Total synthesis of the spermidine alkaloid 13-hydroxyisocyclocelabenzine

Article abstract of DOI:10.1002/hlca.200390058

A convergent total synthesis of 13-hydroxyisocyclocelabenzine was developed. (3S)-Methyl 3-amino-3-phenylpropanoate (4) was used as the chiral building block. The 3,4-dihydro-4-hydroxyisoquinolin-1(2H)-one derivative (5), the key fragment for the total sy

Full text of DOI:10.1002/hlca.200390058

Helvetica Chimica Acta Vol. 86 (2003)
579
Total Synthesis of the Spermidine Alkaloid
13-Hydroxyisocyclocelabenzine
by Yi Li1), Anthony Linden, and Manfred Hesse*
Organisch-chemisches Institut der Universit‰t Z¸rich, Winterthurerstrasse 190, CH-8057 Z¸rich
A convergent total synthesis of 13-hydroxyisocyclocelabenzine was developed. (3S)-Methyl 3-amino-3-
phenylpropanoate (4) was used as the chiral building block. The 3,4-dihydro-4-hydroxyisoquinolin-1(2H)-one
derivative (5), the key fragment for the total synthesis, was prepared by a novel base-catalyzed lactone-lactam
ring enlargement (Scheme 3). The resulting target C(13) epimers 3a/3b from macrocyclization (Scheme 4) were
separated by repeated flash chromatography. The absolute configuration of the synthetic alkaloid was
determined by an X-ray crystal-structure analysis, which enabled us to determine the absolute configuration
(9S,13R) for natural 3a with positive [a]D.
Introduction. The macrocyclic spermidine alkaloid (‡)-13-hydroxyisocyclocela-
benzine (3), together with (‡)-cyclocelabenzine (1) and (‡)-isocyclocelabenzine (2)
was isolated from Maytenus mossambicensis (Klotzsch) Blakelock var. mossambi-
censis (Celastraceae) by Wagner and co-workers [1] (Fig. 1).
The three alkaloids 1 3 show the 13-membered lactam ring of celabenzine being
linked to the benzoyl residue within the spermidine unit to form an appended six-
membered ring (Fig. 1). The 13-hydroxyisocyclocelabenzine is the first known
spermidine alkaloid with a hydroxy function at the macrocyclus.
The structures of these alkaloids were elucidated by spectroscopic methods,
especially 1H- and 13C-NMR spectroscopy. The absolute configurations of cyclo-
celabenzine and isocyclocelabenzine were determined by asymmetric syntheses and X-
ray crystal-structure analysis [2][3].
We now describe a short and efficient asymmetric synthesis of (‡)-13-hydroxy-
isocyclocelabenzine, which allows the determination of its unknown relative and
absolute configuration by an X-ray crystal-structure analysis. Our retro-synthetic
consideration leads to the building blocks 4 and 5 and further to the starting compound
phthalaldehydic acid via 6 8 (Scheme 1). Although the absolute configuration at C(9)
is unknown, it was assumed that this centre probably has the (S)-configuration like all
other structurally known spermidine alkaloids from this source [4]. Therefore, (S)-b-
phenyl-b-alanine ester 4 was used as the chiral building block.
Results and Discussion.
The chiral building block, methyl (3S)-3-amino-3-
phenylpropanoate (4) was synthesized according to reported procedures by resolution
of racemic b-phenyl-b-alanine [5][6] or by direct asymmetric synthesis [7]. The crucial
step of the synthesis leading to 13-hydroxyisocyclocelabenzine was the formation of a
suitably substituted 3,4-dihydroisoquinolin-1(2H)-one fragment. Although a modified
1
)
Part of Ph. D. Thesis of Y. L., Universit‰t Z¸rich, 2002.

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Helvetica Chimica Acta Vol. 86 (2003)
Fig. 1. Spermidine alkaloids isolated from Maytenus mossambicensis
Bischler-Napieralski reaction was used by us to construct the similar 3,4-dihydroiso-
quinolin-1(2H)-one derivatives in the syntheses of isocyclocelabenzine and cyclo-
celabenzine [2][3], the strong acidic reaction conditions employed make this method
inapplicable in the present case due to the susceptible benzylic OH group. In fact, there
is no general procedure available so far giving access to this structure. Our synthetic
strategy to 3,4-dihydro-4-hydroxyisoquinolin-1(2H)-one was based on a novel lactone-
lactam transformation, which took advantage of the relative spatial arrangement of the
O- and N-atom in this fragment.
The commercially available phthalaldehydic acid was treated with potassium
cyanide and HCl at 08. Without isolation, the cyanohydrine generated was subjected to
dehydration in the presence of dicyclohexylcarbodiimide (DCC) to afford the
phthalide-derived nitrile 9 in an excellent yield (Scheme 2) [8]. Alkylation of the
nitrile-stabilized anion derived from 9 with allyl bromide provided 8 in 75% yield. Allyl
bromide was chosen as the electrophilic reagent in the hope that the CˆC bond could
be transformed to an aldehyde group for the coupling with the amino acid building
block. When 2-(bromomethyl)-1,3-dioxolane, the electrophile with an already pro-
tected aldehyde group, was used, no substitution product could be obtained due to the
lower reactivity and higher steric hindrance of this reagent.
The presence of a CˆC bond and ester function in compound 8 made the selective
reduction of the CN group quite thorny. Among methods available for the reduction of
nitriles, catalytic hydrogenation over a metal catalyst such as Pt, Pd, or Raney-Ni would
reduce the CˆC bond simultaneously. On the other hand, the lactone could not survive

