Synthesis of substituted pyrrolidines and piperidines from endocyclic enamine derivatives. Synthesis of (±)-laburnamine

Tetrahedron 61 (2005) 1221–1244

Synthesis of substituted pyrrolidines and piperidines from

endocyclic enamine derivatives. Synthesis of (G)-laburnamine

b

Marta Norton Matos,^a,bCarlos A. M. Afonso^c,and Robert A. Batey

*

a

´ ˆ

REQUIMTE/CQFB, Departamento de Quımica, Faculdade de Ciencias e Tecnologia, Universidade Nova de Lisboa,

2829-516 Caparica, Portugal

^bDepartment of Chemistry, 80 St. George Street, University of Toronto, Toronto, Ont., Canada M5S 3H6

c

´

CQFM, Departmento de Engenharia Quımica, Instituto Superior Tecnico, 1049-001 Lisboa, Portugal

Received 3 September 2004; revised 2 November 2004; accepted 15 November 2004

Available online 23 December 2004

Abstract—Functionalization of the a- and b-positions of readily available endocyclic enamine derivatives provides a convenient method for

the formation of substituted pyrrolidines and piperidines. a-Alkoxy-b-iodopyrrolidines are formed by the electrophilic addition of iodine to

the endocyclic enamine double bond of an N-substituted 2-pyrroline, and nucleophillic attack by an alcohol on the intermediate iodonium

ion. The resultant a-alkoxy-b-iodopyrrolidines can be used in radical cyclization reactions to give bicyclic hemiaminal compounds, which

can be further elaborated using N-acyliminium chemistry to form a,b-cis-dialkylsubstituted pyrrolidines. A strategy for the incorporation of

amino functionality at the b-position was also established by using iodoamination of the enamine double bond, followed by migration of the

amine functionality through an aziridination/methanolysis protocol. An alternative method uses an azidomethoxylation protocol using ceric

ammonium nitrate (CAN) in the presence of NaN₃and methanol. Formation and trapping of the N-acyliminium ions derived from these

substrates, afforded the 3-carbamate and 3-azido-2-substituted products with good diastereoselectivity, with the preferential formation of the

trans and cis stereoisomers, respectively. Using the sequential iodoamination, aziridination in methanol and N-acyliminium transformation,

trans-3-NHCO₂Me-2-allyl-pyrrolidine was prepared, which was used as the key precursor in a synthesis of the natural 1-amidopyrrolizidine

alkaloid, (G)-laburnamine.

1. Introduction

structurally diverse range of pyrrolidines and piperidines,

including the 3-aminopyrrolidine and 3-aminopiperidine

units.

The importance of substituted pyrrolidines and piperidines

as biologically active compounds and their widespread

occurrence in alkaloids, have led to the development of

numerous synthetic methods for their preparation.¹An

example of these targets are 3-aminopyrrolidine and

3-aminopiperidines, which are useful building blocks for

the construction of bioactive compounds.²As part of our

ongoing interest in the functionalization of N-acylated

cyclic enamines, we have developed synthetic method-

ologies for the functionalization of the a and b position of

the pyrrolidine or piperidine ring.³In this paper, we will

present these simple sequential strategies, starting with

oxidation processes using electrophilic iodine or ceric

ammonium nitrate (CAN). Further manipulation through

radical cyclizations, aziridination/methanolysis and/or

N-acyliminium chemistry provides ready access to a

2. Results and discussion

The electron-rich alkene bond of endocyclic N-acyl-

enamides presents numerous synthetic opportunities.

Perhaps the most versatile application of such derivatives

would be the simultaneous addition of an electrophile (E)

and a nucleophile (Nu) to the C]C bond, in what is

formally a three-component coupling reaction (Fig. 1). This

process results in the simultaneous functionalization of the

Keywords: Enamines; Radical cyclizations; Aziridination; N-Acyliminium;

1-Amidopyrrolizidine; (G)-Laburnamine.

* Corresponding author. Tel.: C351 21 8417627; fax: C351 21 8417122;

e-mail: carlosafonso@ist.utl.pt

Figure 1. Three component coupling of an endocyclic enamide with an

electrophile and a nucleophile.

doi:10.1016/j.tet.2004.11.035

1222

M. Norton Matos et al. / Tetrahedron 61 (2005) 1221–1244

Table 1. Examples of iodoetheriﬁcation of N-acyl-enamide precursors

Entry

1

N-Acyl-2-pyrroline

Alcohol

Major product

Method^a

Yield^b(%)

2a

1a

Propargyl alcohol

A

80

2b

2

3

4

5

1a

1b

3-Butyn-1-ol

3-Butyn-2-ol

2-Butyn-1-ol

Propargyl alcohol

A

75

50^c

65

2c

2d

2e

83

2f

6

1a

1c

1a

Methanol

A

B

92

57^c

65

62

74

62

2g, 2g⁰

7

Propargyl alcohol

Allyl alcohol

3-Buten-1-ol

2h

8

2i

9

2j

10

11

Cinnamyl alcohol

Ethyl-(2E)-hydroxy-2-

butenoate

2k

M. Norton Matos et al. / Tetrahedron 61 (2005) 1221–1244

1223

Table 1 (continued)

Entry

N-Acyl-2-pyrroline

Alcohol

Phenol

Major product

Method^a

Yield^b(%)

2l

12

1a

1c

B

57

2m, 2m⁰

13

Allyl alcohol

B

88^d

^aMethod A: 1 was added to a mixture of NIS and ROH in CH₂Cl₂. Method B: NIS was added to a mixture of 1 and ROH in CH₂Cl₂.

^bYield of puriﬁed product isolated by ﬂash chromatography.

^cIsolated as a mixture of two diastereomers, ratio not determined.

^dThe two diastereomers were separated by column chromatography, and isolated in a 57:43 ratio.

a- and b-positions of these substrates, with the electrophilic

addition step to the more electron-rich b-position

triggering the subsequent addition of the nucleophile at

the electrophilic a-position.⁴This process would represent

an excellent strategy for diversiﬁcation of the central

N-heterocyclic scaffold, assuming conditions can be found

that prevent the direct competitive attack of the nucleophile

with the electrophile. One way, in which this can be

accomplished is to use an electrophile–nucleophile combi-

nation that are unreactive together. This situation occurs

when the electrophile and nucleophile are both heteroatom

based, since the direct reaction would result in the

formation of a weak E–Nu bond. We have therefore focused

upon this approach using heteroatom based electrophiles

(e.g. E^CZI^C) to trigger the addition. The addition products

can be further elaborated. In this paper, we describe three

such processes: (i) free radical cyclizations from the

b-position, (ii) substituent rearrangement from the a to

b-position, and (iii) nucleophilic attack at the a-position via

N-acyliminium chemistry.

(acrylamide and triﬂuoracetamide) failed to give stable

products.¹⁰However, the addition of carbamates as the

nucleophilic component did give stable addition products,

affording a trans/cis mixture of 3-iodo-2-carbamate sub-

stituted pyrrolidines 3a–3d in good yields (Table 2). This

transformation occurs at low temperature and uses I₂instead

of N-iodosuccinimide, to prevent competitive nucleophilic

attack of succinimide on the electrophilic intermediate.

Interestingly, in the case of the 6-membered substrate 1d,

only the Boc-carbamate yielded a stable addition product¹¹

(Table 2, entry 5).

Free-radical cyclization methods, particularly in a 5-exo or

6-exo manner, constitute one of the most powerful and

versatile methods for the construction of cyclic systems and

have found extensive application in the synthesis of

carbocycles and heterocycles.¹²Radical cyclization reac-

tions of trans-a-alkoxy-b-iodopyrrolidines 2 using a sodium

cyanoborohydride-catalytic tributylstannane system, gener-

ated the bicyclic compounds 4 (Table 3).^7,13The yields were

moderate to high, except for the 6-exo ring closures where

the direct reduction pathway was strongly competitive

(Table 3, entries 2 and 8). The cyclizations were highly

regiospeciﬁc with only the cis-fused 5-exo or 6-exo products

being formed. Such selectivity is well known in radical

cyclization reactions. In the 5-exo and 6-exo cyclization

onto alkenes a new asymmetric center is formed (Table 3,

entries 7 and 9–12), with the endo-isomer being preferen-

tially formed.¹⁴

The synthetic potential of the N-acyl-enamide endocyclic

double bond, was ﬁrst explored by performing electrophilic

iodine additions. Treatment of enamide substrates 1a,⁵

1b⁵and 1c⁶with various alcohols in the presence of

N-iodosuccinimide (NIS) afforded the trans-2-alkoxy-3-

iodopyrrolidines 2 (Table 1). The high levels of trans

diastereoselectivity arise because the intermediate iodonium

ion undergoes anti nucleophilic attack at the a-position.⁷

The transformations readily occur at K78 8C, even for less

nucleophilic substrates (Table 1, entry 12), and no side

reaction was observed between iodine and the unsaturated

alcohols, because of the greater nucleophilicity of the

enamine p-bond over the alkenol/alkynol p-bonds (Table 1,

entries 8–11 and 13). Reaction of the chiral substrate 1c,

which contains an ester group at the 5-position of the

pyrroline ring, resulted in poor facial selectivity for the

electrophilic addition step, although the products again had

a trans-relationship between the 3-iodo- and 2-alkoxy

substituents (Table 1, entries 7 and 13).

However, as the alkene substituent in 2 becomes bulkier, the

steric interaction at the endo position becomes larger and the

selectivity diminishes. For the 6-exo-trig ring closure and as

expected for acyclic examples,¹⁵a lower selectivity in favor

of the trans product was observed (Table 3, entry 8)

resulting from the exo (1,6-trans) transition state.

The above results illustrate the utility of introducing b-I and

a-N/O functionality on the C]C bond of endocyclic

enamide derivatives. A further goal of our research was to

establish whether the endocyclic enamides 1, or the

corresponding 3-iodo-2-carbamate derivatives 3, could be

functionalized to give compounds having b-amino func-

tionality (i.e. 3-aminopyrrolidines/piperidines). Although

comparable amino functionalization of glycals (cyclic enol

ethers) has been intensively studied in the glycoconjugate

Iodine promoted addition of nitrogen nucleophiles^8,9on

substrates 1a and 1d is also possible. Attempts to use

primary amines (allylamine and propargylamine), dialkyl-

amines (N-methylallylamine and N-cyclohexylamine),

arylamines (aniline, N-acetylaniline) and amides

1224

M. Norton Matos et al. / Tetrahedron 61 (2005) 1221–1244

Table 2. Iodocarbamation of N-Cbz-enamide substrates

Entry

Substrate

Product

Yield (%)^a

d.r.^b

1

2

3

4

5

1a (nZ1)

1d (nZ2)

3a (RZBoc)

3b (RZCbz)

3c (RZCO₂Me)

3d^c(RZTs)

3e (RZBoc)

74

71

70

32^c

75

72:28

77:23

73:27

69:31

—

^aYield of pure product puriﬁed by ﬂash chromatography.

^bDetermined by ¹H NMR.

^cPartial decomposition was observed within a few days at 4 8C.

Table 3. Conversion of pyrrolidines 2 into bicyclic pyrrolidines 4

Entry

Pyrrolidine

Bicyclic

Yield (%)^a

endo/exo

4a

1

2a

71

—

4b

2

3

2b

2c

46^b

—

4c

61

74^c

—

4d

4

2d

4e

5

6

2e

2g

75

61

—

4g, 4g⁰

M. Norton Matos et al. / Tetrahedron 61 (2005) 1221–1244

1225

Table 3 (continued)

Entry

Pyrrolidine

Bicyclic

Yield (%)^a

endo/exo

4h

7

8

2h

92^d

95:5

4i

2i

2j

30^d,e

40:60

74:26

4j

9

66^d

82^d

80:20

4k

10

2k

4m

11

12

2m

96^d

95:5

4m⁰

76^d

2m⁰

^aYield of puriﬁed product isolated by ﬂash chromatography.

^bThe corresponding uncyclized reduced product was isolated in 37% yield.

^cIsolated as a 1:1 mixture of E/Z isomers.

^dThe stereochemistry of the products were assigned by a combination of 1D NMR and 2D NMR NOESY experiments performed at 360 K in 1,1,2,2-d₂-

tetrachloroethane.

^eThe corresponding uncyclized reduced products were also isolated in 26% yield.

chemistry, very few examples are known for N-heterocyclic

equivalents.¹⁶The most straightforward pathway would

involve a direct aminohydroxylation protocol on the

endocyclic substrates 1, but initial attempts to achieve

such reactions have failed.¹⁷However, cis/trans-2-

methoxy-3-N-(triﬂuoroacetyl)aminopyrrolidines have been

prepared,¹⁷albeit in moderate yields, via a formal

aziridination protocol using a manganese nitrido complex.¹⁸

Table 4. Aziridination/methanolysis of 3

Entry

Substrate

Product

Yield (%)^a

d.r.^b(trans/cis)

1

2

3

3a

3b

3c

5a (RZBoc)

5b (RZCbz)

5c (RZMeOCO)

82

73

85

85:15

77:23

78:22

^aYield of puriﬁed pure product isolated by ﬂash chromatography.

1

^bDetermined by H NMR.

1226

M. Norton Matos et al. / Tetrahedron 61 (2005) 1221–1244

give an aziridine intermediate, which is then ring-opened in

situ at low temperature by methanol, to afford inseparable

diastereomeric mixtures of 5a–5c (Table 4). The same

transformation could also be achieved, but in lower yields

(60% for 5a and 59% for 5b), using KOH (0.1 M)/MeOH at

35 8C for 5 h.¹⁹

Surprisingly the aziridination/methanolysis protocol was

unsuccessful on the piperidine substrate 3e. However,

treatment of the enecarbamates 1a or 1d with CAN^20,21in

the presence of sodium azide and methanol afforded

3-azido-2-methoxypyrrolidines 6a and piperidine 6b

respectively, as diastereomeric mixtures (Scheme 1). This

azidomethoxylation protocol allows for the introduction of

latent amino functionality, as an azido group, in the b

position of both pyrrolidines and piperidines. Interestingly,

this reaction occurred in much better yields using the

piperidine substrate 1d than with the pyrrolidine substrate

1a.

Scheme 1. Azidomethoxylation with ceric ammonium nitrate (CAN).

Scheme 2. LiAlH₄Reduction of bicyclic hemiaminal derivatives 4.

Both the bicyclic compounds 4 and the 2-methoxy-3-

substituted-pyrrolidines 2, 5 and 6 constitute versatile

intermediates by virtue of the hemiaminal functionality,

which can undergo reaction with nucleophiles at the

a-position. The simplest nucleophilic addition reaction is

hydride addition, as exempliﬁed by the use of lithium

aluminium hydride.²²For example, substrates 4a and 4e

The adducts described above provide an alternative

approach for the introduction of b-amino functionality. A

migration/methanolysis protocol on 3 allows for the

preparation of 3-amino-2-methoxy functionalized pyrroli-

dines and piperidines. Treatment of compounds 3a–3c with

NaN(SiMe₃)₂in THF and methanol, results in cyclization to

Table 5. N-Acyliminium ion additions of bicyclic hemiaminal derivatives 4

Entry

Substrate

Nucleophile

Major product^a

Yield (%)^b

d.r.^c(cis/trans)

8a

8b

8c

8d

1

4a (RZCbz)

H₂C]CHCH₂SiMe₃

89

76:24

2

3

4

4e (RZAc)

4a (RZCbz)

4e (RZAc)

H₂C]CHCH₂SiMe₃

58

76

64

63:37

67:33

74:26

Me₃SiCN

^aThe stereochemistry of the products were assigned by a combination of 1D and 2D NMR NOESY experiments performed at 360 K in 1,1,2,2-

tetrachloroethane-d₂.

^bYield of puriﬁed pure product isolated by ﬂash chromatography.

^cDetermined by ¹H NMR.

M. Norton Matos et al. / Tetrahedron 61 (2005) 1221–1244

1227

underwent reduction to N-alkyl-3-alkyl-substituted pyrroli-

dines in moderate yields (Scheme 2).

targets due to their toxicological and biological properties,²⁷

and indeed, synthesis of pyrrolizidines have been a fertile

testing ground for new synthetic methodologies.²⁸

1-Aminopyrrolizidines are a relatively rare subclass, and

only a few representatives have been described.²⁹There has

been some synthetic effort to construct related structures.³⁰

Recently Potier and co-workers³¹described the ﬁrst

synthesis of two 1-amidopyrrolizidine alkaloids, absouline

and laburnamine, through a pyrrolizidine-1-one hydro-

chloride intermediate.

More importantly these compounds can be utilized as

N-acyliminium ion precursors in C–C bond forming

reactions²³as exempliﬁed by reactions with allyltrimethyl-

silane or cyanotrimethylsilane. Reaction of 4 with these

nucleophiles in the presence of BF₃$OEt₂gave compounds

8a–8d in moderate diastereoselectivity. The major dia-

stereomers were the cis-isomers,²⁴as determined by

2D-NOESY experiments (Table 5) and, in the case of

compound 8d, further conﬁrmed by an X-ray structure

determination (Fig. 2).

The availability of 3-aminopyrrolidines through the

methodology outlined in this paper, provides an alternative

strategy for the formation of the 1-aminopyrrolizidine

skeleton (Scheme 3). Thus, the major trans-isomer of 9d

was readily separated from the cis-isomer by ﬂash column

chromatography. Hydroboration of compound trans-9d

32

using BH₃$SMe₂followed by oxidative hydrolysis with

NaOH/H₂O₂afforded the alcohol 10. Initial attempts using

BH₃$THF³³or 9-BBN³³required long reaction times and, in

the latter case, resulted in difﬁculties in puriﬁcation. In an

attempt to form a reductive amination precursor, oxidation

of the primary alcohol 10 to the aldehyde was attempted

using NMO/TPAP,³⁴but this intermediate proved to be

unstable. Alternatively tosylation³⁵of the primary alcohol

afforded compound 11 which upon hydrogenation³⁶(5%

Pd/C) cyclized to give 1-carbamate pyrrolizidine 12.

Carbamate deprotection was accomplished with TMSI

followed by methanolysis³⁷and the crude amine was

immediately protected with methylbutyric acyl chloride to

give (G)-laburnamine 13 in an overall yield of 6% starting

from the enecarbamate 1a.

3. Conclusions

Figure 2. Representation of the X-ray structure of 8d.

In summary, strategies for pyrrolidine and piperidine a,b-

funcionalization have been developed, starting from readily

available endocyclic enamine derivatives. A two step

heteroannulation procedure involving iodoetheriﬁcation of

N-acyl-2-pyrrolines followed by radical cyclization, gave

access to the bicyclic compounds 4 which can be used in

further transformations to form substituted pyrrolidines.

3-Amino functionalization of pyrrolidines and piperidines

can be accomplished by two different routes, from the

corresponding endocyclic enamine derivatives. Iodo-

amination followed by aziridination/methanolysis afforded

the 3-carbamate-2-methoxypyrrolidines 5 and azido-

methoxylation with CAN/NaN₃in methanol afforded the

3-azido-2-methoxypyrrolidines 6a and piperidines 6b.

Stereoselective substitution of the 2-methoxy group by

carbon nucleophiles via N-acyliminium intermediates

afforded the 2-substituted-3-carbamate-pyrrolidines

(9a–9d) with good trans-selectivity and the 2-substituted-

3-azido-pyrrolidines and piperidines with good cis-

selectivity (9e and 9f). The resultant compounds are useful

synthetic intermediates, as exempliﬁed by the synthesis of

the natural 1-aminopyrrolizidine alkaloid, (G)-laburn-

amine, starting from the pyrrolidine precursor 9d. Overall,

this study further establishes the utility of electron-rich

endocyclic enecarbamates (or enamides) in electrophilic

addition reactions.

Further transformations of N-acyl-iminium intermediates

derived from 3-carbamate and 3-azido substituted pyrroli-

dines 5 and piperidines 6 would be of special interest

because they would allow for the preparation of potential

precursors for natural and non-natural products synthesis.²⁵

Reaction of allyltrimethylsilane, cyanotrimethylsilane or

tert-butyl[1-ethoxyvinyl)oxy]dimethylsilane with pyrroli-

dines 5a–5c under Lewis acidic conditions afforded the

3-carbamate-2-alkyl-substituted pyrrolidines 9a–9d in

moderate to good yields, and with moderate trans stereo-

selectivity (Table 6, entries 1–4). This observed trans

selectivity can be rationalized by a neighboring group

effect.²⁶In contrast, similar attack of the 3-azido substrates

6a and 6b gave substituted products 9e and 9f with moderate

yields and high cis selectivity²⁴(Table 6, entries 5 and 6).

Analogous N-acyliminium transformations could also be

performed on 3-iodo-2-methoxypyrrolidine 2f to give the

substituted products 9g and 9h in good to excellent yields

(Table 6, entries 7 and 8). These products were obtained

exclusively as the trans diastereomers, presumably via the

intermediacy of an iodonium ion, which exclusively directs

the nucleophilic attack in an anti fashion.

Pyrrolizidines are an important class of alkaloids, present in

many plants and insects. They are important synthetic

1228

M. Norton Matos et al. / Tetrahedron 61 (2005) 1221–1244

Table 6. N-Acyliminium ion additions of 2-methoxy-3-substituted pyrrolidine precursors

Entry

1

Substrate

Nucleophile

Major product^a

Yield (%)^b

d.r.^ccis/trans

9a

9b

5b (nZ1, RZNHCbz)

H₂C]CHCH₂SiMe₃

60

24:76

2

3

4

5

6

7

8

5b (nZ1, RZNHCbz)

5c (nZ1, RZNHCO₂Me)

6a (nZ1, RZN₃)

Me₃SiCN

52

74

79

49

50

93

68^d

30:70

15:85

23:77

88:12

%2:98

9c

CH₂]C(OTBDMS)OEt

H₂C]CHCH₂SiMe₃

CH₂]C(OTBDMS)OEt

H₂C]CHCH₂SiMe₃

CH₂(CO₂Me)₂

9d

9e

9f

6b (nZ2, RZN₃)

9g

2f (nZ1, RZI)

9h

2f (nZ1, RZI)

^aThe stereochemistry of the products were assigned by a combination of 1D and 2D NMR NOESY experiments performed at 360 K in 1,1,2,2-

tetrachloroethane-d₂.

^bYield of puriﬁed pure product isolated by ﬂash chromatography.

^cDetermined by ¹H NMR.

^dPrepared at K78 8C and using TiCl₄as the Lewis acid.

4. Experimental

4.1. General remarks

chromatography (TLC) was performed on silica gel plates

(Merck Kiesegel GF 254, 0.2 mm) and components were

visualized by observation under UV light or by treating the

plates with phosphomolybdic reagent followed by heating.

Column chromatography was carried out using Merck 60H

silica gel or Whatman 230–400 ‘mesh’ silica gel. Solvent

ratios for R_fvalues are reported as v/v.

All chemicals were purchased from commercial sources and

were used without further puriﬁcation. Unless otherwise

stated, all reactions were performed under nitrogen or argon

atmosphere using ﬂame or oven (120 8C) dried glassware.

