Total syntheses of the spermine alkaloids (-)-(R,R)-hopromine and (±)-homaline

Article abstract of DOI:10.1002/1522-2675(200206)85:6<1659::AID-HLCA1659>3.0.CO;2-D

The diastereoselective synthesis of the spermine alkaloid (R,R)-hopromine (2) is described. The as yet unknown absolute configuration of naturally occurring (-)-hopromine (2) is (R,R) and was established by comparison of the reported specific rotation of the natural product with that of the synthetic one. Preparation of the characteristic bis-8-membered lactam scaffold was carried out by convergent build-up of basic chiral azalactam units 21a and 21b and subsequent iterative linking (Schemes 5 and 6). Key steps in the analogous syntheses of 4-alkyl-hexahydro-1,5-diazocin-2(1H)-ones 21a and 21b were the introduction of the unbranched alkyl side chains into their common precursor 14 via cuprate reaction and the Sb(OEt)₃-assisted cyclization of the open-chain intermediates 20a and 20b, respectively (Schemes 3 and 4). The chiral iodoester 14 was prepared from commercially available (+)-L-aspartic acid (12). Based on the synthetic strategy developed for (R,R)-hopromine (2), a rapid access to the parent alkaloid homaline (1) in its (±)-form is given.

Full text of DOI:10.1002/1522-2675(200206)85:6<1659::AID-HLCA1659>3.0.CO;2-D

Helvetica Chimica Acta Vol. 85 (2002)
1659
Total Syntheses of the Spermine Alkaloids (À)-(R,R)-Hopromine and
(Æ)-Homaline
by Corinne Ensch1) and Manfred Hesse*
Organisch-chemisches Institut der Universit‰t Z¸rich, Winterthurerstrasse 190, CH-8057 Z¸rich
(Tel.: ‡ 41-1-6354281; fax: ‡ 41-1-6356812; e-mail: mtbohley@oci.unizh.ch)
The diastereoselective synthesis of the spermine alkaloid (R,R)-hopromine (2) is described. The as yet
unknown absolute configuration of naturally occurring (À)-hopromine (2) is (R,R) and was established by
comparison of the reported specific rotation of the natural product with that of the synthetic one. Preparation of
the characteristic bis-8-membered lactam scaffold was carried out by convergent build-up of basic chiral
azalactam units 21a and 21b and subsequent iterative linking (Schemes 5 and 6). Key steps in the analogous
syntheses of 4-alkyl-hexahydro-1,5-diazocin-2(1H)-ones 21a and 21b were the introduction of the unbranched
alkyl side chains into their common precursor 14 via cuprate reaction and the Sb(OEt)3-assisted cyclization of
the open-chain intermediates 20a and 20b, respectively (Schemes 3 and 4). The chiral iodoester 14 was prepared
from commercially available (‡)-l-aspartic acid (12). Based on the synthetic strategy developed for (R,R)-
hopromine (2), a rapid access to the parent alkaloid homaline (1) in its (Æ)-form is given.
Introduction. The Homalium alkaloids homaline (1), hopromine (2), hoprominol
(3), and hopromalinol (4) constitute a group of alkaloids isolated from the leaves of an
African Homalium species and Homalium pronyense Guillaum. (Flacourtiaceae)
found in the forests of New Caledonia [1] (Fig. 1). They were investigated in the early
seventies by Pais et al. and found to have unique bis-8-membered lactam structures with
a polyamine backbone [2][3]. They are based biogenetically on a combination of two
a,b-unsaturated carboxylic acid residues (fatty or cinnamic acid) with spermine (5).
CH3
O
N
N
R
R'
N
N
O
H3C
1
2
3
4
R = Ph
R' = Ph
R' = Me(CH2)6
R' = Me(CH2)4CH(OH)CH2
R' = Me(CH2)4CH(OH)CH2
homaline
R = Me(CH2)4
R = Me(CH2)4
R = Ph
hopromine
hoprominol
hopromalinol
H
N
NH2
H2N
N
H
5
Fig. 1. The Homalium alkaloids 1 4 and their spermine backbone 5
1
)
Part of the Ph.D. Thesis of C. E., University of Z¸rich, 2002.

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Helvetica Chimica Acta Vol. 85 (2002)
The best-defined member of the Homalium family is the major alkaloid homaline
(1), the structure and absolute (S,S)-configuration of which have been confirmed by X-
ray single-crystal analysis [4] and manifold diastereoselective total synthesis [5][6].
The configuration of the remaining three alkaloids 2 4 is yet to be determined since
the few reported preparations of these unsymmetrically substituted alkaloids are
nonstereospecific [7]. Up to now, the methods employed for building up the
characteristic 8-membered lactam units 6a d (Scheme 1) were either −Zip× ring
expansion in liquid ammonia of 4-substituted azetidin-2-ones 7a d after conversion
into the corresponding N-(3-halopropyl)-b-lactams 8a d, or the conjugate addition-
cyclization reaction of pyrazolidine 9 to optically active vinyl sulfoxide 10 followed by
successive reduction of the chiral auxiliary and reductive cleavage of the NÀN bond of
the bicyclic acylhydrazine 11.
Scheme 1. Methods for the Prepartion of 8-Membered Lactam Building Blocks 6a
d
O
X
3
R
R
R
NH
N
NH
HN
O
O
7a – d
8a – d
6a – d
p-Tol
O
O
S
O
O
N
N
HN
HN
6a
+
H
Ph
Ph
10
9
11
t
a R = Ph
b R = Me(CH2)4
c R = Me(CH2)6
d R = Me(CH2)4CH(OSiMe2 Bu)CH2
We wish to report the convergent and diastereoselective total synthesis of (R,R)-
hopromine (2) starting from (‡)-l-aspartic acid (12). The choice of 12 as chiral starting
material was based on the belief that all members of the Homalium family share the
same three-dimensional orientation of the residues at the corresponding chiral centers.
The stereocontrolled preparation of (R,R)-configured 2 allowed us to determine the
absolute configuration of the natural product by comparison of the specific-rotation
values. In addition to this, the elaboration of the total synthesis of (R,R)-hopromine (2)
led to the establishment of a set of reaction methods whose general applicability of the
preparation of different 4-substituted hexahydro-1,5-diazocin-2-(1H)-ones of the type
6a d was confirmed by the successful synthesis of (Æ)-homaline (1).
Results and Discussion.
Retrosynthetically, (R,R)-hopromine (2) can be
decomposed into two 4-alkyl-substituted 8-membered lactam units 6b and 6c linked
by a C4 bridge (Scheme 2). Each of the lactam blocks 6b and 6c contains a b-alkyl-b-
amino acid portion as the asymmetric structural unit as well as a C3-N moiety. The two

Helvetica Chimica Acta Vol. 85 (2002)
1661
b-amino fatty acid units 13b and 13c, again, were divided into their respective linear
alkyl rests and one common synthon, chiral iodoester 14, easily obtainable from l-
aspartic acid (12) by regioselective modification of its a-carboxylic acid group [8].
Scheme 2. Retrosynthetic Analysis of Hopromine (2)
O
CH3
H
O
N
H
R
H
N
NH
N
H11C5
C7H15
N
HN
O
H3C
6b R = Me(CH2)4
c R = Me(CH2)6
2
O
O
COOH
NH2
OEt
OEt
NHTs
alkyl
side chain
H
HOOC
+
H
H
R
NHTs
I
13b R = Me(CH2)4
c R = Me(CH2)6
12
14
First, the amino group was protected by converting 12 to N-tosyl-l-aspartic acid 15
under biphasic alkaline conditions (Scheme 3). Lengthy exposure of 15 to thionyl
chloride in AcOEt gave the succinic anhydride 16, which, by selective reduction with
NaBH4 [9], led to the lactone 17. Next, reaction of 17 with trimethylsilyl iodide in
EtOH/CH2Cl2 under mild conditions [10] furnished the key chiral intermediate
iodoester 14.
Introduction of the aliphatic C4 and C6 side chains by nucleophilic substitution at 14
was carried out by adding 14 carefully to a twofold excess of the appropriate lithium
organocuprate in Et2O/THF 1:2 at À658 [11]. Bu2CuLi was successfully prepared by
dropwise addition of commercially available BuLi to a suspension of LiCl and CuBr¥
Me2S in Et2O/THF at À658, while Hx2CuLi (Hx ˆ hexyl) was best prepared by first
generating HxLi in situ from tBuLi and iodohexane and then only adding CuBr¥ Me2S.
The temperature of the cuprate reaction after mixture of all the components had to be
kept strictly below À358, since above this limit, the basic character of the lithium
organocuprate induced undesired cyclization of iodoester 14 to aziridine and a,b-
elimination reaction. Aqueous workup finally yielded the chiral ethyl 3-(tosylami-
no)alkanoates 13b,c.
The missing C3-N fragment was inserted into the b-alkyl-b-amino ester portions 13b
and 13c by alkylating their N-tosyl terminus with tert-butyl (3-iodopropyl)carbamate 18
(Scheme 4), readily available from 3-aminopropan-1-ol after Boc-protection to 18' and
iodination. Optimum conditions for the N-alkylation of the sulfonamides 13b and 13c
were heterogeneous deprotonation by cesium carbonate and slow reaction with iodide
18 in DMF at 558 overnight. Subsequent removal of the Boc-protection group from the
resulting N-alkylated sulfonamides 19b,c by means of a several-fold excess of

