Exploring asymmetric catalytic transformations Guduguntla, Sureshbabu
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Efforts towards the development of a new
asymmetric autocatalytic reaction: metal-ligand
approach
In this chapter, efforts towards the development of a new asymmetric autocatalytic reaction based on a metal-ligand approach is discussed.
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6.1 Introduction
Homochirality and self-replication are among the most important properties of biologically relevant molecules as is illustrated in the introduction chapter.1,2,3,4,5 The essential molecules of life, like oligonucleotides, proteins and carbohydrates are homochiral i.e. amino acids are left handed and sugars are right handed.2,3 Furthermore, the origin of homochirality of biomolecules is directly related to the ‛origin of life’ question.6 The origin of homochirality in biologically relevant molecules (amino acids and sugars) is still largely a mystery.1-5
In 1953 Frank et al.7 proposed a theoretical model to understand the concept of amplification of chirality by means of asymmetric autocatalysis. As a proof of concept Soai et al.8 reported an asymmetric autocatalytic reaction in 1995, which satisfied the criteria proposed by Frank et al. Up to now this is the only reliable example known and its mechanistic aspects are still not fully understood.9a-e Therefore it would be a real challenge to find other reactions which show asymmetric autocatalytic behavior.9f-j
The main objective of the research discussed in this chapter was to develop a new asymmetric autocatalytic reaction based on a metal-ligand approach. We choose two different paths: 1) enantioselective nucleophilic addition of Grignard reagents to carbonyl compounds, in particular titanium-promoted catalytic enantioselective addition of Grignard reagents to aldehydes and 2) asymmetric reduction of ketones with borane reagents, especially using the concept of Corey-Bakshi-Shibata (CBS) reduction.
6.1.1 Titanium-promoted catalytic enantioselective addition of Grignard reagents to aldehydes
The catalytic asymmetric nucleophilic addition of organometallic reagents to carbonyl compounds is one of the most widely used method in synthetic organic chemistry for the synthesis of highly valuable chiral secondary or tertiary alcohols.10 This key transformation11 was studied
extensively using different organometallic reagents such as organozinc,12 organoaluminium,13 and organotitanium14 reagents. In comparison to several other organometallic reagents, Grignard reagents and organolithium reagents feature broad commercial availability, higher reactivity, easily accessibility and are more atom efficient since all R or Ar groups are transferred to the substrate. Also they are the least expensive among all organometallic reagents, and are widely used both in laboratory and industry.15 However, their higher reactivity can cause problems in catalytic enantioselective alkylation or arylation of carbonyl compounds, including non-catalyzed background reactions to generate racemic alcohols or reduction of the carbonyl group by β-hydride transfer. As a result, effective methodologies for the enantioselective transformations of carbonyl compounds with Grignard reagents were only very recently discovered.16
Titanium complexes are among most widely used transition metal complexes for enantioselective transformations due to their high abundance,17 nontoxicity18 and low cost. Its high coordination capacity allows for readily modification of the constituting ligands in the complexes, which enhances the possibilities for control of stereochemistry in various chemical processes.19 Enantioselective titanium-mediated transformations have received much attention over the past decade, especially in the area of carbon based nucleophilic addition reactions to carbonyl compounds.20 Since the first enantioselective titanium-promoted addition of diethylzinc to benzaldehyde reported in 1989 by Ohno et al,21 seminal work by Seebach,22 Charette,23 Soai,24 Walsh25 and Ishihara26 reported titanium-promoted catalytic enantioselective nucleophilic addition of poorly reactive organozinc,22-26 and organotitanium22c reagents to carbonyl compounds. Often these reagents had to be derived from their corresponding Grignard reagents or lithium reagents via transmetalation and involved tedious salt exclusion procedures. To the best of our knowledge, the group of Harada16f,27 (Scheme 1) reported the first titanium-mediated highly enantioselective catalytic direct addition of Grignard reagents to aldehydes in 2008. By using low ligand loading (2.0 mol% of L1 or L2) in combination with
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stoichiometric amount of Ti(OiPr)4, alkyl or aryl Grignard nucleophiles
could be added both aliphatic and aromatic aldehydes with very high enantioselectivities in good isolated yields.
Scheme 1: Ti-mediated nucleophilic addition of Grignard reagents to aldehydes in the
presence of L1 or L2.
Building upon these findings,16f the group of Yus 16g,28 (Scheme 2) used BINOL derived ligands L3 – L5 in the Ti-promoted nucleophilic addition of alkyl or aryl Grignard reagents to aldehydes as well as more challenging ketone substrates. By employing 20 mol% of L3 – L5 in combination with super stoichiometric amount of Ti(OiPr)4
(10 – 15 equiv), they synthesized the corresponding secondary or tertiary chiral alcohols with excellent enantioselectivity in high isolated yields.
Scheme 2: Ti-mediated nucleophilic addition of Grignard reagents to aldehydes or
ketones in the presence of L3 – L5.
In all the above described cases, the reactions were considered catalytic in terms of ligand but required superstoichiometric amount of Ti(OiPr)4.
