Fused and bridged bi- and tri-cyclic lactams via sequential metallo-azomethine ylide cycloaddition-lactamisation

TETRAHEDRON

Pergamon

Tetrahedron 58 (2002) 1719±1737

Fused and bridged bi- and tri-cyclic lactams via sequential

metallo-azomethine ylide cycloaddition±lactamisation

Paul Blaney,^aRonald Grigg,^a,pZoran Rankovic,^bMark Thornton-Pett^aand Juan Xu^a

^aMolecular Innovation, Diversity and Automated Synthesis (MIDAS) Centre, School of Chemistry, The University of Leeds,

Leeds LS2 9JT, UK

^bOrganon Laboratories, Newhouse, Lanarkshire ML1 5SH, UK

Received 25 October 2001; revised 29 November 2001; accepted 3 January 2002

AbstractÐAldimines of a-amino esters derived from aldehydes bearing an a-, b- or g-protected amino group undergo AgOAc/R₃N

catalysed cycloaddition to electronegative ole®ns (dipolarophile). Subsequent unmasking of the amino group and lactamisation, spontaneous

in most cases, generates 5±7 membered fused and bridged bi- and tri-cyclic lactams. The regioselectivity of the lactamisation is controlled by

1. Introduction

pyrrolidine and one or two additional 5±7 membered lactam

rings via 1,3-dipolar cycloaddition of metallo-azomethine

ylides using novel aldehydes incorporating a protected

primary amino group which, upon deprotection, undergoes

lactamisation.

The 1,3-dipolar cycloaddition reaction of azomethine ylides

is a powerful method for the synthesis of polysubstituted

pyrrolidines, receiving much attention due to the

presence of pyrrolidines in a number of alkaloids and in

pharmaceutically important compounds.¹There are a

variety of ways to generate azomethine ylides,²with a

number of the major routes having been extensively

developed within our group. Two of these, the 1,2-proto-

tropic³and N-metallation routes,⁴employ readily available

aldimines of a-amino esters as the source of azomethine

ylides (Scheme 1).

2.1. N-Phthalimido protected amino aldehyde route to

bicyclic lactams

2.1.1. 5- and 6-membered fused bicyclic lactams.

N-Phthalimidoacetaldehyde 1a and 3-(N-phthalimido)-

propionaldehyde 1b^5,6were condensed with a-amino esters

2 to give aldimines 3a±h (Scheme 2), which underwent

1,3-dipolar cycloaddition with acrylate esters 4 in toluene,

mediated by AgOAc±NEt₃, to give pyrrolidine endo-

isomers 5a±j (Table 1). Hydrazinolysis of the phthalimide

group gave the corresponding primary amines which

spontaneously cyclised to lactams 6b,c and e±h as the

sole products re¯ecting the kinetic preference for

2. Results and discussions

The investigation described herein was devised to access

fused and bridged polycyclic lactams incorporating a

Scheme 1.

Keywords: azomethine ylide; cycloaddition; heterocycles; lactamisation; bridged and fused rings.

Corresponding author. Tel./fax: 144-113-233-6501; e-mail: r.grigg@chem.leeds.ac.uk

p

PII: S0040-4020(02)00029-7

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P. Blaney et al. / Tetrahedron 58 (2002) 1719±1737

Scheme 2.

Table 1. Sequential 1,3-dipolar cycloaddition±lactamisation of imines

3a±h (Scheme 2)

equiv.) and triethylamine (1.1 mol equiv.) in toluene at

room temperature over 18 h to give pyrrolidines 11a and

11b in 51 and 47% yield, respectively from the aldehyde

9. When 11a and 11b were heated with hydrazine mono-

hydrate (1.5 mol equiv.) in methanol at 558C, the corre-

sponding primary amines 12a and 12b were isolated in

quantitative yield. Re¯uxing 12a,b in methanol or toluene

gave degradation products with no observable lactamisation

whilst re¯uxing 12a,b in methanol with sodium methoxide

(1.5 mol equiv.) for 4.5 h induced lactamisation to give a

4:1 mixture (30%) of epimers 13a and 14a or a 9:1 (12%)

mixture of 13b and 14b. Thus the lactamisation of the amino

acid esters using sodium methoxide in re¯uxing methanol

was low yielding and led to epimeric products. However an

alternative approach circumvented these problems

(Scheme 4). Thus 12b was hydrolysed in re¯uxing 1 M

HCl over 3.5 h to give the diamino diacid dihydrochloride

15 in quantitative yield. This was dissolved in dry aceto-

nitrile (15 is insoluble in neat thionyl chloride) followed by

addition of excess thionyl chloride with stirring at room

temperature for 16 h to give the diacid chloride 16. The

lactamisation was performed according to a similar

literature example.⁸Two solutions comprising diacid

chloride hydrochloride 16 dissolved in a minimum of dry

acetonitrile and diluted with dry benzene and triethylamine

(7 mol equiv.) dissolved in dry benzene were added drop-

wise simultaneously, with stirring, over 40min at room

temperature to dry benzene with overall high dilution

(,0.002 M). This mixture was stirred for a further 2 h

with subsequent addition of excess methanol and stirring

at room temperature for 16 h to give the lactam 13b in an

overall yield of 90% from 12b.

n

Imine R⁰

R

Cycloadduct (%)

Lactam (%)

1

2

3a

3b

3c

3d

3e

3f

3g

3h

Me Me

Me (CH₂)₂SMe

5a (65)

5b (70)

Me 3-Indolylmethyl 5c (40)

6a:7(1:1) 70 (70)

6b (96)

6c (56)

8 (91)

6e (77)

6e (83)

6f (72)

6f (76)

6g (80)

6h (91)

Me (CH₂)₂CO₂Me

Me Bn

Bn Bn

Me Bn

Bn Bn

Me Me

5d (92)

5e (87)

5f (52)

5g (72)

5h (64)

5i (71)

Me 3-Indolylmethyl 5j (62)

5-membered ring formation. In the case of cycloadduct 5a a

1:1 mixture of 5-membered fused, 6a, and 6-membered

bridged lactams 7 was obtained whilst in the case of

cycloadduct 5d [R(CH₂)₂CO₂Me] hydrazinolysis afforded

a [5.5.5]-tricyclic bis-lactam, 8. The use of benzyl acrylate

instead of methyl acrylate gave lower yields in the 1,3-

dipolar cycloaddition step but, the lactamisation onto the

benzyl ester gave higher yields than for the methyl ester.

The structures of lactams 6a, 6e and 6f were unequivocally

established by single crystal X-ray analysis (Fig. 1).

2.1.2. Fused 7-membered bicyclic lactams. 7-Membered

bicyclic lactams were accessed by the 1,3-dipolar cyclo-

addition/lactamisation protocol by employing 9 as the

aldehyde component in imine formation (Scheme 3).

This sequence could not be applied to the analogous diacid

dihydrochloride salt of 12a since it was insoluble in both

acetonitrile and neat thionyl chloride.

4-(N-Phthalimido)-butyraldehyde 9⁵, which was made from

potassium phthalimide and 2-(3-chloropropyl)-1,3-dioxan,⁷

was condensed with alanine and phenylalanine methyl ester

(1.05 mol equiv.) in dichloromethane at room temperature

for 22 h to give the imines 10a and 10b, which underwent

1,3-dipolar cycloaddition reactions with methyl acrylate

(5 mol equiv.) in the presence of silver(I) acetate (1.1 mol

2.1.3. Bridged bicyclic lactams. The 1,3-dipolar cyclo-

addition/lactamisation protocol was extended to the

synthesis of 6- and 7-membered bridged bicyclic lactams

by employing N-methylmaleimide (Scheme 5) or phenyl

vinyl sulfone (Scheme 6) as the dipolarophile. Use of

these dipolarophiles forces lactamisation to take place on

the ester derived from the amino acid moiety.

P. Blaney et al. / Tetrahedron 58 (2002) 1719±1737

1721

Figure 1. X-Ray crystal structures of 6a, 6e and 6f.

The imines 3a±e and 3e,f underwent 1,3-dipolar cyclo-

addition with N-methylmaleimide and phenyl vinyl sulfone

(1.05±1.5 equiv.), respectively using silver(I) acetate

(1.05±1.2 equiv.) and triethylamine (1.05±1.2 equiv.) in

toluene at room temperature. Deprotection of 17a±e and

20 with hydrazine (50±788C, 15±84 h) initiated lactamisa-

tion generating bridged-ring products 18a±e (Scheme 5)

and 21 (Scheme 6) in good yields. A second lactamisation

occurred with 3d [R(CH₂)₂CO₂Me] to produce a tetra-

cyclic bis-lactam 19. Hydrazinolysis of the phthalimide

group of 22 gave primary amine 23 in quantitative yield.

Re¯uxing 23 in methanol with sodium methoxide (1 equiv.)

induced lactamisation to give a 2:1 mixture (71%) of

epimers 24 and 25 (Scheme 7).

exempli®ed by the synthesis of bicyclic urea 26 (Scheme 8).

Amine 23 and triethylamine (2.2 mol equiv.) dissolved in

THF (high dilution) were heated with phosgene (1.05 mol

equiv. as a 20% solution in toluene) at 08C and the reaction

allowed to warm to room temperature with stirring over

16 h. Work up afforded bicyclic urea 26 in 56% yield.

2.2. N-Boc amino aldehyde route to bicyclic lactams

The Boc protecting group was evaluated as an alternative to

the phthalimide group. Thus N-Boc-glycine 27a and N-Boc-

b-alanine 27b were converted to their corresponding mixed

anhydrides with t-butyl chloroformate (1.1 mol equiv.) and

N-methyl morpholine (2.2 mol equiv.) in dichloromethane.

Treatment with N,O-dimethylhydroxylamine hydrochloride

(1 mol equiv.) at 2158C for 15 min then at room tempera-

ture for 18 h gave the Weinreb amides 28a,b in quantitative

yield. The Weinreb amides were reduced using lithium

Where lactamisation does not occur spontaneously on the

removal of the phthalimide protecting group, it is possible to

use the primary amine in intermolecular reactions. This was

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P. Blaney et al. / Tetrahedron 58 (2002) 1719±1737

Scheme 3.

Scheme 4.

Scheme 5.

P. Blaney et al. / Tetrahedron 58 (2002) 1719±1737

1723

Scheme 6.

Scheme 7.

phenylalanine methyl ester gave the imine 30b. An

analogous reaction with 29a failed to give imine, and it

was hypothesised that cyclisation of 30a to 32 had occurred

(Scheme 10). When this latter material was used in the 1,3-

dipolar cycloaddition it was recovered unchanged. Thus the

oxazoline tautomer 32, if formed, was not in equilibrium

with 30a. Imine 30b and methyl acrylate (5 mol equiv.)

reacted, using silver(I) acetate (1.2 mol equiv.) and triethyl-

amine (1.2 mol equiv.) in toluene at room temperature for

36 h, to give endo-pyrrolidine 31b in 50% yield. A similar

yield was obtained when leaving the reaction for 56 h

(48%). The Boc-protecting group was removed using 20%

TFA in dichloromethane at room temperature to give the

Scheme 8.

aluminium hydride (5 mol equiv.) in THF at room tempera-

ture for 20±30 min according to a literature procedure⁹to

give the aldehydes 29a and 29b in 60and 64% yield, respec-

tively (Scheme 9). Condensation of aldehyde 29b with

Scheme 9.

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P. Blaney et al. / Tetrahedron 58 (2002) 1719±1737

Scheme 10.

Scheme 11.

intermediate TFA salt, which was treated with triethylamine

(2.2 mol equiv.) in dichloromethane at room temperature to

give the bicyclic lactam 6f in 82% yield.

in toluene at room temperature for 38 h to give the endo-

pyrrolidine 37 in 53% overall yield from 35. Lactamisation

was achieved by removal of the Boc-group using 20% TFA

in dichloromethane at room temperature to give the TFA

salt of 38, which was treated with triethylamine (2.2 mol

equiv.) in dichloromethane at room temperature to give 38

in 63% yield.

The suggested cyclisation (Scheme 10) involves the Boc-

oxygen atom and requires a Boc-N-H proton for formation

of oxazoline 32. If the Boc-nitrogen was alkylated this

problem would be prevented and have the added advantage

of introducing a further point of diversity. Several literature

methods for the N-alkylation of Boc-protected amino acids

using sodium hydride (.2 mol equiv.) and alkyl halides

(.2 mol equiv.) were found.¹⁰The N-methylation of 27a

was carried out according to these literature examples

using sodium hydride (4 mol equiv.) and methyl iodide

(4 mol equiv.) in THF to give 33 in a 98% yield. This was

then converted to the Weinreb amide 34 in 83% yield

(Scheme 11). Reduction of 34 using lithium aluminium

hydride (5 mol equiv.) in THF at room temperature gave

the aldehyde 35 in 46% yield. This was condensed with

phenylalanine methyl ester (1.1 mol equiv.) in dichloro-

methane to give the imine 36, which underwent cyclo-

addition with methyl acrylate (5 mol equiv.) using silver(I)

acetate (1.2 mol equiv.) and triethylamine (1.2 mol equiv.)

In conclusion, processes for the synthesis of fused and

bridged bicyclic 5±7 membered lactams have been

developed. The phthalimide route is more convenient for

the general synthesis of bicyclic lactams, but the Boc-

protection route offers easy access to N-substituted

lactams.

3. Experimental

3.1. General

Melting points were determined on a Reichert hot-stage

apparatus and are uncorrected. ¹H Nuclear magnetic

resonance spectra were recorded at 250MHz on a Bruker

P. Blaney et al. / Tetrahedron 58 (2002) 1719±1737

1725

AC 250 instrument, at 300 MHz on a Bruker DPX 300

instrument, at 400 MHz on a Bruker WP 400 instrument

or at 500 MHz on a Bruker DRX 500 instrument, and refer-

enced to tetramethylsilane or residual protonated solvent.

Deuterochloroform was used as solvent unless stated other-

wise, and chemical shifts are given in parts per million (d)

down ®eld from tetramethylsilane. Assignments of ¹H

signals were made with the aid of 2D COSY spectra

where necessary. Microanalyses were obtained using a

Carlo Erba Elemental Analyser MOD 1106 instrument.

Infrared spectra were recorded as nujol mulls on a Nicolet

FTIR spectrophotometer. Mass spectra were recorded on a

V.G.-AutoSpec spectrometer using electron impact (EI)

operating at 70eV or by fast atom bombardment (FAB),

as speci®ed. Accurate molecular weights were determined

using per¯uorokerosene as an internal standard. X-Ray

analysis was performed on a Stoe STADI 4-circle machine

or a Nonius Kappa CCD area-detector diffractometer. Flash

column chromatography was performed on silica gel 60

(Merk 230±400 mesh). Ether refers to diethyl ether and

petroleum ether refers to the fraction with boiling point

40±608C. All reagents and solvents were puri®ed according

to literature procedure.¹¹

(100), 130 (20) and 105 (29); n_max(cm²¹): 3056, 2988, 1775

(CvO) and 1717 (CvO).

3.1.3. 4-(N-Phthalimido)-butyraldehyde 9.⁵2-(3-Chloro-

propyl)-1,3-dioxolane (3.92 ml, 29.70mmol) was added to

a stirred suspension of potassium phthalimide (5.00 g,

27.00 mmol) in DMF (200 ml) at 808C and the suspension

was stirred for 18 h. The mixture was allowed to cool,

diluted with water (300 ml) and extracted with dichloro-

methane (3£150ml). The combined organic layers were

washed with 0.4 M NaOH (100 ml), dried (MgSO₄) and

the solvent evaporated to afford 2-[3-(N-phthalimido)-

propyl]-1,3-dioxolane (4.00 g, 54%) as a colourless solid,

mp 109.5±111.08C. (Found: C 63.85; H, 6.0; N, 5.25.

C₁₅H₁₇NO₄´1/2H₂O requires: C, 63.4; H, 6.4; N, 4.95%); d

(250MHz): 1.70±1.83 (m, 6H, NCH CH₂CH₂CH and

2

OCH₂CH₂CH₂O), 3.74 (t, J6.9 Hz, 2H, NCH₂CH₂),

3.81±3.98 (m, 4H, OCH₂CH₂CH₂O), 4.91 (t, J4.2 Hz,

1H, CH₂CH(OCH₂)OCH₂), 7.70±7.73 (m, 2H, ArH) and

7.83±7.86 (m, 2H, ArH). m/z (%): 275 (M¹, 0.2), 274 (1),

216 (5), 174 (16), 160 (56), 104 (24) and 73 (100); n_max

(cm²¹): 3056, 2985±2933, 1773 and 1713 (CvO).

