A novel synthesis of the macrocyclic spermidine alkaloid (+)-(S)-dihydroperiphylline

Article abstract of DOI:10.1002/1522-2675(200201)85:1<161::AID-HLCA161>3.0.CO;2-L

A novel, short, and highly stereoselective synthesis of the macrocyclic spermidine alkaloid (+)-(S)-dihydroperiphylline (15) is described. The key synthetic steps were the stereoselective addition of the chiral amine 1 to the cinnamate 2 and cyclization o

Full text of DOI:10.1002/1522-2675(200201)85:1<161::AID-HLCA161>3.0.CO;2-L

Helvetica Chimica Acta Vol. 85 (2002)
161
A Novel Synthesis of the Macrocyclic Spermidine Alkaloid
(‡)-(S)-Dihydroperiphylline
by Sergey A. Sergeyev1) and Manfred Hesse*
Organisch-chemisches Institut der Universit‰t Z¸rich, Winterthurerstrasse 190, CH-8057 Z¸rich
A novel, short, and highly stereoselective synthesis of the macrocyclic spermidine alkaloid (‡)-(S)-
dihydroperiphylline (15) is described. The key synthetic steps were the stereoselective addition of the chiral
amine 1 to the cinnamate 2 and cyclization of the bis[toluene-4-sulfonamide] precursor 12 in the presence of
Cs2CO3 as a template. Unambiguous assignments of the signals in both the 1H- and 13C-NMR spectra of 15 were
achieved by 2D NMR spectra.
1. Introduction. Macrocyclic lactams, derived from spermidine or spermine, are
ubiquitous in nature. They have attracted the interest of organic chemists as synthetic
targets due to a broad spectrum of biological activity [1]. Dihydroperiphylline (15) is an
alkaloid isolated from leaves of the New Caledonian endemic plant Peripterygia
marginata [2]. The single chiral center in 15 was assumed to have (S)-configuration.
Racemic 15 was synthesized by Wasserman and Matsuyama [3]. The first enantiose-
lective route, based on a 15-step preparation of N-Boc-(S)-b-phenyl-b-alanine from
diethyl l-tartrate, was performed by Kaseda et al. [4], confirming the (S)-configuration.
More recently, alternative syntheses of (S)-15 by cyclization of methyl (S)-12-amino-
4,8-diazadodecanoate in the presence of (Me2N)3B [5] or by ring expansion of (S)-4-
phenyl-2-azetidinone [6] were reported. In the present paper, we report a novel, short,
and highly efficient approach to 15, based on metal-templated macrocyclization as the
key step.
2. Results and Discussion. Our synthetic strategy is outlined in Schemes 1 and 2. A
highly stereoselective preparation of the chiral b-phenyl-b-alanine derivative 3 was
performed according to the method of Davies et al. [7]. Thus, addition of the in situ
generated Li derivative of the optically pure amine 1 (prepared from commercially
available (R)-a-methylbenzylamine, 94% ee, Fluka [8]) to tert-butyl 3-phenylpropen-
oate 2 (prepared by a modification of the published procedure [9]) gave the
corresponding b-phenyl-b-alanine derivative 3 in nearly quantitative yield. Both the N-
benzyl- and N-a-methylbenzyl groups were removed by catalytic hydrogenation [7b] in
the presence of Pearlman×s catalyst, and the deprotected amino ester 4 was isolated in
63% yield after column chromatography. In addition, two side-products were isolated:
tert-butyl 3-phenylpropanoate (5; 14%) and the aminoester 6 (13%). Formation of the
latter indicates the much higher resistance of the N-a-methylbenzyl residue to
reductive removal compared to unsubstituted N-benzyl group, a finding that is
1
)
Part of the Ph. D. Thesis of S. A. S., University of Z¸rich, in preparation.

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Helvetica Chimica Acta Vol. 85 (2002)
consistent with the observation of L i et al. [8]. The amino ester 4 was obtained in 92%
1
ee, which was determined by H-NMR via derivatization with Mosher×s (R)-acid
chloride [10] (see Exper. Part). The amino ester 4 was tosylated to give 7 (84% yield).
Subsequent ester hydrolysis was quantitatively accomplished with CF3COOH (TFA)
at ambient temperature to yield the chiral building block 8 (53% overall yield from 2;
Scheme 1).
Scheme 1
a) 1. BuLi, THF, À808; quant. b) H2, 3.8bar, 10% Pd(OH) 2/C, EtOH; 63%. c) TsCl, Et3N, CH2Cl2, À108; 84%.
d) TFA, r.t.; quant. e) Boc2O, dioxane, r.t.; 85%. f) TsCl, Et3N, CH2Cl2, À108; 87%. g) 1. TFA, CH2Cl2, r.t.; 2.
aq. Na2CO3; 90%.
