Exploring asymmetric catalytic transformations Guduguntla, Sureshbabu
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asymmetric autocatalytic reaction: nucleophilic
addition of dialkyl phosphites to aldehydes
In this chapter, efforts towards the development of a new asymmetric autocatalytic reaction based on nucleophilic addition of dialkyl phosphites to aldehydes are described. The goal was to take advantage of the aggregation behavior of metal alkoxides and to use them as catalysts to promote their own synthesis in a nucleophilic addition reaction.
5.1 Introduction
As illustrated in chapter 1, the study of asymmetric autocatalytic reactions represents a challenging topic in organic chemistry. Asymmetric autocatalysis is an extremely interesting process that may have played an important role in the origin of homochirality on the earth which is a significant prerequisite for life to emerge.1 In an asymmetric autocatalytic reaction, a product is able to catalyze its own formation (Scheme 1).
Scheme 1: General scheme for an asymmetric autocatalytic reaction.
As a proof of concept, Soai et al.2 (Scheme 2) reported an asymmetric autocatalytic reaction in 1995, which involves the nucleophilic addition of diisopropyl zinc to pyrimidine-5-carbaldehyde. This process satisfied the principles for an asymmetric autocatalytic reaction as proposed by Frank et al.3 in 1953. In this reaction, the starting material was seeded with product that contained as little as 0.00005% ee, which allowed, after several cycles, each time using the slightly more enriched product of the previous round as seed, for the product to be obtained in >99.5% ee (Scheme 2). The Soai reaction is in itself very interesting but this transformation did not lead to any biological relevant molecules. Therefore, it remains very challenging and highly important to develop an autocatalytic reaction that can yield biologically relevant molecules, and to investigate if these reactions show enantioselectivity.
The aim of the research described in this chapter was to develop a new asymmetric autocatalytic reaction which would yield biologically relevant molecules. Our approach was based on the concept of enantioselective nucleophilic addition of dialkyl phosphites to aldehydes.
5.1.1 Enantioselective synthesis of α-hydroxy phosphonates: nucleophilic addition of dialkyl phosphites to carbonyl compounds
Chiral α-hydroxyphosphonates and α-hydroxyphosphonic acids have attracted major attention due to their valuable applications in chemical and biological sciences.4 Due to the hydrolytic stability of the C-P bond present in these molecules they can act as enzyme inhibitors.5 Motifs containing the phosphonate unit are used as antiviral,6 anti-HIV7 and anti-bacterial agents,8 herbicides,9 blood pressure regulators10 and insecticides.11 In particular, α-hydroxy phosphonates have a wide range of biological activities.12 A large number of these compounds have exhibited antiviral, antibiotic and antitumor properties.13 Furthermore, many other α-functionalized phosphonates such as α-amino,14 α-acetoxy,15 α-halo,16 and α-keto phosphonates17 are prepared from α-hydroxy phosphonates.
The addition of dialkylphosphites to carbonyl compounds to synthesize α-hydroxyphosphonates, known as the Pudovik reaction (Scheme 3)18
, is a powerful and direct method for construction of C-P bonds.19 With the potential to synthesize biologically important phosphoderivatives of α-hydroxycarboxylic acids, this reaction has received attention lately with a focus on rendering the process highly enantioselective.19,20
Scheme 3: Pudovik reaction.
Several organocatalysts including Cinchona alkaloids,21 chiral phosphoric acids,22 and proline23 are known to be potential catalysts for the asymmetric Pudovik reaction. Lewis acidic metal complexes based
on titanium,24 late transition metals,25 aluminum26,27,28,29 and chiral vanadium catalysts30 have also been utilized for this reaction (Scheme 4).
Scheme 4: Representative catalysts for asymmetric Pudovik reaction.
This approach was further extended to imines as electrophiles to achieve α-aminophosphonates, resulting in a wide range of methods for the synthesis of both chiral α-hydroxy and α-aminophosphonates.19 The mechanism for the enantioselective nucleophilic addition of dialkyl phosphites to the electrophiles depends on the catalyst used,19 although in general activation of the dialkyl phosphite is required. Normally dialkylphosphites exist in the tautomeric forms of phosphonate and phosphite,31 in which the equilibrium favors the phosphonate form (Scheme 5). However, it is known that this equilibrium can be shifted to the phosphite tautomer by use of Lewis acid or Lewis base.19,31,32
The chiral catalyst activates both the carbonyl group and phosphite towards nucleophilic addition reaction. It has been proposed that the chiral backbone of the catalyst controls the stereochemistry of the resulting product through transition state A (Scheme 6).21-30
Scheme 6: General representation for the asymmetric Pudovik reaction.
5.2 Goal
Due to the invaluable applications of α-hydroxyphosphonates in both biology and chemistry,4 we were interested to develop an asymmetric autocatalytic synthesis of these molecules. Our designed approach was based on the Pudovik reaction: nucleophilic addition of dialkyl phosphite
4 to aldehyde 3 would generate chiral α-hydroxyphosphonate 5 (Scheme
6).
Scheme 6: Design of an asymmetric autocatalytic reaction based on the Pudovik
reaction: enantioselective nucleophilic addition of dialkylphosphite 4 to aldehyde 3 in the presence of product 5.