Diethyl ether, tetrahydrofuran (THF), benzene and toluene

were distilled over sodium and benzophenone under argon

or nitrogen. Dichloromethane, t-BuOH and acetonitrile

were distilled over CaH₂. Analytical thin-layer

Nuclear magnetic resonance spectra: ¹H and ¹³C NMR

spectra were recorded on either Varian Gemini 200, Bruker

ARX 400 or Varian XL400 MHz spectrometers. The

following abbreviations are used to indicate signal

M. Norton Matos et al. / Tetrahedron 61 (2005) 1221–1244

1229

Scheme 3. Synthesis of (G)-laburnamine.

multiplicity: s, singlet; d, doublet; t, triplet; q, quartet; m,

multiplet; dd, doublet of doublets; br, broad and J, coupling

constant in Hz. Infrared spectra were recorded on either a

Buck Scientiﬁc M-500 or a Fourier Perkin–Elmer 683

(200 MHz, CDCl₃), rotamers, d 7.36–7.33 (m, 5H, Ar),

5.63–5.54 (m, 1H, N–CH–O), 5.19 (s, 2H, –CH₂Ph), 4.33–

4.31 (m, 2H, –OCH₂C^C), 4.12 (d, JZ3.6 Hz, 1H, –CHI),

3.71–3.49 (m, 2H, –NCH₂CH₂), 2.48–2.11 (m, 3H, –C^CH

and –NCH₂CH₂); ¹³C NMR (100 MHz, CDCl₃), rotamers, d

156.4, 154.2, 136.7, 127.5, 128.5, 129.1, 95.4, 94.3, 80.2,

79.8, 75.2, 67.7, 56.6, 55.5, 45.2, 33.1, 32.5, 26.5, 26.0;

HRMS (EI) m/z calcd for (C₁₅H₁₆INO^C₃): 385.0175, found:

385.0173.

¨

spectrometer. Melting points were measured on a Kopﬂer

instrument, mod. Reichert Termovar and are uncorrected.

Optical activities were measured on an Optical activity,

Mod. AA-1000, with a 5 cm cell. Low-resolution mass

spectra were performed on Bell and Howell 21-490

spectrometer and high resolution mass spectra were

performed on a AEI MS3074 spectrometer (University of

Toronto). X-ray crystallography analysis was performed by

Dr. Alan Lough (Department of Chemistry, University of

Toronto).

4.2.2. trans-Benzyl-2-(3-butynyloxy)-3-iodo-1-pyrroli-

dine carboxylate (2b, Table 1, entry 2). Prepared

following method

A using 3-butyn-1-ol (295 ml,

3.03 mmol), N-iodosuccinimide (716 mg, 3.03 mmol) and

1a (513 mg, 2.53 mmol) to yield the iodoether derivative

which was puriﬁed by ﬂash column chromatography (SiO₂,

10% EtOAc/90% hexane) affording 2b (760 mg, 75%) as a

colorless oil; R_fZ0.42 (20% EtOAc/80% hexane); IR (ﬁlm)

n 3294, 3032, 2953, 1712, 1497, 1407, 1192, 1112, 916, 771,

CCDC-249610 8d contains the supplementary crystallo-

graphic data for this paper. These data can be obtained free

of charge via www.ccdc.cam.ac.uk/conts/retrieving.html

(or from the Cambridge Crystallographic Data Centre, 12

Union Road, Cambridge CB2 1EZ, UK; fax: C44 1223 336

033; or e-mail: deposit@ccdc.cam.ac.uk).

697, 604 cm^K^{1 1}H NMR (200 MHz, CDCl₃), rotamers,

;

7.35 (br, 5H, Ar), 5.42–5.54 (m, 1H, NCH–O), 5.22–5.18

(m, 2H, –CH₂Ph), 4.25 (d, JZ4.8 Hz, 1H, –CHI), 3.76–3.53

(m, 4H, –NCH₂and –OCH₂) 2.45–1.98 (m, 5H, –C^CH,

–NCH₂CH₂and –CH₂C^CH); ¹³C NMR (100 MHz,

CDCl₃), rotamers, d 156.2, 155.3, 136.3, 128.4, 128.3,

128.0, 127.9, 96.2, 96.1, 81.7, 81.5, 69.5, 69.4, 67.3, 67.1,

66.7, 66.4, 33.6, 32.7, 26.9, 26.3, 19.9, 19.8; HRMS (EI) m/z

calcd for (C₁₆H₁₈INO^C₃): 399.0331, found: 399.0316.

4.2. Method A. General procedure for iodoetheriﬁcation

with alkynols

To a solution of N-iodosuccinimide (1.2 mequiv) and the

alcohol (1.2 mequiv) in dry dichloromethane at K78 8C,

was added dropwise N-acyl-2-pyrroline 1 (1.0 mequiv). The

mixture was stirred under argon for 10 min and then poured

into a cold saturated aqueous solution of NaHCO₃. The

aqueous phase was extracted twice with dichloromethane.

The combined organic phases were dried (Na₂SO₄) and the

solvent removed in vacuo to yield the iodoether 2

derivative, which was puriﬁed by ﬂash chromatography.

4.2.3. trans-Benzyl-3-iodo-2-[(1-methyl-2-propynyl)oxy]-

1-pyrrolidinecarboxylate (2c, Table 1, entry 3). Prepared

following method

A using 3-butyn-2-ol (238 ml,

2.95 mmol), N-iodosuccinimide (698 mg, 2.95 mmol) and

1a (500 mg, 2.46 mmol) to yield the iodoether derivative

which was puriﬁed by ﬂash column chromatography (SiO₂,

10% EtOAc/90% hexane) affording 2c (487 mg, 50%) as a

colorless oil; R_fZ0.22 (10% EtOAc/90% hexane); IR (ﬁlm)

n 3294, 2983, 2895, 1706, 1558, 1539, 1505, 1456, 1405,

1358, 1338, 1282, 1259, 1212, 1186, 1113, 1045, 1008, 912,

4.2.1. trans-Benzyl-3-iodo-2-(2-propynyloxy)-1-pyrroli-

dine carboxylate (2a, Table 1, entry 1). Prepared

following method A using propargyl alcohol (172 ml,

2.95 mmol), N-iodosuccinimide (698 mg, 2.95 mmol) and

N-[(benzyloxy)carbonyl)]-2-pyrroline (1a) (500 mg,

2.46 mmol), to yield the iodoether derivative which was

puriﬁed by ﬂash column chromatography (SiO₂, 10%

EtOAc/90% hexane) affording 2a (760 mg, 80%) as a

colorless oil; R_fZ0.5 (10% EtOAc/90% hexane); IR (ﬁlm) n

3290, 3032, 2955, 2117, 1710, 1586, 1498, 1404, 1286,

1

734, 697 cm^K1; H NMR (400 MHz, CDCl₃), rotamers, d

7.35–7.24 (m, 5H, Ar), 5.67 (s, 0.5H, NCHO), 5.53 (s, 0.5H,

NCHO), 5.27–5.07 (m, 2H, –CH₂Ph), 4.57 (q, JZ6.6 Hz,

0.5H, –CHCH₃), 4.38 (t, JZ6.8 Hz, 1H, –CHI), 4.22 (q, JZ

6.7 Hz, 0.5H, –CHCH₃), 3.70–3.52 (m, 2H, –NCH₂), 2.56–

2.39 (m, 2H, –NCH₂CH₂and –C^CH), 2.14–2.08 (m, 1H,

–NCH₂CH₂), 1.38 (d, JZ6.6 Hz, 1.5H, –CHCH₃), 1.24 (d,

1193, 1113, 1052, 972, 915, 772, 697 cm^K^{1 1}H NMR

;

1230

M. Norton Matos et al. / Tetrahedron 61 (2005) 1221–1244

JZ6.8 Hz, 1.5H, –CHCH₃); ¹³C NMR (100 MHz, CDCl₃),

rotamers, d 155.4, 154.5, 136.2, 136.1, 128.4, 128.1, 128.1,

128.0, 127.7, 94.8, 94.3, 83.9, 94.3, 83.9, 83.7, 73.1, 67.4,

67.2, 64.5, 63.8, 44.8, 44.7, 33.6, 32.7, 27.8, 27.0, 22.1,

21.9; HRMS (EI) m/z calcd for (C₁₆H₁₈INO^C₃): 399.0331,

found: 399.0316.

–NCH₂), 3.46 (t, JZ8.8 Hz, 1H, –NCH₂), 3.36 (s, 1.5H,

CH₃), 3.22 (s, 1.5H, CH₃), 2.48–2.41 (m, 1H, –NCH₂CH₂),

2.08–2.03 (m, 1H, –NCH₂CH₂); ¹³C NMR (100 MHz,

CDCl₃), rotamers, d 155.7, 155.9, 136.4, 128.5, 128.1,

127.8, 127.7, 96.7, 96.2, 67.4, 67.2, 66.7, 56.4, 56.0, 44.9,

44.7, 33.8, 32.9, 29.7, 26.5, 25.8; DEPT (100 MHz, CDCl₃),

rotamers, d 128.5(C), 128.1(C), 127.8(C), 127.7(C),

96.7(C), 96.2(C), 67.4(K), 67.2(K), 66.7(K), 56.4(C),

56.0(C), 44.9(K), 44.7(K), 33.8(K), 32.9(K), 29.7(K),

26.5(C), 25.8(C); HRMS (EI) m/z calcd for

(C₁₃H₁₆INO^C₃): 361.0165, found: 361.0175.

4.2.4. trans-Benzyl-2-(2-butynyloxy)-3-iodo-1-pyrroli-

dinecarboxylate (2d, Table 1, entry 4). Prepared following

method A using 2-butyn-1-ol (115 ml, 1.54 mmol), N-iodo-

succinimide (362 mg, 1.54 mmol) and 1a (260 mg,

1.28 mmol) to yield the iodoether derivative which was

puriﬁed by ﬂash column chromatography (SiO₂, 5% EtOAc/

95% hexane) affording 2d (334 mg, 65%) as a colorless oil;

R_fZ0.68 (10% EtOAc/90% hexane); IR (ﬁlm) n 3032, 2954,

1712, 1498, 1407, 1359, 1285, 1192, 1113, 1043, 975, 912,

4.2.7. 1-tert-Butyl-2-methyl-(2S(R),4R(S),5S)-4-iodo-5-

(2-propynyloxy)-1,2-pyrrolidinecarboxylate (2g and

2g⁰, Table 1, entry 7). Prepared following method A

using propargyl alcohol (78 ml, 1.35 mmol), N-iodosuccini-

mide (308 mg, 1.35 mmol) and 1c (252 mg, 1.12 mmol) to

yield the iodoether derivative which was puriﬁed by ﬂash

chromatography (SiO₂, 20% EtOAc/80% hexane) affording

2g and 2g⁰(260 mg, 57%) as a colorless oil; R_fZ0.27 (10%

EtOAc/90% hexane); [a]²_D⁰ZK25.0 (CHCl₃, cZ0.105 g/

100 ml); IR (ﬁlm) n 3269, 2977, 2952, 1760, 1713, 1478,

1439, 1378, 1320, 1258, 1203, 1165, 1054, 980, 903, 860,

771, 698, 603 cm^K1

;

¹H NMR (200 MHz, CDCl₃),

rotamers, d 7.35–7.24 (m, 5H, Ar), 5.9–5.7 (m, 0.4H,

–NCH–O), 5.6 (s, 0.3H, –NCH–O), 5.5 (s, 0.3H, –NCH–O),

5.26–5.1 (m, 2H, –CH₂Ph), 4.56–4.20 (m, 2H, –OCH₂-

C^CH), 4.08–4.07 (m, 1H, –CHI), 3.72–3.5 (m, 2H,

–NCH₂), 2.62–2.46 (m, 1H, –NCH₂CH₂), 2.14–2.04 (m, 1H,

–NCH₂CH₂), 1.84 (s, 1.5H, –C^CCH₃), 1.77(s, 1.5H,

–C^CCH₃); ¹³C NMR (100 MHz, CDCl₃), rotamers, d

155.9, 155.5, 136.1, 136.0, 128.5, 128.4, 128.3, 128.1,

127.8, 95.0, 94.2, 89.8, 89.2, 82.8, 82.7, 74.9, 74.6, 67.4,

67.2, 57.2, 56.5, 45.1, 44.7, 33.6, 33.0, 26.5, 26.3, 3.6, 3.5;

HRMS (EI) m/z calcd for (C₁₆H₁₈INO^C₃): 399.0331, found:

399.0326.

1

804, 773, 749, 665 cm^K1; H NMR (400 MHz, CDCl₃),

rotamers, d 5.59–5.54 (m, 0.8H, –NCHO), 5.38 (s, 0.2H,

–NCHO), 4.61–4.19 (m, 4H, –OCH₂, NCHCO₂CH₃and

–CHI), 3.70–3.68 (m, 3H, CO₂CH₃), 3.08–2.93 (m, 0.5H,

–C^CH), 2.63–2.54 (m, 0.5H, –C^CH), 2.52–2.54 (m,

2H, –NCHCH₂), 1.45 (s, 4.5H, –C(CH₃)₃), 1.38 (s, 4.5H,

–C(CH₃)₃); ¹³C NMR (100 MHz, CDCl₃), rotamers, d

171.9, 171.8, 171.6, 171.3, 154.0, 153.3, 153.2, 96.5, 94.3,

93.9, 81.5, 81.2, 75.2, 74.8, 74.4, 74.3, 58.8, 58.5, 58.1,

57.6, 56.9, 55.5, 54.4, 52.3, 52.1, 38.6, 38.4, 37.7, 37.1,

28.3, 28.1, 25.2, 24.3, 22.1, 20.7; DEPT (100 MHz, CDCl₃),

rotamers, d 96.5(C), 94.3(C), 93.9(C), 81.5(C), 81.2(C),

75.2 (C), 74.8(C), 74.4(C), 74.3(C), 58.8(C), 58.5(C),

58.1(C), 57.6(K), 56.9(K), 55.5(K), 54.4(K), 52.4(C),

52.3(C), 52.1(C), 38.6(K), 38.4(K), 37.7(K), 37.1(K),

28.3(C), 28.1(C), 25.2(C), 24.3(C), 22.1(C), 20.7(C).

4.2.5. trans-1-Acetyl-3-iodo-2-(2-propynyloxy)pyrroli-

dine (2e, Table 1, entry 5). Prepared following method A

using propargyl alcohol (377 ml, 6.48 mmol), N-iodo-

succinimide (1.53 g, 6.48 mmol) and N-[(methyl)car-

bonyl]-2-pyrroline 1b (0.60 g, 5.4 mmol) to yield the

iodoether derivative which was puriﬁed by ﬂash column

chromatography (SiO₂, 30% EtOAc/70% hexane) affording

2e (1.31 g, 83%) as a colorless oil; R_fZ0.28 (30% EtOAc/

70% hexane); IR (ﬁlm) n 3290, 2950, 1667, 1651, 1404,

1

1360, 1263, 1181, 1143, 1055, 921, 845 cm^K1; H NMR

(200 MHz, CDCl₃), rotamers, d 5.41 (s, 0.5H, –NCHO),

5.16 (s, 0.5H, –NCHO), 4.24 (d, JZ4.8 Hz, 0.5H, –CHI),

4.06–3.97 (m, 2.5H, –CHI and –OCH₂), 3.34–3.28 (m, 2H,

N–CH₂), 2.51–2.50 (m, 0.4H, C^CH), 2.36–2.14 (m, 2.6H,

C^CH and –NCH₂CH₂), 1.89 (s, 1.5H, CH₃), 1.84 (s, 1.5H,

–CH₃); ¹³C NMR (100 MHz, CDCl₃), rotamers, d 170.5,

169.6, 93.9, 92.3, 79.3, 77.9, 75.8, 74.2, 56.3, 54.4, 45.0,

43.5, 33.2, 31.3, 26.0, 25.7, 21.8, 21.4; HRMS (EI) m/z

calcd for (C₉H₁₂INO₂CH^C): 293.9991, found: 293.9976.

4.3. Method B. General procedure for iodoetheriﬁcation

with alkenols

To a solution N-acyl-2-pyrroline 1 (1.0 mequiv) and the

alcohol (1.2 mequiv) in dry dichloromethane under argon at

K78 8C was added via cannula a solution of N-iodo-

succinimide (1.0 mequiv) in dry dichloromethane (50 ml)

and cooled to K78 8C. The resulting mixture was stirred for

10 min and then poured into a cold saturated aqueous

solution of NaHCO₃. The aqueous phase was extracted once

with dichloromethane (40 ml). The combined organic

phases were dried (Na₂SO₄) and the solvent removed in

vacuo to yield the iodoether derivative 2, which was puriﬁed

by ﬂash column chromatography.

4.2.6. trans-Benzyl 3-iodo-2-methoxy-1-pyrrolidine-

carboxylate (2f, Table 1, entry 6). Prepared following

method A using N-iodosuccinimide (893 mg, 3.78 mmol),

methanol (2 ml) and 1a (630 mg, 3.15 mmol) to yield the

iodoether derivative which was puriﬁed by ﬂash column

chromatography (SiO₂, 10% EtOAc/90% hexane) affording

2f (1.05 g, 92%) as a colorless oil; R_fZ0.48 (20% EtOAc/

80% hexane); IR (ﬁlm) n 3016, 2950, 2891, 2822, 1709,

1500, 1445, 1406, 1362, 1337, 1283, 1175, 1111, 1072, 954,

4.3.1. trans-Benzyl-2-(allyloxy)-3-iodo-1-pyrrolidine-

carboxylate (2h, Table 1, entry 8). Prepared following

method B using 1a (1.5 g, 7.4 mmol), allyl alcohol (610 ml,

8.9 mmol) and N-iodosuccinimide (1.74 g, 7.39 mmol) to

yield the iodoether derivative which was puriﬁed by ﬂash

column chromatography (SiO₂, 10% EtOAc/90% hexane)

affording 2h (2.1 g, 74%) as a colorless oil; R_fZ0.47 (10%

EtOAc/90% hexane); IR (ﬁlm) n 3031, 2953, 2896, 1713,

915, 773, 700 cm^K1

;

¹H NMR (400 MHz, CDCl₃),

rotamers, d 7.31–7.19 (m, 5H, Ar), 5.38 (s, 0.6H,

–NCHO), 5.27 (s, 0.4H, –NCHO), 5.18–5.06 (m, 2H,

–CH₂Ph), 4.15 (d, JZ4.6 Hz, 1H, –CHI), 3.66–3.59 (m, 1H,

M. Norton Matos et al. / Tetrahedron 61 (2005) 1221–1244

1231

1683, 1652, 1506, 1457, 1398, 1360, 1338, 1286, 1193,

1115, 1056, 917, 878, 771, 697 cm^K1; ¹H NMR (400 MHz,

CDCl₃), rotamers, d 7.36–7.24 (m, 5H, Ar), 5.92–5.84 (m,

0.5H, CH]CH₂), 5.82–5.70 (m, 0.5H, CH]CH₂), 5.54 (s,

0.5H, –NCHO), 5.42 (s, 0.5H, –NCHO), 5.30–5.07 (m, 4H,

–CH₂Ph and –CH]CH₂), 4.23 (d, JZ4.8 Hz, 2H, OCH₂),

3.94 (tt, JZ6.8, 1.2 Hz, 1H, –CHI), 4.10 (tt, JZ6.5, 1.2 Hz,

1H, –CHI), 3.74–3.65 (m, 1H, –NCH₂), 3.56–3.50 (m, 1H,

–NCH₂), 2.61–2.50 (m, 1H, –NCH₂CH₂), 2.12 (ddd, JZ

14.8, 6.8, 2.8 Hz, 1H, –NCH₂CH₂); ¹³C NMR (100 MHz,

CDCl₃), rotamers, d 155.5, 154.6, 136.2, 136.1, 134.2,

133.8, 128.4, 128.1, 128.0, 127.9, 127.6, 117.4, 117.3, 95.1,

94.5, 69.9, 69.4, 67.3, 67.1, 44.8, 44.64, 33.68, 32.7, 27.0,

26.3; HRMS (EI) m/z calcd for (C₁₅H₁₈INO^C₃): 387.0331,

found: 387.0323.

33.6, 32.6, 26.9, 26.3; HRMS (EI) m/z calcd for

(C₁₂H₁₃INO^C₃, corresponds to b-iodopyrrolidine unit):

329.9991, found: 329.9994.

4.3.4. trans-Benzyl-2-([(2E)-4-ethoxy-4-oxo-2-butenyl]-

oxy(-3-iodo-1-pyrrolidinecarboxylate (2k, Table 1,

entry 11). Prepared following method B using 1a

(406 mg, 2.0 mmol), ethyl-(2E)-hydroxy-2-butenoate

(312 mg, 2.4 mmol) and N-iodosuccinimide (460 mg,

2.0 mmol) to yield the iodoether derivative which was

puriﬁed by ﬂash column chromatography (SiO₂, 10%

EtOAc/90% hexane) affording 2k (570 mg, 62%) as a

yellow oil; R_fZ0.42 (20% EtOAc/80% hexane); IR (ﬁlm) n

2979, 2898, 1737, 1716, 1661, 1446, 1403, 1360, 1281,

1179, 1281, 1179, 1109, 1031, 975, 915, 878, 772, 698 cm^K1

;

¹H NMR (400 MHz, CDCl₃), rotamers, d 7.37–7.24 (m, 5H,

Ar), 6.88 (td, JZ15.6, 4.4 Hz, 0.6H, –CH]CHC(]O)), 6.77

(td, JZ15.6, 4.0 Hz, 0.4H, CH]CH–C(]O)), 6.00 (td, JZ

1.6, 16.0 Hz, 0.6H, CH]CH–C(]O)), 5.90 (td, JZ2.0,

16.0 Hz, 0.4H, CH]CH–C(]O)), 5.56 (s, 0.5H, –NCHO),

5.44 (s, 0.5H, –NCHO), 5.27–5.10 (m, 2H, –CH₂Ph), 4.36

(ddd, JZ16.0, 4.4, 2.0 Hz, 0.5H, –CH₂CH]CH), 4.28 (ddd,

JZ16.0, 4.4, 2.0 Hz, 0.5H, –CH₂CH]CH),4.22 (d, JZ

7.2 Hz, 1H, –CHI), 4.16 (q, JZ4.8 Hz, 2H, –OCH₂), 4.12–

4.07 (m, 1H, –CH₂CH]CH), 3.76–3.41 (m, 2H, –NCH₂),

2.61–2.48 (m, 1H, –NCH₂CH₂), 1.6–1.9(m, 1H, –NCH₂CH₂),

1.26 (t, JZ7.2 Hz, 3H, –CH₃); ¹³C NMR (100 MHz, CDCl₃),

rotamers, d 173.3, 166.2, 166.0, 155.8, 155.6, 154.7, 143.7,

143.2, 136.2, 136.0, 128.6, 128.5, 128.5, 128.3, 128.1, 128.0,

127.9, 127.7, 121.3, 121.1, 95.5, 95.41, 94.9, 94.9, 67.8, 67.5,

67.4, 67.3, 67.3, 67.2, 66.8, 60.3, 60.4, 60.3, 45.0, 44.8, 44.6,

33.8, 33.7, 32.8, 32.8, 31.0, 30.8, 26.8, 26.3, 26.1, 25.7, 25.1,

24.9, 14.2; FAB m/z calcd for (C₁₈H₂₂INO₅CNa^C): 481.98,

found: 482.20.