Helvetica Chimica Acta Vol. 86 (2003)
581
Scheme 1. Retrosynthetic Analysis of (‡)-13-Hydroxyisocyclocelabenzine (3)
the hydride reduction of nitriles to amines by those traditional hydride reagents such as
LiAlH4 and LiAlH4 ¥ AlCl3.
Umino et al. [9] reported that both aliphatic and aromatic nitriles can be reduced to
the corresponding amines with sodium trifluoroacetoxy borohydride (NaBH3-
(OCOCF3)) in THF. The application of this reagent to our case was examined. When
compound 8 was treated with 1 equiv. of NaBH3(OCOCF3), generated from NaBH4
and CF3COOH in situ, the desired product 10 was obtained in 40% yield, with recovery
of 20% of starting material. The yield decreased sharply on addition of more reducing
agent; no reduction product could be isolated, and all starting material was destroyed
when 3 equiv. of reducing agent per mol of nitrile were employed. It is well known that
NaBH4 in conjunction with various strong acids is an effective hydroboration agent
[10]. Marshall and Johnson [11] have reported the hydroboration of hex-1-ene with
NaBH4 and AcOH in THF. The vital role played by the acid would be either to

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Helvetica Chimica Acta Vol. 86 (2003)
Scheme 2
a) 1. KCN, HCl, 08; 2. DCC, r.t., 8h; 85%. b) Lithium diisopropylamide, allyl bromide, THF, À 788, 8h; 75%. c)
NaBH3(OCOCF3), THF, r.t. 40%.
protonate the substrate, thus rendering it more susceptible to attack by hydride, as
appears to be the case with nitriles, or to produce diborane or a related species, which,
in turn, attacks the substrate. The analogous reaction between NaBH4 and CF3COOH
in our case may produce a species which, perhaps by its decomposition into diborane, is
capable of effecting hydroboration. So, the reasonable explanation for this reaction
could be that the reduction of the cyano group happened prior to the hydroboration of
the CˆC bond, but excess amount of NaBH3(OCOCF3) converted the reduction
product into alkylboranes.
In view of our finding, this procedure provided a convenient method for the
selective reduction of nitriles to corresponding amines under mild conditions, leaving
the olefinic functions intact. The low yield was compensated by the absence of
saturated product, which could not easily be separated by column chromatography.
Treatment of the amine 10 with acrylonitrile in refluxing MeOH gave monosub-
stituted amino derivative 7 in 87% yield (Scheme 3). The N-alkylation to introduce the
butyl unit of the spermidine moiety was carried out now to circumvent the strong-base-
catalyzed alkylation of an amide at a later stage. The expected reaction that
accomplished the conversion of the intermediate 7 into intermediate 6 took place
very smoothly. When 7 was refluxed in EtOH in the presence of 1 equiv. of NaOMe, the
amino-phthalide-substituted alkene rearranged to 3,4-dihydro-4-hydroxyisoquinolin-
1(2H)-one in an excellent yield. This rearrangement reaction is apparently a base-
catalyzed one, the driving force is the formation of the more stable six-membered
lactam. Ozonolysis of the intermediate 6 at À 788 in MeOH and reduction of the
ozonolysis product with Me2S proceeded quite cleanly and in good yield to furnish
precursor 5.

