Dynamic transfer of chirality in photoresponsive systems
Pizzolato, Stefano Fabrizio
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Pizzolato, S. F. (2017). Dynamic transfer of chirality in photoresponsive systems: Applications of molecular photoswitches in catalysis. University of Groningen.
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Chapter 7
Chapter 6
Studies towards a Photoswitchable Chiral Organic
Phosphoric Acid based on an Overcrowded Alkene
for Organocatalyzed Asymmetric Transformations
This chapter describes the study towards the synthesis and application of a photoswitchable chiral phosphoric acid based on a second generation molecular motor core. Direct derivatization of the 2,2’-biphenol-derived chiral molecular switch described in Chapter 5 provided the target compound. Its photoswitching properties were characterized by NMR, UV-vis and CD spectroscopy. The potential for application of the chiral phosphoric acid as switchable organocatalyst in asymmetric transformations was investigated. In order to increase catalytic activity and stereoselectivity, derivatization in the 3,3’-positions of the biphenyl core was attempted.
7.1
Introduction
The activation of a substrate by a chiral catalyst is now regarded as one of the most powerful strategies that can be employed in the art of asymmetric synthesis.1 The development of small-molecule hydrogen-bond donors has received a tremendous amount of attention, and the quest to reach the levels of control that nature can achieve is a constant challenge.2 Brønsted acids have proven themselves to be highly efficient and versatile catalysts for an ever expanding list of synthetic transformations.3 Their high efficiency relies on the underlying concept of achieving LUMO-activation of substrates via acid catalysis within a constricted chiral cavity. Upon protonation of the electrophile, a higher reactivity toward the nucleophile is triggered while effectively preventing access to a single prochiral substrate face, thereby allowing an asymmetric reaction to occur in a stereoselective fashion. Due their ease of synthesis and derivatization, BINOL-phosphoric acid derivatives such as TRIP and TIPSY or vaulted phosphoric acids derived from biaryl diols like VAPOL (Figure 7.1) have established themselves as most valuable players in the field.3
Figure 7.1. Established examples of chiral phosphoric acid catalysts.
They achieved this status by being highly versatile, easily tunable catalysts and have been shown to catalyze a plethora of asymmetric transformations typically using operationally simple and mild reaction conditions. Representative applications of chiral phosphoric acid are enantioselective metal-free reductive amination,4–7 allylboration8–10 and Friedel–Crafts alkylation11–13 (Scheme 7.1). Extensive investigation successfully broadened their use in over a hundred different reaction types (e.g. acetalization,14 aldol reaction,15 Mannich reaction,16 Hetero-Diels–Alder reaction,17 C-H activation,18 etc.).
Scheme 7.1. Representative applications of chiral phosphate derived Brønsted Acid in organocatalysis.
Common elements of phosphoric acid catalysts are: a rigid chiral aromatic backbone with possibility for functionalization; Brønsted acidic and basic catalytic sites; tunable aromatic groups in proximity of the catalytic center (Figure 7.2). These features were initially conceived by Sir John Cornforth, after a detailed analysis of the requirements of the ideal catalyst to perform stereospecific hydration of alkenes.19
Figure 7.2. Design comparison between current BINOL-based phosphoric acids (left) and phosphinic acid
catalysts (right) developed by Cornforth.19
It should be noted that such strong chiral induction is only governed by the characteristic steric hindrance around the phosphoric acid functionality. In such organocatalysts derived from a C2-symmetric biaryl backbone, the phosphorus center could be described as pseudochiral or P-chirotopic according to the
definition of Mislow and Siegel.20 It is noteworthy that during a reaction course, the P-chirotopic phosphorus center becomes P-chirogenic by interaction with a prochiral substrate. Hence, asymmetric induction is achieved via desymmetrization of the C2-symmetric Brønsted acidic/basic center by generating a diastereoisomeric activated complex with the prochiral substrate. On the other hand,few unconventional P-chirogenic21 organocatalysts22 with acidic properties have been described to date.23–25
Previously in our group, M. Vlatkovic conducted a study on the development of the first photoswitchable phosphoric acid catalysts based on second generation molecular motors (Scheme 7.2).26 However their challenging syntheses were not successful. The high sterically demanding overcrowded alkene core prevented the homocoupling of the halogenated alkene precursor AP towards the creation of the C2-symmetric binaphthyl-derived core featured in PA1 and PA2.
Scheme 7.2. Proposed design for photoswitchable phosphoric acids by M. Vlatković.26
Indeed, the proposed systems suffered from an overly complicated design and highly hindered structures. Moreover, their operating mode relies on the cooperative photoswitching of both overcrowded alkene units to achieve effective inversion of the chiral space around the phosphoric acid functionality. However, such double isomerization process could potentially be affected by intramolecular quenching or detrimental increase of steric hindrance upon photochemical E-Z isomerization of the first alkene functionality, thus preventing or obstructing the photoswitching of the second one. The study was eventually redirected towards the investigation of the photochemically and thermally induced isomerization of the single-alkene precursor and two of its derivatives.
