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Highly enantioselective asymmetric transfer hydrogenation: a practical and scalable method to efficiently access planar chiral [2.2]paracyclophanes Marie-Léonie Delcourt, Simon Felder, Serge Turcaud, Corina H. Pollok, Christian Merten, Laurent Micouin, and Erica Benedetti J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00372 • Publication Date (Web): 19 Mar 2019 Downloaded from http://pubs.acs.org on March 20, 2019
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The Journal of Organic Chemistry
Highly enantioselective asymmetric transfer hydrogenation: a practical and scalable method to efficiently access planar chiral [2.2]paracyclophanes Marie-Léonie Delcourt,a Simon Felder,a Serge Turcaud,a Corina H. Pollok,b Christian Merten,b Laurent Micouin,*a and Erica Benedetti*a a Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques - UMR8601 CNRS, Université Paris Descartes, Sorbonne Paris Cité, UFR Biomédicale, 45 rue des Saints Pères, 75006 Paris, France b Ruhr-Universität Bochum , Fakultät für Chemie und Biochemie , Lehrstuhl für Organische Chemie 2, Universitätsstraße 150 44801 Bochum, Germany ABSTRACT: We report herein a general, practical method based on asymmetric transfer hydrogenations to control the planar chirality of a range of substituted [2.2]paracyclophanes. Our strategy enabled us to perform both the kinetic resolution of racemic compounds and the desymmetrization of centrosymmetric meso derivatives on synthetically useful scales. High selectivities (up to 99% ee) and good yields (up to 48% for the kinetic resolutions, and 74% for the desymmetrization reactions) could be observed for several poly-substituted paracyclophanes, including a series of bromine-containing molecules. The optimized processes could be run up to the gram scale without any loss in the reaction efficiencies. Due to its broad applicability, the asymmetric transfer hydrogenation approach appears to be the method of choice to access planar chiral [2.2]paracyclophanes in their enantiopure form.
INTRODUCTION Originally discovered in a serendipitous fashion by vapor phase pyrolysis of p-xylene,1 [2.2]paracyclophane (pCp) and its derivatives have rapidly gained popularity amongst chemists due to their unique three-dimensional architecture. These compounds incorporate, indeed, two distorted benzene rings covalently locked in a stacked geometry by two ethylene bridges at their para positions.2 The structural constraints and proximity of the two systems (~3.09 Å) favor intramolecular through-bond and through-space interactions, which confer on paracyclophanes both an intriguing photophysical behavior3 and an unusual reactivity.4 One of the most fascinating features of many substituted [2.2]paracyclophanes is their planar chirality. This property, reported by Cram and Allinger as early as 1955, 5 arises from the intrinsic rigidity of pCps, which hampers the free rotation of their aromatic “decks”. Any mono-substituted [2.2]paracyclophane is chiral (I, Figure 1), and a wide variety of optically active derivatives can be rapidly generated by increasing the number of substituents on the pCp core (II-IX, Figure 1). From the early 1990s onwards, planar chiral paracyclophanes have received increasing attention because of their advantageous characteristics, such as a high configurational stability (200 °C), good tolerance to the action of acids and bases, chemical stability towards light or oxidants, and ease of handling.
Figure 1. Different [2.2]paracyclophanes
chiral
structures
of
substituted
As a result, these compounds are nowadays frequently used as chiral inductors in asymmetric catalysis and stereoselective synthesis.6 Enantiopure paracyclophanes have also been successfully employed as scaffolds for the development of various chiral materials, including mesoporous polymers, 7 metalorganic frameworks (MOF),8 and circularly polarized lightemitting compounds.9 A simple, scalable access to enantiopure building blocks is obviously crucial to explore new applications of scalemic [2.2]paracyclophanes. However, despite the development of classical stoichiometric resolution methods10 and a few reports on catalytic synthetic procedures,11 complex enantiopure paracyclophane derivatives are currently still mainly obtained through enantiomers separation by chromatography on chiral
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stationary phases.12 The optimization of new processes providing practical access to enantiopure pCps can therefore be considered as a priority in modern cyclophane chemistry. We have recently reported a new, versatile method for the preparation of chiral formyl-substituted [2.2]paracyclophanes. Our strategy, which relies on highly enantioselective asymmetric transfer hydrogenations (ATH), has been employed to perform the kinetic resolution (KR) of 4formyl[2.2]paracyclophane (R = H, Scheme 1a), 13 and the desymmetrization of centrosymmetric 4,16diformyl[2.2]paracyclophane (R = H, Scheme 1b). 14 The procedure is operationally simple and can be run up to the gramscale without loss in efficiency. Scheme 1. Kinetic Resolutions and Desymmetrizations of Racemic/meso [2.2]Paracyclophanes through ATH Reactions
Herein, we wish to demonstrate the broad applicability of this approach by expanding the scope of the ATH reaction to poly-substituted [2.2]paracyclophanes. We will specifically focus our attention on halogenated derivatives, which include bromine atoms at different positions of the pCp core (R = Br, Figure 1), and may serve as valuable intermediates to rapidly access more complex planar chiral paracyclophane derivatives in their enantiopure form. RESULTS AND DISCUSSION Kinetic Resolutions. The Noyori asymmetric transfer hydrogenation is a technique commonly employed in organic synthesis to access enantiopure benzylic alcohols starting from aromatic ketone precursors.15 Prior to our studies, this reaction was used in an elegant manner to perform the kinetic resolution (KR) of planar-chiral ferrocenyl ketones.16 These inspiring literature reports encouraged us to investigate whether racemic pCps could be efficiently resolved into their pure enantiomers under similar reaction conditions. With this idea in mind, we first explored the reactivity of 4formyl[2.2]paracyclophane, a compound which is frequently employed as a key intermediate in the synthesis of more elaborated paracyclophanes, including several pCp-based chiral ligands.17
Scheme 2. Synthesis 4-Formyl[2.2]paracyclophane (±)-1a.