Helvetica Chimica Acta Vol. 86 (2003)
583
Scheme 3
a) Acrylonitrile, MeOH, reflux, 12 h; 87%. b) NaOMe, EtOH, reflux, 2 h; 90%. c) 1. O3, MeOH, À 788;
2. Me2S; 80%.
The coupling of precursor 5 with the chiral building block 4 was attempted by
reductive amination [12]. Thus, amino ester 4 and intermediate 5 were dissolved in
MeOH, the resulting solution was adjusted to pH 6 with aqueous HCl solution, and the
intermediate imine formed was subsequently reduced by NaBH3CN to give the
coupling product 11 in a good yield of 75% (Scheme 4). Catalytic reduction of the
cyano group of 11 with H2/PtO2 in EtOH containing 2 equiv. of HCl led to the
corresponding amino ester 12. These mild reaction conditions are advantageous as they
permit the reduction of the cyano group in the presence of functional groups that are
susceptible to strongly acidic or basic reagents. In our case, the acetate and benzylic OH
group were not affected by the conditions outlined above.
The last step on the way to 13-hydroxyisocyclocelabenzine was the ring closure to
the 13-membered macrocycle. Although boron-templated cyclization of triamino esters
with tris(dimethylamino)boron has been reported to be highly efficient in the synthesis
of macrocyclic spermidine alkaloids containing 13 ring members [13], attempts to
obtain target molecule 3 directly by ring closure of amino ester 12 according to the
reported procedure [14] only resulted in inseparable mixtures, and no starting material
could be recovered. Therefore, an alternative macrocyclization strategy employing the
coupling reagent under high-dilution conditions was pursued. To this end, amino ester
12 was converted to the amino acid by saponification with LiOH in THF/MeOH/H2O
3 :1:1. Without further purification, the amino acid obtained was treated with diethyl
phosphorocyanidate [15] in the presence of Et3N in DMF to furnish (9S,13R)/(9S,13S)-
13-hydroxyisocyclocelabenzine (3a/3b) as a mixture of the C(13) epimers in a yield of

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Helvetica Chimica Acta Vol. 86 (2003)
Scheme 4
a) 5, NaBH3CN, HCl, MeOH, r.t., 6 h; 75%. b) H2, PtO2, EtOH, r.t., 5 h; 90%. c) 1. LiOH, THF/MeOH/H2O
3 :1 :1, r.t., 3 h; 2. (EtO)2POCN, Et3N, DMF, r.t.; 60%.
60%. The ratio of the two epimers 3a and 3b was determined by 1H-NMR spectroscopy
to be 1:1. The cyclization of the amino acid with Mukaiyama×s reagent [16] failed in
CH2Cl2, the optimal solvent for this reagent, due to the very low solubility of the amino
acid, but worked out in DMF. The separation of the epimers was accomplished by
repeated flash chromatography (see Exper. Part). Both epimers have positive optical
rotations and are colorless amorphous solids. All analytical data ([a]D, NMR, IR, and
MS) of one of the synthesized isomers, i.e. of 3a, are identical to those published for
(‡)-13-hydroxyisocyclocelabenzine isolated from the plant [1].
The assignment of the absolute configuration was carried out by an X-ray crystal-
structure analysis of crystals of 3a obtained from CHCl3 (Fig. 2). On the basis of the
known absolute configuration of the employed (3S)-methyl 3-amino-3-phenylpropa-
noate (4), the absolute configuration of the two chiral centers could be assigned to be
(9S,13R). Thus, the absolute configuration of the natural 13-hydroxyisocyclocelaben-
zine was established to be (9S,13R).
We thank the Swiss National Science Foundation for the generous support, J. Cavegn for assistance with the
determination of the crystal structure, and the analytical department of the University of Zurich for MS and
microanalyses.

Fig. 2. ORTEP Plot [17] of the two symmetry-independent molecules of 3a in the structure of 3a ¥ CHCl3 (50% probability ellipsoids)