7.2
Results and discussion
7.2.1 Design
Due to the plethora of successful applications of chiral phosphoric acids in asymmetric catalysis and chiral induction, we decided to design a switchable chiral phosphoric acid upon derivatization of the previously described bis(2-phenol)-substituted molecular switch 1 (Scheme 7.3). The proposed design was conceived by merging the chiral biaryl-functionalized switch 1 with a flexible 2,2‘-biphenyl phosphoric acid derivative. The study conducted on 1 (see Chapter 5) revealed a strong helicity-transfer of the switch‘s chromophore to the biphenyl due to the high flexibility of the upper half‘s six membered ring. This was expressed in the torsion angle of the biaryl moiety observed via X-ray crystal structure analysis of 1 (ω = 55.71°) and one of its phosphoramidite derivatives L1 (ω = 46.03° in solid state, see Chapter 6). Calculation and experimental evidence supported the concept of coupled transfer of helicity with inversion of local chirality around the coordinating center upon irradiation. Dual stereocontrol was demonstrated for
1 in the asymmetric catalyzed organozinc addition to aldehydes. A combination of change in catalytic
activity and enantioselectivity was observed for its phosphoramidite ligand derivatives L1–5 in the asymmetric copper–catalyzed conjugated addition of diethylzinc to 2-cyclohexen-1-one. Similarly, we
envisioned switchable phosphoric acid catalyst 2 to provide dynamic asymmetric induction upon photoisomerization when applied in an organocatalytic transformation. Moreover, due to the large variety of phosphoric acid-catalyzed reactions, such design holds great expectations for the development of the first artificial switchable catalyst capable of dynamically regulate a stereoselective tandem reaction.
Scheme 7.3. Proposed design of a photoswitchable phosphoric acid 2,2‘-biphenyl-substituted overcrowded
alkene 2, with axial helicity and chirality (green) of the 2,2‘-biphenyl core coupled to axial helicity (blue) and point chirality (red) of the molecular switch scaffold. Here assigned descriptors are based on the structure of compound (S)-1 (for explanation of the chiral descriptors, vide infra). Two states with opposite coupled helicity can be selectively addressed by irradiation with UV-light: (S,M,Ra)-2 (S); (S,P,Sa)-2 (MS). The system described herein features three stereochemical elements (see Scheme 7.3). The first element is the stereogenic center of the switch (highlighted in red), which can exist with either the R or S configuration. The second element is the helicity of the overcrowded alkene (highlighted in blue), which is under thermal diastereoselective control by the configuration of the stereogenic center and can be inverted upon photoisomerization. More precisely, the more stable diastereoisomer (stable state) of the R enantiomer will adopt a P helicity, while the photo-generated diastereoisomer with higher energy (metastable state) will adopt an M helicity. Third is the axial chirality of the biaryl unit (highlighted in green), which can be assigned to either Ra or Sa according to the CIP rules. In Chapter 5 we demonstrated that the biaryl unit of the parent compound 1 can only adopt a conformation in which the lower aryl group is parallel to the fluorenyl lower half. By calculation and experimental evidence, the other conformations, with the biaryl orientated perpendicular with respect to the lower half, were found to induce significant steric strain. Despite such diastereotopic constraint, two distinct atropisomers were observed for both stable and metastable states of compound 1. The singly ortho-substituted lower phenol group was in fact demonstrated to rotate along the aryl-aryl bond, yielding a mixture of syn-conformer (S,M,Ra)-1 and anti-conformer (S,M,Sa)-1. Such biaryl inversion implies a large variation of the aryl-aryl torsional angle (Δθ ≈ 180 °) upon isomerization between o conformers (see Chapter 5, Figure 7.5.3). A thermodynamically favored cyclic seven-membered ring conformation generated upon internal coordination via hydrogen bonding of the two hydroxyl-substituents was proposed. Calculation and experimental evidence suggested that such conformation has access to a transition state with a small barrier for biaryl isomerization, allowing for a fast exchange of two atropisomers in solution at room temperature. Similarly to our previous study, we expected conformations of 2 with matching helicities of biaryl and overcrowded alkene units to be highly favored (Scheme 7.4b-c).
Scheme 7.4. Example of top-down schematic view along the central double bond and front structural view
of S-(S,M,Ra)-2. Assigned stereodescriptors based on the structure of compound (S)-2. b) Schematic representation of the two possible conformations of the biaryl moiety in the stable isomer. The conformer with the aryl perpendicular to the lower half (right) experiences sterical hindrance. c) Schematic representation of switching process between the stable state S-(S,M,Ra)-2 and metastable state MS-(S,P,Sa
)-2.
Hence, our proposed model entails a coupled helical-to-axial transfer of helicity, in which the most favored conformation of the lower aryl substituent is parallel to the fluorenyl lower half of the switch core in either stable and metastable states. Compared with the parent compound 1, the tricyclic biaryl unit of phosphoric acid 2 permits a much more limited range of biaryl torsional angles. Similarly to the proposed cyclic seven-membered ring conformation of 1, the covalently bound biphenyl-2,2′-diyl hydrogenphosphate unit is expected to have access to a transition state with a small barrier for biaryl isomerization. Therefore, only the conformation equivalent to the syn-conformer of 1 is allowed, i.e. (S,M,Ra)-2, while the conformation equivalent to the anti-conformer of 1, i.e. (S,M,Sa)-2, is simply not structurally accessible (see Scheme 7.4b). Such constraint results in both helicity (P/M) and absolute axial chirality (Ra/Sa) of the biaryl unit to
be inextricably connected to the helicity (P/M) of the overcrowded alkene chromophore, having identical biaryl and alkene helicities in each isomer. Two stereodescriptors (R/S and P/M) would be sufficient for the description of any expected isomer reported in this work. However, three stereodescriptors (R/S, P/M and
Ra/Sa) would be used to highlight the coupled three-fold transfer of chirality within the system. Scheme
7.4c illustrates the switching process between stable state (S,M,Ra)-2 and metastable state (S,P,Sa)-2. We envisioned that upon irradiation with UV-light the upper half containing the biaryl motif rotates with respect to the fluorenyl lower half yielding a metastable state with opposite helicity (P→M) and inverted biaryl axial chirality (Ra→Sa).
