg (21%) of

(99%). IR (KBr) (cm^–1): 1787, 1731. H NMR (CDCl₃) δ:

1

7.80 (4H, m, phthalimido ring), 4.20 (2H, t, 6.6 Hz, CH₂ε),

3.67 (3H, s, OCH₃), 2.35 (2H, t, 7.4 Hz, CH₂α), 1.80

(2H, m, CH₂δ), 1.72 (2H, m, CH₂β), 1.55 (2H, m, CH₂γ). ¹³

C

NMR (CDCl₃) δ: 173.06, 163.58, 134.49, 128.90, 123.53,

77.28, 5168, 29.96, 23.52. CI-MS (m/z): 292 ([M + 1]).

Calcd. for C₁₅H₁₇NO₅: C 61.84, H 5.89, N 4.81; found:

C 61.49, H 5.92, N 4.75.

Methyl ε-aminooxyhexanoate

A solution of methyl ε-phthalimidooxyhexanoate (1.05 g,

3.60 mmol) in dichloromethane (19 mL) was cooled to –10 °C;

methylhydrazine (0.29 mL, 0.251 g, 5.4 mmol) was added

dropwise with stirring, and stirring was continued for 1.5 h

at –10 to 0 °C. The mixture was then filtered, and the filtrate

was evaporated. The residue was dissolved in ethyl acetate

(50 mL) and washed with 1:1 saturated sodium chloride:sat-

urated sodium bicarbonate (30 mL). The aqueous extract

was washed with ethyl acetate (50 mL), and the combined

organic layers were dried over anhydrous magnesium sulfate

and evaporated to give an oil (0.567 g, 98%). ¹H NMR

(CDCl₃) δ: 5.10 (2H, br s, NH₂), 3.66 (3H, s, OCH₃), 3.64

(2H, t, 6.6 Hz, CH₂ε), 2.30 (2H, t, 7.4 Hz, CH₂α), 1.64

(2H, m, CH₂δ), 1.58 (2H, m, CH₂β), 1.35 (2H, m, CH₂γ).

1

the product. H NMR (CDCl₃) δ: 5.56 (1H, br s, NH), 4.50

(1H, m, CHα), 3.82 (2H, m, CH₂γ), 2.18 (1H, m, CHβ), 1.78

(1H, m, CHβ), 1.48 (9H, s, C(CH₃)₃).

BOC-α-amino-γ-butyrolactone

A solution of triethylamine (7.75 mL, 5.63 g, 56.0 mmol)

in dichloromethane (10 mL) was added slowly to a suspen-

sion of ^DL-α-amino-γ-butyrolactone hydrobromide (10 g,

55.0 mmol) in dichloromethane (100 mL). The mixture was

cooled to 0 °C, and a solution of BOC anhydride (13.19 g,

60.4 mmol) in dichloromethane (25 mL) was added during

5 min. The resulting suspension was allowed to warm to

room temperature, stirred for 96 h, and then washed succes-

sively with 5% citric acid (50 mL), water (50 mL), and satu-

rated sodium chloride (50 mL), dried over anhydrous

magnesium sulfate, and evaporated to give a white solid.

This was recrystallized from toluene to yield 9.93 g (90%);

mp 124–126 °C. IR (KBr) (cm^–1): 3359, 1787, 1684, 1528.

¹H NMR (CDCl₃) δ: 5.05 (1H, br s, NH), 4.44 (1H, m,

CHγ), 4.34 (1H, m, CHα), 4.24 (1H, m, CHγ), 2.76 (1H, m,

CHβ), 2.18 (1H, m, CHβ), 1.47 (9H, s, C(CH₃)₃). ¹³C NMR

(CDCl₃) δ: 175.68, 155.72, 80.55, 65.83, 50.21, 30.34,

28.30. CI-MS (m/z): 202 ([M + 1]). Calcd. for C₉H₁₅NO₄:

C 53.71, H 7.53, N 6.96; found: C 53.98, H 7.58, N 7.19.

[1,2]Oxazocan-3-one

A 2.0 mol/L solution of trimethylaluminium in heptane

(4.96 mL, 9.92 mmol) was added to toluene (50 mL), cooled

to 0 °C, and a solution of methyl-ε-aminooxyhexanoate

(0.400 g, 2.48 mmol) in toluene (50mL) was added

dropwise. The resulting solution was allowed to warm to

room temperature and was stirred for 6 days. Water (20 mL)

was added dropwise, and the mixture was stirred for 30 min.

Most of the solvent was removed under reduced pressure, and

1:4 dichloromethane:tetrahydrofuran (50 mL) was added. Fil-

tration through Celite and evaporation of the filtrate gave a

trace amount of product. CI-MS (m/z): 130 ([M + 1]).

BOC-homoserine

Method A

α-Amino-γ-butyrolactone hydrobromide

A solution of ^DL-homoserine (0.31 g, 2.6 mmol) in

2.4 mol/L hydrobromic acid (5 mL, 12 mmol, 4.6 equiv)

was refluxed for 3 h and then stirred overnight. Removal of

the solvent afforded a white solid, which was dissolved in

ethanol and cooled to give a solid, which was collected by

To a solution of ^DL-homoserine (5.00 g, 42.0 mmol) in

50% aqueous acetone (50 mL) were added, with stirring,

triethylamine (8.8 mL, 6.34 g, 63.0 mmol) and BOC anhy-

dride (10.1 g, 46.2 mmol). After 14 h, the solvent was re-

moved under reduced pressure, and the residue was

950

Can. J. Chem. Vol. 81, 2003

dissolved in water (30 mL). This solution was acidified to

pH 3–4 with 5% citric acid (130 mL) and extracted with

ethyl acetate (3 × 50 mL). The combined organic extracts

were washed with saturated sodium chloride (50 mL), dried

over anhydrous magnesium sulfate, and evaporated to give a

Methyl α-amino-γ-bromobutyrate hydrochloride

Hydrogen chloride was bubbled for 2 h into a suspension

of α-amino-γ-bromobutyrate hydrobromide (0.165 g,

0.586 mmol) in methanol (5 mL) at such a rate that the tem-

perature did not exceed 40 °C. The solvent was then re-

moved under reduced pressure, the residue was dissolved in

methanol, and the solution was reevaporated. This procedure

was repeated once more, and the residual oil was dried in

vacuo in a desiccator over sodium hydroxide pellets. The re-

sulting crystals were triturated with ether, collected, and

1

yellow oil (6.79 g, 74%). H NMR (CDCl₃) δ: 5.49 (1H,

br s, NH), 4.50 (1H, m, CHα), 3.79 (2H, m, CH₂γ), 2.21

(1H, m, CHβ), 1.77 (1H, m, CHβ), 1.41 (9H, s, C(CH₃)₃). ¹³

C

NMR (CDCl₃) δ: 176.82, 156.40, 80.14, 58.33, 51.50, 35.14,

28.30. CI-MS (m/z): 220 ([M + 1]). Calcd. for C₉H₁₇NO₅:

C 49.30, H 7.83, N 6.39; found: C 48.72, H 7.67, N 6.04.

1

washed with ether to give 89 mg (65%); mp 96–98 °C. H

NMR (D₂O) δ: 4.33 (1H, t, 6.67 Hz, CHα), 3.83 (3H, s,

OCH₃), 3.59 (2H, m, CH₂γ), 2.56 (1H, m, CHβ), 2.39

(1H, m, CHβ). CI-MS (m/z): 196 ([M + 1]), 198 ([M + 3]).

Method B

To a solution of BOC-α-amino-γ-butyrolactone (7.00 g,

34.8 mmol) in dry methanol (80 mL) was added in portions

a solution of potassium hydroxide (3.44 g, 52.2 mmol) in

methanol (20 mL). The mixture was stirred at room temper-

ature for 24 h, and Amberlyst 15 (H ⁺) (14.0 g, 62.6 mmol),

presoaked in methanol, was added. The resin was then re-

moved by filtration, and the solution was evaporated under

reduced pressure to an oil (7.39 g, 97%), identical with the

product of Method A.

Methyl ester of BOC-α-amino-γ-bromobutyric acid

To a solution of methyl α-amino-γ-bromobutyrate hydro-

chloride (29.7 mg, 0.129 mmol) in 50% aqueous acetone

(1 mL) were added, with stirring, triethylamine (0.039 mL,

28.3 mg, 0.258 mmol) and BOC anhydride (30.1 mg,

0.142 mmol). Stirring was continued at room temperature

for 3 h, and the solvent was then removed under reduced

pressure. The residue was purified by preparative layer chro-

matography on silica gel, using 2:1 hexanes:ethyl acetate as

Benzhydryl ester of BOC-homoserine

1

A solution of BOC-homoserine (0.803 g, 3.66 mmol) in a

mixture of dichloromethane (20 mL) and acetonitrile

(20 mL) was treated dropwise, with stirring, with a solution

of diphenyldiazomethane (0.713 g, 3.66 mmol) in dichloro-

methane (3 mL). Stirring was continued for 2 h after the ad-

dition was complete, and the solvent was then removed

under reduced pressure to give a yellow oil. This was dis-

solved in ethyl acetate (50 mL) and washed successively

with water (2 × 50 mL) and saturated sodium chloride

(50 mL), dried over anhydrous magnesium sulfate, and evap-

orated. Purification by flash chromatography on silica gel,

using ethyl acetate – hexanes (1:1) as the eluent, gave the

product as an oil (0.992 g, 70%). IR (neat) (cm^–1): 3499,

the eluent, to give 28.4 mg (75%) of the product. H NMR

(CDCl₃) δ: 5.05 (1H, br d, 7.5 Hz, NH), 4.41 (1H, m, CHα),

3.73 (3H, s, OCH₃), 3.40 (2H, t, 6.8 Hz, CH₂γ), 2.37 (2H, m,

CH₂β), 1.42 (9H, s, C(CH₃)₃).

Methyl ester of BOC-homoserine

A solution of homoserine (5.00 g, 42.0 mmol) in 50%

aqueous acetone (50 mL) was treated with triethylamine

(8.8 mL, 6.39 g, 63.0 mmol) and BOC anhydride (10.1 g,

46.2 mmol) and stirred overnight at room temperature. Re-

moval of the solvent gave the triethylamine salt of BOC-

homoserine (13.5 g, 100%). IR (CH₂Cl₂) (cm^–1): 3413,

1

1709, 1693. H NMR (D₂O) δ: 4.02 (1H, m, CHα), 3.64

1

3321, 1736, 1688. H NMR (CDCl₃) δ: 7.31 (10H, m, Ar),

(2H, m, CH₂γ), 3.18 (2H, q, 7.3 Hz, CH₂CH₃), 1.98 (1H, m,

CHβ), 1.82 (1H, m, CHβ), 1.41 (9H, s, C(CH₃)₃), 1.26 (3H,

t, 7.3 Hz, CH₃). ¹³C NMR (D₂O) δ: 181.68, 160.33, 83.76,

61.09, 55.48, 49.30, 36.57, 30.28, 10.85. CI-MS (m/z): 164

([M + 1 – BOC]).

6.90 (1H, s, CHO), 5.38 (1H, br d, 7.9 Hz, NH), 4.62 (1H, m,

CHα), 3.65 (2H, m, CH₂γ), 3.80 (1H, br s, OH), 2.24 (1H, m,

CHβ), 1.58 (1H, m, CHβ), 1.44 (9H, s, C(CH₃)₃). CI-MS

(m/z): 386 ([M + 1]). Calcd. for C₂₂H₂₇NO₅: C 68.54, H 7.04,

N 3.63; found: C 68.68, H 7.14, N 3.61.