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Racemic
This derivative was then submitted to the kinetic resolution step. In a first series of assays, a ruthenium-based catalyst was used promote the asymmetric transfer hydrogenations, and different hydrogen sources or bases were tested.13 Encouraging preliminary results were obtained when the reduction was performed in the presence RuCl(p-cymene)[(R,R)-Ts-DPEN] (I, 2 mol %), and potassium t-butoxide (10 mol %), in i-PrOH at 10 °C under an inert atmosphere. After 75 min, when the reaction reached 58% conversion, the unreacted aldehyde ()1a and reduced alcohol ()-2a could be resolved to 98% ee and 62% ee respectively (Table 1, entry 1). Aldehyde ()-1a, however, proved to be poorly soluble in cold i-PrOH. Various co-solvents were therefore screened to obtain homogeneous solutions, and thus ensure a good reproducibility of the results. Unfortunately, at 57% conversion, the desired compound ()-1a was obtained in a lower enantiomeric excess when 1:1 mixtures of i-PrOH/DCM or iPrOH/DMF were used as the solvent system (94% and 92% ee respectively, Table 1, entries 2 and 3). High enantioselectivities were once again achieved while running the reaction in iPrOH and MeCN (98% ee, Table 1, entry 4). Varying the cosolvent ratio didn’t change significantly the reaction outcome (Table 1, entries 4-6). Thus, based on kinetic considerations, all following ATH reactions were performed using a solvent/co-solvent volumetric proportion of 1:1. The effect of different commercially available ruthenium complexes was finally examined. RuCl[(S,S)TsDPEN](mesitylene) II and RuCl[(R,R)-FsDPEN](pcymene) III were tested, but both catalysts led to higher reaction rates and a lower enantiomeric excess of 1a (Table 1, entries 7 and 8). As a result, the RuCl(p-cymene)[(R,R)-TsDPEN] complex I, which was employed initially, turned out to be the best catalytic system for the kinetic resolution of ()-1a (Table 1, entry 4 vs entries 7 and 8). With the optimized conditions in hands (Table 1, entry 4), the asymmetric transfer hydrogenation was successfully scaled from 0.13 mmol (30 mg) up to the gram scale. No loss in the reaction efficiency was observed for this process. Table 1. Optimization of the Kinetic Resolution
Racemic 4-formyl[2.2]paracyclophane ()-1a was easily prepared starting from commercially available [2.2]paracyclophane by Rieche formylation (Scheme 2).18
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The Journal of Organic Chemistry
entry
cat.
solvent
t (min)
conv. (%)a
ee (%)b 1a
2a 62 ()
1
I
i-PrOH
75
58
98 ()
2
I
i-PrOH/DCM (1:1)
135
57
94 ()
92 ()
3
I
i-PrOH/DMF (1:1)
135
57
92 ()
90 ()
4
I
i-PrOH/MeCN (1:1)
105
58
98 ()
86 ()
5
I
i-PrOH/MeCN (3:1)
45
56
99 ()
80 ()
6
I
i-PrOH/MeCN (1:3)
120
57
96 ()
86 ()
7
II
i-PrOH/MeCN (1:1)
60
57
94 ()
58 ()
8
III
i-PrOH/MeCN (1:1)
60
57
90 ()
82 ()
a Conversion was determined by 1H-NMR and HPLC analysis of the crude reaction mixture. b Enantiomeric excess was determined by HPLC analysis; the sign of the specific optical rotation is given in brackets.