The excess amount of Ti(OiPr)4 reacts with the corresponding Grignard
reagent to form the alkyl or aryl-Ti(OiPr)3, which are less reactive
compared to the corresponding Grignard reagents and also helps to chelate the salts formed in the reaction. The group of Da29 (Scheme 3) reported the use of an equimolar ratio of bis[2-(N,N-dimethylamino)ethyl] ether (BDMAEE) as additive to chelate the
Grignard reagent and the salts formed in the reaction. This approach finally enabled them to lower the Ti(OiPr)4 loading (0.89 equiv) in the
reaction. By using commercially available and cheap (S)-BINOL (15 mol%) as ligand, the nucleophilic addition of Grignard reagents to aldehydes afforded chiral secondary alcohols with high enantioselectivity in good isolated yields.
Scheme 3: Nucleophilic addition of Grignard to aldehydes catalyzed by L6.
Based on the investigations performed by Bolm and Walsh30 on the Schlenk equilibrium31 (Scheme 4) for the transmetalation of Grignard reagents with Ti(OiPr)4, Da et al29 proposed a mechanism (Scheme 5) for
the reaction. Chelation of BDMAEE to the Grignard reagent generates three possible intermediates, A-C. Notably, coordination of MgBr2 by
BDMAEE decreases its catalytic activity moderately (chelate C). In the presence of Ti(OiPr)4, intermediates A and B react to form the reactive
intermediate R-Ti(OiPr)3, along with chelates D and E. Generally,
chelate E is a moderate reactive Lewis acid compared to chelate C, and R-Ti(OiPr)3 was considerably less reactive than the Grignard reagent
itself. As a result, a mixture of RMgBr-BDMAEE-Ti(OiPr)4 does not
react with an aldehyde in the absence of a chiral ligand such as L6. Nevertheless, when R-Ti(OiPr)3 coordinates to the chiral catalyst
(S)-BINOL-Ti- (OiPr)2, complex F is formed. This intermediate F is able to
coordinate the aldehyde to generates the intermediate G where steric interactions between the R group (aldehyde) and the three bulky isopropoxy groups in the R-Ti(OiPr)3 moiety are minimized. This
configuration will favour the Si-face addition to the aldehyde (Scheme 5).
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Scheme 5: Proposed mechanistic cycle for catalytic Grignard addition by Da et al.29
6.1.2 Asymmetric reduction of ketones using CBS-oxazaborolidine Asymmetric synthesis of chiral alcohols is one of the important transformations in organic synthesis.11,32 Among all, borohydride based catalysts play a key role in asymmetric reductions.33,34,35 The Corey– Bakshi–Shibata (CBS) oxazaborolidine is one of the most widely used catalyst for the synthesis of chiral alcohols through the enantioselective reduction of ketones using borane as reducing agent (Scheme 6).35
Scheme 6: Asymmetric reduction of ketone using CBS oxazaborolidine.
The first step of the CBS reduction35 mechanism involves the coordination of BH3 to the nitrogen atom of the oxazaborolidine CBS
catalyst 1 (Scheme 7). This coordination serves to activate the BH3 as a
endocyclic boron. X-ray crystal structures and 11B-NMR spectroscopic analyses of the coordinated catalyst-borane complex 2 have provided support for this initial step. Subsequently, the endocyclic boron of the catalyst coordinates to the ketone at the sterically more accessible electron lone pair (i.e. the lone pair closer to the smaller substituent, RS).
This preferential binding in 3 acts to minimize the steric interactions between the ketone (the large RL substituent directed away) and the R'
group of the catalyst, and aligns the carbonyl and the coordinated borane for a favorable, face-selective hydride transfer through a six-membered transition state 3. Hydride transfer yields via intermediate complex 4, the chiral alkoxyborane 5, which upon acidic workup yields the chiral alcohol 6. The last step to regenerate the catalyst may take place by two different pathways (Path 1 or 2). The predominant driving force for this face-selective, intramolecular hydride transfer is the simultaneous activation of the borane reagent by coordination to the Lewis basic nitrogen and the enhancement of the Lewis acidity of the endocyclic boron atom for coordination to the ketone.
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6.2 Design
Our interest to develop a new asymmetric autocatalytic reaction based on the metal-ligand concept was inspired by work presented in the literature on the Ti-mediated nucleophilic addition of Grignard reagents to carbonyl compounds (vide supra). It has been demonstrated that, titanium complexes prepared from BINOL or derivatives of BINOL are among the most efficient catalysts in the enantioselective nucleophilic addition of Grignard reagents to carbonyl compounds.16d,e,36 As described earlier, Grignard reagents are generally highly efficient and widely used in organic synthesis.15,16 As such, we envisioned as a proof of concept to develop an asymmetric autocatalytic reaction (Scheme 8) based on the enantioselective nucleophilic addition of Grignard reagent to 2-hydroxy naphthaldehyde 7, which would lead to the chiral diol 8. Diol 8 is expected to chelate titanium in a similar fashion to BINOL, forming titanium complex 9 which may act as chiral catalyst for the enantioselective nucleophilic addition reaction for its own production (or that of chiral diol 8). If this process is shown to accelerate the rate of reaction5 and enhance the enantioselectivity with a positive non-linear effect (+NLE)37, it would have satisfied the requirements of an asymmetric autocatalytic reaction.
Scheme 8: Design for an asymmetric autocatalytic reaction based on Ti-mediated
enantioselective nucleophilic addition of Grignard reagents to 2-hydroxy-1-naphthaldehyde 7 in the presence of chiral diol 8.
