Synthesis of a New Optically Active Triphosphine with

Synthesis of a New Optically Active Triphosphine with a Neopentane Backbone Horst Heidel, G ottfried Huttner*, Laszlo Zsolnai Anorganisch-Chemisches Institut der Universität Heidelberg, Im N euenheim er Feld 270, D-69120 H eidelberg Dedicated to Prof. Raymond Weiss Z. Naturforsch. 50b, 729-734 (1995); received September 9, November 23, 1994 Tripod Ligand, Optically Active Triphosphine, N eopentane Compound, Chiral Malonic Ester The resolution of the racemate (BzlOCH2)(M e)C (C O O H )(C O O E t) (± )1 is the entry point for the enantioselective synthesis of the key compound 7 (M eC(CH 2Cl)(CH 2Br)(C H 2OTfl)). Successive phosphination of 7 furnishes the triphosphine 10 (M eC(CH 2PPh2)(C H 2D BP)(CH 2P(3,5-Me2C6H 3)2) in both enantiomeric forms (DBP = dibenzophospholyl). The structures of the precursors (+)8S (M eC(CH 2PPh2)(C H 2D BP)(CH 2Cl)) and (± )9 (M eC(CH2Br)(C H 2Cl)(CH 2DBP)) have been confirmed by X-ray analysis.

The synthetic potential of terdentate ligands e. g. M eC (C H 2PPh 2)3 ( triphos ) in coordination chemis try has been amply worked out by the groups of L. Sacconi [1] and C. Bianchini [2]. Catalytic properties of rnp/zos-metal-templates have re cently become a topic [3-6]. Some chiral deriva tives of triphos (X (C H 2P R R ')3, X = MeSi, BuSn, HC) have been described [7-9]. One of these C3symmetric ligands has been successfully tested in asymmetric transition metal catalysis [10]. In the tripod ligands presented here the sym metry is reduced from C3 to C l5 by fixing three different R2P-donor groups P (Ps(small), PM(medium) and PL(large)) at the neopentane backbone (Fig. 1). In the case of facial coordination to a metal center the tripodal ligand completely shields one side of the metal center. An appropriate choice of the donor groups Ps, PM and PL should allow the specific shaping of a free coordination site for a substrate in such a complex. Considering the well established potential of chiral diphosphines in enantioselective catalysis, the synthesis of an optically active tripodal ligand e. g.

LTp.

‘

Fig. 1.

* Reprint requests to Prof. Dr. G. Huttner. 0932-0776/95/0500-0729 $06.00

M eC(CH2Ps)(C H 2PM)(C H 2P L) presents itself as an especially rewarding goal. We report here on the EPC-synthesis [11] of such a tripodal ligand with three differently sized phosphino groups in both enantiom eric forms and on the X-ray struc tural analyses of the enantiomerically pure precur sor (+)8S and racemic (± )9 [12], Results The synthesis of racemic tripod ligands of this type has shown that the key for an EPC synthesis is an enantioselective approach to the neopentane compound 7 bearing a bromo, chloro and triflato group [12]. Very recently we have reported an chemo-enzymatic synthesis of 7R , selectively lead ing to one enantiom er in a purity of 72% ee [13]. As an alternative the following route has been developed. The resolution of the easily accessible racemic malonic m onoester (± )1 [14, 15] fur nished both enantiomers. Recrystallization of the ammonium salt with S-(-)-l-phenylethylam ine [16] leads to the R -enantiom er (+)1R in 19% yield. Recovery of (± )1 from the remaining fil trates and recrystallization with R-(+)-l-phenylethylamine yields 30% of ( - ) I S . The yields may be improved by repeating the isolation and recrys tallization procedure. The chiral amine may be re covered and the process as a whole could in prin ciple be autom ated. This process is a more effective source for enantiomerically pure 1 than the enzymatic procedure [13].

