(S)-(-)-α-Methylbenzylamine as an efficient chiral auxiliary in enantiodivergent synthesis of both enantiomers of N-acetylcalycotomine

Article abstract of DOI:10.1016/S0957-4166(99)00370-5

(S)-(-)-α-Methylbenzylamine 2 was used as a chiral auxiliary in the enantiodivergent synthesis of simple isoquinoline alkaloids. The prochiral imine moiety in compound 4 was reduced with different reagents, giving diastereomeric amines 5a or 5b, which sub

Full text of DOI:10.1016/S0957-4166(99)00370-5

Pergamon
Tetrahedron: Asymmetry 10 (1999) 3371–3380
(
S)-(−)-α-Methylbenzylamine as an efficient chiral auxiliary in
enantiodivergent synthesis of both enantiomers of
N-acetylcalycotomine
Marek Ziółkowski, Zbigniew Czarnocki, Andrzej Leniewski and Jan K. Maurin b
a
a,∗
a
a
Department of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warsaw, Poland
b
Drug Institute, Chełmska 30/34, 00-750 Warsaw, Poland
Received 14 July 1999; accepted 19 August 1999
Abstract
(
S)-(−)-α-Methylbenzylamine 2 was used as a chiral auxiliary in the enantiodivergent synthesis of simple
isoquinoline alkaloids. The prochiral imine moiety in compound 4 was reduced with different reagents, giving
diastereomeric amines 5a or 5b, which subsequently were transformed to either (S)-(−)-N-acetylcalycotomine 6 or
(
R)-(+)-N-acetylcalycotomine ent-6 in good enantiomeric excess. 19F NMR of its Mosher’s acid ester was used to
establish the purities of final compounds. © 1999 Elsevier Science Ltd. All rights reserved.
1. Introduction
(
S)-(−)-α-Methylbenzylamine 2 and its enantiomer ent-2, appear to be ideal compounds for use as
1–3
chiral auxiliaries or chiral building blocks. Both enantiomers are inexpensively available in very high
enantiomeric purity, which makes them attractive as stereodifferentiating agents even for large scale
operations. Recently, (S)-(−)-α-methylbenzylamine 2 has been used as a chiral building block in the
1
asymmetric synthesis of tetrahydro-β-carbolines. This method afforded diastereomers of 1-substituted
tetrahydro-β-carbolines in good diastereomeric enrichments. Enantiomerically pure ethyl 2-amino-1-
2
cyclohexanecarboxylate was synthesized via reductive amination of 2-oxo-cyclohexanecarboxylate
with amine 2. The same compound was also used for a five-step synthesis of novel enantiomerically
3
pure cis- and trans-N-(propionyl)hexahydrobenzoxazolidin-2-ones. Good diastereoselectivity, due to
chiral induction originating from (S)-(−)-α-methylbenzylamine 2, allowed the preparation of three
4
pyrrolizidine and indolizidine alkaloids: (+)-tashiromine, (+)-laburnine and (−)-isoretronecanol. On
the other hand, (R)-(+)-α-methylbenzylamine ent-2 served as a chiral building block in the synthesis
∗
Corresponding author. E-mail: czarnoz@chem.uw.edu.pl
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00370-5

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M. Ziółkowski et al. / Tetrahedron: Asymmetry 10 (1999) 3371–3380
5
of (−)- and (+)-chinoin with an excellent enantioinduction (ee>98%). Several examples of enantio-
selective elaboration of the quaternary carbon center in Michael-type additions with the use of (S)-
(
−)-α-methylbenzylamine 2 as chiral inducing agent have recently been presented.6–8 Also, (+)-
vincamine, an indole alkaloid showing a strong vasodilation activity, was prepared from (S)-(+)-2-
ethyl-2-(2-methoxycarbonylethyl)cyclopentanone which had previously been obtained using (R)-(+)-α-
9
methylbenzylamine ent-2 as a chiral building block. The above examples prompted us to explore the
possibility of the application of (S)-(−)-α-methylbenzylamine 2 for the enantioselective synthesis of
isoquinoline alkaloids.
2. Results and discussion
Our synthetic route (Scheme 1) started with the reaction of the known amide-ester 110 with
(
S)-(−)-α-methylbenzylamine 2 in which amide 3 was obtained in quantitative yield. Subsequent
11
Bischler–Napieralski cyclization of amide 3 using PCl under mild conditions gave imine 4 which,
5
as its hydrochloride or as a free base, was subjected to reductions using different reagents (Scheme 2).
Scheme 1. Preparation of imine 4
The ratios of diastereomeric amines thus formed were determined by HPLC analysis. Table 1
summarizes the stereochemical outcome of these reductions.