In another approach to find a new asymmetric autocatalytic reaction we studied the asymmetric reduction of ketones using chiral borane catalyst. Chiral borane reagents are well known in the enantioselective reduction of ketones to alcohols.33-35 As such, we envisioned as a proof of concept
to develop an asymmetric autocatalytic reaction (Scheme 9) based on asymmetric reduction of ketone 10 which will lead to chiral diol 8. Diol 8 is expected to react with borane to form a possible borane complex 11 which may act as chiral catalyst for the asymmetric reduction reaction for its own production (or that of chiral diol 8).
Scheme 9: Design of an asymmetric autocatalytic reaction based on asymmetric
reduction of ketone 10 in the presence of chiral diol 8.
6.3 Results and discussion
Initially we attempted to synthesize the racemic 1-(hydroxy(phenyl)methyl)naphthalen-2-ol 14 by following a known procedure from the literature.38 The reaction between 2-naphthol 12 and benzaldehyde 13 in the presence of K2CO3, however, did not lead to the
desired product (Scheme 10). This might be due to the poor enolate behavior of the potassium 2-naphthoxide.
Scheme 10: Attempted for the synthesis of racemic
1-(hydroxy(phenyl)methyl)naphthalen-2-ol 14.
A different approach involved the nucleophilic addition of PhMgBr (3.0 M in Et2O) to 2-hydroxy-1-naphthaldehyde 7, which led to the racemic
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Scheme 11: Synthesis of racemic 1-(hydroxy(phenyl)methyl)naphthalen-2-ol 14.
We moved on to synthesize the enantioenriched (S)-14. Friedel-Crafts acylation of 2-methoxy naphthalene 15 with benzoyl chloride followed by an in situ deprotection led to the corresponding hydroxy ketone 16 in 90% yield.39 The phenol moiety present in the ketone 16, was protected as TBDMS ether 17 using TBDMSCl.40 The ketone 17 could then be employed in a stereoselective reduction using CBS catalyst41 and borane as a reducing agent to afford (S)-(2-(tert-butyldimethylsilyloxy) naphthalen-1-yl)(phenyl)methanol 18 in 90% isolated yield. Upon deprotection of the TBDMS group with TBAF the desired (S)-1-(hydroxy(phenyl)methyl)naphthalen-2-ol 14 was obtained with very high enantioselectivity (92% ee) in almost quantitative yield (Scheme 12).42
Scheme 12: Synthesis of (S)-1-(hydroxy(phenyl)methyl)naphthalen-2-ol 14.
With the enantiopure (S)-14 in hand, its potential as a chiral ligand for Ti in the enantioselective nucleophilic addition of Grignard reagents to 2-hydroxy-1-naphthaldehyde 7 was investigated. The conditions reported by Da et al. were used, applying bis[2-(N,N-dimethylamino)ethyl] ether in order to remove in situ generated Mg salts and control the reactivity of
Grignard reagents (Scheme 13).29 Approximately 10% conversion was observed after 2 d and longer reaction times did not result in further conversion. This may be due to the free phenol present in the substrate, which can react with the Ph-Ti(OiPr)3 reagent to form a chelated
Ti-alkoxide. This side reaction would reduce the amount of active Ph-Ti(OiPr)3 reagent and also prevent the coordination of the chiral
Ti-complex 19, thus inhibiting the reaction.
Scheme 13: Ti-mediated nucleophilic addition of PhMgBr to
2-hydroxy-1-naphthaldehyde 7 in the presence of (S)-14 with 92% ee.
Since we hypothesized that the free phenol in substrate 7 affected the nucleophilic addition reaction, we modified our approach to protect the free phenol group in the substrate 7 as a methyl ether i.e. 2-methoxy-1-naphthaldehyde 20. In this case we envisioned the reaction to proceed via a possible Ti-complex 22 (scheme 14).
Scheme 14: Alternative approach for the Ti-mediated nucleophilic addition of PhMgBr
to 2-methoxy-1-naphthaldehyde 20 in the presence of 21.
Methoxy-1-naphthaldehyde 20 was prepared in 95% yield from 2-hydroxy-1-naphthaldehyde 7 by performing a methylation reaction using dimethyl sulfate (DMS) (Scheme 15).43
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Scheme 15: Synthesis of 2-methoxy-1-naphthaldehyde 20.
The synthesis of optically active (S)-21 is shown in scheme 16. The compound (2-methoxynaphthalen-1-yl)(phenyl)methanone 23 was
prepared in 95% yield from
(2-hydroxynaphthalen-1-yl)(phenyl)methanone 16 by performing a methylation reaction using DMS.43By performing a stereoselective reduction, using CBS catalyst41 and borane as a reducing agent, of (2-methoxynaphthalen-1-yl)(phenyl)methanone 23 the desired enantioenriched (S)-21 was obtained in 90% isolated yield with 94% ee (Scheme 16).
Scheme 16: Synthesis of (S)-(2-methoxynaphthalen-1-yl)(phenyl)methanol 21.
