Patai S., Rappoport Z. 1996 The chemistry of functional groups. The chemistry of amino, nitroso, nitro and related groups / 0105 157

3. Chiroptical properties of amino compounds

115

−

+

Li

O	O
Al
R	H
[(S)-40] R = CH3	or CH3 CH2

developed which gives synthetic results comparable or superior to those reported using other metal catalysts47,48. The hydrogenation catalyst (R,R)-ethylene-1,2-bis( 5-4,5,6,7- tetrahydro-1-indenyl)titanium hydride [(R,R)-44] is generated in situ from the air-stable titanocene complex (R,R)-ethylene-1,2-bis( 5-4,5,6,7-tetrahydro-1-indenyl)titanium R - 1,10 -binaphth-2,20-diolate [(R,R,R)-45], prepared as described earlier49,50 with a mod-

ification of workup51. The 1,10 -binaphth-2,20-diolate derivative [(R,R,R)-45] serves	as
a precatalyst, and sequential treatment of (R,R,R)-45 in THF with 2 equivalents of	n-

butyllithium and 2.5 3 equivalents of phenylsilane provide the active catalyst (R,R)-44. When the catalyst (R,R)-44 is generated under a hydrogen atmosphere, no silane is required48. Thus the silane serves to stabilize the active catalyst during manipulation. The proposed catalytic cycle for reduction is given in Figure 1, (R,R)-(EBTHI)Ti H

Ti	H	X	Ti	X

[(R,R)-44]

O

X X =

O

[(R,R,R)-45]

116	Howard E. Smith

RL

R

RS N

	R			R
(EBTHI)TI N	RS	(R, R)	(EBTHI)TI H	(EBTHI)TI N
				RS
RL	(R,R,R)			R
				L
intermediate				(R,R,S)
				intermediate
H2				H
				2
	RL			RL
		R		R
	RS	N	RS	N
		H		H
	(R) amine			(S) amine

FIGURE 1. Scheme showing the reduction of the imine RSRLCDN R with hydrogen using the chiral catalyst (R,R)-ethylene-1,2-bis( 5 -4,5,6,7-tetrahydro-1-indenyl)titanium hydride [(R,R)- (EBTHI)Ti H, (R,R)-44], prepared from the precatalyst (R,R)-ethylene-1,2-bis( 5 -4,5,6,7-tetrahydro-1-indenyl)titaniumR -1,10 -binaphthyl-2,20 -diolate [(R,R,R)-45]. Reprinted with permission from Reference 52. Copyright (1994) American Chemical Society

representing the active catalyst (R,R)-4452. The first step of the cycle is reaction of the titanium hydride with an imine to form two diastereomeric titanium amide complexes. The second step is hydrogenolysis of the intermediate amide complexes to regenerate the titanium hydride and to form the two amine enantiomers, the syn and anti imines reacting to give the amines with opposite absolute configurations. For the twelve acyclic ketimines studied51, the enantiomeric excesses of the products correlate roughly with the anti/syn ratio. For example, reduction with hydrogen at 2000 psig and 65 °C of N- (1-cyclohexylethylidene)benzylamine (46), with an anti/syn ratio of 11:1 (E 92%), gaveR -N-benzyl-1-cyclohexylethylamine [ R -47] with an enantiomeric excess of 76%51. High pressures of hydrogen are required to achieve a high degree of asymmetric synthesis. When the hydrogen pressure was reduced to 500 psig for the reduction of imine 46 at 65 °C, the ee of R -41 was reduced to 43%51. The dependence of the ee values on

		(R,R)-44	H
	CH3		CH3
		H2(2000 psig)
	N	65˚C	NHCH2Ph
	CH2Ph
	[(E)-46 (92%)]		[(R)-47 (ee 76%)]

3. Chiroptical properties of amino compounds

117

hydrogen pressure is explained on the basis of the interconversion of the syn and anti isomers of 46 during hydrogenation52. Since in general it is the anti isomer of acyclic ketimine which is the more stable, ketimines are generally converted to the amine with an excess of the R enantiomer, but even at 2000 psig of hydrogen with acyclic ketimines, the enantiomer excesses of the amines, except for N-methylamines, are below the level of practical utility.