4.3.2. trans-Benzyl-2-(3-butenyloxy)-3-iodo-1-pyrroli-

dinecarboxylate (2i, Table 1, entry 9). Prepared following

method B using 1a (340 mg, 1.68 mmol), 3-buten-1-ol

(177 ml, 2.02 mmol) and N-iodosuccinimide (397 mg,

1.68 mmol) to yield the iodoether derivative which was

puriﬁed by ﬂash column chromatography (SiO₂, 10%

EtOAc/90% hexane) affording 2i (414 mg, 62%) as a

colorless oil; R_fZ0.38 (10% EtOAc/90% hexane); IR (ﬁlm)

n 3067, 2951, 2895, 1711, 1640, 1105, 1360, 1335, 1283,

1210, 1192, 1112, 1062, 915, 876, 771, 697 cm^K1; ¹H NMR

(400 MHz, CDCl₃), rotamers, d 7.34–7.26 (m, 5H, Ar),

5.81–5.62 (m, 1H, CH]CH₂), 5.50 (s, 0.5H, –NCHO), 5.38

(s, 0.5H, –NCHO), 5.24–4.96 (m, 4H, –CH₂Ph and

–CH]CH₂), 4.18 (d, JZ3.6 Hz, 1H, –CHI), 3.72–3.40

(m, 4H, –OCH₂and –NCH₂), 2.55–2.43 (m, 1H,

–NCH₂CH₂), 2.28 (dq, JZ6.8, 1.2 Hz, 1H, CH₂CH]CH₂),

2.18 (dq, JZ6.8, 1.2 Hz, 2H, –CH₂CH]CH₂), 2.07 (dd,

JZ14.0, 6.4 Hz, 1H, –NCH₂CH₂); ¹³C NMR (100 MHz,

CDCl₃), rotamers, d 155.2, 154.3, 136.1, 136.0, 134.6,

134.3, 128.2, 127.8, 127.7, 127.6, 127.4, 116.3, 95.1, 94.6,

67.8, 67.5, 67.0, 66.8, 44.6, 44.4, 33.9, 33.7, 33.5, 32.5,

26.9, 26.3; HRMS (EI) m/z calcd for (C₁₆H₂₀INO^C₃):

401.0488, found: 401.0494.

4.3.5. trans-Benzyl-3-iodo-2-phenoxy-1-pyrrolidine-

carboxylate (2l, Table 1, entry 12). Prepared following

method B using 1a (554 mg, 2.73 mmol), phenol (309 mg,

3.28 mmol) and N-iodosuccinimide (774 mg, 3.28 mmol) to

yield the iodoether derivative which was puriﬁed by ﬂash

column chromatography (SiO₂, 10% EtOAc/90% hexane)

affording 2l (0.667 g, 57%) as a colorless oil; R_fZ0.51

(20% EtOAc/80% hexane); IR (ﬁlm) n 3063, 3033, 2954,

2896, 1716, 1596, 1488, 1455, 1407, 1354, 1284, 1210,

1186, 1117, 1079, 1053, 1027, 1002, 969, 917, 810, 752,

4.3.3. trans-Benyzl-3-iodo-2-([(2E)-3-phenyl-2-pro-

penyl]oxy(-1-pyrrolidinecarboxylate (2j, Table 1, entry

10). Prepared following method B using 1a (305 mg,

1.50 mmol), cinnamyl alcohol (241 mg, 1.8 mmol) and

N-iodosuccinimide (353 mg, 1.5 mmol) to yield the

iodoether derivative which was puriﬁed by ﬂash chroma-

tography (SiO₂, 10% EtOAc/90% hexane) affording 2j

(514 mg, 74%) as a yellow oil; R_fZ0.24 (20% EtOAc/80%

hexane); IR (ﬁlm) n 3028, 2951, 2895, 1712, 1496, 1448,

1403, 1356, 1328, 1267, 1210, 1177, 1112, 1070, 1050, 967,

1

732, 692 cm^K1; H NMR (200 MHz, CDCl₃), rotamers, d

7.43–7.06 (m, 7H, Ar), 7.04 (t, JZ8.0 Hz, 2H, Ar), 6.9 (d,

JZ7.6 Hz, 1H, Ar), 6.23 (s, 0.5H, –NCHO), 6.10 (s, 0.5H,

–NCHO), 5.24–5.10 (m, 2H, –CH₂Ph), 4.36 (dt, JZ8.4,

4.8 Hz, 1H, –CHI), 3.84–3.69 (m, 2H, –NCH₂), 2.71–2.57

(m, 1H, –NCH₂CH₂), 2.23–1.32 (m, 1H, –NCH₂CH₂); ¹³C

NMR (100 MHz, CDCl₃), rotamers, d 155.9, 155.9, 154.5,

153.9, 135.9, 135.7, 129.5, 128.3, 128.1, 127.9, 127.6,

127.2, 122.2, 122.1, 116.6, 116.5, 94.5, 94.1, 67.2, 67.1,

45.0, 44.8, 33.2, 32.4, 26.3, 25.5; HRMS (EI) m/z calcd for

(C₁₈H₁₈INO^C₃): 423.0331, found: 423.0316.

1

913, 878, 735, 593 cm^K1; H NMR (400 MHz, CDCl₃),

rotamers, d 7.41–7.24 (m, 10H, Ar), 6.64 (d, JZ16.0 Hz,

0.5H, CH]CHPh), 6.46 (d, JZ16.0 Hz, 0.5H,

–CH]CHPh), 6.33–6.26 (m, 0.5H, –CH]CHPh), 6.19–

6.12 (m, 0.5H, –CH]CHPh), 5.66 (s, 0.5H, –NCHO), 5.54

(s, 0.5H, –NCHO), 5.32–5.16 (m, 2H, –CH₂Ph), 4.41–4.31

(m, 1H, –OCH₂), 4.29 (d, JZ5.2 Hz, 1H, –CHI), 4.18–4.11

(m, 1H, –OCH₂), 3.80–3.63 (m, 1H, –NCH₂), 3.61–3.55 (m,

1H, –NCH₂), 2.66–2.53 (m, 1H, –NCH₂CH₂), 2.12 (dd, JZ

14.4, 6.4 Hz, 1H, –NCH₂CH₂); ¹³C NMR (100 MHz,

CDCl₃), rotamers, d 155.4, 154.5, 136.4, 136.1, 136.0,

128.3, 127.9, 127.9, 127.8, 127.6, 127.5, 126.3, 126.3,

125.3, 124.8, 95.0, 94.3, 69.5, 68.9, 67.2, 67.0, 44.7, 44.5,

4.3.6. 1-tert-Butyl-2-methyl-(2S,4R(S),5S(R))-5-(allyl-

oxy)-4-iodo-1,2-pyrrolidenecarboxylate (2m and 2m⁰,

Table 1, entry 13). Prepared following method B using

1c (520 mg, 2.32 mmol), 3-buten-1-ol (473 ml, 6.96 mmol)

and N-iodosuccinimide (550 mg, 2.34 mmol). Puriﬁcation

by ﬂash chromatography (SiO₂, 10% EtOAc/90% hexane)

1232

M. Norton Matos et al. / Tetrahedron 61 (2005) 1221–1244

afforded the two diastereomers 2m, 2m⁰(835 mg, 88%) as

colorless oils

washed with a Na₂S₂O₃(0.5 M), and with saturated aqueous

Na₂CO₃. The organic phase was dried over Na₂SO₄and the

solvent removed under vacuo. Puriﬁcation by column

chromatography afforded the 3-iodo-2-carbamate pyrroli-

dine derivative 3.

4.3.7. 1-tert-Butyl-2-methyl-(2S,4R,5S)-5-(allyloxy)-4-

iodo-1,2-pyrrolidenecarboxylate (2m, Table 1, entry

13). (480 mg, 57%); R_fZ0.30 (4% EtOAc/96% hexane);

[a]²_D⁰ZC48.39 (cZ0.81 g/100 ml, CHCl₃); IR (ﬁlm) n

3080, 2977, 2952, 2931, 2869, 1760, 1719, 1647, 1478,

1456, 1438, 1377, 1314, 1259, 1169, 1062, 1014, 972, 934,

4.4.1. Benzyl 2-[(tert-butoxycarbonyl)amino]-3-iodo-1-

pyrrolidinecarboxylate (3a, Table 2, entry 1). Prepared

following method C using 1a (203 mg, 1 mmol), tert-

butylcarbamate (119 mg, 1 mmol) and iodine (305 mg,

1.2 mmol) to yield the iodocarbamate derivative which was

puriﬁed by ﬂash chromatography (SiO₂, 30% EtOAc/70%

hexane) affording a trans/cis mixture of 3a (72/28) (332 mg,

74%) as an orange foam; R_fZ0.46 (30% EtOAc/70%

903, 875, 852, 804, 772, 750, 733 cm^K^{1 1}H NMR

;

(400 MHz, CDCl₃), rotamers, d 5.94–5.84 (m, 1H,

–CH]CH₂), 5.54 (s, 0.5H, –NCHO), 5.45 (s, 0.5H,

–NCHO), 5.28 (s, 0.5H, –CH]CH₂), 5.23 (s, 0.5H,

–CH]CH₂), 5.16–5.12 (m, 1H, –CH]CH₂), 4.64 (t, JZ

8.6 Hz, 0.5H, –NCHCO₂CH₃), 4.65 (t, JZ8.44 Hz, 0.5H,

–NCHCO₂CH₃), 4.54 (t, JZ7.6 Hz, 0.5H, –NCHCO₂CH₃),

4.25–4.21 (m, 2H, –OCH₂), 4.10 (dd, JZ12.4, 5.9 Hz, 0.5H,

–CHI), 4.01 (dd, JZ12.3, 5.5 Hz, 0.5H, –CHI), 3.71 (s, 3H,

–OCH₃), 2.68–2.62 (m, 1H, CH₂CHI), 2.49 (dt, JZ7.5,

17.8 Hz, 1H, –CH₂CHI), 1.48 (s, 4.5H, –C(CH₃)₃), 1.42 (s,

4.5H, –C(CH₃)₃); ¹³C NMR (100 MHz, CDCl₃), rotamers, d

154.2, 154.1, 134.4, 134.3, 117.0, 94.9, 94.5, 93.7, 81.6,

81.2, 70.9, 69.0, 68.3, 58.9, 58.2, 52.3, 52.2, 38.7, 37.9,

29.6, 28.3, 28.1, 25.6, 24.8; DEPT (100 MHz, CDCl₃),

rotamers, d 134.4(C), 117.0(K), 94.9(C), 94.5(C), 69.0

(K), 68.3(K), 58.9(C), 58.2(C), 52.3(C), 52.2(C),

38.7(K), 37.9(K), 28.3(C), 28.1(C), 25.6(C), 24.8(C).

hexane); IR (ﬁlm) n_max3320, 2978, 1696, 1499, 1412, 1365,

´

1280, 1249, 1158, 1117, 1050, 1025, 974, 910, 771, 731,

665 cm^K1; ¹H NMR (400 MHz, CDCl₃), rotamers, d 7.26–

7.19 (m, 5H, Ar), 5.66–5.55 (m, 1H, –NCHN–), 5.26 (br,

1H, –NH), 5.20–5.04 (m, 2H, –CH₂Ph), 4.36–4.24 (m, 1H,

–CHI), 3.63–3.45 (m, 2H, –NCH₂CH₂), 2.31–2.01 (m, 2H,

–NCH₂CH₂), 1.32 (br, 9H, –C(CH₃)₃); ¹³C NMR

(100 MHz, CDCl₃), rotamers, d 154.3, 153.9, 136.3,

128.5, 128.1, 127.9, 127.8, 127.4, 80.3, 75.7, 74.6, 67.2,

45.3, 33.8, 33.0, 28.3, 27.1; DEPT (100 MHz, CDCl₃),

rotamers, d 128.5(C), 128.1(C), 127.9(C), 127.8(C),

127.4(C), 80.3(C), 75.7(C), 74.6(C), 67.2(K), 45.3(K),

33.8(K), 33.0(K), 28.3(C), 27.1(C); ¹H NMR (400 MHz,

d₂-tetrachloroethane, TZ360 K), rotamers, d 7.39–7.35 (m,

5H, Ar), 5.67 (d, JZ5.6 Hz, 0.73H, –NCHN–), 5.56 (d, JZ

6.0 Hz, 0.27H, –NCHN–), 5.27–5.2 (m, 2H, –CH₂Ph), 4.9

(d, JZ4.3 Hz, 1H, –NH), 4.72 (s, 0.27H, –CHI), 4.46 (d,

JZ4.0 Hz, 0.73H, –CHI), 3.83–3.72 (m, 1H, –NCH₂CH₂),

3.63–3.54 (m, 1H, –NCH₂CH₂), 2.31–2.01 (m, 2H,

–NCH₂CH₂), 1.48 (br, 9H, –C(CH₃)₃); HRMS (EI) m/z

calcd for (C₁₇H₂₃IN₂O₄): 447.0703, found: 447.0791.

4.3.8. 1-tert-Butyl-2-methyl-(2S,4S,5R)-5-(allyloxy)-4-

iodo-1,2-pyrrolidenecarboxylate (2m⁰, Table 1, entry

13). (355 mg, 43%); R_fZ0.30 (7% EtOAc/93% hexane);

[a]²_D⁰ZK56.38 (cZ0.94 g/100 ml, CHCl₃); IR (ﬁlm) n

3080, 2928, 2858, 1763, 1714, 1647, 1478, 1456, 1437,

1375, 1323, 1296, 1258, 1166, 1122, 1053, 1011, 927, 904,

861, 843, 814, 772, 749, 700, 667 cm^K^{1 1}H NMR

;

(400 MHz, CDCl₃), rotamers, d 5.89–5.85 (m, 1H,

–CH]CH₂), 5.58 (s, 0.5H, –NCHO), 5.36 (s, 0.5H,

–NCHO), 5.29 (s, 0.5H, –CH]CH₂), 5.25 (s, 0.5H,

–CH]CH₂), 5.18 (1H, dd, JZ9.8, 5.5 Hz, –CH]CH₂),

4.52 (d, JZ9.7 Hz, 0.5H, –NCHCO₂CH₃), 4.43 (d, JZ

9.7 Hz, 0.5H, –NCHCO₂CH₃), 4.20–4.05 (m, 3H, –OCH₂

and –CHI), 3.74 (s, 3H, –OCH₃), 3.09–3.02 (m, 1H,

–NCHCH₂), 2.48 (dd, JZ15.0, 6.1 Hz, 1H, –NCHCH₂),

1.49 (s, 4.5H, –C(CH₃)₃), 1.42 (s, 4.5H, –C(CH₃)₃); ¹³C

NMR (100 MHz, CDCl₃), rotamers, d 172.0, 171.4, 153.3,

134.4, 134.0, 117.7, 117.6, 116.5, 96.5, 96.3, 81.2, 81.0,

71.1, 70.6, 58.6, 58.1, 52.3, 52.1, 38.4, 37.2, 31.88, 29.6,

29.3, 28.3, 28.1, 22.6, 22.1, 20.7, 14.1; DEPT (100 MHz,

CDCl₃), rotamers, d d 134.4(C), 134.0(C), 117.7(K),

96.5(C), 96.3(C), 71.1(K), 70.6(K), 58.6(C), 58.1(C),

52.3(C), 52.1(C), 38.4(K), 37.2(K), 29.6(K), 29.3(K),

28.3(C), 28.1(C), 22.1(C), 20.7(C).

4.4.2. Benzyl 2-[(benzyloxycarbonyl)amino]-3-iodo-1-

pyrrolidinecarboxylate (3b, Table 2, entry 2). Prepared

following method C using 1a (340 mg, 1.67 mmol), benzyl

carbamate (504 mg, 3.34 mmol) and iodine (509 mg,

2.0 mmol) to yield the iodocarbamate derivative which

was puriﬁed by ﬂash chromatography (SiO₂, 1:4:4,

EtOAc:Hex:CHCl₃), followed by preparative thin layer

chromatography (40% EtOAc/60% hexane) affording a

trans/cis mixture (77/23) of 3b (569 mg, 71%) as an orange

foam; R_fZ0.5 (30% EtOAc/70% hexane); IR (ﬁlm) n 3304,

3062, 3032, 2953, 2893, 1693, 1586, 1518, 1454, 1410,

1351, 1279, 1244, 1205, 1177, 1116, 1045, 1027, 976, 914,

1

870, 772, 736, 697 cm^K1; H NMR (400 MHz, CDCl₃),

rotamers, d 7.26–7.19 (m, 10H, Ar), 5.66 (d, JZ6.6 Hz,

0.45H, –NCHN–), 5.64 (s, 0.55H, –NCHN–), 5.33 (br,

0.45H, –NH), 5.29 (br, 0.55H, NH), 5.09–5.47 (m, 4H, 2!–

CH₂Ph), 4.39 (br, 0.45H, –CHI), 4.28 (br, 0.55H, –CHI),

3.66–3.59 (m, 1H, –NCH₂CH₂), 3.51–3.41 (m, 1H,

–NCH₂CH₂), 2.30–2.20 (m, 1H, –NCH₂CH₂), 2.07 (dd,

JZ13.9, 5.6 Hz, 1H, –NCH₂CH₂); ¹³C NMR (100 MHz,

CDCl₃), rotamers, d 154.5, 154.3, 136.2, 136.0, 128.6,

128.3, 128.0, 127.9, 127.6, 75.7, 74.9, 67.3, 67.0, 45.4, 34.1,

33.1, 27.2. 26.3; DEPT (100 MHz, CDCl₃), rotamers, d

128.6(C), 128.3(C), 128.3(C), 128.0(C) 127.9(C),

127.6(C), 75.7(C), 74.8(C), 67.3(K), 67.0(K), 45.4(K),

34.1(K), 33.1(K), 27.2(C), 26.3(C).

4.4. Method C. General procedure for iodocarbamation

A solution of I₂(1.2 mequiv) in dry THF was added

dropwise to a stirred solution of the N-[(benzyloxy)car-

bonyl]-2-pyrrolidine 1a (1.0 mequiv) and the corresponding

carbamate (1 or 2 mequiv) in dry THF at K78 8C and under

nitrogen. The resulting mixture was stirred for 10 min and

then water and dichloromethane were added. The organic

phase was separated and the aqueous phase washed with

dichloromethane. The combined organic layers were

M. Norton Matos et al. / Tetrahedron 61 (2005) 1221–1244

1233

4.4.3. Benzyl-3-iodo-2-[(methoxycarbonyl)amino]-1-

pyrrolidinecarboxylate (3c, Table 2, entry 3). Prepared

following method C using 1a (3.41 g, 16.8 mmol), methyl

carbamate (2.6 g, 33.6 mmol) and iodine (5.12 g,

20.2 mmol) to yield the iodocarbamate derivative which

was puriﬁed by ﬂash chromatography (SiO₂, 40% EtOAc/

60% hexane). The excess carbamate was further removed

washing with Et₂O/hexane (20%/80%) to affording a trans/

cis mixture (73/27) of 3c (4.76 g, 70%) as an orange foam;

R_fZ0.26 (30% EtOAc/70% hexane); IR (ﬁlm) n 3301, 2954,

2885, 1703, 1699, 1694, 1683, 1520, 1418, 1353, 1250,

39.2, 29.6, 28.2, 21.2; DEPT (100 MHz, CDCl₃), rotamers,

d 128.3(C), 127.8(C), 127.6(C), 80.7(K), 67.4(K),

65.1(C), 39.2(K), 29.6(C), 28.2(C), 21.2(K); HRMS

(EI) m/z calcd for (C₁₈H₂₅IN₂O₄CH^C): 461.0859, found:

461.0937.

4.5. Method D. General procedure for radical

cyclizations

Iodoether derivative 2 (1.0 mequiv) in dry t-BuOH was

added dropwise to a stirred mixture of NaCNBH₃

(1.2 mequiv), Bu₃SnH (0.05 mequiv) and AIBN

(0.1 mequiv) in dry t-BuOH under nitrogen at 80 8C. After

reﬂuxing for 14 h the mixture was cooled to rt. Three

portions of benzene were added and the azeotropic mixture

was removed under reduced pressure. The residue was taken

up in dichloromethane and ﬁltered through celite. The

solvent was removed in vacuo to yield the bicyclic

derivative 4, which was puriﬁed by ﬂash column

chromatography.

1

1179, 1114.6, 1044, 772, 697 cm^K1; H NMR (400 MHz,

CDCl₃), rotamers, d 7.37–7.28 (m, 5H, Ar), 5.73–5.67 (m,

1H, –NCHN–), 5.58 (br, 1H, –NH), 5.21–5.10 (m, 2H,

–CH₂Ph), 4.46 (br, 0.27H, –CHI), 4.34 (br, 0.73H, –CHI),

3.75–3.54 (m, 5H, –NCH₂and –OCH₃), 2.43–2.37 (m, 1H,

–NCH₂CH₂), 2.35–2.14 (m, 1H, –NCH₂CH₂); ¹³C NMR

(100 MHz, CDCl₃), rotamers, d 155.3, 154.5, 136.4, 128.7,

128.4, 128.3, 128.1, 127.9, 76.0, 75.1, 67.6, 52.5, 45.6, 34.5,

33.4, 27.2, 26.1; HRMS (EI) m/z calcd for (C₁₄H₁₇IN₂O₄C

H^C) requires: 405.0311, found: 405.0314.

4.5.1. Benzyl-3-methylenehexahydro-6H-furo[2,3-b]pyr-

role-6-carboxylate (4a, Table 3, entry 1). Prepared

following method D using 2a (400 mg, 1.04 mmol),

NaCNBH₃(82 mg, 1.25 mmol), Bu₃SnH (15 ml,

0.05 mmol) and AIBN (17.4 mg, 0.104 mmol) to yield the

bicyclic derivative which was puriﬁed by ﬂash column

chromatography (SiO₂, 20% EtOAc/80% hexane) affording

4a (192 mg, 71%) as a colorless oil; R_fZ0.36 (20% EtOAc/

80% hexane); IR (ﬁlm) n 2953, 1710, 1411, 1356, 1272,

4.4.4. Benzyl-3-iodo-2-{[(4-methylphenyl)sulfonyl]-

amino}-1-pyrrolidinecarboxylate (3d, Table 2, entry 4).

Prepared following method C using 1a (335 mg,

1.65 mmol), 4-methylbenzenesulfonamide (TsNH₂;

565 mg, 3.3 mmol) and iodine (503 mg, 1.98 mmol) to

yield the iodocarbamate derivative which was puriﬁed by

ﬂash chromatography (SiO₂, 40% EtOAc/60% hexane)

affording a trans/cis mixture (69/31) of 3d (258 mg, 32%) as

a white solid which decomposed within a few days at 4 8C;

R_fZ0.26 (30% EtOAc/70% hexane); IR (ﬁlm) n 3250, 1701,

1698, 1597, 1496, 1410, 1337, 1278, 1161, 1118, 1094,

1

1171, 1114, 1058, 1025, 888, 770, 698 cm^K1; H NMR

(200 MHz, CDCl₃), rotamers, d 7.36–7.24 (m, 5H, Ar),

5.89–5.84 (m, 1H, –NCHO), 5.26–5.02 (m, 4H, –CH₂Ph and

–C]CH₂), 4.4 (s, 2H, –OCH₂), 3.68–3.63 (m, 1H, –NCH₂),

3.42–3.29 (m, 2H, –CH₂CH and –NCH₂), 2.07–1.84 (m, 2H,

–NCH₂CH₂); ¹³C NMR (100 MHz, CDCl₃), rotamers, d

154.4, 154.2, 149.5, 136.5, 136.3, 128.2, 127.7, 127.6,

127.5, 105.4, 92.8, 92.2, 70.9, 66.7, 47.3, 46.4, 45.4, 45.2,

30.8, 30.4; HRMS (EI) m/z calcd for (C₁₅H₁₇NO^C₃):

259.1208, found: 259.1195.

1

1038, 916, 814, 771, 733, 697, 667, 576, 542 cm^K1; H

NMR (400 MHz, CDCl₃), rotamers, d 7.79 (d, JZ8.2 Hz,

2H, Ar), 7.66 (d, JZ7.7 Hz, 1H, Ar), 7.32–7.10 (m, 7H, Ar),

5.67–5.65 (m, 1H, –NCHN–), 5.23–4.97 (m, 2H, –CH₂Ph),

4.69 (br, 0.31H, –CHI), 4.66 (br, 1H, –NH), 4.50 (d, JZ

4.4 Hz, 0.69H, –CHI), 3.64–3.46 (m, 2H, –NCH₂), 2.57–

2.29 (m, 1H, –NCH₂CH₂), 2.41 (s, 2.07H, Ar-CH₃), 2.34 (s,

0.93H, Ar-CH₃), 2.10 (dd, JZ14.4, 5.6 Hz 1H,

–NCH₂CH₂); ¹³C NMR (100 MHz, CDCl₃), rotamers, d

154.1, 144.3, 143.7, 139.4, 136.5, 136.2, 130.0, 129.9,

128.7, 128.4, 128.3, 127.9, 127.7, 127.6, 127.4, 126.6, 67.7,

67.4, 45.5, 34.0, 32.7, 28.0, 26.4, 21.8, 21.7.