Relatively good diastereomeric enrichment (5a:5b=88:12) was obtained when imine 4 was treated with
sodium borohydride at −78°C. Surprisingly, the ratio was reversed (5a:5b=9:91) when 4 was subjected
to Wilkinson’s hydrogenation conditions. It is noteworthy that the ratios obtained were relatively high,
considering a 1,4-chirality transfer in 4. Different reductions of the hydrochloride of 4 gave much poorer
results. Fortunately, imine 4 appears to be stable enough to tolerate various reducing conditions. On the
other hand, however, amines 5a and 5b decompose slowly and even though they could be effectively
separated by column chromatography and fully characterized, they cannot be stored longer than a few
days. In order to assign the relative stereochemistry on C(1) in 5 we wished to perform an X-ray
structural analysis but despite considerable efforts we were unable to prepare derivatives giving suitable
crystals for that purpose. In the search for such derivatives N-methylation of amines 5a and 5b was
planned but application of the classical Eschweiler–Clarke procedure afforded oxazoloisoquinolinylidene
derivatives 7a and 7b, respectively (Scheme 3). In both proton and carbon NMR spectra of 7a and
7b two components in the ratio of approximately 5:1 were detected, although they could not be
chromatographically separated. On the basis of the relatively high shielding effect on the imine methyl

M. Ziółkowski et al. / Tetrahedron: Asymmetry 10 (1999) 3371–3380
3373
Scheme 2. Preparation of compounds 6 and ent-6
group, deshielding of H-8 aromatic protons and computer assisted energy estimations12 we propose a Z
geometry of the imine double bond. When sodium cyanoborohydride was applied as a reducing agent for
5a and 5b, amines 8a and 8b were obtained.
Table 1
Reduction of imine 4
Diastereomeric amines 5a and 5b could be effectively purified by careful column chromatography,
and an X-ray structural measurement on the hydrochloride prepared from 5a allowed us to assign the
absolute stereochemistry (Fig. 1) of this derivative as (S)-C(1). This result was in accordance with further
correlation of 5a and 5b with N-acetylcalycotomine 6 and ent-6. Thus, both amines 5a and 5b were
subjected to hydrolysis using 18% HCl immediately followed by lithium aluminum hydride reduction

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M. Ziółkowski et al. / Tetrahedron: Asymmetry 10 (1999) 3371–3380
Scheme 3.
Figure 1. Perspective view of the X-ray crystal structure of 5a·HCl
and N-acetylation with acetic anhydride/sodium hydroxide system. Finally, both enantiomers of N-
acetylcalycotomine 6 and ent-6 were obtained, respectively. The enantiomeric purities of 6a and ent-6
19
determined by F NMR of their Mosher’s acid esters gave the value of >98% ee for both compounds.
3. Experimental
Infrared (IR) spectra were obtained using a Nicolet Magna IR 500 spectrophotometer. NMR spectra
1
were recorded on a Varian Gemini spectrometer operating at 200 MHz for H NMR and at 50.3 MHz for
1
3
1
C NMR, and on a Varian Unity Plus spectrometer operating at 500 MHz for H NMR and at 125 MHz
13
19
for C NMR. Tetramethylsilane (TMS) or solvents were used as internal standards. The F NMR spectra
were recorded on a Varian Unity plus-500 spectrometer with C F as external reference. Chemical shifts
6
6
are reported in ppm. Mass spectra were collected on an AMD 604 apparatus; high resolution mass spectra
were acquired using LSIMS (positive ion mode). Optical rotations were measured on a Perkin–Elmer
2
47 MC polarimeter. TLC analyses were performed on Merck 60 silica gel glass plates and visualized
using iodine vapor. Column chromatography was carried out at atmospheric pressure using silica gel
0 (230–400 mesh, Merck) and Al O (III). HPLC analyses were performed on a Knauer (model 64)
6
2
3
apparatus with Eurochrom 2000 software using 4×250 mm silica (5 µm) column model Li-Chrosorb Si-
0 (Knauer) with methyl chloride:methanol 98:2 (v/v) as eluent. For better separation the columns were
cooled to 10°C. Melting points were determined on a Boetius hot-plate microscope and are uncorrected.
6

M. Ziółkowski et al. / Tetrahedron: Asymmetry 10 (1999) 3371–3380
3375
3.1. Preparation of amide 3
A mixture of 10 g (82.6 mmol) of (S)-(−)-1-phenylethylamine 2, 25.5 g (90.9 mmol) of compound
and a catalytic amount of 4-dimethylaminopyridine was refluxed in 200 mL of dioxane for 3 h under
17
argon. The product precipitated upon cooling. Filtration afforded amide 3 as a white solid in 88.5% yield.