586
Helvetica Chimica Acta Vol. 86 (2003)
Experimental Part
General. All reactions involving air-sensitive reagents were performed under Ar. Solvents and reagents
were purchased from Fluka. For hydrogenations, an apparatus of Parr Instruments Company, Inc. was used.
TLC: Merck precoated silica gel 60 F-254 plates. Column chromatography (CC): silica gel (Merck 60, 230 400
mesh); FC ˆ flash chromatography. M.p.: Mettler FP-5/FP-52; uncorrected. IR Spectra: Perkin Elmer 297
spectrometer. 1H- and 13C-NMR Spectra: Bruker ARX-300 at 300 and 75 MHz, resp.; chemical shifts d in ppm
rel. to internal SiMe4. MS: chemical ionization (CI) with NH3 as reactant gas on a Finnigan MAT-90 and
electrospray ionization (ESI) on a Finnigan TSQ-700 mass spectrometer; m/z (rel. %).
1,3-Dihydro-3-oxoisobenzofuran-1-carbonitrile (9). To a soln. of phthalaldehydic acid (6.0 g, 0.04 mol) and
KCN (3.90 g, 0.06 mol) in H2O (40 ml) was slowly added 32% aq. HCl soln. (12 ml) at 08 over 1 h. The resulting
soln. was maintained at this temp. for 40 min and extracted with AcOEt (2 Â 100 ml). The combined extracts
were washed with sat. brine (10 ml). After cooling to 08, the soln. was treated with DCC (10.3 g, 0.05 mol) and
stirred for 8h during which time the mixture was allowed to warm to r.t. Dicyclohexylurea was removed by
filtration, and the filtrate was evaporated. The residue was purified by CC (silica gel; CH2Cl2): 9 (5.4 g, 85%).
Light yellow crystals. A sample was recrystallized from EtOH/hexane to give pure colorless crystals. M.p. 120
1218. IR (KBr): 2940m, 2060w, 1781s, 1602m, 1468m, 1326w, 1273s, 1204s, 1107w, 1044s, 1020s, 953m, 8 96w, 8 56w,
798w, 78 3w, 744s, 711w, 68 5m. 1H-NMR (CDCl3): 8.04 7.95 (m, 1 H); 7.90 7.80 (m, 1 H); 7.77 7.66 (m, 2 H);
6.11 (s, 1 H). 13C-NMR (CDCl3): 167.3, 141.7 (2s); 135.5, 131.3, 126.5 (3d); 124.3 (s); 122.7 (d); 113.8( s);
‡
65.6 (d). CI-MS: 177 (100, [M ‡ NH4] ), 150 (25), 133 (10), 105 (40).
3-Allyl-1,3-dihydro-3-oxoisobenzofuran-1-carbonitrile (8). To a soln. of iPr2NH (1.78g, 17.6 mmol) in THF
(15 ml) was added 1.6m BuLi in hexane (11.0 ml, 17.6 mmol) at À 58. The mixture was stirred at this temp. for
30 min. After cooling to À 788, 9 (2.52 g, 15.8mmol) in THF (15 ml) was added dropwise over 30 min and then
treated with hexamethylphosphoric triamide (HMPA; 5 ml) to afford a reddish-brown soln. A soln. of allyl
bromide (2.40 g, 19.7 mmol) was slowly added. After stirring for 2 h at À 788, the mixture was allowed to warm
to r.t. and then quenched with AcOH. The mixture was diluted with Et2O, the soln. washed with H2O and brine,
dried (Na2SO4) and evaporated, and the residue purified by CC (hexane/Et2O 3 :1): 8 (2.38g, 75%). Colorless
crystals. M.p. 76 778. IR (KBr): 2985w, 1988w, 1779s, 1641w, 1602m, 1467s, 1430m, 1409w, 1341w, 1324w, 1290m,
1246s, 1194m, 1147w, 1113w, 1064s, 1015m, 98 7m, 957s, 927s, 8 8 4w, 8 02w, 758s, 736s, 697s, 68 3m, 654w. 1H-NMR
(CDCl3): 8.01 7.90 (m, 1 H); 7.87 7.77 (m, 1 H); 7.74 7.60 (m, 2 H); 5.80 5.63 (m, 1 H); 5.38 5.21 ( m, 2 H);
3.06 2.86 (m, 2 H). 13C-NMR (CDCl3): 166.9, 145.4 (2s); 135.3, 131.2, 127.3, 126.4 (4d); 124.7 (s); 123.2 (t);
‡
122.2 (d); 43.3 (t). CI-MS: 217 (100, [M ‡ NH4] ), 158(15).
3-Allyl-3-(aminomethyl)isobenzofuran-1(3H)-one (10). To a stirred suspension of NaBH4 (0.19 g, 5 mmol)
in THF (5 ml) was added CF3COOH (0.57 g, 5 mmol) in THF (1 ml) within 10 min at 208. To this soln. of
NaBH3(OCOCF3) was added 8 (1.0 g, 5 mmol) in THF (2 ml). The mixture was stirred at r.t. for 30 min and
then quenched with H2O below 108. The resulting mixture was evaporated, the residue extracted with CH2Cl2,
the extract washed with H2O, dried (Na2SO4), and evaporated, and the residue was submitted to CC (CH2Cl2/
MeOH 30 :1): 10 (0.40 g, 40%) as a colorless oil and starting material 8 (0.205 g). 10: IR (film): 3391w, 2918w,
1759s, 1669w, 1642w, 1613w, 1466m, 1433w, 1333w, 1287m, 1224m, 1086m, 997w, 972w, 923w, 765w, 699w.
1H-NMR (CDCl3): 7.95 7.82 (m, 1 H); 7.77 7.65 (m, 1 H); 7.60 7.50 (m, 1 H); 7.49 7.40 (m, 1 H); 5.63 5.45
(m, 1 H); 5.15 4.90 (m, 2 H); 3.35 3.01 (m, 2 H); 2.88 2.65 (m, 2 H); 1.07 (br., 2 H). 13C-NMR (CDCl3):
169.7, 150.2 (2s); 133.9, 130.3, 129.1 (3d); 127.3 (s); 125.5, 121.4 (2d); 120.0 (t); 89.7 (s); 48.7, 40.2 (2t). CI-MS:
‡
‡
‡
407 (40, [2M ‡ 1] ), 221 (15, [M ‡ NH4] ), 204 (100, [M ‡ 1] ).
3-{[(1-Allyl-1,3-dihydro-3-oxoisobenzofuran-1-yl)methyl]amino}propanenitrile (7). A soln. of 10 (0.180 g,
0.883 mmol) and acrylonitrile (0.070 g, 1.33 mmol) in MeOH (10 ml) was heated to reflux for 12 h. After cooling,
the soln. was evaporated and the residue purified by CC (CH2Cl2/MeOH 30 :1): 7 (0.197 g, 87%). Colorless oil. IR
(film): 3348w, 2919w, 28 50w, 2247w, 1759s, 1642w, 1614w, 1466m, 1418w, 1350w, 128 6m, 1223w, 1134w, 1078w, 996w,
925w, 767w, 700w. 1H-NMR (CDCl3): 7.92 7.84 (m, 1 H); 7.70 7.63 (m, 1 H); 7.57 7.50 (m, 1 H); 7.47 7.40
(m, 1 H); 5.63 5.48( m, 1 H); 5.13 4.99 (m, 2 H); 3.11 (q, J ˆ 13.1, 2 H); 2.92 2.83 (m, 2 H); 2.82 2.68
(m, 2 H); 2.44 2.26 (m, 2 H). 13C-NMR (CDCl3): 169.6, 150.6 (2s); 133.9, 130.4, 129.2 (3d); 126.9 (s); 125.6, 121.5
‡
‡
(2d); 120.2 (t); 118.3, 88.7 (2s); 55.0, 45.3, 40.3, 18.9 (4t). CI-MS: 274 (100, [M ‡ NH4] ), 257 (25, [M ‡ 1] ).
4-Allyl-3,4-dihydro-4-hydroxy-1-oxoisoquinoline-2(1H)-propanenitrile (6). A soln. of 7 (0.62, 2.42 mmol)
in EtOH (20 ml) containing NaOMe (prepared from Na (56 mg, 2.42 mmol) and MeOH) was heated to reflux
for 2 h. After cooling, the soln. was evaporated and the residue purified by CC (CH2Cl2/MeOH 45 :1): 6 (0.55 g,
90%). Slightly yellow oil. IR (film): 3396s, 2936w, 2252w, 1643s, 1603m, 1577m, 1488s, 1429m, 1369w, 1325w,
1242w, 1162w, 1113w, 1046w, 998w, 924w, 767m, 705m. 1H-NMR (CDCl3): 8.06 7.96 (m, 1 H); 7.60 7.49