The synthesis of 15 also required the preparation of monotosylated butane-1,4-
diamine 11. Difficulties arising during a direct monoderivatization of putrescine,
however, are well-documented [11]. Putrescine tends to react at both amino groups to
give symmetric bifunctional derivatives even in the presence of a large excess of the
diamine relative to the functionalizing reagent. However, N-Boc derivatives have been
prepared from terminal aliphatic diamines in high yields [12]. Following the procedure

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163
in [12], we prepared N-Boc-butane-1,4-diamine (9) by reaction of Boc2O with an excess
of putrescine in dioxane (Scheme 1). The reaction of 9 with TsCl afforded N-Boc-N'-
(toluene-4-sulfonyl)butane-1,4-diamine (10). The Boc group was finally cleaved with
TFA to give the compound 11.
To perform the coupling between the two key components, 8 and 11, the protected
amino acid 8 was first converted to the corresponding acyl chloride by the action of an
excess of SOCl2 in the presence of catalytic amounts of DMF. Subsequent reaction with
11 in the presence of Et3N gave the amide 12 in 85% yield (Scheme 2).
Scheme 2
a) 1. SOCl2, DMF (cat.); 2. 11, Et3N, CH2Cl2; À108; 85%. b) X(CH2)3X, Cs2CO3, DMF; X ˆ OTs, 508, 24 h;
56%; X ˆ OMs, r.t., 72 h; 78%). c) electrolysis, EtOH/DMF; quant. d) PhCHˆCHCOCl, DMAP, CH2Cl2,
À808; 94%.
Cyclization reactions, mediated by alkali-metal carbonates in polar aprotic solvents
like DMF or MeCN are known to be effective for the synthesis of a variety of
macrocyclic compounds [13]. This strategy was also successfully applied in our
laboratory to obtain some macrocyclic lactams in moderate to high yields [14]. In the
present case, slow addition of a solution of equimolar amounts of 1,3-bis(tosyl-
oxy)propane [15] and 12 to a suspension of Cs2CO3 in DMF at 508 resulted in the
formation of the desired macrocycle 13 in 56% yield. When the more reactive 1,3-
bis(methylsulfonyl)propane [16] was used, cyclization proceeded even at ambient
temperature, and the yield of 13 increased to 78%. It should be noted that the order of
addition is important. For example, slow addition of the alkylating agent to a mixture of
Cs2CO3 and 12 resulted in a lower yield of 13.
Among various methods for deprotecting tosyl-protected amines [17], electro-
chemical reduction was shown to be the most convenient procedure [18]. In our case,
voltage-controlled electrolysis of 13 gave the corresponding macrocyclic lactam 14 in
quantitative yield. Finally, 14 was selectively acylated [5] with 1 equiv. of 3-phenyl-
propenoyl chloride in the presence of 4-(dimethylamino)pyridine (DMAP) at low

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temperature to afford (S)-dihydroperiphylline (15) in 94% yield. No acylation at the
more hindered N-atom was observed, and the spectral and optical properties of 15 were
in agreement with previously published data [4][5].
In the 1H-NMR spectra of 15 in CDCl3 or (D6)DMSO, many signals were broad at
ambient temperature due to restricted rotations in the disubstitued cinnamoyl amide,
and in the 13C-NMR spectra many signals were either broad or doubled. This problem
could be overcome by recording the NMR spectra at 373 K in (D6)DMSO. Using two
dimensional 1H,1H (COSY) and 1H,13C (HMBC, HSQC) correlation spectra, we were
1
able to make unambiguous assignments of all H and 13C signals (see Exper. Part).
We thank Mr. A. Guggisberg for electrochemical experiments, Dr. N. A. Khanjin for helpful discussions and
the Swiss National Science Foundation for financial support of this work.
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 prior to use.
DMF was stored over flame-dried molecular sieves (4 ä). THF was distilled over Na/benzophenone. (R)-N-
Benzyl-a-methylbenzylamine [8], 1,3-bis(tosyloxy)propane [15] and 1,3-bis(methylsulfonyloxy)propane [16]
were prepared according to published procedures. CC: SiO2, Merck 60 (40 63 mm). TLC: precoated SiO2
plates, Merck 60 F254; detection by UV at 254 nm; Fluram reagent (Fluka) in acetone, fluorescence at 366 nm
(for primary amines), Schlittler reagent [19] (for amines and polyamines). M.p.: Mettler FP-5. ORD: Perkin-
Elmer 241 polarimeter. IR (cmÀ1): Perkin-Elmer Spectrum One; KBr pellets or neat substance. 1H-NMR:
Bruker ARX-300 (300 MHz) or AMX-600 (600 MHz); chemical shifts d in ppm relative to Me4Si as internal
standard; J values in Hz. 13C-NMR: Bruker ARX-300 (75 MHz) or AMX-600 (150 MHz); chemical shifts d in
ppm relative to Me4Si, signals multiplicity determined from DEPT experiments. CI-MS (NH3 as reactant gas):
Finnigan MAT 90. ESI-MS (NaI/MeOH/CH2Cl2): Finnigan TSQ 700; m/z and relative intensities (% of base
peak) are given.
