Diastereo- and enantioselective syntheses of C2-symmetric 1,n-diamines by nucleophilic addition to dialdehyde-SAMP-hydrazones

2542

PAPER

Diastereo- and Enantioselective Syntheses of C₂-Symmetric 1,n-Diamines by

Nucleophilic Addition to Dialdehyde-SAMP-Hydrazones

Dieter Enders,* Michaela Meiers

Institut für Organische Chemie, Rheinisch-Westfälische Technische Hochschule, Professor-Pirlet-Straße 1, 52074 Aachen, Germany

Fax +49(241)8092127; E-mail: enders@rwth-aachen.de

Received 6 August 2002; revised 21 August 2002

Dedicated to Professor Peter Welzel on the occasion of his 65^thbirthday.

nitrones^14hor bis-hydrazones¹⁴ⁱderived from dialdehydes

Abstract: Different protected C₂-symmetric 1,n-diamines (R,R)- or

(H) have been employed in these reactions with success.

(S,S)-4 and 8 can be prepared in high diastereo- and enantiomeric

Most of the reported approaches are based on substitution

purity by nucleophilic 1,2-addition of organocerium reagents to the

reactions of vicinal diols,^15a–eβ-amino alcohols^15f–jand re-

CN double bond of bis-SAMP-hydrazones (S,S)-2a–c. The chiral

starting materials are readily available by reaction of dialdehydes lated compounds by nitrogen nucleophiles (D).¹⁵Starting

with the enantiopure hydrazine 1-amino-2-methoxymethylpyrroli-

from other saturated precursors, ring opening of aziridines

dine (SAMP). Reductive NN bond cleavage of the hydrazines

by nitrogen nucleophiles provides an additional route to

(R,R,S,S)- or (S,S,S,S)-3 and 7 afforded the title compounds (de 72–

diamines (E).¹⁶In addition, the reductive coupling of

98%, ee 96–98%). The novel entry for the asymmetric synthesis of

imines can be performed either under chemoreductive or

N-protected C₂-symmetric diamines presented here is highly flexi-

ble, as both the distance of the amino functions and the introduced

photoreductive conditions (F).¹⁷Another efficient entry to

1,2-diamines is the 1,4-addition of ammonia equivalents

to nitroalkenes followed by reduction of the nitro group

(G).¹⁸Finally, various other methods have been described

in the literature as for example based on imidazolidin-

ones,^19aring closing metathesis,^19bthe nitro-Mannich

reaction,²⁰the Grignard-addition to bis(1,3-oxazolid-

inyl)alkanes,²¹the α-alkylation of N,N-dibenzylami-

noacetaldehyde-SAMP-hydrazones,^22aasymmetric lithi-

ations of imidazolidines^22bor the reaction of lithiated iso-

cyanides with aziridines.²³

We have recently disclosed in a communication¹⁴ⁱa new

asymmetric synthesis of protected 1,n-diamines by a dou-

ble nucleophilic 1,2-addition to the CN double bond²⁴of

dialdehyde-bis-SAMP-hydrazones²⁵according to the gen-

eral route (H). We now wish to describe in detail this flex-

ible, CC-connective and highly diastereo- and enantio-

selective methodology to protected C₂-symmetric 1,n-di-

amines.

residues R can be varied.

Key words: amines, hydrazones, nucleophilic additions, asym-

metric synthesis, cerium

Diastereo- and enantiomerically pure diamines play an

important role in synthetic and medicinal chemistry.¹Es-

pecially, 1,2-diamines are widely used in various

applications²e.g. as chiral auxiliaries,³ligands^4,5in asym-

metric synthesis and as chiral reagents for the resolution

of racemic mixtures⁶or the determination of enantiomeric

ratios.⁷In addition, they are crucial structural features in a

large number of natural products and synthetic com-

pounds of pharmacological interest.

Especially, 1,n-diamines (n 3) are often seen in biological-

ly active compounds. For example, certain peptide-based

HIV-protease inhibitors⁸or antitumor agents⁹contain

such 1,3-, 1,4- and 1,5-diamine structures which represent

essential key units in the structural backbone of these

pharmaceuticals.¹⁰

The hydrazones (S,S)-2a–c were easily prepared by

condensation with the chiral auxiliary 1-amino-2-

methoxymethylpyrrolidine (SAMP),²⁵starting from the

commercially available dialdehydes 1a–c, in 80–88%

yield (Scheme 2). The subsequent nucleophilic 1,2-addi-

tions were carried out by treating the bis-SAMP-hydra-

zones with eight equivalents of the organocerium

reagent²⁶formed in situ from cerium chloride and the or-

gano lithium or Grignard reagent in THF at low tempera-

tures. In addition to unfunctionalized alkyl residues,

functionalized groups like allyl, benzyl and the protected

alcohol in the case of 3d could be introduced.

Due to their synthetic significance, quite a number of ste-

reoselective syntheses of vicinal diamines have been de-

veloped in recent years.^2aThe most common starting

materials for the synthesis of enantioenriched diamines

are depicted in Scheme 1.

For instance, alkenes can be utilized in the direct vicinal

diamination supported by certain metallic promotors

(A).¹¹Alternatively, transformations of CN-double bonds

by nucleophilic 1,2-addition or reduction to obtain the de-

sired diamines have been reported. α-Amino imines,^12a–c

-nitrones^12dor -hydrazones^12e(B),¹²bis-ketimines^13a–cor

-oxime ethers (C)^13das well as bis-aldimines,^14a–gbis-

The resulting metallohydrazides were trapped with meth-

yl chloroformate (MocCl) or acetyl chloride (AcCl) in a

one-pot reaction. The methoxycarbonyl protected hydra-

zines (R,R,S,S)- or (S,S,S,S)-3a–h were obtained in mod-

erate to very good yields (55–93%) and in general with

high diastereomeric excesses (69–91%). However, the

Synthesis 2002, No. 17, Print: 02 12 2002.

Art Id.1437-210X,E;2002,0,17,2542,2560,ftx,en;Z11302SS.pdf.

ISSN 0039-7881

PAPER

Syntheses of C₂-Symmetric 1,n-Diamines

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R*

H

R*

H

N

R¹

R²

( )_m

R²

NO₂

(m = 0, 2, 3, R¹= R²)

R*RN

R¹

R^'R^''N

R²

G

R¹

double

1,2-addition

H

NR^'R^''

diamination

A

1,4-addition/

reduction

Bn₂N

R

H

R²

R

F

B

H

NH₂

N

R

R²/H

R^*

+

R¹

R²

*

reductive

coupling

H/R²

N

1,2-addition

or reduction

R¹

*

NH₂

*

N

[cat.]

E

C

ring

N

R

opening

reduction

X

D

substitution

N

R¹

*

R²

*

NR^'R^''

R²

R¹

+

X

L*

N

R²

R^'R^''N

R

R¹

R²

*

R^'R^''N

*

R¹

*

NR^'R^''

NH₂

X

Scheme 1

O

R

O

R

O

( )_m

H

R'

NH HN

( )_m

R'

27 - 75%

1a - c

m = 0, 2, 3

(R,R) - or (S,S)-4

de = 72 - ≥ 98%

ee = ≥ 98%

OCH₃

80 - 88%

P = Moc, Ac, EtCO

R' = MeO, Me, Et

N

NH₂

c

34 - 87 %

a, b

N

H

N

H

P P

N

R

44 % - quant.

OCH₃

N

H₃CO

( )_m

H₃CO

OCH₃

( )_m

R

(S,S) -2a - c

(R,R,S,S)- or (S,S,S,S)-3

de = 69 - 98%

R = Me, Et, n-Pr, n-Bu, n-Hex,

allyl,(CH₂)₃OTBS, Bn

M = MgCl, MgBr, Li

Scheme 2 Reagents and conditions: (a) 8 equiv RM/CeCl₃, THF, –100 °C → r.t. (b) 24 equiv MocCl, 0 °C → r.t., 24 equiv AcCl, –78 °C

→ 0 °C or 24 equiv EtCOCl, –78 °C → 0 °C (c) Li/NH₃, THF, –33 °C.

yields achieved in the case of the N-acetyl hydrazines Since the total yields using methyl formate or acetyl as

(R,R,S,S)- or (S,S,S,S)-3i–l were lower (44–78%), where- protecting and activating groups were not satisfactory for

as the diastereomeric excesses were better (de 84–98%) a general synthetic method, we were looking for a trap-

(Table 1, Scheme 2).

ping reagent which would afford good chemical yields in

both reactions. The reagent of choice turned out to be pro-

pionyl chloride (Scheme 2).

In the case of the methyl cerium reagent addition products

of the N-Moc-protected hydrazines (R,R,S,S)-3a,e and the

N-acetyl hydrazine (R,R,S,S)-3i acceptable yields were Nucleophilic 1,2-addition of various organocerium re-

obtained for the reductive cleavage of the auxiliary group. agents to the hydrazones (S,S)-2 and subsequent trapping

The cleavage of the activated NN bond with lithium in liq- with an excess of propionyl chloride led to N-propionyl

uid ammonia²⁷(56–62%) furnished the 1,n-diamines hydrazines (R,R,S,S)- or (S,S,S,S)-3m–u in good to excel-

(R,R)-4a,e,i with excellent de and ee values (de 87–98%, lent yields (46%–quantitative) and with diastereomeric

ee 98%) (Table 2).

excesses (67–98%) comparable to the previous trapping

experiments. The NN bond was then cleaved with lithium

Synthesis 2002, No. 17, 2542–2560 ISSN 0039-7881 © Thieme Stuttgart · New York

2544

D. Enders, M. Meiers

PAPER

Table 1 Diastereoselective Synthesis of Methoxycarbonyl or Acetyl Protected 1,n-bis-SAMP-hydrazines (R,R,S,S)- or (S,S,S,S)-3

3

a

b

c

d

e

f

P

R

n

4

5

2

4

5

Yield (%)

de^a(%)

[α]_D^r.t.(c, CHCl₃)

–85.3 (0.93)

–78.2 (0.97)

–65.3 (0.90)

–45.8 (1.01)

–75.8 (0.92)

–77.5 (1.15)

–70.5 (1.15)

–64.9 (0.91)

–99.5 (0.99)

–68.6 (1.08)

–43.6 (1.08)

–37.6 (0.98)

Config.

CH₃CO

Me

68

55

93

66

85

66

58

85

50

47

44

78

86

(R,R,S,S)

(S,S,S,S)

(R,R,S,S)

(S,S,S,S)

(R,R,S,S)

(S,S,S,S)

b

Et

b

Bu

c

TBSO(CH₂)₃

Me

91

76

69

82

98

84

85

84

Et

g

h

i

Bu

Allyl

Me

j

Me

k

l

Allyl

^aDetermined by gas chromatography.

^bThe de value could not be determined by either gas chromatography or by NMR spectroscopy.

^cThe organo lithium reagent was used for the addition.

Table 2 Diastereo- and Enantioselective Synthesis of Methoxycarbonyl or Acetyl Protected C₂-Symmetric 1,n-Diamines (R,R)- or (S,S)-4

4

a

e

i

n

4

5

2

R

P

de^a3 (%) Yield 2 4^b(%)

[α]_D^r.t.4 (c, CHCl₃)

+20.3 (1.02)

de^a4 (%)

ee^c4 (%)

Config.

(R,R)

Me

CH₃OCO 86

CH₃OCO 91

38 (30)

52 (46)

31 (27)

87

91

98

–6.3 (1.06)

(R,R)

CH₃CO

98

+44.9 (0.049)^d

(R,R)^e

^aDetermined by gas chromatography.

^bIn parentheses: overall yield 1 4.

^cAccording to GC-analysis employing a chiral stationary phase.

^dButanone was used as the solvent.

^eDetermined by correlation of optical rotation with literature data.²⁴

in liquid ammonia without racemization to give the propi- (4i,m) because of side-reactions depending on the nucleo-

onyl protected 1,n-diamines (R,R)- or (S,S)-4m–u in mod- phile and the trapping agent employed. Addition of vari-

erate to very high yields (26–87%) with acceptable to high ous organocerium reagents to the hydrazone (S,S)-2a led

diastereomeric excesses (de 65–98%) and excellent to the chiral cyclic urea derivatives (R,R,S,S)-5a,b in mod-

enantiomeric excesses (ee 98%). When necessary, the erate yields (42–65%) and high diastereomeric excesses

meso compound could be removed chromatographically (de 90–94%) instead of the expected carbamates. When

to obtain a single diastereoisomer (Table 3).

(S,S)-2a was treated with the organocerium reagent pre-

pared from ethyl magnesium bromide and cerium trichlo-

ride, followed by trapping with acetyl chloride, the mono-

protected hydrazine (R,R,S,S)-6 was obtained in 51%

yield and good diastereoselectivity (de 85%).

Whereas our method described up to this point represents

a very good diastereo- and enantioselective access to pro-

tected 1,4- and 1,5-diamines, 1,3-diamines are not avail-

able in this manner, due to the easy deprotonation of the

corresponding malonaldehyde-bis-SAMP-hydrazone pre- The formation of the side products 5 and 6 can be ex-

venting nucleophilic 1,2-additions. The important C₂- plained by assuming a common intermediate by cycli-

symmetric 1,2-diamines were obtained only in moderate sation after the first hydrazide acylation (Scheme 3,

yields in the case of the 2,3-diamino butane derivatives Table 4).

Synthesis 2002, No. 17, 2542–2560 ISSN 0039-7881 © Thieme Stuttgart · New York

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Syntheses of C₂-Symmetric 1,n-Diamines

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Table 3 Diastereo- and Enantioselective Synthesis of Propionyl Protected C₂-Symmetric 1,n-Diamines (R,R)- or (S,S)-4

3, 4

n

R

Yield 2 3 de^a3

Yield 2 4^b[α]_D^r.t.4

de^a,c4 (%) ee^d4 (%) Config.

(%)

(c, CHCl₃)

m

n

o

p

q

r

2

4

5

Me

Et

46

98

34 (30)

33 (26)

42 (33)

62 (49)

59 (47)

85 (75)

57 (50)

53 (47)

81 (71)

+65.5 (0.91)

+32.4 (0.88)

+56.3 (0.32)

+35.1 (1.03)

+25.5 (0.55)

–15.5 (1.06)

–17.3 (1.01)

–37.5 (0.12)

–30.9 (1.02)

98

(R,R)

(S,S)

97

87

86 (86)

98

e

66

96

Bu

98

83.5:16.0:0.5^f

91 (65)

98 (67)

94

98

Hex

Me

Bu

91

84.0:15.3:0.7^f

96^g

98

94

68

83

s

87

72

98^h

98

t

Allyl

Bn

90

77

u

quant.

86ⁱ

98ⁱ

^aDetermined by gas chromatography.

^bIn parentheses: overall yield 1 4.

^cAfter chromatography; in parentheses: the de value of the crude diamine.

^dAccording to GC-analysis employing a chiral stationary phase.

^eThe de value could not be determined by either gas chromatography or by NMR spectroscopy.

^fThe diastereomeric ratio (dr) is given.

^gThe ee value was determined by NMR-shift experiments.

^hThe ee value could not be determined, it is given in analogy to 4p,r,t,u.

ⁱThe de and ee values were determined by HPLC on a chiral stationary phase.

OCH₃

O

N

O

N

CH₃

a,b

c, d

N

2 a

N

H₃C

65%, 42%

51%

N

R

H

OCH₃

H₃CO

5a (R = Me, de = 90%)

5b (R = n-Bu, de = 94%)

(de = 85%)

R' = CH₃

6

O

N

R'

N

R' = OCH₃

R

OCH₃

H₃CO

Scheme 3 Reagents and conditions: (a) 8 equiv RLi/CeCl₃, THF, –100 °C → r.t. (b) MocCl, 0 °C → r.t. (c) 10 equiv EtMgBr/CeCl₃,

THF, –100 °C → r.t. (d) 12 equiv AcCl, –78 °C → 0 °C.

Table 4 Syntheses of the Cyclic Urea Derivatives 5 and the mono-Protected Hydrazine 6

R

RCOCl

Yield (%)

[α]_D^r.t.(c, CHCl₃) de^a(%)

Config.

5a

5b

6

Me

Bu

Et

CH₃OCOCl

CH₃COCl

65

42

51

–159.2 (0.91)

–122.5 (0.72)

–112.0 (0.52)

90

94

85

(R,R,S,S)

^aDetermined by GC or ¹³C NMR spectroscopy.

Synthesis 2002, No. 17, 2542–2560 ISSN 0039-7881 © Thieme Stuttgart · New York

2546

D. Enders, M. Meiers

PAPER

In order to overcome the problems of side reactions

caused by the necessary activation through N-acylation of

the intermediate hydrazides before reductive auxiliary

cleavage, we changed our protocol for the asymmetric

synthesis of 1,2-diamines. The glyoxal bis-SAMP-hydra-

zone (S,S)-2a was treated with various organocerium

compounds as described above, followed by hydrolysis of

the 1,2-addition products giving rise to the unprotected

hydrazines (R,R,S,S)-7 in virtually quantitative yields and

with good asymmetric inductions (de 82–91%). Attempts

to purify the bis-hydrazines by chromatography led to sig-

nificant loss of material and therefore the crude hydra-

zines were directly used in the subsequent auxiliary

removal step. The NN-bond cleavage of the non-activated

hydrazines by Raney-nickel/hydrogen²⁸has two general

disadvantages: very often epimerization occurs during the

hydrogenation and the generated diamines may serve as

chelating ligands for released Ni²⁺-cations. Based on a lit-

erature procedure to reductively cleave the NN-bond of

hydrazines by borane,²⁹a procedure was developed to

cleave the trisubstituted hydrazines derived from alde-

hyde-SAMP-hydrazones.³⁰The crude hydrazines were

dissolved in THF, treated at room temperature with a large

excess of BH₃·THF, and heated under reflux for several

days. The resulting crude diamines were directly convert-

ed into the corresponding carbamates (R,R)-8, which are

easier to purify. Moderate to good yields (22–74%) and

high stereoselectivities (de 85–98%, ee 96–98%) were

obtained (Scheme 4, Table 5).

O

H

N

H

N

H

OR²

O

R¹

19 - 64%

R¹

1a

R²O

O

(R,R)-8^a

87%

OCH₃

de = 85 - ≥ 96%^b

ee = ≥ 96 - ≥ 98%

N

NH₂

b, c 22 - 74%

N

H

N

H

OCH₃

H

N

R¹

N

H

OCH₃

H₃CO

R¹

H₃CO

N

a

99% - quant.

(S,S)-2a

(R,R,S,S)-7

R¹= n-Bu, Ph, Bn

R²= t-Bu, Bn

de = 82 - 91%

^aIn the case of 8c, the Boc-protected five membered

cyclic urea was synthesized.