Helvetica Chimica Acta Vol. 86 (2003)
587
(m, 2 H); 7.48 7.35 ( m, 1 H); 5.92 5.75 (m, 1 H); 5.35 5.10 (m, 2 H); 3.94 3.72 (m, 2 H); 3.71 3.51
(m, 2 H); 3.07 (br., 1 H); 2.80 2.68 (m, 2 H); 2.67 2.58( m, 2 H). 13C-NMR (CDCl3): 164.3, 143.5 (2s);
132.6, 132.1, 128.2, 128.1 (4d); 126.6 (s); 123.7 (d); 120.0 (t); 118.1, 70.2 (2s); 57.0, 44.5, 43.9, 16.4 (4t). CI-MS:
‡
‡
274 (100, [M ‡ NH4] ), 257 (21, [M ‡ 1] ).
3,4-Dihydro-4-hydroxy-1-oxo-4-(2-oxoethyl)isoquinoline-2(1H)-propanenitrile (5). A soln. of 6 (0.530 g,
2.07 mmol) in MeOH (30 ml) was cooled to À 788, and then an excess of ozone was passed through the mixture
( ! deep blue soln. when saturated with ozone). After the mixture was purged with N2 for 20 min at À 788, it
was treated with Me2S (2 ml). The cold bath was removed, and the mixture was allowed to warm to r.t. and
stirred for 2 h. Evaporation provided crude 5, which was purified by CC (CH2Cl2/MeOH 30 :1): 5 (0.43 g, 80%).
Colorless oil. IR (film): 3382s, 2928w, 2251w, 1717s, 1650s, 1603m, 1578m, 1487m, 1424m, 1324m, 1297m, 1237w,
1162w, 1130w, 1094w, 1030m, 953w, 768w, 704w. 1H-NMR (CDCl3): 9.77 (t, 1 H); 7.99 7.91 (m, 1 H); 7.64 7.50
(m, 2 H); 7.44 7.36 (m, 1 H); 4.80 (br., 1 H); 3.89 3.75 (m, 2 H); 3.72 3.59 (m, 2 H); 2.90 (d, 2 H); 2.78 2.65
(m, 2 H). 13C-NMR (CDCl3): 201.5 (d); 164.2, 143.1 (2s); 132.9, 128.3, 128.2 (3d); 126.3, 123.6, 118.3, 69.9 (4s);
‡
‡
56.9, 51.1, 44.1, 16.3 (4t). CI-MS: 276 (100, [M ‡ NH4] ), 259 (10, [M ‡ 1] ), 248(15), 232 (44), 215 (11).
Methyl (bS)-b-{{2-[2-(2-Cyanoethyl)-1,2,3,4-tetrahydro-4-hydroxy-1-oxoisoquinolin-4-yl]ethyl}amino}ben-
zenepropanoate (11). To a soln. of 4 (0.316 g, 1.76 mmol) in dry MeOH (15 ml) was added 5n HCl/MeOH
(0.71 ml, 3.53 mmol), followed by 5 (0.455 g, 1.76 mmol) and NaBH3CN (0.138g, 2.20 mmol). The mixture was
stirred at r.t. for 12 h. The residue obtained after evaporation was purified by CC (CH2Cl2/MeOH 30 :1): 11
(0.564 g, 75%). Colorless oil. IR (film): 3291s, 2952m, 2855m, 2250w, 1732s, 1651s, 1603m, 1578w, 1477m, 1435m,
1366w, 1317m, 1293m, 1195w, 1164m, 1130w, 1082w, 1029w, 919w, 8 45w, 766m, 702m. 1H-NMR (CDCl3): 8.01
7.98( m, 1 H); 7.66 7.55 (m, 1 H); 7.49 6.98( m, 7 H); 4.12 3.98( m, 1 H); 3.95 3.10 (m, 8H); 2.92 2.45
(m, 6 H); 2.04 1.78( m, 2 H). 13C-NMR (CDCl3): 171.8, 164.5, 145.2, 144.8, 140.8, 140.7 (6s); 132.4, 131.9, 128.7,
128.0, 127.8, 127.7, 127.4, 127.3, 127.2, 127.0 (10d); 126.1 (s); 124.3, 124.1 (2d); 118.2, 118.0, 72.0, 71.8 (4s); 59.7,
59.6 (2d); 58.8, 56.9 (2t); 51.8( q); 44.3, 44.2, 43.1, 42.8, 41.5, 41.1, 37.5, 37.1, 16.5, 16.4 (10t). CI-MS: 422 (100,
‡
[M ‡ 1] ), 404 (15), 306 (35), 260 (12), 232 (26), 206 (28), 180 (11).
Methyl (bS)-b-{{2-[2-(3-Aminopropyl)-1,2,3,4-tetrahydro-4-hydroxy-1-oxoisoquinolin-4-yl]ethyl}amino}-
benzenepropanoate (12). To a soln. of 11 (0.535 g, 1.27 mmol) in EtOH was added 32% aq. HCl soln. (0.32 g,