It should be noted that the chiral molecular switch backbone of 2 lacks of the C2-symmetry characteristic of common BINOL-derived phosphoric acid catalysts. Such aspect has already been discussed for the analogous phosphoramidite derivatives described in Chapter 6, which feature a fixed P-chirogenic phosphorus center and a C1-symmetric chiral switch core. However, we envisioned a different behavior for the design of 2 herein reported, due to its P-chirotopic center (Scheme 7.5). Indeed, the phosphoramidite ligands L1–5 were obtained as a mixture of diasteroisomers, each of the latter displaying a distinctive
activity and opposite stereoselectivity in the asymmetric copper–catalyzed conjugated addition of diethylzinc to 2-cyclohexen-1-one. It should be stressed that in L1–5 the reversal of helical and axial chirality provided by the switch unit is not followed by an inversion of the phosphorus center. Hence, the photo-generated metastable state (S,SP,P,Sa)-L would resemble the enantiomer of the stable state of the opposite diastereoisomer (R,SP,P,Sa)-L (Scheme 7.5a). Consequently, a sharp change in catalytic activity and stereoselectivity was observed. In comparison, the dynamic exchange of axial chirality should not, in principle, significantly affect the catalytic potency of the P-chirotopic phosphoric acid center in 2. Due to proton shift, the Brønsted acidic (P–OH) and basic (P=O) catalytic sites can exchange to provide the most favorable substrate coordination and subsequent activation. Despite the tunable chiral induction provide by the switch unit, the phosphoric center remains P-chirotopic until an activated catalyst-substrate complex is formed. Therefore, we can suggest that upon irradiation and subsequent inversion of the local biaryl axial chirality, the metastable state (S,P,Sa)-2 would effectively resemble the enantiomer of the stable state (S,M,Ra)-2 (Scheme 7.5b), providing an opposite chiral induction in a stereoselective event while maintaining a high catalytic efficiency.
Scheme 7.5. Comparison between P-chirogenic phosphoramidite switch derivatives L (see Chapter 6) and
P-chirotopic phosphoric acid derivative 2.
Compared with the design of PA1 and PA2 proposed by M. Vlatkovic (see Scheme 7.2), the switchable photoswitchable phosphoric acid 2 features: simpler structural and operational designs, easier access to large amount of enantioenriched starting material via chiral resolution, successful precedence of effective reversible transfer of chirality. However, due the lower chiral constriction around the phosphoric acid site of 2, functionalization of the 3,3‘-biaryl positions may be required to achieve efficient chiral transfer towards the catalysis products.
In summary, our proposal is based on the following elements: a) the selective and reversible photo-isomerization of the overcrowded alkene bond; b) the unique change in helicity featured by molecular motors and switches; c) the coupled change in axial chirality of the biaryl core achieved via a central-to-helical-to-axial transfer of chirality, d) the use of a switchable biaryl phosphoric acid functionality with potentially manifold applications in asymmetric catalysis and chiral recognition.
7.2.2 Synthesis
The synthesis of photoswitchable phosphoric acid 2 starting from 2,2‘-biphenol-derived molecular switch 1 is illustrated in Scheme 7.6 (for synthesis and chiral resolution of 1, see Chapter 5). Optically enriched (S,M,Ra/Sa)-1 (90% ee) was reacted with POCl3 to yield (S,RP/SP,M,Ra)-3, which was obtained as 55:45 mixture of two diastereoisomers due to the newly generated P-chirogenic center. Upon heating at reflux in pyridine in the presence of water, 3 was converted to the target compound (S,M,Ra)-2 as a single diastereoisomer (95% yield over two steps, 90% ee).
Scheme 7.6. Synthesis of phosphoric acid switch derivative 2. 7.2.3 NMR spectroscopy
In order to investigate the photochemical behavior of 2, an NMR sample of stable state S-(S,M,Ra)-2 in CDCl3 was irradiated with UV light (365 nm) for 60 min at room temperature. A schematic representation of the photochemical E-Z isomerization of 2 with partial assignment of absorptions is presented in Figure 7.3a. 1H NMR spectra were taken before (Figure 7.3b), during (Figure 7.3c) and after irradiation (Figure 7.3d). Upon irradiation a new set of absorptions with intensities increasing over time was observed, which is indicative of the photo-induced isomerization to the metastable state MS-(S,P,Sa)-2. At the photostationary state, the relative integration revealed a final ratio of, respectively, S-(S,M,Ra )-2:MS-(S,P,Sa)-2 = 20:80. The reverse photoisomerization towards the stable state was observed upon irradiation of the sample with visible light (420 nm) over 180 min. 1H NMR spectra were also taken during (Figure 7.3e-f) and after irradiation (Figure 7.3g) at longer wavelength. The original set of absorption assigned to the stable state was recovered. No evidence of decomposition was observed as suggested by the clean profile of the final spectrum. At the photostationary state, the relative integration revealed a final ratio of, respectively, S-(S,M,Ra)-2:MS-(S,P,Sa)-2 = 85:15. This preliminary experiment demonstrates the high photoswitching efficiency of 2 in terms of PSS ratios and resistance to prolonged irradiation, as opposed to the more sensitive precursor 1 (see Chapter 5).