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Helvetica Chimica Acta Vol. 85 (2002)
Scheme 3. Synthesis of the Common Precursor 14 and Subsequent Cuprate Reactions
O
O
COOH
NH2
COOH
NHTs
a)
b)
c)
O
O
H
H
HOOC
HOOC
TsHN
TsHN
O
15
16
12
17
d)
O
OEt
NHTs
H
O
H
11C5
e)
OEt
NHTs
13b
H
I
f )
O
14
OEt
H
H15C7
NHTs
13c
a) TsCl, aq. 4n NaOH, Et2O, r.t., overnight; quant. b) SOCl2, AcOEt, r.t., 4 h; 81%. c) 1. NaBH4, THF, 08, 2 h;
2. conc. HCl soln., EtOH, reflux, 2 h; 63%. d) Me3SiI, EtOH, CH2Cl2, 08 ! r.t., overnight; 88%. e) BuLi, LiCl,
t
CuBr¥ Me2S, Et2O/THF 1:2, À658 !À 408, 5 h; 66%. f) 1. C6H13I, BuLi, Et2O, À658 !À 408, 2 h; 2. CuBr¥
Me2S, Et2O/THF, À658 !À 408, 5 h, 79%.
Scheme 4. Synthesis of the 8-Membered N-Tosylated 4-Substituted Hexahydro-1,5-diazocin-2(1H)-ones 21a
c
O
O
c)
OEt
OEt
H
R
H
R
+
RHN
X
NHTs
N
NHBoc
Ts
18 R = Boc X = I
18' R = Boc X = OH
13a R = Ph
b R = Me(CH2)4
c R = Me(CH2)6
19a R = Ph
b R = Me(CH2)4
c R = Me(CH2)6
b)
a)
R = H
X = OH
d)
O
O
N
H
R
e)
OEt
NH
H
R
TsN
NH2
Ts
20a R = Ph
b R = Me(CH2)4
c R = Me(CH2)6
21a R = Ph
b R = Me(CH2)4
c R = Me(CH2)6
a) Boc2O, Et3N, CH2Cl2, reflux, overnight; 99%. b) I2, PPh3, 1H-imidazole, CH2Cl2, r.t., 3.5 h; 84%. c) Cs2CO3,
DMF, 558, overnight; 19a: 80%; 19b: 73%; 19c: 69%. d) CF3COOH, CHCl3, 408, overnight, quant. e) Sb(OEt)3,
dry benzene, 4-ä mol. sieves, reflux, 16 h; 21a: 83%; 21b: 88%; 21c: 91%.

Helvetica Chimica Acta Vol. 85 (2002)
1663
CF3COOH in CHCl3 yielded quantitatively the amino esters 20b,c as linear ring
precursors.
Since all attempts to close the 8-membered lactam rings by methods commonly
employed in peptide synthesis (e.g., DCC/DMAP (ˆdicyclohexylcarbodiimide/N,N-
dimethylpyridin-4-amine), (Bu3N/2-chloro-1-methyl-pyridinium iodide)-, or (dipyridyl
disulfid)-mediated condensation of amino acids [12], or the anhydride method [13])
were unsuccessful, we had recourse to the works of Yamamoto and Furuta [14].
Notwithstanding the apparent risk of forming undesired sixteen-membered dimers, we
decided to try cyclizing 20b and 20c, with the aid of Sb(OEt)3, which had already been
successfully used in the macrolactamization of linear tetraamino esters [15] and is
supposed to assist cyclization of polyamino esters by a template effect [16]. Refluxing
20b and 20c, with 1.2 equiv. of Sb(OEt)3 under high-dilution conditions in dry benzene
for 16 h yielded the 8-membered lactams 21b and 21c in 88 and 91%, respectively. The
exclusive formation of monomeric 4-substituted hexahydro-1,5-diazocin-2-(1H)-ones
21b,c was confirmed by ESI-MS analysis. In addition to the mass-spectrometric
evidence, a single-crystal X-ray analysis of 21b (Fig. 2) allowed us to verify both the
monomeric 8-membered ring structure and the (R)-configuration at the stereogenic
centre. In fact, due to the presence of anomalous scattering in the compound, e.g., of the
S-atom, it was possible to independently determine the absolute configuration by X-
ray-diffraction analysis. Refinement of the absolute structure parameter [17] yielded a
value of 0.05(6), which confidently confirms that the refined coordinates represent the
true enantiomorph.
Fig. 2. ORTEP [26] Representation of the N-tosylated 4-substituted 8-membered lactam 21b (50% probability
ellipsoids; H-atoms are omitted for clarity)
Bridging of both lactam units 21b and 21c by the C4 chain was accomplished
iteratively [6][18]: first 21b was mono-alkylated with 1,4-dibromobutane under the
action of powdered KOH in dry DMSO at room temperature overnight, then the
resulting bromo derivative 22 was attached to 21c by adding a mixture of both to a

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Helvetica Chimica Acta Vol. 85 (2002)
frozen suspension of KOH in dry DMSO at 08 and slowly defreezing the solid reaction
mixture overnight (Scheme 5). This treatment gave the bis-8-membered core 23 in 71%
yield. The identification of the coupling product by NMR spectroscopy was not
unambiguously possible. Most probably due to the interconversion of conformational
ring isomers, the 1H-NMR spectrum showed no clearly interpretable signals, nor in the
13C-NMR spectrum could all signals be detected. The structural characterization of 23
was thus based on the fragmentation pattern obtained by nano ESI-MS/MS analysis of
the isolated product.
Scheme 5. Iterative Coupling of the Lactam Rings and Completion of the Synthesis of Hopromine (2)
O
O
H
H
Br
H11C5
H11C5
a)
NH
N
TsN
TsN
21b
22
b)
R
O
N
H
H
N
N
H11C5
C7H15
N
O
R
23 R = Ts
24 R = H
c)
d)
2
R = CH3
a) Br(CH2)4Br, KOH, dry DMSO, r.t., overnight; 82%. b) 21c, KOH, dry DMSO, 08 ! r.t., overnight; 71%. c)
Electrolysis, (Me4N)Cl, aq. EtOH soln., 58; 64%. d) 1. 37% aq. HCOH soln., AcOH, 08, 15 min; 2. NaBH3CN,
MeOH, 08 ! r.t., 4 h; quant.
Mild electrolytic detosylation of 23 in EtOH [19] afforded 64% of crude
didemethylhopromine 24, which was quantitatively converted to the title compound
(R,R)-hopromine (2) by reductive methylation upon treatment with excess aqueous
formaldehyde solution and AcOH at 08 and subsequent exposure to NaBH3CN/MeOH
at room temperature for 4 h.
Synthetic (R,R)-hopromine (2) was characterized by IR, 1H-, 13C-NMR, and mass
spectra and revealed to be equal in all respects to the natural product as described in
[3]. Both the synthetic and the natural products showed comparable specific rotation
values, so that the postulated (R,R)-configuration of natural (À)-hopromine (2) can be
assumed. It should be noted that, despite the different stereodescriptors (S,S) vs. (R,R)
(change of CIP priority of Ph vs. alkyl), homaline (1) and hopromine (2), respectively,
have the same three-dimensional orientation of their residues at the stereogenic
center.
The ease with which the 8-membered 4-alkyl-substituted lactam units 21b and 21c
could be prepared in only a few steps from the fatty acid moieties 13b and 13c,
respectively, tempted us to apply the same ring-construction strategy to the preparation

Helvetica Chimica Acta Vol. 85 (2002)
1665
of 4-phenyl-hexahydro-1,5-diazocin-2-(1H)-one (21a) from ethyl (Æ)-3-phenyl-3-
(tosylamino)propanoate (13a) and hence to the total synthesis of (Æ)-homaline (1)
[20]. Compound 13a was readily obtained by conversion of commercially available (Æ)-(3-
amino-3-phenylpropanoic acid by N-tosylation with TsCl and subsequent esterification
with EtOH/SOCl2. Treatment of 13a analogous to that of 13b,c, i.e., N-alkylation
followed by Boc-deprotection and Sb(OEt)3-assisted ring closure (Scheme 4), led to
the cyclic lactam 21a in good yields. The symmetric, bis-8-membered scaffold 25 was
built up by double alkylation of 1,4-dibromobutane with 21a and powdered KOH in dry
DMSO [6][18] (Scheme 6) under conditions comparable to those employed for the
iterative linking of 21b with 21c. Electrolytic detosylation of 25 similarly to that of 23
and reductive methylation of didemethylhomaline 26 as described for 24 completed the
total synthesis of (Æ)-homaline (1).
Scheme 6. Synthesis of (Æ)-Homaline (1)
R
O
O
N
N
Ph
TsN
Ph
R
a)
Ph
NH
N
N
O
21a
25 R = Ts
26 R = H
b)
c)
1
R = CH3
a) Br(CH2)4Br, KOH, dry DMSO, 08 ! r.t., overnight; 53%. b) Electrolysis, (Me4N)Cl, MeOH/DMF, 58; 76%.
c) 1. 37% aq. HCOH soln., AcOH, 08, 15 min; 2. NaBH3CN, MeOH, 08 ! r.t., 3.5 h; 88%.
Conclusions. The naturally occurring spermine alkaloid (À)-(R,R)-hopromine (2)
was successfully prepared by convergent synthesis from two chiral 4-alkyl-substituted
hexahydro-1,5-diazocin-2-(1H)-ones. The diastereoisomer purity of the target com-
pound 2 was guaranteed by the use of the commercially available chiral-pool material
(‡)-l-aspartic acid (12) as the starting material. Ring closure of the linear amino esters
20a c to the 8-membered lactam building blocks 21a c under the assistance of
Sb(OEt)3 worked remarkably well and with total conservation of the configuration of
the chiral-ring precursors. The synthetic strategies described should also be applicable
to the preparation of the remaining members of the Homalium family.
We thank the analytical departments of our institute for all measurements and gratefully acknowledge the
financial support of the Swiss National Science Foundation. Special thanks go to Richard Detterbeck for many
fruitful discussions and his helping hand with the optimization of the cuprate reactions, and to Armin
Guggisberg for performing the electrolytic detosylation reactions. Dr. A. Linden is thanked for recording of the
X-ray crystallographic data and for his assistance with the evaluation and presentation of the latter.

