New chiral catalysts for phospho-transfer

Article abstract of DOI:10.1016/S0040-4039(00)01002-9

Chiral salcyan complexes of aluminium are effective air and water tolerant enantioselective catalysts for the hydrophosphonylation of carbonyls. Complexes of the form [(R,R)-salcyan]A1X (X = OH, OR) result in product enantioselectivity changes (Aee) of ca

Full text of DOI:10.1016/S0040-4039(00)01002-9

Tetrahedron Letters 41 (2000) 6181±6184
New chiral catalysts for phospho-transfer
Caroline V. Ward, Mingliang Jiang and Terence P. Kee*
School of Chemistry, University of Leeds, Woodhouse Lane, Leeds LS2 9JT, UK
Received 19 May 2000; accepted 14 June 2000
Abstract
Chiral salcyan complexes of aluminium are e€ective air and water tolerant enantioselective catalysts for
the hydrophosphonylation of carbonyls. Complexes of the form [(R,R)-salcyan]AlX (X=OH, OR) result
in product enantioselectivity changes (Áee) of ca. 100% compared to those returned in the presence of
related complexes [(R,R)-salcyen]AlX even though they both possess a chiral ligand framework with the
same absolute stereochemistry. # 2000 Elsevier Science Ltd. All rights reserved.
Keywords: salcyan; aluminium complexes; hydrophosphonylation; asymmetric; catalysis.
The enantioselective hydrophosphonylation of carbonyls (or phospho±aldol1 reaction) is a
crucial and highly valuable phospho-transfer reaction for the synthesis of a-functionalised
(commonly amino or hydroxy) phosphonate esters (Scheme 1). Such phosphorus compounds
have considerable medicinal application including bio-phosphate mimics,2 transition state
models,3 anti-biotic,4 anti-viral5 and anti-tumour activity.6 Various metal complexes have been
found to act as e€ective catalysts for the reaction, including titanium7 and lanthanide8 systems.
We have been examining salcyen±metal complexes9 as catalysts for carbonyl hydrophosphonyl-
ation and recently reported that complexes of the general form [(R,R)-salcyen]AlX (X=Me,
OSiMet2Bu) a€ord ee's <50% in the addition of dimethyl-H-phosphonate (DMHP) to
substituted benzaldehydes.
Scheme 1. R=alkyl, aryl etc.; CAT=catalyst; X=O (phospho-aldol), NR (phospho-Mannich)
* Corresponding author.
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01002-9

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We report here the ®rst examples of chiral salan complexes of aluminium and their application
in asymmetric catalysis, speci®cally in the phospho-aldol reaction. Complexes [(R,R)-salcyan]-
Al(OH) 1 and [(R,R)-tBu4-salcyan]Al(OH) 2 were prepared using procedures developed by
Atwood and co-workers10 for achiral variants (Scheme 2). We ®nd that both 1 and 2 act as highly
active precursors for the catalytic addition of dimethyl-H-phosphonate (DMHP) to benzalde-
hydes but signi®cant di€erences in catalytic behaviour to their close relatives, [(R,R)-salcye-
n]AlMe 3 and [(R,R)-tBu4-salcyen]AlMe 4, are noteworthy.
Scheme 2. Syntheses of 1 and 2; (i) AlMe3; (ii) H2O. Dimeric structure of 2 from X-ray di€raction
Unsubstituted complex 3 a€ords greater stereoselectivities than the t-butyl derivative 49 in the
phospho±aldol reaction whereas the reverse is true of (R,R)-salcyan systems. Complex 1 a€ords
ee's <10%, whereas ee's <60% result in the presence of complex 2 (Table 1). Moreover, it is
intriguing to note that with the (R,R)-salcyen systems the dominant product stereochemistry is R,
whereas with the (R,R)-tBu4-salcyan systems it is S!11 Indeed, in some cases a Áee of ca. 100% is
observed between these two ligand systems.9
Enantioselectivities increase as catalyst loading decreases (runs 1±7) but seem to level o€ at ca.
1%. We envisage these results to suggest a more stereoselective catalytic species is generated as
dilution increases, similar to the ®ndings of North and co-workers in a related system for
carbonyl hydrocyanation employing titanium salcyen complexes.12 Water appears to be a
competitive inhibitor of reaction but neither kills the catalyst nor a€ects enantioselectivity (runs 8
and 9). Consistently, the addition of a 4 A molecular sieve prior to catalysis increases reaction
yield but not ee (runs 10±13). Switching from THF solvent to either CH2Cl2 or toluene does not
a€ect ee but signi®cantly compromises yield, especially for CH2Cl2 (runs 17±21). With the notable
exception of 4-Me2NC6H4CHO, the presence of electron withdrawing groups in the 4-position of
the aldehyde substrate results in lower ee's than for the electron donating groups. This is con-
sistent with carbonyl activation upon metal binding being conducive to higher ee's as found in the
salcyen systems.9 We presume that competitive achiral catalysis results from the basic NMe2
function leading to the lower than expected ee of 22% (run 16). There is little di€erence in the ee
between DMHP (runs 5, 10, 12, 14 and 15) and DEHP (runs 22±26) although the latter results in
lower turnover numbers, presumably for steric reasons.
From structural analyses of several chiral salcyen complexes9 it is clear that the salcyen ligand
prefers a meridional rather than a twisted facial coordination geometry, a feature well-documented
in achiral salen chemistry.13 However, in 2 the conformationally more ¯exible salcyan ligand
adopts a twisted facial coordination geometry in the solid-phase as part of a bridged dimeric
structure (Scheme 2, box). This has been con®rmed by a single-crystal X-ray analysis of 2.
Although the solution is not of sucient quality to warrant more detailed analysis, it clearly
identi®es both a dimeric hydroxy-bridged structure with the twisted ligand geometry shown in
Scheme 2. Such a structure should reveal itself by four distinct tBu-resonances in the solution 1H

