Enantiospecific synthesis and receptor binding of novel dopamine receptor ligands employing natural 4-hydroxyproline as a practical and flexible building block

TETRAHEDRON:

ASYMMETRY

Pergamon

Tetrahedron: Asymmetry 14 (2003) 3153–3172

Enantiospeciﬁc synthesis and receptor binding of novel dopamine

receptor ligands employing natural 4-hydroxyproline as a

practical and ﬂexible building block

Cornelia Heindl, Harald Hu¨bner and Peter Gmeiner*

Department of Medicinal Chemistry, Emil Fischer Center, Friedrich-Alexander University, Schuhstr. 19,

D-91052 Erlangen, Germany

Received 3 June 2003; revised 15 August 2003; accepted 19 August 2003

Abstract—Starting from natural 4-hydroxyproline, an ex-chiral pool approach is described giving access to 2-aminoalkylpyrro-

lidine derivatives that were used as chiral building blocks for the synthesis of bioactive 2-methoxybenzamide derivatives. The

4-hydroxy substituent can be displaced employing organocuprates as useful carbanion equivalents. Dopamine and serotonin

binding studies involving the subtypes D1, D2_long, D2_short, D3 and D4 as well as 5-HT1_Aand 5-HT2, respectively, provided

interesting insights into stereoselective structure activity relationships. The (2S,4R)-2-aminomethylpyrrolidine derivative ent-66

and the (2R,4S)-2-aminoethylpyrrolidine derivative 68 showed remarkable afﬁnity and preference for the dopamine D3 and D4

receptor subtypes, respectively, both being putatively associated to the symptoms of schizophrenia.

1. Introduction

exploiting chemo-, regio- and stereoselective functional

group transformations at the 2- and 4-positions of the

pyrrolidine moiety. Subsequent coupling reactions of

these compounds with pharmacophoric 2-methoxyben-

zoic acid derivatives were performed leading to target

compounds of type 1 in a variety of stereochemical

conﬁgurations (Scheme 1). Finally, dopamine and sero-

tonin receptor binding studies were done to gain

insights into structure activity relationships, especially

with respect to the stereochemistry of the test

compounds.

In connection with our program on the development of

atypical antipsychotic 2-methoxybenzamide deriva-

tives,¹we have reported a ﬂexible approach to enan-

tiomerically pure dopamine receptor ligands with

4-amino- and 4-aminomethylprolinol substructure when

a practical ex-chiral pool synthesis starting from natu-

ral 4-hydroxyproline was employed.²Dopamine and

serotonin receptor binding studies involving the sub-

types D1, D2_long, D2_short, D3 and D4 as well as 5-HT1_A

and 5-HT2 displayed interesting structure activity rela-

tionships, especially with respect to the absolute and

relative conﬁguration of the test atoms within the

diaminopropane substructure. In order to decrease D2

related extrapyramidal side-effects,³an extension of the

study was envisioned involving a structural hybridiza-

tion of the antipsychotic drug sulpiride and our previ-

ously developed D3 ligand FAUC 21.⁴We herein

describe an ex-chiral pool synthesis of 2-aminomethyl-

4-hydroxy-pyrrolidines as well as their 2-aminoethyl

homologues starting from natural 4-hydroxyproline by

* Corresponding author. Tel.: +49-9131-8529383; fax: +49-9131-

8522585; e-mail: gmeiner@pharmazie.uni-erlangen.de

Scheme 1.

doi:10.1016/j.tetasy.2003.08.020

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C. Heindl et al. / Tetrahedron: Asymmetry 14 (2003) 3153–3172

LiCN resulted in formation of the nitriles 12 and 13 in

2. Synthesis

51 and 70% yield, respectively.^2,7–12During the synthe-

sis that obviously proceeded through an aziridinium

intermediate, rearrangement occurred giving the pipe-

ridine derivatives 15 and 17 as side products.^9,10,12–18In

the case of the trans-substituted derivatives, the pyrro-

lidine- and the piperidine-derivatives were formed in a

7:3 mixture of isomers. For the cis-isomers an 8:2 ratio

was observed. Structural determination was performed

by ¹H NMR and mass spectroscopy displaying diagnos-

tic a-cleavage in the neighborhood of the amine nitro-

gens. Reduction of the carbonitriles 12 and 15 gave

access to the primary amines 14 and 16.⁴Following an

alternative pathway renouncing temporary O-protec-

tion, selective functionalization^2,7–9,11was accomplished

by reduction of the ethyl esters 6 and 7^2,12and subse-

quent regiocontrolled activation of the primary alcohol

functionality of the hydroxyprolinols 19 and 20 with

SOCl₂resulting in the formation of alkyl halides 21 and

22 that were isolated as analytically pure hydrochlo-

rides in 74 and 80% yield, respectively.¹⁹Employing

classical Kolbe conditions (NaCN, EtOH 80%,

reﬂux)^13,18crude 21 and 22 were transformed into the

carbonitriles 23 and 24 besides minor amounts of the

respective C-2 epimers and the rearrangement products

27 and 28. LiAlH₄promoted reduction of 23 and 24

afforded the aminoethyl substituted hydroxypyrrolidi-

nes 25 and 26 that were used in their crude form for

coupling reactions with pharmacophoric methoxyben-

zoic acids. Preparation of the corresponding 2-

aminomethyl derivatives 4 and 5 was also done starting

from the precursors 6 and 7, respectively, employing

subsequent aminolysis and reduction.^6,20,21The optical

antipodes ent-25, ent-26, ent-4 and ent-5 were readily

synthesized along the same reaction sequence starting

from ent-6 and ent-7 in comparable yields. As an

extension, the piperidine derivative 15 was transformed

into the conformationally constrained GABA analogue

18 by reﬂuxing 15 in concentrated HCl (99% yield).²²

Our initial synthetic investigations were directed to the

preparation of 2-aminomethyl- and 2-aminoethyl-4-

hydroxypyrrolidines in all possible stereoisomeric forms

when a benzyl group was utilized as a pharmacophoric

unit directed at the pyrrolidine nitrogen. Our synthetic

route involved chemo- and regioselective functional

group transformations of 4-hydroxyproline derivatives

using the readily available trans-substituted ethyl ester

6, the corresponding diastereomeric ethyl ester 7 as well

as the antipodes ent-6 and ent-7 as the central building

blocks.²Two alternative synthetic pathways leading to

N-benzyl-substituted 2-aminoethylpyrrolidine deriva-

tives 14, 25 and 26 were elaborated (Scheme 2).

Following the ﬁrst strategy, the functionalization

involved a temporary O-silylation of 6 and 7.^5–9Reduc-

tion of the thus obtained silylethers 8 and 10 with

LiAlH₄gave the primary alcohols 9 and 11, respec-

tively.^5,7In the case of the cis-substituted derivative 10,

the reaction time had to be shortened to circumvent

cleavage of the silylether function. Under these condi-

tions the desired alcohol 11 was isolated only in moder-

ate yield (26%) besides the diol 20. Successive

O-activation of the protected hydroxyproline-deriva-

tives 9 and 11 and nucleophilic displacement using

Bearing in mind that the hydrophobic effects played an

important role in receptor binding, we tried to

exchange the hydroxyl function at the 4-position of the

pyrrolidine moiety by lipophilic alkyl substituents

(Scheme 3).

For an EPC synthesis of 4-alkylpyrrolidines²³we took

advantage of our previously described displacement

reactions at the 4-position of proline derivatives.²Start-

ing from the secondary alcohol 7, the introduction of

nucleophiles was accomplished by O-sulfonylation and

treatment of the intermediate 38 with organo cuprates

(Me₂CuLi or Bu₂CuLi)^10,24–28or Grignard reagents

(MeMgBr, PrMgCl). Employing Gilman cuprates, the

success of the synthesis of the 4-alkyl substituted

derivatives 39 and 40 was strongly dependent on the

amount of nucleophile used for the reaction. For the

preparation of the 4-methyl derivative 39, 7 equivalents

of the cuprate reagent (Me₂CuLi) resulted in formation

of the desired product in 70% yield. The ester function

was preserved under these reaction conditions. Epimer-

ization at the 2-position could not be observed. On the

other hand, the use of 7 equivalents of Bu₂CuLi under

Scheme 2. Reagents and conditions: (a) NH₃in MeOH, rt, 10

days (2: 98%, 3: 98%); (b) LiAlH₄, Et₂O, reﬂux, 2 days (4:

95%, 5: 89%); (c) 6, TBSCl, imidazole, DMF, 0°C/3 hrt/7 h

(89%) or: 7, TBSCl, imidazole, DMF, 0°Crt/24 h (96%); (d)

LiAlH₄, THF, 0°C, 2 h (99%); (e) LiAlH₄, THF, 0°C, 10 min

(26%); (f) 1. NEt₃, Ms₂O, CHCl₃, 0°C, 3 h; 2. LiCN (0.5 M

in DMF), 0°Crt, 24 h (12: 51%, 15: 18%, 13/17: 84%); (g)

LiAlH₄, Et₂O, 0°C, 2 h (14: 64%, 16: 81%); (h) conc. HCl,

reﬂux, 2 h (18×HCl: 99%); (i) LiAlH₄, THF, 0°C, 1 h (19:

98%, 20: 98%); (j) SOCl₂, CHCl₃, reﬂux, 3.5 h (21×HCl: 74%,

22×HCl: 80%); (k) NaCN, EtOH (80%), reﬂux, 24 h (23, 24,

27, 57%, 23, 24, 28, 76%); (l) LiAlH₄, THF, 0°C, 1 h.

C. Heindl et al. / Tetrahedron: Asymmetry 14 (2003) 3153–3172

3155

The synthesis of the cis-diastereomers 30 and 31 was

performed starting from the tosylate 29 which was

readily available from the hydroxyprolinate 6. Treat-

ment of 29 with 7 equivalents of Me₂CuLi obtained the

desired 4-methylproline derivative 30 in only 11% yield

along with the tertiary alcohol 32 as the main product

(55%). For the synthesis of the 4-butylproline 31, we

initially employed 1.8 equivalents of Bu₂CuLi as

applied for the synthesis of the trans-derivative 40 when

24% of the desired cis-4-butyl-derivative 31 was iso-

lated. As already observed for the trans-derivatives, a

reductive elimination occurred giving 34% of the ring-

opened derivative 34. Increasing the amount of Gilman

reagent to 11 equivalents, 45% of 31 was obtained.

Cyanocuprates^28–31or the use of Kochi’s catalyst^32–34

proved not to be advantageous for the synthesis of the

cis-substituted derivatives since selective attack at the

carboxylate function occurred, affording 32 or 33 in

80–86% yield, respectively. Reacting organomagnesium

cuprates^28,31,35,36with the tosylates 29 and 38 furnished

the iodides and 36 and ent-35, respectively, with com-

plete inversion. Starting from the trans-substituted

tosylate 29, we succeeded in a phenylation by organo-

zinc reagents.^37–40In order to create a suitable leaving

group for a Negishi coupling,⁴¹replacement of the tosyl

function by an iodo-substituent⁴²was performed upon

reﬂuxing 29 and NaI in acetone to give a diastereomeric

mixture of the iodides 35 and 36, which were then

separated by ﬂash chromatography. NOE experiments

established the inversion of stereochemistry at the 4-

position during the displacement reactions. Metalation

of 35 and 36 with Zn and subsequent palladium assisted

coupling with iodobenzene resulted in formation of the

4-phenylpyrrolidine 37 as a mixture of diastereomers in

55% yield besides the ring-opening product 34.^37–40

Interestingly, exclusive formation of the protected allyl-

glycine 34 in 94% yield was accomplished when reacting

only the cis-diastereomer 36 under identical reaction

conditions. To circumvent the problem of chemoselec-

tivity during the nucleophilic attack, the displacement

reaction at the 4-position was performed after reducing

the carboxylate function at the 2-position. Thus, the

ethyl ester 38 was reacted with LiAlH₄to afford the

primary alcohol 44 (92%).^5,7Subsequent O-protection^5–

9 using TBSCl in the presence of imidazole gave access

to the protected tosylate 45 in 95% yield, which was

readily transformed to the protected 4-alkylpyrolinol

derivatives 46 and 47 upon treatment of 45 under

Grignard reaction conditions with MeMgBr and

PrMgCl, respectively.

Scheme 3. Reagents and conditions: (a) Ref. 2; (b) Me₂CuLi (7

equiv.), Et₂O, 0°C, 2 h (30: 11%, 32: 55%); Li₂CuCl₄,

MeMgBr, THF, 0°C, 3 h (32: 86%); n-Bu₂CuLi (1.8 equiv.),

Et₂O, −20°C, 2 h (31: 24%) or: n-Bu₂CuLi (11 equiv.), Et₂O,

−20°C, 3.5 h (31: 45%) or n-Bu₂CuCNLi₂(1 equiv.), Et₂O,

−40°C, 3 h (33: 80%), (c) NaI, acetone, reﬂux, 48 h (35/36:

97%); (d) 35/36, Zn, DMF, Pd₂(dba)₃, P(o-Tol)₃, C₆H₅I, rt, 24

h (37: 55%) or: 36, Zn, DMF, Pd₂(dba)₃, P(o-Tol)₃, C₆H₅I, rt,

24 h (34: 94%); (e) Ref. 2; (f) Me₂CuLi (7 equiv.), Et₂O, 0°C,

1.5 h (39: 70%) or: n-Bu₂CuLi (1.8 equiv.), Et₂O, −20°C, 2 h

(40: 74%) or: Bu₂CuLi (7 equiv.), Et₂O, −20°C, 1 h (41: 74%);

(g) LiAlH₄, THF, 0°C, 1 h (92%); (h) TBSCl, imidazole,

DMF, 0°Crt, 24 h (95%); (i) MeMgBr, Et₂O, 0°C, 90

minrt, 5 h (46: 75%); n-PrMgCl, Et₂O, 0°C/90 minrt/3 h

(47: 79%); (j) 5 M HCl, 60°C, 48 h (42×HCl, 43×HCl, 99%).

identical conditions gave nucleophilic attack at both

possible reaction centers resulting in the formation of

74% of the tertiary alcohol 41. Reducing the amount of

Bu₂CuLi to 1.8 equivalents, 40 was synthesized in 74%

yield along with the protected allylglycine ent-34 as a

side product that is obviously formed by metallation

and subsequent b-elimination. NOE experiments clearly

established the trans-conﬁguration of 39 and 40 and

thus the S_N2-type character of the coupling reaction.

Hydrolylsis of the ethyl ester functions gave the N-pro-

tected 4-alkylprolines 42 and 43. Starting from the

building block ent-7, the optical antipodes ent-42 and

ent-43 could be prepared under identical reaction con-

ditions. In order to investigate the stereochemical

integrity of the reaction sequence, HPLC analysis on a

chiral stationary phase was performed indicating an

enantiomeric purity of >99%.

Further functional group transformations at the 2-posi-

tion of the pyrrolidine moiety of the 4-alkylproline

derivatives 39 and 40 led to the respective 2-

aminomethyl- and aminomethylpyrrolidines 50, 58 and

51, 59, respectively, as shown in Scheme 4.

In particular, the reactive intermediates 54 and 55 were

synthesized from 39 and 40 by LiAlH₄-reduction^5,7and

activation of the resulting primary alcohols 52 or 53 by

SOCl₂.²⁰Nucleophilic displacement of crude 54 and 55

under Kolbe conditions^13,18resulted in the formation of

the nitriles 56 and 57 in high overall yield along with

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C. Heindl et al. / Tetrahedron: Asymmetry 14 (2003) 3153–3172

bovine striatal membranes and the selective antagonist

[³H]SCH 23390 as a radioligand.⁴⁶Binding studies on

the subtypes of the D2 family were performed using

membrane preparations of CHO cells stably expressing

43

the human dopamine receptors D2_long, D2_short

,

D3⁴⁴

and D4.4⁴⁵and [³H]spiperone as the radioligand. Since

both dopamine and serotonin receptors play an impor-

tant part in psychotic disorders and some methoxy-

benzamides are known for their serotoninergic

properties,⁴⁷5-HT-binding was also investigated

employing porcine cortical membrane preparations

and

the

radioligands

[³H]8-OH-DPAT

and

[³H]ketanserin for 5-HT1_Aand 5-HT2, respectively.

The antipsychotic drug sulpiride and the D3 receptor

preferring ligand FAUC 21 were utilized as reference

compounds. The results are presented in Table 1 (K_i

values in nM as means of two to three competition

experiments). Binding data provided interesting results

concerning the binding afﬁnity and receptor subtype

selectivity with respect to the substitution pattern and

the stereochemical entities of the pyrrolidine moiety.

In particular, the aminomethylpyrrolidine derivatives

62, 63, ent-62 and ent-63 displayed substantial afﬁni-

Scheme 4. Reagents and conditions: (a) NH₃, MeOH, rt, 10

days (48: 94%, 49: 66%); (b) LiAlH₄, Et₂O, reﬂux, 24 h (50:

85%, 51: 96%); (c) LiAlH₄, THF, 0°C, 30–60 min, (52: 92%,

53: 98%); (d) SOCl₂, CHCl₃, reﬂux, 4–24 h; (e) 54 or 55,

SOCl₂, CHCl₃, reﬂux, 4 h; (e) NaCN, EtOH (80%), reﬂux,

24–48 h (49–72%); (f) LiAlH₄, THF, 0°C, 1 h.

the cis-epimers 60 and 61. Finally, reduction of the

carbonitriles 56 and 57 afforded the primary amines

58 and 59, respectively. Preparation of the correspond-

ing aminomethylpyrrolidines 50 and 51 was accom-

plished starting from 39 or 40 by aminolysis of the

ester function and further reduction.^6,19,21The

antipodes ent-50, ent-51 as well as their homologues

ent-58 and ent-59 were synthesized along the same

sequence starting from ent-39 and ent-40.

ties to the subtypes of the D2 family including D2_long

,

D2_short, D3 and D4.4. In contrast, the aminoethyl sub-

stituted homologues showed only modest receptor

binding indicating, as already observed for our previ-

ously developed nemonapride analogues,²that the dis-

tance between the basic pyrrolidine nitrogen and the

methoxybenzamide functionality as the major pharma-

cophoric elements is crucial for the receptor recogni-

tion. With regard to the aminomethylpyrrolidine

derivatives, the (2R)-conﬁgured isomers showed sub-

stantially higher binding afﬁnities compared to the

(2S)-stereoisomers. Among the (2R)-isomers, the

(2R,4S)-derivative 63 displayed high binding afﬁnity

but poor subtype selectivity. Compared to the 4-

hydroxy-substituted derivatives, the binding afﬁnities

of the 4-alkylpyrrolidines were generally higher. Look-

ing at the trans-substituted derivatives, the 4-methyl

substituted target compound ent-66 displayed high D3

afﬁnity with a K_ivalue of 20 nM and a selectivity

pattern of 700, 17, 14, 73, 37 and 150 when compared

to D1 (K_i=14000 nM), D2_long(K_i=330 nM), D2_short

(K_i=280 nM), D4 (K_i=1500 nM), 5HT1A (K_i=740

nM) and 5HT2 (K_i=3000 nM), respectively. In com-

parison to sulpiride, an increased D3/D4- and D2/D3-

For the synthesis of the target compounds of type 1,

DCC/HOBt promoted coupling of the amines 25, 26,

4, 5, 58 and 59 as well as their antipodes ent-25,

ent-26, ent-4, ent-5, ent-58 and ent-59 to 5-chloro-2-

methoxy-4-methylaminobenzoic acid gave access to the

2-methoxybenzamides 62–69 as well as to their

antipodes ent-62–ent-69, respectively (Scheme 5).

selectivity

was

noticed

for

ent-66.