With (S)-(2-methoxynaphthalen-1-yl)(phenyl)methanol 21 in hand, this alcohol was tested as a chiral ligand for Ti in the enantioselective nucleophilic addition of PhMgBr (3.0 M in Et2O) to
2-methoxy-1-naphthaldehyde 20 (Table 1). The conditions reported in the literature were used, applying bis[2-(N,N-dimethylamino)ethyl] ether in order to remove in situ generated Mg salts and in order to control the reactivity of Grignard reagents.29 Since enantiomerically enriched chiral alcohol 21 (20 mol%) was added to the reaction mixture as a ligand, even if the reaction was not enantioselective, the product is expected have some ee. When the reaction mixture was stirred for 16 h at rt, approximately 15% conversion was reached and the product with 16% ee isolated (Table 1, entry 1). Considering that 20 mol% of chiral alcohol 21 was added as catalyst, one would expect the product to possess at least 53.7% ee, even
169
if the chiral catalyst had no effect on the stereoselectivity of the reaction (entry 1). After stirring the reaction mixture for 48 h, around 37% conversion was found with the same enantioselectivity (16% ee, entry 2). Longer reaction times (6 d) led to approximately 90% conversion and the product 21 was almost racemic (entry 3). Considering that 20 mol% chiral alcohol 21 was added as catalyst, one would expect that product to possess at least 17.1% ee, even if the addition of enantiomerically enriched product 21 had no effect on stereochemistry of the reaction (entry 3).
Table 1: Nucleophilic addition of PhMgBr to 2-methoxy-1-naphthaldehyde 20 in the presence of product (S)-21, 94% ee.
S.No. Time Conversion
(%)a Expected ee without chiral amplification (%) ee observed (%)b 1 16 h 15 53.7 16 2 48 h 37 33.0 16 3 6 d 90 17.1 0.2
(a) The conversion was determined by GC – MS using n-dodecane as internal standard. (b) Determined by chiral HPLC (see experimental section).
Based on these observations, we suspected that the enantiomerically enriched alcohol 21 was racemizing during the course of reaction via the pathway proposed in Scheme 17.
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Scheme 17: Possible pathway for the racemization of (S)-21.
The chelation of enantioenriched alcohol (S)-21 to Ti(OiPr)4 initially
forms Ti-complex (S)-24. The coordination of Ti could increases the leaving group ability of the alcohol in transition state A, and the C–O bond at the stereocenter may cleave to form a carbocation stabilised by its adjacent aromatic groups. Intramolecular attack by the oxide anion can occur on either face of this carbocation, leading to the formation of both enantiomers of 24. Based on the above observations, we performed a control experiment in order to better understand the formation and racemization of enantioenriched (S)-(2-methoxynaphthalen-1-yl)(phenyl)methanol 21 under the reaction conditions. Catalytic enantioselective nucleophilic addition of PhMgBr (3.0 M in Et2O) to
2-methoxy-1-naphthaldehyde 20 in the presence of 20 mol% (S)-BINOL as catalyst was performed (Table 2) under the conditions reported by Da et al.29 When the reaction mixture was stirred at rt for 16 h, around 12 % conversion was observed, and the product had 54% ee (Table 2, entry 1). Almost similar enantioselectivity (56% ee) and around 35% of conversion to the alcohol 21 was observed after stirring for 48 h at rt (entry 2). Longer reaction time (6 d) improved the conversion approximately to 95% , but almost complete racemization of the alcohol 21 was observed (entry 3). These observations support that racemization of enantioenriched (S)-(2-methoxynaphthalen-1-yl)(phenyl)methanol 21 occurs under the reaction conditions.
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Table 2: Nucleophilic addition of PhMgBr to 2-methoxy-1-naphthaldehyde 20 in the presence of (S)-BINOL.
S.No. Time Conversion (%)a ee (%)b
1 16 h 12 54
2 48 h 35 56
3 6 d 95 0.3
(a) The conversion was determined by GC – MS using n-dodecane as internal standard. (b) Determined by chiral HPLC (see experimental section).
Finally we tested (S)-1-(hydroxy(phenyl)methyl)naphthalen-2-ol 14 as a ligand to boron for the asymmetric reduction of ketone 16 (Scheme 17). We performed the reduction on the corresponding (2-hydroxynaphthalen-1-yl)(phenyl)methanone 16 using catalytic amount (20 mol%) of diol 14 with 10% ee. Since diol 14 with 10% ee was added to the reaction mixture as a chiral ligand, even if the reaction was not enantioselective, the product was expected to have some ee. Assuming the reaction went to full completion, one would expect the product with at least 2% ee, even if the addition of product 14 with 10% ee had no effect on the stereochemical outcome of the reaction. After purification of the product, diol 14 was obtained with 5.8 % ee. Since this value was within the error margin for chiral HPLC measurement (~3-5%), it cannot be concluded that enantioinduction occurred in the reaction.
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Scheme 17: Asymmetric reduction of (2-hydroxynaphthalen-1-yl)(phenyl)methanone 16 in the presence of (S)- 14 with 10% ee.
To get more insight in this transformation, we treated (2-hydroxynaphthalen-1-yl)(phenyl)methanone 16 with borane in the absence of catalyst. It was observed that the reduction is complete in a similar reaction time (30 min) as the previous catalytic reduction. A possible explanation is that the free phenolic group present in (2-hydroxynaphthalen-1-yl)(phenyl)methanone 16 activates the borane to transfer the hydride via intermediate 26 (Scheme 18).
Scheme 18: Reduction of ketone 16 with borane.