Figure 7.3. Schematic representation of the photochemical E-Z isomerization of stable state S-(S,M,Ra)-2 to metastable state MS-(S,P,Sa)-2.
1
H NMR spectra of 2 (4.0 mg, CDCl3 (0.65 mL), 25 °C): b) S-(S,M,Ra)-2; c-d) after irradiation with UV light (365 nm) over 30 min and 60 min, respectively, of S-(S,M,Ra)-2 to MS-(S,P,Sa)-2 (PSS365 S:MS = 20:80); e-f-g) after irradiation with visible light (420 nm) over 60 min, 120 min and 180 min, respectively, of PSS365 mixture towards S-(S,M,Ra)-2 (PSS420 S:MS = 85:15). Partial absorptions assignment indicated by letters.
7.2.4 Photochemical isomerization
The switching properties of (S)-2 were monitored by UV-vis absorption and circular dichroism (CD) spectroscopy (Figure 7.4). A solution of S-(S,M,Ra)-2 (90% ee, chloroform, 6.2·10−5 M) in a quartz cuvette was purged with argon and irradiated at room temperature towards either the metastable state using UV light (365 nm, Figure 7.4a, black to red gradient) or the stable state using visible light (420 nm, Figure 7.4b, red to blue gradient). The reversible photochemical E-Z isomerization was found to be characterized by a clear isosbestic point at 367 nm, indicating the absence of side reactions. A bathochromic shift of the major absorption band (π→π*) of about 40 nm was observed, indicative of an increase in alkene strain and consistent with other second generation motors and switches as is expected for the metastable form MS-(S,P,Sa)-2.
27
In parallel, the same starting solution S-(S,M,Ra)-2 (90% ee, chloroform, 6.2·10−5 M) was subjected to CD spectroscopy in order to perform a qualitative analysis of the change in its helical structure (Figure 7.4c). The compound displayed a strong Cotton effect in the area of ~250–320 nm and slightly smaller Cotton effects of opposite sign at higher wavelengths (λ > 320 nm). The presence of such negative Cotton effect around 400 nm is an indication of the characteristic helical shape of the overcrowded alkenes studied in our group. Upon irradiation with 365 nm light an inversion of the absorption band was observed, which is indicative of an inversion in helicity and shows that the photochemical isomerization of the stable S-(S,M,Ra)-2 to the metastable MS-(S,P,Sa)-2 has occurred. Upon irradiation with 420 nm light, the original absorption band could be partially recovered.
Figure 7.4. a) Experimental UV-vis absorption spectra of stable (S,M,Ra)-2 (90% ee, CHCl3, 6.2·10−5 M, black) and irradiation with UV-light (365 nm) of (S,M,Ra)-2 towards metastable state affording a PSS365 mixture (S:MS = 20:80, red) with isosbestic point at 367 nm. b) Experimental UV-vis absorption spectra of irradiation of the previous PSS365 sample using visible light (420 nm), resulting in reversed E-Z isomerization towards the stable state affording a new PSS420 mixture (S:MS = 85:15). c) Experimental and CD spectra of (S)-2 (CHCl3, 6.2·10−1 M): black, starting stable state (S,M,Ra)-2; red: CD spectra of PSS365 mixture; blue: CD spectra of PSS420 mixture. Note: PSS ratios determined by
1
H NMR analysis.
7.2.5 Switchable asymmetric catalysis
Having established the two-step reversible switching process of 2, we investigated its catalytic properties by its use as a chiral catalyst in a few model asymmetric organocatalysis reactions.3 Due to its ability to change chiral helicity upon application of an external stimulus and proven versatility of chiral phosphoric acids in organocatalysis, we envisioned such system to permit dual stereocontrol in a variety of Brønsted acid catalyzed transformations. Ultimate display of unprecedented efficiency in photoswitchable catalysis would be the consecutive stereoselectivity control in a one-pot multi-step synthetic sequence. The assisted tandem transformation may be composed of two processes generating distinct stereogenic centers.28 Noteworthy, the configuration of the secondly generated stereogenic center may be subject to stereospecific substrate control exerted by the previously generated stereogenic center rather than by stereoselective induction from the chiral catalyst. A large variety of switchable systems based on external activation of a Brønsted acid and base catalysts have been reported.29–35 However, very limited examples have been shown to achieve dual stereocontrol.36–39 In particular, no precedent system was harnessing the internal transfer
from helical to axial to point chirality before the work reported in this thesis. Because the field has been extensively analyzed, we suggest the reader to refer to the recent comprehensive reviews for further details.40–44
Five previously reported Brønsted acid-catalyzed transformations were selected for the testing of 2: a) aldol reaction;45 b) Friedel–Crafts alkylation;12 c) Strecker reaction;46 d) reductive amination;6 e) allylboration of aldehydes.8 The reactions were chosen based on the following criteria: low catalyst loading, high selectivity in previously reported studies, commercial accessibility of substrates, mild reaction conditions to avoid thermal relaxation of the metastable state, similar reaction media to possibly extend the system towards a tandem synthetic sequence. The results of the catalysis tests using (S,M,Ra)-2 are presented in Scheme 7.6.
Scheme 7.7. Attempted Brønsted acid-catalyzed transformations using (S,M,Ra)-2. No asymmetric induction was achieved in any of the tested reactions. Yield in absence of catalyst, as reported by references: a) 0%;45 b) <5%;12 c) 0%,46 d) NR;6 e) NR.8 NR = not reported.