4.5.2. Benzyl-4-methylene hexahydropyrano[2,3-b]pyr-

role-7(2H)-carboxylate (4b, Table 3, entry 2). Prepared

following method D using 2b (261 mg, 0.65 mmol),

NaCNBH₃(52 mg, 0.78 mmol), Bu₃SnH (9 ml,

0.033 mmol) and AIBN (10 mg, 0.065 mmol) to yield the

bicyclic derivative which was puriﬁed by ﬂash column

chromatography (SiO₂, 10% EtOAc/90% hexane) affording

4b (83 mg, 46%) as a colorless oil; R_fZ0.53 (20% EtOAc/

80% hexane); IR (ﬁlm) n 3067, 3033, 2954, 1713, 1651,

1498, 1450, 1415, 1354, 1285, 1271, 1256, 1235, 1178,

4.4.5. Benzyl-2-[(tert-butoxycarbonyl)amino]-3-iodo-1-

piperidinecarboxylate (3e, Table 2, entry 5). Prepared

following method C using benzyl 3,4-dihydro-1(2H)-

pyridinecarboxylate 1d (166 mg, 0.77 mmol), tert-butyl-

carbamate (184 mg, 1.54 mmol) and iodine (196 mg,

0.77 mmol) to yield the iodocarbamate derivative which

was puriﬁed by ﬂash chromatography (SiO₂, 30% EtOAc/

70% hexane) affording 3e (0.57 mmol, 75%) as a colorless

oil; R_fZ0.3 (20% EtOAc/80% hexane); IR (ﬁlm) n 3485,

1

1121, 1085, 1055, 987, 922, 798, 771, 736, 698 cm^K1; H

NMR (200 MHz, CDCl₃), rotamers, d 7.37–7.25 (m 5H,

Ar), 5.29–5.26 (m, 1H, –NCHO), 5.19–5.03 (m, 2H,

–CH₂Ph), 4.88–4.84 (m, 2H, C]CH₂), 4.00–3.95 (m, 1H,

–NCH₂), 3.67–3.62 (m, 1H, –OCH₂), 3.46–3.35 (m, 2H,

–OCH₂and –NCH₂), 2.70–2.64 (m, 1H, –OCH₂CH₂), 2.46

(dt, JZ14.0, 5.6 Hz, 1H, CHC]CH₂), 2.24–2.16 (m, 1H,

–OCH₂CH₂), 2.07–2.03 (m, 1H, –NCH₂CH₂), 1.89–1.82

(m, 1H, and –NCH₂CH₂); ¹³C NMR (100 MHz, CDCl₃),

rotamers, d 154.9, 154.7, 154.3, 143.1, 137.1, 136.7, 136.4,

128.4, 128.4, 128.3, 128.0, 127.8, 127.8, 127.7, 111.7,

111.6, 110.3, 89.6, 86.7, 86.2, 67.0, 66.9, 66.5, 66.4, 65.4,

3323, 2976, 1694, 1597, 1515, 1423, 1165, 874, 734 cm^K1

;

¹H NMR (400 MHz, CDCl₃), rotamers, d 7.38–7.27 (m, 5H,

Ph), 6.02 (d, JZ6.4 Hz, 1H, –NCHN), 5.21–5.13 (m, 2H,

–CH₂Ph), 4.83 (br, 1H, –NH), 4.52 (br, 1H, –CHI), 4.07 (d,

JZ11.2 Hz, 1H, –NCH₂CH₂), 3.0 (br, 1H, –NCH₂CH₂),

2.02–1.92 (m, 4H, –NCH₂(CH₂)₂CHI–), 1.42 (s, 9H,

–C(CH₃)₃); ¹³C NMR (100 MHz, CDCl₃), rotamers, d

155.1, 136.4, 128.3, 127.8, 127.6, 80.7, 79.4, 67.4, 65.1,

1234

M. Norton Matos et al. / Tetrahedron 61 (2005) 1221–1244

65.3, 47.3, 46.5, 46.2, 45.8, 45.5, 31.5, 30.5, 29.5, 27.7,

26.8, 25.7, 24.9; HRMS (EI) m/z calcd for (C₁₆H₁₉NO^C₃):

273.1365, found: 273.1371; and the corresponding reduced

product benzyl-2-(3-butynyloxy)-1-pyrrolidinecarboxylate

(66 mg, 37%) as a colorless oil; R_fZ0.44 (20% EtOAc/

80% hexane); IR (ﬁlm) n 3296, 2955, 1714, 1640, 1506,

1456, 1404, 1382, 1288, 1180, 1102, 970, 917, 754,

14.7, 14.4; HRMS (EI) m/z calcd for (C₁₆H₁₉NO^C₃):

273.1365, found: 273.1352.

4.5.5. 6-Acetyl-3-methylenehexahydro-2H-furo[2,3-

b]pyrrole (4e, Table 3, entry 5). Prepared following

method D using 2e (1.08 g, 3.69 mmol), NaCNBH₃

(292 mg, 4.43 mmol), Bu₃SnH (50 ml, 0.18 mmol) and

AIBN (62 mg, 0.4 mmol) to yield the bicyclic derivative

which was puriﬁed by ﬂash column chromatography (SiO₂,

60% EtOAc/40% hexane) affording 4e (464 mg, 75%) as a

colorless oil; R_fZ0.19 (60% EtOAc/40% hexane); IR (ﬁlm)

n 3079, 2951, 2876, 1657, 1417, 1348, 1208, 1169, 1051,

697 cm^K^{1 1}H NMR (400 MHz, CDCl₃), rotamers, d

;

7.35–7.24 (m, 5H, Ar), 5.33 (d, JZ4.8 Hz, 0.5H,

–NCHO), 5.22 (d, JZ5.2 Hz, 0.5H, –NCHO), 5.20–5.08

(m, 2H, –CH₂Ph), 3.75–3.67 (m, 1H, –NCH₂), 3.58–3.48

(m, 2H, –OCH₂), 3.40–3.33 (m, 1H, –NCH₂), 2.43 (tt, JZ

6.8, 2.4 Hz, 1H, –CH₂–C^CH), 2.40 (dt, JZ6.8, 4.4 Hz,

1H, –CH₂–C^CH), 2.30–2.08 (m, 1H, –C^CH), 2.07–

1.73 (m, 4H, –NCH₂CH₂and –NCH₂CH₂CH₂); ¹³C NMR

(100 MHz, CDCl₃), rotamers, d, 155.7, 154.7, 136.6, 136.3,

128.5, 128.2, 128.1, 128.0, 127.8, 87.9, 87.3, 87.5, 81.5,

81.2, 69.2, 69.0, 67.2, 66.9, 66.3, 65.8, 46.0, 45.8, 32.9,

32.4, 22.6, 21.7, 20.0, 19.8.

1

972, 895 cm^K1; H NMR (400 MHz, CDCl₃), rotamers, d

5.78 (d, JZ6.0 Hz, 0.15H, –NCHO), 5.55 (d, JZ5.6 Hz,

0.85H, –NCHO), 4.89–4.83 (m, 2H, –C]CH₂), 4.21–4.18

(m, 2H, –OCH₂), 3.59–3.53 (m, 1H, –NCH₂), 3.38–3.29 (m,

0.3H, CHC]CH₂), 3.20–3.18 (m, 1H, –NCH₂), 3.11–3.04

(m, 0.7H, CHC]CH₂),1.96 (s, 2.6H, CHCH₃), 1.91–1.70

(m, 2.4H, CHCH₃and N–CH₂–CH₂); ¹³C NMR (100 MHz,

CDCl₃), rotamers, d 170.0, 169.5, 149.1, 149.8, 105.5,

105.3, 92.7, 90.9, 70.8, 70.6, 70.5, 47.6, 47.4, 46.4, 45.7,

44.1, 30.6, 29.1, 22.5, 21.3; DEPT (100 MHz, CDCl₃),

rotamers, d 105.3(K), 92.7(C), 90.9(C), 70.8(K), 70.6(K),

70.5(C), 47.6(C), 47.4(C), 46.4(C), 45.7(K), 44.1(K),

30.6(K), 29.1(K), 22.5(C), 21.3(C); HRMS (EI) m/z calcd

for (C₉H₁₃NO^C₃): 167.0946, found: 167.0945.

4.5.3. Benzyl-2-methyl-3-methylenehexahydro-6H-

furo[2,3-b]pyrrole-6-carboxylate (4c, Table 3, entry 3).

Prepared following method D using 2c (180 mg,

0.45 mmol), NaCNBH₃(35.6 mg, 0.54 mmol), Bu₃SnH

(6.2 ml, 0.023 mmol) and AIBN (8 mg, 0.05 mmol) to

yield the bicyclic derivative which was puriﬁed by ﬂash

column chromatography (SiO₂, 10% EtOAc/90% hexane)

affording 4c (75 mg, 61%) as a colorless oil; R_fZ0.63 (20%

EtOAc/80% hexane); IR (ﬁlm) n 2974, 2875, 1716, 1447,

1418, 1356, 1322, 1274, 1208, 1176, 1112, 1073, 1001, 900,

4.5.6. 6-tert-Butyl 5-methyl (3aR,5S,6aS)-3-methylene-

hexahydro-6H-furo[2,3-b]pyrrole-5,6-dicarboxylate (4g,

Table 3, entry 6) and 6-tert-butyl 5-methyl (3aS,5S,6aR)-

3-methylenehexahydro-6H-furo[2,3-b]pyrrole-5,6-dicar-

boxylate (4g⁰, Table 3, entry 6). Prepared following

method D using a mixture of diastereomers 2g⁰(240 mg,

0.59 mmol), NaCNBH₃(46 mg, 0.71 mmol), Bu₃SnH (8 ml,

0.03 mmol) and AIBN (10 mg, 0.06 mmol) to yield the two

bicyclic diastereomers. Puriﬁcation by ﬂash chromato-

graphy (SiO₂, 10% EtOAc/90% hexane) afforded the two

diastereomers 4g and 4g⁰(101 mg, 61%) as a colorless oil.

771, 737, 698 cm^K1

;

¹H NMR (200 MHz, CDCl₃),

rotamers, d 7.39–7.24 (m, 5H, Ar), 5.88–5.72 (m, 1H,

–NCHO), 5.32–5.28 (m, 1H, –C]CH₂), 5.26–4.91 (m, 3H,

–CH₂Ph and C]CH₂), 4.55–4.52 (m, 1H, –OCH), 3.72–

3.55 (1H, m, –NCH₂), 3.43–3.29 (m, 3H, –NCH₂and

CHC]CH₂), 2.11–2.02 (m, 1H, –NCH₂CH₂), 1.89–1.80

(m, 1H, –NCH₂CH₂), 1.33–1.28 (m, 3H, –CHCH₃); ¹³C

NMR (100 MHz, CDCl₃), rotamers, d 154.8, 154.6, 154.4,

154.3, 154.2, 136.8, 136.4, 128.3, 128.0, 127.8, 105.7,

105.4, 105.2, 91.0, 90.5, 90.4, 77.9, 77.8, 76.4, 66.9, 66.8,

48.0, 47.1, 47.0, 45.6, 45.3, 45.1, 45.0, 31.8, 31.5, 30.8,

30.0, 20.9, 20.6, 19.9, 19.8; HRMS (EI) m/z calcd for

(C₁₆H₁₉NO^C₃): 273.1365, found: 273.1354.

4.5.7. 6-tert-Butyl 5-methyl (3aR,5S,6aS)-3-methylene-

hexahydro-6H-furo[2,3-b]pyrrole-5,6-dicarboxylate (4g,

Table 3, entry 6). (46 mg, 46%); R_fZ0.3 (20%EtOAc/80%

hexane); [a]²_D⁰ZK112.54 (CDCl₃, cZ1.18 g/100 ml); IR

(ﬁlm) n 2976, 1749, 1706, 1477, 1455, 1436, 1392, 1366,

1301, 1257, 1204, 1366, 1301, 1257, 1204, 1163, 1132,

1063, 1044, 1022, 980, 917, 856, 778, 667 cm^K1; ¹H NMR

(400 MHz, CDCl₃), rotamers, d 5.79 (d, JZ5.4 Hz, 0.6H,

–NCHO), 5.60 (d, JZ5.2 Hz, 0.4H, –NCHO), 4.93 (s, 1H,

–C]CH₂), 4.87 (s, 1H, –C]CH₂), 4.47–4.44 (m, 1H,

NCHCO₂CH₃), 4.37–4.25 (m, 2H, –OCH₂), 3.65 (s, 3H,

CO₂CH₃), 3.25 (br, 1H, –CHC]CH₂), 2.15–2.10 (m, 2H,

–NCHCH₂), 1.41 (s, 4H, –C(CH₃)₃), 1.33 (s, 5H,

–C(CH₃)₃); ¹³C NMR (100 MHz, CDCl₃), rotamers, d

172.8, 172.6, 153.9, 153.3, 148.6, 148.5, 106.0, 93.2, 93.9,

81.1, 81.0, 70.6, 70.4, 60.8, 60.4, 52.2, 52.1, 46.8, 45.8,

34.6, 33.9, 28.2, 28.1; DEPT (100 MHz, CDCl₃), rotamers,

d 106.0(K), 93.2(C), 93.9(C), 70.6(K), 70.4(K), 60.8(C),

60.4(C), 52.2(C), 52.1(C), 46.8(C), 45.8(C), 34.6(K),

33.9(K), 28.2(C), 28.1(C).

4.5.4. Benzyl-(3Z)-ethylidinehexahydro-6H-furo[2,3-

b]pyrrole-6-carboxylate (4d, Table 3, entry 4). Prepared

following method D using 2d (140 mg, 0.35 mmol),

NaCNBH₃(63 mg, 0.42 mmol), Bu₃SnH (5 ml,

0.02 mmol) and AIBN (7 mg, 0.04 mmol) to yield the

bicyclic derivative which was puriﬁed by ﬂash column

chromatography (SiO₂, 20% EtOAc/80% hexane) affording

4d (69.0 mg, 74%) as a colorless oil; R_fZ0.31 (20% EtOAc/

80% hexane); IR (ﬁlm) n 2952, 1715, 1498, 1411, 1352,

1272, 1170, 1115, 882, 771, 698 cm^K1

;

¹H NMR

(200 MHz, CDCl₃), rotamers, d 7.37–7.26 (m, 5H, Ar),

5.88–5.85 (m, 1H, –NCHO), 5.44–5.01 (m, 3H, –CH₂Ph and

–C]CHCH₃), 4.44–4.31 (m, 2H, –OCH₂), 3.66–3.27 (m,

3H, –NCH₂and CHC]CHCH₃), 2.10–1.80 (m, 2H,

NCH₂CH₂), 1.64 (d, 1.5H, ]CHCH₃), 1.59 (dd, JZ5.4,

1.8 Hz, 1.5H, ]CHCH₃); ¹³C NMR (100 MHz, CDCl₃),

rotamers, d 154.5, 140.9, 136.8, 128.3, 127.9, 127.7, 116.2,

115.6, 110.3, 93.0, 92.8, 92.4, 92.2, 71.1, 68.9, 66.9, 66.8,

47.3, 46.4, 45.5, 45.3, 44.4, 43.5, 31.3, 30.9, 29.9, 29.4,

4.5.8. 6-tert-Butyl 5-methyl (3aS,5S,6aR)-3-methylene-

hexahydro-6H-furo[2,3-b]pyrrole-5,6-dicarboxylate

(4g⁰, Table 3, entry 6). (55 mg, 54%); R_fZ0.3 (20%

M. Norton Matos et al. / Tetrahedron 61 (2005) 1221–1244

1235

EtOAc/80% hexane); [a]²_D⁰ZC106.06 (CDCl₃, cZ

0.664 g/100 ml); IR (ﬁlm) n 2953, 1755, 1706, 1456,

1436, 1392, 1366, 1280, 1257, 1164, 1122, 1069, 1053,

–NCHO, –CH₂Ph), 3.92–3.30 (m, 4H, –OCH₂and –NCH₂),

2.14–1.58 (m, 5H, –CHCHCH₃, –NCH₂CH₂and

–OCH₂CH₂), 1.48–1.30 (m, 1H, CHCHCH₃), 1.19–1.14

1

1034, 1008, 981, 937, 918, 890, 847, 808, 773, 668 cm^K1

;

(m, 2H, CHCH₃), 0.96–0.90 (m, 1H, CHCH₃); H NMR

¹H NMR (400 MHz, CDCl₃), rotamers, d 5.81 (d, JZ

5.2 Hz, 0.5H, –NCHO), 5.74 (d, JZ4.9 Hz, 0.5H, –NCHO),

4.91 (d, JZ0.9 Hz, 1H, –C]CH₂), 4.87 (d, JZ1.9 Hz, 1H,

C]CH₂), 4.53 (d, JZ1.5 Hz, 0.5H, –NCHCO₂CH₃), 4.49

(d, JZ1.3 Hz, 0.5H, –NCHCO₂CH₃), 4.39–4.25 (m, 2H,

–OCH₂), 3.58 (s, 3H, –CO₂CH₃), 3.18 (br, 1H,

–CHC]CH₂), 2.41–2.37 (m, 1H, –NCHCH₂), 2.13–2.10

(br, 1H, –NCHCH₂), 1.41 (s, 4.5H, –C(CH₃)₃), 1.34 (s,

4.5H, –C(CH₃)₃); ¹³C NMR (100 MHz, CDCl₃), rotamers, d

154.0, 149.9, 105.8, 93.7, 80.8, 70.9, 59.3, 58.7, 52.0, 46.9,

46.0, 34.4, 34.0, 29.7, 28.2.

(400 MHz, d₂-tetracloroethane, TZ385 K) d 7.40–7.31 (m,

5H, Ar), 5.27 (d, JZ4.0 Hz, 0.6H, –NCHO), 5.20 (br, 2H,

–CH₂Ph), 5.12 (d, JZ2.2 Hz, 0.4H, –NCHO), 3.89–3.86

(m, 4H, –OCH₂and –NCH₂), 2.14–1.79 (m, 4H,

–CHCHCH₃, –NCH₂CH₂and –CHCHCH₃), 1.50–1.22 (m,

2H, –OCH₂CH₂), 1.20 (d, JZ7.2 Hz, 1.8H, –CHCH₃), 1.02

(d, JZ6.4 Hz, 1.2H, –CHCH₃); ¹³C NMR (100 MHz,

CDCl₃), rotamers, d 154.8, 154.4, 136.8, 136.5, 128.4,

128.3, 127.9, 127.8, 127.7, 85.8, 85.38, 82.9, 82.5, 66.8,

66.7, 65.3, 65.2, 60.5, 45.4, 45.2, 45.0, 44.8, 44.1, 43.3,

29.6, 29.5, 29.1, 28.5, 28.4, 27.4, 27.0, 26.6, 25.8, 21.3,

20.4, 20.04, 19.3, 16.4, 13.5; HRMS (EI) m/z calcd for

(C₁₆H₂₁NO^C₃): 275.1521, found: 275.1521; and the corre-

sponding reduced product benzyl-2-(3-butenyloxy)-1-pyr-

rolidinecarboxylate (13 mg, 6%) as a colorless oil; R_fZ0.37

4.5.9. Benzyl-3-methylhexahydro-6H-furo[2,3-b]pyr-

role-6-carboxylate (4h, Table 3, entry 7). Prepared

following method D using 2h (162 mg, 0.42 mmol),

NaCNBH₃(36 mg, 0.50 mmol), Bu₃SnH (7 ml,

0.02 mmol) and AIBN (8 mg, 0.05 mmol) to yield the

bicyclic derivative which was puriﬁed by ﬂash column

chromatography (SiO₂, 10% EtOAc/90% hexane) affording

a mixture of isomers endo/exo (95:5) 4h (88 mg, 92%) as a

white solid; mp: 42–44 8C; R_fZ0.45 (20% EtOAc/80%

hexane); IR (ﬁlm) n 2960, 2877, 1712, 1497, 1455, 1409,

1353, 1309, 1258, 1213, 185, 1118, 1096, 1050, 1006, 907,

1

(10% EtOAc/90% hexane); H NMR (200 MHz, CDCl₃),

rotamers, d 7.39–7.26 (m, 5H, Ar), 5.75 (br, 1H, CH₂-

CH]CH₂), 5.14 (br, 5H, –NCHO, –CH₂Ph and CH₂-

CH]CH₂), 3.53–3.43 (m, 4H, –NCH₂and –OCH₂), 2.4–

1.62 (m, 4H, NCH₂CH₂and CH₂CH]CH₂); and benzyl-1-

pyrrolidinecarboxylate (30 mg, 20%) as a colorless oil; R_fZ

0.24 (10% EtOAc/90% hexane); ¹H NMR (200 MHz,

CDCl₃), rotamers, d 7.36–7.15 (m, 5H, Ar), 5.14 (s, 2H,

–CH₂Ph), 3.42–3.35 (m, 4H, –N(CH₂)₂), 1.86–1.79 (m, 4H,

–N(CH₂CH₂)₂).

677, 773, 737, 698, 512 cm^K^{1 1}H NMR (400 MHz,

;

CDCl₃), rotamers, d 7.37–7.23 (m, 5H, Ar), 5.74 (d, JZ

4.8 Hz, 0.5H, –NCHO), 5.68 (d, JZ5.2 Hz, 0.5H, –NCHO),

5.30–5.24 (m, 0.6H, –CH₂Ph), 5.12–5.04 (m, 1.4H,

–CH₂Ph), 3.92–3.88 (t, JZ7.5 Hz, 1H, –OCH₂), 3.54–3.37

(m, 3H, –OCH₂and –NCH₂), 2.76–2.72 (m, 1H,

CHCHCH₃), 2.41–2.39 (m, 1H, CHCHCH₃), 1.98–1.72

(m, 2H, NCH₂CH₂), 1.02 (d, JZ6.8 Hz, 0.15H, CHCH₃),

4.5.11. Benzyl-3-benzylhexahydro-6H-furo[2,3-b]pyr-

role-6-carboxylate (4j, Table 3; entry 9). Prepared

following method D using 2j (1.06 g, 2.23 mmol),

NaCNBH₃(181 mg, 2.75 mmol), Bu₃SnH (31 ml,

0.11 mmol) and AIBN (46 mg, 0.02 mmol) to yield the

bicyclic derivative which was puriﬁed by ﬂash column

chromatography (SiO₂, dichloromethane) affording a mix-

ture of isomers endo/exo-4j (74:26) (510 mg, 66%) as a

colorless oil; R_fZ0.16 (dichloromethane); IR (ﬁlm) n 2941,

2875, 1712, 1602, 1500, 1454, 1410, 1353, 1278, 1213,

1

0.96 (d, JZ6.8 Hz, 2.85H, CHCH₃); H NMR (400 MHz,

d₂-tetrachloroethane, TZ350 K) d 7.42–7.35 (m, 5H, Ar),

5.78 (d, JZ5.4 Hz, 1H, –NCHO), 5.26–5.17 (m, 2H,

–CH₂Ph), 3.95 (t, JZ7.8 Hz, 1H, –OCH₂), 3.55 (t, JZ

7.8 Hz, 2H, –NCH₂), 3.45 (t, JZ9.6 Hz, 1H, –OCH₂), 2.83–

2.76 (m, 1H, CHCHCH₃), 2.52–2.40 (m, 1H, CHCHCH₃),

1.96–1.72 (m, 2H, NCH₂CH₂), 1.11 (d, JZ6.8 Hz, 0.15H,

CHCH₃), 1.05 (d, JZ6.8 Hz, 2.85H, CHCH₃); ¹³C NMR

(100 MHz, CDCl₃), rotamers, d 154.5, 136.6, 128.3, 127.7,

93.1, 92.4, 72.5, 66.8, 47.2, 46.9, 46.7, 45.7, 35.6, 23.2,

22.4, 10.9; DEPT (100 MHz, CDCl₃), rotamers, d 128.3(C),

127.7(C), 93.1(C), 92.4(C), 72.5(K), 66.8(K), 47.2(K),

46.9(K), 46.7(C), 45.7(C), 35.6(C), 23.2(K), 22.4(K),

10.9(C); HRMS (EI) m/z calcd for (C₁₅H₁₉NO₃): 261.1365,

found: 261.1372.

