The macrocyclic spermidine alkaloid (-)-(S)-neoperiphylline: Revision of the structure based on the total synthesis

Article abstract of DOI:10.1002/hlca.200390046

The total synthesis of the two isomeric macrocyclic enamides 2 and 17 is described. The precursor 14 was synthesized by means of template-assisted macrocyclization (Scheme 2). Isomerization of 14 in the presence of [Fe(CO)₅] gave 2 and 17 (Sche

Full text of DOI:10.1002/hlca.200390046

Helvetica Chimica Acta Vol. 86 (2003)
465
The Macrocyclic Spermidine Alkaloid (À)-(S)-Neoperiphylline:
Revision of the Structure Based on the Total Synthesis
by Sergey A.Sergeyev 1) and Manfred Hesse*
Organisch-chemisches Institut der Universit‰t Z¸rich, Winterthurerstrasse 190, CH-8057 Z¸rich
(tel.: ‡41-01-6354281; fax: ‡41-1-6356812; e-mail: mtbohley@oci.unizh.ch)
The total synthesis of the two isomeric macrocyclic enamides 2 and 17 is described. The precursor 14 was
synthesized by means of template-assisted macrocyclization (Scheme 2). Isomerization of 14 in the presence of
[Fe(CO)5] gave 2 and 17 (Scheme 4). Structure 2 was previously assigned to the alkaloid neoperiphylline.
However, the synthetic 2 showed completely different properties compared to the earlier described data of the
natural compound. Surprisingly, analytical data of the second synthetic product 17 were very close to those of
the natural neoperiphylline. We conclude that the previously assigned structure of neoperiphylline is erroneous
and should be corrected to that of (À)-(4S,12Z)-4-phenyl-9-[(2E)-3-phenylprop-2-enoyl]-1,5,9-triazacyclotri-
dec-12-en-2-one (17).
Introduction. Macrocyclic lactams derived from polyamines have attracted the
interest of organic chemists due to structural diversity and broad biological activity [1].
Hocquemiller et al. have isolated novel spermidine alkaloids from the leaves of the New
Caledonian endemic plant Peripterygia marginata [2]. Proposed structures of periphyl-
line (1) and neoperiphylline (2) are shown in the Figure. The enamide CˆC bond in
these alkaloids represents an unusual structural feature. To the best of our knowledge,
other macrocyclic derivatives with an enamide moiety incorporated in the macrocycle
are hitherto unknown. We are interested in the structure verification and biosynthesis
of these alkaloids.
O
O
O
N
N
N
H
H
H
N
N
N
Ph
N
H
Ph
N
H
Ph
N
H
O
O
O
Ph
Ph
Ph
1
2
3
Figure. Proposed structures of periphylline (1) and neoperiphylline (2) and structure of dihydroperiphylline
(3) [2].
In this paper, we report the total synthesis of 2. However, remarkable difference in
the spectral properties of synthetic 2 and natural neoperiphylline [2] suggest that this
structure was assigned to the natural alkaloid erroneously. We propose the alternative
structure 17 for neoperiphylline (see discussion below).
1
)
Part of the Ph. D. Thesis of S. A. S., University of Z¸rich, 2002.

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Helvetica Chimica Acta Vol. 86 (2003)
Recently, we reported [3] a new method for the synthesis of the macrocyclic
spermidine alkaloid dihydroperiphylline (3) isolated from the same plant as neo-
periphylline. Dihydroperiphylline has the same C,N backbone as neoperiphylline but
without an additional CˆC bond in the macrocycle. The single stereogenic center in 3,
as well as in 1 and 2, has (S)-configuration. For the synthetic construction of the
macrocyclic moiety of neoperiphylline, we used the same strategy as in the synthesis of
dihydroperiphylline.
Synthesis. The synthesis of chiral N-tosylated (S)-b-phenyl-b-alanine 10, based on
a stereoselective Michael addition [4], was described previously [3]. Another necessary
building block is the monotosylated (E)-but-2-ene-1,4-diamine 9. (E)-But-2-ene-1,4-
diamine itself is not commercially available although its preparation by the Gabriel or
Delepine methods is described (see [5] and [6], resp.). To make the synthesis of 9
shorter and more efficient, we decided to introduce the already tosylated N-atom by
nucleophilic substitution of the Br-atom in the commercially available (E)-1,4-
dibromobut-2-ene (4). First, N-[(tert-butoxy)carbonyl]-4-methylbenzenesulfonamide
(TsNHBoc) was alkylated with 4 to give the monobromo derivative 5 (Scheme 1). It
should be noted that TsNHBoc could not be replaced by the extremely cheap TsNH2
because of the formation of a complex mixture of polyalkylated products. Substitution
of the remaining Br-atom in 5 by the phthalimido (Phth) moiety afforded fully
protected diamine 6. N-Boc and N-phthalimido groups can be successively removed by
the action of CF3COOH and hydrazine, respectively, affording the unsaturated
building block 9 in good yield.
Scheme 1
Br
Ts
Br
Ts
NPhth
a)
b)
Br
N
N
R
Boc
4
5
6 R = Boc
c)
7 R = H
e)
d)
Ts
N(Boc)2
Ts
NH2
c)
N
N
H
Boc
8
9
a) TsNHBoc, Cs2CO3, DMF, r.t.; 60%. b) K-phthalimide, DMF, 508; 93%. c) CF3COOH, CH2Cl2, r.t.; quant.
d) N2H4 ¥ H2O, EtOH, 508; 82%. e) Boc2NH, Cs2CO3, DMF, r.t.; 98%.