A solution of the salt (7.49 g, 23.4 mmol) in dimethyl-

formamide (50 mL) was cooled to 0–10 °C and stirred;

iodomethane (1.6 mL, 3.65 g, 25.7 mmol) was added; the

cooling bath was removed, and stirring was continued over-

night. Most of the solvent was removed under reduced pres-

sure, and the residue was diluted with ethyl acetate (80 mL)

and washed with water (20 mL). The aqueous extract was

washed with ethyl acetate (2 × 25 mL), and the combined

organic extracts were washed successively with 5% citric

acid (2 × 15 mL), water (15 mL), saturated sodium sulfite

(15 mL), saturated sodium bicarbonate (2 × 15 mL), and sat-

urated sodium chloride (2 × 15 mL), dried over anhydrous

magnesium sulfate, and evaporated to give a colourless oil

Benzhydryl ester of BOC-α-amino-γ-succinimidooxy-

butyric acid

A solution of the benzhydryl ester (1.01 g, 2.62 mmol)

and N-hydroxysuccinimide (0.313 g, 2.72 mmol) in tetra-

hydrofuran (12 mL) was cooled to 15 °C, and triphenylphos-

phine (0.702 g, 2.67 mmol) and diethyl azodicarboxylate

(0.45 mL, 0.498 g, 2.86 mmol) were added successively. The

reaction mixture was allowed to warm to room temperature,

stirred overnight, and the solvent was then removed under

reduced pressure. Purification by flash chromatography on

silica gel using 3:1 hexanes:ethyl acetate as the eluent gave a

white solid (0.589 g, 47%). ¹H NMR (CDCl₃) δ: 7.33

(10H, m, Ar), 6.92 (1H, s, CHO), 5.81 (1H, br d, 8.2 Hz,

NH), 4.62 (1H, m, CHα), 4.13 (2H, m, CH₂γ), 2.65 (4H, s,

succinimido ring), 2.27 (2H, m, CH₂β), 1.44 (9H, s,

C(CH₃)₃). CI-MS (m/z): 383 ([M + 1 – BOC]). Calcd. for

1

(5.15 g, 94%). H NMR (CDCl₃) δ: 5.43 (1H, br s, NH),

4.52 (1H, m, CHα), 3.80 (3H, s, CH₃O), 3.73 (2H, m,

CH₂γ), 3.26 (1H, br s, OH), 2.11 (1H, m, CHβ), 1.64

(1H, m, CHβ), 1.49 (9H, s, C(CH₃)₃). ¹³C NMR (CDCl₃) δ:

173.62, 156.80, 80.16, 58.65, 52.50, 51.04, 36.18, 28.66. CI-

MS (m/z): 234 ([M + 1]).

.

C₂₆H₃₀N₂O₇H₂O: C 62.38, H 6.46; found: C 62.38, H 6.60.

Wolfe et al.

951

(2 × 25 mL), and the combined organic layers were washed

successively with 5% citric acid (2 × 15 mL), water

(15 mL), saturated sodium sulfite (15 mL), saturated sodium

bicarbonate (2 × 15 mL), and saturated sodium chloride (2 ×

15 mL), dried over anhydrous magnesium sulfate, and evap-

orated to give a pale yellow oil (2.02 g, 60%). IR (CH₂Cl₂)

Mesylation of the BOC methyl ester (26, R₁= t-BuO,

R₂= Me)

Methanesulfonyl chloride (2.14 mL, 3.16 g, 27.6 mmol)

was added dropwise at –15 to –10 °C to a solution of the

methyl ester of BOC-homoserine (5.6 g, 24.0 mmol) and tri-

ethylamine (4.0 mL, 2.90 g, 28.8 mmol) in dichloromethane

(80 mL). The reaction mixture was allowed to warm to 0 °C

and was stirred at that temperature for 1 h. Cold 10% potas-

sium bisulfate (25 mL) was added, and the aqueous layer

was separated and washed with dichloromethane (2 ×

25 mL). The combined organic layers were washed with so-

dium bicarbonate (2 × 35 mL), dried over anhydrous magne-

sium sulfate, and evaporated to give a pale yellow oil

1

(cm^–1): 3297, 1743, 1658. H NMR (CDCl₃) δ: 7.32 (5H, m,

Ar), 6.38 (1H,br d, 6.8 Hz, NH), 4.73 (1H, m, CHα), 3.73

(3H, s, CH₃), 3.64 (1H, m, CHγ), 3.63 (2H, s, PhCH₂), 3.49

(1H, m, CHγ), 2.33 (1H, br s, OH), 2.13 (1H, m, CHβ), 1.56

(1H, m, CHβ). ¹³C NMR (CDCl₃) δ: 172.94, 172.15, 134.21,

129.32, 129.09, 127.56, 58.09, 52.64, 49.66, 43.45, 35.63.

CI-MS (m/z): 252 ([M + 1]).

1

(7.25 g, 97%). H NMR (CDCl₃) δ: 5.25 (1H, br s, NH),

4.75 (1H, m, CHα), 4.35 (2H, m, CH₂γ), 3.82 (3H, s,

CH₃O), 3.07 (3H, s, SO₂CH₃), 2.36 (1H, m, CHβ), 2.15

(1H, m, CHβ), 1.49 (9H, s, C(CH₃)₃).

Mesylation of the methyl ester of phenylacetamido

homoserine (26, R₁= PhCH₂, R₂= Me)

A solution of the methyl ester (1.90 g, 7.56 mmol) and

triethylamine (1.26 mL, 0.91 g, 9.07 mmol) in dichloro-

methane (30 mL) was cooled to –15 to –10 °C and methane-

sulfonyl chloride (0.67 mL, 1.00 g, 8.70 mmol) was added

dropwise. The mixture was allowed to warm to 0 °C and

was stirred at that temperature for 1 h. Cold 10% potassium

bisulfate (15 mL) was added, and the aqueous layer was sep-

arated and washed with dichloromethane (2 × 15 mL). The

combined organic layers were washed with sodium bicar-

bonate (2 × 25 mL), dried over anhydrous magnesium sul-

α-Phenylacetamido-γ-butyrolactone

Triethylamine (7.7 mL, 5.6 g, 55.0 mmol) was added

slowly to a suspension of α-amino-γ-butyrolactone hydro-

bromide (5.0 g, 27.5 mmol) in dichloromethane (50 mL).

The mixture was stirred for 10 min, cooled to –5 °C, and

treated, during 30 min, with a solution of phenylacetyl chlo-

ride (3.3 mL, 3.83 g, 24.8 mmol) in dichloromethane

(20 mL). The mixture was allowed to warm to room temper-

ature, stirred for 3 h, and then washed successively with wa-

ter (25 mL), 1 N hydrochloric acid (15 mL), water (15 mL),

and 1:1 water:saturated sodium bicarbonate (20 mL), dried

over anhydrous magnesium sulfate, and evaporated to give a

white solid (5.14 g, 95%); mp 124–126 °C. IR (KBr) (cm^–1):

1

fate, and evaporated to give a yellow oil (2.23 g, 90%). H

NMR (CDCl₃) δ: 7.38 (5H, m, Ar), 6.19 (1H, br d, 7.1 Hz,

NH), 4.70 (1H, m, CHα), 4.17 (2H, t, 6.2 Hz, CH₂γ), 3.76

(3H, s, COCH₃), 3.64 (2H, s, PhCH₂), 2.90 (3H, s, SO₂CH₃),

2.34 (1H, m, CHβ), 2.12 (1H, m, CHβ). ¹³C NMR (CDCl₃)

δ: 171.73, 171.02, 134.36, 129.34, 129.12, 127.55, 65.68,

52.77, 49.34, 43.63, 37.16, 31.46. CI-MS (m/z): 330 ([M +

1]).

1

3305, 1779, 1652. H NMR (CDCl₃) δ: 7.33 (5H, m, Ar),

5.97 (1H, br s, NH), 4.50 (1H, m, CHγ), 4.43 (1H, t, 9.1 Hz,

CHα), 4.25 (1H, m, CHγ), 3.63 (2H, s, PhCH₂), 2.79

(1H, m, CHβ), 2.08 (1H, m, CHβ). ¹³C NMR (CDCl₃) δ:

174.98, 171.49, 134.06, 129.39, 129.13, 127.59, 65.95,

49.37, 43.31, 30.32. CI-MS (m/z): 220 ([M + 1]). Calcd. for

C₁₂H₁₃NO₃: C 65.73, H 5.99, N 6.39; found: C 65.69,

H 5.97, N 6.12.

Synthesis of 27 (R₁= t-BuO, R₂= Me)

1,8-Diazabicyclo[5.4.0]undec-7-ene (3.2 mL, 3.18 g,

20.9 mmol) was added dropwise to a solution of N-hydroxy-

phthalimide (3.40 g, 20.9 mmol) in dimethylformamide

(30 mL). The solution was stirred for 30 min, cooled to 10–

15 °C, and a solution of 26 (R₁= t-BuO, R₂= Me) (6.5 g,

20.9 mmol) in dimethylformamide (10 mL) was added

dropwise. The mixture was then allowed to warm to room

temperature and stirred for 48 h. Approximately 30 mL of

solvent was removed under reduced pressure, and ethyl ace-

tate (100 mL) and water (30 mL) were added. The layers

were separated, and the aqueous layer was washed with

ethyl acetate (2 × 50 mL). The combined organic layers

were washed successively with saturated sodium bicarbonate

(5 × 30 mL), water (30 mL), 5% citric acid (30 mL), water

(30 mL), and saturated sodium chloride (30 mL), dried over

anhydrous magnesium sulfate, and evaporated to yield

8.58 g of a solid. Recrystallization from hot ethanol gave

white crystals, 5.07 g (64%); mp 135–136 °C. IR (KBr)

Phenylacetamido homoserine

A solution of potassium hydroxide (4.51 g, 68.8 mmol) in

methanol (20 mL) was added in portions to a suspension of

α-phenylacetamido-γ-butyrolactone (10.1 g, 45.9 mmol) in

dry methanol (100 mL). The mixture was stirred at room

temperature for 24 h, and Amberlyst 15 (H ⁺) (18.5 g,

82.5 mmol), presoaked in methanol, was added. The mixture

was filtered, and the filtrate was evaporated to an oil (10.9 g,

96%), which was used directly in the next step.

Methyl ester of phenylacetylamido homoserine (25,

R₁= PhCH₂, R₂= Me)

A solution of phenylacetamido homoserine (3.19 g,

13.5 mmol) in dimethylformamide (30 mL) was treated

dropwise with a solution of triethylamine (1.88 mL, 1.36 g,

13.5 mmol) in dimethylformamide (10 mL). Then

iodomethane (1.68 mL, 3.82 g, 26.9 mmol) was added in

one portion, and stirring was continued overnight. Most of

the solvent was removed under reduced pressure, and the

residue was diluted with ethyl acetate (100 mL) and water

(20 mL). The aqueous layer was washed with ethyl acetate

1

(cm^–1): 3365, 1746, 1725, 1680. H NMR (CDCl₃) δ: 7.81

(4H, m, phthalimido ring), 5.68 (1H, d, 7.6 Hz, NH), 4.55

(1H, m, CHα), 4.31 (2H, t, 6.1 Hz, CH₂γ), 3.76 (3H, s,

CH₃), 2.30 (2H, m, CH₂β), 1.45 (9H, s, C(CH₃)₃). CI-MS

(m/z): 379 ([M + 1]). Calcd. for C₁₈H₂₂N₂O₇: C 57.13,

H 5.87, N 7.40; found: C 57.21, H 5.93, N 7.33.

