ω-Amino acids and lactams with chiral biaryl axis

Article abstract of DOI:10.1016/S0957-4166(98)00361-9

The optically active amino acids (R)-7 and (S)-8 were prepared as the first representatives of ω-amino acids possessing a biaryl axis as the sole element of chirality.

Full text of DOI:10.1016/S0957-4166(98)00361-9

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 3497–3504
ω-Amino acids and lactams with chiral biaryl axis †
Miloš Tichý, Jana Holanová and Jiˇrí Závada ∗
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, 166 10 Prague, Czech Republic
Received 1 September 1998; accepted 7 September 1998
Abstract
The optically active amino acids (R)-7 and (S)-8 were prepared as the first representatives of ω-amino acids
possessing a biaryl axis as the sole element of chirality. © 1998 Elsevier Science Ltd. All rights reserved.
1. Introduction
Many important properties and functions of amino acids depend on their chirality which usually
originates from the presence of a stereogenic carbon atom. Recently, however, we have reported the
first α-amino acid (1) whose chirality does not result from a stereogenic carbon but from a chiral biaryl
axis.1 Subsequently, Mazaleyrat with coworkers2 have described an analogous axially chiral β-amino
acid (2).
Continuing in this endeavour, we have now examined lactams 3–5 and their hydrolytic cleavage into
the corresponding axially chiral ω-amino acids 6–8 (Scheme 1). Both the lactams and the ω-amino acids
may find interesting application in the design of peptidomimetics3,4 and also in the synthesis of helical
polymers.5–7
∗
†
Corresponding author. E-mail: zavada@uochb.cas.cz
Dedicated to the memory of Professor Otto Wichterle.
0957-4166/98/$ - see front matter © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00361-9

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Scheme 1.
2. Results and discussion
2.1. Synthesis
The lowest homologue, 1,10-dimethylphenanthridone (3), is already known and was prepared accord-
ing to the literature.8
The seven-membered lactam (RS)-4 was prepared starting from dialdehyde (RS)-10, which was con-
verted by Cannizzaro reaction into the hydroxy acid (RS)-11 (Scheme 2). The reaction required vigorous
conditions (4 h reflux with 10M sodium hydroxide), presumably because of the steric compression of the
methyls in the transition state.9 The acid (RS)-11 was treated with boiling 40% HBr to give bromo acid
(RS)-12 which was esterified with diazomethane and the obtained ester (RS)-12 was converted into azido
ester (RS)-14 by reaction with sodium azide. Reduction over 10% Pd/C gave the amino ester (RS)-15,
which partially cyclized on standing, and therefore was directly subjected to sodium methoxide-induced
cyclization to the lactam (RS)-4. The overall yield of the whole reaction sequence (RS)-10 to (RS)-4 was
65%. The same route was applied to the enantiomerically pure series, starting from dialdehyde (R)-10
which in turn was obtained from enantiomerically pure diol (R)-9 of known absolute configuration10
(Scheme 2). In spite of some steps performed at reflux temperature (about 100°C), the whole reaction
sequence proceeded without racemization and the obtained lactam (R)-4 was free from the other antipode
as shown by chiral HPLC (Whelk, Merck).
The eight-membered ring lactam (S)-5 was prepared by Beckmann rearrangement of the oxime (S)-
18 at 0°C (Scheme 2). The parent ketone (S)-17 of known absolute configuration11 was obtained by
preparative HPLC resolution (triacetylcellulose) of the racemate (RS)-17, prepared in good yield by
reaction of dibromide (R,S)-16 with tosylmethyl isocyanide12.
The amino acids (R)-7 and (S)-8 were obtained by acid hydrolysis of the corresponding lactams (R)-4
and (S)-5, respectively (Scheme 1). Whereas the eight-membered lactam (S)-5 was hydrolyzed smoothly
on reflux with conc. hydrochloric acid for 2 h, the seven-membered one (R)-4 required 15 h reflux with