Alternatively, di(tert-butyl) imidodicarbonate Boc2NH can be used for the
introduction of the second amino group. Application of this reagent in the synthesis
of amines from halides represents an excellent alternative to the traditional Gabriel
method [7]. Alkylation of Boc2NH with 4 provided derivative 8 in excellent yield
(Scheme 1). The use of Cs2CO3 as a phase-transfer catalyst allowed us to avoid the
preparation of the potassium salt of Boc2NH, as required by the original method of
Grehn and Ragnarsson [8]. Finally, 8 was smoothly deprotected by the action of

Helvetica Chimica Acta Vol. 86 (2003)
467
CF3COOH to yield the trifluoroacetate of 9, which was used directly in the further
synthesis.
The synthesis of macrocyclic intermediate 14 was performed in essentially the same
manner as the synthesis of (S)-dihydroperiphylline [3]. The tosylated amino acid 10
was first converted to the corresponding acyl chloride. Subsequent reaction with either
protected (E)-but-2-ene-1,4-diamine 9 or its trifluoroacetate gave the amide 11 in 73%
yield (Scheme 2).
Scheme 2
O
O
O
OH
N
N
a)
b)
H
H
HN
N
Ph
NH
Ts
Ph
NH
Ts
Ts
Ph
N
R
R
10
11
12 R = Ts
13 R = H
c)
O
d)
N
H
N
Ph
N
H
O
Ph
14
a) 1. SOCl2, DMF (cat.); 2. 9, Et3N, CH2Cl2, 08; 73%. b) MsO(CH2)3OMs, Cs2CO3, DMF, r.t.; 49%.
c) Electrolysis, EtOH/DMF; 98%. d) (E)-PhCHˆCHCOCl, DMAP, CH2Cl2, À808; 92%.
Cyclization of 11 with propane-1,3-diyl bis[methanesulfonate] afforded the macro-
cyclic derivative 12. However, the yield was remarkably lower (49%) compared to that
obtained for the saturated macrocycle 16 (78%) [3], because the formation of a
significant amount of the open-chain by-product 15 was observed. Upon increasing the
reaction temperature to 508, 15 became the main product. Formation of 15 must be
explained by a retro-Michael reaction (Scheme 3), which proceeds relatively easily due
to higher ring strain in the macrocycle 12 compared to its saturated analog 16.
Scheme 3
-
B
O
O
O
H
N
N
N
H
H
H
N
N
N
Ph
N
Ph
HN
Ph
N
Ts
Ts
Ts
Ts
Ts
Ts
12
15
16
Electrochemical deprotection of 12 [3][9] gave the macrocyclic lactam 13 in almost
quantitative yield. Finally, 13 was selectively acylated [3][10] with 1 equiv. of 3-

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Helvetica Chimica Acta Vol. 86 (2003)
phenylprop-2-enoyl chloride in the presence of N,N-(dimethyl)pyridin-4-amine
(DMAP) at low temperature to afford the unsaturated macrocyclic precursor 14 in
92% yield.
Recently, we reported [11] that N-(prop-1-enyl)amides can be easily prepared by
the isomerization of the corresponding N-allylamides in the presence of [Fe(CO)5]. We
used this method to perform the double bond shift in 14. Heating 14 with [Fe(CO)5] in
PhCl caused complete isomerization of the starting material after 12 h (TLC). Workup
and column chromatography of the reaction mixture gave two new compounds 2 and 17
(Scheme 4).
Scheme 4
O
N
H
N
Ph
N
H
O
Ph
14
a)
O
O
13
13
3
3
N
H
N
10
10
+
H
N
N
6
6
8
8
Ph
N
H
Ph
N
H
O
O
Ph
Ph
2
17
a) [Fe(CO)5], PhCl, 1208; 20% 2, 36% 17.
1
Structure of Neoperiphylline: Analytical Data and Discussion. In the H-NMR
spectra of both 2 and 17 in CDCl3, many signals were broad at room temperature due to
restricted rotation in the disubstituted amide, and in 13C-NMR spectra many signals
were either broad or doubled. This problem could be overcome by recording the NMR
1
spectra in (D6)DMSO at 363 383 K. By means of two-dimensional H,1H (COSY)
experiments and 1H,13C correlation spectra (HMBC, HSQC), we could unambiguously
assign all 1H- and 13C-signals in the spectra of 2 and 17 (see Exper. Part).
The characteristic signal at d 5.58( dt, J ˆ 14.0, 7.0 Hz) in the 1H-NMR spectrum of 2 ((D6)DMSO, 363 K)
clearly indicates the presence of the N-enylamide functionality. The value of coupling constant (14 Hz) confirms
the (E)-configuration of the endocyclic double bond. The signal of the CHˆCHN group appears at d 6.95 as a
sharp d (J ˆ 14 Hz). The (Z)-configuration of the endocylic CˆC bond in 17 can be judged from the value of the
coupling constant between HÀC(12) and HÀC(13) (J ˆ 8.5 Hz).
The synthesized cyclic enamide 2 has a structure that was suggested [2] for natural
neoperiphylline based on the following arguments. EI-MS of natural neoperiphylline
1
has the molecular mass 403, and typical signals at d 4.97 and 6.75 in H-NMR spectra

Helvetica Chimica Acta Vol. 86 (2003)
469
(CDCl3, room temperature) indicate the presence of the N-enylamide moiety (Table).
In addition, hydrogenation of periphylline (1), dihydroperiphylline (3), and neo-
periphylline afforded the same derivative [2]. The structure of dihydroperiphylline (3)
was later confirmed by total synthesis [3][10][12]. This undoubtedly established that
neoperiphylline contains the same 13-membered lactam ring, derived from dicinna-
moylspermidine as 1 and 3, and only the position of the endocyclic CˆC bond is
uncertain. A priori, four positions are possible for this CˆC bond: HC(6)ˆHC(7),
HC(7)ˆHC(8), HC(10)ˆHC(11), and HC(12)ˆHC(13). The structures with
H(6)ˆC(7)H and H(7)ˆC(8)H must be excluded, since they require the signal of
two CH2 groups at 1.5 2.0 ppm. In the two remaining cases, the N-enylamide CˆC
bond can have either (E)- or (Z)-configuration. The structure with (E)-
HC(12)ˆHC(13) corresponds to periphylline (1), isolated from the same plant. Based
on the assumption that the endocyclic CˆC bond in the molecule of neoperiphylline
also has the (E)-configuration, Hocquemiller et al. [2] deduced structure 2 as the only
possibility for neoperiphylline.