We envisioned that α-hydroxyphosphonate 5 could coordinate to a metal cation to form metal alkoxide 6, which could potentially act as a catalyst for the nucleophilic addition reaction to generate more of itself (or α-hydroxyphosphonate 5). If this process is shown to accelerate the rate of reaction33 it would have satisfied the requirements of an autocatalytic reaction.
Furthermore, seeding with a catalytic amount of enantioenriched product
5 should form enantioenriched metal alkoxide 6. By the same reasoning,
this could act as an asymmetric catalyst for the nucleophilic addition reaction to generate α-hydroxyphosphonate 5 enantioselectively. If this process would show an enhancement in enantioselectivity with a positive non-linear effect (+NLE),34 this would imply an asymmetric autocatalytic reaction.
5.3 Results and discussion
We began our studies of this reaction by screening as catalysts Lewis acids, Lewis bases or a combination of both as catalysts. We were also interested to test the behavior of the product as a ligand for metals towards its own formation. As initial conditions we chose equimolar amounts of benzaldehyde 7 and diisopropyl phosphite 8 at rt in water (considered as prebiotic solvent)1 in the presence of a catalyst (Table 1). Racemic compound 9 was synthesized from a known literature procedure.35 Using catalytic amounts of anhyd. MgCl2, Et3N, product 9 or a combination of the three in equimolar ratios did not lead to the desired product even after prolonged reaction times (8 d) (Table 1, entries 1 – 8). This may be due to the reduction of the Lewis acidic nature of MgCl236 in water as a result of the formation of hydrates MgCl2(H2O)x,37 which prevents activation of the aldehyde. We next tested LaCl3,38 a rare earth metal based strong Lewis acid, for the three component reaction. The use of La-complexes for asymmetric Lewis acid catalysis in both water and organic solvents is well described in literature39. No reaction occurred either when we used catalytic amounts of anhyd. LaCl3 (entry 9). In contrast the combination of anhyd. LaCl3 and Et3N (Lewis acid-base pair) in catalytic amounts led to the formation of product 9 in 30% over 2 d; no further conversion was observed after 8 d (entry 10). When we employed catalytic amounts of product 9 and anhyd. LaCl3 there was no reaction after 8 d (entry 11). The combination of Lewis acid-base pair (anhyd. LaCl3 and Et3N) and product 9 in catalytic amounts gave around 25% conversion to the product after 2 d. When the reaction time was prolonged to 8 d at rt no further conversion
was observed (Table 1, entry 12). These results suggests that the combination of anhyd. LaCl3 and Et3N acts as catalyst for the Pudovik reaction at rt in water. But the reaction did not go to full conversion, which may be due to the formation of lanthanum hydrates (LaCl3•7H2O)38 in water causing LaCl3 to lose its Lewis acidity. These results also showed that reactions which were seeded with product 9 did not have any significant improvement compared with their non-seeded reactions. This might indicate that the product 9 did not possess any interaction with the metal.
Table 1: Nucleophilic addition of diisopropyl phosphite 8 to
benzaldehyde 7 in the presence of Lewis acid and/or base in water.
entrya catalystb conversion (%) in time
c,d 2 d 6 d 8 d 1 – 0 0 0 2 9 0 0 0 3 MgCl2 0 0 0 4 9 + MgCl2 0 0 0 5 Et3N 0 0 0 6 9 + Et3N 0 0 0 7 MgCl2 + Et3N 0 0 0 8 9 + MgCl2 + Et3N 0 0 0 9 LaCl3 0 0 0 10 LaCl3 + Et3N 30 30 30 11 9 + LaCl3 0 0 0 12 9 + LaCl3 + Et3N 25 25 25
a) All the reactions were performed on 1 mmol scale of benzaldehyde. b) All the reagents were used in catalytic amounts (10 mol%). c) Conversions based on crude 31P NMR in CDCl3 solvent (31P NMR for 8 δ = 4.4 ppm and product δ = 19.7 ppm). d) In the case of product seeded reaction, the conversion is indicated with the exclusion of the initial 10% of product.
The previous observations indicated that the amount of Lewis acid present in the reaction mixture to activate the aldehyde was lowered via the formation of MgCl2(H2O)x and LaCl3•7H2O hydrates in water.37 It also suggested that a base was needed in order to activate the phosphite to increase its nucleophilicity. We therefore performed the reaction in dry toluene and screened several strong bases as catalysts (Table 2). Conversion of the reaction was monitored at intervals by 31P-NMR in CDCl3 (31P NMR for 8 δ = 4.4 ppm and product δ = 19.7 ppm). We were interested in using bases which would not hydrolyse the dialkyl phosphite and would not undergo any unwanted side reactions with the aldehyde. Using a catalytic amount of product 9 in combination with
iPrMgCl•LiCl led to full conversion to the product in 24 h (Table 2, entry
1). Complete conversion of the starting material was also observed when we used catalytic amounts of either product 9 and iPrMgBr or iPrMgBr alone in similar reaction times (entries 2 and 3). We also screened other organometallic reagents such as MeLi and Et2AlCl as catalysts for the reaction. Using the more reactive MeLi in catalytic amount promoted the reaction in 1 h to complete conversion (entry 4). Combination of product
9 and MeLi in equimolar ratios as catalyst led to full conversion in a
nearly comparable period (entry 5). Employing a milder reagent Et2AlCl in catalytic amount led to 80 % conversion to the product (entry 6). Interestingly, when we added 1.0 equiv of K2CO3 to the reaction mixture we observed full conversion in 4 d (entry 7). We observed almost similar results when we employed in addition catalytic amounts of product 9 in the reaction (entries 8 and 9). Finally when we used a catalytic amount of NaH and LiCl (entry 10) full conversion was observed in 1 h. Lowering the amount of NaH from 20 to 5 mol% also led to full conversion in a similar time period (entries 11 and 12). A combination of product 9 and NaH also led to complete conversion in this short reaction time (entry 13).