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H. Heidel et al. • Optically Active Triphosphine with a N eopentane Backbone

Using the procedures already established [13], the functionalization of 1 to 7 results in slightly better yields than reported for the methylester analogue of 1 (Scheme 1) [13]. The configuration of the compounds 1 and 2 can be related to the known absolute configuration of ( - ) 3 S [13, 14]. 1) CICOjEt, NEtj 2) NaBH,

CCI,, P(Ph)3 83%

Cl OBzl

1) Br3-lmidazol, Imidazol, P(Ph)3 2) Hg, Pd/C

68% Fig. 2. Structure of (+)8S, undisordered molecule.

(-)4R

(+)6R

7R

The selective stepwise substitution of the three different leaving groups, chloride, bromide and triflate by three differently sized phosphines occurs under the same conditions as described for racemic 7 [12].

Ft = 3.5-Me2C6H3, (-)10S

Treating 7 with 1.2 eq. of lithium dibenzophospholide (LiDBP) in TH F at -2 0 °C yields the monophosphine 8 which reacts with 1.2 eq. of lith ium diphenylphosphide in TH F at 0 °C to give the diphosphine 9. The remaining chloride at the neo pentyl backbone needs the potassium di(3,5-di

methylphenyl)phosphide in DMSO at 130 °C for an effective substitution to produce the target mol ecule 10. The tripod ligand 10 contains three dif ferently sized phosphino groups: dibenzophospholyl (DBP), PPh2 and P(3,5-Me2C6H 3)2. Slow cooling of a hot saturated solution of the m onophosphine (+)8S in ethanol yields single crystals suitable for an X-ray structural analysis [17] to prove the constitution, conform ation and absolute configuration (Table I, II, Fig. 2). There are two independent molecules in the chiral unit cell (space group P2!). Anomalous dispersion un ambiguously shows that both molecules have the absolute configuration S as expected. O n the basis of the experimental data (Table II) the agreem ent factor is R x = 6.4% for the S-configuration (Flacks X-Param eter [20]: 0.0298 (esd = 0.0211)), while for the wrong /?-enantiomer it augments to 6.9% (Flacks X-Param eter [20]: 0.1236 (esd = 00200)). The weighted agreement factors evaluated on the basis of F2 differ correspondingly in R w = 20.5% for S and R w = 21.5% for the wrong enantiom eric form. From the two independent molecules (+)8S within the unit cell only one is completely un affected by disorder phenomena. Fig. 2 and Table I refer to the data of that molecule. About 80% of the disordered molecules adopt a conformation derived from the conformation of the undisordered


H. Heidel et al. • Optically Active Triphosphine with a N eopentane Backbone______________________________ 731 Bond lengths [pm] Compound P l - C3 P l - -C6 P l - -C 17 B rl - C l C ll - C 2

Compound P l- Cl P l - -C 12 P l - -C 13 P 2 --C18 P 2 --C24 P 2 --C 17 C l- C 15

Bond angles [°]

(+)8S (undisordered molecule) 188.6(11) C 3 -P 1 -C 6 179.0(9) C 3 -P 1 -C 1 7 182.1(10) C 6 -P 1 -C 1 7 195.6(9) Br 1- C l - C 5 177.6(11) Cl 1- C 2 - C 5 P 1 -C 3 -C 5

Table I. Selected bond lengths, angles and to r sion angles.

Torsion angles [°] 101.2(5) 103.9(5) 91.7(5) 113.2(7) 112.8(7) 114.0(9)

C 6 - P 1- C 3 - C 5 C 1 6 -C 1 7 -P 1 -C 3 Cl 1 - C 2 - C 5 - C 4 Cl 1- C 2 - C 5 - C 3 Br 1- C 1- C 5 - C 4 Br 1- C 1 - C 5 - C 3 P 1 -C 3 -C 5 -C 4

-156.6 - 80.0 179.1 56.6 61.1 -177.9 - 62.3

89.1(2) 101.8(2) 104.6(2) 104.0(2) 99.1(2) 102.5(3) 114.1(4) 116.2(3)