^bAfter chromatography or recrystallization.

Scheme 4 Reagents and conditions: (a) 1. 8 equiv R¹M/CeCl₃,

THF, –100 °C → r.t. 2. aq NaHCO₃(b) 1.20 equiv BH₃·THF, THF,

65 °C. 2. HCl or MeOH (c) R²OCOX (X = Cl, BocO).

The advantage of the borane cleavage of the hydrazine

NN bond is that aromatic rings present are not affected un-

der the reaction conditions. The use of Raney-nickel could

lead to reduced rings and with the lithium in liquid ammo-

nia reductive cleavage the benzylic CN bond would be

cleaved instead of the NN bond. Fortunately, the borane

cleavage turned out not to be limited to the asymmetric

synthesis of 1,2-diamines. As shown in Scheme 5, the

protected 1,4-diamine (S,S)-9, related to some C₂-sym-

metric HIV-protease inhibitors, was obtained in the same

manner (23%, de 64%, ee 98%). Additionally, the NMR

analysis of the bis-MTPA amide proved the absolute con-

figuration of the diamine as (S,S)-9.

Whereas the diastereomeric and enantiomeric excesses of

the diamines were determined by GC and HPLC using

chiral stationary phases or ¹H NMR shift experiments, the

absolute configurations are based on polarimetric data and

comparison with known diamines and assuming a uni-

form reaction mechanism for all title compounds (see Ta-

Table 5 Diastereo- and Enantioselective Synthesis of Carbamate Protected C₂-Symmetric 1,2-Diamines (R,R)-8

7, 8

R

Yield 2 7 (%) de^a7

Yield 2 8^b[α]_D^r.t.8

de^c8

ee^d8

Config.

(%)

(c, CHCl₃)

+43.2 (1.03)

–9.6 (0.53)

–6.4 (0.5)

(%)

a

Bu

Ph

Bn

quantitative

99

82

58 (50)

22 (19)

74 (64)

85

96

98

(R,R)

(R,R)^e

(R,R)

b

c^f

91

96

g

quantitative

98^h

^aDetermined by ¹³C NMR spectroscopy.

^bIn parentheses: overall yield 1 8.

^cAfter chromatography or crystallisation; determined by GC (8a) or ¹H NMR spectroscopy (8b,c).

^dAccording to GC-analysis employing a chiral stationary phase (8a) or NMR shift experiments (10b).

^eBy comparison of the optical rotation of (R,R)-8b with literature data and NMR shift experiments with original material.

^fInstead of the bis-Boc-protected diamine the corresponding bis-Boc-protected urea was synthesised by variation of the reaction conditions

(CH₃CN, Boc₂O, Et₃N, DMAP).

^gThe de value could not be determined by NMR spectroscopy.

^hThe ee value could not be determined, it is given in analogy to 8a, b, 4i, 6a.

Synthesis 2002, No. 17, 2542–2560 ISSN 0039-7881 © Thieme Stuttgart · New York

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Syntheses of C₂-Symmetric 1,n-Diamines

2547

gave the pure hydrazones 2a c as colorless or pale yellow highly

viscous oils.

bles and experimental). These stereochemical results are

in agreement with the relative topicity typical for all 1,2-

additions to SAMP-hydrazones investigated so far.

Hydrazines (R,R,S,S)-/(S,S,S,S)-3, 7; General Procedure 2 (GP

2)

O

Cerium trichloride heptahydrate (8 mmol) was dried for 2 h at

140 °C and 0.1 Torr with cautious stirring. After cooling, the flask

was flushed with argon and the solid suspended in THF (35 mL) at

r.t. for 2 h, and ultrasound was applied for 1 h. The colorless suspen-

sion was cooled to –70 °C and then a soln of the organolithium re-

agent (8 mmol) was added slowly, or in the case of Grignard

reagents, the procedure was carried out at 0 °C. Using organolithi-

um reagents the suspension turned canary yellow, Grignard re-

agents normally led to a gray suspension (exceptions: AllylMgCl:

orange, BnMgCl: light yellow), was stirred for further 2 h and then

cooled to –100 °C. The resulting organocerium reagent was treated

with a soln of bis-hydrazone (S,S)-2 (1 mmol) in THF (6 mL), and

then the reaction mixture was allowed to warm slowly to r.t. over 15

h. To obtain the unprotected hydrazines (R,R,S,S)-7 the reaction was

hydrolyzed at 0 °C with sat. NaHCO₃soln (20 mL). The organic

layer was separated and the residue extracted with Et₂O (4 25

mL). The combined organic layers were then dried over MgSO₄and

the solvent removed on a rotary evaporator.

tBu

O

NH

a - c

2b

23 %

HN

OBut

O

(S,S)-9

de = 64%, ee = 98%

Scheme 5 Reagents and conditions: (a) 1. 8 equiv CeCl₃/BnMgCl,

THF, –100 °C → r.t. 2. aq NaHCO₃. (b) 1. 20 equiv BH₃·THF, THF,

65 °C. 2. aq HCl, then K₂CO₃(c) (Boc)₂O, Et₃N, MeOH.

In summary, we have developed an efficient and flexible

C-C-connective asymmetric synthesis of N-protected, C₂-

symmetric 1,n-diamines. Starting from simple dialde-

hydes the key step of the procedure is the nucleophilic

double 1,2-addition of nucleophiles to the CN double

bond of the corresponding bis-SAMP-hydrazones and

subsequent reductive removal of the auxiliary group. The

title compounds are of enormous importance in synthetic

and medicinal chemistry.

The air- and temperature sensitive hydrazines were purified by

chromatography, which led to losses in yields so the crude hydra-

zine was introduced into the next step without further purification.

For the synthesis of N-Moc protected hydrazines, methyl chlorofor-

mate (24 mmol) was added at 0 °C and the soln stirred for 20 h at

r.t. Alternatively, the soln was again cooled to –70 °C and acetyl or

propionyl chloride (24 mmol) was added. The soln was stirred for

0.5 h at this temperature and for another h at 0 °C to yield the

N-acylated hydrazines. The reaction was terminated by addition of

a sat. NaHCO₃soln (20 mL). The isolation procedure was similar to

the one of the unprotected hydrazines. After purification of the yel-

low-brown crude products by chromatography (SiO₂, Et₂O–petrol-

eum ether), colorless to light-yellow highly viscous oils were

obtained.

All moisture sensitive reactions were carried out using standard

Schlenk techniques under argon. Solvents were dried and purified

by conventional methods prior to use. THF was freshly distilled

from potassium, Et₂O from sodium, MeOH from magnesium meth-

oxide, and CH₂Cl₂from CaH₂under argon. Anhyd CH₃CN was pur-

chased from Aldrich. Petroleum ether refers to the fraction with bp

40–80 °C. Reagents of commercial quality were used from freshly

opened containers or purified by common methods. Methyl lithium

[1.6 M (15%) in Et₂O] and BuLi [1.6 M (15%) in hexane] were pur-

chased from Merck, Darmstadt. 1a and c were used as their com-

mercially available aq solutions. 1b was liberated from 2,5-

dimethoxytetrahydrofuran.³¹SAMP was synthesized according to

literature procedures from (S)-proline;³²SAMP and RAMP are

commercially available. Analytical TLC: Merck glass-backed silica

gel 60 F₂₅₄plates. Column chromatography: Merck silica gel 60,

0.040–0.063 or 0.063–0.100 mm (230–400 mesh). In some cases

the silica gel was deactivated by the addition of 0.6 vol.% Et₃N to

the eluent. Analytical GC: Siemens Sichromat 2 or 3 equipped with

an OV-1-CB, OV-17-CB, and SE-54-CB (25 m 0.25 mm), carrier

gas nitrogen, FID. Optical rotations: Perkin–Elmer P 241 polari-

meter; solvents of Merck Uvasol quality. IR spectra: Perkin–Elmer

1740 and Perkin–Elmer FT/IR 1750. ¹H NMR-spectra (300 or 500

MHz), ¹³C NMR-spectra (75 or 125 MHz): Varian VXR 300, Vari-

an Gemini 300, Varian Unity 500 (TMS as internal standard). Mass

spectra: Varian MAT 212 (EI 70 eV), Finnigan SSQ 7000. Elemen-

tal analyses: Heraeus CHN-O-Rapid, elementar vario EL. HRMS:

Finnigan MAT, MAT 95. Chemical nomenclature was verified by

the programme Autonom (Version 1.1, Beilstein Informationssyste-

me GmbH, 1994).

N-Protected Diamines (R,R)-/(S,S)-4; General Procedure 3 (GP

3)

Lithium (4.8 mmol) was dissolved in liquid ammonia (25 mL) at

–70 °C. Then a soln of the hydrazides 3 (0.5 mmol) in THF (5 mL)

was added. The cooling bath was removed and the soln allowed to

warm up to reflux for 1–3 h. NH₄Cl (9.6 mmol) was then carefully

added in order to terminate the reaction. After the ammonia had

evaporated, the residue was extracted with CH₂Cl₂(3 20 mL) and

filtered. After removal of the solvent on a rotary evaporator and

purification by flash chromatography (SiO₂, Et₂O, Et₂O–petroleum

ether, Et₂O–MeOH) gave the acylated diamines as colorless solids.

Amines: General Procedure 4 (GP 4)

The hydrazines 7a c (0.3 mmol) were dissolved in THF (15 mL)

and refluxed for 5 to 6 d with BH₃·THF (6 mL, 6 mmol, 1 M soln in

THF). The reaction was terminated by addition of MeOH (2 mL)

(path A) or 10% HCl (2 mL) (path B).

Path A

After the addition of the MeOH, the solvent was evaporated in vac-

uo, the residue was dissolved in MeOH (10 mL) and refluxed for 1

h. This soln was introduced into the next protecting step.

Bis-Hydrazones (S,S)-2; General Procedure 1 (GP 1)

The dialdehydes 1 (15 mmol) were dissolved in CH₂Cl₂(30 mL) at

0 °C. The SAMP hydrazine (30 mmol) was added and stirring was

continued until reaction was complete (6–12 h). The organic phase

was washed with H₂O, drying with MgSO₄, and purification by

flash chromatography (deactivated SiO₂, Et₂O–petroleum ether)

Path B

After the hydrolysis with HCl, the reaction mixture was stirred at r.t.

for 2 h. The solvent was evaporated in vacuo and the remaining soln

of the diamino hydrochloride was extracted with Et₂O (2 3 mL).

To obtain the crude diamines the aq soln was saturated with solid

K₂CO₃and extracted with CH₂Cl₂(3 15 mL). The combined ex-

Synthesis 2002, No. 17, 2542–2560 ISSN 0039-7881 © Thieme Stuttgart · New York

2548

D. Enders, M. Meiers

PAPER

tracts were carefully washed with brine (2 5 mL) and dried with

Na₂SO₄. After the solvent was removed on a rotary evaporator the

crude diamine was obtained, which was used directly in the next

protecting step.

MS (70 eV): m/z (%) = 324 (5) [M⁺], 196 (13), 195 (100), 156 (11),

123 (20), 117 (25), 114 (33), 111 (34), 84 (15), 70 (35), 55 (11), 45

(12).

Anal. calcd for C₁₇H₃₂N₄O₂(324.5): C, 62.93; H, 9.94; N, 17.27.

Found: C, 62.92; H, 9.91; N, 17.53.

(2S,2′S)-(–)-2-{[2-(Methoxymethyl)pyrrolidine-1-yl]imino}-

ethylidene-2-(methoxymethyl)pyrrolidine-1-ylamine [(S,S)-2a]

Glyoxal (1a, 40% aq soln, 2.2 g, 15 mmol) and SAMP (3.9 g, 30

mmol) were allowed to react according to GP 1. Flash chromatog-

raphy (deactivated SiO₂, Et₂O–petroleum ether, 4:1) yielded 2a

(3.69 g, 87%) as a light yellow viscous oil which solidified in the

freezer.

(1R,4R,2′S,2′′S)-(–)-N-(2-Methoxymethylpyrrolidine-1-yl)-N-

{4-[(2-methoxy-methylpyrrolidine-1-yl)-methoxycarbonylami-

no]1-methylpentyl}-methyl-carbamate [(R,R,S,S)-3a]

An organocerium reagent (13 mmol) prepared from CeCl₃and

MeMgBr (2.5 M soln in Et₂O) was treated according to GP 2 with

hydrazone 2b (0.31 g, 1 mmol). After the addition was complete

(TLC) the reaction was trapped with methyl chloroformate (4.72 g,

50 mmol). Flash chromatography (SiO₂, Et₂O–petroleum ether, 2:1)

yielded 3a (0.31 g, 68%) as a colorless highly viscous oil.

23

[α]_D–211 (c 1.07, CHCl₃), {lit. [α]_D²⁰– 246 (c 50–100 mg/mL,

THF)}.

The spectroscopic data of 2a corresponded with those reported.³³

De 86% (GC); [α]_D²⁵–85.8 (c 0.93, CHCl₃).

(2S,2′S)-(–)-4-{[2-(Methoxymethyl)pyrrolidine-1-yl]imino}-bu-

tylidene-2-(methoxymethyl)pyrrolidine-1-ylamine [(S,S)-2b]

Concd HCl (0.5 mL, 6 mmol) was added dropwise to 2,5-dime-

thoxytetrahydrofuran (1.32 g, 10 mmol) in H₂O (5 mL) and stirred

30 min at r.t. The acid soln was neutralized with solid NaHCO₃.

This soln of the in situ prepared succinic aldehyde 1b and SAMP

(2.60 g, 20 mmol) were allowed to react according to GP 1. Flash

chromatography (deactivated SiO₂, Et₂O–petroleum ether, 4:1)

yielded 2b (2.48 g, 80%) as a light yellow viscous oil.

IR (CHCl₃): 2954–2826, 2744, 2317, 2073, 1701 (C=O), 1531,

1440, 1385, 1368, 1324, 1305, 1260, 1111, 1037, 973, 633, 601,

576, 535 cm^–1.

¹H NMR (CDCl₃): δ = 1.14 (d, J = 6.7 Hz, 6 H, CH₃CH), 1.35–2.20

(m, 12 H, NCH₂CH₂CH₂, CHCH₂CH₂CH), 3.05–4.20 (m, 12 H,

NCH₂, CHCH₂O, CH₃CH), 3.33 (s, 6 H, CH₂OCH₃), 3.69 (br s, 6 H,

OCOCH₃).

¹³C NMR (CDCl₃): Due to the limited rotation of the NN single

bond only broad signals could be observed. δ = 19.11 (CH₃CH),

23.49 (NCH₂CH₂), 27.70 (NCH₂CH₂CH₂), 31.66 (CHCH₂CH₂CH),

52.10 (CH₃OCO), 54.60 (NCH₂), 54.60, 58.89, 61.31, 62.24

(CH₃CH, CHCH₂OCH₃), 75.47 (CH₂O). A carbonyl signal was not

detected.

23

[α]_D–162.4 (c 1.01, CHCl₃).

IR (film): 2952–2828, 1728, 1605 (w, C=N), 1461–1450, 1341,

1302, 1282, 1197, 1121, 1004, 973, 924–904, 733, 673–646, 556–

525 cm^–1.

¹H NMR (CDCl₃): δ = 1.75–2.00 (m, 8 H, NCH₂CH₂CH₂), 2.41 (m,

4 H, N=CHCH₂), 2.71 (m, 2 H, NCHH), 3.37 (s, 6 H, OCH₃), 3.32–

3.45, (m, 6 H, NCHH, CH₂O), 3.56 (m, 2 H, CHCH₂O), 6.66 (t,

J = 4.7 Hz, 2 H, HC=N).

¹³C NMR (CDCl₃): δ = 22.12 (NCH₂CH₂), 26.55 (NCH₂CH₂CH₂),

31.24 (N=CHCH₂), 50.28 (NCH₂), 59.16 (OCH₃), 63.49 (CHCH₂),

74.76 (CH₂O), 137.63 (HC=N).

MS (70 eV): m/z (%) = 297 (12) [M⁺+ 1], 296 (70) [M⁺], 251 (54),

182 (86), 155 (15), 150 (12), 136 (57), 114 (77), 112 (19), 111 (12),

109 (17), 103 (36), 85 (14), 84 (28), 83 (15), 82 (57), 81 (10), 80

(15), 71 (55), 70 (77), 69 (40), 68 (33), 67 (14), 56 (13), 55 (41), 45

(100).

MS (70 eV): m/z (%) = 458 (7) [M⁺], 414 (23), 413 (100) [M⁺–

+

CH₂OCH₃], 184 (12), 156 (18), 143 (15), 114 (19), 112 (15), 111

+

(16), 70 (20), 68 (10), 55 (10), 45 (13) [CH₂OCH₃].

Anal. calcd for C₂₂H₄₂N₄O₆(458.6): C, 57.62; H, 9.23; N, 12.22.

Found: C, 57.67; H, 9.67; N, 12.40.

(1R,4R,2′S,2′′S)-(–)-N-(2-Methoxymethylpyrrolidine-1-yl)-N-

{4-[(2-methoxy-methylpyrrolidine-1-yl)-methoxycarbonylami-

no]-1-ethylhexyl}methyl-carbamate [(R,R,S,S)-3b]

An organocerium reagent (13 mmol) prepared from CeCl₃and Et-

MgBr (1 M soln in THF) was treated according to GP 2 with hydra-

zone 2b (0.31 g, 1 mmol). After the addition was complete (TLC)

the reaction was trapped with methyl chloroformate (4.72 g, 50

mmol). Flash chromatography (SiO₂, Et₂O–petroleum ether, 2:1)

yielded 3b (0.27 g, 55%) as a colorless solid.

Anal. calcd for C₁₆H₃₀N₄O₂(310.4): C, 61.90; H, 9.74; N, 18.05.

Found: C, 61.90; H, 9.93; N, 18.29.

(2S,2′S)-(–)-5-{[2-(Methoxymethyl)pyrrolidine-1-yl]imino}-

pentylidene-2-(methoxymethyl)pyrrolidine-1-ylamine [(S,S)-

2c]

Glutaric aldehyde (1c, 50% aq soln, 6 g, 30 mmol) and SAMP (7.8

g, 60 mmol) were allowed to react according to GP 1. Flash chro-

matography (deactivated SiO₂, Et₂O–petroleum ether, 4:1) yielded

2c (8.6 g, 88%) as a light yellow viscous oil.

Mp 72 °C; [α]_D²⁵–78.2 (c 0.97, CHCl₃).

IR (film): 2964–2825 1702 (C=O), 1529, 1440, 1380, 1333, 1286,

1265, 1194, 1112, 1024, 993, 973, 922, 787, 765, 602, 543 cm^–1.