Table 2: Nucleophilic addition of diisopropyl phosphite 8 to
benzaldehyde 7 in the presence of different bases.
entry catalysta time conversion (%)b,c
1 9 + iPrMgCl•LiCl (1.3 M in
THF) 24 h full
2 9 + iPrMgBr (3.0 M in
2-MeTHF) 24 h full
3 iPrMgBr (3.0 M in 2-MeTHF) 24 h full
4 MeLi (1.6 M in Et2O) 1 h full
5 9 + MeLi (1.6 M in Et2O) 1 h full
6d Et2AlCl (1.8 M in toluene) 4 d 80 7d,e Et2AlCl (1.8 M in toluene) +
K2CO3
4 d full
8d 9 + Et2AlCl (1.8 M in toluene) 4 d 78
9d,e 9 + Et2AlCl (1.8 M in toluene) + K2CO3
4 d full
10 NaH (60 % in oil) + LiCl 1 h full
11 NaH (60 % in oil) 1 h full
12f NaH (60 % in oil) 1 h full
13f 9 + NaH (60 % in oil) 1 h full
a) All the reagents were used in catalytic amount (20 mol%). b) Conversions based on crude 31P NMR in CDCl3 solvent (31P NMR for 8 δ = 4.4 ppm and product δ = 19.7 ppm). c) In the case of reactions seeded with product, the conversion is indicated with the exclusion of the initial 5-20% of product. d) 10 mol% of Et2AlCl used e) 1.0 equiv of K2CO3 was used. f) Each reagent was used in 5 mol%.
These results showed that there was no prominent effect of the addition of LiCl in the nucleophilic addition reaction (Table 2, entry 1 vs 2 and entry 4 vs 5). There was also no considerable difference in rate between the reactions either seeded initially with product 9 or not. This reason might be that the phosphite acts as a strong nucleophile in the presence of a strong base, such that the preactivation of aldehyde was not required.
After having made the above observations we were interested to test the ligand properties of enantiopure product 9 in the nucleophilic addition of diisopropyl phosphite 8 to benzaldehyde 7. We synthesized (S)-diisopropyl hydroxy(phenyl)methylphosphonate 9 (Scheme 7) by following a known procedure from the literature.40 Oxidation of racemic diisopropyl hydroxy(phenyl)methylphosphonate 9 using PDC and TMSCl led to diisopropyl benzoylphosphonate 10. Asymmetric reduction of ketone 10 using NaBH4 and (+)-tartaric acid led to the desired (S)-9 in 65% isolated yield with 72% ee.40
Scheme 7: Synthesis of (S)-diisopropyl hydroxy(phenyl)methylphosphonate 9.
We also synthesized (R)-dimethylhydroxy(phenyl)methylphosphonate 12 (Scheme 8) following a known procedure from literature.41 Addition of dimethyl phosphite 11 to benzaldehyde 7 in the presence of titanium-diisopropyl tartrate at 0 °C led to (R)-12 in 90% isolated yield with 36%
ee.
Scheme 8: Synthesis of (R)-dimethyl hydroxy(phenyl)methylphosphonate 12.
With the enantioenriched α-hydroxy phosphonates 9 and 12 in hand, their potential as chiral ligands for Mg, Li and Al in the enantioselective nucleophilic addition of dialkylphosphites was investigated. We first
mixed an equimolar amount (10 mol%) of both (S)-9 (72% ee) and
iPrMgBr (3.0 M in 2-MeTHF) at 40 °C to form the proposed chiral
Mg-alkoxide complex 13 in situ (Scheme 9).42 Using this preformed catalyst
13 we attempted the nucleophilic addition of diisopropyl phosphite 8 to
benzaldehyde 7 at 40 °C. After 24 h approximately 10% conversion was observed; an almost similar conversion was observed after 48 h. Finally if the reaction mixture was allowed to warm to rt and stirred for 24 h, almost complete conversion to product 9 was found.
