Synthesis of the spermidine alkaloids (-)-(2R,3R)- and (-)-(2R,3S)-3-hydroxycelacinnine: Macrocyclization with oxirane-ring opening and inversion via cyclic sulfamidates

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Helvetica Chimica Acta Vol. 86 (2003)

Synthesis of the Spermidine Alkaloids (À)-(2R,3R)- and (À)-(2R,3S)-3-

Hydroxycelacinnine: Macrocyclization with Oxirane-Ring Opening and

Inversion via Cyclic Sulfamidates

by Nikolai A. Khanjin and Manfred Hesse*

Organisch-chemisches Institut der Universit‰t Z¸rich, Winterthurerstrasse 190, CH-8057 Z¸rich

Dedicated to Dr. Annalaura Lorenzi-Riacci on the occasion of her 70th birthday

The two epimers (À)-1a and (À)-1b of the macrocyclic lactam alkaloid 3-hydroxycelacinnine with the

(2R,3R) and (2R,3S) absolute configurations, respectively, were synthesized by an alternative route involving

macrocyclization with the regio- and stereoselective oxirane-ring opening by the terminal amino group

(Schemes 2 and 6). Properly N-protected chiral trans-oxirane precursors provided (2R,3R)-macrocycles after a

one-pot deprotection-macrocyclization step under moderate dilution (0.005 0.01m). The best yields (65 85%)

were achieved with trifluoroacetyl protection. Macrocyclization of the corresponding cis-oxiranes was

unsuccessful for steric reasons. Inversion at OHÀC(3) via nucleophilic displacement of the cyclic sulfamidate

derivative with NaNO₂led to (2R,3S)-macrocycles. The synthesized (À)-(2R,3S)-3-hydroxycelacinnine ((À)-1b)

was identical to the natural alkaloid.

Introduction. Macrocyclic lactams derived from polyamines are of particular

interest as synthetic targets for organic chemists because of their structural complexity

¬

and broad biological activity [1][2]. Seguineau et al. have isolated several novel

hydroxylated spermidine alkaloids (Fig. 1) from the leaves of a New Caledonian

Celastraceae, Pleurostylia opposita (Wa l l . ) Merrill-Metcalf [3][4]. The presence

of an OH group at the a-position to the lactam carbonyl group represents a new feature

in such alkaloids. An interesting biosynthetic pathway of their formation involving a

trans-epoxy precursor has been suggested [3][4] (Scheme 1). Therefore, we are

interested in the structure verification and biosynthesis of these alkaloids.

Scheme 1. ProposedBiosynthetic Macrocyclization

O

HO

Ph

N

H

N

R

N

R

O

Ph

N

H

H₂N

In the previous paper, we described the eight-step synthesis of (Æ)-(2RS,3RS)-3-

hydroxycelacinnine ((Æ)-1a) in 10% overall yield starting from potassium trans-

phenylglycidate ((Æ)-5) [5]. The key transformations involved stereo- and regiose-

lective oxirane-ring opening with Mg(N₃)₂and macrocyclic coupling of ditosylated

Helvetica Chimica Acta Vol. 86 (2003)

2029

Fig. 1. Proposedstructures of the novel hydroxylatedalkaloids 3-hydroxycelacinnine ((Æ)-1a), 7-hydroxypleuro-

styline (2a), and7-hydroxypleurocorine (3a) from Pleurostylia opposita [3][4] andtheir correctedstructures

(À)-1b, 2b, and 3b (this work)

diamine precursor with 1,4-dibromobutane promoted by Cs₂CO₃in DMF. NMR Data

of the synthesized (Æ)-1a suggested that the natural 3-hydroxycelacinnine is the cis-

epimer 1b with the (2R*,3S*) relative configuration (Fig. 1). The same conclusion

holds for 7-hydroxypleurostyline (2) and 7-hydroxypleurocorine (3) as well since all

three natural alkaloids had almost identical ¹H- and ¹³C-NMR data for the b-amino-a-

hydroxy-lactam moiety (Fig. 1) [3][4]. In addition, despite the reported zero [a]_Dvalue

and the absence of CD effect for the natural 3-hydroxycelacinnine [3], we have

proposed (2R,3S) absolute configuration (as in (À)-1b) for the natural alkaloid. This

assumption was based on the observation that all macrocyclic spermine and spermidine

alkaloids with the known absolute configuration have the same relative configuration

of the three substituents at C(2) (N-atom, phenyl or alkyl group, and substituted or

unsubstituted acetamide moiety) [6]. The assumption should also be extended to

alkaloids 2 and 3. Thus, the newly assumed absolute configuration at the b-amino-a-

hydroxy-lactam moiety in all three alkaloids requires further confirmation.

In this paper, we report the preparation of (À)-(2R,3R)-3-hydroxycelacinnine ((À)-

1a) and (À)-(2R,3S)-3-hydroxycelacinnine ((À)-1b) via the more efficient −biomimetic×

route (Scheme 1) and confirm the assumed (2R,3S) absolute configuration for the

natural alkaloid (À)-1b. Without any precedent literature data for the intramolecular

macrocyclic oxirane-ring opening with amines, we investigated such a novel macro-

cyclization method with trans- and cis-oxirane precursors. The macrocyclization with

trans-oxiranes went smoothly under moderate dilution (0.01m) to give macrocycles with

the unnatural (2R,3R) configuration with excellent yields (up to 85%). However,

reaction of the corresponding cis-oxiranes led only to numerous by-products for steric

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Helvetica Chimica Acta Vol. 86 (2003)

reasons. This suggests an alternative biosynthetic formation of (À)-1b. Macrocycles

with the natural (2R,3S) configuration were finally obtained from epimeric (2R,3R)-

precursors by mean of inversion at C(3) involving nucleophilic displacement of a cyclic

sulfamidate derivative. To the best of our knowledge, this is the first application of

cyclic sulfamidates for epimerization of vicinal amino alcohols (for an example of

epimerization of the taxol side chain via dihydrooxazole, see [7][8]). It might be an

efficient method for epimerization of b-amino-a-hydroxy acids and their derivatives in

general.

Synthesis of 1a. The optimized synthetic route to (À)-1a is depicted in Scheme 2.

Saponification of the commercially available 3-phenylglycidate 4 (trans/cis 9 :1) with

KOH in EtOH led to precipitation of pure potassium trans-3-phenylglycidate

( potassium trans-3-phenyloxirane-2-carboxylate; (Æ)-5) [5][9]. It was resolved via

diastereoisomeric salts with (À)-(S)-phenylethylamine to give crystalline (À)-6 and

then with ()-(R)-phenylethylamine to give ()-6 according to a described procedure

[9][10]. The optically pure (2R,3S)- and (2S,3R)-potassium phenylglycidates ((À)- and

()-5, resp.) were regenerated from (À)- and ()-6, respectively, by quantitative (98%)

precipitation from EtOH with ethanolic KOH and Et₂O. It is interesting to note that

the use of NaOH led to gel formation instead of precipitation of the corresponding

nonracemic sodium phenylglycidate. Glycidate (À)-5 (2R,3S) was required for the

generation of (2R,3R)-macrocycles including (À)-1a after intramolecular opening with

the terminal amine.

Initially, we prepared several N-protected phenylglycidic spermidines 10a f,h for

the desired macrocyclization step starting from racemic (Æ)-5 for optimization. The

latter was converted to amide (Æ)-8 [5] via acid chloride (Æ)-7 [11] followed by Cs₂CO₃-

promoted N,C-coupling with a slight excess of N,N'-protected putrescines 9a,c f (1.2

1.5equiv.) in a minimal amount of DMF (2 ml for 1 g of 8). The yields are summarized

in Table 1. Initial attempts to carry out the N,C-coupling promoted by anhydrous

K₂CO₃in DMSO led to a slow reaction and undesired hydrolysis of the bromide

functionality of 8. However, in the presence of Cs₂CO₃in DMF, the reaction proceeded

smoothly with all N-sulfonylated putrescines 9a,c f. Due to the lower acidity of

CF₃CO-protected amines, bis-trifluoroacetylated putrescine 9b reacted much slower

under the same conditions with significant formation of N-allyl-phenylglycidamide

from the competitive base-promoted HBr elimination. N-Protected putrescines 9a f

were easily prepared according to general or published procedures from putrescine in

one to three steps as described in the Exper. Part. Alternatively, acid chloride (Æ)-7 was

coupled with ditosylated spermidine 9h [12] in the presence of Et₃N in CH₂Cl₂to give

(phenylglycidyl)spermidine 10h in 92% yield.

The results of deprotection and subsequent macrocyclization of 10a h are

summarized in Table 1. From several protective groups tested for the terminal primary

amine (Boc ((tert-butoxy)carbonyl), Ts ((4-methylphenyl)sulfonyl), Troc ((2,2,2-

trichloroethoxy)carbonyl), and CF₃CO) in acyclic precursors 10a e,h, the best yields

of the desired macrocyclic products (up to 85%, Table 1) were achieved with the

CF₃CO group. Deprotection of other groups were accompanied either by complete

(Ts, Boc) or by partial oxirane cleavage (Troc). In particular, electrochemical

detosylation of 10h also led to non-regioselective oxirane reduction with the formation

Helvetica Chimica Acta Vol. 86 (2003)

2031

Scheme 2. Synthesis of ( À )-(2R,3R)-3-Hydroxycelacinnine ((À)-1a)

TFA CF₃CO, Ts 4-MeC₆H₄SO₂, cinnanoyl (2E)-PhCHCHCO

of 16a and 16b (Scheme 3). In case of Boc-protected 10e, either both Boc and oxirane

(with CF₃COOH in CH₂Cl₂or Me₃SiCl/PhOH in CH₂Cl₂) or only the oxirane were

cleaved (Amberlyst-15 (H -form) in CH₂Cl₂) under acidic conditions.

With the Troc-protected 10d, initial deprotection with Zn in THF/1m aqueous buffer

5:1 [13] at pH 5.5 (aqueous 1 m KH₂PO₄/Na₂HPO₄) for 4 h followed by reflux in

biphasic THF/aqueous Na₂CO₃solution gave the desired macrocycle 12 in 26.5% yield.

By-products from the oxirane and Troc reduction were also isolated including the

hydroxy-amino-amide 17 (17% yield), aminocinnamamide 18 (33.6%), and the

dichloroethyl oxiranylcarbamate 19 (7%), as well as product 21 (3.7%) from coupling

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Helvetica Chimica Acta Vol. 86 (2003)

Table 1. Preparation of the Acyclic Precursors, their Deprotection, andMacrocyclization

9

R¹

R²

10 (yield [%])

R³

Macrocycle (yield [%])

9a

9b

9c

9d

9e

9f

9g

9h

Ts

CF₃CO

b-C₁₀H₇SO₂

Ts

H

CF₃CO

10a (75)

10b (17)

10c (79)

10d (63)

Ts

H

12 (85)^a)^b)

13 (67)^a

b-C₁₀H₇SO₂

Ts

15 (85)^a)

12 (53)^c)

Troc (Cl₃CCH₂OCO)

Boc

H

10e (74)^d)

10f (> 50)^e)

10g (0)^f)

10h (92)^g)

Ts

^a) Optimized conditions: aq. Na₂CO₃soln./i-PrOH 708, 36 h. ^b) For details, see discussion and Exper. Part; for

product distribution, see also Scheme 5. ^c) Optimized conditions: 1. Zn/sat. aq. Na₂HPO₄soln./THF 2. D; for

product distribution under different pH conditions, see Scheme 4. ^d) Boc deprotection also led to complete

oxirane cleavage. ^e) 10f was observed on TLC as the major product, but one-pot macrocyclization in DMFat 708

failed. ^f) Direct macrocyclization between putrescine and (Æ)-8 to give 13 in EtOH/Na₂CO₃under heating

failed. ^g) Electrochemical tosyl deprotection also led to complete oxirane cleavage.

Scheme 3

of 18 and 19 (Scheme 4). In the presence of NH₄OAc buffer (pH 7), deprotection-

macrocyclization proceeded with a better yield of 12 (33%). The oxirane cleavage was

minimized (Scheme 4), and the yield of 12 was improved to 53% when Troc

deprotection was performed very slowly at pH 8 (sat. aqueous Na₂HPO₄solution,

22 h), followed by macrocyclization. In this case, cinnamamide 18 could not be

detected in the reaction mixture (<1%), but other by-products were isolated from it,

including 17 (8.2%), 19 (10.4%), and 20 (4.2%). However, 18 was the major product

Helvetica Chimica Acta Vol. 86 (2003)

2033

Scheme 4

a) Sat. aq. Na₂HPO₄soln., pH 8 22 h. b) 0.5m KH₂PO₄/0.5m Na₂HPO₄, pH 5.5, 4 h. c) 1m NH₄OAc, pH 7, 16 h. d)

1m AcOH, pH 3, 10 min. e) 1m KH₂PO₄, 85min. f) 1m NaOH.

when deprotection was performed at a faster rate and thus in uncontrolled fashion

under higher-(1m NaOH) or lower-pH conditions (1m AcOH or 1m KH₂PO₄).

With the CF₃CO-protected substrates, the best yields of macrocyclic products

(85%) were observed after one-pot deprotection-macrocyclization at 708 for 36 h in

aqueous Na₂CO₃/i-PrOH. In contrast to many other macrocyclization reactions, high-

dilution conditions were not required in this case. The reaction could easily be

performed on a 1-g scale under moderate dilution (0.01m or 1 g in ca. 200 ml). The

bimacrocyclic product 23 (Scheme 5) was observed in only 1.1% yield after

deprotection-macrocyclization at 0.005m dilution in aqueous Na₂CO₃/EtOH at reflux

for 22 h. In this case, the yield of 12 was also excellent (85%). However, unlike with the

more hindered i-PrOH solvent, product 22 from oxirane opening by the solvent was

also observed in 7% yield (Scheme 5). Also, heating at higher temperature (e.g., reflux)

for a longer reaction time led to a small decrease in yield due to partial lactam

hydrolysis and other competive side reactions. In a biphasic THF/aq. Na₂CO₃system,

the initial CF₃CO deprotection proceeded very slowly and resulted in a higher ratio of

by-products after reflux for 3 days with the decreased 65% yield of 12. To accelerate the

initial deprotection step, it was found necessary to use diluted aqueous Na₂CO₃solution

(3 times from sat. aqueous Na₂CO₃solution in case of EtOH or i-PrOH, and 10 times in

case of THF). Otherwise CF₃CO cleavage proceeded slowly in these biphasic systems.

The intermediate free amino-amide 11 could be separated when CF₃CO removal was

performed at room temperature with K₂CO₃in MeOH. However, product 11 was not

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Helvetica Chimica Acta Vol. 86 (2003)

Scheme 5

O

HO

NH₂

N

H

10a

12

+

Ts

aq. sat. Na₂CO₃soln.

EtOH, , 22 h

Ph

O

OEt

85%

22, 6.9%

Ts

H

N

HO

Ph

N

H

+

H

N

OH

N

H

Ts

O

23, 1.1%

stable in pure form due to slow self-condensation between the oxirane and amino

moieties present in the same molecule.

With the bis-trifluoroacetyl precursor 10b, deprotection-macrocyclization proceed-

ed with lower yield (67.5%) under formation of unprotected macrocycle 13 (Table 1).

Several minor by-products were observed in this case due to the release of two

unprotected N-atoms both capable of oxirane opening. Unprotected macrocycle 13

could be converted directly to the final product 1a without additional deprotection as in

case of the monotosylated lactam 12. However, the preparation of 10b and the

purification of 13 should be further optimized.

After optimization of the reaction conditions, the synthesis was repeated starting

from (À)-5 to give optically pure ()-12 with the (2R,3R) absolute configuration.

Quantitative electrochemical removal of the Ts group according to a general procedure

of Guggisberg et al. [14] as we used in the previous synthesis of (Æ)-1a [5] provided

unprotected lactam ()-13. To avoid electrochemical detosylation, the b-naphthylsul-

fonyl protecting group was used instead of Ts such as in (À)-15, which was obtained by

the same synthetic route as tosylated ()-12 (Table 1). The reductive cleavage of the b-

naphthylsulfonyl group requires a lower potential, or this group can be removed

chemically with Mg/MeOH [15]. But, of course, other easily cleaved sulfonyl groups,

e.g., 2-nitrophenylsulfonyl, can be used instead.

Unprotected lactam ()-13 was selectively diacylated at the less hindered N(10)

and OHÀC(3) with an excess of cinnamoyl chloride promoted by N,N-dimethylpyr-

idin-4-amine (DMAP) in CH₂Cl₂or CDCl₃to give ()-14. Although the conditions for

such N(10) over N(1) regioselection require low temperatures according to Yamamoto

and Maruoka [16], no acylation took place at the more hindered N(1) of ()-13 at room

temperature. On the contrary, excess cinnamoyl chloride led to complete O-acylation

of the basic OHÀC(3). Thus, ()-13 was diacylated at room temperature to ()-14

(92% isolated yield) followed by one-pot saponification with NaOH in MeOH to the

final (À)-(2R,3R)-3-hydroxycelacinnine ((À)-1a) (90% yield).

Helvetica Chimica Acta Vol. 86 (2003)

2035

Synthesis of ( À )-1b. The optimized synthetic route to (À)-1b from ()-12 via

inversion at C(3) is depicted in Scheme 6. To quickly confirm our hypothesis

concerning the (2R*,3S*) relative configuration of the natural 3-hydroxycelacinnine,

we obtained the racemic C(3) epimer (Æ)-35 of (Æ)-12 by means of a nucleophilic

displacement of its cyclic sulfamidate derivative (Æ)-33 (see below). The small

¹H-NMR HÀC(2)ÀC(3)ÀH coupling constant and corresponding chemical shifts in

the epimer (Æ)-35 were in excellent agreement with the values of the natural alkaloid.

However, the preparation of (Æ)-33 required further optimization. Then we attempted

to reproduce the above −biomimetic× synthetic route starting from corresponding cis-

oxirane derivatives (Scheme 7) and investigated other methods for epimerization

(Scheme 9).

Scheme 6. Synthesis of ( À )-(2R,3S)-3-Hydroxycelacinnine ((À)-1b)

O

N

O

N

a) SOCl₂/ Et₃N

CH₂Cl₂, -78¡ to r.t.

20%

O

NH

N

NH

N

S

NaIO₄/ [RuCl₃]

98%

(+)-12

Ph

or b) SOCl₂/ Im, 0¡

(2R,3R)

100%

Ts

(Ð)-32

(Ð)-33

1. NaNO₂/ DMF, 70¡

2. AcOH

O

HO

-2.25 V

1. RCOCl

N

H

N

H

(Ð)-1b

NH

N

2. NaOH

100%

Ph

N

H

Ph

N

X

(2R,3S)

86%

(Ð)-36, (2R,3S)

34 X = SO₃Na

(Ð)-35 X = H, (2R,3S)

70% from 33

Amberlyst-15

Ts 4-MeC₆H₄SO₂, R(E)ÀPhCHCH

First, we attempted to convert trans-oxiranecarboxamide (Æ)-10a to cis-isomer (Æ)-

30a by the procedure of Tung and Speziale [17] for the conversion of trans-N,N-diethyl-

3-phenylglycidamide or trans-ester 4 to corresponding cis-oxirane derivatives via

chlorohydrins. Unfortunately, oxirane opening with HCl proceeded with almost no

threo-erythro stereoselectivity in case of the secondary amide (Æ)-10a. However, we

found that the erythro-chlorohydrin could be kinetically resolved with 100% selectivity

from the reaction mixture by conversion back to the trans-oxirane under the mild basic

conditions (aqueous NaHCO₃solution/EtOH, room temperature, 30 min). The desired

unreacted threo-isomer could be separated by chromatography and converted to the

cis-oxirane under more-basic conditions (aqueous NaOH solution/benzene or Amber-

lite IRA 420/OH^Àform) or at higher temperature (508 in aqueous Na₂CO₃solution/

acetone). However, the procedure seemed impractical. We also attempted to use

TsOH, camphorsulfonic acid, and polymer-supported sulfonic acid, e.g., Amberlyst-15,

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Helvetica Chimica Acta Vol. 86 (2003)

Scheme 7. Synthesis of the Acyclic cis-Oxirane Precursors andtheir AttemptedMacrocyclization

CO₂R

HO

CO₂Et

Na₂CO₃

HCl

O

4

acetone

50¡, 16 h

Ph

Cl

25, R=Et, 77%

26, R= K, 82%

KOH

24a, 52.5%

resolution

Me

+

-

+

-

CO

₂H₂N

Me

OH

COCl

Ph

CO₂H₂N

Me

OH

(COCl)₂

+

O

Ph Ph

(+)-(2S,3S)

Ph

(Ð)-(2R,3R)

(Ð)-(1R,2S)

(+)-(1S,2R)

28, (2S,3S)

(Ð)-27a, 46.1%

(+)-27b, 23.1%

O

R

N

Cs₂CO₃/ DMF

Br

H

O

H

O

9a or 9b

Ph

(+)-29, (2S,3S), 70%

NHTFA

(+)-30a R=Ts, (2S,3S), 75%

30b R=TFA, (2S,3S), 25%

O

R

N

HO

aq. K₂CO₃soln.

