Catalytic enantioselective pudovik reaction of aldehydes and aldimines with tethered bis(8-quinolinato) (TBOx) aluminum complex

Article abstract of DOI:10.1021/ja803859p

New chiral tethered bis(8-quinolinolato) (TBOx) aluminum(III) complexes effectively catalyze the addition of phosphites to aldehydes and aldimines to give enantioenriched α-hydroxy and α-amino phosphonates in high yields and enantioselectivities with unpr

Full text of DOI:10.1021/ja803859p

Published on Web 07/22/2008
Catalytic Enantioselective Pudovik Reaction of Aldehydes and Aldimines with
Tethered Bis(8-quinolinato) (TBOx) Aluminum Complex
Joshua P. Abell and Hisashi Yamamoto*
Department of Chemistry, The UniVersity of Chicago, 5735 South Ellis AVenue, Chicago, Illinois 60637
Received May 22, 2008; E-mail: yamamoto@uchicago.edu
Scheme 1. Synthesis of (R)-TBOxAlCl
The addition of dialkylphosphites to carbonyl compounds to
generate R-hydroxyphosphonates, known as the Pudovik reaction,
is a powerful and direct method for construction of C-P bonds.
With the potential to synthesize biologically important phospho-
derivatives of R-hydroxycarboxylic acids, this reaction has
received deserved attention lately to make the process highly
enantioselective.1 To date several organocatalysts including
Cinchona alkaloids2 and chiral phosphoric acids,3 Lewis acids
including titanium,4 late transition metals,5 aluminum6a
SALALEN,6b SALEN,7 SALAN,7 BINOL,8 and chiral vanadium
catalyst9 have been utilized for this reaction. Unfortunately, these
catalysts typically require high catalyst loading and long reaction
times, usually g5 mol % or greater and several days.
Table 1. Reaction Optimization
Due to the recent success using the ligand 1 developed in our
laboratory,10 we envisaged that our ligand, when complexed with
aluminum, could prove to be a highly selective and active catalyst
for the Pudovik reaction. With the chiral tethered bis(8-quinolinato)
(TBOxH) ligand in hand, complexation took place smoothly at room
temperature by addition of a solution of Et2AlCl (Scheme 1). This
catalyst 2 was used under previously reported conditions; however,
only low yields and enantioselectivities were observed (Table 1,
entries 1-4). With these positive results we set out to find a more
reactive system.
entry
R
T(°C)
yield (%)a
ee (%)b
1
Me
Et
Me
Ph
RT
RT
RT
RT
RT
RT
-15
RT
RT
20
18
94
48
94
30
27
93
94
24
23
20
<5
48
<5
50
65
78
2
3c
4
5d
6
CH2CF3
CH(CF3)2
CH2CF3
CH2CF3
CH2CF3
7e
8f
9g
While the actual mechanism has not been experimentally
confirmed, it is believed that the first step is deprotonation of
the phosphite to generate a more highly nucleophilic species.1d
The proton on the phosphite was found to be crucial for the
enantioselectivity of the reaction.11 Using a more electron
withdrawing alkyl group on the phosphite the yield could be
improved to synthetically useful levels. As shown in Table 1,
the bis(2,2,2-trifluoroethyl) phosphite increased the yield to 94%
and the enantioselectivity to 48% (entry 5).12 With efforts now
focused on increasing the enantioselectivity, increasing the size
of the alkyl group only decreased the yield and selectivity (entry
6), possibly due to decreased nucleophilicity of the phosphite
and increased steric environment. Decreasing the reaction
temperature only decreased the reactivity while not increasing
the enantioselectivity (entry 7). Interestingly, after screening the
reaction conditions, decreasing the catalyst loading of the
reaction increased the enantioselectivity while maintaining the
same reactivity and yield (entry 8). This phenomenon was also
observed with the work of North in the enantioselective
silylcyanation reaction13 and more closely related with Kee’s
hydrophosphonylation reaction.7 Furthermore, it was found that
nonpolar solvents gave higher enantioselectivity, with hexanes
giving the highest reactivity and selectivity (entry 9).
a Isolated yield after column chromatography. b Determined by HPLC
analysis. c 5.0 equiv of phosphite was employed. d Reaction was
completed after 1 h. e Reaction not complete after 24 h. f 1 mol %
catalyst employed. g Hexanes used as solvent.
at the 5,5′-position of the quinoline ring led to a dramatic
increase in enantioselectivity (entry 2). Pleased with this result
we further examined other derivatives and found catalysts 4 and
5 to be most reactive and selective (entries 3 and 4). Since there
was no change in yield and enantioselectivites of the most
selective catalysts, catalyst 4 was chosen for further examination.
Having optimized reaction conditions, the substrate scope of
the reaction was explored (Table 3). It was found that electron
rich compared to electron poor aromatic aldehydes proved to
be more reactive and selective (entries 6, 7, 9, 10). Aliphatic
aldehydes could also be used, further establishing the utility of
our system (entries 11,12). All reactions proceeded very quickly,
with high yields and enantioselectivity. Furthermore, the catalyst
loading could be decreased to 0.5 mol % with essentially no
loss in enantioselectivity or yield with slightly prolonged reaction
