Synthesis of novel chiral, cage-annulated macrocycles

Methods used to prepare several new cage-annulated chiral macrocycles (i.e., 3a-3d , 5 , 7 , and 12 ) are reported. These novel host systems were synthesized either by incorporating an optically active monosaccharide derivative or a tartaric acid derivative into each crown ether to provide the source of chirality


Introduction
Several chiral macrocylic crown ethers and related host systems have been synthesized, many of which are capable of forming complexes enantioselectively with chiral organic ammonium salts. 1 Despite some early successes, there is a clear need for the design and synthesis of additional chiral host molecules that will lead to an overall improvement in host-guest complexation efficiency, particularly with regard to enantioselectivity.
Incorporation of one or more chiral units into crown ethers was first reported by Cram 2 and subsequently by several other investigators. 3The ability of optically active host systems of this type (i) to discriminate between the enantiomers of guest alkylammonium salts and (ii) to function as catalysts for a variety of organic reactions suggests their potential use as enzyme mimics. 4 particularly interesting group of chiral crown ethers contains carbohydrate units as the source of chirality.Compounds of this type have been reported by Stoddart, 3a,b Penades, 5 and more recently by Seebach and coworkers. 6Carbohydrates (monosaccharides) and simple derivatives of optically active tartaric acid are ideally suited for this purpose due to their ready availability and the ease with which they can be employed to prepare peripherally polyhydroxylated crown ethers by using routine synthetic protocols.
Pursuant to our ongoing interest in the synthesis of novel polycarbocyclic cage compounds, 7 we recently prepared several examples of cage functionalized molecular clefts 8 and crown ethers. 9Compounds of this type are of interest as members of new class of host systems for the study of host-guest interactions (i.e., molecular recognition and inclusion phenomena).In part, the incorporation of a cage moiety into chiral macrocycles affects their overall conformational mobility by introducing a measure of rigidity into the crown ether system.In addition, the cage moiety has been shown to influence the ability of cage-annulated crown ethers to serve as complexing ligands (relative to the corresponding noncage-containing crown ethers) by helping to define the size of the host cavity.Finally, the cage moiety serves as a lipophilic component, thereby improving the solubility of cage-containing crown ethers in nonpolar solvents relative to that of the corresponding noncage-containing systems.
As an extension of past investigations of host-guest interactions that involve cageannulated crown ethers as hosts, our attention has turned to the synthesis of chiral analogs, i.e., 3a-3d, 5, 7, and 12 (Scheme 1).Compounds 2a-2d, which were prepared from optically active (+)-diethyl Ltartrate), 10 provide the source of optical activity in crown ethers 3a-3d.Simple monosaccharides provide the source of optical activity in the remaining host molecules, i.e., 5, 7, and 12.The requisite syntheses and product characterizations are described below.

Scheme 2
Subsequently, 8 (Scheme 3) was prepared from D-mannitol in three steps by following a literature procedure. 14The terminal CH2OH groups in 8 were protected via conversion of 8 to the corresponding bis(O-trityl) derivative, i.e., 9. Sequential reaction of the remaining secondary OH groups in 9 with MsCl-pyridine followed by treatment of the resulting bis(mesylate ester) with benzylamine 15 afforded 10.Subsequent acid promoted cleavage of the two O-trityl groups in 10 produced 11 16 in 70% yield (Scheme 3).
In summary, we have demonstrated herein that the chiral fragments 2a-2d, 4, 6, and 11, all of which can be prepared readily by starting with either L-tartaric acid or D-mannitol, can be coupled efficiently to a cage-containing moiety in a manner that results in the production of seven novel, optically active crown ethers (i.e., 3a-3d, 5, 7, and a diastereoisomeric mixture of 12a and 12b, respectively).We plan to report the results of our efforts to investigate the enantioselective complexation properties 17 of these unusual host systems in a future publication.

Experimental Section
General Procedures.Melting points are uncorrected.Elemental microanalytical data were obtained by personnel at M-H-W Laboratories, Phoenix, AZ.All 13 C NMR spectral integrations were performed on gated-decoupled NMR spectra.High-resolution mass spectral data reported herein were obtained at the Mass Spectrometry Facility at the Department of Chemistry and Biochemistry, University of Texas at Austin by using a ZAB-E double sector high-resolution mass spectrometer (Micromass, Manchester, England) that was operated in the chemical ionization mode.