MeOH, r.t.

N

H

O

N

R

H₂N

∆

Ph

31 R=Ts, (2S,3S)

TFA CF₃CO, Ts 4-MeC₆H₄SO₂

Ph

N

H

for oxirane opening on solid support. The threo-erythro stereoselectivity was also poor

in this case. In addition, selective cleavage of the trans-oxiranecarboxamide (Æ)-10a

from the polymer-supported intermediate threo/erythro hydroxysulfonates with

NaHCO₃failed due to a faster and uncontrolled ring closure to a mixture of both

oxiranes (Æ)-10a and (Æ)-35a. Thus, the trans- to cis-oxirane isomerization had to be

initiated at the beginning of the synthetic route starting from trans-4 according to the

original procedure of Tung and Speziale [17].

Instead of a three-step procedure for the preparation of pure trans-4 [10],

commercial 4 was treated directly with HCl in toluene at 08 to give a 4 :1 mixture of

threo- and erythro-chlorohydrin derivatives 24a and 24b, respectively, followed by

Helvetica Chimica Acta Vol. 86 (2003)

2037

Scheme 8. Rationalization of the Successful andUnsuccessful Macrocyclization of trans- and cis-Oxiranecar-

boxamides: Restricting the Phenyl Group in cis-Oxirane Derivatives Prevents the Formation of the (2R,3S)-

Macrocycle

O

NH

N

R

N

R

H

O

H

trans

cis

NH₂

H

NH₂

O

HO

Ph

HO

Ph

N

H

N

R

N

R

N

H

N

H

crystallization of pure threo-isomer 24a in 52% yield (Scheme 7). Addition of HCl to

trans-4 proceeded predominantly with double inversion at C(3) involving neighboring

ester O-atom participation. Compound 24a was closed to cis-oxiranecarboxylate 25

with aqueous Na₂CO₃solution in acetone as described for the corresponding

bromohydrin [10]. Then 25 was saponified with KOH to 26 and resolved with ()-

and (À)-ephedrines according to Harada and Nakajima [10][18] to give the ephedrine

salts ()-27b and (À)-27a. The latter was converted directly to the intermediate acid

chloride 28 with (COCl)₂. Then CF₃CO-protected cis-oxiranecarboxamides ()-30a

and 30b were prepared via ()-29 as described above for the corresponding trans-

oxiranecarboxamides 10a and 10b.

Treatment of 30a and 30b under the conditions described above for the macro-

cyclization of 10a and 10b led to complete decomposition of the starting cis-

oxiranecarboxamides into a complex mixture of products without formation of the

desired macrocycles. Thus the CF₃CO group of 30a was cleaved with the formation of

free amino-cis-oxiranecarboxamide 31 as described for amino-trans-oxiranecarboxa-

mide 11. Unlike the latter, 31 was stable at room temperature in pure form and

remained unreacted under the macrocyclization conditions after a short period of time.

However, longer reaction time or heating at reflux in various solvents (THF, dioxane,

EtOH, toluene) led to complete degradation of 31 without formation of the desired

macrocycle 35. The unsuccessful macrocyclization can be rationalized by the blocking

of the nucleophilic approach by the restricting phenyl group in the cis-arrangement to

the amide function (Scheme 8). Therefore, S_N2 oxirane opening in case of cis-oxirane

derivatives 35a and 35b is sterically unfavored, leading to a mixture of competitive by-

products presumably from S_N1 opening and eliminative oxirane cleavage.

This in vitro model reaction of the proposed biosynthetic formation of 1b suggests

that the macrocyclization with cis-oxirane derivatives does not occur spontaneously in

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Helvetica Chimica Acta Vol. 86 (2003)

vivo and perhaps would require an enzymatic influence. Nevertheless, it is conceivable

to propose an alternative biosynthetic pathway that involves mono-oxidation of the

naturally occurring (2R)-celacinnine into (2R,3S)-3-hydroxycelacinnine assisted by

cytochrome P-450. Enzymatic radical monooxidation involving intramolecular addi-

tion of the forming intermediate radical to a CC bond of the cinnamoyl group or the

phenyl ring of 1b may also explain the formation of alkaloids with an unusual bicyclic

structure with a five- or seven-membered ring such as in caesalpinine [19], pleurosty-

line, 7-hydroxypleurostyline (2), and 7-hydroxypleurocorine (3). Alternatively, the

oxidation may simply occur by air during storage. But of course, these proposals require

further investigation.

The desired epimer 1b could be obtained by nucleophilic inversion at the activated

HOÀC(3). To avoid neighboring N(1) participation as a potential competitive side

reaction in classical methods with inversion of sulfonates or Mitsunobu betains, we

attempted to prepare and displace cyclic sulfamidate (À)-33 (Scheme 6). In this case,

the N-atom is protected, and, at the same time, the O-atom is activated for the

nucleophilic displacement. Using a described two-step procedure for the preparation of

cyclic sulfamidates [20], we were able to isolate the desired intermediate sulfamidite

(Æ)-32 in only 20% yield after the first step due to unexpected neighboring N-atom

participation in the formation of aziridine derivative (Æ)-38 in 31% yield (Scheme 9).

The latter is presumably formed from the intermediate 37 with the O-atom activated by

the positively charged Et₃N S(O)ÀOÀC(3) as a good leaving group. Aziridine

Scheme 9

Ts 4-MeC₆H₄SO₂, TFA CF₃CO, TFAA (CF₃CO)₂O

Helvetica Chimica Acta Vol. 86 (2003)

2039

derivative (Æ)-38 was also formed as the major product (79% yield) after an attempt to

prepare tosyloxy derivative (Æ)-39 from (Æ)-12. In this case, N(1) remained intact due

to the steric hindrance, and tosylation occurred only at the O-atom to form unstable

intermediate (Æ)-39, which was never observed in a reaction mixture.

The isolated sulfamidite (Æ)-32 was oxidized to cyclic sulfamidate (Æ)-33 and

displaced with NaNO₂( ! (Æ)-34) according to a general procedure (for displacement

of sulfonates with KNO₂, see [21]; for displacement of cyclic sulfates with KNO₂, see

[22]). The desired cis-epimer (Æ)-35 was isolated in 14% overall yield from trans-

1

epimer (Æ)-12 after acidic workup. The H-NMR data of (Æ)-35 (HÀC(3) at d 4.05,

HÀC(2) at d 4.16, and a small ³J(2,3) of 0.93 Hz) were in excellent agreement with the

data of natural 3-hydroxycelacinnine (d 4.16, d 4.27, and J 1.2 Hz, resp.).

Alternatively, N(1) could be protected with CF₃CO ((CF₃CO)₂O/Et₃N, CH₂Cl₂) to

give (Æ)-40 followed by O-tosylation with formation of (Æ)-41 (87% yield) (Scheme 9).

The tosyloxy group of (Æ)-41 was displaced with NaNO₂in DMF (14 h, 708) to give

epimeric N-nitroso-cis-macrocycle (Æ)-42 in ca. 85% yield according to the analysis of

1

the reaction mixture after workup. Again the typical H-NMR data were observed

(³J(2,3) 1.9, HÀC(2) at d 6.12, and HÀC(3) at d 4.86). Cleavage of the N-nitroso

function of (Æ)-42 was troublesome and gave only 20% yield of (Æ)-35 after heating

with K₂CO₃in MeOH. Thus, this route should be further investigated and optimized.

Cyclic sulfamidates can be obtained from hydroxy-N-triflates by base-promoted

cyclization into sulfamidate under CF^À₃elimination [23][24]. However, smooth

t

protection of OHÀC(3) with BuMe₂Si followed by N-triflation was not achieved in

good yield.

Finally, the desired cyclic sulfamidate (À)-33 was prepared by treating ()-12 with

1,1'-sulfinylbis[1H-imidazole] (room temperature) generated in situ from SOCl₂and

1H-imidazole (Scheme 6). Unlike with Et₃N as base, the formation of the positively

charged leaving group such as in 37 (see Scheme 9) was avoided and allowed to prepare

sulfamidate (À)-33 in almost quantitative overall yield (98%) from ()-12 via

intermediate sulfamidite (À)-32. The obtained sulfamidate (À)-33 was then treated

with NaNO₂under heating in DMF at 708 for 15h. The intermediate nitrite was

instantly cleaved to give 34 after mild acidic workup with AcOH. The remaining

monosulfamidate function of 34 was then smoothly removed by treatment with

Amberlyst-15 (H form) as described by Khanjin and Montero for monosulfate

cleavage [25]. Thus, cis-epimer (À)-35 was isolated in 70% yield. No starting trans-

epimer ()-12 was detectable by NMR, thus confirming a highly stereoselective

inversion. Finally, (À)-1b was obtained from (À)-35 by quantitative electrochemical

detosylation ( ! (À)-36) followed by acylation with cinnamoyl chloride as described

above for (À)-1a. The optical purity of (À)-1b is assumed to be 100% based on the

optical purity of the starting (À)-5 and on the diastereoisomer purity of the Mosher

1

ester derivative 44 as determined by its H-NMR data (Scheme 10).

Characterization and Comparison with the Natural Sample. ¹H- and ¹³C-NMR-

signal assignments for the synthesized (À)-1b and monotosylated precursor (À)-35

were obtained from the 2D NMR data (COSY, HMBC, and HSQC). They are

summarized in Table 2 and compared with the original data of natural 3-hydroxyce-

lacinnine [3]. Due to the restricted rotation in the cinnamamide moiety, many ¹H- and

2040

Helvetica Chimica Acta Vol. 86 (2003)

Scheme 10

¹³C-NMR signals of (À)-1b in CDCl₃were broad, overlapped, or doubled with the

1

approximate integral ratio 2 :3. The exact H- and ¹³C-NMR chemical shifts for each

nucleus of both rotamers were obtained mostly from the HSQC data. Prof. Richomme

(University d×Angers) kindly provided original hardcopies of the 2D, ¹H-, and

¹³C-NMR spectra of 3-hydroxycelacinnine [26]. They were identical to those of

synthesized (À)-1b, except for some very minor differences due to the temperature and

concentration dependence of chemical shifts (especially those of the amide NH), and

sensitivity to H₂O, CD₃OD, or other H-bonding impurities.

The original 10-year old sample of 3-hydroxycelacinnine was also provided by Prof.

Richomme and compared with the synthesized (À)-1b by ¹H-NMR and HPLC-MS/MS.

In addition to the major component 1b in the sample, the NMR data indicated the

presence of at least two other minor components A and B in the molar ratio 1b/A/B of

ca. 4 :1:1 in agreement with HPLC. The retention times of the synthesized (À)-1b and

the major component of the natural sample were completely identical and reproducible

(t_R14.55 min) after several runs with both individual samples and their mixtures. For

comparison, the trans-epimer (À)-1a had t_Rof 15.35 min under the same gradient

conditions and was nicely separable by HPLC from the prepared mixture with the

synthesized (À)-1b and the natural sample. Fragmentation of (À)-1a and (À)-1b in the

MS/MS experiment were completely identical. Component A (t_R13.55 min) was

identified as 3-hydroxycelallocinnine (43; see Scheme 10) with the (Z)-cinnamoyl

group according to the same m/z 422 ([M((À)-1b) 1] ), identical fragmentation with

isomeric (À)-1b in the MS/MS experiment, hypsochromic and hypochromic UV shift

(l_max255 nm for 43, vs. l_max287 nm for (À)-1b), and the presence of characteristic.

¹H-NMR olefin signals of the (Z)-cinnamoyl moiety (d 6.56, 6.57 (2 d of two rotamers,

3

³J_cis 12.6 Hz) and d 5.98, 5.99 (2 d of 2 rotamers, J_cis 12.6 Hz). Presumably, A was

formed from 3-hydroxycelacinnine after light-induced (E) ! (Z) CC bond isomer-

ization upon long-time storage. Component B (t_R11.3 min) with m/z 438 ([M((À)-

1b) 16 1] ) and a UV l_max< 215nm might correspond to some unidentified mono-

oxidized derivative, for example 3-hydroxyleurocorine (3a,b). Components A, B, and

Helvetica Chimica Acta Vol. 86 (2003)

2041

Table 2. Comparison of ¹H- and ¹³C-NMR Data of Natural 3-Hydroxycelacinnine [3], the Synthesized( À)-

(2R,3S)-3-Hydroxycelacinnine ((À)-1b), and (À)-35

1b [3]^a)

¹H

(À)-1b, (2R,3S) (this work)^b)

(À)-35, (2R,3S) (this work)^c)

¹³C

64.01,

¹H

¹³C

¹H

¹³C

63.94

HÀC(2)

HÀC(3)

4.27

(d, J(2,3) 1.2)

4.31 (br. s (unres. d),

J(2,3) < 1.5)

64.08, 4.16 (s (unres. d),

J(2,3) < 1.5)

64.38

76.16

64.38

75.94

4.16

(d, J(2,3) 1.2)

4.18 (br. s (unres. d),

J(2,3) < 1.5)

4.05 (s (unres. d),

J(2,3) < 1.5)

75.61

76.16

172.50,

172.34

C(4)

173.98,

173.91

173.21

NH(5)

CH₂(6)

CH₂(7)

CH₂(8)

7.00 (t)

7.09 (br. s, 0.4 H)

7.03 (br. s, 0.6 H)

3.78, 2.98

3.79, 2.99

2.22, 1.67

7.16 (br. t)

3.80 (m),

3.00 (m)

2.25( m),

1.70 (m)

3.75( m),

36.72,

36.16

27.92,

30.39

43.03,

36.59, 3.65 (m)

36.13 2.91 (m)

27.99, 2.06 (m)

30.26 1.62 (m)

44.37, 3.25

(t, J 7.7, 2 H)

36.99

29.6

2.20, 1.68

3.63, 3.55

46.19

3.43 (m)

3.57 (m),

3.38 (m)

1.92 (m),

1.62 (m)

1.65( m),

1.45( m)

2.86 (m),

2.31 (m)

44.59^d) 3.69, 3.4543.38

CH₂(10)

CH₂(11)

CH₂(12)

CH₂(13)

44.01,

3.53, 3.38

44.96

46.56

3.3 (m)

2.91 (m)

24.42, 1.82 (m)

47.69

24.20

25.59

45.56

46.80^d) 3.52, 3.39

24.88^e), 1.92, 1.56

25.12

1.92, 1.63

26.18

24.64

1.55 (m)

1.42 (m, 2 H)

24.22^e), 1.47, 1.58

26.06

46.55,

46.46

2.46, 2.82

46.18, 2.69 (dt (ddd),

3

47.04

²J 12.2, J 4.8)

2.33 (m)

OHÀC(3)

Phenyl:

C(1')

142.35,

142.44

140.82,

140.54

127.357.32

141.17

HÀC(2'),

HÀC(6')

HÀC(3'),

HÀC(5')

HÀC(4')

7.35( m)

127.76^f) 7.37

126.99^f) 7.37

127.56^f) 7.30

127.19

128.57

127.88

7.33

7.26

128.88

127.72

Cinnamoyl or tosyl:

OC

165.16,

165.82

117.53

166.66,

166.38

117.46

CHCHCO 6.30

6.80

(d, J(2,3) 15.4)

(br. (d, J 15.5)

CHCHCO 7.66

(d, J(2,3) 15.4)

140.79

7.66 (d, J 15.5)

142.78,

142.65

135.35

127.88

C(1'')

135.41

128.78

137.15

127.3

HÀC(2''),

HÀC(6'')

HÀC(3''),

HÀC(5'')

HÀC(4'')

MeÀC(4'')

7.52 (m)

7.35( m)

7.51 (br. d)

7.37

7.67 (d, J 8.2)

7.29 (d, J 8.2)

128.78

129.49

128.88

129.72

129.88

7.36

143.34

21.68

2.42

^a) Spectra in CDCl₃at room temperature with SiMe₄as internal reference; ¹H- and ¹³C-NMR at 270 and

b

67.5MHz, resp. ) ¹H- and ¹³C-NMR and 2D NMR: 6 mg in 0.8 ml of CDCl₃, d(SiMe₄) 0.00(¹H, 500 MHz),

d(CDCl₃) 77.23 (¹³C, 125MHz). Due to a low sample concentration, some ¹³C-NMR signals were not resolved:

these d are based on a more concentrated sample of (À)-1b: 40 mg in 0.6 ml of CDCl₃ 0.05ml of CD ₃OD,

c

d(CDCl₃) 77.23 (¹³C, 75MHz). ) 38 mg in 0.7 ml of CDCl₃, 300 K, d(Me₄Si) 0.00 (¹H, 600 MHz), d(CDCl₃)

77.23 (¹³C, 150 MHz). ^d)^e)^f) Interchangeable values each.

2042

Helvetica Chimica Acta Vol. 86 (2003)

1b were poorly separable by prep. TLC with several eluent systems investigated. Thus,

it was not possible to make a pure sample of natural 1b and to make a definite

conclusion about the absolute configuration based on [a]_Dvalues of the synthetic (À)-

1b ([a]_D À38.5) and the old natural sample ([a]_D À18) due to impurities.

However, it was possible to convert both 3-hydroxycelacinnine ((À)-1b) and 3-

hydroxycelallocinnine (43 or A) from the natural sample into the same compound, i.e.,

dihydro-3-hydroxycelacinnine (À)-45, after hydrogenation with H₂over Pd/C

(Scheme 10). The latter compound was also prepared either from the unprotected

lactam (À)-36 by acylation with 3-phenylpropanoyl chloride or by hydrogenation of the

synthesized (À)-1b. Component B remained unchanged upon catalytic hydrogenation

and was not separable by prep. TLC. However, it remained a minor component (ca.

1

15%) in the mixture with 45 according to H-NMR.

Crude natural 45 and synthesized (À)-45 (5.0 mg each in 10 ml MeOH) gave nearly

identical CD curves (Fig. 2). The difference in amplitude between their CD spectra

corresponds exactly to a lower amount of 45 (ca. 80%) in the hydrogenated natural

sample. It should be noted that it was not possible to record CD spectra of (À)-1b with a

reasonable signal-to-noise ratio due to the strong UV-absorbing cinnamoyl group at

N(9) distant from the chiral center at C(2) with the weakly absorbing Ph group.

Moreover, crude (S)-Mosher esters prepared from both synthesized (À)-1b (see 44)

and from the crude natural 1b were completely identical and diastereoisomerically pure

by ¹H-NMR. Thus, the absolute configuration of natural 3-hydroxycelacinnine is

(2R,3S) as in the identical synthetic (À)-(2R,3S)-3-hydroxycelacinnine ((À)-1b).

Fig. 2. CD Curves of synthetic (À)-45) and hydrogenated natural 3-hydroxycelacinnine

Conformational Analysis of Epimeric Macrocycles. The relative (2R*,3R*) trans-

configuration in 1a and cis-configuration (2R*,3S*) in 1b can be indirectly confirmed by

means of a Monte Carlo Multiple Minimum (MCMM) conformational search with

MM2*, MM3*, and Amber force fields, followed by calculation of the Boltzmann-

Helvetica Chimica Acta Vol. 86 (2003)

2043

averaged ¹H-NMR ³J(2,3) coupling constants based on the Altona modification [27] of

the Karplus equation all implemented in MacroModel [28]. Since the experimental

3

values of J(2,3) of trans-macrocycles 1a, 12 15, 40, and 41 were practically identical

(³J(2,3) 9 10 Hz) as well as those of cis-macrocycles 1b, 34 36, 42, and 44 (³J(2,3) <

2 Hz), the conformational search on all rotatable bonds was performed only with the

lowest-molecular-mass representatives 13 and 36. MCMM on these structures

generated several thousands of conformers within a 25-kcal/mol energy window

relative to the found global minimum. Although all three force fields predicted three

different global minima and conformation-energy distributions for each epimer, one

family of conformers distinguished by the dihedral angle around C(2)ÀC(3) (anti-

periplanar) was more stable than the other (gauche). Anti conformers of 13 or 36 with

ca. 1808 torsion between the two bulky substituents Ph at C(3) and CONHR at C(3)

were calculated to be more stable by 3 7 kcal/mol (depending on the force field) than

corresponding gauche conformers. Thus, an ideal anti-periplanar arrangement of Ph

and CONH forces the two vicinal HÀC(2) and HÀC(3) to the anti-periplanar

arrangement in case of trans-macrocycle 13 corresponding to a very large calculated

and experimental ³J(2,3) (Fig. 3). In the case of the cis-macrocycle 36, the theoretical

608 torsion between vicinal H-atoms is distorted due to the repulsive interaction

between remaining substituents OH and NHR in the gauche arrangement to Ph and

CONHR, respectively. Thus, vicinal H-atoms are in ca. 908 torsion corresponding to a

3

very small calculated J(2,3) (0.8 2 Hz, depending on the force field), in excellent

agreement with the observed values for cis-macrocycles including (À)-1b.