1

1187, 1091, 1038, 1006, 917, 748, 600 cm^K1; H NMR

(400 MHz, CDCl₃), rotamers, d 7.37–7.16 (m, 10H, Ar),

5.75–5.70 (m, 1H, –NCHO), 5.32–5.08 (m, 2H,

–(C]O)CH₂Ph), 3.92–3.90 (m, 1H, –OCH₂), 3.67–3.62

(m, 2H, –NCH₂), 3.48–3.43 (m, 1H, –OCH₂), 2.72–2.66 (m,

4H, CHCHCH₂Ph, CHCHCH₂Ph and CHCH₂Ph), 1.99–

1

1.83 (m, 2H, –NCH₂CH₂); H NMR (400 MHz, toluene,

TZ370 K) d 7.38–6.93 (m, 10H, Ar), 5.78 (d, JZ5.8 Hz,

0.24H, –NCHO), 5.71 (d, JZ5.04 Hz, 0.76H, –NCHO),

5.17 (s, 2H, –(C]O)CH₂Ph), 3.78–3.71 (m, 1H, –OCH₂),

3.51–3.29 (m, 3H, –OCH₂and –NCH₂), 2.48–2.32 (m,

3.52H, –CHCH₂Ph, CHCHCH₂Ph and CHCHCH₂Ph),

2.27–2.23 (m, 0.24H, CHCHCH₂Ph), 2.02–1.99 (m,

0.24H, CHCHCH₂Ph), 1.72–1.63 (m, 0.76H, CH₂CH₂N),

1.62–1.57 (m, 0.24H, –NCH₂CH₂), 1.51–1.39 (m, 0.76H,

NCH₂CH₂), 1.32–1.27 (m, 0.24H, NCH₂CH₂); ¹³C NMR

(100 MHz, CDCl₃), rotamers, d 155.0, 154.5, 139.8, 139.6,

128.7, 128.5, 128.4, 128.2, 127.9, 127.8, 126.2, 93.1, 92.4,

71.7, 71.0, 66.9, 47.2, 46.9, 45.6, 44.6, 43.3, 33.2, 23.3,

22.5; DEPT (100 MHz, CDCl₃), rotamers, d 128.7(C),

128.5(C), 128.4,(C) 128.2(C),127.9(C), 127.8(C),

126.2(C), 93.1(C), 92.4(C), 71.7(K), 71.0(K), 66.9 (K),

47.2(K), 46.9(K), 45.6(C), 44.6(C), 43.3(C), 33.2(K),

4.5.10. Benzyl-4-methylhexahydropyrano[2,3-b]pyrrole-

7(2H)carboxylate (4i, Table 3, entry 8). Prepared follow-

ing method D using 2i (302 mg, 0.75 mmol), NaCNBH₃

(59 mg, 0.9 mmol), SnBu₃H (10 ml, 0.04 mmol) and AIBN

(12 mg, 0.07 mmol) to yield the bicyclic derivative 4i which

was puriﬁed by ﬂash column chromatography (SiO₂, 10%

EtOAc/90% hexane) affording a mixture of endo/exo

isomers (40:60) (63 mg, 30%) as a colorless oil; R_fZ0.16

(10% EtOAc/90% hexane); IR (ﬁlm) n 2954, 1712, 1453,

1411, 1352, 1271, 1213, 1185, 1116, 1077, 991, 971, 920,

771, 751, 698 cm^K^{1 1}H NMR (400 MHz, CDCl₃),

;

rotamers, d 7.35–7.26 (m, 5H, Ar), 5.30–5.03 (m, 3H,

1236

M. Norton Matos et al. / Tetrahedron 61 (2005) 1221–1244

23.3(K), 22.5(K); HRMS (EI) m/z calcd for (C₂₁H₂₃NO^C₃):

337.1678, found: 337.1696.

71.7(K), 60.7(C), 60.4(C), 52.0(C), 46.4(C), 45.5(C),

35.9(C), 28.2(C), 27.1(K), 18.7(C), 10.6(C).

4.5.14. 6-tert-Butyl-5-methyl-(3aS,5S,6aR)-3-methyl-

hexahydro-6H-furo[2,3-b]pyrrole-5,6-dicarboxylate

(4m⁰, Table 3, entry 12). Prepared following method D

using 2m⁰(323 mg, 0.79 mmol), NaCNBH₃(62 mg,

0.95 mmol), Bu₃SnH (11 ml, 0.04 mmol) and AIBN

(13 mg, 0.08 mmol) to yield the bicyclic derivative 4m⁰

which was puriﬁed by ﬂash chromatography (SiO₂, 40%

EtOAc/60%hexane) affording a mixture of the isomers

endo/exo (95:5) (170 mg, 76%) as a colorless oil; R_fZ0.5

(40% EtOAc/60% hexane); [a]²_D⁰ZK113.33 (cZ

1.043 g/100 ml, CHCl₃); IR (ﬁlm) n 2973, 1748, 1704,

1478, 1456, 1436, 1391, 1365, 1312, 1257, 1204, 1169,

1134, 1091, 1050, 1023, 1004, 983, 930, 877, 857, 781,

4.5.12. Benzyl-3-(2-ethoxy-2-oxoethyl)hexahydro-6H-

furo[2,3-b]pyrrole-6-carboxylate (4k, Table 3, entry

10). Prepared following method D using 2k (207 mg,

0.45 mmol), NaCNBH₃(36 mg, 0.54 mmol), Bu₃SnH (6 ml,

0.02 mmol) and AIBN (7 mg, 0.04 mmol) to yield the

bicyclic derivative which was puriﬁed by ﬂash column

chromatography (SiO₂, 30% EtOAc/70% hexane) affording

a mixture of isomers endo/exo (80:20) 4k (123 mg, 82%) as

a colorless oil; R_fZ0.32 (30% EtOAc/70% hexane); IR

(ﬁlm) n 2978, 1737, 1713, 1497, 1455, 1414, 1356, 1259,

1101, 1122, 1092, 1042, 1006, 920, 773, 736, 699 cm^K1; ¹H

NMR (400 MHz, CDCl₃), rotamers d 7.34–7.24 (m, 5H,

Ar), 5.73–5.68 (m, 1H, –NCHO), 5.27–5.04 (m, 2H, –CH₂-

Ph), 4.10 (dq, JZ7.7, 1.8 Hz, 2H, –OCH₂CH₃), 4.01 (t, JZ

7.9 Hz, 1H, –OCH₂), 3.57–3.40 (m, 3H, –OCH₂and

–NCH₂), 2.90–2.88 (m, 0.8H, CHCHCH₂), 2.72 (br, 0.8H,

CHCHCH₂), 2.54 (br, 0.2H, CHCHCH₃), 2.41–2.30 (m, 2H,

CHCH₂(C]O)), 2.05–1.20 (m, 0.2H, CHCHCH₂), 1.86–

1.73 (m, 2H, –NCH₂CH₂), 1.22 (d, JZ7.2 Hz, 3H,

1

666 cm^K1; H NMR (200 MHz, CDCl₃), rotamers, d 5.61

(d, JZ5.4 Hz, 0.5H, –NCHO–), 5.53 (d, JZ5.3 Hz, 0.5H,

–NCHO–), 4.23 (dd, JZ19.5, 9.0 Hz, 1H, –NCHCO₂CH₃),

3.70 (t, JZ7.7 Hz, 1H, –OCH₂), 3.52 (s, 3H, –OCH₃), 3.32–

3.26 (m, 1H, –OCH₂), 2.68–2.62 (m, 1H, –NCHCH), 2.29–

2.22 (m, 1H, –CHCHCH₃), 2.02–1.92 (m, 1H, –NCHCH₂),

1.68–1.63 (m, 1H, –NCHCH₂), 1.29 (s, 4.5H, –C(CH₃)₃),

0.77 (s, 4.5H, –C(CH₃)₃), 0.86 (d, JZ6.9 Hz, 0.05H,

–CHCH₃), 0.77 (d, JZ6.8 Hz, 0.95H, CHCH₃); ¹³C NMR

(100 MHz, CDCl₃), rotamers, d 173.0, 172.7, 153.6, 93.4,

93.1, 80.5, 80.3, 71.5, 60.6, 60.3, 51.9, 51.8, 45.7, 4.6, 35.5,

28.1, 27.9, 27.4, 26.6, 10.20, 10.16; DEPT (100 MHz,

CDCl₃), rotamers, d 93.4(C), 93.1(C), 71.5(K), 60.6(C),

60.3(C), 51.9 (C), 51.8(C), 45.7(C), 4.6(C), 35.5(C),

28.1(C), 27.9(C), 27.4(K), 26.6(K), 10.2(C).

1

CH₂CH₃); H NMR (400 MHz, d₂-tetrachloroethane, TZ

360 K) d 7.40–7.34 (m, 5H, Ar), 5.90 (d, JZ5.4 Hz, 1H,

–NCHO), 5.25–5.20 (m, 2H, –CH₂Ph), 4.20 (q, JZ7.1 Hz,

2H, –OCH₂CH₃), 4.05 (t, JZ7.9 Hz, 1H, –OCH₂), 3.62–

3.48 (m, 3H, –OCH₂and –NCH₂), 2.96–2.92 (m, 0.8H,

CHCHCH₃), 2.80–2.74 (m, 0.8H, CHCHCH₃), 2.57 (br,

0.2H, CHCHCH₃), 2.50–2.36 (m, 2H, CHCH₂(C]O)),

2.20–2.06 (m, 0.2H, CHCHCH₃), 1.90–1.81 (m, 2H,

–NCH₂CH₂), 1.30 (d, JZ7.1 Hz, 3H, CH₂CH₃); ¹³C NMR

(100 MHz, CDCl₃), rotamers, d 171.8, 171.7, 154.8, 154.4,

136.5, 136.3, 128.4, 128.4, 128.32, 128.3, 128.2, 128.2,

128.1, 127.8, 92.8, 92.1, 91.4, 71.8, 70.5, 66.9, 60.6, 60.5,

48.7, 47.7, 47.1, 46.8, 45.7, 45.4, 44.4, 41.3, 37.6, 37.6,

32.0, 29.0, 28.4, 23.2, 22.6, 14.0; HRMS (EI) m/z calcd for

(C₁₈H₂₃NO^C₅): 333.1576, found: 333.1590.

4.6. Method E. General procedure for aziridination/

methanolysis

A solution of NaN(SiMe₃)₂(1.1 mequiv) in THF was added

dropwise to a stirred solution of the iodocarbamate 3 in dry

THF and dry methanol (excess) at K78 8C and under

nitrogen. The mixture was stirred for 5 min at K78 8C and

then allowed to reach rt. A saturated aqueous solution of

NaHCO₃and diethyl ether were added, the organic layer

separated and the aqueous layer extracted with diethyl ether.

The combined organic phases were dried (Na₂SO₄) and the

solvent removed in vacuo to yield the 3-carbamoyl-2-

methoxy derivative 5, which was puriﬁed by ﬂash

chromatography.

4.5.13. 6-tert-Butyl-5-methyl-(3aR,5S,6aS)-3-methyl-

hexahydro-6H-furo[2,3-b]pyrrole-5,6-dicarboxylate

(4m, Table 3, entry 11). Prepared following method D

using 2m (480 mg, 1.18 mmol), NaCNBH₃(93 mg,

1.4 mmol), Bu₃SnH (16 ml, 0.06 mmol) and AIBN (20 mg,

0.12 mmol) to yield the bicyclic derivative 4m which was

puriﬁed by ﬂash chromatography (SiO₂, 20% EtOAc/80%

hexane) affording a mixture of the endo/exo isomers (95:5)

(320 mg, 96%) as a colorless oil; R_fZ0.35 (20% EtOAc/

80% hexane); [a]²_D⁰ZC55.06 (cZ0.77 g/100 ml in

CHCl₃); IR (ﬁlm) n 2974, 2879, 1756, 1710, 1478, 1454,

1436, 1366, 1315, 1258, 1198, 1170, 1124, 1099, 1045,

4.6.1. Benzyl-3-[tert-butoxycarbonyl)amino]-2-methoxy-

1-pyrrolidinecarboxylate (5a, Table 4, entry 1). Prepared

following method E using 3a (298 mg, 0.67 mmol) and

NaN(SiMe₃)₂(0.5 M in toluene, 1.46 ml, 0.73 mmol) to

yield the crude product which was puriﬁed by ﬂash

chromatography (SiO₂, 30% EtOAc/70% hexane) affording

a cis/trans mixture (15:85) of 5a (184 mg, 82%) as a yellow

oil; R_fZ0.3 (20% EtOAc/80% hexane); IR (ﬁlme) n 3336,

2976, 1711, 1518, 1453, 1410, 1365, 1285, 1247, 1169,

1

1001, 930, 906, 882, 858, 798, 772, 733, 665 cm^K1; H

NMR (400 MHz, CDCl₃), rotamers, d 5.70 (br, 1H,

–NCHO–), 4.15–4.30 (m, 1H, –NCHCO₂CH₃), 3.87 (t,

JZ7.9 Hz, 1H, –OCH₂), 3.70 (s, 3H, –OCH₃), 3.50 (dd, JZ

11.0, 8.6 Hz, 1H, –OCH₂), 2.75 (br, 1H, –NCHCH), 2.38

(br, 1H, –CHCHCH₃), 2.13–2.05 (m, 1H, –NCHCH₂), 1.84–

1.75 (m, 1H, –NCHCH₂), 1.44 (s, 4.5H, C(CH₃)₃), 1.37 (s,

4.5H, –C(CH₃)₃), 0.93 (d, JZ7.0 Hz, 0.05H, –CHCH₃),

0.85 (d, JZ6.8 Hz, 0.95H, CHCH₃); ¹³C NMR (100 MHz,

CDCl₃), rotamers, d 172.0, 171.6, 153.4, 93.6, 92.8, 80.8,

71.7, 60.7, 60.4, 52.0, 46.4, 45.5, 35.9, 28.2, 27.1, 18.7,

10.6; DEPT (100 MHz, CDCl₃), rotamers, d 93.6(C),

1116, 1078, 1048, 1020, 973, 915, 881, 750, 698, 665 cm^K1

;

¹H NMR (400 MHz, CDCl₃), rotamers, d 7.32–7.23 (m, 5H,

Ar), 5.19–5.07 (m, 2H, –CH₂Ph), 5.02 (s, 0.5H, –NCHO),

4.95 (s, 0.5H, –NCHO), 4.85 (br, 1H, –NH), 4.10 (br, 0.3H,

–CHNHBoc), 3.98 (br, 0.7H, –CHNHBoc), 3.51–3.30 (m,

5H, –NCH₂and –OCH₃), 2.28 (br, 1H, –NCH₂CH₂), 1.76

(br, 1H, –NCH₂CH₂), 1.41 (br, 9H, –C(CH₃)₃); ¹³C NMR

M. Norton Matos et al. / Tetrahedron 61 (2005) 1221–1244

1237

(100 MHz, CDCl₃), rotamers, d 155.0, 136.3, 133.1, 130.9,

128.5, 128.1, 127.9, 93.0, 92.4, 67.2, 56.4, 55.9, 55.2, 54.4,

43.9, 43.7, 28.3, 28.2, 27.5, 18.5; DEPT (100 MHz, CDCl₃),

rotamers, d 128.5(C), 128.1(C), 127.9(C), 93.0(C),

92.4(C), 67.2(K), 56.4(C), 55.9(C), 55.2(C), 54.4(C),

43.9(K), 43.7(K), 28.3(C), 28.2(C), 27.5(K).

Water and diethyl ether were added and the organic layers

separated and washed with ice-cold water. The aqueous

layer was extracted once again with diethyl ether, the

combined organic layers dried (Na₂SO₄) and the solvent

removed in vacuo. Puriﬁcation by column chromatography

afforded the 3-azido-2-methoxy derivative 6.

4.6.2. Benzyl-3-[(benzyloxycarbonyl)amino]-2-methoxy-

1-pyrrolidinecarboxylate (5b, Table 4, entry 2). Prepared

following method E using 3b (298 mg, 0.62 mmol) and

NaN(SiMe3)₂(0.5 M in toluene, 1.49 ml, 0.74 mmol) to

yield the crude product which was puriﬁed by ﬂash column

chromatography (SiO₂, 30% EtOAc/70% hexane) affording

a cis/trans mixture (23:77) of 5b (173 mg, 73%) as a yellow

oil; R_fZ0.38 (30% EtOAc/70% hexane); IR (ﬁlm) n 3323,

3032, 2952, 1704, 1531, 1454, 1408, 1338, 1295, 1240,

4.7.1. Benzyl-3-azido 2-methoxy-1-pyrrolidinecarboxyl-

ate (6a, Scheme 1). Prepared following method F using 1a

(1.0 g, 4.93 mmol), sodium azide (480 mg, 7.4 mmol), and

CAN (5.4 g, 9.8 mmol) to yield the crude product which

was puriﬁed by ﬂash chromatography (SiO₂, 10% EtOAc/

90% hexane), affording a mixture of cis/trans-6a (30/70)

(372 mg, 27%) as a colorless oil; R_fZ0.44 (20% EtOAc/

80% hexane); IR (ﬁlm) n 3033, 2954, 2835, 2105, 1716,

1694, 1699, 1641, 1498, 1455, 1418, 1337.5, 1176, 1115,

1

1112, 1240, 1078, 968, 912, 773, 739, 697, 667 cm^K1; H

1029, 985, 931, 772, 753, 698, 605 cm^K^{1 1}H NMR

;

NMR (400 MHz, CDCl₃), rotamers, d 7.26–7.20 (m, 5H,

Ar), 5.24–4.94 (m, 5.5H, –NCHO–, NH and 2!(–CH₂Ph)),

4.59 (s, 0.5H, –NH), 4.01 (br, 0.8H, –CHNHCbz), 3.89 (br,

0.2H, –CHNHCbz), 3.44–3.23 (m, 5H, –NCH₂CH₂and

–OCH₃), 2.26–2.16 (m, 1H, –NCH₂CH₂), 1.74–1.71 (m, 1H,

–NCH₂CH₂); ¹³C NMR (100 MHz, CDCl₃), rotamers, d

155.9, 155.8, 155.2, 154.9, 141.3, 136.3, 128.5, 128.4,

128.2, 128.1, 127.9, 127.6, 127.4, 126.9, 92.9, 92.4, 86.8,

86.3, 67.5, 67.3, 67.2, 66.9, 64.9, 57.2, 56.6, 56.3, 55.8,

55.7, 55.1, 53.2, 52.5, 44.1, 43.8, 43.4, 28.5, 28.3, 27.3;

DEPT (100 MHz, CDCl₃), rotamers, d 128.5(C), 128.4(C),

128.2(C), 128.1(C), 127.9(C), 127.4(C), 126.9(C),

92.9(C), 92.4(C), 86.8(C), 86.3(C), 67.5(K), 67.3(K),

67.2(K), 66.9(K), 57.2(C), 56.6(C), 56.3(C), 55.8(C),

55.7(C), 55.1(C), 53.2(C), 52.5(C), 44.1(K), 43.8(K),

43.4(K), 28.5(K), 28.3(K), 27.3(K).

(400 MHz, CDCl₃), rotamers, d 7.36–7.29 (m, 5H, Ar),

5.25–4.89 (m, 3H, –CH₂Ph and –NCHO–), 3.93 (d, JZ

6.4 Hz, 0.7H, –CHN₃), 3.54–3.42 (m, 5.3H, –OCH₃, 0.3!–

CHN₃and –NCH₂), 2.31–2.24 (m, 1H, –NCH₂CH₂), 2.20–

1.96 (m, 1H, –NCH₂CH₂); ¹H NMR (300 MHz, d₂-

tetrachloroethane, TZ365 K), rotamers, d 7.40–7.35 (m,

5H, Ar), 5.24–5.19 (m, 2.7H, –CH₂Ph and 0.7!–NCHO–),

5.08 (br, 0.3H, –NCHO–), 3.97 (d, JZ5.1 Hz, 0.7H,

–CHN₃), 3.63–3.39 (m, 5.3H, –OCH₃, 0.3!–CHN₃and

–NCH₂), 2.36–2.00 (m, 2H, NCH₂CH₂); ¹³C NMR

(100 MHz, CDCl₃), rotamers, d 156.0, 136.6, 128.8,

128.7, 128.4, 128.3, 128.2, 128.0, 92.2, 91.6, 88.5, 88.2,

67.6, 67.4, 64.8, 64.2, 60.8, 60.2, 57.4, 56.9, 56.5, 55.9,

44.4, 44.2, 43.3, 43.2, 28.2, 27.3, 26.3, 25.3; HRMS (EI) m/z

calcd for (C₁₃H₁₆N₄O^C₃) requires: 275.1144, found:

275.1108.

4.6.3. Benzyl-2-methoxy-3-[(methoxycarbonyl)amino]-

1-pyrrolidinecarboxylate (5c, Table 4, entry 3). Prepared

following method E using 3c (4.76 g, 11.8 mmol) and

NaN(SiMe₃)₂(0.5 M in toluene, 25.9 ml, 12.9 mmol) to

yield the crude product which was puriﬁed by ﬂash column

chromatography (SiO₂, 40% EtOAc/60% hexane) affording

a cis/trans mixture (22:77) of 5c (3.1 g, 85%). as a yellow

oil; R_fZ0.23 (30% EtOAc/70% hexane); IR (ﬁlm) n 3321,

2954, 1683, 1694, 1699, 1713, 1538, 1455, 1418, 1348,

4.7.2. Benzyl-3-azido-2-methoxy-1-piperidinecarboxyl-

ate (6b, Scheme 1). Prepared following method F using

1d (0.76 g, 3.5 mmol), sodium azide (0.34 g, 5.25 mmol)

and CAN (5.82 g, 10.5 mmol) to yield the crude product

which was puriﬁed by ﬂash column chromatography (SiO₂,

40% EtOAc/60% hexane) affording a mixture of cis/trans-

6b (40/60) (0.69 g, 71%) as a colorless oil; R_fZ0.65 (20%

EtOAc/80% hexane); IR (ﬁlm) n 3032, 2946, 2103, 1699,

1498, 1418, 1345, 1307, 1263, 1162, 1121, 1079, 1039,

965 cm^K1; ¹H NMR (400 MHz, CDCl₃), rotamers, d 7.37–

7.26 (m, 5H, Ar), 5.5 (br, 0.6H, –NCH–O), 5.36 (br, 0.4H,

–NCHO–), 5.24–5.08 (m, 2H, –CH₂Ph), 3.96–3.87 (m, 1H,

–NCH₂), 3.76 (br, 0.4H, –CHN₃), 3.35–2.91 (m, 4.6H,

–OCH₃, 0.6!–CHN₃and 1!–NCH₂), 2.03–1.43 (m, 4H,

–NCH₂(CH₂)₂);¹H NMR (300 MHz, d₂-tetrachloroethane,

TZ350 K), rotamers, d 7.43–7.39 (m, 5H, Ar), 5.46 (br,

0.6H, –NCHO–), 5.31 (br, 0.4H, –NCHO–), 5.23–5.20 (m,

2H, –CH₂Ph), 4.03–3.93 (m, 1H, –NCH₂), 3.77 (br, 0.4H,

–CHN₃), 3.37 (s, 1.8H, –OCH₃), 3.30 (s, 1.2H, –OCH₃),

3.15 (d, JZ12.3 Hz, 0.6H, –CHN₃), 3.02–2.94 (m, 1H,

NCH₂), 2.05–1.51 (m, 4H, NCH₂(CH₂)₂); ¹³C NMR

(100 MHz, CDCl₃), rotamers, d 155.8, 155.2, 128.8,

128.7, 128.6, 128.4, 128.3, 128.1, 84.1, 83.8, 83.1, 67.8,

67.9, 59.2, 59.1, 58.2, 55.6, 55.2, 38.0, 37.6, 24.5, 24.2,

23.5, 23.3, 23.2, 19.6.

