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Beilstein Journal ofOrganic Chemistry

lstein Journal of Organic Chemistry

Beilstein Journal of Organic Chemistry

Open AcceFull Research PaperAn exceptional P-H phosphonite: Biphenyl-2,2'-bisfenchylchlorophosphite and derived ligands (BIFOPs) in enantioselective copper-catalyzed 1,4-additionsT Kop-Weiershausen, J Lex, J-M Neudrfl and B Goldfuss*

Address: Institut fr Organische Chemie, Universitt zu Kln, Greinstrasse 4, 50939 Kln, Germany

Email: T Kop-Weiershausen - t.kop-weiershausen@uni-koeln.de; J Lex - johann.lex@uni-koeln.de; J-M Neudrfl - aco48@uni-koeln.de; B Goldfuss* - Goldfuss@Uni-Koeln.de

* Corresponding author

phosphorus ligandschiralitybiarylsasymmetric conjugate additionsphosphoramiditesphosphitesphosphonitesX-ray analyses

AbstractBiphenyl-2,2'-bisfenchol (BIFOL) based chlorophosphite, BIFOP-Cl, exhibits surprisingly highstabilities against hydrolysis as well as hydridic and organometallic nucleophiles. Chloridesubstitution in BIFOP-Cl proceeds only under drastic conditions. New enantiopure, stericallydemanding phosphorus ligands such as a phosphoramidite, a phosphite and a P-H phosphonite(BIFOP-H) are hereby accessible. In enantioselective Cu-catalyzed 1,4-additions of ZnEt2 to 2-cyclohexen-1-one, this P-H phosphonite (yielding 65% ee) exceeds even the correspondingphosphite and phosphoramidite.

IntroductionChiral monodentate phosphorus ligands with C2-sym-metric diol backbones, e.g. with the prominent BINOLs orTADDOLs, are fundamental for the construction of effi-cient enantioselective transition metal catalysts, especiallyfor copper-catalyzed 1,4-additions. [1-18] Such asymmet-ric conjugate additions of diethylzinc to enones are oftenhighly enantioselective, especially with phosphoramidites(amidophosphites) and phosphites. [19-42] These chiralligands (L*) exhibit large steric demands and good metalto ligand back bonding abilities. Such ligands generateactive R-CuI-L* catalysts and support the rate determiningreductive elimination in the catalytic cycle (Scheme 1).[43-48]Common basis for diol-based phosphoramidites andphosphites are highly reactive chlorophosphites. [49-52]

These intermediates are converted usually in situ withamines or alcohols to the modular, enantiopure ligands(Scheme 2). [19-42].Modular fencholates were recently applied in chiral orga-nolithium reagents [53-59] and in organozinc [60-63] aswell as in organopalladium catalysts [64-68] to study ori-gins of enantioselectivities in C-C-couplings. The rigid,terpene-based bicyclo[2.2.1]heptane unit enables effi-cient, stereoselective access to crystalline diol ligands suchas BIFOL (biphenyl-bisfenchol), [69-73] which we hereapply for constructions of new BIFOL-based, phosphorusligands, i.e. biphenylbisfencholphosphanes (BIFOPs).BIFOPs with high steric demand and good acceptor abili-ties are then employed in enantioslective Cu-catalyzed1,4-additions.

Published: 26 August 2005

Beilstein Journal of Organic Chemistry 2005, 1:6 doi:10.1186/1860-5397-1-6

Received: 29 June 2005Accepted: 26 August 2005

This article is available from: http://bjoc.beilstein-journals.org/content/1/1/6

2005 Kop-Weiershausen et al; licensee Beilstein-Institut. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Beilstein Journal of Organic Chemistry 2005, 1:6 http://bjoc.beilstein-journals.org/content/1/1/6

Scheme 1: Monodentate phosphorus ligands, e.g. BINOL-based phosphoramidites or TADDOL-based phosphites, are highly efficient in copper catalyzed enantioselective conjugate additions.

Scheme 2: Modular phosphoramidites (R= NR'2) or phosphites (R= OR') from reactive chlorophosphite intermediates.

Scheme 3: Synthesis of biphenyl-2,2'-bisfenchol (BIFOL) based phosphane derivatives (BIFOPs).

Results and DiscussionCoupling of bis-lithiated biphenyl-2,2'-bisfenchol(BIFOL), synthesized from 2,2'-dilithiobiphenyl and (-)-fenchone, [69-73] with PCl3 or PBr3 yields the enantiop-ure halophosphites BIFOP-Cl, 1 (62% yield) and BIFOP-Br, 2 (69% yield, Scheme 3), which are air stable (nohydrolysis or oxidation) over weeks, crystalline and ana-lyzable via X-ray diffraction. [74-77] In close analogy tothe hydrogen bonded M-BIFOL, [69-73] only minus-(M)-conformations of biaryl axes are found in these BIFOP(biphenylbisfencholphosphane) halides (Figures 1 and 2).Surprisingly, the halophosphites 1 (BIFOP-Cl) and 2(BIFOP-Br) are very reluctant in reactions with variousnucleophilic reagents to give halide substitution (Table1). [78,79] No nucleophilic substitution [19-42] isobserved for 1 in treatments with equimolar suspensionsof LiAlH4 in hexanes or THF at 25C for 3 h (Table 1,entries 1 and 2). Only elevated temperatures (69C),longer reaction times (12 h) and an excess of LiAlH4 yieldsthe P-H phosphonite BIFOP-H, 3 (79% yield, Table 1,