6.4 Conclusions
We successfully synthesized (S)-1-(hydroxy(phenyl)methyl)naphthalen-2-ol 14 and (S)-(2-methoxynaphthalen-1-yl)(phenyl)methanol 21 in good yields with high enantioselectivity as potential chiral products for autocatalytic reactions. 2-Hydroxynaphthaldehyde 7 was not a suitable substrate in the Ti-mediated enantioselective catalytic nucleophilic addition reaction with Grignard reagents. A possible explanation could be the free phenolic group present in the substrate 7, which inhibited the catalytic system by forming an undesired titanium complex. (S)-(2-Methoxynaphthalen-1-yl)(phenyl)methanol 21 may be acting as a ligand to Ti to form active species (S)-24 for the enantioselective nucleophilic
addition of Grignard reagents to 2-methoxy naphthaldehyde 20. Longer reaction time was required in order to achieve full conversion and racemization of the product was observed during the course of reaction. There was no significant influence of the diol 14 in the asymmetric reduction of (2-hydroxynaphthalen-1-yl)(phenyl)methanone 16. This might be due to the presence of free phenol present in substrate 16 which would activate the borane in order to transfer the hydride to the carbonyl group through the possible achiral intermediate 26.
Our studies have shown that BINOL type compounds are difficult substrates for autocatalysis following a metal-ligand approach. This may be due to strong chelation of the substrate to the metal, leading to undesired reactions. In addition, the product is prone to racemization under the reaction conditions, so we were unable to conclusively state that enantioselective autoinduction had occurred. As such, we moved on to investigating the Mannich and phospha-Mannich reactions for asymmetric autocatalysis as discussed in chapter 7.
6.5 Experimental section
6.5.1 General procedures
Flash column chromatography: Merck silica gel type 9385 230-400 mesh, TLC: Merck silica gel 60, 0.25 mm. Components were visualized 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),
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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.
6.5.2 Synthesis of racemic 1-(hydroxy(phenyl)methyl)naphthalen-2-ol (14)
To a solution of 2-hydroxy-1-naphthaldehyde 7 (2.00 g, 11.6 mmol, 1.0 equiv) in dry THF (30 mL, 0.39 M) at 0 °C was added dropwise a solution of PhMgBr (3.0 M in Et2O, 9.70 mL, 29.1 mmol, 2.5 equiv).
The mixture was stirred at rt. After complete consumption of the starting material (monitored by TLC) it was cooled to 0 °C and quenched with aq. 1 N HCl (20 mL). Et2O (20 mL) was added, the layers were separated
and the aqueous layer was extracted with Et2O (3x20 mL). The combined
organic layers were dried over anhydrous MgSO4, filtered and the
volatiles were evaporated under vacuum. The residue was purified by flash column chromatography on silica gel using mixture of solvents (Et2O/pentane, 5:95 to 20:80) to afford the desired racemic
1-(hydroxy(phenyl)methyl)naphthalen-2-ol 14 (2.6 g, yield = 90%) as a white solid. Chiral separation on HPLC using Chiralcel OD column, n-heptane/i-PrOH 90:10, 40 °C, 230 nm, retention times (min): 13.00 and 22.90. 1H NMR (400 MHz, CDCl3) δ 9.29 (s, 1H), 7.76 (t, J = 8.6 Hz,
2H), 7.64 (d, J = 8.5 Hz, 1H), 7.43 (d, J = 8.9 Hz, 1H), 7.40 – 7.34 (m, 2H), 7.34 – 7.24 (m, 3H), 7.18 (d, J = 8.9 Hz, 1H), 6.78 (s, 1H), 3.12 (s, 1H); 13C NMR (101 MHz, CDCl3) δ 154.6, 141.3, 131.5, 130.2, 128.9,
128.8, 128.7, 128.5, 127.2, 126.8, 123.0, 121.4, 120.0, 115.7, 74.7. HRMS (ESI+, m/z): calculated for C17H13O [M–OH]+: 233.0961, found:
233.0958.