¹H NMR (CDCl₃): Due to the limited rotation of the NN single bond

only broad signals could be observed. δ = 0.88 (t, J = 7.4 Hz, 6 H,

CH₃CH₂), 1.36–2.20 (m, 16 H, NCH₂CH₂CH₂, CHCH₂CH₂CH,

CH₃CH₂), 3.0–4.0 (m, 12 H, NCH₂, CHCH₂O, CH₃CH), 3.33 (s, 6

H, CH₂OCH₃), 3.68 (br s, 6 H, OCOCH₃).

[α]_D²⁵–168.2 (c 0.97, CHCl₃).

IR (film): 2922–2828, 2079, 1727, 1605 (m, C=N), 1460, 1368–

1340, 1302–1282, 1197–1121, 1003, 973, 926, 904–868, 745, 684,

637 8w), 606, 528 cm^–1.

¹H NMR (CDCl₃): δ = 1.66 (m, 2 H, CH₂CH₂CH₂), 1.75–2.00 (m, 8

H, NCH₂CH₂CH₂), 2.27 (m, 4 H, N=CHCH₂), 2.71 (m, 2 H,

NCHH), 3.32–3.44 (m, 6 H, NCHH, CH₂O), 3.37 (s, 6 H, OCH₃),

3.56 (m, 2 H, CHCH₂O), 6.64 (t, J = 5.5 Hz, 2 H, HC=N).

¹³C NMR (CDCl₃): δ = 22.13 (NCH₂CH₂), 26.00 (N=CHCH₂CH₂),

26.54 (NCH₂CH₂CH₂), 32.60 (N=CHCH₂), 50.30 (NCH₂), 59.14

(OCH₃), 63.41 (CHCH₂), 74.79 (CH₂O), 138.30 (HC=N).

¹³C NMR (CDCl₃): Due to the limited rotation of the NN single

bond only broad signals could be observed. δ = 11.31 (CH₃CH₂),

23.84 (NCH₂CH₂), 26.24, 27.50 (CH₃CH₂, NCH₂CH₂CH₂), 29.25

(CHCH₂CH₂CH), 52.06 (CH₃OCO), 54.19, 55.16 (rotamer)

(NCH₂), 58.89, 60.21, 62.06, 63.22 (rotamer) (CH₃CH,

CHCH₂OCH₃), 75.26 (CH₂O), 156.02 (C=O).

MS (70 eV): m/z (%) = 486 (9) [M⁺], 442 (26), 441 (100) [M⁺–

CH₂OCH₃], 198 (10), 184 (12), 157 (10), 143 (27), 114 (20), 112

(13), 111 (17), 71 (13), 70 (22), 69 (13), 68 810), 55 (12), 45 (13).

Synthesis 2002, No. 17, 2542–2560 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER

Syntheses of C₂-Symmetric 1,n-Diamines

2549

Anal. calcd for C₂₄H₄₆N₄O₆(486.7): C, 59.23; H, 9.53; N, 11.51.

Found: C, 59.21; H, 9.68; N, 11.39.

¹³C NMR (CDCl₃): Due to the limited rotation of the NN single

bond only broad signals could be observed. δ = –5.30 [Si(CH₃)₂],

18.35 [SiC(CH₃)₃], 23.80 (NCH₂CH₂), 25.96 [SiC(CH₃)₃], 27.50

(NCH₂CH₂CH₂), 29.62, 29.97 (3 C) (CH₂CHCH₂CH₂), 52.13

(OCOCH₃), 54.20 (NCH₂), 58.46, 58.88, 62.07 (CHCH₂CH₂CH,

CHCH₂OCH₃), 63.08 (CH₂OSi), 75.27 (CH₂OSi), 156 (C=O).

(1R,4R,2′S,2′′S)-(–)-N-{1-Butyl-4-[(2-methoxymethylpyrrol-

idine-1-yl)-methoxy-carbonylamino]-octyl}-N-(2-methoxy-

methylpyrrolidine-1-yl)-methyl-carbamate [(R,R,S,S)-3c]

An organocerium reagent (20 mmol) prepared from CeCl₃and BuLi

(1.6 M soln in hexane) was treated according to GP 2 with hydra-

zone 2b (0.62 g, 2 mmol). After the addition was complete (TLC)

the reaction was trapped with methyl chloroformate (7.0 g, 74

mmol). Flash chromatography (SiO₂, Et₂O–petroleum ether, 1:1)

yielded 3c (1.01 g, 93%) as a colorless highly viscous oil.

MS (70 eV): m/z (%) = 775 (0.73) [M⁺], 732 (21), 731 (53), 730

(100) [M⁺– CH₂OCH₃], 718 (20), 643 (29), 641 (53), 143 (18), 114

(9).

Anal. calcd for C₃₈H₇₈N₄O₈Si₂(775.2): C, 58.88; H, 10.14; N, 7.23.

Found: C, 59.20; H, 9.89; N, 7.44.

[α]_D²⁵–65.3 (c 0.90, CHCl₃).

(1R,5R,2′S,2′′S)-(–)-N-(2-Methoxymethylpyrrolidine-1-yl)-N-

{5-[(2-methoxy-methylpyrrolidine-1-yl)-methoxy-carbonyl-

amino]-1-methylhexyl}-methyl-carbamate [(R,R,S,S)-3e]

An organocerium reagent (13 mmol) prepared from CeCl₃and

MeMgBr (2.5 M soln in Et₂O) was treated according to GP 2 with

hydrazone 2c (0.32 g, 1 mmol). After the addition was complete

(TLC) the reaction was trapped with methyl chloroformate (4.72 g,

50 mmol). Flash chromatography (SiO₂, Et₂O–petroleum ether, 4:1)

yielded 3e (0.40 g, 85%) as a colorless highly viscous oil.

IR (film): 2955–2874, 2826, 1748, 1702 (C=O), 1529, 1440, 1384,

1334, 1286, 1253, 1230, 1193, 1112, 1076, 1029, 993, 973, 925,

765, 666, 602, 549 cm^–1.

¹H NMR (CDCl₃): Due to the limited rotation of the NN single bond

only broad signals could be observed. δ = 0.88 (t, J = 7.0 Hz, 6 H,

CH₃CH₂), 1.20–2.25 (m, 24 H, NCH₂CH₂CH₂, CHCH₂CH₂CH,

CH₃CH₂CH₂CH₂), 3.00–4.10 (m, 12 H, NCH₂, CHCH₂O, CH₃CH),

3.33 (s, 6 H, CH₂OCH₃), 3.67 (br s, 6 H, OCOCH₃). ¹³C NMR

(CDCl₃): Due to the limited rotation of the NN single bond only

broad signals could be observed. δ = 14.11 (CH₃CH₂), 22.79, 23.85

(CH₃CH₂, NCH₂CH₂), 27.51, 28.78 (CH₃CH₂CH₂, NCH₂CH₂CH₂),

29.64, 33.07 (CH₂CHCH₂CH₂CH), 52.07 (CH₃OCO), 54.15

(NCH₂), 58.29, 58.89, 62.09, 63.16 (rotamer) (CH₃CH,

CHCH₂OCH₃), 75.20 (CH₂O). A carbonyl signal was not detected.

De 91% (GC); [α]_D²⁵–75.8 (c 0.92, CHCl₃).

IR (CHCl₃): 2952–2740, 2078, 1703 (C=O), 1615, 1531, 1441,

1385, 1369, 1320, 1240, 1195, 1110, 1056, 998, 973, 919, 906, 799,

767, 633 cm^–1.

¹H NMR (CDCl₃): Due to the limited rotation of the NN single bond

only broad signals could be observed. δ = 1.13 (d, J = 6.8 Hz, 6 H,

CH₃CH), 1.21–2.2 (m, 14 H, CHCH₂CH₂CH₂CH, NCH₂CH₂CH₂),

3.00–4.20 (m, 12 H, NCH₂, CHCH₂O, CH₃CH), 3.33 (br s, 6 H,

CH₂OCH₃), 3.69 (br s, 6 H, OCOCH₃).

MS (70 eV): m/z (%) = 542 (7) [M⁺], 498 (32), 497 (100) [M⁺–

CH₂OCH₃], 384 (10), 226 (12), 143 (25), 114 (18), 112 (10), 111

(16), 71 (11), 70 (17), 69 (10), 55 (13), 45 (14) [CH₂OCH₃].

+

Anal. calcd for C₂₈H₅₄N₄O₆(542.8): C, 61.96; H, 10.03; N, 10.32.

Found: C, 61.46; H, 9.72; N, 11.35.

¹³C NMR (CDCl₃): Due to the limited rotation of the NN single

bond only broad signals could be observed. δ = 19.06 (CH₃CH),

23.48

(NCH₂CH₂),

24.12

(CH₃CHCH₂CH₂),

27.68

(1S,4S,2′S,2′′S)-(–)-N-{7-t-Butyldimethylsilyloxy-1-(3-t-butyl-

dimethylsilyloxy-propyl)-4-[(2-methoxymethylpyrrolidine-1-

yl)-methoxycarbonylamino]-heptyl}-N-(2-methoxymethyl-

pyrrolidine-1-yl)-methylcarbamate [(S,S,S,S)-3d]

(NCH₂CH₂CH₂), 34.68 (CH₃CHCH₂), 52.07 (OCOCH₃), 54.30

(NCH₂), 55.20, 58.89, 61.36 (CH₃CH, CHCH₂OCH₃), 75.52

(CH₂O), 155.22 (C=O).

MS (70 eV): m/z (%) = 472 (3) [M⁺], 428 (24), 427 (100) [M⁺–

CH₂OCH₃], 191 (12),157 (10), 143 (20), 114 (23), 113 (10), 112

(20), 111 (16), 80 (10), 70 (17), 68 813), 55 (10), 45 (13).

To 3-tert-butyldimethysillyloxypropyliodide (0.84 g, 2.8 mmol) in

Et₂O (3 mL) was added dropwise t-butyllithium (1.6 M soln in pen-

tane) (4.2 mL, 6.7 mmol) at –78 °C. The reaction mixture was

stirred for 0.5 h and then allowed to warm to 0 °C and stirred for an

additional 2 h. The resulting yellow soln was added dropwise at

–100 °C to the hydrazone 2b (0.31 g, 1 mmol) in Et₂O (8 mL) and

then the reaction mixture was allowed to warm up slowly to r.t. over

15 h. Methyl chloroformate (1.51 g, 16 mmol) was added at 0 °C

and the soln stirred for 20 h at r.t. The reaction was terminated by

addition of a sat. NaHCO₃soln (20 mL). The organic layer was sep-

arated and the residue extracted with Et₂O (4 25 mL). The com-

bined organic layers were then dried over MgSO₄and the solvent

removed on a rotary evaporator. Flash chromatography (SiO₂,

Et₂O–petroleum ether, 1:1) yielded 3d (0.51 g, 66%) as a colorless

highly viscous oil.

Anal. calcd for C₂₃H₄₄N₄O₆(472.6): C, 58.45; H, 9.38; N, 11.85.

Found: C, 59.00; H, 9.71; N, 12.03.

(1R,5R,2′S,2′′S)-(–)-N-(2-Methoxymethylpyrrolidine-1-yl)-N-

{5-[(2-methoxy-methylpyrrolidine-1-yl)-methoxycarbonyl-

amino]-1-ethylheptyl}-methyl-carbamate [(R,R,S,S)-3f]

An organocerium reagent (20 mmol) prepared from CeCl₃and Et-

MgBr (1 M soln in THF) was treated according to GP 2 with hydra-

zone 2c (0.64 g, 2 mmol). After the addition was complete (TLC)

the reaction was trapped with methyl chloroformate (7.0 g, 74

mmol). Flash chromatography (SiO₂, Et₂O–petroleum ether, 2:1)

yielded 3f (0.66 g, 66%) as a colorless highly viscous oil.

De n.d.; [α]_D²⁶–45.8 (c 1.01, CHCl₃)

De 76% (GC); [α]_D²⁵–77.5 (c 1.15, CHCl₃).

IR (CHCl₃): 2953, 2930, 2858, 2738, 1688 (C=O), 1561, 1509,

1472, 1461, 1441, 1386, 1361, 1333, 1288, 1255, 1217, 1193, 1106

(SiO), 1006, 972, 939, 837 (m, SiOC), 814, 757, 667, 521, 476, 465

cm^–1.

¹H NMR (CDCl₃): Due to the limited rotation of the NN single bond

only broad signals could be observed. δ = 0.04 [s, 12 H, Si(CH₃)₂],

0.88 [s, 18 H, SiC(CH₃)₃], 1.20–2.25 (m, 18 H, NCH₂CH₂CH₂,

CH₂CHCH₂CHH), 3.00–4.10 (m, 18 H, NCH₂, CHHCH₂OSi,

CHCH₂O, CHCH₂CH₂CH), 3.33 (s, 6 H, CH₂OCH₃), 3.67 (br s, 6

H, CH₃OCO).

IR (film): 2965–2877, 2825, 1702 (C=O), 1530, 1459, 1441, 1385,

1337, 1299–1262, 1194, 1104, 1025, 994, 973, 923, 906, 757, 667

cm^–1.

¹H NMR (CDCl₃): Due to the limited rotation of the NN single bond

only broad signals could be observed. δ = 0.87 (t, J = 7.0 Hz, 6 H,

CH₃CH₂), 1.20–2.25 (m, 18 H, NCH₂CH₂CH₂, CHCH₂CH₂CH₂CH,

CH₃CH₂), 3.00–3.95 (m, 12 H, NCH₂, CHCH₂O, CH₃CH), 3.33 (s,

6 H, CH₂OCH₃), 3.67 (br s, 6 H, OCOCH₃).

¹³C NMR (CDCl₃): Due to the limited rotation of the NN single

bond only broad signals could be observed. δ = 11.33 (CH₃CH₂),

23.82 (NCH₂CH₂), 24.13 (CHCH₂CH₂CH₂CH), 26.01, 27.52

Synthesis 2002, No. 17, 2542–2560 ISSN 0039-7881 © Thieme Stuttgart · New York

2550

D. Enders, M. Meiers

PAPER

(CH₃CH₂, NCH₂CH₂CH₂), 32.94 (CH₃CH₂CHCH₂), 52.09

(CH₃OCO), 54.05, 54.96 (rotamer) (NCH₂), 58.89, 61.26, 62.12,

63.27 (rotamer) (CH₃CH, CHCH₂OCH₃),75.38 (CH₂O). A carbonyl

signal was not detected.

CH₂=CHCH₂CH), 75.43 (CH₂O), 116.56 (CH=CH₂), 136.05

(CH₂=CH), 155.67 (C=O).

MS (70 eV): m/z (%) = 525 (1.12) [M⁺+ 1], 524 (3) [M⁺], 480 (31),

479 (100), [M⁺–C₃H₅O], 217 (12), 143 (30), 114 (22), 112 (11), 111

(29), 71 (11), 70 (21), 69 (11), 68 (14), 45 (16).

MS (70 eV): m/z (%) = 500 (5) [M⁺], 456 (28), 455 (100) [M⁺–

CH₂OCH₃], 143 (23), 114 (14), 112 (11), 111 (17), 70 (14), 45 (12).

Anal. calcd for C₂₇H₄₈N₄O₆(524.7): C, 61.81; H, 9.22; N, 10.68.

Found: C, 62.14; H, 9.52; N, 10.66.

Anal. calcd for C₂₅H₄₈N₄O₆(500.7): C, 59.97; H, 9.97; N, 11.19.

Found: C, 59.88; H, 9.79; N, 11.03.

(1R,2R,2′S,2′′S)-(–)-N-{2-[Acetyl-(2-methoxymethylpyrroli-

dine-1-yl)-amino]-1-methylpropyl}-N-(2-methoxymethylpyr-

rolidine-1-yl)-acetamide [(R,R,S,S)-3i]

An organocerium reagent (13 mmol) prepared from CeCl₃and

MeLi (1.6 M soln in Et₂O) was treated according to GP 2 with hy-

drazone 2a (0.28 g, 1 mmol). After the addition was complete

(TLC) the reaction was trapped with AcCl (1.22 g, 15.6 mmol).

Flash chromatography (SiO₂, Et₂O–petroleum ether, 4:1) yielded 3i

(0.20 g, 50%) as a light yellow solid.

(1R,5R,2′S,2′′S)-(–)-N-{1-Butyl-5-[(2-methoxymethylpyrroli-

dine-1-yl)-methoxy-carbonylamino]-nonyl}-N-(2-methoxyme-

thylpyrrolidine-1-yl)-methylcarbamate [(R,R,S,S)-3g]

An organocerium reagent (6 mmol) prepared from CeCl₃and BuLi

(1.6 M soln in hexane) was treated according to GP 2 with hydra-

zone 2c (0.28 g, 0.86 mmol). After the addition was complete (TLC)

the reaction was trapped with methyl chloroformate (1.7 g, 18

mmol). Flash chromatography (SiO₂, Et₂O–petroleum ether, 1:1)

yielded 3g (0.28 g, 58%) as a light yellow highly viscous oil.

Mp 50–51 °C; de 98% (GC); [α]_D²⁵–99.5 (c 0.99, CHCl₃).

De 69% (GC); [α]_D²⁵–70.5 (c 1.15, CHCl₃).

IR (CHCl₃): 2979–2829, 1734, 1661 (C=O), 1447, 1416, 1380,

1360, 1317, 1259, 1197, 1110, 1076, 1038, 973, 914, 735, 702, 678,

617 cm^–1.

¹H NMR (CDCl₃): δ = 1.35 (d, J = 6.3 Hz, 6 H, CH₃CH), 1.60–1.90

(m, 8 H, NCH₂CH₂CH₂), 2.02 (s, 6 H, CH₃CO), 2.80–3.30 (m, 10

H, CH₂NCHCH₂), 3.28 (s, 6 H, OCH₃), 4.11 (m, 2 H, CHCH).

¹³C NMR (CDCl₃): δ = 17.08 (CH₃CH), 21.31 (CH₃CO), 21.97

(NCH₂CH₂), 25.84 (NCH₂CH₂CH₂), 50.53 (NCH₂), 54.48 (CHCH),

57.92, 58.10 (CHCH₂OCH₃), 73.66 (CH₂O), 175.71 (C=O).

IR (film): 2956–2874, 2826, 2249, 1699 (C=O), 1531, 1441, 1385,

1337–1285, 1230, 1194, 1110, 1075, 1027, 994, 973, 922, 766, 737,

704 cm^–1.

