Chiroptical Properties of the Protoverbine Class of Macrocyclic Spermine Alkaloids

Article abstract of DOI:10.1002/(SICI)1522-2675(19981007)81:10<1773::AID-HLCA1773>3.0.CO;2-X

The chiroptical properties (circular dichroism, CD) of the 17-membered macrocyclic spermine lactam alkaloids (-)-protoverbine (16), its N,N′-methylene-bridged natural analogue (+)-protomethine (17), their natural derivatives (-)-verbacine (1), (-)-verballocine (2), (-)-verbascenine (3), (-)-verballoscenine (4), (+)-verbamethine (5), (+)-incasine C (6), (+)-verdoline (incasine B′, 30), (+)-incasine B (31), and some of their isosteric analogues were studied. By chemical and chiroptical correlation, it was confirmed that an amidically bonded (S)-β-phenyl-β-alanine fragment forms the chiral moiety in all of these natural compounds. The signs of the registered Cotton effects (CEs) are interpreted in terms of the Smith's quadrant rule for the ¹L_b CEs of chiral α-substituted benzylamines and the Ogura's sign rule for n→π* CEs of lactams. Some of the conclusions regarding configuration are supported for the rigid bicyclic compound (-)-(9S)-9-phenyl-1,6-diazabicyclo[4.3.1]decan-7-one (15) by the X-ray crystal structure of the racemate.

Full text of DOI:10.1002/(SICI)1522-2675(19981007)81:10<1773::AID-HLCA1773>3.0.CO;2-X

Helvetica Chimica Acta ± Vol. 81 (1998)
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Chiroptical Properties of the Protoverbine Class of Macrocyclic Spermine
Alkaloids
by Konstantin Drandarov, Armin Guggisberg, Anthony Linden, and Manfred Hesse*
Organisch-chemisches Institut der Universität Zürich, Winterthurerstrasse 190, CH-8057 Zürich
The chiroptical properties (circular dichroism, CD) of the 17-membered macrocyclic spermine lactam
alkaloids ( )-protoverbine (16), its N,N'-methylene-bridged natural analogue (‡)-protomethine (17), their
natural derivatives ( )-verbacine (1), ( )-verballocine (2), ( )-verbascenine (3), ( )-verballoscenine (4), (‡)-
verbamethine (5), (‡)-incasine C (6), (‡)-verdoline (incasine B', 30), (‡)-incasine B (31), and some of their
isosteric analogues were studied. By chemical and chiroptical correlation, it was confirmed that an amidically
bonded (S)-b-phenyl-b-alanine fragment forms the chiral moiety in all of these natural compounds. The signs of
the registered Cotton effects (CEs) are interpreted in terms of the Smithꢀs quadrant rule for the 1Lb CEs of chiral
a-substituted benzylamines and the Oguraꢀs sign rule for n !p* CEs of lactams. Some of the conclusions
regarding configuration are supported for the rigid bicyclic compound ( )-(9S)-9-phenyl-1,6-diazabicy-
clo[4.3.1]decan-7-one (15) by the X-ray crystal structure of the racemate.
Introduction. ± The macrocyclic spermine alkaloids ( )-verbacine (1) and ( )-
verballocine (2) have been isolated from Verbascum pseudonobile Stoj. et Stef.
(Scrophulariaceae) [1] (see Scheme 1). The N-acetylated analogues ( )-verbascenine
(3) and ( )-verballoscenine (4) have been isolated from V. phoeniceum L. [2][3]. In
this plant, ( )-verbacine (1) and ( )-verballocine (2) have also been detected. They are
probable biogenetic precursors of ( )-verbascenine (3) and ( )-verballoscenine (4)
[3]. Compounds 1 ± 4 are 17-membered macrocyclic lactam alkaloids, which contain, as
structural units, spermine, 3-phenylpropionyl, cinnamoyl ((E) for 1 and 3, and (Z) for 2
and 4), and the Ac group (in the case of 3 and 4).
Comparison of the ORD (optical rotatory dispersion) spectra of ( )-(S)-N-ethyl-
a-phenylethylamine and ( )-(S)-a-phenylethylamine led to the conclusion that an
amidically bonded (S)-b-phenyl-b-alanine fragment forms the chiral part of the 17-
membered macrocycle in ( )-dihydroverbascenine (8, cf. Scheme 2) and its natural
unsaturated analogue, ( )-verbascenine (3) [2]. The absolute configuration of the
related alkaloids ( )-verbacine (1), ( )-verballocine (2), and ( )-verballoscenine (4)
was deduced by chemical and chiroptical ([a]D ) correlation with ( )-verbascenine (3)
[1][3].
Together with ( )-verbacine (1) and ( )-verballocine (2), the N,N'-methylene-
bridged derivatives, namely the cyclic aminals (‡)-verbamethine (5) and (‡)-
isoverbamethine ( ˆ incasine C; 6), have been isolated from V. pseudonobile.
Compounds 5 and 6 arise quantitatively by N,N'-cyclization of 1 and 2 with HCHO.
It is possible that they are formed by reaction with HCHO produced from the solvents
used as extractants. Because of the lack of evidence for their natural origin, 5 and 6
were considered as artifacts of 1 and 2 [1]. Compounds 5 and 6 (Scheme 1), and their
dihydro derivative 11 (cf. Scheme 2) have opposite signs for their optical rotation

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Helvetica Chimica Acta ± Vol. 81 (1998)
Scheme 1
([a]D ) as compared to the unbridged compounds 1, 2, and 7. The difference between
these closely related compounds was interpreted in terms of conformational changes in
the neighborhood of the center of chirality [1]. By mild acid hydrolysis in the presence
of NH2OH, which acts as an interceptor HCHO, the aminals (‡)-verbamethine (5),
(‡)-isoverbamethine (6), and (‡)-dihydroverbamethine (11) were converted quanti-

Helvetica Chimica Acta ± Vol. 81 (1998)
1775
tatively to ( )-verbacine (1), ( )-verballocine (2), and ( )-dihydroverbacine (7),
respectively (Schemes 1 and 2). Thus, it was confirmed that these six compounds have
the same absolute configuration, namely (S) [1][3].
The biogenetic precursor of the alkaloids 1 ± 4 is ( )-protoverbine (16,
cf. Scheme 4) and the precursor of the N,N'-methylene-bridged bases 5 and 6 is (‡)-
protomethine (17). Compounds 16 and 17 were isolated from the alkaloid extract of V.
pseudonobile and will be published elsewhere [4].
(‡)-Verballocine (2) and its N,N'-methylene-bridged derivative 6 were isolated
recently from Incarvillea sinensis Lam. (Bignoniaceae); compound 6 was named
incasine C [5]. However, from the chiroptical properties of its dihydro derivative 11
(comparison of the CD spectrum with that of (‡)-(R)-(1-phenylethyl)amine), the
absolute configurations of 11 and 6 were determined to be (R). It will be shown in this
paper that this conclusion has to be corrected.
Because of the confusion concerning the absolute configuration of 6 and 11 and the
open question about the nature of the chiroptical changes of 5, 6, and 11 in comparison
with the N,N'-unsubstituted analogues 1, 2, and 7, a more detailed investigation of the
chiroptical properties (CD) of this group of similar compounds is needed. Due to the
presence of the strongly absorbing (E)- or (Z)-cinnamoyl groups in most of these
alkaloids, the CD curves of their dihydro derivatives were compared. The resulting
conclusions regarding the configuration are applicable to the corresponding unsatu-
rated natural alkaloids.
Results and Discussion. ± Synthesis. We first examined the absolute configuration
of ( )-dihydroverbacine (7), its N,N'-methylene-bridged derivative (‡)-dihydrover-
bamethine (11), ( )-dihydroverbascenine (8), and their side-chain-unsaturated natural
analogues ( )-verbacine (1), ( )-verballocine (2), ( )-verbascenine (3), ( )-verbal-
loscenine (4), (‡)-verbamethine (5), and (‡)-incasine C (6) by their chemical
transformation to derivatives which are unambiguously chiroptically comparable with
suitable model compounds of known absolute configuration. The rings of the
macrocyclic spermine alkaloids are usually very flexible and, therefore, not suitable
for an unambiguous establishment of their absolute configuration. Thus, we tried to
obtain derivatives which possess an additional ring that would provide rigidity of the
spermine macrocycle.
( )-Dihydroverbacine (( )-(8S)-1-(3-phenylpropanoyl)-8-phenyl-1,5,9,13-tetra-
azacycloheptadecan-6-one; 7) was prepared by a published method by catalytic
hydrogenation of ( )-verbacine (1) [1]. Regioselective acetylation of 7 by Ac2O in
AcOH yielded ( )-dihydroverbascenine (8) almost quantitatively (Scheme 2). Both 7
and 8 were transformed to the diacetyl derivative ( )-10 on treatment with Ac2O/Et3N.
Compound 8 was then cyclized with HCHO in the presence of AcOH to give the
corresponding hexahydropyrimidinone derivative ( )-9.
Similarly, the bicyclic derivative ( )-15 was prepared from the nine-membered
model compound ( )-14 and HCHO. Compound ( )-14 has been used as an
intermediate in the asymmetric total synthesis of the spermidine alkaloid mayfoline [6].
To eliminate any possible sterical influences of the macrocyclic ring on the CD
spectral properties of the aromatic and lactam chromophores in the bicyclic compound
( )-9, a selective chemical degradation of 11 was performed (Scheme 3). As was done