Indeed, starting from 1 g of racemic 4formyl[2.2]paracyclophane, enantiopure ()-1a was obtained in 39% yield (Scheme 3). The enantioenriched alcohol ()-2a, was also isolated in 56% yield and 68% ee (Scheme 3). This product could be easily recycled through oxidation and subsequent kinetic resolution of the corresponding enantioenriched aldehyde ()-1a.13 Scheme 3. Scale up of the Kinetic Resolution
Scheme 4. Synthesis of Racemic Bromoaldehyde ()-1b
Bromoaldehyde ()-1c, on its side, was prepared starting from commercially available 4,16dibromo[2.2]paracyclophane 5 through a bromine-lithium exchange and formylation with DMF (Scheme 5).22 The reaction was conducted at a low temperature (78 °C) in order to observe a higher selectivity towards the desired monoformylated adduct. Scheme 5. Synthesis of Racemic Bromoaldehyde ()-1c
Compound ()-1b successfully underwent the kinetic resolution process under the previously optimized reaction conditions (Scheme 6). Indeed, while employing RuCl[(R,R)-TsDPEN](p-cymene) I as the catalyst in this transformation, aldehyde ()-1b was isolated in 46% yield and 95% ee together with alcohol ()-2b, which was obtained in 51% yield and 90% ee (Scheme 6). Scheme 6. Kinetic Resolution of Bromoaldehyde ()-1b
The absolute configuration of the resolved products ()-1a and ()-2a, generated by using the RuCl(p-cymene)[(R,R)-TsDPEN] catalyst I, was assigned by comparison of their specific optical rotations with previously reported values (Scheme 3).19 We next focused our interest on expanding the substrate scope and applicability of the kinetic resolution process. We therefore turned our attention to pseudo-gem and pseudo-para bromoaldehydes ()-1b and ()-1c. Compound ()-1b was obtained in five steps starting from non-substituted [2.2]paracyclophane. The synthetic procedure first involved a Friedel-Craft acylation with oxalyl chloride, followed by a selective decarbonylation reaction and subsequent esterification to isolate methyl ester ()-320 in 79% yield (Scheme 4). This compound was then submitted to a bromination step, which took place selectively at the pseudo-gem position.21 A reduction-oxidation sequence finally afforded the desired product ()-1b in 52% overall yield (Scheme 4).
A chemical correlation between compound ()-2b and alcohol ()-(Sp)-2a was easily established by dehalogenation (Scheme 7). We could therefore assign the Rp absolute configuration to the levorotatory product 2b, and the Sp one to aldehyde ()-1b.
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Scheme 7. Determination of the Absolute Configuration of Product ()-2b
Bromoaldehyde ()-1c was also submitted to the kinetic resolution process using the conditions previously optimized for compounds )-1a. In this case, however, low enantiomeric excess were observed for both products ()-1c and ()-2c (Table 2, entry 1). This result was attributed to the poor solubility of (-1c in the reaction medium (i-PrOH/MeCN mixture). Accordingly, different co-solvents were tested.
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Finally, a few attempts were directed toward the optimization of a reverse kinetic resolution23 based on the asymmetric oxidation of racemic 4-hydroxyl[2.2]paracyclophane ()-2a. In this case, the best results were obtained while running the reaction in a 2:1 mixture of acetone/DCM, using the catalytic species (R,R)-I (5 mol %), and KOH as the base (25 mol %, Scheme 9). Under these conditions, however, the oxidation reached 36% of conversion only after 5 h at room temperature. In addition, a moderate enantiomeric excess was observed for both aldehyde ()-1a and alcohol ()-2a (66% and 42% ee respectively, Scheme 9). The reduction pathway was thus confirmed to be the best strategy to access enantioenriched paracyclophanes in good yields and reasonable time. Scheme 9. An Attempt of Reverse Kinetic Resolution
Table 2. Kinetic Resolution of Bromoaldehyde ()-1c
entry
co-solvent
t (min)
1
MeCN
45
Yield (%)
ee (%)a
1c
2c
1c
2c
40
34
42 (+)
40
() ()
2
DMF
90
27
60
99 (+)
3
DMF
60
37
48
98 (+)
() 42 80
a
Determined by HPLC analysis; the sign of the specific optical rotation is given in brackets.