The

(2R,4S)-conﬁgured 4-butylpyrrolidine 68 displayed

high D4 afﬁnity with a K_ivalue of 8 nM and a

selectivity of 118, 275 and 200, when compared to D3

(K_i=945 nM), 5HT1A (K_i=2200 nM) and 5HT2

(K_i=1600 nM), but with low selectivity (4,3), when

compared to D2_long(K_i=35 nM) and D2_short(K_i=21

nM).

Scheme 5.

3. Pharmacology

The novel methoxybenzamide derivatives were evalu-

ated in vitro with respect to their binding afﬁnities and

receptor subtype selectivities by radioligand binding

assays for the dopamine receptors D1–D4^43–46and for

the serotonin receptors 5-HT1_Aand 5-HT2. Afﬁnities

for the D1 receptor were determined by employing

In conclusion, chirospeciﬁc transformations of hydroxy-

proline derivatives led to a number of bioactive

methoxybenzamides displaying receptor binding proﬁ-

les that proved strongly dependant on the absolute

and relative conﬁguration of the test compounds.

C. Heindl et al. / Tetrahedron: Asymmetry 14 (2003) 3153–3172

3157

Table 1. Binding afﬁnities of the methoxybenzamides 62–69, ent-62–ent-69 and the reference compounds sulpiride and

FAUC 21 to the bovine dopamine D1, the human D2_long, D2_short, D3 and D4.4 as well as to the porcine 5-HT1_Aand

5-HT2 receptors

Compound

R

Pos. 2

Pos. 4

n

K_ivalues [nM]^a

[³H]Spiperone

[³H]SCH23390

D1

[³H]8-OH-DPAT [³H]Ketanserin

D2_longD2_shortD3

D4.4

120

2500

42

5-HT1_A

5-HT2

62

ent-62

63

ent-63

64

ent-64

65

ent-65

66

ent-66

67

ent-67

68

ent-68

69

OH

Me

R

S

R

S

R

S

R

S

R

S

R

S

R

S

R

S

R

S

R

S

R

S

R

S

R

S

R

1

2

1

2

12000

3600

500

440

19

1800

320

2900

2700

5300

67

330

230

35

530

24

480

1300

14

430

500

29

1300

2600

410

2400

3100

530

11000

14000

28000

14000

62000

6700

14000

930

7200

16000

17000

2400

7000

50000

2800

2100

190

2000

3800

42

510

1300

8600

2400

20000

140

20

40000

100

8400

1100

21000

800

5100

2400

8200

3000

2500

1800

740

9000

1200

15000

4800

15000

2300

3000

3100

2900

1600

2200

3800

1600

4300

n.d.

Me

280

92

1500

260

n-Bu

Me

n-Bu

67

850

120

21

600

15

96

51

52

1000

1600

2200

650

3700

1400

9800

n.d.

950

1600

540

310

88

8.0

370

160

130

2100

200

ent-69

Sulpiride

FAUC 21

140

120

190

31

^aK_ivalue in [nM] are the means of two to three competition experiments each done in triplicate.

4. Experimental

4.2. (2S,4R)-1-Benzyl-4-hydroxypyrrolidine-2-carbox-

amide 2

4.1. General procedures

A solution of 6²(1.098 g, 4.4 mmol) and MeOH saturated

with NH₃(30 mL) at −20°C were allowed to warm up

to rt and stirred for 10 days. The solvent was then

removed under reduced pressure to give pure 2 (0.95 g,

98%) as a yellowish, crystalline solid. Mp: 39°C; EI-MS

m/z=220 [M⁺]; TLC: R_f=0.17 (CH₂Cl₂/MeOH=95:5);

IR (ﬁlm): w 3421, 1670, 1454, 1333, 1127, 1082, 735, 700

Et₂O, THF and toluene were distilled from Na,

CHCl₃, CH₂Cl₂from CaH₂, and EtOH from Mg

immediately before use. Dry DMF, DMSO and dry

pyridine were purchased from FLUKA. All liquid

reagents were puriﬁed by distillation. All reactions

were conducted under anhydrous N₂. Evaporation of

the ﬁnal product solution was performed under vac-

uum with a rotatory evaporator. Flash chromatogra-

phy was carried out with 230–400 mesh silica gel.

Melting points: Bu¨chi melting point apparatus, uncor-

rected. IR spectra: PERKIN–ELMER FT/IR 241 or

Jasco FT/IR 410 spectrometer. Mass spectra: FINNI-

GAN MAT TSQ 70 instrument. High resolution mass

1

cm⁻¹; H NMR (CDCl₃, 360 MHz): l 2.10 (ddd, 1H,

J=13.4, 8.2, 6.6 Hz, H-3a), 2.25 (ddd, 1H, J=13.4, 8.2,

4.2 Hz, H-3b), 2.48 (dd, 1H, J=10.6, 4.5 Hz, H-5a), 3.30

(dd, 1H, J=10.6, 5.5 Hz, H-5b), 3.54 (dd, 1H, J=8.2,

8.2 Hz, H-2), 3.63 (d, 1H, J=13.0 Hz, NCH₂Ph), 3.98

(d, 1H, J=13.0 Hz, NCH₂Ph), 4.41 (m, 1H, H-4), 5.54

(brs, 1H, NH₂), 7.13 (brs, 1H, NH₂), 7.24–7.38 (m, 5H,

Ar); Anal. calcd for C₁₂H₁₆N₂O₂(220.27): C, 65.43; H,

7.32; N, 12.72, found: C, 65.44; H, 7.26; N, 12.79;

[h]²_D⁰=−79.6 (c 1.0, CHCl₃).

1

spectrometry: FINNIGAN MAT 8200. H NMR and

¹³C NMR spectra: BRUKER AM 360 spectrometer

at 360 and 90 MHz. Spectra were measured in CDCl₃

using TMS as an internal standard. Optical rotations

were measured at 23°C with a PERKIN–ELMER

241 polarimeter. Elementary analyses were performed

by the Organic Chemistry Department of the

Friedrich-Alexander-University Erlangen-Nu¨rnberg or

by Beetz Microanalysis Laboratory, Kronach, Ger-

many. For all new compounds satisfactory micro-

analyses were obtained C 0.39, H 0.17, N 0.29,

S 0.13.

ent-2²¹was prepared under the same reaction conditions

as described for 2, starting from ent-6; [h]²_D⁰=+76.5 (c 1.0,

CHCl₃).

4.3. (2R,4R)-1-Benzyl-4-hydroxypyrrolidine-2-carbox-

amide 3

A mixture of 7 (725 mg, 2.9 mmol) and sat. NH₃/

MeOH (20 mL) was reacted and worked up as

3158

C. Heindl et al. / Tetrahedron: Asymmetry 14 (2003) 3153–3172

described for 2 to give pure 3 (627 mg, 98%) as a yellow

solid. Mp: 78–79°C; EI-MS m/z=220 [M⁺]; TLC: R_f=

0.30 (CH₂Cl₂/MeOH=9:1); IR (ﬁlm): w 3418, 1668,

(m, 2H, CH6 ₂NH₂/H-2), 3.62 (d, 1H, J=13.4 Hz,

NCH₂Ph), 3.82 (d, 1H, J=13.4 Hz, NCH₂Ph), 4.09 (m,

1H, H-4), 7.19–7.33 (m, 5H, Ar); HR-EIMS: 176.10783

(Anal. calcd for C₁₁H₁₄NO: 176.10754); [h]²_D⁰=+30.3 (c

1.0, CHCl₃).

1

1453, 1311, 1124, 1085, 700 cm⁻¹; H NMR (CDCl₃,

360 MHz): l 1.99 (brdd, 1H, J=14.2, 4.5 Hz, H-3a),

2.51 (m, 2H, H-3b/H-5a), 3.04 (brd, 1H, J=10.3 Hz,

H-5b), 3.24 (dd, 1H, J=10.8, 4.5 Hz, H-2), 3.53 (d, 1H,

J=13.0 Hz, NCH₂Ph), 3.96 (d, 1H, J=13.0 Hz,

NCH₂Ph), 4.34 (m, 1H, H-4), 7.39–7.17 (m, 5H, Ar);

¹³C NMR (CDCl₃, 62.90 MHz): l 39.97 (C-3), 59.27

(NCH₂Ph), 61.54 (C-5), 66.02 (C-2), 70.73 (C-4),

ent-5 was prepared under the same reaction conditions

as described for 5, starting from ent-5; [h]²_D⁰=−21.6 (c

0.08, CHCl₃).

4.6. Ethyl (2S,4R)-1-benzyl-4-(tert-butyldimethylsilyl-

oxy)prolinate 8

127.42, 128.51, 128.78, 137.89 (C-Ar), 177.89 (C6 ONH₂);

Anal. calcd for C₁₂H₁₆N₂O₂(220.27): C, 65.43; H, 7.32;

N, 12.72, found: C, 65.48; H, 7.39; N, 12.65; [h]²_D⁰=

+39.6 (c 1.0, CHCl₃).

To a solution of 6 (1.6 g, 6.2 mmol) in DMF (250 mL)

was added imidazole (1.3 g, 18.7 mmol) and TBSCl

(1.4g, 9.4 mmol) at 0°C. After stirring at 0°C for 3 h,

the mixture was allowed to warm up to rt and stirring

continued for another 7 h. An aqueous saturated solu-

tion of NH₄Cl was then added and the reaction mixture

extracted with Et₂O. The organic layer was dried over

MgSO₄and evaporated. The residue was puriﬁed by

ﬂash chromatography (petroleum ether/EtOAc=7:3) to

give 8 (2.0 g, 89%) as a colorless oil; EI-MS m/z=363

[M⁺] TLC: R_f=0.69 (petroleum ether/EtOAc=1:1); IR

(ﬁlm): w 3086–2801, 1747, 1471, 1375, 1255, 1181, 1096,

ent-3 was prepared under the same reaction conditions

as described for 3, starting from ent-7; [h]²_D⁰=−42.9 (c

0.9, CHCl₃).

4.4. (3R,5S)-5-Aminomethyl-1-benzylpyrrolidin-3-ol 4

To a stirred solution of 2 (48.5 mg, 0.22 mmol) in Et₂O

(10 mL) was added LiAlH₄(0.88 mL, 1 M solution in

Et₂O) and the resulting mixture left to reﬂux for 2 days.

After cooling to rt, the mixture was worked up as

described for 19 (extraction was performed with

MeOH, eluent for ﬂash chromatography: CH₂Cl₂/

MeOH=8:2+3 mL of NH₃-saturated MeOH) to leave

pure 4²¹(43.2 mg, 95%) as a colorless crystalline solid.

Mp: 157–158°C; CI-MS m/z=207 [M+1⁺]; TLC: R_f=

0.18 (CH₂Cl₂/MeOH=8:2+3 mL of NH₃-saturated

MeOH/500 mL eluent); IR (ﬁlm): w 3352, 1572, 1453,

1

1031, 835, 776, 700 cm⁻¹; H NMR (CDCl₃, 360 MHz):

l

0.02 (s, 6H, OSi(CH_{3 2}

6

) tBu), 0.09 (s, 9H,

),

OSi(CH₃)₂tBu), 1.23 (t, 3H, J=7.0 Hz, CO₂CH₂CH₃

6

2.01 (ddd, 1H, J=12.9, 8.2, 4.3 Hz, H-3a), 2.17 (ddd,

1H, J=12.9, 7.8, 7.4 Hz, H-3b), 2.34 (dd, 1H, J=9.7,

5.1 Hz, H-5a), 3.23 (dd, 1H, J=9.7, 5.7 Hz, H-5b), 3.49

(dd, 1H, J=8.2, 7.8 Hz, H-2), 3.56 (d, 1H, J=12.7 Hz,

NCH₂Ph), 3.92 (d, 1H, J=12.7 Hz, NCH₂Ph), 4.10 (m,

1

1331, 1122, 1027, 743, 700 cm⁻¹; H NMR (CDCl₃, 360

2H, CO₂CH6 ₂CH₃), 4.39 (m, 1H, H-4), 7.20–7.34 (m,

MHz): l 1.83 (ddd, 1H, J=13.2, 7.8, 4.0 Hz, H-4a),

2.02 (ddd, 1H, J=13.2, 7.7, 7.6 Hz, H-4b), 2.34 (dd,

1H, J=10.4, 4.8 Hz, H-2a), 2.75 (dd, 1H, J=13.1, 2.9

5H, Ar); Anal. calcd for C₂₀H₃₃NO₃Si (363.58): C,

66.07; H, 9.15; N, 3.85, found: C, 65.69; H, 9.31; N,

3.81; [h]²_D⁰=−41.0 (c 1.0, CHCl₃).

Hz, CH

6 ₂NH₂), 2.83 (dd, 1H, J=13.1, 5.0 Hz,

CH₂NH₂), 2.99 (m, 1H, H-5), 3.29 (dd, 1H, J=10.4, 5.6

6

ent-8 was prepared under the same reaction conditions

as described for 8, starting from ent-6; [h]²_D⁰=+38.8 (c

1.0, CHCl₃).

Hz, H-2b), 3.47 (d, 1H, J=13.1 Hz, NCH₂Ph), 4.03 (d,

1H, J=13.1 Hz, NCH₂Ph), 4.38 (m, 1H, H-3), 7.19–

7.38 (m, 5H, Ar); HR-EIMS: 176.10749 (Anal. calcd

for C₁₁H₁₄NO: 176.10754), 188.13138 (Anal. calcd for

C₁₂H₁₆N₂: 188.13135); [h]²_D⁰=−54.6 (c 1.0, CHCl₃).

4.7. (3R,5S)-1-Benzyl-3-(tert-butyldimethylsilyloxy)-5-

hydroxymethylpyrrolidine 9

ent-4 was prepared under the same reaction conditions

as described for 4, starting from ent-2; [h]²_D⁰=+57.1 (c

0.04, CHCl₃).

A mixture of 8 (1.2 g, 3.4 mmol) and LiAlH₄(6.6 mL,

1 M solution in THF) in THF (30 mL) was reacted for

2 h and worked up (extraction with Et₂O instead of

CH₂Cl₂) as described for 19 to leave pure 9¹²(1.1 g,

99%) as yellowish crystals. Mp: 37°C; EI-MS m/z=290

(a-cleavage, [M−CH₂OH]⁺); TLC: R_f=0.14 (petroleum

ether/EtOAc=1:1); IR (ﬁlm): w 3428, 3063–2856, 1471,

4.5. (3R,5R)-5-Aminomethyl-1-benzylpyrrolidin-3-ol 5

A solution of 3 (291 mg, 1.32 mmol) in Et₂O (5 mL)

and LiAlH₄(5.3 mL, 1 M solution in Et₂O) was reacted

and worked up (CH₂Cl₂/MeOH=8:2+6 mL of NH₃-

saturated MeOH/500 mL eluent) as described for 4 to

give pure 5 (242.8 mg, 89%) as a yellow oil; EI-MS

m/z=176 (a-cleavage, [M−CH₂NH₂]⁺); TLC: R_f=0.17

(CH₂Cl₂/MeOH=8:2+6 mL of NH₃-saturated MeOH/

500 mL eluent); IR (ﬁlm): w 3363, 3061–2793, 1584,

1

1254, 1111, 1051, 835, 777 cm⁻¹; H NMR (CDCl₃, 360

MHz): l 0.02 (s, 6H, OSi(CH6 ₃)₂tBu), 0.86 (s, 9H,

OSi(CH₃)₂tBu), 1.81 (ddd, 1H, J=13.5, 8.4, 4.6 Hz,

H-4a), 2.05 (ddd, 1H, J=13.5, 13.2, 6.7 Hz, H-4b), 2.35

(dd, 1H, J=9.8, 5.7 Hz, H-2a), 3.04 (m, 1H, H-5), 3.12

(dd, 1H, J=9.8, 5.5 Hz, H-2b), 3.37 (dd, 1H, J=11.0,

1.7 Hz, CH₂OH), 3.46 (d, 1H, J=13.0, NCH₂Ph), 3.63

(dd, 1H, J=11.0, 3.4 Hz, CH₂OH), 3.95 (d, 1H, J=

13.0, NCH₂Ph), 4.25 (m, 1H, H-3), 7.20–7.36 (m, 5H,

Ar); [h]²_D⁰=−36.5 (c 1.0, CHCl₃).

1

1453, 1340, 1126, 1026, 969, 738, 700 cm⁻¹; H NMR

(CDCl₃, 360 MHz): l 1.64 (brd, 1H, J=13.7 Hz, H-3a),

2.31 (m, 2H, H-3b/H-5a), 2.45 (dd, 1H, J=9.7, 3.1 Hz,

CH6 ₂NH₂), 2.64 (dd, 1H, J=12.5, 3.3 Hz, H-5b), 2.98

C. Heindl et al. / Tetrahedron: Asymmetry 14 (2003) 3153–3172

3159

ent-9 was prepared under the same reaction conditions

as described for 9, starting from ent-8; [h]²_D⁰=+38.6 (c

1.0, CHCl₃).

Additional analytical data of ent-11: [h]²_D⁰=−45.9 (c 1.0,

CHCl₃).

4.10. (2S,4R)-[1-Benzyl-4-(tert-butyldimethylsilyloxy)-

pyrrolidin-2-yl]acetonitrile 12 and (3R,5R)-1-benzyl-5-

(tert-butyldimethylsilyloxy)piperidine-3-carbonitrile 15

4.8. Ethyl (2R,4R)-1-benzyl-4-(tert-butyldimethylsilyl-

oxy)prolinate 10

To a solution of 9 (338 mg, 1.1 mmol) in CHCl₃(15

mL) was added NEt₃(0.04 mL, 0.29 mmol) and Ms₂O

(41.8 mg, 0.2 mmol) at 0°C. After 3 h of stirring at 0°C,

a cold solution of LiCN (4 mL, 0.5 M in DMF) was

added. Then, the mixture was allowed to warm up to rt

and stirring continued for another 24 h. An aqueous

saturated solution of Na₂CO₃was added and the mix-

ture extracted with Et₂O. The combined organic layers

were dried over MgSO₄and evaporated. The residue

was puriﬁed by ﬂash chromatography (petroleum ether/

EtOAc=95:5 and successive gradient eluent: pure

petroleum ether, petroleum ether/EtOAc=95:5 to 8:2)

to give 12 (179 mg, 51%) and 15 (63.1 mg, 18%) as a

white solid, respectively.