The ketal (2.00 g, 7.27 mmol) was dissolved in acetone

(60ml) and 2 M HCl (30ml) at room temperature and the

resulting solution stirred for 16 h then poured into water

(120ml) and extracted with dichloromethane (3 £80ml).

The combined organic layers were washed with saturated

sodium bicarbonate, dried (MgSO₄) and the solvent

evaporated to afford the product (1.14 g, 72%) as a pale

yellow glass. d (250MHz): 2.02 (quintet, J6.8 Hz, 2H,

CH₂CH₂CH₂), 2.55 (t, J7.2 Hz, 2H, CH₂CH₂CHO), 3.75

(t, J6.8 Hz, 2H, NCH₂CH₂), 7.69±7.77 (m, 2H, ArH),

7.83±7.89 (m, 2H, ArH) and 9.78 (s, 1H, CHO); m/z (%):

217 (M¹, 1), 215 (11), 174 (46), 160 (100), 130 (14), 104

(21) and 76 (27); n_max(cm²¹): 3057, 2985, 1774 (CvO) and

1714 (CvO).

3.1.1. Phthalimidoacetaldehyde 1a. 6N HCl (60ml) was

added to a solution of phthalimidoacetaldehyde diethyl

acetal (2.95 g, 1.5 mmol) in THF (60ml) at room tempera-

ture with stirring and stirring was continued for 14 h. The

solvent was then removed under reduced pressure, and the

residue was treated with saturated aqueous NaHCO₃and

extracted with DCM. The organic layer was dried

(MgSO₄), ®ltered, and the ®ltrate evaporated to afford the

product 1a (2.84 g) in quantitative yield as colourless

needles from EtOAc±petroleum ether, mp 110±1128C.

(Found: C, 63.30, H, 3.80, N, 7.45. C₁₀H₇O₃N requires: C,

63.50, H, 3.70, N, 7.40%); d 4.58 (s, 2H, CH₂), 7.77 and

7.90(2 £m, 2£2H, ArH) and 9.67 (s, 1H, CHO); m/z (%):

189 (M¹, 4), 160 (100), 147 (5), 133 (19), 104 (22), 76 (33)

and 50(24); n_max(cm²¹): 3056, 2988, 1781 (CvO) and

1723 (CvO).

3.2. General method for the preparation of imines 3a±h

and 10a,b

3.1.2. 3-(N-Phthalimido)-propionaldehyde 1b.^5,6

A

Ê

Method A. Excess MgSO₄, Na₂SO₄or 4 A molecular sieves

solution of DMSO (2.06 ml, 29.04 mmol) in dichloro-

methane (20ml) was added dropwise (15 min) to a stirred

solution of oxalyl chloride (1.27 ml, 14.54 mmol) in

dichloromethane (90ml) at 2708C (isopropanol/dry ice)

and the mixture was stirred at 2708C for 5 min. A solution

N-(3-hydroxypropyl)-phthalimide (2.71 g, 13.22 mmol) in

dichloromethane (40ml) was added dropwise (15 min)

and the solution was stirred at 2708C for 40min. when

triethylamine (9.33 ml, 66.10mmol) was added dropwise

(5 min) and the mixture stirred at 2708C for 5 min, then

allowed to warm to room temperature. The mixture was

washed with water (150ml), 1 M HCL (80ml), saturated

sodium bicarbonate (80ml) and water (80ml). The organic

layer was dried (Na₂SO₄) and the solvent evaporated. The

residue was puri®ed by ¯ash column chromatography (3:2

v/v ether±petroleum ether) to afford the product (2.59 g,

97%) as a colourless solid, mp 125.5±126.58C (lit. 126.0±

127.08C). d (400 MHz): 2.87 (dt, J1.0and 7.0Hz, 2H,

CH₂CH₂CHO), 4.04 (t, J7.0Hz, 2H, NC H₂CH₂), 7.71±

7.74 (m, 2H, ArH), 7.84±7.86 (m, 2H, ArH) and 9.82 (t,

J1.2 Hz, CH₂CHO); m/z (%): 203 (M¹, 9), 175 (56), 160

were added to a stirred solution of aldehyde (1 equiv.) and

a-amino acid ester (1.05±1.1 equiv.) in dichloromethane at

room temperature and the mixture was stirred for 16±48 h.

The mixture was ®ltered and the ®ltrate evaporated to give

the imines, which were used without puri®cation.

Method B. Excess MgSO₄or Na₂SO₄were added to stirred

solution of aldehyde (1 equiv.), a-amino acid ester hydro-

chloride (1.05±1.1 equiv.) and triethylamine (1.05±

1.1 equiv.) in dichloromethane at room temperature and

the mixture was stirred for 16±20h. The mixture was

®ltered and the ®ltrate was washed with saturated brine

(£2). The organic layer was dried (MgSO₄) and the solvent

evaporated to give the imines, which were used without

puri®cation.

3.2.1. Methyl (6) 2-[2-(N-phthalimido)ethylideneamino]-

propionate 3a. Prepared according to the general procedure

(Method A) from aldehyde 1a (283 mg, 1.5 mmol) and

Ê

alanine methyl ester (170mg, 1.65 mmol) over 4 A

molecular sieves (1 g) in dichloromethane (10ml) for 16 h

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P. Blaney et al. / Tetrahedron 58 (2002) 1719±1737

to afford the product 3a as a pale yellow syrup (400 mg,

97%). d 1.39 (d, J6.8 Hz, 3H, Me), 3.71 (s, 3H, OMe),

4.08 (q, J6.8 Hz, 1H, CH), 4.51 (d, J3.0Hz, 2H, CH ₂),

7.74 (m, 3H, NvCH and 2£ArH) and 7.88 (m, 2H, ArH);

m/z (%): 274 (M¹, 6), 259 (14), 231 (13), 215 (100), 197

(13), 170 (10), 161 (61), 147 (5), 133 (15), 114 (13), 104

(33), 88 (38), 76 (39), 68 (53) and 59 (33).

3.2.6. Methyl (6) 2-[3-(N-phthalimido)-propylidenamino]-

3-phenylpropionate 3f. Prepared according to the general

procedure (Method A) from aldehyde 1b (0.591 g,

2.910mmol) and l-phenylalanine methyl ester (0.574 g,

3.207 mmol) over MgSO₄(1.7 g) in dichloromethane

(15 ml) for 16 h to afford the product 3f (1.162 g, 100%)

as a colourless syrup d (400 MHz): 2.58 (dt, J4.5 and

7.0Hz, 2H, CH ₂CH₂CH), 2.95 (dd, J9.0and 13.6 Hz,

1H, CHCHHPh), 3.21 (dd, J5.5 and 13.6 Hz, 1H,

CHCHHPh), 3.63 (s, 3H, CO₂Me), 3.78±3.89 (m, 2H,

NCH₂CH₂), 3.91±3.95 (m, 1H, NCH(CO₂Me)CH₂), 7.09±

7.14 (m, 3H, ortho and para ArH), 7.16±7.24 (m, 2H, meta

ArH), 7.35 (t, J4.5 Hz, 1H, CH₂CHvN), 7.70±7.72 (m,

2H, ArH) and 7.82±7.84 (m, 2H, ArH); m/z (ES1, %): 365

(M1H¹, 9) and 180 (100).

3.2.2. Methyl (6) 2-[2-(N-phthalimido)ethylideneamino]-

4-methylsulfanylbutyrate 3b. Prepared according to the

general procedure (Method A) from aldehyde 1a (756 mg,

4 mmol) and methionine methyl ester (705 mg, 4.3 mmol)

over MgSO₄(2 g) in dichloromethane (20ml) for 16 h to

afford the product 3b as a pale yellow syrup (1.34 g) in

quantitative yield. d 2.05 (s, 3H, SMe), 2.09 (m, 2H,

CH₂), 2.51 and 2.70(2 £m, 2£1H, CH₂), 3.71 (s, 3H,

OMe), 4.06 (dd, J5.0and 8.4 Hz, 1H, CH), 4.52 (d,

J2.8 Hz, 2H, NCH₂) and 7.74 and 7.87 (2£m, 5H,

NvCH and 4£ArH); m/z (%): 334 (M¹, 3), 275 (15), 227

(10), 213 (8), 201 (16), 174 (100), 160 (24), 133 (8), 114

(12), 104 (29), 100 (12), 87 (11), 80 (17) and 61 (84).

3.2.7. Methyl (6) 2-[3-(N-phthalimido)propylidenamino]-

propionate 3g. Prepared according to the general procedure

(Method B) from aldehyde 1b (0.400 g, 1.970 mmol),

l-alanine

methyl

ester

hydrochloride

(0.289 g,

2.069 mmol) and triethylamine (0.30 ml, 2.069 mmol)

over Na₂SO₄(1 g) in dichloromethane (12 ml) for 16 h to

afford the product 3g (0.592 g, 100%) as a colourless syrup.

d (250MHz): 1.33 (d, J6.9 Hz, 3H, CHMe), 2.69 (dt,

J1.7 and 6.6 Hz, 2H, CH₂CH₂CHvN), 3.63 (s, 3H,

OMe), 3.91 (q, J6.9 Hz, 1H, NCHMeCO₂Me), 3.98 (t,

J6.7 Hz, 2H, NCH₂CH₂) and 7.70±7.86 (m, 5H, ArH

and CH₂CHvN).

3.2.3. Methyl (6) 2-[2-(N-phthalimido)ethylideneamino]-

3-(3⁰-indolyl)propionate 3c. Prepared according to the

general procedure (Method A) from aldehyde 1a (869 mg,

4.6 mmol) and tryptophan methyl ester (1.1 g, 5 mmol) over

MgSO₄(2 g) in dichloromethane (25 ml) for 23 h to afford

the product 3c as an amorphous pale yellow solid (1.88 g) in

quantitative yield. d 3.06 (dd, J9.3 and 14.4 Hz, 1H,

CHH), 3.40(dd, J4.2 and 14.4 Hz, 1H, CHH), 3.72 (s,

3H, OMe), 4.04 (dd, J4.2 and 9.3 Hz, 1H, CH), 4.36 (m,

2H, NCH₂) and 6.98±8.10(m, 11H, N vCH and 10£ArH);

m/z (%): 389 (M¹, 4), 229 (27), 169 (19), 160(10), 130

(100), 115 (5), 103 (8), 84 (8), 77 (13) and 49 (10).

3.2.8. Methyl (6) 2-[3-(N-phthalimido)propylidenamino]-

3-(3⁰-indolyl)propionate 3h. Prepared according to the

general procedure (Method A) from aldehyde 1b (0.225 g,

1.108 mmol) and l-tryptophan methyl ester (0.266 g,

1.219 mmol) over Na₂SO₄(1 g) in dichloromethane

(10ml) for 16 h to afford the product 3h (0.480 g, 100%)

as a pale brown syrup. d (250MHz): 2.51±2.57 (m, 2H,

NCH₂CH₂CHvN), 3.09 (dd, J8.7 and 14.5 Hz, 1H,

CHCHHAr), 3.38 (dd, J5.0and 14.4 Hz, 1H, CHCH HAr),

3.65 (s, 3H, OMe), 3.79 (t, J7.1 Hz, 2H, NCH₂CH₂CH),

4.03 (dd, J5.2 and 8.7 Hz, 1H, NCH(CH₂)CO₂Me), 6.98±

7.39 (m, 5H, ArH and CH₂CHvN), 7.60±7.64 (m, 2H,

ArH), 7.78±7.86 (m, 2H, ArH) and 8.02 (br s, 1H, indole

NH); m/z (%): 403 (M¹, 5), 229 (13), 169 (10) and 130

(100).

3.2.4. Methyl (6) 2-[2-(N-phthalimido)-ethylideneamino]-

pentanedioate 3d. Prepared according to the general pro-

cedure (Method A) from aldehyde 1a (718 mg, 3.8 mmol)

and glutamic acid dimethyl ester (718 mg, 4.1 mmol) over

MgSO₄(2 g) in dichloromethane (20ml) for 48 h to afford

the product 3d as a pale yellow syrup (1.28 g, 97%). d 2.01±

2.33 (m, 4H, 2£CH₂), 3.62 and 3.68 (2£s, 2£3H, 2£OMe),

3.91 (dd, J4.8 and 8.3 Hz, 1H, CH), 4.50(d, J2.9 Hz,

2H, NCH₂), 7.66 (t, J2.9, 1H, NvCH) and 7.73 and 7.86

(2£m, 2£2H, ArH); m/z (%): 346 (M¹, 2), 287 (10), 227 (6),

186 (8), 160 (23), 147 (12), 116 (8), 104 (24), 84 (100), 76

(29), 56 (24) and 41 (29).

3.2.9. Methyl (6) 2-[4-(N-phthalimido)butylidenamino]-

3-phenylpropionate 10a. Prepared according to the general

procedure (Method A) from aldehyde

9 (0.805 g,

3.2.5. Methyl (6) 2-[2-(N-phthalimido)-ethylidenamino]-

3-phenylpropionate 3e. Prepared according to the general

procedure (Method A) from aldehyde 1a (850mg,

4.5 mmol) and phenylalanine methyl ester (844 mg,

4.72 mmol) over MgSO₄(2 g) in dichloromethane (20ml)

for 16 h to afford the product 3e as a pale yellow syrup

(1.62 g) in quantitative yield. d 2.95 (dd, J9.2 and

13.4 Hz, 1H, PhCHH), 3.21 (dd, J4.5 and 13.4 Hz, 1H,

PhCHH), 3.71 (s, 3H, OMe), 3.96 (dd, J4.5 and 9.2 Hz,

1H, CH), 4.35 (dd, J2.8 and 16.8 Hz, 1H, NCHH), 4.43

(dd, J3.4 and 16.8 Hz, 1H, NCHH) and 7.08±7.86 (m,

10H, NvCH and 9£ArH); m/z (%): 350(M ¹, 3), 291

(18), 259 (70), 199 (46), 190 (28), 172 (19), 160 (37), 144

(32), 130(22), 120(73), 112 (11), 104 (32), 91 (75), 88

(100), 77 (31), 65 (20) and 51 (14).

3.710mmol) and l-phenylalanine methyl ester (0.697 g,

3.900 mmol) over Na₂SO₄(1.7 g) in dichloromethane

(20ml) for 20h to afford the product 10a (1.410 g, 100%)

as a colourless syrup. d (250MHz): 1.70±1.80 (m, 2H,

CH₂CH₂CH₂), 2.21±2.24 (m, 2H, CH₂CH₂CHvN), 2.85±

3.35 (m, 2H, CHCH₂Ph), 3.55±3.65 (m, 2H, NCH₂CH₂),

3.72 (s, 3H, OMe), 7.09±7.28 (m, 6H, ArH and

CH₂CHvN), 7.69±7.73 (m, 2H, ArH) and 7.81±7.86 (m,

2H, ArH); m/z (%): 379 (M1H¹, 5), 295 (22), 160(94), 120

(70) and 91 (100).

3.2.10. Methyl (6) 2-[4-(N-phthalimido)butylidenamino]-

propionate 10b. Prepared according to the general pro-

cedure (Method B) from aldehyde

1.238 mmol), l-alanine methyl ester hydrochloride

9

(0.268 g,

P. Blaney et al. / Tetrahedron 58 (2002) 1719±1737

1727

(0.190 g, 1.362 mmol) and triethylamine (0.19 ml,

1.362 mmol) over Na₂SO₄(1 g) in dichloromethane (8 ml)

for 16 h to afford the product 10b (0.379 g, 100%) as a

colourless syrup. d (250MHz): 1.41 (d, J6.8 Hz, 3H,

CHMe), 1.71±1.83 (m, 2H, CH₂CH₂CH₂), 1.90±2.02 (m,

3.3.3. Dimethyl (6) endo-5-[(N-phthalimido)-methyl]-2-

(3⁰-indolylmethyl)pyrrolidine-2,4-dicarboxylate

5c.