6.5.3 Synthesis of (S)-1-(hydroxy(phenyl)methyl)naphthalen-2-ol (14)
(2-Hydroxynaphthalen-1-yl)(phenyl)methanone (16)
To a suspension of AlCl3 (3.60 g, 27.9 mmol, 2.2 equiv) in dry DCM (40
mL) was added a solution of 2-methoxynaphthalene 15 (2.00 g, 12.6 mmol, 1.0 equiv) in dry DCM (60 mL, 0.21 M) at rt. This was followed by the dropwise addition of benzoyl chloride (1.76 mL, 15.2 mmol, 1.2 equiv). After stirring at rt for 48 h under nitrogen, the reaction mixture was poured into a beaker containing ice cold water (100 mL) and conc. HCl (20 mL) and stirred for 1h. The layers were separated, the aqueous layer was extracted with DCM (3x50 mL). The combined organic layers were was washed with water (100 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 (Et2O/pentane, 5:95 to 20:80) to afford the desired
(2-hydroxynaphthalen-1-yl)(phenyl)methanone 16 (2.5 g, yield = 80%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 11.20 (s, 1H), 7.98 – 7.90
(m, 1H), 7.79 – 7.71 (m, 1H), 7.68 – 7.61 (m, 2H), 7.59 – 7.52 (m, 1H), 7.45 7.37 (m, 2H), 7.35 – 7.21 (m, 3H), 7.20 – 7.13 (m, 1H); 13C NMR (101 MHz, CDCl3) δ 200.4, 161.3, 140.3, 136.3, 132.7, 132.4, 130.2,
129.4, 128.6, 128.6, 126.7, 126.3, 123.7, 119.2, 114.4. The physical data of the compound matches with those reported in the literature.39
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(2-(tert-Butyldimethylsilyloxy)naphthalen-1-yl)(phenyl)methanone (17)
To a solution of (2-hydroxynaphthalen-1-yl)(phenyl)methanone 16 (630 mg, 2.54 mmol, 1.0 equiv) in dry DCM (15 mL, 0.17 M) at rt was added Et3N (0.430 mL, 3.05 mmol, 1.2 equiv) and DMAP (35.0 mg, 0.254
mmol, 0.1 equiv). After stirring at rt for 10 min, a solution of tert-butylchlorodimethylsilane (TBDMSCl) (460 mg, 3.05 mmol, 1.2 equiv) in dry DCM (5 mL, 0.61 M) was added dropwise. Upon complete consumption of the starting material (monitored by TLC) the reaction mixture was quenched with water (10 mL). The layers were separated and the aqueous layer was extracted with DCM (3x10 mL). The combined organic layers were dried over anhydrous MgSO4, filtered and
the volatiles were evaporated under vacuum. The residue was purified by flash column chromatography on silica gel using mixture of solvents (Et2O/pentane, 5:95 to 10:90) to afford the desired
(2-(tert-butyldimethylsilyloxy)naphthalen-1-yl)(phenyl)methanone 17 (910 mg, yield = 98%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.94 – 7.78
(m, 4H), 7.63 – 7.50 (m, 2H), 7.47 – 7.33 (m, 4H), 7.11 (d, J = 8.9 Hz, 1H), 0.70 (s, 9H), 0.12 (s, 6H); 13C NMR (101 MHz, CDCl3) δ 200.5, 152.9, 140.6, 136.0, 134.8, 133.4, 132.5, 131.7, 131.1, 130.7, 129.9, 128.0, 126.8, 126.8, 122.8, 27.9, 20.5, –1.6. (S)-(2-(tert-Butyldimethylsilyloxy)naphthalen-1-yl)(phenyl)methanol (18) To a solution of (2-(tert-butyldimethylsilyloxy)naphthalen-1-yl)(phenyl)methanone 17 (100 mg, 0.280 mmol, 1.0 equiv) and (S)-(−)-2-methyl-CBS-oxazaborolidine (16.0 mg, 0.056 mmol, 0.2 equiv) in dry THF (5.0 mL, 0.056 M) at rt was added dropwise a solution of BH3•THF
consumption of the starting material (TLC), the reaction mixture was cooled to 0 °C, quenched with MeOH (2 mL) and water (2 mL). The layers were separated and the aqueous layer was extracted with DCM (3x10 mL). The combined organic layers were dried over anhydrous MgSO4, filtered and the volatiles were evaporated under vacuum. The
residue was purified by flash column chromatography on silica gel using mixture of solvents (Et2O/pentane, 5:95 to 15:85) to afford the desired
(S)-(2-(tert-butyldimethylsilyloxy)naphthalen-1-yl)(phenyl)methanol 18 (97 mg, yield = 97%) as a white solid. 1H NMR (400 MHz, CDCl3) δ
7.98 (d, J = 8.3 Hz, 1H), 7.84 – 7.71 (m, 2H), 7.41 – 7.31 (m, 4H), 7.31 – 7.23 (m, 2H), 7.23 – 7.17 (m, 1H), 7.15 (d, J = 8.9 Hz, 1H), 6.78 (d, J = 6.6 Hz, 1H), 3.59 (d, J = 7.3 Hz, 1H), 0.92 (s, 9H), 0.27 (s, 3H), 0.13 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 151.3, 144.0, 132.6, 129.8, 129.6, 128.4, 128.1, 126.7, 126.5, 126.0, 125.3, 124.2, 123.7, 120.2, 69.5, 25.7, 18.3, –3.7, –4.1. (S)-1-(Hydroxy(phenyl)methyl)naphthalen-2-ol (14) To a solution of (S)-(2-(tert-butyldimethylsilyloxy)naphthalen-1-yl)(phenyl)methanol 18 (100 mg, 0.280 mmol, 1.0 equiv) in dry THF (5 mL, 0.056 M) at 0 °C was added dropwise a solution of tetrabutylammonium fluoride solution (1.0 M in THF, 0.42 mL, 0.42 mmol, 1.5 equiv). After complete consumption of the starting material (TLC), water (10 mL) was added to the reaction mixture. The layers were separated and the aqueous layer was extracted with Et2O (3x10 mL). The
combined organic layers were dried over anhydrous MgSO4, filtered and
the volatiles were evaporated under vacuum. The residue was purified by flash column chromatography on silica gel using mixture of solvents (Et2O/pentane, 5:95 to 20:80) to afford the desired
(S)-1-(hydroxy(phenyl)methyl)naphthalen-2-ol 14 (68 mg, yield = 97%) as a white solid. [α]D20 = +13.6 (c = 1.0 in CHCl3). 92% ee, using chiral
178
HPLC (Chiralcel OD column, n-heptane/i-PrOH 90:10, 40 °C, 230 nm, retention times (min): 12.99 (major) and 22.87 (minor)).