Unfortunately, slow reaction rates (conversions from 20% up to 90% after 7 d) and no asymmetric induction were observed in each case. It should be noted that most of the selected transformations were optimized and developed upon use of TRIP and TiPSY catalysts, featuring large substituents in proximity of the catalytic pocket. However, the methodology for three-component Strecker reaction reported by Ma and co-workers does make successful use of the unsubstituted BINOL-derived phosphoric acid.8 However, only racemic products were obtained, unless the corresponding catalyst derivative featuring phenanthren-9-yl-substituted acid at the 3,3‘-positions of the binaphthyl scaffold was used (73%, 40% ee). The catalytic activity has been shown to vary greatly depending on the nature of the phosphoric acid.47,48 Rueping and Leito disclosed a full study on establishing an acidity scale for the commonly used Brønsted acid catalysts.49 The study investigated the correlation between Brønsted acidity and reactivity. A Nazarov cyclization was chosen as a model reaction because no product inhibition occurred. The result was a clear relationship between the observed rate constant and the acidity of the catalyst. In general, the more acidic catalysts resulted in higher rate constants. BINOL-derived phosphoric acid diesters BPA1–5 displayed pKa values in acetonitrile in the range of 12–14 (Figure 7.5). More precisely, BPA4 and BPA5 were found to have pKa values of 13.3 and 14.0, respectively, and a difference in reaction rate of approximately two-fold in favor of the first. Notably, BPA5 and 2 feature a less extended aromatic system than BPA4, thus relating the lower proton acidity with reduced capacity to stabilize the generated anionic charge upon deprotonation. On the other hand, BPA1 was reported to be the most acidic, arguably due to a less hindered acid center which could allow a more efficient stabilization of the generated local charge by the polar solvent.
Figure 7.5. Acidity scale for selected BINOL-derived Brønsted acids
It should be pointed out that enantioselectivity is dependent on catalyst architecture. Nevertheless, activation (and thus reactivity) can be directly correlated to acidity if no catalyst inhibition occurs. It appeared clear from the disappointing catalysis tests and the extremely limited number of applications of unsubstituted BINOL-derived phosphoric acids in catalysis46,50, that a structural improvement of our design was needed.
7.2.6 Attempted synthesis of 3,3’-distituted biaryl switch core
For the introduction of substituents at the 3,3′-positions of BINOL-derivatives, the most commonly used routes by research groups include: MOM-protection of BINOL; installation of either boronic esters or halogen substituents at the 3,3′-positions using, respectively, a borylation or a lithiation-halogenation strategy; installation of aryl substituents via palladium-catalyzed cross-coupling; MOM-deprotection; phosphorylation.3,51 Inspired by previously reported catalytic systems based, we proposed an analogous retrosynthetic analysis of 3,3‘-biaryl substituted phosphoric acid-switch derivative 4 as presented in Scheme 7.8.
Scheme 7.8. Proposed retrosynthetic analysis of phosphoric acid 4 featuring a 3,3‘-disubstituted-biaryl
switch core.
Unfortunately, reaction of (S,M,Ra/Sa)-1 with MOM-Cl in presence of sodium hydride yielded the desired product 7 in poor yield (20%), which was obtained as a 80:20 mixture of syn- and anti-conformers (Scheme 7.9).
Scheme 7.9. Synthesis of 2,2‘-bis-MOM-protected biaryl switch-derivative 7.
The major isolated fraction (75%) was composed of a single MOM-protected compound, and was displaying an unusual absorption pattern different from common overcrowded alkene species, as observed by 1H NMR spectroscopy analysis. In particular the distinctive heptet assigned to the proton at the stereogenic center was not observed (expected signal: heptet, δ = 4.2–3.8 ppm, J = 7.0–7.4 Hz, 1H). Structure 8 was proposed, which could be obtained upon base-triggered addition of the lower phenolate anion to the overcrowded alkene functionality. Such unexpected decomposition path for 1 and its triflate derivatives was also observed in presence of other strong inorganic bases such as sodium hydroxide and potassium hydroxide, while the corresponding dimethylated precursor was stable under the identical conditions for an indefinite period of time (see Chapter 8). An alternative procedure for MOM-protection of binaphthol derivatives previously reported52 was also tested, using NaH (2.2 equiv), MOM-Cl (2.4 equiv) in THF (0.03 M). However, similar low selectivity and yield towards the bis-protected switch derivative 7 were observed. A posteriori, alternative methodologies for MOM-protection of alcohols involving use of MOM-chloride in presence of a milder organic base such as iPr2NEt
53,54
or iPr2NEt and catalyst DMAP 55,56 could have resulted in a higher selectivity (see Chapter 6, Phosphoramidite synthesis).
The synthesis of 3,3‘-dibromo-2,2‘-bis-MOM-protected- biaryl switch 9 from 7 was attempted by a modified procedure previously reported.57 Double ortho-lithiation of (S,M,Ra/Sa)-7 was conducted with
tBuLi at low temperature, followed by lithium-halogen exchange upon addition of
1,2-dibromo-1,1,2,2-tetrachloroethane (Scheme 7.10).
Three distinct fractions were obtained upon purification of the reaction residue by column chromatography. As suggested by the 1H NMR spectra, each species was still funtionalized with two MOM-protecting groups. The 1H NMR spectrum of the major early fraction (Rf = 0.6, pentane:EtOAc = 20:1) displayed two
sets of absorptions in 75:25 ratio which were lacking the typical pattern of the overcrowded alkene functionality. Similar to compound 8, the distinctive heptet assigned to the proton at the stereogenic center was not observed, which is an indication of the decomposed switch core. The 1H NMR spectrum of the middle fraction (Rf = 0.45, pentane:EtOAc = 20:1) displayed two sets of absorptions in an 85:15 ratio
(Figure 7.6).