HN

O

HN

H

O

Computed values:

H

N

H

N

ca. 180¡

ca. 90¡

J(2,3) = 9Ð11 Hz J(2,3) = 0.8Ð2 Hz

H

OH

HO

H

Ph

(2R,3R)

(2R,3S)

Fig. 3. Lowest-energy conformations aroundC(2) ÀC(3) andcalculated Boltzmann-averaged J(2,3) for

(2R,3R)- and(2 R,3S)-macrocycles

Conclusions.

We confirmed the absolute configuration of the natural 3-

hydroxycelacinnine by means of the total synthesis of its two diastereoisomers (À)-

(2R,3R)- and (À)-(2R,3S)-3-hydroxycelacinnine ((À)-1a and (À)-1b, resp.). A new

macrocyclization method via oxirane opening by the terminal amino group was

developed. Also, a new inversion method of vicinal amino alcohols via cyclic

sulfamidates was discovered. Synthesized (À)-1b was identical in every respect with

the natural alkaloid. In the light of our negative results with the macrocyclization of cis-

oxirane precursors 30a, 30b, and 31, we conclude that the proposed biosynthetic

pathway might work for the unnatural (À)-1a generated from trans-oxirane

(Scheme 1), but it is unlike for the epimeric natural (À)-1b, which should be formed

from cis-oxirane. The alkaloid (À)-1b as well as bicyclic alkaloids 2 and 3 from the same

2044

Helvetica Chimica Acta Vol. 86 (2003)

natural source are presumably synthesized in vivo by an alternative pathway, for

example, by oxidation of (À)-(2R)-celacinnine in the presence of some mono-

oxygenase enzyme or simply on exposure to air.

We greatfully acknowledge the Swiss National Science Foundation for the generous support of this work

and for the postdoctoral fellowship award to N.A.K. Special thanks go to Professor P. Richomme (University

d×Angers) for providing the original data and sample of 3-hydroxycelacinnine and to Dr. K. Drandarov for his

help with CD measurements.

Experimental Part

General. See [5]. HPLC: t_Rin min. [a]_D: Perkin-Elmer 241 polarimeter. UV: l_maxin nm. CD Spectra: Jasco

J-715 spectropolarimeter.

Chiral Resolution of Potassium trans-3-Phenyloxiranecarboxylate (5) with Phenylethylamine. Salt (Æ)-5

[5][9] (34.02 g, 168.4 mmol) was resolved with ()-(R)-phenylethylamine, which crystallized with the ()-

(2S,3R)-acid to give ()-6 (16.5g, 34.3%; [ a]_D 125.8 (c 1.14, EtOH); [10]: 125.4) and then with (À)-(S)-

phenylethylamine to give with the (À)-(2R,3S)-acid a crystalline salt (À)-6 (15.55 g, 32.4%; [a]_D À124)

according to Thijs et al. [10].

Potassium ( À )-(2R,3S)-trans-3-Phenyloxiranecarboxylate ((À)-5). The suspension of (À)-6 (14.59 g,

51.2 mmol) in EtOH (200 ml) was sonicated for 5 min followed by addition of KOH (3.77 g, 67.3 mmol) in

EtOH (50 ml) and cooled in an ice/water bath. The precipitate was filtered, washed with EtOH, acetone, and

Et₂O to give 9.19 g of (À)-5 ([a]_D À139.5( c 1.14, H₂O)). The supernatant gave additional 970 mg of the

product ([a]_D À138.2 (c 1.24)) after quenching with Et₂O. ¹H-NMR (300 MHz, 20 mg in 0.6 ml of D₂O;

d(DHO) 4.8): 7.43 7.58 (m, 5arom. H); 4.08 ( d, J 1.9, HÀC(3)); 3.67 (d, J 1.9, HÀC(2)). ¹³C-NMR

(75 MHz): 175.32 (CO); 135.62 (C_ipso); 128.95(C _p); 128.75(C _m); 126.03 (C_o); 58.86, 57.47 (C(2), (C(3)).

( À )-(2R,3S)-trans-N-(3-Bromopropyl)-3-phenyloxiranecarboxamide ((À)-8) was obtained from (À)-5 by

the same procedure as (Æ)-8 [5]. An anal. sample was prepared after purification by FC (SiO₂, 35% AcOEt/

hexane) and crystallization from AcOEt/hexane. Colorless fibers. M.p. 100.0 100.38. [a]_D À46.8 (c 1.4,

CHCl₃). Other data: completely identical with those of (Æ)-8 [5].

2,2,2-Trifluoro-N-{4-{[(4-methylphenyl)sulfonyl]amino}butyl}acetamide (9a). MethodA: To a stirred soln.

of N-(4-aminobutyl)-4-methyl benzenesulfonamide (9f) [29] (860 mg, 3.554 mmol) in CH₂Cl₂(15ml),

(CF₃CO)₂O (0.583 ml, 4.19 mmol) was added dropwise during 1 min. After 25 min, the mixture was evaporated

under h.v. to give 1.27 g of colorless crystalline solid. The product was crystallized from EtOH/0.5m aq. HCl to

give a white powder (82.6% yield).

MethodB: To a stirred soln. of 9e (8.058 g, 23.56 mmol) in CH₂Cl₂(80 ml), (CF₃CO)₂O (15ml) was added,

followed by dropwise addition of CF₃COOH (10 ml) at 08. After 17 h at r.t., the mixture was evaporated to give

10.13 g of a pale brown solid, which was crystallized from EtOH (50 ml) and H₂O (300 ml): 9a (7.002 g, 87.9%).

M.p. 95 101 8. FT-IR (KBr): 3314s (NÀH), 3254s (NÀH), 3104w, 3070w, 2968m, 2954m, 2932m, 2892w, 2865m,

2760w, 1924w, 1698s (CO), 1600m, 1561s, 1496w, 1475m, 1441m, 1400w, 1381w, 1353m, 1322s, 1306s, 1292m,

1246m, 1212s, 1183s, 1159s, 1091m, 1065m, 1038m, 1019w, 896m, 815s, 803w, 744m, 726s, 706m, 660m, 634w, 5 96w,

571s, 5 5 s0, 5 20m. ¹H-NMR (300 MHz, CDCl₃): 7.72 (d, J 8.3, H_o); 7.30 (d, J 8.0, 2 H_m); 6.94 (br. t, NHCO);

5.19 (br. s, NHTs); 3.31 (q, J 6.6, CH₂NHCO); 2.94 (t, J 6.5, CH₂NHTs); 2.42 (s, Me); 1.61, 1.53 (2 m,

2 CH₂). ¹³C-NMR (75MHz, CDCl ₃; d(CDCl₃) 76.91): 157.39 (q, J 36.7, NHCO); 143.57 (C_pof Ts); 136.47

(C_ipsoof Ts); 129.68 (C_mof Ts); 126.88 (C_oof Ts); 115.75 (q, J 288, CF₃); 42.44 (CH₂NHTs); 39.23 (br.,

CH₂NHCO); 26.43, 25.65 (CH₂CH₂); 21.33 (Me). ESI-MS: 361 ([M Na] ).

N,N'-Butane-1,4-diylbis[2,2,2-trifluoroacetamide] (9b). To

a cold (ice/water bath) stirred soln. of

(CF₃CO)₂O (31.4 g, 149.6 mmol) in CH₂Cl₂(150 ml), putrescine ( butane-1,4-diamine; 5.276 g, 59.85 mmol)

in CH₂Cl₂(75ml) was added. The mixture was stirred for 60 min and evaporated to give a solid mixture of two

products. The latter was dissolved in hot EtOH (100 ml). Then 1n aq. HCl was added (20 ml) and the mixture

slowly diluted with hot H₂O (125ml), allowed to cool in an ice/water bath, and filtered. The solid was washed

with H₂O and dried under h.v.: 9b (7.06 g, 42%). M.p. 154.4 154.68. FT-IR (KBr): 3312s, 3115m, 2993w, 2968m,

2936w, 2904w, 2869w, 1705s, 1566s, 1450m, 1375m, 1346w, 1324w, 1245s, 1205s, 1177s, 1044w, 986m, 944m, 838w,

767w, 722s, 700s, 5 26w, 477w. ¹H-NMR (300 MHz, 31 mg in 0.6 ml (D₆)DMSO; d((D₆)DMSO) 2.5): 9.37 (br. t,

NHCO); 3.19 (unresolved m, 2 CH₂N); 1.48 (quint., J 3.2, 2 CH₂). ¹³C-NMR (75MHz, (D ₆)DMSO;

d((D₆)DMSO) 39.38): 156.08 (q, J 36.5, NHCO); 115.82 (q, J 288, CF₃); 38.58 (CH₂NH); 25.36 (CH₂).

Helvetica Chimica Acta Vol. 86 (2003)

2045

2,2,2-Trifluoro-N-{4-[(naphthalen-2-ylsulfonyl)amino]butyl}acetamide (9c). To a soln. of monoprotected

N-[(tert-butoxy)carbonyl]putrescine [30] (1.615g, 8.59 mmol) and Et ₃N (4 ml) in CH₂Cl₂(25ml), naphthalene-

2-sulfonyl chloride (1.947 g, 8.59 mmol) was added in portions and stirred for 60 min. The mixture was

evaporated, the residue dissolved in CHCl₃, and the soln. washed with 10% citric acid (2 Â 20 ml), then with sat.

aq. NaHCO₃soln. The org. phase was dried (Na₂SO₄) and evaporated under h.v. to give 3.449 g of pale brown oil

used in the next step without further purification. This oil was treated with an excess of (CF₃CO)₂O/CF₃COOH

as described above for 9a (MethodB ) and crystallized from hot EtOH/H₂O: 9c (2.5g, 77%). White crystals.

M.p. 100 1028. FT-IR (KBr): 3265s, 3111m, 3061w, 2981w, 2924m, 2865m, 1716s, 1697s, 1626w, 1570s, 1503w,

1470w, 1457m, 1441m, 1370m, 1351m, 1316s, 1216s, 1186s, 1154s, 1126s, 1077m, 1061s, 1017w, 971w, 95 8w, 947w,

1

910m, 877m, 827s, 748s, 722s, 702s, 65 7m, 640m, 617w, 5 61w, 5 34w, 5 17w, 484m. H-NMR (300 MHz, 10 mg in

0.5ml of CDCl ₃): 8.43 (d, J 1.2, 1 H); 7.80 8.04 (m, 4 H); 7.63 (m, 2 H); 6.66 (br. s, NHCOCF₃); 5.08

(br. t, J 5.8, NHSO₂); 3.32 (q, J 6.7, 2 H); 3.01 (q, J 5.4, 2 H); 1.48 1.7 (m, 4 H). ¹³C-NMR (75MHz,

CDCl₃; d(CDCl₃) 76.90): 157.32 (q, J 36.6, COCF₃); 136.31, 134.75, 132.05 (3 quat. arom. C); 129.53, 129.1,

128.8, 128.32, 127.82, 127.57, 122.02 (7 arom. CH); 42.51 (CH₂NHS); 39.21 (CH₂NHCO); 26.58, 25.74

(CH₂CH₂). ESI-MS: 397 (100, [M Na] ), 771 (95, [2M Na] ).

2,2,2-Trichloroethyl {4-{[(4-Methylphenyl)sulfonyl]amino}butyl}carbamate (9d). To a cold (ice/water bath)

stirred soln. of 9f [29] (1.2 g, 4.959 mmol) and DMAP (0.606 g, 4.959 mmol) in CH₂Cl₂(20 ml), 2,2,2-

trichloroethyl carbonochloridate (TrocCl; 0.669 ml, 4.959 mmol) was added dropwise. After 3 h, the mixture

was evaporated, the residue partitioned between 10% citric acid (2 Â 20 ml) and CH₂Cl₂, the org. phase washed

with sat. aq. NaHCO₃soln., dried (Na₂CO₃), and evaporated under h.v., and the pale brown oil (2.317 g)

crystallized: 9d (2.069 g, 100%), which was used in the next step without further purification. M.p. 89 918. R_f

(AcOEt/hexane 1 :1) 0.6. FT-IR (KBr): 3351m (NÀH), 3226m (NÀH), 3048w, 2952w, 2937w, 2878w, 1906w,

1725s (CO), 1600w, 1536s, 1494w, 1479w, 1459w, 1451w, 1441w, 1379w, 1356w, 1323s, 1304m, 1284m, 1245s,

1184w, 1157s, 1131m, 1086m, 1056m, 1025w, 986w, 95 2w, 916w, 864w, 848w, 810s, 771w, 733s, 704m, 694m, 65 7w,

569m, 5 5 m1 , 5 24m. ¹H-NMR (300 MHz, CDCl₃): 7.74 (d, J 8.3, 2 H_oof Ts); 7.31 (d, J 8.2, 2 H_mof Ts); 5.04

(br. t, NHTs); 4.73 (overlapping br. t, J 6.3, NHCO₂); 4.70 (overlapping s, CH₂O); 3.20 (q, J 6.4,

CH₂NHCO); 2.96 (q, J 6.4, CH₂NHTs); 2.43 (s, Me of Ts); 1.47 1.63 (2 overlapping quint., CH₂CH₂).

¹³C-NMR (75MHz, CDCl ₃; d(CDCl₃) 76.89): 154.56 (CO); 143.37 (C_p); 136.84 (C_ipso); 129.63 (C_m); 126.97

(C_o); 42.60 (CH₂NHTs); 40.5( CH₂NHCO); 26.70, 26.59 (CH₂CH₂); 21.38 (Me). ESI-MS: 439, 441, 443, 445

(100, 95, 45, 4 [M Na] ). CI-MS (NH₃): 286 ([TsNH(CH₂)₄NHCONH₂] ).

1,1-Dimethylethyl {4-{[(4-Methylphenyl)sulfonyl]amino}butyl}carbamate (9e) [31]. R_f(AcOEt/hexane

1:1) 0.62. ¹H-NMR (300 MHz, CDCl₃): 7.74 (d, J 8.3, 2 H_o); 7.29 (d, J 8.1, 2 H_m); 5.08 (br. s, NHTs); 4.6

(br. s, NHBoc); 3.05(br. s, CH₂NHBoc); 2.93 (br. s, CH₂NHTs); 2.42 (s, Me of Ts); 1.44 1.52 (m, 2 CH₂); 1.42

(s, Me₃C). ¹³C-NMR (75MHz, CDCl ₃; d(CDCl₃) 76.93): 155.89 (CO); 143.19 (C_p); 136.94 (C_ipso); 129.56 (C_m);

126.96 (C_o); 79.13 (Me₃C); 42.69 (CH₂NHTs); 39.82 (br., CH₂NHCO); 28.28 (Me₃C); 27.04, 26.61 (CH₂CH₂);

21.35(Me of Ts).

N-[4-Aminobutyl]4-methylbenzenesulfonamide (9f) [29]. ¹H-NMR (10 mg in 0.6 ml of CDCl₃, 300 MHz):

7.74 (d, J 8.3, 2 H_o); 7.29 (d, J 8.1, 2 H_m); 2.8 3.2 (br., NH₂, NHTs); 2.92 (t, J 6.45, CH₂NHTs); 2.67 (t, J

6.3, CH₂NH₂); 2.42 (s, Me of Ts); 1.4 1.6 (2 m, 2 CH₂). ¹³C-NMR (75MHz, CDCl ₃; d(CDCl₃) 76.94): 142.93

(C_p); 137.25(C _ipso); 129.49 (C_m); 126.91 (C_o); 42.9 (CH₂NH); 41.17 (CH₂NH₂); 30.21, 27.25(2 CH ₂); 21.34 (Me).

N-(3-Aminopropyl)-4-methyl-N-{4-{[(4-methylphenyl)sulfonyl]amino}butyl}benzenesulfonamide (9h)

1

[12]. R_f(CH₂Cl₂/MeOH/25% aq. NH₃soln. 90 :9 :1) 0.3. H-NMR (300 MHz, 30 mg in 0.7 ml of CDCl₃): 7.77

(d, J 8.3, 2 H_oof TsNH); 7.63 (d, J 8.3, 2 H_oof TsN); 7.26 (d, J 8.1, 2 H_mof TsNH); 7.23 (d, J 8.3, 2 H_mof

TsN); 6.6 7.0 (br. s, 4 H, NHTs, NH₂, H₂O); 3.1 3.25( m, CH₂N(Ts)CH₂); 2.98 (t, J 7.2, CH₂NH₂); 2.88

(t, J 6.0, CH₂NHTs); 2.36, 2.37 (2s, 2 Me of 2 Ts); 2.15( quint., J 7.1, NCH₂CH₂CH₂N); 1.63 (unres.

quint., J 6.5, CH₂); 1.46 (unres. m, CH₂). ¹³C-NMR (75MHz, CDCl ₃; d(CDCl₃) 76.90): 143.27 (C_pof TsN);

143.04 (C_pof TsNH); 136.98 (C_ipsoof TsNH); 135.50 (C_ipsoof TsN); 129.68, 129.62 (4 C_mof 2 Ts); 127.1, 126.99

(4 C_oof 2 Ts); 49.54, 46.79 (CH₂NCH₂); 42.41 (CH₂NHTs); 37.95(CH NH₂); 27.29 (NCH₂CH₂CH₂N); 26.38

2

(overlapping 2 CH₂); 21.32 (2 Me of 2 Ts).

( Æ )-(2RS,3SR)-N-{3-{[(4-Methylphenyl)sulfonyl]{4-[(trifluoroacetyl)amino]butyl}amino}propyl}-3-phe-

nyloxiranecarboxamide ((Æ)-10a). A mixture of (Æ)-8 (845mg, 2.975mmol), 9a (1.09 g, 3.22 mmol), Cs₂CO₃

(1.11 g, 3.407 mmol), and DMF (3.5ml) was stirred at r.t. under N ₂for 7 h and partitioned between H₂O

(100 ml) and CH₂Cl₂(75ml). The aq. layer was extracted with CH ₂Cl₂(2 Â 40 ml) and the combined org. phase

dried (Na₂SO₄) and evaporated under h.v. (12 h, r.t.): 2.015g of brown oil. The oil was dissolved in CH ₂Cl₂/CCl₄

1:1 (6 ml) and submitted to FC (SiO₂(100 ml), AcOEt/hexane 1:1 (500 ml), then 6 :4 (200 ml): pure (Æ)-10a

(1.055 g, 65.5%). White foam. R_f(AcOEt/hexane 1:1) 0.15. FT-IR (neat, NaCl): 3325s (br., NÀH), 3088m,

2046

Helvetica Chimica Acta Vol. 86 (2003)

3066m, 2942m, 2872m, 1717s (CO), 1668s (CO), 1598w, 1540s, 1496m, 1459m, 1380m, 1335s, 1306w, 1289w,

1267w, 1210s, 1184s, 1157s, 1090m, 1020w, 890w, 860w, 815m, 75 7w, 736m, 699m, 65 3w, 5 97w, 5 73w, 5 48w.