Table. Comparison of [a]D Values and 1H-NMR Spectra (CDCl3, r.t.) of the Natural Neoperiphylline [2] and the
Synthetic Isomeric Compounds 2, 17.
Natural
Synthetic 2
Synthetic 17
neoperiphylline [2]
(this work)
(this work)
[a]D
À 34 (c ˆ 0.5, CHCl3)
1.50 1.95 (m, 3 H)
‡ 130.5 (c ˆ 0.84, CHCl3) À 34.7 (c ˆ 0.91, CHCl3)
NCH2CH2CH2N, PhCHNH
NCH2CH2CH2N
CH2CO
1.45 1.95 (m, 3 H)
2.25 2.70 (m, 6 H)
3.05 3.15 (m, 1 H)
3.60 3.95 (m, 3 H)
4.10 4.20 (m, 1 H)
5.45 5.60 (m, 1 H)
6.73 (d, J ˆ 13.6, 1 H)
6.85 (d, J ˆ 15.5, 1 H)
7.15 7.40 (m, 8H)
7.50 7.66 (m, 2 H)
7.66 (d, J ˆ 15.5, 1 H)
1.50 2.00 (m, 3 H)
2.40 2.85 (m, 6 H)
3.25 4.10 (m, 5 H)
2.20 2.80 (m, 6 H)
3.05 4.30 (m, 5 H)
NCHˆCHCH2CH2
PhCHNH
CHˆCHN
4.97 (m, 1 H)
6.75 (m, 1 H)
4.85 5.00 (m, 1 H)
6.75 7.00 (m, 2 H)
CHˆCHN
PhCHˆCHCO
2 Ph
6.85 (d, J ˆ 15.5, 1 H)
7.35 (m, 10 H)
7.15 7.35 ( m, 8 H)
7.47 7.54 (m, 2 H)
7.68(br. d, J ꢀ 15, 1 H)
PhCHˆCHCO
7.70 (d, J ˆ 15.5, 1 H)
However, synthetic 2 showed completely different properties compared to those
reported for natural neoperiphylline [2]. First, the value of optical rotation of the
synthetic material is ‡130.5 instead of À 34 for the natural compound. Then, in the
1H-NMR spectra of 2 (CDCl3, room temperature), the characteristic m of CHˆCHN
is shifted by ca. 0.5 ppm downfield compared to natural neoperiphylline (see Table).
We concluded that the structure 2 was assigned to neoperiphylline erroneously.
Surprisingly, the properties of the second synthetic product 17 were very similar to
those of the natural neoperiphylline. The value of the optical rotation of the synthetic
1
17 was identical to that of the natural product. Comparison of H-NMR spectra of
synthetic 17 and the natural neoperiphylline in CDCl3 at room temperature exhibited
only minor differences in the chemical shifts of most signals (Table), which can be
explained by different measuring conditions. Finally, the assumption about the (E)-
configuration of the endocyclic CˆC bond in natural neoperiphylline was apparently
1
incorrect. Determination of coupling constants from H-NMR spectra in CDCl3 at

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Helvetica Chimica Acta Vol. 86 (2003)
room temperature is hardly possible because of line broadening (see above).
Unfortunately, the authentic sample of natural compound was not available, and
direct comparison of spectral data was not possible.
In summary, we conclude that the structure of neoperiphylline suggested in [2] is
erroneous and should be corrected to the (À)-(4S,12Z)-4-phenyl-9-[(2E)3-phenylprop-
2-enoyl]-1,5,9-triazacyclotridec-12-en-2-one (17).
We thank Mr. A. Guggisberg for electrochemical experiments and the Swiss National Science Foundation
for financial support.
Experimental Part
General. All chemicals and solvents were obtained from commercial sources (Fluka, Aldrich, Merck) and
used without further purification unless stated otherwise. Technical grade solvents were distilled before use.
DMF was stored over flame-dried molecular sieves (4 ä). Reactions were carried out under dry N2 or Ar. (3S)-
3-{[(4-Methylphenyl)sulfonyl]amino}-3-phenylpropanoic acid (10) [3] and propane-1,3-diyl bis[methanesulfo-
nate] [13] were prepared according to the published procedures. Column chromatography (CC): SiO2, Merck 60
(40 63 mm). TLC: precoated SiO2 plates, Merck 60 F254; detection by UVat 254 nm, Fluram reagent (Fluka) in
acetone, fluorescence at 366 nm (for primary amines), Schlittler reagent [14] (for amines and polyamines), or
KMnO4 (for unsaturated compounds). M.p.: Mettler FP-5. Optical rotations: Perkin-Elmer 241 polarimeter. IR
(cmÀ1): Perkin-Elmer Spectrum One; KBr pellets or neat substance. NMR: Bruker ARX-300 (300 (1H) or
75 MHz (13C)) or AMX-600 (600 (1H) or 150 MHz (13C)); chemical shifts d in ppm rel. to Me4Si as internal
standard, J values in Hz. 13C multiplicities from DEPT experiments. CI-MS (NH3 as reactant gas): Finnigan
MAT 90. ESI-MS (NaI/MeOH/CH2Cl2): Finnigan TSQ 700; in m/z (rel. intensity in % of base peak).