¹H NMR (CDCl₃): Due to the limited rotation of the NN single bond

only broad signals could be observed. δ = 0.88 (t, J = 7.0 Hz, 6 H,

CH₃CH₂), 1.20–2.30 (m, 26 H, NCH₂CH₂CH₂, CHCH₂CH₂CH₂CH,

CH₃CH₂CH₂CH₂), 3.00–4.05 (m, 12 H, NCH₂, CHCH₂O, CH₃CH),

3.33 (s, 6 H, CH₂OCH₃), 3.66 (br s, 6 H, OCOCH₃).

¹³C NMR (CDCl₃): Due to the limited rotation of the NN single

bond only broad signals could be observed. δ = 14.09 (CH₃CH₂),

22.79 (CH₃CH₂), 23.83 (NCH₂CH₂), 24.11 (CHCH₂CH₂CH₂CH),

27.55 (NCH₂CH₂CH₂), 28.81 (CH₃CH₂CH₂), 32.89, 33.22

(CH₃CH₂CH₂CH₂CHCH₂), 52.05 (CH₃OCO), 54.04, 54.96

(NCH₂), 58.86, 59.34, 62.11, 63.21 (CH₃CH, CHCH₂OCH₃), 75.34

(CH₂O), 155.89, 157.68 (C=O).

MS (70 eV): m/z (%) = 398 (5) [M⁺], 228 (15), 227 (100), 199 (10),

183 (21), 171 (10), 158 (11), 157 (83), 141 (14), 127 (11), 125 (17),

114 (71), 111 (18), 85 (10), 84 (29), 83 (12), 82 (13), 73 (16), 72

(12), 71 (21), 70 (40), 69 (10), 57 (15), 55 (13), 45 (25).

Anal. calcd for C₂₀H₃₈N₄O₄(398.6): C, 60.27; H, 9.61; N, 14.06.

Found: C, 59.90; H, 9.84; N, 13.65.

MS (70 eV): m/z (%) = 556 (6) [M⁺], 512 (33), 511 (100) [M⁺–

CH₂OCH₃], 233 (13), 143 (29), 114 (15), 111 (19), 70 (12), 55 (10),

45 (11).

(1R,4R,2′S,2′′S)-(–)-N-(2-Methoxymethylpyrrolidine-1-yl)-N-

{4-[(2-methoxy-methylpyrrolidine-1-yl)-acetylamino]-1-meth-

yl-pentyl}-acetamide [(R,R,S,S)-3j]

Anal. calcd for C₂₉H₅₆N₄O₆(556.8): C, 62.56; H, 10.14; N, 10.06.

Found: C, 62.46; H, 10.37; N, 10.40.

An organocerium reagent (16 mmol) prepared from CeCl₃and

MeLi (1.6 M soln in Et₂O) was treated according to GP 2 with hy-

drazone 2b (0.62 g, 2 mmol). After the addition was complete

(TLC) the reaction was trapped with acetyl chloride (3.77 g, 48

mmol, 3.41 mL). Flash chromatography (SiO₂, Et₂O) yielded 3j

(0.40 g, 47%) as a light yellow highly viscous oil.

(1S,5S,2′S,2′′S)-(–)-N-{1-Allyl-5-[(2-methoxymethylpyrroli-

dine-1-yl)-methoxy-carbonylamino]-oct-7-enyl}-N-(2-methoxy-

methylpyrrolidine-1-yl)-methyl-carbamate [(S,S,S,S)-3h]

The organocerium reagent (20 mmol) prepared from CeCl₃and al-

lylMgCl (1 M soln in THF) was treated according to GP 2 with hy-

drazone 2c (0.64 g, 2 mmol). After the addition was complete (TLC)

the reaction was trapped with methyl chloroformate (7.0 g, 74

mmol). Flash chromatography (SiO₂, Et₂O–petroleum ether, 2:1)

yielded 3h (0.89 g, 85%) as a light yellow highly viscous oil.

De 84% (¹³C NMR); [α]_D²⁹–68.6 (c 1.08, CHCl₃).

IR (CHCl₃): 2970, 2934, 2874, 2830, 2300, 1717, 1657 (C=O),

1442, 1363, 1326, 1256, 1197, 1123, 1036, 972, 940, 922, 897, 852,

754, 664, 611, 565, 511, 490 cm^–1.

¹H NMR (CDCl₃): δ = 1.14 (d, J = 6.5 Hz, 6 H, CH₃CH), 1.50–2.15

(m, 12 H, NCH₂CH₂CH₂, CH₃CHCH₂), 2.07 (s, 6 H, CH₃CO),

2.80–3.40 (m, 12 H, NCH₂, CHCH₂O, CH₃CH), 3.34 (s, 6 H,

OCH₃).

¹³C NMR (CDCl₃): δ = 18.93 (CH₃CH), 21.28 (NCH₂CH₂), 22.53

(CH₃CO), 26.27 (NCH₂CH₂CH₂), 33.11 (CH₃CHCH₂), 51.15

(NCH₂), 51.73, 58.56, 59.12 (CHCH₂OCH₃, CH₃CH), 74.01

(CH₂O), 174.37 (C=O).

MS (70 eV): m/z (%) = 426 (0.24) [M⁺], 381 (35) [M⁺– C₂H₅O],

255 (22), 173 (12), 142 (26), 141 (21), 140 (23), 127 (24), 114 (100)

[C₆H₁₂NO⁺], 98 (20), 97 86 (10), 85 (11), 84 (33), 83 (14), 82 (12),

71 (11), 70 (32), 68 (17), 45 (19), 44 (10), 43 (17).

De 82% (GC); [α]_D²⁴–64.9 (c 0.91, CHCl₃).

IR (CHCl₃): 3077, 3012, 2976, 2953, 2876, 2827, 2453, 1694

(C=O), 1642, 1441, 1385, 1335, 1299, 1272, 1237, 1217, 1195,

1110, 1025, 995, 972, 917, 757, 667, 648, 603, 538, 500 cm^–1.

¹H NMR (CDCl₃): Due to the limited rotation of the NN single bond

only broad signals could be observed. δ = 1.20–2.50 (m, 16 H,

CHCH₂CH₂CH₂CH, NCHHCH₂CH₂), 3.0 4.1 (m, 10 H, NCHH,

CHCH₂O, CH₂=CHCH₂CH), 3.33 (s, 6 H, CH₂OCH₃), 3.68 (s, 6 H,

OCOCH₃), 5.02 (m, 4 H, CH=CH₂), 5.75 (m, 2 H, CH₂=CH).

¹³C NMR (CDCl₃): Due to the limited rotation of the NN single

bond only broad signals could be observed. δ = 23.77, 24.06

(CHCH₂CH₂CH₂CH, NCH₂CH₂), 27.68 (NCH₂CH₂CH₂), 32.45

(CHCH₂CH₂CH₂CH), 37.86 (CH₂=CHCH₂), 52.17 (OCOCH₃),

54.32, 55.12 (NCH₂), 58.92, 59.45, 62.18, 63.16 (CHCH₂OCH₃,

Anal. calcd for C₂₂H₄₂N₄O₄(426.60): C, 61.94; H, 9.92; N, 13.13.

Found: C, 62.30; H, 9.68; N, 12.97.

Synthesis 2002, No. 17, 2542–2560 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER

Syntheses of C₂-Symmetric 1,n-Diamines

2551

(1S,4S,2′S,2′′S)-(–)-N-{1-Allyl-4-[(2-methoxymethylpyrroli-

dine-1-yl)-acetyl-amino]-hept-6-enyl}-N-(2-methoxymeth-

ylpyrrolidine-1-yl)-acetamide [(S,S,S,S)-3k]

(1R,2R,2′S,2′′S)-(–)-N-(2-Methoxymethylpyrrolidine-1-yl)-N-

{2-[(2-methoxy-methylpyrrolidine-1-yl)-propionylamino]-1-

methylpropyl}propionamide [(R,R,S,S)-3m]

An organocerium reagent (16 mmol) prepared from CeCl₃and al-

lylMgCl (1.6 M soln in THF) was treated according to GP 2 with

hydrazone 2b (0.62 g, 2 mmol). After the addition was complete

(TLC) the reaction was trapped with AcCl (3.77 g, 48 mmol, 3.41

mL). Flash chromatography (SiO₂, Et₂O–petroleum ether, 6:1)

yielded 3k (0.42 g, 44%) as a light yellow highly viscous oil.

An organocerium reagent (8 mmol) prepared from CeCl₃and MeLi

(1.6 M soln in Et₂O) was treated according to GP 2 with hydrazone

2a (0.28 g, 1 mmol). After the addition was complete (TLC) the re-

action was trapped with propionyl chloride (2.22 g, 24 mmol, 2.1

mL). Flash chromatography (SiO₂, Et₂O–petroleum ether, 4:1)

yielded 3m (0.20 g, 46%) as a light yellow highly viscous oil.

De 85% (GC); [α]_D²⁹–43.6 (c 1.08, CHCl₃).

De 98% (GC); [α]_D²³–89.9 (c 0.82, CHCl₃).

IR (film): 3074, 2975, 2925, 2874, 2830, 1721, 1658 (C=O), 1445,

1363, 1330, 1300, 1257, 1197, 1124, 1035, 999, 973, 916, 779, 683,

648, 611, 556, 453 cm^–1.

¹H NMR (CDCl₃): δ = 1.60–2.10 (m, 12 H, NCH₂CH₂CH₂,

CHCH₂CH₂CH), 2.07 (s, 6 H, CH₃CO), 2.50–3.40 (m, 16 H,

CHCH₂O, CH₂=CHCH₂CH, NCH₂), 3.34 (s, 6 H, OCH₃), 5.05 (m,

4 H, CH=CH₂), 5.73 (m, 2 H, CH₂=CH).

IR (KBr): 2976, 2937, 2876, 2828, 2733, 2459, 2246, 2069, 1738,

1660 (C=O), 1551, 1462, 1447, 1423, 1378, 1346, 1290, 1271,

1240, 1196, 1112, 1074, 1019, 993, 973, 961, 916, 900, 852, 806,

788, 755, 700, 666, 646, 606, 580, 529, 465 cm^–1.

¹H NMR (CDCl₃): δ = 1.02 (t, J = 7.4 Hz, 6 H, CH₃CH₂), 1.42 (d,

J = 6 Hz, 6 H, CH₃CH), 1.60–2.00 (m, 8 H, NCH₂CH₂CH₂), 2.49

(m, 4 H, CH₃CH₂), 2.85–3.40, 4.20 (m, 12 H, CH₂NCHCH₂,

CHNCO), 3.33 (s, 6 H, OCH₃).

¹³C NMR (CDCl₃): δ = 8.93 (CH₃CH₂), 18.07 (CH₃CH), 22.33

(NCH₂CH₂), 26.70, 27.17 (CH₃CH₂, NCH₂CH₂CH₂), 51.61

(NCH₂), 55.44 (NCHCH₃), 58.89, 59.17 (CHCH₂OCH₃), 74.63

(CH₂O), 179.45 (C=O).

¹³C NMR (CDCl₃): δ = 21.24 (NCH₂CH₂), 22.23 (CH₃CO), 26.29

(NCH₂CH₂CH₂), 32.00 (CHCH₂CH₂CH), 37.45 (CH₂=CHCH₂),

51.88

(NCH₂),

56.42,

58.53,

59.02

(CHCH₂OCH₃,

CHCH₂CH₂CH), 74.21 (CH₂O), 117.03 (CH=CH₂), 136.12

(CH₂=CH), 174.72 (C=O).

MS (70 eV): m/z (%) = 479 (1.23) [M⁺+ 1], 478 (0.84) [M⁺], 434

(25), 433 (100) [M⁺– C₂H₅O], 324 (36), 320 (14), 307 (18), 194

(21), 173 (13), 152 (11), 150 (10), 141 (17), 127 (49), 114 (98)

[C₆H₁₂NO⁺], 112 (12), 110 (18), 97 (12), 85 (16), 84 (10), 83 (14),

82 (16), 71 (19), 70 (40), 69 (11), 68 (22), 67 (1255 (14), 45 (14).

MS (70 eV): m/z (%): 426 (1.87) [M⁺], 242 (15), 241 (100) [M⁺–

C₉H₁₇N₂O₂], 213 (12), 183 (20), 157 (74), 155 (13), 141 (14), 114

(68) [C₆H₁₂NO⁺], 111 (3284 (28), 71 (22), 70 (63), 57 (40), 55 (12),

45 (40), 44 (14), 43 (11), 42 (15), 41 (18).

HRMS (EI): m/z calcd for C₂₂H₄₂N₄O₄, 426.3206; found, 426.3204.

Anal. calcd for C₂₆H₄₆N₄O₄(478.7): C, 65.24; H, 9.69; N, 11.70.

Found: C, 65.29; H, 9.39; N, 11.28.

(1R,4R,2′S,2′′S)-(–)-N-(2-Methoxymethylpyrrolidine-1-yl)-N-

{4-[(2-methoxy-methylpyrrolidine-1-yl)-propionylamino]-1-

methylpentyl}-propionamide [(R,R,S,S)-3n]

An organocerium reagent (8 mmol) prepared from CeCl₃and MeLi

(1.6 M soln in Et₂O) was treated according to GP 2 with hydrazone

2b (0.31 g, 1 mmol). After the addition was complete (TLC) the re-

action was trapped with propionyl chloride (2.22 g, 24 mmol, 2.1

mL). Flash chromatography (SiO₂, Et₂O–petroleum ether, 2:1)

yielded 3n (0.44 g, 97%) as a light yellow highly viscous oil.

(1S,5S,2′S,2′′S)-(–)-N-{1-Allyl-5-[(2-methoxymethylpyrroli-

dine-1-yl)-acetyl-amino]-oct-7-enyl}-N-(2-methoxymethylpyr-

rolidine-1-yl)-acetamide [(S,S,S,S)-3l]

An organocerium reagent (16 mmol) prepared from CeCl₃and al-

lylMgCl (1.6 M soln in THF) was treated according to GP 2 with

hydrazone 2c (0.64 g, 2 mmol). After the addition was complete

(TLC) the reaction was trapped with acetyl chloride (3.77 g, 48

mmol, 3.41 mL). Flash chromatography (SiO₂, Et₂O–petroleum

ether, 2:1) yielded 3l (0.77 g, 78%) as a colorless solid.

De 87% (GC); [α]_D²⁴–84.2 (c 0.5, CHCl₃).

IR (Et₂O): 2973, 2937, 2875, 2830, 1656 (s, C=O), 1463, 1441,

1375, 1356, 1276, 1249, 1226, 1197, 1125, 1050, 952, 930, 886,

848, 805, 581, 540 cm^–1.

¹H NMR (CDCl₃): δ = 1.03 (t, J = 7.4 Hz, 6 H, CH₃CH₂), 1.41 (d,

J = 6.6 Hz, 6 H, CH₃CH), 1.60–2.40 (m, 16 H, NCH₂CH₂CH₂,

CHCH₂CH₂CH, CH₂CH₃), 2.80–3.40 (m, 12 H, CH₃CH,

CH₂NCHCH₂), 3.32 (s, 6 H, OCH₃).

¹³C NMR (CDCl₃): δ = 9.04 (CH₃CH₂), 18.89 (CH₃CH), 21.21

(NCH₂CH₂), 26.16, 26.60 (NCH₂CH₂CH₂, CH₃CH₂), 33.50

(CHCH₂CH₂CH), 51.19 (NCH₂), 51.60 (NCHCH₃), 58.53, 58.98

(CHCH₂OCH₃), 73.90 (CH₂O), 177.23 (C=O).

MS (70 eV): m/z (%): 455 (0.2) [M⁺+ 1], 454 (0.03) [M⁺], 410 (26),

409 (100) [M⁺– C₂H₅O], 296 (15), 269 (17), 157 (12), 154 (21), 141

(25), 114 (95) [C₆H₁₂NO⁺], 98 (16), 84 (15), 70 (24).

Mp 131 °C; de 84% (GC); [α]_D²⁶–37.6 (c 0.98, CHCl₃).

IR (KBr): 3077, 2968, 2927, 2868, 2827, 2811, 2086, 1645 (C=O),

1561, 1543, 1509, 1447, 1421, 1365, 1328, 1302, 1288, 1247, 1197,

1134, 1112, 1033, 1000, 957, 911, 880, 773, 740, 688, 651, 609,

564, 510 cm^–1.

¹H NMR (CDCl₃): δ = 1.32 (m, 2 H, CHCH₂CH₂CH₂CH), 1.60–

2.20 (m, 12 H, NCH₂CH₂CH₂, CH₂=CHCH₂CHCH₂), 2.07 (s, 6 H,

CH₃CO), 2.40–3.60 (m, 16 H, CHCH₂O, CH₂=CHCH₂CH, NCH₂),

3.32 (s, 6 H, OCH₃), 5.05 (m, 4 H, CH=CH₂), 5.73 (m, 2 H,

CH₂=CH).

¹³C NMR (CDCl₃): δ = 21.03 (NCH₂CH₂), 22.57 (CH₃CO), 25.40

(CHCH₂CH₂CH₂CH),

26.45

(NCH₂CH₂CH₂),

33.58

(CH₂=CHCH₂CHCH₂), 36.74 (CH₂=CHCH₂), 51.55 (NCH₂),

56.16, 58.49, 59.14 (CHCH₂OCH₃, CH₂=CHCH₂CH), 74.19

(CH₂O), 116.89 (CH=CH₂), 136.37 (CH₂=CH), 174.67 (C=O).

MS (70 eV): m/z (%) = 493 (0.34) [M⁺+ 1], 492 (0.55) [M⁺], 448

(20), 447 (70) [M⁺– C₂H₅O], 338 (18), 173 (13), 141 (29), 127

(43), 114 (100) [C₆H₁₂NO⁺], 85 (11), 82 (12), 70 (29), 68 (12), 45

(15).

Anal. calcd for C₂₄H₄₆N₄O₄(454.7): C, 63.40; H, 10.20; N, 12.32.

Found: C, 63.48; H, 10.19; N, 12.20.

2-Methoxymethylpyrrolidine-1-yl)-N-{4-[(2-methoxy-meth-

ylpyrrolidine-1-yl)-propionylamino]-1-ethylhexyl}-propiona-

mide [(R,R,S,S)-3o]

Anal. calcd for C₂₇H₄₈N₄O₄(492.7): C, 65.82; H, 9.82; N, 11.37.

Found: C, 65.30; H, 9.83; N, 11.19.

An organocerium reagent (8 mmol) prepared from CeCl₃and EtMg-

Br (1 M soln in THF) was treated according to GP 2 with hydrazone

2b (0.31 g, 1 mmol). After the addition was complete (TLC) the re-

action was trapped with propionyl chloride (2.22 g, 24 mmol, 2.1

Synthesis 2002, No. 17, 2542–2560 ISSN 0039-7881 © Thieme Stuttgart · New York

2552

D. Enders, M. Meiers

PAPER

mL). Flash chromatography (SiO₂, Et₂O–petroleum ether, 2:1)

yielded 3o (0.32 g, 66%) as a light yellow highly viscous oil.