2
3
−1
Mp 168–171°C, [α]D −66.5 (c 1.05, CHCl ). IR (KBr, cm ): 3290, 1650, 1520, 1275, 1245, 1155,
3
1
0
140, 1030, 770, 700. H NMR (500 MHz, CDCl ): 7.84 (d, 1H, J=8.3 Hz, H-2 ), 7.64 (apparent t, 1H,
3
1
0
0
J=5.4 Hz, H-2), 7.26–7.35 (m, 5H, H-6 –H-10 ), 6.79 (d, 1H, J=8.0 Hz, H-8), 6.72 (dd, 1H, J =8.0 Hz,
J =2.0 Hz, H-9), 6.69 (d, 1H, J=2.0 Hz, H-5), 5.05 (dq, 1H, J =7.3 Hz, J =8.3 Hz, H-3 ), 3.85 and 3.84
1
0
2
1
2
(
3
two s, 3H each, 2×OCH ), 3.53 (apparent q, 2H, J=6.8 Hz, 2H-3), 2.79 (t, 2H, J=6.8 Hz, H-4), 1.55 (d,
3
0
13
H, J=7.3 Hz, 3H-4 ). C NMR (125 MHz, CDCl ): 159.72, 158.82, 148.99, 147.73, 142.04, 130.56,
3
128.70, 127.60, 126.07, 120.54, 111.68, 111.32, 55.84, 55.78, 49.39, 40.98, 34.94, 21.68. EI 70eV 8 kV
(%): 356 (19), 164 (100), 151 (27), 105 (12), 91 (2).
3.2. Preparation of imine 4
To a stirred and cooled (0°C) solution of 10 g (28.1 mmol) of amide 3 in 120 mL of dry methylene
chloride 14 g (67.1 mmol) of PCl was added in five portions. After 3 h stirring the resulting red mixture
5
was poured slowly into a suspension of 28.4 g (267.9 mmol) sodium bicarbonate. The organic layer
was then separated, washed twice with brine and dried (MgSO ). After evaporation, the red residue was
4
subjected to column chromatography on silica gel. Elution with CHCl gave imine 4 in 90% yield as an
3
amorphous yellow solid.
23
−1
[
α]D −39.9 (c 0.99, MeOH). IR (KBr, cm ): 3300, 2940, 2830, 1650, 1600, 1510, 1270, 1210, 1140,
1
0
030, 700. H NMR (500 MHz, CDCl ): 8.00 (s, 1H, H-8), 7.85 (d, 1H, J=8.3 Hz, H-2 ), 7.22–7.38 (m,
3
1
5
3
0
0
0
H, H-6 –H-10 ), 6.65 (s, 1H, H-5), 5.16–5.20 (m, 1H, H-3 ), 3.89 and 3.89 (two s, 3H each, 2×OCH ),
3
0
13
.71 (t, 2H, J=6.8 Hz, 2H-3), 2.61 (t, 2H, J=6.8 Hz, H-4), 1.56 (d, 3H, J=6.8 Hz, 3H-4 ). C NMR (125
MHz, CDCl ): 163.70, 158.31, 151.22, 147.19, 143.25, 131.91, 128.68, 127.30, 126.16, 119.39, 111.83,
3
109.74, 56.08, 55.91, 48.71, 47.16, 25.48, 22.14. EI 70eV 8 kV (%): 338 (29), 323 (9), 219 (10), 191
(
100), 176 (10), 164 (18), 120 (36), 105 (8). For imine 4 hydrochloride: mp 147–150°C (methanol:ether),
23
−1
[
1
α]D −37.2 (c 0.84, CHCl ). IR (KBr, cm ): 3400, 3150, 2650, 1670, 1550, 1340, 1280, 1210, 1150,
3
1
0
040. H NMR (500 MHz, CDCl ): 10.06 (br s, 1H, H-2), 7.55 and 7.56 (two s, 1H each, H-2 and
3
0
0
0
H-8), 7.23–7.35 (m, 5H, H-6 –H-10 ), 6.77 (s, 1H, H-5), 5.20–5.23 (m, 1H, H-3 ), 3.99 (br s, 5H, OCH
and 2H-3), 3.70 (s, 3H, OCH ), 3.10 (br s, 2H, 2H-4), 1.71 (d, 3H, J=6.8 Hz, 3H-4 ). C NMR (125
3
0
13
3
MHz, CDCl ): 164.17, 158.31, 157.21, 148.55, 142.68, 134.79, 128.64, 127.40, 126.65, 115.68, 113.89,
3
110.80, 56.65, 56.05, 51.00, 41.22, 25.09, 21.97.