6.5.4 Synthesis of 2-methoxy-1-naphthaldehyde (20)
To a solution of 2-hydroxy-1-naphthaldehyde 7 (1.0 g, 5.8 mmol, 1.0 equiv) in dry acetone (20 mL, 0.29 M) was added K2CO3 (1.04 g, 7.54
mmol, 1.3 equiv) portion wise. After stirring for 30 min at the same temperature dimethyl sulphate (0.660 mL, 6.96 mmol, 1.2 equiv) was added dropwise. The reaction mixture was warmed to rt and then heated to reflux. After complete consumption of the starting material (monitored by TLC), the reaction mixture was cooled to rt and the volatiles were evaporated under vacuum. Water (20 mL) and Et2O (20 mL) was added,
the layers were separated and the aqueous layer was extracted with Et2O
(3x20 mL). The combined organic layers were 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 (Et2O/pentane, 5:95 to 20:80) to afford the desired
2-methoxy-1-naphthaldehyde 20 (1.04 g, yield = 96%) as a yellow solid.
1 H NMR (400 MHz, CDCl3) δ 10.90 (s, 1H), 9.28 (d, J = 8.4 Hz, 1H), 8.06 (d, J = 9.0 Hz, 1H), 7.78 (d, J = 7.8 Hz, 1H), 7.67 – 7.57 (m, 1H), 7.50 – 7.37 (m, 1H), 7.37 – 7.22 (m, 1H), 4.06 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 192.0, 163.9, 137.6, 131.5, 129.9, 128.5, 128.2, 124.9, 124.7, 116.6, 112.5, 56.5.
6.5.5 Synthesis of (S)-(2-Methoxynaphthalen-1-yl)(phenyl)methanol (21)
(2-Methoxynaphthalen-1-yl)(phenyl)methanone (23)
To a solution of (2-hydroxynaphthalen-1-yl)(phenyl)methanone 16 (446 mg, 1.80 mmol, 1.0 equiv) in dry acetone (15 mL, 0.12 M) was added K2CO3 (330 mg, 2.34 mmol, 1.3 equiv) portion wise. After stirring for 30
min at the same temperature dimethyl sulphate (0.210 mL, 2.16 mmol, 1.2 equiv) was added dropwise. The reaction mixture was warmed to rt and then heated to reflux. After complete consumption of the starting material (monitored by TLC), the reaction mixture was cooled down to rt and the volatiles were evaporated under vacuum. Water (20 mL) and Et2O (10 mL) was added, the layers were separated and the aqueous layer
was extracted with Et2O (3x10 mL). The combined organic layers were
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 (Et2O/pentane,
(5:95 to 10:90) to afford the desired (2-methoxynaphthalen-1-yl)(phenyl)methanone 23 (449 mg, yield = 95%) as a yellow thick oil. 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 9.1 Hz, 1H), 7.92 – 7.82 (m, 3H), 7.61 – 7.54 (m, 1H), 7.53 – 7.48 (m, 1H), 7.42 (t, J = 7.7 Hz, 2H), 7.40 – 7.31 (m, 3H), 3.83 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 197.7, 154.1, 151.2, 137.9, 133.4, 131.7, 131.1, 129.6, 128.8, 128.5, 128.1, 127.4, 124.1, 124.1, 113.1, 56.6. (S)-(2-Methoxynaphthalen-1-yl)(phenyl)methanol (21) To a solution of (2-methoxynaphthalen-1-yl)(phenyl)methanone 23 (150 mg, 0.570 mmol, 1.0 equiv) and (S)-(−)-2-methyl-CBS-oxazaborolidine (32.0 mg, 0.115 mmol, 0.2 equiv) in dry THF (5.0 mL, 0.115 M) at rt
180
was added dropwise a solution of BH3•THF (1.0 M in THF, 0.57 mL,
0.57 mmol, 1.0 equiv). After complete consumption of the starting material (TLC), the reaction mixture was cooled to 0 °C, quenched with MeOH (2 mL) and water (2 mL). The layers were separated and the aqueous layer was extracted with DCM (3x10 mL). The combined organic layers were 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 (Et2O/pentane, 5:95 to 15:85) to afford the desired
(S)-(2-methoxynaphthalen-1-yl)(phenyl)methanol 21 (140.0 mg, yield = 92%) as a colourless oil. [α]D20 = –128.7 (c = 1.0 in CHCl3). 94% ee, using
chiral HPLC (Chiralcel AD column, n-heptane/i-PrOH 95:5, 40 °C, 230 nm, retention times (min): 17.16 (major) and 25.41 (minor)). 1H NMR (400 MHz, CDCl3) δ 8.07 (d, J = 8.6 Hz, 1H), 7.87 (d, J = 9.0 Hz, 1H),
7.83 (d, J = 8.1 Hz, 1H), 7.45 (t, J = 7.0 Hz, 1H), 7.41 – 7.34 (m, 3H), 7.34 – 7.25 (m, 2H), 7.23 (d, J = 7.2 Hz, 1H), 6.77 (d, J = 6.5 Hz, 1H), 4.12 (d, J = 9.5 Hz, 1H), 3.86 (s, 3H); 13C NMR (101 MHz, CDCl3) δ
154.9, 144.3, 132.1, 130.0, 129.5, 128.6, 128.1, 126.9, 126.7, 125.8, 124.2, 123.8, 123.5, 113.7, 69.8, 56.6. HRMS (ESI+, m/z): calculated for C18H15O [M–OH]+: 247.1117, found: 247.1115.