C 1 -P 1 -C 1 3 -C 1 4 C 1 1 - C 1 2 - P 1 -C 1 3 C 1 9 - C 1 8 - P 2 -C 1 7 C 2 9 - C 2 4 - P 2 -C 1 7 C 1 8 - P 2 -C 1 7 -C 1 4 C 1 -C 1 5 -C 1 4 -C 1 6 P 1 -C 1 3 -C 1 7 -P 2 P 1 -C 1 3 -C 1 4 -C 1 7

140.3 78.2 36.9 -120.5 98.7 -177.6 8.8 -175.2

(±)9 182.3(6) 182.7(5) 187.2(5) 182.6(6) 183.4(6) 187.5(5) 178.5(6)

C 1 -P 1 -C 1 2 C 1 -P 1 -C 1 3 C 1 2 - P 1 -C 1 3 C 1 7 - P 2 - C 18 C 1 7 - P 2 -C 2 4 C 1 8 - P 2 -C 2 4 C 1 -C 1 5 -C 1 4 P 1 -C 1 3 -C 1 4

+i

Table II. X-ray structural analysis of compounds (+)8S and ( Compound Formula Crystal dimensions Crystal system Space group Lattice constants

(+)8S (±)9 C 17H 17BrClP C29H 27C1P2 0.20x0.30x0.25 mm 0.20x0.30x0.20 mm monoclinic orthorhom bic P na2j P2i a - 1116.8(4) pm a = 1022.7(3) pm b = 983.7(2) pm b = 1406.7(6) pm c = 1533.6(4) pm c = 1720.4(5) pm ß = 69.68(2)° 4978(4)-106 pm3 2475(12)-106 pm3 Z =4 Z =4 1.546 g/cm3 1.269 g/cm3 Siemens (Nicolet Syntex). R3m /V -D iffractom eter MoK„, G raphite-M onochrom ator 200 K 200 K 5 < 26 < 54.1° 4.9 < 2d < 49.1° a»-Scan, Aco = 0.60° ey-Scan, Acu = 0.60° 7.0 < &> < 29.3° m in- 1 5.5 < oj < 29.3° m in-1 23 25

Cell volume Molecular units per cell Density (calculated) Diffractometer Radiation Tem perature Scan range M ethod Scan speed Number of reflections for cell refinem ent 3787 2135 M easured reflections 3609 Unique reflections 2135 2490 1761 Observed reflections (I > 2 ct) 384 Param eters refined 295 Maximum of residual electron density 0.62-10 6 e/pm3 0.51 •10~6 e/pm3 Corrections Lorentz and Polarisation factors, exp. absorption correction; ^-scan, Axp = 10° Structure solution direct methods least squares method Refinement Programms SHELXS-86 (G. Sheldrick, University of Göttingen, 1986) SHELXL-93 (G. Sheldrick, University of Göttingen, 1993) Agreem ent factors /?, = 6.4% R x = 4.5% R w= 20.5% R w= 10.7%

molecule (Fig. 2) by a +45° rotation of C 3 -C 5 around C 3 -P 1 and a +120° rotation of the C (C H 2B r)(C H 2C l)(C H 3) moiety around C 3 -C 5 .

The configuration of this molecule is also definitely S. The remaining 20% of the molecules in this position show an conform ation almost identi-


732

H. Heidel et al. ■ Optically Active Triphosphine with a N eopentane Backbone

that the phosphide substitution processes leading from 7 to 10 do not destroy the chiral information. A wide range of enantiomerically enriched tripod ligands should thus be accessible.