tert-Butyl (E)-3-Phenylprop-2-enoate (2). 3-Phenylprop-2-enoyl chloride (49.8g, 0.30 mol) was added in
portions to a vigorously stirred mixture of t-BuOH (32.8ml, 0.35 mol) and Et 3N (48.4 ml, 0.45 mol). The
mixture was stirred at 908 for 12 h (a white solid precipitated), then cooled to r.t., Et2O (100 ml) and H2O
(50 ml) were added, and stirring was continued until all the solid was dissolved. The org. layer was separated,
washed with 1n aq. HCl (3 Â 50 ml), sat. aq. NaHCO3 (50 ml), H2O (50 ml), dried (MgSO4) and concentrated.
Distillation of the residue in vacuo afforded 44.8g (73%) of 2. Colorless liquid. B.p. 72 738/0.1 Torr ([20]: 80
818/0.3 Torr). For IR, MS, 1H- and 13C-NMR spectra, see [20].
tert-Butyl (3S,aR)-3-[N-Benzyl-N-(1-phenylethyl)amino]-3-phenylpropanoate (3). A stirred soln. of (R)-
N-benzyl-a-methylbenzylamine (15.8g, 75 mmol) in dry THF (150 ml) was cooled to À808 and treated
dropwise with BuLi (1.6m soln. in hexane, 44 ml, ca. 70 mmol). The resulting red soln. was stirred for 1 h. Then, a
soln. of 2 (10.2 g, 50 mmol) in dry THF (40 ml) was added dropwise. Stirring was continued for 1 h. Sat. aq.
NH4Cl (60 ml) was added, and the mixture was allowed to reach r.t. THF was removed in vacuo, and the residue
was partitioned between H2O (50 ml) and CH2Cl2 (150 ml). The org. phase was washed with 10% citric acid
(2 Â 100 ml), H2O (50 ml), dried (MgSO4), and evaporated to give nearly pure 3 (20.8g, 100%), which was used
without further purification. Yellow oil. Rf 0.82 (CH2Cl2). IR (neat): 3085m, 3002m, 3062m, 3028s, 2976s, 2932m,
1948w, 1877w, 1807w, 1727s, 1601m, 1493s, 1478m, 1453s, 1367s, 1301m, 1237m, 1152s, 1083m, 1057w, 1028m,
962m, 912m, 749s, 699s, 647w, 549w. 1H-NMR (CDCl3): 1.20 (s, t-Bu); 1.24 (d, J ˆ 6.8, Me); 2.48 (dd, J ˆ 14.6, 9.4,
1 H, CH2CO); 2.55 (dd, J ˆ 14.6, 5.8, 1 H, CH2CO); 3.67 (s, PhCH2); 3.98( q, J ˆ 6.8, MeCH); 4.40 (dd, J ˆ 9.4,
5.8, CH2CH); 7.15 7.32 (m, 15 arom. H). 13C-NMR (CDCl3): 16.34 (q, Me); 27.77 (q, Me3C); 38.50 (t, CH2CO);
50.86 (t, PhCH2); 57.10, 59.68(2 d, 2 CH); 80.05 (s, Me3C); 126.45, 126.76, 127.03 (3d, 3 arom. CH); 127.80
128.25 (several d, 12 arom. CH); 141.66, 141.80, 144.15 (3s, 3 arom. C); 171.03 (s, CˆO). CI-MS: 416 (100, [M ‡
‡
1] ), 300 (12).
tert-Butyl (S)-3-Amino-3-phenylpropanoate (4). A soln. of 3 (20.8g, 50 mmol) in dry EtOH (200 ml) was
placed in a pressure-resistant bottle. The bottle was purged with N2, and Pearlman×s catalyst (10% Pd(OH)2 on
charcoal, 4.0 g) was added. The pressure head was adjusted, the bottle was placed in a Parr apparatus, evacuated,
purged with N2, and, then, 3 times with H2. The pressure was set to 3.8bar, and the bottle was vigorously shaken

Helvetica Chimica Acta Vol. 85 (2002)
165
for 72 h. Then, the pressure was released, the mixture was filtered through Celite, and EtOH was evaporated. CC
(CH2Cl2, then CH2Cl2/MeOH 20 :1) afforded 4 (6.96 g, 63%) as well as 5 (1.48g, 14%) and 6 (2.11 g, 13%).