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Helvetica Chimica Acta ± Vol. 81 (1998)
Scheme 2
with the macrocyclic spermidine alkaloid celacinnine [7], the macrocycle was opened
by hydrolysis to give the corresponding amino acid 23. The same amino acid 23 could be
obtained by hydrolysis of ( )-dihydroverbacine (7) under the same conditions.
Compound 23 was esterified to 24. By regioselective acetylation of 24, the partially
acetylated ester 25 was formed. Compound 25 was transformed, in quantitative yield, to
the amide 26 by Cu2‡-catalyzed aminolysis with BuNH2. Cyclization of 26 with HCHO
yielded the target hexahydropyrimidinone derivative ( )-27.
On the other hand, by starting with an authentic sample of methyl ( )-(3S)-3-
amino-3-phenylpropanoate (( )-19; Scheme 3) [6], the above-mentioned mild, Cu2‡-
catalyzed aminolysis with BuNH2 led to the amide ( )-20 in quantitative yield. The
corresponding N,N'-dibutyl derivative ( )-21 was prepared by reductive alkylation of
the primary amine ( )-20 with PrCHO and NaBH4. Addition of HCHO to ( )-21

Helvetica Chimica Acta ± Vol. 81 (1998)
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Scheme 3
yielded the target hexahydropyrimidinone (‡)-22. This compound was used as a model
compound for the natural-product derivatives ( )-9 and ( )-27. We preferred to
introduce the Bu moiety at the benzylic amino group in the model compounds ( )-21
and (‡)-22, as this is the N-substituent which is similar to the long-chain residue at the
benzylic N-atom in the degradation product ( )-27 (Scheme 3).

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By reacting ( )-dihydroverbacine (7) with HCHO, the corresponding (‡)-N,N'-
methylene-bridged derivative 11 was obtained (Scheme 2). To compare its CD spectral
properties, we prepared two other N,N'-bridged derivatives, i.e., 12 and 13 (Scheme 2).
( )-Dihydroverbacine (7) was treated in CHCl3 with phosgene to form the cyclic urea
12 [1] (Scheme 2). Compound 12 has been prepared earlier by catalytic hydrogenation
of verbaskine 28 [8] and its (Z)-isomer 29 [1]. ( )-Verbaskine (28) was earlier thought
to be a natural secondary metabolite, but later it was found to be an artifact [1].
The second N,N'-bridged derivative, the amidinium chloride 13, was obtained in
excellent yield by direct cyclization of 7 with formamidine hydrochloride (Scheme 2).
Together with the (E)- and (Z)-isomeric side-chain unsaturated analogues 30 and 31,
compound 13 has also been the subject of published work [5].
Finally, treatment of ( )-protoverbine (16) or (‡)-protomethine (17) with an
excess of HCHO in the presence of AcOH in boiling EtOH gave the tricyclic
compound (‡)-18 (Scheme 4) which was not detected in the plant [4]. At room
temperature and with 1 equiv. of HCHO, but without AcOH, 16 yielded 17.
CD Spectral Analyses. General. The results of the CD measurements are presented
in Table 1. The compounds in which the chiral center is part of a rigid hexahydropyr-
imidinone ring show ellipticities of equal sign. By this comparison, the absolute (S)-
configuration was unambiguously confirmed for ( )-verbacine (1), ( )-verballocine
(2), ( )-dihydroverbacine (7), ( )-verbascenine (3), ( )-verballoscenine (4), ( )-
dihydroverbascenine (8), (‡)-verbamethine (5), (‡)-incasine C (6), and (‡)-
dihydroverbamethine (11).

Helvetica Chimica Acta ± Vol. 81 (1998)
1779
Scheme 4
The compounds under investigation can be described as chiral monoalkyl-
substituted benzene derivatives which have an amine function directly bonded to the
benzylic chiral center. All compounds have a secondary (or tertiary) amide group in b-
position with respect to the benzene ring, namely the open-chain species ( )-19 ± ( )-
21); the cyclic six-membered ((‡)-22 and ( )-27), nine-membered (( )-14), and 17-
membered ring compounds (7, 8, ( )-10, and 16), the bicyclic compounds (( )-9, 11, 12,
13, ( )-15, and 17), and the tricyclic compound 18.
These alkaloids show two absorption bands in the UV region, a weak one above,
and a strong below 240 nm. Since the corresponding ellipticities arise by different
mechanisms, the established signs of the Cotton effects (CEs) in these absorption
regions will be discussed separately below.
Circular Dichroism above 240 nm. In the UV region between 240 and 270 nm, the
compounds reported in Table 1 show a weak absorption band with fine structure, which
is typical for a monosubstituted benzene chromophore (1Lb band) [9]. The recorded
1
CD spectra contain a number of CEs corresponding to the Lb absorption transitions.
1
As shown quite recently, the sign of the Lb CEs for benzene derivatives with a
chiral center bonded to the benzene ring depends only on the rotatory contribution of
the groups directly attached to the chiral center [10 ± 12]. On the basis of the
established sequences of the strength of the rotatory contributions for several different
functional groups, a quadrant rule has been formulated for the prediction of the sign of
the 1Lb CEs (i.e., for the absolute configuration) for chiral (1-phenylalkyl)amines and
related compounds in which one substituent at the contiguous chiral center is a H-atom
[10 ± 12]. For such compounds, the preferred conformation has been confirmed to be