times (entries 1, 3, 7).
With the influence of the phosphite and solvent now estab-
lished, the ligand structure was examined (Table 2). The ligand
structure was found to be highly influential on the enantiose-
lectivity of the product. Simply attaching a phenyl substituent
Upon further investigation of this ligand system with previ-
ously synthesized ligands by our group, it was found that the
substitution at the 5,5′-position of the quinoline ring had a
dramatic increase on the rate of the reaction. To demonstrate
9
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C O M M U N I C A T I O N S
Table 2. Catalyst Optimization
Table 4. Aldimine Protection Group Screening
entry
P
yield (%)a
ee (%)b
1
2
3
4
Boc
Bn
trace
62
35
ND
<5
15
Ph
DPPc
95
96
a Isolated yield after column chromatography. b Determined by HPLC
analysis. c DPP ) diphenylphosphinoyl.
entry
catalyst
yield (%)a
ee (%)b
Table 5. Aldimine Reaction Scopec
1
2
3
4
2
3
4
5
94
95
96
95
78
91
96
96
a Isolated yield after column chromatography. b Determined by HPLC
analysis.
entry
R
yield (%)a
ee (%)b
1
2
3
4
5
6
7
8
9
Ph
98
85
88
90
91
92
93
90
96
89
93
96
90
92
88
90
96
98
90
92
91
94
Table 3. Aldehyde Reaction Scoped
4-ClC6H4
4-BrC66H4
4-NO2C6H4
4-MeOC6H4
4-MeC6H4
3-MeOC6H4
2-MeC6H4
2-MeC6H4
2-furyl
entry
R
time (min)
yield (%)a
ee (%)b
1
2
3
4
5
6
7
8
9
Ph
10
15
15
15
10
10
5
20
10
5
95 (94)
98
94 (93)
96
93
93
94 (94)
93
93
95
95
96 (95)c
95
2-naphthyl
4-ClC6H4
4-BrC6H4
4-NO2C6H4
4-MeOC6H4
4-MeC6H4
3-MeOC6H4
2-MeOC6H4
2-MeC6H4
c-hexyl
10
11
95 (93)c
95
2-thienyl
a Isolated yield after column chromatography. b Determined by HPLC
analysis (see Supporting Information). c Absolute configuration
determined by optical rotation in comparison with previously reported
R-amino phosphonic acid.
92
97
94 (94)c
95
93
95
82
82
10
11e
12e
25
20
as antifungal16 and antibacterial16 agents highly depends on the
absolute configuration of the R-carbon. To date only a few
examples of catalyzed hydrophosphonylation to aldimines with
a direct C-P bond formation exist.12,17,18 Still improvements
in the area of catalyst loading and reaction times can be made.
n-hexyl
91
a Isolated yield after column chromatography. b Determined by HPLC
analysis. c 0.5 mol
%
was employed in parentheses. d Absolute
configuration determined by X-ray analysis of entry 4. e Ee determined
after conversion to benzoate ester.
After screening several imines it was found that N-diphe-
nylphosphinoyl imines provided the highest enantioselectivity
and yield (Table 4). N-Diphenylphosphinoyl imines have been
demonstrated previously as versatile electrophiles in a number
of asymmetric reactions.19 This labile nitrogen protection group
is easily cleaved in mildly acidic conditions.
Scheme 2. Ligand Competition Experiment
Using the typical reaction conditions the substrate scope of
this reaction was established (Table 5). A variety of imines are
well suited for this catalyst system including a number of
subsituents and hetereoatoms. Electron rich aldimines showed
higher reactivity (entries 5-9), while electron poor aldimines
showed slightly diminished reactivity but still high yields of the
protected amines (entries 2-4). This high enantioselection using
both aldehydes and aldmines has been shown previously, albeit
with longer reaction times and higher catalyst loadings.17
the difference in reactivity, the enantiopure 5,5′-substituted ligand
((R)-Al cat. 4) and an enantiopure unsubstituted oppositely
stereoconfigured ligand ((S)-Al cat. 2) were added in equal
catalytic amounts to a reaction vessel and subjected to the typical
reaction conditions (Scheme 2). It was found that the product
was favored for the substituted ligand in the same enantiose-
lection as the same ligand alone.
In light of the recent success with the simple synthesis of
R-hydroxyphosphonates we expected that our aluminum catalyst
could also be applicable to other electrophiles and the natural
extension of aldehydes is aldimines. Synthesis of optically active
R-aminophophonates has been the pursuit of several research
groups.12,14 Their potential use as proteinase inhibtors15 as well
The use of optically active R-hydroxy- and R-aminophopho-
nates to test for biological activity requires that the phosphorus
moiety be deprotected to the free acid. Serveral reported
procedures utilize either TMSBr,1,20 TMSCl, and NaI1,21 at room
temperature or BBr3 at elevated temperatures to deprotect the
phosphonate ester; however, in our hands these procedures
22
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C O M M U N I C A T I O N S
Scheme 3. Synthesis of R-Hydroxy- and R-Aminophosphonic Acids
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Acknowledgment. Support of this research was provided by
the National Science Foundation (CHE-0717618). We would like
to thank Marina Naodovic and also Dr. Ian M. Steele (X-ray
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Supporting Information Available: Experimental procedures,
spectral data for all new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
JA803859P
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