[α]_D³⁰–74.9 (c 0.72, CHCl₃).

(TLC) the reaction was trapped with propionyl chloride (2.22 g, 24

mmol, 2.1 mL). Flash chromatography (SiO₂, Et₂O–petroleum

ether, 1:1) yielded 3q (0.54 g, 91%) as a light yellow highly viscous

oil.

IR (film): 2969, 2935, 2875, 2829, 1721, 1657 (C=O), 1461, 1429,

1375, 1357, 1254, 1198, 1124, 1017, 973, 923, 898, 876, 804, 582,

Dr 84.0:15.3:0.7 (GC); [α]_D²³–49.2 (c 1.09, CHCl₃).

1

454 cm .

IR (CHCl₃): 2957, 2929, 2873, 2858, 2464, 1733, 1648 (C=O),

1462, 1376, 1358, 1248, 1216, 1198, 1124, 1077, 1016, 973, 922,

804, 755, 665, 582 cm^–1.

¹H NMR (CDCl₃): Only the chemical shifts of the main diastereo-

¹H NMR (CDCl₃): δ = 0.87 (t, J = 7.7 Hz, 6 H, CH₃CH₂CH), 1.04

(t, J = 7.4 Hz, 6 H, CH₃CH₂CO), 1.60–2.10 (m, 16 H,

NCH₂CH₂CH₂, CHCH₂CH₂CH, CH₃CH₂CH), 2.20–2.55 (m, 4 H,

CH₃CH₂CO), 2. 70–3.04 (m, 8 H, CHNCO, CH₂NCHCH₂), 3.22–

3.36 (m, 4 H, CH₂O), 3.31 (s, 6 H, OCH₃).

mer are given. δ = 0.87 (m, 6 H, CH₃CH₂CH₂), 1.03 (t, J = 7.4 Hz,

6

H, CH₃CH₂CO), 1.09–2.58 (m, 38 H, acyclic CH₂,

NCHHCH₂CH₂, CH₃CH₂CO), 2.76–3.40 (m, 10 H, CHNCO,

CHHNCHCH₂), 3.31 (s, 6 H, OCH₃).

¹³C NMR (CDCl₃): δ = 9.19 (CH₃CH₂CO), 11.95 (CH₃CH₂CH),

21.12 (NCH₂CH₂), 25.62, 26.10, 26.53 (NCH₂CH₂CH₂,

CH₃CH₂CH, CH₃CH₂CO), 32.96 (CHCH₂CH₂CH), 51.71 (NCH₂),

57.98, 58.47, 59.00 (CHCH₂CH₃, CHCH₂OCH₃), 73.99 (CH₂O),

177.39 (C=O).

MS (70 eV): m/z (%) = 482 (0.75) [M⁺], 438 (11), 437 (41) [M⁺–

C₂H₅O], 324 (12), 297 (20), 187 (14), 185 (10), 184 (19), 155 (16),

142 (12), 141 (38), 126 (24), 114 (100) [C₆H₁₂NO⁺], 85 (11), 84

(22), 71 (10), 70 (24), 69 (14), 57 (11), 55 (14), 45 (13), 44 (10), 41

(12).

¹³C NMR (CDCl₃): Only the chemical shifts of the main diastereo-

mer are given. δ = 9.23 (CH₃CH₂CO), 14.09 (CH₃CH₂CH₂), 21.22,

22.66 (CH₃CH₂CH₂, NCH₂CH₂), 26.11, 26.56, 27.67 (CH₃CH₂CO,

NCH₂CH₂CH₂, CH₃CH₂CH₂), 29.55 (CH₃CH₂CH₂CH₂), 31.85,

33.01, 33.25 (CH₂CH₂CHCH₂), 51.73 (NCH₂), 56.93, 58.46, 59.00

(CHCH₂CH₂CH, CHCH₂OCH₃), 73.95 (CH₂O), 177.54 (C=O).

MS (70 eV): m/z (%) = 595 (1.67) [M⁺+ 1], 551 (11), 550 (55), 549

(100) [M⁺– C₂H₅O], 537 (15), 437 (12), 436 (42), 409 (32), 392

(22), 377 (20), 296 (14), 294 (26), 252 (35), 246 (17), 238 (29), 236

(10), 227 (21), 187 (22), 185 (14), 181 (12), 155 (15), 154 (24), 142

(11), 140 (79), 129 (10), 115 (11), 114 (96) [C₆H₁₂NO⁺], 112 (11),

97 (17), 85 (18), 84 (14), 83 (14), 82 (14), 71 (18), 70 (39), 69 (18),

68 (12), 57 (37), 55 (18), 45 (19).

Anal. calcd for C₂₆H₅₀N₄O₄(482.7): C, 64.69; H, 10.44; N, 11.61.

Found: C, 64.56; H, 10.42; N, 11.95.

(1R,4R,2′S,2′′S)-(–)-N-{1-Butyl-4-[(2-methoxymethylpyrroli-

dine-1-yl)-propionylamino]-octyl}-N-(2-methoxymethylpyrro-

lidine-1-yl)-propionamide [(R,R,S,S)-3p]

An organocerium reagent (8 mmol) prepared from CeCl₃and BuLi

(1.6 M soln in hexane) was treated according to GP 2 with hydra-

zone 2b (0.31 g, 1 mmol). After the addition was complete (TLC)

the reaction was trapped with propionyl chloride (2.22 g, 24 mmol,

2.1 mL). Flash chromatography (SiO₂, Et₂O–petroleum ether, 2:1)

yielded 3p (0.53 g, 98%) as a light yellow highly viscous oil.

Anal. calcd for C₃₄H₆₆N₄O₄(594.9): C, 68.64; H, 11.18; N, 9.42.

Found: C, 68.70; H, 11.18; N, 9.32.

(1R,5R,2′S,2′′S)-(–)-N-(2-Methoxymethylpyrrolidine-1-yl)-N-

{5-[(2-methoxy-methylpyrrolidine-1-yl)-propionylamino]-1-

methylhexyl}-propionamide [(R,R,S,S)-3r]

An organocerium reagent (8 mmol) prepared from CeCl₃and MeLi

(1.6 M soln in Et₂O) was treated according to GP 2 with hydrazone

2c (0.32 g, 1 mmol). After the addition was complete (TLC) the re-

action was trapped with propionyl chloride (2.22 g, 24 mmol, 2.1

mL). Flash chromatography (SiO₂, Et₂O–petroleum ether, 4:1)

yielded 3r (0.46 g, 98%) as a light yellow highly viscous oil.

Dr 83.5:16.0:0.5 (GC); [α]_D²⁹–52.2 (c 1.16, CHCl₃).

IR (CHCl₃): 2959, 2932, 2874, 1734, 1647 (C=O), 1462, 1377,

1357, 1274, 1244, 1216, 1197, 1124, 1077, 1014, 973, 923, 900,

804, 755, 665, 583 cm^–1.

¹H NMR (CDCl₃): δ = 0.88 (t, J = 7.1 Hz, 6 H, CH₃CH₂CH₂), 1.03

(t, J = 7.4 Hz, 6 H, CH₃CH₂CO), 1.10–1.43, 1.60–2.10 (m, 24 H,

NCH₂CH₂CH₂, CH₃CH₂CH₂CH₂, CHCH₂CH₂CH), 2.44 (m, 6 H,

CH₃CH₂CO, NCHH), 2.76–3.40 (m, 10 H, NCHH, CHCH₂CH₂CH,

CHCH₂O), 3.31 (s, 6 H, OCH₃).

¹³C NMR (CDCl₃): δ = 9.22 (CH₃CH₂CO), 14.14 (CH₃CH₂CH₂),

21.20, 22.97 (CH₃CH₂CH₂, NCH₂CH₂), 26.11, 26.55

(NCH₂CH₂CH₂, CH₃CH₂CO), 29.92 (CH₂CH₂CH₃), 32.94, 32.98

(CH₂CHCH₂CH₂CHCH₂), 51.73 (NCH₂), 56.91, 58.43, 59.00

(CHCH₂CH₂CH, CHCH₂OCH₃), 73.95 (CH₂O), 177.59 (C=O).

De 94% (GC); [α]_D²⁴–63.0 (c 0.96, CHCl₃).

IR (CHCl₃): 2976, 2936, 2876, 2458, 2401, 1730, 1646 (C=O),

1463, 1435, 1375, 1357, 1238, 1216, 1126, 972, 927, 891, 755, 667,

582 cm^–1.

¹H NMR (CDCl₃): Only the chemical shifts of the main diastereo-

mer are given. δ = 1.04 (t, J = 7.5 Hz, 6 H, CH₃CH₂), 1.40 (d,

J = 6.7 Hz, 6 H, CH₃CH), 1.60–2.60 (m, 14 H, NCH₂CH₂CH₂,

CHCH₂CH₂CH₂CH), 2.47 (q, J = 7.5 Hz, 4 H, CH₃CH₂), 2.82–3.40

(m, 12 H, CHNCO, CH₂NCHCH₂), 3.32 (s, 6 H, OCH₃).

¹³C NMR (CDCl₃): Only the chemical shifts of the main diastereo-

mer are given. δ = 9.08 (CH₃CH₂), 18.45 (CH₃CH), 21.05

(NCH₂CH₂), 26.38, 26.77 (2C) (CH₃CH₂, NCH₂CH₂CH₂,

CH₃CHCH₂CH₂), 34.64 (CH₃CHCH₂), 50.92 (NCH₂), 51.49

(NCHCH₃), 58.57, 59.10 (CHCH₂OCH₃), 74.07 (CH₂O), 177.45

(C=O).

MS (70 eV): m/z (%) = 424 (15), 423 (67) [M⁺– C₂H₅O], 149 (11),

141 (28), 115 (6), 114 (100) [C₆H₁₂NO⁺], 112 (11), 85 (10), 84 (11),

83 (14), 71 (15), 70 (33), 69 (10), 58 (14), 57 (26), 55 (20), 45 (27),

44 (12), 43 (59), 41 (20).

MS (70 eV): m/z (%) = 539 (0.21) [M⁺+ 1], 538 (0.44) [M⁺], 494

(30), 493 (100) [M⁺– C₂H₅O], 380 (21), 353 (20), 224 (10), 187

(12), 182 (17), 142 (13), 141 (50), 114 (75) [C₆H₁₂NO⁺], 86 (10), 85

(12), 83 (11), 71 (13), 70 (24), 57 (62), 55 (15).

Anal. calcd for C₃₀H₅₈N₄O₄(538.8): C, 66.87; H, 10.85; N, 9.62.

Found: C, 66.95; H, 10.85; N, 10.12.

(1R,4R,2′S,2′′S)-(–)-N-{1-Hexyl-4-[(2-methoxymethylpyrroli-

dine-1-yl)-propionylamino]-decyl}-N-(2-methoxymethylpyr-

rolidine-1-yl)-propionamide [(R,R,S,S)-3q]

An organocerium reagent (8 mmol) prepared from CeCl₃and n-hex-

yl lithium (2 M soln in hexane) was treated according to GP 2 with

hydrazone 2b (0.31 g, 1 mmol). After the addition was complete

Anal. calcd for C₂₅H₄₈N₄O₄(468.7): C, 64.07; H, 10.32; N, 11.95.

Found: C, 64.06; H, 10.34; N, 11.79.

Synthesis 2002, No. 17, 2542–2560 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER

Syntheses of C₂-Symmetric 1,n-Diamines

2553

(1R,5R,2′S,2′′S)-(–)-N-{1-Butyl-5-[(2-methoxymethylpyrroli-

dine-1-yl)-propionylamino]-nonyl}-N-(2-methoxymethylpyr-

rolidine-1-yl)-propionamide [(R,R,S,S)-3s]

(1S,5S,2′S,2′′S)-(+)-N-{1-Benzyl-5-[(2-methoxymethylpyrroli-

dine-1-yl)-propionylamino]-6-phenylhexyl}-N-(2-methoxyme-

thylpyrrolidine-1-yl)-propionamide [(S,S,S,S)-3u]

An organocerium reagent (8 mmol) prepared from CeCl₃and BuLi

(1.6 M soln in hexane) was treated according to GP 2 with hydra-

zone 2c (0.32 g, 1 mmol). After the addition was complete (TLC)

the reaction was trapped with propionyl chloride (2.22 g, 24 mmol,

2.1 mL). Flash chromatography (SiO₂, Et₂O–petroleum ether, 4:1)

yielded 3s (0.48 g, 87%) as a light yellow highly viscous oil.

An organocerium reagent (8 mmol) prepared from CeCl₃and Bn-

MgCl (1 M soln in THF) was treated according to GP 2 with hydra-

zone 2c (0.32 g, 1 mmol). After the addition was complete (TLC)

the reaction was trapped with propionyl chloride (2.22 g, 24 mmol,

2.1 mL). Flash chromatography (SiO₂, Et₂O–petroleum ether, 2:1)

yielded 3u (0.63 g, quant.) as a colorless highly viscous oil.

De 68% (GC); [α]_D²⁹–48.6 (c 1.66, CHCl₃).

De 83% (¹³C NMR); [α]_D²⁶+17.8 (c 0.99, CHCl₃).

IR (film): 2956, 2932, 2872, 2735, 1733, 1658 (C=O), 1461, 1428,

1396, 1376, 1357, 1266, 1246, 1196, 1113, 1077, 1014, 973, 923,

901, 856, 805, 734, 580 cm^–1.

IR (KBr): 3027, 2963, 2930, 2867, 2827, 1650 (C=O), 1495, 1458,

1427, 1375, 1355, 1279, 1258, 1194, 1114, 1081, 1016, 976, 920,

875, 842, 801, 750, 703, 586, 543, 500 cm^–1.

¹H NMR (CDCl₃): Only the chemical shifts of the main diastereo-

mer are given. δ = 0.88 (t, J = 7.4 Hz, 6 H, CH₃CH₂CH₂), 1.04 (t,

J = 7.4 Hz, 6 H, CH₃CH₂CO), 1.10–1.40 (m, 10 H, CH₃CH₂CH₂,

CHCH₂CH₂CH₂CH), 1.60–2.55 (m, 20 H, NCH₂CH₂CH₂,

CH₂CH₂CHCH₂CH₂, CH₃CH₂CO), 2.78–3.62 (m, 12 H, CHNCO,

CH₂NCHCH₂), 3.32 (s, 6 H, OCH₃).

¹³C NMR (CDCl₃): Only the chemical shifts of the main diastereo-

mer are given. δ = 9.24 (CH₃CH₂CO), 14.15 (CH₃CH₂CH₂), 21.01,

22.99 (NCH₂CH₂, CH₃CH₂CH₂), 26.41, 26.77 (2C) (CH₃CH₂CO,

CHCH₂CH₂CH₂CH, NCH₂CH₂CH₂), 30.00 (CH₃CH₂CH₂), 32.63,

33.99 (CH₃CH₂CH₂CH₂CHCH₂), 51.42 (NCH₂), 56.66, 58.34,

59.13 (CHNCO, CHCH₂OCH₃), 74.08 (CH₂O), 177.70 (C=O).

¹H NMR (CDCl₃): δ = 1.08 (t, J = 7.4 Hz, 6 H, CH₃CH₂), 1.30–2.35

(m 18 H, NCH₂CH₂CH₂, CH₂CH₂CHCH₂Ph), 2.43 (q, J = 7.4 Hz, 4

H, CH₃CH₂), 2.80–3.50 (m, 12 H, CH₂NCHCH₂O, CHNCO), 3.28

(s, 6 H, OCH₃), 7.20 (m, 10 H, Ph).

¹³C NMR (CDCl₃): δ = 9.33 (CH₃CH₂), 20.83 (NCH₂CH₂), 25.77

(PhCH₂CHCH₂CH₂), 26.28, 26.98 (CH₃CH₂, NCH₂CH₂CH₂),

33.91 (PhCH₂CHCH₂), 37.12 (PhCH₂), 50.03 (NCH₂), 58.31,

58.66, 59.13 (CHNCO, CHCH₂OCH₃), 74.12 (CH₂O), 126.29

(C_para), 128.22, 129.85 (C_ortho, C_meta), 140.24 (C_ipso), 178.09 (C=O).

MS (70 eV): m/z (%) = 620 (0.06) [M⁺], 575 (19) [M⁺– C₂H₅O],

416 (21), 384 (12), 265 (19), 187 (17), 174 (12), 155 (20), 154 (10),

141 (62), 131 (11), 129 (10), 114 (100) [C₆H₁₂NO⁺], 97 (11), 91

MS (70 eV): m/z (%) = 552 (0.15) [M⁺], 507 (3.51) [M⁺– C₂H₅O],

196 (11), 187 (13), 155 (19), 142 (53), 114 (100) [C₆H₁₂NO⁺], 85

(13), 84 (10), 82 (12), 74 (11), 70 (24), 69 (10), 57 (12), 55 (17), 45

(11).

(73) [C₇H₇], 85 (13), 82 (10), 71 (10), 70 (21), 57 (23), 45 (11).

+

HRMS (EI): m/z calcd for C₃₅H₅₁N₄O₃(M⁺– C₂H₅O), 575.3961;

found, 575.3961.

Anal. calcd for C₃₁H₆₀N₄O₄(552.8): C, 67.35; H, 10.94; N, 10.13.

Found: C, 66.99; H, 10.82; N, 10.00.

(1R,4R)-(+)-N-(1-Methyl-4-methoxycarbonylaminopentyl)-me-

thylcarbamate [(R,R)-4a]

Hydrazide 3a (850 mg, 1.85 mmol) was allowed to react according

to GP 3. After reductive cleavage (3 h) and work up flash column

chromatography (SiO₂, Et₂O–petroleum ether, 4:1) yielded 4a (240

mg, 56%) as a colorless solid.

(1S,5S,2′S,2′′S)-(–)-N-{1-Allyl-5-[(2-methoxymethylpyrroli-

dine-1-yl)-propionylamino]-oct-7-enyl}-N-(2-methoxymeth-

ylpyrrolidine-1-yl)-propionamide [(S,S,S,S)-3t]

An organocerium reagent (8 mmol) prepared from CeCl₃and al-

lylMgCl (1 M soln in THF) was treated according to GP 2 with hy-

drazone 2c (0.32 g, 1 mmol). After the addition was complete (TLC)

the reaction was trapped with propionyl chloride (2.22 g, 24 mmol,

2.1 mL). Flash chromatography (SiO₂, Et₂O–petroleum ether, 2:1)

yielded 3t (0.47 g, 90%) as a colorless highly viscous oil which

crystallized at 2 °C as needles.