The hydrogenation of eleven cyclic imines to corresponding cyclic amines, such as 2-phenyl-1-pyrroline (48) to R-2-phenylpyrrolidine [R-49] using (R,R)-44 as catalyst, however, was found to occur with excellent degrees of asymmetric synthesis, and the enantiomeric excesses obtained with cyclic imines are virtually insensitive to changes in hydrogen pressure48. The reaction can be carried out at low pressure (80 psig) and higher temperature (65 °C) or at medium pressure (500 psig) and lower temperature (21 45 °C) with little or no change in the ee of the product, and five-, sixand seven-membered cyclic imines are reduced with excellent enantioselectivity48. Reduction of 48 at 500 psig and 21 °C and at 80 psig and 65 °C each gave R-49 with the same enantiomeric excess48.

N

(R,R)-44

H2(80 psig)

65˚C

(48)

H

N

H

[(R)-49 (ee 99%)]

E. Amination of Alkenes with Chiral Borohydride Reagents

The earliest use of a borohydride reagent for the enantioselective preparation of a chiral amine by amination of the corresponding alkene53 employed diisopinocampheylborane (50) prepared from C -˛-pinene54. Thus cis-2-butene [Z-51] was treated with 50 in diglyme to form an organoborane intermediate which, on treatment with hydroxylamine- O-sulphonic acid (52) in diglyme, gave R-2-aminobutane [R-53], which after correction for the low enantiomeric excess of the C -˛-pinene (68%) used to form 50, had an ee of 76%, but in rather low chemical yield (13%)53.

			)2 BH
				H2 N		OSO3 H
		(50)	(52)
	H	H				H
			1.50 / diglyme
	C C
				CH3CH2 C CH3
	H3C	CH3	1.52 / diglyme
						NH2
	[(Z)-51]					[(R)-53 (ee 76%)]

118	Howard E. Smith

A similar reaction sequence was used to prepare a number of chiral primary amines utilizing the preferential migrating tendency of secondary alkyl groups as compared to primary groups in the reaction of organoboranes with hydroxylamine-O-sulphonic acid (52)55. An example of this rather long sequence is the preparation of (1S,2S)-trans-2- methylcyclohexylamine hydrochloride [(1S,2S)-54ÐHCl] from 1-methylcyclohexene (55) using isopinocampheylborane (56), prepared from C -˛-pinene55. Reaction of 55 with the borane 56, in a one-pot synthesis by way of the intermediates 57, 58 and 59, gave 2-[(1S,2S)-trans-2-methylcyclohexyl]-1,3,2-dioxaborninane [(1S,2S)-60] in 85% yield. Treatment of (1S,2S)-60 in ether at 78 °C with methyllithium in ether and then acetyl chloride gave the crude boronic ester 61 in quantitative yield. The latter was dissolved in THF, and solid 52 was added. Treatment of the reaction product with water and then hydrochloric acid gave (1S,2S)-54ÐHCl in 76% yield with an ee of 99%55.

						H
		H2 B				B
		+		n eat
	(55)		[56 (ee 100%)]			[57 (ee 99%)]
							CH3 CHO/ether
	O
	B	HO		B(OH)2			B(OEt)2
	O	HO				1. NaOH
						+
						2. H
	[(1S,2S)-60		(59)			[58 (ee 99%)]
	(ee 99%)]

1.MeLi / −78˚C

2.CH3 COCl

	O(CH2 )3 OAc			+	O(CH2 )3 OAc
B
	CH3			NH2 B	CH3
		52 / THF
(61)			1. H2 O	(62)
			2. HCl
			NH3 Cl

[(1S,2S)-54 HCl (ee 99%)]

3. Chiroptical properties of amino compounds

119

Other chiral acyclic and cyclic amine hydrochlorides with ee values of at least 99% were prepared in a similar way55, and since both C - and -˛-pinene are available with ee values of 100%, both enantiomers of trans-2-methylcyclohexylamine hydrochloride (54ÐHCl) and other hydrochlorides thus prepared are available by the same synthetic route.