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Helvetica Chimica Acta Vol. 85 (2002)
Experimental Part
General. All commercially available reagents were used without further purification. Solvents were either
puriss. p.a. grade (Fluka) or were distilled prior to use. Benzene, THF, and Et2O were dried over NaH or Na-
benzophenone and freshly distilled before use. Dry DMSO was purchased from Fluka and stored over 4-ä
molecular sieves. CuBr¥ Me2S was prepared by recrystallization of CuBr from Me2S. Sb(OEt)3 was purchased
from Aldrich and had to be handled with care under Ar. Reactions were carried out under N2, unless otherwise
stated (TLC monitoring). TLC: Merck precoated silica-gel plates 60 F254. Column chromatography (CC): silica
gel 60 (230 400 mesh ASTM) from Merck. M.p.: Mettler FP5. Optical rotations [a]2D1: in CHCl3 (Fluka, for IR
spectroscopy), unless otherwise stated; Perkin-Elmer 241 polarimeter. IR Spectra: in CHCl3 (Fluka, for IR
spectroscopy); Perkin-Elmer 781; in cmÀ1. NMR Spectra: in CDCl3, unless otherwise stated; Bruker ARX-300
(300 (1H) or 75 MHz (13C)) or Bruker DRX-600 (600 (1H) or 150 MHz (13C)); chemical shifts d in ppm rel. to
Me4Si (ˆ0 ppm) as internal standard, coupling constants J in Hz. MS: Finnigan SSQ-700 for chemical ionization
(CI) with NH3, Finnigan MAT-90 for electron impact (EI, 70 eV), and Finnigan TSQ-700 for electrospray
ionization (ESI); m/z (rel. intensity in %).
(‡)-(2S)-2-(Tosylamino)butanedioic Acid (ˆ N2-Tosyl-l-aspartic Acid; 15). To a soln. of (‡)-l-aspartic
acid (12; 34 g, 0.26 mol) in aq. 4n NaOH (130 ml) at 08, a soln. of TsCl (73 g, 0.38mol, 1.5 equiv.) in Et 2O
(300 ml) was added, followed by a supplementary volume of aq. 4n NaOH (210 ml). The resulting biphasic
mixture was vigorously stirred at r.t. overnight. The Et2O layer was then discarded and the basic aq. layer
washed with Et2O (2 Â 100 ml). Then the aq. phase was acidified at À108 with conc. HCl soln. to pH 1 and
extracted with AcOEt (3 Â 200 ml). The combined org. extracts were washed with brine, dried (MgSO4), and
evaporated: 15 (72 g, 98%). Colorless, amorphous solid. M.p. 112 1148. [a]2D1 ˆ ‡12.1 (c ˆ 4.0, MeOH). IR:
3500 2500s, 1730s, 1600w, 1500w, 1410m, 1330m, 1308w, 1290w, 1230w, 1190w, 1160s, 1120w, 1090s, 1040w,
1010w, 960w, 8 60w, 8 40w, 8 15m, 78 0s, 705s, 665s, 625w. 1H-NMR: 8.07 (br. s, 2 H); 7.72 (d, J ˆ 8.3, 2 H); 7.26
(d, J ˆ 8.6, 2 H); 6.57 (d, J ˆ 8.3, 1 H); 4.13 (m, 1 H); 3.06 (dd, J ˆ 17.5, 3.8, 1 H); 2.86 (dd, J ˆ 17.5, 4.6, 1 H);
2.39 (s, 3 H). 13C-NMR: 174.5, 173.9, 144.0, 136.1 (4 s); 129.7, 127.1, 51.5 (3 d); 37.4 (t); 21.4 (q). CI-MS: 305 (29,
‡
‡
[M ‡ NH4] ) 287 (100, [M ‡ NH4 À H2O] ).
(À)-(3S)-3,4-Dihydro-3-(tosylamino)furan-2,5-dione (16). To a soln. of 15 (72 g, 0.25 mol) in AcOEt
(200 ml), SOCl2 (73 ml, 1.0 mmol, 4.0 equiv.) was aded over 45 min. The slightly yellow mixture was stirred at
r.t. for 4 h and then carefully evaporated. The sticky oily residue was washed with toluene and dried in vacuo: 16
(54.5 g, 81%). Pale yellow solid, which was considered sufficiently pure for use in the next step. M.p. 118 1208.
[a]2D1 ˆ À14.1 (c ˆ 1.35, DMSO). IR: 3640w, 3420m, 3300s, 3070w, 2950m, 1870s, 1790s, 1730m, 1597s, 1495w,
1
1450s, 1400m, 1340m, 1300m, 1255w, 1200s, 1160s, 1090m, 1065m, 1030m, 965m, 907m, 655w, 8 17m. H-NMR
((D6)DMSO): 8.10 (d, J ˆ 9.2, 1 H); 7.60 (d, J ˆ 8.3, 2 H); 7.30 (d, J ˆ 8.6, 2 H); 4.71 (m, 1 H); 2.91 (dd, J ˆ 18.1,
9.7, 1 H); 2.56 (dd, J ˆ 18.1, 6.9, 1 H); 2.29 (s, 3 H). 13C-NMR ((D6)DMSO): 170.8, 168.7, 143.2, 137.8 (4 s); 129.7,
‡
‡
126.3, 52.0 (3 d); 35.4 (t); 20.9 (q). CI-MS: 287 (100, [M ‡ NH4] ), 286 (59, [M ‡ NH3 À H2O ‡ NH4] ).
(À)-(4S)-4,5-Dihydro-4-(tosylamino)furan-2(3H)-one (17). To a stirred suspension of NaBH4 (8.4 g,
0.22 mol, 1.1 equiv.) in dry THF (150 ml) at 08, soln. of 16 (54.5 g, 0.20 mol) in THF (300 ml) was added
dropwise. The intensively yellow colored mixture was allowed to warm to r.t. and then stirred for 1 h before
being cooled to 08. Then EtOH (50 ml) and conc. HCl soln. (10 ml) were slowly added. The resulting mixture
was stirred for 2 h under reflux and then allowed to cool to r.t. and partially evaporated. The residual oil was
quenched with sat. aq. NaCl soln. (100 ml) and extracted with AcOEt (3 Â 150 ml). The combined extracts were
washed with sat. aq. NaHCO3 soln., dried (MgSO4), and evaporated. The crude product was recrystallized from
AcOEt/hexane to yield pure 17 (32.6 g, 63%). Colorless solid. M.p. 109 1128. [a]2D1 ˆ À6.3 (c ˆ 2.0, CHCl3). IR:
3490w, 3270s, 3260s, 3006m, 2940m, 2905w, 2780w, 1925w, 1770s, 1600s, 1460s, 1405w, 1375w, 1340s, 1305w, 1290w,
1245w, 1190s, 1160s, 1090s, 1060w, 1000s, 920m, 8 8 w0, 8 40w, 8 15m, 750w, 700m, 665s. 1H-NMR: 7.75 (d, J ˆ 8.3,
2 H); 7.33 (d, J ˆ 8.1, 2 H); 5.51 (d, J ˆ 6.9, 1 H); 4.38( m, 1 H); 4.15 (m, 2 H); 2.67 (dd, J ˆ 17.9, 7.5, 1 H); 2.44
(s, 3 H); 2.39 (dd, J ˆ 17.9, 5.1, 1 H). 13C-NMR: 174.3, 144.3, 136.6 (3 s); 130.0, 126.9 (2 d); 72.9 (t); 49.7 (d); 34.8
‡
(t); 21.4 (q). CI-MS: 273 ([M ‡ NH4] ).
Ethyl (À)-(3S)-4-Iodo-3-(tosylamino)butanoate (14). To a soln. of 17 (13 g, 51 mmol) and abs. EtOH
(15 ml, 0.26 mol, 5.0 equiv.) in dry CH2Cl2 (150 ml) at 08 under N2, Me3SiI (17.3 ml, 0.13 mol, 2.5 equiv.) was
added dropwise over 40 min. The soln. was kept at 08 for 3 h and then stirred at r.t. overnight. H2O (100 ml) was
added and stirring continued for 10 min. The org. layer was washed with 5% aq. Na2S2O3 soln. and H2O, dried
(MgSO4), and evaporated. The resulting crude oil was subjected to flash CC (CH2Cl2/MeOH 30 :1): 14 (18.3 g,
88%). Pale yellow solid. M.p. 60 628. [a]2D1 ˆ À6.0 (c ˆ 1.0, CHCl3). IR: 3363w, 3020s, 2980w, 2920w, 1726s,
1600w, 1495w, 1414m, 1378m, 1340s, 1306w, 1207s, 1185m, 1160s, 1090m, 1025m, 955m, 8 72m, 8 15m, 760s, 676s,