2.81 mmol) and PtO2 (0.100 g). The hydrogenation was carried out at r.t./50 psi H2 for 6 h. Then the mixture was
¾
filtered through a pad of Celite . The filtrate was evaporated and the residue purified by CC (CH2Cl2/MeOH/
25% aq. NH4OH soln. 90 :10 :1): 12 (0.471 g, 87%). Colorless oil. IR (CHCl3): 3300m, 3000m, 2940m, 2880m,
1730s, 1640s, 1600m, 1580m, 1490m, 1475m, 1440m, 1300m, 1260w, 1160w, 1120s, 1010w, 700m. 1H-NMR
(CDCl3): 7.99 7.88 (m, 1 H); 7.62 7.47 (m, 1 H); 7.44 6.96 (m, 7 H); 4.09 3.94 (m, 1 H); 3.72, 3.67 (2s, 3 H);
3.65 3.36 (m, 4 H); 3.30 2.94 (m, 3 H); 3.24, 2.98(2 d, 1 H); 2.88 2.40 (m, 6 H); 1.95 1.46 (m, 4 H).
13C-NMR (CDCl3): 171.9, 171.8, 164,1, 164.0, 144.8, 144.0, 140.8, 140.7 (8s); 131.8, 131.4, 128.7, 128.7, 127.9, 127.8,
127.3, 127.2, 127.1, 127.0 (10d); 126.9 (s); 123.9, 123.7 (2d); 71.9, 71.7 (2s); 59.8, 59.7 (2d); 56.8, 55.3 (2t); 51.7 (q);
‡
44.2, 44.1, 43.0, 42.7, 41.6, 41.2, 38.8, 37.4, 37.1, 30.8 (10t). CI-MS: 426 (100, [M ‡ 1] ), 408(15), 292 (10), 278
(30), 264 (90), 246 (75).
(‡)-(9S,13R)- and (‡)-(9S,13S)-13-Hydroxyisocyclocelabenzine (ˆ(9S,13R)- and (9S,13S)-
3,4,5,6,8,9,10,11,12,13-Decahydro-13-hydroxy-9-phenyl-2,13-methano-2H-2,6,10-benzotriazacyclopentadecine-
1,7-dione, resp.; 3a and 3b, resp.). A soln. of 12 (0.330 g, 0.776 mmol) and LiOH ¥ H2O (35.8mg, 0.853 mmol) in
THF/MeOH/H2O 3 :1 :1 (10 ml) was stirred at r.t. for 4 h, and the solvent was evaporated. The residue was
dissolved in EtOH (10 ml) and the soln. evaporated; this process was repeated twice. After further drying under
h.v., the residue was dissolved in dry DMF (50 ml) and added to a soln. of (EtO)2POCN (0.190 g, 1.16 mmol)
and Et3N (2 ml) in DMF (100 ml) at r.t. within 5 h. The mixture was stirred at r.t. for another 24 h and
evaporated. The residue was dissolved in sat. aq. NaHCO3 soln. and extracted with CH2Cl2. The combined org.
phase was evaporated and the residue purified by CC (CH2Cl2/MeOH/25% aq. NH4OH soln. 90 :10 :1): 3a/3b
(185 mg, 60%), 1:1 by NMR. IR (CHCl3): 3306s, 3064w, 2926m, 2853m, 1728w, 1638s, 1603w, 1550w, 1492w,
‡
1449w, 1430w, 1309m, 1236w, 1160w, 1113m, 1038w, 8 77w, 765m, 702m. ESI-MS: 416 ([M ‡ Na] ).
The two epimers were separated by repeated FC (CH2Cl2/MeOH/25% aq. NH4OH soln. 94 :6 :0.6):
optically pure, natural 13-hydroxyisocyclocelabenzine (3a; 80 mg) and 3b (85 mg).
Data of 3a: Colorless solid. M.p. 136 1388. [a]D ˆ ‡108( c ˆ 0.93, CHCl3). 1H-NMR (CDCl3): 8.03 (d, J ˆ
7.7, 1 H ): 7.88 ( t, 1 H); 7.58( d, J ˆ 7.1, 1 H); 7.50 (t, J ˆ 7.5, 1 H); 7.34 (t, J ˆ 7.6, 1 H); 7.12 7.03 (m, 3 H); 6.73
6.66 (m, 2 H); 4.05 3.91 (m, 3 H); 3.90 3.78( m, 2 H); 3.60 (d, J ˆ 12.3, 1 H); 2.98 2.82 ( m, 1 H); 2.71 (t, J ˆ
11.2, 1 H); 2.48 2.35 ( m, 1 H); 2.34 2.23 (m, 2 H); 2.17 (t, J ˆ 12.4, 1 H); 1.85 1.55 (m, 3 H). 13C-NMR
(CDCl3): 172.4, 164.9, 145.9, 142.9 (4q); 132.5, 128.4, 127.8, 126.9, 125.9, 123.6 (7d); 70.3 (q); 61.5 (d); 53.7, 45.5,
43.6, 42.9, 40.9, 38.2, 24.1 (7t).