Aldehyde ()-1c could be isolated in 27% yield and 99% ee while preforming the asymmetric transfer hydrogenation at 0 °C, for 90 min, in a 1:1 mixture of i-PrOH/DMF. Alcohol ()2c was also obtained in 60% yield and 42% ee (Table 2, entry 2). A shorter reaction time (60 min) eventually allowed us to improve both the yield of aldehyde ()-1c (up to 37%), and the enantiomeric excess of alcohol ()-2c (80% ee, Table 2, entry 3). A dehalogenation reaction was again used to correlate the absolute configuration of product ()-2c with that of derivative ()-(Sp)-2a (Scheme 8). As a result, the Rp descriptor could be assigned to the levorotatory compound ()-2c, while the Sp descriptor was attributed to aldehyde ()-1c. Scheme 8. Determination of the Absolute Configuration of Product ()-2c
Desymmetrizations. As all other resolution approaches, the methodology described above suffers from being limited to a maximum theoretical yield of 50% of each optically pure enantiomer.24 To overcome this constraint, our efforts have next been directed towards the preparation of enantiopure paracyclophanes through scalable desymmetrization reactions, which present the potential to reach 100% yield.25 The desymmetrization strategy usually enables the differentiation of enantiotopic functional groups whithin meso compounds which possess internal planes of symmetry. 26 On the contrary, desymmetrizations have scarcely been applied to centrosymmetric molecules27 that show an inversion center as their sole symmetry element. This is certainly very surprising, especially if one considers that centrosymmetric motifs are frequently observed in natural products and biologically active compounds.28 Depending on their substitution patterns, paracyclophanes can also present centrosymmetric structures. Prior to our studies,14 however, there were no reports describing the desymmetrization of such original meso derivatives. The ATH process being a particularly efficient tool for the kinetic resolution of monoformylated pCps, we considered the possibility to develop a desymmetrization of centrosymmetric paracyclophanes based on our reduction strategy. To this end, 4,16-diformyl[2.2]paracyclophane 6a was prepared starting from 4,16-dibromo[2.2]paracyclophane 5 via a double bromine-lithium exchange followed by formylation (Scheme 10).22,29 A precise control of both temperature and reaction time was required to obtain the desired product in good yield on a multigram scale. Scheme 10. Synthesis of Centrosymmetric Dialdehyde 6a
With derivative 6a in hand, a first attempt of desymmetrization was conducted under the conditions previously optimized for the kinetic resolution of monoformylated pCp ()-1a.
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Compound 6a underwent the reaction smoothly, affording the desired 4-formyl-16-hydroxymethyl[2.2]paracyclophane ()7a in 61% yield and 99% ee. 4,16-Bishydroxymethyl[2.2]paracyclophane 8a, and traces of unreacted precursor 6a were also recovered after the reaction (20% and 9% yield respectively, Table 3, entry 1). Different commercially available ruthenium-based catalysts (II and III, Table 1) were tested in an effort to optimize the reaction conditions, but, again, the RuCl(p-cymene)[(R,R)-Ts-DPEN] I proved to be the best catalyst to promote the asymmetric reduction (Table 3, entry 1 vs entries 2 and 3). Table 3. Optimization of the Desymmetrization by ATH
entry
Cat.
T (°C)
t (min)
6a
1
I
10
120
9
2
II
10
120
5
3
III
10
120
6
4
I
20
150
38
5
I
0
45
18
6
I
20
20
1
7
I
0
50
6
8
I
0
60
5
9c
I
0
100
2
10d
I
0
25
9
11e
I
0
60
3
12f
I
0
75
3
7aa,b 61 (99, ) 8 (98, ) 61 (99, ) 45 (99, ) 71 (99, ) 66 (99, ) 66 (99, ) 69 (99, ) 71 (99, ) 65 (99, ) 63 (99, ) 74 (99, )
pound ()-7a when the ATH was conducted at 0 °C (71% yield, Table 3, entry 5). At higher temperatures (20 °C), the desymmetrization proceeded more rapidly, and significant quantities of fully reduced product 8a were isolated (15% yield, Table 3, entry 6). Longer reaction times also favoured the formation of by-product 8a (Table 3, entries 7 and 8). The variation of the catalytic loading had no impact on the selectivity of the reduction, but only affected the reaction rate (Table 3, entries 9 and 10). Finally, while screening different cosolvents (Table 3, entries 11 and 12), DMF was found to promote the formation of the desired enantiopure product ()-7a in a better yield (74%, Table 3, entry 11). The optimized conditions (Table 3, entry 11) were successfully used to scale up the process. Remarkably, no loss in the reaction efficiency and selectivity were observed while performing the desymmetrization starting from 1 g of compound 6a (Scheme 11). Scheme 11. Scale-up of the Desymmetrization Process
8a 20 45 28 9 6
Product ()-7a could easily be converted into the known alcohol ()-(Sp)-2a following a three step procedure which involved the protection of the free alcohol as a silyl ether, a decarbonylation reaction promoted by Pd(OAc)2, and the removal of the protecting group (Scheme 12). This strategy allowed us to assign the Rp absolute configuration to the levorotatory compound 7a. Scheme 12. Determination of the Absolute Configuration of Product ()-7a
15 12 17 8 16 20