F. Aziridination of Alkenes with Chiral Diimine-based Catalysts

The first catalytic, asymmetric aziridination of an alkene in good yield and high enantioselectivity was recently reported56. Thus styrene (63) was treated with [N-(p- toluenesulphonyl)imino]phenyliodinane (64) and an asymmetric copper catalyst to yieldR -N-(p-toluenesulphonyl)-2-phenylaziridine [ R -65] in 97% yield with an ee of 61%, the catalyst being the complex formed in situ in chloroform from the chiral bis[ S -4- tert-butyloxazoline] [(S,S)-66] and copper(I) triflate (CuOTf)56, the reaction proceeding by way of a nitrene transfer57.

									Ph
Ph		CH		CH2 +	PhI		NTs	(S,S)-66-CuOTf
								CHCl3	N
(63)					(64)				Ts
									[(R)-65 (ee 61%)]

Benzylidene derivatives of the enantiomers of 1,2-diaminocyclohexane are also excellent ligands for the Cu(I)-catalyzed asymmetric aziridination of olefins with 64, but the enantioselectivities using acyclic alkenes were about the same as those using ligand (S,S)-6658. When (S,S)-bis-(2,4-dichlorobenzylidenediamino)cyclohexane [(S,S)-67] was employed with Cu(I) triflate, 6-cyano-2,2-dimethylchromene (68) was converted to (R,R)-69 in a 75% yield with an ee greater than 98%58.

H3C	CH3		H	H
O	O
		Cl	N	N	Cl
N	N		Cl	Cl
(CH3)3C		C(CH3)3
[(S,S)-66]				[(S,S)-67]

When the ligand (S,S)-70 was used, methyl cinnamate (71) was converted to the corresponding aziridine (S,S)-72 in 63% yield with an ee of 94%59, but the optimal conditions for the aziridination of the cinnamate esters cannot be reliably extrapolated to other acyclic olefins59. Reductive ring opening of (S,S)-72 by transfer hydrogenation60 afforded the corresponding R -methyl N-(p-toluenesulphonyl)phenylalaninate [ R -73] and established the absolute configuration of (S,S)-7259. This latter reaction and other reactions of the

120	Howard E. Smith
							O
	O
		(S,S)-67-CuOTf						H
		64 / CH2	Cl2		NC
NC						H	N
								Ts
(68)					[(R,R)-69	(ee > 98%)]

enantiomers of chiral aziridines in stereoselective transformations10,59,61 demonstrates the general usefulness of such compounds in asymmetric synthesis.

			H3C	CH3
		O		O
			N	N
		Ph		Ph
			[(S,S)-70]
		Ph		CO2CH3			O
	CO2CH3	(S,S)-70-CuOTf			HCO2 H / Pd
						Ph	OCH3
Ph			N
					CH3 OH
		64 / C6 H6					NHTs
			Ts
(71)		[(S,S)-72 (ee 94%)]					[(R)-73]

G. Kinetic Resolution Using a Modified Sharpless Reagent

Kinetic resolution of secondary allylic alcohols by Sharpless asymmetric epoxidation using tert-butylhydroperoxide in the presence of a chiral titanium tartrate catalyst has been widely used in the synthesis of chiral natural products. As an extension of this synthetic procedure, the kinetic resolution of ˛-(2-furfuryl)alkylamides with a modified Sharpless reagent has been used62. Thus treatment of racemic N-p-toluenesulphonyl- ˛-(2-furfuryl)ethylamine [ š -74] with tert-butylhydroperoxide, titanium isopropoxide [Ti(OPr-i)4], calcium hydride (CaH2), silica gel and L- C -diisopropyl tartrate [L- C - DIPT] gave S-N-p-toluenesulphonyl-˛-(2-furfuryl)ethylamine [S-74] in high chemical yield and enantiomeric excess62. Similarly prepared were the S-N-p-toluenesulphonyl- ˛-(2-furfuryl)-n-propylamine and other homologues of S-74 using L- C -DIPT. When D- -DIPT was used, the enantiomers were formed62.