Since enantiomerically enriched (S)-diisopropyl
(hydroxy(phenyl)methyl)phosphonate 9 was added to the reaction mixture as a ligand, even if the reaction was not enantioselective some ee is expected. Assuming the reaction went to full completion, the 10 mol% of (S)-9 added as chiral ligand would mean the product should contain around 6.6% ee if no enantioinduction occurred. After purification of the product, (S)-diisopropyl (hydroxy(phenyl)methyl)phosphonate 9 was obtained in 95% yield and showing an ee of 6%. Since this is close to the theoretical 6.6% ee, it can be concluded that there was no significant effect of 13 as chiral catalyst in the transformation (Scheme 9).
Scheme 9: Enantioselective nucleophilic addition of diisopropyl phosphite 8 to
benzaldehyde 7 in the presence of a proposed chiral Mg-alkoxide 13.
Next, we mixed an equimolar amount of both enantioenriched product 9 (72% ee) and MeLi (1.6 M in Et2O) at –60 °C to form the proposed chiral Li-alkoxide complex 14.25,43 Using a catalytic amount of 14 (5 mol%) at –60 °C, we performed the nucleophilic addition of diisopropyl phosphite
8 to benzaldehyde 7. Almost complete conversion to the product 9 was
138
As before a minimal ee of 3.5% could be expected due to the addition of enantiopure product. After purification of the product, (S)-9 was obtained in 94% isolated yield which showed an ee of 5.2%. Since this difference was too small to be significant, it was concluded that there was no significant effect of 14 in the chiral transformation (Scheme 10).
Scheme 10: Enantioselective nucleophilic addition of diisopropyl phosphite 8 to
benzaldehyde 7 in the presence of a proposed chiral Li-alkoxide 14.
We then turned our attention to form proposed chiral Al-alkoxide complex 15 by addition of Et2AlCl (1.8 M in toluene) (10 mol%) to a solution of (S)-diisopropyl hydroxy(phenyl)methylphosphonate 9 (20 mol%) in dry toluene at 40 °C.26-29,39a In the presence of chiral Al-alkoxide 15 and K2CO3 (1.0 equiv), the nucleophilic addition of diisopropyl phosphite 8 to benzaldehyde 7 was carried out at rt. After 2 d almost complete conversion was observed (Scheme 11).
As before, due to the presence of enantiopure product at the start of the reaction a minimal ee of 12% can be expected. After purification of the product, (S)-diisopropyl (hydroxy(phenyl)methyl)phosphonate 9 was obtained in 96% isolated yield with 10% ee. It can therefore be concluded that there was no significant effect of 15 in the chiral transformation (Scheme 11).
139
Scheme 11: Enantioselective nucleophilic addition of diisopropyl phosphite 8 to
benzaldehyde 7 in the presence of a proposed chiral Al-alkoxide 15.
Finally we investigated the effect of non-symmetric dialkyl phosphites in the asymmetric nucleophilic addition reaction. As these phosphites are chiral at phosphorus, we envisioned that the reaction might proceed via kinetic resolution.44 Based on the aggregation behavior of Li-alkoxides,43a,45 we proposed that chiral Li-alkoxide C may catalyse the reaction by preferentially activating one enantiomer of the dialkylphosphite 16 over the other (Scheme 12), thus more rapidly forming one enantiomer and diastereomer of product 17, while leaving the other enantiomer of dialkylphosphite 16 mostly unreacted.
Scheme 12: Proposed reaction for the kinetic resolution of racemic dialkylphosphites.
We first synthesized different chiral non-symmetric dialkyl phosphites (Scheme 13) according to the literature procedures.46 By stirring an equimolar mixture of dialkyl phosphites and tetrabutylammonium h dro ide at 1 1 °C over 3 h the corresponding tetrabutylammonium phosphite salts were obtained in almost quantitative yields. These phosphite anions were subjected to an O-alkylation reaction to give the desired chiral non-symmetrical dialkyl phosphite in good yield (Scheme 13).
140
Scheme 13: Synthesis of racemic dialkyl phosphites.
Having different racemic dialkyl phosphites in hand, we tested them for the enantioselective nucleophilic addition reaction in the presence a catalytic amount of enantioenriched Li-alkoxide 28. Li-alkoxide 28 was prepared by mixing an equimolar ratio of compound 12 (36% ee) and MeLi at 60 °C (Scheme 14). In the presence of 5 mol% chiral Li-alkoxide 28 as a catalyst at 60 °C, the nucleophilic addition of ethylmethyl phosphite 24 to benzaldehyde 7 was performed. Following stirring for 1 h at 60 °C, almost complete consumption of the starting material was observed. After purification, the desired compound 28 was isolated as a 1:1 diastereomeric mixture (Scheme 14), where both diastereomers proved to be racemic.
Scheme 14: Nucleophilic addition of ethylmethyl phosphite 24 to benzaldehyde 7 in the
presence of a proposed chiral Li-alkoxide 28.