AgOAc (300 mg, 1.8 mmol), methyl acrylate (677 ml,

7.5 mmol), imine 3c (584 mg, 1.5 mmol) and triethylamine

(251 ml, 1.8 mmol) in toluene (10ml) were reacted by the

general procedure for 40h. Flash chromatography (3:1 v/v

Et₂O±petroleum ether) afforded the product 5c (282 mg,

40%) as colourless needles from CH₂Cl₂/petroleum ether,

mp 158±1608C. (Found: C, 65.45, H, 5.40, N, 8.80.

C₂₆H₂₅N₃O₆requires: C, 65.70, H, 5.30, N, 8.85%); d

2.20(dd, J7.4 and 13.8 Hz, 1H, CHH), 2.70(dd, J4.1

and 13.8 Hz, 1H, CHH), 2.91 (m, 2H, NH and CH), 2.98 and

3.15 (2£d, J14.1 Hz, 2£1H, indole-CH₂), 3.51 (m, 1H,

NCH), 3.60(dd, J9.5 and 13.6 Hz, 1H, NCHH), 3.66

and 3.69 (2£s, 2£3H, 2£OMe), 3.77 (dd, J4.1 and

13.6 Hz, 1H, NCHH), 6.61 (t, J7.8 Hz, 1H, ArH), 6.96

(m, 2H, ArH), 7.23 and 7.51 (2£d, J7.8 Hz, 2£1H,

ArH), 7.74 and 7.83 (2£m, 2£2H, ArH) and 8.06 (br s, 1H,

NH); m/z (%): 476 (M¹11, ,1), 416 (7), 345 (100), 253 (9),

160(34), 138 (29), 130(11), 104 (5), 84 (16) and 49 (47).

1H,

CH₂CHHCHvN),

2.33±2.41

(m,

1H,

CH₂CHHCHvN), 3.62±3.73 (m, 2H, NCH₂CH₂), 3.72 (s,

3H, OMe), 3.92 (q, J6.8 Hz, 1H, CHMe), 7.67±7.76 (m,

3H, ArH and CH₂CHvN) and 7.81±7.86 (m, 2H, ArH).

3.3. General method for the preparation of cycloadducts

5a±j, 11a,b, 17a±e, 20 and 22

Silver(I) acetate (1.05±1.3 equiv.), dipolarophile [methyl

acrylate (1.5±5 equiv.), benzyl acrylate (1.5 equiv.),

N-methylmaleimide (1.2±2 equiv.), or phenyl vinyl sulfone

(1.05±1.1 equiv.)] and triethylamine (1.05±1.3 equiv.) were

added (in the dark for AgOAc) to a stirred solution of imine

(1 equiv.) in toluene at room temperature and the mixture

was stirred for 16±48 h. The mixture was diluted with

dichloromethane and washed with saturated ammonium

chloride (£2) and water. The organic layer was dried

(MgSO₄) and the solvent evaporated. The residue was

puri®ed via ¯ash column chromatography to afford the

cycloadducts.

3.3.4. Dimethyl (6) endo-5-[(N-phthalimido)-methyl]-2-

(2-methoxycarbonyl-ethyl)pyrrolidine-2,4-dicarboxylate

5d. AgOAc (300 mg, 1.8 mmol), methyl acrylate (677 ml,

7.5 mmol), imine 3d (519 mg, 1.5 mmol) and triethylamine

(251 ml, 1.8 mmol) in toluene (10ml) were reacted by the

general procedure for 48 h. Flash chromatography (Et₂O)

afforded the product 5d (596 mg, 92%) as colourless prisms

from Et₂O±petroleum ether, mp 109±1118C. (Found: C,

58.10, H, 5.60, N, 6.65. C₂₁H₂₄N₂O₈requires: C, 58.35, H,

5.60, N, 6.60%); d 1.82 (m, 1H, CHH), 2.04 (3£m, 3£1H,

CHH and CH₂), 2.38 (m, 1H, CHH), 2.64 (dd, J3.7 and

13.9 Hz, 1H, CHH), 2.87 (br s, 1H, NH), 3.07 (m, 1H, CH),

3.52, 3.69 and 3.79 (3£s, 3£3H, 3£OMe), 3.68 (m, 2H,

NCH and NCHH), 3.89 (dd, J3.3 and 13.7 Hz, 1H,

NCHH), 7.74 and 7.86 (2£m, 2£2H, ArH); m/z (%): 433

(M¹11, ,1), 401 (5), 373 (92), 341 (16), 313 (13), 272

(100), 253 (6), 240 (27), 226 (12), 212 (10), 194 (7), 180

(26), 166 (18), 160(86), 152 (24), 134 (49), 122 (7), 104

(30), 94 (17), 80 (50), 77 (27), 67 (12) and 55 (34).

3.3.1. Dimethyl (6) endo-5-[(N-phthalimido)methyl]-2-

methyl-pyrrolidine-2,4-dicarboxylate

5a.

AgOAc

(280mg, 1.68 mmol), methyl acrylate (227 mg,

2.5 mmol), imine 3a (385 mg, 1.4 mmol) and triethylamine

(240 ml, 1.68 mmol) in toluene (10ml) were reacted by the

general procedure for 40h. Flash chromatography (Et ₂O)

afforded the product 5a (328 mg, 65%) as colourless prisms

from Et₂O±petroleum ether, mp 117±1198C. (Found: C,

59.95, H, 5.55, N, 7.50. C₁₈H₂₀N₂O₆requires: C, 60.00, H,

5.60, N, 7.75%); d 1.34 (s, 3H, Me), 1.97 (dd, J7.6 and

13.7 Hz, 1H, CHH), 2.67 (dd, J4.9 and 13.7 Hz, 1H,

CHH), 2.9 (br s, 1H, NH), 3.10(m, 1H, CH), 3.66 (m,

1H, NCH), 3.69 and 3.78 (2£s, 2£3H, 2£OMe), 3.84 (m,

2H, NCH₂) and 7.71 and 7.83 (2£m, 2£2H, ArH); m/z (%):

(FAB) 361 (M¹11, 100), 301 (50), 200 (9), 160 (12), 154

(5), 140(6), 122 (10), 94 (25) and 82 (6).

3.3.5. Dimethyl (6) endo -5-[(N-phthalimido)-methyl]-2-

benzyl-pyrrolidine-2,4-dicarboxylate 5e. AgOAc (300 mg,

1.8 mmol), methyl acrylate (677 ml, 7.5 mmol), imine 3e

(525 mg, 1.5 mmol) and triethylamine (251 ml, 1.8 mmol)

in toluene (10ml) were reacted by the general procedure

for 16 h. Flash chromatography (2:1 v/v Et₂O±petroleum

ether) afforded the product 5e (570mg, 87%) as colourless

prisms from Et₂O±petroleum ether, mp 80±828C. (Found: C,

65.95, H, 5.60, N, 6.30. C₂₄H₂₄N₂O₆requires: C, 66.05, H,

5.55, N, 6.40%); d 2.12 (dd, J7.4 and 13.9 Hz, 1H, CHH),

2.68 (dd, J5.0and 13.9 Hz, 1H, CH H), 2.75 (br s, 1H, NH),

2.80(d, J13.1 Hz, 1H, PhCHH), 2.86 (m, 1H, CH), 2.94 (d,

J13.1 Hz, 1H, PhCHH), 3.66 (s, 3H, OMe), 3.68 (m, 3H,

NCH and NCH₂), 3.72 (m, 3H, OMe), 7.10(m, 5H, 5ArH)

and 7.75 and 7.88 (2£m, 2£2H, ArH); m/z (%): (FAB) 437

(M¹11, 100), 377 (47), 345 (40), 276 (6), 198 (9), 170 (24),

160(26) and 91 (31); n_max(cm²¹): 3056±3033, 2988±2954,

1775 (CvO), 1717 (CvO), 1615 and 1496.

3.3.2. Dimethyl (6) endo-5-[(N-phthalimido)-methyl]-2-

(2-methylsulfanyl-ethyl)pyrrolidine-2,4-dicarboxylate

5b. AgOAc (250mg, 1.5 mmol), methyl acrylate (542 ml,

6 mmol), imine 3b (422 mg, 1.26 mmol) and triethylamine

(209 ml, 1.5 mmol) in toluene (10ml) were reacted by the

general procedure for 16 h. Flash chromatography (2:1 v/v

Et₂O±petroleum ether) afforded the product 5b (363 mg,

70%) as colourless prisms from CH₂Cl₂/petroleum ether,

mp 116±1178C. (Found: C, 57.15, H, 5.85, N, 6.65, S,

7.70. C₂₀H₂₄N₂O₆S requires: C, 57.15, H, 5.75, N, 6.65, S,

7.60%); d 1.72 (m, 1H, CHH), 1.84±2.00 (m, 5H, CH₂and

SMe), 2.22 and 2.52 (2£m, 2£1H, CH₂), 2.65 (dd, J3.9

and 13.9 Hz, 1H, CHH), 2.89 (br s, 1H, NH), 3.04 (m, 1H,

CH), 3.69 (s, 3H, OMe), 3.62±3.79 (m, 5H, NCH, NCHH

and OMe), 3.90(dd, J3.6 and 12.6 Hz, 1H, NCHH) and

7.74 and 7.86 (2£m, 2£2H, ArH); m/z (%): 420(M ¹, 5), 361

(100), 345 (17), 313 (14), 260 (99), 228 (28), 214 (8), 186

(9), 160(34), 152 (33), 138, (13), 126 (9), 104 (13), 94 (15),

77 (10) and 61 (68).

3.3.6. (6) endo-5-[(N-Phthalimido)-methyl]-2-benzyl-

pyrrolidine-2-carboxylic acid methyl ester-4-carboxylic

acid benzyl ester 5f. AgOAc (0.238 g, 1.425 mmol), benzyl

1728

P. Blaney et al. / Tetrahedron 58 (2002) 1719±1737

acrylate (0.963 ml, 5.94 mmol), imine 3e (0.410 g,

1.188 mmol) and triethylamine (0.20 ml, 1.425 mmol) in

toluene (15 ml) were reacted by the general procedure for

16 h. Flash chromatography (2:1 v/v Et₂O±petroleum ether)

afforded the product 5f (0.315 g, 52%) as a colourless syrup.

(Found: C, 70.05; H, 5.70; N, 5.45. C₃₀H₂₈N₂O₆requires: C,

70.30; H, 5.50; N, 5.45%); d (250MHz): 2.12 (dd, J7.5

and 14.0Hz, 1H, CHC HHC), 2.69 (dd, J4.6 and 14.0Hz,

1H, CHCHHC), 2.75 (br s, 1H, NH), 2.78 (d, J13.1 Hz,

1H, CHCHHPh), 2.93 (d, J12.9 Hz, 1H, CHCHHPh),

2.90±2.94 (m, 1H, CHCH(CO₂Bn)CH₂), 3.63 (s, 3H,

CO₂Me), 3.47±3.68 (m, 3H, NCH₂CH(NH)CH), 5.05 (d,

J12.1 Hz, PhCHHOCO), 5.13 (d, J12.0Hz, 1H,

PCHHOCO), 7.09±7.34 (m, 10H, ArH) 7.71±7.74 (m,

2H, ArH) and 7.837.87 (m, 2H, ArH). m/z (ES1, %): 513

(M1H¹, 100); n_max(cm²¹): 3056, 2988±2955, 1775

(CvO), 1717 (CvO) and 1496.

2.156 mmol), methyl acrylate (0.88 ml, 9.800 mmol), imine

3g (0.587 g, 1.960 mmol) and triethylamine (0.19 ml,

2.156 mmol) in toluene (20ml) were reacted by the general

procedure for 18 h. Flash chromatography (3:1 v/v Et₂O±

petroleum ether) afforded the product 5i (0.520 g, 71%) as

a colourless solid, mp 97.0±98.08C. (Found: C, 60.80; H,

5.95; N, 7.20. C₁₉H₂₂N₂O₆requires: C, 60.95; H, 5.90; N,

7.50%); d (250MHz): 1.39 (s, 3H, CMe), 1.68±1.93 (m,

3H, NCH₂CH₂CH and NH), 1.92 (dd, J7.5 and 13.8 Hz,

1H, CCHHCH), 2.63 (dd, J3.5 and 13.9 Hz, 1H,

CCHHCH), 3.06±3.12 (m, 1H, CHCH(CO₂Me)CH₂), 3.33±

3.41 (m, 1H, NHCH(CH₂)CH), 3.65 and 3.77 (2£s, 2£3H,

2£CO₂Me), 3.82±3.89 (m, 2H, NCH₂CH₂), 7.70±7.74 (m,

2H, ArH) and 7.81±7.96 (m, 2H, ArH); m/z (%): 375

(M11, 1), 359 (2), 315 (100), 255 (13), 200(25), 160(50)

and 10 8 (42);n_max(cm²¹): 3057, 2987±2954, 1774 (CvO),

1713.

3.3.7. Dimethyl (6) endo-5-[2-(N-phthalimido)-ethyl]-2-

benzyl-pyrrolidine-2,4-dicarboxylate 5g. AgOAc (0.192 g,

1.153 mmol), methyl acrylate (0.43 ml, 4.805 mmol), imine

3f (0.350 g, 0.961 mmol) and triethylamine (0.16 ml,

1.153 mmol) in toluene (10ml) were reacted by the general

procedure for 18 h. Flash chromatography (2:1 v/v Et₂O±

petroleum ether) afforded the product 5g (0.310 g, 72%) as

a colourless syrup. (Found: C, 66.75; H, 6.05; N, 6.00.

C₂₅H₂₆N₂O₆requires: C, 66.60; H, 5.85; N, 6.20%); d

(400 MHz): 1.71±1.77 (m, 2H, CH₂CH₂CH), 2.05 (dd,

J7.0and 14.1 Hz, 1H, CHC HHC), 2.63 (dd, J3.2 and

13.7 Hz, 1H, CHCHHC), 2.75 (br s, 1H, NH), 2.84 (d,

J13.0Hz, 1H, CC HHPh), 2.89±2.93 (m, 1H, CHCH(CO_2-

Me)CH₂), 2.98 (d, J13.0Hz, 1H, CHCH HPh), 3.48 (q,

J7.0Hz, 1H, CHC H(CO₂Me)CH₂), 3.62 and 3.68 (2£s,

2£3H, 2£CO₂Me), 3.76±3.90(m, 2H, NC H₂CH₂), 7.12±

7.26 (m, 5H, Ph), 7.71±7.75 (m, 2H, ArH) and 7.82±7.87

(m, 2H, ArH); m/z (ES1, %): 451 (M1H¹, 100); n_max

(cm²¹): 3056, 2988±2954, 1773 (CvO) and 1714 (CvO).

3.3.10. Dimethyl (6) endo-5-[2-(N-phthalimido)-ethyl]-

2-[3⁰-indolylmethyl]-pyrrolidine-2,4-dicarboxylate 5j.

AgOAc (0.202 g, 1.210 mmol), methyl acrylate (0.50 ml,

5.500 mmol), imine 3h (0.470 g, 1.100 mmol) and triethyl-

amine (0.17 ml, 1.210 mmol) in toluene (10 ml) were

reacted by the general procedure for 18 h. Flash chromato-

graphy (3:1 v/v Et₂O±petroleum ether) afforded the product

5j (0.332 g, 62%) as a pale yellow solid, mp 67.5±69.08C.