1246, 1082, 974, 773, 698 cm^K^{1 1}H NMR (400 MHz,

;

CDCl₃), rotamers, d 7.31–7.26 (m, 5H, Ar), 5.45 (d, JZ

5.2 Hz, 0.78H, –NCHO–), 5.35 (br, 0.22H, –NCHO–),

5.19–4.95 (m, 3H, –CH₂Ph and –NH), 4.01 (br, 0.78H,

–CHNH(CO₂Me)), 3.86 (br, 0.22H, –CHNH(CO₂Me)),

3.66–3.29 (m, 4H, 1!–NCH₂CH₂and –OCH₃), 2.29 (br,

1H, –NCH₂CH₂), 1.76 (br, 1H, –NCH₂CH₂), 1.83–1.74 (m,

1H, –NCH₂CH₂); ¹³C NMR (100 MHz, CDCl₃), rotamers, d

156.6, 156.0, 155.4, 136.5, 128.7, 128.3, 128.1, 93.1, 92.6,

67.5, 67.4, 56.5, 56.0, 55.8, 55.2, 52.4, 44.2, 44.0, 28.6,

27.6.

4.7. Method F. General procedure for

azidomethoxylation

CAN (3 mequiv) dissolved in acetonitrile was added

dropwise to a cooled (ice-bath) mixture of sodium azide

(1.5 mequiv) and the enecarbamate (1 mequiv), in dry

acetonitrile and dry methanol and under nitrogen. The

mixture was gradually brought to rt and stirred overnight.

4.8. Method G. General procedure for LiAlH₄reduction

To a stirred suspension of LiAlH₄(5 mequiv) in dry THF at

1238

M. Norton Matos et al. / Tetrahedron 61 (2005) 1221–1244

0 8C and under nitrogen was slowly added a solution of the

bicyclic compound 4 (1 mequiv) in THF. After reﬂuxing for

14 h, the mixture was cooled to rt and carefully treated with

H₂O, aqueous NaOH (15%), and again with H₂O. The white

precipitate was ﬁltered and washed several times with Et₂O.

After acidiﬁcation with aqueous H₂SO₄(10%), the ethereal

phase was separated, the aqueous layer basiﬁed (pHZ14)

and extracted with dichloromethane. Removal of the solvent

in vacuo afforded the N-alkyl-3-alkyl-pyrrolidine derivative

7.

allyltrimethylsilane (1.39 ml, 8.75 mmol) and BF₃$OEt₂

(0.887 ml, 7.0 mmol) to yield the 2,3-dialkylsubstituted

pyrrolidine derivative which was puriﬁed ﬂash column

chromatography (SiO₂, 40% EtOAc/60% hexane) affording

a mixture of cis/trans-8a (76/24) (450 mg, 89%) as a

colorless oil; R_fZ0.18 (30% EtOAc/70% hexane); IR (ﬁlm)

n 3431, 3074, 2952, 1685, 1420, 1357, 1185, 1113, 913, 767,

1

735, 698 cm^K1; H NMR (400 MHz, CDCl₃), rotamers d

7.34–7.24 (m, 5H, Ar), 5.86–5.64 (m, 1H, –CH₂CH]CH₂),

5.29–4.93 (m, 5H, –CH₂Ph and 3!(–C]CH₂)₂), 4.85 (d,

JZ12.8 Hz, 1H, 1!–C]CH₂), 4.18–4.15 (m, 0.4H,

–NCHCH), 4.06 (s, 2H, –CH₂OH), 3.93–3.85 (m, 0.6H,

–NCHCH), 3.77–3.28 (m, 2H, –NCH₂CH₂), 2.79–2.76 (m,

0.4H, –NCHCH), 2.64 (br, 0.8H, CH₂CH]CH₂), 2.47–2.39

(m, 0.6H, –NCHCH), 2.36–1.79 (m, 2.2H, 1.2!CH_2-

CH]CH₂and 1!–NCH₂CH₂), 1.78–1.72 (m, 1H,

–NCH₂CH₂); ¹³C NMR (100 MHz, CDCl₃) d 154.7,

154.5, 154.3, 149.0, 149.0, 145.4, 145.3, 136.5, 136.4,

136.2, 136.1, 135.2, 135.2, 134.0, 133.8, 128.0, 128.0,

127.8, 127.6, 127.6, 127.5, 127.4, 127.21, 117.5, 117.5,

116.4, 111.0, 110.7, 108.9, 66.6, 66.2, 65.3, 65.2, 64.3, 61.0,

60.6, 57.7, 57.4, 45.6, 45.3, 44.4, 44.3, 43.6, 38.0, 37.0,

35.0, 34.7, 28.8, 28.0, 25.8, 24.9; HRMS (EI) m/z calcd for

(C₁₈H₂₃NO₃CH^C): 302.1756, found: 302.1748.

4.8.1. 2-(1-Methyl-3-pyrrolidinyl)-2-propen-1-ol (7a,

Scheme 2). Prepared following method G using 4a

(128 mg, 0.49 mmol) and LiAlH₄(93 mg, 2.45 mmol) to

yield the 7a (43.6 mg, 62%) as a colorless oil; IR (ﬁlm) n

3367 (O–H), 2945, 2789, 1648, 1450, 1349, 1233, 1151,

1081, 1037, 894, 701 cm^K1; ¹H NMR (400 MHz, CDCl₃) d

4.84–4.83 (m, 1H, C]CH₂), 4.78 (m, 1H, –C]CH₂), 4.18–

4.14 (dd, JZ13.6, 1.2 Hz, 1H, –CH₂]CCH₂OH), 4.00–

3.96 (dd, JZ13.6, 1.2 Hz, 1H, –CH₂]CCH₂OH), 3.01–

2.96 (m, 1H, –NCH₂CH₂), 2.93 (dt, JZ8.8, 3.6 Hz, 1H,

–NCH₂CH), 2.72 (dd, JZ9.6, 2.8 Hz, 1H, –NCH₂CH),

2.48–2.31 (m, 1H, –NCH₂CH), 2.32 (s, 3H, N–CH₃), 2.24–

2.14 (m, 1H, NCH₂CH), 2.10–2.01 (m, 1H, –NCH₂CH₂),

1.85–1.39(m, 1H, –NCH₂CH₂);¹³C NMR(100 MHz, CDCl₃)

d 151.6, 111.5, 64.3, 61.8, 55.5, 43.3, 41.2, 29.2; HRMS (EI)

m/z calcd for (C₈H₁₅NO^C): 141.1154, found: 141.1151.

4.9.2. 2-(1-Acetyl-2-allyl-3-pyrrolidinyl)-2-propen-1-ol

(8b, Table 5, entry 2). Prepared following method H

using 4e (205 mg, 1.23 mmol), allyltrimethylsilane

(0.98 ml, 6.15 mmol) and BF₃$OEt₂(0.623 ml,

4.92 mmol) to yield a mixture of the cis/trans-2,3-

dialkylsubstituted pyrrolidine derivative which was puriﬁed

by ﬂash chromatography (SiO₂, 80% EtOAc/20% hexane)

affording the cis-8b and trans-8b(combined yield 58%).

4.8.2. 2-(1-Ethyl-3-pyrrolidinyl)-2-propen-1-ol (7b,

Scheme 2). Prepared following method G using 4e

(117 mg, 0.7 mmol) and LiAlH₄(133 mg, 3.5 mmol) to

yield 7b (63.3 mg, 58%) as a colorless oil; IR (ﬁlm) n 3359,

2960, 2927, 2808, 1652, 1483, 1455, 1390, 1346, 1216,

1158, 1106, 1042, 896 cm^K1; ¹H NMR (400 MHz, CDCl₃)

d 4.82 (s, 1H, –C]CH₂), 4.7 (d, JZ1.4 Hz, 1H, –C]CH₂),

4.15–4.12 (dd, JZ13.2, 0.7 Hz, 1H, CH₂]CCH₂–OH),

3.95 (d, JZ13.2 Hz, 1H, CH₂]CCH₂–OH), 2.98–2.92 (m,

2H, –NCH₂CH₂and –NCH₂CH), 2.76 (dd, 1H, JZ9.5,

2.6 Hz, –NCH₂CH₂), 2.31 (q, JZ7.2 Hz, 2H, –NCH₂CH₃),

2.28–2.25 (m, 1H, –NCH₂CH₃), 2.23–2.16 (m, 1H,

–CHC]CH₂), 2.14–2.00 (m, 1H, –NCH₂CH₂), 1.79–1.76

(m, 1H, –NCH₂CH₂), 1.06 (t, JZ7.3 Hz, 3H, –NCH₂CH₃);

¹³C NMR (100 MHz, CDCl₃) d 151.6, 111.4, 64.2, 59.3,

53.0, 49.2, 42.6, 28.4, 13.6; HRMS (EI) m/z calcd for

(C₉H₁₇NO^C): 155.1310, found: 155.1308.

4.9.3. trans-2-(1-Acetyl-2-allyl-3-pyrrolidinyl)-2-propen-

1-ol (trans-8b). (56 mg, 21%) as a yellow oil; R_fZ0.43

(EtOAc); IR (ﬁlm) n 3392, 3077, 2926, 1620, 1446, 1430,

1358, 1036, 912 cm^K^{1 1}H NMR (400 MHz, CDCl₃),

;

rotamers, d 5.65–5.56 (m, 1H, –CH₂CH]CH₂), 5.13–4.94

(m, 2.8H, –C]CH₂), 4.73 (s, 0.9H, –C]CH₂), 4.67 (s,

0.3H, –C]CH₂), 4.15 (dt, JZ8.5, 3.5 Hz, 0.67H,

–NCHCH), 4.07 (s, 2H, –CH₂OH), 3.80 (ddd, JZ8.8, 4.0,

1.7 Hz, 0.33H, N–CHCH), 3.69–3.61 (m, 0.32H,

–NCH₂CH₂), 3.52–3.36 (m, 1.68H, N–CH₂CH₂), 2.72–

2.71 (m, 0.35H, –NCHCH), 2.66 (dt, JZ7.0, 4.0 Hz, 0.65H,

–NCHCH), 2.53–2.46 (m, 0.84H, –CH₂CH]CH₂), 2.38–

1.78 (m, 3.16H, 1.16!–CH₂CH]CH₂and –NCH₂CH₂),

2.08 (s, 0.78H, –CH₃), 2.02 (s, 2.22H, –CH₃); ¹³C NMR

(100 MHz, CDCl₃) d 169.5, 169.2, 149.8, 149.2, 145.4,

134.3, 133.4, 118.4, 118.0, 117.5, 116.6, 111.7, 109.0, 67.9,

64.7, 64.6, 64.4, 62.6, 60.4, 50.2, 46.8, 46.3, 45.5, 45.1,

44.6, 44.5, 43.2, 39.4, 36.9, 29.6, 28.9, 27.8, 27.1, 22.6,

21.9; DEPT (100 MHz, CDCl₃), rotamers, d 134.3(C),

133.4(C), 118.4(K), 118.0(K), 117.5(K), 116.6(K),

111.7(K), 109.0(K), 64.6(K), 64.4(K), 62.6(C), 60.4(C),

50.2(C), 46.8(K), 46.3(K), 45.5(C), 45.1(C), 44.6(C),

44.5(C), 43.2(C), 39.4(K), 36.9(K), 29.6(K), 28.9(K),

27.8(K), 27.1(K), 22.6(C), 21.9(C); HRMS (EI) m/z calcd

for (C₁₂H₁₉NO₂CH^C): 210.1494, found: 210.1483.

4.9. Method H. General procedure for nucleophilic

substitution of 4 via N-acyl-iminium formation

To a stirred solution of the bicyclic compound (1 quiv) and

the nucleophile (5 quiv) in dry dichloromethane at 0 8C was

added BF₃.OEt₂(4 quiv). The resulting mixture was stirred

at rt (1 h for the N-Cbz-bicyclic substrate and 2 days for the

N-acetyl-bicyclic substrate). Na₂CO₃(sat. aq. soln) was then

added, the phases were separated and the aqueous phase

extracted with dichloromethane. The combined organic

layers were dried (Na₂SO₄) and the solvent removed in

vacuo to yield the 2,3-dialkylsubstituted pyrrolidine

derivative 8, which was puriﬁed by ﬂash chromatography.

4.9.1. Benzyl-2-allyl-3-[1-hydroxymethy)vinyl]-1-pyrro-

lidinecarboxylate (8a, Table 5, entry 1). Prepared

following method H using 4a (453 mg, 1.75 mmol),

4.9.4. cis-2-(1-Acetyl-2-allyl-3-pyrrolidinyl)-2-propen-1-

ol (cis-8b). (94 mg, 37%) as a yellow oil; R_fZ0.26

(EtOAc); IR (ﬁlm) n 3390, 3077, 2932, 2887, 1619, 1445,

M. Norton Matos et al. / Tetrahedron 61 (2005) 1221–1244

1239

1429, 1352, 1184, 1067, 1040, 999, 908 cm^K1; H NMR

(400 MHz, CDCl₃), rotamers, d 5.83–5.66 (m, 1H,

–CH₂CH]CH₂), 5.27–4.25 (m, 1H, –C]CH₂), 5.04–4.90

(m, 3H, –C]CH₂), 4.34 (q, JZ6.5 Hz, 0.68H, –NCHCH),

4.18–4.06 (m, 2H, –CH₂OH), 4.01 (q, JZ6.5 Hz, 0.32H,

–NCHCH), 3.57–3.65 (m, 2H, –NCH₂CH₂), 2.90 (dt, JZ

13.2, 7.5 Hz, 0.32H, –NCHCH), 2.75 (dt, JZ13.0, 7.5 Hz,

0.68H, –NCHCH), 2.28–1.84 (m, 4H, –CH₂CH]CH₂and

–NCH₂CH₂), 2.07 (s, 0.94H, –CH₃), 2.01 (s, 2.06H, –CH₃);

¹³C NMR (100 MHz, CDCl₃) d 169.6, 169.5, 145.6, 135.6,

134.6, 118.0, 117.4, 116.3, 112.0, 111.0, 65.7, 65.3, 59.4,

56.8, 46.0, 45.4, 45.3, 43.6, 43.4, 34.9, 34.2, 26.2, 25.8,

24.4, 22.4, 22.1; DEPT (100 MHz, CDCl₃) d 135.6(C),

134.6(C), 118.0(K), 117.4(K), 116.3(K),112.0(K),

111.0(K), 65.7(K), 65.3(K), 59.4(C), 56.8(C), 46.0(K),

45.4(C), 45.3(K), 43.6(C), 43.4(C), 34.9(K), 34.2(K),

26.2(K), 25.8(K), 24.4(K), 22.4(C), 22.1(C); HRMS

(EI) m/z calcd for (C₁₂H₁₉NO₂CH^C): 210.1494, found:

210.1489

2892, 1644, 1651, 1417, 1359, 1300, 1260, 1184, 1037, 917,

1

834 cm^K1; H NMR (400 MHz, CDCl₃), rotamers, d 5.38

(br, 1H, C]CH₂), 5.21–5.13 (m, 1.74H, C]CH₂and

–NCHCN), 4.92 (d, JZ7.1 Hz, 0.26H, –NCHCN), 4.28–

4.16 (m, 2H, –CH₂OH), 3.79–3.70 (m, 1H, –NCH₂CH₂),

3.53–3.39 (m, 1H, –NCH₂CH₂), 3.17–3.13 (m, 0.26H,

–CHC]CH₂), 3.10–3.04 (m, 0.74H, –CHC]CH₂), 2.38–

2.33 (m, 1H, –NCH₂CH₂), 2.26–2.19 (m, 1H, –NCH₂CH₂),

2.22 (s, 0.5H, –CH₃), 2.09 (s, 2.5H, –CH₃); ¹³C NMR

(100 MHz, CDCl₃) d 170.1, 169.5, 143.4, 143.1, 116.2,

115.8, 114.6, 114.0, 66.1, 65.6, 52.5, 50.3, 45.9, 45.0,

44.5, 27.8, 26.1, 22.3, 21.6; DEPT (100 MHz, CDCl₃),

rotamers, d 115.7(C), 114.8(C), 67.0(C), 66.3(C),

52.5(K), 50.3(K), 46.1(C), 45.0(K), 44.7(C), 44.5(K),

29.6(C), 28.1(C), 26.3(C), 22.3(K), 21.6(K); HRMS

(EI) m/z calcd for (C₁₀H₁₄N₂O^C₂): 194.1055, found:

194.1053.

4.9.7. Benzyl-2-allyl-3[(benzyloxycarbonyl)amino]-1-

pyrrolidinecarboxylate (9a, Table 6, entry 1). Prepared

following method H using 5b (55 mg, 0.14 mmol),

allyltrimethylsilane (46 ml, 0.28 mmol, 2 quiv) and

BF₃$OEt₂(36 ml, 0.28 mmol, 2 quiv) to yield the substituted

pyrrolidine which was puriﬁed by preparative thin layer

chromatography (SiO₂, 40%EtOAc/60% hexane) affording

the cis (24%) and trans (76%) isomers of 9a (35 mg, 60%)

as colorless oils.

4.9.5. Benzyl-2-cyano-3-[1-hydroxymethyl)vinyl]-1-pyr-

rolidinecarboxylate (8c, Table 5, entry 3). Prepared

following method H using 4a (150 mg, 0.58 mmol),

cyanotrimethylsilane (386 ml, 2.9 mmol) and BF₃$OEt₂

(293 ml, 2.32 mmol) to yield the 2,3-dialkyl-substituted

pyrrolidine derivative which was puriﬁed by ﬂash column

chromatography (SiO₂, 60% EtOAc/40% hexane) affording

a mixture of cis/trans-8c (67:33) (125 mg, 76%) as a

colorless oil; R_fZ0.32 (50% EtOAc/50% hexane); IR (ﬁlm)

n 3440, 2950, 2891, 1705, 1494, 1416, 1357, 1214, 1190,

4.9.8. trans-Benzyl-2-allyl-3-[(benzyloxycarbonyl)-

amino]-1-pyrrolidinecarboxylate (trans-9a). R_fZ0.37

(30% AcOE/70% hexane); IR (ﬁlm) n 3313, 3064, 3032,

2952, 1698, 1586, 1532, 1498, 1454, 1415, 1349, 1278,

1244, 1114, 1028, 1002, 916, 846, 769, 697, 666 cm^K1; ¹H

NMR (400 MHz, CDCl₃), rotamers d 7.27–7.16 (m, 5H,

Ar), 5.70 (br, 1H, –CH₂CH]CH₂), 5.13–4.93 (m, 7H, NH,

2!(–CH₂Ph) and –C]CH₂), 4.29 (br, 1H, –NH), 4.00 (br,

1H, –CHNH), 3.74 (br, 1H, –NCHCH), 3.47–3.32 (m, 2H,

–NCH₂CH₂), 2.46 (br, 0.5H, –CH₂CH]CH₂), 2.33 (br,

0.5H, –CH₂CH]CH₂), 2.13–2.11 (br, 2H, –CH₂CH]CH₂

and –NCH₂CH₂), 1.77 (br, 1H, –NCH₂CH₂); ¹³C NMR

(100 MHz, CDCl₃), rotamers, d 155.6, 136.2, 133.6, 128.5,

128.2, 128.0, 127.9, 118.2, 67.0, 66.8, 63.6, 54.9, 54.0, 44.4,

44.1, 37.7, 36.8, 29.9, 29.0; DEPT (100 MHz, CDCl₃),

rotamers, d 133.6(C), 128.5(C), 128.2(C), 128.0(C),

127.9(C), 118.2(K), 67.0(K), 66.8(K), 63.6(C), 54.9(C),

54.0(C), 44.4(K), 44.1(K), 37.7(K), 36.8(K), 29.9 (K),

29.0(K).

1126, 1057, 1028, 915, 763, 694 cm^K1

;

¹H NMR

(400 MHz, CDCl₃), rotamers, d 7.39–7.31 (m, 5H, Ar),

5.34 (s, 1H, –C]CH₂), 5.27–5.13 (m, 3H, 1!–C]CH₂

and CH₂Ph), 4.99–4.89 (m, 0.67H, –NCHCN), 4.57–4.49

(m, 0.33H, –NCHCN), 4.19–4.10 (m, 2H, –CH₂OH), 3.72–

3.36 (m, 1H, –NCH₂CH₂), 3.52–3.50 (m, 0.33H,

–NCH₂CH₂), 3.43–3.35 (m, 0.67H, –NCH₂CH₂), 3.26–

3.22 (m, 0.33H, –CHC]CH₂), 3.09–3.04 (m, 0.67H,

–CHC]CH₂), 2.27–2.10 (m, 2H, –NCH₂CH₂); ¹³C NMR

(100 MHz, CDCl₃) d 154.2, 153.6, 145.1, 135.8, 128.5,

128.2, 128.1, 128.0, 118.8, 118.4, 116.8, 116.7, 115.2,

114.8, 112.8, 112.6, 68.6, 68.0, 67.8, 67.7, 67.6, 66.6, 66.4,

65.0, 52.2, 51.8, 51.6, 51.2, 47.5, 46.4, 45.8, 45.4, 45.2,

45.1, 45.0, 44.2, 29.6, 28.8, 27.6, 26.7; DEPT (100 MHz,

CDCl₃), rotamers, d 128.5(C), 128.2(C), 128.1(C),

128.0(C), 118.8(K), 118.4(K), 116.8(K), 116.7(K),

115.2(K), 114.8(K), 112.8(K), 112.6(K), 68.6(K),

68.0(K), 67.8(K), 67.7(K), 67.6(K), 66.6(K), 66.4(K),

65.0(K), 52.2(C), 51.8(C), 51.6(C), 51.2(C), 47.5(C),

46.4(C), 45.8(K), 45.4(K), 45.2(K), 45.1(K), 45.0(K),

44.2(C), 29.6(K), 28.8(K), 27.6(K), 26.7(K); HRMS

(EI) m/z calcd for (C₁₆H₁₈N₂O^C₃): 286.1317, found:

286.1330.