6.5.6 General procedure: nucleophilic addition of PhMgBr to aldehydes in the presence of a chiral ligand.
In flask A, Ti(OiPr)4 (0.12 mL, 0.39 mmol, 1.35 equiv) was added
dropwise to a solution of appropriate ligand (0.058 mmol, 0.2 equiv) in dry MTBE (5 mL, 0.012 M) under a N2 atmosphere at rt and the mixture
was stirred at rt for another 30 min. In flask B, PhMgBr (3.0 M in Et2O,
0.34 mL, 1.02 mmol, 3.5 equiv) was added slowly to a solution of BDMAEE (198 µL, 1.02 mmol, 3.5 equiv) in dry MTBE (2.0 mL, 0.51 M) at 0 °C under a N2 atmosphere and the mixture was stirred at the
same temperature for 30 min. The mixture A was then transferred to mixture B at 0 °C. After it was allowed to warm to rt, the combined milk yellow mixture was stirred another 1 h at the same temperature. Then the reaction mixture was cooled back to 0 °C and a solution of appropriate
181
aldehyde (0.291 mmol, 1.0 equiv) in dry MTBE (2.0 mL, 0.146 M) was added dropwise. The mixture was warmed to rt and allowed to stir at rt. The progress of the reaction was monitored by 1H-NMR and GC–MS of aliquots (0.3 mL) over the indicated time period. After complete consumption of the starting material, the reaction mixture was quenched with 5% cold aq. HCl (10 mL) solution and the layers were separated. The aqueous layer was extracted with Et2O (3x10 mL). The combined
organic layers were dried over anhydrous MgSO4 and the volatiles were
evaporated under vacuum to afford the desired product.
6.5.7 Nucleophilic addition of PhMgBr to 2-hydroxy-1-naphthaldehyde 7 in the presence of (S)-14 with 92% ee.
The reaction was performed using the above general procedure with (S)-1-(hydroxy(phenyl)methyl)naphthalen-2-ol 14 (14.6 mg, 0.058 mmol, 0.2 equiv) as ligand to Ti and 2-hydroxy-1-naphthaldehyde 7 (50.0 mg, 0.291 mmol, 1.0 equiv) as substrate. 1H-NMR and GC–MS analysis showed approximately 10% conversion of the starting material in 2d. After stirring for 6 d no further conversion was observed. Due to the poor conversion no attempts to isolate the product were performed.
6.5.8 Nucleophilic addition of PhMgBr to 2-methoxy-1-naphthaldehyde 20 in the presence of (S)-21 with 94% ee (Table 1). The reaction was performed using the above general procedure with (S)-(2-methoxynaphthalen-1-yl)(phenyl)methanol 21 (15.4 mg, 0.058 mmol, 0.2 equiv) as ligand to Ti and 2-methoxy-1-naphthaldehyde 20 (54.2 mg, 0.291 mmol, 1.0 equiv) as substrate. The product 21 was obtained as a colourless oil.
6.5.9 Nucleophilic addition of PhMgBr to 2-methoxy-1-naphthaldehyde 20 in the presence of (S)-BINOL.
The reaction was performed using the above general procedure with (S)-BINOL (16.7 mg, 0.058 mmol, 0.2 equiv) as ligand to Ti and
2-methoxy-182
1-naphthaldehyde 20 (54.2 mg, 0.291 mmol, 1.0 equiv) as substrate. The product 21 was obtained as a colourless oil.
6.5.10 Asymmetric reduction of (2-hydroxynaphthalen-1-yl)(phenyl)methanone 16 in the presence (S)-14 with 10% ee.
To a solution of (S)-1-(hydroxy(phenyl)methyl)naphthalen-2-ol 14 with 10% ee (14.1 mg, 0.056 mmol, 0.2 equiv) in dry THF (2.0 mL, 0.028 M) at rt was added dropwise a solution of BH3•THF (1.0 M in THF, 199 µL,
0.199 mmol, 0.71 equiv). After stirring at rt for 30 min a solution of (2-hydroxynaphthalen-1-yl)(phenyl)methanone 16 (69.5 mg, 0.28 mmol, 1.0 equiv) in dry THF (2.0 mL, 0.14 M) was added dropwise. After complete consumption of the starting material in 30 min (monitored by TLC), the reaction mixture was cooled to 0 °C, quenched with MeOH (2 mL) and water (2 mL). The layers were separated and the aqueous layer was extracted with DCM (3x10 mL). The combined organic layers were dried over anhydrous MgSO4, filtered and the volatiles were evaporated under
vacuum to afford product 14 as a white solid.
6.5.11 Reduction of ketone 16 with borane.
To a solution of (2-hydroxynaphthalen-1-yl)(phenyl)methanone 16 (69.5 mg, 0.280 mmol, 1.0 equiv) in dry THF (2.0 mL, 0.14 M) at rt was added dropwise a solution of BH3•THF (1.0 M in THF, 199 µL, 0.199 mmol,
0.71 equiv). After complete consumption of the starting material in 30 min (monitored by TLC), the reaction mixture was cooled to 0 °C, quenched with MeOH (2 mL) and water (2 mL). The layers were separated and the aqueous layer was extracted with DCM (3x10 mL). The combined organic layers were dried over anhydrous MgSO4, filtered
and the volatiles were evaporated under vacuum to afford product 14 as a white solid.
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