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Helvetica Chimica Acta ± Vol. 81 (1998)
Table 1. CD Data (96% EtOH) and [a]D Values of the Compounds Studied
Compound
(conc. in %)
CD (l ([V])a)
l < 240 nm
[a]D
l > 240 nm
max [V]
min and 0 [V]
7b) (( )-Dihydroverbacine; 230 ( 3961) 256 (‡ 229)
252 (Æ 0)
22 (c ˆ 3.7, CHCl3) [1]
0.03)
262 (‡ 468)
258 (‡ 255)
265 (‡ 252)
273 (Æ 0)
268 (‡ 477)
(
)-7c) (0.03)
230 ( 723)
233 ( 777)
249 (‡ 136)d)
255 (‡ 268)
257 (‡ 261)
261 (‡ 383)
268 (‡ 333)
245 (Æ 0)
256 (‡ 255)
258 (‡ 253)
265 (‡ 210)
272 (Æ 0)
8b) (( )-Dihydroverbasce-
nine; 0.032)
230 ( 6818) 256 (‡ 168)
254 (Æ 0)
7 (c ˆ 0.41, MeOH) [2]
252 ( 99)d)
262 (‡ 429)
268 (‡ 452)
259 (‡ 165)
266 (‡ 200)
276 (Æ 0)
(
)-8c) (0.032)
230 ( 2222) 244 ( 218)d)
249 (‡ 82)
248 (Æ 0)
252 (‡ 113)
258 (‡ 132)
265 (‡ 94)
272 (Æ 0)
255 (‡ 200)
261 (‡ 314)
267 (‡ 254)
(
(
)-9 (0.09)
230 ( 2414) 250 ( 212)d)
232 ( 2663) 256 ( 32)
261 (‡ 78)
254 ( 32)
258 (Æ 0)d)
264 (‡ 56)
271 (‡ 92)
8.5 (c ˆ 2.0, CHCl3)
268 (‡ 139)
)-10 (0.02)
230 (‡ 10179) 255 ( 300)
251 (Æ 0)
51 (c ˆ 0.44, MeOH) [2]
‡ 8.6 (c ˆ 1.38, CHCl3) [1]
262 ( 360)
258 ( 259)
265 ( 192)
273 (Æ 0)
269 ( 327)
11 ((‡)-Dihydroverba-
methine ˆ Dihydroincasine
C; 0.02)
230 ( 3549) 249 ( 54)
256 ( 194)
248 (Æ 0)
252 (Æ 0)
258.5 ( 217)d) 258 ( 160)
262 ( 435)
268 ( 407)
266 ( 166)
274 (Æ 0)
(
)-12 (0.02)
230 (‡ 10617) 245 (‡ 445)d)
248 (Æ 0)
45.2 (c ˆ 1.92, CHCl3) [1]
‡ 60 (c ˆ 0.85, CHCl3)
250 ( 128)d)
251 ( 146)
258 ( 353)
266 ( 317)
273 (Æ 0)
255 ( 404)
262 ( 647)
269 ( 594)
13 ((‡)-Dihydroverdoline ˆ 230 (‡ 18577) 251 (‡ 1977)d) 260 (‡ 287)
254 (‡ 1090)d) 266 (‡ 139)
Dihydroincasine B; 0.0064)
256 (‡ 989)
263 (‡ 690)
269 (‡ 327)
272 (Æ 0)
(
)-14b) (0.036)
230 ( 26865) 256 ( 1797)d) 260 ( 1279)
232 ( 30134) 262 ( 1433)
269 ( 1006)
151 (c ˆ 0.936, CHCl3) [6]
267 ( 766)
278 (Æ 0)

Helvetica Chimica Acta ± Vol. 81 (1998)
CD (l ([V])a)
1781
Table 1 (cont.)
Compound
[a]D
(conc. in %)
l < 240 nm
l > 240 nm
max [V]
min and 0 [V]
(
)-14c) (0.036)
230 ( 20978) 258 ( 289)d)
262 (‡ 82)
256 ( 361)
260 (Æ 0)
265 (Æ 0)
271 (Æ 0)
268 (‡ 188)
(
(
)-15b) (0.038)
)-15c) (0.038)
230 ( 10714) 254 ( 2755)d) 258 ( 2132)
235 ( 24905) 261 ( 2132)d) 264 ( 1729)
268 ( 1784)d) 280 (Æ 0)
122.8 (c ˆ 0.56, CHCl3)
230 ( 18619) 259 ( 337)d)
262 (‡ 103)
257 ( 447)
261 (Æ 0)
265 (Æ 0)
272 (Æ 0)
268 (‡ 139)
16 (( )-Protoverbine; 0.027) 230 ( 1750)
256 (‡ 130)
252 (Æ 0)d)
258 (‡ 135)
266 (‡ 131)
274 (Æ 0)
28.6 (c ˆ 1.47, CHCl3)
‡ 4.9 (c ˆ 1.39, CHCl3)
247 ( 210)d) 262 (‡ 283)
268 (‡ 275)
17 ((‡)-Protomethine; 0.027) 230 ( 1117)
243 ( 81)d)
234 ( 652)d) 246 ( 10)d)
239 ( 216)d) 249 ( 38)
256 ( 135)
248 ( 16)
251 (Æ 0)
258 ( 110)
265 ( 134)
273 (Æ 0)
262 ( 290)
268 ( 277)
(‡)-18 (0.04)
230 (‡ 6091)
230 (‡ 840)
254 (‡ 319)d)
259 (‡ 7)d)
262 ( 242)
269 ( 362)
250 (‡ 111)d)
256 (‡ 171)
262 (‡ 233)
268 (‡ 197)
257 (Æ 0)
‡ 24 (c ˆ 1.4, CHCl3)
266 ( 162)
271 ( 322)
(
(
)-19b) (0.105)
)-19c) (0.105)
247 (‡ 101)
252 (‡ 121)
259 (‡ 157)
265 (‡ 110)
274 (Æ 0)
245 (‡ 43)
249 (‡ 42)
259 (‡ 60)
265 (‡ 34)
271 (Æ 0)
20.3 (c ˆ 1.5, CHCl3) [6]
230 (‡ 338)
247 (‡ 44)
252 (‡ 49)d)
254 (‡ 58)d)
257 (‡ 68)
261 (‡ 68)
262.5 (‡ 60)d)
267 (‡ 51)
(
(
)-20b) (0.07)
)-20c) (0.07)
230 (‡ 546)
230 (‡ 649)
249 (‡ 92)d)
251 (‡ 107)d)
256 (‡ 162)
262 (‡ 226)
268 (‡ 193)
245 (‡ 76)
258 (‡ 154)
265 (‡ 111)
273 (Æ 0)
31 (c ˆ 1.05, CHCl3)
242 (‡ 100)d)
248 (‡ 73)d)
254 (‡ 117)
261 (‡ 170)
267 (‡ 144)
245 (‡ 59)
251 (‡ 74)
257 (‡ 116)
265 (‡ 85)
272 (Æ 0)

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Helvetica Chimica Acta ± Vol. 81 (1998)
Table 1 (cont.)
Compound
CD (l ([V])a)
[a]D
(conc. in %)
l < 240 nm
l > 240 nm
max [V]
min and 0 [V]
(
(
)-21b) (0.21)
)-21c) (0.21)
230 ( 365)
233 ( 538)
256 (‡ 190)
262 (‡ 336)
268 (‡ 324)
248 (Æ 0)
41 (c ˆ 2.24, CHCl3)
251 (‡ 45)d)
258 (‡ 174)
265 (‡ 152)
276 (Æ 0)
230 (‡ 712)
242 (‡ 101)d)
249 (‡ 122)
255 (‡ 211)
261 (‡ 308)
267 (‡ 264)
244 (‡ 89)
251 (‡ 121)
258 (‡ 176)
265 (‡ 134)
275 (Æ 0)
(‡)-22 (0.03)
230 ( 3620)
230 ( 6026)
262 (‡ 97)
258 (Æ 0)
265 (‡ 47)
272 (Æ 0)
‡ 4 (c ˆ 2.25, CHCl3)
3 (c ˆ 2.4, CHCl3)
268 (‡ 133)
(
)-27 (0.029)
257 (‡ 63)
263 (‡ 184)
269 (‡ 247)
256 (Æ 0)
259 (‡ 96)
265 (‡ 179)
272 (‡ 191)
a) l in nm, in parentheses molar ellipticity [V]. b) Free base. c) After acidification of the solution (EtOH
solution of HCl). d) Shoulder.
that one in which the benzene-ring plane eclipses or almost eclipses the H-atom at the
benzylic chiral center ([10] and ref. cit. therein). The quadrant projection of (S)-(1-
phenylethyl)amine is given in Fig. 1. The CD curve of (S)-(1-phenylethyl)amine in the
1Lb region (between ca. 240 and 300 nm) is in the positive part of the scale. In the
established sequences, the Me (respectively CH2) group makes a larger contribution to
1
the Lb CEs than does an amino, ammonium, or N-alkylamino group attached to the
chiral center [10 ± 12]. Thus, for (1-phenylalkyl)amines the right upper quadrant is
positive (Fig. 1)
Fig. 1. The quadrant projection of (S)-(1-phenylethyl)amine (according to Smith and co-workers [10 ± 12]).
ꢁThe sequences for the summation of contributions to the 1Lb CEs (given by Smith and Fontana [10]) are SH,
‡
‡
‡
COO , Me3C > Me, CH2 > NH2, NH3, Me3N , OH, MeO, Cl; and Me > COOH > NH3, OH, MeO. These
sequences may be used in connection with the sector signs in quadrant projection and will have a general
usefulness for the establishment of the absolute configuration of related chiral benzene compounds in which
one substituent at the contiguous chiral center is a hydrogen atomꢀ.