Data of 4: colorless oil. Rf 0.60 (CH2Cl2/MeOH 10 :1). [a]d ˆ À19.3 (c ˆ 1.06, CHCl3). IR (neat): 3382m,
3314m, 3063m, 3029m, 2978s, 2931m, 1953w, 1725s, 1604m, 1494m, 1479w, 1454m, 1392m, 1368s, 1319m, 1256m,
1209m, 1150s, 1028w, 1015w, 955m, 909w, 8 46m, 755m, 700s, 593w. 1H-NMR (CDCl3): 1.41 (s, t-Bu); 1.77 (br. s,
NH2); 2.58( d, J ˆ 6.9, CH2CO); 4.37 (t, J ˆ 6.9, CHN); 7.24 7.37 (m, 5 arom. H). 13C-NMR (CDCl3): 27.95
(q, C(CH3)3); 45.23 (t, CH2); 52.69 (d, CHN); 80.60 (s, C(CH3)3); 126.20 (d, 2 arom. CH); 127.16 (d, 1 ar-
‡
om. CH); 128.41 (d, 2 arom. CH); 144.64 (s, 1 arom. C); 171.20 (s, CˆO). CI-MS: 443 (24, [2M ‡ 1] ), 222 (100,
‡
[M ‡ 1] ). 1H-NMR of Mosher×s amide of 4 (selected signals): (S,S)-isomer: 3.32 (q, 5J(H,F) ˆ 1.4, OCH3);
(S,R)-isomer: 3.40 (q, 5J(H,F) ˆ 1.4, OCH3); integral ratio (S,S)/(S,R) ˆ 23.6 :1, corresponding to ee 92%.
Data of 5: colorless liquid. 1H-NMR: 1.41 (s, t-Bu); 2.54 (t, J ˆ 7.8, CH 2CO); 2.91 (t, J ˆ 7.8, PhCH2); 7.18
‡
‡
7.27 (m, 5 arom. H). CI-MS: 224 (72, [M ‡ NH4] ), 168(100, [( M À C4H8) ‡ NH4] ).
Data of 6: colorless oil. Rf 0.62 (CH2Cl2/MeOH 20 :1). IR (neat): 3328w, 3062w, 3028m, 2976m, 2930m,
1950w, 1726s, 1602w, 1493m, 1453m, 1367s, 1296m, 1258m, 1151s, 1079w, 1028w, 957m, 911w, 8 45m, 761m, 699s,
665w. 1H-NMR (CDCl3): 1.34 (d, J ˆ 6.5, Me); 1.36 (s, t-Bu); 1.85 (br. s, NH); 2.59 (dd, J ˆ 10.7, 7.1, CH2); 3.66
(q, J ˆ 6.5, MeCH); 4.15 (dd, J ˆ 7.7, 6.3, CHN); 7.18 7.32 ( m, 10 arom. H). 13C-NMR (CDCl3): 22.19 (q, Me);
27.90 (q, Me3C); 43.84 (t, CH2); 54.48, 57.03 (2t, 2 CHN); 80.35 (s, Me3C); 126.46 127.02 (several d,
6 arom. CH); 128.20, 128.27 (2d, 2  2 arom. CH); 142.77, 145.97 (2s, 2 arom. C); 170.86 (s, CˆO). CI-MS:
‡
326 ([M ‡ 1] ).
tert-Butyl (S)-3-{[(4-Methylphenyl)sulfonyl]amino}-3-phenylpropanoate (7). A stirred soln. of 4 (3.09 g,
14 mmol) and Et3N (2.8ml, 20 mmol) in CH 2Cl2 (50 ml) was cooled to À108 and treated dropwise with TsCl
(2.67 g, 14 mmol) in CH2Cl2 (20 ml), stirred for 30 min at À108 and another 30 min at r.t. The resulting mixture
was washed with 10% citric acid (20 ml), H2O (2 Â 20 ml), dried (MgSO4), and concentrated in vacuo. CC
(CH2Cl2/AcOEt 20 :1) afforded 7 (4.43 g, 84%). White solid. Rf 0.52 (CH2Cl2/AcOEt 20 :1). M.p. 71 728. [ad ˆ
À35.6 (c ˆ 1.0, CHCl3). IR (KBr): 3250s, 3033m, 3062m, 2988s, 2753w, 2642w, 2293w, 1900w, 1717s, 1686s,
1600m, 1496m, 1456s, 1427s, 1326s, 1303s, 1252m, 1207m, 1159s, 1096s, 1060s, 968s, 8 58m, 8 09m, 771m, 703s, 665s,
603m, 555s, 534s, 467m. 1H-NMR (CDCl3): 1.30 (s, t-Bu); 2.34 (s, Me); 2.63 (dd, J ˆ 15.4, 6.5, 1 H, CH2CO); 2.73
(dd, J ˆ 15.4, 6.5, 1 H, CH2CO); 4.70 (dt, J ˆ 7.8, 6.5, CHN); 5.97 (d, J ˆ 7.8, NH); 7.08 7.18 (m, 5 H of Ph, 2 H
of Ts); 7.57 (d, J ˆ 8.3, 2 H of Ts). 13C-NMR (CDCl3): 21.30 (q, Me); 27.75 (q, Me3C); 42.36 (t, CH2); 54.61
(d, CHN); 81.47 (s, Me3C); 126.49, 126.97 (2d, 2 Â 2 arom. CH); 127.43 (d, 1 arom. CH); 129.24, 130.13 (2d, 2 Â 2
‡
arom. CH); 137.55, 139.33, 142.92 (3s, 3 arom. C); 169.82 (s, CˆO). CI-MS: 393 (18, [M ‡ NH4] ), 337 (100,
‡
[(M À C4H8) ‡ NH4] ), 189 (6).