The above results suggest that the metal alkoxides 13, 14, 15 and 28 have no significant effect on the chiral transformation in nucleophilic addition of dialkyl phosphites to benzaldehyde. A reason could be that the metal alkoxides are not sufficiently Lewis acidic to activate the aldehydes. Instead they may act as strong base to increase the nucleophilicity of the phosphite, which would promote the non-catalyzed background reaction. In addition, the flexible structure of the alkoxide ligands in the aggregated state may not effectively control the stereochemical outcome of the reaction.47
5.4 Conclusions
In our efforts to design a model autocatalytic asymmetric transformation we studied many conditions for the nucleophilic addition of diisopropyl phosphite to benzaldehyde. When run in water using MgCl2, Et3N or mixtures of both, no reaction could be observed. This might be due to loss of Lewis acidic nature of MgCl2 in water by forming hydrates MgCl2(H2O)x, which inhibits activation of the aldehyde. The combination of LaCl3 and Et3N led to product formation, however, conversion remained low and the reaction stopped after 20-30% of product formation. Longer reaction times did not lead to full conversion either. This may be due to the formation of lanthanum hydrates (LaCl3•7H2O) in water and LaCl3 losing its Lewis acidity. Catalytic amount of strong base was needed in order to achieve complete conversion of the starting material. The base could activate the phosphite to increase the nucleophilicity such that the preactivation (by Lewis acid) of aldehyde was not required. There was no prominent difference between the reactions either seeded initially with product or not. Furthermore we synthesized the enantioenriched α-hydroxy phosphonates 9 and 12 with good isolated yields. We also synthesized different chiral non-symmetrical dialkyl phosphites in good yields. We did not observed any chirality transfer from chiral alkoxides 13, 14, 15 and 28 in the nucleophilic addition reaction examined here. This might be due to their strong basicity and flexibility of the structure.
Interestingly, the combination of LaCl3 and Et3N showed some activity in the Pudovik reaction, resulting in product formation. Further attempts might focus on optimizing the conditions in order to achieve complete conversion to product and studies of the reaction kinetics.
5.5 Experimental section
5.5.1 General procedures
Flash column chromatography: Merck silica gel type 9385 230-400 mesh, TLC: Merck silica gel 60, 0.25 mm. Components were visualized
142
by UV, phosphomolybdic acid and potassium permanganate staining. Progress and conversion of the reaction were determined by GC-MS (GC, HP6890: MS HP5973) with an HP1 or HP5 column (Agilent Technologies, Palo Alto, CA). Mass spectra were recorded on an AEI-MS-902 mass spectrometer (EI+) or a LTQ Orbitrap XL (ESI+). 1H- and 13
C-NMR were recorded on a Varian AMX400 (400 and 100.59 MHz, respectively) or a Varian VXR300 (300 and 75 MHz, respectively) using CDCl3 as solvent. Chemical shift values are reported in ppm with the solvent resonance as the internal standard (CHCl3: 7.26 for 1H, 77.0 for 13C). Data are reported as follows: chemical shifts, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br = broad, m = multiplet), coupling constants (Hz), and integration. Optical rotations were measured on a Schmidt + Haensch polarimeter (Polartronic MH8) with a 10 cm cell (c given in g/100 mL). Enantiomeric ratios were determined by HPLC analysis using a Shimadzu LC-10ADVP HPLC equipped with a Shimadzu SPD-M10AVP diode array detector.
All reactions were carried out under nitrogen atmosphere using oven dried glassware and using standard Schlenk techniques. Dry solvents were used from the solvent purification system (MBRAUN SPS systems, MB-SPS-800). All starting materials were purchased from commercial sources, and used without further purification unless indicated.
Note: Benzaldehyde was freshly distilled prior to use.
5.5.2 Synthesis of (S)-diisopropyl hydroxy(phenyl)methylphosphonate (9)40
Diisopropyl benzoylphosphonate (10)
To a stirred suspension of pyridinium dichromate (4.50 g, 12.0 mmol, 3.1 equiv) in dry DCM (40 mL, 0.3 M) at 0 °C, chlorotrimethylsilane (3.60
143
mL, 27.8 mmol, 7.2 equiv) was added dropwise. After stirring for 10 min at the same temperature, a solution of (±)-9 (1.05 g, 3.86 mmol, 1.0 equiv) dissolved in dry DCM (20 mL, 0.2 M) was added dropwise. The reaction mixture was stirred at rt for 18 h to get complete consumption of the starting material (monitored by TLC). The reaction mixture was then passed through a pad of silica gel and washed with EtOAc (2x10 mL). The volatiles were evaporated under vacuum to afford the crude product mixture. This residue was purified by flash column chromatography on silica gel with mixtures of solvents (EtOAc/pentane, 5:95 to 20:80) to afford the product diisopropyl benzoylphosphonate (10) as a pale yellow oil (626 mg, yield = 60%). Spectral data in agreement with literature.48