3
3
1
.3. Preparation of diastereomeric amines 5a and 5b
.3.1. Reduction a
A solution of 60 mg (0.161 mmol) of the hydrochloride of imine 4 in 5 mL of glacial acetic acid and
5 mL of methylene chloride was treated with 25 mg (0.398 mmol) of solid sodium cyanoborohydride
at 0°C. After 1 h of stirring, addition of sodium bicarbonate solution and brine, extraction with
chloroform (4×10 mL) and evaporation of solvent, 50 mg of an orange residue was obtained. The ratio
of diastereomeric amines (5a:5b=49:51) was estimated with HPLC analysis.

3376
M. Ziółkowski et al. / Tetrahedron: Asymmetry 10 (1999) 3371–3380
3.3.2. Reduction b
A solution of 120 mg (0.355 mmol) of imine 4 in 10 mL of glacial acetic acid and 30 mL of dry
THF was hydrogenated at atmospheric pressure over 10 mg of platinum(II) oxide at 0°C. After 16 h the
hydrogen was replaced by argon, the catalyst was filtered off and the solution was carefully poured onto
a suspension of 7 g of sodium bicarbonate in 100 mL of water. The water layer was then extracted with
4
×20 mL of chloroform. The organic phase, after drying (MgSO ) and evaporation, afforded the mixture
4
of diastereomeric amines in the ratio 5a:5b=44:56.
3
4
3
.3.3. Reduction c
The hydrogenation was performed exactly as described above except that the hydrochloride of imine
was used. In this case a ratio of 5a:5b=42:58 was obtained.
.3.4. Reduction d
To a solution of 52 mg (0.139 mmol) of hydrochloride of imine 4 in 15 mL of ethanol 50 mg of
sodium borohydride was added in two portions at 0°C. After 1 h of stirring at the same temperature
ethanol was evaporated and 30 mL of brine was added. The water layer was then extracted with 4×15
mL of chloroform and the organic solution was dried (MgSO ). Evaporation of solvent afforded the
4
mixture of diastereomeric amines in the ratio 5a:5b=66:34.
3.3.5. Reduction e
A sample of 2.4 g (0.063 mol) of sodium borohydride was poured into 25 mL of ethanol. After 1 h of
stirring 5 mL of the resulting solution was slowly introduced into the mixture of 120 mg (0.355 mmol)
of imine 4 in 30 mL of ethanol at −78°C. After 4 h of stirring at the same temperature a cooling-bath
was removed and stirring was continued for 12 h. Subsequent evaporation of the solvent, addition of
brine (30 mL) and extraction with chloroform afforded the mixture of diastereomeric amines in the ratio
5a:5b=88:12.
3.3.6. Reduction f
A solution of sodium borohydride in absolute ethanol (5 mL) prepared as above was added dropwise
at −20°C to a solution of 52 mg (0.139 mmol) of the hydrochloride of imine 4 in 50 mL of absolute
ethanol, to which 1.6 mL of acetyl chloride had been added previously. The mixture was stirred for 1 h at
−20°C and then allowed to warm to ambient temperature. The standard work-up of the reaction mixture
gave rise to the formation of diastereomeric amines in the ratio 5a:5b=40:60.
3.3.7. Reduction g
A solution of 60 mg (0.177 mmol) of imine 4 in 5 mL of degassed methylene chloride was hydro-
genated over 15 mg of chlorotris(triphenylphosphine)rhodium(I) (Wilkinson’s catalyst) under 100 atm of
hydrogen during 24 h. The catalyst was removed by filtration through a pad of silica gel. HPLC analysis
of this mixture revealed the presence of two components 5a:5b in the ratio 9:91.
Both diastereomers could be separated by careful column chromatography on alumina (activity III)
2
3
using 2% (v/v) methanol in chloroform as eluent. Analytical data of amine 5a: mp 174–176°C, [α]
D
−1
1
−
61.5 (c 0.94, CHCl ). IR (KBr, cm ): 3310, 2940, 1640, 1520, 1230, 1120, 710. H NMR (500 MHz,
CDCl ): 7.48 (br d, 1H, J=8.3 Hz, H-2 ), 7.14–7.28 (m, 5H, H-6 –H-10 ), 6.97 (s, 1H, H-8), 6.56 (s,
3
0
0
0
3
0
1
H, H-5), 5.04–5.12 (m, 1H, H-3 ), 4.49 (s, 1H, H-1), 3.76 and 3.85 (two s, 3H each, 2×OCH ), 3.05
3
(
1
apparent dd, 2H, J =6.8 Hz, J =5.8 Hz, 2H-3), 2.77 (dt, 1H, J =16.1 Hz, J =6.8 Hz, H-4 ), 2.66 (dt,
1 2 1 2 eq
0
H, J =16.1 Hz, J =5.8 Hz, H-4 ), 1.80 (br s, 1H, H-2), 1.48 (d, 3H, J=6.8 Hz, 3H-4 ). C NMR (125
1 2 ax
13

M. Ziółkowski et al. / Tetrahedron: Asymmetry 10 (1999) 3371–3380
3377
MHz, CDCl ): 172.09, 147.92, 147.04, 143.34, 128.48, 127.06, 126.53, 125.85, 124.26, 111.37, 110.53,
3
59.76, 55.81, 55.79, 48.44, 41.42, 28.80, 22.17. EI 70eV 8 kV (%): 340 (0.2), 323 (9), 192 (100), 176
(
9), 148 (5), 131 (2), 105 (2).