(S)-3-{[(4-Methylphenyl)sulfonyl]amino}-3-phenylpropanoic Acid (8). A mixture of 7 (2.14 g, 5.71 mmol)
and TFA (5 ml) was stirred at r.t. for 3 h. Evaporation of volatile materials and drying of the residue in vacuo
afforded 8 (1.82 g, 100%). White solid. Rf 0.31 (CH2Cl2/MeOH 10 :1). M.p. 148 150 8. [a]d ˆ À33.1 (c ˆ 1.0,
MeOH). IR (KBr): 3270s, 3063m, 3028m, 2980m, 2917m, 2679m, 2577m, 1960w, 1907w, 1710s, 1598m, 1495m,
1460m, 1447m, 1414m, 1379w, 1352m, 1326s, 1306s, 1211m, 1162s, 1086m, 1064m, 1028w, 1019w, 955m, 8 43m,
810m, 763m, 703s, 670s, 616m, 573m, 551m, 527m, 477m. 1H-NMR (CDCl3): 2.37 (s, Me); 2.81 (dd, J ˆ 16.4, 6.2,
1 H, CH2); 2.92 (dd, J ˆ 16.4, 6.2, 1 H, CH2); 4.73 (dt, J ˆ 7.6, 6.2, CHN); 5.67 (d, J ˆ 7.6, NH); 7.08 7.21 ( m, 5 H
of Ph, 2 H of Ts); 7.59 (d, J ˆ 8.3, 2 H of Ts); 11.5 12.5 (very br. s, COOH). 13C-NMR ((D6)DMSO): 20.74
(q, Me); 42.00 (t, CH2); 54.38( d, CHN); 126.19, 126.51 (2d, 2 Â 2 arom. CH); 126.86 (d, 1 arom. CH); 127.86,
‡
128.96 (2d, 2  2 arom. CH); 138.38, 140.57, 141.91 (3s, 3 arom. C); 170.86 (s, CˆO). ESI-MS: 342 ([M ‡ Na] ).
tert-Butyl (4-{[(4-Methylphenyl)sulfonyl]amino}butyl)carbamate (10). A stirred soln. of 9 (4.00 g,
21.3 mmol) and Et3N (5.5 ml, 40 mmol) in CH2Cl2 (100 ml) was cooled to À108, and treated dropwise with a
soln. of TsCl (4.19 g, 22 mmol) in CH2Cl2 (20 ml). The mixture was stirred for 30 min at 08 and another 30 min at
r.t. The resulting mixture was washed with 10% citric acid (25 ml), H2O (2 Â 25 ml), dried (MgSO4), and
evaporated. Extraction of the residue with hexane (3 Â 50 ml) gave 7.25 g of crude product, which solidified
upon standing. Crystallization from hexane/AcOEt gave pure 10 (6.30 g, 87%). White solid. Rf 0.19
(CH2Cl2/AcOEt 10 :1). M.p. 85 878 ([21]: 87.5 88.58). For IR, 1H- and 13C-NMR spectra, see [21].
‡
‡
‡
ESI-MS: 365 (84, [M ‡ Na] ), 309 (39, [(M À C4H8) ‡ Na] ), 265 (10, [(M À C4H8 À CO2) ‡ Na] ), 243 (100,
‡
[(M À C4H8 À CO2) ‡ 1] ).