(S)-Diisopropyl hydroxy(phenyl)methylphosphonate (9)
To a suspension of sodium borohydride (224 mg, 5.92 mmol, 4.0 equiv) in dry THF (25 mL, 0.24 M) at 0 °C was added (2R,3R)-(+)-tartaric acid (886 mg, 5.92 mmol, 4.0 equiv) portionwise and the reaction mixture was heated at reflux for 4 h. After this time the reaction mixture was cooled to – 30 °C and a solution of ketophosphonate 10 (400 mg, 1.48 mmol, 1.0 equiv) in dry THF (5 mL, 0.3 M) was added dropwise. The reaction mixture was stirred at the same temperature for 24 h, diluted with EtOAc (20 mL) and quenched with aq. 1 N HCl (20 mL) slowly. The mixture was warmed to rt, the layers were separated and the aqueous layer was extracted with EtOAc (2x20 mL). The combined organic layers were washed with saturated aq. Na2CO3 (20 mL), dried over anhydrous MgSO4, filtered and the volatiles were evaporated under vacuum. The residue was purified by flash column chromatography on silica gel using a mixture of solvents (acetone/pentane, 10:90 to 20:80) to afford the desired (S)-diisopropyl hydroxy(phenyl)methylphosphonate (9) as a white solid (260 mg, yield = 65%) with 72% ee. Chiralcel OD-H column,
n-heptane/i-PrOH 95:5, 40 °C, 215 nm, retention times (min): 9.39
(S)-enantiomer (45% ee): [α]D20 = – 12.0 (c = 1.0 in CHCl3)]. Spectral data in agreement with literature.40
5.5.3 Synthesis of (R)-dimethyl hydroxy(phenyl)methylphosphonate (12)41
To a stirred solution of D-(−)-diisopropyl tartrate (461 mg, 1.97 mmol, 0.2 equiv) at rt in dry toluene (5 mL, 0.39 M) was added Ti(OiPr)4 (0.580 mL, 1.97 mmol, 0.2 equiv). The reaction mixture was stirred for 2 h at rt, after which it was cooled to 0 °C and a solution of dimethyl phosphite (1.06 mL, 11.6 mmol, 1.18 equiv) in dry toluene (3 mL, 3.88 M) was added dropwise. After stirring for 30 min at 0 °C, a solution of benzaldehyde (1.00 mL, 9.84 mmol, 1.0 equiv) in dry toluene (3.0 mL, 3.28 M) was added dropwise and the reaction mixture was stirred for another 16 h at the same temperature. The reaction mixture was quenched with saturated aq. NaHCO3 (10 mL), the layers were separated and the aqueous layer was extracted with Et2O (3x20 mL). The combined organic layers were washed with saturated aq. NaCl (10 mL), dried over anhydrous MgSO4, filtered and the volatiles were evaporated under vacuum. The residue was purified by flash column chromatography on silica gel using a mixture of solvents (acetone/pentane, 20:80 to 50:50) to afford the (R)-dimethyl hydroxy(phenyl)methylphosphonate (12) as a white solid (1.8 g, yield = 90%). 36% ee. Chiralcel AS-H column, n-heptane/i-PrOH 95:5, 40 °C, 215 nm, retention times (min): 25.50 (major) and 34.63 (minor). [α]D20 = + 18.7 (c = 1.0 in CHCl3); [lit.49 (R)-enantiomer (84% ee): [α]D20 = + 38.0 (c = 0.330 in CHCl3)]. Spectral data in agreement with literature.50
145
5.5.4 General procedure for the synthesis of chiral (racemic) non-symmetrical dialkyl phosphites
Step 1: An equimolar mixture of dialkyl phosphite (15 mmol, 1.0 equiv)
and a solution of tetra butyl ammonium hydroxide (1.5 M in H2O, 10 mL, 15 mmol, 1.0 equiv) was stirred at 10 – 15 °C. After complete consumption of the starting dialkyl phosphite (monitored by 31P NMR), the reaction mixture was diluted with DCM (20 mL). The layers were separated and the aqueous layer was extracted with DCM (2x20 mL). The combined organic layers were dried over anhydrous MgSO4, filtered and the volatiles were evaporated under vacuum to afford tetrabutylammonium phosphite salt which was used directly in the step without any further purification.
Step 2: The tetrabutylammonium phosphite salt (10 mmol, 1.0 equiv)
derived from step 1 was dissolved in acetonitrile (20 mL, 0.5 M) and the corresponding alkyl iodide or alkyl bromide (10 mmol, 1.0 equiv) was added. The reaction mixture was heated to 70 °C. After complete consumption of the starting material (monitored by 31P NMR) the volatiles were evaporated under vacuum to afford a waxy solid. To this solid was added Et2O (10 mL) and after stirring for 10 min a white precipitate was observed. The white solid was filtered and washed with Et2O (2x10 mL). The combined filtrates were evaporated under vacuum to afford a crude mixture. This residue was purified by flash column chromatography (FCC) on silica gel using a mixture of solvents as mentioned in each entry.
Note: The final products were unstable at rt and hydrolysis was observed.
Hence steps are not completely optimized and full characterization was not possible.
Ethyl methyl phosphonate (24) Diethyl phosphite (2.07 g, 15.0 mmol,
1.0 equiv) and MeI (0.94 mL, 15 mmol, 1.0 equiv) was used. Purified by FCC (SiO2, 50 to 100% EtOAc/pentane) to afford ethyl methyl
146
phosphonate (19) (930 mg, yield = 50%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 6.81 (d, J = 695.5 Hz, 1H), 4.27 – 4.14 (m, 2H), 3.80 (d, J = 11.9 Hz, 3H), 1.39 (t, J = 7.1 Hz, 3H); 31P NMR (162 MHz, CDCl3) δ 8.9.