(Found: C, 66.50; H, 5.60; N, 8.30. C₂₇H₂₇N₃O₆requires: C,

66.25; H, 5.55; N, 8.60%); d (250MHz): 1.58±1.77 (m, 3H,

NCH₂CH₂CH and NH), 2.13 (dd, J7.5 and 13.8 Hz, 1H,

CCHHCH), 2.66 (dd, J3.5 and 13.8 Hz, 1H, CCHHCH),

2.91±2.97 (m, 1H, CHCH(CO₂Me)CH₂), 3.01 (d, J14.2 Hz,

1H, CCHHAr), 3.15±3.22 (m, 1H, NHCH(CH₂)CH), 3.23 (d,

J14.2 Hz, 1H, CCHHAr), 3.62 (s, 2£CO₂Me), 3.81 (dt,

J6.8 and 13.8 Hz, 2H, NCH₂CH₂), 7.03±7.14 (m, 2H,

ArH), 7.21±7.29 (m, 2H, ArH), 7.64 (d, J7.4 Hz, 1H,

ArH), 7.70±7.74 (m, 2H, ArH), 7.80±7.86 (m, 2H, ArH)

and 8.0 3 (br s, 1H, indole NH); m/z (%): 458 (M2CO₂Me^e1,

1), 430(7), 359 (100), 267 (20), 160(52) and 130(84);

(cm²¹): 3056, 2988, 1775 (CvO), 1715 (CvO).

n_max

3.3.8. (6) endo-5-[2-(N-Phthalimido)-ethyl]-2-benzyl-

pyrrolidine-2-carboxylic acid methyl ester-4-carboxylic

acid benzyl ester 5h. AgOAc (0.201 g, 1.206 mmol), ben-

zyl acrylate (0.245 ml, 1.506 mmol), imine 3f (0.366 g,

1.005 mmol) and triethylamine (0.17 ml, 1.206 mmol) in

toluene (10ml) were reacted by the general procedure for

18 h. Flash chromatography (2:1 v/v Et₂O±petroleum ether)

afforded the product 5h (0.340 g, 64%) as a colourless solid,

mp 84.5±85.58C. (Found: C, 70.45; H, 5.85; N, 5.15.

3.3.11. Dimethyl (6) endo-5-[3-(N-phthalimido)-propyl]-

2-benzyl-pyrrolidine-2,4-dicarboxylate 11a. AgOAc

(0.225 g, 1.347 mmol), methyl acrylate (0.55 ml,

6.125 mmol), imine 10a (0.500 g, 1.225 mmol) and triethyl-

amine (0.19 ml, 1.347 mmol) in toluene (8 ml) were reacted

by the general procedure for 18 h. Flash chromatography

(3:1 v/v Et₂O±petroleum ether) afforded the product 11a

(0.290 g, 51%) as colourless oil. (Found: C 66.65; H,

6.15; N, 6.25. C₂₆H₂₈N₂O₆´1/4H₂O requires: C, 66.60; H,

6.10; N, 5.95%); d (500 gMHz): 1.39 (q, J7.6 Hz, 2H,

CH₂), 1.78±1.85 (br m, 3H, NH and CH₂), 2.04 (dd,

J7.6 and 13.9 Hz, 1H, MeCO₂CHCHH), 2.61 (dd, J3.2

and 13.9 Hz, 1H, MeCO₂CHCHH), 2.82 (d, J13.0Hz, 1H,

PhCHH), 2.81±2.84 (m, 1H, MeCO₂CH), 2.99 (d,

J13.0Hz, 1H, PhCH H), 3.12 (q, J6.8 Hz, 1H,

NCHCH₂), 3.60and 3.66 (2 £s, 2£3H, 2£CO₂Me), 3.69±

3.77 (m, 2H, NCH₂), 7.20±7.27 (m, 5H, ArH), 7.70±7.72

(m, 2H, ArH) and 7.82±7.85 (m, 2H, ArH); m/z (%): 465

(M1H¹, 41), 405 (48), 373 (100), 309 (19), 281 (42), 160

(53) and 91 (59); n_max(cm²¹): 3057, 2985, 1715 (CvO).

1

C₃₁H₃₀N₂O₆requires: C, 70.70; H, 5.75; N, 5.30%); d H

(400 MHz): 1.63±1.69 (m, 2H, CH₂CH₂CH), 2.06 (dd,

J7.5 and 14.1 Hz, 1H, CHCHHC), 2.65 (dd, J3.2 and

13.7 Hz, 1H, CHCHHC), 2.75 (br s, 1H, NH), 2.82 (d,

J13.0Hz, 1H, CC HHPh), 2.97 (d, J13.0Hz, 1H,

CCHHPh), 2.95±2.99 (m, 1H, CHCH(CO₂Bn)CH₂), 3.09

(q, J6.7 Hz, 1H, NHCH(CH₂)CH), 3.61 (s, 3H, CO₂Me),

3.66±3.76 (m, 1H, NCHHCH₂), 3.79±3.86 (m, 1H,

NCHHCH₂), 5.03 (d, J12.0Hz, 1H, PhC HHOCO), 5.09

(d, J12.0Hz, 1H, PhCH HOCO), 7.09±7.31 (m, 10H,

ArH), 7.70±7.75 (m, 2H, ArH), and 7.83±7.87 (m, 2H,

ArH); m/z (ES1, %): 527 (M1H¹, 100); n_max(cm²¹):

3057, 2988±2953, 1774 (CvO), 1713 (CvO) and 1496.

3.3.9. Dimethyl (6) endo-5-[2-(N-phthalimido)-ethyl]-2-

methyl-pyrrolidine-2,4-dicarboxylate 5i. AgOAc (0.360 g,

3.3.12. Dimethyl (6) endo-5-[3-(N-phthalimido)-propyl]-

2-methyl-pyrrolidine-2,4-dicarboxylate 11b. AgOAc

P. Blaney et al. / Tetrahedron 58 (2002) 1719±1737

1729

(0.223 g, 1.337 mmol), methyl acrylate (0.55 ml,

6.075 mmol), imine 10b (0.370 g, 1.215 mmol) and triethyl-

amine (0.19 ml, 1.34 mmol) in toluene (8 ml) were reacted

by the general procedure for 18 h. Flash chromatography

(2:1 v/v ethyl acetate/petroleum ether) afforded the product

11b (0.220 g, 47%) as colourless oil. (Found: C 61.55; H,

6.15; N, 7.20. C₂₆H₂₈N₂O₆requires: C, 61.85; H, 6.25; N,

7.20%); d (500 MHz): 1.39 (s, 3H, CMe), 1.40±1.60 (m,

2H, CH₂), 1.78±1.88 (m, 2H, CH₂), 1.90(dd, J7.6 and

13.8 Hz, 1H, MeCO₂CHCHH), 2.15 (br s, 1H, NH) 2.59

(dd, J3.6 and 13.8 Hz, 1H, MeCO₂CHCHH), 2.96±3.00

(m, 1H, NCHCH₂), 3.34 (q, J7.4 Hz, 1H, MeCO₂CH),

3.62 and 3.75 (2£s, 2£3H, 2£CO₂Me), 3.70(dt, J2.2

and 6.9 Hz, 2H, NCH₂), 7.69±7.73 (m, 2H, ArH) and

7.81±7.85 (m, 2H, ArH); m/z (%): 389 (M1H¹, 56), 329

(100), 269 (32), 200 (42) and 160 (37); n_max(cm²¹): 3054,

2985, 1774 (CvO), 1713 (CvO).

0.3 mmol) in toluene (3 ml) were reacted by the general

procedure for 10h. Flash chromatography (4:1 v/v

CH₂Cl₂±EtOAc) afforded the product 17c (51 mg, 41%)

as colourless needles from CH₂Cl₂/petroleum ether, mp

279±2818C. (Found: C, 64.90, H, 4.80, N, 10.95.

C₂₇H₂₄N₄O₆requires: C, 64.80, H, 4.85, N, 11.20%); d

2.65 (br s, 1H, NH), 3.00(s, 3H, NMe), 3.10(d,

J14.6 Hz, 1H, indole-CHH), 3.43 (m, 2H, 2£CH), 3.46

(d, J14.6 Hz, 1H, indole-CHH), 3.69 (dd, J10.6 and

14.3 Hz, 1H, NCHH), 3.74 (s, 3H, OMe), 3.90(m, 1H,

NCH), 4.40(dd, J12.1 and 14.3 Hz, 1H, NCHH), 6.41

and 6.80(2 £t, J8.1 Hz, 2£1H, ArH), 6.92 (d, J2.0Hz,

1H, ArH), 7.15 and 7.31 (2£d, J8.1 Hz, 2£1H, ArH), 7.74

and 7.79 (2£m, 2£2H, ArH) and 8.0(br s, 1H, NH); m/z

(%): 500 (M¹, ,1), 370 (100), 223 (8), 191 (15), 160 (27),

130 (66), 104 (9) and 77 (10).

3.3.16. Methyl (6) endo-3-[(N-phthalimido)-methyl]-1-

(2-methoxycarbonyl-ethyl)-5-methyl-4,6-dioxo-octahydro-

3.3.13. Methyl (6) endo-3-[(N-phthalimido)-methyl]-1,5-

dimethyl-4,6-dioxo-octahydro-pyrrolo[3,4-c]pyrrole-1-

carboxylate 17a. AgOAc (100 mg, 0.6 mmol), N-methyl-

maleimide (83 mg, 0.75 mmol), imine 3a (137 mg,

0.5 mmol) and triethylamine (82 ml, 0.6 mmol) in toluene

(4 ml) were reacted by the general procedure for 40h. Flash

chromatography (1:1 v/v EtOAc±CH₂Cl₂) afforded the

product 17a (164 mg, 85%) as colourless prisms from

CH₂Cl₂, mp 217±2198C. (Found: C, 58.95, H, 5.15, N,

10.85. C₁₉H₁₉N₃O₆requires: C, 59.20, H, 4.95, N,

10.90%); d 1.41 (s, 3H, Me), 2.75 (d, J11.9 Hz, 1H,

NH), 3.01 (s, 3H, NMe), 3.25 (d, J7.7 Hz, 1H, CH),

3.48 (t, J7.7 Hz, 1H, CH), 3.79 (m, 5H, OMe, NCH and

NCHH), 4.39 (dd, J1.7 and 13.5 Hz, 1H, NCHH) and 7.72

and 7.85 (2£m, 2£2H, ArH); m/z (%): 386 (M¹11, 1), 326

(100), 238 (15), 225 (77), 193 (6), 179 (53), 165 (78), 160

(29), 138 (5), 133 (8), 130 (8), 122 (12), 108 (46), 104 (18),

94 (42), 80(26), 53 (12) and 42 (12).

pyrrolo[3,4-c]pyrrole-1-carboxylate

17d.

AgOAc

(300 mg, 1.8 mmol), N-methylmaleimide (278 mg,

2.5 mmol), imine 3d (519 mg, 1.5 mmol) and triethylamine

(251 ml, 1.8 mmol) in toluene (10ml) were reacted by the

general procedure for 40h. Flash chromatography (3:1 v/v

Et₂O±EtOAc) afforded the product 17d (231 mg, 33%) as

colourless needles from CH₂Cl₂/petroleum ether, mp 175±

1778C. (Found: C, 57.55, H, 5.10, N, 9.45. C₂₂H₂₃N₃O₈

requires: C, 57.75, H, 5.05, N, 9.20%); d 1.99 (m, 1H,

CHH), 2.14 (m, 2H, CH₂), 2.26 (m, 1H, CHH), 2.69 (d,

J11.1 Hz, 1H, NH), 3.00 and 3.18 (2£s, 2£3H, NMe

and OMe), 3.24 (d, J7.7 Hz, 1H, CH), 3.48 (t,

J7.7 Hz, 1H, CH), 3.69 (dd, J11.3 and 14.1 Hz, 1H,

NCHH), 3.80(s, 3H, OMe), 3.82 (m, 1H, NCH), 4.37 (dd,

J2.2 and 14.1 Hz, 1H, NCHH) and 7.73 and 7.86 (2£m,

2£2H, ArH); m/z (%): 458 (M¹11, 1), 426 (7), 398 (56),

370(12), 338 (47), 310(9), 297 (83), 265 (19), 251 (33), 237

(15), 219 (13), 205 (30), 191 (15), 177 (61), 160 (100), 148

(11), 134 (22), 120 (30), 104 (45), 94 (28), 77 (43) and 59

(23).

3.3.14. Methyl (6) endo-3-[(N-phthalimido)-methyl]-5-

methyl-1-(2-methylsulfanyl-ethyl)-4,6-dioxo-octahydro-

pyrrolo[3,4-c]pyrrole-1-carboxylate 17b. AgOAc (250mg,

1.5 mmol), N-methylmaleimide (222 mg, 2.5 mmol), imine

3b (422 mg, 1.26 mmol) and triethylamine (209 ml,

1.5 mmol) in toluene (10ml) were reacted by the general

procedure for 16 h. Flash chromatography (Et₂O) afforded

the product 17b (396 mg, 71%) as colourless prisms from

CH₂Cl₂/petroleum ether, mp 162±1648C. (Found: C, 56.60,

H, 5.30, N, 9.35, S, 6.95. C₂₁H₂₃N₃O₆S requires: C, 56.60, H,

5.20, N, 9.45, S, 7.20%); d 1.78 (m, 1H, CHH), 1.92 (s, 3H,

NMe), 2.20(m, 1H, CH H), 2.35 (m, 2H, CH₂), 2.73 (d,

J11.2 Hz, 1H, NH), 3.00 (s, 3H, SMe), 3.28 (d,

J7.5 Hz, 1H, CH), 3.50(t, J7.5 Hz, 1H, CH), 3.78 (m,

2H, NCH and NCHH), 3.80(s, 3H, OMe), 4.35 (d,

J11.4 Hz, 1H, NCH₂) and 7.74 and 7.85 (2£m, 2£2H,

ArH); m/z (%): 445 (M¹, 2), 386 (59), 370(25), 338 (52),

285 (56), 253 (13), 239 (10), 224 (24), 211 (10), 191 (23), 178

(8), 168 (19), 160(53), 138 (12), 130(12), 106 (25), 94 (19),

77 (25) and 61 (100).

3.3.17. Methyl (6) endo-1-benzyl-3-[(N-phthalimido)-

methyl]-5-methyl-4,6-dioxo-octahydro-pyrrolo[3,4-c]-

pyrrole-1-carboxylate 17e. AgOAc (300 mg, 1.8 mmol),

N-methylmaleimide (278 mg, 2.5 mmol), imine 3e

(525 mg, 1.5 mmol) and triethylamine (251 ml, 1.8 mmol)

in toluene (10ml) were reacted by the general procedure for

16 h. Flash chromatography (Et₂O) afforded the product 17e

(551 mg, 80%) as colourless rods from Et₂O, mp 160±

1628C. (Found: C, 65.15, H, 5.10, N, 9.40. C₂₅H₂₃N₃O₆

requires: C, 65.05, H, 5.00, N, 9.10%); d 2.47 (d,

J9.3 Hz, 1H, NH), 2.85 (d, J13.2 Hz, 1H, PhCHH),

3.01 (s, 3H, NMe), 3.36 (d, J13.2 Hz, 1H, PhCHH),

3.37 (d, J7.6 Hz, 1H, CH), 3.46 (t, J7.6 Hz, 1H, CH),

3.76 (s, 3H, OMe), 3.83 (dd, J10.7 and 14.0 Hz, 1H,

NCHH), 3.95 (m, 1H, NCH), 4.35 (dd, J2.4 and

14.0Hz, 1H, NCH H), 6.81±7.00 (m, 5H, 5ArH) and 7.77

and 7.87 (2£m, 2£2H, ArH); m/z (%): (FAB) 461 (M¹,

100), 402 (37), 370 (57), 223 (5), 170 (11), 160 (15) and

91 (11).

3.3.15. Methyl (6) endo-3-[(N-phthalimido)-methyl]-1-

(1H-indol-3-ylmethyl)-5-methyl-4,6-dioxo-octahydro-

pyrrolo[3,4-c]pyrrole-1-carboxylate 17c. AgOAc (50mg,

0.3 mmol), N-methylmaleimide (67 mg, 0.6 mmol), imine

3c (97 mg, 0.25 mmol) and triethylamine (42 ml,

3.3.18. Methyl (6) endo-5-[(N-phthalimido)-methyl]-4-

benzenesulfonyl-2-benzyl-pyrrolidine-2-carboxylate 20.