Analytical data of amine 5b: mp 148–150°C, [α]D23 −30.8 (c 0.97, CHCl ). IR (KBr, cm ): 3280,
−1
3
1
2
910, 1650, 1525, 1250, 1210, 1110, 770, 710. H NMR (500 MHz, CDCl ): 7.61 (br d, 1H, J=8.3 Hz,
3
0
0
0
0
H-2 ), 7.24–7.36 (m, 5H, H-6 –H-10 ), 7.14 (s, 1H, H-8), 6.57 (s, 1H, H-5), 5.06–5.13 (m, 1H, H-3 ),
4
.47 (s, 1H, H-1), 3.86 and 3.87 (two s, 3H each, 2×OCH ), 3.07 (apparent dd, 2H, J =5.4 Hz, J =5.9 Hz,
3
1
2
2H-3), 2.79 (dt, 1H, J =16.1 Hz, J =5.9 Hz, H-4 ), 2.66 (dt, 1H, J =16.1 Hz, J =5.4 Hz, H-4 ), 1.87
1
2
eq
13
1
2
ax
0
(br s, 1H, H-2), 1.42 (d, 3H, J=6.8 Hz, 3H-4 ). C NMR (125 MHz, CDCl ): 171.95, 147.94, 147.13,
3
1
2
43.40, 128.65, 127.26, 126.62, 126.13, 124.43, 111.33, 110.66, 59.33, 55.94, 55.82, 48.49, 41.33, 28.87,
1.92. EI 70eV 8 kV (%): 340 (0.1), 192 (100), 176 (5), 148 (2), 105 (2).
3.4. Preparation of N-methylamines 8a and 8b
A sample of 60 mg (0.176 mmol) of amines 5a or 5b in 6 mL of dry EtOH, containing 0.5 mL of
glacial acetic acid and 1 mL of aqueous formaldehyde solution, was stirred at 0°C for 12 h. Sodium
cyanoborohydride (80 mg) was then added in three portions during 30 min. After 15 min stirring at the
same temperature the cooling-bath was removed and the mixture was stirred at room temperature for
20 min. Evaporation of the solvents, addition of 20% sodium bicarbonate solution and extraction with
CHCl afforded a colourless amorphous solid which was purified by column chromatography to give
3
23
a white solid in 90% yield. Analytical data of N-methylamine 5a: mp >260°C, [α]
−27.8 (c 1.03,
D
−1
1
CHCl ). IR (KBr, cm ): 3420, 3280, 2940, 2780, 1650, 1525, 1255, 1220, 1150, 1020, 710. H NMR
3
0 0 0 0
500 MHz, CDCl ): 7.15–7.24 (m, 4H, H-6 –H-10 except H-8 ), 7.03 and 7.01 (two br s, 2H, H-2 and
3
(
0
0
H-8 ), 6.90 (s, 1H, H-8), 6.57 (s, 1H, H-5), 5.02–5.09 (m, 1H, H-3 ), 3.85 (s, 3H, OCH ), 3.83 (s, 1H,
3
H-1), 3.68 (s, 3H, OCH ), 3.00 (apparent t, 2H, J=11.0 Hz, 2H-3), 2.50–2.70 (m, 2H, 2H-4), 2.46 (s, 3H,
3
0
13
3
1
2
H-2), 1.47 (d, 3H, J=7.0 Hz, 3H-4 ). C NMR (125 MHz, CDCl ): 172.29, 147.86, 147.26, 143.26,
3
28.34, 126.91, 125.71, 125.29, 124.03, 110.84, 109.14, 70.27, 55.80, 55.75, 50.96, 48.11, 44.61, 28.71,