A solution of 7 (10.8 g, 43.4 mmol) in DMF (200 mL),

imidazole (8.9 g, 130.2 mmol) and TBSCl (9.79 g, 65.0

mmol) was reacted and worked up (eluent for ﬂash

chromatography: petroleum ether/EtOAc=1:1) as

described for 8 to give 10 (15.1 g, 96%) as a colorless

oil; EI-MS m/z=363 [M⁺]; TLC: R_f=0.61 (petroleum

ether/EtOAc=6:4); IR (ﬁlm): w 2954–2856, 1741, 1471,

1

1253, 1181, 1098, 835, 776 cm⁻¹; H NMR (CDCl₃, 360

MHz): l 0.01 (s, 6H, OSi(CH

OSi(CH₃)₂tBu), 1.27 (t, 3H, J=7.0 Hz, CO₂CH₂CH₃

1.98 (ddd, 1H, J=12.8, 7.5, 5.1 Hz, H-3a), 2.41 (ddd,

1H, J=12.8, 7.5, 7.5 Hz, H-3b), 2.70 (dd, 1H, J=9.9,

6.5 Hz, H-5a), 2.94 (dd, 1H, J=9.9, 3.8 Hz, H-5b), 3.34

(dd, 1H, J=7.5, 7.5 Hz, H-2), 3.62 (d, 1H, J=13.4 Hz,

NCH₂Ph), 3.98 (d, 1H, J=13.4 Hz, NCH₂Ph), 4.16 (m,

6

₃)₂tBu), 0.75 (s, 9H,

),

6

Analytical data of 12: Mp: 26–30°C; EI-MS m/z=330

[M⁺], 290 (a-cleavage, [M−CH₂CN]⁺); TLC: R_f=0.19

(petroleum ether/EtOAc=9:1); IR (ﬁlm): w 3027–2856,

2H, CO₂CH6 ₂CH₃), 4.35 (m, 1H, H-4), 7.19–7.38 (m,

5H, Ar); Anal. calcd for C₂₀H₃₃NO₃Si (363.58): C,

66.07; H, 9.15; N, 3.85, found: C, 66.13; H, 9.04; N,

3.71; [h]²_D⁰=+42.0 (c 1.0, CHCl₃).

1

2247, 1471, 1360, 1255, 1101, 836, 777, 700 cm⁻¹; H

NMR (CDCl₃, 360 MHz):

OSi(CH₃)₂tBu), 0.04 (s, 3H, OSi(CH_{3 2}

9H, OSi(CH₃)₂C(CH₃)₃), 1.9 (m, 2H, H-3a/H-3b), 2.33

l

0.02 (s, 3H,

6

6 ) tBu), 0.87 (s,

ent-10 was prepared under the same reaction conditions

as described for 10, starting from ent-7; [h]²_D⁰=−38.5 (c

1.0, CHCl₃).

6

(dd, 1H, J=10.0, 4.8 Hz, H-5a), 2.41 (m, 2H, CH₂CN/

CH₂CN), 3.13 (m, 1H, H-2), 3.21 (dd, 1H, J=10.0, 5.7

Hz, H-5b), 3.53 (d, 1H, J=13.1 Hz, NCH₂Ph), 3.92 (d,

1H, J=13.1 Hz, NCH₂Ph), 4.36 (m, 1H, H-4), 7.21–

7.37 (m, 5H, Ar); ¹³C NMR (CDCl₃, 62.90 MHz): l

4.9. (3R,5R)-1-Benzyl-3-(tert-butyldimethylsilyloxy)-5-

hydroxymethylpyrrolidine 11 and (3R,5R)-1-benzyl-5-

hydroxymethylpyrrolidin-3-ol 20

17.96 (OSi(C

(OSi(CH₃)₂C(CH₃)₃), 41.22 (C-3), 58.66 (C-2), 59.02

(NCH₂Ph), 62.69 (C-5), 69.95 (C-4), 118.06 (CN),

6 H₃)₂tBu), 23.20 (C6 H₂CN), 25.77

6

A mixture of 10 (3.09 g, 8.49 mmol) and LiAlH₄(12.7

mL, 1 M solution in THF) in THF (50 mL) was reacted

for 10 min and worked up (petroleum ether/EtOAc=

75:25) as described for 20 to leave pure 11 (874 mg,

32%) as a weakly yellowish oil; EI-MS m/z=321 [M⁺];

290 (a-cleavage, [M−CH₂OH]⁺); TLC: R_f=0.41

(petroleum ether EtOAc=1:1); IR (ﬁlm): w 3443, 3027–

6

127.17, 128.39, 128.55, 138.92 (C-Ar); Anal. calcd for

C₁₉H₃₀N₂OSi: C, 69.04; H, 9.15; N, 8.47, found: C,

69.09; H, 9.08; N, 8.42; [h]²_D⁰=−41.0 (c 0.63, CHCl₃).

Analytical data of 15: Mp: 50–55°C; EI-MS m/z=330

[M⁺]); TLC: R_f=0.29 (petroleum ether/EtOAc=9:1);

IR (ﬁlm): w 3026–2803, 2239, 1463, 1255, 1102, 837, 776

cm⁻¹; ¹H NMR (CDCl₃, 360 MHz): l 0.03 (s, 3H,

1

2793, 1471, 1254, 1052, 835, 776, 698 cm⁻¹; H NMR

(CDCl₃, 360 MHz): l 0.04 (s, 6H, OSi(CH6 ₃)₂tBu), 0.88

(s, 9H, OSi(CH₃)₂tBu), 1.87 (ddd, 1H, J=13.6, 5.2, 3.9

Hz, H-4a), 2.21 (ddd, 1H, J=13.6, 9.6, 5.8 Hz, H-4b),

2.43 (dd, 1H, J=9.9, 4.5 Hz, H-2a), 2.88 (m, 2H,

H-2b/H-5), 3.41 (d, 1H, J=13.4 Hz, NCH₂Ph), 3.45

(brd, 1H, J=10.6 Hz, CH₂OH), 3.72 (brd, 1H, J=10.6

OSi(CH_{3 2}

9H, OSi(CH₃)₂C(CH_{3 3}

6

) tBu), 0.05 (s, 3H, OSi(CH_{3 2}

6 ) tBu), 0.08 (s,

6

) ), 1.64 (ddd, 1H, J=13.1, 8.5,

4.7 Hz, H-4ax), 2.00 (brddd, 1H, J=13.1, 5.0, 5.0 Hz,

H-4eq), 2.23 (brdd, 1H, J=11.0, 7.5 Hz, H-6a), 2.42

(brd, 1H, J=10.3 Hz, H-2a), 2.72 (m, 2H, H-2b/H-6b),

3.03 (brddd, 1H, J=8.5, 4.7, 5.0, H-3eq), 3.51 (d, 1H,

J=13.7 Hz, NCH₂Ph), 3.66 (d, 1H, J=13.7 Hz,

NCH₂Ph), 4.02 (dddd, 1H, J=8.5, 7.5, 5.0, 4.7 Hz,

H-5eq), 7.20–7.40 (m, 5H, Ar); ¹³C NMR (CDCl₃,

Hz, CH6 ₂OH), 4.02 (d, 1H, J=13.4 Hz, NCH₂Ph), 4.26

(m, 1H, H-3), 7.21–7.40 (m, 5H, Ar); Anal. calcd for

C₁₈H₃₁NO₂Si (321.54): C, 67.24; H, 9.72; N, 4.36,

found: C, 67.36; H, 9.85; N, 4.37; [h]²_D⁰=+46.2 (c 1.0,

CHCl₃).

62.90 MHz): l 18.00 (OSi(C

35.83 (C-4), 53.86 (C-2), 60.08 (C-6), 61.92 (NC

65.16 (C-5), 121.26 (CN), 127.22, 128.33, 128.62, 137.61

(C-Ar); Anal. calcd for C₁₉H₃₀N₂OSi: C, 69.04; H, 9.15;

N, 8.47, found: C, 69.09; H, 9.22; N, 8.40; [h]²_D⁰=+18.4

(c 1.0, CHCl₃).

6

H₃)₂tBu), 25.74 (C-3),

H₂Ph),

6

Compound 20 can also be isolated in pure form (1.105

g, 63%), too, when the eluent is changed to CH₂Cl₂

/MeOH=9:1.

ent-11 and ent-20 were prepared under the same reac-

tion conditions as described for 11 and 20, starting

from ent-10.

ent-12 and ent-15 were prepared under the same reac-

tion conditions as described for 12, starting from ent-9.

3160

C. Heindl et al. / Tetrahedron: Asymmetry 14 (2003) 3153–3172

4.11. (2R,4R)-[1-Benzyl-4-(tert-butyldimethylsilyloxy)-

([M−CH₂NH₂]⁺); TLC: R_f=0.32 (CH₂Cl₂/MeOH 8:2+

1.5 mL NH₃-saturated MeOH/1000 mL eluent); IR

(NaCl): w 3062–2799, 1575, 1471, 1387, 1359, 1304,

pyrrolidin-2-yl]acetonitrile 13

1

A mixture of 11 (279 mg, 0.87 mmol), NEt₃(0.36 mL,

2.60 mmol), Ms₂O (378 mg, 2.17 mmol) and then a cold

solution of LiCN (20 mL, 0.5 M in DMF) in CHCl₃(15

mL) was reacted and worked up as described for 12 to

give 13 (200.8 mg, 70%) as a colorless crystalline solid.

Mp: 40°C; EI-MS m/z=330 [M⁺], 290 (a-cleavage,

[M−CH₂CN]⁺); TLC: R_f=0.07 (petroleum ether/

EtOAc=95:5); IR (ﬁlm): w 3028–2801, 1471, 1360,

1255, 1099, 1031, 835, 776, 699 cm⁻¹; ¹H NMR (CDCl₃,

1253, 1091, 1037, 835, 775, 736, 699 cm⁻¹; H NMR

(CDCl₃, 360 MHz): l 0.01 (s, 3H, OSi(CH_{3 2}

0.03 (s, 3H, OSi(CH₃)₂C(CH₃)₃), 0.88 (s, 9H,

OSi(CH₃)₂C(CH₃)₃), 1.48 (m, 2H, H-4ax/H-4eq), 1.89

6 ) C(CH₃)₃),

6

(m, 1H, H-3), 2.23 (dd, 1H, J=10.8, 6.2 Hz, H-2a),

2.31 (dd, 1H, J=10.8, 6.3 Hz, H-2b), 2.45 (m, 2H,

CH₂NH₂/CH₂NH₂), 2.62 (dd, 1H, J=12.6, 6.2 Hz,

H-6a), 2.72 (dd, 1H, J=12.6, 8.1 Hz, H-6b), 3.38 (d,

1H, J=13.5 Hz, NCH₂Ph), 3.64 (d, 1H, J=13.5 Hz,

NCH₂Ph), 3.91 (m, 1H, H-5), 7.18–7.37 (m, 5H, Ar);

HR-EIMS: 304.20901 (Anal. calcd for C₁₈H₃₀NOSi:

304.20966), 172.11297 (Anal. calcd for C₁₂H₁₄N:

172.11263); [h]_D²⁰=+42.2 (c 0.32, CHCl₃).

360 MHz): l 0.01 (s, 3H, OSi(CH_{3 2}

3H, OSi(CH₃)₂C(CH₃)₃), 0.87 (s, 9H, OSi(CH₃)₂-

C(CH₃)₃), 1.80 (m, 1H, H-3a), 2.29 (ddd, 1H, J=13.5,

6 ) C(CH₃)₃), 0.03 (s,

6

7.8, 5.7 Hz, H-3b), 2.54 (m, 2H, CH₂CN/CH₂CN), 2.60

(dd, 1H, J=10.3, 5.1 Hz, H-5a), 2.89 (brd, 1H, J=10.3

Hz, H-5b), 3.06 (m, 1H, H-2), 3.55 (d, 1H, J=13.4 Hz,

NCH₂Ph), 3.93 (d, 1H, J=13.4 Hz, NCH₂Ph), 4.32 (m,

1H, H-4), 7.22–7.35 (m, 5H, Ar); Anal. calcd for

C₁₉H₃₀N₂OSi (330.55): C, 69.04; H, 9.15; N, 8.47,

found: C, 69.07; H, 9.26; N, 8.51; [h]²_D⁰=+35.3 (c 1.0,

CHCl₃).

4.14. (3R,5R)-1-Benzyl-5-hydroxypiperidine-3-car-

boxylic acid hydrochloride 18

To 15 (10.3 mg, 0.03 mmol) was added conc. HCl (15

mL) and the mixture reﬂuxed for 2 h. After cooling to

rt, the mixture was evaporated to leave 18 (8.4 mg,

99%) as a white solid. Mp: 210–220°C; EI-MS m/z=

235 ([M-HCl]⁺); IR (ﬁlm): w 3363, 2923, 2360, 1731,

ent-13 was prepared under the same reaction conditions

as described for 13, starting from ent-11; [h]²_D⁰=−37.6 (c

1.0, CHCl₃).

1

1650, 1457, 1434, 1037, 898 cm⁻¹; H NMR (D₂O, 360

MHz): l 1.76 (ddd, 1H, J=14.2, 12.9, 1.8 Hz, H-4a),

2.20 (brd, 1H, J=14.2 Hz, H-4b), 3.03–3.33 (m, 4H,

H-6a, H-6b, H-2a, H-2b), 3.71 (brd, 1H, J=11.7 Hz,

H-3), 4.30 (d, 1H, J=13.2 Hz, NCH₂Ph), 4.40 (d, 1H,

J=13.2 Hz, NCH₂Ph), 4.70 (m, 1H, H-5/D₂O), 7.44–

7.54 (m, 5H, Ar); HR-EIMS: 235.12121 (Anal. calcd

for C₁₃H₁₇NO₃: 235.12085), 190.08714 (Anal. calcd for

C₁₁H₁₂NO₂: 190.08681), 144.06660 (Anal. calcd for

C₆H₁₀NO₃: 144.06607); [h]²_D⁰=−0.2 (c 2.68, MeOH).

4.12. (2S,4R)-2-[1-Benzyl-4-(tert-butyldimethylsilyloxy)-

pyrrolidin-2-yl]ethylamine 14

To a stirred solution of 12 (22.1 mg, 0.067 mmol) in

Et₂O (5 mL) was added LiAlH₄(0.17 mL, 1 M solution

in Et₂O) at 0°C. After 2h, the reaction was quenched

with an aqueous solution of saturated NaHCO₃, the

mixture ﬁltered through Celite and the ﬁlter cake

extracted with MeOH. The ﬁltrate was evaporated and

the residue puriﬁed by ﬂash chromatography (CH₂Cl₂/

MeOH=8:2+3 mL of NH₃-saturated MeOH/500 mL

eluent) to leave pure 14 (14.40 mg, 64%) as a yellow oil;

EI-MS m/z=290 (a-cleavage, [M−CH₂CH₂NH₂]⁺);

TLC: R_f=0.28 CH₂Cl₂/MeOH=8:2+3 mL of NH₃-sat-

urated MeOH/500 mL eluent); IR (ﬁlm): w 3292–2797,

4.15. (3R,5S)-1-Benzyl-5-hydroxymethylpyrrolidin-3-ol

19

Compound ent-19 has already been described in the

literature^2,12. According to literature^2,12preparation of

19 was performed in a slightly modiﬁed way as follows.

To a stirred solution of 6 (69.7 mg, 0.28 mmol) in THF

(10 mL) was added LiAlH₄(0.54 mL, 1 M solution in

THF) at 0°C. After 1 h, the reaction was quenched with

saturated aqueous NaHCO₃. The mixture was ﬁltered

through Celite and the ﬁlter cake extracted with

CH₂Cl₂(3×10 mL). The ﬁltrate was evaporated to leave

pure 19 (57.2 mg, 98%) as a colorless oil; EI-MS

m/z=207 [M⁺]; TLC: R_f=0.18 (CH₂Cl₂/MeOH=9:1);

IR (ﬁlm): w 3360, 1495, 1454, 1097, 1029, 749, 700 cm⁻¹;

¹H NMR (CDCl₃, 360 MHz): l 1.85 (ddd, 1H, J=13.1,

8.3, 4.2 Hz, H-4a), 2.17 (ddd, 1H, J=13.1, 7.3, 7.5 Hz,

H-4b), 2.40 (dd, 1H, J=10.1, 5.0 Hz, H-2a), 3.07 (m,

1H, H-5), 3.27 (dd, 1H, J=10.1, 5.5 Hz, H-2b), 3.41

(dd, 1H, J=11.0, 1.7 Hz, CH₂OH), 3.49 (d, 1H, J=

13.0 Hz, NCH₂Ph), 3.66 (dd, 1H, J=11.0, 3.4 Hz,

CH₂OH), 4.00 (d, 1H, J=13.0 Hz, NCH₂Ph), 4.32 (m,

1H, H-3), 7.20–7.38 (m, 5H, Ar); [h]²_D⁰=−58.4 (c 1.0,

CHCl₃), {lit.: [h]_D²⁰=−79.8, (c 1.12, MeOH)}.

1

1583, 1471, 1378, 1255, 1126, 835, 776 cm⁻¹; H NMR

(CDCl₃, 360 MHz): l 0.01 (s, 6H, OSi(CH_{3 2}

6 ) C(CH₃)₃),

0.86 (s, 9H, OSi(CH₃)₂C(CH₃)₃), 1.56 (dddd, 1H, J=

6

13.8, 7.9, 7.9, 6.0 Hz, H-3a), 1.81 (m, 3H, H-3b/H-6a/

H-6b), 2.17 (dd, 1H, J=9.9, 5.5 Hz, H-5a), 2.35 (brs,

2H, CH₂CH₂NH₂

6 ), 2.79 (m, 3H, CH₂CH6 ₂NH6 ₂/

CH₂CH₂NH₂/H-2), 3.11 (dd, 1H, J=9.9, 6.2 Hz, H-

6

5b), 3.28 (d, 1H, J=12.8 Hz, NCH₂Ph), 4.05 (d, 1H,

J=12.8 Hz, NCH₂Ph), 4.29 (m, 1H, H-4), 7.20–7.36

(m, 5H, Ar); HR-EIMS: 171.1045752 (Anal. calcd for

C₁₂H₁₃N: 171.10480), 304.21028 (Anal. calcd for

C₁₈H₃₀NOSi: 304.20966); [h]²_D⁰=−68.0 (c 1.0, CHCl₃).

4.13. (3S,5R)-(1-Benzyl-5-(tert-butyldimethylsilyloxy)-

piperidin-3-yl)methylamine 16

A stirred solution of 15 (12.1 mg, 0.037 mmol) in Et₂O

(5 mL) and LiAlH₄(0.17 mL, 1 M solution in Et₂O)

was reacted and worked up as described for 14 to give

pure 16 (9.9 mg, 81%) as a yellow oil; EI-MS m/z=304

ent-19 was prepared under the same reaction condi-

tions, starting from ent-6; [h]²_D⁰=+63.4 (c 0.6, CHCl₃).

C. Heindl et al. / Tetrahedron: Asymmetry 14 (2003) 3153–3172

3161

4.16. (3R,5R)-1-Benzyl-5-hydroxymethylpyrrolidin-3-ol

3.2 Hz, CH₂Cl), 4.17 (dd, 1H, J=13.1, 7.5 Hz, CH₂Cl),

4.29 (d, 1H, J=13.1 Hz, NCH₂Ph), 4.49 (m, 1H, H-3),

4.61 (d, 1H, J=13.1 Hz, NCH₂Ph), 5.00 (brs, 1H, -OH),

7.23–7.64 (m, 5H, Ar); ¹³C NMR (CDCl₃, 90.56 MHz):

l 35.70 (C-3), 58.20 (C-2), 58.33 (NCH₂Ph), 61.25 (C-5),

62.13 (CH₂Cl), 68.01 (C-2), 68.25 (C-4), 128.66, 129.27,

131.65, 130.34 (C-Ar); HR-EIMS: 225.09184 (Anal.

calcd for C₁₂H₁₆NOCl: 225.09204), 176.10749 (Anal.

calcd for C₁₁H₁₄NO: 176.10754), 134.03759 (Anal. calcd

for C₅H₉NOCl: 134.03726); [h]²_D⁰=+8.8 (c 0.1, CHCl₃).