952

Can. J. Chem. Vol. 81, 2003

CH₃), 3.67 (2H, s, PhCH₂), 2.30 (2H, m, CH₂␤). CI-MS

(m/z): 397 ([M + 1]). Calcd. for C₂₁H₂₀N₂O₆: C 63.62,

H 5.10, N 7.07; found: C 63.97, H 5.19, N 7.12.

Methyl BOC-α-amino-γ-aminooxybutyrate (28, R₁= t-

BuO, R₂= Me)

A solution of 27, R₁= t-BuO, R₂= Me (0.50 g, 1.32 mmol),

in dichloromethane (20 mL) was cooled to –10 °C and methyl-

hydrazine (0.10 mL, 91.1 mg, 1.98 mmol) was added

dropwise with stirring. Stirring was continued for 2 h at –10

to 0 °C, and the mixture was then filtered. The filtrate was

concentrated and the residue, in ethyl acetate (15 mL), was

washed with 1:1 saturated sodium chloride:saturated sodium

bicarbonate (10 mL). The aqueous layer was washed with

ethyl acetate (15 mL), and the combined organic layers were

dried over anhydrous magnesium sulfate and evaporated to

give a white solid (0.325 g, 100%). IR (KBr) (cm^–1): 3336,

Methyl 2-phenylacetamido-4-aminooxybutyrate (28,

R₁= PhCH₂, R₂= Me)

Methylhydrazine (0.20 mL, 0.174 g, 3.78 mmol) was

added dropwise at –10 °C to a solution of 27, R₁= PhCH₂,

R₂= Me (1.0 g, 2.52 mmol), in dichloromethane (40 mL).

The cooling bath was removed, and stirring was continued

for 3 h. The mixture was then filtered, and the filtrate was

evaporated. The residue, in ethyl acetate (30 mL), was

washed with 1:1 saturated sodium chloride:saturated sodium

bicarbonate (6 mL). The aqueous layer was extracted with

ethyl acetate (30 mL), and the combined organic extract was

dried over anhydrous magnesium sulfate and evaporated to

1

1738, 1698. H NMR (CDCl₃) δ: 5.62 (2H, br s, ONH₂),

5.29 (1H, d, 6.0 Hz, NH), 4.41 (1H, m, CHα), 3.75 (3H, s,

CH₃), 3.75 (2H, t, 6.2 Hz, CH₂γ), 2.07 (2H, m, CH₂β), 1.45

(9H, s, C(CH₃)₃). CI-MS (m/z): 249 ([M + 1]). Calcd. for

C₁₀H₂₀N₂O₅: C 48.37, H 8.13, N 11.28; found: C 48.77, H

7.96, N 11.36.

1

give a pale yellow oil (0.664 g, 99%). H NMR (CDCl₃) δ:

7.35 (5H, m, Ph), 6.50 (1H, br s, NH), 4.68 (1H, m, CHα),

3.75 (3H, s, COCH₃), 3.65 (2H, t, 5.8 Hz, CH₂γ), 3.65

(2H, s, PhCH₂), 2.03 (2H, m, CH₂β). CI-MS (m/z): 267

([M + 1]).

4-tert-Butoxycarbonylamino-[1,2]oxazinan-3-one (29,

R = t-BuO)

A solution of 28 (R₁= t-BuO, R₂= Me) (0.150 g,

0.607 mmol) in tetrahydrofuran (15 mL) was cooled to 0 °C

and a 2.0 mol/L solution of trimethylaluminium in heptane

(0.60 mL, 1.21 mmol) was added dropwise. The reaction

mixture was allowed to warm to room temperature and was

stirred for 4 h. Water (2 mL) was added dropwise, and after

15 min, the solution was concentrated to near dryness, di-

luted with 1:4 dichloromethane:tetrahydrofuran (50 mL),

and filtered through Celite. The filtrate was concentrated to

give a white solid (128 mg, 98%); mp 119–120 °C. IR (KBr)

4-Phenylacetamido-[1,2]oxazinan-3-one (10)

A 2.0 mol/L solution of trimethylaluminium in hexanes

(1.13 mL, 2.25 mmol) was added dropwise at 0 °C to a solu-

tion of 28, R₁= PhCH₂, R₂= Me (0.300 g, 1.13 mmol), in

toluene (20 mL). The ice bath was removed, and stirring was

continued for 4 h. The reaction mixture was then treated

dropwise with water (1 mL). After an additional 15 min, the

solvent was removed under reduced pressure to near-

dryness; 1:4 dichloromethane:tetrahydrofuran (150 mL) was

added, and the mixture was filtered through Celite. The fil-

trate was concentrated, and the residue was purified by short

column chromatography on silica gel with a gradient solvent

system (hexanes to ethyl acetate) to give a white solid

(91.2 mg, 35%); mp 164–165 °C. IR (KBr) (cm^–1): 3307,

1

(cm^–1): 3364, 1696, 1679, 1528. H NMR (CDCl₃) δ: 8.65

(1H, br s, ONH), 5.43 (1H, br s, NH), 4.54 (1H, m, CHα),

4.21 (1H, m, CHγ), 4.08 (1H, m, CHγ), 2.88 (1H, m, CHβ),

1.74 (1H, m, CHβ), 1.46 (9H, s, C(CH₃)₃). ¹³C NMR

(CDCl₃) δ: 174.11, 155.35, 80.03, 69.77, 47.78, 29.74,

28.09. CI-MS (m/z): 217 ([M + 1]). Calcd. for C₉H₁₆N₂O₄:

C 49.98, H 7.47, N 12.96; found: C 50.17, H 7.47, N 12.74.

1

1694, 1660. H NMR (CDCl₃) δ: 8.17 (1H, br s, ONH), 7.32

(5H, m, Ar), 6.41 (1H, br s, NH), 4.72 (1H, m, CHα), 4.23

(1H, m, CHγ), 4.04 (1H, m, CHγ), 3.63 (2H, s, PhCH₂), 2.98

(1H, m, CHβ), 1.63 (1H, m, CHβ). ¹³C NMR (CDCl₃) δ:

173.52, 171.08, 134.45, 129.30, 128.96, 127.37, 69.84,

47.02, 43.56, 28.99. CI-MS (m/z): 235 ([M + 1]). Calcd. for

C₁₂H₁₄N₂O₃: C 61.52, H 6.04, N 11.96; found: C 61.32,

H 6.04, N 11.92.

Methyl α-phenylacetamido-γ-phthalimidooxybutyrate

(27, R₁= PhCH₂, R₂= Me)

Triethylamine (0.95 mL, 0.69 g, 6.78 mmol) was added

slowly to a solution of N-hydroxyphthalimide (1.11 g,

6.78 mmol) in acetonitrile (15 mL). The solution was stirred

for 20 min, cooled to 10–15 °C, and a solution of 26 (R₁=

PhCH₂, R₂= Me) (2.23 g, 6.78 mmol) in acetonitrile (5 mL)

was added dropwise. The reaction mixture was allowed to

warm to room temperature, and stirring was continued for

24 h. The solvent was removed, and the residue was dis-

solved in ethyl acetate (50 mL). This solution was washed

successively with water (2 × 15 mL), saturated sodium bi-

carbonate (8 × 15 mL), water (15 mL), 5% citric acid

(15 mL), water (15 mL), and saturated sodium chloride

(15 mL), dried over anhydrous magnesium sulfate, and evap-

orated. The resulting solid was recrystallized from hot etha-

nol to give 2.25 g (84%); mp 138–139 °C. IR (KBr) (cm^–1):

TFA salt of cyclocanaline

The BOC derivative 27, R = t-BuO (50.9 mg, 0.235 mmol),

was added, with stirring, to a cooled (0 to –5 °C) solution of

trifluoroacetic acid (0.75 mL). The mixture was allowed to

warm to room temperature and was stirred for 1 h. The sol-

vent was then removed under reduced pressure, and the resi-

due was triturated with ether to give a white solid (53.0 mg,

1

98%). H NMR (D₂O) δ: 4.29 (1H, m, CHγ), 4.09 (1H, m,

CHγ), 4.08 (1H, m, CHα), 2.77 (1H, m, CHβ), 2.06 (1H, m,

CHβ).

4-Phenoxyacetamido-[1,2]oxazinan-3-one

1

3348, 1792, 1735, 1664. H NMR (CDCl₃) δ: 7.81 (4H, m,

Triethylamine (0.2 mL, 0.145 g, 1.43 mmol) was added

slowly to a suspension of the trifluoroacetic acid salt of

cyclocanaline (0.150 g, 0.63 mmol) in dichloromethane

phthalimido ring), 7.24 (5H, m, Ph), 6.15 (1H, br s, NH),

4.87 (1H, m, CHα), 4.21 (2H, t, 5.8 Hz, CH₂γ), 3.73 (3H, s,

Wolfe et al.

953

(5 mL); the mixture was cooled to –10 °C, and a solution of

phenoxyacetyl chloride (0.079 mL, 97.2 mg, 0.57 mmol) in

dichloromethane (2 mL) was added dropwise. The reaction

mixture was allowed to warm to room temperature and was

stirred overnight and then washed successively with water

(2 mL), 5% citric acid (2 mL), water (2 mL), and 1:1 satu-

rated sodium chloride:saturated sodium bicarbonate (2 mL),

dried over anhydrous magnesium sulfate, and evaporated.

The residue was purified by short column chromatography on

silica gel, using hexanes to ethyl acetate gradient solvent sys-

tem, to give a white solid (29.8 mg, 38%). IR (KBr) (cm^–1):

Methyl ester of R-carbobenzoxyhomoserine

A solution of potassium hydroxide (0.716 g, 12.77 mmol)

in methanol (8 mL) was added dropwise to a stirred suspen-

sion of the carbobenzoxy lactone (2.00 g, 8.51 mmol) in

methanol (12 mL). The resulting solution was stirred at room

temperature for 18 h, and the reaction was then quenched

with a stream of carbon dioxide. Evaporation of the solvent

produced a white crystalline solid. This solid was dissolved

in dimethylformamide (10 mL), and iodomethane (1.72 mL,

0.028 mmol) was added. The reaction mixture was stirred at

room temperature for 66 h, and the solvent was evaporated.

The residue was shaken with ethyl acetate (40 mL) and wa-

ter (10 mL). The aqueous phase was extracted with ethyl ac-

etate (2 × 10 mL), and the combined organic extracts were

washed successively with water (10 mL), saturated sodium

thiosulfate (10 mL), saturated sodium bicarbonate (10 mL),

brine (10 mL), and dried over anhydrous magnesium sulfate.

Removal of the solvent afforded 1.73 g (76%) of the product

as a pale yellow oil. ¹H NMR (100 MHz, CDCl₃): 1.60 (m,

1H, NHCHCHH), 2.40 (m, 1H, NHCHCHH), 3.60–3.90 (m,

5H, NHCHCH₂CH₂and CO₂CH₃), 4.40–4.70 (m, 1H,

NHCH), 5.20 (s, 2H, CH₂Ph), 5.70 (br. s, 1H, NH), 7.40 (s,

5H, ArH).