De 87% (GC); ee 98% [GC_CSP: XE-60-S-Valin-S-X-Phenylethyla-

mid, H₂= 1.0 bar, T = 140–3–190 of (R,R)-6a]; [α]_D²⁹+20.3

(c 1.02, CHCl₃).

IR (KBr): 3319 (NH), 3070, 2969, 2950, 2908, 2860, 2848, 2797,

2373, 2345, 2199, 2053, 1688 (C=O), 1657, 1618, 1547, 1451,

1377, 1346, 1310, 1296, 1266, 1207, 1198, 1176, 1112, 1093, 1058,

1034, 1023, 963, 935, 868, 779, 708, 672, 519 cm^–1.

¹H NMR (CDCl₃): Due to the limited rotation of the NN single bond

only broad signals could be observed. δ = 1.14 (d, J = 6.5 Hz, 6 H,

CH₃CH), 1.46 (m, 4 H, CH₂), 3.65 (br s, 8 H, OCH₃, CH), 4.63 (br

m, 2 H, NH).

¹³C NMR (CDCl₃): Due to the limited rotation of the NN single

bond only broad signals could be observed. δ = 21.44 (CH₃CH),

33.66 (CH₂), 47.02 (CH), 51.90 (OCH₃), 156.54 (C=O).

MS (70 eV): m/z (%) = 233 (1.09) [M⁺+ 1], 232 (7) [M⁺], 173 (17),

156 (10), 142 (14), 102 (100), 58 (9).

De 83% (GC); [α]_D²⁵–28.2 (c 1.23, CHCl₃).

IR (film): 3075, 2975, 2935, 2875, 1735, 1657, 1462, 1447, 1395,

1375, 1358, 1278, 1240, 1196, 1125, 1112, 1076, 998, 973, 917,

877, 829, 806, 700, 648, 566 cm^–1.

¹H NMR (CDCl₃): Only the chemical shifts of the main diastereo-

mer are given. δ = 1.04 (t, J = 7.5 Hz, 6 H, CH₃CH₂), 1.60–3.65 (m,

34 H, CH₂, CH except CH=CH₂), 3.32 (s, 6 H, OCH₃), 5.04 (m, 4

H, CH=CH₂), 5.72 (m, 2 H, CH=CH₂).

¹³C NMR (CDCl₃): Only the chemical shifts of the main diastereo-

mer are given. δ = 9.29 (CH₃CH₂), 20.97 (NCH₂CH₂), 26.42, 26.76

(2 C) (NCH₂CH₂CH₂, CH₃CH₂, CHCH₂CH₂CH₂CH), 33.75

(CHCH₂CH₂CH₂CH), 36.77 (CH₂CH=CH₂), 51.65 (NCH₂), 56.03,

58.50, 59.14 (CHNCO, CHCH₂OCH₃), 74.14 (CH₂O), 116.92

(CH₂=CH), 136.39 (CH=CH₂), 177.93 (C=O).

MS (70 eV): m/z (%) = 476 (17), 475 (52) [M⁺– C₂H₅O], 366 (21),

187 (10), 155 (15), 141 (43), 114 (100) [C₆H₁₂NO⁺], 110 (10), 97

(11), 85 (15), 82 (12), 71 (15), 70 (28), 68 (12), 57 (28).

Anal. calcd for C₁₀H₂₀N₂O₄(232.3): C, 51.71; H, 8.68; N, 12.06.

Found: C, 51.71; H, 8.67; N, 12.00.

(1R,5R)-(–)-N-(1-Methyl-5-methoxycarbonylaminohexyl)-me-

thylcarbamate [(R,R)-4e]

Hydrazide 3e (790 mg, 1.67 mmol) was allowed to react according

to GP 3. After reductive cleavage (2 h) and work up flash column

chromatography (SiO₂, Et₂O–PE 4:1) yielded 4e (250 mg, 61%) as

a colorless solid.

Anal. calcd for C₂₉H₅₂N₄O₄(520.8): C, 66.89; H, 10.07; N, 10.76.

Found: C, 66.73; H, 10.08; N, 10.70.

Mp 105 °C; de 91% (GC); ee 98% (GC_CSP: 7-CD PERME 25 m,

H₂= 1 bar, T = 100–1–190); [α]_D²⁸–6.3 (c 1.06, CHCl₃).

Synthesis 2002, No. 17, 2542–2560 ISSN 0039-7881 © Thieme Stuttgart · New York

2554

D. Enders, M. Meiers

PAPER

IR (film): 3305 (NH), 3065, 2969–2947, 2864, 2850, 2850, 2798,

1717, 1693, 1544, 1452, 1374, 1357, 1341, 1296, 1260, 1235, 1193,

1161, 1097, 1064–1033, 1016, 977, 950, 920, 884, 847, 814, 783,

710, 669 cm^–1.

¹H NMR (CDCl₃): δ = 1.13 (d, J = 6.0 Hz, 6 H, CH₃CH) 1.14 (t,

J = 7.7 Hz, 6 H, CH₃CH₂), 1.45 (m, 4 H, CHCH₂), 2.18 (q, J = 7.7

Hz, 4 H, CH₃CH₂), 3.96 (m, 2 H, CH), 5.51 (br d, J = 8.0 Hz, 2 H,

NH).

¹H NMR (CDCl₃): δ = 1.13 (d, J = Hz, 6 H, CH₃CH), 1.39 (m, 6 H,

CH₂), 3.66 (br s, 6 H, OCH₃), 4.5–4.8 (br, 4 H, NH, CH).

¹³C NMR (CDCl₃): δ = 9.97 (CH₃CH₂), 21.02 (CH₃CH), 29.87

(CH₃CH₂), 33.58 (CHCH₂), 45.07 (CH), 173.25 (C=O).

¹³C NMR (CDCl₃): δ = 21.66 (CH₃CH), 22.20 (CH₂CH₂CH₂),

36.63 (CHCH₂), 46.55 (CH), 51.86 (OCH₃), 156.79 (C=O).

MS (70 eV): m/z (%) = 246 (2.07) [M⁺], 171 (11), 156 (17), 102

MS (70 eV): m/z (%) = 228 (4.20) [M⁺], 171 (45) [M⁺– C₃H₅O],

154 (38), 129 (23), 128 (16), 111 (11), 101 (31), 100 (77), 99 (12),

98 (67), 97 (17), 95 (10), 87 (14), 85 (19), 84 (31), 83 (20), 82 (10),

81 (12), 74 (22), 73 (20), 72 (10), 71 (29), 70 (13), 69 (19), 60 (18),

58 (13), 57 (50), 56 (13), 55 (31), 44 (100).

HRMS (EI): m/z calcd for C₁₂H₂₄N₂O₂(M⁺), 228.1838; found,

228.1837.

(100), 58 (14), 44 (23).

Anal. calcd for C₁₁H₂₂N₂O₄(232.3): C, 53.64; H, 9.00; N, 11.37.

Found: C, 54.07; H, 9.08; N, 11.39.

(1R,2R)-(+)-N-(2-Acetylamino-1-methylpropyl)acetamide

[(R,R)-4 i]

Hydrazide 3i (60 mg, 0.15 mmol) was allowed to react according to

GP 3. After reductive cleavage (2 h) and work up flash column

chromatography (SiO₂, Et₂O–MeOH 8:1) yielded 4i (16 mg, 62%)

as a colorless solid.

(1R,4R)-(+)-N-(1-Ethyl-4-propionylaminohexyl)-propiona-

mide [(R,R)-4o]

Hydrazide 3o (140 mg, 0.29 mmol) was allowed to react according

to GP 3. After reductive cleavage (3 h) and work up flash column

chromatography (SiO₂, Et₂O–MeOH, 20:1) yielded 3o (47 mg,

63%) as a colorless solid.

Mp 191 °C; de 98% (GC); ee 98% (GC_CSP: 7-CD PERME 25 m,

H₂= 1 bar, T = 120–1–190); [α]_D²⁸+44.9 (c 0.049, butanone);

{Lit.: [α]_D²⁸–54.9 (c 0.049, butanone for (S,S)-4i)}.

Mp 179 °C; de 98% (GC); ee 96% (GC_CSP: Lipodex E 25 m,

H₂= 1.6 bar, T = 140–1–190); [α]_D²⁵+56.3 (c 0.32, CHCl₃).

IR (KBr): 3292 (NH), 3079, 2969, 2940, 2877, 2857, 2785, 2373,

2345, 1642 (C=O), 1548, 1462, 1376, 1286, 1269, 1249, 1237,

1196, 1149, 1115, 1082 ((m), 1039, 1011, 997, 974, 945, 924, 911,

880, 853, 783, 710, 582, 548 cm^–1.

¹H NMR (CDCl₃): δ = 0.89 (t, J = 7.4 Hz, 6 H, CH₃CH₂CH), 1.15

(t, J = 7.4 Hz, 6 H, CH₃CH₂CO), 1.22–1.63 (m, 8 H, CH₂CHCH₂),

2.20 (q, J = 7.4 Hz, 4 H, CH₃CH₂CO), 3.81 (m, 2 H, CH), 5.31 (br

d, J = 9.1 Hz, 2 H, NH).

The spectroscopic data of 4i corresponded with those reported in

ref.³⁴

(1R,2R)-(+)-N-(1-Methyl-2-propionylaminopropyl)propiona-

mide [(R,R)-4m]

Hydrazide 3m (104 mg, 0.24 mmol) was allowed to react according

to GP 3. After reductive cleavage (3 h) and work up flash column

chromatography (SiO₂, Et₂O–MeOH 20:1) yielded 4m (35 mg,

73%) as a colorless solid.

¹³C NMR (CDCl₃): δ = 10.12, 10.22 (CH₃), 27.93, 29.97, 31.42

Mp 162–165 °C; de 98% (GC); ee 98% (GC_CSP: XE-60-S-Valin-S-

X-Phenylethylamide, H₂= 1.4 bar, T = 110–3–190); [α]_D²⁵+65.5

(c 0.91, CHCl₃).

(CH₂), 50.50 (CH), 173.63 (C=O).

MS (70 eV): m/z (%) = 257 (4.48) [M⁺+ 1], 256 (1.57) [M⁺], 199

(33) [M⁺– C₃H₅O], 182 (24), 154 (44), 142 (13), 126 (40), 115 (21),

114 (47), 100 (12), 98 (88), 74 (20), 58 (100), 57 (52), 56 (19), 55

(13).

HRMS (EI): m/z calcd for C₁₄H₂₈N₂O₂(M⁺), 256.2151; found,

256.2153.

IR (KBr): 3288 (NH), 3083, 2970, 2929, 2877, 1641 (C=O), 1551,

1450, 1374, 1275, 1238, 1158, 1095, 1076, 1019, 980, 915, 699,

588, 518 cm^–1.

¹H NMR (CDCl₃): δ = 1.12 (t, J = 7.7 Hz, 6 H, CH₃CH₂), 1.18 (d,

J = 6.3 Hz, 6 H, CH₃CH), 2.16 (q, J = 7.7 Hz, 4 H, CH₂), 3.84 (m,

2 H, CH), 6.22 (br s, 2 H, NH).

¹³C NMR (CDCl₃): δ = 9.94 (CH₃CH₂), 18.46 (CH₃CH), 29.83

(CH₂), 50.78 (CH), 174.47 (C=O).

MS (70 eV): m/z (%) = 201 (1.98) [M⁺+ 1], 200 (0.28) [M⁺], 127

(31) [C₇H₁₃NO⁺], 101 (100) [C₅H₁₁NO⁺], 100 (24) [C₅H₁₀NO⁺], 86

(15), 72 (19), 57 (31).

(1R,4R)-(+)-N-(1-Butyl-4-propionylaminooctyl)propionamide

[(R,R)-4p]

Hydrazide 3p (270 mg, 0.5 mmol) was allowed to react according

to GP 3. After reductive cleavage (3 h) and work up flash column

chromatography (SiO₂, Et₂O–MeOH, 20:1) yielded 4p (98 mg,

63%) as a colorless solid.

Mp 190 °C; de 91% (after chromatography, crude: 65%, GC); ee

98% (GC_CSP: XE-60-S-Valin-S-X-Phenylethylamide, H₂= 1.6 bar,

T = 190-iso); [α]_D²³+35.1 (c 1.03, CHCl₃).

HRMS (EI): m/z calcd for C₁₀H₂₀N₂O₂(M⁺– H), 201.1603; found,

201.1596.

IR (KBr): 3292 (NH), 3077, 2938, 2857, 1642 (C=O), 1548, 1465,

1376, 1287, 1241, 1146, 1094, 906, 730 cm^–1.

¹H NMR (CDCl₃): δ = 0.88 (t, J = 6.7 Hz, 6 H, CH₃CH₂CH₂), 1.15

(t, J = 7.7 Hz, 6 H, CH₃CH₂CO), 1.20–1.60 (m, 16 H, CH₂except

CH₃CH₂CO), 2.19 (q, J = 7.7 Hz, 4 H, CH₃CH₂CO), 3.87 (m, 2 H,

CH), 5.40 (d, J = 8.7 Hz, 2 H, NH).

(1R,4R)-(+)-N-(1-Methyl-4-propionylaminopentyl)propiona-

mide [(R,R)-4n]

Hydrazide 3n (290 mg, 0.55 mmol) was allowed to react according

to GP 3. After reductive cleavage (3 h) and work up flash column

chromatography (SiO₂, Et₂O–MeOH, 20:1) yielded 4n (43 mg,

34%) as a colorless solid.

Mp 183 °C; de 86% (GC); ee 98% (GC_CSP: XE-60-S-Valin-S-X-

Phenylethylamide, H₂= 1.0 bar, T = 140–3–190); [α]_D²⁴+32.4

(c 0.88, CHCl₃).

¹³C NMR (CDCl₃): δ = 10.13 (CH₃CH₂CO), 14.04 (CH₃CH₂CH₂),

22.63 (CH₃CH₂CH₂), 28.09, 29.94, 31.87 (CH₃CH₂CH₂CH₂,

CH₃CH₂CO), 34.95 (CHCH₂CH₂CH), 49.12 (CH), 173.49 (C=O).

IR (KBr): 3855, 3839, 3287 (NH, s), 3078, 2961, 2925, 2855, 2372,

2345, 1641 (C=O), 1548, 1499, 1463, 1423, 1378, 1343, 1307,

1288, 1256, 1208, 1159, 1143, 1117, 1081, 1064, 1041, 1016, 954,

911, 875, 805, 765, 738, 701, 581, 532 cm^–1.

MS (70 eV): m/z (%) = 313 (1.39) [M⁺+ 1], 255 (39) [M⁺– C₃H₅O],

239 (11), 238 (48), 183 (18), 182 (100), 170 (21) [M⁺– C₈H₁₆NO],

143 (12), 142 (52), 126 (86), 114 (19), 100 (12), 86 (71), 74 (20), 57

(45), 56 (15), 55 (14).

PAPER

Syntheses of C₂-Symmetric 1,n-Diamines

2555

HRMS (EI): m/z calcd for C₁₈H₃₆N₂O₂(M⁺), 312.2777; found,

312.2772.

Mp 138 °C; de 72% (¹H NMR); ee 98% [according to (R,R)-4p,r,

(S,S)-4t,u]; [α]_D²⁷–17.3 (c 1.01, CHCl₃).

IR (KBr): 3290 (NH), 3081, 2956, 2939, 2874, 2857, 2372, 2345,

1643(C=O), 1550, 1465, 1428, 1375, 1288, 1268, 1244, 1212, 1159,

1146, 1119, 1098, 1070, 1009, 945, 908, 732, 591, 467 cm^–1.

¹H NMR (CDCl₃): Isomers: major C₂-diastereomer: minor meso-

diastereomer; δ = 0.88 (t, J = 6.9 Hz, 6 H, CH₃CH₂CH₂), 1.15:1.16

(t, J = 7.7 Hz, 6 H, CH₃CH₂CO), 1.20 1.60 (m, 18 H, CH₂except

CH₃CH₂CO), 2.20 (q, J = 7.7 Hz, 4 H, CH₃CH₂CO), 3.86 (m, 2 H,

CH), 5.54 5.35 (d, J = 8.7 Hz, 2 H, NH).

¹³C NMR (CDCl₃): δ = 10.18 (CH₃CH₂CO), 14.05 (CH₃CH₂CH₂),

21.90 (CHCH₂CH₂CH₂CH), 22.66 (CH₃CH₂CH₂), 28.11, 29.90,

34.52, 35.60 (CH₃CH₂CH₂CH₂CHCH₂, CH₃CH₂CO), 48.46 (CH),

173.85 (C=O).

MS (70 eV): m/z (%) = 327 (2.02) [M⁺+ 1], 326 (5.57) [M⁺], 269

(24) [M⁺– C₃H₅O], 197 (14), 196 (100), 156 (14), 142 (18), 140

(68), 128 (13), 86 (34), 74 (23), 69 (5), 57 (16), 56 (12).

(1R,4R)-(+)-N-(1-Hexyl-4-propionylaminodecyl)-propiona-

mide [(R,R)-4q]

Hydrazide 3q (180 mg, 0.3 mmol) was allowed to react according

to GP 3. After reductive cleavage (3 h) and work up flash column

chromatography (SiO₂, Et₂O–MeOH, 20:1) yielded 4q (72 mg,

65%) as a colorless solid.

Mp 162–165 °C; de 98% (GC, after chromatography,crude: 67%);

ee 96% [¹H-Shift-NMR with (R)-1-Anthryl-2,2,2-trifluoroethanol];

[α]_D²⁴+25.5 (c 0.55, CHCl₃).

IR (KBr): 3292 (NH), 3078, 2928, 2855(m), 1642 (C=O), 1548,

1464, 1377, 1253, 1205, 1143, 945, 903, 724, 581 cm^–1.

¹H NMR (CDCl₃): δ = 0.87 (t, J = 6.9, 6 H, CH₃CH₂CH₂), 1.15 (t,

J = 7.7 Hz, 6 H CH₃CH₂CO), 1.20–1.70 (m, 24 H, CH₂except

CH₃CH₂CO), 2.19 (q, J = 7.7 Hz, 4 H, CH₃CH₂CO), 3.86 (m, 2 H,

CH), 5.17 (d, J = 9.1, 2 H, NH).

HRMS (EI): m/z calcd for C₁₉H₃₈N₂O₂(M⁺), 326.2933; found,

326.2931.

¹³C NMR (CDCl₃): δ = 10.12 (CH₃CH₂CO), 14.07 (CH₃CH₂CH₂),

22.60 (CH₃CH₂CH₂), 25.89, 29.25, 29.96 (CH₃CH₂CO,

CH₂CH₂CH₂CH),

(CHCH₂CH₂CH), 49.18 (CH), 173.47 (C=O).