Helvetica Chimica Acta ± Vol. 81 (1998)
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The compounds reported in Table 1 have the same arrangement around the chiral
center, and for them the quadrant rule, depicted above, is primarily applicable. In
accordance with Smithꢀs rule [10 ± 12], the open-chained compounds ( )-19 ± ( )-21,
the six-membered ring species (‡)-22 and ( )-27, the bicyclic compounds ( )-9 and 13,
1
and the 17-membered cycles 7, 8, and 16 all show a positive sign for the Lb CEs. It
seems that, for these compounds, the orientation of the benzene ring and the benzylic
substituents is (in EtOH solution) predominantly as given in Fig. 1, with the CH2 group
in the positive quadrant. In the crystalline state, such an orientation for the benzene
ring has been established by an X-ray crystal-structure analysis of the 13-membered
macrocyclic spermidine alkaloid (S)-mayfoline [6].
According to the quadrant rule, a negative sign for the 1Lb CEs should by the result
of an alternative orientation of the benzene ring, in which the C N bond at the chiral
center is eclipsed or almost eclipsed. Such an orientation of the benzene ring was
established for the crystalline state of compound (Æ)-15 by X-ray crystallography
(Fig. 2,a). The quadrant projection of the (S)-isomer from the crystal structure of (Æ)-
15 shows that the CH2 group attached to the chiral center is placed in the lower right,
negative quadrant (C(8) C(9) C(11) C(12) torsion angle is ‡ 96.2 (3)8) (Fig. 2,b).
We can conclude that such a conformation is also highly populated in an EtOH solution
of ( )-(S)-15, since a negative sign was observed for the 1Lb CEs in this solvent.
Fig. 2. a) ORTEP Plot [13] of one of the symmetry-independent molecules in the structure of (Æ)-15 and
b) quadrant projection of its crystal structure
By assuming the presence of a similar, preferred orientation of the benzene ring, it
1
is possible to explain the established negative sign of the Lb CEs for the compounds
diacetyldihydroverbacine (( )-10), (‡)-dihydroverbamethine (11), ( )-dihydrover-
baskine (12), (‡)-protomethine (17), the tricyclic compound (‡)-18, and the model
compound ( )-14.

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1
The recorded negative Lb CEs of the free base ( )-14 becomes positive after
acidification of its EtOH solution. In agreement with the established sequences for the
strengths of the rotatory contribution [10 ± 12] (see Fig. 1), the formed ammonium ion
is still a weaker contributor than the CH2 group attached to the chiral center. It is
expected that an increase in the effective volume of the solvated, charged (protonated)
secondary amino group in ( )-14 causes a clockwise repulsion of the benzene ring to a
predominant position in which the CH2 group is in the upper right (positive) quadrant.
Acidification of the EtOH solution of the bicyclic compounds (‡)-11, ( )-15, (‡)-
1
17, and of the tricyclic compound (‡)-18 also converts the sign of their Lb CEs from
negative to positive. These changes can be explained in the same way. The acidification
of the solutions of the other compounds, i.e., 7, 8, ( )-19 ± ( )-21, did not cause changes
in the sign of the 1Lb CEs.
The non-substituted 17-membered lactam alkaloid ( )-protoverbine (16; Scheme 4)
was isolated from the total alkaloid-containing extract of V. pseudonobile. This is the
biogenetic precursor of the present class of spermine alkaloids (Scheme 1 and 28 ± 31)
1
[4]. Similar to ( )-dihydroverbacine (7) and ( )-dihydroverbascenine (8), the Lb
spectral region for ( )-protoverbine (16) shows positive CEs. Thus, establishing the
(S)-chirality of 16 [4]. The N,N'-methylene-bridged alkaloid (‡)-protomethine (17,
Scheme 4) exhibits, like the corresponding aminal, (‡)-dihydroverbamethine (11), a
negative 1Lb CEs.
It has been reported earlier that the hydroxylation or methoxylation of the benzene
ring bonded to the chiral center changes the sign of the 1Lb CEs of the (1-
phenylalkyl)amines [12][14]. Thus, for the related (S)-spermine alkaloid ( )-
buchnerine (32) and its 1-[(Z)-4-methoxycinnamoyl] derivative 33 (in form of its
1
dihydro derivative), we can expect negative Lb CEs, opposite to those of ( )-(S)-
protoverbine (16) and ( )-(S)-dihydroverbacine (7). The absolute configuration of
( )-buchnerine (32) and its derivative 33 has been postulated to be (S) without any
chiroptical (CD or ORD) arguments [15].
Circular Dichroism below 240 nm. All compounds reported in this paper exhibit
intense UV-light absorption below 240 nm owing the presence of aromatic (1La p !p*
absorption transition with lmax ca. 200 nm) and lactam (amide) chromophores (n !p*
transition with lmax ca. 220 nm). The registered CD spectra in this region show strong
ellipticities, mainly corresponding to the lactam n !p* absorption band.

Helvetica Chimica Acta ± Vol. 81 (1998)
1785
All compounds with the (S)-configured chiral center incorporated into a six-
membered lactam ring (9, ( )-15, (‡)-22, and ( )-27) show a negative-signed plain CD
curve or negative CE between 230 and 240 nm.
It has been shown for chiral four-, five-, six-, and seven-membered lactams that the
sign of the n !p* CE (ca. 220 nm) depends only on the ring conformation [16 ± 19]. On
this bases, Takayanagi and Ogura have postulated a sign rule for the prediction of the
ring conformation of chiral six-membered lactams [19]. The possible conformations of
such compounds have been classified into two types, type A (positive CE) and type B
(negative CE), by the enantiomeric nature of the ring system (Fig. 3).
Fig. 3. Projection of the two enantiomeric types of six-membered lactams which cause a positive and negative
lactam n !p* Cotton effect, respectively (according to Takayanagi and Ogura [19])
If we assume that the six-membered lactams (‡)-22 and ( )-27 and the
bicyclo[12.3.1] lactam ( )-9 have a preferred quasi-chair conformation of the
hexahydropyrimidinone part with an equatorially oriented benzene ring and a
pseudoequatorial N,N'-alkyl residue, the ring will have the type-B chirality according
to Takayanagi and Ogura (Fig. 3) [19], which is in agreement with the obtained
negative-signed n ! p* ellipticities for these compounds. However, the X-ray structure
analysis of the bicyclo[4.3.1] compound 15 showed that the rigid six-membered
hexahydropyrimidinone ring has the boat conformation (Fig. 2). Nevertheless, a
negative sign of n !p* ellipticity was also recorded for ( )-15.
A negative sign for the ellipticities in the spectral region below 240 nm was also
established for the macrocyclic compounds ( )-dihydroverbacine (7), ( )-dihydro-
verbascenine (8), (‡)-dihydroverbamethine (11), (‡)-protoverbine (16), (‡)-proto-
methine (17), and the model compound ( )-14. It is of interest to note that the
orientation of the lactam CˆO group should be almost the same in the rigid six-
membered azalactams 9, ( )-15, (‡)-22, and ( )-27, and in the flexible macrocyclic
compounds 7, 8, 11, ( )-14, 16, and 17. All of these compounds display a negative sign
for the corresponding n !p* ellipticities.
A positive sign for the CEs below 240 nm was established for the macrocycles ( )-
10, 12, 13, and (‡)-18. The additional chromophores at the N-atoms in compounds ( )-
10, 12, and 13 (an Ac group in 10, a carbamoyl in 12, and formamidinium in 13) makes
an interpretation of the observed CD spectra uncertain in terms of the above-
mentioned lactam sign rule. For these compounds, an exciton coupling can be expected
between the benzene chromophore at the chiral center and the additional chromo-
phores at the benzylic N-atom. This is not the case with the tricyclic compound (‡)-18.
There is no additional chromophore directly attached to the chiral center, nevertheless,
it shows a strong positive shorter wavelength ellipticity. This fact clearly indicates that
the ellipticity below 240 nm in the compounds under investigation has a complex origin.
It is assumed that there is a coupling between the 1La p !p* absorption transition of