Helvetica Chimica Acta Vol. 85 (2002)
1667
617w, 58 0w, 550m. 1H-NMR: 7.76 (d, J ˆ 8.3, 2 H); 7.32 (d, J ˆ 8.0, 2 H); 5.29 (d, J ˆ 8.9, 1 H); 4.10 (m, 2 H); 3.56
(m, 1 H); 3.33 (dd, J ˆ 10.3, 4.1, 1 H); 3.24 (dd, J ˆ 10.3, 6.7, 1 H); 2.70 (dd, J ˆ 16.6, 5.3, 1 H); 2.54 (dd, J ˆ 16.6,
6.2, 1 H); 2.43 (s, 3 H); 1.24 (t, J ˆ 7.2, 3 H). 13C-NMR: 170.3, 143.7, 137.4 (3 s); 129.7, 127.0 (2 d); 61.0 (t); 50.4
‡
‡
(d); 38.8 (t); 21.4, 13.9 (2 q); 10.4 (t). CI-MS: 429 (100, [M ‡ NH4] ), 412 (11, [M ‡ H] ), 301 (42, [M À HI ‡
‡
‡
NH4] ), 284 (25, [M À HI ‡ H] ).
Ethyl 3-Phenyl-3-(tosylamino)propanoate (13a). To a soln. of (Æ)-3-amino-3-phenylpropanoic acid (3.0 g,
18.2 mmol) in aq. 2n NaOH (36 ml) at 08, a soln. of TsCl (5.7 g, 29.9 mmol, 1.6 equiv.) in Et2O (50 ml) was
added. The resulting biphasic mixture was vigorously stirred at r.t. overnight, after which the Et2O layer was
discarded and the pH of the alkaline aq. phase adjusted to pH 1 by the addition of conc. HCl soln. at 08. The aq.
layer was then extracted with AcOEt (3 Â 50 ml) and the combined org. extract washed with brine, dried
(MgSO4), and evaporated to give 3-phenyl-3-(tosylamino)propanoic acid as a colorless, amorphous solid
(3.55 g, 61%). The crude N-tosylated acid (3.55 g, 11.1 mmol) was dissolved in EtOH (50 ml) and cooled to 08
before SOCl2 (1.61 ml, 22.2 mmol, 2.0 equiv.) was carefully added by syringe. After the addition, the mixture
was allowed to warm to r.t. over 2.5 h. The solvent and excess SOCl2 were evaporated, and the residual oil was
taken up in AcOEt (50 ml) and washed twice with H2O. The aq. layer was extracted with AcOEt (2 Â 50 ml) and
the combined extract washed with brine, dried (MgSO4), and evaporated: 13a (3.72 g, 96%). Colorless,
amorphous powder, which was pure enough (by 1H- and 13C-NMR) to be used in the next step without further
purification. M.p. 75.5 77.58. IR: 3500 3150w, 3460w, 3020w, 2980w, 2930w, 1725s, 1600w, 1495w, 1465w, 1450w,
1430 1385m, 1375m, 1345s, 1330s, 1305m, 1290w, 1270w, 1235w, 1190m, 1180m, 1160s, 1120m, 1090s, 1070w,
1
1025w, 965w, 950w, 8 8 w5, 8 60w, 8 10m, 700m, 660m, 615w. H-NMR: 7.59 (d, J ˆ 8.3, 2 H); 7.18 7.09 (m, 7 H);
5.73 (d, J ˆ 7.7, 1 H); 4.73 (dt, J ˆ 13.9, 6.2, 1 H); 3.99 (q, J ˆ 7.1, 2 H); 2.82 (dd, J ˆ 15.8, 6.2, 1 H); 2.72 (dd, J ˆ
15.8, 6.3, 1 H); 2.37 (s, 3 H); 1.12 (t, J ˆ 7.2, 3 H). 13C-NMR: 170.5, 143.1, 139.3, 137.4, (4 s); 129.3, 128.4, 127.6,
127.0, 126.4 (5 d); 60.6 (t); 54.3 (d); 41.2 (t); 21.3, 13.9 (2 q).
Ethyl (‡)-(3R)-3-(Tosylamino)octanoate (13b). At À658, 1.6m BuLi in hexane (3.27 ml, 5.2 mmol,
2.0 equiv.) was added dropwise to a mixture of LiCl (222 mg, 5.2 mmol, 2 equiv.) and CuBr¥ Me2S (538mg,
2.6 mmol, 1.0 equiv.) in dry Et2O/THF (30 ml, 1:2). The resulting deep-orange suspension was warmed up to
À408 until all the copper(I) salts were dissolved and then cooled to À658 before a soln. of 14 (1.1 g, 2.6 mmol,
1.0 equiv.) in dry THF (5 ml) was added. The mixture was stirred at À658 !À 408 for 5 h and then quenched
with sat. aq. NH4Cl soln. (40 ml). Stirring was continued for 0.5 h until a clear blue aq. phase was obtained,
which was subsequently extracted with Et2O. The combined org. layer was washed with brine, dried (MgSO4),
and evaporated and the resulting crude oil subjected to CC (AcOEt/hexane 1:3): 13b (587 mg, 66%). Colorless
oil. [a]2D1 ˆ ‡19.5 (c ˆ 0.8, CHCl3). IR: 3380w, 3020w, 2960m, 2930m, 2860w, 1725s, 1600w, 1425w, 1415m, 1375m,
1340s, 1185w, 1160s, 1095m, 1025w, 970w, 8 12m, 705w, 660s. 1H-NMR: 7.75 (d, J ˆ 8.3, 2 H); 7.29 (d, J ˆ 8.0, 2 H);
5.15 (d, J ˆ 9.0, 1 H); 4.07 (m, 2 H); 3.50 (m, 1 H); 2.42 (s, 3 H); 2.39 (m, 2 H); 1.45 (m, 2 H); 1.22 (t, J ˆ 7.15,
3 H); 1.26 1.10 (m, 6 H); 0.81 (t, J ˆ 6.4, 3 H). 13C-NMR: 171.3, 143.1, 138.1 (3 s); 129.5, 127.0 (2 d); 60.5 (t);
50.6 (d); 38.7, 34.6, 31.1, 25.3, 22.3 (5 t); 21.4, 14.0, 13.7 (3 q).
Ethyl (‡)-(3R)-3-(Tosylamino)decanoate (13c). To a soln. of 1-iodohexane (0.77 ml, 5.2 mmol, 2.0 equiv.)
t
in dry Et2O (10 ml) at À658, 1.5m BuLi in hexane (7.0 ml, 10.5 mmol, 4.0 equiv.) was added dropwise over
10 min. The mixture was stirred at À658 !À 408 for 2 h and diluted with dry THF (20 ml) before being cooled
down to À658 again. Then CuBr¥ Me2S (538mg, 2.6 mmol, 1.0 equiv.) was added and the resulting suspension
allowed to warm to À408 until all the crystalline CuBr¥ Me2S was dissolved. The homogeneous mixture was
again cooled to À658 prior to the addition of a soln. of 14 (1.08g, 2.6 mmol, 1.0 equiv.) in THF (5 ml) and then
stirred below À408 for 5 h until no more educt 14 could be traced by TLC. The mixture was then quenched with
sat. aq. NH4Cl soln. (40 ml), and stirring was continued for 0.5 h until a clear blue aq. phase was obtained. The
aq. layer was extracted with Et2O, the combined extract washed with brine, dried (MgSO4), and evaporated, and
the remaining crude residue purified by CC (AcOEt/hexane 1 :3): 13c (764 mg, 79%). Pale yellow oil. [a]D21
ˆ
‡26.7 (c ˆ 0.6, CHCl3). IR: 3380(br.), 3020w, 2980w, 2960s, 2930s, 2860w, 1725s, 1600w, 1465w, 1415w, 1380w,
1
1340s, 1305w, 1185w, 1160s, 1095m, 1020w, 960(br.), 865w, 8 10m, 705w, 660m. H-NMR: 7.75 (d, J ˆ 8.3, 2 H);
7.29 (d, J ˆ 8.0, 2 H); 5.15 (br. d, J ˆ 9.0, 1 H); 4.10 (m, 2 H); 3.50 (m, 1 H); 2.41 (s, 3 H); 2.38( m, 1 H); 2.34
(d, J ˆ 4.7, 1 H); 1.45 (m, 2 H); 1.22 (t, J ˆ 7.15, 3 H); 1.28 1.10 ( m, 10 H); 0.84 (t, J ˆ 6.3, 3 H). 13C-NMR:
171.3, 143.2, 138.0 (3 s); 129.5, 127.0 (2 d); 60.5 (t); 50.6 (d); 40.2, 38.6, 34.6, 31.5, 28.9, 25.6, 22.5 (7 t); 21.4, 14.0,
‡
‡
13.9 (3 q). CI-MS: 387 (100, [M ‡ NH4] ), 370 (35, [M ‡ H] ).
tert-Butyl (3-Hydroxypropyl)carbamate (18'). A soln. of 3-aminopropan-1-ol (3.0 g, 40 mmol) in dry
CH2Cl2 (50 ml) was treated with Et3N (5.6 ml, 40 mmol, 1.0 equiv.) at r.t. for 0.5 h before a soln. of Boc2O (9.6 g,
44 mmol, 1.1 equiv.) in CH2Cl2 (50 ml) was added slowly. During the dropwise addition of the Boc2O soln.,
warming and thickening of the mixture was observed. The resulting colorless mixture was stirred under reflux