¹H-NMR (300 MHz, 45mg in 0.6 ml of CDCl ₃): 7.66 (d, J 8.3, 2 H_oof Ts); 7.23 7.4 (m, 7 arom. H,

NHCOCF₃); 6.80 (br. t, J 6.1, NHCO); 3.94 (d, J 1.9, HÀC(3)); 3.48 (d, J 1.9, HÀC(2)); 3.31 3.46

(m, 4 H); 3.02 3.23 (m, 4 H); 2.41 (s, Me); 1.78 (quint., J 6.7, NCH₂CH₂CH₂N); 1.64 (2 overlapping m,

CH₂CH₂). ¹³C-NMR (75MHz, CDCl ₃; d(CDCl₃) 76.93): 167.85(CONH); 157.35( q, J 36.5, CF₃CO); 143.57

(C_pof Ts); 135.7 (C_ipsoof Ts); 134.85(C _ipsoof Ph); 129.75(C _mof Ts); 128.88 (C_pof Ph); 128.52 (C_mof Ph); 126.98

(C_oof Ts); 125.67 (C_oof Ph); 115.86 (q, J 288, CF₃); 58.87, 58.77 (overlapping C(2), C(3)); 49.08, 46.88

(CH₂NCH₂); 39.12 (CH₂NHCOCF₃); 36.26 (CH₂NHCO); 28.74 (NCH₂CH₂CH₂N); 26.16, 25.79 (CH₂CH₂);

21.33 (Me). ESI-MS: 564 ([M Na] ).

( À )-(2R,3R)-N-{3-{[(4-Methylphenyl)sulfonyl]{4-[(trifluoroacetyl)amino]butyl}amino}propyl}-3-phenyl-

oxiranecarboxamide ((À)-10a) was prepared from (À)-8 by the same procedure as (Æ)-10a and was identical to

the latter. [a]_D À25.7 (c 1.6, CHCl₃).

( Æ )-(2RS,3SR)-3-Phenyl-N-{3-{(trifluoroacetyl){4-[(trifluoroacetyl)amino]butyl}amino}propyl]oxirane-

carboxamide (10b). A mixture of (Æ)-8 (500 mg, 1.76 mmol), 9b (2.03 g, 7.25mmol), Cs ₂CO₃(2.23 g,

7.04 mmol), and DMF (4 ml) was stirred at r.t. under N₂for 38 h. The mixture was quenched with H₂O/CH₂Cl₂,

and the excess 9b was filtered off. The aq. layer was extracted with CHCl₃(4Â), dried, and evaporated. The

residue (283 mg) was chromatographed by FC (SiO₂(25ml), gradient of 20 70% AcOEt/hexane): 10b

(146 mg, 17.2%). White foam. R_f(AcOEt/hexane 1:1) 0.15. FT-IR (neat, NaCl): 3313s (br., NÀH), 3094m,

2948m, 2869m, 2253w, 1715s (CO), 1682s (CO), 1546s, 1498w, 1460m, 1443m, 1383m, 1330w, 1313w, 1285w,

1202s, 1183s, 1152s, 1118m, 1028w, 912m, 893m, 85 9w, 75 8m, 735s, 698m, 666w, 649w, 5 97w. ¹H-NMR (300 MHz,

30 mg in 0.5ml of CDCl ₃; rotamers A/B 6 :4): 7.32 7.39 (m, 3 arom. H); 7.23 7.30 (m, 2 arom. H); 7.04 7.20

(br. m, NHCOCF₃of A and B); 6.77 (br. t, J 6.1, 0.6 H, NHCO of A); 6.52 (br. t, J 6, 0.4 H, NHCO of B);

3.92 (d, J 1.9, 0.6 H, HÀC(3) of A); 3.87 (d, J 1.9, 0.4 H, HÀC(3) of B); 3.51 (d, J 1.9, 0.4 H, HÀC(2) of

B); 3.49 (d, J 1.9, 0.6 H, HÀC(2) of A); 3.36 3.50 (m, 6 H); 3.20 3.36 (m, 2 H); 1.78 1.94 (m, 2 H,

NCH₂CH₂CH₂N); 1.55 1.76 (m, CH₂CH₂). ¹³C-NMR (75MHz, CDCl ₃; d(CDCl₃) 76.96): 167.94 (CONH);

157.49 (q, J 37.2, CF₃CONH); 157.18 (q, J 36, CF₃CONH); 156.7 (q, J 36, CF₃CO); 134.75, 134.52 (C_ipsoof

Ph of A and B, resp.); 129.05, 128.92 (C_pof Ph of B and A, resp.); 128.6, 128.53 (C_mof Ph of B and A, resp.);

125.65 (C_oof Ph); 116.36 (q, J 288, CF₃); 115.83 (q, J 288, CF₃CONH); 58.83, 58.80, 58.70, 58.65

(overlapping C(2), C(3) of A and B); 47.18, 46.53, 45.41, 44.27 (CH₂NCH₂of A and B); 38.99, 38.93

(CH₂NHTFA of B and A, resp.); 36.1, 36.0 (CH₂NHCO of B and A, resp.); 28.90, 27.31 (NCH₂CH₂CH₂N of B

and A, resp.); 25.86, 25.79, 25.65, 23.9 (CH₂CH₂of A and B). ESI-MS: 506 ([M Na] ).

( À )-(2R,3S)-N-{3-{(Naphthalen-2-ylsulfonyl){4-[(trifluoroacetyl)amino]butyl}amino}propyl}-3-phenyl-

oxiranecarboxamide ((À)-10c). A mixture of (À)-8 (704 mg, 2.479 mmol), 9c (1.134 mg, 3.032 mmol), and

Cs₂CO₃(1.094 g, 3.358 mmol) in DMF (2 ml) was stirred at r.t. for 60 h. Usual workup and purification by FC

(SiO₂(100 ml), AcOEt/hexane 65:35) provided ( À)-10c (1.136 g, 9.4%). Amorphous glass-like solid. M.p. 38

478. R_f(AcOEt/hexane 1:1) 0.15. [a]_D À27.9 (c 1.29, CHCl₃). FT-IR (KBr): 3378s (br., NÀH), 3091w,

3067w, 2939m, 2872m, 1718s (CO), 1667s (CO), 1545s, 1503w, 1460m, 1419w, 1382w, 1335s, 1211s, 1184s,

1155s, 1130s, 1073m, 1020w, 965w, 889w, 85 7w, 818w, 75 4m, 722m, 698m, 65 1w, 615w, 5 97w, 5 47m, 477w. ¹H-NMR

(300 MHz, 45mg in 0.6 ml of CDCl ₃): 8.37 (d, J 1.4, H_aof naphth.); 7.97 (d, J 8.4, 2 H); 7.91 (d, J 7.6, 1 H);

7.75( dd, J 1.7, 8.6, 1 H); 7.63 (dquint., J 1.5, 7, 2 H); 7.31 7.39 (m, 3 H of Ph); 7.24 7.30 (m, 2 H of Ph); 7.22

(br. t, NHCO); 6.79 (br. t, J 6.1, NHCOCF₃); 3.94 (d, J 1.9, HÀC(3)); 3.49 (d, J 1.9, HÀC(2)); 3.33 3.51

(m, 4 H); 3.08 3.32 (m, 4 H); 1.81 (quint., J 6.7, NCH₂CH₂CH₂N); 1.68 (m, CH₂CH₂). ¹³C-NMR (75MHz;

d(CDCl₃) 76.92): 167.88 (CONH); 157.35 (q, J 37, CF₃CO); 135.58, 134.80, 134.71, 132.11 (4 quat. arom. C);

129.50, 129.11, 128.91, 128.81, 128.54, 128.40, 127.81, 127.62, 125.68, 122.12 (arom. CH); 115.85 (q, J 288, CF₃);

58.94, 58.80 (C(2), C(3)); 49.22, 47.04 (CH₂NCH₂); 39.13 (CH₂NHCOCF₃); 36.33 (CH₂NHCO); 28.82

(NCH₂CH₂CH₂N); 26.30, 25.81 (CH₂CH₂). ESI-MS: 600 ([M Na] ).

( Æ )-(2RS,3SR)-N-{3-{[(4-Methylphenyl)sulfonyl]{4-{[(2,2,2-trichloroethoxy)carbonyl]amino}butyl}ami-

no}propyl}-3-phenyloxiranecarboxamide (10d). A mixture of (Æ)-8 (549 mg, 1.933 mmol), 9d (1.049 g,

2.513 mmol), and Cs₂CO₃(819 mg, 2.513 mmol) in DMF (5 ml) was stirred at r.t. for 60 h. The mixture was

quenched with CH₂Cl₂(200 ml) and washed with 5% aq. citric acid (60 ml), the org. phase dried (Na₂CO₃) and

evaporated, and the obtained brown oil (1.44 g) dissolved in a small amount of CH₂Cl₂/CCl₄1:1 and

chromatographed (SiO₂(150 ml), with AcOEt/hexane 1:1 (800 ml)): unreacted 9d, then 10d (760 mg, 63.3%).

Colorless foam, amorphous solid. M.p. 39 408. R_f(AcOEt/hexane 1 :1) 0.16. FT-IR (neat, NaCl): 3353m (br.,

NÀH), 3064w, 2946m, 2871w, 1737s (amide CO), 1671s (carbamate CO), 1598w, 1537s, 1460m, 1335s,

1306m, 1242s, 1157s, 1090m, 1030w, 95 5w, 889w, 816m, 75 8m, 734s, 700m, 65 4m, 5 98w, 5 71w, 5 49m. ¹H-NMR

Helvetica Chimica Acta Vol. 86 (2003)

2047

(300 MHz, 25mg in 0.6 ml of CDCl ₃): 7.68 (d, J 8.3, 2 H_oof Ts); 7.25 7.38 ( m, 7 arom. H); 6.78 (br. t, J 6.0,

NHCO); 5.32 (br. t, NHTroc); 4.73, 4.68 (2 −d× (AB), ²J 12, CH₂O); 3.95( d, J 2.0, HÀC(3)); 3.51 (d, J 2.0,

HÀC(2)); 3.30 3.52 (2 overlapping m, ³J 6.6, CH₂NHCO); 3.02 3.29 (overlapping m, 2 CH₂N); 3.24

(overlapping q, J 6.4, CH₂N); 2.42 (s, Me); 1.79 (quint., J 6.7, NCH₂CH₂CH₂N); 1.5 1.68 (2 overlapping m,

CH₂CH₂). ¹³C-NMR (75MHz, CDCl ₃; d(CDCl₃) 76.91): 167.69 (CONH); 154.62 (OCONH); 143.44 (C_pof Ts);

135.99 (C_ipsoof Ts); 134.94 (C_ipsoof Ph); 129.71 (C_mof Ts); 128.85(C _pof Ph); 128.51 (C_mof Ph); 127.02 (C_oof

Ts); 125.71 (C_oof Ph); 95.61 (CCl₃); 74.35(CH ₂O); 58.92 (overlapping C(2) and C(3)); 48.90, 46.41

(CH₂NCH₂); 40.53 (CH₂NHTroc); 35.87 (CH₂NHCO); 28.70 (NCH₂CH₂CH₂N); 26.79, 26.1 (CH₂CH₂); 21.37

(Me of Ts). ESI-MS: 642, 644, 646, 648 (100, 95, 35, 7, [M Na] ).

( Æ )-(2RS,3SR)-N-{3-{{4-{[(1,1-Dimethylethoxy)carbonyl]amino}butyl}[(4-methylphenyl)sulfonyl]ami-

no}propyl}-3-phenyloxiranecarboxamide (10e). A mixture of (Æ)-8 (491 mg, 1.729 mmol), 9e (1.183 g,

3.458 mmol), and anh. Cs₂CO₃(1.127 g, 3.458 mmol) in anh. DMF (16 ml) was stirred at r.t. until full

consumption of starting 8 (17 h) monitored by TLC (5% MeOH/CHCl₃). After partitioning between H₂O

(100 ml) and CH₂Cl₂(75ml), the aq. layer was extracted with CH ₂Cl₂(2 Â 40 ml), the combined org. phase

dried (Na₂CO₃) and evaporated under h.v., and the obtained pale brown oil (1.92 g) dissolved in a small amount

of CH₂Cl₂/CCl₄1:1 and submitted to FC (SiO₂(150 ml), AcOEt/hexane 1:1 (500 ml; ! unreacted 9e), then

7:3): 10e (700 mg, 74.3%). White foam, glass-like oil. R_f(AcOEt/hexane 1 :1) 0.18. FT-IR (neat, NaCl): 3339s

(NÀH), 3065s, 2976s, 2934s, 2870s, 1694s (CO), 1598m, 1537s, 1460s, 1392m, 1366m, 1335s, 1253s, 1170s,

1090m, 1020m, 999m, 889m, 864w, 816m, 75 8s, 736s, 699m, 65 4m, 5 98w, 5 74m, 5 49m. ¹H-NMR (300 MHz, 25mg

in 0.6 ml of CDCl₃): 7.68 (d, J 8.3, 2 H_oof Ts); 7.25 7.37 ( m, 7 arom. H); 6.84 (br. t, J 6.0, NHCO); 4.64

(br. s, NHBoc); 3.96 (d, J 2.0, HÀC(3)); 3.50 (d, J 2.0, HÀC(2)); 3.30 3.51 (2 overlapping m, ³J 6,

CH₂NHCO); 3.03 3.25( m, 3 CH₂N); 2.42 (s, Me); 1.79 (quint., J 6.7, NCH₂CH₂CH₂N); 1.4 1.65(2

overlapping m, CH₂CH₂); 1.43 (s, Me₃C). ¹³C-NMR (75MHz, CDCl ₃; d(CDCl₃) 76.91): 167.63 (CONH);

155.91 (OCONH); 143.35 (C_pof Ts); 136.14 (C_ipsoof Ts); 135.02 (C_ipsoof Ph); 129.68 (C_mof Ts); 128.80 (C_pof

Ph); 128.48 (C_mof Ph); 127.0 (C_oof Ts); 125.71 (C_oof Ph); 79.08 (Me₃C); 58.87 (overlapping C(2), C(3)); 48.78,

46.02 (CH₂NCH₂); 39.81 (br., CH₂NHBoc); 35.61 (CH₂NHCO); 28.60 (NCH₂CH₂CH₂N); 28.3 (Me₃C); 27.23,

26.07 (CH₂CH₂); 21.36 (Me of Ts). CI-MS (NH₃): 563 (4, [M NH₄] ), 546 (6, [M H] ), 446 (100, [M À t-

BuOCO 2 H] ).

( Æ )-(2RS,3SR)-N-{3-{[(4-Methylphenyl)sulfonyl]{4-{[(4-methylphenyl)sulfonyl]amino}butyl}amino}-

propyl}-3-phenyloxiranecarboxamide (10h). Oxalyl chloride (0.429 ml, 2 equiv.) was added to a cold (ice/water

bath) suspension of 5 (1.009 g, 5.0 mmol) in THF. The cold bath was removed and stirring continued until the

gas evolution ceased (30 min). After evaporation under h.v., the solid colorless mixture of acid chloride 7 and

KCl [5] was dissolved in CH₂Cl₂(20 ml) and allowed to cool (ice/water bath). After addition of amine 9h

(2.265g, 5.0 mmol) in CH ₂Cl₂(20 ml) and Et₃N (3 ml), the bath was removed and the mixture stirred at r.t. for

20 min, then evaporated. The residue was partitioned between Et₂O and H₂O and the org. layer washed with aq.

5% citric acid (2 Â 30 ml), H₂O (2 Â 20 ml), and sat. aq. NaHCO₃soln. (2 Â 30 ml), dried (Na₂CO₃) and

evaporated under h.v. (408, 60 min): pure 10h (2.755 g, 92%). White solid. FT-IR (KBr): 3350m (NÀH), 3287m

(NÀH), 3065w, 2938m, 2870m, 1667s (CO), 1598m, 1539s, 1495w, 1459m, 1381w, 1330s, 1306m, 1289m, 1229w,

1159s, 1091s, 1020w, 889w, 860w, 815m, 75 7m, 726m, 699m, 65 5m, 5 70m, 5 5s0. ¹H-NMR (300 MHz, 38 mg in

0.7 ml of CDCl₃): 7.71 (d, J 8.3, 2 H_oof TsNH); 7.65( d, J 8.3, 2 H_oof TsN); 7.22 7.4 (m, 9 arom. H); 6.80

(br. t, J 6.1, NHCO); 5.20 (t, J 6.25, NHTs); 3.97 (d, J 2.0, HÀC(3)); 3.51 (d, J 2.0, HÀC(2)); 3.29 3.48

(m, ³J 6.8, CH₂NHCO); 3.0 3.2 (m, overlapping 2 CH₂N); 2.92 (q (ddd), J 6.5, CH₂NHTs); 2.39, 2.41 (2 s, 2

Me); 1.79 (quint., J 6.6, NCH₂CH₂CH₂N); 1.45 1.66 (2 overlapping m, 4 H, CH₂CH₂). ¹³C-NMR (75MHz,

CDCl₃; d(CDCl₃) 76.93): 167.82 (CONH); 143.42 (C_pof TsN); 143.14 (C_pof TsNH); 136.99 (C_ipsoof TsNH);

135.86 (C_ipsoof TsN); 135.0 (C_ipsoof Ph); 129.72, 129.57 (4 C_mof 2 Ts); 128.80 (C_pof Ph); 128.48 (C_mof Ph);

127.01, 126.89 (4 C_oof 2 Ts); 125.76 (C_oof Ph); 58.86 (overlapping C(2), C(3)); 48.91, 46.57 (CH₂NCH₂); 42.48

(CH₂NHTs); 36.07 (CH₂NHCO); 28.73 (NCH₂CH₂CH₂N); 26.42, 25.96 (CH₂CH₂); 21.36 (2 Me of 2 Ts). ESI-

MS: 622 ([M Na] ).

( Æ )-(2RS,3SR)-N-{3-{[(4-Methylphenyl)sulfonyl](4-aminobutyl)amino}propyl}-3-phenyloxiranecarboxa-

mide (11). A soln. of 10a (52 mg, 0.096 mmol), K₂CO₃(145mg) in MeOH (5ml), and H ₂O (2 ml) was stirred at

r.t. and monitored by TLC (8 h), then quenched with sat. aq. Na₂CO₃soln. (10 ml) followed by extraction with

CH₂Cl₂(3 Â 10 ml). The combined org. soln. gave 44 mg of oil after drying (Na₂CO₃) and evaporation under h.v.

The product was slowly converted to the dimer after intermolecular oxirane opening with amine. R_f(CHCl₃/

MeOH/25% aq. NH₃soln. 90 :9 :1) 0.15. ¹H-NMR (300 MHz, 44 mg in 0.6 ml of CDCl₃; contains ca. 25% of the

dimer): 7.68 (d, J 8.3, 2 H_oof Ts); 7.24 7.4 (m, 7 arom. H); 6.86 (br. t, J 6.2, NHCO); 3.95( d, J 1.9,

HÀC(3)); 3.5( d, J 1.9, HÀC(2)); 3.30 3.49 (m, 2 H); 3.05 3.25 ( m, 4 H); 2.67 (t, J 6.7, CH₂NH₂); 2.42

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(s, Me); 1.79 (quint., J 6.7, NCH₂CH₂CH₂N); 1.57 (quint. (unres. m), J 7.3, 2 H); 1.40 (quint. (unres. m), J

7.3, 2 H). ¹³C-NMR (75MHz, CDCl ₃; d(CDCl₃) 76.93): 167.60 (CONH); 143.30 (C_pof Ts); 136.26 (C_ipsoof Ts);

135.01 (C_ipsoof Ph); 129.65(C _mof Ts); 128.79 (C_pof Ph); 128.48 (C_mof Ph); 126.99 (C_oof Ts); 125.7 (C_oof Ph);

58.85 (overlapping C(2), C(3)); 48.88, 45.79 (CH₂NCH₂); 41.5(CH ₂NH₂); 35.59 (CH₂NHCO); 30.62

(NCH₂CH₂CH₂N); 28.54, 26.16 (CH₂CH₂); 21.35(Me). ESI-MS: 446 (100, [ M H] ), 468 (10, [M Na] ),

891 (16, [2M H] ), 913 (4, [2M Na] ).

One-Pot Deprotection-Macrocyclization of ( Æ )-10a in EtOH under Reflux. A biphasic mixture of (Æ)-10a

(374 mg, 0.691 mmol) in EtOH (150 ml), sat. aq. Na₂CO₃soln. (15ml), and H ₂O (15ml) was stirred under

reflux and N₂for 22 h. Evaporation to a small volume, dilution with H₂O (30 ml), and extraction with CHCl₃

(4 Â 20 ml) yielded an org. soln. that was dried (Na₂CO₃) and evaporated. The crude product was analyzed by

¹H-NMR. FC (SiO₂(25ml), 2% MeOH/CHCl ₃(100 ml; ! (Æ)-12 (264 g, 85.8%; see below)), then 4% MeOH/

CHCl₃(50 ml), CHCl₃/MeOH/25% aq. NH₃soln. 90 :9 :1 (100 ml), and CHCl₃/MeOH/25% aq. NH₃soln.