1786
Helvetica Chimica Acta ± Vol. 81 (1998)
the benzene chromophore at the chiral center and the electric (or magnetic) dipoles of
the lactam chromophore in the b-position to the chiral center [20]. It seems that, for
some of the compounds under study, such a mechanism dominates the origin of the
ellipticities below 240 nm. Such a possibility should be supported by additional
investigation.
For the open-chain compounds ( )-19 and ( )-20, a positive sign was observed for
the ellipticities in this region. No change of the sign was observed upon acidification.
This is in contrast with the N,N'-dibutyl derivative ( )-21, which shows a negative sign
as the free base, but a positive sign after acidification. Acidification of the solutions of
7, 8, and ( )-14 only decreases the magnitudes of their negative-signed ellipticities.
Conclusion. ± For the compounds of the present study, the recorded CD curves
between 230 and 280 nm are complex due to the superposition of the ellipticities from
1
two different chromophores. The CEs above 240 nm are clearly derived from the Lb
p !p* absorption transitions of the benzene chromophore, which is directly attached
to the chiral center. According to Smithꢀs quadrant rule, the sign of these CEs depends
on the orientation of the plane of the benzene ring towards the CH2 group bonded to
the chiral center. In different members of the studied series of isosteric (S)-compounds,
the preferred orientation of the benzene ring in EtOH solution change the localization
of the neighboring CH2 group in the upper or lower right quadrants and causes a
1
positive- or negative-signed Lb CEs, respectively.
The ellipticities below 240 nm were associated with the n !p* absorption
transitions of the lactam chromophore in the b-position to the chiral center. For
compounds containing a (6S)-6-phenylhexahydropyrimidin-4-one ring, the observed
negative sign of the n !p* ellipticities is in agreement with the earlier proposed
Oguraꢀs sign rule for six-membered lactams with a quasi-chair conformation. However,
a rigid bicyclic analogue with a sterically fixed boat conformation of the six-membered
azalactam ring and an equatorial Ph substituent of the (S)-chiral center also showed a
negative sign of ellipticity.
For six-, nine-, 13- [6][21], and 17-membered azalactams in which (S)-b-phenyl-b-
alanine is the chiral part of the cycle, the sign of the n !p* ellipticities is negative. The
introduction of an additional chromophore at the chiral center can convert the sign.
The independent origin of the observed CEs above and below 240 nm, and their
high sensitivity to conformational and substitutional changes seriously limits the
predictability of the CD-spectral method for the present type of macrocyclic lactam
alkaloids. Compounds with one and the same chromophore and chirality but different
substitution in the neighborhood of the chiral center can exhibit different, even
enantiomorphic CD curves (Fig. 4). It was found that different members of the tested
1
group of isosteric (S)-compounds displayed all possible combinations of signs of Lb
CEs for the benzene and n !p* ellipticities of the lactam chromophores (above and
below 240 nm) as shown in Fig. 4. Direct comparison of the obtained chiroptical
properties with those of simpler compounds that have a similar arrangement of the
chiral center ((S)- or (R)-(1-phenylethyl)amine in the case of ( )-dihydroverbasce-
nine (8) and (‡)-dihydroverbamethine (dihydroincasine C; 11)) can be a source of
incorrect conclusions regarding the configuration, as in the case of (‡)-incasine C (6).
Thus, the CD-spectral method for these types of natural products is limited almost only

Helvetica Chimica Acta ± Vol. 81 (1998)
1787
Fig. 4. CD Curves in EtOH of ( )-(S)-dihydroverbaskine (12), (‡)-(S)-dihydroincasine B (13), ( )-(S)-
protoverbine (16), and (‡)-(S)-protomethine (17)
to comparison of the CD-spectral properties of compounds with an almost identical
environment around the chiral center. The corresponding conclusions regarding
configuration should be additionally supported by alternative methods.
We thank the Swiss National Science Foundation for generous support. K.D. thanks the Prof. Dr. Hans E.
Schmid Foundation for the financial support.
Experimental Part
General. TLC: Merck precoated silica-gel 60 F254 plates and Polygramꢂ-Alox N/UV254, Macherey-Nagel
(Germany); detection by Dragendorffꢀs and ninhydrine reagents (No. D 156a and D 127a in [22]); for more
details about the TLC retention of the (E/Z)-isomeric pairs of macrocyclic spermine alkaloids, their dihydro
derivatives and simpler cinnamamides, see [23]. CC: silica gel 60 (70 ± 230 mesh) Merck, and Alumina N, act. 1,