M. Tichý et al. / Tetrahedron: Asymmetry 9 (1998) 3497–3504
3499
Scheme 2.
a mixture of conc. hydrochloric acid and acetic acid, thus reflecting different chemical stabilities of the
lactam systems. Upon heating to their melting points, both amino acids decomposed by formation of the
starting lactams.
Attempted hydrolysis of the six-membered lactam 3 by prolonged boiling with conc. hydrochloric acid
completely failed. Undoubtedly, mesomeric stabilization of the lactam ring is the responsible factor.13–17
2.2. Enantiomeric excess and stability
The enantiomeric excess of lactams (R)-4 and (S)-5 has been confirmed by HPLC on a chiral column
(Whelk). Both the lactams were configurationally stable on heating at 120°C in toluene for 10 h. Of note
is their configurational stability on sublimation. When either of them is heated under its melting point
[230°C for (S)-5 or 260°C for (R)-4] on a Kofler hot stage, it sublimes to the microscope cover glass
without any loss of enantiomeric excess (HPLC); only after melting does it gradually racemize. Also, the
amino acids (R)-7 and (S)-8 did not racemize on heating at 120°C (in 0.5M HCl) for 10 h and since they
were prepared from the enantiomerically pure lactams, they undoubtedly are enantiomerically pure.
Unlike the configurationally highly stable and HPLC-resolvable seven- and eight-membered lactams,
the lowest member of the series, lactam 3, could not be resolved on chiral HPLC (triacetylcellulose or
Whelk). Apart from the possibility of unsuitable chiral selector, one may a priori expect that the lactam
3 (in contrast to the corresponding amino acid 6) will be configurationally labile. Pertinent information
in this respect may be drawn from the available data on 4,5-dimethylphenanthrene.18 This compound,
which is non-planar (the dihedral angle between the mean phenyl planes being 27.9°), possesses a barrier
to racemization of 16.1 kcal/mol and its antipodes can be separated at cryogenic temperatures. As we

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have recently demonstrated in a closely similar situation, the racemization barriers of axially chiral biaryl
dilactams and their carbocyclic analogues are almost identical.19
3. Conclusion
Novel axially chiral lactams 4 and 5 and the corresponding ω-amino acids 7 and 8 were prepared enan-
tiomerically pure. The very high configurational stability established for these compounds constitutes an
important prerequisite20 for application in the synthesis of homochiral polyamide polymers.
4. Experimental
4.1. (RS)-6,60-Dimethyl-1,10-biphenyl-2,20-dicarboxaldehyde (RS)-10
A solution of diol10c (RS)-9 (3.1 g, 12.8 mmol) in CH2Cl2 (60 ml) was added to a stirred suspension
of pyridinium chlorochromate21 (8.5 g, 15 mmol) in CH2Cl2 (50 ml) under cooling with cold water.
After stirring for 2 h the mixture was diluted with ether (300 ml), stirred for 20 min, decanted from
solid material and passed through a column of silica gel. Evaporation of the eluate gave pure dialdehyde
(RS)-10, mp 118–119°C (reported22 mp 114°C). Yield 2.95 g (96%).
4.2. (RS)-20-Hydroxymethyl-6,60-dimethyl-1,10-biphenyl-2-carboxylic acid (RS)-11
A stirred mixture of the dialdehyde (RS)-10 (2.38 g, 10 mmol), NaOH (40 g, 1.0 mol), water (80 ml)
and dioxane (15 ml) was refluxed for 4 h. After cooling, the mixture was diluted with water, extracted with
ether, and the aqueous phase acidified with conc. hydrochloric acid. The product was taken up in ether,
the extract was washed with water, dried, and the solvent was evaporated. The residue was triturated with
light petroleum to give 2.19 g (86%) of hydroxy acid (RS)-11, mp 140–142°C (ether–light petroleum).
1H NMR (200 MHz, CDCl3): δ 7.20–7.75 (m, 6H), 4.28 (d, 1H, J=12 Hz); 4,19 (d, 1H, J=12 Hz), 1.87
(s, 3H), 1.84 (s, 3H). MS (FAB): 239 (M+1−H2O). Anal. calcd for C16H16O3: C, 74.98; H, 6.29. Found:
C, 75.16; H, 6.39.
4.3. (RS)-20-Bromomethyl-6,60-dimethyl-1,10-biphenyl-2-carboxylic acid (RS)-12
The crude hydroxy acid (RS)-11 (2.19 g, 8.6 mmol) was refluxed with 40% aqueous HBr (45 ml) for 3
h. The mixture was diluted with water, the product taken up in ether and the extract washed with water.
After addition of sodium sulfate and charcoal, the mixture was filtered and the solvent evaporated. The
product was pure according to TLC (ether:light petroleum=1:1), mp 101–102°C (heptane). Yield 2.71 g
(98%). 1H NMR (200 MHz, CDCl3): δ 7.93–7.16 (m, 6H), 4.08 (s, 2H), 1.98 (s, 3H), 1.88 (s, 3H). MS
(EI): 318, 320 (M+, 19), 239 (61), 195 (100), 179 (49), 165 (31). Anal. calcd for C16H15BrO2: Br, 25.04.
Found: Br, 24.87.
4.4. (RS)-1,11-Dimethyl-6,7-dihydro-5H-dibenzo[c,e]azepin-5-one (RS)-4
The bromo acid (RS)-12 (2.71 g, 8.5 mmol) was esterified with ethereal diazomethane and the solvent
was evaporated. The obtained bromo ester (RS)-13 was stirred with sodium azide (3.2 g, 50 mmol) in