Prepared according to the general procedure from imine

1730

P. Blaney et al. / Tetrahedron 58 (2002) 1719±1737

3e (1.274 g, 3.448 mmol), silver(I) acetate (0.863 g,

5.172 mmol), phenyl vinyl sulfone (0.638 g, 3.793 mmol)

and triethylamine (0.19 ml, 5.172 mmol) in toluene

(40ml) for 18 h. The residue was puri®ed (3:1 v/v ether±

petroleum ether) to afford the product 20 (0.610 g, 34%) as a

yellow solid, mp 169.0±170.08C. (Found: C 64.25; H, 5.10;

N, 5.25; S, 6.30. C₂₈H₂₆N₂O₆S´1/4H₂O requires: C 64.30; H,

5.10; N, 5.35; S, 6.10%); d (500 MHz): 2.06 (dd, J7.5 and

14.5 Hz, 1H, SO₂CHCHH), 2.69 (d, J13.2 Hz, 1H,

PhCHH), 2.78 (dd, J6.4 and 13.2 Hz, 1H, SO₂CHCHH),

2.83 (d, J13.2 Hz, 1H, PhCHH), 3.16 (q, J6.7 Hz, 1H,

SO₂CH), 3.44±3.52 (m, 1H, NCH), 3.81 (s, 3H, CO₂Me),

4.15 (dd, J3.2 and 14.3 Hz, 1H, NCHH), 4.24 (dd, J11.1

and 14.3 Hz, 1H, NCHH), 6.96±6.98 (m, 4H, ArH), 7.25±

7.27 (m, 1H, ArH), and 7.59±7.90(m, 9H, Ar H). m/z (FAB,

%): 541 (M1Na¹, 9), and 519 (M1H¹, 100); n_max(cm²¹):

3056, 2987, 1772 (CvO), 1730(C vO) and 1716 (CvO).

petroleum ether, mp 182±1848C. (Found: C, 54.30, H, 7.20,

N, 14.05. C₉H₁₄N₂O₃requires: C, 54.55, H, 7.10, N,

14.15%); d 1.42 (s, 3H, Me), 1.85 (dd, J12.2 and

13.3 Hz, 1H, CHH), 2.31 (br s, 1H, NH), 2.61 (dd, J5.3

and 13.3 Hz, 1H, CHH), 3.14 (dd, J2.4, and 13.0Hz, 1H,

NCHH), 3.35 (m, 1H, COCH), 3.49 (dd, J4.5 and 13.0Hz,

1H, NCHH), 3.70(s, 3H, OMe), 3.94 (m, 1H, NCH) and

5.93 (br s, 1H, CONH); m/z (%): 198 (M¹, 10), 170 (5), 155

(9), 141 (66), 139 (29), 111 (7), 108 (5), 96 (45), 94 (22), 82

(100), 67 (8), 55 (10) and 42 (22).

Isomer 6a: obtained as colourless needles from CH₂Cl₂/

petroleum ether, mp 111±1138C. (Found: C, 54.55, H,

7.20, N, 14.05. C₉H₁₄N₂O₃requires: C, 54.55, H, 7.10, N,

14.15%); d 1.39 (s, 3H, Me), 2.00 (dd, J9.8 and 13.4 Hz,

1H, CHH), 2.42 (br s, 1H, NH), 2.64 (dd, J2.5, 13.4 Hz,

1H, CHH), 2.79 (ddd, J2.5, 6.7 and 9.8 Hz, 1H,

COCH), 3.30(d, J10.7 Hz, 1H, NCHH), 3.59 (dd, J6.7

and 10.7 Hz, 1H, NCHH), 3.70(s, 3H, OMe), 4.80

(t, J6.7 Hz, 1H, NCH) and 6.76 (br s, 1H, CONH);

m/z (%): 198 (M¹, 6), 139 (100), 122 (12), 108 (5), 96

(55), 94 (70), 82 (91), 67 (18), 58 (21), 55 (20) and

42 (48).

3.3.19. Methyl (6) endo-5-[(N-phthalimido)-ethyl]-4-

benzenesulfonyl-2-benzyl-pyrrolidine-2-carboxylate 22.

Prepared according to the general procedure from imine

3f (0.990 g, 2.45 mmol), silver(I) acetate (0.429 g,

2.572 mmol), phenyl vinyl sulfone (0.432 g, 2.572 mmol)

and triethylamine (0.19 ml, 2.572 mmol) in toluene

(12 ml) for 18 h. The residue was puri®ed (3:1 v/v ether±

petroleum ether) to afford the product 22 (0.867 g, 67%) as a

yellow solid, mp 86.5±88.08C. (Found: C 65.3; H, 5.45; N,

5.0; S, 5.9. C₂₉H₂₈N₂O₆S requires: C 65.4; H, 5.3; N, 5.25; S,

6.0%); d (500 MHz): 2.05 (dd, J7.7 and 14.8 Hz,

SO₂CHCHH), 2.15±2.19 and 2.41±2.46 (2£m, 2£1H,

NCHCH₂), 2.67 (dd, J4.6 and 14.9 Hz, 1H, SO₂CHCHH),

2.75 (d, J13.0Hz, 1H, PhC HH), 2.90(d, J13.0Hz, 1H,

PhCHH), 3.01±3.05 (m, 1H, NCH), 3.41±3.45 (m, 1H,

SO₂CH), 3.77 (s, 3H, OMe), 3.77±3.82 and 3.99±4.05

(2£m, 2£1H, NCH₂), 6.92±7.21 (m, 5H, ArH), 7.52±7.67

(m, 3H, ArH), and 7.73±7.92 (m, 6H, ArH); m/z (ES1, %):

533 (M1H¹, 49); n_max(cm²¹): 3057, 2988, 1772 (CvO),

1714 (CvO), 1495, 1398 and 1146.

3.4.2. Methyl (6) endo-2-(2-methylsulfanyl-ethyl)-4-oxo-

octahydro-pyrrolo[3.4-b]pyrrole-2-carboxylate 6b. Reac-

tion of 5b (76 mg, 0.181 mmol) and hydrazine monohydrate

(11 ml, 0.22 mmol) in ethanol (3 ml) at 788C for 15 h

afforded, after ¯ash chromatography (Et₂O, then 3:1 v/v

EtOAc±MeOH), the product 6b (45 mg, 96%) as colourless

prisms from CH₂Cl₂/petroleum ether, mp 87±898C. (Found:

C, 50.85, H, 7.05, N, 11.05, S, 12.50. C₁₁H₁₈N₂O₃S requires:

C, 51.15, H, 7.00, N, 10.85, S, 12.40%); d 1.83 (m, 1H,

CHH), 2.05 (dd, J9.7 and 13.6 Hz, 1H, pyrrolidine CHH),

2.09 (s, 3H, SMe), 2.10 and 2.27 (2£m, 2£1H, CH₂), 2.42 (br

s, 1H, NH), 2.49 (m, 1H, CHH), 2.61 (dd, J1.9 and 13.6 Hz,

1H, pyrrolidine CHH), 2.95 (m, 1H, COCH), 3.30(d,

J10.8 Hz, 1H, NCHH), 3.60(dd, J6.3 and 10.8 Hz, 1H,

NCHH), 3.71 (s, 3H, OMe), 4.01 (t, J6.3, 1H, NCH) and

6.67 (br s, 1H, CONH); m/z (%): 259 (M¹11, ,1), 199

(100), 183 (15), 151 (40), 142 (18), 94 (22), 80 (15), 61

(39) and 41 (7).

3.4. General method for the hydrazinolysis

Hydrazine monohydrate (1±2 equiv.) was added to a solu-

tion of the cycloadduct (1 equiv.) in methanol or ethanol and

the solution was stirred at 50±788C for 18±80h. The

solvent was removed and the residue was triturated with

dichloromethane, ®ltered and the ®ltrate evaporated to

give the product (5- and 6-membered fused and

6-membered bridged bicyclic lactams or primary amines).

Products were puri®ed via ¯ash column chromatography

(lactams) or used in the next step without puri®cation

(primary amines).

3.4.3. Methyl (6) endo-2-(3⁰-indolylmethyl)-4-oxo-octa-

hydro-pyrrolo[3.4-b]pyrrole-2-carboxylate 6c. Reaction

of 5c (156 mg, 0.33 mmol) and hydrazine monohydrate

(20 ml, 0.4 mmol) in methanol (8 ml) at 508C for 48 h

afforded, after ¯ash chromatography (3:1 v/v EtOAc±

MeOH), the starting material 4e (20mg, 13%) and the

product 6c (57 mg, 56%) as colourless prisms from

MeOH/CH₂Cl₂/petroleum ether, mp 171±1738C. Found:

C, 65.30, H, 6.00, N, 13.55. C₁₇H₁₉N₃O₃requires: C,

65.15, H, 6.10, N, 13.40%); d 2.20(dd, J9.9 and

13.4 Hz, 1H, CHH), 2.60(br s, 1H, NH), 2.66 (dd, J1.9

and 13.4 Hz, 1H, CHH), 2.90(m, 1H, CH), 3.20 (d,

J14.4 Hz, 1H, indole-CHH), 3.14 (d, J10.7 Hz, 1H,

NCHH), 3.28 (d, J14.4 Hz, 1H, indole-CHH), 3.38 (dd,

J6.0, 10.7 Hz, 1H, NCHH), 3.54 (s, 3H, OMe), 3.98 (m,

1H, NCH), 6.53 (br s, 1H, NH), 6.96 (s, 1H, ArH), 7.11 (m,

2H, ArH), 7.29 and 7.54 (2£d, J7.7 Hz, 2£1H, ArH) and

8.84 (br s, 1H, NH); m/z (%): 313 (M¹, 3), 254 (14), 183

(90), 151 (9), 130 (100), 126 (10), 123 (9), 103 (8), 82 (7),

80(7) and 77 (8).

3.4.1. Methyl (6) endo-1-methyl-2-oxo-3,8-diaza-bicyclo-

[3.2.1]octane-6-carboxylic acid methyl ester 7 and endo-

2-methyl-4-oxo-octahydro-pyrrolo[3.4-b]pyrrole-2-car-

boxylate 6a. Reaction of 5a (370mg, 1.03 mmol) and

hydrazine monohydrate (75 ml, 1.5 mmol) in methanol

(15 ml) at re¯ux for 70h afforded, after ¯ash chromato-

graphy (Et₂O then 1:1 v/v EtOAc±MeOH), two separated

regioisomers 7 and 6a (142 mg, 70% combined yield) in a

1:1 ratio.

Isomer 7: obtained as colourless plates from MeOH/EtOAc/

P. Blaney et al. / Tetrahedron 58 (2002) 1719±1737

1731

3.4.4. Polycyclic lactam 8. Reaction of 5d (259 mg,

0.6 mmol) and hydrazine monohydrate (45 ml, 0.9 mmol)

in methanol (7 ml) at 508C for 4d afforded, after ¯ash chro-

matography (10:1±4:1 v/v EtOAc±MeOH), the starting

material 5d (10mg, 5%), and the product 8 (130mg,

91%) as colourless prisms from CH₂Cl₂/petroleum ether,

mp 182±1848C. (Found: C, 55.25, H, 6.20, N, 11.45.

C₁₁H₁₄N₂O₄requires: C, 55.45, H, 5.90, N, 11.75%); d

1.95 (dd, J8.2 and 13.2 Hz, 1H, pyrrolidine CHH), 2.16

(m, 1H, CHH), 2.47 (m, 2H, CHH and COCHH), 2.82 (m,

1H, COCHH), 3.00 (d, J13.2 Hz, 1H, pyrrolidine CHH),

3.27 (t, J8.2 Hz, 1H, CH), 3.47 (d, J11.0Hz, 1H,

NCHH), 3.72 (m, 4H, NCHH and OMe), 4.66 (t,

J8.2 Hz, 1H, NCH) and 7.34 (br s, 1H, NH); d (¹³C):

(62.5 MHz) 176.3 (CO), 174.4 (CO), 173.1 (CO), 76.9

(C), 52.6, 52.5, 47.8 (CH₂), 47.6, 37.8 (CH₂), 33.6 (CH₂)

and 32.9 (CH₂); m/z (%): 238 (M¹, ,1), 179 (100), 134 (8),

122 (15), 82 (9), 55 (19) and 39 (5).

3.18 (m, 1H, NHCHHCH₂), 3.41±3.48 (m, 1H,

NHCHHCH₂), 3.67 (m, 4H, NHCH(CH₂)CH and CO₂Me),

6.11 (br s, 1H, CONH), 7.14±7.16 (m, 2H, meta ArH), and

7.20±7.29 (m, 3H, ortho and para ArH); m/z (ES1, %): 289

(M1H¹, 100); n_max(cm²¹): 3056, 2988±2955, 1730

(CvO), 1662 (CvO).

3.4.7.

Methyl

(6)

2-methyl-4-oxo-octahydro-

pyrrolo[3.4-b]-pyridine-2-carboxylate 6g. Reaction of 5i

(0.169 g, 0.452 mmol) and hydrazine monohydrate

(0.030 ml, 0.62 mmol) in methanol (8 ml) at 558C for 22 h

afforded, after ¯ash chromatography (4:1 v/v ethyl acetate±

methanol), the product 6g (0.077 g, 80%) as colourless

needles, mp 106.5±108.08C. (Found: C 55.30; H, 7.70; N,

13.15. C₁₀H₁₆N₂O₃´1/4H₂O requires: C 55.40; H, 7.70; N,

12.95%); d (250MHz): 1.41 (s, 3H, CMe), 1.70±1.79 (m,

1H, CH₂CHHCH), 1.88±2.00 (m, 1H, CH₂CHHCH), 2.17

(br s, 1H, NH), 2.19 (dd, J9.0and 13.4 Hz, 1H,

CCHHCH), 2.49 (dd, J7.3 and 13.4 Hz, 1H, CCHHCH),

2.91±3.00 (m, 1H, CHCH(CO₂Me)CH₂), 3.17±3.24 (m, 1H,

NHCH(CH₂)CH), 3.43±3.51 (m, 1H, NCHHCH₂), 3.67±

3.75 (m, 1H, NCHHCH₂), 3.72 (s, 3H, OMe) and 6.33 (br

s, 1H, CONH); m/z (%): 213 (M1H¹, 1), 153

(M2CO₂Me¹, 100) and 108 (72); n_max(cm²¹): 3056,

2988, 1730(C vO), 1662 (CvO).

3.4.5. Methyl (6) endo-2-benzyl-4-oxo-octahydro-

pyrrolo[3.4-b]pyrrole-2-carboxylate 6e. From 5e. Reac-

tion of 5e (174 mg, 0.4 mmol) and hydrazine monohydrate

(28 ml, 0.56 mmol) in methanol (7 ml) at 508C for 3d

afforded, after ¯ash chromatography (EtOAc, then 5:1 v/v

EtOAc±MeOH), the starting material 5e (29 mg 13%), and

the product 6e (80mg, 77%).

3.4.8. Methyl (6) 2-(3⁰-indolylmethyl)-4-oxo-octahydro-

pyrrolo[3.4-b]-pyridine-2-carboxylate 6h. Reaction of 5j

(0.150 g, 0.307 mmol) and hydrazine monohydrate

(0.018 ml, 0.365 mmol) in methanol (8 ml) at 558C for

42 h afforded, after ¯ash chromatography (3:1 v/v ethyl

acetate±methanol), the product 6h (0.091 g, 91%) as pale

yellow needles, mp 139.5±141.08C. (Found: C 63.85; H,

6.60; N, 12.30. C₁₈H₂₁N₃O₃´1/2H₂O requires: C 64.25; H,

6.60; N, 12.50%); d (250MHz): 1.59±1.69 (m, 1H,

CH₂CHHCH), 1.75±1.90(m, 1H, CH ₂CHHCH), 2.43±

2.60(m, 2H, CC H₂CH), 2.76 (br s, 1H, NH), 2.82±2.94

(m, 1H, CHCH(CO₂Me)CH₂), 3.04±3.14 (m, 1H,

NHCH(CH₂)CH), 3.08 (d, J14.4 Hz, 1H, CCHHAr),

3.30(d, J14.4 Hz, 1H, CCHHAr), 3.39±3.51 (m, 1H,

NCHHCH₂), 3.60(s, 3H, OMe), 3.6±03.73 (m, 1H,

NCHHCH₂), 6.55 (br s, 1H, CONH), 7.05±7.2) (m, 2H,

ArH), 7.31 and 7.58 (2£d, J7.7 Hz, 2£1H, ArH) and

8.66 (br s, 1H, ArNH); m/z (ES1, %): 350(M 1Na¹, 20),

328 (M1H¹, 100) and 197 (45); n_max(cm²¹): 3056, 2988±

2932, 1728 (CvO), 1660(C vO).

From 5f. Reaction of 5f (0.253 g, 0.494 mmol) and

hydrazine monohydrate (0.041 ml, 0.741 mmol) in

methanol (8 ml) at 508C for 66 h afforded, after ¯ash chro-

matography, the product 6e (0.112 g, 83%) as colourless

prisms from CH₂Cl₂/petroleum ether, mp 161±1638C.