31.78

(CH₂CH₂CH₂CH),

35.25

(1S,5S)-(–)-N-(1-Allyl-5-propionylaminooct-2-enyl)propiona-

mide [(S,S)-4t]

Hydrazide 3t (260 mg, 0.5 mmol) was allowed to react according to

GP 3. After reductive cleavage (3 h) and work up flash column

chromatography (SiO₂, Et₂O–MeOH, 20:1) yielded 4t (87 mg,

59%) as a colorless solid.

MS (70 eV): m/z (%) = 368 (9.98) [M⁺], 311 (41) [M⁺– C₃H₅O],

295 (11), 294 (24), 238 (34), 211 (12), 210 (90), 199 (10), 198 (21),

171 (18), 170 (62), 155 (10), 154 (91), 115 (16), 114 (100), 100

(11), 74 (48), 69 (21), 57 (55), 56 (22), 55 (26), 44 (32), 43 (31), 41

(17).

Mp 112 °C; de 77% (GC); ee 98% (GC_CSP: Lipodex E 25 m,

HRMS (EI): m/z calcd for C₂₂H₄₄N₂O₂(M⁺), 368.3403; found,

H₂= 1.5 bar, T = 100–2–190); [α]_D²⁷–37.5 (c 0.12, CHCl₃).

368.3402.

IR (KBr): 3283 (NH), 3078, 2978, 2942, 2854, 2372, 1645(C=O),

1549, 1463, 1375, 1279, 1255, 1156, 1126, 990, 917, 741, 722, 525

cm^–1.

¹H NMR (CDCl₃): δ = 1.14 (t, J = 7.4 Hz, 6 H, CH₃), 1.20–1.52 (m,

10 H, CH₂except CH₃CH₂), 2.19 (q, J = 7.4 Hz, 4 H, CH₃CH₂), 3.94

(m, 2 H, CH), 5.07 (m, 4 H, CH₂=CH), 5.75 (m, 4 H, CH=CH₂, NH).

¹³C NMR (CDCl₃): δ = 10.13 (CH₃), 21.95 (CH₂CH₂CH₂), 29.85,

33.70 (CH₂CH₂CH₂, CH₃CH₂), 39.95 (CH₂CH=CH₂), 47.78

(NCH), 117.61 (CH₂=CH), 134.55 (CH=CH₂), 173.98 (C=O).

MS (70 eV): m/z (%) = 295 (1.46) [M⁺+ 1], 294 (0.87) [M⁺], 181

(11), 180 (85) [M⁺– C₃H₆NO–C₃H₆], 125 (10), 124 (100), 82 (10),

70 (10), 57 (19), 56 (14).

(1R,5R)-(–)-N-(1-Methyl-5-propionylaminohexyl)propiona-

mide [(R,R)-4r]

Hydrazide 3r (140 mg, 0.3 mmol) was allowed to react according to

GP 3. After reductive cleavage (3.5 h) and work up flash column

chromatography (SiO₂, Et₂O–MeOH, 20:1) yielded 4r (63 mg,

87%) as a colorless solid.

Mp 150 °C; de 94% (GC); ee 9% (GC_CSP: XE-60-S-Valin-S-X-Phe-

nylethylamid, H₂= 1.0 bar, T = 120–1–190); [α]_D²⁸–15.5 (c 1.06,

CHCl₃).

IR (KBr): 3292 (NH), 3077, 2970, 2941, 2876, 2857, 1640 (C=O),

1548, 1463, 1374, 1297, 1244, 1158, 1121, 1068, 1016, 911, 742,

586 cm^–1.

HRMS (EI): m/z calcd for C₁₇H₃₀N₂O₂(M⁺), 294.2307; found,

¹H NMR (CDCl₃): δ = 1.13 (d, J = 6.4 Hz, 6 H, CH₃CH), 1.14 (t,

J = 7.7 Hz, 6 H, CH₃CH₂), 1.24–1.55 (m, 6 H, CH₂CH₂), 2.19 (q,

J = 7.7 Hz, 4 H, CH₃CH₂), 3.94 (m, 2 H, CH), 5.81 (d, J = 8.1 Hz,

2 H, NH).

294.2308.

(1S,5S)-(–)-N-(1-Benzyl-6-phenyl-5-propionylaminohexyl)pro-

pionamide [(S,S)-4u]

Hydrazide 3u (310 mg, 0.5 mmol) was allowed to react according

to GP 3. After reductive cleavage (3 h) and work up flash column

chromatography (SiO₂, Et₂O–MeOH, 20:1) yielded 4u (145 mg,

81%) as a colorless solid.

Mp 129 °C; de 86% (¹³C NMR); ee 98% [HPLC_CSP: (S,S)-Whelk-

O, eluent: cyclohexane i-PrOH 9:1,R_t: 15.45 min]; [α]_D²⁵–30.9

(c 1.02, CHCl₃).

¹³C NMR (CDCl₃): δ = 10.10 (CH₃CH₂), 21.60 (CH₃CH), 22.34

(CH₂CH₂CH₂), 29.87, 36.42 (CHCH₂CH₂, CH₃CH₂), 44.48 (CH),

173.69 (C=O).

MS (70 eV): m/z (%) = 243 (1.38) [M⁺+ 1], 242 (8.23) [M⁺], 185

(22) [M⁺– C₃H₅NO], 142 (12), 114 (43), 112 (15), 101 (26), 100

(30), 98 (20), 74 (21), 58 (11), 57 (23), 55 (13), 44 (100).

HRMS (EI): m/z calcd for C₁₃H₂₆N₂O₂(M⁺), 242.1994; found,

242.1995.

IR (KBr): 3303 (NH), 3064, 3028, 2976, 2943, 2856, 2375, 2164,

1644(C=O), 1545, 1497, 1456, 1374, 1240, 1196, 1125, 1075, 1032,

915, 750, 700, 509 cm^–1.

¹H NMR (CDCl₃): δ = 1.07 (t, J = 7.7 Hz, 6 H, CH₃), 1.23–1.45 (m,

6 H, CHCH₂CH₂), 2.12 (q, J = 7.7 Hz, 4 H, CH₃CH₂), 2.74 (m, 4 H,

CH₂Ph), 4.10 (m, 2 H, CH), 5.76 (d, J = 8.5 Hz, 2 H, NH), 7.12–

7.32 (m, 10 H, Ph).

¹³C NMR (CDCl₃): δ = 10.58 (CH₃), 22.57 (CHCH₂CH₂), 30.35,

33.86 (CH₃CH₂, CHCH₂CH₂), 42.29 (CH₂Ph), 50.06 (CH), 126.95

(C_para), 128.95, 129.93 (C_ortho, C_meta), 138.85 (C_ipso), 174.59 (C=O).

(1R,5R)-(–)-N-(1-Butyl-5-propionylaminononyl)propionamide

[(R,R)-4s]

Hydrazide 3s (170 mg, 0.3 mmol) was allowed to react according to

GP 3. After reductive cleavage (3.5 h) and work up flash column

chromatography (SiO₂, Et₂O–MeOH, 20:1) yielded 4s (64 mg,

65%) as a colorless solid.

2556

D. Enders, M. Meiers

PAPER

(1R,2R,2′S,2′′S)-(–)-N-[1-Ethyl-2-(2-methoxymethylpyrroli-

dine-1-ylamino)-butyl]-N-(2-methoxymethylpyrrolidine-1-

yl)acetamide [(R,R,S,S)-6]

MS (70 eV): m/z (%) = 395 (0.45) [M⁺+ 1], 303 (10) [M⁺– C₇H₇],

231 (11), 230 (66), 175 (14), 174 (100), 91 (42) [C₇H₇], 82 (14), 57

(33), 56 (23).

+

An organocerium reagent (20 mmol) prepared from CeCl₃and Et-

MgBr (1 M soln in THF) was treated according to GP 2 with hydra-

zone 2a (0.56 g, 2 mmol). After the addition was complete (TLC)

the reaction was trapped with AcCl (1.88 g, 24 mmol). Flash chro-

matography (SiO₂, Et₂O–petroleum ether, 2:1) yielded 6 (0.39 g,

51%) as a yellowish oil.

HRMS (EI): m/z calcd for C₁₈H₂₇N₂O₂(M⁺– C₇H₇), 303.2073;

found, 303.2072.

(4R,5R,2′S,2′′S)-(–)-1,3-Bis-(2-methoxymethyl)pyrrolidine-1-

yl-4,5-dimethyl-imidazolidin-2-one [(R,R,S,S)-5a]

An organocerium reagent (6.5 mmol mmol) prepared from CeCl₃

and MeLi (1.6 M soln in Et₂O) was treated according to GP 2 with

hydrazone 2a (0.14 g, 0.5 mmol). After the addition was complete

(TLC) the reaction was trapped with methyl chloroformate (2.36 g,

25 mmol). Flash chromatography (SiO₂, Et₂O–petroleum ether, 2:1)

yielded 5a (0.11 g, 65%) as a colorless oil.

De 85% (¹³C NMR); [α]_D²⁵–112.0 (c 0.52, CHCl₃).

IR (Et₂O): 3259 (m, NH), 2966, 2933, 2875, 2829, 2058, 1729,

1660(C=O), 1459, 1377, 1365, 1323, 1297, 1244, 1197, 1110, 1048,

1016, 972, 941, 922, 881, 857, 803, 681, 646, 609, 559, 504, 484,

464 cm^–1.

¹H NMR (CDCl₃): δ = 0.92 (t, J = 7.5 Hz, 3 H, CH₃CH₂), 1.06 (t,

J = 7.5 Hz, 3 H, CH₃CH₂), 1.26–2.42 (m, 13 H, NCH₂CH₂CH₂,

CH₃CH₂, NH), 2.17 (s, 3 H, CH₃C=O), 2.60 –3.80 (m, 11 H, NCH₂,

CHCH₂O, CHCH, CHCHHO (Hydrazine), 3.10 (s, 3 H, OCH₃),

3.22 (s, 3 H, OCH₃), 3.83 (dd, J = 3.5, 8.5 Hz, 1 H, CHHO (Hydra-

zine).

¹³C NMR (CDCl₃): δ = 8.82, 12.67 (CH₃CH₂), 21.44, 22.32, 22.84,

23.68 (NCH₂CH₂, CH₃CH₂), 22.58 (CH₃C=O), 27.11, 27.68

(NCH₂CH₂CH₂), 52.72, 56.53 (NCH₂), 58.60, 58.83, 60.11, 60.32,

66.04 (CHCH, CHCH₂OCH₃), 76.41, 76.69 (CH₂O), 174.14 (C=O).

De 90% (GC); [α]_D²⁵–159.2 (c 0.91, CHCl₃).

IR (film): 2969–2826, 2739, 2083, 1711(C=O), 1460, 1377, 1335,

1286, 1230, 1200, 1117, 1080, 1012, 973, 919, 767, 707, 647, 596,

531 cm^–1.

¹H NMR (CDCl₃): δ = 1.20 (d, 6 H, J = 6.7 Hz, CH₃CH), 1.60–2.10

(m, 8 H, NCH₂CH₂CH₂), 2.90 (m, 2 H, NCHH), 3.02 (m, 2 H,

NCHH), 3.15–3.40 (m, 6 H, CHCH, CHCHHO), 3.34 (s, 6 H,

OCH₃), 3.80 (m, 2 H, CHHO).

¹³C NMR (CDCl₃): δ = 17.04 (CH₃CH), 22.81 (NCH₂CH₂), 26.88

(NCH₂CH₂CH₂), 47.72 (NCH₂), 57.80, 58.92, 61.24 (CHCH,

CHCH₂OCH₃), 74.82 (CH₂O), 160.19 (C=O).

MS (70 eV): m/z (%) = 340 (38) [M⁺], 308 (15), 296 (18), 295 (100)

[M⁺– C₂H₅O], 263 (35), 227 (20), 226 (34), 206 (11), 195 (12), 183

(19), 182 (90), 180 (23), 163 (13), 157 (99), 155 (11), 142 (11), 139

(15), 125 (68), 115 (10), 114 (64), 113 (48), 82 (27), 71 (14), 70

(58), 69 (20), 68 (19), 67 (15), 57 (21), 56 (15), 55 (43), 45 (26), 44

(14), 43 (29).

MS (70 eV): m/z (%) = 384 (6) [M⁺], 172 (10), 171 (100)

[C₉H₁₉N₂O⁺], 114 (14) [C₆H₁₂NO⁺], 70 (23).

Anal. calcd for C₂₀H₄₀N₄O₃(384.6): C, 62.47; H, 10.48; N, 14.57.

Found: C, 62.09; H, 10.50; N, 14.57.

(5R,6R,2′S,2′′S)-(–)-N,N-Di[2-(methoxymethyl)pyrrolidine-1-

yl]-decane-5,6-diamine [(R,R,S,S)-7a]

An organocerium reagent (8 mmol) prepared from CeCl₃and BuLi

(1.6 M soln in hexane) was treated according to GP 2 with hydra-

zone 2a (0.28 g, 1 mmol). After the addition was complete (TLC)

the reaction was terminated by the addition of sat. NaHCO₃. Flash

chromatography (deactivated SiO₂, Et₂O–petroleum ether, 4:1)

yielded 7a (crude: 0.44 g, quantitative; after chromatography: 0.11

g, 28%) with great losses in chemical yield as a brownish oil.

Anal. calcd for C₁₇H₃₂N₄O₃(340.5): C, 59.97; H, 9.47; N, 16.46.

Found: C, 59.67; H, 9.08; N, 16.79.

(4R,5R,2′S,2′′S)-(–)-1,3-Bis-(2-methoxymethyl)pyrrolidine-1-

yl-4,5-dibutyl-imidazolidin-2-one [(R,R,S,S)-5b]

An organocerium reagent (8 mmol) prepared from CeCl₃and BuLi

(1.6 M soln in hexane) was treated according to GP 2 with hydra-

zone 2a (0.28 g, 1 mmol). After the addition was complete (TLC)

the reaction was trapped with methyl chloroformate (2.27 g, 24

mmol). Flash chromatography (SiO₂, Et₂O–petroleum ether, 1:1)

yielded 5b (0.18 g, 42%) as a colorless oil.

25

De 89% (¹³C NMR, after chromatography, crude: 82%); [α]_D

–100.1 (c 0.77, CHCl₃).

IR (CHCl₃): 2956, 2929, 2873, 2827, 1680, 1460, 1379, 1344, 1285,

1216, 1197, 1117, 969, 920, 756, 666, 529 cm^–1.

De 94% (GC); [α]_D³⁰–122.5 (c 0.72, CHCl₃).

¹H NMR (C₆D₆): δ = 0.98 (t, J = 7 Hz, 6 H, CH₃CH₂), 1.36–1.92 (m,

20 H, NCH₂CH₂CH₂, CH₃CH₂CH₂CH₂), 2.10, 2.70 (q, J = 9 Hz, m,

6 H, NCH₂, NH), 3.01, 3.31 (m, m, 4 H, CHCH, CHCH₂O), 3.22 (s,

6 H, OCH₃), 3.40 (dd, J = 9.0, 7.0 Hz, 2 H, CHHO), 3.77 (dd,

J = 9.0, 4.0 Hz, 2 H, CHHO).

¹³C NMR (C₆D₆): δ = 14.47 (CH₃CH₂), 21.44, 23.71 (CH₃CH₂,

NCH₂CH₂), 27.35, 29.16 (CH₃CH₂CH₂, NCH₂CH₂CH₂), 30.50

(CH₂CHCH), 57.23 (NCH₂), 58.82, 59.91, 66.10 (CHCH,

CHCH₂OCH₃), 76.35 (CH₂O).

MS (70 eV): m/z (%) = 398 (7.72) [M⁺], 200 (20), 199 (100)

[C₁₁H₂₃N₂O⁺], 154 (18), 153 (54), 114 (16) [C₆H₁₂NO⁺], 70 (33), 45

(10).

HRMS (EI): m/z calcd for C₂₂H₄₆N₄O₂(M⁺), 398.3621; found,

398.3620.

IR (CHCl₃): 2958, 2930, 2873, 2828, 2738, 2458, 1700(C=O),

1457, 1385, 1345, 1285, 1254, 1237, 1216, 1199, 1113, 973, 951,

918, 756, 666, 603, 516, 504 cm^–1.

¹H NMR (CDCl₃): δ = 0.93 (t, J = 6.5 Hz, 6 H, CH₃CH₂), 1.20–2.20

(m, 20 H, NCH₂CH₂CH₂, aliph. CH₂), 3.00–3.40, 3.90 (m, m, 12 H,

NCH₂, CHCH, CHCH₂O), 3.33 (s, 6 H, OCH₃).

¹³C NMR (CDCl₃): δ = 14.12 (CH₃CH₂), 22.76, 23.11 (NCH₂CH₂,

CH₃CH₂), 26.84, 26.87 (NCH₂CH₂CH₂, CHCH₂CH₂), 32.39

(CHCHCH₂), 48.45 (NCH₂), 58.90, 58.92, 61.28 (CHCH,

CHCH₂OCH₃), 74.78 (CH₂O), 159.84 (C=O).

MS (70 eV): m/z (%) = 425 (8.56) [M⁺+ 1], 424 (32) [M⁺], 380

(18), 379 (64) [M⁺– C₂H₅O], 347 (29), 279 (10), 267 (10), 266 (51),

264 (18), 200 (14), 199 (100) [C₁₁H₂₃N₂O⁺], 197 (25), 168 (14), 167

(75), 153 (32), 142 (16), 114 (77) [C₆H₁₂NO⁺], 111 (13), 84 (62), 83

(36), 82 (23), 71 (14), 70 (74), 69 (26), 57 (10), 55 (20), 45 (18), 43

(21), 41 (33).

(1R,2R)-(+)-N-(1-Butyl-2-t-butyloxycarbonylaminohexyl)-t-bu-

tylcarbamat [(R,R)-8a]

The crude hydrazine 7a (120 mg, 0.3 mmol) was allowed to react

according to GP 4. After reductive cleavage (5 d) and work up (path

A), the soln containing the crude diamine was treated with Et₃N (1

mL) and di-tert-butyl dicarbonate (0.52 g, 2.4 mmol) at 0 °C and

Anal. calcd for C₂₃H₄₄N₄O₃(424.6): C, 65.06; H, 10.44; N, 13.19.

Found: C, 64.64; H, 10.24; N, 12.65.