Figure 7.6. Top: Structure of (S,M,Ra/Sa)-9 with highlighted proton assignment. Bottom: 1
H NMR (400 MHz, CDCl3) of isolated middle fraction upon halogenation of 7 towards 9 with expansion of aromatic region. Proton G (expected singlet peak) could not be assigned.
The absorptions assigned to the major species were found coherent with an intact overcrowded alkene functionality. Consistency with the structure of product (S,M,Ra)-9 (21% yield) obtained via successful double lithium-halogen exchange was hypothesized upon analysis of the gCOSY spectrum (Figure 7.7).
Figure 7.7. gCOSY (400 MHz, CDCl3) of previous sample.
However, the total integral of the aromatic proton absorptions was found equal to 11 units (expected aromatic proton count: 12). The assignment of the identified absorptions was executed by elucidating the correct cross-peak signals from the gCOSY spectrum (Figure 7.8). The missing absorption was assigned to the aromatic proton in the upper phenol ring in meta to the MOMO-substituent (expected signal: singlet, 1H). The presence of the unidentified absorption underneath the residual solvent peak cannot be excluded. Out of the second set of absorptions (minor species of a 85:15 mixture) observed in the 1H NMR spectrum of the middle fraction, only few resolved absorptions could be clearly characterized, due to their low intensity and major overlap with the absorptions previously assigned to product (S,M,Ra)-9. The unidentified minor species was hypothesized to be assigned to either the opposite anti-conformer (S,M,Sa)-9 or the mono-halogenated intermediates 10 or 11. The final fraction (Rf = 0.25, pentane:EtOAc = 20:1)
was mainly composed of unreacted substrate 7. Due to the low yield obtained in the 3,3‘-biaryl functionalization steps, the study described herein was eventually interrupted.
Figure 7.8. Expansion of aromatic region from gCOSY (400 MHz, CDCl3) of previous sample.
A larger amount of enantiomerically enriched biphenol switch 1 was in fact required to continue the optimization of the synthetic route towards a more structurally complex switchable phosphoric acid derivative. Moreover, the valuable compound 1 constituted also the starting material for the development of the chiral switchable bis-phosphine ligand described in Chapter 8. Eventually the limited amount of time left did not allow synthesizing other batches of 1 to proceed further with the parallel investigation for these two projects.
7.3
Conclusion
The synthesis of photoresponsive phosphoric acid 2 based on a molecular switch core is reported. The proposed design implies a coupled helical-to-axial transfer of chirality, in which the hybrid chirality generated by the stereogenic center and the dynamic helical structure of the overcrowded alkene is transferred to the helical and axial chirality of the biaryl unit. Thus, the local chirality of the biaryl derived phosphoric acid motif can be reversibly controlled upon irradiation via photochemical E-Z isomerization (PEZI). Experimental analysis by UV-vis absorption, CD and 1H NMR spectroscopy proved the reversible photoswitching properties of 2. Its applicability as a switchable stereoselective organocatalyst was
investigated in a selection of previously reported Brønsted acid-catalyzed transformations. Unfortunately, slow reaction rates and no asymmetric induction were observed in each case. In attempt to increase catalytic efficiency and asymmetric induction, a more complex design of a 3,3‘-biaryl substituted phosphoric acid switch derivative 4 was proposed. The attempted synthesis was complicated by low yielding MOM-protection and ortho-functionalization of the starting 2,2‘-biphenol derivative 1 and was eventually interrupted due to lack of time and starting material 1. Despite the unfinished study, this responsive system holds promise to modulate catalysts activity and switch stereoselectivity with high spatio-temporal control ultimately arriving at a catalyst that can perform multiple enantioselective transformation in a sequential manner. In addition, this switch system has considerable potential as chirality selector for a wide range of applications, beyond the field of asymmetric catalysis, such as control of supramolecular architecture, liquid crystal morphology and chiral recognition.
7.4
Experimental section
7.4.1 General methods
General experimental details can be found in Chapters 5 and 6.
7.4.2 Synthetic procedures
(12S,13bR)-6-chloro-13-(9H-fluoren-9-ylidene)-12-methyl-10,11,12,13-tetrahydrobenzo[d]naphtho[1,2-f][1,3,2]dioxaphosphepine 6-oxide (3).