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Table 1
Addition of DOHP (DMHP=dimethyl-H-phosphonate; DEHP=diethyl-H-phosphonate) to aldehydes in various
distilled solvents in the presence of complex 2. All reactions were performed in air at 298K unless speci®ed otherwise.
aConversions (Con) obtained after 4 h. No product other than a-hydroxyphosphonate ester was observed. bDe-
termined by 31P{1H} NMR in the presence of quinine as a chiral solvating agent (þ2%). Absolute con®gurations
determined to be S by correlation of 31P NMR shifts to optical rotations. cYield=87% and ee=53% (S) when reaction
was performed at 273K. dAfter 12 h. eAfter 24 h. fWith 20 mol% water added. g100 mol% water added. hIn presence of
4 A molecular sieves
NMR spectrum; however, NMR analyses in both CDCl3 and C6D6 suggest a considerably more
complex scenario with more than ten such resonances observable.
Although a full solid and solution phase structural analysis of 2 is currently underway, we
suggest a dimer$monomer equilibrium in solution with the monomer retaining a twisted ligand
geometry (Scheme 3). E€ective stereocontrol may then be achieved through complexation of both
H-phosphonate and carbonyl in either a single-metal or twin-metal scenario (Scheme 3). We
envisage further that since monomer should be favoured at an increasing catalyst dilution,
increasing the ee's in this order may point to the monomeric form being the more stereoselective.
Similarly, we propose that excessive water in the system leads to catalytic inhibition due to
competitive binding of water to aluminium. Electrospray mass spectrometric analysis of 2 in a
THF/MeOH solvent reveals both dimeric species m/z 1168 due to {[Al]-O-[Al]}+ and m/z 608 due
to monomeric [Al]-OMe with the latter dominating. Detailed studies to address the important
questions: (i) what is the exact nature of the catalytically active metal complex(es); (ii) what are

6184
the important features in¯uencing stereocontrol; and (iii) how can we combine mechanistic and
structure±activity studies to optimise stereoselectivities in phosphonylation processes, are in
progress.
Scheme 3. Suggested role of 2 in phospho-aldol catalysis
Acknowledgements
We thank the China Scholarship Council for ®nancial support (to M.J.), Thomas Podesta and
Colin Kilner for their e€orts on the X-ray structure of 2, and the EPSRC National Mass
Spectrometry Service (Swansea) for electrospray analysis of 2. We are grateful also to Professor
David Atwood (University of Kentucky) for helpful communications.
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