1

3314, 1686, 1655. H NMR (CDCl₃) δ: 7.53 (1H, br s, NH),

7.15 (5H, m, Ar), 4.84 (1H, m, CHα), 4.55 (2H, s, PhOCH₂),

4.28 (1H, m, CHγ), 4.11 (1H, m, CHγ), 3.03 (1H, m, CHβ),

1.78 (1H, m, CHβ). ¹³C NMR (CDCl₃) δ: 173.06, 168.47,

157.20, 129.75, 122.17, 114.79, 69.89, 67.29, 46.66, 28.94.

CI-MS (m/z): 251 ([M + 1]).

Carbobenzoxy ^D-methionine

D-Methionine (29.4 g, 0.20 mol) was added to a solution

of 2 N sodium bicarbonate (500 mL). The mixture was

cooled in an ice bath, and benzyl chloroformate (37 mL,

0.26 mol) was added dropwise. After the addition, the mix-

ture was allowed to warm to room temperature and was

stirred for 22 h. The unreacted benzyl chloroformate was

then removed by extraction with ether (4 × 300 mL). The pH

of the aqueous solution was adjusted to 2–3 using 6 N HCl

(a whitish precipitate formed), and the mixture was extracted

with ethyl acetate (5 × 200 mL). These extracts were dried

over anhydrous sodium sulfate, and the solvent was removed

to give 41.72 g (74%) of a light yellow oil. ¹H NMR

(100 MHz, CDCl₃): 2.10 (s, 3H, -SCH₃), 2.15 (t, 2H,

NHCHCH₂), 2.60 (t, 2H, NHCHCH₂CH₂), 4.60 (m, 1H,

NHCH), 5.20 (s, 2H, CH₂Ph), 5.50 (d, 1H, NH), 7.40 (s, 5H,

ArH).

Mesylation of the methyl ester of R-carbobenzoxyhomo-

serine

The carbobenzoxy methyl ester (1.71 g, 6.40 mmol) was

dissolved in methylene chloride (30 mL), and triethylamine

(1.2 mL, 8.499 mmol) was added in one portion. After 5 min

of stirring, the reaction mixture was cooled (–5 to –10 °C),

and methanesulfonyl chloride (0.63 mL, 8.206 mmol) was

added dropwise. The reaction mixture was stirred at 0 °C for

2 h, diluted with methylene chloride (20 mL), and washed

successively with water (2 × 10 mL), 1 N hydrochloric acid

(10 mL), water (10 mL), saturated sodium bicarbonate

(10 mL + 10 mL of water), and dried over anhydrous mag-

nesium sulfate. Removal of the solvent afforded 2.10 g

Carbobenzoxy R-α-amino-γ-butyrolactone

1

(100%) of the mesylate as a yellow oil. H NMR (100 MHz,

Carbobenzoxy ^D-methionine (41.72 g, 0.1474 mol) was

dissolved in a mixture of glacial acetic acid (44.5 mL) and

80% HF (89 mL); iodomethane (16.7 mL, 0.268 mol) was

added, and the mixture was left in the dark for 15 h, produc-

ing a clear, orange solution. This solution was concentrated

in vacuo below 40 °C, and the resulting oily residue was

triturated with dry ether (3 × 20 mL). The ether-insoluble or-

ange oil was dissolved in 1 N sodium hydroxide (180 mL).

The white crystals that appeared after cooling to 0 °C were

collected, washed well with water, and maintained at 1 torr

(1 torr = 133.322 Pa) for 5 h. The mother liquor from the

washings was then acidified to pH 2 with concentrated hy-

drochloric acid, allowed to stand at room temperature for

1 h, and extracted with ethyl acetate (3 × 200 mL). The

combined extracts were washed with 4% sodium bicarbonate

(2 × 100 mL), brine (2 × 100 mL), and dried over anhydrous

magnesium sulfate. Removal of the solvent afforded a yel-

low precipitate, which was crystallized from isopropyl alco-

CDCl₃): 2.30 (m, 2H, NHCHCH₂), 3.02 (s, 3H, SO2CH₃),

3.82 (s, 3H, CO₂CH₃), 4.25–4.55 (m, 3H, NHCH and

NHCHCH₂CH₂), 5.18 (s, 2H, CH₂Ph), 5.55 (br. d, 1H, NH),

7.45 (d, 5H, ArH).

Methyl ester of R-2-carbobenzoxyamido-4-phthalimido-

oxybutyric acid

1,8-Diazabicyclo[5.4.0]undec-7-ene (1.74 mL, 11.62 mmol)

was added portionwise, with stirring, to a solution of N-

hydroxyphthalimide (2.08 g, 12.75 mmol) in dimethylform-

amide (12 mL). After 20 min, the dark red reaction mixture

was cooled to 10–15 °C, and a solution of the mesylate

(2.10 g, 6.68 mmol) in dimethylformamide (10 mL) was

added dropwise with stirring. The reaction mixture was

stirred at room temperature for 24 h and then diluted with

ethyl acetate (80 mL) and washed with water (6 × 15 mL)

until a pale yellow aqueous phase was obtained. The organic

layer was washed with saturated sodium bicarbonate (9 ×

12 mL) and saturated brine (2 × 12 mL), dried over anhy-

drous magnesium sulfate, and evaporated. The resulting pale

yellow solid (2.32 g) was recrystallized from 85% ethanol to

yield 1.81 g (66%) of the mesylate as a white powder; mp

1

hol. The total yield of product was 6.62 g (20%). H NMR

(100 MHz, CDCl₃): 2.30 (m, 1H, NHCHCHH), 2.80 (m, 1H,

NHCHCHH), 4.20 (m, 3H, NHCH and NHCHCH₂CH₂),

5.20 (s, 2H, CH₂Ph), 5.40 (br. s, 1H, NH), 7.40 (s, 5H,

ArH).

954

Can. J. Chem. Vol. 81, 2003

102–104 °C. ¹H NMR (100 MHz, CDCl₃): 2.30 (q, 2H,

NHCHCH₂), 3.80 (s, 3H, CO₂CH₃), 4.38 (t, 2H,

NHCHCH₂CH₂), 4.70 (m, 1H, NHCH), 5.20 (s, 2H,

CH₂Ph), 6.20 (br. d, 1H, NH), 7.40 (s, 5H, ArH), 7.85 (m,

4H, ArH from N-hydroxyphthalimide).

the combined filtrates were evaporated to yield 77.1 mg

(62%) of yellow crystals. H NMR (100 MHz, D₂O): 1.20–

2.00 (m, 2H, NH₂CHCH₂), 3.00–3.30 (m, 1H, NH₂CH), 3.40

(t, 2H, NH₂CHCH₂CH₂).

1

BOC-R-cycloserine (30)

Methyl ester of R-2-carbobenzoxyamido-4-aminooxy-

butyric acid

To a suspension of R-cycloserine (2.00 g, 19.6 mmol) in

50% aqueous acetone (25 mL) were added triethylamine

(4.1 mL, 2.98 g, 29.4 mmol) and BOC-ON (5.31 g,

21.5 mmol). The reaction mixture was stirred overnight at

room temperature; most of the solvent was removed under

reduced pressure, and ethyl acetate (70 mL) was added. The

aqueous layer was separated, acidified to pH 3–4 with 5%

citric acid (75 mL), and extracted with ethyl acetate

(90 mL). The latter extract was washed successively with

water (3 × 90 mL) and saturated sodium chloride (90 mL),

dried over anhydrous magnesium sulfate, and evaporated.

Purification by flash chromatography on silica gel, using

ethyl acetate – hexanes (2:1) as the eluent, gave 2.41 g

(61%) of the product; mp 140–142 °C. IR (CH₂Cl₂) (cm^–1):

A solution of methylhydrazine (0.34 mL, 6.305 mmol) in

tetrahydrofuran (2 mL) was added dropwise, with cooling at

5 °C and stirring, to a solution of the phthalimidooxy com-

pound (2.00 g, 4.85 mmol) in tetrahydrofuran (15 mL). The

reaction mixture was allowed to warm to room temperature,

and stirring was continued for 24 h. A white precipitate was

then removed by filtration, and the filtrate was evaporated to

dryness. The residue was then dissolved in methylene chlo-

ride (10 mL) and filtered through a plug of Silica Gel 60H

for TLC, with elution by methylene chloride (35 mL). Evap-

oration of the solvent afforded 1.18 g (86%) of the product

1

as a pale yellow oil. H NMR (100 MHz, CDCl₃): 2.10 (m,

1

2H, NHCHCH₂), 3.75 (m, 5H, NHCHCH₂CH₂and

CO₂CH₃), 4.55 (m, 1H, NHCH), 4.15 (s, 2H, CH₂Ph), 5.65

(br. d, 1H, NH), 7.40 (s, 5H, ArH).

1711, 1689. H NMR (CDCl₃) δ: 9.88 (1H, br s, NH), 5.50

(1H, br s, BOCNH), 4.79 (1H, m, CHβ), 4.58 (1H, m, CHα),

4.10 (1H, m, CHβ), 1.45 (9H, s, C(CH₃)). ¹³C NMR (CDCl₃)

δ: 170.81, 155.73, 80.78, 74.80, 52.77, 28.24. CI-MS (m/z):

203 ([M + 1]). Calcd. for C₈H₁₄N₂O₄: C 47.52, H 6.98,

N 13.85; found: C 47.67, H 7.07, N 13.10.

Carbobenzoxy R-cyclocanaline

A solution of the carbobenzoxy methyl ester (1.15 g,

4.08 mmol) in tetrahydrofuran (65 mL) was treated dropwise

at 0–5 °C with trimethylaluminium (2.45 mL of a 2 mol/L

solution in hexane, 4.89 mmol). Stirring of the colourless re-

action mixture was continued for 1 h, and the cooling bath

was then removed while stirring continued for another 2 h.

The slightly yellowish reaction mixture was then cooled to

0 °C, water (7 mL) was added dropwise, and stirring was

continued for 1 h. Removal of the solvent afforded a white

solid, which was triturated with ethyl acetate (100 mL) and

filtered through a plug of Sililca Gel 60H for TLC. Elution

with ethyl acetate (100 mL) and evaporation of the solvent

yielded 1.17 g of a pale yellow semi-solid, which was fur-

ther purified by column chromatography on silica gel (30%

ethyl acetate – hexanes to 60% ethyl acetate – hexanes) to

give 456 mg (44%) of carbobenzoxy ^D-cyclocanaline as a

white solid (mp 126–127 °C). ¹H NMR (100 MHz, CD₃CN):

1.60–2.10 (m, 1H, NHCHCHH), 2.40–2.80 (m, 1H,

Mitsunobu reaction of 30 with ethyl S-lactate

Diethyl azodicarboxylate (0.058 mL, 64.1 mg,

0.371 mmol) was added to a solution of triphenylphosphine

(0.103 g, 0.393 mmol) in tetrahydrofuran (3.2 mL) and cooled

to –56 to –50 °C. The solution was stirred for 10 min; ethyl

S-lactate (0.031 mL, 32.3 mg, 0.272 mmol) was added, and

stirring was continued for an additional 10 min at –50 °C, at

which time BOC-R-cycloserine (50.0 mg, 0.247 mmol) was

added. Stirring was continued while the resulting mixture

was allowed to warm to room temperature during 2.5 h. The

solvent was then removed under reduced pressure. Purifica-

tion of the residue by flash chromatography on silica gel, us-

ing 2:1 hexanes:ethyl acetate as the eluent, yielded a 1:1

mixture of diastereomeric products (64.7 mg, 87%). ¹H

NMR (CDCl₃) δ: 5.25 (1H, br s, BOCNH, both isomers),

4.96 (1H, q, 6.9 Hz, CHCH₃, one isomer), 4.80 (1H, q,

7.5 Hz, CHCH₃, second isomer), 4.71 (1H, m, CHβ, both

isomers), 4.57 (1H, m, CHα, both isomers), 4.22 (2H, q,

7.1 Hz, CH₂CH₃, one isomer), 4.21 (2H, q, 7.1 Hz, CH₂CH₃,

second isomer), 4.21 (1H, m, CHβ, both isomers), 1.58 (3H,

d, 6.7 Hz, CHCH₃, one isomer), 1.53 (3H, d, 7.4 Hz,

CHCH₃, second isomer), 1.45 (9H, s, C(CH₃), one isomer),

1.44 (9H, s, C(CH₃), second isomer), 1.29 (3H, t, 7.1 Hz,

CH₂CH₃, one isomer), 1.28 (3H, t, 7.1 Hz, CH₂CH₃, second

isomer). CI-MS (m/z): 303 ([M + 1]) (both isomers).