		CH	CH3	t-BuOOH
	O			Ti(OPr-i)4
		NHTs		CaH2
				silica gel
	[(±)-74]			L-(+)-DIPT

	H			O
	C CH3	+
O	NHTs	HO	N	CH3
[(S)-74]			Ts

3. Chiroptical properties of amino compounds

121

III.ESTIMATION OF ENANTIOMERIC EXCESS

A.Quantitative Aspects

For a nonracemic mixture of enantiomers prepared by resolution or asymmetric synthesis, the composition of the mixture was given earlier as percent optical purity (equation 1), an operational term, which is determined by dividing the observed specific rotation [˛]obs of a particular sample of enantiomer with that of the pure enantiomer [˛]max , both of which were measured under identical conditions. Since at the present, the amount of enantiomers in a mixture is often measured by nonpolarimetric methods, use of the term percent optical purity is obsolete, and in general has been replaced by the term percent enantiomeric excess (ee) (equation 2) introduced in 197163, usually equal to the percent optical purity, [R] and [S] representing the relative amounts of the respective enantiomers in the sample.

Percent optical purity D [˛]obs/[˛]max 100	(1)
Percent enantiomeric excess D [R] [S]/[R] C [S] 100	(2)

Various methods, including polarimetry, competitive reaction methods and isotopedilution techniques, are available to determine the specific rotation of a pure enantiomer64. More precise and convenient estimation of ee values is made by measurement of the relative amounts of the enantiomers in a sample by gas chromatography (GC) and high performance liquid chromatography (HPLC) methods, and NMR techniques64. The relative amount of enantiomers can be determined by chromatography on an achiral support if they are derivatized using an enantiomerically pure reagent (chiral derivatizing agent, CDA) so as to prepare two diastereomers which are separated by the chromatography. Outlined below are direct chromatographic methods employing chiral stationary phases (CSPs) on which the enantiomers of chiral amines are separated by both GC65,66 and HPLC methods67.

B. Chromatography Using Chiral Stationary Phases

In the gas chromatographic (GC) separation of enantiomers, solutions of chiral metal ˇ-diketonates such as nickel(II) bis[(1R)-3-(heptafluorobutyryl)camphorate] [(1R)-75] in squalene are used as highly selective chiral stationary phases (CSP) coating the inside of a capillary column and using nitrogen as the carrier gas68. Thus resolution of š -1-chloro-2,2-dimethylaziridine [ š -76] was reported by gas chromatographic separation on 1R-7568. The nitrogen atom in 76 constitutes the sole chiral center in the molecule which, in the constrained N-chloroaziridine structure, is stable to inversion on GC using a CSP prepared from 1R-7568. Using a different but related chiral

	O	1
		CH3	H
	Ni/2
	O	CH3	CH3
		N	N
	CF2CF2CF3	Cl	Cl
	[(1R)-75]	[(S)-76]	[(1S,2S)-77]

122	Howard E. Smith

FIGURE 2. Record of the gas chromatographic resolution of š -trans-1-chloro-2-methylaziridine [ š -77] on nickel(II) bis[(1R)-3-(heptafluorobutyryl)camphorate] [(1R)-75] (0.156 M in squalene) at 63 °C. Column, 100 m ð 0.5 mm nickel capillary; carrier gas 2.9 mL/min N2; split ratio 1:50. (Left chromatograph) š -77; (right chromatograph) (1S,2S)-77 (ee 99%). Reprinted with permission from Reference 69. Copyright (1982) American Chemical Society

stationary phase, slow racemization of 76 was detected69, indicating that the metal chelate may participate in decreasing the activation barrier of nitrogen inversion in 76. In related experiments, chlorination of 2-methyaziridne gave a mixture of cis- and trans-1-chloro-2-methylaziridine (77) which were identified by GCMS69. On standing at elevated temperature the cis diastereomer disappeared, and GC of the remaining more thermodynamically stable trans racemate on (1R)-75 dispersed in squalene as the stationary phase showed complete resolution of the two enantiomers (Figure 2). When an enantiomer of 77 was synthesized from L-alanine, (1S,2S)-77 was obtained with an ee

3. Chiroptical properties of amino compounds

123

of 99% (Figure 2), showing that the separation shown in the left panel of Figure 2 is a true enantiomeric separation and allowing, on the basis of the synthesis, the assignment of the absolute configuration to the respective peaks in Figure 269. It is to be noted that this column, the stationary phase prepared from (1R)-75 dispersed in squalene, has low sample capacity, but may be suitable for isolation of the pure enantiomers in mg quantities, sufficient for the determination of chiroptical data on the analytes70. When only one chromatographic peak is detected, care must be exercised to be sure it represents one enantiomer by use of another sample known to be the racemate or partially racemic mixture of the analyte under investigation.