+
+
2.11. LSIMS (+) 8 kV (%): 377 (M+Na) (2), 355 (M+H) (19), 206 (100), 192 (12), 105 (12), 95 (14).
Analytical data of N-methylamine 8b: Mp >260°C, [α]D2 −11.2 (c 1.04, CHCl ). IR (KBr, cm ):
3
−1
3
1
3
7
3
310, 2930, 2780, 1650, 1520, 1260, 1225, 1140, 1025, 825, 700, 560. H NMR (500 MHz, CDCl ):
3
0
0
0
.24–7.36 (m, 6H, H-6 –H-10 and H-2 ), 7.11 (s, 1H, H-8), 6.57 (s, 1H, H-5), 5.02–5.11 (m, 1H, H-
0
), 3.86 and 3.86 (two s, 3H each, 2×OCH ), 3.79 (s, 1H, H-1), 2.98 (apparent dd, 2H, J =5.0 Hz,
3
1
J =7.0 Hz, 2H-3), 2.63 (apparent d, 1H, J=16.0 Hz, H-4 ), 2.52 (apparent dd, 1H, J =16.0 Hz, J =7.0
2
eq
1
2
0
13
Hz, H-4 ), 2.33 (s, 3H, 3H-2), 1.35 (d, 3H, J=7.0 Hz, 3H-4 ). C NMR (125 MHz, CDCl ): 172.25,
ax
3
1
5
1
47.86, 147.36, 143.36, 128.59, 127.23, 126.18, 125.50, 124.29, 110.78, 109.26, 69.85, 55.93, 55.77,
0.88, 48.25, 44.69, 28.77, 21.51. LSIMS (+) 8 kV (%): 377 (M+Na) (7), 355 (M+H) (39), 206 (100),
92 (6), 105 (7).
+
+
3.5. Preparation of oxazoloisoquinolinylidene derivatives 7a and 7b
A solution of 100 mg (0.294 mmol) of amine 5a or 5b in 6 mL of formic acid and 1.5 mL of
formaldehyde was refluxed for 1 h. After this period, 1 mL of formaldehyde solution was added and the
mixture was refluxed for an additional 2 h. After evaporation of the solvents, 20% of a sodium bicarbonate
solution was added and the water layer was extracted with 3×30 mL of chloroform. The organic layer was
then dried (MgSO ) and concentrated in vacuo affording an orange oil which was chromatographed on
4
silica gel. Elution with 0.5% (v/v) methanol in chloroform gave the oxazoloisoquinolinylidene derivative

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M. Ziółkowski et al. / Tetrahedron: Asymmetry 10 (1999) 3371–3380
2
3
as a yellowish oil in 80% yield. Analytical data for compound 7a: [α]
−155.8 (c 0.98, CHCl ). IR
D
3
−1
1
(
KBr, cm ): 3350, 2930, 2850, 1700, 1520, 1230, 1225, 1125, 1020, 750, 700. H NMR (500 MHz,
CDCl ): 7.22–7.36 (m, 5H, H-6 –H-10 ), 7.14 (s, 1H, H-8), 6.57 (s, 1H, H-5), 5.39 (q, 1H, J=6.8 Hz,
0
0
3
0
H-3 ), 4.53 (d, 1H, J=7.8 Hz, H-2 ), 3.93 and 3.85 (two s, 3H each, 2×OCH ), 3.91 (s, 1H, H-1), 2.79
eq
3
(
d, 1H, J=7.8 Hz, H-2 ), 2.75–2.84 (m, 2H, 2H-3), 2.67 (dt, 1H, J =14.7 Hz, J =4.4 Hz, H-4 ), 2.57
ax 1 2 eq
0
13
(
apparent dt, 1H, J =14.7 Hz, J =3.4 Hz, H-4 ), 1.60 (d, 3H, J=6.8 Hz, 3H-4 ). C NMR (125 MHz,
1
2
ax
CDCl ): 171.30, 148.15, 147.59, 139.56, 128.66, 127.78, 127.35, 126.98, 125.99, 110.79, 110.54, 64.96,
3
+
6
2.30, 55.96, 55.88, 49.31, 46.98, 26.92, 22.10. LSIMS (+) 8 kV (%): 353 (M+H) (37), 247 (13), 205
(
24), 192 (14), 123 (43), 109 (64), 95 (100).