entry 3, Figure 3). Even the strong C-nucleophilic reagentsmethyllithium, ethyllithium, n-butyllithium and t-butyl-lithium gave no expected conversions at low tempera-tures. Ethylation of BIFOP-Cl (1) yielding BIFOP-Et (4)was observed with ethyllithium only at elevated tempera-tures (Table 1, entry 7) or with a large excess of diethylzincat room temperature (Table 1, entry 13). Similarly, 1 wasconverted to BIFOP-nBu (5, Figure 4) only with an excessof n-BuLi at elevated temperatures. The resistance ofBIFOP-Cl (1) to O-and N-nucleophiles is apparent fromreactions with H2O, LiOPh and LiNEt2. While no hydrol-ysis of 1 is observed at ambient temperature, only refluxand basic conditions (KOH) yield complete hydrolysis of1 to BIFOP(O)-H, 8 (98%, Table 1, entry 14, Figure 5).[80,81] The phosphite BIFOP-OPh, 6 (40%, Figure 6) andthe phosphoramidite BIFOP-NEt2, 7 (47%, Figure 7) areaccessible from 1 only at elevated temperatures withLiOPh or LiNEt2. The oxo-derivative BIFOP(O)-Cl (9) issynthesized by coupling of BIFOL with POCl3 (65%, Fig-ure 8).

O OL*, CuOTf2, ZnEt2

in situ reduction

CuII to CuI Et

O

CuIII

Et

OTf

ZnEt

L*

Ox.

Add.

O

CuI

Et

OTf

Zn

L*

Et Red. El.ratedetermining

- CuEtL*- catalyst

O

Et

ZnEt

O

O

P N P

O

O

O

O

PhPh

Ph Ph

OL*, e.g.:

Ph

Ph

Feringa, phosphoramidite (98%ee)

Ph

Alexakis, phosphite (96%ee)

SS

R

R

1. nBuLi

2. PCl3

amines or

alcohols

*chiral diol reactivechlorophosphiteintermediates

P

O

O

*

Cl P

O

O

*

NR'2

OH

OH

*

P

O

O

*

OR'

or

1. nBuLi

2. PHal3

BIFOL BIFOP-Cl (1)BIFOP-Br (2)

OHOH

O

OPX

O

OPHal

X-nucleophiles

halidesubstitution

BIFOP-H (3)BIFOP-Et (4)BIFOP-nBu (5)BIFOP-OPh (6)BIFOP-NEt2 (7)

O

OPX

oxidized: O

BIFOP(O)-H (8)BIFOP(O)-Cl (9)

Page 2 of 9(page number not for citation purposes)

Beilstein Journal of Organic Chemistry 2005, 1:6 http://bjoc.beilstein-journals.org/content/1/1/6

Scheme 4: Geometries of BIFOP-systems with respect to biaryl dihedral angles (C2-C1-C1-C2, BAA), fenchyl-aryl dihedral angles (C1-C2-C3-O1) on the lone pair-side of phosphorus (FAA-lp) and at the substituent (X) side (FAA), the pyramidality of phosphorus measuredas angle sum and the distance of phosphorus to the biaryl axis (C1-C1).

The high steric demand of the embedding fenchane unitsprovides explanations for the unexpectedly low reactivityof the > P-Cl moiety in BIFOP-Cl (1). The geometries of allBIFOP-derivatives are remarkable with respect to theirbiaryl-angles, the fenchyl-aryl-angles, the pyramidality atthe phosphorus atoms as well as the positions of thephosphorus atom in the hydrophobic fenchane cavities(Scheme 4, Table 2).

A strong preference for the minus (M)-biaryl conformationwas found in BIFOL (Scheme 3) and was attributed tohydrogen bond linked chiral fenchole units, in the solidestate and in solution. [69-73] Similarly, all phosphoruslinked BIFOPs exhibit M-biarly axes with dihedral anglesvarying from -91 to -99 (Scheme 4, Table 2). The alter-native plus (P)-conformations were not found experimen-tally, they are computed to be disfavored by ca. 20 to 35kcal mol-1 (Table 2). As in M-BIFOL, [69-73] the strongdestabilization of these plus-(P)-conformations arise fromsteric repulsion of endo-oriented fenchane units in

O1

O2

PX

21

3

fenchyl-aryl angle (FAA-lp)

fenchyl-aryl angle (FAA)

biaryl-angle (BAA)

2' 3'

angle sum atphosphorus

1'

distance(d)

C2C3C5 C1

C6

C4 O1Ar

R2Pfenchyl-aryl dihedral

angle (O1-C1-C2-C3)

methyl-methylenebifurcation

X-ray crystal structure of BIFOP-Cl (1)Figure 1X-ray crystal structure of BIFOP-Cl (1). Distances are given in . (BAA = biaryl angle between C2-C1-C1'-C2'; FAA-lp = fenchyl-aryl dihedral angle between C1-C2-C3-O1; FAA = fenchyl-aryl dihedral angle between C1'-C2'-C3'-O2). The probability of ellipsoids is 40% (CDC 270531).

Table 1: Reactivity of BIFOP-Cl (1) with various nucleophilic

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