tert-Butyl [(2E)-(4-Bromobut-2-enyl][(4-methylphenyl)sulfonyl]carbamate (5). A mixture of BocNHTs
(10.8g, 0.04 mol), (2 E)-1,4-dibromobut-2-ene (4; 25.7 g, 0.12 mol), Cs2CO3 (13.1 g, 0.04 mol), and DMF
(100 ml) was stirred for 16 h at r.t. The DMF was evaporated, the residue dissolved in CH2Cl2 (150 ml), the
mixture filtered, and the filtrate evaporated. CC of the residue (hexane/CH2Cl2 1:1, then pure CH2Cl2) afforded
5 (9.7 g, 60%). Colorless oil. Rf (CH2Cl2) 0.54. IR (neat): 2981m, 2929m, 1784w, 1731s, 1598m, 1495m, 1435m,
1395m, 1357s, 1291s, 1257m, 1207m, 1042m, 1019m, 968m, 915w, 8 47m, 8 15m, 771w, 720m, 675s. 1H-NMR
(CDCl3): 1.36 (s, Me3C); 2.44 (s, Me); 3.97 (d, J ˆ 7.2, CH2N); 4.45 (d, J ˆ 5.8, CH2Br); 5.88 (dt, J ˆ 15.2, 5.8,
CHˆCHCH2Br); 5.97 (dt, J ˆ 15.2, 7.2, CHˆCHCH2N); 7.31 (d, J ˆ 8.2, 2 H of Ts); 7.80 (d-like m, 2 H of Ts).
13C-NMR (CDCl3): 21.5 (q, Me); 27.8 (q, Me3C); 31.5 (t, CH2Br); 47.1 (t, CH2N); 84.4 (s, Me3C); 128.1, 129.1 (2d,
2  2 arom. CH); 130.0 (2 overlapping d, CHˆCH); 136.9, 144.2 (2s, 2 arom. C); 150.5 (s, CˆO). CI-MS: 421,
‡
‡
423 (13, 13, [M ‡ NH4] ), 365, 367 (98, 100, [(M À C4H8) ‡ NH4] ), 321, 323 (15, 15, [(M À C4H8 À CO2) ‡
‡
NH4] ).
tert-Butyl [(2E)-4-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)but-2-enyl][(4-methylphenyl)sulfonyl]carba-
mate (6). A mixture of 5 (4.81 g, 11.9 mmol), potassium phthalimide (2.20 g, 11.9 mmol), and DMF (30 ml)
was stirred at 508 for 12 h. The mixture was allowed to reach r.t. and poured into ice/H2O (200 ml). The
precipitate was filtered, washed with H2O, and dried in vacuo: 6 (5.19 g, 93%). White solid. Rf (CH2Cl2/AcOEt
10 :1) 0.78. M.p. 123 124.58. IR (KBr): 2990m, 2937m, 1771s, 1720s, 1612w, 1596m, 1468m, 1429m, 1391s, 1352s,
1260m, 1152m, 1121s, 1086m, 1027m, 971m, 907m, 8 48m, 8 20m, 794w, 770m, 753m, 720s, 673s. 1H-NMR (CDCl3):
1.30 (s, Me3C); 2.42 (s, Me); 4.31 (d, J ˆ 4.1, CH2N); 4.41 (d, J ˆ 4.7, CH2N); 5.75 5.87 (m, CHˆCH); 7.29 (d,
J ˆ 8.0, 2 H of Ts); 7.68 7.76 (m, 2 H of Ts, 2 H of Phth); 7.83 7.90 (m, 2 H of Phth). 13C-NMR (CDCl3): 21.4 (q,
Me); 27.6 (q, Me3C); 38 .7, 47.2 (2t, 2 CH2N); 84.1 (s, Me3C); 123.1 (d, 2 arom. CH); 127.9 (2 overlapping d, 2
arom. CH, CHˆ); 128.3 (d, CHˆ); 129.2 (d, 2 arom. CH); 133.9 (s, 2 arom. C); 136.9 (s, arom. C); 137.0 (d, 2
‡
arom. CH); 144.0 (s, arom. C); 150.5 (s, CˆO of Boc); 167.6 (s, 2 CˆO of Phth). CI-MS: 488 (67, [M ‡ NH4] ),
‡
‡
432 (59, [(M À C4H8) ‡ NH4] ), 388 (100, [(M À C4H8 À CO2) ‡ NH4] ).
N-[(2E)-4-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)-but-2-enyl]-4-methylbenzenesulfonamide (7). A stirred
soln. of 6 (5.17 g, 11 mmol) in CH2Cl2 (40 ml) was treated with CF3COOH (3.8ml, 0.05 mol) in one portion and
stirred for 4 h at r.t. The soln. was evaporated and the residue dried in vacuo: 7 (3.49 g, 100%). White solid. M.p.
141 1428. Rf (CH2Cl2/AcOEt 10 :1) 0.52. IR (KBr): 3275s, 3050m, 2930m, 2854m, 1774s, 1720s, 1614m, 1595m,
1493m, 1466m, 1456m, 1434s, 1396s, 1320s, 1265m, 1188m, 1155s, 1089s, 1067m, 1022m, 972s, 922m, 8 8 4m, 8 20m,
1
790m, 720s, 702s. H-NMR (CDCl3): 2.38( s, Me); 3.55 (d, J ˆ 4.2, CH2N); 4.17 (d, J ˆ 4.3, CH2N); 4.82 (br.,

Helvetica Chimica Acta Vol. 86 (2003)
471
NH); 5.53 5.67 (m, CHˆCH); 7.25 (d, J ˆ 8.0, 2 H of Ts); 7.65 7.75 (m, 2 H of Ts, 2 H of Phth); 7.77 7.85 (m,
2 H of Phth). 13C-NMR (CDCl3): 21.4 (q, Me); 38.6, 44.4 (2t, 2 CH2N); 123.2 (d, 2 arom. CH); 126.8( d, CHˆ);
127.0 (d, 2 arom. CH); 128.4 (d, CHˆ); 129.6 (d, 2 arom. CH); 131.9 (s, 2 arom. C); 134.0 (d, 2 arom. CH); 136.8,
‡
‡
143.3 (2s, 2 arom. C); 167.6 (s, 2 CˆO). CI-MS: 388 (100, [M ‡ NH4] ), 371 (6, [M ‡ 1] ).