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Helvetica Chimica Acta Vol. 86 (2003)
Crystals of 3a suitable for the X-ray crystal-structure analysis were grown from CHCl3.
Data of 3b: Colorless solid. M.p. 121 1258. [a]D ˆ ‡48.7 (c ˆ 1.35, CHCl3). 1H-NMR (CDCl3): 8.00
(t, 1 H); 7.94 (d, J ˆ 7.4, 1 H); 7.38 7.09 ( m, 2 H); 7.28 7.20 ( m, 1 H); 7.17 7.07 (m, 3 H); 7.05 7.00 (m, 2 H);
3.96 (t, J ˆ 7.4, 1 H); 3.86 3.74 (m, 1 H); 3.71 3.64 (m, 2 H); 3.42 3.10 (m, 3 H); 3.08 2.94 ( m, 3 H); 2.53
2.38( m, 1 H); 2.36 (d, J ˆ 7.3, 2 H); 2.13 1.87 (m, 3 H); 1.85 1.72 (m, 1 H). 13C-NMR (CDCl3): 172.4, 164.7,
143.2, 142.2 (4q); 132.1, 128.7 (2d); 128.4 (q); 128.0, 127.9, 127.4, 126.1, 123.1 (5d); 70.1 (q); 61.9 (d); 56.4, 47.1,
45.3, 43.3, 38.2, 35.8, 28.0 (7t).
X-Ray Crystal-Structure Determination of 3a (see Table and Figs. 2 and 3)2). All measurements were made
on a Nonius-KappaCCD diffractometer [18] with graphite-monochromated MoKa radiation (l ˆ 0.71073 ä)
Table 1. Crystallographic Data of Compound 3a
Crystallized from
CHCl3
Empirical formula
Formula weight [g molÀ1
Crystal color, habit
C23H27N3O3 ¥ CHCl3
512.86
colorless, prism
]
Crystal dimensions [mm]
Temperature [K]
0.17 Â 0.17 Â 0.25
160 (1)
Crystal system
monoclinic
Space group
C2 (#5)
Z
8(2 formula units per asymmetric unit)
50789
Reflections for cell determination
2q Range for cell determination [8]
4 50
Unit cell parameters a [ä]
42.5469 (6)
b [ä]
9.0286 (2)
c [ä]
13.2181 (2)
a [8]
90
b [8]
97.6897 (8)
g [8]
V [ä3]
90
5031.9 (2)
F(000)
2144
1.354
0.394
w
Dx [g cmÀ3
]
m(MoKa) [mmÀ1
Scan type
]
2q(max) [8]
50
Transmission factors (min; max)
Total reflections measured
Symmetry-independent reflections
Rint
0.795; 0.971
43491
8846
0.072
Reflections with I > 2s(I)
Reflections used in refinement
Parameters refined; restraints
Final
7669
8843
576; 1
R(F) (I > 2s (I) reflections)
0.0415
wR(F2) (all data)
Weights:
Goodness-of-fit
0.1016
w ˆ [s2(F2o ) ‡ (0.0602P)2]À1 where P ˆ (Fo2 ‡ 2F2c )/3
1.052
Final Dmax/s
0.001
D1 (max; min) [e äÀ3
s (d(CÀC)) [ä]
]
0.28; À 0.29
0.003 0.005
2
)
Crystallographic data (excluding structure factors) for the structure reported in this paper have been
deposited with the Cambridge Crystallographic Data Centre as deposition No. CCDC-203556 Copies of
the data can be obtained, free of charge, on application to the CCDC, 12 Union Road, Cambridge
CB21EZ, U.K. (fax: ‡44-(0)1223-336033; e-mail: deposit@ccdc.cam.ac.uk).