N-(4-Aminobutyl)-4-methylbenzenesulfonamide (11). A stirred soln. of 10 (3.42 g, 10 mmol) in CH2Cl2
(25 ml) was treated with TFA (3.8ml, 50 mmol) in one portion and stirred for 1 h at r.t. The acid was
evaporated, the residue was treated with 10% aq. Na2CO3 (50 ml) and extracted with CH2Cl2 (5 Â 75 ml). The
combined extracts were dried (MgSO4) and evaporated to afford 11 (2.15 g, 89%), which solidified upon
standing. Slightly yellow solid. Rf 0.41 (CH2Cl2/MeOH/25% aq. NH3 70 :30 :3). M.p. 64 668 ([22]: 65 688). IR

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Helvetica Chimica Acta Vol. 85 (2002)
(neat): 3583m, 3362m, 3276s, 3064s, 2936s, 1867s, 1924w, 1688m, 1598m, 1495m, 1452m, 1323s, 1201m, 1157s,
1094s, 1019w, 916w, 8 16m, 737w, 707m, 660s, 618w, 572m, 551s. 1H-NMR (CDCl3): 1.38 1.58( m, 2 CH2CH2N);
2.42 (s, Me); 2.66 (t, J ˆ 6.3, CH2N); 2.92 (t, J ˆ 6.5, CH2N); 3.8(br. s, 3 H, NH2 ‡ NH); 7.29 (d, J ˆ 8.1,
2 arom. H); 7.74 (d, J ˆ 8.1, 2 arom. H). 13C-NMR (CDCl3): 21.33 (q, Me); 27.05, 29.53 (2t, 2 CH2CH2N); 40.90,
42.80 (2t, 2 CH2N); 126.89, 129.49 (2d, 2  2 arom. CH); 137.17, 142.95 (2s, 2 arom. C). ESI-MS: 485 (38, [2M ‡
‡
‡
‡
1] ), 265 (21, [M ‡ Na] ), 243 (100, [M ‡ 1] ).
(S)-3-[(4-Methylphenyl)sulfonylamino]-N-{4-[(4-methylphenyl)sulfonyl]aminobutyl}-3-phenylpropan-
amide (12). To 8 (1.276 g, 4 mmol) was added SOCl2 (4 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 to give the corresponding acyl chloride
which was dissolved in CH2Cl2 (20 ml) and added dropwise to stirred soln. of 11 (1.09 g, 4.5 mmol) and Et3N
(0.83 ml, 6 mmol) in CH2Cl2 (30 ml) at À108. Stirring was continued for 30 min at À108 and for another 30 min
at r.t. The resulting soln. was washed with 10% citric acid (20 ml), H2O (2 Â 20 ml), dried (MgSO4) and
concentrated in vacuo. Purification of the residue by CC (CH2Cl2/MeOH 20 :1) afforded 12 (1.85 g, 85%). White
solid. Rf 0.57 (CH2Cl2/MeOH 10 :1). M.p. 138 139 8. [a]d ˆ À26.5 (c ˆ 1.00, MeOH). IR (KBr): 3744w, 3287m,
2928m, 2866w, 1914w, 1805w, 1647s, 1598m, 1542s, 1495m, 1455m, 1423m, 1322s, 1211w, 1155s, 1092s, 1067m,
967w, 8 42w, 8 13m, 744w, 703m, 671s, 604w, 573m, 551s. 1H-NMR (CDCl3): 1.44 (m, 2 CH2CH2N); 2.30, 2.41 (2s,
2 Me); 2.50 (dd, J ˆ 14.4, 5.2, 1 H, CH2CO); 2.58( dd, J ˆ 14.4, 8.0, 1 H, CH2CO); 2.85 (m, CH2NHTs); 3.03
(m, 1 H, CH2NHCO); 3.21 (m, 1 H, CH2NHCO); 4.74 (ddd, J ˆ 8.1, 5.2, 8.0, CHN); 5.42 (t, J ˆ 6.1, CH2NHTs);
6.30 (t, J ˆ 5.7, CH2NHCO); 6.72 (d, J ˆ 8.1, CHNHTs); 7.01 7.06 (m, 5 H of Ph, 2 H of Ts); 7.29 (d, J ˆ 8.0, 2 H
of Ts); 7.48( d, J ˆ 8.3, 2 H of Ts); 7.73 (d, J ˆ 8.3, 2 H of Ts). 13C-NMR (CDCl3): 21.26, 21.38(2 q, 2 Me); 26.14,
26.40 (2t, 2 CH2CH2N); 38.66 (t, CH2CO); 42.77, 43.38(2 t, 2 CH2N); 55.43 (d, CHN); 126.39, 126.89, 126.96 (3d,
3 Â 2 arom. CH); 127.15 (d, 1 arom. CH); 128.18, 129.10, 129.64 (3d, 3 Â 2 arom. CH); 136.54, 137.45, 139.75,
‡
‡
142.74, 143.33 (5s, 5 arom. C); 170.09 (s, CˆO). CI-MS: 561 (45, [M ‡ NH4] ), 544 (81, [M ‡ 1] ), 390 (38,
‡
‡
[(M À TsNH2) ‡ NH4] ), 373 (100, [(M À TsNH2) ‡ 1] ), 189 (80).