4.9.9. cis-Benzyl-2-allyl-3-[(benzyloxycarbonyl)amino]-

1-pyrrolidinecarboxylate (cis-9a). R_fZ0.26 (30%

EtOAc/70% hexane); IR (ﬁlm) n 3304, 3065, 3031, 2915,

1693, 1538, 1452, 1412, 1358, 1239, 1113, 1026, 916,

746 cm^K1; ¹H NMR (400 MHz, CDCl₃), rotamers, d 7.28–

7.19 (m, 5H, Ar), 5.70 (br, 1H, –CH₂CH]CH₂), 5.09–4.84

(m, 7H, NH, 2!(–CH₂Ph) and –CH]CH₂), 4.24 (br, 1H,

–CH₂CHNH), 4.15–4.12 (m, 1H, –NCHCH–), 3.40 (dt, JZ

8.8, 2.0 Hz, 2H, –NCH₂CH₂), 2.20 (br, 3H, –CH₂CH]CH₂

and –NCH₂CH₂), 1.74–1.69 (m, 1H, –NCH₂CH₂); ¹³C

NMR (100 MHz, CDCl₃), rotamers, d 155.7, 155.1, 135.1,

128.6, 128.5, 128.3, 128.2, 128.0, 117.3, 77.2, 67.0, 56.8,

52.5, 43.4, 34.3, 29.7; DEPT (100 MHz, CDCl₃), rotamers,

d 128.6(C), 128.5(C), 128.3(C), 128.2(C), 128.0(C),

117.3(K), 77.2(C), 67.0(K), 56.8(C), 52.5(C), 43.4(K),

4.9.6. 1-Acetyl-3-[1-(hydroxymethyl)vinyl]-2-pyrro-

lidinecarbonitrile (8d, Table 5, entry 4). Prepared

following method H using 4e (160 mg, 0.96 mmol),

cyanotrimethylsilane (638 ml, 4.8 mmol) and BF₃$OEt₂

(486 ml, 3.84 mmol) to yield the 2,3-dialkylsubstituted

pyrrolidine derivative which was puriﬁed by ﬂash column

chromatography (SiO₂, 90%EtOAc/10% hexane) affording

a mixture of cis/trans-8d (74:26) (120 mg, 64%) as a

colorless oil; R_fZ0.26 (EtOAc); IR (ﬁlm) n 3390, 2947,

1240

M. Norton Matos et al. / Tetrahedron 61 (2005) 1221–1244

34.3(K), 29.7(K); HRMS (EI) m/z calcd for

(C₂₃H₂₆N₂O₄CH^C): 395.1970, found: 395.1971.

2.20 (m, 1H, –NCH₂CH₂), 1.94–1.86 (m, 1H, –NCH₂CH₂),

1.32–1.24 (m, 3H, –OCH₂CH₃); ¹³C NMR (100 MHz,

CDCl₃) d 170.3, 155.6, 154.5, 136.7, 136.5, 128.4, 127.9,

127.8, 127.7, 66.9, 66.8, 60.8, 60.4, 56.1, 50.4, 44.4, 43.6,

37.7, 29.9, 13.9; DEPT (100 MHz, CDCl₃) d 128.4(C),

127.9(C), 127.8(C), 127.7(C), 66.9(K), 66.8(K), 60.8(K),

60.4(C), 56.1(C), 50.4(K), 44.4(K), 43.6(K), 37.7(K),

29.9(K), 13.9(C); HRMS (EI) m/z calcd (C₂₄H₂₈N₂O₆–H^C):

439.1869, found: 439.1866.

4.9.10. Benzyl-3-[(benzyloxycarbonyl)amino]-2-cyano-1-

pyrrolidinecarboxylate (9b, Table 6, entry 2). Prepared

following method H using 5b (89 mg, 0.23 mmol),

cyanotrimethylsilane (63 ml, 0.46 mmol, 2 quiv) and

BF₃$OEt₂(58 ml, 0.46 mmol, 2 quiv) to yield the substituted

pyrrolidine which was puriﬁed by ﬂash chromatography

(SiO₂, 40%EtOAc/60% hexane) affording the cis (30%)

and trans (70%) isomers of 9b (44.8 mg, 52%) as colorless

oils.

4.9.14. Benzyl-2-allyl-3-[(methoxycarbonyl)amino]-1-

pyrrolidinecarboxylate (9d, Table 6, entry 4). Prepared

following method H using 5c (475 mg, 1.54 mmol),

allyltrimethylsilane (489 ml, 3.08 mmol, 2 quiv) and

BF₃$OEt₂(782 ml, 6.2 mmol, 4 quiv) to yield the substituted

pyrrolidine which was puriﬁed by ﬂash chromatography

(SiO₂, 40%EtOAc/60% hexane) affording a cis/trans-9d

mixture (23/77) (385 mg, 79%) as a colorless oil; R_fZ(10%

EtOAc/90% hexane); IR (ﬁlm) n 3316, 3061, 3030, 2951,

1703, 1699, 1694, 1683, 1538, 1455, 1418, 1350, 1280,

4.9.11. trans-Benzyl-3-[(benzyloxycarbonyl)amino]-2-

cyano-1-pyrrolidinecarboxylate (trans-9b). R_fZ0.29

(30% EtOAc/70%hexane); IR (ﬁlm) n 3307, 3071, 3031,

2956, 1710, 1536, 1454, 1413, 1358, 1284, 1244, 1218,

1172, 1133, 1027, 913, 738, 697 cm^K1

;

¹H NMR

(400 MHz, CDCl₃), rotamers, d 7.36–7.19 (m, 5H, Ar),

5.36–5.30 (m, 1H, –NCHCN), 5.21–5.05 (m, 4H, 2!

(–CH₂Ph)), 4.63–4.57 (m, 1H, –NH), 4.47 (br, 1H,

–CH₂CHNH), 3.61–3.20 (m, 2H, –NCH₂CH₂), 1.27–1.79

(m, 2H, –NCH₂CH₂); ¹³C NMR (100 MHz, CDCl₃),

rotamers, d 155.4, 155.3, 135.7, 128.6, 128.5, 128.4,

128.2, 128.0, 116.9, 76.7, 68.0, 67.9, 66.3, 58.9, 56.3,

55.3, 53.1, 44.5, 44.1, 30.3, 29.2, 18.6; DEPT (100 MHz,

CDCl₃), rotamers, d 128.6(C), 128.5(C), 128.4(C),

128.2(C), 128.0(C), 76.7(K), 68.0(K), 67.9(K), 66.3(K),

58.9(C), 56.3(C), 55.3(C), 53.1(C), 44.5(K), 44.1(K),

30.3(K), 29.2(K),18.6(K).

1248, 1194, 1114, 918, 770, 700 cm^K1

;

¹H NMR

(400 MHz, CDCl₃), rotamers, d 7.34–7.26 (m, 5H, Ar),

5.82–5.20 (m, 1H, –CH]CH₂), 5.16–5.04 (m, 5H, –CH₂Ph

and –CH]CH₂and –NH), 4.04 (br, 1H, –CHNH(CO₂Me)),

3.79 (br, 1H, –NCHCH₂), 3.68 (s, 3H, –OCH₃), 3.64–3.43

(m, 2H, –NCH₂CH₂), 2.55–2.38 (m, 1H, CH₂CH]CH₂),

2.21–2.14 (m, 2H, 1!CH₂CH]CH₂and 1!–NCH₂CH₂),

1

2.12–1.83 (m, 1H, –NCH₂CH₂); H NMR (400 MHz, d₂-

tetrachloroethane, TZ365 K), d 7.39–7.31 (m, 5H, Ar),

5.81–5.78 (m, 1H, –CH]CH₂), 5.19–5.06 (m, 5H, –CH₂Ph

and –CH]CH₂and –NH), 4.00 (br, 1H, –CHNH(CO₂Me)),

3.79 (d, JZ4.8 Hz, 1H, –NCHCH₂), 3.64 (s, 3H, –OCH₃),

3.51–3.45 (m, 2H, –NCH₂CH₂), 2.53 (br, 0.5H, CH₂-

CH]CH₂), 2.42 (br, 0.5H, CH₂CH]CH₂), 2.19–2.18 (m,

2H, 1!CH₂CH]CH₂and 1!–NCH₂CH₂), 1.83 (br, 1H,

–NCH₂CH₂); ¹³C NMR (100 MHz, CDCl₃), rotamers, d

156.5, 133.9, 128.7, 128.2, 128.1, 118.3, 67.2, 67.0, 63.9,

55.1, 54.3, 52.3, 44.7, 44.4, 37.9, 37.0, 30.2, 29.2; HRMS

(EI) m/z calcd for (C₁₇H₂₂N₂O₄CH^C): 319.1658, found:

319.1665.

4.9.12. cis-Benzyl-3-[(benzyloxycarbonyl)amino]-2-

cyano-1-pyrrolidinecarboxylate (cis-9b). R_fZ0.22 (30%

EtOAc/70% hexane); IR (ﬁlm) n 3321, 3033, 2957, 1711,

1532, 1454, 1413, 1357, 1284, 1241, 1177, 1114, 1040, 980,

1

913, 738, 698, 666 cm^K1; H NMR (400 MHz, CDCl₃),

rotamers, d 7.28–7.19 (m, 5H, Ar), 5.23–5.19 (m, 1H,

–NCHCN), 5.15–5.05 (m, 4H, 2!(–CH₂Ph)), 4.85 (br, 1H,

–NH), 4.34 (br, 1H, –CH₂CHNH), 3.59–3.57 (m, 1H,

–NCH₂CH₂), 3.35–3.32 (m, 1H, –NCH₂CH₂), 2.25–2.20

(m, 1H, –NCH₂CH₂), 1.93–1.91 (m, 1H, NCH₂CH₂); ¹³C

NMR (100 MHz, CDCl₃), rotamers, d 155.6, 153.6, 135.7,

128.6, 128.4, 128.2, 115.9, 68.1, 67.9, 67.5, 53.4, 52.5, 52.3,

51.5, 51.3, 43.8, 29.6, 28.5.

4.9.15. Benzyl-3-azido-2-(2-ethoxy-2-oxoethyl)-1-pyrro-

lidinecarboxylate (9e, Table 6, entry 5). Prepared follow-

ing method H using 6a (237 mg, 0.86 mmol), tert-butyl[1-

ethoxyvinyl)oxy]dimethylsilane (347 mg, 1.72 mmol) and

BF₃$OEt₂(435 ml, 3.4 mmol) to yield the pyrrolidine

derivative which was puriﬁed by ﬂash chromatography

(SiO₂, 20% EtOAc/80% hexane) affording a cis/trans

mixture (88/12) 9e (140 mg, 49%) as a colorless oil; R_fZ

0.24 (10% EtOAc/90% hexane); IR (ﬁlm) n 2977, 2893,

2099, 1726, 1691, 1448, 1413, 1352, 1261, 1189, 1117,

4.9.13. Benzyl-3-[(benzyloxycarbonyl)amino]-2-(ethoxy-

2-oxoethyl)-1-pyrrolidinecarboxylate (9c, Table 6, entry

3). Prepared following method H using 5b (58 mg,

0.15 mmol), tert-butyl[1-ethoxyvinyl)oxy]dimethylsilane

(202 mg, 0.6 mmol, 4 quiv) and BF₃$OEt₂(38 ml,

0.30 mmol, 2 quiv) to yield the 2,3-disubstituted pyrrolidine

which was puriﬁed by ﬂash chromatography (SiO₂, 40%

EtOAc/60% hexane) affording a cis/trans-9c mixture (15/

85) (49 mg, 74%) as a colorless oil; R_fZ0.56 (40% EtOAc/

60% hexane); IR (ﬁlm) n 3322, 3032, 2980, 2897, 1703,

1586, 1532, 1498, 1454, 1416, 1350, 1288, 1241, 1204,

1029, 899, 766, 694, 598 cm^K^{1 1}H NMR (400 MHz,

;

CDCl₃), rotamers, d 7.36–7.26 (m, 5H, Ar), 5.12 (br, 2H,

–CH₂Ph), 4.34 (br, 2H, –NCH and CHN₃), 4.19–4.09 (m,

2H, –OCH₂CH₃), 3.62–3.56 (m, 1H, –NCH₂), 3.56–3.39 (m,

1H, –NCH₂), 2.66–2.49 (m, 2H, –CH₂(C]O)), 2.13–2.19

(m, 2H, –NCH₂CH₂), 1.29–1.25 (m, 3H, CH₂CH₃); ¹H

NMR (400 MHz, d₂-tetrachloroethane, TZ365 K) d 7.42–

7.34 (m, 5H, Ar), 5.19 (br, 2H, –CH₂Ph), 4.45–4.41 (m, 1H,

–NCH), 4.32 (q, JZ6.4 Hz, 0.88H, –CHN₃), 4.21 (dq, JZ

7.2, 1.6 Hz, 2H, –OCH₂CH₃), 4.88–4.87 (m, 0.12H,

–CHN₃), 3.67–3.61 (m, 1H, –NCH₂), 3.58–3.45 (m, 1H,

–NCH₂), 2.99 (dd, JZ16.4, 4.0 Hz, 0.88H, –CH₂(C]O)),

1116, 1057, 1028, 978, 915, 770, 739 cm^K^{1 1}H NMR

;

(400 MHz, d₂-tetrachloroethane, TZ340 K) d 7.41–7.34

(m, 5H, Ar), 5.17 (s, 2H, –CH₂Ph), 5.14 (s, 2H, –CH₂Ph),

4.98 (d, JZ5.0 Hz, 1H, –NH), 4.32–4.07 (m, 4H, –CHNH,

NCHCH₂, –OCH₂CH₃), 3.65–3.59 (m, 1H, –NCH₂CH₂),

3.53–3.47 (m, 1H, –NCH₂CH₂), 2.88–2.84 (m, 1H,

–CH₂(C]O)), 2.56–2.50 (m, 1H, –CH₂(C]O)), 2.26–

M. Norton Matos et al. / Tetrahedron 61 (2005) 1221–1244

1241

2.91 (dd, JZ15.6, 3.6 Hz, 0.12H, –CH₂(C]O)), 2.70–2.61

(m, 0.88H, –CH₂(C]O)), 2.48–2.41 (m, 0.12H,

–CH₂(C]O)), 2.22–2.00 (m, 2H, –NCH₂CH₂), 1.31 (t,

JZ7.2 Hz, 3H, –OCH₂CH₃); ¹³C NMR (100 MHz, CDCl₃),

rotamers, d 170.4, 169.7, 168.3, 157.4, 153.7, 135.6,

127.6, 127.2, 127.1, 66.1, 61.8, 60.0, 59.8, 56.3, 55.4,

44.1, 43.4, 34.2, 33.1, 29.0, 28.1, 13.4; HRMS (EI)

m/z calcd for (C₁₆H₂₀N₄O₄CH^C): 333.1576, found:

333.1571.

2.19 (m, 2H, 1!CH₂CH]CH₂and 1!NCH₂CH₂); ¹³C

NMR (100 MHz, CDCl₃), rotamers, d 154.6, 136.5, 136.3,

133.6, 133.4, 128.5, 128.0, 127.7, 118.4, 69.0, 68.6, 67.0,

66.9, 45.6, 45.3, 38.8, 38.0, 35.6, 35.8, 25.5, 24.8; DEPT

(100 MHz, CDCl₃), rotamers, d 133.6(C), 133.4(C),

128.5(C), 128.0(C), 127.7(C), 118.4(K), 69.0(C),

68.6(C), 67.0(K), 66.9(K), 45.6(K), 45.3(K), 38.8(K),

38.0(K), 35.6(K), 35.8(K), 25.5(C), 24.8(C).

4.9.18. trans-Dimethyl-2-{[(benzyloxy)carbonyl]-3-iodo-

2-pyrrolidinyl}malonate (9h, Table 6, entry 8). To a

stirred solution of 2f (191 mg, 0.53 mmol) and dimethyl-

malonate (92 ml, 0.79 mmol, 1.5 quiv) in dry dichloro-

methane, under argon and cooled to K78 8C was slowly

added a solution of TiCl₄(100 ml, 0.53 mmol) in dry

dichloromethane. The resulting mixture was stirred at

K78 8C for 2 h, warmed to rt and stirred for an additional

2 h. A basic work-up (method F) yielded the substituted

pyrrolidine which was puriﬁed by preparative thin layer

chromatography (40% EtOAc/60% hexane) affording 9h

(165 mg, 68%) as a colorless oil; R_fZ0.35 (30% EtOAc/

70% hexane); IR (ﬁlm) n 3037, 2952, 2894, 1735, 1704,

1498, 1435, 1410, 1360, 1335, 1307, 1261, 1198, 1152,

1113, 1028, 974, 753, 698, 665; ¹H NMR (400 MHz,

CDCl₃) d 7.28–7.22 (m, 5H, Ar), 5.09–5.06 (m, 2H,

–CH₂Ph), 4.73 (d, JZ5.5 Hz, 0.5H, –CH(CO₂Me)₂), 4.59

(br, 0.5H, –CH(CO₂Me)₂), 3.90–3.31 (m, 10H, –CHI,

–NCHCH(CO₂Me)₂, –O(CH₃)₂and –NCH₂CH₂), 2.20–

2.14 (m, 2H, NCH₂CH₂); ¹³C NMR (100 MHz, CDCl₃),

rotamers, d 167.7, 166.8, 155.4, 137.0, 136.5, 128.8, 128.2,

127.7, 68.6, 68.0, 67.4, 67.1, 54.2, 53.4, 52.7, 52.5, 52.4,

45.9, 45.6, 41.1, 36.3, 35.5, 22.7, 22.0; DEPT (100 MHz,

CDCl₃), rotamers, d 128.8(C), 128.2(C), 127.7(C),

68.6(C), 68.0(C), 67.4(K), 67.1(K), 54.2(C), 53.4(C),

52.7(C), 52.5(C), 52.4(C), 45.9(K), 45.6(K), 41.1(K),

36.3(K), 35.5(K), 22.7(C), 22.0(C).

4.9.16. Benzyl-2-allyl-3-azido-1-piperidinecarboxylate

(9f, Table 6, entry 6). Prepared following method H

using 6b (70 mg, 0.24 mmol), allyltrimethylsilane (77 ml,

0.48 mmol, 2 quiv) and BF₃$OEt₂(122 ml, 0.96 mmol,

4 quiv) to yield the 3-azido-2-allyl-piperidine which was

puriﬁed by ﬂash chromatography (SiO₂, 10% EtOAc/90%

hexane) affording a cis/trans mixture (88/12) 9f (36 mg,

50%) as a colorless oil; R_fZ0.32 (10% EtOAc/90%

hexane); IR (ﬁlm) n 2949, 2855, 2100, 1698, 1425, 1347,

1252, 1196, 1146, 1028, 917, 763, 698, 666 cm^K1; ¹H NMR

(400 MHz, CDCl₃), rotamers, d 7.36–7.26 (m, 5H, Ar), 5.68

(br, 1H, –CH]CH₂), 5.15–5.03 (m, 4H, –CH₂Ph and

–CH]CH₂), 4.38 (br, 1H, –NCH), 4.12 (d, JZ12.8 Hz, 1H,

–NCH₂), 3.69 (br, 1H, –NCHN₃), 2.86 (dt, JZ12.8, 4.0 Hz,

1H, –NCH₂), 2.47–2.24 (m, 3H, CH₂CH]CH₂and 1!–

NCH₂CH₂), 1.82–1.49 (m, 3H, 1!–NCH₂CH₂and

–NCH₂CH₂CH₂); ¹H NMR (400 MHz, d₂-tetrachloro-

ethane, TZ365 K), rotamers, d 7.40–7.33 (m, 5H, Ar),

5.78–5.72 (m, 1H, –CH]CH₂), 5.19–5.09 (m, 4H, –CH₂Ph

and –CH]CH₂), 4.43 (t, JZ7.2 Hz, 0.88H, –NCH), 4.30–

4.20 (m, 0.12H, –NCH), 4.13 (d, JZ11.4 Hz, 1H, –NCH₂),

3.68 (d, JZ1.4 Hz, 1H, –NCHN₃), 2.91 (dt, JZ12.0,

4.0 Hz, 1H, –NCH₂), 2.51–2.41 (m, 1H, CH₂CH]CH₂),

2.37–2.27 (m, 1H, CH₂CH]CH₂), 1.83–1.77 (m, 4H,

–NCH₂CH₂and –NCH₂CH₂CH₂); ¹³C NMR (100 MHz,

CDCl₃), rotamers, d 156.0, 137.0, 133.8, 128.8, 128.6,

128.4, 128.2, 128.1, 128.1, 128.0, 118.2, 70.4, 67.6, 67.4,

58.3, 56.3, 55.6, 54.3, 53.9, 40.4, 38.7, 34.3, 26.05, 23.5,

22.1, 19.8; HRMS (EI) m/z calcd for (C₁₆H₂₀N₄O₂CH^C):

301.1664, found: 301.1663.

4.10. Synthesis of (G)-laburnamine

4.10.1. trans-Benzyl-2-(3-hydroxypropyl)-3-[(methoxy-

(10,

carbonyl)-amino]-1-pyrrolidinecarboxylate

4.9.17. trans-Benzyl-2-allyl-3-iodo-1-pyrrolidinecar-

boxylate (9g, Table 6, entry 7). Prepared following method

H using 2f (525 mg, 1.45 mmol), allyltrimethylsilane

(467 ml, 2.9 mmol, 2 quiv) and BF₃$OEt₂(369 ml,

2.9 mmol, 2 quiv) to yield the substituted pyrrolidine

which was puriﬁed by ﬂash chromatography (SiO₂,

20%EtOAc/80% hexane) affording 9g (500 mg, 93%) as a

colorless oil; R_fZ0.43 (20% EtOAc/80% hexane); IR (ﬁlm)

n 3068, 3033, 2891, 1703, 1641, 1498, 1445, 1411, 1358,

1336, 1287, 1267, 1155, 1110, 916, 875, 768, 735, 697,

Scheme 3). BH₃$SMe₂(30 ml, 0.31 mmol) was added

dropwise to a solution of trans-9d (300 mg, 0.94 mmol) in

dry THF (9 ml), cooled in an ice-bath and under nitrogen.

The mixture was stirred at rt for 1 h and the solvent removed

in vacuo yielding the boronate as a white foam which was

dissolved in THF (9 ml). The solution was cooled with an

ice-bath and an aqueous 3 M NaOH solution (346 ml,

1.04 mmol) followed by a dropwise addition of an aqueous

30% H₂O₂solution (343 ml, 3.02 mmol) were added. The

mixture was stirred at 40 8C for 2 h and then cold water

(10 ml) together with diethyl ether were added (10 ml).