The observation that some racemic amino acids gave two spots on paper chromatography71 was the first indication that chiral recognition by cellulose in high performance liquid chromatography (HPLC) might be feasible. Since then, various derivatives of cellulose have been examined as chiral absorbants72. One such chiral stationary phase (CSP) is microcrystalline cellulose triacetate (MCCTA or CTA-I) (78) which is the product of the heterogeneous acetylation of microcrystalline cellulose72. Although CSP 78 has been used for the resolution of Troger’s base [ š -79], 78 and other derivatives of cellulose and of other polysaccharides are not generally useful for the resolution of simple chiral amines72. The application of these HPLC columns to the separation of enantiomers of chiral substances incorporating multiple functional groups has been studied extensively, but it is difficult to determine exactly what structural features are required for enantioseparation. On an empirical basis, however, various CSP of this type have been found useful for the resolution of many substances including many materials useful as pharmaceuticals and agrochemicals. The packing materials are commercially available (Daicel Chemical Industries, Ltd), but currently the loading capacity of these columns is limited, and the technology for preparative separation of enantiomers remains to be developed.

CH2 OAc		N
H	O	CH3
H
OAc H
O	H	H3 C
	n	N
H	OAc
(78)		[(±)-79]

Other types of CSP have been investigated for enantiomeric separation, both for the estimation of enantiomer ratios in partially racemic samples and for preparative separation of enantiomers73, and those that act by attractive interactions between nonionic functionalities are termed donor acceptor CSPs (DA CSPs). By optimization of hydrogen bonding, donor acceptor, dipole stacking and steric interactions between the CSP and the analyte, a number of highly selective CSPs suitable for a broad range of analytes and showing high chromatographic efficiencies have been prepared73. These CSP are prepared by covalently linking a monolayer of chiral precursor to a support, usually silica (80), with good mechanical properties. Typically, unfunctionalized molecules will show little or no separability on most DA CPSs, and quite often derivatization is required for separation. Nevertheless, DA CSPs are generally the most practical wide-spectrum CSPs available for HPLC73.

An easily accessible DA CSP derived from L-N-(2-naphthyl)valine (80) was used to separate appropriately derivatized amines, amino alcohols and thiols, derivatization consisting of N-, O- and S-acylation with 3,5-dinitrobenzoyl chloride or 3,5-dinitrophenyl

124	Howard E. Smith
	H	C2 H5O O
		CH(CH3 )2
	N	CO2 (CH2 )11 Si

O

H

(80)

isocyanate74. Using a 4.6 ð 250-mm column packed with 80, the 3,5-dinitrophenyl isocyanate derivatives of 2-aminobutane [ š -81)], ˛-phenylethylamine [ š -82] and other amines were completely separated on elution with 10% 2-propanol in hexane, R-81 and S-82 being the more strongly retained74. This particular DA CSP is commercially available (Regis Chemical Co.), and it and similar DA CSP will be of utility in the preparation of the pure enantiomers of chiral amines.

NO2

CH3

CHNHCONH

R

NO2

[(±)-81] R = CH3 CH2 [(±)-82] R = C6 H5

C. Nuclear Magnetic Resonance Methods

Since nuclear magnetic resonance instruments are ubiquitous in organic chemistry laboratories, NMR methods for the estimation of enantiomer ratios are easily and rapidly done75. Since enantiomers give identical NMR signals in an achiral medium, the ratio of enantiomers requires the use of a chiral auxiliary or an achiral reagent that converts the mixture of enantiomers into a diastereomeric mixture. As long as there is a large enough chemical shift nonequivalence for the respective diastereomers to give baseline resolution of the appropriate signals, integration gives a direct measure of the diastereomeric composition which can be related directly to the enantiomeric composition of the original

mixture.
There are three types of chiral	auxiliary that are used: chiral derivatizing
agents (CDAs), chiral lanthanide shift	reagents (CLSRs) and chiral solvating agents

(CSAs)75. Chiral derivatizing agents (CDAs), such as the enantiomers of ˛-methoxy-˛- (trifluoromethyl)phenylacetic acid (MTPA, 83)76, require the separate formation of discrete

CO2 H

CH3 OCCF3

		CH3
			CHNH2
		CH2 CH(CH3 )3
[(S)-83]	[(±)-84]