1668
Helvetica Chimica Acta Vol. 85 (2002)
overnight and quenched with sat. aq. NH4Cl soln. The aq. layer was re-extracted twice with CH2Cl2, and the
combined org. extracts were washed with brine, dried (MgSO4), and evaporated: crude 18' (6.9 g, 99%).
Colorless oil which was pure enough (by 1H-NMR) to be used in the next step without further purification.
1H-NMR: 5.25 (br. s, 1 H); 3.8 4 d(t, J ˆ 11.6, 5.8, 2 H); 3.71 (br. s, OH); 3.45 (dt, J ˆ 12.45, 6.2, 2 H); 1.87
(m, 2 H); 1.63 (s, 9 H). 13C-NMR: 156.9, 85.1 (2 s); 59.2, 36.9, 32.6 (3 t); 28.2 (3 q).
tert-Butyl (3-Iodopropyl)carbamate (18). I2 (2.6 g, 10.3 mmol, 1.2 equiv.) was added portionwise to a soln.
of 1H-imidazole (0.7 g, 10.3 mmol, 1.2 equiv.) and PPh3 (2.69 g, 10.3 mmol, 1.2 equiv.) in CH2Cl2 (50 ml) at 08.
The resulting, deep-yellow suspension was warmed to r.t. before a soln. of 18' (1.5 g, 8.6 mmol) in CH2Cl2
(10 ml) was added. The mixture was stirred at r.t. for 3.5 h, filtered over Celite, and washed twice with 5% aq.
Na2S2O3 soln. The combined washing phases were extracted with CH2Cl2 and the combined org. layers dried
(MgSO4) and evaporated. The residual yellow oil was subjected to CC (AcOEt/hexane 1:1): 18 (1.86 g, 84%).
Amorphous, pale yellow solid. M.p. 37 408. IR: 3457m, 3020s, 2980m, 2936w, 1710s, 1506s, 1455w, 1390m, 1370s,
1250s, 1230s, 1170s, 1070w, 1040w, 970w, 8 65w, 790s, 745 720s, 670s, 617w. 1H-NMR: 4.65 (br. s, 1 H); 3.20
(m, 4 H); 1.99 (m, 2 H); 1.44 (s, 9 H). 13C-NMR: 155.8, 79.3 (2 s); 41.0, 33.4 (2 t); 28.3 (3 q); 2.98( t). CI-MS: 571
‡
‡
‡
‡
(15, [2 M ‡ H] ), 471 (34, [2M À Boc ‡ H] ), 461 (6, [2 M À I ‡ NH4] ), 387 (6, [2 M À I À C4H8] ), 303 (100,
‡
‡
‡
‡
[M ‡ NH4] ), 286 (30, [M ‡ H] ), 247 (41, [M À C4H8 ‡ NH4] ), 186 (28, [M À Boc ‡ H] ), 176 (6, [M À I
‡
‡ NH4] ), 119 (57).
N-Alkylation of Sulfonamides 13: General Procedure A (G.P.A). A soln. of sulfonamide 13 (1 equiv.) in dry
DMF (10 ml/mmol) was treated with Cs2CO3 (1.1 equiv., dried in vacuo prior to use) at r.t. for 0.5 h before a
soln. of 18 (1.2 equiv.) in DMF (2 ml/mmol) was added dropwise. The pale yellow suspension was heated to 558,
vigorously stirred overnight, and evaporated. The crude product was taken up in AcOEt and washed with 5%
aq. Na2S2O3 soln. and H2O. The combined aq. phases were twice extracted with AcOEt and the collected org.
layers again washed with brine, dried (MgSO4), and evaporated. The residual oil was subjected to CC for
purification of the alkylation product 19.
Boc Deprotection of 19: General Procedure B (G.P.B). A soln. of N-Boc-protected 19 in CHCl3 (10 ml/
mmol) was treated with CF3COOH (15 equiv.) at 408 overnight. The mixture was then alkalinized at r.t. with aq.
4n NaOH, and stirring was continued for 0.5 h to ensure that the CF3COOH salt was quantitatively reconverted
to the free amino ester. The aq. layer was twice extracted with CH2Cl2, the extract washed with sat. aq. NH4Cl
soln., dried (MgSO4), and evaporated, and the residual oil purified by CC, characterized, and stored at À208 in
dry benzene (10 ml/mmol), if not immediately used in the next step, since degradation by intermolecular
transamidation reactions occurred rather quickly at r.t.
Sb(OEt)3-Assisted Ring-Closing Reaction of 20: General Procedure C (G.P.C). A dry flask fitted with an N2
inlet and a pressure-equalized addition funnel (half-filled with 4-ä molecular sieves (beads) and functioning as
Soxhlet extractor) surmounted by a reflux condenser was charged with the unbranched amino ester 20 and dry
benzene (100 ml/mmol). Under N2, the soln. was brought to reflux. After 2 h, refluxing was briefly interrupted,
and a soln. of Sb(OEt)3 (1.2 equiv.) in dry benzene (1 ml/mmol) was rapidly added. The mixture was stirred
under reflux for 16 h, then cooled to r.t., and quenched with sat. aq. NH4Cl soln. Stirring was continued for
15 min before the biphasic mixture was filtered over Celite to discard the inorganic salts. The clear aq. layer was
then extracted 3 Â with AcOEt and the combined org. phase washed with brine, dried (MgSO4), and
evaporated. The crude ring-closed product 21 was purified either by recrystallization or by CC.
Electrolytic Detosylation of the Ditosylated Bicyclic Compounds 23 and 25: General Procedure D (G.P.D).
A general method for the mild removal of Ts protection groups by electrolysis is described in [19]: the tosylated
23 or 25 was taken up in 0.1m (Me4N)Cl (1.1 g, 10 mmol) in 94% aq. EtOH soln. (100 ml) as catholyte and
electrolyzed at 58 under Ar in a divided cell, at À2.25 V (vs. SCE); cathode: mercury pool; anode: graphite rod.
After depletion of the electrolysis current to background level, the reaction was complete and the ethanolic
catholyte was evaporated. The residual salts were diluted in a minimum quantity of H2O, and the resulting aq.
soln. was saturated with solid K2CO3 before being extracted with CH2Cl2 (3 Â 30 ml). The combined extracts
were washed with brine, dried (MgSO4), and evaporated to give the crude deprotected product 24 or 26, resp.
Reductive Methylation of Didemethylhopromine 24 and Didemethylhomaline 26: General Procedure E
(G.P.E). To a soln. of the didemethyl compound 24 or 26 (1 equiv.) in AcOH (ca. 48ml/mmol) at 0 8, 37% aq.
formaldehyde soln. (ca. 15 ml/mmol) was carefully added. Stirring was continued at 08 for 15 min before a soln.
of NaBH3CN (19 equiv.) in MeOH (8ml/mmol of didemethyl compound) was slowly added. After the addition,
the cooling bath was removed and the mixture could slowly warm to r.t. over 3 4 h. Then the mixture was
cooled to 08 again, quenched with 2n aq. HCl and evaporated. The residue was taken up in sat. aq. Na2CO3 soln.,
the aq. layer extracted with CH2Cl2, and the combined org. phase washed with brine, dried (MgSO4), and
evaporated: 2 and 1, resp.

Helvetica Chimica Acta Vol. 85 (2002)
1669
Ethyl 3-{{3-{[(tert-Butoxy)carbonyl]amino}-propyl}tosylamino}-3-phenylpropanoate (19a). According to
G.P.A., with (Æ)-13a (1 g, 2.88 mmol) and 18 (1.23 g, 4.32 mmol, 1.5 equiv.). CC (AcOEt/hexane 1:3) yielded
19a (1.16 g, 80%). Pale yellow oil. 1H-NMR: 7.72 (d, J ˆ 8.3, 2 H); 7.31 7.25 (m, 5 H); 7.15 (m, 2 H); 5.45
(dd, J ˆ 10.6, 4.9, 1 H); 5.29 (br. s, 1 H); 4.02 (q, J ˆ 7.1, 2 H); 3.11 2.95 (br. m, 5 H); 2.67 (dd, J ˆ 15.5, 4.9,
1 H); 2.44 (s, 3 H); 1.45 1.40 (br. m, 2 H); 1.42 (s, 9 H); 1.12 (t, J ˆ 7.1, 3 H ) . 13C-NMR: 169.9, 155.8, 143.3,
137.4, 137.2 (5 s); 129.6, 128.5, 128.2, 127.6, 127.1 (5 d); 78.9 (s); 60.6 (t); 57.0 (d); 42.2, 37.2 (br.), 36.8, 30.6 (4t);
28.3 (3 q); 21.4, 13.8(2 q).
Ethyl (À)-(3R)-3-[(3-{[(tert-Butoxy)carbonyl]amino}propyl)tosylamino]octanoate (19b). According to
G.P.A, with 13b (570 mg, 1.67 mmol). CC (CH2Cl2/MeOH 40 :1) (607 mg, 73%) yielded 19b. Pale yellow oil
[a]2D1 ˆ À7.2 (c ˆ 1.0, CHCl3). IR: 3450w, 3000w, 2980m, 2960m, 2930m, 2870w, 2860w, 1725s, 1710s, 1600w,
1505m, 1455(br.), 1390w, 1370m, 1340m, 1305w, 1270(br.), 1250w, 1160s, 1090m, 1025w, 975(br.), 910w, 8 60w,
815m, 705w, 695w, 68 5w, 655m, 615w. 1H-NMR: 7.72 (d, J ˆ 8.3. 2 H); 7.27 (d, J ˆ 8.0, 2 H); 4.85 (br. s, 1 H); 4.10
(m, 3 H); 3.14 (m, 4 H); 2.41 (s, 3 H); 2.39 (m, 2 H); 1.80 (br. m, 2 H); 1.45 (s, 9 H); 1.43 (m, 2 H); 1.23 (t, J ˆ
7.1, 3 H); 1.21 1.10 (m, 6 H); 0.81 (br. t, J ˆ 6.7, 3 H). 13C-NMR: 171.0, 156.1, 143.3, 137.7 (4 s); 129.6, 127.3
(2 d); 79.2 (s); 60.6 (t); 55.5 (d); 41.7, 39.4, 38.5 (br.), 33.4, 31.4, 31.2 (6 t); 28.3 (3 q); 25.9, 22.3 (2 t); 21.3, 14.0,
13.7 (3 q).
Ethyl (À)-(3R)-3-[(3-{[(tert-Butoxy)carbonyl]amino)propyl)tosylamino]decanoate (19c). According to
G.P.A, with 13c (750 mg, 2.03 mmol). CC (CH2Cl2/MeOH 40 :1) gave 19c (738mg, 69%). Colorless oil. [ a]D21
ˆ
À11.6 (c ˆ 1.15, CHCl3). IR: 3450w, 3000w, 2980w, 2960m, 2920s, 2870w, 2855w, 1730s, 1710s, 1600w, 1510m,
1505m, 1455(br.), 1390w, 1368m, 1340m, 1305w, 1275(br.), 1245w, 1160s, 1090m, 1030w, 1020w, 865(br.), 810m,
805w, 705w, 690w, 68 5w, 655m, 615w. 1H-NMR: 7.71 (d, J ˆ 8.3, 2 H); 7.27 (d, J ˆ 7.9, 2 H); 4.82 (br. s, 1 H); 4.08
(m, 3 H); 3.14 (m, 4 H); 2.41 (s, 3 H); 2.37 (m, 2 H); 1.80 (br. m, 2 H); 1.45 (s, 9 H); 1.45 1.42 (br. m, 2 H); 1.23
(t, J ˆ 7.1, 3 H); 1.21 1.10 (m, 10 H); 0.86 (t, J ˆ 6.9, 3 H). 13C-NMR: 170.8, 155.9, 143.1, 137.6 (4 s); 129.5, 127.2
(2 d); 79.1 (s); 60.6 (t); 55.6 (d); 41.8, 39.4, 38.6 (br.), 33.4, 31.5, 31.4, 29.0, 28.9 (8 t); 28.3 (3 q); 26.3, 22.5 (2 t);
21.3, 14.0, 13.9 (3 q).
Ethyl 3-[(3-Aminopropyl)tosylamino]-3-phenylpropanoate (20a). According to G.P.B, with 19a (221 mg,
0.44 mmol) CC (CH2Cl2/MeOH/25% aq. NH3 soln. 80 :20 :1) yielded pure 20a (175 mg, 99%). Colorless oil.
1H-NMR: 7.72 (d, J ˆ 8.3, 2 H); 7.30 7.25 (m, 5 H); 7.16 (m, 2 H); 5.45 (dd, J ˆ 10.5, 4.9, 1 H); 4.02 (q, J ˆ 7.1,
2 H); 3.15 2.06 (m, 3 H); 2.72 (dd, J ˆ 15.6, 4.9, 1 H); 2.51 (br. t, J ˆ 6.5, 2 H); 2.44 (s, 3 H); 1.54 1.46
(m, 1 H); 1.45 1.33 (m, 1 H); 1.39 (br. s, 2 H); 1.13 (t, J ˆ 7.1, 3 H ) . 13C-NMR: 170.2, 143.4, 137.8, 137.5 (4 s);
129.7, 128.6, 128.2, 127.8, 127.3 (5 d); 60.8( t); 57.1 (d); 42.7, 39.1, 37.2, 33.9 (4 t); 21.5, 14.0 (2 q).
Ethyl (À)-(3R)-3-[(3-Aminopropyl)tosylamino]octanoate (20b). According to G.P.B, with 19b (585 mg,
1.17 mmol) CC (CH2Cl2/MeOH/25% aq. NH3 soln. 100 :20 :1) gave pure 20b (442 mg, 95%). Pale yellow oil.
[a]2D1 ˆ À14.8( c ˆ 1.7, CHCl3). IR: 3400w, 3300 3100w, 3030w, 2960s, 2930s, 2870m, 2860m, 1730s, 1710s, 1655m,
1600w, 1495w, 1465m, 1455m, 1445w, 1390w, 1370m, 1335s, 1305m, 1290m, 1250 1230w, 1175w, 1160s, 1150s,
1135w, 1090m, 1025w, 990 930w, 920 880w, 8 12m, 710w, 700w, 695w, 68 5w, 670w, 655m, 615w. 1H-NMR: 7.73
(d, J ˆ 8.3, 2 H); 7.27 (d, J ˆ 7.9, 2 H); 4.06 (m, 3 H); 3.17 (m, 2 H); 2.78( t, J ˆ 6.6, 2 H); 2.40 (s, 3 H); 2.38
(m, 2 H); 2.22 (br. s, 2 H); 1.8 2 m( , 2 H); 1.43 (br. m, 2 H); 1.24 (t, J ˆ 7.1, 3 H); 1.21 1.08( m, 6 H); 0.81
(br. t, J ˆ 6.7, 3 H). 13C-NMR: 171.0, 143.2, 137.7 (3 s); 129.6, 127.3 (2 d); 60.7 (t); 55.7 (d); 42.1, 39.4, 39.1, 33.8,
33.4, 31.2, 26.0, 22.3 (8 t); 21.3, 14.0, 13.8(3 q).
Ethyl (À)-(3R)-3-[(3-Aminopropyl)tosylamino]decanoate (20c). According to G.P.B, with 19c (382 mg,
0.72 mmol). CC (CH2Cl2/MeOH/25% aq. NH3 soln. 100 :20 :1) yielded 20c (279 mg, 90%). Pale yellow oil.
[a]2D1 ˆ À16.8( c ˆ 0.9, CHCl3). IR: 3400w, 3300 3100w, 3020w, 2960s, 2930s, 2875m, 2855m, 1730s, 1710s,
1655m, 1595w, 1495w, 1475w, 1465m, 1455m, 1445w, 1395w, 1370m, 1340s, 1305m, 1290m, 1270 1230w, 1185w,
1160s, 1110(br.), 1090m, 1030w, 1015w, 970 930(br.), 880w, 8 10m, 710m, 68 5w, 68 0w, 655w, 650m, 615w.
1H-NMR: 7.73 (d, J ˆ 8.3, 2 H); 7.27 (d, J ˆ 7.9, 2 H); 4.08( m, 3 H); 3.17 (m, 2 H); 2.78( t, J ˆ 6.7, 2 H); 2.40
(s, 3 H); 2.38( m, 2 H); 2.04 (br. s, 2 H); 1.8 3 m( , 2 H); 1.43 (br. m, 2 H); 1.23 (t, J ˆ 7.1, 3 H); 1.23 1.08
(m, 10 H); 0.86 (br. t, J ˆ 7.0, 3 H). 13C-NMR: 170.9, 143.0, 137.7 (3 s); 129.4, 127.2 (2 d); 60.6 (t); 55.6 (d); 42.0,
39.4, 39.1, 34.0, 33.4, 31.6, 29.0, 28.9, 26.3, 22.5 (10 t); 21.3, 14.0, 13.9 (3 q).
Hexahydro-4-phenyl-5-tosyl-1,5-diazocin-2(1H)-one (21a). According to G.P.C, with 20a (650 mg,
1.6 mmol). Recrystallization from CH2Cl2 gave 21a (476 mg, 83%). Colorless solid. M.p. 198 1998. IR:
3600 3100w, 3400w, 3000w, 2960w, 2920w, 1665s, 1600w, 1495w, 1465m, 1450m, 1440w, 1400w, 1370w, 1337m,
1305w, 1290w, 1260w, 1175m, 1155s, 1130 1070m, 1035w, 970m, 930w, 8 60w, 8 30w, 8 15w, 700m, 650m, 620m.
1H-NMR: 7.71 (d, J ˆ 8.3, 2 H); 7.25 (m, 7 H); 5.70 (dd, J ˆ 10.5, 4.8, 1 H); 5.60 (br. t, 1 H); 3.88 (dm, J ˆ 16.1,
1 H); 3.35 3.29 (br. m, 2 H); 3.11 (m, 2 H); 2.90 (dd, J ˆ 13.1, 4.9, 1 H); 2.41 (s, 3 H); 2.05 1.89 (br. m, 1 H);
1.54 1.43 (m, 1 H). 13C-NMR: 173.7, 143.4, 137.7, 137.5 (4 s); 129.6, 128.6, 127.7, 127.6, 126.8 (5 d); 59.7 (d); 43.6,