20

A mixture of 7 (44.6 mg, 0.18 mmol) and LiAlH₄(0.32

mL, 1 M solution in THF) in THF (8 mL) was reacted

and worked up (eluent for ﬂash chromatography:

CH₂Cl₂/MeOH=95:5) as described for 19 to leave pure

20 (36.5 mg, 98%) as opaque crystals. Mp: 41–42°C;

EI-MS m/z=207 [M⁺]; TLC: R_f=0.10 (CH₂Cl₂/

MeOH=95:5); IR (ﬁlm): w 3363, 3025–2796, 1452, 1338,

1132, 1025, 746, 700 cm⁻¹; ¹H NMR (CDCl₃, 360 MHz):

l 1.79 (brd, 1H, J=14.2 Hz, H-4a), 2.35 (ddd, 1H,

J=14.2, 10.3, 6.0 Hz, H-4b), 2.45 (dd, 1H, J=10.1, 3.7

Hz, H-2a), 2.86 (m, 1H, H-5), 3.00 (dd, 1H, J=10.1, 2.0

Hz, H-2b), 3.39 (dd, 1H, J=11.1, 1.4 Hz, CH₂OH), 3.49

(d, 1H, J=13.3 Hz, NCH₂Ph), 3.58 (dd, 1H, J=11.1,

3.0 Hz, CH₂OH), 3.93 (d, 1H, J=13.3 Hz, NCH₂Ph),

4.19 (m, 1H, H-3), 7.22–7.37 (m, 5H, Ar); Anal. calcd

for C₁₂H₁₇NO₂(207.27): C, 69.54; H, 8.27; N, 6.76,

found: C, 69.24; H, 8.41; N, 6.65; [h]²_D⁰=+35.8 (c 1.0,

CHCl₃).

ent-22 was prepared under the same reaction conditions

as described for 22, starting from ent-20; [h]²_D⁰=−8.3 (c

0.1, CHCl₃).

4.19. (2S,4R)-(1-Benzyl-4-hydroxypyrrolidin-2-yl)-

acetonitrile 23 and (3R,5R)-1-benzyl-5-hydroxypipe-

ridine-3-carbonitrile 27

To a solution of 21 (130 mg, 0.5 mmol) in 80% EtOH

(25 mL) was added NaCN (460 mg, 9.4 mmol) and the

mixture allowed to reﬂux for 24 h. After cooling to rt,

an aqueous saturated solution of NaHCO₃was added

and the mixture extracted with CH₂Cl₂. The organic

layer was dried over MgSO₄and evaporated. The

residue was puriﬁed by ﬂash chromatography

ent-20 was prepared under the same reaction conditions

as described for 20, starting from ent-7; [h]²_D⁰=−37.2 (c

1.2, CHCl₃).

4.17. (3R,5S)-1-Benzyl-5-chloromethylpyrrolidin-3-ol

hydrochloride 21

(petroleum

ether/EtOAc=85:15)

to

give

a

diastereomeric mixture of 23 and 24 and the piperidine

27 in an overall yield of 60.8 mg (57%). 23 and 24 were

isolated as colorless oils and 27 isolated as a white,

crystalline solid. Mp: 104–105°C.

A mixture of 19 (316 mg, 1.53 mmol) and SOCl₂(0.16

mL, 2.3 mmol) in CHCl₃(15 mL) was reacted and

worked up as described for 22 to leave pure 21 (292 mg,

85%) as an opaque, creamy mass; EI-MS m/z=225

[M⁺]; TLC: R_f=0.15 (petroleum ether/EtOAc=8:2); IR

(ﬁlm): w 3316, 2935, 2584, 1454, 1214, 1103, 995, 748,

Analytical data of 23: colorless oil; EI-MS m/z=216

[M⁺], 176 (a-cleavage, [M−CH₂CN]⁺); TLC: R_f=0.10

(petrolum ether/EtOAc=6:4); IR (ﬁlm): w 3421, 3085–

2807, 2248, 1450, 1353, 1130, 1091, 744, 701 cm⁻¹; 1H

NMR (CDCl₃, 360 MHz): l 2.05 (m, 2H, H-3a/H-3b),

2.38 (dd, 1H, J=10.6, 4.6 Hz, H-5a), 2.43 (dd, 1H,

J=16.8, 6.2 Hz, CH₂CN), 2.49 (dd, 1H, J=16.8, 3.8

Hz, CH₂CN), 3.18 (m, 1H, H-2), 3.34 (dd, 1H, J=10.6,

5.5 Hz, H-5b), 3.55 (d, 1H, J=13.2 Hz, NCH₂Ph), 3.96

(d, 1H, J=13.2 Hz, NCH₂Ph), 4.46 (m, 1H, H-4),

7.21–7.40 (m, 5H, Ar); Anal. calcd for C₁₃H₁₆N₂O

(216.29): C, 72.19; H, 7.46; N, 12.95, found: C, 72.06; H,

7.42; N, 12.82; [h]²_D⁰=−67.1 (c 1.0, CHCl₃).

1

701 cm⁻¹; H NMR (CDCl₃, 360 MHz): l 2.10 (m, 1H,

H-4a), 2.52 (m, 1H, H-4b), 3.39 (brd, 1H, J=11.4 Hz,

H-2a), 3.80 (m, 3H, H-2b/H-5/NCH₂Ph), 4.12 (m, 1H,

CH₂Cl), 4.45 (brdd, 1H, J=13.0, 5.9 Hz, CH₂Cl), 4.65

(m, 2H, NCH₂Ph/H-3), 7.22–7.75 (m, 5H, Ar); HR-

EIMS: 225.09184 (Anal. calcd for C₁₂H₁₆NOCl:

225.09204), 134.03798 (Anal. calcd for C₅H₉NOCl:

134.03726); [h]²_D⁰=+2.3 (c 1.0, CHCl₃).

ent-21 was prepared under the same reaction conditions

as described for 21, starting from ent-19; [h]²_D⁰=−2.2 (c

0.8, CHCl₃).

ent-23 was prepared under the same reaction conditions

as described for 23, starting from ent-21; [h]²_D⁰=+62.7 (c

0.75, CHCl₃).

4.18. (3R,5R)-1-Benzyl-5-chloromethylpyrrolidin-3-ol

hydrochloride 22

Analytical data of 27: white crystalline solid; Mp: 104–

105°C; EI-MS m/z=216 [M⁺]; TLC: R_f=0.14

(petroleum ether/EtOAc=6:4); IR (ﬁlm): w 3432, 2919,

2807, 2240, 1600, 1153, 1045, 941, 748, 698 cm⁻¹; 1H

NMR (CDCl₃, 360 MHz, at 330 K): l 1.72 (ddd, 1H,

J=13.3, 10.3, 3.0 Hz, H-4ax), 1.92 (ddd, 1H, J=13.3,

4.8, 4.3 Hz, H-4eq), 2.35 (m, 2H, H-2a/H-6a), 2.58 (dd,

1H, J=11.7, 5.0 Hz, H-6b), 2.80 (dd, 1H, J=10.6, 4.5

Hz, H-2b), 2.96 (dddd, 1H, J=9.5, 10.3, 4.5, 4.8 Hz,

H-3ax), 3.50 (s, 2H, NCH₂Ph/NCH₂Ph), 3.91 (m, 1H,

H-5eq), 7.16–7.28 (m, 5H, Ar); Anal. calcd for

C₁₃H₁₆N₂O (216.29): C, 72.19; H, 7.46; N, 12.95, found:

C, 72.26; H, 7.57; N, 12.83; [h]²_D⁰=−7.0 (c 1.0, CHCl₃).

To a solution of 20 (341 mg, 1.64 mmol) in CHCl₃(20

mL) was added SOCl₂(0.18 mL, 2.46 mmol) after which

the mixture was reﬂuxed for 3.5 h. After cooling to rt,

the mixture was extracted with acetone/H₂O (1:1) and

the acetone/H₂O-layer then evaporated to leave pure 22

(334.3 mg, 80%) as an opaque, creamy mass; EI-MS

m/z=225 [M⁺]; TLC: R_f=0.07 (petroleum ether/

EtOAc=8:2); IR (ﬁlm): w 3309, 3066–2611, 1454, 1214,

1

1052, 752, 701 cm⁻¹; H NMR (CDCl₃, 360 MHz): l

2.07 (brdd, 1H, J=14.6, 4.6 Hz, H-4a), 2.34 (ddd, 1H,

J=14.6, 9.9, 5.3 Hz, H-4b), 3.02 (brd, 1H, J=10.6 Hz,

H-2a), 3.69 (m, 2H, H-2b/H-5), 3.96 (dd, 1H, J=13.1,

3162

C. Heindl et al. / Tetrahedron: Asymmetry 14 (2003) 3153–3172

ent-27 was prepared under the same reaction conditions

as described for 27, starting from ent-21; [h]²_D⁰=+11.5 (c

0.21, CHCl₃).

reacted and worked up as described for 19 to leave

crude 26. Crude 26 was used for the next reaction step

without further puriﬁcation.

4.20.

(2R,4R)-(1-Benzyl-4-hydroxypyrrolidin-2-yl)-

ent-26 was prepared under the same reaction conditions

as described for 26, starting from ent-24.

acetonitrile 24 and (3S,5R)-1-benzyl-5-hydroxy-pipe-

ridine-3-carbonitrile 28

4.23. Ethyl (2S,4S)-1-benzyl-4-methylprolinate 30 and

(3R,5S)-[1-benzyl-5-(1-hydroxy-1-methylethyl)-pyrro-

lidin-3-yl]tosylate 32

A solution of 22 (224 mg, 0.85 mmol) and NaCN

(400.0 mg, 8.16 mmol) in 80% EtOH (25 mL) were

reacted and worked up (petroleum ether/EtOAc=1:1)

as described in section 4.20. to give 24, 23 and 28

(overall yield: 139 mg, 76%).

A suspension of Cu(I)I (3728 mg, 1.96 mmol) in Et₂O

(10 mL) and a solution of MeLi (2.3 mL, 1.6 M in

Et₂O) were reacted as described for 39. Compound 29

(107 mg, 0.27 mmol) in Et₂O was then added. The

mixture was further reacted and worked up to give 30

(7.5 mg, 11%) as a colorless oil as well as 32, a white

solid, as the main product (31.7 mg, 55%).

Analytical data of 24: colorless oil; EI-MS m/z=216

+

[M ]; TLC: R_f=0.1 (petroleum ether/EtOAc=1:1); IR

(ﬁlm): w 3428, 3062–2807, 2248, 1492, 1450, 1349, 1130,

1

1076, 748, 701 cm⁻¹; H NMR (CDCl₃, 360 MHz): l

1.79 (brdd, 1H, J=14.6, 5.3 Hz, H-3a), 2.48 (m, 4H,

H-3b/H-5a/CH₂CN/CH₂CN), 2.86 (m, 1H, H-2), 2.99

(dd, 1H, J=10.5, 1.2 Hz, H-5b), 3.48 (d, 1H, J=13.0

Hz, NCH₂Ph), 3.93 (d, 1H, J=13.0 Hz, NCH₂Ph), 4.23

(m, 1H, H-4), 7.25–7.36 (m, 5H, Ar); HR-EIMS:

216.12651 (Anal. calcd for C₁₃H₁₆N₂O: 216.12627),

176.10749 (Anal. calcd for C₁₁H₁₄NO: 176.10754);

[h]²_D⁰=+40.3 (c 0.3, CHCl₃).

Analytical data of 30: EI-MS m/z=247.3 [M⁺]; 174

(a-cleavage,

[M−CO₂C₂H₅]⁺);

TLC:

R_f=0.42

(petroleum ether/EtOAc=8:2); IR (ﬁlm): w 3033–2800,

1

1729, 1454, 1375, 1183, 1029, 745, 699 cm⁻¹; H NMR

(CDCl₃, 360 MHz): l 1.05 (d, 3H, J=6.5 Hz, CH₃),

1.25 (t, 3H, J=7.0 Hz, CO₂CH₂CH₃), 1.58 (ddd, 1H,

J=12.2, 7.5, 7.2 Hz, H-3a), 2.27 (m, 2H, H-4/H-3b),

2.65 (m, 2H, H-5a/H-5b), 3.36 (dd, 1H, J=7.9, 7.5 Hz,

H-2), 3.55 (d, 1H, J=13.2 Hz, NCH₂Ph), 3.92 (d, 1H,

Analytical data of 28: colorless oil; EI-MS m/z=216

[M⁺]; TLC: R_f=0.15 (petroleum ether/EtOAc=1:1); IR

(ﬁlm): w 3390, 3062–2807, 2240, 1454, 1361, 1153, 1068,

J=13.2 Hz, NCH₂Ph), 4.14 (m, 2H, CO₂CH6 ₂CH₃),

7.20–7.37 (m, 5H, Ar); HR-EIMS: 174.12835 (Anal.

calcd for C₁₂H₁₆N: 174.12828); [h]²_D⁰=−43.2 (c 0.04,

CHCl₃).

1

941, 748, 701 cm⁻¹; H NMR (CDCl₃, 360 MHz): l

1.78 (m, 1H, H-4a), 2.06 (brd, 1H, J=13.0 Hz, H-2a),

2.39 (m, 2H, H-4b/H-6a), 2.71 (brd, 1H, J=9.3 Hz,

H-6b), 2.93 (brd, 1H, J=13.0 Hz, H-2b), 3.05 (m, 1H,

H-3), 3.58 (s, 2H, NCH₂Ph/NCH₂Ph), 4.00 (m, 1H,

H-5), 7.25–7.36 (m, 5H, Ar); HR-EIMS: 216.12629

(Anal. calcd for C₁₃H₁₆N₂O: 216.12627), 171.09202

(Anal. calcd for C₁₁H₁₁N₂: 171.09222), 125.07116

(Anal. calcd for C₆H₉N₂O: 125.07149); [h]²_D⁰=+17.3 (c

0.13, CHCl₃).

4.24. Ethyl (2S,4S)-1-benzyl-4-butylprolinate 31

A suspension of Cu(I)I (90.2 mg, 0.48 mmol) in Et₂O

(10 mL) and n-BuLi (0.53 mL, 1.6 M in Et₂O) was

reacted as described for 40. A solution of 29 (108 mg,

0.27 mol) in Et₂O was then added and the reaction and

work-up performed to give 31 (18.7 mg, 24%) as a

colorless oil. EI-MS m/z=216 (a-cleavage, [M−

CO₂C₂H₅]⁺); TLC: R_f=0.7 (petroleum ether/EtOAc=

1:1); IR (ﬁlm): w 2956–2857, 1730, 1454, 1375, 1180,

ent-24 [h]²_D⁰=−42.1 (c 1.0, CHCl₃) and ent-28 [h]²_D⁰=

−18.5 (c 0.3, CHCl₃) were prepared under the same

reaction conditions as described for 24 and 28, starting

from ent-22.

1

1028, 739, 699 cm⁻¹; H NMR (CDCl₃, 360 MHz): l

0.88 (m, 6H, CO₂CH₂CH

6 ₃/CH₂CH₂CH₂CH6 ₃), 1.30 (m,

6H, CH₂CH₂CH₂CH₃), 1.60 (m, 1H, H-3a), 2.09 (ddd,

6

4.21. (3R,5R)-5-(2-Aminoethyl)-1-benzylpyrrolidin-3-ol

25

1H, J=14.5, 7.2, 7.5 Hz, H-3b), 2.29 (m, 1H, H-4), 2.62

(dd, 1H, J=8.6, 8.9 Hz, H-5a), 2.72 (dd, 1H, J=8.9,

6.0 Hz, H-5b), 3.36 (dd, 1H, J=7.8, 7.5 Hz, H-2), 3.55

(d, 1H, J=13.0 Hz, NCH₂Ph), 3.91 (d, 1H, J=13.0 Hz,

NCH₂Ph), 4.13 (q, 2H, J=6.7 Hz, CO₂CH₂CH₃), 7.18–

7.40 (m, 5H, Ar).

A mixture of 23 (24.7 mg, 0.11 mmol) and LiAlH₄(0.23

mL, 1 M solution in THF) in THF (5 mL) were reacted

and worked up as described for 19 to leave crude 25.

Crude 25 was used for the next reaction step without

further puriﬁcation.

A second experiment was performed using 11 equiva-

lents of Bu₂CuLi and prolonged reaction conditions

(3.5 h) to give 31 in an overall yield of 45%.

ent-25 was prepared under the same reaction conditions

as described for 25, starting from ent-23.

4.22. (3R,5S)-5-(2-Aminoethyl)-1-benzylpyrrolidin-3-ol

26

4.25. (3R,5S)-[1-Benzyl-5-(1-hydroxy-1-methylethyl)-

pyrrolidin-3-yl]tosylate 32

A mixture of 24 (13.7 mg, 0.06 mmol) and LiAlH₄(0.13

mL, 1 M solution in THF) in THF (10 mL) were

To a solution of 29 (68.6 mg, 0.17 mmol) in THF (10

mL) was added Li₂CuCl₄(0.05 mL, 0.1 M in THF) at

C. Heindl et al. / Tetrahedron: Asymmetry 14 (2003) 3153–3172

3163

0°C after which the mixture was stirred for 15 min. A

solution of MeMgBr (0.07 mL, 3 M in Et₂O) was then

added and the mixture stirred for another 3 h. Then the

mixture was extracted with Et₂O and the organic layer

dried over MgSO₄and evaporated. The resulting

residue was puriﬁed by ﬂash chromatography

(petroleum ether/EtOAc, 9:1) to leave 32 (56.6 mg,

86%); Mp: 51–52°C; EI-MS m/z=374 ([M−CH₃]⁺);

TLC: R_f=0.07 (petroleum ether/EtOAc=8:2); IR

(ﬁlm): w 3454, 3028–2862, 1453, 1363, 1176, 897, 723

cm⁻¹; ¹H NMR (CDCl₃, 360 MHz): l 1.09 (s, 3H,

C₆H₅I (20.3 mL, 0.18 mmol) were added. After stirring

for another 24 h, the mixture was diluted with EtOAc

(15 mL) and washed with brine. The organic layer was

dried over MgSO₄and evaporated. The residue was

puriﬁed by ﬂash chromatography (petroleum ether/

EtOAc=9:1) to give 34 (31.0 mg, 94%) as a colorless

oil; EI-MS m/z=233 [M⁺]; TLC: R_f=0.12 (petroleum

ether/EtOAc=9:1); IR (ﬁlm): w 3066–2935, 1731, 1454,

1184, 1025, 740, 698 cm⁻¹; ¹H NMR (CDCl₃, 360

MHz): l 1.28 (t, 3H, J=7.0 Hz, CO₂CH₂CH6 ₃), 2.43 (m,

2H, H-3a/H-3b), 3.35 (dd, 1H, J=6.5, 6.5 Hz, H-2),

3.67 (d, 1H, J=13.0 Hz, NCH₂Ph), 3.83 (d, 1H, J=

C(CH

14.1, 8.8, 4.8 Hz, H-4a), 2.16 (m, 1H, H-4b), 2.44 (s,

3H, OSO₂C₆H₄CH₃), 2.83 (brd, 1H, J=13.4 Hz, H-2a),

6 ₃)₂), 1.27 (s, 3H, C(CH6 ₃)₂), 1.99 (ddd, 1H, J=

13.0 Hz, NCH₂Ph), 4.19 (m, 2H, CO₂CH6 ₂CH₃), 5.10

6

(m, 2H, H-5a/H-5b), 5.77 (m, 1H, H-4), 7.22–7.35 (m,

2.93 (dd, 1H, J=13.4, 3.4 Hz, H-2b), 3.12 (dd, 1H,

J=8.8, 7.5 Hz, H-5), 3.84 (d, 1H, J=14.1 Hz,

NCH₂Ph), 4.06 (d, 1H, J=14.1 Hz, NCH₂Ph), 4.93 (m,

5H, Ar); ¹³C NMR (CDCl₃, 90.56 MHz): l 14.35

(CO₂CH₂C

(CO₂CH₂CH₃),

(NCH₂Ph), 127.05, 128.25, 128.36, 133.67 (C-Ar),

139.75 (-CHꢀCH₂); Anal. calcd for C₁₄H₁₉NO₂

6

H₃), 37.71 (C-3), 60.24 (C-2), 60.62

6

117.92 (CH₂-CHꢀCH₂), 51.95

6

1H, H-3), 7.22–7.37 (m, 7H, Ar/OSO₂C₆H₄

6 CH₃), 7.79

6

(m, 2H, OSO₂C₆H₄CH₃); Anal. calcd for C₂₁H₂₇NO₄S

6

(389.52): C, 64.76; H, 6.99; N, 3.60; S, 8.23, found: C,

64.77; H, 6.95; N, 3.66; S, 8.30; [h]²_D⁰=−26.1 (c 0.23,

CHCl₃).