23
−1
Analytical data for compound 7b: [α]D −33.7 (c 1.01, CHCl ). IR (KBr, cm ): 3360, 2940, 2840,
3
1
1
5
710, 1510, 1450, 1425, 1375, 1230, 1125, 1025, 770, 705. H NMR (500 MHz, CDCl ): 7.23–7.39 (m,
3
0
0
0
H, H-6 –H-10 ), 7.15 (s, 1H, H-8), 6.59 (s, 1H, H-5), 5.39 (q, 1H, J=7.0 Hz, H-3 ), 4.19 (d, 1H, J=7.0
Hz, H-2 ), 4.13 (d, 1H, J=7.8 Hz, H-2 ), 3.92 and 3.85 (two s, 3H each, 2×OCH ), 3.90 (s, 1H, H-1),
eq
ax
3
0
13
2
.86–2.98 (m, 2H, 2H-3), 2.70–2.84 (m, 2H, 2H-4), 1.54 (d, 3H, J=7.0 Hz, 3H-4 ). C NMR (125 MHz,
CDCl ): 171.00, 148.16, 147.65, 139.43, 128.79, 128.48, 127.85, 126.86, 125.77, 110.88, 110.34, 64.51,
3
+
6
1.92, 55.99, 55.88, 49.39, 46.59, 26.00, 22.69. LSIMS (+) 8 kV (%): 353 (M+H) (50), 339 (6), 261
(16), 247 (28), 205 (50), 192 (28), 105 (80), 95 (100).
3.6. Preparation of N-acetylcalycotomine 6
A mixture of 340 mg (1 mmol) of amine 5a and 10 mL of 18% HCl was refluxed for 8 h. After
evaporation of the HCl solution, three portions of toluene (20 mL) were added and the mixture evapo-
rated. The residue was additionally dried overnight in a vacuum dessicator over P O and subsequently
2
5
refluxed with 40 mL of absolute ethanol to which 1 mL of thionyl chloride had been added. Evaporation
with toluene and drying were repeated and the residue was refluxed in 20 mL of dry THF with 350 mg
of lithium aluminum hydride. After 2 h the reaction was quenched by the addition of 20% NaOH and
the precipitate was filtered off. To the precipitate 50 mL of chloroform was added four times and the
suspensions were heated under reflux for 15 min. The combined organic extracts were dried (MgSO4)
and evaporated leaving 240 mg of a yellow oil. This oil was dissolved in 30 mL of CH Cl and 50 mL
2
2
of 30% NaOH was added. After cooling to 0°C, 1.5 mL of acetic anhydride was added dropwise and the
solution was stirred for 0.5 h. The water layer was then extracted with 3×30 mL portions of chloroform.
The organic phase after drying (MgSO ) and evaporation afforded an orange residue which was subjected
4
to column chromatography on silica gel. Elution with 1.5% (v/v) methanol in chloroform gave 50 mg of
N-acetylcalycotomine 6 as white crystals.
23
−1
Mp 192–194°C, [α]D −141 (c 0.9, MeOH). IR (KBr, cm ): 3330, 2950, 1610, 1525, 1470, 1440,
1
360, 1260, 1230, 1120, 1060, 990, 790. Two conformers were observed in NMR spectra. Data for major
1
conformer: H NMR (500 MHz, CDCl ): 6.71 (s, 1H, H-8), 6.63 (s, 1H, H-5), 5.63 (dd, 1H, J =8.8 Hz,
3
1
0
0
J =3.9 Hz, H-1 ), 3.91–3.96 (m, 2H, H-1 and H-1), 3.86 and 3.86 (two s, 3H each, 2×OCH ), 3.75–3.81
2
3
(
m, 2H, 2H-3), 3.63–3.69 (m, 1H, H-4 ), 2.79–2.91 (m, 1H, H-4 ), 2.22 (s, 3H, NAc), 1.82 (br s, 1H,
eq ax
1
OH). Data for minor conformer: H NMR (500 MHz, CDCl ): 6.63 (s, 1H, H-8), 6.62 (s, 1H, H-5), 4.92
3
0
(
dd, 1H, J =9.3 Hz, J =3.9 Hz, H-1), 4.74 (dd, 1H, J =12.7 Hz, J =4.9 Hz, H-1 ), 3.87 and 3.86 (two s,
1
2
1
2
0
3
H each, 2×OCH ), 3.26 (br s, 1H, OH), 3.04 (td, 1H, J =12.7 Hz, J =3.9 Hz, H-1 ), 2.79–2.91 (m, 3H,
3
1
2
13
H-4 and 2H-3), 2.64 (br d, 1H, J=15.1 Hz, H-4 ), 2.28 (s, 3H, NAc). C NMR (125 MHz, CDCl ,
eq
ax
3
two stable conformers were present): 172.17, 170.89, 148.32, 148.16, 147.90, 147.60, 127.20, 126.31,
25.00, 124.28, 111.67, 111.17, 110.24, 109.82, 67.45, 65.10, 59.20, 56.06, 55.95, 55.26, 41.98, 34.86,
1

M. Ziółkowski et al. / Tetrahedron: Asymmetry 10 (1999) 3371–3380
3379
+
+
2
8.52, 27.85, 22.11, 21.99. LSIMS (+) 8 kV (%): 288 (M+Na) (11), 266 (M+H) (100), 248 (11), 234
(63), 222 (7), 206 (10), 192 (16), 176 (11), 95 (35).