NHCHCHH),

3.90–4.70

(m,

3H,

NHCH

and

NHCHCH₂CH₂), 5.80–6.20 (br. d, 1H, NHCH), 7.30–7.50

(s, 5H, ArH), 8.60–9.00 (br. s, 1H, ONH). CI-MS (isobu-

tane) m/z: 251 ([M⁺+ 1]). Calcd. for C₁₂H₁₄N₂O₄: C 57.65,

H 5.64, N 11.20; found: C 57.89, H 5.71, N 11.34.

R-Cyclocanaline

The carbobenzoxy compound (268 mg, 1.071 mmol) was

treated in one portion with 30% hydrogen bromide in acetic

acid (0.80 mL) in a flask protected with a calcium chloride

drying tube. A gas was produced immediately. The mixture

was allowed to stand at room temperature for 1 h with occa-

sional shaking, and ether (5 mL) was then added. The

supernatant was decanted, and the precipitated solid was

triturated with ether, maintained at 1 torr for 2 h, and then

dissolved in methanol and treated, with shaking for 5 min,

with an ion-exchange resin (CGA-540, OH^–form, 1.15 g).

The resin was filtered, rinsed with methanol (10 mL), and

Mitsunobu reaction of 21 with ethyl S-lactate

Ethyl S-lactate (0.062 mL, 64.6 mg, 0.544 mmol) was

added at room temperature to a stirred solution of

[1,2]oxazinan-3-one (21) (45.4 mg, 0.449 mmol) in di-

chloromethane (2.8 mL). Triphenylphosphine (0.157 g,

0.597 mmol) was added; stirring was continued for 10 min

at room temperature; the reaction mixture was cooled in an

ice bath, and diethyl azodicarboxylate (0.093 mL, 0.103 g,

Wolfe et al.

955

0.593 mmol) was added dropwise. The solution was allowed

to warm to room temperature overnight, with stirring. The

solvent was removed under reduced pressure, and the resi-

due was purified by preparative layer chromatography on

silica gel, using 7:4 hexanes:ethyl acetate as the eluent, to

give 46.4 mg (51%) of the N-alkylated adduct 33 and 6.7 mg

3.75 (1H, q, 7.0 Hz, CH), 3.69 (2H, t, 6.3 Hz, CH₂γ), 3.65

(3H, s, OCH₃), 2.33 (2H, t, 7.4 Hz, CH₂α), 1.87 (2H, m,

CH₂β), 1.23 (3H, d, 7.0 Hz, CHCH₃). ¹³C NMR (CDCl₃) δ:

174.11, 173.89, 135.67, 128.55, 128.28, 128.11, 73.01,

66.55, 58.88, 51.54, 30.68, 23.91, 14.75. CI-MS (m/z): 296

([M + 1]).

1

(7%) of the O-alkylated adduct 34. N-Alkylated adduct: H

NMR (CDCl₃) δ: 5.03 (1H, q, 6.9 Hz, CH), 4.23 (2H, q,

7.1 Hz, CH₂CH₃), 3.87 (2H, m, CH₂γ), 2.34 (2H, m, CH₂α),

2.03 (2H, m, CH₂β), 1.51 (3H, d, 7.0 Hz, CHCH₃), 1.31 (3H,

Cyclization of 35

A solution of 35 (1.63 g, 5.5 mmol) in toluene (80 mL)

was cooled to 0 °C and a 2.0 mol/L solution of trimethyl-

aluminium in toluene (5.4 mL, 10.8 mmol) was added

dropwise. The reaction mixture was allowed to warm to room

temperature, stirred overnight, and then cooled to 0 °C,

treated dropwise with methanol (16 mL), and stirred for

20 min. Water (10 mL) was added; the ice bath was re-

moved, and stirring was continued for another 15 min. The

solution was then concentrated to near-dryness, 1:4 dichloro-

methane:tetrahydrofuran (200 mL) was added, and the mix-

ture was filtered through Celite. The filtrate was evaporated

to give the crude product, 1.19 g, together with some

unreacted starting material. Purification by flash chromatog-

raphy on silica gel using an ethyl acetate – hexanes gradient

solvent system, 10–40%, gave a clear oil (0.99 g, 84%). IR

1

t, 7.1 Hz, CH₂CH₃). O-Alkylated adduct: H NMR (CDCl₃)

δ: 5.20 (1H, q, 7.3 Hz, CH), 4.24 (2H, q, 7.1 Hz, CH₂CH₃),

4.17 (2H, m, CH₂γ), 2.56 (2H, m, CH₂α), 2.14 (2H, m,

CH₂β), 1.50 (3H, d, 7.3 Hz, CHCH₃), 1.29 (3H, t, 7.2 Hz,

CH₂CH₃).

Benzyl (S)-lactate

1,8-Diazabicyclo[5.4.0]undec-7-ene (18 mL, 18.3 g,

0.12 mol) was added slowly, with stirring, to a solution of

85% S-lactic acid (12.7 g, 0.12 mol) in methanol (50 mL).

The solvent was removed under reduced pressure at 70–

80 °C, and the resulting oil, in dimethylformamide (50 mL),

was cooled to 15 °C. Benzyl bromide (11.9 mL, 17.1 g,

0.10 mol) was added dropwise, and the reaction mixture was

stirred at room temperature for 30 h. After removal of ap-

proximately 40 mL of solvent by vacuum distillation, ethyl

acetate (100 mL) was added, followed by water (30 mL).

The aqueous layer was washed with ethyl acetate (2 ×

30 mL), and the combined organic extracts were washed

successively with water (30 mL), 5% citric acid (30 mL),

water (30 mL), saturated sodium bicarbonate (3 × 30 mL),

and saturated sodium chloride (2 × 30 mL), dried over anhy-

drous magnesium sulfate, and evaporated. The crude product

was distilled, to give a colourless oil (13.8 g, 76%); bp 119–

(neat) (cm^–1): 1744, 1660. H NMR (CDCl₃) δ: 7.35 (5H, m,

1

Ar), 5.24 (1H, q, 7.3 Hz, CH), 5.20 (1H, d, 13.0 Hz, PhCH),

5.14 (1H, d, 13.0 Hz, PhCH), 4.14 (1H, m, CHγ), 3.98

(1H, m, CHγ), 2.51 (2H, m, CH₂α), 2.08 (2H, m, CH₂β),

1.50 (3H, d, 7.3 Hz, CHCH₃). ¹³C NMR (CDCl₃) δ: 170.90,

170.13, 135.45, 128.53, 128.30, 128.07, 69.32, 67.09, 53.17,

28.32, 22.11, 13.76. CI-MS (m/z): 264 ([M + 1]).

Hydrogenolysis of 36

To ethyl acetate (15 mL) was added 10% palladium on ac-

tivated carbon (83.0 mg, 0.078 mmol), and the suspension

was stirred in an atmosphere of hydrogen for 1 h. The

benzyl ester 36 (0.206 g, 0.78 mmol) in ethyl acetate

(15 mL) was then added, and stirring was continued for

24 h. The mixture was filtered through Celite, which was

washed with ethyl acetate (2 × 4 mL), and the combined fil-

trates were evaporated to give 37 as a white solid (0.13 g,

1

123 °C at 1 torr. IR (neat) (cm^–1): 3483, 1738. H NMR

(CDCl₃) δ: 7.37 (5H, m, Ar), 5.21 (2H, s, PhCH₂), 4.32 (1H,

q, 6.9 Hz, CH), 2.38 (1H, br s, OH), 1.43 (3H, d, 6.9 Hz,

CH₃). ¹³C NMR (CDCl₃) δ: 175.52, 135.23, 128.66, 128.54,

128.22, 67.31, 66.84, 20.37. CI-MS (m/z): 181 ([M + 1]).

Calcd. for C₁₀H₁₂O₃: C 66.64, H 6.73; found: C 66.30,

H 6.75.

99%). IR (KBr) (cm^–1): 1744, 1621. H NMR (CDCl₃) δ:

1

5.22 (1H, q, 7.3 Hz, CH), 4.23 (1H, m, CHγ), 4.05 (1H, m,

CHγ), 2.56 (2H, m, CH₂α), 2.13 (2H, m, CH₂β), 1.52 (3H, d,

7.3 Hz, CHCH₃). ¹³C NMR (CDCl₃) δ: 173.78, 171.18,

69.61, 53.19, 28.26, 22.09, 13.58. CI-MS (m/z): 174 ([M +

1]). Calcd. for C₇H₁₁NO₄: C 49.54, H 6.61, N 8.09; found:

C 49.36, H 6.52, N 7.86.