(233.31): C, 72.07; H, 8.21; N, 6.00, found: C, 71.87; H,

8.39; N, 5.90; [h]²_D⁰=−18.0 (c 0.28, CHCl₃).

4.28. Ethyl (2S,4R,S)-1-benzyl-4-iodoprolinate 35,36

4.26. (2S,4R)-[1-Benzyl-5-(1-butyl-1-hydroxypentyl)-

pyrrolidin-3-yl]tosylate 33

To a solution of 29 (2.09 g, 5.16 mmol) in acetone (50

mL) was added NaI (15.3 mg, 130 mmol) after which

the mixture was reﬂuxed for 48 h. After cooling to rt,

the mixture was evaporated and the resulting residue

extracted in Et₂O. To improve the yield of compounds

35 and 36, the extracted residue was redissolved in

acetone, evaporated and the resulting residue washed

again with Et₂O (three times). The combined organic

layers were dried over MgSO₄and evaporated. The

residue was puriﬁed by ﬂash chromatography

(petroleum ether/EtOAc=97:3) to give a diastereomeric

mixture of 35 and 36 (1.807 g, 97%) as a brown liquid.

To a suspension of CuCN (29.0 mg, 0.32 mmol) in

Et₂O (10 mL) was added a solution of BuLi (0.36 mL,

1.6 M in hexane) at −40°C. The mixture was allowed to

warm up to 0°C and then stirred for 15 min. After-

wards the mixture was cooled down to −40°C again

whereupon 29 (73.6 mg, 0.18 mmol) in Et₂O was added

and stirring continued at −40°C for another 3 h. An

aqueous saturated solution of NH₄Cl was added and

the mixture extracted with Et₂O. The combined organic

layers were dried over MgSO₄and evaporated. The

residue was puriﬁed by ﬂash chromatography

(petroleum ether/EtOAc=95:5) to give 33 (36.1 mg,

42%) as a white crystalline solid. Mp: 69–72°C; TLC:

R_f=0.60 (petroleum ether/EtOAc, 1:1); IR (KBr): w

3029–2870, 1713, 1598, 1494, 1454, 1365, 1176, 1097,

Analytical data of 35: EI-MS m/z=358 [M⁺]; TLC:

R_f=0.21 (petroleum ether/EtOAc=9:1); IR (ﬁlm): w

3085–2803, 1735, 1450, 1373, 1272, 1187, 1029, 744, 701

cm⁻¹; ¹H NMR (CDCl₃, 360 MHz): l 1.24 (t, 3H,

1

891, 815, 723, 700 cm⁻¹; H NMR (CDCl₃, 360 MHz):

l 0.89 (m, 6H, CH₂CH₂CH₂CH

1.17–1.49 (m, 13H,

CH₂CH₂CH₂CH₃/H-3a), 2.06 (m, 1H, H-3b), 2.40 (dd,

1H, J=12.96, 7.4 Hz, H-5a), 2.44 (s, 3H,

OSO₂C₆H₄CH₃), 3.24 (m, 1H, H-5b), 3.47 (dd, 1H,

6

₃/CH₂CH₂CH₂CH₃

6 ),

J=7.0 Hz, CO₂CH₂CH6 ₃), 2.53 (ddd, 1H, J=13.8, 8.8,

CH₂CH₂CH₂CH₃/

6

7.1 Hz, H-3a), 2.62 (ddd, 1H, J=13.8, 7.9, 6.0 Hz,

H-3b), 2.93 (dd, 1H, J=9.9, 7.5 Hz, H-5a), 3.54 (m,

2H, H-5b/H-2), 3.69 (d, 1H, J=13.0 Hz, NCH₂Ph),

4.03 (d, 1H, J=13.0 Hz, NCH₂Ph), 4.13 (m, 2H,

6

J=8.4, 4.6 Hz, H-2), 3.86 (d, 1H, J=13.7 Hz,

NCH₂Ph), 3.95 (d, 1H, J=13.7 Hz, NCH₂Ph), 4.93 (m,

CO₂CH6 ₂CH₃), 4.28 (m, 1H, H-4), 7.22–7.37 (m, 5H,

Ar); Anal. calcd for C₁₄H₁₈INO₂(359.21): C, 46.81; H,

5.05; N, 3.90, found: C, 46.94; H, 5.03; N, 3.82; [h]²_D⁰=

−62.1 (c 1.0, CHCl₃).

1H, H-4), 7.24–7.34 (m, 7H, Ar/OSO₂C₆H₄

6 CH₃), 7.8

(m, 2H, OSO₂C₆H₄CH₃); Anal. calcd for C₂₇H₃₉NO₄S

6

(473.68): C, 68.46; H, 8.30; N, 2.96; S, 6.77, found: C,

68.52; H, 8.23; N, 3.02; S, 6.66; [h]²_D⁰=−28.8 (c 0.8,

CHCl₃).

Analytical data of 36: EI-MS m/z=358 [M⁺], 360 [M⁺];

TLC: R_f=0.27 (petroleum ether/EtOAc=9:1); IR

(ﬁlm): w 3062–2803, 1735, 1450, 1187, 1029, 744 cm⁻¹;

¹H NMR (CDCl₃, 360 MHz): l 1.28 (t, 3H, J=7.0 Hz,

4.27. Ethyl (2S)-2-benzylaminopent-4-enoate 34

CO₂CH₂CH6 ₃), 2.50 (ddd, 1H, J=14.0, 8.1, 6.7 Hz,

Zinc drops (four pieces) were dipped into conc. HCl,

washed with EtOH/acetone (1:1) and then placed into a

ﬂask, containing DMF (15 mL). A solution of 36 (51.4

mg, 0.14 mmol) in DMF was added and the mixture

was stirred at rt for 1.5 h. Then, Pd₂(dba)₃(4.12 mg,

0.0043 mmol), P(o-Tol)₃(5.61 mg, 0.018 mmol) and

H-3a), 2.83 (ddd, 1H, J=14.0, 6.9, 6.7 Hz, H-3b), 3.05

(dd, 1H, J=10.8, 6.5 Hz, H-5a), 3.35 (m, 1H, J=10.8,

5.8 Hz, H-5b), 3.52 (dd, 1H, J=8.1, 6.7 Hz, H-2), 3.74

(d, 1H, J=13.4 Hz, NCH₂Ph), 4.04 (d, 1H, J=13.4 Hz,

NCH₂Ph), 4.20 (m, 3H, CO₂CH6 ₂CH₃/H-4), 7.22–7.44

3164

C. Heindl et al. / Tetrahedron: Asymmetry 14 (2003) 3153–3172

(m, 5H, Ar); Anal. calcd for C₁₄H₁₈INO₂(359.21): C,

46.81; H, 5.05; N, 3.90, found: C, 46.92; H, 4.96; N,

3.82; [h]²_D⁰=−20.9 (c 1.0, CHCl₃).

129.20, 138.47 (C-Ar); Anal. calcd for C₁₅H₂₁NO₂

(247.34): C, 72.84; H, 8.56; N, 5.66, found: C, 72.63; H,

8.54; N, 5.48; [h]²_D⁰=+48.7 (c 1.0, CHCl₃).

ent-35 and ent-36 were prepared under the same reac-

ent-39 [h]²_D⁰=−52.5 (c 1.0, CHCl₃) was prepared under

the same reaction conditions as those described for 39,

starting from ent-38.

tion conditions.

4.29. Ethyl (2S,4R,S)-1-benzyl-4-phenylprolinate 37

4.31. Ethyl (2R,4S)-1-benzyl-4-butylprolinate 40

Zinc drops (four pieces) were prepared as described for

34. A diastereomeric mixture of 35 and 36 (87.2 mg,

0.24 mmol) in DMF, was then added and the mixture

stirred at rt for 4 h. Pd₂(dba)₃(6.99 mg, 0.0072 mmol),

P(o-Tol)₃(9.47 mg, 0.03 mmol) and C₆H₅I (34.26 mL,

0.31 mmol) were added and the mixture reacted and

worked up (petroleum ether/EtOAc=9:1) to give 34

and a diastereomeric mixture of 37 (41.2 mg, 55%);

EI-MS m/z=309 [M⁺]; TLC: R_f=0.06 (petroleum

ether/EtOAc=9:1); IR (ﬁlm): w 3060–2814, 1730, 1453,

1182, 1027, 741, 698 cm⁻¹; ¹H NMR (CDCl₃, 360

To a suspension of Cu(I)I (1.7 g, 9.16 mmol) in Et₂O

(250 mL) was added a solution of n-BuLi (10.1 mL, 1.6

M in hexane) at −50°C. The mixture was allowed to

warm up to −20°C. After 30 min, 38 (2.06 g, 5.09

mmol), dissolved in Et₂O, was added and stirring con-

tinued for another 2 h at −20°C. An aqueous saturated

solution of Na₂CO₃was added and the mixture

extracted with Et₂O. The combined organic layers were

dried over MgSO₄and evaporated. The residue was

puriﬁed by ﬂash chromatography (petroleum ether/

EtOAc=95:5) to give 40 (1.471 g, 74%) as a colorless

oil; EI-MS m/z=289 [M⁺]; TLC: R_f=0.67 (petroleum

ether/EtOAc=1:1); IR (ﬁlm): w 3063–2793, 1746, 1454,

1270, 1181, 1029, 699 cm⁻¹; ¹H NMR (CDCl₃, 360

MHz): l *1.25 (t, 3H, J=7.0 Hz, CO₂CH₂CH₃

6 ), 1.26 (t,

3H, J=7.0 Hz, CO₂CH₂CH₃), 1.76 (m, 2H, 2×H-3),

6

1.92 (m, 3H, 2×H-3/H-4), 2.13 (m, 1H, H-4), 2.40 (dd,

1H, J=8.6, 8.6 Hz, H-2 or H-5), 2.58 (m, 2H, H-5 or

H-2), 3.03 (m, 1H, H-2 or H-5), 3.23 (dd, 1H, J=8.7,

6.3 Hz, H-2 or H-5), 3.41 (dd, 1H, J=6.5, 6.5 Hz, H-5

or H-2), 3.55 (d, 1H, J=13.0 Hz, NCH₂Ph), 3.69 (d,

1H, J=13.4 Hz, NCH₂Ph), 3.86 (d, 1H, J=13.0 Hz,

NCH₂Ph), 3.92 (d, 1H, J=13.4 Hz, NCH₂Ph), 4.13 (m,

MHz): l 0.88 (t, 3H, J=7.0 Hz, CH₂CH₂CH₂CH₃

6 ),

1.27 (m, 9H, CH₂CH₂CH₂CH₃, CO₂CH₂CH₃), 1.75

6

(ddd, 1H, J=12.6, 9.6, 7.9 Hz, H-3a), 2.01 (dd, 1H,

J=8.8, 8.8 Hz, H-5a), 2.14 (ddd, 1H, J=12.6, 9.0, 5.9

Hz, H-3b), 2.26 (m, 1H, H-4), 3.16 (dd, 1H, J=8.8, 6.9

Hz, H-5b), 3.28 (dd, 1H, J=9.6, 5.9 Hz, H-2), 3.53 (d,

1H, J=12.7 Hz, NCH₂Ph), 3.93 (d, 1H, J=12.7 Hz,

2H, CO₂CH6 ₂CH₃), 4.19 (m, 2H, CO₂CH6 ₂CH₃), 7.15–

7.40 (m, 10H, Ar). Anal. calcd for C₂₀H₂₃NO₂(309.41):

C, 77.64; H, 7.49; N, 4.53, found: C, 77.62; H, 7.57; N,

4.48.

NCH₂Ph), 4.14 (m, 2H, CO₂CH₂

5H, Ar); ¹³C NMR (CDCl₃, 62.90 MHz): l 13.97

(CH₂CH₂CH₂CH₃), 14.24 (CO₂CH₂CH₃), 22.73, 31.91,

34.84 (CH₂CH₂CH₂CH₃), 36.55 (C-3), 36.90 (C-4),

59.17 (NCH₂Ph), 60.03 (CO₂CH₂CH₃), 60.47 (C-5),

6 CH₃), 7.21–7.41 (m,

6

*Signals were not exactly related to each diastereomer.

6

4.30. Ethyl (2R,4S)-1-benzyl-4-methylprolinate 39

65.19 (C-2), 127.03, 128.14, 129.22, 138.42 (C-Ar);

Anal. calcd for C₁₈H₂₇NO₂(289.42): C, 74.70; H, 9.40;

N, 4.84, found: C, 75.19; H, 9.62; N, 4.73; [h]²_D⁰=+59.0

(c 1.0, CHCl₃).

To a suspension of Cu(I)I (330 mg, 1.74 mmol) in Et₂O

(10 mL) was added a solution of MeLi (2.02 mL, 1.6 M

in Et₂O) at −20°C. The mixture was allowed to warm

up to 0°C and stirring continued for 30 min. A solution

of 38 (107 mg, 0.27 mmol) in Et₂O was then added to

the mixture. After another 1.5 h, an aqueous saturated

solution of Na₂CO₃was added and the mixture

extracted with Et₂O. The combined organic layers were

dried over MgSO₄and evaporated. The residue was

puriﬁed by ﬂash chromatography (petroleum ether/

EtOAc=9:1) to give 39 (46.1 mg, 70%) as a colorless

oil; EI-MS m/z=247 [M⁺]; TLC: R_f=0.38 (petroleum

ether/EtOAc=8:2); IR (ﬁlm): w 3027–2792, 1745, 1454,

ent-40 [h]²_D⁰=−56.5 (c 1.0, CHCl₃) was prepared under

the same reaction conditions as described for 40, start-

ing from ent-38.

4.32. (2R,4S)-5-(1-Benzyl-4-butylpyrrolidin-2-yl)nonan-

5-ol 41

To a suspension of Cu(I)I (120 mg, 0.63 mmol) in Et₂O

(10 mL) was added a solution of n-BuLi (0.73 mL, 1.6

M in hexane) at −30°C and the mixture stirred for 30

min 38 (36.5 mg, 0.09 mmol), dissolved in Et₂O was

then added and the mixture warmed up to −20°C. After

1 h, the reaction was quenched with an aqueous solu-

tion of NaHCO₃and the mixture extracted with Et₂O.

The organic layer was dried over MgSO₄and evapo-

rated. The resulting residue was puriﬁed by ﬂash chro-

matography (petroleum ether/EtOAc=99:1) to give 41

(24.1 mg, 74%) as a white crystalline solid. Mp: 275°C;

EI-MS m/z=302 ([M−C₄H₉]⁺); TLC: R_f=0.72 (petro-

lether/ethylacetat, 1:1); IR (KBr): w 3500, 3027–2791,

1713, 1494, 1454, 1376, 1132, 1027, 996, 909, 732, 699

1

1375, 1271, 1182, 1029, 699 cm⁻¹; H NMR (CDCl₃,

360 MHz): l 0.98 (d, 3H, J=6.5 Hz, CH₃), 1.24 (t, 3H,

J=7.0 Hz, CO₂CH₂CH₃), 1.69 (ddd, 1H, J=12.7, 9.6,

7.9 Hz, H-3a), 1.99 (dd, 1H, J=8.9, 8.9 Hz, H-5a), 2.14

(ddd, 1H, J=12.7, 8.9, 5.9 Hz, H-3b), 2.34 (m, 1H,

H-4), 3.13 (dd, 1H, J=8.9, 6.9 Hz, H-5b), 3.29 (dd, 1H,

J=9.6, 5.9 Hz, H-2), 3.52 (d, 1H, J=12.7 Hz,

NCH₂Ph), 3.92 (d, 1H, J=12.7 Hz, NCH₂Ph), 4.11 (m,

2H, CO₂CH₂

(CDCl₃, 62.90 MHz): l 1424 (CO₂CH₂C

(CH₃), 31.35 (C-4), 37.72 (C-3), 59.14 (NCH₂Ph), 60.46

(CO₂CH₂₆CH₃), 61.54 (C-5), 65.33 (C-2), 127.02, 128.13,

6

CH₃), 7.20–7.36 (m, 5H, Ar); ¹³C NMR

H₃), 18.83

6

1

6

cm⁻¹; H NMR (CDCl₃, 360 MHz): l 0.81–1.63 (m,

C. Heindl et al. / Tetrahedron: Asymmetry 14 (2003) 3153–3172

3165

19H, H-3a/CH₂

6

CH₂

6

CH₂

6

CH₃

6

), 1.94 (dd, 1H, J=9.3, 9.3

EtOAc=1:1); IR (ﬁlm): w 3432, 3062–2803, 1596, 1357,

1

Hz, H-5a), 2.04 (m, 2H, H-3b/H-4), 2.90 (dd, 1H,

J=9.8, 2.2 Hz, H-2), 3.03 (brdd, 1H, J=9.3, 6.3 Hz,

H-5b), 3.50 (d, 1H, J=13.4 Hz, NCH₂Ph), 4.18 (d, 1H,

J=13.4 Hz, NCH₂Ph), 7.21–7.41 (m, 5H, Ar); Anal.

calcd for C₂₄H₄₁NO (359.60): C, 80.16; H, 11.49; N,

3.90, found: C, 80.04; H, 11.42; N, 4.00; [h]²_D⁰=+16.1 (c

0.32, CHCl₃).