M. Tichý et al. / Tetrahedron: Asymmetry 9 (1998) 3497–3504
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DMF (30 ml) at rt for 3 h. The mixture was partitioned between water and ether and the ethereal extract
was thoroughly washed with water and dried. Evaporation of the solvent gave 2.34 g (93%) of the azido
ester (RS)-14 as an oil. 1H NMR (200 MHz, CDCl3): δ 7.20–7.85 (m, 6H, H-arom.), 3.91 (s, 2H, CH2),
3.58 (s, 3H, OCH3), 1.93 (s, 3H, CH3), 1.92 (s, 3H, CH3). The crude azido ester (RS)-14 (2.34 g, 7.9
mmol) was hydrogenated in methanol (100 ml) over 10% Pd/C (500 mg) in a stream of hydrogen. After
the reduction was over (1 h, TLC), the catalyst was filtered off and the solvent evaporated to afford oily
amino ester (RS)-15 (2.09 g, 98%). 1H NMR (200 MHz, CDCl3): δ 7.8–7.1 (m, 6H, H-arom.), 3.91 (s,
2H, CH2), 3.58 (s, 3H, OCH3), 1.93 (s, 3H, CH3), 1.88 (s, 3H, CH3).
The crude amino ester (RS)-15 (2.09 g, 8.7 mmol) was dissolved in 0.1M methanolic sodium
methoxide (6 ml, 0.6 mmol) and set aside at rt overnight. The deposited crystals were collected and
washed with cold methanol to give 1.49 g (84%) of lactam (RS)-4, mp 293–295°C (ethanol). The overall
1
yield starting from the dialdehyde (RS)-10 was thus 65%. H NMR (200 MHz, CDCl3): δ 7.80–7.10
(m, 6H, H-arom.), 6.88 (t, 1H, NH), 4.12 (dd, 1H, J(gem)=6.4 Hz, J(CH,NH)=14.3 Hz, CH2), 3.82 (dd, 1H,
J
(gem)=6.4 Hz, J(CH,NH)=14.3 Hz, CH2), 2.22 (s, 3H, CH3), 2.15 (s, 3H, CH3). MS (FAB): 238 (M+1).
Anal. calcd for C16H15NO: C, 80.98; H, 6.37; N, 5.90. Found: C, 80.89; H, 6.48; N, 6.05.
4.5. (R)-6,60-Dimethyl-1,10-biphenyl-2,20-dicarboxaldehyde (R)-10
22
The optically active compound, mp 116–117°C (ether), [α]D +88.2 (c 0.5; ethanol), was obtained
in 92% yield from 3.0 g of the optically active diol10c (R)-9 ([α]D +105.7 (c 0.5; benzene)), using the
22
same procedure as described for the racemic compound (RS)-10.
4.6. (R)-1,11-Dimethyl-6,7-dihydro-5H-dibenzo[c,e]azepin-5-one (R)-4
The optically active lactam, mp 315–316°C, [α]D22 +39.2 (c 0.2; chloroform), was prepared from the
dextrorotatory dialdehyde (R)-10 (2.70 g, 11.3 mmol) in 54% overall yield in exactly the same manner as
described for the racemic series, except that no crystallization was involved along the synthetic path. The
22
intermediate compounds (R)-11 ([α]D22 +8.6 (c 0.5; methanol)), (R)-12 ([α]D −70.6 (c 0.5; methanol)),
(R)-13, (R)-14 and (R)-15 had identical 1H NMR spectra with those of the racemic ones.
4.7. (R)-20-Aminomethyl-6,60-dimethyl-1,10-biphenyl-2-carboxylic acid (R)-7
Lactam (R)-4 (200 mg, 0.84 mmol) was refluxed with a mixture of conc. hydrochloric acid (7 ml) and
acetic acid (4 ml). After 8 h, another portion of hydrochloric acid (1 ml) was added and the reflux was
continued for further 8 h. The volatiles were evaporated in vacuo, the residue was dissolved in water (20
ml) and the insoluble material was removed by filtration. The filtrate was reduced in vacuo and the residue
was coevaporated with water. The dry hydrochloride was dissolved in water and passed through a column
of Dowex 50X. Elution with 3% ammonium hydroxide, evaporation and crystallization from water gave
22
free acid (R)-7 (100 mg, 46%), mp 300–302°C (decomp.) with transition at 255–260°C, [α]D +155.0
(c 0.5; methanol). Anal. calcd for C16H17NO2·0.5H2O: C, 72.79; H, 6.86; N, 5.31. Found: C, 72.60; H,
1
6.67; N, 5.25. H NMR (200 MHz, CD3OD): δ 7.70–7.45 (m, 6H, H arom.), 4.02 (d, 1H, J(gem)=12.5
Hz, CH2), 3.70 (d, 1H, J(gem)=12.5 Hz, CH2), 2.16 and 2.03 (2×s, 2×3H (2×CH3).