Coupling of 20 with the triflate of benzyl S-lactate

A solution of 2,6-lutidine (0.35 mL, 0.32 g, 3.0 mmol) in

dichloromethane (3 mL) was added at –78 °C to a solution

of benzyl S-lactate (0.271 g, 1.5 mmol) in dichloromethane

(15 mL). The solution was stirred for 10 min, trifluoro-

methanesulfonic anhydride (0.25 mL, 0.42 g, 1.5 mmol) was

added dropwise, and stirring was continued for 30 min at –78

to –50 °C. A solution of methyl γ-aminooxybutyrate

(0.170 g, 1.28 mmol) and 2,6-lutidine (0.175 mL, 0.16 g,

1.5 mmol) in dichloromethane (6 mL) was then added

dropwise at –78 °C. The reaction mixture was allowed to

warm to room temperature, stirred for 18 h, and then washed

with water (2 × 10 mL). The organic phase was further

washed with saturated sodium chloride (10 mL), dried over

anhydrous magnesium sulfate, and evaporated. Purification

by flash chromatography on silica gel using a gradient sys-

tem, hexanes to ethyl acetate, gave 1.63 g (74%) of 35. IR

Alkylation of 28, R₁= PhCH₂, R₂= Me, with the triflate

of benzyl S-lactate

A solution of 2,6-lutidine (0.60 mL, 0.54 g, 5.0 mmol) in

dichloromethane (3 mL) was added, with stirring, to a cooled

(–78 °C) solution of benzyl S-lactate (0.450 g, 2.5 mmol) in

dichloromethane (15 mL). After 10 min, trifluoromethane-

sulfonic anhydride (0.42 mL, 0.71 g, 2.5 mmol) was added

dropwise, and stirring was continued at –78 to –50 °C for an

additional 30 min. A solution of methyl 2-phenylacetamido-

4-aminooxybutyrate (28) (0.678 g, 2.5 mmol) and 2,6-

lutidine (0.30 mL, 0.27 g, 2.5 mmol) in dichloromethane

(15 mL) was then added dropwise. When the addition was

complete, the reaction mixture was allowed to warm to room

1

(neat) (cm^–1): 3264, 1741, 1736. H NMR (CDCl₃) δ: 7.34

(5H, m, Ar), 5.19 (2H, s, PhCH₂), 5.14 (1H, br d, ONH),

956

Can. J. Chem. Vol. 81, 2003

temperature and stirred for 18 h. Water (2 × 10 mL) was

added, and the separated organic phase was washed with sat-

urated sodium chloride (10 mL), dried over anhydrous mag-

nesium sulfate, and evaporated. The residue was purified by

flash chromatography on silica gel using a gradient system,

hexanes to ethyl acetate, to give an oil (0.304 g, 29%). 4-

Phenylacetamido-[1,2]oxazinan-3-one (10) was also found

as a side product (0.136 g, 23%). IR (CH₂Cl₂) (cm^–1): 3286,

1742, 1660. ¹H NMR of 38 (CDCl₃) δ: 7.34 (10H, m,

PhCH₂CO, PhCH₂O, both isomers), 6.35 (1H, d, 7.9 Hz,

CONH, one isomer, exchanges in CD₃OD), 6.32 (1H, d,

7.5 Hz, CONH, second isomer, exchanges in CD₃OD), 5.77

(1H, d, 9.5 Hz, ONH, one isomer, exchanges in CD₃OD),

5.74 (1H, d, 8.9 Hz, ONH, second isomer, exchanges in

CD₃OD), 5.16 (2H, d, 4.12 Hz, PhCH₂O, one isomer), 5.15

(2H, d, 4.12 Hz, PhCH₂O, second isomer), 4.62 (1H, m, CH

α, both isomers), 3.69 (2H, t, 6.3 Hz, CH₂γ, both isomers),

3.68 (3H, s, OCH₃, one isomer), 3.67 (3H, s, OCH₃, second

isomer), 3.68–3.66 (1H, m, CHCH₃, both isomers), 3.59

(2H, m, PhCH₂CO, both isomers), 2.01 (2H, m, CH₂β, both

isomers), 1.19 (3H, d, 7.2 Hz, CHCH₃, one isomer) 1.18

(3H, d, 7.2 Hz, CHCH₃, second isomer). ¹³C NMR (CDCl₃)

δ:173.56, 172.32, 170.82, 135.55, 134.74, 129.37, 128.90,

128.87, 128.59, 128.21,.127.25, 70.30 (PhCH₂O, one iso-

mer), 70.09 (PhCH₂O, second isomer), 66.76 (CH₂γ, both

isomers), 58.63(CHCH₃, one isomer), 58.57 (CHCH₃, sec-

ond isomer), 52.36 (PhCH₂CO, both isomers), 50.23 (OCH₃,

both isomers), 43.50 (CHα, both isomers), 30.45 (CH₂β,

both isomers), 14.72 (CHCH₃, one isomer), 14.62 (CHCH₃,

second isomer). CI-MS (m/z): 429 ([M + 1]). Calcd. for

The reaction mixture was then diluted with ethyl acetate

(40 mL) and filtered through a pad of Silica Gel 60H (for

TLC), which was washed with ethyl acetate (30 mL). The

filtrate was washed with water (4 × 30 mL), 10% potassium

bisulfate (15 mL), saturated sodium bicarbonate (15 mL),

and brine (30 mL), and dried over anhydrous magnesium

sulfate. Removal of the solvent provided 0.621 g of a yel-

lowish oil, which was purified by flash chromatography (Sil-

ica Gel 60, 15% ethyl acetate – hexanes → 70% ethyl

acetate – hexanes) to afford 40a (0.183 g, 26%) and 40b

(0.215 g, 31%) as colourless oils.

40a

1

IR (film) (cm^–1): 3319, 2988, 1737, 1658, 1537, 1370. H

3

NMR (400 MHz, CDCl₃): 1.42 (3H, d, J = 7.4, a-Me), 1.44

(9H, CMe₃), 1.69 (1H, m,²J = –12.1, J = 10.0, 12.0, C5-

3

2

3

H1), 2.91 (1H, m, J = –12.1, J = 4.8, 6.9, 7.0, C5-H2),

3.60 (2H, CH₂Ph), 4.14 (1H, m, J = –10.1, J = 7.0, 10.0,

C6-H4), 4.40 (1H, m, J = –10.1, J = 4.8, 10.0, C6-H3),

4.67 (1H, m, J = 6.8, 6.9, 12.0, C4-H5), 4.95 (1H, q, J =

7.4, a-CH), 6.49 (1H, br. d, ³J = 6.8, NH), 7.26–7.37 (5H, m,

Ph). ¹³C NMR (100 MHz, CDCl₃): 14.06, 27.93, 29.24,

47.51, 54.33, 69.00, 82.30, 127.34, 128.94, 129.32, 134.51,

169.21, 170.28, 170.86. CI-MS (isobutane) m/z: 363 ([M⁺+

1]).

2

3

2

3

40b

1

IR (film) (cm^–1): 3311, 2981, 1739, 1657, 1539, 1370. H

NMR (400 MHz, CDCl₃): 1.42 (9H, CMe₃), 1.44 (3H, d,

³J = 7.3, a-Me), 1.61 (1H, m,²J = –12.4, C5-H1), 2.95

2

3

.

(1H, m, J = –12.4, J = 4.9, 7.2, 10.1, C5-H2), 3.62 (2H,

C₂₃H₂₈N₂O₆0.75H₂O: C 62.51, H 6.68, N 6.34; found:

C 62.36, H 6.35, N 6.38.

2

3

CH₂Ph), 4.02 (1H, m, J = –10.2, J = 4.9, 10.1, C6-H4),

4.24 (1H, m, ²J = –10.2, ³J = 6.9, 10.3, C6-H3), 4.71

3

(1H, m, J = 5.6, 7.2, 11.7, C4-H5), 4.87 (1H, q, J = 7.3, a-

Cyclization of 38

3

CH), 6.48 (1H, br. d, J = 5.6, NH), 7.24–7.37 (5H, m, Ph).

A 2.0 mol/L solution of trimethylaluminium in hexanes

(0.20 mL, 0.4 mmol) was added dropwise, at 0 °C, to a solu-

tion of 38 (42 mg, 0.10 mmol) in toluene (10 mL). The cool-

ing bath was removed, and the reaction mixture was stirred

overnight. Water (1 mL) was then added slowly, and stirring

was continued for 15 min. The solvent was evaporated to

near-dryness under reduced pressure; 1:4 dichloro-

methane:tetrahydrofuran (100 mL) was added, and the mix-

ture was filtered through Celite. The filtrate was evaporated

to give an oil (18 mg). Purification by short column chroma-

tography, using a hexanes to ethyl acetate gradient solvent

system, gave 3.9 mg of one isomer as a white solid; mp

¹³C NMR (CDCl₃): 13.40, 27.90, 28.94, 43.67, 47.77, 54.86,

69.15, 82.38, 127.36, 128.96, 129.35, 134.52, 168.27,

170.87, 171.94. CI-MS (isobutane) m/z: 363 ([M + 1]).

Deprotection of 40a

Ice-cold trifluoroacetic acid (1.5 mL) was added dropwise

to 40a (0.149 g, 0.41 mmol), with cooling (0 to –5 °C) and

stirring. The reaction mixture was stirred for 1 h at room

temperature and evaporated to dryness under reduced pres-

sure. The semisolid residue was triturated with dry ether and

dried in vacuo to afford 0.075 g (60%) of the acid 5a as a

white solid; mp 58–60 °C. IR (KBr) (cm^–1): 3280, 2950,

1735, 1654, 1544, 1454. ¹H NMR (400 MHz, CD₃OD): 1.46

1

106–107 °C. H NMR (CD₃OD): 7.31 (10H, m, PhCH₂CO,

PhCH₂O), 6.44 (1H, d, 5.6 Hz, CONH), 5.14 (2H, q, 8.8 Hz,

PhCH₂O), 5.10 (1H, q, 7.2 Hz, CHCH₃), 4.66 (1H, m, CHa),

4.22 (1H, m, CH γ), 4.06 (1H, m, CH γ), 3.61 (2H, s,

PhCH₂), 2.85 (1H, m, CH β), 1.60 (1H, m, CH β), 1.48 (3H,

d, 7.3 Hz, CH₃). ¹³C NMR (CD₃OD): 170.88, 170.42,

170.03, 135.03, 134.46, 129.35, 129.00, 128.66, 128.30,

127.41, 69.01, 67.43, 53.67, 47.51, 43.68, 29.15.

3

(3H, d, J = 7.3, a-Me), 1.96 (1H, m,²J = –12.5, J = 6.5,

2

3

9.5, C5-H1), 2.56 (1H, m, J = –12.5, J = 5.4, 7.4, 9.5, C5-

H2), 3.61 (2H, CH₂Ph), 4.18 (1H, m, J = –10.3, J = 6.5,

10.3, C6-H4), 4.43 (1H, m, J = –10.3, J = 5.4, 9.5, C6-

H3), 4.76 (1H, dd, J = 7.4, 10.5, C4-H5), 5.04 (1H, q, J =

7.3, a-CH), 7.21–7.38 (5H, m, Ph). ¹³C NMR (CD₃OD):

14.23, 30.05, 43.61, 48.36, 55.01, 70.19, 127.90, 129.55,

130.23, 136.70, 171.89, 173.26, 174.20. CI-MS (isobutane),

m/z: 307 ([M + 1]).

2

3

2

3

Synthesis of the tert-butyl esters 40a and 40b

To a stirred solution of 4-phenylacetylamido-[1,2]oxazinan-

3-one (10) (0.447 g, 1.91 mmol) and tert-butyl S-α-bromo-

propionate (0.398 g, 1.91 mmol) in dry dimethylformamide

(15 mL) was added KF–Al₂O₃(40 wt %, 1.94 g) in one por-

tion. Stirring was continued at room temperature for 63 h.

Deprotection of 40b

Repetition of the above experiment with 40b afforded the

acid 5b in 58% yield as a white solid; mp 189–190 °C. IR

Wolfe et al.

957

1

(KBr) (cm^–1): 3284, 2935, 1712, 1671, 1645, 1541, 1438. ¹H

1600 (s). H NMR (D₂O, 400 MHz): 4.02 (d, 1H, H_c, J_bc

2.3 Hz), 3.94 (ddd, 1H, H_b, J_ab= 7.7 Hz, J_a′b= 5.2 Hz, J_bc

=

3

NMR (400 MHz, CD₃OD): 1.49 (3H, d, J = 7.3, a-Me),

3

1.93 (1H, m,²J = –12.7, J = 6.9, 9.0, 11.6, C5-H1), 2.54

2.2 Hz), 3.65 (ABX, 1H, H_a′, J_aa′= 11.6 Hz, J_a′b= 5.2 Hz),

3.58 (ABX, 1H, H_a, J_aa′= 11.6 Hz, J_ab= 7.7 Hz).