1176, 948, 898, 752, 701 cm⁻¹; H NMR (CDCl₃, 360

MHz): 2.00 (ddd, 1H, J=15.1, 6.9, 1.9 Hz, H-4a), 2.19

(ddd, 1H, J=15.1, 8.7, 6.9 Hz, H-4b), 2.35 (s, 3H,

OSO₂C₆H₄CH6 ₃), 2.38 (dd, 1H, J=11.7, 4.5 Hz, H-2a),

2.64 (m, 1H, H-5), 3.02 (brd, 1H, J=11.7 Hz, H-2b),

3.19 (d, 1H, J=13.4 Hz, NCH₂Ph), 3.35 (dd, 1H,

J=11.4 Hz, CH₂OH), 3.65 (brd, 1H, J=11.4 Hz,

CH₂OH), 3.91 (d, 1H, J=13.4 Hz, NCH₂Ph), 4.88 (m,

4.33. (2R,4S)-1-Benzyl-4-methylpyrrolidin-2-carboxyli-

1H, H-3), 7.20–7.67 (m, 7H, Ar/OSO₂C₆H₄

6 CH₃), 7.74

cacid hydrochloride 42

(m, 2H, OSO₂C₆H₄CH₃); Anal. calcd for C₁₉H₂₃NO₄S

6

(361.46): C, 63.14; H, 6.41; N, 3.87; S, 8.87, found: C,

63.18; H, 6.34; N, 3.86; S, 8.82; [h]²_D⁰=+38.9 (c 1.0,

CHCl₃).

To 39 (110 mg, 0.44 mmol) was added 5 M HCl (4 mL)

after which the mixture was stirred for 48 h at 60°C.

The mixture was then evaporated to leave pure 42

(1136 mg, 99%) as a white solid. Mp: 240–242°C; IR

(ﬁlm): w 3367–2927, 1712, 1662, 1457, 1357, 1207, 1025,

ent-44 was prepared under the same reaction conditions

as described for 44, starting from ent-38.

1

752, 701 cm⁻¹; H NMR (CDCl₃, 360 MHz): l 1.05 (d,

3H, J=6.3 Hz, CH₃), 2.15 (m, 1H, H-3a), 2.31 (m, 2H,

H-3b/H-4), 2.93 (dd, 1H, J=11.1, 10.3 Hz, H-5a), 3.65

(dd, 1H, J=11.1, 6.2 Hz, H-5b), 4.39 (m, 3H, NCH₂Ph/

NCH₂Ph/H-2), 7.40–7.55 (m, 5H, Ar); ¹³C NMR

(CDCl₃, 90.56 MHz): l 16.61 (CH₃), 32.16 (C-4), 36.81

(C-3), 59.68 (NCH₂Ph), 61.64 (C-5), 67.63 (C-2),

130.25, 130.72, 131.13, 131.68 (C-Ar), 173.41 (COOH);

Anal. calcd for C₁₃H₁₇NO₂×0.25 H₂O (255.10): C,

60.09; H, 7.18; N, 5.39, found: C, 59.80; H, 7.58; N,

5.16; [h]²_D⁰=+33.9 (c 1.0, CHCl₃).

4.36. (3R,5R)-1-Benzyl-5-(tert-butyldimethylsilyloxy-

methyl)pyrrolidin-3-yl tosylate 45

A solution of 44 (183 mg, 0.51 mmol) in DMF (15 mL),

imidazole (138 mg, 2.02 mmol) and TBSCl (153 mg,

1.01 mmol) were reacted and worked up (petroleum

ether/EtOAc=1:1) as described for 10 to give 45 (228

mg, 95%) as a yellowish solid. Mp: 50–57°C; EI-MS

m/z=344 ([M−OTBS]⁺); TLC: R_f=0.68 (petroleum

ether/EtOAc=1:1); IR (ﬁlm): w 3062–2800, 1600, 1465,

1

1361, 1253, 1176, 1099, 898, 775, 701 cm⁻¹; H NMR

ent-42 [h]²_D⁰=−33.7 (c 0.74, CHCl₃) was prepared under

the same reaction conditions as described for 42, start-

ing from ent-39.

(CDCl₃, 360 MHz): l 0.02 (s, 6H, OSi(CH6 ₃)₂tBu), 0.86

(s, 9H, OSi(CH₃)₂tBu), 1.82 (brdd, 1H, J=13.9, 6.7 Hz,

H-4a), 2.27 (ddd, 1H, J=13.9, 7.6, 7.6 Hz, H-4b), 2.35

(dd, 1H, J=11.7, 5.1 Hz, H-2a), 2.42 (s, 3H,

4.34. (2R,4S)-1-Benzyl-4-butylpyrrolidin-2-carboxylic

OSO₂C₆H₄CH₃

J=11.7 Hz, H-2b), 3.32 (d, 1H, J=13.4 Hz, NCH₂Ph),

3.51 (dd, 1H, J=10.0, 6.7 Hz, CH₂OTBS), 3.70 (dd,

1H, J=10.0, 5.5 Hz, CH₂OTBS), 4.09 (d, 1H, J=13.4

Hz, NCH₂Ph), 4.92 (m, 1H, H-3), 7.20–7.31 (m, 7H,

Ar/OSO₂C₆H₄CH₃), 7.72 (m, 2H, OSO₂C₆H₄CH₃);

Anal. calcd for C₂₅H₃₇NO₄SSi (475.73): C, 63.12; H,

7.84; N, 2.94; S, 6.74, found: C, 63.06; H, 7.67; N, 2.88;

S, 6.58; [h]²_D⁰=+76.7 (c 1.0, CHCl₃).

6 ), 2.67 (m, 1H, H-5), 2.96 (brd, 1H,

acid hydrochloride 43

6

A mixture of 40 (63.8 mg, 0.22 mmol) and 5 M HCl (4

mL) was reacted and worked up as described for 42 to

leave pure 43 (64.9 mg, 99%) as a white solid. Mp:

198–202°C; EI-MS m/z=261 [M⁺], 216 (a-cleavage,

-HCl); IR (ﬁlm): w 2954–2391, 1712, 1457, 1357, 1207,

6

1

998, 817, 752, 701 cm⁻¹; H NMR (CDCl₃, 360 MHz):

l 0.80 (t, 3H, J=6.7 Hz, CH₂CH₂CH₂CH₃

6 ), 1.31 (m,

6H, CH₂CH₂CH₂CH₃), 2.22 (m, 3H, H-3a/H-3b/H-4),

6

ent-45 was prepared under the same reaction conditions

as described for 45, starting from ent-44.

2.94 (dd, 1H, J=11.0, 11.0 Hz, H-5a), 3.65 (dd, 1H,

J=11.0, 6.3 Hz, H-5b), 4.28 (m, 1H, H-2), 4.34 (d, 1H,

J=12.8 Hz, NCH₂Ph), 4.43 (d, 1H, J=12.8 Hz,

NCH₂Ph), 7.40–7.55 (m, 5H, Ar); Anal. calcd for

C₁₆H₂₃NO₂x HCl (297.83): C, 64.53; H, 8.12; N, 4.70,

found: C, 64.50; H, 7.98; N, 4.93; [h]²_D⁰=+37.1 (c 0.85,

CHCl₃).

4.37. (2R,4S)-1-Benzyl-2-(tert-butyldimethylsilyloxy-

methyl)-4-methylpyrrolidine 46

To a solution of 45 (310 mg, 0.65 mmol) in Et₂O (30

mL) was added MeMgBr (0.43 mL, 3 M in Et₂O) at

0°C. The solution was stirred for 90 min at 0°C and

another 5 h at rt, after which an aqueous saturated

solution of NH₄Cl was added and the resulting mixture

extracted with Et₂O. The organic layer was dried over

MgSO₄and evaporated. The residue was puriﬁed by

ﬂash chromatography (petroleum ether/EtOAc=9:1) to

leave 46 (156.6 mg, 75%) as a colorless liquid; EI-MS

m/z=319 [M⁺]; TLC: R_f=0.29 (petroleum ether/

EtOAc=9:1); IR (ﬁlm): w 3085–2807, 1465, 1369, 1253,

ent-43 was prepared under the same reaction conditions

as described for 43, starting from ent-40.

4.35. (3R,5R)-1-Benzyl-5-hydroxymethylpyrrolidin-3-yl

tosylate 44

A mixture of 38 (2.8 g, 7.01 mmol) and LiAlH₄(14.0

mL, 1 M solution in THF) in THF (30 mL) were

reacted and worked up as described for 19 to give 44

(2.33 g, 92%) as a white crystalline solid. Mp: 40–41°C;

EI-MS m/z=361 [M⁺]; TLC: R_f=0.2 (petroleum ether/

1

964, 836, 775, 698 cm⁻¹; H NMR (CDCl₃, 360 MHz):

l

0.02 (s, 6H, OSi(CH_{3 2}

6 ) tBu), 0.87 (s, 9H,

OSi(CH₃)₂tBu), 0.94 (d, 3H, J=6.4 Hz, CH₃), 1.39 (m,

3166

C. Heindl et al. / Tetrahedron: Asymmetry 14 (2003) 3153–3172

1H, H-3a), 1.66 (m, 1H, H-5a), 1.97 (m, 2H, H-3b/H-

5b), 2.96 (m, 1H, H-4), 3.16 (m, 1H, H-2), 3.47 (m, 2H,

CH6 ₂OSi(CH₃)₂tBu/CH6 ₂OSi(CH₃)₂tBu), 3.71 (d, 1H,

4.40. (2R,4S)-1-Benzyl-4-butylpyrrolidine-2-carbox-

amide 49

J=14.2 Hz, NCH₂Ph), 3.93 (d, 1H, J=14.2 Hz,

NCH₂Ph), 7.20–7.38 (m, 5H, Ar); ¹³C NMR (CDCl₃,

360 MHz): l 16.12, 18.22, 22.06 (C-Tbs), 25.91 (C-

CH₃), 26.33 (C-5), 31.32 (C-3), 52.57 (NCH₂Ph), 56.26

(C-2), 61.66 (C-4), 65.57 (C-CH₂), 126.54, 128.10,

128.40, 132.12 (C-Ar); Anal. Calcd for C₁₉H₃₃NOSi

(319.57): C, 71.41; H, 10.41; N, 4.38, found: C, 71.57;

H, 10.56; N, 4.25; [h]²_D⁰=+63.2 (c 0.85, CHCl₃).

A solution of NH₃-saturated MeOH (30 mL) and 40

(228 mg, 0.79 mmol) were reacted and worked up as

described for 2. The resulting residue was puriﬁed by

ﬂash chromatography (CH₂Cl₂/MeOH=9:1) to give

pure 49 (136 mg, 66%) as opaque crystals. Mp: 89–

90°C; EI-MS m/z=260 [M⁺]; TLC: R_f=0.04

(petroleum ether/EtOAc=7:3); IR (ﬁlm): w 3424, 3185,

3062–2800, 1677, 1573, 1454, 1373, 1311, 1261, 1029,

1

802 cm⁻¹; H NMR (CDCl₃, 360 MHz): l 0.35 (t, 3H,

J=7.0

6H,CH₂

Hz,

CH₂CH₂

CH₂CH₂CH₂CH₃

6 CH₃), 1.84 (m, 1H, H-3a), 2.05 (m,

6

),

1.25

(m,

4.38. (2R,4S)-1-Benzyl-2-(tert-butyldimethylsilyloxy-

6

methyl)-4-propylpyrrolidine 47

3H, H-5a/H-3b/H-4), 3.09 (dd, 1H, J=8.9, 5.5 Hz,

H-5b), 3.24 (dd, J=10.6, 3.8 Hz, H-2), 3.47 (d, 1H,

J=12.7 Hz, NCH₂Ph), 3.92 (d, 1H, J=12.7 Hz,

NCH₂Ph), 5.57 (brs, 1H, NH₂), 7.25–7.36 (m, 6H,

Ar/NH₂); Anal. calcd for C₁₆H₂₄N₂O (260.38): C,

73.81; H, 9.29; N, 10.76, found: C, 73.86; H, 9.27; N,

10.64; [h]²_D⁰=+82.3 (c 1.0, CHCl₃).

To a solution of 45 (276 mg, 0.58 mmol) in Et₂O (30

mL) was added PrMgCl (0.58 mL, 2 M in Et₂O) at 0°C.

After stirring for 90 min at 0°C and for a further 3h at

rt, the mixture was worked up as described for 46 to

leave 47 (95.8 mg, 75%) as a colorless oil; EI-MS

m/z=347 [M⁺]; TLC: R_f=0.38 (petroleum ether/

EtOAc=98:2); IR (ﬁlm): w 3062–2803, 1461, 1361,

ent-49 [h]²_D⁰=−79.7 (c 1.0, CHCl₃) was prepared under

the same reaction conditions as described for 34, start-

ing from ent-40.

1

1253, 1099, 836, 775, 698 cm⁻¹; H NMR (CDCl₃, 360

MHz): l 0.01 (s, 6H, OSi(CH

6

₃)₂tBu), 0.86 (m, 12H,

1.14 (m, 2H,

OSi(CH₃)₂tBu/CH₂CH₂CH₃),

6

CH₂CH₂CH₃), 1.32 (m, 1H, CH₂CH₂CH₃), 1.52 (m,

2H, H-3a/CH₂CH₂CH₃), 1.67 (m, 1H, H-5a), 1.91 (m,

2H, H-5b/H-3b), 2.98 (m, 2H, H-2/H-4), 3.48 (m, 2H,

4.41. (2R,4S)-(1-Benzyl-4-methylpyrrolidin-2-yl)methyl-

amine 50

CH

6

₂OSi(CH₃)₂tBu/CH₂

6

OSi(CH₃)₂tBu), 3.77 (d, 1H,

A solution of 48 (29.2 mg, 0.13 mmol) in Et₂O (10 mL)

and LiAlH₄(0.54 mL, 1 M solution in Et₂O) were

reacted (reaction time: 24 h) and worked up (extraction

was performed with CH₂Cl₂, ﬂash chromatography was

not necessary) as described for 4 to leave pure 50 (23.2

mg, 85%) as a weakly yellowish oil; EI-MS m/z=174

(a-cleavage, [M−CH₂NH₂]⁺); IR (ﬁlm): w 3062–2788,

1577, 1454, 1261, 1025, 798, 698 cm⁻¹; ¹H NMR

(CDCl₃, 360 MHz): l 0.96 (d, 3H, J=7.0 Hz, CH₃),

1.49 (m, 1H, H-3a), 1.85 (m, 2H, H-3b/H-5a), 2.14 (m,

1H, H-4), 2.70 (m, 3H, CH₂NH₂/CH₂NH₂/H-2), 3.00

(dd, 1H, J=8.5, 6.4 Hz, H-5b), 3.30 (d, 1H, J=13.1

Hz, NCH₂Ph), 3.95 (d, 1H, J=13.1 Hz, NCH₂Ph),

7.22–7.34 (m, 5H, Ar); HR-EIMS: 174.12812 (Anal.

calcd for C₁₂H₁₆N: 174.12828); [h]²_D⁰=+70.4 (c 0.13,

CHCl₃).

J=14.2 Hz, NCH₂Ph), 3.92 (d, 1H, J=14.2 Hz,

NCH₂Ph), 7.20–7.37 (m, 5H, Ar); Anal. calcd for

C₂₁H₃₇NOSi (347.62): C, 72.56; H, 10.73; N, 4.03,

found: C, 72.33; H, 10.76; N, 4.07; [h]²_D⁰=+39.5 (c 0.41,

CHCl₃).

4.39. (2R,4S)-1-Benzyl-4-methylpyrrolidine-2-carbox-

amide 48

A solution of NH₃-saturated MeOH (20 mL) and 39

(216 mg, 0.87 mmol) were reacted and worked up as

described for 2. The resulting residue was puriﬁed by

ﬂash chromatography (petroleum ether/EtOAC=7:3,

then CH₂Cl₂/MeOH=1:1) to give pure 48 (178.3 mg,

94%) as a white crystalline solid. Mp: 68–70°C; EI-MS

m/z=218 [M⁺]; TLC: R_f=0.03 (petroleum ether/

EtOAc=7:3); IR (ﬁlm): w 3424, 3255, 3062–2723, 1681,

1454, 1373, 1319, 1130, 752, 698 cm⁻¹; ¹H NMR

ent-50 [h]²_D⁰=−75.0 (c 0.025, CHCl₃) was prepared

under the same reaction conditions as described for 4,

starting from ent-48.

(CDCl₃, 360 MHz): 0.98 (d, 3H, J=6.5 Hz, CH6 ₃), 1.83

(ddd, 1H, J=12.8, 10.6, 10.4 Hz, H-3a), 2.01 (dd, 1H,

J=10.3, 8.6 Hz, H-5a), 2.09 (ddd, 1H, J=12.8, 8.6, 4.1

Hz, H-3b), 2.18 (m, 1H, H-4), 3.07 (dd, 1H, J=8.6, 5.7

Hz, H-5b), 3.28 (dd, 1H, J=10.6, 4.1 Hz, H-2), 3.49 (d,

1H, J=12.7 Hz, NCH₂Ph), 3.92 (d, 1H, J=12.7 Hz,

NCH₂Ph), 5.27 (brs, 1H, NH₂), 7.20–7.39 (m, 6H,

Ar/NH₂); Anal. calcd for C₁₃H₁₈N₂O (218.30): C,

71.53; H, 8.31; N, 12.83, found: C, 71.58; H, 8.31; N,

12.80; [h]²_D⁰=+74.9 (c 0.7, CHCl₃).

4.42. (2R,4S)-(1-Benzyl-4-butylpyrrolidin-2-yl)methyl-

amine 51

A mixture of 49 (25.1 mg, 0.10 mmol) and LiAlH₄(0.39

mL, 1 M solution in Et₂O) in Et₂O (10 mL) was reacted

and worked up as described for 4. Pure 51 (22.8 mg,

96%) was obtained as a yellowish oil without further

puriﬁcation; EI-MS m/z=216 (a-cleavage, [M−

CH₂NH₂]⁺); TLC: R_f=0.07 (CH₂Cl₂/MeOH=9:1); IR

(ﬁlm): w 3062–2792, 1673, 1577, 1454, 1261, 1025, 798,

1

ent-48 [h]²_D⁰=−69.3 (c 0.67, CHCl₃) was prepared under

the same reaction conditions as described for 33, start-

ing from ent-39.

698 cm⁻¹; H NMR (CDCl₃, 360 MHz): l 0.95 (t, 3H,

J=7.0 Hz, CH₂CH₂CH₂CH₃), 1.35 (m, 6H,

CH₂CH₂CH₂CH₃), 1.53 (m, 1H, H-3a), 1.91 (m, 2H,

C. Heindl et al. / Tetrahedron: Asymmetry 14 (2003) 3153–3172

3167

H-3b/H-5a), 2.12 (m, 1H, H-4), 2.75 (m, 2H, CH₂NH₂/

H-2), 2.84 (dd, 1H, J=12.3, 5.5 Hz, CH₂NH₂), 3.12

(dd, 1H, J=8.2, 6.5 Hz, H-5b), 3.38 (d, 1H, J=13.0

Hz, NCH₂Ph), 4.04 (d, 1H, J=13.0 Hz, NCH₂Ph),

7.28–7.48 (m, 5H, Ar); HR-EIMS: 216.17558 (Anal.

calcd for C₁₅H₂₂N: 216.17523); [h]²_D⁰=+84.0 (c 0.08,

CHCl₃).

ent-53 [h]²_D⁰=−85.3 (c 0.23, CHCl₃)) was prepared

under the same reaction conditions as described for 53,

starting from ent-40.