(Found: C, 65.65, H, 6.70, N, 10.40. C₁₅H₁₈N₂O₃requires:

C, 65.70, H, 6.60, N, 10.20%); d 2.17 (dd, J9.7 and

13.4 Hz, 1H, CHH), 2.47 (br s, 1H, NH), 2.64 (dd, J2.5

and 13.4 Hz, 1H, CHH), 2.82 (d, J13.3 Hz, 1H, PhCHH),

2.93 (m, 1H, CH), 3.12 (d, J13.3 Hz, 1H, PhCHH), 3.24

(d, J10.7 Hz, 1H, NCHH), 3.52 (dd, J6.4 and 10.7 Hz,

1H, NCHH), 3.62 (s, 3H, OMe), 4.02 (t, J6.4 Hz, 1H,

NCH), 6.68 (br s, 1H, NH), 7.10(m, 2H, ArH) and 7.27

(m, 3H, ArH); m/z (%): 275 (M¹11, ,1), 215 (54), 183

(100), 170 (7), 158 (5), 151 (10), 126 (14), 123 (13), 91 (38),

82 (10), 80 (11) and 65 (8); n_max(cm²¹): 3056, 2988, 1731

(CvO), 1702 (CvO).

3.4.6. Methyl (6) 2-benzyl-4-oxo-octahydro-pyrrolo[3.4-

b]-pyridine-2-carboxylate 6f. From 5g. Reaction of 5g

(0.270 g, 0.600 mmol) and hydrazine monohydrate

(0.052 ml, 0.900 mmol) in methanol (10 ml) at 508C for

66 h afforded, after ¯ash chromatography (5:1 v/v ethyl

acetate±methanol), the product 6f (0.125 g, 72%).

3.4.9. Dimethyl (6) endo-5-[3-aminopropyl]-2-benzyl-

pyrrolidine-2,4-dicarboxylate 12a. Reaction of 11a

(0.133 g, 0.286 mmol) and hydrazine monohydrate

(0.023 ml, 0.486 mmol) in methanol (8 ml) at 558C for

18 h afforded the product 11a (0.073 g, 76%) as a colourless

oil. d (250MHz): 1.25±1.85 (m, 5H, CH ₂CH₂CH, NH and

NH₂), 2.05 (dd, J7.6 and 14.0Hz, 1H, CC HHCH), 2.60

(dd, J3.7 and 13.9 Hz, 1H, CCHHCH), 2.71±2.85 (m, 2H,

NH₂CH₂CH₂CH₂), 2.82 (d, J13.0Hz, 1H, CC HHPh), 2.99

(d, J13.0Hz, 1H, CCH HPh), 3.07±3.15 (m, 1H,

CHCH(CO₂Me)CH₂), 3.55±3.99 (m, 3H, NH₂CH₂CH₂,

and NHCH(CH₂)CH), 3.59 and 3.68 (2£s, 2£3H, 2£OMe)

and 7.22±7.28 (m, 5H, ArH).

From 5h. Reaction of 5h (0.265 g, 0.504 mmol) and hydra-

zine monohydrate (0.042 ml, 0.756 mmol) in methanol

(8 ml) at 508C for 66 h afforded, after ¯ash chromatography,

the product 6f (0.110 g, 76%) as colourless needles, mp

123.5±124.58C. (Found: C 66.55; H, 6.95; N, 9.85.

C₁₆H₂₀N₂O₃requires: C 66.65; H, 7.00; N, 9.70%); d

(400 MHz): 1.66±1.74 (m, 1H, CH₂CHHCH), 1.85±1.92

(m, 1H, CH₂CHHCH), 2.40(dd, J9.0and 13.6 Hz, 1H,

CHCHHC), 2.50(dd, J7.0and 13.6 Hz, 1H, CHCH HC),

2.81±2.87 (m, 1H, CHCH(CO)CH₂), 2.88 (d, J13.6 Hz,

1H, CCHHPh), 3.11 (d, J13.1 Hz, 1H, CCHHPh), 3.12±

3.4.10. Dimethyl (6) endo-5-[3-aminopropyl]-2-methyl-

pyrrolidine-2,4-dicarboxylate 12b. Reaction of 11b

1732

P. Blaney et al. / Tetrahedron 58 (2002) 1719±1737

(0.118 g, 0.304 mmol) and hydrazine monohydrate

(0.018 ml, 0.365 mmol) in methanol (8 ml) at 558C for

18 h afforded the product 12b (0.068 g, 87%) as a colourless

oil. d (250MHz): 1.32±1.66 (m, 4H, CH ₂CH₂CH₂CH), 1.41

(s, 3H, CMe), 1.92 (dd, J7.5 and 13.8 Hz, 1H, CCHHCH),

1.99 (br s, 3H, NH and NH₂), 2.60(dd, J3.6 and 13.8 Hz,

1H, CCHHCH), 2.70(t, J6.8 Hz, 2H, NH₂CH₂CH₂),

2.97±3.04 (m, 1H, CHCH(CO₂Me)CH₂), 3.29±3.37 (m,

1H, NHCH(CH₂)CH) and 3.65 and 3.77 (2£s, 2£3H,

2£OMe).

in methanol (5 ml) at re¯ux for 84 h afforded, after ¯ash

chromatography (EtOAc then 4:1 v/v EtOAc±MeOH), the

product 19 (31 mg, 40%) as colourless needles from MeOH/

CH₂Cl₂/petroleum ether, mp .2908C. (Found: C, 54.60, H,

4.95, N, 15.80. C₁₂H₁₃N₃O₄requires: C, 54.75, H, 5.00, N,

15.95%); d 2.29, 2.41 and 2.53 (3£m, 3H, CH₂and

COCHH), 2.99 (s, 3H, NMe), 3.16 (m, 1H, COCHH),

3.30(d, J9.9 Hz, 1H, COCH), 3.42 (d, J11.3 Hz, 1H,

NCHH), 3.68 (m, 2H, NCHH and COCH), 4.81 (m, 1H,

NCH) and 6.00 (br s, 1H, NH); m/z (%): 263 (M¹, 100),

235 (22), 204 (25), 178 (43), 164 (6), 149 (63), 134 (34), 121

(39), 106 (9), 93 (21), 80 (22), 67 (10), 55 (16) and 39 (13).

3.4.11. (6) endo-4,7-Dimethyl-4,9,11-triaza-tricyclo-

[5.3.1.0 2,6]undecane-3,5,8-trione 18a. Reaction of 17a

(177 mg, 0.46 mmol) and hydrazine monohydrate (25ml,

0.51 mmol) in methanol (10 ml) at 508C for 90h afforded,

after ¯ash chromatography (1:1 v/v EtOAc±MeOH), the

product 18a (78 mg, 76%) as colourless prisms from

MeOH, mp 256±2588C. (Found: C, 53.65, H, 5.90, N,

18.90. C₁₀H₁₃N₃O₃requires: C, 53.80, H, 5.85, N,

18.80%); d 1.50(s, 3H, Me), 2.0(br s, 1H, NH), 2.98 (s,

3H, NMe), 3.18 (m, 2H, 2£COCH), 3.32 (dd, J5.9 and

10.3 Hz, 1H, NCHH), 3.46 (dd, J5.0and 10.3 Hz, 1H,

NCHH), 4.32 (m, 1H, NCH) and 5.94 (br s, 1H, NH); m/z

(%): 223 (M¹, 62), 195 (25), 180 (10), 166 (42), 164 (60)

138 (71), 123 (16), 107 (50), 94 (57), 81 (100), 67 (6), 53

(11) and 40(14).

3.4.15. (6) endo-7-Benzyl-4-methyl-4,9,11-triaza-tricyclo-

[5.3.1.0 2,6]undecane-3,5,8-trione 18e. Reaction of 17e

(102 mg, 0.22 mmol) and hydrazine monohydrate (17 ml,

0.32 mmol) in ethanol (4 ml) at 788C for 48 h afforded,

after ¯ash chromatography (EtOAc, then 4:1 v/v EtOAc±

MeOH), the product 18e (40mg, 61%) as colourless prisms

from CH₂Cl₂/petroleum ether, mp 199±2018C. (Found: C,

63.95, H, 5.85, N, 14.25. C₁₆H₁₇N₃O₃requires: C, 64.20, H,

5.70, N, 14.05%); d 2.78 (s, 3H, NMe), 2.97 and 3.11 (2£d,

J13.5 Hz, 2£1H, PhCH₂), 3.14 (m, 2H, COCH and

NCHH), 3.39 (m, 2H, COCH and NCHH), 3.96 (t,

J5.2 Hz, 1H, NCH), 6.56 (br s, 1H, NH), 7.15 (m, 3H,

ArH) and 7.28 (m, 2H, ArH); m/z (%): 299 (M¹, 4), 208

(100), 156 (9), 151 (63), 123 (23), 91 (18), 80 (29), 65 (7)

and 53 (8).

3.4.12. (6) endo-4-Methyl-7-(2-methylsulfanyl-ethyl)-

4,9,11-triaza-tricyclo[5.3.1.0 2,6]undecane-3,5,8-trione

18b. Reaction of 17b (113 mg, 0.25 mmol) and hydrazine

monohydrate (20 ml, 0.4 mmol) in ethanol (5 ml) at 788C

for 48 h afforded, after ¯ash chromatography (EtOAc then

3:1 v/v EtOAc±MeOH), the product 18b (30mg, 42%) as

colourless ®ne needles from MeOH/CH₂Cl₂/petroleum

ether, mp 146±1488C. (Found: C, 50.60, H, 6.30, N,

14.65, S, 11.40. C₁₂H₁₇N₃O₃S requires: C, 50.85, H, 6.05,

N, 14.85, S, 11.30%); d 2.06 (m, 2H, CH₂), 2.11 (s, 3H,

SMe), 2.49 (m, 3H, CH₂and NH), 2.98 (s, 3H, NMe), 3.19

(d, J10.7 Hz, 1H, NCHH), 3.31 (m, 2H, 2£COCH), 3.47

(dd, J4.8 and 10.7 Hz, 1H, NCHH), 4.29 (s, 1H, NCH) and

5.78 (br s, 1H, NH); m/z (%): 283 (M¹, 27), 268 (12), 236

(11), 209 (100), 181 (30), 177 (15), 165 (27), 151 (31), 137

(22), 123 (12), 106 (10), 94 (31), 84 (32), 80 (79), 74 (11),

67 (8), 61 (21), 53 (18) and 40(10).

3.4.16. Phenyl (6) 1-benzyl-2-oxo-3,8-diaza-bicyclo-

[3.2.1]octane-6-sulfone 21. Reaction of 20 (0.300 g,

0.579 mmol) and hydrazine monohydrate (0.039 ml,

0.811 mmol) in methanol (15 ml) at 558C for 80h afforded,

after ¯ash chromatography (5:1 v/v ethyl acetate±

methanol), the product 21 (0.125 g, 61%) as pale yellow

needles, mp 190.0±191.08C. (Found: C 63.50; H, 5.75; N,

7.95. C₁₉H₂₀N₂O₃S´1/4H₂O requires: C 63.25; H, 5.70; N,

1

7.95%); d H (250MHz): 1.82±1.87 (m, 1H, CHC HHC),

2.00 (br s, 1H, CHNHC), 2.52 (dd, J6.2 and 13.6 Hz,

1H, CHCHHC), 2.96 (d, J13.9 Hz, CCHHPh), 3.43

(dd, J4.6 and 12.2 Hz, 1H, CHCHHNH), 3.62±3.72

(m, 1H, CHCH(SO₂Ph)CH₂), 3.98±4.06 (m, 2H,

CHCH(NH)CHHNH), 5.66 (br s, 1H, CONH), 7.21±7.31

(m, 5H, ArH), 7.61±7.68 (m, 3H, ArH ortho and para to

S) and 7.88±7.90(m, 2H, ArH meta to S); m/z (FAB, %):

379 (M1Na¹, 12), 357 (M1H¹, 100) and 158 (70); n_max

(KBr disc, cm²¹): 3373, 3275, 3056±3027, 2964±2853,

1668 (CvO) and 1146.

3.4.13. (6) endo-7-(3-Indolyl-methyl)-4-methyl-4,9,11-

triaza-tricyclo[5.3.1.0 2,6]undecane-3,5,8-trione 18c.

Reaction of 17c (37 mg, 0.074 mmol) and hydrazine mono-

hydrate (7.5 ml, 0.15 mmol) in ethanol (7 ml) at re¯ux for

3 d afforded, after ¯ash chromatography (4:1 v/v EtOAc±

MeOH), the product 18c (13 mg, 52%) as colourless prisms

from CHCl₃, mp 147±1498C. (Found (HRMS): 338.1379.

C₁₈H₁₈N₄O₃requires: 338.1380); d 2.80(s, 3H, NMe), 3.16

(m, 2H, 2£COCH), 3.21 and 3.34 (2£d, J14.2 Hz, 2£1H,

indole-CH₂), 3.39 (dd, J5.0and 10.3 Hz, 1H, NC HH),

3.46 (d, J10.3 Hz, 1H, NCHH), 4.03 (m, 1H, NCH),

5.51 (br s, 1H, CONH), 7.18 (m, 3H, ArH), 7.38 and 7.60

(2£d, J7.5 Hz, 2£1H, ArH) and 8.22 (br s, 1H, NH); m/z

(%): 338 (M¹, 10), 130 (100), 86 (12), 84 (20), 77 (5) and 49

(12).

3.4.17. Methyl (6) endo-5-[2-aminoethyl]-4-benzenesul-

fonyl-2-benzyl-pyrrolidine-2-carboxylate 23. Reaction of

22 (0.150 g, 0.282 mmol) and hydrazine monohydrate

(0.023 ml, 0.479 mmol) in methanol (9 ml) at 558C for

18 h afforded the product 23 (0.118 g, 100%) as a colourless

oil.

d (250MHz): 1.85±2.40 (m, 6H, CH CH₂CH,

2

CCHHCH, NH and NH₂), 2.64 (dd, J4.5 and 14.7 Hz,

1H, CCHHCH), 2.77 (d, J13.0Hz, 1H, CC HHPh),

2.84±2.91 (m, 2H, NHCH(CH₂)CH(SO₂Ph)CH₂), 2.91 (d,

J13.0Hz, CCH HPh), 3.23±3.30(m, 2H, NH CH₂CH₂),

2

3.74 (s, 3H, OMe), 7.12±7.22 (m, 5H, ArH), 7.55 (t,

J7.4 Hz, 2H, ArH meta to SO₂), 7.62 (t, J7.3 Hz, 1H,

ArH para to SO₂) and 7.78 (d, J7.5 Hz, 2H, ArH ortho to

SO₂).

3.4.14. Polycyclic lactam 19. Reaction of 17d (120mg,

0.26 mmol) and hydrazine monohydrate (25 ml, 0.5 mmol)

P. Blaney et al. / Tetrahedron 58 (2002) 1719±1737

1733

3.5. General procedure for the base catalysed

lactamisation of amino esters

The quantity of 14b was too small to collect spectroscopic

data.

Compound 13b: d (250MHz): 1.40 (s, 3H, CMe), 1.45±

2.09 (m, 6H, CH₂CH₂CH₂CH, CCHHCH and NH), 2.73

(dd, J6.6 and 13.8 Hz, 1H, CCHHCH), 3.14±3.49 (m,

4H, NHCH₂CH₂and NHCH(CH₂)CH(CO)CH₂), 3.76 (s,

3H, OMe) and 5.84 (br s, 1H, CONH).

Sodium methoxide (1 equiv.) was added to a stirred solution

of primary amino ester (1 equiv.) in methanol and the

mixture was heated to re¯ux for 4.5±16 h. The mixture

was allowed to cool, the solvent evaporated, the residue

dissolved in dichloromethane and washed with saturated

ammonium chloride (2£) and brine. The organic layer

was dried (MgSO₄) and the solvent evaporated. The residue

was puri®ed via ¯ash column chromatography to afford the

product.