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Helvetica Chimica Acta Vol. 85 (2002)
‡
‡
41.9, 37.6, 31.1 (4 t); 21.5 (1 q). CI-MS: 377 (20), 376 (100, [M ‡ NH4] ), 359 (10, [M ‡ H] ), 229 (8, [M À
‡
C9H9NO ‡ NH4] ).
(À)-(4R)-Hexahydro-4-pentyl-5-tosyl-1,5-diazocin-2(1H)-one (21b). According to G.P. C, with 20b
(550 mg, 1.4 mmol). The crude colorless, amorphous solid 21b (427 mg, 88%) was crystallized from CHCl3.
M.p. 172.5 174.08. [a]2D1 ˆ À63.0 (c ˆ 1.0, CHCl3). IR: 3600 3100w, 3400w, 3030w, 3000w, 2960m, 2920m,
2870w, 2860w, 1690w, 1655s, 1600w, 1495w, 1465m, 1440w, 1395w, 1375w, 1335m, 1305w, 1195w, 1185w, 1160s,
1115m, 1090m, 1040w, 1017w, 950w, 925w, 900(br.), 835w, 8 12w, 705w, 695w, 690m, 68 5w, 650m, 620m. 1H-NMR:
7.71 (d, J ˆ 8.3, 2 H); 7.29 (d, J ˆ 8.0, 2 H); 6.02 (br. s, 1 H); 4.12 (br. m, 1 H); 3.59 (dd, J ˆ 15.6, 4.4, 1 H); 3.46
(m, 1 H); 3.27 (m, 1 H); 2.99 2.85 (m, 2 H); 2.47 2.41 (m, 1 H); 2.42 (s, 3 H); 2.19 (m, 1 H); 1.63 1.45 (br. m,
2 H); 1.24 0.88 (br. m, 7 H); 0.78( t, J ˆ 6.8, 3 H). 13C-NMR: 173.8, 143.3, 137.7 (3 s); 129.5, 127.0, 55.7 (3 d)
40.0 (br.), 39.4 (br.), 38.8 (br.), 32.1, 31.2, 30.4 (br.), 25.8, 22.2 (8 t); 21.4, 13.7 (2 q). CI-MS: 370 (100, [M ‡
‡
‡
‡
‡
NH4] ), 353 (19, [M ‡ H] ), 199 (12), 197 (10, [M À C7H7SO2] ). EI-MS: 281 (28, [M À C5H11] ), 239 (76), 197
‡
‡
‡
(17, [M À C7H7SO2] ), 155 (21, C7H7SO2), 91 (100, C7H7 ). ESI-MS: 727 (28, [2 M ‡ Na] ), 705 (98, [2 M ‡
‡
‡
H] ), 353 (100, [M ‡ H] ).
(À)-(4R)-4-Heptylhexahydro-5-tosyl-1,5-diazocin-2(1H)-one (21c). According to 20c G.P. C, with (279 mg,
0.65 mmol). CC (CH2Cl2/MeOH 30 :1) gave 21c (226 mg, 91%). Colorless oil. [a]2D1 ˆ À54.0 (c ˆ 1.0, CHCl3).
IR: 3600 3100w, 3400w, 3030w, 3000w, 2960m, 2925m, 2855w, 1655s, 1600w, 1495w, 1465m, 1440w, 1400w, 1375w,
1338m, 1305w, 1160s, 1120(br.), 1090m, 1040w, 1017w, 925(br.), 840w, 8 15w, 695m, 68 5w, 650m, 620m. 1H-NMR:
7.72 (d, J ˆ 8.3, 2 H); 7.28 (d, J ˆ 8.0, 2 H); 6.01 (br. m, 1 H); 4.13 (br. m, 1 H); 3.59 (dd, J ˆ 15.5, 4.5, 1 H); 3.47
(m, 1 H); 3.22 (m, 1 H); 2.99 2.89 (m, 1 H); 2.87 2.79 (br. m, 1 H); 2.44 2.39 (m, 1 H); 2.41 (s, 3 H); 2.19
(br. m, 1 H); 1.61 1.47 (m, 2 H); 1.27 0.92 (br. m, 11 H); 0.86 (t, J ˆ 7.0, 3 H). 13C-NMR: 173.6, 143.3, 137.7
(3 s); 129.5, 127.0, 55.6 (3 d); 39.9 (br.), 39.4 (br.), 38.9 (br.), 32.1, 31.5, 30.8 (br.), 29.0, 28.9, 26.2, 22.5 (10 t);
‡
‡
21.4, 13.9 (2 q). CI-MS: 399 (14), 398(54, [ M ‡ NH4] ), 382 (21), 381 (100, [M ‡ H] ), 227 (14), 225 (13, [M À
‡
C7H7SO2] ).
(À)-(4R)-1-(4-Bromobutyl)hexahydro-4-pentyl-5-tosyl-1,5-diazocin-2(1H)-one (22). To a suspension of
powdered KOH (24 mg, 0.43 mmol, 1.5 equiv.; dried in vacuo prior to use) in dry DMSO (1 ml) at r.t., a mixture
of 21b (100 mg, 0.28mmol) and 1,4-dibromobutane (74 ml, 0.62 mmol, 2.2 equiv.) in dry DMSO (1.5 ml) was
added dropwise. The resulting pale yellow suspension was vigorously stirred at r.t. overnight (no educt left). The
mixture was quenched at 08 with sat. aq. NH4Cl soln., washed with H2O, and extracted with Et2O (3 Â 10 ml).
The combined Et2O layers were washed with brine, dried (MgSO4), and evaporated. The residual crude oil was
subjected to CC (CH2Cl2/MeOH 30 :1): 22 (113 mg, 82%). Pale yellow oil. [a]2D1 ˆ À34.5 (c ˆ 2.3, CHCl3). IR:
3600 3100w, 2990w, 2955m, 2930m, 2860w, 1630s, 1600w, 1460m, 1430(br.), 1395w, 1380w, 1340m, 1305w, 1260
1200w, 1180w, 1155s, 1115m, 1090m, 1045w, 1020w, 1000 930w, 955m, 910m, 8 60w, 8 40w, 8 10w, 700 630w,
650m, 615w. 1H-NMR (263 K)2): 7.70 (d, J ˆ 8.3, 2 H); 7.28 (d, J ˆ 8.0, 2 H); 4.02 (m, 1 H); 3.82 3.67 (m, 2 H);
3.49 (m, 1 H); 3.42 (t, J ˆ 6.4, 2 H); 3.19 (dm, J ˆ 16, 1 H); 3.3 (dm, J ˆ 13.7, 1 H); 2.84 (m, 1 H); 2.72 (tm, J ˆ
13.7, 1 H); 2.44 (dd, J ˆ 13.7, 5.0, 1 H); 2.42 (s, 3 H); 2.13 (m, 1 H); 1.84 1.58 (m, 5 H); 1.43 (m, 1 H); 1.22 1.08
(br. m, 1 H); 1.07 0.94 (m, 4 H); 0.94 0.77 (m, 2 H); 0.72 (t, J ˆ 6.7, 3 H). 13C-NMR (263 K): 170.7, 143.3, 137.0
(3 s); 129.5, 126.9, 55.5 (3 d); 44.7, 43.9, 40.3, 38.7, 33.2, 31.2, 29.8, 29.6, 29.4, 26.2, 25.8, 22.2 (12 t); 21.3, 13.7
‡
‡
‡
‡
(2 q). ESI-MS: 511 (67, [M ‡ Na ‡ 2] ), 509 (50, [M ‡ Na] ), 489 (92, [M ‡ H ‡ 2] ), 487 (82, [M ‡ H] ), 445
‡
‡
(31), 443 (52), 429 (58, [M À HBr‡ Na] ), 407 (100, [M À HBr‡ H] ).
The mass balance of the reaction was equilibrated by the isolation of a small quantity of the symmetric,
bicyclic by-product (À)-(4R,4'R)-1,1'-(butane-1,4-diyl)bis[hexahydro-4-pentyl-5-tosyl-1,5-diazocin-2(1H)-one]
(14 mg, 18%). [a]D21 ˆ À53.6 (c ˆ 0.75, CHCl3).
(À)-(4R)-4-Heptylhexahydro-1-[(4R)-octahydro-2-oxo-4-pentyl-5-tosyl-1,5-diazocin-1-yl]-5-tosyl-1,5-diaz-
ocin-2(1H)-one (23). Powdered KOH (34 mg, 0.62 mmol, 2.0 equiv., dried in vacuo prior to use) was suspended
in dry DMSO (1 ml) and stirred at r.t. for 15 min before the mixture was cooled to 08. A soln. of 22 (120 mg,
0.29 mmol, 1.0 equiv.) and 21c (117 mg, 0.31 mmol, 1.1 equiv.) in dry DMSO (2 ml) was slowly canulated under
N2 into the frozen suspension at 08. The resulting frozen mixture was progressively thawed under vigorous
stirring overnight, then quenched with H2O, and extracted with Et2O (3 Â 10 ml). The combined Et2O phase was
washed with brine, dried (MgSO4), and evaporated. Purification by CC (CH2Cl2/MeOH 30 :1) afforded 23
The 1H- and 13C-NMR spectra of 22 recorded at r.t. were uninterpretable due to conformational isomerism
of the molecule. Only the absence of d(H) of the amide proton and the clearly detectable d(H) and d(C) of
the CH2Br group (3.42 (t, J ˆ 6.4, 2 H) and 33.2 (t), resp.) indicated the incorporation of the bromobutyl
chain. The fully reported data were obtained at 600 MHz and À108 in CDCl3.
2
)