Synthesis of crown ether (3a).
A suspension of NaH (76 mg, 1.59 mmol, obtained as a 60% dispersion in mineral oil) in dry THF (5 mL) under argon was cooled to 0 °C via application of an external ice-water bath.To this cooled suspension was added dropwise with stirring under argon a solution of optically active diol (76 mg, 0.45 mmol) in dry THF (10 mL) during 15 minutes.After all of the diol had been added, the external ice-water bath was removed, and the reaction mixture was allowed to warm gradually to ambient temperature while stirring during 2 h.At that time, a solution of 1 9c (320 mg, 0.51 mmol) in dry THF (20 mL) was added dropwise with stirring to the reaction mixture during 1 h.After the addition of 1 had been completed, the reaction mixture was refluxed under argon during 4 days.The reaction mixture then was cooled 0 °C via application of an external ice-water bath, and the cooled reaction mixture subsequently was quenched via careful, dropwise addition of water (4 mL).The reaction mixture was concentrated in vacuo and the residue was dissolved in EtOAc (40 mL).The resulting solution was washed sequentially with water (2 × 25 mL) and brine (1 × 30 mL).The organic layer was dried (Na 2 SO 4 ) and filtered, and the filtrate was concentrated in vacuo.The residue thereby obtained was purified via column chromatography on silica gel by eluting with 20% EtOAc in hexane to afford 3a (172 mg, 76%), as a colorless viscous oil.[α] D +9.4° (c 1.5, CHCl 3 ); IR (film) 2941 (s), 2858 (s), 1448 (w), 1371 (w), 1250 (m), 1116 cm -1 (s); 1 H NMR (CDCl 3 ) δ 1.40 (s, 6 H), 1.48 (AB, JAB = 11.9Hz, 1 H), 1.83 (AB, JAB = 11.9Hz, 1 H), 1.96-2.06(m, 4 H), 2.37 (br s, 2 H), 2.56-2.63(m, 6 H), 3.56-3.71(m, 16 H), 3.95-3.99(m, 2 H); 13 C NMR (CDCl 3 ) δ 26.9 (q, 2 C), 32. 4  After all of the Ph 3 CCl had been added, the external ice-water bath was removed, and the reaction mixture was allowed to warm gradually to ambient temperature while stirring during 24 h.At that time, water (50 mL) and CH 2 Cl 2 (50 mL) were added.The organic layer was separated and was washed successively with water (50 mL) and brine (30 mL).The organic layer was dried (Na 2 SO 4 ) and filtered, and the filtrate was concentrated in vacuo.

Preparation of 10.
A solution of 9 (516 mg, 6.0 mmol) in CH 2 Cl 2 (10 mL) under argon was cooled to 0 °C via application of an external ice-water bath.To this cooled solution was added NEt 3 (150 mg, 1.53 mmol).This was followed sequentially by dropwise addition with stirring of MsCl (150 mg, 1.345 mmol).After all of the MsCl had been added, the external ice-water bath was removed, and the reaction mixture was allowed to warm gradually to ambient temperature while stirring under argon during 24 h.The reaction was quenched via careful addition of water (20 mL), and the resulting aqueous suspension was extracted with Et 2 O (2 × 50 mL).The layers were separated, and the organic layer was washed successively with water (20 mL) and brine (15 mL).The organic layer was dried (Na 2 SO 4 ) and filtered, and the filtrate was concentrated in vacuo.The corresponding di-O-mesyl derivative of 9 (360 mg, 60%) was thereby obtained; this material was used as obtained in the next synthetic step, without further purification or characterization.A mixture of the di-O-mesyl derivative of 9 (360 mg, 0.36 mmol, vide supra) and PhCH 2 NH 2 (4 mL, 37 mmol, excess) was heated with stirring at 90 °C during 24 h.The mixture was allowed to cool to ambient temperature, whereupon pentane (100 mL) and 2 N aqueous NaOH (50 mL) were added successively to the reaction mixture.The organic layer was separated, and the aqueous layer was extracted with pentane (3 × 30 mL).The combined organic layers were washed successively with water (2 × 30 mL) and brine (20 mL), dried (Na 2 SO 4 ) and filtered, and the filtrate was concentrated in vacuo.

Synthesis of a mixture of diastereoisomeric crown ethers (12a) and (12b).
A a suspension of NaH (0.57 mg, 1.43 mmol, obtained as a 60% dispersion in mineral oil) in THF (5 mL) under argon was cooled to 0 °C via application of an external ice-water bath.To this cooled solution was added dropwise with stirring under argon a solution of 11 (280 mg, 0.65 mmol) in THF (3 mL).After the addition of reagents had been completed, the external ice-water bath was removed, and the reaction was allowed to warm slowly to ambient temperature while stirring during 1 h.The reaction mixture once again was cooled to 0 °C via application of an external ice-water bath, and a solution of 1 (282 mg, 0.71 mmol) in THF (3 mL) was added dropwise with stirring.After the addition of reagents had been completed, the external ice-water bath was removed, and the reaction was allowed to warm slowly to ambient temperature while stirring during 4 days.The reaction was quenched via addition of water (5 mL).The resulting aqueous suspension was extracted with EtOAc (3 × 30 mL).The combined organic extracts were dried (Na 2 SO 4 ) and filtered, and the filtrate was concentrated in vacuo.