3.5.3. Phenyl (6) 1-benzyl-2-oxo-3,9-diaza-bicyclo-

[4.2.1]octane-7-sulfone 24 and phenyl (6) 1-benzyl-2-

oxo-3,9-diaza-bicyclo[4.2.1]octane-7-sulfone 25. Prepared

according to the general procedure from primary amino

ester 23 (0.124 g, 0.308 mmol), and sodium methoxide

(0.017 g, 0.308 mmol) in methanol (8 ml) at re¯ux for

4.5 h. The residue was puri®ed (5:1 v/v ethyl acetate±

methanol) to afford a 2:1 mixture of 24 and 25 (0.081 g,

71%) as a pale yellow solid, mp 104.0±106.08C. (Found: C

64.35; H, 5.95; N, 7.70; S, 8.35. C₂₀H₂₂N₂O₃S´1/4H₂O

requires: C 64.05; H, 6.00; N, 7.45; S, 8.35%); m/z (%):

370(M ¹, 1), 279 (2), 229 (36), 201 (26), 158 (98) and 91

(100); n_max(cm²¹): 3056, 2987, 1652 (CvO) and 1140.

3.5.1. Methyl (6) 2-benzyl-4-oxodecahydropyrrolo[3,2-

c]azepine-2-carboxylate 13a and methyl (6) 2-benzyl-

4-oxodecahydropyrrolo[3,2-c]azepine-2-carboxylate 14a.

Prepared according to the general procedure from primary

amino ester 12a (0.162 g, 0.431 mmol), and sodium

methoxide (0.024 g, 0.431 mmol) in methanol (8 ml) at

re¯ux for 4.5 h. The residue was puri®ed (5:1 v/v ethyl

acetate±methanol) to afford a 4:1 mixture of 13a and 14a

(0.037 g, 30%) as a colourless gum. Further puri®cation

gave pure epimers 13a (0.005 g) and 14a (0.003 g) for analy-

sis. (Found: C 65.00; H, 7.50; N, 8.45. C₁₇H₂₂N₂O₃´3/4H₂O

requires: C 64.65; H, 7.50; N, 8.80%); m/z (ES1, %): 325

(M1Na¹, 15), 30 3 (M1H¹, 100) and 243 (85); n_max(cm²¹):

3056, 2988, 1733 (CvO), 1669 (CvO).

Compound 24:

d

(250MHz): 2.00±2.17 (m, 1H,

CH₂CHHCH), 2.07 (dd, J8.5 and 13.7 Hz, 1H,

CCHHCH), 2.48±2.57 (m, 1H, CH₂CHHCH), 2.64 (dd,

J11.3 and 13.7 Hz, 1H, CCHHCH), 2.90(d, J13.9 Hz,

1H, CCHHPh), 2.98±3.06 (m, 1H, CHCH(SO₂Ph)CH₂),

3.29 (d, J13.9 Hz, 1H, CCHHPh), 3.43±3.51 (m, 2H,

NHCH₂CH₂), 3.86±3.92 (m, 1H, NHCH(CH₂)CH), 6.04

(br s, 1H, CONH), 7.10±7.32 (m, 5H, ArH) and 7.53±

7.77 (m, 5H, ArH).

Compound 13a:

d

(500 MHz): 1.50±1.61 (m, 2H,

CH₂CH₂CH), 1.75±1.79 (m, 1H, CH₂CHHCH₂), 1.96±

2.00 (m, 1H, CH₂CHHCH₂), 2.02 (br hump, 1H, NH),

2.12 (dd, J8.8 and 13.5 Hz, 1H, CCHHCH), 2.87 (d,

J13.3 Hz, 1H, CCHHPh), 2.88 (dd, J5,6 and 13.5 Hz,

1H, CCHHCH), 3.14 (d, J13.4 Hz, 1H, CCHHPh),

3.14±3.22 (m, 2H, CHCH(CO)CH₂and NHCHHCH₂),

3.28±3.34 (m, 1H, NHCHHCH₂), 3.44±3.48 (m, 1H,

NHCH(CH₂)CH), 3.70(s, 3H, OMe), 5.57 (br t,

J6.4 Hz, 1H, CONH) and 7.17±7.27 (m, 5H, ArH).

Compound 25:

d

(250MHz): 1.70±1.81 (m, 1H,

CH₂CHHCH), 2.19±2.23 (m, 1H, CCHHCH), 2.39 (dd,

J8.0and 13.4 Hz, 1H, CCH HCH), 2.75±2.81 (m, 1H,

CH₂CHHCH), 2.93 (d, J14.1 Hz, 1H, CCHHPh), 3.41±

3.50(m, 1H, CHC H(SO₂Ph)CH₂), 3.57 (d, J13.9 Hz,

1H, CCHHPh), 3.70±3.85 (m, 2H, NHCH₂CH₂), 4.23±

4.29 (m, 1H, NHCH(CH₂)CH), 6.16 (br s, 1H, CONH),

7.10±7.32 (m, 5H, ArH) and 7.53±7.77 (m, 5H, ArH).

Compound 14a:

d

(500 MHz): 1.49±1.56 (m, 2H,

CH₂CH₂CH), 1.82±1.85 (m, 1H, CH₂CHHCH₂), 2.05

(br hump, 1H, NH), 2.26±2.29 (m, 1H, CH₂CHHCH₂),

2.47 (dd, J7.8 and 13.5 Hz, 1H, CCHHCH), 2.54 (dd,

J10.9 and 13.6 Hz, CCHHCH), 2.67±2.73 (m, 1H,

CHCH(CO₂-Me)CH₂), 2.93 (d, J13.3 Hz, 1H,

3.6. Lactamisation via acid chloride

3.6.1. (6) endo-5-[3-Aminopropyl]-2-benzyl-pyrrolidine-

2,4-dicarboxylic acid dihydrochloride 15. A stirred

solution of primary amino ester 12a (0.072 g,

0.215 mmol) in 1 M HCl (10 ml) was heated to re¯ux for

3.5 h. The solution was allowed to cool and the solvent

evaporated, azeotroping the residue with toluene (£3) to

afford the product (0.088 g, 100%) as brown gum. This

was used without further puri®cation.

CCHHPh),

3.04

(dt,

J3.4

and

10.3 Hz,

NHCH(CH₂)CH), 3.16 (d, J13.3 Hz, 1H, CCHHPh),

3.17±3.20(m, 1H, NHC HHCH₂), 3.25±3.28 (m, 1H,

NHCHHCH₂), 3.67 (s, 3H, OMe), 6.07 (br s, 1H,

CONH) and 7.18±7.26 (m, 5H, ArH).

3.5.2. Methyl (6) 2-methyl-4-oxodecahydropyrrolo[3,2-

c]azepine-2-carboxylate 13b and methyl (6) 2-methyl-4-

oxodecahydropyrrolo[3,2-c]azepine-2-carboxylate 14b.

Prepared according to the general procedure from primary

amino ester 12b (0.098 g, 0.380 mmol), and sodium

methoxide (0.021 g, 0.380 mmol) in methanol (8 ml) at

re¯ux for 4.5 h. The residue was puri®ed (3:1 v/v ethyl

acetate±methanol) to afford a 10:1 mixture of 13b and

14b (0.010 g, 12%) as a colourless gum. (HRMS: M1H¹

C₁₁H₁₉N₂O₃requires 227.1395; found 227.1396); m/z (%):

227 (M1H¹, 1), 167 (M2CO₂Me¹, 100), 139 (11) and 122

(34); n_max(cm²¹): 3056, 2988, 1733 (CvO), 1669 (CvO).

3.6.2. Methyl (6) 2-benzyl-4-oxodecahydropyrrolo[3,2-

c]azepine-2-carboxylate 13b. Excess thionyl chloride

(5 ml) was added to a stirred solution of diacid dihydro-

chloride 15 (0.048 g, 0.126 mmol) in acetonitrile (5 ml) at

room temperature and the solution was stirred for 16 h. The

solvent was evaporated and the residue was dissolved in

acetonitrile (10ml) and transferred to a dropping funnel,

diluting with benzene (15 ml). This was added dropwise

(40min) to a 3-necked ¯ask containing benzene (30ml)

with simultaneous dropwise addition (40min) of a solution

1734

P. Blaney et al. / Tetrahedron 58 (2002) 1719±1737

of triethylamine (0.12 ml, 0.846 mmol) in benzene (15 ml)

at room temperature. The mixture was stirred for 2 h

followed by the addition of methanol (5 ml) and stirring

for a further 16 h. The solvents were evaporated and the

solid residue was extracted with toluene (£2), ®ltered and

the ®ltrate evaporated. The residue was puri®ed via ¯ash

column chromatography (5:1 v/v ethyl acetate±methanol)

to afford the product (0.034 g, 90%) as a colourless gum.

Analytical data as previously described for 13b.

2H, NHCH₂CO) and 5.30(br s, 1H, N H); m/z (FAB, %): 241

(M1Na¹, 11), 219 (M1H¹, 75) and 163 (100).

3.8.2. N-Boc-b-alanine-N⁰-methyl-N⁰-methoxyamide 27b.¹²

Prepared according to the general procedure from Boc-b-

alanine (2.50g, 13.21 mmol), N-methylmorpholine (3.19 ml,

29.06 mmol), isobutylchloroformate (1.88 ml, 14.53 mmol)

and N,O-dimethylhydroxylamine hydrochloride (1.29 g,

13.21 mmol) in dichloromethane (100 ml) to afford the

product (3.15 g, 100%) as a colourless oil. d (250MHz):

1.43 (s, 9H, CMe₃), 2.64 (t, J5.4 Hz, 2H, CH₂CH₂CO),

3.19 (s, 3H, NMe), 3.42 (q, J5.9 Hz, 2H, NHCH₂CH₂),

3.68 (s, 3H, OMe), and 5.25 (br s, 1H, NH); m/z (FAB, %):

255 (M1Na¹, 8), 233 (M1H¹, 53), 177 (87), 133 (88), and 73

(100).

3.7. Synthesis of bicyclic ureas

3.7.1. Methyl (6) 7-benzyl-1-oxo-5-(phenylsulfonyl)-

octahydropyrrolo[1,2-c]pyrimidine-7-carboxylate

26.

Phosgene (0.085 ml, 0.162 mmol as a 20% solution in

toluene) was added dropwise to a stirred solution of primary

amine 23 (0.062 g, 0.154 mmol) and triethylamine

(0.047 ml, 0.340 mmol) in THF (8 ml) at 08C (ice/water)

and the mixture was stirred for 1 h, then at room tempera-

ture for 15 h. The mixture was diluted with chloroform and

washed with saturated sodium bicarbonate (£2). The

organic layer was dried (MgSO₄) and the solvent evapo-

rated. The residue was puri®ed via ¯ash column chromato-

graphy (ethyl acetate!95:5 v/v ethyl acetate±methanol) to

give the product (0.037 g, 56%) as a colourless foam.

(HRMS: M1H¹C₂₂H₂₅N₂O₅S requires 429.1484; found

429.1484); d (d₆-DMSO, 300 MHz): 1.87 (dd, J7.7 and

13.0Hz, 1H, CHC HHC), 1.94±2.05 (m, 1H,

NHCH₂CHHCH), 2.28±3.36 (m, 1H, NHCH₂CHHCH),

2.69 (dd, J9.6 and 13.0Hz, 1H, CHCH HC), 2.83 (br s,

1H, NHCO), 2.95 (d, J13.1 Hz, 1H, CCHHPh), 2.99±3.40

(m, 4H, NCH(CH₂CH₂NH)CH(SO₂)CH₂), 3.27 (d,

J13.2 Hz, 1H, CCHHPh), 3.63 (s, 3H, CO₂Me), 7.02±

7.32 (m, 5H, ArH) and 7.61±7.84 (m, 5H, ArH); m/z

(FAB, %): 429 (M1H¹, 57), 227 (7); n_max(cm²¹): 3056,

2987±2955, 1741 (CvO), 1667 (CvO), 1495 and 1152.

3.8.3.

N-Boc-N-methylamino-N⁰-methyl-N⁰-methoxy

acetamide 33.¹³Prepared according to the general pro-

cedure from Boc-sarcosine¹⁰(1.297 g, 6.862 mmol),

N-methylmorpholine (1.66 ml, 15.096 mmol), isobutyl-

chloroformate (0.98 ml, 7.584 mmol) and N,O-dimethyl-

hydroxylamine hydrochloride (0.669 g, 6.862 mmol) in

dichloromethane (70ml) to afford the product (1.320g,

83%) as

a colourless oil. d (250MHz): 1.45 (d,

J13.2 Hz, 9H, CMe₃), 2.93 (s, 3H, BocNMe), 3.19 (s,

3H, NMe), 3.72 (s, 3H, OMe) and 4.12 (d, J18.9 Hz,

2H, NCH₂CO); m/z (%): 172 (6), 159 (13), 116 (30), 88

(19), 57 (100) and 44 (78).

General procedure for the reduction of Weinreb amides.

Lithium aluminium hydride (5 equiv.) was added to a stirred

solution of Weinreb amide (1 equiv.) in THF at room

temperature and the mixture was stirred for 20min. The

reaction was quenched with 0.2 M potassium bisulfate

(25 ml) and extracted with ether (£3). The combined

organic layers were washed with 2 M HCl (£3), saturated

sodium bicarbonate (£3) and brine (£3). The organic layer

was dried (MgSO₄) and the solvent removed to afford the

product which was used directly for the next step.

3.8. Synthesis of bicyclic lactams: Boc-amino-aldimine

route

3.8.4. N-Boc-aminoacetaldehyde 29a.¹²Prepared accord-

ing to the general procedure from Weinreb amide 28a

(0.500 g, 2.290 mmol) and lithium aluminium hydride

(0.109 g, 2.867 mmol) in THF (25 ml) to afford the product

(0.218 g, 60%) as a colourless oil. d (300 MHz): 1.44 (s, 9H,

CMe₃), 4.07 (br d, J4.4 Hz, 2H, NHCH₂CO), 5.10(br s,

1H, NH) and 9.65 (s, 1H, CHO).

General procedure for the synthesis of Weinreb amides.

Isobutyl chloroformate (1.1 equiv.) was added dropwise to

a stirred solution of Boc-amino acid (1 equiv.) and

N-methylmorpholine (2.2 equiv.) in dichloromethane

(70±100 ml) at 2158C (ice/methanol) and the mixture

was stirred for 15 min. N,O-Dimethylhydroxylamine hydro-

chloride (1 equiv.) was added and stirring was continued at

2158C for 15 min, then at room temperature for 16 h. The

mixture was washed with 0.2 M potassium bisulfate (50±

100 ml), the organic layer separated and the aqueous

extracted with dichloromethane (£2). The combined

organic layers were dried (MgSO₄) and the solvent evapo-

rated to afford the product.

3.8.5. 3-(N-Boc-amino)-propionaldehyde 29b.¹²Prepared

according to the general procedure from Weinreb amide 28b

(0.610 g, 2.625 mmol) and lithium aluminium hydride

(0.125 g, 3.281 mmol) in THF (18 ml) to afford the product

(0.292 g, 64%) as a colourless oil. d (300 MHz): 1.43 (s, 9H,

CMe₃), 2.71 (t, J5.8 Hz, 2H, CH₂CH₂CHO), 3.42 (q,

J5.9 Hz, 2H, NHCH₂CH₂), 4.90(br s, 1H, N H) and 9.81

(s, 1H, CHO). m/z (FAB, %): 174 (M1H¹, 3), 173 (17), 147

(14) and 73 (100).

3.8.1. N-Boc-glycine-N⁰-methyl-N⁰-methoxyamide 27a.¹²

Prepared according to the general procedure from Boc-

glycine (2.50g, 14.27 mmol),

N-methylmorpholine

(3.45 ml, 31.40mmol), isobutylchloroformate (2.10ml,

15.70mmol) and N,O-dimethylhydroxylamine hydro-

chloride (1.39 g, 14.27 mmol) in dichloromethane

(100 ml) to afford the product (3.04 g, 97%) as a colourless

solid, mp 77.0±78.08C. d (250MHz): 1.46 (s, 9H, CMe ₃),

3.21 (s, 3H, NMe), 3.72 (s, 3H, OMe), 4.08 (d, J4.7 Hz,

3.8.6. N-Boc-N-methylglycinal 35.¹⁴Prepared according to

the general procedure from Weinreb amide 34 (0.600 g,

2.586 mmol) and lithium aluminium hydride (0.123 g,

3.232 mmol) in THF (18 ml) to afford the product

(0.205 g, 46%) as a colourless oil. d (250MHz): 1.55 (d,

P. Blaney et al. / Tetrahedron 58 (2002) 1719±1737

1735

J12.5 Hz, 9H, CMe₃), 2.97 (d, J8.2 Hz, 3H, NMe), 4.00

(d, J25.0Hz, 2H, NC H₂CHO) and 9.63 (s, 1H, CHO). m/z

(FAB, %): 174 (M1H¹, 11), 147 (13), 144 (24), 131 (8),

118 (23) and 57 (100).