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Helvetica Chimica Acta ± Vol. 81 (1998)
ICN Biomedicals. CD Spectra: at r.t. in EtOH in a 1-cm quartz cell between 230 and 280 nm; JASCO J-715
spectropolarimeter. Optical rotation: Perkin-Elmer 241 polarimeter; for [a]D values, see Table 1. UV: Perkin-
1
Elmer 555: Perkin-Elmer 297 film; in cm
.
1H-NMR: Bruker AC-300, ARX-300, or AMX-600. 13C-NMR:
Bruker AMX-600 (150 MHz); chemical shifts in ppm (d scale) and CDCl3 as solvent, TMS as internal standard,
r.t. EI-MS (at 70 eV), CI-MS (NH3 as reactant gas): Finnigan-MAT 90. ESI-MS: Finnigan TSQ 700 mass
spectrometer.
(‡)-(2S)-2-Phenyl-9-(3-phenylpropanoyl)-1,5,9,14-tetraazabicyclo[12.3.1]octadecan-4-one (11). To an
EtOH soln. of a sample of 7 [1], a molar excess of 40% aq. HCHO soln. was added. After several min, the
mixture was evaporated to give 11 which was purified by CC (neutral alumina; AcOEt/MeOH 9 :1). TLC (silica
gel; AcOEt/MeOH 4 :1): Rf 0.7. 1H-NMR: 7.37 ± 7.05 (m, 10 arom. H); 3.98 (t, PhCHN); 3.90 ± 2.50
(m, 12 CH2N); 2.50 ± 1.35 (m, 16 aliph. CH2). 13C-NMR: 171.47, 171.40 (CˆO); 141.51, 141.39 (arom. quat. C);
128.41, 128.39, 128.21, 128.18, 127.97, 127.91, 127.87, 127.84, 126.07, 126.02 (arom. CH); 64.10 (PhCHN); 50.84,
47.02, 45.12, 44.10, 36.43, 34.84, 31.71, 31.60, 27.14, 26.13, 25.59, 25.09, 21.53, 21.17 (aliph. C). ESI-MS: 499 ([M ‡
‡
‡
Na] ), 477 ([M ‡ H] ).
(
)-(2S)-2-Phenyl-9-(3-phenylpropanoyl)-1,5,9,14-tetraazabicyclo[12.3.1]octadecane-4,18-dione
(12).
From 7 and COCl2 in CHCl3 according to [1]. Compound 12 was purified by CC (neutral alumina; AcOEt/
1
MeOH 9 :1). TLC (silica gel; AcOEt/MeOH 4 :1): Rf 0.8. H-NMR: 7.37 ± 7.20 (m, 10 arom. H); 6.13 (t, 1 H,
CONH); 4.46 ± 4.30 (m, H C(2)); 3.8 ± 2.5 (m, 8 CH2); 2.0 ± 1.25 (m, 5 CH2). 13C-NMR (2 conformers): 171.80/
171.79, 170.57/170.39, 157.42/157.30 (3 CˆO); 141.75/141.59, 139.33/139.15 (2 arom. quat. C); 128.88, 128.65,
128.61, 128.60, 128.06, 127.98, 127.65, 126.28, 126.27 (arom. CH); 47.52, 45.51, 44.76/44.45, 44.35/44.24, 44.14/
43.82, 37.61/37.36, 36.73, 35.29/35.09, 31.84/31.81, 28.19, 27.13, 24.19, 23.07/22.82, 22.36/22.08 (aliph. C). EI-MS:
.
‡
‡
490 (38, M ), 357 (100, [M PhCH2CH2CˆO] ).
(
)-(8S)-13-Acetyl-8-phenyl-1-(3-phenylpropanoyl)-1,5,9,13-tetraazacycloheptadecan-6-one (8) [2].
A
mixture of 7 (17 mg, 0.037 mmol) Ac2O (40 ml, 40 mg, 0.41 mmol), and AcOH (2 ml) was heated at 608 for
1 h. After dilution with H2O and extraction with CHCl3, the extract was washed with H2O, dried (Na2SO4), and
evaporated: 13 mg (72%) of 8 as a colorless amorphous solid. Compound 8 was purified by CC (neutral
alumina; acetone and acetone/MeOH 10 :1). TLC (silica gel; AcOEt/MeOH 4 :1): Rf 0.24. IR: 1635s (CˆO,
1
amide I), 1550m (CONH, amide II). H-NMR: identical with the earlier published one [2]. EI-MS: 506 (53,
.
‡
‡
‡
M
), 463 (16, [M COMe] ), 451(100), 373 (15, [M PhCH2CH2CˆO] ), 361(18), 318(27), 146(56),
105(49), 91(79).
(
)-(8S)-9,13-Diacetyl-8-phenyl-1-(3-phenylpropanoyl)-1,5,9,13-tetraazacycloheptadecan-6-one (10). Ac-
cording to [1][2], ( )-10 was prepared from 8 (or 7) in CHCl3 with a molar excess of Ac2O in the presence of
Et3N at r.t. overnight. Compound ( )-10 was purified by CC (silica gel; acetone). TLC (silica gel; AcOEt/
MeOH 4 :1): Rf 0.36. IR: 1635s (CˆO, amide I), 1545m (CONH, amide II). 1H-NMR: identical with the earlier
‡
published one [2]. ESI-MS: 571 ([M ‡ Na] ).
(‡)-(2S)-2-Phenyl-9-(3-phenylpropanoyl)-1,5,9-triaza-14-azoniabicyclo[12.3.1]octadec-14(18)-en-4-one
Chloride (13). Compound 7 (13 mg, 0.028 mmol) was treated with 30 mg (0.37 mmol) of formamidine
hydrochloride in 0.5 ml of EtOH 20 h at r.t. After evaporation, conc. aq. HCl was added, the mixture extracted
with CHCl3, the org. extract washed with H2O and evaporated. The remaining crude product was purified by CC
(silica gel; CHCl3/MeOH 4 :1): 12 mg (84%) of pure 13. Colorless amorphous solid. TLC (silica gel; CHCl3/
‡
MeOH 4 :1): Rf 0.52. IR: 1680s (CˆN ), 1640s (amide I), 1550m (amide II, CONH). 1H-NMR (2 conformers):
‡
10.10/9.96 (2s, N ˆCHN); 8.75/8.45 (br. 2d, CONH); 7.40 ± 7.31 (m, 4 arom. CH); 7.30 ± 7.24 (m, 3 arom. CH);
7.21 ± 7.15 (m, 3 arom. CH); 5.17 (br. t, H C(2)); 4.82/4.18 (br. 2t, H C(17)); 4.29 (br. t, H C(3)); 3.70 ± 2.90
(m, 14 H); 2.67 ± 2.45 (m, 3 H); 2.07 ± 1.40 (m, 9 H). 13C-NMR: 171.85/171.71, 168.69/168.42 (2 CˆO); 151.94
‡
(N ˆCHN); 141.48/141.32, 136.55/136.45 (arom. quat. C); 129.53, 129.29, 129.26, 128.43, 128.41, 128.36, 126.85,
126.82, 126.06 (arom. CH); 65.98/65.87 (PhCHN); 53.47/52.76; 47.17/46.54; 45.74/45.61; 43.72/43.55; 42.07;
39.24/39.02; 36.79/36.25; 35.07/34.83; 31.53/31.51; 29.66/29.10; 27.39; 24.21; 22.93/22.60/22.30; 18.95
‡
(14 aliph. C). ESI-MS: 475 (M ).
(
)-(17S)-5-Acetyl-17-phenyl-10-(3-phenylpropanoyl)-1,5,10,14-tetraazabicyclo[12.3.1]octadecan-15-one
(9). A mixture of 50 mg (0.1 mmol) of 8, 0.5 ml of 40% aq. HCHO, 0.5 ml of AcOH, and 2 ml of EtOH was
refluxed for 1 h. After evaporation to dryness, H2O was added to the residue, the mixture alkalized with 25% aq.
ammonia and extracted with CHCl3. The org. extract was washed with H2O, dried (Na2SO4), and evaporated: 9
(almost quant.). Colorless, glass-like solid, after CC (neutral alumina; AcOEt/MeOH 9 :1). TLC (silica gel;
AcOEt/MeOH 8 :2): Rf 0.31. IR: 1638s (CˆO, amide I), no amide-II band (CONH). 1H-NMR: 7.42 ± 7.15
(m, 10 arom. H); 4.1 ± 4.0 (m, H C(17)); 4.0 ± 2.25 (m, 8 CH2); 2.05, 2.03, 1.99 (3s, COMe, mixture of
‡
conformers); 1.95 ± 1.5 (m, 5 CH2). ESI-MS: 541 ([M ‡ Na] ).