Phosphorochloridate 3 was prepared from 1 by a modified procedure previously reported.58 A flame-dried Schlenk tube was equipped with vacuum/nitrogen stopcock and a magnetic stirring bar. The tube was charged with 2,2‘-biphenol derived switch (S,M,Ra/Sa)-1 (60 mg, 0.144 mmol) and three cycles of vacuum and backfilling of Argon was applied. Dry CH2Cl2 (2 mL) and freshly distilled NEt3 (44 mg, 0.06 mL, 0.432 mmol, 3 equiv) were added. POCl3 (44 mg, 0.027 mL, 0.288 mmol, 2.1 equiv) was added at 0 °C and the solution was stirred at rt over 16 h, until TLC indicated that the reaction was completed. The reaction was quenched with water (5 mL) and the mixture was diluted with CH2Cl2 (10 mL). The organic phase was washed with brine (5 mL), dried over Na2SO4, filtered and the solvent was removed under reduced pressure. The product phosphorochloridate (S,RP/SP,M,Ra)-3 (68 mg, 0.137 mmol, 95%) was obtained without further purification in a 55:45 mixture of two diastereoisomers as a yellow foam solid. The absolute configurations of the diastereoisomers were not assigned. 1H NMR (400 MHz, CDCl3, A:B = 55:45 mixture of diastereoisomers) δ 7.92–7.85 (m, 1H, A+B), 7.57–7.51 (m, 1H, A+B), 7.51–7.46 (m, 1H, A+B), 7.47–7.42 (m, 1.5H, A+B), 7.41–7.32 (m, 1.5H, A+B), 7.32–7.25 (m, 3H, A+B), 7.11–7.04 (m, 1H, A+B), 7.02–6.94 (m, 1.2H, A), 6.94–6.89 (m, 0.9H, B), 6.87–6.79 (m, 2H, A+B), 6.60 (dt, J = 7.9, 0.8 Hz, 0.55H, A), 6.53 (dt, J = 7.9, 0.9 Hz, 0.45H, B), 4.21 (app. hept, J = 7.0 Hz, 1H, A+B), 2.82–2.74 (m, 1H, A+B), 2.56–2.42 (m, 2H, A+B), 1.60 (app. dd, J = 10.0, 7.0 Hz, 3H, A+B), 1.38–1.23 (m, 2H, A+B). 31P NMR (162 MHz, CDCl3, A:B = 55:45 mixture of diastereoisomers) δ 10.76 (A), 10.40 (B).
(12S,13bR)-13-(9H-fluoren-9-ylidene)-6-hydroxy-12-methyl-10,11,12,13-tetrahydrobenzo[d]naphtho[1,2-f][1,3,2]dioxaphosphepine 6-oxide (2).
Phosphoric acid 2 was prepared from 3 by a modified procedure previously reported.59 A Schlenk tube was equipped with a magnetic stirring bar and charged with phosphorochloridate (S,RP/SP,M,Ra)-3 (68 mg, 0.137 mmol, 90% ee). A 1:1 mixture of pyridine/water (2 mL) was added and the mixture was heated at reflux over 2 h. After cooling, CH2Cl2 (10 ml) was added and the organic layers is washed with aq. HCl 1M (3x8 mL) to remove pyridine residues unitl acqueous layer was pH=1-2. The organic layer was washed with brine (10 mL) and dried over Na2SO4, filtered and the solvent was removed under reduced pressure. The product was purified by column chromatography (SiO2, CH2Cl2:MeOH= 10:1) to yield phosphoric acid (S,M,Ra)-2 (65 mg, 0.137 mmol, quant., 90% ee) as a dark yellow solid. m.p. 226–228 °C. 1H NMR (400 MHz, CDCl3) δ 7.88 (dd, J = 5.9, 3.2 Hz, 1H), 7.54 (dd, J = 5.5, 3.3 Hz, 1H), 7.43 (d, J = 7.8 Hz, 1H), 7.35 (t, J = 8.4 Hz, 2H), 7.32–7.23 (m, 5H), 7.01–6.89 (m, 2H), 6.86 (d, J = 3.9 Hz, 2H), 6.72 (q, J = 3.7 Hz, 1H), 6.68 (d, J = 7.8 Hz, 1H), 4.46 (s, 2H), 4.19 (h, J = 7.2 Hz, 1H), 2.73–2.64 (m, 1H), 2.51–2.34 (m, 2H), 1.59 (d, J = 6.9 Hz, 3H), 1.35–1.20 (m, 1H). 13C NMR (75 MHz, CDCl3) δ 141.7, 140.8, 140.4, 138.5, 137.9, 137.3, 136.7, 135.1, 130.7, 129.4, 129.3, 128.4, 127.3, 127.2, 126.8, 126.6, 126.5, 124.8, 124.2, 124.1, 123.7, 121.7, 121.3, 119.3, 118.1, 34.6, 31.4, 29.7, 29.4, 21.6. 31P NMR (162 MHz, CDCl3) δ 3.76. HRMS (ESI, m/z):
calcd for C30H24O4P [M+H] +
: 479.1407, found: 479.1401. [ ] -41.6 (c 0.17, CHCl
3) for (S,M,Ra)-2 (90% ee); [ ] -17.7 (c 0.27, MeOH) for (S,M,Ra)-2 (90% ee).