Benzyl isopropyl phosphonate (25) Diisopropyl phosphite (2.49 g, 15.0
mmol, 1.0 equiv) and benzyl bromide (1.78 mL, 15.0 mmol, 1.0 equiv) was used. Purified by FCC (SiO2, 50 to 100% Et2O/pentane) to afford benzyl isopropyl phosphonate (20) (1.54 g, yield = 48%) as a colorless oil. Chiral separation on Chiralcel AS-H column, n-heptane/i-PrOH 98:2, 40 °C, 208 nm, retention times (min): 30.80 and 35.55. 1H NMR (400 MHz, CDCl3) δ 7.48 – 7.28 (m, 5H), 6.88 (d, J = 697.5 Hz, 1H), 5.09 (d, J = 9.4 Hz, 2H), 4.81 – 4.67 (m, 1H), 1.33 (t, J = 6.4 Hz, 6H); 31P NMR (162 MHz, CDCl3) δ 6.1.
Benzyl methyl phosphonate (26)
Dimethyl phosphite (1.65 g, 15.0 mmol, 1.0 equiv) and benzyl bromide (1.78 mL, 15.0 mmol, 1.0 equiv) was used. Purified by FCC (SiO2, 50 to 100% Et2O/pentane) to afford benzyl methyl phosphonate (21) (1.12 g, yield = 40%) as a colorless oil. Chiral separation on Chiralcel OD-H column, n-heptane/i-PrOH 95:5, 40 °C, 210 nm, retention times (min): 16.76 and 19.16. 1H NMR (400 MHz, CDCl3) δ 7.50 – 7.29 (m, 5H), 6.83 (d, J = 703.0 Hz, 1H), 5.10 (d, J = 9.7 Hz, 2H), 3.70 (d, J = 12.1 Hz, 3H); 31P NMR (162 MHz, CDCl3) δ 9.1.
5.5.5 General procedure for the entries in Table 1
A 20 mL screw capped vial was equipped with a stirring bar and charged with aldehyde (1 mmol) and all other reactants (10 mol% each). Water (5 mL) was added, the vial was closed and the reaction mixture was stirred at rt. The progress of the reaction was monitored by 31P NMR (31P NMR for 8 δ = 4.4 ppm and product δ = 19.7 ppm) via aliquots (0.1 mL) over
147
the indicated time period. The aliquots were diluted with CDCl3 (0.5 mL), passed through a plug of anhydrous MgSO4 and 31P NMR was acquired. Due to low conversions, the isolation of the product was not performed.
5.5.6 General procedure for the entries 3, 4, 6, 7, 10, 11 and 12 in Table 2.
An oven dried Schlenk tube equipped with a septum and stirring bar under a N2 atmosphere was charged with a solution of diisopropyl phosphite (170 µL, 1.00 mmol, 1.0 equiv) in dry toluene (4.0 mL, 0.25 M). This solution was cooled to 0 °C and the corresponding base was added portionwise (5 – 20 mol%). After stirring for 15 min at 0 °C, a solution of benzaldehyde (0.1 mL, 1.0 mmol, 1.0 equiv) in dry toluene (1.0 mL, 1 M) was added dropwise and the reaction mixture was warmed to rt. After complete consumption of the starting material (monitored by 31P-NMR), the reaction mixture was quenched with water (5 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3x5 mL). The combined organic layers were dried over anhydrous MgSO4, filtered and the volatiles were evaporated under the vacuum to afford almost pure product (>98%).
5.5.7 General procedure for the entries 1, 2, 5, 8, 9 and 13 in Table 2.
An oven dried Schlenk tube equipped with a septum and stirring bar under a N2 atmosphere was charged with a solution of (±)-9 (5 – 20 mol%) in dry toluene (5 mL, 0.01 – 0.04 M). This solution was cooled to 0 °C and the corresponding base was added portion-wise (5 – 20 mol%). After stirring for 15 min at 0 °C, diisopropyl phosphite (170 µL, 1.00 mmol, 1.0 equiv) and benzaldehyde (0.1 mL, 1.0 mmol, 1.0 equiv) were added and the solution was warmed to rt. After complete consumption of the starting material (monitored by 31P-NMR), the reaction mixture was quenched with water (5 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3x5 mL). The combined organic layers were dried
over anhydrous MgSO4, filtered and the volatiles were evaporated under the vacuum to afford almost pure product (>98%).
5.5.8 General procedure: Nucleophilic addition of diisopropyl phosphite 8 to benzaldehyde 7 in the presence of chiral Mg-alkoxide 13.
An oven dried Schlenk tube equipped with a septum and stirring bar under a N2 atmosphere was charged with a solution of (S)-9 (30 mg, 0.11 mmol, 0.1 equiv) in dry toluene (5 mL, 0.022 M). The reaction mixture was cooled to 40 °C and a solution of iPrMgBr (3.0 M in 2-MeTHF, 37 µL, 0.11 mmol, 0.1 equiv) was added dropwise. After stirring for 15 min at the same temperature, both diisopropyl phosphite (180 µL, 1.10 mmol, 1.00 equiv) and benzaldehyde (112 µL, 1.00 mmol, 1.0 equiv) were added. The reaction mixture was stirred for 48 h at 40 °C and at rt for 24 h. After complete consumption of the starting material (monitored by 31
P-NMR), the reaction mixture was quenched with water (5 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3x5 mL). The combined organic layers were dried over anhydrous MgSO4, filtered and the volatiles were evaporated under the vacuum. Purification of the residue by flash column chromatography on silica gel using a mixture of solvents (acetone/pentane, 10:90 to 20:80) to afford the product 9 as a white solid (285 mg, yield = 95%) with 6% ee.