Helvetica Chimica Acta ± Vol. 81 (1998)
1789
(
)-(9S)- and (Æ)-9-Phenyl-1,6-diazabicyclo[4.3.1]decan-7-one (( )- and (Æ)-15, resp.). As described for
9, from ( )-14 [6]: ( )-15, as colorless solid. Compound (Æ)-15 was prepared from 65 mg (0.3 mmol) of ( Æ )-14
[6] and recrystallized from hexane. M.p. 96 ± 988. TLC (silica gel; AcOEt/MeOH 9 : 1): Rf 0.71 (Rf (14) in the
same mobile phase 0.56). 1H-NMR: 7.38 ± 7.33 (m, 4 arom. H); 7.27 ± 7.24 (m, 1 arom. H); 4.55 (d, J ˆ 14.3,
1 H, NCH2N); 4.34 ± 4.28 (m, 1 H C(5)); 4.01 (d, J ˆ 14.3, 1 H, NCH2N); 3.71, 3.72 (2d, J ˆ 12.8, 1 H C(9));
2.97, 2.96 (2d, J ˆ 13.5, 1 H C(5)); 2.89 ± 2.82 (m, 2 H C(2)); 2.80, 2.79 (2d, J ˆ 14.8, 1 H C(8)); 2.57, 2.55
(2d, J ˆ 14.8, 1 H C(8)); 2.17 ± 2.12 (m, 1 H C(4)); 1.85 ± 1.77 (m, 1 H C(4)); 1.60 ± 1.51 (m, 2 H C(3)).
13C-NMR: 173.99 (CˆO); 143.95 (arom. C(1')); 128.63, 127.14, 126.04 (arom.C(2') ± C(6')); 63.61 (C(10));
.
‡
61.42 (C(9)); 58.25 (C(2)); 42.35 (C(5)); 41.70 (C(8)); 27.68 (C(4)); 24.34 (C(3)). EI-MS: 230 (100, M ),
215(12), 202(9), 187(15), 171(17), 159(43), 131(20), 118(50), 104(62), 91(43), 84(23).
(
)-(3S)-3-Amino-N-butyl-3-phenylpropanamide (( )-20). Compound ( )-19 [6] (540 mg, 3 mmol) was
treated with 0.5 ml of BuNH2 in the presence of 1 mg of Cu(AcO)2 for 15 h at r.t. The mixture was concentrated,
a minimal amount of 50% aq. MeOH added to the residue, the mixture alkalinized with K2CO3, heated at 608
for 30 min (for saponification of the traces of unchanged starting ester), and extracted with CH2Cl2. The extract
was washed with H2O, dried (Na2SO4), and evaporated: ( )-20 (almost quant.). In the absence of Cu2‡ ions, for
15 h, this reaction gave only ca. 30% yield. Colorless crystals. M.p. 64 ± 67%. TLC (silica gel; CHCl3/MeOH
10 :1): Rf 0.23. 1H-NMR: 7.4 ± 7.2 (m, 5 arom. H); 6.82 (br. s, CONH); 4.37 (br. s, 1 H C(3)); 3.22
(q, CONHCH2); 2.5 (br. s, CH2CO); 1.87 (br. s, NH2); 1.5 ± 1.25 (m, MeCH2CH2); 0.9 (t, Me). EI-MS: 220
.
‡
‡
(10, M ), 119(51), 106 (100, [PhCHˆNH2] ).
(
)-(3S)-N-Butyl-3-(butylamino)-3-phenylpropanamide (( )-21). To a soln. of 300 mg (1.4 mmol) of 20 in
3 ml of MeOH, 140 ml (113 mg, 1.6 mmol) of PrCHO and 2 drops of AcOH were added. While cooling to 2 ± 58,
100 mg (2.6 mmol) of NaBH4 were added portionwise. After 30 min stirring at r.t., the solvent was evaporated,
H2O added to the residue, and the mixture extracted with CHCl3. The extract was washed with H2O and
evaporated. The crude material was purified by CC (neutral alumina; hexane/acetone 5 :1): 265 mg (70%) of
(
)-21. Colorless oil. TLC (silica gel; CHCl3/MeOH 10 :1): Rf 0.50. TLC (Al2O3, hexane/acetone 5 :1): Rf 0.30.
IR: 1640s (CˆO, amide I), 1550s (CONH, amide II). 1H-NMR: 7.50 (br. s, CONH); 7.38 ± 7.20 (m, 5 arom. H);
3.95, 3.93 (2d, 1 H C(3)); 3.23 (q, CONHCH2); 2.60 ± 2.40 (m, 2 H C(2), NHCH2); 1.70 (br. s, NH C(3));
1.50 ± 1.25 (m, MeCH2CH2); 0.94 ± 0.85 (m, 2 Me). CI-MS (NH3); 277 ([M ‡ H] ).
‡
(‡)-(6S)-1,3-Dibutylhexahydro-3-phenylpyrimidin-4-one ((‡)-22). A mixture of 265 mg (0.1 mmol) of
(
)-21, 0.5 ml of 40% aq. HCHO, 0.5 ml of AcOH, and 2 ml of EtOH was refluxed for 1 h. After evaporation to
dryness, H2O was added to the residue, the mixture alkalinized with 25% aq. soln. of NH3 and extracted with
CHCl3. The org. extract was washed with H2O, dried (Na2SO4), and evaporated: (‡)-22 (almost quant.).
Colorless oil which was purified through a short column (neutral alumina; hexane/acetone 5 :1). TLC (Al2O3,
hexane/acetone 5 :1): Rf 0.44. IR: 1650s (CˆO, amide I), no amide-II band (CONH). 1H-NMR: 7.39 ± 7.22
(m, 5 arom. H); 4.13 (d, J ˆ 11.5, 1 H, NCH2N); 4.04 ± 3.98 (m, therein 4.00 (d, J ˆ 11, 6, 1 H, NCH2N) and 4.02
(t, 1 H C(6))); 3.45 ± 3.35 (m, CONHCH2); 2.8 ± 2.3 (m, CH2CO, CH2N(1)); 1.6 ± 1.2 (m, MeCH2CH2); 0.93,
‡
0.84 (2t, 2 Me). CI-MS (NH3): 289 ([M ‡ H] ).
Methyl (3S)-8-Acetyl-18-oxo-3-phenyl-13-(3-phenylpropanoyl)-4,8,13-triazanonadecanoate (25). A mix-
ture of 203 mg (0.43 mmol) of 11 and 5 ml of 6n aq. soln. of HCl was refluxed for 2 h. Compound 11 was
completely transformed to 23 (TLC (silica gel; CHCl3/MeOH/25% aq. soln. of NH3 4 :3 :1, ninhydrine): Rf 0.3).
After evaporation, the residue was dissolved in MeOH, saturated with gas. HCl, and refluxed for 1 h. TLC (silica
gel; CHCl3/MeOH/25% aq. soln. of NH3 4 :3 :1, ninhydrine) showed 24 as the main compound (Rf 0.5). After
evaporation, the residue was dissolved in MeOH, and the pH of the soln. was adjusted to 8 with an aq. soln. of
NaHCO3. After addition of 1 ml of AcOH, the mixture was evaporated. The residue was dissolved in 2 ml of
AcOH, 0.4 ml (4 mmol) Ac2O was added and the mixture heated at 608 for 3 h. After dilution with H2O and
extraction with CHCl3, TLC of the H2O-washed CHCl3 extract (silica gel; AcOEt/MeOH 8 :3) showed the
presence of the partially acetylated ester 25 (Rf 0.2) and some fully (additionally at N(4)) acetylated by-product
(Rf 0.32). Compound 25 was isolated by CC (silica gel; CHCl3, AcOEt, then AcOEt/MeOH 8 :2): 69 mg (26%
overall yield) of 25. TLC (silica gel; CHCl3/MeOH/25% aq. soln. of NH3 9 :1:0.1): Rf 0.72. TLC (Al2O3; CHCl3/
1
acetone 1:1): Rf 0.25. IR: 1735s (CˆO, ester), 1630s (CˆO, amide I), 1545m (CONH, amide II). H-NMR:
7.42 ± 7.15 (m, 10 arom. H); 4.05 (m, H C(3)); 3.7 ± 3.6 (m, COOMe, mixture of conformers); 2.10 ± 1.98
(m, 2 NCOMe). 13C-NMR: 172.77, 172.24, 170.42, 170.21 (4 CˆO); 142.38, 141.05 (2 arom. quat. C); 128.64/
128.54, 128.47/128.46, 128.43/128.41, 128.40/128.39, 128.38/128.37, 128.34/128.32, 127.59, 126.96, 126.81, 126.20
(10 arom. CH); 59.59/59.57/59.48 (PhCN); 51.65/51.59 (ester C); 48.23/48.18; 47.34; 46.56; 44.71/44.41; 42.62/
42.58; 42.35 (6 C N); 35.66, 34.79, 31.64, 29.35, 27.23, 26.02, 24.98, 23.45, 21.45 (MeCO, acyl. CH2, aliph. CH2).
‡
‡
CI-MS: 581 (42, [M ‡ 1] ), 419 (33, [M ‡ H PhCHˆCH COOMe] ), 362(9), 277(21), 180 (100,
‡
‡
[PhCHˆCHCOOMe ‡ NH4] ), 163 (73, [PhCHˆCHCOOMe ‡ H] ).