4.45. (2R,4S)-1-Benzyl-4-methyl-2-chloromethylpyrro-

lidine hydrochloride 54

A solution of 52 (405 mg, 1.98 mmol) in CHCl₃(25

mL) and SOCl₂(0.22 mL, 2.97 mmol) were reacted

(reaction time: 24 h) and worked up as described for 55

to leave crude 54. Crude 54 was used for the next

reaction without further puriﬁcation.

ent-51 [h]²_D⁰=−80.0 (c 0.09, CHCl₃) was prepared under

the same reaction conditions as described for 51, start-

ing from ent-49.

4.43. (2R,4S)-(1-Benzyl-4-methylpyrrolidin-2-yl)-

methanol 52

ent-54 was prepared under the same reaction conditions

as described for 54, starting from ent-52.

A solution of 39 (585 mg, 2.4 mmol) in THF (50 mL)

and LiAlH₄(4.73 mL, 1 M solution in THF) were

reacted (reaction time: 1 h) and worked up as described

for 20 to give 52 (444.7 mg, 92%) as a colorless oil;

EI-MS m/z=205 [M⁺]; TLC: R_f=0.28 (CH₂Cl₂/

MeOH=9:1); IR (ﬁlm): w 3388, 3027–2780, 1454, 1375,

4.46. (2R,4S)-1-Benzyl-4-butyl-2-chloromethylpyrro-

lidine hydrochloride 55

To a solution of 53 (113 mg, 0.46 mmol) in CHCl₃(20

mL) was added SOCl₂(0.07 mL, 0.92 mmol) with the

resulting mixture reﬂuxed for 4 h. After cooling to rt,

the mixture was evaporated to leave pure 55 (135 mg,

98%) as a weakly yellowish solid. Mp: 185–190°C;

EI-MS m/z=265 [M⁺]; TLC: R_f=0.83 (CH₂Cl₂/

MeOH=9:1); IR (ﬁlm): w 3062–2857, 2468, 1457, 1261,

1

1028, 746, 700 cm⁻¹; H NMR (CDCl₃, 360 MHz): l

0.95 (d, 3H, J=6.4 Hz, CH₃), 1.54 (ddd, 1H, J=12.7,

9.5, 9.5 Hz, H-3a), 1.97 (m, 2H, H-3b/H-5a), 2.14 (m,

1H, H-4), 2.83 (m, 1H, H-2), 3.03 (dd, 1H, J=8.5, 6.0

Hz, H-5b), 3.36 (d, 1H, J=13.1 Hz, NCH₂Ph), 3.39

(dd, 1H, J=10.7, 2.1 Hz, CH₂OH), 3.62 (dd, 1H,

J=10.7, 3.4 Hz, CH₂OH), 3.94 (d, 1H, J=13.1 Hz,

NCH₂Ph), 7.22–7.35 (m, 5H, Ar); Anal. calcd for

C₁₃H₁₉NO (205.30): C, 76.06; H, 9.33; N, 6.82, found:

C, 75.86; H, 9.27; N, 6.87; [h]²_D⁰=+63.5 (c 1.0, CHCl₃).

1

1025, 752, 701 cm⁻¹; H NMR (CDCl₃, 360 MHz): l

0.80 (t, 3H, J=6.9 Hz, CH₂CH₂CH₂CH₃

6 ), 1.22 (m, 6H,

CH₂CH₂CH₂CH₃), 1.82 (ddd, 1H, J=13.6, 10.0, 10.0

6

Hz, H-3a), 2.22 (ddd, 1H, J=13.6, 7.8, 6.0 Hz, H-3b),

2.40 (dd, 1H, J=18.8, 10.6 Hz, H-5a), 2.56 (m, 1H,

H-4), 3.58 (m, 2H, H-5b/H-2), 3.87 (m, 2H, NCH₂Ph/

NCH₂Ph), 4.15 (dd, 1H, J=13.1, 5.3 Hz, CH₂Cl), 4.31

(dd, 1H, J=13.1, 5.0 Hz, CH₂Cl), 7.11–7.68 (m, 5H,

Ar); Anal. calcd for C₁₆H₂₄ClN×HCl (302.14): C, 63.57;

H, 8.34; N, 4.63, found: C, 63.80; H, 9.03; N, 4.16;

[h]²_D⁰=+24.8 (c 0.61, CHCl₃).

ent-52 [h]²_D⁰=−65.1 (c 0.98, CHCl₃) was prepared under

the same reaction conditions as described for 52, start-

ing from ent-39.

4.44. (2R,4S)-(1-Benzyl-4-butylpyrrolidin-2-yl)methanol

53

ent-55 [h]²_D⁰=−29.3 (c 0.2, CHCl₃) was prepared under

the same reaction conditions as described for 55, start-

ing from ent-53.

A solution of 40 (686 mg, 2.37 mmol) in THF (50 mL)

and LiAlH₄(4.74 mL, 1 M solution in THF) were

reacted and worked up (eluent for ﬂash chromatogra-

phy: CH₂Cl₂/MeOH=9:1, extraction with CH₂Cl₂) as

described for 19 to leave pure 53 (575 mg, 98%) as an

opaque solid. Mp: 58°C; EI-MS m/z=216 (a-cleavage);

TLC: R_f=0.36 (CH₂Cl₂/MeOH=9:1); IR (ﬁlm): w 3401,

3085–2792, 1604, 1454, 1133, 1033, 971, 917, 748, 701

cm⁻¹; ¹H NMR (CDCl₃, 360 MHz): l 0.85 (t, 3H,

J=7.0 Hz, CH₂CH₂CH₂CH₃), 1.24 (m, 6H,

4.47. (2R,4S)-(1-Benzyl-4-methylpyrrolidin-2-yl)-

acetonitrile 56 and (2S,4S)-(1-benzyl-4-methyl-

pyrrolidin-2-yl)acetonitrile 60

To a solution of 54 (443 mg, 1.98 mmol) in 80% EtOH

(20 mL) was added NaCN (1.94 g, 39.5 mmol) and the

mixture reﬂuxed for 48 h. After cooling to rt, an

aqueous saturated solution of NaHCO₃was added and

the mixture extracted with Et₂O. The organic layer was

dried over MgSO₄and evaporated. The residue was

puriﬁed by ﬂash chromatography (petroleum ether/

EtOAc=9:1) to give 56 and 60 (overall yield: 209 mg,

49%, two steps).

CH6 ₂CH6 ₂CH6 ₂CH₃), 1.55 (m, 1H, H-3a), 1.97 (m, 3H,

H-5a, H-4, H-3b), 2.80 (m, 1H, H-2), 3.05 (dd, 1H,

J=8.5, 6.2 Hz, H-5b), 3.34 (d, 1H, J=13.0 Hz,

NCH₂Ph), 3.39 (dd, 1H, J=10.7, 1.7 Hz, CH₂

3.63 (dd, 1H, J=10.7, 3.3 Hz, CH₂OH), 3.94 (d, 1H,

J=13.0 Hz, NCH₂Ph), 7.19–7.37 (m, 5H, Ar); ¹³C

6 OH),

6

NMR

(CH₂CH₂CH₂C

(CH₂CH₂C

(NCH₂Ph), 60.98 (C-5), 62.18 (C

127.15, 128.36, 128.80, 138.91 (C-Ar); Anal. calcd for

C₁₆H₂₅NO (247.38): C, 77.68; H, 10.19; N, 5.66, found:

C, 77.61; H, 10.09; N, 5.65; [h]²_D⁰=+78.0 (c 1.0, CHCl₃).

(CDCl₃,

90.56

22.79,

MHz):

30.54,

l

13.98

34.00

Analytical data of 56: EI-MS m/z=174 (a-cleavage,

[M-CH₂CN]⁺); TLC: R_f=0.42 (petroleum ether/

EtOAc=8:2); IR (ﬁlm): w 3027–2796, 2248, 1454, 1373,

1133, 1060, 744, 701 cm⁻¹; ¹H NMR (CDCl₃, 360

MHz): l 0.98 (d, 3H, J=6.7 Hz, CH₃), 1.69 (ddd, 1H,

J=12.9, 9.1, 9.1 Hz, H-3a), 1.92 (m, 2H, H-3b/H-5a),

2.35 (m, 3H, H-4/CH₂CN/CH₂CN), 2.94 (m, 1H, H-2),

6

H₃),

6

H₂CH₃), 35.07 (C-3), 37.50 (C-4), 58.73

H₂OH), 64.25 (C-2),

6

3168

C. Heindl et al. / Tetrahedron: Asymmetry 14 (2003) 3153–3172

3.07 (dd, 1H, J=8.9, 6.4 Hz, H-5b), 3.49 (d, 1H,

J=12.9 Hz, NCH₂Ph), 3.87 (d, 1H, J=12.9 Hz,

NCH₂Ph), 7.24–7.34 (m, 5H, Ar); Anal. calcd for

C₁₄H₁₈N₂(214.31): C, 78.46; H, 8.47; N, 13.07, found:

C, 78.46; H, 8.47; N, 13.07; [h]²_D⁰=−72.6 (c 0.6, CHCl₃).

4.51. (2R,4R)-N-[(1-Benzyl-4-hydroxypyrrolidin-2-

yl)methyl]-5-chloro-2-methoxy-4-methylaminobenzamide

62

A

suspension

of

5-chloro-2-methoxy-4-(methyl-

amino)benzoic acid (42.0 mg, 0.19 mmol), HOBt (26.8

mg, 0.18 mmol) and DCC (36.7 mg, 0.18 mmol) in

EtOAc (15 mL) was reacted and worked up (gradient:

CH₂Cl₂/MeOH=98:2 to 94:6) as described for ent-63

to give 62 (58.2 mg, 89%) as an opaque, yellowish solid.

Mp: 50–51°C; TLC: R_f=0.20 (CH₂Cl₂/MeOH=9:1);

IR (ﬁlm): w 3356, 3062–2800, 1627, 1515, 1333, 1281,

1245, 1214, 1154, 1135, 1035, 911, 809, 731, 700 cm⁻¹;

¹H NMR (CDCl₃, 360 MHz): l 1.66 (brdd, 1H, J=

14.0, 6.0 Hz, H-3a), 2.36 (m, 2H, H-3b/H-5a), 2.83 (m,

ent-56 [h]²_D⁰=+95.6 (c 0.3, CHCl₃) was prepared under

the same reaction conditions as described for 56, start-

ing from ent-54.

4.48. (2R,4S)-(1-Benzyl-4-butylpyrrolidin-2-yl)-

acetonitrile 57 and (2S,4S)-(1-benzyl-4-butylpyrrolidin-

2-yl)acetonitrile 61

A solution of 55 (83.5 mg, 0.31 mmol) in 80% EtOH

(10 mL) and NaCN (307 mg, 6.26 mmol) were reacted

and worked up (petroleum ether/EtOAc=95:5) as

described for 23 to give 57 and 61 (overall yield: 51.3

mg, 72%, two steps). Compound 57 could be isolated as

a yellowish, creamy mass; EI-MS m/z=216 (a-cleavage,

[M−CH₂CN]⁺); TLC: R_f=0.2 (petroleum ether/

EtOAc=95:5); IR (ﬁlm): w 3085–2800, 2248, 1731,

1454, 1373, 1214, 1141, 755, 701 cm⁻¹; ¹H NMR

1H, H-2), 2.95 (brd, 3H, J=5.3 Hz, NHCH

1H, J=12.8 Hz, NCH₂Ph), 3.39 (brd, 1H, J=12.8 Hz,

H-5b), 3.91 (m, 5H, CH₂NH/CH₂NH/OCH₃), 4.09 (d,

1H, J=12.8 Hz, NCH₂Ph), 4.14 (m, 1H, H-4), 4.73 (m,

1H, NHCH₃), 6.12 (s, 1H, CHCOCH₃), 7.22–7.36 (m,

5H, Ar), 8.14 (s, 1H, CHCCl), 8.25 (brd, 1H, J=7.8

Hz, NHCH₂); Anal. calcd for C₂₁H₂₆ClN₃O₃(403.91):

6 ₃), 3.27 (d,

6

C, 62.45; H, 6.49; N, 10.40, found: C, 62.36; H, 6.54; N,

10.42; [h]²_D⁰=+47.2 (c 0.62, CHCl₃).

(CDCl₃, 360 MHz):

l

0.86 (t, 3H, J=7.0 Hz,

CH₂CH₂CH₃),

CH₂CH₂CH₂CH₃), 1.26 (m, 6H, CH₂

6

ent-62 was synthesized under the same reaction condi-

tions, starting from 5; [h]²_D⁰=−79.4 (c 0.41, CHCl₃).

1.72 (ddd, 1H, J=13.0, 9.1, 9.1 Hz, H-3a), 1.88 (ddd,

1H, J=13.0, 8.5, 4.9 Hz, H-3b), 1.95 (dd, 1H, J=9.4,

9.4 Hz, H-5a), 2.21 (m, 1H, H-4), 2.32 (dd, 1H, J=

16.7, 6.5 Hz, CH₂CN), 2.39 (dd, 1H, J=16.7, 4.3 Hz,

CH₂CN), 2.91 (m, 1H, H-2), 3.08 (dd, 1H, J=9.4, 6.5

Hz, H-5b), 3.47 (d, 1H, J=13.0 Hz, NCH₂Ph), 3.87 (d,

1H, J=13.0 Hz, NCH₂Ph), 7.24–7.35 (m, 5H, Ar);

Anal. calcd for C₁₇H₂₄N₂(256.39): C, 79.64; H, 9.44; N,

10.93, found: C, 79.68; H, 9.39; N, 10.70; [h]²_D⁰=+41.4

(c 0.1, CHCl₃).

4.52. (2S,4R)-N-[(1-Benzyl-4-hydroxypyrrolidin-2-yl)-

methyl]-5-chloro-2-methoxy-4-methylaminobenzamide

ent-63

A

suspension

of

5-chloro-2-methoxy-4-(methyl-

amino)benzoic acid (44.75 mg, 0.21 mmol), HOBt

(28.59 mg, 0.189 mmol) and DCC (38.97 mg, 0.19

mmol) in EtOAc (15 mL) was stirred at rt for 15 min.

Compound 4 (35.5 mg, 0.17 mmol), dissolved in

EtOAc, was then added and stirring continued for a

further 24 h. The mixture was ﬁltered through Celite

and the ﬁltrate was evaporated. The residue was

puriﬁed by ﬂash chromatography (CH₂Cl₂/MeOH=

95:5) to give ent-63 (36.7 mg, 53%) as a glutinous,

colorless mass; TLC: R_f=0.07 (CH₂Cl₂/MeOH=9:1);

IR (ﬁlm): w 3363, 3027–2803, 1601, 1516, 1333, 1280,

ent-57 [h]²_D⁰=−43.0 (c 0.5, CHCl₃) was prepared under

the same reaction conditions as those described for 57

starting from ent-55.

4.49. (2R,4S)-2-(1-Benzyl-4-methylpyrrolidin-2-yl)-

ethylamine 58

A solution of 56 (6.9 mg, 0.03 mmol) in THF (5 mL)

and LiAlH₄(0.07 mL, 1 M solution in THF) were

reacted and worked up as described for 20 to leave

crude 56. Crude 56 was used for the next reaction

without further puriﬁcation.

1

1246, 1213, 1036, 910, 809, 731, 700 cm⁻¹; H NMR

(CDCl₃, 360 MHz): l 1.89 (m, 1H, H-3a), 2.01 (ddd,

1H, J=13.8, 7.1, 7.1 Hz, H-3b), 2.39 (m, 1H, H-5a),

2.96 (d, 3H, J=5.0 Hz, NHCH

2), 3.39 (brd, 1H, J=14.2 Hz, CH

J=12.7 Hz, NCH₂Ph), 3.85 (m, 4H, OCH

4.11 (d, 1H, J=12.7 Hz, NCH₂Ph), 4.34 (m, 1H, H-4),

4.73 (m, 1H, NHCH₃), 6.12 (s, 1H, CHCOCH₃), 7.20–

7.39 (m, 5H, Ar), 8.12 (s, 1H, CHCCl), 8.27 (brd, 1H,

J=6.0 Hz, NH

CH₂); ¹³C NMR (CDCl₃, 62.89 MHz): l

30.19 (NHCH₃), 38.45 (C-3), 40.19 (CH₂NH), 55.87

(OCH₃), 58.51 (NCH₂Ph), 62.02 (C-5/C-2), 70.11 (C-4),

93.04 (C

132.38 (C

6

₃), 3.28 (m, 2H, H-5b/H-

₂NH), 3.47 (d, 1H,

₃/CH₂NH),

6

4.50. (2R,4S)-2-(1-Benzyl-4-butylpyrrolidin-2-yl)-

ethylamine 59

6

A mixture of 56 (10.7 mg, 0.04 mmol) and LiAlH₄(0.08

mL, 1 M solution in THF) in THF (10 mL) were

reacted and worked up as described for 19 to leave

crude 59. Crude 59 was used for the next reaction step

without further puriﬁcation.

6

HCOCH₃), 127.15, 128.31, 128.79 (C-Ar),

HCCl), 148.14, 158.22, 165.12 (C-Ar); Anal.

6

calcd for C₂₁H₂₆ClN₃O₃(403.91): C, 62.45; H, 6.49; N,

10.40, found: C, 62.54; H, 6.36; N, 10.30; [h]²_D⁰=−122.2

(c 0.09, CHCl₃).

ent-59 was prepared under the same reaction conditions

as described for 59, starting from ent-56.

C. Heindl et al. / Tetrahedron: Asymmetry 14 (2003) 3153–3172

3169

Compound 63 was synthesized under the same reaction

conditions, starting from ent-5; [h]²_D⁰=+114.6 (c 0.19,

CHCl₃).

OCH₃), 4.06 (d, 1H, J=13.5 Hz, NCH₂Ph), 4.38 (m,

1H, H-4), 4.72 (m, 1H, NHCH₃), 6.11 (s, 1H,

CHCOCH₃), 7.19–7.34 (m, 5H, Ar), 7.76 (brs, 1H,

NHCH₂), 8.11 (s, 1H, CHCCl); HR-EIMS: 417.18210

(Anal. calcd for C₂₂H₂₈ClN₃O₃: 417.18192), 326.12712

(Anal. calcd for C₁₅H₂₁ClN₃O₃: 326.12714), 198.03241

(Anal. calcd for C₉H₉ClNO₂: 198.03218); [h]²_D⁰=−36.8

(c 0.13, CHCl₃).

6

4.53. (2S,4R)-N-[(2-(1-Benzyl-4-hydroxypyrrolidin-2-

yl)ethyl]-5-chloro-2-methoxy-4-methylaminobenzamide

64

Compound 26 was synthesized from 24 (17.1 mg, 0.08

mmol) and was used as an amine precursor instead of 4

together with a suspension of 5-chloro-2-methoxy-4-

(methylamino)benzoic acid (21.1 mg, 0.09 mmol),

HOBt (13.1 mg, 0.09 mmol) and DCC (17.8 mg, 0.09

mmol) in EtOAc (10 mL) and reacted as described for

ent-63 to give 64 (9.0 mg, 27% over two reaction steps)

as a red solid. Mp: 183–189°C. Puriﬁcation was per-

formed by ﬂash chromatography (CH₂Cl₂/MeOH=

99:1) and HPLC (column: RP 18, eluent:

MeOH/H₂O=95:5). EI-MS m/z=399 (C₂₂H₂₆ClN₃O₂);

TLC: R_f=0.15 (CH₂Cl₂/MeOH=9:1); IR (ﬁlm): w 3397,

2923, 2854, 1735, 1631, 1600, 1519, 1457, 1334, 1280,

1249, 1214, 1130, 1033, 971, 917, 809, 755, 698 cm⁻¹; ¹H

NMR (CDCl₃, 360 MHz): l 1.65–2.41 (m, 6H, H-3a/H-

Compund 65 was synthesized under the same reaction

conditions, starting from ent-65; [h]²_D⁰=+22.9 (c 0.09,

CHCl₃).