85:14 :1 (100 ml)) gave crude 22 (25mg, 6.9% by NMR) contaminated with dimeric macrocycle 23 (1.1% by

¹H-NMR).

Data of ( Æ )-(aRS,bRS)-N-{3-{(4-Aminobutyl)[(4-methylphenyl)sulfonyl]amino}propyl}-b-ethoxy-a-hy-

droxybenzenepropanamide (22). R_f(CHCl₃/MeOH/25% aq. NH₃soln. 85:14 :1) 0.13. ¹H-NMR (300 MHz,

20 mg in 0.6 ml of CDCl₃): 7.61 (d, J 8.2, 2 H_oof Ts); 7.20 7.36 (m, 7 arom. H); 6.92 (br. t, J 6.1, NHCO);

4.67 (d, J 4.4, HÀC(b)); 4.41 (d, J 4.9, HÀC(a)); 3.47 (q with fine splitting, J 7, OCH₂Me); 3.29 (dt

(dddd), ³J 6.5, ²J 14, CH₂NHCO); 2.92 3.20 (m, 3 H); 2.81 (t with fine splitting, J 6.5, CH₂N); 2.68 (t, J

6.7, CH₂NH₂); 2.43 (s, Me of Ts); 1.34 1.66 (m, 3 CH₂); 1.20 (t, J 6.9, Me of Et). ¹³C-NMR (75MHz;

d(CDCl₃) 76.90): 170.88 (CONH); 143.16 (C_pof Ts); 137.09 (C_ipsoof Ts); 136.29 (C_ipsoof Ph); 129.55 (C_mof Ts);

127.84 (overlapping C_p, C_m, C_oof Ph); 127.02 (C_oof Ts); 81.57 (C(b)); 74.09 (C(a)); 64.45(CH ₂O); 48.81, 45.63

(CH₂NCH₂); 41.29 (CH₂NH₂); 35.43 (CH₂NHCO); 30.06 (NCH₂CH₂CH₂N); 28.49, 26.14 (CH₂CH₂); 21.36 (Me

of Ts); 15.17 (Me of Et). ESI-MS: 492 (100, [M H] ), 514 (95, [M Na] ).

Data of 23 (extracted from the ¹H-NMR of crude 22): ¹H-NMR (selected d): 4.61 (d, J 3.9, PhCH); 4.09

(d, J 3.9, CHOH). ESI-MS: 913 ([M Na] ), 891 ([M H] ).

One-Pot Deprotection-Macrocyclization of ( Æ )-10a in i-PrOH under Reflux. Concentration of (Æ)-10a and

workup as described in the previous experiment with EtOH. A soln. of (Æ)-10a (157 mg, 0.290 mmol) in i-PrOH

(63 ml), sat. aq. Na₂CO₃soln. (6.3 ml) and H₂O (6.3 ml) was stirred under reflux for 23 h. FC after workup gave

(Æ)-12 (105mg, 81.3%). A crude mixture of at least three by-products (24 mg) was eluted with CHCl ₃/MeOH/

25% aq. NH₃soln. 85:14 :1.

One-Pot Deprotection-Macrocyclization of ( À )-10a in i-PrOH at 708. A soln. of (À)-10a (546 mg,

1.008 mmol) in i-PrOH (300 ml), sat. aq. Na₂CO₃soln. (30 ml), and H₂O (90 ml) was stirred at 708 for 36 h. FC

after workup gave ()-12 (382 mg, 85%).

One-Pot Deprotection-Macrocyclization of ( Æ )-10a in THF at Reflux. A mixture of (Æ)-10a (119 mg,

0.220 mmol) in THF (30 ml), sat. aq. Na₂CO₃soln. (5ml), and H ₂O (45ml) was stirred under reflux and N ₂until

no (Æ)-10a or the intermediate amine 11 could be observed (48 h). FC after workup gave (Æ)-12 (64 mg,

65.4%).

Preparation of ()-12 via One-Pot N,C Coupling, CF₃CO Deprotection, andMacrocyclization . (Bromo-

propyl)oxiranecarboxamide (À)-8 (2.004 g, 7.052 mmol), anh. Cs₂CO₃(2.836 g, 1.25equiv.), 9a (2.895g,

1.2 equiv.), and anh. DMF were stirred at r.t. under N₂for 22 h. The mixture was quenched with i-PrOH

(500 ml), sat. aq. Na₂CO₃soln. (50 ml), and H₂O (150 ml) and stirred at 708 for 48 h. Usual workup and FC gave

()-12 (1.647 g, 52.4%).

Data of ( Æ )-(2RS,3RS)-3-Hydroxy-9-[(4-methylphenyl)sulfonyl]2-phenyl-1,5,9-triazacyclotridecan-4-one

1

((Æ)-12): For H- and ¹³C-NMR assignments from 2D NMR data (600 MHz), see also [5]. White foam. M.p.

80 928 (reproducible and reversible). R_f(5% MeOH/CHCl₃) 0.2. FT-IR (neat, NaCl): 3375s (br.), 3313s (br.),

3064w, 3029w, 2931s, 2858m, 2254w, 1919w, 1810w, 1652s (CO), 1599w, 1538s, 1494w, 1454s, 1402w, 1331s,

1306m, 1231w, 1197w, 1155s, 1122m, 1106m, 1089m, 1063m, 1030m, 981w, 912m, 816m, 731s, 701m, 65 6m, 5 64m,

548m. ¹H-NMR (600 MHz, 38 mg in 0.7 ml of CDCl₃): 8.49 (br. t, NHCO); 7.68 (d, J 8.2, 2 H_oof Ts); 7.37

(t, J 7.5, 2 H _mof Ph); 7.32 (d, J 8.3, 2 H_mof Ts); 7.29 (t, J 7.4, H_pof Ph); 7.23 (d, J 7.3, 2 H_oof Ph); 3.99

(m, J(2,3) 10.1, HÀC(3)); 3.70 (br. s, OH); 3.5 3 m( , 1 HÀC(6)); 3.47 (d, J(2,3) 10.1, HÀC(2)); 3.39

(m, 1 HÀC(10)); 3.28 (overlapping m, 1 HÀC(8)); 3.25(overlapping m, 1 HÀC(6)); 3.16 (m, 1 HÀC(8)); 2.88

(ddd, ³J 4.6, 9.2, ²J 13.9, 1 HÀC(10)); 2.60 (ddd, ³J 4.2, 5.6, ²J 12.6, HÀC(13)); 2.43 (s, Me); 2.35

(ddd, ³J 4.1, 9.2, ²J 12.9, HÀC(13)); 1.90 1.99 (m, CH₂(7)); 1.83 (m, 1 HÀC(11)); 1.69 (m, 1 HÀC(11));

1.48, 1.41 (2m, CH₂(12)). ¹H-NMR (300 MHz, 9 mg in 0.7 ml of CDCl₃; selected resonances, the rest is identical

to the preceding spectrum): 3.99 (dd, ³J(2,3) 10.1, ³J(CH,OH) 2.5, HÀC(3)); 3.69 (d, ³J(CH,OH) 2.5,

Helvetica Chimica Acta Vol. 86 (2003)

2049

OH); 3.48 (d, ³J(2,3) 10.1, HÀC(2)). ¹H-NMR (300 MHz, 30 mg in 0.6 ml of (D₆)DMSO; d((D₆)DMSO) 2.5,

selected resonances): 7.92 (t, J 5.8, NHCO); 5.06 (d, J 6.4, OH); 3.74 (dd, J 6.4, 9.5, HÀC(3)); 3.47

(br. d, J 9.1, HÀC(2)). ¹³C-NMR (75MHz, CDCl ₃, d(SiMe₄) 0): 173.61 (CONH); 143.60 (C_pof Ts); 140.46

(C_ipsoof Ph); 136.32 (C_ipsoof Ts); 129.95(C _mof Ts); 128.91 (C_mof Ph); 128.0 (C_pof Ph); 127.56 (C_oof Ph); 127.40

(C_oof Ts); 72.61 (HÀC(3)); 66.06 (HÀC(2)); 48.55 (CH₂(10)); 46.59 (CH₂(8)); 43.96 (CH₂(13)); 37.36

(CH₂(6)); 29.08 (CH₂(7)); 25.29 (CH₂(12)); 24.20 (CH₂(11)); 21.69 (Me). ESI-MS: 446 (100, [M H] ), 468 (8,

[M Na] ).

Data of ()-(2R,3R)-3-Hydroxy-9-[(4-methylphenyl)sulfonyl]-2-phenyl-1,5,9-triazacyclotridecan-4-one

(()-12): Amorphous glass-like solid. M.p. 87 938 (irreversible). [a]_D 10.3 (c 1.02, CHCl₃). FT-IR

(KBr): 3381s (br., NÀH), 3062w, 3027w, 2928s, 2860m, 1656s (CO), 1599w, 1550s, 1495w, 1454m, 1402w, 1333s,

1305m, 1224w, 1195w, 1156s, 1108w, 1089m, 1058m, 1029m, 980w, 816m, 75 2m, 701m, 65 5m, 5 64m, 5 47m. NMR:

identical to those of (Æ)-12. ESI-MS: 446 (100, [M H] ), 468 (35, [M Na] ).

( Æ )-(2RS,3RS)-3-Hydroxy-2-phenyl-1,5,9-triazacyclotridecan-4-one ((Æ)-13). The biphasic mixture of

(Æ)-10b (43 mg, 0.089 mmol) in EtOH (20 ml), sat. aq. Na₂CO₃soln. (2 ml), and H₂O (4 ml) was stirred at 608

under N₂for 72 h. After evaporation to a small volume, the mixture was quenched with sat. aq. Na₂CO₃soln.

(20 ml) and extracted with CHCl₃(4 Â 20 ml) and the combined org. phase dried (Na₂CO₃) and evaporated

under h.v.: crude (Æ)-13 (29 mg, 70% by NMR). FC (Al₂O₃(20 ml), CHCl₃/MeOH/aq. 25% NH₃soln.

95:4.5:0.5 (50 ml), then CHCl ₃/MeOH/aq. 25% NH₃soln. 90 :9 :1 (100 ml)) gave (Æ)-13 (17.5mg, 67.5%).

Data completely identical to those of ()-13; see also [5].

()-(2R,3R)-3-Hydroxy-2-phenyl-1,5,9-triazacyclotridecan-4-one (()-13). According to [5], ()-12

(210 mg, 0.471 mmol) was electrochemically detosylated (see also detosylation of 10h below). The obtained

soln. after electrolysis was evaporated, treated with H₂O (40 ml) and sat. aq. Na₂CO₃soln. (40 ml) followed by

extraction with CH₂Cl₂(4 Â 15ml). The combined org. phase was dried (Na ₂CO₃) and evaporated under h.v.:

()-13 (138 mg, 100%). White foam, >95% purity by NMR, which was used in the next step without further

purification. R_f(SiO₂, CHCl₃/MeOH/aq. 25%. NH₃soln. 70:25:5) 0.15. R_f(Al₂O₃, CHCl₃/MeOH/aq. 25% NH₃

soln. 90 :9 :1) 0.25. [a]_D 10.0 (c 1.07, CHCl₃). FT-IR (KBr): 3390s (br.), 3288s (br.), 3081m, 3062m, 3028m,

2924s, 2852s, 1653vs (CO), 1550s, 1496m, 1454s, 1437s, 1369m, 1305m, 1258m, 1230m, 1190m, 1122s, 1064m,

1

958w, 85 6w, 763m, 700s, 617w. H-NMR (300 MHz, 12 mg in 0.6 ml of CDCl₃): 9.17 (br. s, NHCO); 7.33 7.41

(m, 2 arom. H); 7.26 7.32 (m, 3 arom. H); 3.99 (d, J 10.0, HÀC(3)); 3.68 (m, 1 HÀC(6)); 3.56 (d, J 10.0,

HÀC(2)); 3.34 (m, 1 HÀC(6)); 2.76 2.92 (complex m, CH₂(8)); 2.63 2.72 (m, CH₂(10)); 2.58 (ddd, J 2.7,

5.8, 11.7, 1 HÀC(13)); 2.43 (ddd, J 2.8, 9.5, 11.5, 1 HÀC(13)); 1.67 1.8 (m, 2 H); 1.52 1.67 (m, 3 H); 1.36

1.52 (m, 1 H). ¹³C-NMR (75MHz; d(CDCl₃) 76.93): 172.92 (CONH); 140.77 (C_ipso); 128.44 (C_m); 127.36

(overlapping C_o, C_p); 72.24 (C(3)); 66.25(C(2)); 49.93, 48.33 (C(8), C(10)); 45.47 (C(13)); 40.21 (C(6)); 27.72,

27.67, 27.57 (overlapping C(7), C(11), C(12)). ESI-MS: 292 (100, [M H] ), 304 (15, [M Na] ).

()-(2R,3R)-9-[(2E)-1-Oxo-3-phenylprop-2-enyl]-3-{[(2E)-1-oxo-3-phenylprop-2-enyl]oxy}-2-phenyl-

1,5,9-triazacyclotridecan-4-one (()-14). To a cold (ice/water bath) soln. of ()-13 (40.1 mg, 0.138 mmol) in

CH₂Cl₂(4 ml), cinnamoyl chloride (58 mg, 0.345 mmol), and DMAP (51 mg, 0.414 mmol) were added and

stirred for 30 min. The obtained mixture was submitted to FC (SiO₂(20 ml), gradient CH₂Cl₂! 2% MeOH/

CH₂Cl₂): ()-14 (70 mg, 92%). Glass-like amorphous solid. R_f(5% MeOH/CHCl₃) 0.3. [a]_D 35.0 (c 1.0,

CHCl₃). FT-IR (KBr): 3418m (br., NÀH), 3299s (br., NÀH), 3083w, 3060m, 3027m, 2926s, 2853m, 1955w,

1886w, 1715s, 1679s, 1648vs, 1599s, 1578m, 1553m, 1496m, 1450s, 1437s, 1377m, 1332s, 1306m, 1281m, 1244s,

1202s, 1164s, 1125m, 1072m, 1060m, 1027m, 976m, 915w, 861m, 764s, 734w, 701s, 684m, 613w, 5 90w, 5 5 7w, 5 37m,

1

484w. H-NMR (300 MHz, 60 mg in 0.6 ml of CDCl₃): 7.71 (m, J_trans 15.5, PhCHCHCON); 7.50 (m, 2 H of

PhCHCH); 7.2 7.45( m, 14.5H); 7.07 (br. s, 0.5H, NHCO); 6.83 ( d, J_trans 15.4, 1 H, PhCHCHCON); 6.21

(m, J_trans 16, PhCHCHCO₂); 5.28 (2d, J 10, 0.5 0.5H, CH ÀO); 4.11 (d, J 10.2, PhCHNH); 5.25 5.85

(br. m, 5H); 3.1 (br. m, 1 H); 2.74 (br. m, 1 H); 2.48 (br. m, 1 H); 2.16 (br. m, 1 H); 1.76 2.03 (br. m, 2 H);

1.48 1.75(br. m, 2 H); 1.39 (br. m, 1 H). ¹³C-NMR (75MHz; d(CDCl₃) 76.96, two rotamers A and B): 169.36

(CO); 166.13 (CO); 165.76 (CO); 145.85 (CH); 142.47, 142.26 (CH of A and B); 140.13 (C_ipso); 135.28,

133.93 (2 C_ipsoof 2 PhCH); 130.4, 129.43 (2 C_pof 2 PhCH); 128.73, 128.68, 128.56, 128.03, 127.69, 127.21

(arom. CH); 117.53, 116.76 (2 CH); 76.25, 76.15 (CHO of A and B); 63.98, 63.86 (CHNH of A and B); 46.61,

45.74, 44.44, 44.07, 42.94 (3 CH₂N of A and B); 37.13, 36.65( CH₂NHCO of A and B); 27.48, 25.65, 24.46, 23.67,

23.57, 23.7 (3 CH₂of A and B). ESI-MS: 552 (100, [M H] ), 574 (100, [M Na] ).

( À )-(2R,3R)-3-Hydroxy-9-[(2E)-1-oxo-3-phenylprop-2-enyl]-2-phenyl-1,5,9-triazacyclotridecan-4-one

(( À )-(2R,3R)-3-Hydroxycelacinnine; (À)-1a). A soln. of ()-14 (67 mg, 0.121 mmol) in MeOH (5ml) and

NaOH (250 mg) was stirred at r.t. for 60 min. Then the mixture was partitioned between H₂O (30 ml) and

CH₂Cl₂(4 Â 10 ml), the org. phase dried (Na₂CO₃) and evaporated, and the residue (50 mg) purified by FC

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Helvetica Chimica Acta Vol. 86 (2003)

(SiO₂(20 ml), 5% MeOH/CHCl₃): (À)-1a (46 mg, 90%). Colorless glass-like amorphous solid. M.p. 112 1148,

irreversible. [a]_D À3.2 (c 0.73, CHCl₃/MeOH 30 :1). FT-IR and NMR: identical to the data of (Æ)-1a [5].

ESI-MS: 422 (100, [M H] ), 444 (65, [M Na] ).

( À )-(2R,3R)-3-Hydroxy-9-(naphthalene-2-ylsulfonyl)-2-phenyl-1,5,9-triazacyclotridecan-4-one ((À)-15).

A soln. of (À)-10c (1.092 g, 1.893 mmol) in i-PrOH (300 ml), sat. aq. Na₂CO₃soln. (30 ml), and H₂O

(100 ml) was stirred at 708 for 22 h. Usual workup and FC (SiO₂(50 ml), 2% MeOH/CHCl₃) gave (À)-15

(772 mg, 84.8%). Amorphous solid. M.p. 96 1008. [a]_D À1.5( c 1.14, CHCl₃). FT-IR (KBr): 3383s (br.),

3057w, 3026w, 2929s, 2858m, 1656s (CO), 1589w, 1547s, 1503w, 1454m, 1331s, 1269w, 1196w, 1154s, 1128s,

1073s, 1027m, 981w, 95 1w, 85 8w, 819w, 75 1s, 700s, 65 3s, 615m, 5 45s, 477w. ¹H-NMR (300 MHz, 33 mg in 0.6 ml of

CDCl₃): 8.44 (br. t, NHCO); 8.38 (d, J 1.4, HÀC(a) of naphth.); 7.84 8.0 (m, 3 H); 7.77 (dd, J 1.7, 8.8, 1 H);

7.58 7.68 (m, 2 H); 7.20 7.40 (m, 5H); 3.98 ( d, J(2,3) 10.1, HÀC(3)); 3.67 (br. s, OH); 3.40 3.6 (over-

lapping, 1 HÀC(6), 1 HÀC(10)); 3.47 (overlapping d, J(2,3) 10.1, HÀC(2)); 3.17 3.40 (m, CH₂(8),

HÀC(6)); 2.97 (ddd, ³J 4.6, 9.2, ²J 13.9, 1 HÀC(10)); 2.58 (ddd, ³J 4.6, 5.2, ²J 12.6, 1 HÀC(13)); 2.35

2

(ddd, ³J 4.1, 9.2, J 12.9, 1 HÀC(13)); 1.91 2.02 (m, CH₂(7)); 1.83 (m, 1 HÀC(11)); 1.69 (m, 1 HÀC(11));

1.32 1.55 (2m, CH₂(12)). ¹³C-NMR (75MHz; d(CDCl₃) 76.94): 173.3 (CONH); 140.05, 136.06, 134.68, 132.14

(4 quat. arom. C); 129.37, 129.1, 128.69, 128.62, 128.36, 127.82, 127.72, 127.52, 127.29, 122.38 (arom. CH); 72.37

(C(3)); 65.76 (C(2)); 48.23 (CH₂(10)); 46.25(CH ₂(8)); 43.69 (CH₂(13)); 37.06 (CH₂(6)); 28.87 (CH₂(7)); 24.89

(CH₂(12)); 23.93 (CH₂(11)). ESI-MS: 482 ([M H] ).

Electrochemical Detosylation of 10h. A soln. of 10h (411 mg, 0.686 mmol) in 0.1n Me₄NCl/EtOH (200 ml)

was electrolyzed according to [5] and evaporated to a small volume. The obtained soln. was acidified with aq.

10% citric acid soln. (15ml), washed with CH ₂Cl₂(4 Â 20 ml), saturated with K₂CO₃, and extracted with CH₂Cl₂

(6 Â 20 ml). The combined org. extract was dried (Na₂CO₃) and evaporated under h.v., and the hygroscopic

solid (318 mg) submitted to FC (SiO₂(50 ml), CH₂Cl₂/MeOH/aq. 25%. NH₃soln. 70 :25:5(200 ml), followed

by CH₂Cl₂/MeOH/aq. 25%. NH₃soln. 65:28 :7 (200 ml)): 16a (28 mg, 15%) then 16b (58 mg, 29%).