2

3

(1H, m, J = –12.7, J = 5.3, 7.5, 9.0, C5-H2), 3.60 (2H,

CH₂Ph), 4.14 (1H, m, ²J = –10.9, ³J = 5.3, 9.0, C6-H4), 4.26

2

3

(1H, m, J = –10.9, J = 6.9, 9.0, C6-H3), 4.77 (1H, dd, J =

Methyl 2,4-dibromo-2,4-dideoxy-^L-erythronate (43)

Calcium ^L-threonate (34.98 g, 0.11 mol) was stirred for

24 h with 30% w/w hydrogen bromide – acetic acid solution

(210 mL, 1.05 mol), and methanol (420 mL) was then

added. The solution was stirred at room temperature for an

additional 12 h, and the mixture was then refluxed for 2 h.

The solvent was evaporated under reduced pressure to give

an oil, which was dissolved in ethyl acetate (250 mL). This

solution was washed with brine (100 mL), dried over sodium

sulfate, and evaporated to give 43 (27.38 g, 90.2%) as an oil.

IR (film) (cm^–1): 3340 (m), 1745 (s). ¹H NMR (CDCl₃,

400 MHz): 4.32 (d, 1H, H_c, J_bc= 8.8 Hz), 4.24 (m, 1H, H_b),

3.81 (s, 3H, CO₂Me), 3.80 (AB, 2H, H_aH_a′). CI-MS (m/z):

277 ([M + 1]).

3

7.5, 11.6, C4-H5), 4.99 (1H, q, J = 7.3, a-CH), 7.19–7.40

(5H, m, Ph). ¹³C NMR (CD₃OD): 13.80, 29.98, 43.63,

48.36, 55.42, 70.44, 127.91, 129.57, 130.23, 136.66, 172.74,

172.81, 174.01. CI-MS (isobutane), m/z: 307 ([M + 1]).

Benzyl ester of homolactivicin

A

solution of dicyclohexylcarbodiimide (0.357 g,

1.73 mmol) in acetonitrile (10 mL) was added dropwise to a

stirred solution of the oxazinone 10 (0.311 g, 1.33 mmol)

and benzyl 2-oxoglutarate (0.408 g, 1.73 mmol) in aceto-

nitrile (20 mL). After three days of stirring, a white precipi-

tate was collected by filtration and washed with methylene

chloride. The filtrate was evaporated under reduced pressure

to give 0.85 g of a dark semi-solid, which was purified by

flash column chromatography (Silica Gel 60, ethyl acetate)

to afford diastereomers 41a (0.189 g) and 41b (0.126 g)

(52% total yield) as white solids.

Methoxymethylation of 43

Boron trifluoride etherate (9.35 mL, 74 mmol) was added

dropwise under nitrogen during 10 min at 0–5 °C to a solu-

tion of 43 (16.55 g, 60 mmol) in dichloromethane (70 mL)

and dimethoxymethane (33 mL). The reaction mixture was

stirred at room temperature for 10–12 h, cooled to 0–5 °C,

and quenched by dropwise addition of water (50 mL) during

15 min. Dichloromethane (80 mL) was added, and the or-

ganic layer was washed with saturated sodium bicarbonate

(2 × 50 mL) and brine (100 mL), dried over anhydrous so-

dium sulfate, and evaporated under reduced pressure to give a

Homolactivicin

To a 1:1 mixture of 41a and 41b (0.217 g, 0.48 mmol) in

ethyl acetate (30 mL) was added 5% Pd–C (0.106 g) in one

portion. The mixture was stirred at room temperature, under

hydrogen, for 7.5 h. The catalyst was then removed by filtra-

tion through a pad of Silica Gel 60H (for TLC), followed by

washing with ethyl acetate (50 mL) and tetrahydrofuran

(50 mL). The combined filtrates were evaporated under re-

duced pressure, and the white solid residue was triturated

with dry ether (3 × 5 mL) and dried in vacuo to afford

0.0945 g (54%) of racemic homolactivicin (a mixture of

diastereoisomers) as a white powder; mp 150–152 °C (de-

composition temperature (dec)). IR (KBr) (cm^–1): 3348,

pale yellow oil (18.10 g, 92%). IR (film) (cm^–1): 1747 (s). H

NMR (CDCl₃, 400 MHz): 4.71 (AB, 2H, H_d, MeOCH₂O-),

4.43 (d, 1H, H_c, J_bc= 9.1 Hz), 4.16 (dt, 1H, H_b, J_ab~ J_a′b

2.9 Hz, J_bc= 9.1 Hz), 3.86 (ABX, 2H, H_aH_a′, J_aa′= 11.5 Hz,

J_ab= 2.8 Hz, J_a′b= 3.1 Hz), 3.79 (s, 3H, CO₂Me), 3.41 (s,

3H, MeOCH₂O).

1

=

1

2942, 1804, 1713, 1542, 1185, 1032. H NMR (400 MHz,

CD₃CN): 1.85 (1H, br.m), 2.45 (1H, br m), 2.56 (2H, br m),

2.72 (1H, br m), 2.90 (2H, br m), 3.52 (2H, CH₂Ph), 4.13

(1H, br m), 4.26 (2H, br m), 4.71 (1H, br m), 6.71 (br s,

NH), 7.2–7.4 (5H, m, Ph). Calcd for C₁₇H₁₈N₂O₇: C 56.35,

H 5.01, N 7.73; found: C 56.31, H 5.11, N 7.69.

Methyl 2-azido-4-bromo-2,4-dideoxy-3-methoxymethoxy-

L-threonate (44)

Sodium azide (2.18 g, 33.5 mmol) was added in one por-

tion at 10–15 °C to a solution of the MOM derivative

(10.23 g, 32.0 mmol) in dimethylformamide (40 mL). The

mixture was stirred at 10 °C to room temperature for 12 h.

Water (35 mL) was then added at 0–5 °C, and the mixture

was extracted with ethyl acetate (2 × 80 mL). The combined

extracts were washed with water (3 × 20 mL) and brine

(20 mL), dried over anhydrous sodium sulfate, and evapo-

rated under reduced pressure to give an oil. Purification by

flash chromatography using 5% ethyl acetate as eluent

yielded 6.40 g (71%) of 44. IR (film) (cm^–1). 2115 (s), 1744

(s). ¹H NMR (CDCl₃, 400 MHz): 4.67 (AB, 2H,

Calcium ^L-threonate

Calcium carbonate (60.06 g, 0.6 mol) was added to a solu-

tion of ^L-ascorbic acid (52.8 g, 0.3 mol) in water (410 mL).

The slurry was cooled to 0–5 °C and hydrogen peroxide

(50% w/w, 61.2 mL, 0.9 mol) was added dropwise during

1 h at 5–20 °C. Stirring was continued at room temperature

for 16 h, and the reaction mixture was then heated at 70–

75 °C for 1 h until gas was no longer evolved. The suspen-

sion was filtered hot, and the filter cake was washed with

50–60 °C hot water (2 × 30 mL). The combined filtrates

were concentrated to about 120 mL under reduced pressure

,

MeOCH₂O), 4.33 (ddd, 1H, H_b, J_ab= 9.0 Hz, J_{a b}= 5.0 Hz,

J_bc= 2.5 Hz), 4.29 (d, 1H, H_c,J_bc= 2.5 Hz), 3.85(s, 3H,

CO₂Me), 3.58 (ABX, 1H, H_a′, J_aa′= 10.2 Hz, J_a′b= 5.0 Hz),

3.53 (ABX, 1H, H_a, J_aa′= 10.2Hz, J_ab= 9.0 Hz), 3.36 (s, 3H,

MeOCH₂O-). CI-MS (m/z) 282 ([M + 1]), 284 ([M + 3]),

along with 0.40 g (5.2%) of the diazide-compound. IR (film)

o

at 55 C. Methanol (250 mL) was added dropwise to the

warm concentrate (50 °C) until the solution became cloudy,

and the mixture was then stirred at room temperature for

12 h, filtered, and the precipitate was washed with methanol

(3 × 30 mL). The solid was dried to a constant weight at

60 °C (3 h) to give 45.2 g (94.6%) of 42. IR (KBr) (cm^–1):

1

(cm^–1): 2109 (vs), 1751 (s). H NMR (CDCl₃, 400 MHz):

4.68 (AB, 2H, MeOCH₂O), 4.18 (ddd, 1H, H_b, J_ab= 7.3 Hz,

,

J

_{a b}= 6.1 Hz, J_bc= 2.9 Hz), 3.95 (d, 1H, H_c,J_bc= 2.9 Hz),

958

Can. J. Chem. Vol. 81, 2003

3.84 (s, 3H, CO₂Me), 3.62 (ABX, 1H, H_a′, J_aa′= 12.4 Hz,

11.2 Hz, J_a′b= J_ab= 6.2 Hz), 3.31 (s, 3H, MeOCH₂O-),

1.47 (s, 9H, -CO₂CMe₃). CI-MS (m/z): 309 ([M + 1]).

J_a′b= 6.1 Hz), 3.49 (ABX, 1H, H_a, J_aa′= 12.4 Hz, J_ab

=

7.3 Hz), 3.36 (s, 3H, MeOCH₂O-). CI-MS (m/z) 245 ([M + 1]).

Reaction of 46 with the triflate of benzyl ^L-lactate

Reduction of 44 and protection as the BOC derivative 45

A 5% Pd–C suspension (0.60 g) in ethyl acetate (55 mL)

was stirred for 2 h in a hydrogen atmosphere, and a solution

of 44 (4.30 g, 15.0 mmol) and di-tert-butyl dicarbonate

(4.00 g, 18.0 mmol) in ethyl acetate (25 mL) was added. The

mixture was stirred under hydrogen until the starting mate-

rial had disappeared (48 h) and then filtered through Celite.

The Celite pad was washed with ethyl acetate (3 × 10 mL),

and the filtrate was concentrated under reduced pressure.

The crude product was purified by flash chromatography

(12% ethyl acetate in hexane) to give 4.03 g (74%) of 45 as

Trifluoromethanesulfonic anhydride (0.79 mL, 4.69 mmol)

was added dropwise, with stirring at –78 °C, to a solution of

benzyl ^L-lactate (0.84 g, 4.66 mmol) and 2,6-lutidine

(0.70 g, 6.53 mmol) in dichloromethane (35 mL). After

20 min a solution of 46 (1.30 g, 4.22 mmol) and 2,6-lutidine

(0.46 g, 4.29 mmol) in dichloromethane (20 mL) was added

dropwise at –78 to –60 °C. Stirring was continued at –78 to

–50 °C for 1 h, and the cooling bath was then removed. Af-

ter an additional 10 h of stirring the reaction mixture was

washed with cold water (2 × 5 mL), dried over anhydrous

sodium sulfate, and evaporated to give an oil. Purification by

flash chromatography using 25% ethyl acetate in hexane as

eluent yielded 1.31 g (66%) of 47. IR (film) (cm^–1): 3445

(b), 3367 (m), 1744 (s), 1719 (s). ¹H NMR (CDCl₃,

400 MHz): 7.37 (m, 5H, PhCH₂-), 6.07 (d, 1H, ONH,

J_ONHHd= 8.8 Hz), 5.23 (d, 1H, NH, J_NHHc= 9.9 Hz), 5.18

(AB, 2H, PhCH₂-), 4.56 (AB, 2H, MeOCH₂O), 4.43 (d, 1H,

H_c, J_NHHc= 9.9 Hz), 4.32 (t, 1H, H_b,J_ab= 6.0 Hz), 3.80 (m,

1

a colourless oil. IR (film) (cm^–1): 1754 (s), 1721 (s). H

NMR (CDCl₃, 400 MHz): 5.19 (d, 1H, NH, J_NHHc

=

10.0 Hz), 4.72 (d, 1H, H_c, J_NHHc= 10.3 Hz), 4.64 (AB, 2H,

MeOCH₂O-), 4.36 (t, 1H, H_b, J_ab= 6.4 Hz), 3.77 (s, 3H,

CO₂Me), 3.43 (ABX, 2H, H_a, J_ab= 6.4 Hz), 3.31 (s, 3H,

MeOCH₂O-), 1.48 (s, 9H, -CO₂CMe₃). CI-MS (m/z):

356([M + 1]), 358 ([M + 3]).