4.55. (2R,4S)-N-[(1-Benzyl-4-methylpyrrolidin-2-yl)-

methyl]-5-chloro-2-methoxy-4-methylaminobenzamide 66

Compound 50 was synthesized from 48 (29.2 mg, 0.13

mmol) and used as an amine precursor to react with a

suspension of 5-chloro-2-methoxy-4-(methylamino)-

benzoic acid (34.89 mg, 0.16 mmol), HOBt (22.2 mg,

0.15 mmol) and DCC (30.67 mg, 0.15 mmol) in EtOAc

(10 mL) as described for ent-63 to give 66 (9.0 mg, 27%

over two reaction steps) as a colorless, glutinous mass.

Puriﬁcation was performed by ﬂash chromatography

(CH₂Cl₂/MeOH=99:1) and HPLC (column: RP 18,

eluent: MeOH/H₂O=95:5). EI-MS m/z=401 [M⁺];

TLC: R_f=0.34 (CH₂Cl₂/MeOH=9:1); IR (ﬁlm): w 3370,

2927–2796, 1643, 1600, 1515, 1457, 1369, 1330, 1280,

3b/H-5a/CH₂

2.89 (brd, 1H, J=10.6 Hz, H-5b), 2.96 (brd, 3H, J=5.0

Hz, NHCH₃), 3.18 (d, 1H, J=13.1 Hz, NCH₂Ph), 3.56

(m, 2H, CH₂CH₂NH/CH₂CH₂NH), 3.90 (s, 3H,

OCH₃), 4.09 (d, 1H, J=13.1 Hz, NCH₂Ph), 4.16 (m,

1H, H-4), 4.71 (m, 1H, NHCH₃), 6.10 (s, 1H,

CHCOCH₃), 7.19–7.37 (m, 5H, Ar), 7.80 (brs, 1H,

NHCH₂), 8.12 (s, 1H, CHCCl); HR-EIMS: 399.17149

6 CH₂NH/CH6 ₂CH₂NH), 2.50 (m, 1H, H-2),

6

1

6

1245, 1137, 1037, 917, 809, 748, 698 cm⁻¹; H NMR

6

(CDCl₃, 360 MHz): l 0.94 (d, 3H, J=6.7 Hz, CH₃),

1.55 (m, 1H, H-3a), 1.87 (m, 2H, H-3b/H-5a), 2.10 (m,

(Anal. calcd for C₂₂H₂₆ClN₃O₂: 399.17136), 198.03255

(Anal. calcd for C₉H₉ClNO₂: 198.03218), 176.10714

(Anal. calcd for C₁₁H₁₄NO: 176.10754), 112.07583

(Anal. calcd for C₆H₁₀NO: 112.07624), 198.03241

(Anal. calcd for C₉H₉NO₂Cl: 198.03218); [h]²_D⁰=+40.0

(c 0.05, CHCl₃).

1H, H-4), 2.96 (m, 5H, H-5b/H-2/NHCH

1H, J=12.8 Hz, NCH₂Ph), 3.33 (ddd, 1H, J=13.8, 3.9,

2.5 Hz, CH₂NH), 3.79 (ddd, 1H, J=13.8, 7.7, 2.6 Hz,

CH₂NH), 3.87 (s, 3H, OCH₃), 4.04 (d, 1H, J=13.0 Hz,

NCH₂Ph), 4.71 (m, 1H, NHCH₃), 6.12 (s, 1H,

CHCOCH₃), 7.19–7.38 (m, 5H, Ar), 8.15 (s, 1H,

CHCCl), 8.36 (m, 1H, NH

CH₂); ¹³C NMR (CDCl₃,

90.56 MHz): 18.53 (CH₃), 31.72 (C-4), 35.65

(NHCH₃), 37.04 (C-3), 41.39 (CH₂NH₂), 56.37 (OCH₃),

58.51 (NCH₂Ph), 61.98 (C-2), 62.23 (C-5), 112.35

6 ₃), 3.27 (d,

6

ent-64 could be synthesized under the same reaction

conditions as described for 64. Puriﬁcation of ent-64 by

HPLC was not necessary.

6

l

6

4.54. (2S,4R)-N-[(2-(1-Benzyl-4-hydroxypyrrolidin-2-

yl)ethyl]-5-chloro-2-methoxy-4-methylaminobenzamide

ent-65

(C

6

HCOCH₃), 127.06, 128.26, 128.68 (C-Ar), 134.09

HCCl), 144.53, 156.80, 163.29 (C-Ar), 170.15

(C

6

(CONH); HR-EIMS: 401.18726 (Anal. calcd for

C₂₂H₂₈ClN₃O₂: 401.18701), 174.12785 (Anal. calcd for

C₁₂H₁₆N: 174.12828); [h]²_D⁰=+69.5 (c 0.14, CHCl₃).

Compound 25 was synthesized from 21 (11.5 mg, 0.053

mmol) and used as an amine precursor instead of 4 to

react with

a

suspension of 5-chloro-2-methoxy-4-

ent-66 could be synthesized under the same reaction

conditions as described for 66; [h]²_D⁰=−70.0 (c 0.2,

CHCl₃).

(methylamino)benzoic acid (13.9 mg, 0.06 mmol),

HOBt (8.7 mg, 0.06 mmol) and DCC (12.0 mg, 0.06

mmol) in EtOAc (15 mL) as described for ent-63 to

give ent-65 (9.3 mg, 41%) as an opaque solid. Mp:

110°C. Puriﬁcation was performed by ﬂash chromatog-

raphy (CH₂Cl₂/MeOH=99:1) and HPLC (column: RP

18, eluent: MeOH/H₂O=95:5). EI-MS m/z=417 [M⁺];

TLC: R_f=0.1 (CH₂Cl₂/MeOH=9:1); IR (ﬁlm): w 3394,

2923, 2854, 1739, 1604, 1519, 1461, 1373, 1334, 1280,

1249, 1214, 1033, 809, 752, 698 cm⁻¹; ¹H NMR (CDCl₃,

360 MHz): l 1.41–2.26 (m, 6H, H-3a/H-3b/H-5a/CH₂-

CH₂-NH/CH₂-CH₂-NH), 2.88 (m, 1H, H-2), 2.96 (brd,

4.56. (2R,4S)-N-[(1-Benzyl-4-butylpyrrolidin-2-yl)-

methyl]-5-chloro-2-methoxy-4-methylaminobenzamide 67

Compound 51 (22.0 mg, 0.92 mmol) and a suspension

of 5-chloro-2-methoxy-4-(methylamino)benzoic acid

(21.69 mg, 0.10 mmol), HOBt (15.09 mg, 0.10 mmol)

and DCC (21.16 mg, 0.10 mmol) in EtOAc (15 mL)

was reacted and worked up (CH₂Cl₂/MeOH=98:) as

described for ent-63 to give 67 (22.6 mg, 60%) as a

yellowish, glutinous mass. TLC: R_f=0.3 (CH₂Cl₂/

3H, J=5.0 Hz, NHCH₃

6 ), 3.28 (m, 2H, NCH₂Ph/H-5b),

3.51 (m, 2H, CH₂-CH₂-NH/CH₂-CH₂-NH), 3.91 (s, 3H,

3170

C. Heindl et al. / Tetrahedron: Asymmetry 14 (2003) 3153–3172

MeOH=9:1); IR (ﬁlm): w 3367, 3062–2796, 1600, 1511,

1457, 1334, 1280, 1245, 1214, 1153, 1037, 809, 752, 698

cm⁻¹; ¹H NMR (CDCl₃, 360 MHz): l 0.83 (t, 3H,

give 69 (6.9 mg, 37% over two reaction steps) as a

colorless, opaque solid. Mp: 78°C; EI-MS m/z=457

[M⁺]; TLC: R_f=0.36 (CH₂Cl₂/MeOH=9:1); IR (ﬁlm): w

3409, 3062–2792, 1639, 1604, 1519, 1457, 1330, 1280,

1245, 1214, 1153, 1130, 1037, 917, 809, 752, 698 cm⁻¹;

CH₂CH₂CH₂CH6 ₃), 1.22 (m, 6H, CH6 ₂CH6 ₂CH6 ₂CH₃),

1.55 (m, 1H, H-3a), 1.85 (m, 2H, H-3b/H-5a), 1.99 (m,

1H, H-4), 2.88 (m, 1H, H-2), 2.96 (d, 3H, J=5.1 Hz,

¹H NMR (CDCl₃, 360 MHz):

CH₂CH₂CH₂CH₃

l

0.85 (t, 3H,

CH₂CH₂CH₃),

1.53–2.15 (m, 7H, H-3a/H-3b/H-4/H-5a/CH₂-CH₂-NH/

NHCH

1H, J=13.0 Hz, NCH₂Ph), 3.35 (ddd, 1H, J=13.7, 3.8,

2.4 Hz, CH₂NH), 3.79 (ddd, 1H, J=13.7, 7.6, 2.3 Hz,

CH₂NH), 3.85 (s, 3H, OCH₃), 4.04 (d, 1H, J=13.0 Hz,

NCH₂Ph), 4.71 (m, 1H, NHCH₃), 6.13 (s, 1H,

CHCOCH₃), 7.19–7.39 (m, 5H, Ar), 8.16 (s, 1H,

CHCCl), 8.36 (brd, 1H, J=3.8 Hz, NHCH₂); Anal.

6

₃), 3.03 (dd, 1H, J=8.2, 6.2 Hz, H-5b), 3.24 (d,

6

), 1.25 (m, 6H, CH₂

6

CH₂-CH₂-NH), 2.60 (m, 1H, H-2), 3.00 (m, 4H,

6

NHCH6 ₃/H-5b), 3.18 (d, 1H, J=12.1 Hz, NCH₂Ph),

6

3.53 (m, 2H, CH₂-CH₂-NH/CH₂-CH₂-NH), 3.89 (s, 3H,

OCH₃), 4.02 (d, 1H, J=12.1 Hz, NCH₂Ph), 4.71 (m,

6

1H, NH

5H, Ar), 7.80 (brs, 1H, NH

HR-EIMS: 457.24973 (Anal. calcd for C₂₆H₃₆ClN₃O₂:

457.24960), 366.19450 (Anal. calcd for C₁₉H₂₉ClN₃O₂:

366.19482), 216.17526 (Anal. calcd for C₁₅H₂₂N:

216.17523), 152.14337 (Anal. calcd for C₁₀H₁₈N:

152.14392); [h]²_D⁰=+67.8 (c 0.2, CHCl₃).

6

CH₃), 6.10 (s, 1H, CH

6

COCH₃), 7.17–7.39 (m,

CCl);

calcd for C₂₅H₃₄ClN₃O₂(444.02): C, 67.63; H, 7.72; N,

9.46, found: C, 67.23; H, 7.75; N, 9.35; [h]²_D⁰=+89.5 (c

0.29, CHCl₃).

6

CH₂), 8.11 (s, 1H, CH

6

ent-67 could be synthesized under the same reaction

conditions as described for 67; [h]²_D⁰=−96.5 (c 0.45,

CHCl₃).

ent-69 could be synthesized under the same reaction

conditions as described for 69; [h]²_D⁰=−55.7 (c 0.31,

CHCl₃).

4.57. (2R,4S)-N-[(2-Benzyl-4-methylpyrrolidin-2-yl)-

ethyl)]-5-chloro-2-methoxy-4-methylaminobenzamide 68

Compound 58 was synthesized from 56 (11.7 mg, 0.055

mmol) and reacted with a suspension of 5-chloro-2-

methoxy-4-methylaminobenzoic acid (14.37 mg, 0.07

mmol), HOBt (9.05 mg, 0.06 mmol) and DCC (12.36

mg, 0.06 mmol) in EtOAc (10 mL) and worked up

(CH₂Cl₂/MeOH=99:1) as described for ent-63 to give

68 (8.0 mg, 35% over two reaction steps) as an orange,

opaque solid. Mp: 118°C. EI-MS m/z=415 [M⁺]; TLC:

R_f=0.45 (CH₂Cl₂/MeOH=9:1); IR (ﬁlm): w 3413,

2927–2792, 1724, 1639, 1604, 1519, 1457, 1330, 1280,

4.59. Dopamine receptor binding studies

Receptor binding studies were carried out as described

in the literature.⁴⁶In brief, the dopamine D1 receptor

assay was done with bovine striatal membranes at a

ﬁnal protein concentration of 45 mg/assay tube and the

radioligand [³H]SCH 23390 at 0.3 nM (K_d=0.35–0.75

nM).

1

1245, 1214, 1130, 1037, 809, 752, 698 cm⁻¹; H NMR

Competition experiments with the human D2_long

,

(CDCl₃, 360 MHz): l 0.96 (d, 3H, J=6.4 Hz, CH₃),

D2_short, D3 and D4.4 receptors were run with prepara-

tions of membranes from CHO cells expressing the

corresponding receptor and [³H]spiperone at a ﬁnal

concentration of 0.1 nM. The assays were carried out at

a protein concentration of 5–25 mg/assay tube and K_d

values of 0.10 nM for D2_longand D2_short, 0.10–0.40 nM

for D3 and 0.10–0.45 nM for D4.4.

1.88 (m, 7H, H-3a/H-3b/H-5a/CH₂

CH₂-NH-), 2.27 (m, 1H, H-4), 2.63 (m, 1H, H-2), 2.98

(m, 4H, H-5b/NHCH₃), 3.20 (d, 1H, J=12.8 Hz,

NCH₂Ph), 3.53 (m, 2H, CH₂-CH₂-NH-/CH₂-CH₂-NH-

), 3.88 (s, 3H, OCH₃), 4.01 (d, 1H, J=12.8 Hz,

NCH₂Ph), 4.70 (m, 1H, NHCH₃), 6.10 (s, 1H,

CHCOCH₃), 7.19–7.37 (m, 5H, Ar), 7.80 (brs, 1H,

NHCH₂), 8.11 (s, 1H, CHCCl); HR-EIMS: 415.20226

6 -CH₂-NH-/CH6 ₂-

6

Protein concentration was established by the method of

Lowry using bovine serum albumin as standard.⁴⁸

(Anal. calcd for C₂₃H₃₀ClN₃O₂: 415.20267), 324.14785

(Anal. calcd for C₁₆H₂₃ClN₃O₂: 324.14789), 174.12863

(Anal. calcd for C₁₂H₁₆N: 174.12828), 110.09727 (Anal.

calcd for C₇H₁₂N: 110.09698); [h]²_D⁰=+48.4 (c 0.15,

CHCl₃).

4.60. 5-HT receptor binding studies

ent-68 could be synthesized under the same reaction

conditions as described for 68; [h]²_D⁰=−56.5 (c 0.09,

CHCl₃).

Receptor binding experiments were done with cortical

homogenates prepared from porcine brain which was

obtained from the local slaughterhouse. The cortex

material was dissected and frozen at −80°C. Mem-

branes were prepared by thawing, cutting up and

homogenizing in an aqueous solution of sucrose (0.1

M). The suspension was washed by centrifugation at

2,500 g. The resulting supernatant was then pelleted by

centrifugation at 80,000 g for 40 min. The pellet was

resuspended in Tris–EDTA buffer (50 mM Tris–HCl, 1

mM EDTA; pH 7.4), homogenized with a Potter–Elve-

hjam homogenizer and stored at −80°C in small

aliquots.

4.58. (2R,4S)-N-[(2-(1-Benzyl-4-butylpyrrolidin-2-yl)-

ethyl)]-5-chloro-2-methoxy-4-methylaminobenzamide 69

Compound 59 was synthesized from 57 (10.5 mg, 0.04

mmol) and was reacted with a suspension of 5-chloro-2-

methoxy-4-(methylamino)benzoic acid (10.6 mg, 0.05

mmol), HOBt (6.78 mg, 0.05 mmol) and DCC (9.29

mg, 0.05 mmol) in EtOAc (10 mL) and further worked

up (CH₂Cl₂/MeOH=99:1) as described for ent-63 to

C. Heindl et al. / Tetrahedron: Asymmetry 14 (2003) 3153–3172

3171

For 5-HT1_Areceptor binding assay porcine cortical

membranes were diluted with binding buffer (50 mM

Tris–HCl, 4 mM CaCl₂, 0.1% ascorbic acid and 10 nM

pargyline; pH 7.4) to a ﬁnal concentration of 460 mg

protein/assay tube (K_dvalues from 2.4–4.8 nM). Tubes

were prepared with the radioligand [³H]8-OH-DPAT

(0.5 nM) (speciﬁc activity 135.0 Ci/mmol; PerkinElmer)

and varying concentrations of test compounds (from

0.01–10,000 nM). Nonspeciﬁc binding was determined

in the presence of serotonine (10 mM). Incubation was

started by adding membranes to the assay tube with a

ﬁnal volume of 800 mL, was continued for 60 min at

37°C and stopped by rapid ﬁltration through GF/B

ﬁlters precoated with 0.3% polyethylenimine, using an

automated cell harvester (Inotech, CH). Filters were

washed ﬁve times with ice-cold Tris–EDTA buffer,

5. Cossy, J.; Dumas, C.; Michel, P.; Gomez Pardo, D.

Tetrahedron Lett. 1995, 36, 549.

6. Watanabe, K.; Fukumura, T.; Sasaki, S.; Maeda, M.;

Takehara, S. Chem. Pharm. Bull. 1991, 39, 3211.

7. Gmeiner, P.; Ka¨rtner, A.; Junge, D. Tetrahedron Lett.

1993, 34, 4325.

8. Gmeiner, P.; Ka¨rtner, A. Synthesis 1995, 83.

9. Gmeiner, P.; Junge, D.; Ka¨rtner, A. J. Org. Chem. 1994,

59, 6766.

10. Gmeiner, P. Arch. Pharm. (Weinheim Ger.) 1991, 324,

551.

11. Weber, K.; Gmeiner, P. Synlett 1998, 885.

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dried and counted in

(PerkinElmerWallac).

a

MicroBeta Trilux

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4.61. Data analysis

The resulting competition curves were analyzed by non-

linear regression using the algorithms in PRISM

(GraphPad Software, San Diego, CA). The data was

initially ﬁtted using a sigmoid model to provide an IC₅₀

value, representing the concentration corresponding to

50% of maximal inhibition. The IC₅₀values were trans-

formed to K_ivalues according to the equation of Cheng

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Acknowledgements

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The authors wish to thank Dr. H. H. M. Van Tol

(Clarke Institute of Psychiatry, Toronto), Dr. J.-C.

Schwartz and Dr. P. Sokoloff (INSERM, Paris) as well

as Dr. J. Shine (The Garvan Institute of Medical

Research, Sydney) for providing dopamine D4, D3 and

D2 receptor expressing cell lines, respectively. This

work was supported by the Deutsche Forschungsge-

meinschaft (DFG).

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Article Doi

Enantiospecific synthesis and receptor binding of novel dopamine receptor ligands employing natural 4-hydroxyproline as a practical and flexible building block

DOI: 10.1016/j.tetasy.2003.08.020

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