(S)-5,9-Bis[(4-methylphenyl)sulfonyl]-4-phenyl-1,5,9-triazacyclotridecan-2-one (13). Method A. A stirred
suspension of Cs2CO3 (0.717 g, 2.2 mmol) in dry DMF (30 ml) was warmed to 508 and treated dropwise with a
soln. of 12 (0.543 g, 1.0 mmol) and 1,3-bis(tosyloxy)propane (0.384 g, 1.0 mmol) in dry DMF (40 ml) during 2 h.
After the addition was completed, stirring was continued for 24 h, then the reaction mixture was cooled to r.t.
The solvent was evaporated in vacuo and the residue was partitioned between CH2Cl2 (50 ml) and H2O (20 ml).
The org. layer was washed with H2O (2 Â 20 ml), dried (MgSO4), and concentrated in vacuo. CC of the residue
(CH2Cl2/AcOEt 4 :1) afforded 13 (0.328g, 56%). White foam. Rf 0.53 (CH2Cl2/AcOEt 1:1). [a]d ˆ ‡1.3 (c ˆ
1.27, CHCl3). IR (KBr): 3380m, 3062w, 3030w, 2927m, 2866m, 1918w, 1751m, 1667s, 1598m, 1535m, 1495m,
1452m, 1335s, 1215m, 1155s, 1121m, 1089m, 1035w, 996w, 952w, 919w, 8 15m, 763m, 701m, 726m, 68 7m, 655m,
607w, 568m, 549s. 1H-NMR (CDCl3): 1.42, 1.56 (2m, 2 H, CH2CH2N); 1.76 2.03 (m, 3 H, CH2CH2N); 2.11
(m, 1 H, CH2CH2N); 2.26, 2.41 (2s, 2 Me); 2.69 (dd, J ˆ 14.6, 2.0, 1 H, CH2CO); 2.92 (m, 1 H, CH2NHCO);
3.11 3.38( m, 6 H, 3 CH2NHTs); 3.67 (dd, J ˆ 14.6, 11.6, 1 H, CH2CO); 3.90 (m, 1 H, CH2NHCO); 5.07
(dd, J ˆ 11.6, 2.0, CHN); 6.26 (dd, J ˆ 8.6, 3.4, CH2NHCO); 6.89 (d, J ˆ 8.3, 2 H of Ts); 6.98 7.21 (m, 5 H of Ph,
2 H of Ts); 7.28( d, J ˆ 8.4, 2 H of Ts); 7.68 (d, J ˆ 8.3, 2 H of Ts). 13C-NMR (CDCl3): 21.16, 21.34 (2q, 2 Me);
22.42, 24.73, 28.52 (3t, 3 CH2CH2N); 38.48 (t, CH2CO); 41.86, 44.28, 46.75, 48.03 (4t, 4 CH2N); 62.21 (d, CHN);
127.03 128.29 (several d, 9 arom. CH); 128.78, 129.53 (2d, 2 Â 2 arom. CH); 136.65, 136.92, 137.73, 142.47,
‡
‡
142.88 (5s, 5 arom. C); 170.64 (s, CˆO). ESI-MS: 1189 (17, [2M ‡ Na] ), 606 (100, [M ‡ Na] ), 584 (13, [M ‡
‡
1] ).
Method B. A stirred suspension of Cs2CO3 (0.717 g, 2.2 mmol) in dry DMF (30 ml) was treated dropwise at
r.t. with a soln. of 12 (0.543 g, 1.0 mmol) and 1,3-bis(methylsulfonyloxy)propane (0.384 g, 1.0 mmol) in dry DMF
(40 ml) during 2 h. After the addition was complete, stirring was continued for 72 h. The same workup as above
afforded 13 (0.457 g, 78%).