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4.8. (R)- and (S)-5,7-Dihydro-1,11-dimethyl-6H-dibenzo[a,c]cyclohepten-5-one (R)-17 and (S)-17
A solution of NaOH (3.8 g, 95 mmol in 5 ml water) was added at 0°C to a mixture of dibromide10c
(RS)-16 (7.0 g, 19 mmol), tosylmethyl isocyanide (4.1 g, 21 mmol), tetrabutylammonium iodide (0.35 g,
1.0 mmol) and dichloromethane (50 ml). After stirring at rt overnight, the organic layer was separated,
dried and the solvent was evaporated. The residue (10.0 g) was mixed with dichloromethane (15 ml)
and ether (40 ml) and stirred with conc. HCl (6 ml) for 4 h. The reaction mixture was partitioned
between water and ether, the ether layer was washed with water and NaHCO3, dried and the solvent was
evaporated. The residue was extracted with light petroleum (50 ml), the extract was mixed with charcoal,
filtered and concentrated. Chromatography of the residue (4.6 g) on silica gel in ether:light petroleum
(1:5) afforded ketone (RS)-17 (3.5 g, 78%), mp 72–74°C (reported11 mp 61–63°C). The racemic ketone
(2.0 g) was separated into enantiomers by chromatography on a 4×80 cm column of triacetylcellulose
(TAC) in ethanol (five 400 mg/5 ml injections, flow rate 3 ml/min). The chromatography gave 754 mg
(38%) of (S)-17, mp 60–62°C, [α]D −610.8 (c 1; benzene) (reported11b mp 61–63°C, [α]D −628
22
28
(c 1; benzene)) and 702 mg (35%) of (R)-17, mp 60–62°C, [α]D +597 (c 1; benzene) (reported11b mp
61.5–63°C, [α]D +617 (c 1.6; benzene)). According to analytical HPLC on TAC, both antipodes were
22
23
enantiomerically pure.
4.9. (S)-5,7-Dihydro-1,11-dimethyl-6H-dibenzo[a,c]cyclohepten-6-one oxime (S)-18
The compound was prepared by oximation of ketone (S)-17 in 94% yield, mp 186–188°C (toluene:light
22
petroleum), [α]D −439 (c 0.5; ethanol), enantiomerically pure according to HPLC (triacetylcellulose,
1
ethanol). Anal. calcd for C17H17NO: C, 81.24; H, 6.82; N,5.57. Found: C, 81.51; H, 6.77; N, 5.65. H
NMR (200 MHz, CDCl3): δ 7.2–7.05 (m, 6H, H arom.), 4.15 (d, 1H, CHH), 3.24 (s, 2H, CH2), 2.96 (d,
1H, CHH), 2.16 and 2.14 (2×s, 2×3H, 2×CH3).
4.10. (S)-7-Aza-5,7-dihydro-1,11-dimethyl-6H-dibenzo[a,c]cycloocten-6-one (S)-5
To a stirred ice-cold solution of the oxime (S)-18 (627 mg, 2.5 mmol) in acetone (15 ml) was added 2M
NaOH (2 ml, 4 mmol) followed by a solution of benzenesulfonyl chloride (700 mg, 4 mmol) in acetone
(10 ml). After cooling for 30 min, the ice bath was removed and the mixture was stirred at rt for 4 h and
then set aside overnight. The solvent was evaporated in vacuo and the dry residue was partitioned between
dichloromethane and a solution of NaHCO3. The organic layer was dried and evaporated. Crystallization
22
of the residue from toluene afforded 408 mg (76%) of the product, mp 242–243°C, [α]D −315 (c
0.5; ethanol). Pure according to chiral HPLC (Whelk, Merck, 15% i-PrOH in heptane). Anal. calcd for
C17H17NO: C, 81.24; H, 6.82; N, 5.57. Found: C, 81.21; H, 6.84; N, 5.37.
4.11. (S)-20-Aminomethyl-6,60-dimethyl-1,10-biphenyl-2-acetic acid (S)-8
Lactam (S)-5 (90 mg, 0.36 mmol) was refluxed with hydrochloric acid (1:1, 4 ml) for 2 h. The resulting
solution was evaporated and the residue co-evaporated with water (2×) and the free amino acid was
liberated on Dowex 50X by the usual procedure. Yield 93 mg (96%) of amino acid (S)-8, mp 233–235°C
22
(decomp.) (water), [α]D −233 (c 0.5; methanol). Anal. calcd for C17H19NO2·0.5H2O: C, 73.36; H,
1
7.24; N, 5.03. Found: C, 73.24; H, 6.99; N, 4.86. H NMR (200 MHz, CD3OD): δ 7.6–7.4 (m, 6H, H
arom.), 4.00 and 3.61 (2×d, 2×1H, J(gem)=12.8 Hz, CH2N), 3.50 and 3.10 (2×d, 2×1H, J(gem)=14.2 Hz,
CH2CO), 2.07 and 2.04 (2×s, 2×3H, 2×CH3).