Helvetica Chimica Acta Vol. 85 (2002)
1671
(160 mg, 71%). Colorless oil. [a]2D1 ˆ À50.2 (c ˆ 1.5, CHCl3). IR: 3600 3100w, 3030w, 3000w, 2960m, 2930m,
2870w, 2860w, 1630s, 1600w, 1490w, 1470m, 1465m, 1440(br.), 1395(br.), 1380w, 1335m, 1305w, 1290w, 1275
1230w, 1195w, 1185w, 1155s, 1115m, 1090s, 1045m, 1025w, 1015w, 990 940(br.), 875w, 8 35w, 8 12m, 705w, 695m,
690w, 650m, 640w, 615w. 1H-NMR3): 7.70 (d, J ˆ 8.3, 4 H); 7.28 (d, J ˆ 8.0, 4 H); 4.08 (br. m, 2 H); 3.80 2.81
(br. m, 14 H); 2.47 (br. m, 2 H); 2.41 (s, 6 H); 2.11 (br. m, 2 H); 1.84 1.36 (br. m, 9 H); 1.28 -0.98 (br. m,
17 H); 0.86 (t, J ˆ 7.0, 3 H); 0.78( t, J ˆ 6.7, 3 H). 13C-NMR (263 K): 170.7, 143.4, 137.0 (3 s); 129.7, 127.0 (2 d);
53.4 (br. d); 44.7 43.9 (br. t); 40.1 38.9 (br. t); 31.7, 31.4, 29.5, 29.2, 29.0, 26.4, 26.0, 25.1, 22.6, 22.4 (10 t); 21.5,
‡
‡
14.0, 13.8(4 q). Nano ESI-MS: 809 (100, [M ‡ Na] ), 787 (79, [M ‡ H] ). Nano ESI-MS/MS (m/z 787.5): 787
‡
(15, [M ‡ H] ), 663 (100), 635 (86), 616 (21), 435 (26), 407 (36), 283 (12).
(‡)-(4R)-4-Heptylhexahydro-[(4R)-octahydro-2-oxo-4-pentyl-1,5-diazocin-1-yl]-1,5-diazocin-2(1H)-one
(ˆ Didemethylhopromine; 24). According to G.P. D, with 23 (160 mg, 0.20 mmol): crude 24 (62 mg, 64%). Pale
yellow oil, which was pure enough (by NMR and MS) to be used in the next step without further purification.
[a]2D1 ˆ ‡13.8( c ˆ 0.4, CHCl3). IR: 3600 3100w, 3000w, 2960m, 2930s, 2870w, 2860m, 2510 2400w, 1620s,
1490 1440w, 1430w, 1420w, 1375w, 1352w, 1335w, 1300(br.), 1280 1230w, 1215m, 1170m, 1120(br.), 1100
1060w, 1050w, 1000w, 990 930w, 710m, 660w, 640(br.), 615w. 1H-NMR: 3.86 td, J ˆ 13.3, 3.4, 2 H); 3.71
(m, 2 H); 3.23 (dm, J ˆ 14.8, 2 H); 3.07 (dm, J ˆ 14.8, 2 H); 2.97 2.85 (m, 4 H); 2.51 (dd, J ˆ 12.5, 9.7, 2 H);
2.41 2.26 (m, 4 H); 1.99 1.80 (br. s, 2 H); 1.76 1.20 (m, 28H); 0.87 ( m, 6 H). 13C-NMR: 173.5 (2 s); 59.6
(2 d); 45.2, 44.8, 43.6, 42.9, 37.1, 31.6, 31.2, 29.4, 29.1, 26.2, 25.8, 25.1, 22.5, 22.4 (14 t); 13.9, 13.8(2 q). ESI-MS:
‡
‡
479 (48, [M ‡ H] ), 240 (100, [(M ‡ 2 H)/2] ).
(À)-(4R)-4-Heptylhexahydro-5-methyl-1-[(4R)-octahydro-2-oxo-4-pentyl-1,5-diazocin-1-yl]-1,5-diazocin-
2(1H)-one (ˆ Hopromine; 2). According to the G. P. E, with 24 (60 mg, 0.12 mmol). CC (CHCl3/MeO/25% aq.
NH3 soln. 90 :10 :0.7) gave 2 (63 mg, 99%). Colorless oil. [a]2D1 ˆ À14.4 (c ˆ 2.1, CHCl3) (for natural hopromine,
see [3]: [a]2D1 ˆÀ 10 (c ˆ 3, CHCl3) IR: 2810w, 2780w, 2520 2400w, 1725w, 1620s, 1465m, 1430w, 1420w, 1375w,
1360w, 1350w, 1320w, 1285 1190w, 1170w, 1120w, 1110w, 1070w, 1050w, 1020 930(br.), 910m, 8 60w, 835(br.),
660w, 605w. 1H-NMR: 3.47 3.30 (m, 6 H); 3.20 (m, 2 H); 2.96 2.82 (m, 4 H); 2.56 2.44 (m, 6 H); 2.41
(s, 6 H); 1.88 1.68 (br. m, 2 H); 1.65 1.20 (m, 26 H); 0.88 (m, 6 H). 13C-NMR: 173.5 (2 s); 63.2 (2 d); 47.5, 47.1
(br.); 45.4 (3 t); 39.6 (2 br. q); 38.4, 31.8, 31.7, 30.8 (br.), 29.5, 29.2, 28.6, 26.9, 26.5, 25.2, 22.5 (11 t);13.95, 13.90
‡
(2 q). CI-MS: 507 ([M ‡ H] ).
Diastereoisomer Mixture 1,1'-(Butane-1,4-diyl)bis[hexahydro-4-phenyl-5-tosyl-1,5-diazocin-2(1H)-one]
(25). Powdered KOH (69 mg, 1.23 mmol, 2.2 equiv.; dried in vacuo prior to use) was suspended in dry DMSO
(1 ml) and stirred at r.t. for 15 min. Then the mixture was cooled to 08 and a soln. of 1,4-dibromobutane (36 ml,
0.31 mmol, 0.55 equiv.) and 21a (200 mg, 0.56 mmol, 1.0 equiv.) in dry DMSO (1 ml) was added dropwise by
syringe to the frozen suspension. The mixture was allowed to defreeze slowly overnight upon which it was
diluted with Et2O (10 ml) and quenched with sat. aq. NH4Cl soln. (15 ml). After extraction of the aq. phase with
Et2O (3 Â 10 ml), the combined extracts were washed with brine, dried (MgSO4), and evaporated. The residual
pale yellow solid was recrystallized from CH2Cl2: 25 (113 mg, 53%). Colorless solid. M.p. 243 2458. IR: 3600
3100w, 3000w, 2960w, 2920w, 2860w, 1635s, 1600w, 1495w, 1485w, 1470m, 1450w, 1425w, 1375w, 1335m, 1305w,
1260w, 1155s, 1130 1090m, 1045w, 965m, 8 35w, 8 10w, 700m, 650m, 620m. 1H-NMR4): 7.65 (m, 4 H); 7.25 7.19
(m, 14 H); 5.66 (m, 2 H); 3.90 (m, 2 H); 3.52 2.70 (br. m, 14 H); 2.39 (s, 3 H); 2.38( s, 3 H); 2.12 1.42 (br. m,
10 H). 13C-NMR4): 170.4, 143.4, 137.7, 137.5 (4 s); 129.4, 128.4, 127.3, 127.0, 126.6 (5 d); 59.8( d); 46.1, 44.2 (br.),
‡
‡
‡
38.8, 29.1 (br.), 24.9 (5 t); 21.3 (2 q). ESI-MS: 809 (48, [M ‡ K] ), 793 (100, [M ‡ Na] ), 771 (71, [M ‡ H] ).
Diastereoisomer Mixture 1,1'-(Butane-1,4-diyl)bis[hexahydro-4-phenyl-1,5-diazocin-2(1H)-one (ˆ Di-
demethylhomaline; 26). According to G.P. D, with 25 (107 mg, 0.14 mmol). CC (CH2Cl2/MeOH/25% aq. NH3
soln. 90 :10 :0.7) yielded 26 (49 mg, 76%). Colorless, amorphous solid. 1H-NMR: 7.40 7.23 (m, 10 H); 4.20
4.07 (m, 2 H); 4.02 (dd, J ˆ 10.9, 1.6, 2 H); 3.95 3.78( m, 2 H); 3.26 (dd, J ˆ 14.9, 2.8, 2 H); 3.15 (dm, J ˆ 14.8,
2 H); 3.10 2.89 (m, 4 H); 2.49 (dt, J ˆ 12.7, 2.0, 2 H); 2.38( ddd, J ˆ 12.0, 11.6, 3.5, 2 H); 1.86 1.55 (m, 10 H).
13C-NMR: 172.9; 144.9 (2 s); 128.5, 127.4, 126.3 (3 d); 64.6 (d); 45.4, 45.0, 44.9, 44.7, 44.1, 31.5, 25.3, 25.2 (8 t). CI-
‡
MS: 464 (31), 463 (100, [M ‡ H] ).
In the 1H-NMR spectrum of 23, no fine structures were detectable, except for the Ts groups and the
terminal Me groups of the alkyl side chains. Identification of 23 was based on a nano ESI-MS analysis
measured with Bruker Esquire LC-00028.
In the 1H-NMR spectrum of 25, no clear signals were observed, and in the 13C-NMR spectrum not all the
signals could be detected. Compound 25 was identified on the basis of its ESI-MS analysis.
3
)
4
)