3.7. Determination of the enantiomeric composition of N-acetylcalycotomine 6
A solution of 0.12 mL (1.4 mmol) of oxalyl chloride was added to a solution of 66 mg (0.28 mmol)
of (R)-(+)-MTPA and 0.022 mL (0.28 mmol) of DMF in 12 mL of hexane. After 1 h the mixture was
filtered and concentrated in vacuo and the residue was used without any further treatment. A solution
of 20 mg (0.08 mmol) of (−)-N-acetylcalycotomine 6, 1 mL of triethylamine and a catalytic amount of
4-dimethylaminopyridine in 3 mL of dichloromethane was treated with the above prepared Mosher’s
acid chloride in 3 mL of dichloromethane. The mixture was then stirred for 24 h at room temperature
followed by washing with an aqueous solution of citric acid, sodium bicarbonate and brine. The water
layer was extracted with two portions of chloroform and the combined extracts were dried (MgSO ) and
4
19
evaporated, and the residue was filtered through a pad of silica gel using CHCl as eluent. The F NMR
3
spectrum was recorded on a Varian Unity plus-500 spectrometer with C F as external reference. In the
6
6
19
F NMR spectrum, a pair of signals (due to the presence of stable conformers) were observed at −71.18
and −71.54 ppm (S enantiomer) with relative intensities 1.00:2.32; the R enantiomer was not observed.
3.8. X-Ray crystallography
A number of 1821 data from the θ range 2.75 through 73.32° were collected with the MACH-3 κ-axis
diffractometer, using graphite monochromatized CuKα radiation. Unit cell parameters were obtained
from the least-squares treatment performed for 15 reflections with 22.7≤2θ≤40.2°. The orthorhombic
space group was chosen based on lattice dimensions and symmetry of a diffraction pattern. The structure
13
was solved using direct methods from the SHELXS-86 program and refined by full matrix least-squares
2
14
treatment based on F using SHELXL-93 software. All the hydrogen atoms were included in the
calculated positions with isotropic displacement parameters taken as 1.2 times the isotropic equivalents
for carbons or nitrogens they are bonded to (1.5 factor was applied for methyl hydrogens). Final R and
2
2
2
wR were 0.0366 and 0.0960, respectively. The weights were w=1/[σ (Fo )+(0.0527P) +0.2171P] where
2
2
P=(Fo +2Fc )/3. GOF=1.035.
3.9. Crystal data for compound 5a
C H ClN O , M=376.87, space group P2 2 2 , a=7.847(2) Å, b=8.052(2) Å, c=32.109(6) Å,
2
0
25
2
3
1 1 1
3
−3
−1
V=2028.8(8) Å , Z=4, D =1.234 g cm , F(000)=800 µ, (CuKα)=1.836 cm .
c
Acknowledgements
We thank Professor Janusz Jurczak for allowing us the use of the high-pressure hydrogenation
apparatus.
References
1. Soe, T.; Fukui, N.; Hino, T.; Nakagawa, M. Heterocycles 1996, 42, 347–358.
2. Xu, D.; Prasad, K.; Repic, O.; Blacklock, T. J. Tetrahedron: Asymmetry 1997, 9, 1445–1451.

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4
. Parrodi, C. A.; Juaristi, E.; Quintero, L.; Clara-Sosa, A. Tetrahedron: Asymmetry 1997, 7, 1072–1082.
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5
6
. Szakonyi, Z.; Fülöp, F.; Bernáth, G.; Török, G.; Péter, A. Tetrahedron: Asymmetry 1998, 8, 993–999.
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9. Alves, J. C. F.; Simas, A. B. C.; Costa, P. R. R. Tetrahedron: Asymmetry 1999, 10, 297–306.
1
1
1
0. Battersby, A. R.; Edwards, T. P. J. Chem. Soc. 1959, 1909–1912.
1. Dörnyei, G.; Szantay, Cs. Acta Chim. Acad. Sci. Hung. 1976, 89, 161.
2. MM+ Geometry optimalization method (HyperChem ver. 5.11 Pro — a molecular modelling program of Hypercube, Inc.,
Gainesville, FL 32601, USA) for 7a and 7b with standard program parameters gave the following results: (Z)-7a=17.16
kcal/mol, (E)-7a=22.98 kcal/mol; (Z)-7b=17.47 kcal/mol, (E)-7a=22.62 kcal/mol.
1
1
3. Sheldrick, G. M., Kruger, C., Eds. Crystallographic Computing 3; Oxford University Press: Oxford, UK, 1985; p. 175.
4. Sheldrick, G. M. SHELXL93, Program for Crystal Structure Refinement, University of Göttingen, Göttingen, Germany,
1993.