1H, H_d,J_de= 7.2Hz,, J_ONHHd= 8.8 Hz), 3.77 (d, 2H, H_a,J_ab

=

Conversion of 45 to the phthalimidooxy compound

A solution of N-hydroxyphthalimide (2.40 g, 14.8 mmol)

and DBU (2.20 g, 14.4 mmol) in dimethylformamide

(25 mL) was added dropwise with stirring at 10–15 °C to a

solution of 45 (4.40 g, 12.4 mmol) in dimethylformamide

(10 mL). The mixture was stirred for 60 h and allowed to

warm to room temperature. Ethyl acetate (120 mL) was then

added, and the organic layer was washed with saturated so-

dium bicarbonate (5 × 15 mL) and brine (20 mL), dried over

anhydrous sodium sulfate, and evaporated to give an oil. Pu-

rification by flash chromatography using 30% ethyl acetate

in hexane as eluent afforded 2.93 g (54.0%) of the phthali-

midooxy compound as a colourless oil. IR (film) (cm^–1):

6.4 Hz), 3.75 (s, 3H, CO₂Me), 3.27 (s, 3H, MeOCH₂O-),

1.45 (s, 9H, -CO₂CMe₃), 1.24 (d, 3H, H_e, J_de= 7.2 Hz). CI-

MS (m/z): 471 ([M + 1]).

Cyclization of 46

A 2.0 mol/L solution of trimethylaluminium in hexane

(1.68 mL, 3.36 mmol) was added dropwise, with stirring at

0–5 °C, to a solution of 46 (0.86 g, 2.80 mmol) in dry

tetrahydrofuran (70 mL). Stirring was continued for 40 min

after addition was complete, and for 3.5 h after the cooling

bath was removed. Ice-cold water (1 mL) was added, and af-

ter 20 min, the solvent was removed under reduced pressure.

The residue was triturated with tetrahydrofuran (6 × 5 mL)

and dichloromethane (4 × 5 mL) and filtered through a short

silica gel – Celite pad. The filtrate was evaporated to give

48, 0.70 g (90%), as an oil. IR (film) (cm^–1): 3342 (m), 3232

1

1739 (s), 1732 (s), 1719 (s). H NMR (CDCl₃, 400 MHz):

7.80 (AB, 4H), 5.28 (d, 1H, NH, J_NHHc= 9.8 Hz), 4.76 (AB,

2H, MeOCH₂O-), 4.65 (d, 1H, H_c, J_NHHc= 9.8 Hz), 4.58 (m,

1H, H_b, J_ab= 7.0 Hz, J_a′b= 4.8 Hz, J_bc= 1.5 Hz), 4.36 (ABX,

1H, H_a′, J_aa′= 10.6 Hz, J_a′b= 4.8 Hz), 4.28 (ABX, 1H, H_a,

J_aa′= 10.6 Hz, J_ab= 7.0 Hz), 3.79 (s, 3H, CO₂Me), 3.31 (s,

3H, MeOCH₂O-), 1.43 (s, 9H, -CO₂CMe₃). CI-MS (m/z):

439 ([M + 1]).

1

(m), 1698 (vs). H NMR (CDCl₃, 400 MHz): 8.80 (s, 1H,

NH_e), 5.19 (d, 1H, NH_d,J_NHdHc= 7.0 Hz), 4.69 (AB, 2H,

MeOCH₂O-_,J = 7.0 Hz), 4.57 (dd, 1H, H_c,J_NHdHc= 7.1 Hz,

J_bc= 7.1 Hz), 4.26 (ABM, 1H, H_a′,J_aa′= 12.2 Hz, J_a′b

5.9 Hz), 4.14 (ABM, 1H, H_a,J_aa′= 12.2 Hz, J_ab= 3.3 Hz),

3.99 (ddd, 1H, H_b, J_ab= 3.3 Hz, J_a′b= 5.9 Hz, J_bc= 7.8 Hz),

3.37 (s, 3H, MeOCH₂O-), 1.45 (s, 9H, -CO₂CMe₃). CI-MS

(m/z): 277 ([M + 1]).

=

Formation of the aminooxy compound 46

A solution of the phthalimidooxy compound (2.40 g,

5.48 mmol) in dichloromethane (25 mL) was treated, with

stirring at –15 °C, with a solution of methylhydrazine

(0.38 g, 8.26 mmol) in dichloromethane (2 mL). The cooling

bath was then removed, and stirring was continued for 4 h.

The solvent and excess methylhydrazine were evaporated

under reduced pressure, and the residue was triturated with

ethyl acetate (6 × 3 mL) and filtered through a short silica

gel plug. The filtrate was evaporated to give 1.44 g (85.3%)

of 46 as a colourless oil. IR (film) (cm^–1): 3451 (b), 3323

Cyclization of 47

A 2.0 mol/L solution of trimethylaluminium in hexane

(3.40ml, 6.82 mmol) was added dropwise, with stirring at 0–

5 °C, to a solution of 47 (0.76 g, 1.62 mmol) in dry toluene

(70 mL). Stirring was continued for 40 min at 0–5 °C and

then for 4 h after removal of the cooling bath. Ice-cold water

(1 mL) was added, the mixture was stirred for 20 min, and

the solvent was then removed under reduced pressure. The

residue was triturated with tetrahydrofuran (8 × 6 mL) and

dichloromethane (3 × 6 mL) and filtered through a short sil-

ica gel – Celite pad. Evaporation of the filtrate gave an oil,

which was purified by flash chromatography (using ethyl ac-

etate:hexane (20:80) as eluent); this eluted to yield 0.45 g

1

(m), 1745 (s), 1714 (s). H NMR (CDCl₃, 400 MHz): 5.54

(b, 2H, -ONH₂), 5.25 (d, 1H, NH, J_NHHc= 9.6 Hz), 4.61

(AB, 2H, MeOCH₂O-), 4.47 (dd, 1H, H_c, J_bc= 1.6 Hz,

J_NHHc= 9.8 Hz), 4.40 (td, 1H, H_b,J_ab~ J_a′b= 6.2 Hz, J_bc

1.6 Hz), 3.76 (s, 3H, CO₂Me), 3.73 (ABX, 2H, H_aa′, J_aa′

=

Wolfe et al.

959

(62.6%) of 49. IR (film) (cm^–1): 3351 (w), 1745 (s), 1719

(s), 1687 (s). H NMR (CDCl₃, 400 MHz): 7.37 (m, 5H,

(25 mg 92%) as a white powder. IR (KBr) (cm^–1): 3459 (b),

3283 (w), 1727 (w), 1666 (s), 1644 (vs). H NMR (CD₃OD,

1

PhCH₂-), 5.16 (AB, 2H, PhCH₂-), 5.13 (q, 1H, H_d,J_de

7.3 Hz), 4.71 (m, 1H, H_c), 4.64 (AB, 2H, MeOCH₂O), 4.54

(ABM, 1H, H_a′,J_aa′= 11.9 Hz, J_a′b= 6.6 Hz), 4.00 (ABX,

=

400 MHz): 7.30 (m, 5H, Ph-), 4.97 (q, 1H, H_d,J_de= 7.3 Hz),

4.80 (m, 1H, H_c), 4.57 (m, 1H, H_b,J_ab= 1.8 Hz, J_a′b

7.4 Hz, J_bc= 3.7 Hz), 4.52 (ABM, 1H, H_a′,J_aa′= 10.9 Hz,

J_a′b= 7.4 Hz), 3.92 (ABX, 1H, H_a,J_aa′= 10.9 Hz, J_ab

1.8 Hz), 3.68 (AB, 2H, PhCH₂CONH-), 1.50 (d, 3H, H_e,

_de= 7.3 Hz). CI-MS (m/z): 323 ([M + 1]).

=

1H, H_a,J_aa′= 11.9 Hz, J_ab= 3.1 Hz), 3.86 (ddd, 1H, H_b, J_ab

=

3.1 Hz, J_a′b= 6.6 Hz, J_bc= 8.5 Hz), 3.34 (s, 3H, MeOCH₂O-),

1.50 (d, 3H, J_de= 7.3 Hz), 1.45 (s, 9H, -CO₂CMe₃). CI-MS

(m/z): 439 ([M + 1]).

J

Bioassays

Removal of the BOC and MOM groups of 49

The data of Table 2 were obtained using seeded agar

plates, prepared as described in ref 1. MIC (minimum inhib-

itory concentration) data were provided by the Health Sci-

ences Centre, Winnipeg, and by NAEJA Pharmaceuticals,

Edmonton.

Trifluoroacetic acid (1.25 mL, 16.30 mmol) was added

dropwise with stirring at 0–5 °C to a solution of 49 (0.25 g,

0.57 mmol) in dichloromethane (1.0 mL) and anisole

(0.5 mL). After removal of the cooling bath, stirring was

continued for 10 h. The solvent was then removed under re-

duced pressure, and the residue was washed with ether (2 ×

3 mL) to give a solid. The solid that resulted was dried in

vacuo to 70 mg (30%) of 50 as an off-white powder. IR

Acknowledgements

1

(KBr) (cm^–1): 3459 (b), 3217 (m), 1731 (s), 1683 (vs). H

This research was supported financially by an Individual

Operating Grant from the Natural Sciences and Engineering

Research Council of Canada (NSERC) and by the Western

Technology Seed Investment Fund. The authors thank Dr.

Raymond Batchelor for the crystal structures and Sarah

Chinapoo for technical assistance.

NMR (CD₃OD, 400 MHz): 7.36 (m, 5H, Ph-), 5.18 (q, 1H,

H_d,J_de= 7.3 Hz), 5.17 (AB, 2H, PhCH₂OCO-), 4.70 (ddd,

1H, H_b, J_ab= 2.6 Hz, J_a′b= 7.1 Hz, J_bc= 4.3 Hz), 4.58

(ABM, 1H, H_a′,J_aa′= 11.8 Hz, J_a′b= 7.1 Hz), 4.27 (d, 1H,

H_c, J_bc= 4.3 Hz), 3.98 (ABX, 1H, H_a,J_aa′= 11.8 Hz, J_ab

=

2.6 Hz), 1.54 (d, 3H, H_e, J_de= 7.3 Hz). CI-MS (m/z): 295

([M]⁺).

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Article Doi

Cyclic hydroxamates, especially multiply substituted [1,2]oxazinan-3-ones

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