Di(tert-butyl) N-{(2E)(4-{[(tert-Butoxy)carbonyl][(4-methylphenyl)sulfonyl]amino}but-2-enyl}imidodi-
carbonate (8). A mixture of 5 (5.90 g, 14.6 mmol), Boc2NH (3.47 g, 16 mmol), Cs2CO3 (5.22 g, 15 mmol),
and DMF (50 ml) was stirred for 16 h at r.t. The DMF was evaporated, the residue distributed between CH2Cl2
(100 ml) and H2O (50 ml), and the org. phase washed with H2O (2 Â 50 ml), dried (MgSO4), and evaporated: 8
(7.70 g, 98%). Colorless oil. Rf (CH2Cl2/AcOEt 20 :1) 0.58. IR (neat): 2980m, 2935m, 1788m, 1732s, 1695s,
1598m, 1478m, 1456m, 1367s, 1298s, 1257m, 1225s, 1151s, 973w, 8 52m, 8 14w, 771w, 720m, 673m. 1H-NMR
(CDCl3): 1.33 (s, Me3C); 1.49 (s, 2 Me3C); 2.43 (s, Me); 4.19 (d, J ˆ 4.3, CH2N); 4.42 (d, J ˆ 4.7, CH2N); 5.69
5.83 (m, CHˆCH); 7.31 (d, J ˆ 8.2, 2 H of Ts); 7.78 (d, J ˆ 8.2, 2 H of Ts). 13C-NMR (CDCl3): 21.4 (q, Me); 27.8
(q, Me3C); 27.9 (q, 2 Me3C); 47.1, 47.5 (2t, 2 CH2N); 82.3 (s, 2 Me3C); 84.0 (s, Me3C); 127.3 (d, CHˆ); 128.0, 129.1
(2d, 2  2 arom. CH); 129.8( d, CHˆ); 137.1, 143.9 (2s, 2 arom. C); 150.6 (s, CˆO); 152.1 (s, 2 CˆO). ESI-MS:
‡
563 ([M ‡ Na] ).
N-[(2E)-4-Aminobut-2-enyl]-4-methylbenzenesulfonamide (9). Method A. A stirred soln. of 7 (3.49 g,
11 mmol) in EtOH (60 ml) was treated in one portion at 508 with N2H4 ¥ H2O (4.0 ml, ca. 0.08mol). Stirring was
continued for 1 h. Then the soln. was cooled to r.t., the precipitate filtered off, the filtrate evaporated, and the
residue redissolved in CH2Cl2 (100 ml). The soln. was filtered, the filtrate evaporated, and the residue dried in
vacuo: 9 (2.16 g, 82%). White solid. Rf (CH2Cl2/MeOH/25% aq. NH3 soln. 80 :12 :2) 0.28. M.p. 95 96.58. IR
(KBr): 3355m, 3027m, 2922m, 2858m, 2768m, 2691m, 1647w, 1590m, 1478m, 1466m, 1447m, 1395m, 1322s,
1230w, 1152s, 1108m, 1091m, 1031m, 974m, 908m, 8 29s, 8 10s, 761m, 706w, 661s. 1H-NMR (CDCl3): 2.42 (s, Me);
3.20 (dd, J ˆ 5.6, 1.3, CH2N); 3.53 (dd, J ˆ 6.0, 1.5, CH2N); 5.46 (dtt, J ˆ 15.2, 6.0, 1.5, CHˆ); 5.68( dtt, J ˆ 15.2,
5.6, 1.3, CHˆ); 7.29 (d, J ˆ 8.4, 2 H of Ts); 7.74 (d, J ˆ 8.4, 2 H of Ts). 13C-NMR (CDCl3): 21.5 (q, Me); 43.2, 44.8
(2t, 2 CH2N); 124.9 (d, CHˆ); 127.2, 129.7 (2d, 2  2 arom. H); 134.6 (d, CHˆ); 137.3, 143.3 (2s, 2 arom. C). CI-
‡
MS: 241 ([M ‡ 1] ).
Method B. A stirred soln. of 8 (5.40 g, 10 mmol) in CH2Cl2 (20 ml) was treated with CF3COOH (7.6 ml,
0.1 mol) in one portion and stirred for 4 h at r.t. The soln. was evaporated and the residue dried in vacuo to give
ca. 3.4 g of crude 9 ¥ CF3COOH, which was used without further purification. 1H-NMR (CD3OD): 2.41 (s, Me);
3.42 3.52 (m, 2 CH2N); 5.63 5.89 (m, CHˆCH); 7.35 (d, J ˆ 8.2, 2 H of Ts); 7.70 (d, J ˆ 8.2, 2 H of Ts).
13C-NMR (CD3OD; signals of CF3COOÀ not given): 21.3 (q, Me); 41.6, 44.9 (2t, 2 CH2N); 124.4 (d, CHˆ);
128.0, 130.7 (2d, 2  2 arom. H); 134.6 (d, CHˆ); 138.7, 144.8 (2s, 2 arom. C).
(À)-(3S)-3-{[(4-Methylphenyl)sulfonyl]amino}-N-{(2E)-4-{[(4-methylphenyl)sulfonyl]amino}but-2-enyl}-
3-phenylpropanamide (11). To 10 (2.87 g, 10 mmol) was added SOCl2 (10 ml) followed by DMF (ca. 0.05 ml).