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Helvetica Chimica Acta ± Vol. 81 (1998)
(3S)-8-Acetyl-N-butyl-18-oxo-3-phenyl-13-(3-phenylpropanoyl)-4,8,13,17-tetraazanonadecanamide (26).
As described for ( )-21, with 25 mg (0.04 mmol) of 25, 0.5 ml of BuNH2, and 1 mg of Cu(AcO)2 for 72 h: 26
(almost quant.). Colorless, glass-like solid. TLC (silica gel; CHCl3/MeOH/25% aq. soln. of NH3 9 :1 :0.1):
‡
Rf 0.55. TLC (Al2O3; CHCl3/acetone 1:1): Rf 0.18. ESI-MS: 622 ([M ‡ H] ).
(
)-(6S)-1-[4-Acetyl-12-acetamido-9-(phenylpropanoyl)-4,9-diazadodecyl]-3-butylhexahydro-6-phenyl-
pyrimidin-4-one ( ˆ N-[3-(Acetylamino)propyl]-N-(4-{acetyl[3-(3-butylhexahydro-4-oxo-6-phenylpyrimidin-1-
yl)propyl]amino}butyl)-3-phenylpropanamide; ( )-27). From 20 mg (0.03 mmol) of 26, 0.5 ml of 40% aq. soln.
of HCHO, 0.5 ml of AcOH, and 2 ml of EtOH, ( )-27 was obtained quantitatively after 1 h reflux. Colorless
solid after purification by CC (neutral alumina; CHCl3/acetone 10 : 3). TLC (silica gel; CHCl3/MeOH/25% aq.
soln. of NH3 9 : 1 : 0.1): Rf 0.75. TLC (Al2O3, CHCl3/acetone 1 : 1): Rf 0.37. IR: 1640s (CˆO, amide I), 1550m
(amide II, CONH; terminal acetamide). 1H-NMR: 7.4 ± 7.12 (m, 10 arom. H); 6.92, 6.76 (2 br. t, CNHCOMe);
4.2, 4.19 (2d, J ˆ 11.7, 1 H, NCH2N); 4.1± 3.95 (m, 2 H, PhCHN, 1 H, NCH2N); 3.5 ± 2.9 (m, 7 CH2N); 2.75±1.85
(m, 12 H, therein 8 sharp signals (6 H) for conformers of NCOMe at 2.02, 2.00, 1.99, 1.98, 1.97, 1.95, 1.94, 1.91);
‡
‡
‡
1.75 ± 1.2 (m, 6 C CH2 C); 0.93 (t, MeCH2). ESI-MS: 634 ([M ‡ H ]), 656 ([M ‡ Na] ), 673 ([M ‡ K] ).
Crystal-Structure Determination of Compound (Æ)-151). All measurements were conducted on a Rigaku
AFC5R diffractometer using graphite-monochromated MoKa radiation (l ˆ 0.71069 Š) and a 12-kW rotating
anode generator. The intensities were collected using w/2q scans and three standard reflections, which were
measured after every 150 reflections, remained stable throughout the data collection. The intensities were
corrected for Lorentz and polarization effects, but not for absorption. The structure was solved by direct
methods using SHELXS86 [24] which revealed the positions of all non-H-atoms. There are two independent
molecules in the asymmetric unit. There are no significant differences in their conformations, but no additional
symmetry could be found. The non-H-atoms were refined anisotropically. All of the H-atoms were fixed in
geometrically calculated positions (d(C H) ˆ 0.95 Š), and they were assigned fixed isotropic displacement
parameters with a value equal to 1.2Ueq of the parent C-atom. A correction for secondary extinction was applied.
Refinement was carried out on F using full-matrix least-squares procedures which minimized the function
P
w( j Fo j j Fc j )2, where w ˆ [s2(Fo) ‡ (0.005Fo)2] 1. The data collection and refinement parameters are listed
in Table 2. A view of one of the independent molecules is shown in Fig. 2. Neutral atom scattering factors for
non-H-atoms were taken from [25a] and the scattering factors for H-atoms from [26]. Anomalous dispersion
effects were included in Fc [27]; the values for f ' and f '' were taken from [25b]. All calculations were performed
using the TEXSAN crystallographic software package [28].
REFERENCES
[1] K. Drandarov, Tetrahedron Lett. 1995, 36, 617.
[2] K. Seifert, S. Johne, M. Hesse, Helv. Chim. Acta 1982, 65, 2540.
[3] K. Drandarov, Phytochemistry 1997, 44, 971.
[4] K. Drandarov, A. Guggisberg, M. Hesse, in preparation.
[5] Y.-M. Chi, F. Hashimoto, W.-M. Yan, T. Nohara, Tetrahedron Lett. 1997, 38, 2713.
[6] P. Kuehne, A. Linden, M. Hesse, Helv. Chim. Acta 1996, 79, 1085.
[7] S. M. Kupchan, H. P. J. Hintz, R. M. Smith, A. Karim, M. W. Cass, W. A. Court, M. J. Yatagai, J. Chem.
Soc., Chem. Commun. 1974, 329.
Â
Ï
[8] Z. Koblicova, F. Turecek, P. Ninova, J. Trojanek, K. Blaha, Tetrahedron Lett. 1983, 24, 4381.
[9] K. Nakanishi, N. Berova, R. W. Woody, Eds., ꢁCircular Dichroism: Principals and Applicationsꢀ, VCH,
New York, 1994.
[10] H. E. Smith, L. P. Fontana, J. Org. Chem. 1991, 56, 432.
[11] H. E. Smith, J. R. Neergaard, J. Am. Chem. Soc. 1996, 118, 7694.
[12] H. E. Smith, J. R. Neergaard, J. Am. Chem. Soc. 1997, 119, 116.
[13] C. K. Johnson, ꢁORTEP IIꢀ. Report ORNL-5138, Oak Ridge National Laboratory, Oak Ridge, Tennessee,
1976.
[14] G. Gottarelli, B. Samori, J. Chem. Soc. (B) 1971, 2418.
1
)
Crystallographic data (excluding structure factors) for the structure reported in this paper have been
deposited with the Cambridge Crystallographic Data Centre as supplementary publication No. CCDC-
102010. Copies of the data can be obtained free of charge on application to the CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK (fax: ‡ 44-(0)1223-336033; email: deposit@ccdc.cam.ac.uk).

Helvetica Chimica Acta ± Vol. 81 (1998)
Table 2. Crystallographic Data for (Æ)-15
1791
Crystallized from
hexane
Empirical formula
Formula weight
C14H18N2O
230.31
Crystal color, habit
colorless, prism
Crystal dimensions [mm]
Temperature [K]
0.18 Â 0.23 Â 0.50
273(1)
Crystal system
Space group
triclinic
P1 (#2)
Å
Z
4
Reflections for cell determination
25
2q Range for cell determination [8]
Unit cell parameters a [Š]
34 ± 40
10.898(1)
19.505(3)
6.1565(8)
92.25(2)
98.90(1)
76.70(1)
1258.3(3)
1.216
b [Š]
c [Š]
a [8]
b [8]
g [8]
V [Š3]
3
Dx [g cm
]
1
m(MoKa) [mm
2q(max) [8]
]
0.0775
55
Total reflections measured
Symmetry-independent reflections
Reflections used [I > 2s(I)]
Parameters refined
R
6042
5743
2972
308
0.0572
0.0494
1.860
wR
Goodness of fit
7
Secondary extinction coefficient
7(1) Â 10
Final Dmax/s
D1 (max; min) [e Š
0.0003
3
]
0.20; 0.23
0.003 ± 0.005
Range of s(d(C C)) [Š]
[15] S. Lumbu, C. Hootele, J. Nat. Prod. 1993, 56, 1418.
[16] H. Ogura, H. Takayanagi, K. Furuhata, Chem. Lett. 1973, 387.
[17] H. Ogura, H. Takayanagi, K. Kubo, K. Furuhata, J. Am. Chem. Soc. 1973, 95, 8056.
[18] H. Ogura, H. Takayanagi, K. Furuhata, J. Chem. Soc., Perkin Trans. 1 1976, 665.
[19] H. Takayanagi, H. Ogura, Croat. Chem. Acta 1989, 62, 135.
[20] J. A. Schellman, Acc. Chem. Res. 1968, 1, 144.
[21] P. Kuehne, A. Guggisberg, M. Hesse, Helv. Chim. Acta 1997, 80, 1802.
[22] I. M. Hais, K. Macek, Eds., ꢁHandbuch der Papierchromatographieꢀ, 2nd edn., G. Fischer, Jena, 1963,
Vol. I, pp. 932 and 523.
[23] K. Drandarov, I. M. Hais, J. Chromatogr., A 1996, 724, 416.
[24] G. M. Sheldrick, SHELXS86. Acta Crystallogr., Sect. A 1990, 46, 467.
[25] a) E. N. Maslen, A. G. Fox, M. A. OꢀKeefe, in ꢁInternational Tables for Crystallographyꢀ, Ed. A. J. C. Wil-
son, Kluwer Academic Publishers, Dordrecht, 1992, Vol. C, Table 6.1.1.1, pp. 477 ± 486; b) D. C. Creagh,
W. J. McAuley, ibid., Table 4.2.6.8, pp. 219 ± 222.
[26] R. F. Stewart, E. R. Davidson, W. T. Simpson, J. Chem. Phys. 1965, 42, 3175.
[27] J. A. Ibers, W. C. Hamilton, Acta Crystallogr. 1964, 17, 781.
[28] TEXSAN. Single Crystal Structure Analysis Software, Version 5.0. Molecular Structure Corporation, The
Woodlands, Texas, 1989.
Received July 2, 1998