PAPER

Syntheses of C₂-Symmetric 1,n-Diamines

2557

stirred at r.t. until the reaction was complete (2 d). The solvent was

removed in vacuo and the residue solved in Et₂O (15 mL). The or-

ganic layer was washed with a sat. soln of NH₄Cl (3 7 mL), brine

(3 7 mL) and dried with MgSO₄. Evaporation of the solvent under

reduced pressure and purification of the residue by flash column

chromatography (SiO₂, Et₂O–petroleum ether, 1:4) yielded 8a (65

mg, 58%) as a colorless solid.

(4R,5R)-(–)-Di(t-butyl)-4,5-dibenzyl-2-oxo-1,3-imidazolidin-di-

carboxylate [(R,R)-8c]

An organocerium reagent (8 mmol) prepared from CeCl₃and

BnMgBr (1 M soln in THF) was treated according to GP 2 with hy-

drazone 2a (0.18 g, 0.64 mmol). After the addition was complete

(TLC) the reaction was terminated by the addition of a sat.

NaHCO₃. Work up yielded the crude hydrazine 7c (0.503 g, 60%

purity) as a brownish oil which was introduced into the reductive

cleavage without further purification.

¹H NMR (C₆D₆): δ = 1.22–1.86 (m, 8 H, NCH₂CH₂CH₂), 2.21–2.88

(m, 10 H, NCH₂, CH₂Ph, NH), 3.04–3.60 (m, 8 H, CHCH,

CHCH₂O), 3.14 (s, 6 H, OCH₃), 6.97–7.41 (m, 10 H, Ph).

¹³C NMR (C₆D₆): Only the peaks of the main product are given.

δ = 21.57 (NCH₂CH₂), 27.46 (NCH₂CH₂CH₂), 36.57 (CH₂Ph),

57.56 (NCH₂), 58.73, 61.13, 66.36 (CHCH, CHCH₂OCH₃), 75.94

(CH₂O), 126.13–129.67 (C_ortho, C_meta, C_para), 141.25 (C_ipso).

Mp 120 ° C; de 85% (GC); ee 98% (GC_CSP: Chirasil-Dex CB,

H₂= 1.2 bar, T = 160–35iso–2–190); [α]_D²⁹+43.2 (c 1.03, CHCl₃).

IR (KBr): 3346 (m, NH), 2960, 2932, 2860, 1687(C=O), 1540,

1456, 1390, 1367, 1303, 1274, 1251, 1182, 1118, 1099, 1071, 1041,

1009, 871, 780, 756, 647 cm^–1.

¹H NMR (CDCl₃): Due to the limited rotation of the NN single bond

only broad signals could be observed. δ = 0.89 (br t, J = 7.0 Hz, 6

H, CH₃CH₂), 1.20–1.60 (m, 12 H, CH₂), 1.44 [s, 18 H, C(CH₃)₃],

3.54 (m, 2 H, CH), 4.56 (m, 2 H, NH).

The crude hydrazine 7c (60% purity, 125 mg, 0.15 mmol) was al-

lowed to react according to GP 4. After reductive cleavage (6d) and

work up (path B) the crude diamine was treated with di-tert-butyl

dicarbonate (0.33 g, 1.5 mmol), Et₃N (0.3 g, 3 mmol, 0.42 mL), cat-

alytic amounts DMAP in CH₃CN (2 mL) at 0 °C and stirred at r.t.

for 2 d. The solvent was removed in vacuo and the residue solved in

Et₂O (10 mL). The organic layer was washed with a sat. NH₄Cl

(3 4 mL), brine (3 4 mL) and dried with MgSO₄. Evaporation of

the solvent under reduced pressure and purification of the residue

by flash column chromatography (SiO₂, Et₂O–petroleum ether, 1:2)

yielded 8c (52 mg, 74%) as a colorless solid.

¹³C NMR (CDCl₃): Due to the limited rotation of the NN single

bond only broad signals could be observed. δ = 14.01 (CH₃CH₂),

22.60 (CH₃CH₂), 28.02 (CH₂CH₂CH), 28.44 [C(CH₃)₃], 32.75

(CH₂CH), 54.38 (CH), 79.05 (Cq), 156.52 (C=O).

MS (70 eV): m/z (%) = 372 (0.98) [M⁺], 271 (18), 200 (14), 186

+

(17) [C₁₀H₂₀NO₂], 185 (13), 144 (15), 142 (10), 130 (70), 129 (11),

+

86 (71), 69 (13), 57 (100) [t-C₄H₉], 55 (13).

HRMS (EI): m/z calcd for C₂₀H₄₀N₂O₄(M⁺), 372.2988; found,

372.2986.

Mp 156–158 °C; de 98% (¹H NMR); ee 98% (according to 8a,b;

(1R,2R)-(–)-N-(1-Phenyl-2-benzyloxycarbonylamino-2-phenyl-

ethyl)benzyl-carbamate [(R,R)-8b]

4i,m); [α]_D²⁸–6.4 (c 0.5, CHCl₃).

An organocerium reagent (8 mmol) prepared from CeCl₃and

PhMgBr (1 M soln in THF) was treated according to GP 2 with hy-

drazone 2a (0.24 g, 0.84 mmol). After the addition was complete

(TLC) the reaction was terminated by the addition of sat. NaHCO₃.

Work up yielded the crude hydrazine 7b (0.405 g, 99%) as a yellow

oil which was introduced into the reductive cleavage without further

purification.

IR (KBr): 3061, 3026, 2974, 2928, 2855, 1797, 1713(C=O), 1604,

1496, 1455, 1387, 1369, 1320, 1285, 1252, 1222, 1160, 1079, 1041,

1004, 985, 921, 843, 777, 750, 737, 702, 635, 591, 500 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 1.52 [s, 18 H, C(CH₃)₃], 2.67 (dd,

J = 9.0, 13.5 Hz, 2 H, CHHPh), 2.93 (dd, J = 3.5, 13.5 Hz, 2 H,

CHHPh), 4.03 (dd, J = 3.5, 8.5 Hz, 2 H, CH), 6.55 (m, 4 H, Ph), 7.17

(m, 6 H, Ph).

De 91% (¹³C NMR).

¹³C NMR (125 MHz, CDCl₃): δ = 28.09 [C(CH₃)₃], 38.81 (CH₂Ph),

¹H NMR (C₆D₆): δ = 1.35–1.83 (m, 8 H, NCH₂CH₂CH₂), 2.17 (q,

J = 8 Hz, 2 H, NCHH), 2.77 (m, 2 H, NCHH), 3.06–3.32 (m, 4 H,

NCHCHHO), 3.09 (s, 6 H, OCH₃), 3.53 (dd, J = 4.0, 5.0 Hz, 2 H,

CHHO), 4.06 (br, 2 H, NH), 4.23 (s, 2 H, CHCH), 6.80 – 7.32, 7.46

(m, 10 H, Ph).

56.27 (CH), 83.28 (C_q), 126.89 (C_para), 128.73, 129.15 (C_ortho

C_meta), 135.35 (C_ipso), 148.09 (NC=ON), 150.17 (NC=OO).

,

MS (70 eV): m/z (%) = 354 (3.38) [M⁺– 2 C₄H₈], 219 (44)

+

[C₁₃H₁₇NO₂], 175 (32), 91 (49) [C₇H₇], 57 (100) [t-C₄H₉], 56

(25), 55 (15).

¹³C NMR (C₆D₆): δ = 21.97 (NCH₂CH₂), 27.80 (NCH₂CH₂CH₂),

57.08 (NCH₂), 59.27, 66.47, 69.72 (CHCH, CHCH₂OCH₃), 76.52

(CH₂O), 127.46 (C_para), 128.40, 129.36 (C_ortho, C_meta), 143.51 (C_ipso).

HRMS (EI): m/z calcd for: C₁₉H₁₈N₂O₅(M⁺– C₈H₁₆), 354.1216;

found, 354.1215.

The crude hydrazine 7b (123 mg, 0.3 mmol) was allowed to react

according to GP 4. After reductive cleavage (5.5 d) and work up

(path B) the crude diamine was treated with benzyloxycarbonyl

chloride (0.31 g, 1.8 mmol) and K₂CO₃(90 mg) in CH₂Cl₂(10 mL)

at 0 °C and stirred for 2 h at r.t. The reaction mixture was hydro-

lyzed with a sat. NaHCO₃(30 mL) and extracted with CH₂Cl₂

(3 50 mL), the combined extracts were dried with MgSO₄and af-

ter removal of the solvent using a rotary evaporator and recrystalli-

zation from EtOH the protected diamine 8b was obtained in

colorless needles (34 mg, 22%).

Mp 187 °C (lit.³⁵188 °C); de 96% (¹H NMR); ee 96% (¹H Shift

NMR with (R)-1-Anthryl-2,2,2-trifluoroethanol); [α]_D²⁸–9.6

(c 0.53, CHCl₃, after 6 h equilibration); {Lit.³⁵[α]_D²⁸–10.2 (c 1.03,

CHCl₃)}.

(1S,4S)-(–)-N-(1-Benzyl-4-benzyloxycarbonylamino-5-phenyl-

pentyl)-t-butyl-carbamate [(S,S)-9]

An organocerium reagent (8 mmol) prepared from CeCl₃and

BnMgBr (1 M soln in THF) was treated according to GP 2 with hy-

drazone 2b (0.31 g, 1 mmol). After the addition was complete

(TLC) the reaction was terminated by the addition of a sat.

NaHCO₃. Work up yielded the crude hydrazine (0.680 g, 70% puri-

ty) as a brownish oil which was introduced into the reductive cleav-

age without further purification.

De 64% (¹³C NMR).

¹H NMR (C₆D₆): δ = 1.38–1.90 (m, 12 H, NCH₂CH₂CH₂,

CHCH₂CH₂CH), 2.42–2.70 (m, 6 H, NCHH, CH₂Ph), 2.90–3.32

(m, 8 H, NCHH, CHCH₂Ph, CHCHHO, NH), 3.16 (s, 6 H, OCH₃),

3.64 (dd, J = 4, 8.5 Hz, 2 H, CHHO), 7.08 (m, 10 H, Ph).

¹³C NMR (C₆D₆): δ = 21.37 (NCH₂CH₂), 27.03, 28.17

(NCH₂CH₂CH₂, CHCH₂CH₂CH), 40.91 (CH₂Ph), 56.91 (NCH₂),

58.80, 60.53, 65.85 (CHCH₂Ph, CHCH₂OCH₃), 75.94 (CH₂O),

126.03 (C_para), 128.55–129.89 (C_ortho, C_meta), 141.91 (C_ipso).

The spectroscopic data of 8b corresponded with those reported in

ref.³⁵

2558

D. Enders, M. Meiers

PAPER

(4) For reviews see also: (a) Jacobsen, E. N. In Catalytic

The crude hydrazine (70% purity, 204 mg, 0.3 mmol) was allowed

to react according to GP 4. After reductive cleavage (5 d) and work

up (path B) the crude diamine was treated with Et₃N (1.2 g, 12

mmol, 1.7 mL) and di-tert-butyl dicarbonate (1.31 g, 6 mmol) in

MeOH (10 mL) at 0 °C and stirred at r.t. until the reaction was com-

plete (2 d). The solvent was removed in vacuo and the residue was

dissolved in Et₂O (15 mL). The organic layer was washed with a sat.

NH₄Cl (3 7 mL), brine (3 7 mL) and dried with MgSO₄. Evap-

oration of the solvent under reduced pressure and purification of the

residue by flash column chromatography (SiO₂, Et₂O–petroleum

ether, 1:2) yielded 9 (33 mg, 23%) as a colorless solid.

Asymmetric Synthesis; Ojima, I., Ed.; VCH: New York,

1993, 159. (b) Katsuki, T. Coord. Chem. Rev. 1995, 140,

189 For recent examples see: . (c) Fujii, A.; Hashiguchi, S.;

Uematsu, N.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1996,

118, 2521. (d) Nishibayashi, Y.; Arikawa, Y.; Ohe, K.;

Uemura, S. J. Org. Chem. 1996, 61, 1172. (e) Ohkuma, T.;

Ooka, H.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am.

Chem. Soc. 1995, 117, 2675. (f) Alexakis, A.; Kanger, T.;

Mangeney, P.; Rose-Munch, R.; Perrotey, A.; Rose, E.

Tetrahedron: Asymmetry 1995, 6, 2135. (g) Gamez, P.;

Fache, F.; Lemaire, M. Terahedron: Asymmetry 1995, 6,

705. (h) Murata, K.; Ikariya, T. J. Org. Chem. 1999, 64,

2186. (i) Pénicaud, V.; Maillet, C.; Janvier, P.; Pipelier, M.;

Bujoli, B. Eur. J. Org. Chem. 1999, 1745. (j) Li, X.;

Schenkel, L. B.; Kozlowski, M. C. Org. Lett. 2000, 2, 875.

(k) Wiberg, K. B.; Bailey, W. F. Tetrahedron Lett. 2000, 41,

9365. (l) Barett, S.; O’Brien, P.; Steffens, H. C.; Towers, T.

D.; Voith, M. Tetrahedron 2000, 56, 9633.

Mp 145 °C; de 64% (Determined by ¹H NMR analysis of the corre-

sponding Mosher amide); ee 98% (Determined by ¹H NMR analy-

sis of the corresponding Mosher amide); [α]_D²⁷–5.2 (c 0.82,

CHCl₃).

IR (KBr): 3364 (NH), 3063, 3027, 2983, 2948, 2861, 2172,

1683(C=O), 1524, 1453, 1391, 1367, 1304, 1250, 1170, 1079, 1033,

997, 909, 878, 773, 753, 700, 632, 539, 493 cm^–1.

¹H NMR (CDCl₃): Due to the limited rotation of the NN single bond

only broad signals could be observed. δ = 1.33–1.60 (m, 4 H,

CHCH₂CH₂), 1.39 [s, 18 H, C(CH₃)₃], 2.72 (d, J = 6 Hz, 4 H,

CH₂Ph), 3.77 (br s, 2 H, CH), 4.25 (m, 2 H, NH) 7.10–7.30 (m, 10

H, Ph).

¹³C NMR (CDCl₃): Due to the limited rotation of the NN single

bond only broad signals could be observed. δ = 28.38 [C(CH₃)₃],

30.91 (CHCH₂CH₂), 41.53 (CH₂Ph), 51.43 (CH), 79.09 [C(CH₃)₃],

126.33 (C_para), 128.34, 129.48 (C_ortho, C_meta), 138.01 (C_ipso), 155.46

(C=O).

(5) For examples of 12-diamines as building blocks in ligand

construction see: (a) Gao, J.-X.; Ikariya, T.; Noyori, R.

Organometallics 1996, 15, 1087. (b) Trost, B. M.; Shi, Z. J.

Am. Chem. Soc. 1996, 118, 3037. (c) Trost, B. M.; Bunt, R.

C. Angew. Chem., Int. Ed. Engl. 1996, 35, 99; Angew. Chem.

1996, 108, 70.

(6) For examples see: (a) Kawashima, M.; Hirata, R. Bull.

Chem. Soc. Jpn. 1993, 66, 2002. (b) Brunner, H.;

Schiessling, H. Angew. Chem., Int. Ed. Engl. 1994, 33, 125;

Angew. Chem. 1994, 106, 130. (c) Alexakis, A.; Mangeney,

P.; Marek, I.; Rose-Munch, F.; Rose, R.; Semra, A.; Robert,

F. J. Am. Chem. Soc. 1992, 114, 8288. (d) Alexakis, A.;

Mangeney, P.; Lensen, N.; Tranchier, J.-P.; Gosmini, R.;

Raussou, S. Pure Appl. Chem. 1996, 68, 531.

MS (70 eV): m/z (%) = 469 (0.23) [M⁺+ 1], 295 (9) [M⁺– t-C₄H₉O-

t-C₅H₉O₂], 261 (10), 260 (50), 205 (15), 204 (100), 161 (12), 160

(96), 117 (10), 91 (19), 57 (73).

(7) For examples see: (a) Kido, J.; Okamoto, Y.; Brittain, H. G.

J. Org. Chem. 1991, 56, 1412. (b) Alexakis, A.; Frutos, J.

C.; Mutti, S.; Mangeney, P. J. Org. Chem. 1994, 59, 3326.

(c) Devitt, P. G.; Mitchell, M. C.; Weetman, J. M.; Taylor,

R. J.; Kee, T. P. Tetrahedron: Asymmetry 1995, 6, 2039.

(d) Staubach, B.; Buddrus, J. Angew. Chem., Int. Ed. Engl.

1996, 35, 1344; Angew. Chem. 1996, 108, 1443.

(8) (a) Lippard, S. J. Pure Appl. Chem. 1987, 59, 731.

(b) Pasini, A.; Zunino, F. Angew. Chem., Int. Ed. Engl. 1987,

26, 615; Angew. Chem. 1987, 99, 632. (c) Reedijk, J. Pure

Appl. Chem. 1987, 59, 181. (d) Hanessian, S.; Wang, J. Can.

J. Chem. 1993, 71, 886.

HRMS (EI): m/z calcd for C₁₉H₂₃N₂O (M⁺– C₉H₁₇O₃), 295.1810;

found, 295.1812.

Acknowledgements

This work was supported by the Deutsche Forschungsgemeinschaft

(Leibniz Prize) and by the Fonds der Chemischen Industrie. We

thank the companies Degussa AG, BASF AG, Bayer AG, the for-

mer Hoechst AG, and Wacker Chemie for the donation of chemi-

cals. The help of Dr. Bert Nolte during the preparation of the

manuscript is appreciated.

(9) (a) Erickson, J. W. In Perspectives in Drug Discovery and

Design; 1993, Kluwer: Norwell, MA, 1, 109. (b) De Clerq,

E. J. J. Med. Chem. 1995, 38, 2491. (c) Hultén, J.; Bonham,

N. M.; Nillroth, U.; Hansson, T.; Zuccarello, G.; Bouzide,

A.; Åqvist, J.; Classon, B.; Danielson, U. H.; Karlén, A.;

Kvarnström, I.; Samuelsson, B.; Hallberg, A. J. Med. Chem.

1997, 40, 885.

(10) For recent examples see: (a) Tanaka, K.; Sawanishi, H.

Tetrahedron: Asymmetry 2000, 11, 3837. (b) Spielvogel,

D.; Kammerer, J.; Keller, M.; Prinzbach, H. Tetrahedron

Lett. 2000, 41, 7863. (c) Benedetti, F.; Norbedo, S. Chem.

Commun. 2001, 203.

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Syntheses of C₂-Symmetric 1,n-Diamines

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Article Doi

Diastereo- and enantioselective syntheses of C2-symmetric 1,n-diamines by nucleophilic addition to dialdehyde-SAMP-hydrazones

DOI: 10.1055/s-2002-35628

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Article abstract of DOI:10.1055/s-2002-35628

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