The resulting mixture was stirred at r.t. for 2 h. The excess of SOCl2 was evaporated, and the obtained chloride
was dissolved in CH2Cl2 (30 ml) and added dropwise to a stirred soln. of 9 ¥ CF3COOH (3.4 g, 10 mmol) and
Et3N (6.9 ml, 50 mmol) in CH2Cl2 (100 ml) at 08. Stirring was continued for 30 min at 08 and for another 30 min
at r.t. The resulting soln. was washed with 10% aq. citric acid (50 ml), H2O (2 Â 50 ml), dried (MgSO4), and
evaporated. Crystallization of the residue from CHCl3 afforded 11 (3.95 g, 73%). White solid. Rf (CH2Cl2/
AcOEt 1:1) 0.32. [a]D ˆ À18.7 (c ˆ 1.17, MeOH). M.p. 149 149.58. IR (KBr): 3336s, 3276s, 3032w, 2922w,
1917w, 1643s, 1598m, 1536s, 1495w, 1458m, 1446m, 1430m, 1380w, 1325s, 1288m, 1244w, 1211w, 1156s, 1091m,
1067m, 1048m, 1013w, 975m, 922w, 8 48m, 8 14m, 760w, 704s, 673s, 609w. 1H-NMR (CDCl3): 2.06, 2.29 (2s, 2 Me);
2.53 (dd, J ˆ 14.3, 5.2, 1 H, CH2CO); 2.64 (dd, J ˆ 14.3, 8.3, 1 H, CH2CO); 3.38 3.44 ( m, CH2NHTs); 3.60 3.70
(m, CH2NHCO); 4.72 4.77 (m, CHN); 5.37 (dt, J ˆ 15.5, 5.4, CHˆ); 5.49 (dt, J ˆ 15.5, 5.0, CHˆ); 5.58( t, J ˆ
5.8, NH); 6.61 (t, J ˆ 5.7, NH); 6.82 (d, J ˆ 6.1, CHNHTs); 7.00 7.10 (m, 5 H of Ph, 2 H of Ts); 7.25 (d, J ˆ 8.0,
2 H of Ts); 7.46 (d, J ˆ 8.3, 2 H of Ts); 7.71 (d, J ˆ 7.8, 2 H of Ts ) . 13C-NMR (CDCl3): 21.4, 21.5 (2q, 2 Me); 40.5,
43.5, 44.7 (3t, 3 CH2); 55.6 (d, CHN); 126.5 129.7 (several d, 13 arom. CH, CHˆCH); 136.6, 137.5, 139.8, 142.9,
‡
143.5 (5s, 5 arom. C); 170.3 (s, CˆO). ESI-MS: 564 ([M ‡ Na] ).
( ‡ )-(4S,11E)-5,9-Bis[(4-methylphenyl)sulfonyl]-4-phenyl-1,5,9-triazacyclotridec-11-en-2-one (12). A stir-
red suspension of Cs2CO3 (1.14 g, 3.5 mmol) in dry DMF (20 ml) was treated dropwise with a soln. of 11 (0.811 g,
1.5 mmol) and propane-1,3-diyl bis[methanesulfonate] (0.348g, 1.5 mmol) in dry DMF (40 ml) during 2 h. After
the addition was completed, stirring was continued for 120 h. Then the DMF was evaporated and the residue
partitioned between CH2Cl2 (50 ml) and H2O (20 ml). The org. layer was washed with H2O (2 Â 20 ml), dried
(MgSO4), and evaporated. CC of the residue (CH2Cl2/AcOEt 5 :1) afforded 12 (0.424 g, 49%). White solid. M.p.
119 1208. Rf (CH2Cl2/AcOEt 1:1) 0.64. [a]D ˆ ‡79.0 (c ˆ 1.05, CHCl3). IR (KBr): 3385m, 3030w, 2928m,
2247w, 1733w, 1668s, 1598m, 1526m, 1495m, 1453m, 1335s, 1208w, 1155s, 1107m, 1089m, 1033w, 969m, 923m,

472
Helvetica Chimica Acta Vol. 86 (2003)
839w, 8 16m, 764m, 736s, 690m, 654m. 1H-NMR (CDCl3): 2.00 2.12 (m, 2 HÀC(7)); 2.23, 2.41 (2s, 2 Me); 2.56
(dd, J ˆ 13.6, 3.3, 1 HÀC(3)); 2.97 3.11 (m, 2 HÀC(8), 1 HÀC(10)); 3.18 3.30 ( m, 2 HÀC(6), 1 HÀC(13));
3.73 (dd, J ˆ 13.6, 12.4, 1 HÀC(3)); 4.12 (dd, J ˆ 12.4, 4.8, 1 HÀC(10)); 4.23 4.28( m, 1 HÀC(13)); 4.81 (dd,
J ˆ 12.4, 3.3, HÀC(4)); 5.64 (ddd, J ˆ 14.9, 9.7, 5.0, HÀC(12)); 5.98( ddd, J ˆ 14.9, 9.8, 5.1, HÀC(11)); 6.70 (dd,
J ˆ 8.2, 4.7, NH); 6.87 (d, J ˆ 8.2, 2 H of Ts); 6.95 (d, J ˆ 8.4, 2 H of Ts); 7.07 7.20 (m, 5 H of Ph); 7.31 (d, J ˆ
8.0, 2 H of Ts); 7.68 (d, J ˆ 8.2, 2 H of Ts). 13C-NMR (CDCl3): 21.1, 21.3 (2q, 2 Me); 30.1 (t, C(7)); 40.2 (t,
C(13)); 41.6 (t, C(3)); 46.3 (t, C(8)); 49.4 (t, C(6)); 53.3 (t, C(10)); 63.7 (d, C(4)); 126.8 129.6 (several d, 13
arom. CH); 130.1 (d, C(12)); 131.5 (d, C(11)); 135.3, 136.9, 137.0, 142.4, 143.1 (5s, 5 arom. C); 170.8( s, CˆO).
‡
‡
ESI-MS: 604 (100, [M ‡ Na] ), 582 (45, [M ‡ 1] ).