The aqueous phase was extracted with diethyl ether, the

combined organic layers were dried (Na₂SO₄) and the

solvent removed in vacuo. The crude mixture was puriﬁed

by ﬂash chromatography (SiO₂, 80% EtOAc/20% hexane)

affording 10 (170 mg, 55%) as a colorless oil; R_fZ(10%

EtOAc/90% hexane); IR (ﬁlm) n 3427, 3313, 3064, 3033,

2951, 1694, 1542, 1498, 1455, 1420, 1351, 1285, 1251,

1

665 cm^K1; H NMR (400 MHz, CDCl₃) rotamers d 7.29–

7.19 (m, 5H, Ar), 5.70–5.68 (m, 1H, –CH₂CH]CH₂), 5.16–

4.95 (m, 4H, –CH₂Ph and –CH₂CH]CH₂), 4.20 (br, 2H,

CHI and –NCHCH₂), 3.72–3.70 (m, 1H, –NCH₂CH₂), 3.46–

3.43 (m, 1H, –NCH₂CH₂), 2.43–2.03 (m, 4H, –CH₂-

CH]CH₂and NCH₂CH₂); ¹H NMR (400 MHz, d₂-

tetrachloroethane, TZ360 K) d 7.41–7.35 (m, 5H, Ar),

5.83–5.76 (m, 1H, –CH₂CH]CH₂), 5.22 (s, 2H, –CH₂Ph),

5.19–5.10 (m, 2H, –CH₂CH]CH₂), 4.39–4.26 (m, 2H,

–CHI and –NCHCH₂), 3.87–3.81 (m, 1H, –NCH₂CH₂), 3.54

(dt, JZ8.4, 2.8 Hz, 1H, –NCH₂CH₂), 2.51–2.47 (m, 1H,

–CH₂CH]CH₂), 2.42–2.33 (m, 1H, –NCH₂CH₂), 2.26–

1

1116, 1045, 987, 916, 877, 770, 739, 698, 605 cm^K1; H

NMR (400 MHz, CDCl₃), rotamers, d 7.33–7.26 (m, 5H,

Ar), 5.30, 5.29 (s, 1H, NH), 5.19–5.01 (m, 2H, –CH₂Ph),

3.96 (br, 1H, –CHNH(CO₂Me)), 3.80–3.79 (m, 1H,

1242

M. Norton Matos et al. / Tetrahedron 61 (2005) 1221–1244

–NCHCH₂), 3.62 (s, 3H, CO₂CH₃), 3.67–3.23 (m, 4H,

–NCH₂CH₂and –CH₂CH₂–OH), 2.18–2.15 (m, 1H,

–NCH₂CH₂), 1.83–1.77 (m, 1H, –NCH₂CH₂), 1.65–1.24

(m, 4H, –CH₂CH₂CH₂–OH); ¹³C NMR (100 MHz, CDCl₃),

rotamers, d 155.8, 155.3, 136.8, 128.7, 128.3, 128.1, 128.0,

67.2, 67.1, 64.4, 64.2, 62.3, 55.6, 55.1, 52.3, 44.5, 44.2,

30.1, 29.8, 29.3, 29.0; HRMS (EI) m/z calcd for

(C₁₇H₂₄N₂O₅CH^C): 337.1763, found: 337.1767.

4.10.4. trans-N-Hexahydro-1H-pyrrolizin-1-yl-2-methyl-

butanamide((G)-laburnamine) (13, Scheme 3). To a

solution of 12 (50 mg, 0.27 mmol) in dry chloroform

(0.27 ml) under argon was added iodo(trimethyl)silane

(47 ml, 0.32 mmol). The mixture was heated to 60 8C and

stirred for 4 h. Methanol (0.1 ml) was then added and the

volatile components removed in vacuo. The residue was

redissolved in methanol and sodium methoxide was added

(8 mg, 0.14 mmol). The mixture was stirred for 10 min at

60 8C and the volatile components removed in vacuo, to

yield the crude amine, which was immediately used in the

next reaction. To a solution of crude amine (50 mg,

0.27 mmol) in THF (2,7 ml), cooled in an ice bath and

under argon, was added triethylamine (56 ml, 0.4 mmol)

followed by (G)-2-methylbutyric acyl chloride (40 ml,

0.32 mmol). The reaction mixture was stirred for 4 h at rt

and the solvent removed in vacuo. The residue was

dissolved in methanol (5 ml) and a KOH pellet was

added. After stirring for 10 min the solvent was removed

in vacuo and the crude reaction mixture was puriﬁed by

preparative thin layer chromatography (MeOH/CH₂Cl₂/

NH₄OH, 10:89:1), to yield the (G)-laburnamine 13

(36.4 mg, 64%) as an orange oil; R_fZ0.3 (CH₂Cl₂/MeOH/

NH₄OH: 8/2/0.1, I₂); IR (ﬁlm) n 3437, 3270, 2965, 2934,

4.10.2. trans-Benzyl-3-[(methoxycarbonyl)amino]-2-(3-

{[(4-methylphenyl)sulfonyl]oxy}propyl)-1-pyrrolidine-

carboxylate (11, Scheme 3). To a solution of 10 (170 mg,

0.5 mmol) in dry chloroform (0.5 ml) cooled with an ice

bath and under argon was added tosyl chloride (194 mg,

1.0 mmol) and right after, pyridine (82 ml, 1.0 mmol). The

reaction mixture was stirred for 3 h at rt and water (2 ml)

was then added followed by diethyl ether (5 ml). The

organic phase was washed with an HCl (2 M, 3 ml), 5%

NaHCO₃aqueous solution (3 ml), water (3 ml) and dried

with anhydrous MgSO₄. The reaction mixture was stirred

for 3 h at rt. The solvent was removed in vacuo and the

residue puriﬁed by preparative thin layer chromatography

(60% EtOAc/40% hexane) to yield 11 (60 mg, 68%) as a

colorless oil; R_fZ0.64 (80% EtOAc/20% hexane); IR (ﬁlm)

n 3319, 2956, 1704, 1532, 1435, 1359, 1175, 1097, 925,

664 cm^K1; ¹H NMR (400 MHz, CDCl₃), rotamers, d 7.73–

7.67 (m, 2H, Ar), 7.29–7.20 (m, 7H, Ar), 5.11–4.83 (m, 2H,

CH₂Ph), 4.83 (br, 1H, NH), 4.02–3.93 (m, 1H, –CH₂OTs),

3.89 (br, 1H, –CHNH(CO₂Me)), 3.82 (br, 1H, –NCHCH₂),

3.57 (s, 3H, –OCH₃), 3.66–3.36 (m, 2H, –CH₂OTs and

–NCH₂CH₂), 2.38 (s, 3H, Ar-CH₃), 2.25–2.06 (m, 1H,

–NCH₂CH₂), 1.79–1.19 (m, 5H, 1!–NCH₂CH₂and

–CH₂CH₂CH₂OTs); ¹³C NMR (100 MHz, CDCl₃),

rotamers, d 156.2, 154.9, 144.7, 136.6, 133.0, 129.8,

129.5, 128.8, 128.5, 128.0, 127.8, 126.0, 125.7, 70.5, 70.3,

70.02, 67.05, 66.9, 63.7, 55.4, 54.7, 52.1, 44.2, 43.9, 29.8,

29.6, 29.3, 28.8, 25.6, 21.6; HRMS (EI) m/z calcd for

(C₂₄H₃₀N₂O₇SCH^C): 491.1851, found: 491.1844.

1704, 1645, 1548, 1463, 1386, 1289, 1238, 1089, 1013 cm^K1

;

¹H NMR (400 MHz, CDCl₃) d 4.32 (br, 1H, NH), 3.71–3.65

(m, 1H, H₁), 3.58–3.43 (m, 1H, H₈), 3.39–3.19 (m, 1H, H₃),

2.81–2.67 (m, 2H, H₃, H₅), 2.21–2.14 (m, 3H, 2!H₂, H₅),

0

2.01–1.81 (m, 4H, 2!H₆, H₇, H₂), 1.75–1.57 (m, 2H, H₇,

0

H₃), 1.46–1.36 (m, 1H, H₃), 1.11–1.09 (m, 3H, 3!H₅),

13

0.89–0.71 (m, 3H, 3!H₄); C NMR (100 MHz, CDCl₃) d

0

71.2, 55.0, 53.8, 53.0, 42.6, 31.7, 30.1, 27.2, 25.3, 17.3, 11.8;

DEPT (100 MHz, CDCl₃) d 71.2(C), 55.0(K), 53.8(C),

53.0(K), 42.6(C), 31.7(K), 30.1(K), 27.2(K), 25.3(K),

17.3(C), 11.8(C); HRMS (EI) m/z calcd for (C₁₂H₂₂N₂OC

H^C): 211.1810, found: 211.1812.

4.10.3. trans-Methyl-hexahydro-1H-pyrrolizin-1-ylcar-

bamate (12, Scheme 3). To a solution of 11 (96 mg,

0.196 mmol) in dry ethanol (0.2 ml), cooled in an ice bath

and under argon, was added palladium over carbon (19 mg).

The reaction mixture was placed in a hydrogen atmosphere

and stirred vigorously overnight. The solvent was removed

and a KOH 2 M aqueous NaCl saturated solution (5 ml) was

added to the residue and extracted with diethyl ether (4!

5 ml). The combined organic layers were dried under

Na₂SO₄and the solvent removed in vacuo. The residue was

puriﬁed by preparative thin layer chromatography (MeOH/

CH₂Cl₂/NH₄OH, 10:89:1) to yield 12 (20 mg, 56%) as an

orange oil; R_fZ0.2 (CH₂Cl₂/MeOH/NH₄OH: 8/2/0.1, I₂);

IR (ﬁlm) n 3451, 2951, 2514, 1711, 1536, 1452, 1254, 1193,

Acknowledgements

1

909, 780, 666 cm^K1; H NMR (400 MHz, CDCl₃) d 4.2–

ˆ

This work was supported by the Fundac¸a˜o para a Ciencia e

4.15 (m, 2H, H₁and H₈), 3.93–3.68 (m, 1H, H₃), 3.9–3.63

(m, 1H, H₅), 3.6 (s, 3H, –OCH₃), 2.98–2.87 (m, 2H, H₃and

H₅), 2.32–2.18 (m, 2!H₂and 1!H₇), 2.05–1.97 (m, 1!H₆

and 1!H₇), 1.84–1.76 (m, 1!H₆); ¹³C NMR (100 MHz,

CDCl₃) d 157.1, 71.5, 55.9, 55.2, 53.2, 52.4, 31.7, 31.1,

30.0, 25.4; HRMS (EI) m/z calcd for (C₉H₁₆N₂O₂CH^C):

185.1290, found: 185.1280.

Tecnologia and FEDER (Ref. PRAXIS XXI PCEX/

QUI/53/96 and PRAXIS XXIBD/9040/96) and the National

Science and Engineering Research Council (NSERC) of

Canada. We thank Mr. Paul Lee and Mr. Timothy

McGarvey for running some preliminary experiments. We

thank Dr. A. B. Young for mass spectroscopic analysis and

Dr. A. J. Lough for X-ray crystal structure determination.

M. Norton Matos et al. / Tetrahedron 61 (2005) 1221–1244

1243

lactam: Nagasaka, T.; Tamano, H.; Maekawa, T.; Hamaguchi,

F. Heterocycles 1987, 26, 1245–1249.

References and notes

11. For an iodine promoted nitrogen nucleophilic addition to a

dihydropyridine substrate see: (a) Lavilla, R.; Coll, O.; Kumar,

R.; Coll, O.; Masdeu, C. J. Chem. Commun. 1998, 2715–2716.

(b) Lavilla, R.; Coll, O.; Kumar, R.; Bosch, J. J. Org. Chem.

1998, 63, 2728–2730.

1. For reviews see: (a) Cardillo, G.; Orena, M. Tetrahedron 1990,

46, 3321–3408. (b) Nadin, A. J. Chem. Soc., Perkin Trans. 1

1998, 3493–3513. (c) Nadin, A. Comtemp. Org. Synth. 1997,

4, 387–414. For more recent examples see: (d) Tu, T.; Dai,

L.-X. Org. Lett. 2003, 5, 3651–3653. (e) Goti, A.; Cicchi, S.;

Mannucci, V.; Cardona, F.; Guarna, F.; Merino, P.; Tejero, T.

Org. Lett. 2003, 5, 4235–4238. (f) Back, T. G.; Parvez, M.;

Zhai, H. J. Org. Chem. 2003, 68, 9389–9393. (g) Senten, K.;

12. Motherwell, W. B.; Crich, D. Free Radical Chain Reactions in

Organic Synthesis; Academic: London, 1992.

13. Stork, G.; Sher, M. J. Am. Chem. Soc. 1986, 108, 303–304.

14. (a) Houk, K. N.; Spellmeyer, D. C. J. Org. Chem. 1987, 52,

959–974. (b) Curran, D. P.; Rakiewicz, D. M. Tetrahedron

1985, 41, 3943–3958. (c) Keck, G. E.; Cressman, E. N. K.;

Enholm, E. J. J. Org. Chem. 1989, 54, 4345–4349. (d)

Beckwith, A. L. J.; Phillipou, G.; Serelis, A. K. Tetrahedron

Lett. 1981, 22, 2811–2814.

´

Van der Veken, P.; De Meester, I.; Lambeir, A.-M.; Scharpe,

S.; Haemers, A.; Augustyns, K. J. Med. Chem. 2003, 46,

5005–5014. (h) Korshin, E. E.; Bilokin, Y. V.; Zheng, H.;

Bachi, M. D. J. Am. Chem. Soc. 2004, 126, 2708–2709.

2. (a) Andres, C. J.; Lee, P. H.; Nguyen, T. H.; Meyers, A. I.

J. Org. Chem. 1995, 60, 3189–3193 and references cited

therein. (b) Smith, P. D.; Millwood, P. A.; Bailey, P. D. Chem.

Commun. 1998, 633–640. (c) Borthwich, A. D.; Crame, A.;

Exall, A.; Mason, A.; Pennell, A. Tetrahedron Lett. 1999, 40,

3061–3062. (d) Radom, M. O. Tetrahedron Lett. 1998, 39,

857–860. (e) Huang, P. Q.; Wang, S. L.; Zheng, H.; Fei, X. S.

Tetrahedron Lett. 1997, 38, 271–272. (f) Semple, J. E. Bioorg.

Med. Chem. Lett. 1998, 8, 2501–2506. (g) Chandrasekhar, S.;

Mohanty, P. K. Tetrahedron Lett. 1999, 40, 5071–5072. (h)

Dax, S. L.; Wei, C. C. J. Org. Chem. 1992, 57, 744–746. (i)

Moreno, V.; Cervantes, G.; Onoa, G. B.; Sampedro, F.;

15. Curran, D. P.; Porter, N. A.; Giese, B. Stereochemistry of

Radical Reactions: Concepts, Guidelines and Synthetic

Applications; VCH: Weinheim, 1996.

16. Liu, J.; Gin, D. Y. J. Am. Chem. Soc. 2002, 124, 9789–9797

and references therein.

17. Sunose, M.; Anderson, K. M.; Orpen, A. G.; Gallagher, T.;

Macdonald, S. J. F. Tetrahedron Lett. 1998, 39, 8885–8888.

18. Du Bois, J.; Tamooka, C. S.; Hong, J.; Carreira, E. M. J. Am.

Chem. Soc. 1997, 119, 3179–3180.

19. Hassner, A.; Heathcock, C. J. Org. Chem. 1964, 29,

3640–3645.

´

Santalo, P.; Solans, X.; Font-Bardıa, M. Polyhedron 1997, 16,

4297–4303. (j) Ghodousi, A.; Huang, X.; Cheng, Z.; Skibo,

E. B. J. Med. Chem. 2004, 47, 90–100.

20. Lemieux, R. U.; Ratcliffe, R. M. Can. J. Chem. 1979, 57,

1244–1250.

21. For an example of CAN-mediated azidomethoxylation of

alkenes see: Chavan, S. P.; Subbarao, Y. T. Tetrahedron Lett.

1999, 40, 5073–5074.

3. (a) Norton Matos, M. R. P.; Afonso, C. A. M.; McGarvey, T.;

Lee, P.; Batey, R. A. Tetrahedron Lett. 1999, 40, 9189–9193.

(b) Norton Matos, M. R. P.; Afonso, C. A. M.; Batey, R. A.

Tetrahedron Lett. 2001, 42, 7007–7010.

22. Froelich, O.; Desos, P.; Quiron, J. C.; Husson, H. P. J. Org.

Chem. 1996, 61, 6700–6705.

4. For other examples of electrophilic transformations on

endocyclic enamines see: (a) Correia, C. R. D.; Caroll, P. J.;

Sugisaki, C. H. Tetrahedron Lett. 1998, 39, 3413–3416. (b)

Hootele, C.; Plehiers, M. Tetrahedron Lett. 1993, 34,

7569–7570. (c) Shono, T.; Terauchi, J.; Ohki, Y.; Matsumura,

Y. Tetrahedron Lett. 1990, 31, 6385–6386. (d) Powell, D. A.;

Batey, R. A. Org. Lett. 2002, 4, 2913–2916. (e) Batey, R. A.;

Powell, D. A. Chem. Commun. 2001, 2362–2363. (f) Batey,

R. A.; MacKay, D. B. Tetrahedron Lett. 2000, 41, 9935–9938.

(g) Batey, R. A.; MacKay, D. B.; Santhakumar, V. J. Am.

Chem. Soc. 1999, 121, 5075–5076. (h) Batey, R. A.; Simoncic,

P.; Lin, D.; Smyj, R.; Lough, A. J. Chem. Commun. 1999,

651–652.

23. (a) Methods of Organic Chemistry. Helmchen, G., Hoffmann,

R. W., Mulzer, J., Schaumann, E., Eds.; Stereoselective

Synthesis; Houben-Weyl, 1995; Vol. E21, pp 1953–2009. (b)

Speckamp, W. N.; Moolenaar, M. J. Tetrahedron 2000, 56,

3817–3856. (c) Maryanoff, B. E.; Zhang, H.-C.; Cohen, J. H.;

Turchi, I. J.; Maryanoff, C. A. Chem. Rev. 2004, 104,

1431–1628.

24. The observed preference for a cis product in the absence of a

neighbouring group effect is consistent with similar additions

to N-acyl iminium ions. See for example: (a) Klitzke, C. F.;

Pilli, R. A. Tetrahedron Lett. 2001, 42, 5605–5608. (b)

Ungureaunu, I.; Bologa, C.; Chayer, S.; Mann, A. Tetrahedron

Lett. 1999, 40, 5315–5318. (c) Thaning, M.; Wistrand, L. G.

J. Org. Chem. 1990, 55, 1406–1408.

5. For the preparation of 1a and 1b see: Kraus, G. A.;

Neuenschwander, K. J. Org. Chem. 1981, 46, 4791–4792.

6. For the preparation of 1c and 1d see: Oliveira, D. F.; Miranda,

P. C. M. L.; Correia, C. R. D. J. Org. Chem. 1999, 64,

6646–6652 and references therein.

25. For the preparation of similar building blocks see: Macdonald,

S. J. F.; Belton, D. J.; Buckley, D. M.; Spooner, J. E.; Anson,

M. S.; Harrison, L. A.; Mills, K.; Upton, R. J.; Dowle, M. D.;

Smith, R. A.; Molloy, C. R.; Risley, C. J. Med. Chem. 1998,

41, 3919–3922 and Borthwick, A. D.; Crame, A. J.; Ertl, P. F.;

Exall, A. M.; Haley, T. M.; Hart, G. J.; Mason, A. M.; Pennell,

A. M. K.; Singh, O. M. P.; Weingartenm, G. G.; Woolven,

J. M. J. Med. Chem. 2002, 45, 1–18.

7. For a similar transformation see, Hoffman, H. M. R.; Albrecht,

U.; Wartchow, R. Angew. Chem. Int. Ed. 1992, 31, 910–913.

8. For a recent example of a NIS promoted pyrimidine addition to

a pyrrolidine enecarbamate, see: Costenaro, E. R.; Fontoura,

L. A. M.; Oliveira, D. F.; Correia, C. R. D. Tetrahedron Lett.

2001, 42, 1599–1602.

26. For a similar example of trans selectivity in N-acyliminium

reactions see: MacDonald, S. J. F.; Clarke, G. D. E.; Dowle,

M. D.; Harrison, L. A.; Hodgson, S. T.; Inglis, G. G. A.;

Johnson, M. R.; Shah, P.; Upton, R. J.; Walls, S. B. J. Org.

Chem. 1999, 64, 5166–5175.

9. Similar transformations have been performed in carbohydrate

chemistry. See for example (a) Danishefsky, S. J.; Bilodeau,

M. T. Angew. Chem., Int. Ed. Engl. 1996, 35, 1380–1419. (b)

Prinzbach, H.; Erbeck, S. Tetrahedron Lett. 1997, 38,

2653–2656.

27. (a) Mattocks, A. R. Chemistry and Toxicology of Pyrrolizidine

Alkaloids; Academic: New York, 1986. (b) Stegelmeier, B. L.;

10. Similar C–N bond instability has been already reported for a

1244

M. Norton Matos et al. / Tetrahedron 61 (2005) 1221–1244

Edgar, J. A.; Colegate, S. M.; Gardner, D. R.; Schoch, T. K.;

Coulombe, R. A.; Molyneux, R. J. J. Nat. Toxins 1999, 8, 95–

116.

Pearson, W. H.; Celebuski, J. E.; Poon, Y.-F.; Dixon, B. R.;

Glans, J. H. Tetrahedron Lett. 1986, 27, 6301–6304. (e) Giri,

N.; Petrini, M.; Profeta, R. J. Org. Chem. 2004, 69,

7303–7308.

28. (a) Robins, D. J. J. Nat. Prod. 1992, 9, 313–321. (b) Robins,

D. J. J. Nat. Prod. 1993, 10, 487–495. (c) Robins, D. J. J. Nat.

Prod. 1994, 11, 613–616. (d) Liddell, J. R. J. Nat. Prod. 1995,

12, 413–418. (e) Liddell, J. R. J. Nat. Prod. 1996, 13, 187–193.

(f) Liddell, J. R. J. Nat. Prod. 1997, 14, 653–659.

31. (a) Poupat, C.; Christine, C. M.; Ikhiri, K.; Ahond, A.;

Mourabit, A. A.; Potier, P. Tetrahedron 2000, 56, 1837–1850.

(b) Neuner-Jehle, N.; Nesvadba, H.; Spiteller, G. Monatsh.

Chem. 1965, 96, 321–338.

29. (a) Suri, K. A.; Suri, O. P.; Atal, C. K. Indian J. Chem. 1983,

22B, 822–823. (b) Flynn, D. L.; Zabrowski, D. L.; Becker,

D. P.; Nosal, R.; Villamil, C. I.; Gullikson, G. W.; Moummi,

C.; Yang, D.-C. J. Med. Chem. 1992, 35, 1486–1489. (c)

Tofern, B.; Kaloga, M.; Witte, L.; Hartmann, T.; Eich, E.

Phytochemistry 1999, 51, 1177–1180. (d) Justus, M.; Witte,

L.; Hartmann, T. Phytochemistry 1997, 44, 1177–1180. (e)

Wilson, R. S.; Sawicki, R. A.; Huffman, J. C. J. Org. Chem.

1981, 46, 3887–3891.

32. Mandal, A. K.; Brown, H. C. J. Org. Chem. 1980, 45, 916–917.

33. Zaidlewicz, M. In Wilkinson, G., Stone, F. G. A., Abel, E. W.,

Eds.; Comprehensive Organometallic Chemistry; Pergamon:

Oxford, 1981; Vol. 7, p 34.

34. (a) Paquette, L. A. Encyclopedia of Reagents for Organic

Synthesis; Wiley: England, 1995; pp 3545–3547. (b) Ley,

S. V.; Norman, J.; Grifﬁth, W. P.; Marsden, S. P. Synthesis

1994, 639–666.

35. Kabalka, G. W.; Varma, M.; Varma, R. S.; Srivastava, P. C.;

Knapp, F. F. J. Org. Chem. 1986, 51, 2386–2388.

36. Janda, K. D.; Ashley, J. A. Synth. Commun. 1990, 20,

1073–1082.

30. For some synthetic approaches to the 1-substituted-pyrrolizi-

dine unit see: (a) Adams, R.; Miyani, S.; Flus, D. J. Am. Chem.

Soc. 1960, 82, 1466–1468. (b) Culvenor, C. C. J.; Smith, L. W.

Aust. J. Chem. 1959, 12, 255–263. (c) Wasserman, H. H.;

Dion, R. P. Tetrahedron Lett. 1982, 23, 1413–1416. (d)

37. Lyster, M. A.; Jung, E. M. Chem. Comm. 1978, 315–316.

Article Doi

Synthesis of substituted pyrrolidines and piperidines from endocyclic enamine derivatives. Synthesis of (±)-laburnamine

DOI: 10.1016/j.tet.2004.11.035

Source and publish data:

Authors:

Article abstract of DOI:10.1016/j.tet.2004.11.035

Full text of DOI:10.1016/j.tet.2004.11.035

Products guided by the article

R&D Labs maybe for 141197-02-6

Relevant to this article

Hot Product