Helvetica Chimica Acta Vol. 86 (2003)
589
Fig. 3. Crystal packing of 3a
and an Oxford-Cryosystems-Cryostream-700 cooler. The intensities were corrected for Lorentz and polarization
effects, and an absorption correction based on the multi-scan method [19] was applied. Data collection and
refinement parameters are given in the Table. A view of the molecule is shown in Fig. 2.
The structure was solved by direct methods using SHELXS97 [20], which revealed the positions of all non-
H atoms. The non-H atoms were refined anisotropically. The hydroxy and amine H-atoms were placed in the
positions indicated by a difference electron density map, and their positions were allowed to refine together with
individual isotropic displacement parameters. All remaining H-atoms were placed in geometrically calculated

590
Helvetica Chimica Acta Vol. 86 (2003)
positions and refined using a riding model where each H-atom was assigned a fixed isotropic displacement
parameter with a value equal to 1.2 Ueq of its parent C-atom. Refinement of the structure was carried out on F2
by means of full-matrix least-squares procedures, which minimized the function Sw(F2o Fc2 )2. A correction for
secondary extinction was not applied.
Neutral-atom scattering factors for non-H-atoms were taken from [21a] and the scattering factors for H-
atoms from [22]. Anomalous dispersion effects were included in Fc [23]; the values for f ' and f ''were those of
Creagh and McAuley [21b]. The values of the mass attenuation coefficients are those of Creagh and Hubbel
[21c]. All calculations were performed by using the SHELXL97 [24].
There are two symmetry-independent polycyclic substrate molecules and two CHCl3 molecules in the
asymmetric unit. The need to model one disordered CHCl3 molecule was overcome by using SQUEEZE [25].
The space group is polar, and the presence of CHCl3 in the structure allowed the absolute structure and absolute
configuration of the polycyclic molecule to be determined independently by the diffraction experiment
(absolute structure parameter: 0.05(4)). Both symmetry-independent molecules A and B are of the same
enantiomer and have the (9S,13R) configuration, thus being in agreement with the (S) configuration at C(9)
known from the synthesis of the compound. The conformations of the two symmetry-independent molecules are
quite similar with only small differences in the puckering of the 13-membered rings, shown by differences of up
to 128 in the corresponding torsion angles. The most significant difference between the two molecules is the
orientation of the OH group, which in molecule B is pivoted about the OÀC axis by a ca. 238 compared with its
orientation in molecule A. The presence of two symmetry-independent molecules is probably due to packing
considerations and differences in the H-bonding pattern of each molecule. A complex system of intermolecular
H-bonds links the molecules into infinite two-dimensional networks (Fig. 3).
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[23] J. A. Ibers, W. C. Hamilton, Acta Crystallogr. 1964, 17, 78 1.
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Received July 31, 2002