Experimental Generally see [12, 13]. For all structurally new compounds satisfactory microanalyses have been obtained: C ± 0.3, H ± 0.3, Cl ± 0.3. The com pounds (± )1 [14, 15] and 4 -1 0 [12, 13] have been synthesized following published procedures. The spectroscopic data were fully consistent with those reported [12, 13]. Resolution o f (±)2-benzyloxym ethyl-2-m ethylmalonicacidmonoethylester ( ( ± ) 1) into its enantiomers f - j l S and (+J1R [13, 16]

cal to the one observed for the undisordered mol ecules, so their configuration is S as well. The pure enantiom ers of 9 crystallize only in thin needles by slow cooling of a hot saturated ethanolic solution. These were not suitable for an X-ray structural analysis, but the racem ate [12] furnishes suitable single crystals (Table I, II, Fig. 3) [17]. In the molecule (± )9 the bond lengths and angles at the DBP-phosphorus atom (P I) corre spond to the relevant bond lengths and angles of the tripodal ligand M eC(CH2D B P)3 [18]. The geometry around the diphenylphosphino phos phorus atom (P2) agrees with the corresponding bond lengths and angles of M eC(CH2PPh 2)3 [19] (Table I). Resümee

The overall yield for this 9 step process 1 —»• 10 is 13%. The synthesis has been perform ed starting from both enantiom ers 1. All the chiral com pounds have been fully characterized and are op tically active. All of the enantiom eric pairs show the same absolute value of optical rotation in the opposite directions. This should exclude a racemization along the pathway 1 —►10. This is an im por tant finding in so far as the enantiomerically pure interm ediate 7 is easily prepared and as it shows

(-)-S-l-phenylethylam ine (32 ml, 0.252 mol) was added to a solution of (± )1 (67.0 g, 0.252 mol) in diisopropyl ether (270 ml) and ethanol (90 ml) at 50 °C. The solution was slowly cooled to 20 °C by removing the heater. As soon as crystallization started the suspension was cooled in an ice bath and vigorously stirred for 2.5 h. The voluminous solid was filtered off and washed with diethyl ether (2x60 ml). Drying of the solid at 50 °C in vacuo yielded 12.4 g (26%, 62% ee) of the am monium salt of (+)1R as a colourless microcrystal line solid. A second crystallization (s.a.) from di isopropyl ether (240 ml) and ethanol (70 ml) furnished the ammonium salt of (+)1R; yield: 9.4 g (19%, > 9 5 % ee); m.p. 107-108 °C. Extraction of the acidified filtrate (pH 2) with diethyl ether (4x200 ml) and evaporation of the solvent in va cuo at 50 °C yielded (± )1 (53.3 g, 0.2 mol). Alcalization of the aqueous layer with N aO H and ex traction with ether (3x100 ml) yielded after destination S-(-)-l-phenylethylam ine (16.4 ml. 0.13 mol). Three crystallizations (s.a.) of the re isolated (± )1 with (+)-R-l-phenylethylam ine (1 equ.) yielded the ammonium salt of ( - ) I S ; yield: 14.6 g (30%, >95% ee). The % d e value of the ammonium salts were controlled by jH NMR analysis [13]. Suspending the ammonium salt of (+)1R or ( - ) I S , respectively, (20.5 g, 0.053 mol) in diluted HC1 (2 M, 200 ml), extraction with ether (4x150 ml) and evaporation of the solvent in va cuo at 50 °C furnished (+)1R and ( - ) i s , respec tively, as colourless syrup; yield: 13.3 g (94%); (+)1R: [a]D +10.63° (c = 2.05, M eOH); ( - ) I S : [a]D -10.76° (c = 3.00, M eOH. - *H NMR (200 MHz; CDC13): d = 1.26 (t, 3/ HH = 7.1 Hz, 6H .


H. Heidel et al. ■ Optically Active Triphosphine with a N eopentane Backbone

C 0 2CH2CH3), 1.55 (s, 3H , CqC H 3), 3.82 (s, 2H , CFhOBzl), 4.22 (q, 3/ HH = 7-1 Hz, COzCFLCH,), 4.57 (s, 2H , PhCFLO), 7.39-7.24 (m, 5H , Ph). 13C NMR (50 MHz; CDC13):