(500 MHz): 1.42±1.45 (m, 1H, NCH₂CHH), 1.46 (s, 9H,

CMe₃), 1.70±1.78 (m, 1H, NCH₂CHH), 2.06 (dd, J7.4

and 14.0Hz, 1H, MeCO ₂CHCHH), 2.60(dd, J3.0and

14.0Hz, 1H, MeCO ₂CHCHH), 2.81±2.85 (m, 1H,

MeCO₂CH), 2.83 (d, J13.1 Hz, 1H, PhCHH), 2.99±3.04

(m, 1H, NCHCH₂), 3.02 (d, J13.1 Hz, 1H, PhCHH), 3.15±

3.22 (m, 1H, NCHH), 3.25±3.33 (m, 1H, NCHH), 3.62 and

3.71 (2£s, 2£3H, 2£CO₂Me), 5.11 (br s, 1H, NHCO) and

7.20±7.30 (m, 5H, ArH); m/z (%): 421 (M1H¹, 1), 361 (1),

347 (13), 329 (14), 273 (50), 229 (100), 186 (73), 91 (88)

and 57 (87); n_max(cm²¹): 3056, 2985±2954,1731 (CvO),

1708 (CvO) and 1508.

General procedure for the preparation of imines. Excess

MgSO₄was added to a stirred solution of aldehyde

(1 equiv.) and phenylalanine methyl ester (1.1 equiv.) in

dichloromethane at room temperature and the mixture was

stirred for 40h, ®ltered and the ®ltrate evaporated to give

the imines, which were used without puri®cation.

3.8.7. Methyl (6) 2-[3-(N-Boc-amino)-propylidene-

amino]-3-phenyl propionate 30b. Prepared according to

the general procedure from aldehyde 29b (0.283 g,

1.636 mmol) and l-phenylalanine methyl ester (0.322 g,

1.799 mmol) over MgSO₄(1.0g) in dichloromethane

(20 ml) for 40 h to afford the product (0.622 g, 100%) as a

colourless gum. d (300 MHz): 1.44 (s, 9H, CMe₃), 2.31±

2.36 (m, 2H, NHCH₂CH₂), 2.99±3.07 (m, 1H, CHCHHPh),

3.26±3.32 (m, 2H, CHCHHPh and CH₂CHHCvN), 3.51 (d,

J5.2 Hz, 1H, CH₂CHHCvN), 3.76 (s, 3H, CO₂Me), 3.94

(dd, J4.3 and 9.8 Hz, 1H, NCH(CH₂)CO₂Me), 4.90(br s,

1H, NH) and 7.11±7.31 (m, 6H, ArH and CH₂CHvN); m/z

(FAB, %): 335 (M1H¹, 17), 311 (29), 218 (31), 199 (36)

and 57 (100).

3.8.10. Dimethyl (6) endo-5-[(N-Boc-N-methylamino)-

methyl]-2-benzylpyrrolidine-2,4-dicarboxylate 37. Pre-

pared according to the general procedure from imine 36

(0.393 g, 1.130 mmol), silver(I) acetate (0.245 g,

1.469 mmol), methyl acrylate (0.51 ml, 5.650 mmol) and

triethylamine (0.21 ml, 1.469 mmol) in toluene (10 ml) for

36 h. The residue was puri®ed (2:1 v/v ether±petroleum

ether) to afford the product (0.240 g, 51%) as a colourless

gum. (Found:

C

62.20; H, 7.55; N, 6.65.

C₂₂H₃₂N₂O₆´1/4H₂O requires: C 62.15; H, 7.70; N,

6.60%); d (500 MHz): 1.46 (s, 9H, CMe₃), 2.07 (dd,

J7.5 and 13.8 Hz, 1H, MeCO₂CHCHH), 2.59±2.64 (m,

1H, MeCO₂CHCHH), 2.76±2.85 (m, 2H, PhCHH and

MeCO₂CH), 2.90(s, 3H, NMe), 2.92±3.19 (m, 2H,

PhCHH and NH), 3.15±3.25 (br m, 2H, NCHH), 3.30±

3.50(br m, 1H, NC HCH₂), 3.63±3.69 (2£s, 2£3H,

2£CO₂Me), and 7.23 (s, 5H, ArH); m/z (FAB, %): 421

(M1H¹, 100), 321 (28), 276 (62), 229 (32) and 91 (55);

n_max(cm²¹): 3057, 2985, 1736 (CvO), 1691 (CvO).

3.8.8. Methyl (6) 2-[2-(N-Boc-N-methylamino)-ethyl-

idenamino]-3-phenylpropionate 36. Prepared according

to the general procedure from aldehyde 35 (0.196 g,

1.133 mmol) and l-phenylalanine methyl ester (0.233 g,

1.246 mmol) over MgSO₄(1.0g) in dichloromethane

(10 ml) for 40 h to afford the product (0.393 g, 100%) as a

colourless gum. d (250MHz): 1.42 (br s, 9H, CMe ₃), 2.63

(br d, J7.3 Hz, 3H, NMe), 3.03 (dd, J9.6 and 13.5 Hz,

1H, CCHHPh), 3.29 (dd, J4.6 and 13.5 Hz, 1H,

CHCHHPh), 3.72 (d, J3.0Hz, 2H, NC H₂CHvN), 3.76

(s, 3H, CO₂Me), 4.00 (dd, J4.5 and 9.6 Hz, 1H,

NCH(CH₂Ph)CO₂Me), and 7.11±7.34 (m, 6H, ArH and

CHvN); m/z (FAB, %): 369 (20), 281 (6), 221 (7), 147

(21) and 69 (100).

3.9. General procedure for Boc-deprotection/

lactamisation

Cycloadduct (1 equiv.) was dissolved in dichloromethane

and TFA at room temperature and the solution was stirred

for 16 h. The solvents were evaporated and the residue was

dissolved in dichloromethane, followed by the addition of

triethylamine (2.2 equiv.) and stirring for 16 h at room

temperature. The mixture was diluted with dichloromethane

and washed with water (£3). The organic layer was dried

(MgSO₄) and the solvent evaporated. The residue was puri-

®ed via ¯ash column chromatography to afford the bicyclic

lactams.

General procedure for the 1,3-dipolar cycloaddition of Boc-

aminoaldimines. Silver(I) acetate (1.3 equiv.), methyl

acrylate (5 equiv.), and triethylamine (1.3 equiv.) were

added to a stirred solution of imine (1 equiv.) in toluene

(10±15 ml) at room temperature and the mixture was stirred

for 36 h. The mixture was diluted with dichloromethane

(50ml) and washed with saturated ammonium chloride

(£2) and water. The organic layer was dried (MgSO₄) and

the solvent evaporated. The residue was puri®ed via ¯ash

column chromatography to afford the cycloadducts.

3.9.1. Methyl (6) 2-benzyl-4-oxo-octahydro-pyrrolo[3.4-

b]-pyridine-2-carboxylate 6f. Prepared according to the

general procedure from cycloadduct 31b (0.08 g,

0.19 mmol) in dichloromethane (8 ml) and TFA (2 ml),

then dichloromethane (10 ml) and triethylamine (0.06 ml,

0.42 mmol). The residue was puri®ed (5:1 v/v ethyl

acetate±methanol) to afford the product (0.045 g, 82%) as

colourless prisms, mp 123.5±124.58C. Analytical data as

previously described for 6f.

3.8.9. Dimethyl (6) endo-2-benzyl-5-[2-(N-Boc-amino)-

ethyl]-pyrrolidine-2,4-dicarboxylate

31b.

Prepared

according to the general procedure from imine 30b

(0.622 g, 1.630 mmol), silver(I) acetate (0.408 g,

2.445 mmol), methyl acrylate (0.73 ml, 8.150 mmol) and

triethylamine (0.34 ml, 2.445 mmol) in toluene (15 ml) for

36 h. The residue was puri®ed (2:1 v/v ether±petroleum

ether) to afford the product (0.342 g, 50%) as a colourless

solid, mp 94.5±96.08C. (Found: C 63.00; H, 7.75; N, 6.85.

C₁₀H₁₆N₂O₃requires: C 62.85; H, 7.65; N, 6.65%); d

3.9.2. Methyl (6) 2-benzyl-4-oxo-octahydro-N-methyl-

pyrrolo[3.4-b]pyrrole-2-carboxylate 38. Prepared accord-

ing to the general procedure from cycloadduct 37 (0.16 g,

0.38 mmol) in dichloromethane (8 ml) and TFA (2 ml), then

dichloromethane (10ml) and triethylamine (0.18 ml,

0.84 mmol). The residue was puri®ed (10:1 v/v ethyl

1736

P. Blaney et al. / Tetrahedron 58 (2002) 1719±1737

acetate±methanol) to afford the product (0.069 g, 63%) as a

colourless syrup. (Found: C 62.60; H, 7.05; N, 9.00.

C₂₂H₃₂N₂O₆´H₂O requires: C 62.70; H, 7.25; N, 9.15%); d

(250MHz): 2.15 (dd, J9.3 and 13.3 Hz, 1H, CCHHC),

2.68±2.71 (m, 1H, CHCHHC), 2.73 (s, 3H, NMe), 2.81

(d, J13.2 Hz, 1H, CCHHPh), 2.97±3.04 (m, 1H,

Structure re®nement. Number of parameters329, isotropic

extinction parameter x0.034(4), goodness of ®t s0.864;

weighting parameters x, y0.0388, 0.0000; wR₂0.0876,

R₁0.0340.

3.10.3.

Crystal

data

for

6f.

C₁₆H₂₀N₂O₃,

0.50£0.20£0.11 mm³, M288.34, triclinic, space group

CHCH(CO₂Me)CH₂),

3.21

(d,

J11.3 Hz,

1H,

ꢀ

Ê

P1; a5.9152(2), b9.9712(2), c13.6560(4) A, a

NMeCHHCH), 3.52±3.61 (m, 2H, NMeCHHCH), 7.08±

7.12 (m, 2H, ArH meta) and 7.21±7.31 (m, 3H, ArH

ortho and para); m/z (FAB, %): 311 (M1Na¹, 16), 289

(M1H¹, 62), 229 (100), 197 (33), 147 (18), and 73 (80);

Ê ³

73.133(1), b78.563(1), g75.759(2)8, U740.09(4) A ,

Z2, D_c1.29 Mg m²³

T150K.

,

m0.09 mm²¹

,

F(000)308,

n

1605 and 1496.

_max(cm²¹): 3056, 2987±2883, 1732 (CvO), 1683 (CvO),

Data collection. As for 6a above with 1.0,2u,52.08,

11777 data collected 2900 of which were unique

[R_int0.048]. There 2426 re¯ections with F_o.4.0s(F_o).

3.10. Single crystal X-ray diffraction analysis of 6a, 6e

and 6f

Structure re®nement. Number of parameters200, isotropic

extinction parameter x0.063(9), goodness of ®t s1.043;

weighting parameters x, y0.0469, 0.1349; wR₂0.1008,

R₁0.0381.

Crystallographic data for all three compounds were

collected on a Nonius KappaCCD area-detector diffract-

ometer using 18 f- and omega-slices. All structures were

solved by direct methods using SHELXS-86¹⁵and were

re®ned by full-matrix least-squares (based on F²) using

Crystallographic data (excluding structure factors) for the

structures in this paper have been deposited with the

Cambridge Crystallographic Data Centre as supplementary

publication numbers CCDC 172732 (compound 6a), CCDC

172733 (compound 6e) and CCDC 172734 (compound 6f).

Copies of the data can be obtained, free of charge, on

application to CCDC, 12 Union Road, Cambridge,

CB2) 1EZ, UK [fax: 144(0)-1223-336033 or e-mail:

deposit@ccdc.cam.ac.uk].

SHELXL-97.¹⁶The weighting scheme used in all re®ne-

ments was ws²ꢀF_o²1ꢀxP²1yP

where P

21

2

(F_o12F_c)/3. In all cases all non-hydrogen atoms were

re®ned with anisotropic displacement parameters whilst

hydrogen atoms were constrained to predicted positions.

All re®nements included an isotropic extinction parameter,

x, so that F⁰_ckF_c110:001xF_c²l³²¹⁼⁴where k is the

overall scale factor. The residuals wR₂and R , given

P

P ¹

2

1=2

below, are de®ned as wR₂ꢀ wꢀF_o2F_c² = wF_o⁴

P

and R₁ uuF_ou2uF_cuu= uF_ou:

Acknowledgements

3.10.1.

Crystal

data

for

6a.

C₉H₁₄N₂O₃,

0.48£0.46£0.19 mm³, M546.53, monoclinic, space

We thank the ORS and Tetley and Lupton for a scholarship

(to J. X.) and the EPSRC, Leeds University and Organon

Laboratories for support.

group

11.2632(2) A, b122.9790(13)8, U1925.94(7) A , Z8,

C2=c;

Ê

a17.3718(3),

b11.7339(3),

c

Ê ³

D_c1.37 Mg m²³, m0.10 mm²¹, F(000)848, T190K.

References

Data collection. Graphite monochromated Mo Ka radia-

Ê

tion, l0.71073 A. The detector was positioned with

1. (a) Massioltz, G.; Delaude, C. The Alkaloids 1986, 27, 269±

322. (b) Patvardhan, S. P.; Joshi, K. S.; Vadlamudi, R. V. S. V.;

Deshpande, S. G. Ind. J. Pharm. Sci. 1998, 60, 384. (c) Gupta,

P.; Butler, P.; Shepperson, N. B.; McHarg, A. Eur. J.

Pharmacol. 2000, 398, 73. (d) Bauer, J. H. Am. J. Med.

1984, 77, 43. (e) Sternsfeld, F.; Guibin, A. R.; Jelley, R. A.;

Matassa, V. G.; Reeve, A. J.; Hunt, P. A.; Beer, M. S.; Heald,

A.; Stanton, J. A.; Sohal, B.; Watt, A. P.; Street, L. J. J. Med.

Chem. 1999, 42, 677.

2u08 and a 1808 rotation of 1.08 f-slices were measured

at x08. `Cusp' data was measured at x908 and

comprised 18 omega-slices over 558; 6.94,2u,60.48,

8682 data collected 2263 of which were unique,

R_int0.0385, R_sig0.0306. There were 1967 re¯ections

with F_o.4.0s(F_o).

Structure re®nement. Number of parameters138, isotropic

extinction parameter x0.044(6), goodness of ®t s1.081;

weighting parameters x, y0.0672, 0.4792; wR₂0.1163,

R₁0.0389.

2. Tsuge, O.; Kanemasa, S. Adv. Heterocycl. Chem. 1989, 45,

232.

3. Grigg, R. Chem. Soc. Rev. 1987, 16, 89.

3.10.2.

Crystal

data

for

6e.

C₁₅H₁₈N₂O₃,

0.55£0.35£0.28 mm³, M274.31, monoclinic, space

4. Grigg, R.; Sridharan, V. Adv. Cycloaddition 1993, 3, 161.

5. Li, A-H.; Moro, S.; Forsyth, N.; Melman, N.; Ji, X-D.;

Jacobson, K. A. J. Med. Chem. 1999, 42, 706.

group

17.0575(6) A, b110.9180(14)8, U1361.65(7) A , Z2,

P2₁/c,

Ê

a13.6998(5),

b6.2380(1),

c

Ê ³

6. Prabhakaran, P. C.; Gould, S. J.; Orr, G. R.; Coward, J. K.

J. Am. Chem. Soc. 1988, 110, 5779.

D_c1.34 Mg m²³, m0.09 mm²¹, F(000)584, T190K.

7. (a) Ismaid, A. M.; Angeles, J. D. L.; Teitler, M.; Ingher, S.;

Glennon, R. A. J. Med. Chem. 1993, 36, 2519. (b) Mann, J.;

Shervington, L. A. J. Chem. Soc., Perkin Trans. 1 1991, 2961.

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Article Doi

Fused and bridged bi- and tri-cyclic lactams via sequential metallo-azomethine ylide cycloaddition-lactamisation

DOI: 10.1016/S0040-4020(02)00029-7

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