( ‡ )-(4S,11E)-4-Phenyl-1,5,9-triazacyclotridec-11-en-2-one (13). A soln. of 12 (995 mg, 1.71 mmol) in a
minimal amount of DMF was added to 0.1m Me4NCl in EtOH (100 ml). The resulting soln. was subjected to
electrolysis under Ar at À2.25 V in a three electrode cell with a Hg cathode, graphite rod anode, and standard
calomel electrode as reference electrode (see [9] for detailed procedure). After the electrolysis was completed,
the solvents were evaporated, the residue dissolved in 20% aq. K2CO3 soln. (10 ml), and the soln. extracted with
CH2Cl2 (4 Â 75 ml). The combined extracts were dried (MgSO4) and evaporated: 13 (457 mg, 98%). Colorless
oil. Rf (CH2Cl2/MeOH/25% aq. NH3 soln. 70 :30 :3) 0.46. [a]D ˆ ‡14.2 (c ˆ 0.97, CHCl3). IR (KBr): 3425m,
3285m, 3055m, 3020m, 2932m, 2845m, 1643s, 1546s, 1495m, 1452m, 1430m, 1356m, 1310m, 1255w, 1222w, 1190w,
1130w, 1074w, 974m, 763m, 703s. 1H-NMR (CDCl3): 1.38 1.48, 1.52 1.60 (2 m, 2 HÀC(7)); 1.98(br. s, 2 NH);
2.34 2.55 (m, 2 HÀC(3), 2 HÀC(6)); 2.62 2.79 (m, 2 HÀC(8)); 3.05 3.35 (m, 2 HÀC(10)); 3.48 3.54 ( m, 1
HÀC(13)); 3.92 (dd, J ˆ 10.0, 4.4, HÀC(4)); 4.00 4.08( m, 1 HÀC(13)); 5.76 5.91 (m, CHˆCH); 7.20 7.35
(m, 5 arom. H); 7.50 (br. s, CONH). 13C-NMR (CDCl3): 28.9 (t, C(7)); 39.7 (t, C(13)); 41.4 (t, C(8)); 42.8 (t,
C(6)); 45.5 (t, C(3)); 49.0 (t, C(10)); 61.1 (d, C(4)); 126.3 (d, 2 arom. CH); 127.3 (d, arom. CH); 128.6 (d, 2 arom.
‡
CH); 130.2, 133.1 (2d, CHˆCH); 143.1 (s, arom. C); 171.7 (s, CˆO). CI-MS: 274 ([M ‡ 1] ).
( À )-(4S,11E)-4-Phenyl-9-[(2E)-3-phenylprop-2-enoyl]-1,5,9-triazacyclotridec-11-en-2-one (14). A stirred
soln. of 13 (435 mg, 1.59 mmol) and DMAP (585 mg, 4.80 mmol) in CH2Cl2 (25 ml) was cooled to À808 and
treated dropwise with a soln. of cinnamoyl chloride (265 mg, 1.59 mmol) in CH2Cl2 (10 ml). The mixture was
stirred for 1 h at À808, allowed to reach r.t., washed with H2O (2 Â 10 ml), and evaporated. CC of the residue
(CH2Cl2/MeOH 10 :1) afforded 14 (588 mg, 92%). Colorless amorphous solid. Rf (CH2Cl2/MeOH 10 :1) 0.61.
[a]D ˆ À73.5 (c ˆ 1.15, CHCl3). IR (KBr): 3425m, 3295s, 3060m, 3025m, 2927s, 2855m, 1645s, 1595s, 1545m,
1495m, 1425s, 1360m, 1304m, 1204m, 1160m, 1115m, 1072w, 1030w, 975m, 8 5w3, 763s, 702s. 1H-NMR
((D6)DMSO, 373 K): 1.53 1.63, 1.72 1.82 (2m, 2 HÀC(7)); 2.28 2.30 ( m, 2 HÀC(3), 1 HÀC(6)); 2.58( ddd,
J ˆ 12.7, 7.6, 4.8, 1 HÀC(6)); 2.90 (br. s, NH); 3.37 3.45 (m, 1 HÀC(8)); 3.55 3.66 (m, 1 HÀC(8), 1
HÀC(13)); 3.78 3.85 ( m, 1 HÀC(13)); 3.91 (dd, J ˆ 14.7, 5.8, 1 HÀC(10)); 4.02 (t, J ˆ 7.3, HÀC(4)); 4.33 (dd,
J ˆ 14.7, 5.8, 1 HÀC(10)); 5.82 6.00 (m, HÀC(11), HÀC(12)); 7.03 (d, J ˆ 15.5, CHˆCHCO); 7.19 7.22 (m, 1
arom. CH); 7.24 7.43 (m, 7 arom. CH); 7.49 (d, J ˆ 15.5, CHˆCHPh); 7.58 7.63 ( m, 2 arom. CH); 7.96 (br. s,
CONH). 13C-NMR ((D6)DMSO, 373 K): 28.5 (t, C(7)); 38.5 (t, C(13)); 43.5 (2 overlapping t, C(6), C(8)); 44.8
(t, C(3)); 48.1 (t, C(10)); 59.8( d, C(4)); 119.4 (d, CHˆCHCO); 125.6 (d, 2 arom. CH); 125.8( d, C(11)); 126.8
(d, 2 arom. CH); 127.3 (d, arom. CH); 127.4, 127.8(2 d, 2 x 2 arom. CH); 128.3 (d, arom. CH); 130.2 (d, C(12));
135.0 (s, arom. C); 139.6 (d, CHˆCHPh); 143.8( s, arom. C); 165.3 (s, CHˆCHCˆO); 170.1 (s, CONH). CI-
‡
MS: 404 ([M ‡ 1] ).
(‡)-(4S,10E)-4-Phenyl-9-[(2E)-3-phenylprop-2-enoyl]-1,5,9-triazacyclotridec-10-en-2-one (2) and (À)-
(4S,2Z)-4-Phenyl-9-[(2E)-3-phenylprop-2-enoyl]-1,5,9-triazacyclotridec-12-en-2-one (17). A mixture of 14
(285 mg, 0.71 mmol), [Fe(CO)5] (0.1 ml, ca. 1 mmol), and PhCl (1 ml) was stirred for 12 h at 1208. Volatile
materials were evaporated, and the residue was dissolved in CHCl3/acetone 5 :1 (ca. 20 ml). The soln. was
filtered through Celite, the filtrate evaporated, and the residue purified by CC (CH2Cl2/AcOEt 1:1, then
CH2Cl2/acetone 2 :1, and then CH2Cl2/acetone 1:1): 17 (first-eluted; 104 mg, 36%) and 2 (58mg, 20%).