Data of N-{3-[(4-Aminobutyl)amino]propyl}benzenepropanamide (16a): ¹H-NMR (300 MHz, 28 mg in

0.8 ml of CDCl₃): 7.14 7.33 (m, 5arom. H); 6.88 (br. s (unres. t), NHCO); 3.29 (q (dt), J 6.0, CH₂NHCO);

2.95( t, J 7.7, PhCH₂); 2.71 (t, J 6.1, CH₂NH); 2.62, 2.57 (2 overlapping t, J 6.3, 6.5, resp., CH₂NH,

CH₂NH₂); 2.46 (t, J 7.7, CH₂CO); 2.41 (br. s, NH, NH₂); 1.61 (quint., J 6.1, NCH₂CH₂CH₂N); 1.50, 1.51 (2

overlapping quint., CCH₂CH₂C). ¹³C-NMR (75MHz, CDCl ₃; d(CDCl₃) 76.93): 172.05(CONH); 140.95(C _ipso);

128.32, 128.27 (C_o, C_m); 126.0 (C_p); 49.35, 47.70, 41.62 (3 CH₂); 38.41 (2 overlapping CH₂); 31.71, 30.98, 28.4,

27.17 (4 CH₂).

Data of ( Æ )-N-{3-[(4-Aminobutyl)amino]propyl}-a-hydroxybenzenepropanamide (16b): ¹H-NMR

(300 MHz, 58 mg in 1 ml of CDCl₃): 7.56 (br. t, NHCO); 7.2 7.34 (m, 5arom. H); 4.22 ( dd, J 3.6, 8.5,

CHOH); 3.29 (br. q, J 5.7, CH₂NHCO); 3.21 (dd, ³J 3.6, ²J 13.8, PhCH₂); 3.21 (dd, ³J 8.5, ²J 13.8,

PhCH₂); 2.59 (overlapping m, 2 CH₂); 2.49 (overlapping m, CH₂); 2.3 2.7 (overlapping br. s, OH, NH, NH₂);

1.59 (m, NCH₂CH₂CH₂N); 1.42 (m, CCH₂CH₂C). ¹³C-NMR (75MHz, CDCl ₃; d(CDCl₃) 76.95): 173.66

(CONH); 138.21 (C_ipso); 129.54 (C_o); 128.12 (C_m); 126.27 (C_p); 72.47 (CHOH); 49.03, 47.76, 41.32, 41.01, 37.9,

30.34, 28.73, 26.83 (8 CH₂).

Reductive Troc Cleavage with Zn in the Presence of NH₄OAc Buffer (pH 7) [13] Followedby

Macrocyclization. A mixture of Zn powder (1 g), 0.5m sat. aq. NH₄OAc soln. (5ml), 10d (160 mg, 0.258 mmol),

and THF (25ml) was stirred vigorously under N ₂for 16 h at r.t. After quenching with sat. aq. Na₂CO₃soln.

(10 ml), the mixture was refluxed for 36 h. The solid residue was filtered, the soln. extracted with CH₂Cl₂, the

extract evaporated, and the oil (145mg) submitted to FC (SiO ₂(25ml), 5% MeOH/CHCl ₃)): crude (Æ)-12

(50 mg). Additional FC (SiO₂(20 ml), CHCl₃(40 ml), 1% MeOH/CHCl₃(40 ml), and 2% MeOH/CHCl₃) gave

(Æ)-12 (38 mg, 33% yield).

Reductive Troc Cleavage with Zn in the Presence of KH₂PO₄/Na₂HPO₄Buffer (pH 5.5) [13] Followedby

Macrocyclization. A mixture of Zn powder (1.1 g), 1m aq. KH₂PO₄(2 ml), 1m aq. Na₂HPO₄(2 ml), 10d (200 mg,

0.322 mmol), and THF (20 ml) was stirred vigorously under N₂for 4 h at r.t. After filtration, the residue was

washed with THF. To the combined soln. (150 ml), sat. aq. NaHCO₃(20 ml) and sat. aq. Na₂CO₃soln. (20 ml)

were added. The biphasic soln. was stirred at 558 for 21 h, then refluxed for 36 h. After evaporation of THF, the

mixture was extracted with CH₂Cl₂(3 Â 20 ml), the extract dried (Na₂CO₃) and evaporated, and the colorless oil

(143 mg) submitted to FC (SiO₂(25ml). Elution with 2% MeOH/CHCl ₃(50 ml) gave 19 (13 mg, 6.9%), with

3% MeOH/CHCl₃(50 ml) 12 (38 mg, 26.5%), and with CHCl₃/MeOH/aq. 25% NH₃soln. 95:4.5:0.5(50 ml) 21

(6 mg, 3.7%). After subsequent elution with CHCl₃/MeOH/aq. 25% NH₃soln. 90 :9 :1 (100 ml), CHCl₃/MeOH/

aq. 25% NH₃soln. 85:14 :1 (70 ml) eluted 18 (46.5mg, 33.6%) and finally 17 (24.5mg, 17%).

Helvetica Chimica Acta Vol. 86 (2003)

2051

Data of ( Æ )-N-{3-{(4-Aminobutyl)[(4-methylphenyl)sulfonyl]amino}propyl}-a-hydroxybenzenepropan-

amide (17): R_f(CHCl₃/MeOH/aq. 25% NH₃soln. 85:14 :1) 0.18. ¹H-NMR (300 MHz, 17 mg in 0.6 ml of CDCl₃):

7.63 (d, J 8, 2 H_oof Ts); 7.24 7.33 (m, 7 arom. H); 7.08 (br. t, J 6, NHCO); 4.28 (dd, J 3.8, 8.1, CHOH);

3.24 3.43 (m, CH₂NHCO); 3.20 (dd, J 3.8, 13.9, 1 H, PhCH₂); 2.95 3.13 ( m, 2 CH₂N); 2.89 (dd, J 8.1, 13.9,

1 H, PhCH₂); 2.63 (br. t, CH₂NH₂); 2.42 (s, Me); 1.71 (m, NCH₂CH₂CH₂N); 1.52, 1.38 (2m, CH₂CH₂). ¹³C-NMR

(75MHz, CDCl ₃; d(CDCl₃) 76.90): 173.33 (CONH); 143.25(C _pof Ts); 137.40 (C_ipsoof Ts); 136.12 (C_ipsoof Ph);

129.60, 129.52 (overlapping C_mof Ts and C_pof Ph); 128.31 (C_mof Ph); 127.01 (C_oof Ts); 126.54 (C_oof Ph); 72.57

(CHOH); 48.83, 45 .93 C(H₂NCH₂); 41.23 (CH₂NH₂); 40.80 (CH₂); 35.73 (CH₂NHCO); 30.05

(NCH₂CH₂CH₂N); 28.64, 26.1 (CH₂CH₂); 21.35(Me). ESI-MS: 448 (100, [ M H] ), 470 (12, [M Na] ).

Data of (2E)-N-{3-{(4-Aminobutyl)[(4-methylphenyl)sulfonyl]amino}propyl}-3-phenylprop-2-enamide

(18): R_f(CHCl₃/MeOH/aq. 25% NH₃soln. 85:14 :1) 0.22. ¹H-NMR (300 MHz, 29 mg in 0.8 ml of CDCl₃):

7.67 (d, J 8.4, 2 H_oof Ts); 7.62 (d, J 15.7, CHCH); 7.48 7.54 (m, 2 arom. H); 7.25 7.39 ( m, 5arom. H);

6.64 (br. t, J 5.7, NHCO); 6.45 (d, J 15.6, CHCH); 3.51 (q, J 6.1, CH₂NHCO); 3.20 (t, J 6.4, CH₂N);

3.11 (t, J 7.6, CH₂N); 2.67 (t, J 6.8, CH₂NH₂); 2.41 (s, Me); 1.83 (quint., J 6.1, NCH₂CH₂CH₂N); 1.57,1.4

(2m, CH₂CH₂). ¹³C-NMR (75MHz, CDCl ₃; d(CDCl₃) 76.91): 165.98 (CONH); 143.36 (C_pof Ts); 140.53

(CHCH); 136.18 (C_ipsoof Ts); 134.86 (C_ipsoof Ph); 129.68 (C_mof Ts); 129.44 (C_pof Ph); 128.66 (C_mof Ph);

127.69 (C_oof Ts); 126.93 (C_oof Ph); 120.98 (CHCH); 48.89, 46.02 (CH₂NCH₂); 41.47 (CH₂NH₂); 36.05

(CH₂NHCO); 30.56 (NCH₂CH₂CH₂N); 28.24, 26.16 (CH₂CH₂); 21.35(Me of Ts). ESI-MS: 430 ([ M H] ).

Data of ( Æ )-(2RS,3SR)-N-{3-{{4-{[(2,2-Dichloroethoxy)carbonyl]amino}butyl}[(4-methylphenyl)sulfonyl]-

amino}propyl}-3-phenyloxiranecarboxamide (( Æ )-2,2-Dichloroethyl {4-{[(4-Methylphenyl)sulfonyl]{3-

{{[(2RS,3SR)-3-phenyloxiran-2-yl]carbonyl}amino}propyl}amino}butyl}carbamate; 19): Colorless syrup.

¹H-NMR (300 MHz, 13 mg in 0.7 ml of CDCl₃): 7.68 (d, J 8.3, 2 H_oof Ts); 7.25 7.40 ( m, 7 arom. H); 6.76

(br. t, J 6.2, amide NH); 5.81 (t, J 6.0, CHCl₂); 5.13 (br. t, NHCO₂); 4.38 (d, J 6.0, CH₂OCO); 3.95( d, J

2.0, HÀC(3)); 3.51 (d, J 2.0, HÀC(2)); 3.30 3.52 (2 overlapping m, ³J 6.6, CH₂NHCO); 3.02 3.26

(m, 3 CH₂N); 2.43 (s, Me); 1.79 (quint., J 6.7, NCH₂CH₂CH₂N); 1.5 1.68 ( m, CH₂CH₂). ¹³C-NMR (75MHz,

CDCl₃; d(CDCl₃) 76.89): 167.69 (CONH); 154.75 (OCONH); 143.44 (C_pof Ts); 135.99 (C_ipsoof Ts); 134.94

(C_ipsoof Ph); 129.71 (C_mof Ts); 128.86 (C_pof Ph); 128.51 (C_mof Ph); 127.02 (C_oof Ts); 125.71 (C_oof Ph); 68.95

(CHCl₂); 68.62 (CH₂O); 58.93, 58.89 (overlapping C(2) and C(3)); 48.91, 46.43 (CH₂NCH₂); 40.41

(CH₂NHCO₂); 35.84 (CH₂NHCO); 28.71 (NCH₂CH₂CH₂N); 26.81, 26.14 (CH₂CH₂); 21.36 (Me of Ts). ESI-

MS: 608, 610, 612 (100, 68, 15[ M Na] ).

Data of ( Æ )-2,2-Dichloroethyl {(11RS,12SR,24Z)-11-Hydroxy-5,18-bis[(4-methylphenyl)sulfonyl]10,23-

dioxo-12,25-diphenyl-5,9,13,18,22-pentaazapentacos-24-en-1-yl}carbamate (21): R_f(CHCl₃/MeOH/aq. 25% NH₃

soln. 85:14 :1) 0.5. ¹H-NMR (300 MHz, 13 mg in 0.7 ml of CDCl₃): 7.67 (d, J 8.5, 2 H_oof Ts); 7.62 (overlapping

d, J 8.4, 2 H_oof Ts); 7.61 (overlapping d, J 15, CHCH); 7.48 7.53 (m, 2 arom. H); 7.20 7.40 (m, 12 ar-

om. H); 7.16, 6.58 (2 br. t, 2 amide NH); 6.45( d, J 15.6, CHCH); 5.84 (t, J 6.0, CHCl₂); 5.24 (br. t,

NHCO₂); 4.39 (d, J 6.0, CH₂OCO); 4.33 (d, J 5.1, CHOH); 4.04 (d, J 5.0, CHNH); 3.50 (q, J 6.1,

CH₂NHCO); 2.88 3.28 (m, 10 H); 2.77 (m, 2 H); 2.57 (m, 2 H); 2.41, 2.43 (2s, 2 Me); 1.25 1.9 ( m, 12 H). ESI-

MS: 1015, 1017, 1019 (90, 100, 20, [M H] ).

Reductive Troc Cleavage with Zn in the Presence of Na₂HPO₄Buffer (pH 8) Followedby Macrocyclization .

A mixture of Zn powder (230 mg), <1m sat. aq. Na₂HPO₄soln. (1 ml), 10d (143 mg, 0.23 mmol), and THF

(5ml) was stirred vigorously under N ₂for 22 h at r.t. After filtration, the residue was washed with THF, and the

combined soln. diluted to 100 ml with THF. The mixture was heated under reflux for 30 h; however,

macrocyclization proceeded slowly in pure THF. Then, sat. aq. Na₂CO₃soln. (10 ml) was added and reflux

continued for additional 36 h. After evaporation of THF, the aq. soln. was extracted with CH₂Cl₂(5 Â 10 ml),

the extract dried (Na₂CO₃) and evaporated, and the residue (170 mg) submitted to FC (SiO₂(25ml). Elution

with 2% MeOH/CHCl₃(100 ml) gave 19 (14 mg, 10.4%) and lactam 12 (54 mg, 53%). After subsequent elution

with 5% MeOH/CHCl₃(100 ml) and CHCl₃/MeOH/aq. 25% NH₃soln. 95:4.5:0.5(50 ml), CHCl ₃/MeOH/aq.

25% NH₃soln. 90 :9 :1 (100 ml) gave 20 (5mg, 4.2%) and two unidentified crude products. Finally CHCl ₃/

MeOH/aq. 25% NH₃soln. 85:14 :1 (100 ml) eluted 17 (8.5mg, 8.2%).

Data of ( Æ )-2,2-Dichloroethyl {(11RS,12RS,24RS)- and(11 RS,12RS,24SR)-11,24-Dihydroxy-5,18-bis[(4-

methylphenyl)sulfonyl]-10,23-dioxo-12,25-diphenyl-5,9,13,18,22-pentaazapentacos-1-yl}carbamate (20): ESI-

1

MS: 1033 ([M H] ). H-NMR (300 MHz, CDCl₃): in agreement with the proposed structure similar to 21;

but 20 appeared as a ca. 1:1 mixture of two diastereoisomers.

Ethyl ( Æ )-(aRS,bSR)-b-Chloro-a-hydroxybenzenepropanoate (24a). Dry HCl gas was bubbled into a soln.

of 4 (32.45g, 0.169 mmol) in dry toluene (150 ml) in an ice/water bath until absorption of gas stopped (4 h). The

1

mixture was allowed to warm to r.t. and evaporated. H-NMR indicated the formation of a mixture of threo-

2052

Helvetica Chimica Acta Vol. 86 (2003)

isomer 24a, its erythro-isomer 24b, and an unidentified olefin with the ratio 8 :2 :1. The mixture was treated with

hot hexane and allowed to cool, and the separated solid was recrystallized from hot benzene (50 ml) and hexane

(200 ml): pure crystalline 24a (20.27 g, 52.5%). ¹H-NMR (300 MHz, 33 mg in 0.7 ml of CDCl₃): 7.51 (m, 2 H_oof

Ph); 7.31 7.40 (m, 3 arom. H); 5.3 (d, J 2.5, HÀC(3)); 4.5(br. d (unres. dd), HÀC(2)); 4.26, 4.34

(2 overlapping dt, ²J 10.7, ³J 7, MeCH₂); 3.29 (br. d, J 7, OH ) ; 1.31 (t, J 7, MeCH₂). ¹³C-NMR

(75MHz; d(CDCl₃) 76.94): 171.08 (CO); 137.56 (C_ipsoof Ph); 128.63 (C_pof Ph); 128.35(C of Ph); 127.84

m

(C_oof Ph); 74.52 (C(2)); 63.72 (C(3)); 62.41 (CH₂); 14.0 (MeCH₂).

Potassium cis-3-Phenyloxiranecarboxylate (26). The biphasic mixture of 24a (16.64 g, 72.77 mmol) in

acetone (17 ml) and Na₂CO₃(11.57 g, 109.1 mmol) in H₂O (100 ml) was stirred at 508. After 8 h, additional

Na₂CO₃(5.75 g) was added and stirred at 358 for 12 h, then at 508 for 3 h. The mixture was diluted with H₂O and

extracted with CHCl₃(4 Â 20 ml) and the combined org. phase dried (Na₂CO₃) and evaporated: crude 25

(10.8 g, 77.6%) as a pale yellow oil contaminated with ca. 10% of unreacted 24a. The crude 25 (56.19 mmol) was

stirred with KOH soln. (4.04 g, 72.1 mmol) in EtOH (100 ml) added by portions until full conversion (90 min)

was achieved. The excess KOH was neutralized by bubbling CO₂until the soln. turned from brown to pale

yellow. After concentration to a small volume and quenching with Et₂O (100 ml), the solid was filtered: 9.3 g

(82%) of pure 26. White solid. ¹H-NMR (300 MHz, 30 mg in 0.7 ml of D₂O; d (DHO) 4.8): 7.49 7.59

(m, 5arom. H); 4.45( d, J 5.2, HÀC(3)); 3.98 (d, J 5.4, HÀC(2)). ¹³C-NMR (75MHz): 173.66 (CO); 134.43

(C_ipsoof Ph); 128.3 (C_p, C_mof Ph); 126.33 (C_oof Ph); 58.53, 57.2 (C(2), (C(3)).

Data of Ethyl cis-3-Phenyloxiranecarboxylate (25): ¹H-NMR (300 MHz, 20 mg in 0.7 ml of CDCl₃): 7.41

(m, 2 H_o); 7.28 7.36 (m, 3 arom. H); 4.25( d, J 4.5, HÀC(3)); 4.03, 3.96 (2 overlapping dt, ²J 10.9, ³J 7,

MeCH₂); 3.81 (d, J 4.6, HÀC(2)); 1.01 (t, J 7, MeCH₂). ¹³C-NMR (75MHz, CDCl ₃; d(CDCl₃) 76.90): 166.5

(CO); 132.84 (C_ipsoof Ph); 128.29 (C_pof Ph); 127.87 (C_mof Ph); 126.55 (C_oof Ph); 61.04 (MeCH₂); 57.25, 55.61

(C(2), (C(3)); 13.73 (MeCH₂).

Resolution of ( Æ )-26 with ( À )- and( )-Ephedrine. Racemic 26 (9.3 g, 45.98 mmol) was resolved

according to [10] to give ephedrine salts (À)-27a (6.98 g, 46.1%) from (À)-ephedrine and ()-27b (3.5g, 23%)

from ()-ephedrine.

Data of ( À )-(1R,2S)-Ephedrine (2S,3S)-cis-3-Phenyloxiranecarboxylate ((À)-27a): [a]_D À27.2 (c 1.5,

1

EtOH; [10]: À28.3). H-NMR (300 MHz, 27 mg in 0.6 ml of D₂O; d(DHO) 4.8): 7.40 7.60 (m, 10 arom. H);

5.19 (d, J 3.4, CHOH); 4.37 (d, J 5.2, HÀC(3), oxirane); 3.90 (d, J 5.2, HÀC(2), oxirane); 3.58 (dq, J

3.6, 6.7, CHMe); 2.82 (s, MeN); 1.19 (d, J 6.9, MeCH). ¹³C-NMR (75MHz): 173.52 (CO); 138.45(C

of

ipso

ephedrine Ph); 134.33 (C_ipsoof Ph); 128.74, 128.35, 128.21 (C_p, C_mof 2 Ph); 126.27, 126.01 (4 C_oof 2 Ph); 71.30

(CHOH); 59.83 (CHNH); 58.47, 57.12 (CHÀCH, oxirane); 30.62 (MeN); 9.60 (Me).

Data of ()-(1S,2R)-Ephedrine (2R,3R)-cis-3-Phenyloxiranecarboxylate (()-27b): [a]_D 27.3 (c 1.5,

EtOH).