M. Tichý et al. / Tetrahedron: Asymmetry 9 (1998) 3497–3504
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4.12. Attempted hydrolysis of 1,10-dimethylphenanthridone 3
1,10-Dimethylphenanthridone8 (3) (44 mg) in concentrated hydrochloric acid (4 ml) was refluxed for
20 h with addition of further acid (2 ml) after 8 and 15 h. The reaction mixture was evaporated in vacuo,
the residue was dissolved in water (10 ml) and filtered. The filtrate on evaporation gave no discernible
residue.
4.13. Racemization experiments
4.13.1. Lactams
Lactam (R)-4 or (S)-5 (3 mg) was dissolved in hot toluene (5 ml) and the solution was heated in a
glass autoclave at 120°C for 10 h. The solvent was evaporated and the residue analyzed on a Whelk-
R,R column (Merck), elution with 15% 2-propanol in heptane (flow rate 1.0 ml/min). In both cases the
chromatography did not detect the presence of the second antipode (less than 0.5%).
4.13.2. Acids
A solution of acid (R)-7 or (S)-8 in 0.5M HCl (c ≈0.5) was heated in a sealed ampoule at 120°C for
10 h. After cooling to room temperature, the optical rotation of the solution was compared with that
measured before the heating. No significant differences were observed.
4.13.3. Sublimation
Optically active lactam (R)-4 or (S)-5 was placed on a microscope glass in a Kofler hot stage. A 2
mm high metal ring was put on the glass and another microscope glass was placed on the top of the
ring. Heating at the appropriate temperature [230°C for (S)-5 or 260°C for (R)-4] resulted in relatively
rapid sublimation to the upper glass from which the sublimate was scratched off and analyzed by HPLC
(Whelk).
4.13.4. Melting experiments
Optically active amino acid (R)-7 or (S)-8 was heated in a Kofler hot stage apparatus until it melted. The
microscope glass with the melt was then taken out, cooled and the solid analyzed by HPLC on a Whelk
column. The obtained lactams contained the other antipode in quantities which depended on how rapidly
the material was removed from the stage. The same melting procedure performed with enantiomerically
pure lactams (R)-4 or (S)-5 gave lactams whose enantiomeric excess depended on the time for which the
compound remained in the molten state.
Acknowledgements
The financial support by the Grant Agencies of the Czech Republic (grant no. 203/96/0288) and of the
Academy of Sciences of the Czech Republic (grant no. A405501) is gratefully acknowledged.
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