5.5.9 General procedure: Nucleophilic addition of diisopropyl phosphite 8 to benzaldehyde 7 in the presence of chiral Li-alkoxide 14.
An oven dried Schlenk tube equipped with a septum and stirring bar under a N2 atmosphere was charged with a solution of (S)-9 (27.0 mg, 0.098 mmol, 0.05 equiv) in dry toluene (6 mL, 0.016 M). The reaction mixture was cooled to 60 °C and a solution of MeLi (1.6 M in Et2O, 61.5 µL, 0.098 mmol, 0.05 equiv) was added dropwise. After stirring for 15 min at the same temperature, both diisopropyl phosphite (330 µL, 1.97 mmol, 1.0 equiv) and benzaldehyde (200 µL, 1.97 mmol, 1.0 equiv) were added.
149
After stirring for 1 h at the same temperature, almost complete consumption of the starting material was observed (monitored by 31 P-NMR). The reaction mixture was quenched with water (5 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3x5 mL). The combined organic layers were dried over anhydrous MgSO4, filtered and the volatiles were evaporated under the vacuum. Purification of the residue by flash column chromatography on silica gel using a mixture of solvents (acetone/pentane, 10:90 to 20:80) to afford the product 9 as a white solid (504.5 mg, yield = 94%) with 5.2% ee.
5.5.10 General procedure: Nucleophilic addition of diisopropyl phosphite 8 to benzaldehyde 7 in the presence of chiral Al-alkoxide 15.
An oven dried Schlenk tube equipped with a septum and stirring bar under a N2 atmosphere was charged with a solution of (S)-9 (107 mg, 0.394 mmol, 0.2 equiv) in dry toluene (6 mL, 0.066 M). The reaction mixture was cooled to 40 °C and a solution of Et2AlCl (1.8 M in toluene, 110 µL, 0.197 mmol, 0.1 equiv) was added dropwise and followed by K2CO3 (273 mg, 1.97 mmol, 1.0 equiv). After stirring for 15 min at the same temperature, both diisopropyl phosphite (330 µL, 1.97 mmol, 1.0 equiv) and benzaldehyde (200 µL, 1.97 mmol, 1.0 equiv) were added. The reaction mixture was stirred at rt for 48 h in order to get complete consumption of the starting material (monitored by 31P-NMR). The reaction mixture was quenched with water (5 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3x5 mL). The combined organic layers were dried over anhydrous MgSO4, filtered and the volatiles were evaporated under the vacuum. Purification of the residue by flash column chromatography on silica gel using a mixture of solvents (acetone/pentane, 10:90 to 20:80) to afford the product 9 as a white solid (515 mg, yield = 96%) with 10% ee.
150
5.5.11 General procedure: Nucleophilic addition of ethylmethyl phosphite 24 to benzaldehyde 7 in the presence of chiral Li-alkoxide 28.
An oven dried Schlenk tube equipped with a septum and stirring bar under a N2 atmosphere was charged with a solution of (R)-12 (85.0 mg, 0.394 mmol, 0.2 equiv) in dry toluene (6.0 mL, 0.066 M). The reaction mixture was cooled to 60 °C and a solution of MeLi (1.6 M in Et2O, 0.250 mL, 0.394 mmol, 0.2 equiv) was added dropwise. After stirring for 15 min at the same temperature, both chiral ethylmethyl phosphite 22 (245 mg, 1.97 mmol, 1.0 equiv) and benzaldehyde (200 µL, 1.97 mmol, 1.0 equiv) were added. After stirring for 1 h at the same temperature, complete consumption of the starting material was observed (monitored by 31 P-NMR). The reaction mixture was quenched with water (5 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3x5 mL). The combined organic layers were dried over anhydrous MgSO4, filtered and volatiles were evaporated under the vacuum. Purification of the residue by flash column chromatography on silica gel using a mixture of solvents (acetone/pentane, 10:90 to 20:80) to afford the product 25 as a pale yellow thick oil (408 mg, yield = 90%).
50:50 dr, 50:50 er for each diastereomer. Chiralcel AS-H column, n-heptane/i-PrOH 95:5, 40 °C, 210 nm, retention times (min): 15.62, 19.84, 24.42 and 30.34. 1 H NMR (400 MHz, CDCl3) δ 7.47 – 7.38 (m, 2H), 7.36 – 7.22 (m, 3H), 5.03 – 4.93 (m, 1H), 3.71 – 3.52 (m, 5H), 1.25 – 1.18 (m, 3H); 31P NMR (162 MHz, CDCl3) δ 23.6, 22.6.
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