()-(2S,3S)-N-(3-Bromopropyl)-3-phenyloxiranecarboxamide (()-29). Oxalyl chloride (0.775ml,

9 mmol) was added to a cold (ice/water bath) stirred suspension of (À)-27a (1.52 g, 4.61 mmol) in anh. THF

(45ml). The cold bath was removed and the mixture stirred for 30 min. Additional oxalyl chloride (0.775ml)

was introduced followed by Et₃N (0.04 ml), and the mixture stirred for 30 min. The obtained suspension was

poured into hexane (200 ml), stirred for 5min, and filtered to give 852 mg (96%, corrected for purity) of the

acid chloride 28 after evaporation under h.v. (¹H-NMR: only ca. 5mol-% of ephedrine derivative). To the

obtained crude 28 in CH₂Cl₂(24 ml), 3-bromopropanamine hydrobromide (1.41 g, 6.44 mmol) was added

followed by Et₃N (1.79 ml, 12.88 mmol). After stirring at r.t. for 30 min, the mixture was diluted with CH₂Cl₂

(150 ml), the org. phase washed with 5% citric acid (2 Â 50 ml) and NaHCO₃soln. (2 Â 50 ml), dried (Na₂CO₃),

and evaporated under h.v.: ()-29 (1.054 g, 69%), 86% purity by NMR. Crystalline solid, which was used in the

next step without further purification. [a_D 11.3 (c 1.64, CHCl₃). FT-IR (KBr): 3309s, 3068w, 3039w, 3014w,

2999w, 2969m, 2938m, 2860w, 1963w, 1899w, 1824w, 1653s (CO), 1585w, 1544s, 1497m, 1441s, 1406m, 1368m,

1358m, 1340m, 1320m, 1292m, 1257s, 1212m, 1184w, 1162w, 1122w, 1079m, 1052w, 1030w, 924w, 896s, 846m,

799m, 773m, 746s, 698s, 65 0w, 620m, 5 94w, 5 30m, 481w, 470w. ¹H-NMR (300 MHz, 29 mg in 0.5ml of CDCl ₃):

7.30 7.40 (m, 5arom. H); 6.0 (br. s, NH); 4.33 (d, J 4.7, HÀC(3)); 3.78 (d, J 4.8, HÀC(2)); 3.33 (dq (dddd),

²J 13.7, ³J 7, 1 H, CH₂NH); 2.97 (overlapping m, 1 H, CH₂NH); 2.92 (overlapping dt, ²J 10.1, ³J 6.5, 1 H,

CH₂Br); 2.66 (dt, ²J 10.2, ³J 6.7, 1 H, CH₂Br); 1.58 (quint. J 6.5, CH₂). ¹³C-NMR (75MHz; d(CDCl₃)

76.93): 166.37 (CONH); 133.1 (C_ipso); 128.56 (C_p); 128.40 (C_m); 126.4 (C_o); 57.93 (C(2)); 56.03 (C(3)); 36.95

(CH₂NH); 31.75(CH ₂); 30.09 (CH₂Br). ESI-MS: 306, 308 (97, 100, [M Na] ), 284, 286 (15, 15, [M H] ), 204

(18, [M À Br] ).

Helvetica Chimica Acta Vol. 86 (2003)

2053

1

Data of (2S,3S)-3-Phenyloxiranecarbonyl Chloride (28): H-NMR (300 MHz, CDCl₃): 7.31 7.41 (m, 5ar-

om. H); 4.48 (d, J 4.5, HÀC(3)); 4.25( d, J 4.5, HÀC(2)). ¹³C-NMR (75MHz; d(CDCl₃) 76.92): 167.33

(COCl); 130.83 (C_ipso); 129.41 (C_p); 128.31 (C_m); 126.47 (C_o); 61.88 (C(2)); 59.04 (C(3)).

()-(2S,3S)-N-{3-{[(4-Methylphenyl)sulfonyl]{4-[(trifluoroacetyl)amino]butyl}amino}propyl}-3-phenylox-

iranecarboxamide (()-30a). A mixture of ()-29 (414 mg, 1.458 mmol), 9a (739 mg, 2.187 mmol), Cs₂CO₃

(713 mg, 2.187 mmol), and DMF (2 ml) was stirred at r.t. under N₂for 14 h and partitioned between 5% citric

acid (20 ml) and CH₂Cl₂(5 Â 5ml). The combined org. phase was dried (Na ₂CO₃) and evaporated under h.v.

and the pale yellow oil (1.3 g) submitted to FC (SiO₂(60 ml), 50 ! 70% AcOEt/hexane): 30a (500 mg, 74.7%).

White foam. R_f(AcOEt/hexane 3 :1) 0.35. [a]_D 8.6 (c 1.5, CHCl₃). FT-IR (neat, NaCl): 3331s (br., NÀH),

3091m, 3068w, 3034w, 2944s, 2873m, 2253w, 1917w, 1718s (CO), 1666s (CO of CF₃CO), 1598w, 1541s, 1496w,

1452s, 1379m, 1335s, 1306m, 1290w, 1211s, 1184s, 1157s, 1090m, 1038w, 1020w, 1001w, 909s, 85 0w, 815m, 732s,

699m, 65 3m, 5 72w, 5 49m. ¹H-NMR (300 MHz, 45mg in 0.6 ml of CDCl ₃): 7.62 (d, J 8.2, 2 H_oof Ts); 7.43 (br. t,

NHCOCF₃); 7.23 7.38 (m, 7 arom. H); 6.42 (br. t, J 6.2, NHCO); 4.31 (d, J 4.8, HÀC(3)); 3.76 (d, J 4.9,

2

3

HÀC(2)); 3.27 3.38 (m, CH₂NHCOCF₃); 322 (dq (dddd), J 13.8, J 7, CH₂NHCO); 2.97 3.1 (m, 2 H);

2.73 2.87 (m, 2 H); 2.67 (dt, ²J 13.5, ³J 6.1, 1 H); 2.43 (s, Me); 1.44 1.62 (m, 4 H); 1.14 1.4 (m, 2 H).

¹³C-NMR (75MHz; d(CDCl₃) 76.95): 166.43 (CONH); 157.33 (q, J 36.5, COCF₃); 143.48 (C_pof Ts); 135.82

(C_ipsoof Ts); 133.17 (C_ipsoof Ph); 129.66 (C_mof Ts); 128.28 (C_pof Ph); 128.19 (C_mof Ph); 126.93 (C_oof Ts);

126.46 (C_oof Ph); 115.89 (q, J 288, CF₃);57.84 (C(2)); 56.14 (C(3)); 48.86, 46.34 (CH₂NCH₂); 39.12

(CH₂NHCOCF₃); 35.48 (CH₂NHCO); 28.44 (NCH₂CH₂CH₂N); 26.14, 25.68 (CH₂CH₂); 21.33 (Me). ESI-MS:

564 ([M Na] ).

(2S,3S)-N-{3-{[(Trifluoroacetyl)amino]{4-[(trifluoroacetyl)amino]butyl}amino}propyl}-3-phenyloxirane-

carboxamide (30b). A mixture of 29 (104 mg, 0.366 mmol), 9b (277 mg, 1.098 mmol), and Cs₂CO₃(239 mg,

0.732 mmol) in DMF (0.5ml) was stirred at r.t. under N ₂for 28 h and partitioned between H₂O (10 ml) and

CHCl₃(4 Â 10 ml). The combined org. phase was dried (Na₂SO₄) and evaporated and the residue (95mg)

submitted to FC (SiO₂(25ml), 50 ! 70% AcOEt/hexane): 30b (44 mg, 25%). Colorless oil. R_f(AcOEt/hexane

3 :1) 0.15. ¹H-NMR (300 MHz, CDCl₃): mixture of two rotamers with broad signals. ESI-MS: 506 ([M Na] ).

(2S,3S)-N-{3-{[(4-Methylphenyl)sulfonyl][4-aminobutyl]amino}propyl}-3-phenyloxiranecarboxamide

(31). CF₃CO-protected 30a (149 mg) was treated with K₂CO₃(300 mg) in H₂O (2 ml) and MeOH (5ml). After

stirring for 8 h, the mixture was quenched with sat. aq. Na₂CO₃soln. and extracted with CH₂Cl₂(5 Â 10 ml). The

extract was dried (Na₂CO₃), and a small portion was evaporated and the residue characterized. ¹H-NMR

(300 MHz, 22 mg in 0.7 ml of CDCl₃): 7.65( d, J 8.3, 2 H_oof Ts); 7.39 (m, 2 H_oof Ph); 7.25 7.35

(m, 5arom. H); 6.50 (br. t, J 5.9, NHCO); 4.31 (d, J 4.8, HÀC(3)); 3.78 (d, J 4.8, HÀC(2)); 3.19 (dq

(dddd), ²J 13.5, ³J 7, 1 H, CH₂NHCO); 2.95 3.09 ( m, 3 H); 2.75( m, 2 H); 2.66 (m, 2 H); 2.44 (s, Me);

1.30 1.50 (m, 5H); 1.12 1.28 ( m, 1 H). ¹³C-NMR (75MHz; d(CDCl₃) 76.91): 166.25(CONH); 143.22 (C _pof

Ts); 136.48 (C_ipsoof Ts); 133.33 (C_ipsoof Ph); 129.58 (C_mof Ts); 128.16 (overlapping C_p, C_mof Ph); 126.95(C _oof

Ts); 126.61 (C_oof Ph); 57.78 (C(2)); 56.18 (C(3)); 48.7, 45.37, (CH₂NCH₂); 41.48 (CH₂NH₂); 35.85

(CH₂NHCO); 30.56 (NCH₂CH₂CH₂N); 28.27, 26.12 (CH₂CH₂); 21.37 (Me). ESI-MS: 446 (100, [M H] ),

468 (40, [M Na] ).

( À )-(12R,15R)-6-[(4-Methylphenyl)sulfonyl]-15-phenyl-13-oxa-14-thia-1,6,10-triazabicyclo[10.2.1]penta-

decan-11-one 14-Oxide ((À)-32). To a cold (ice/water bath) stirred soln. of 1H-imidazole (792 mg, 11.6 mmol) in

CH₂Cl₂(60 ml), SOCl₂(0.169 ml, 2.328 mmol) was added dropwise. After 5min, ( )-12 (518 mg, 1.162 mmol)

in CH₂Cl₂(25ml) was added slowly and stirred at 58 for 30 min. The mixture was quenched with H₂O

(100 ml) and extracted with CHCl₃(3 Â 20 ml). The combined org. phase was washed with aq. 1n HCl, dried

(Na₂SO₄), and evaporated under h.v.: (À)-32 (581 mg, >100%). White foam, which appeared to be a 6 :1

mixture of two diastereoisomers A and B. R_f(5% MeOH/CHCl₃) 0.5( A), 0.75( B). [a]_D À242 (c 1.28,

CHCl₃). FT-IR (KBr): 3385s, 3027w, 2933m, 2867m, 1675s, 1599w, 1529s, 1495w, 1456s, 1380w, 1336s, 1306m,

1207w, 1157s, 1117w, 1091m, 1030m, 997m, 969s, 933w, 870w, 816m, 75 0s, 704s, 65 5m, 631w, 5 5m8. ¹H-NMR

(300 MHz, 53 mg in 0.7 ml of CDCl₃; isomer A): 7.72 (d, J 8.4, 2 H_oof Ts); 7.28 7.42 (m, 5arom. H); 7.23

(dd, ⁴J 1.3, ³J 7.8, 2 H_oof Ph); 6.55 (br. d (dd), J 8, NHCO); 5.13, 5.16 (2d of AB, J 6.2, CHCH); 3.61

3

3.76 (m, 1 H); 3.3 3.44 (m, 2 H); 3.02 3.24 (m, 2 H); 2.96 (dt, ²J 13, J 3.2, 1 H); 2.6 2.83 (m, 2 H); 2.45

(s, Me); 1.86 2.04 (m, 2 H); 1.5 6 1.8 (m, 4 H). ¹³C-NMR (75MHz; d(CDCl₃) 76.96): 165.55 (CONH); 143.36

(C_pof Ts); 137.16 (C_ipsoof Ts); 129.7 (C_mof Ts); 129.57 (C_ipsoof Ph); 129.49 (overlapping C_m, C_pof Ph); 128.44

(C_oof Ph); 127.02 (C_oof Ts); 85.38 (HÀC(12)); 64.89 (HÀC(15)); 48.34 (CH₂(5)); 45.23 (CH₂(7)); 42.33

(CH₂(2)); 36.03 (CH₂(9)); 30.29 (CH₂(8)); 25.28,22.99 (CH₂(2), CH₂(3)); 21.41 (Me). ESI-MS: 514 (100, [M

Na] ), 466 (10, [M Na À SO] ).

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Helvetica Chimica Acta Vol. 86 (2003)

( À )-(12R,15R)-6-[(4-Methylphenyl)sulfonyl]-15-phenyl-13-oxa-14-thia-1,6,10-triazabicyclo[10.2.1]penta-

decan-11-one 14,14-Dioxide ((À)-33). Crude (À)-32 (527 mg, 1.053 mmol) was dissolved in CH₂Cl₂/MeCN/H₂O

1:1:1 (60 ml) followed by addition of NaIO₄(915mg, 4.3 mmol) and RuCl ₃(2.5mg), and the mixture was

stirred vigorously for 90 min with the formation of a single product. After quenching with H₂O (200 ml), the

mixture was extracted with CH₂Cl₂(4 Â 20 ml), the combined org. phase dried (Na₂SO₄) and evaporated, and

the residue dissolved in CH₂Cl₂and filtered via a short plug of SiO₂(2 g) with 2% MeOH/CHCl₃. Drying under

h.v. gave (À)-33 (533 mg, 99%). White foam, amorphous colorless solid. R_f(5% MeOH/CHCl₃) 0.8. [a]_D

À154 (c 1.18, CHCl₃). FT-IR (KBr): 3425s, 3060w, 3038w, 2938m, 2875m, 1688s (CO), 1599w, 1536s, 1496w,

1459s, 1342s, 1269w, 1232w, 1215w, 1158s, 1183s, 1092m, 1032w, 971s, 932w, 909w, 870w, 813m, 785m, 760s, 739m,

1

717w, 700m, 65 5m, 5 71m, 5 5 m9 , 5 48m, 5 26m. H-NMR (300 MHz, 39 mg in 0.7 ml of CDCl₃): 7.70 (d, J 8.2,

3

2 H_oof Ts); 7.38 7.48 (m, 3 arom. H); 7.32 (d, J 7.8, 2 H); 7.26 (dd, ⁴J 1.6, J 7.8, 2 H_oof Ph); 7.05(br. d

(dd), J 8.3, NHCO); 5.05, 5.02 (2 d of AB, J 5.6, CHCH); 3.92 (m, (dddd), 1 H); 3.67 (ddd, 1 H); 3.33

(ddd, 1 H); 3.16 3.26 (m, 2 H); 2.68 2.88 (m, 3 H); 2.44 (s, Me); 1.83 2.1 (m, 4 H); 1.52 1.76 (m, 2 H).

¹³C-NMR (75MHz; d(CDCl₃) 76.94): 163.68 (CONH); 143.27 (C_pof Ts); 136.34 (C_ipsoof Ts); 130.42 (C_pof Ph);

129.68 (C_mof Ts); 129.32 (C_mof Ph); 128.8 (C_oof Ph); 128.59 (C_ipsoof Ph); 127.0 (C_oof Ts); 83.27 (HÀC(12));

67.57 (HÀC(15)); 50.58 (CH₂(5)); 45.97 (CH₂(7)); 43.73 (CH₂(2)); 36.2 (CH₂(9)); 31.97 (CH₂(8)); 24.48, 23.17

(CH₂(2), CH₂(3)); 21.38 (Me). NMR: Table 2. ESI-MS: 530 ([M Na] ).

( À )-(2R,3S)-3-Hydroxy-9-[(4-methylphenyl)sulfonyl]-2-phenyl-1,5,9-triazacyclotridecan-4-one ((À)-35).

A mixture of (À)-33 (513 mg, 1.011 mmol), NaNO₂(1.25g), and DMF (25ml) was stirred at 70 8 under N₂

for 27 h and evaporated under h.v. A small portion of the residue was acidified with AcOH, then partitioned

between H₂O and CHCl₃to give the intermediate sulfate salt sodium (2R,3S)-3-hydroxy-9-[(4-methylphenyl)-

sulfonyl]-4-oxo-2-phenyl-1,5,9-triazacyclotridecane-1-sulfonate (34) after evaporation of the aq. phase. The

combined residue was dissolved in MeOH (25ml) followed by addition of Amberlyst-15 (H form; 3 g) [25].

After stirring for 30 min, the mixture was quenched with 25% aq. NH₃soln., stirred for 20 min, and extracted

thoroughly with CHCl₃(6 Â 10 ml). The org. phase was washed with H₂O and sat. aq. Na₂CO₃soln. and the aq.

phase extracted with CHCl₃. The combined org. phase was dried (Na₂CO₃) and evaporated and the white foam

(356 mg) purified by FC (SiO₂(50 ml), 300 ml of 2% MeOH/CHCl₃): (À)-35 (315mg, 70%). White foam,

amorphous solid. M.p. 84 878. [a]_D À30.0 (c 1.11, CHCl₃). FT-IR (KBr): 3397s (br.), 3086w, 3061w, 3027w,

2930s, 2862m, 1650s (CO), 1599w, 1534s, 1494w, 1454s, 1399w, 1333s, 1306m, 1289w, 1184w, 1156vs, 1090s,

1059w, 1032m, 990w, 963w, 929w, 890w, 816m, 744m, 705s, 65 5m, 5 68m, 5 48s. NMR: see Table 2. ESI-MS: 468

(100, [M Na] ).

Data of 34: ¹H-NMR (300 MHz, CD₃OD; selected resonances): 5.6 (d, J 2.5, HÀC(2)); 4.64 (d, J 2.5,

HÀC(3)).

( À )-(2R,3S)-3-Hydroxy-2-phenyl-1,5,9-triazacyclotridecan-4-one ((À)-36). As described above for 10h,

(À)-35 (246 mg, 0.552 mmol) was electrochemically detosylated. The obtained soln. after electrolysis was

evaporated, treated with H₂O (40 ml) and sat. aq. Na₂CO₃soln. (40 ml), followed by extraction with CH₂Cl₂

(4 Â 15ml). The combined org. phase was dried (Na ₂CO₃) and evaporated under h.v.: (À)-36 (159 mg, 99%)

>95% purity by NMR. White foam that was used in the next step without further purification. R_f(SiO₂, CHCl₃/

MeOH/aq. 25% NH₃soln. 70 :25:5) 0.15. [ a]_D À39.8 (c 1.08, CHCl₃). FT-IR (KBr): 3388s (OÀH), 3291m,

3061m, 3029m, 2927s, 2852s, 2669m (br., NÀH), 1955w, 1656vs (CO), 1585w, 1520s, 1455s, 1440s, 1363w,

1323m, 1298w, 1246w, 1190w, 1121s, 1087s, 1055w, 1031w, 1012w, 965w, 923w, 879w, 841w, 793w, 780w, 75 2w, 705s,

682w, 618w, 5 73m, 5 09m. ¹H-NMR (300 MHz, 20 mg in 0.6 ml of CDCl₃): 7.48 (br. d (unres. dd), NHCO); 7.30

7.40 (m, 4 arom. H); 7.22 7.29 (m, 1 arom. H); 4.21 (d, J 1.6, HÀC(2)); 4.05( d, J 1.6, HÀC(3)); 3.80

(m, 1 HÀC(6)); 2.7 3.6 (very br. s, NH,OH); 2.97 (m, 1 HÀC(6)); 2.70 (m, CH₂(8)); 2.61 (m, 1 HÀC(13));

2.51 (m, CH₂(10)); 2.34 (m, 1 HÀC(13)); 1.81 (m, 1 HÀC(7)); 1.29 1.68 (m, 5 H). ¹³C-NMR (75MHz;

d(CDCl₃) 76.91): 173.12 (CONH); 141.1 (C_ipso); 128.32 (C_m); 127.33 (C_o); 127.22 (C_p); 74.63 (C(3)); 64.0 (C(2));

49.23 (overlapping C(8), C(10)); 46.49 (C(13)); 39.3 (C(6)); 28.11, 27.81, 27.54 (3 CH₂). ESI-MS: 292 ([M

H] ).