(S)-4-Phenyl-1,5,9-triazacyclotridecan-2-one (14). A soln. of 13 (0.419 g, 0.72 mmol) in a minimal amount
of DMF was added to a 0.1m soln. of 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 [18] for detailed procedure). After the electrolysis was complete, the
solvents were removed in vacuo, the remainder was dissolved in 20% aq. K2CO3 (10 ml) and extracted with
CH2Cl2 (4 Â 50 ml). The combined extracts were dried and evaporated to afford 14 (0.198g, 100%). Colorless
oil. Rf 0.20 (CH2Cl2/MeOH/25% aq. NH3 70 :30 :3). [a]d ˆ À5.2 (c ˆ 0.89, CHCl3). IR (KBr): 3269s, 3025m,
3061m, 2927s, 2855s, 2803m, 1952w, 1881w, 1812w, 1657 (sh), 1636s, 1554s, 1491m, 1453m, 1436m, 1356m, 1308m,
1272w, 1233m, 1185m, 1130m, 1069m, 1028m, 960m, 925w, 8 44w, 799w, 763m, 703s, 646w, 619w, 595m, 569w,
543m, 521m. 1H-NMR (CDCl3): 1.69 1.88 (m, 6 H, 3 CH2CH2N); 2.38 2.54 ( m, CH2); 2.60 2.84 (m, 4 H,

Helvetica Chimica Acta Vol. 85 (2002)
167
CH2 ‡ 2 NH); 3.00 3.10 (m, CH2); 3.48 3.69 ( m, 2 CH2N); 4.01 (dd, J ˆ 11.5, 2.8, CHN); 7.21 7.35 (m, 5 H,
Ph); 8.52 (br. t, CONH). 13C-NMR: 26.33, 26.61, 27.41 (3t, 3 CH2CH2N); 39.53 (t, CH2CO); 44.33, 45.14, 48.19,
49.00 (4t, 4 CH2N); 59.99 (d, CHN); 126.23 (d, 2 arom. CH); 127.18( d, 1 arom. CH); 128.56 (d, 2 arom. CH);
‡
‡
142.71 (s, 1 arom. C); 171.84 (s, CˆO). CI-MS: 276 (100, [M ‡ 1] ), 91 (22, [C7H7] ).
(S)-4-Phenyl-9-(3-phenylprop-2-enoyl)-1,5,9-triazacyclotridecan-2-one (ˆ(S)-Dihydroperiphylline; 15). A
stirred soln. of 14 (0.169 g, 0.61 mmol) and DMAP (0.223 g, 1.83 mmol) in CH2Cl2 (15 ml) was cooled to À808
and treated dropwise with a soln. of cinnamoyl chloride (101.5 mg, 0.60 mmol) in CH2Cl2 (5 ml). The mixture
was stirred for 1 h at À808, allowed to reach r.t., washed with H2O (2 Â 10 ml) and concentrated. CC of the
residue (CH2Cl2/MeOH 10 :1) afforded 15 (230 mg, 94%). White solid. Rf 0.40 (CH2Cl2/MeOH 10 :1). M.p. 81
828 ([4]: 82.5 83.58). [a]d ˆ ‡3.2 (c ˆ 0.5, CHCl3). IR (KBr): 3744w, 3400m, 3296m, 3060m, 3026m, 2926m,
2856m, 1952w, 1885w, 1825w, 1646s, 1597s, 1552m, 1495m, 1452s, 1427s, 1375m, 1327m, 1304m, 1254w, 1192m,
1174m, 1114m, 1073m, 1028w, 976m, 911w, 8 55m, 763s, 702s, 58 8w, 555m, 534m. 1H-NMR ((D6)DMSO, 373 K):
1.48 1.62/1.70 1.88 (2 m, CH2(7), CH2(11), CH2(12)); 2.24 (ddd, J ˆ 12.4, 8.8, 3.7, 1, HÀC(6)); 2.28( dd, J ˆ
13.3, 4.3, 1 HÀC(3)); 2.37 (dd, J ˆ 13.3, 10.4, 1 HÀC(3)); 2.51 (m, HÀN(5)); 2.55 (ddd, J ˆ 12.4, 7.0, 3.8,
1 HÀC(6)); 3.22, 3.35 (2m, 2 H, CH2(13)); 3.47 3.66 (m, CH2(8), CH2(10)); 3.98( dd, J ˆ 10.4, 4.3, CHN); 7.00
(d, J ˆ 15.4, CHˆCHCO); 7.21 (m, 1 arom. H); 7.30 7.43 (m, 7 arom. H); 7.45 (d, J ˆ 15.4, CHˆCHCO); 7.61
(m, 2 H of CHˆCHPh); 7.72 (br. t, CONH). 13C-NMR ((D6)DMSO, 373 K): 24.64 (2 overlapping t, C(11),
C(12)); 29.00 (t, C(7)); 37.36 (t, C(13)); 42.25 (t, C(6)); 43.22 (t, C(10)); 45.33 (t, C(3)); 47.50 (t, C(8)); 59.24
(d, C(4)); 119.07 (d, CHˆCHCO); 125.80 (d, 2 arom. CH); 126.06 (d, 1 arom. CH); 127.11, 127.70, 128.10 (3d,
3  2 arom. CH); 128.55 (d, 1 arom. CH); 135.02 (s, 1 arom. CH); 139.85 (d, CHˆCHCO); 143.85 (s, 1 ar-
om. C); 164.79 (s, CHˆCHCO); 170.33 (CONH). CI-MS: 406 (100, [M ‡ 1], 276 (8).
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Received July 7, 2001