Data of 2. Colorless oil. Rf (CH2Cl2/acetone 1:1) 0.42. [a]D ˆ ‡130.5 (c ˆ 0.84, CHCl3). IR (KBr): 3292m,
3059m, 3026m, 2926m, 1957w, 1888w, 1645s, 1606m, 1547m, 1494m, 1450m, 1404m, 1356m, 1336m, 1253w,
1203m, 1187m, 1110w, 1070w, 976m, 951m, 912w, 8 57w, 763m, 701m. 1H-NMR ((D6)DMSO, 363 K): 1.52 1.62,
1.80 1.90 (2m, 2 HÀC(7)); 2.26 2.52 (m, 2 HÀC(3), 2 HÀC(8), 2 HÀC(12)); 3.00 (br. s, NH); 3.21 3.28,
3.43 3.50 (2m, 2 HÀC(13)); 3.69 3.88 (m, 2 HÀC(6)); 3.98( dd, J ˆ 10.8, 3.2, HÀC(4)); 5.58( dt, J ˆ 14.0, 7.0,
HÀC(11)); 6.95 (d, J ˆ 14.0, HÀC(10)); 7.08( d, J ˆ 15.5, CHˆCHCO); 7.19 7.22 (m, 1 arom. CH); 7.29 7.43
(m, 7 arom. CH); 7.53 (d, J ˆ 15.5, CHˆCHPh); 7.63 7.69 (m, 2 arom. CH); 7.84 (br. s, CONH). 13C-NMR
((D6)DMSO, 363 K): 27.8( t, C(7)); 29.0 (t, C(12)); 36.8( t, C(13)); 42.5 (t, C(6)); 43.2 (t, C(8)); 45.7 (t, C(3));
59.4 (d, C(4)); 115.6 (d, C(11)); 118.7 (d, CHˆCHCO); 126.0 (d, 2 arom. CH); 126.2 (d, arom. CH); 127.4, 127.7,
128.2 (3d, 3  2 arom. CH); 129.0 (d, arom. CH); 129.8( d, C(10)); 134.7 (s, arom. C); 141.5 (d, CHˆCHPh);

Helvetica Chimica Acta Vol. 86 (2003)
473
‡
143.6 (s, arom. C); 163.7 (s, CHˆCHCˆO); 170.0 (s, CONH). ESI-MS: 426 (100, [M ‡ Na] ), 404 (25, [M ‡
‡
1] ).
Data of 17. Colorless oil. Rf (CH2Cl2/acetone 1:1) 0.73. [a]D ˆ À34.7 (c ˆ 0.91, CHCl3). IR (KBr): 3440m,
3269m, 3140m, 3082m, 3059m, 2938m, 2861m, 1955w, 1887w, 1731w, 1685s, 1648s, 1601s, 1520s, 1495m, 1453m,
1423s, 1377m, 1327m, 1258m, 1195m, 1166m, 1119m, 1072m, 1030w, 976m, 946w, 8 95m, 8 68m, 8 25w, 763s, 702s,
685m, 644m, 618w. 1H-NMR ((D6)DMSO, 383 K): 1.61 1.70, 1.80 1.90 (2m, 2 HÀC(7)); 2.26 (dd, J ˆ 15.9, 2.2,
1 HÀC(3)); 2.30 2.56 (m, 2 HÀC(11), 2 HÀC(6)); 2.74 (dd, J ˆ 15.9, 11.4, 1 HÀC(3)); 2.85 (br. s, NH); 3.40
3.48( m, 1 HÀC(10)); 3.66 3.81 (m, 2 HÀC(8), 1 HÀC(10)); 3.94 (dd, J ˆ 11.4, 2.2, HÀC(4)); 4.91 (dt, J ˆ 8.5,
7.8, H ÀC(12)); 6.71 6.78( m, HÀC(13)); 7.04 (d, J ˆ 15.5, CHˆCHCO); 7.23 7.42 (m, 8arom. CH); 7.49 ( d,
J ˆ 15.5, CHˆCHPh); 7.62 (m, 2 arom. CH); 10.70 (br. d, CONH). 13C-NMR ((D6)DMSO, 383 K): 23.7 (t,
C(11)); 30.0 (t, C(7)); 41.8 (t, C(8)); 42.6 (t, C(6)); 43.1 (t, C(3)); 44.5 (t, C(10)); 58.8 (d, C(4)); 105.1 (d, C(12));
118.8 (d, CHˆCHCO); 123.7 (d, C(13)); 125.8( d, 2 arom. CH); 126.4 (d, arom. CH); 127.0, 127.7, 130.0 (3d, 3 x 2
arom. CH); 128.5 (d, arom. CH); 134.9 (s, arom. C); 140.2 (d, CHˆCHPh); 142.6 (s, arom. C); 165.0 (s,
‡
‡
CHˆCHCˆO); 167.7 (s, CONH). ESI-MS: 426 (100, [M ‡ Na] ), 404 (33, [M ‡ 1] ).
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¬
[2] A. Hocquemiller, A. Cave, H.-P. Husson, Tetrahedron 1977, 33, 645.
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œ
¬
¬
œ
[6] N. Blazevic, D. Kolbah, B. Belin, V. Sunjic, F. Kajfez, Synthesis 1979, 161.
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[8] L. Grehn, U. Ragnarsson, Synthesis 1987, 275.
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[11] S. A. Sergeyev, M. Hesse, Synlett 2002, 1313.
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Received July 23, 2002