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Helvetica Chimica Acta Vol. 85 (2002)
Diastereoisomer Mixture 1,1'-(Butane-1,4-diyl)bis[hexahydro-5-methyl-4-phenyl-1,5-diazocin-2(1H)-one
(ˆ Homaline; 1). According to G.P. E, with 26 (49 mg, 0.11 mmol). The crude solid was recrystallized from
CH2Cl2: 1 (46 mg, 88%). Colorless solid. M.p. 195 1968. IR: 3600 3100w, 3080w, 3060w, 3020w, 2990s, 2930s,
2860m, 2800w, 2780w, 1620vs, 1485s, 1470s, 1450s, 1430w, 1420m, 1375m, 1350m, 1315m, 1260m, 1240w, 1195
1060w, 1030 965w, 925w, 8 60w, 700s, 660m, 630w, 615w. 1H-NMR: 7.35 7.21 (m, 10 H); 4.00 (dd, J ˆ 11.6, 3.1,
2 H); 3.93 3.70 (m, 4 H); 3.32 (m, 2 H); 3.25 3.05 (m, 4 H); 3.04 2.93 (m, 2 H); 2.60 2.45 (m, 4 H); 2.26
(s, 6 H); 1.90 1.74 (m, 2 H); 1.73 1.52 (m, 6 H). 13C-NMR: 173.3, 142.0 (2 s); 128.2, 127.4, 127.0 (3 d); 67.9 (d);
‡
50.9, 48.0, 47.9, 45.9, 45.7 (5 t); 43.6 (d); 41.2, 29.9, 29.8, 25.5, 25.4 (5 t). ESI-MS: 513 (10, [M ‡ Na] ), 492 (34),
‡
‡
491 (100, [M ‡ H] ). CI-MS: 492 (33), 491 (100, [M ‡ H] ).
X-Ray Crystal-Structure Determination of Compound 21b5). The data collection and refinement
parameters are summarized in the Table, and a view of the molecule is shown in Fig. 2. All measurements
were made on a Rigaku AFC5R diffractometer with graphite-monochromated MoKa radiation (l 0.71069 ä)
and a 12-kW rotating anode generator. The intensities were collected by means of w/2q scans and were corrected
for Lorentz and polarization effects, but not for absorption. Equivalent reflections, other than Friedel pairs, were
merged. The structure was solved by direct methods with SIR92 [21], which revealed the positions of all non-H-
atoms. The non-H-atoms were refined anisotropically. All of the H-atoms were fixed in geometrically calculated
positions (d(CÀH) ˆ 0.95 ä), and each was assigned a fixed isotropic displacement parameter with a value
equal to 1.2Ueq of its parent atom. Refinement of the structure was carried out on F with full-matrix least-
squares procedures, which minimized the function Sw(j Fo jÀj Fc j )2. A correction for secondary extinction was
applied. Neutral-atom scattering factors for non-H-atoms were taken from [22], and the scattering factors for H-
atoms from [23]. Anomalous dispersion effects were included in Fc [24]; the values for f ' and f '' were those of
[22b]. The values of the mass attenuation coefficients were those of [22c]. All calculations were performed with
the teXsan crystallographic software package [25].
Table. Crystallographic Data for Compound 21b
Crystallized from
Empirical formula
Mr
CHCl3
C18H28N2O3S
352.49
Dx [g cmÀ3
]
1.283
0.196
55
m(MoKa) [mmÀ1
2q(max) [8]
]
Crystal color, habit
Crystal dimensions [mm]
Temperature [K]
Crystal system
Space group
colorless, tablet
Total reflections measured
4816
4181
3755
219
0.0373
0.0372
1.652
0.20 Â 0.45 Â 0.45 Symmetry-independent reflections
173 (1)
orthorhombic
P212121
4
Reflections used (I > 2s(I))
Parameters refined
Final
R
Z
wR (w ˆ [s2(Fo) ‡ (0.005Fo)2]À1
)
Reflections for cell determination 25
Goodness-of-fit s
2q range for cell determination [8] 33 40
Secondary extinction coefficient
Final Dmax/s
D1 (max, min) [e äÀ3
]
4.5 (5) ¥ 10À7
0.0006
0.27; À0.33
Unit cell parameters a [ä]
13.914 (2)
b [ä]
c [ä]
V [ä3]
15.942 (1)
8.228 (1)
1825.0 (3)
REFERENCES
¬
[1] A. Guillaumin, −Flore de la Nouvelle Caledonie×, Paris, 1948.
¬
[2] M. Pais, G. Ratle, R. Sarfati, F.-X. Jarreau, C. R. Acad. Sci., Ser. C 1968, 266, 37; M. Pais, R. Sarfati, F.-X.
¬
Jarreau, R. Goutarel, C. R. Acad. Sci., Ser. C 1971, 272, 1728; M. Pais, R. Sarfati, F.-X. Jarreau, Bull. Soc.
¬
Chim. Fr. 1973, 331; M. Pais, G. Ratle, R. Sarfati, F.-X. Jarreau, C. R. Acad. Sci., Ser. C 1968, 267, 8 2.
[3] M. Pais, R. Sarfati, F.-X. Jarreau, R. Goutarel, Tetrahedron 1973, 29, 1001.
[4] O. Lefebvre-Soubeyran, Acta Crystallogr., Sect. B 1976, 32, 1305.
5
)
Crystallographic data (excluding structure factors) for the structure of 21b have been deposited with the
Cambridge Crystallographic Data Centre as supplementary publication No. CCDC-176204. Copies of the
data can be obtained, free of charge, on application to the CCDC, 12 Union Road, Cambridge CB2 1EZ,
UK (fax: ‡ 44 (1223)336033; e-mail: deposit@ccdc.cam.ac.uk).

Helvetica Chimica Acta Vol. 85 (2002)
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