( À )-(2R,3S)-3-Hydroxy-9-[(2E)-1-oxo-3-phenylprop-2-enyl]-2-phenyl-1,5,9-triazacyclotridecan-4-one

(( À )-(2R,3S)-3-Hydroxycelacinnine; (À)-1b). To a cold (ice/water bath) stirred soln. of (À)-36 (40.4 mg,

0.139 mmol) and DMAP (34 mg, 0.278 mmol) in anh. CH₂Cl₂(5ml), cinnamoyl chloride (30 mg, 0.18 mmol) in

CH₂Cl₂(1 ml) was added dropwise. After 60 min, volatiles were evaporated, and the residue was treated with

NaOH (100 mg) in MeOH (4 ml) for 60 min with stirring. The mixture was partitioned between H₂O (10 ml)

and CH₂Cl₂(4 Â 5ml), the combined org. phase dried (Na ₂CO₃) and evaporated, and the crude product

(100 mg) purified by FC (SiO₂(25ml), 7% MeOH/CHCl ₃): (À)-1b (50 mg, 85.5%). Colorless amorphous solid.

M.p. 234 2448 (dec.). [a]_D À38.5( c 1.09, CHCl₃/MeOH 30 :1). FT-IR (KBr): 3295s (br.), 3060w, 3026w,

Helvetica Chimica Acta Vol. 86 (2003)

2055

2926m, 2847m, 1646vs (CO), 1594s, 1530s, 1497m, 1443m, 1433s, 1376w, 1357w, 1323m, 1276w, 1264w, 1229w,

1196m, 1169w, 1132m, 1089m, 1074w, 1030w, 991m, 914w, 849m, 763s, 731m, 699s, 685m, 5 68m, 5 03w. ¹H-NMR

(500 MHz, 6 mg in 0.8 ml of CDCl₃, 278; two rotamers A and B): 7.66 (d, J 15.5, PhCHCH); 7.51 (d, J 7.5,

2 H_oof PhCHCH); 7.37 (overlapping m, 4 H_mof 2 Ph, 2 H_oof PhÀC(2)); 7.36 (overlapping m, H_pof

PhCHCH); 7.30 (m, H_pof PhÀC(2)); 7.09 (br. s, 0.4 H, NHCO); 7.03 (br. s, 0.6 H, NHCO); 6.80 (d, J 15.5,

PhCHCH); 4.31 (br. s (unres. d), HÀC(2)); 4.18 (br. s (unresolved d), HÀC(3)); 3.78, 3.79 (br., 1 H_AÀC(6));

3.63, 3.69 (br., 1 H_AÀC(8)); 3.48 3.59 (overlapping 3 m at 3.55 (0.5 H, H'_BÀC(8)), at 3.52 (0.5 H, H_AÀC(10)),

and at 3.53 (0.5 H, H_AÀC(10)); 3.45(br., 0.5H, H '_AÀC(8)); 3.39, 3.38 (br., 1 H'_BÀC(10)); 2.98, 2.99 (br.,

1 H_BÀC(6)); 2.82 (br., 1 H_AÀC(13)); 2.46 (m, 1 H_BÀC(13)); 2.22 (br., 1 H_AÀC(7)); 1.92 (br., 1 H_AÀC(11));

1.67, 1.68 (br., 1 H_BÀC(7)); 1.56, 1.63 (br., 1 H_BÀC(11)); 1.58 (br., 1 H_AÀC(12)); 1.47 (1 H_BÀC(12)). ¹³C-NMR

(75MHz, 40 mg in 0.6 ml of CDCl ₃ 0.05ml of CD ₃OD; d(CDCl₃) 77.23; 238; two rotamers): 173.98, 173.91

(CONH); 166.66, 166.38 (C(O)CHCH); 142.78, 142.65(Ph CHCH); 140.82, 140.54 (C_ipsoof PhÀC(2));

135.35 (C_ipsoof PhCHCH); 129.72 (C_pof PhCHCH); 128.88, 128.57 (C_mof 2 Ph); 127.88 (C_pof PhÀC(2));

127.35(C of PhÀC(2)); 117.46 (PhCHCH); 75.94 (C(3)); 64.38, 64.08 (C(2)); 47.04, 46.18 (C(13)); 46.56,

o

44.96 (C(10)); 44.37, 43.38 (C(8)); 36.59, 36.13 (C(6)); 30.26, 27.99 (C(7)); 26.18, 24.42 (C(11)); 24.64 (C(12)).

1

For H- and ¹³C-NMR: see also Table 2. ESI-MS: 422 ([M H] ).

(12RS,13SR)-6-[(4-Methylphenyl)sulfonyl]-13-phenyl-1,6,10-triazabicyclo[10.1.0]tridecan-11-one ((Æ)-

38). To a soln. of (Æ)-12 (46 mg, 0.103 mmol) in CH₂Cl₂(1 ml), TsCl (59.1 mg, 0.31 mmol) was added,

followed by Et₃N (0.2 ml) and DMAP (45mg). The mixture was stirred for 6 h and evaporated. FC (SiO ₂

(25ml), CHCl ₃(100 ml), then 1% MeOH/CHCl₃(100 ml)) gave 38 (35mg, 79%). ¹H-NMR (300 MHz, 35mg

in 0.6 ml of CDCl₃): 7.66 (d, J 8.1, 2 H_oof Ts); 7.24 7.33 (m, 7 arom. H); 6.77 (br. s, 0.3 H); 3.8 (br. s, 0.3 H);

2.48 3.6 (several br. m, 8 H): 3.32 (br. s, ca. 2 H); 3.07 (br. dt, ³J 5.1, ²J 14.8, 1 H); 2.62 (d, J 2.7, ca. 1 H);

2.57 (m, ca. 1 H); 2.43 (s, Me); 2.13 (br., 0.7 H); 1.4 2.0 (br., 5.3 H). ¹³C-NMR (75MHz; d(CDCl₃) 76.92,

several br. signals): 143.31 (C_pof Ts); 135.65 (C_ipsoof Ts); 129.63 (C_mof Ts); 128.20 (C_mof Ph); 127.14 (C_oof Ts);

126.3 (br.); 77.13, 76.34 (overlapping with CDCl₃); 49.16 (C(10)?); 47.85(br., CH ₂); 44.3 (br.); 38.9 (br.); 28.1

(br., CH₂); 26.69 (CH₂); 25.8 (br.); 21.35 (Me). ESI-MS: 428 ([M H] ).

( Æ )-(2RS,3RS)-9-[(4-Methylphenyl)sulfonyl]-3-{[(4-methylphenyl)sulfonyl]oxy}-2-phenyl-1,5,9-triaza-1-

(trifluoroacetyl)cyclotridecan-4-one (41). To a stirred soln. of (Æ)-12 (30.2 mg, 0.0677 mmol) and (CF₃CO₂)₂O

(57 mg, 0.271 mmol) in CH₂Cl₂(1 ml), Et₃N (0.021 ml, 0.15mol) was added and stirred for 40 min at r.t. The

mixture was quenched with CHCl₃, the org. phase washed with 5% aq. citric acid and then aq. NH₃soln., dried

(Na₂CO₃), and evaporated: crude 40 (41 mg), which was used in the next step without purification. Crude 40

was dissolved in CDCl₃(0.6 ml) followed by addition of TsCl (23 mg, 0.121 mmol) and Et₃N (0.023 ml).

¹H-NMR indicated a very slow reaction. After 2 h, DMAP (11 mg) was added and the mixture kept at r.t. for

4 h. The obtained soln. was diluted with CHCl₃, washed with aq. Na₂CO₃soln., 1n aq. HCl, dried (Na₂CO₃), and

evaporated (64 mg). Purification by FC (SiO₂(20 ml), AcOEt/hexane 1:1) gave 41 (41 mg, 87%). White foam.

R_f(AcOEt/hexane 1 :1) 0.3. ¹H-NMR (300 MHz, 41 mg in 0.6 ml of CDCl₃): 7.97 (d, J 8.1, 0.3 H); 7.7

(overlapping d, J 8.2, 2 H); 7.66 (overlapping d, J 8, 0.3 H); 7.41 (overlapping br. d, J 7.9, 1.7 H); 7.04 7.48

(m, 12 H); 6.12 (d, J 10.3, 0.7 H); 5.75 (s, 0.3 H); 4.44 (br. s, 0.7 H); 3.6 4.04 (m, 2 H); 3.3 3.6 (m, 2 H);

2.95 3.26 ( m, 2 H); 2.7 2.92 (m, 4 H); 2.44 (s, 3.3 H, Me); 2.4 (s, 2.7 H, Me); 1.82 2.12 (m, 3 H); 1.52 1.82

(m, 3 H). ¹³C-NMR (75MHz; d(CDCl₃) 76.92): 166.82 (CONH); 157.5 (q, J 36.7, COCF₃); 144.72 (C_pof

TsO); 143.74 (C_pof TsN); 134.83, 134.32, 132.08 (C_ipsoof Ts, Ph); 129.91 (CH); 129.76, 129.61 (4 C_mof 2 Ts);

129.23 (br., 2 C_mof Ph); 128.42 (2 C_oof Ph); 128.33 (C_pof Ph); 127.91, 127.19 (4 C_oof 2 Ts); 116.08 (q, J 289,

CF₃); 76.54 (HÀC(3)); 66.0 (br., HÀC(2)); 52.3, 48.19 (2s, CH₂(13)); 51.12, 50.44 (C(8), C(10)); 39.69

(CH₂(6)); 27.63 (CH₂(7)); 25.76 (CH₂(12)); 24.67 (CH₂(11)); 21.46, 21.37 (2 Me). ESI-MS: 524 (100, [M À

TsO] ), 718 (12, [M Na] ).

Data of ( Æ )-(2RS,3RS)-3-Hydroxy-9-[(4-methylphenyl)sulfonyl]-2-phenyl-1-(trifluoroacetyl)-1,5,9-triaza-

cyclotridecan-4-one (40). ¹H-NMR (300 MHz, CDCl₃): 2 :3 mixture of two rotamers. ESI-MS: 564 ([M Na] ).

( Æ )-(2RS,3SR)-3-Hydroxy-9-[(4-meth ylphenyl)sulfonyl]-1-nitroso-2-phenyl-1,5,9-triazacyclotridecan-4-

one (42). The suspension of NaNO₂(237 mg) and 41 (40 mg) in DMF (1 ml) was stirred at 708 for 14 h,

quenched with H₂O (1 ml) and AcOH (0.2 ml), and extracted with Et₂O: crude 42 (34 mg) of ca. 85% purity by

¹H-NMR. Pale brown solid. R_f(5% MeOH/CHCl₃) 0.33. ¹H-NMR (300 MHz, 34 mg in 0.7 ml of CDCl₃): 7.64

(d, J 8.2, 2 H_oof Ts); 7.56 (br. dd, J 4, 7.1 NH); 7.26 7.38 (7 H); 6.12 (d, J(2,3) 1.9, HÀC(2)); 4.86

(d, J(2,3) 1.9, HÀC(2)); 3.78 3.92 (m, CH₂(6)); 3.36 (m, 1 HÀC(10)); 3.20 (ddd, J 4, 8, 12.7, 1 HÀC(8));

2.98 3.14 (3 H); 2.60 (dt (ddd), ³J 5, 5.6, ²J 13.6); 2.43 (s, Me); 1.90 2.16 (m, 2 H); 1.45 1.7 ( m, 2 H);

1.32 1.44 (m, 1 H); 0.8 0.92 (m, 1 H). ¹³C-NMR (75MHz; d(CDCl₃) 76.92): 171.89 (CONH); 143.49 (C_pof

Ts); 135.93 (C_ipsoof Ph); 135.4 (C_ipsoof Ts); 129.7 (C_mof Ts); 128.94 (C_mof Ph); 128.48 (C_pof Ph); 127.27 (C_oof

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Helvetica Chimica Acta Vol. 86 (2003)

Ph); 127.11 (C_oof Ts); 75.55 (HÀC(3)); 67.08 (HÀC(2)); 50.15 (CH₂(10)); 48.02 (CH₂(8)); 44.36 (CH₂(13));

38.19 (CH₂(6)); 28.24 (CH₂(7)); 25.74 (CH₂(12)); 24.96 (CH₂(11)); 21.38 (Me). ESI-MS: 497 (100, [M Na] ),

467 (20, [M Na À NO] ), 446 (40, [M À NO 2 H] ), 410 (40).

(2R,3S)-9-[(2E)-1-Oxo-3-phenylprop-2-enyl]-2-phenyl-3-{[(2S)-3,3,3-trifluoro-2-methoxy-1-oxo-2-phenyl-

propyl]oxy}-1,5,9-triazacyclotridecan-4-one ((aS)-a-Methoxy-a-(trifluoromethyl)benzeneacetic Acid(2 R,3S)-

4-Oxo-9-[(2E)-1-oxo-3-phenylprop-2-enyl]-2-phenyl-1,5,9-triazacyclotridec-3-yl Ester 44). To a soln. of 1b

(6 mg, 0.0142 mmol) and DMAP (5.7 mg, 0.0466 mmol) in CDCl₃(0.6 ml), (À)-(R)-Mosher acid chloride

(7.5mg, 0.0297 mmol) was added. ¹H-NMR indicated an immediate complete reaction. FC (SiO₂(10 ml), 1%

MeOH/CHCl₃) gave 44 (8.4 mg, 93%). Oil. R_f(5% MeOH/CHCl₃) 0.3. ¹H-NMR (300 MHz, 8.4 mg in 0.6 ml of

CDCl₃): 7.69 (d, J 15.5, PhCHCH); 7.18 7.55 (15 arom. H); 6.80 (d, J 15.4, PhCHCH); 5.93, 5.77

(2 br. s, 0.4 and 0.6 H, resp., NHCO); 5.59 (d, J 1.8, HÀC(3)); 4.43 (br. s, HÀC(2)); 3.15 3.84 (overlapping

3

br. m, 8 H); 3.63 3.84 (1.6 H); 3.44 3.63 (1.7 H); 3.31 3.44 (1.1 H); 3.28 (s, MeO); 2.79 (dt, ²J 12, J 4.3,

1 H); 2.71 (br. m, 1 H); 2.39 (br. m, 1 H); 2.19 (br. m, 1 H); 1.85(br. m, 1 H); 1.34 1.76 (br. m, 4 H). ESI-MS:

638 ([M H] ).

Mosher Esterification of the Natural Sample. A crude natural sample of 3-hydroxycelacinnine (3 mg) was

treated with (À)-(R)-Mosher acid chloride as described above for 44. The mixture was purified by prep. TLC to

give a crude product which was diastereoisomerically pure (¹H-NMR) and completely identical to synthetic 44.

¹H-NMR: 5.59 (s, HÀC(3)); 4.43 (s, HÀC(2)); 3.28 (s, MeO).

( À )-(2R,3S)-3-Hydroxy-9-(1-oxo-3-phenylpropyl)-2-phenyl-1,5,9-triazacyclotridecan-4-one ((À)-45).

MethodA . To a soln. of (À)-36 (19 mg, 0.0652 mmol) and DMAP (27 mg) in CDCl₃, 3-phenylpropanoyl

chloride (25mg) was added. ¹H-NMR indicated a fully complete reaction after 5min. The mixture was

evaporated and the residue dissolved in MeOH (5ml). Aq. 1 n NaOH (1 ml) was added and the mixture stirred

for 5h. Partition between aq. Na ₂CO₃soln. and CH₂Cl₂, followed by FC purification (SiO₂, 4% MeOH/CHCl₃)

gave (À)-45 (24 mg, 87%). White solid.

MethodB . Synthetic (À)-1b (7 mg) was hydrogenated with H₂over 10% Pd/C in MeOH. Filtration over a

plug of SiO₂and evaporation gave (À)-45 in ca. 96% yield. M.p. 210 2128. R_f(5% MeOH/CHCl₃) 0.12. [a]_D

À22.9 (c 0.48, CHCl₃). ¹H-NMR (300 MHz, 19 mg in 0.6 ml of CDCl₃): 7.15 7.38 ( m, 10 arom. H); 7.04

(dd, J 4.4, 7.7, 0.4 H, NHCO); 6.98 (dd, J 4, 7.8, 0.6 H, NHCO); 4.20 (br., HÀC(2)); 4.11 (br. s, HÀC(3));

3.47 3.76 (br. m, 2 H); 3.05 3.46 (br. m, 4 H); 2.91 (overlapping t, J 8, PhCH₂); 2.87 (overlapping m, 1 H);

2.72 (br. m, 1 H); 2.5 4 (m, CH₂CO); 2.33 (br. m, 1 H); 1.9 2.18 (br. m, 1.4 H); 1.64 1.9 (br. m, 1.6 H); 1.22

1.63 (br. m, 4 H). ESI-MS: 424 ([M H] ).

Hydrogenation of the Natural Sample. A crude natural sample of 3-hydroxycelacinnine (7.7 mg) was

hydrogenated with H₂over 10% Pd/C (3.7 mg) in MeOH (2 ml) and purified by prep. TLC: crude 45 (7 mg) of

ca. 80% purity. ESI-MS: 424 (100, [M H] ), 437 (10, unidentified impurity). CD (5mg in 10 ml of MeOH):

Fig. 2.

HPLC-UV-MS/MS Studies of ( À )-1a, ( À )-1b, andthe Natural Sample of 3-Hydroxycelacinnine . The

HPLC-UV(DAD)-MS experiments were performed on an HP1100 system (Hewlett-Packard, Palo Alto, CA,

USA). HPLC: Uptisphere-UP3 HDO-C₁₈(3 mm) column (200 mm long, 4.6 mm i.d.; Interchim, MontluÁon,

France) at 228; flow rate 0.5ml min ^À1; diode-array detection (DAD), detector setting at 280 nm; mobile phase:

gradient 0.1% HCO₂H in H₂O (solvent A) to 0.1% HCO₂H in MeCN (solvent B); gradient: within 30 min, 0

100% B. The APCI-MS (atmospheric-pressure-chemical-ionization mass spectrometry) detector was interfaced

directly to the output of the UV detector. HPLC-UV(DAD)-tandem mass spectrometry (MS/MS): APCI-MS

with a Bruker Esquire-LC quadrupole ion-trap instrument (Bruker Daltonik, Bremen, Germany) connected to

an orthogonal electrospray ion source (Hewlett-Packard); MS detector: N₂nebulizer gas 40 psi; N₂dry gas

81 min^À1; dry temp. 3008; APCI temp. 3508, HV capillary 4770 V; HV end-plate offset À787 V; capillary exit

108.2 V; cap. exit offset 73.2 V; trap drive 40.4; auto MS/MS acquisitions under ion-charge-control (ICC)

conditions (10×000) in the mass range from m/z 50 to 800; isolation width, 4 m/z; fragmentation amplitude, 1 V in

the SmartFrag mode (20 200%).

HPLC-UV-MS/MS Data of ()-1a: t_R15.35. UV: 287. MS/MS of m/z 422 ([M 1] ): 404 (6, [M 1 À

H₂O] ), 382 (10), 347 (3), 321 (20), 317 (21), 307 (60), 292 (5), 274 (13), 202 (30), 160 (100), 131 (13).

HPLC-UV-MS/MS Data of ( À )-1b: t_R14.55. UV: 287. MS/MS of m/z 422 ([M 1] ): 404 (8, [M 1 À

H₂O] ), 347 (5), 321 (11), 317 (17), 307 (77), 292 (5), 274 (11), 221 (5), 202 (40), 160 (100), 131 (11).

HPLC-UV-MS/MS Data of the Natural Sample: mixture of three components 1b, A ( 3-hydroxycelallo-

cinnine (43)), and B ca. 4 :1 :1. HPLC-UV-MS/MS was also performed with the prepared mixture of the natural

sample with (À)-1b and (À)-1a. Data of natural 1b were completely identical to the data of synthesized (À)-1b.

Helvetica Chimica Acta Vol. 86 (2003)

2057

Data of 43 (A): t_R13.55 min. UV: 255. MS/MS of m/z 422 ([M 1] ): 404 (7, [M 1 À H₂O] ), 321 (6), 317

(11), 307 (29), 292 (25), 274 (6), 221 (1), 202 (11), 188 (4), 160 (100), 131 (6).

Data of B (unidentified impurity): t_R11.3. UV: <215. MS/MS of m/z 438 ([M 1] ): 420 (100, [M 1 À

H₂O] ), 361.6 (5), 332 (2), 290 (3), 261 (6), 218 (55), 203 (10), 196 (4), 160 (7), 154 (3), 143 (35), 128 (17).

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ReceivedAugust 22, 2002

Article Doi

Synthesis of the spermidine alkaloids (-)-(2R,3R)- and (-)-(2R,3S)-3-hydroxycelacinnine: Macrocyclization with oxirane-ring opening and inversion via cyclic sulfamidates

DOI: 10.1002/hlca.200390160

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Full text of DOI:10.1002/hlca.200390160

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