9-((2S,8R)-7-(methoxymethoxy)-8-(2-(methoxymethoxy)phenyl)-2-methyl-3,4-dihydronaphthalen-1(2H)-ylidene)-9H-fluorene (7)
Bis-MOM-protected 2,2‘-biphenol switch 7 was prepared from 1 by a modified procedure previously reported.60 A flame dried Schlenk tube was equipped with a magnetic stirring bar and charged with NaH (60% dispersion in oil, 88 mg, 1.32 mmol, 2.4 equiv), dry THF (6 mL) and dry DMF (2 mL). After the temperature was lowered to 0° C, a solution of (S,M,Ra/Sa)-1 (230 mg, 0.55 mmol, 1 equiv) was added dropwise and the mixture was stirred for 8 h at room temperature. The reaction was quenched by adding 10 mL of water, extracted with EtOAc (3 x 10 mL), the combined organic phase was washed with brine (2 x 10 mL), dried over MgSO4, filtered and the solvent was removed under reduced pressure. 1H NMR analysis of the crude residue revealed a 1:6 mixture of species 7:8. The residue was purified by column chromatography (SiO2, pentane:EtOAc = 8:1) to yield bis-MOM-protected 2,2‘-biphenol switch (S,M,Ra/Sa)-7 (40 mg, 0.08 mmol, 14%) in a 80:20 mixture of atropisomers as a yellow foam. 1H NMR (300 MHz, CDCl3, A:B = 80:20 mixture of diastereoisomers) δ 7.84–7.77 (m, 0.8H, A), 7.77–7.66 (m, 0.4H, B), 7.65–7.60 (m, 0.8H, A), 7.50 (d, J = 7.6 Hz, 0.8H, A), 7.36–7.23 (m, 5H, A+B), 7.22–7.09 (m, 1.7H, A+B), 7.01 (t, J = 9.3 Hz, 0.2H, B), 6.97–6.81 (m, 3.6H, A+B), 6.75–6.67 (m, 0.8H, A), 6.63 (d, J = 8.1 Hz, 0.2H, B), 6.46 (t, J = 7.1 Hz, 0.2H, B), 5.17 (d, J = 6.5 Hz, 0.8H, A), 5.06 (t, J = 6.2 Hz, 0.5H, B), 4.99 (t, J = 5.8 Hz, 1H, A+B), 4.92 (d, J = 6.6 Hz, 0.2H, B), 4.72 (d, J = 6.9 Hz, 0.8H, A), 4.52 (d, J = 6.9 Hz, 0.8H, A), 4.12 (h, J = 7.2 Hz, 0.8H, A), 4.02 (h, J = 7.5 Hz, 0.2H, B), 3.38 (s, 2.4H, A), 3.36 (s, 0.6H, B), 3.33 (s, 2.4H, A), 3.33 (s, 0.6H, B), 2.71–2.60 (m, 1.2H, A+B), 2.48–2.28 (m, 2H, A+B), 1.55 (d, J = 6.9 Hz, 2.4H, A), 1.02–0.82 (m, 5.1H, A+B). 13C NMR (75 MHz, CDCl3, A:B = 80:20 mixture of diastereoisomers) δ 156.2, 154.6, 154.3, 154.2, 146.3, 144.7, 140.4, 140.3, 139.1, 138.9, 138.8, 138.5, 138.3, 138.3, 137.7, 136.1, 135.3, 135.0, 131.8, 130.2, 128.4, 128.2, 128.1, 126.9, 126.8, 126.7, 126.7, 126.6, 126.4, 126.4, 126.3, 126.1, 126.0, 125.5, 124.9, 124.4, 124.4, 124.3, 120.2, 120.1, 119.3, 119.2, 118.9, 118.2, 116.4, 116.0, 114.2, 113.9, 96.4, 95.5, 95.1, 95.0, 63.4, 63.1, 63.0, 61.2, 55.8, 55.7, 55.4, 35.1, 31.6, 29.7, 29.4, 29.4, 28.8, 26.7, 22.7, 22.3.
(6S,6aR)-6a-(9H-fluoren-9-yl)-1-(methoxymethoxy)-6-methyl-4,5,6,6a-tetrahydrobenzo[kl]xanthene
Major decomposition of the overcrowded alkene functionality occurred during the synthesis of 7 from 1, as determined by 1H NMR spectroscopy of the isolated early fraction after flash column chromatography. The structure of the compound was eventually assigned to cyclized species 8 (205 mg, 0.44 mmol, 81%). 1H NMR (300 MHz, CDCl3) δ 8.61 (d, J = 8.0 Hz, 1H), 8.09–7.98 (m, 1H), 7.75–7.68 (m, 1H), 7.63 (d, J = 7.6 Hz, 1H), 7.42–7.36 (m, 2H), 7.30 (d, 2H), 7.28–7.24 (m, 1H), 7.21 (t, J = 7.5 Hz, 1H), 7.10–7.02 (m, 2H), 6.90 (td, J = 7.6, 1.2 Hz, 1H), 5.82 (d, J = 7.7 Hz, 1H), 5.38 (d, J = 6.7 Hz, 1H), 5.31 (d, J = 6.7 Hz, 1H), 4.66 (s, 1H), 3.59 (s, 3H), 2.60 (ddd, J = 17.9, 10.8, 7.3 Hz, 1H), 2.16–2.00 (m, 2H), 1.10–0.98 (m, 0H), 0.95 (d, J = 6.9 Hz, 3H), 0.90–0.69 (m, 2H).
Synthesis of 9-((2S,8R)-7-(methoxymethoxy)-8-(2-(methoxymethoxy)phenyl)-2-methyl-3,4-dihydronaphthalen-1(2H)-ylidene)-9H-fluorene (9)
The synthesis of 3,3‘-dibromo-2,2‘-bis-MOM-protected- biaryl switch 9 from 7 was attempted by a modified procedure previously reported.57 A flame dried Schlenk tube was equipped with a magnetic stirring bar and charged with bis-MOM-protected 2,2‘-biphenol switch (S,M,Ra/Sa)-7 (23 mg, 0.05 mmol, 1 equiv). Dry THF (1.5 mL) was added and the solution was cooled to -78 °C.
tBuLi (1.9 M in hexane, 0.048 mL, 0.091 mmol, 2 equiv) was added slowly and
the solution was stirred for 1 h. Then the solution was warmed to 0 °C and 1,2-dibromo-1,1,2,2-tetrachloroethane (45 mg, 0.14 mmol, 3 equiv) was added. The mixture was warmed up to room temperature overnight before quenching with saturated aq. NH4Cl (4 mL) solution. The layers were separated and the aqueous layer was extracted with CH2Cl2 (3 x 5 mL). The combined organic layers were dried over Na2SO4, filtered and the solvent was removed under reduced pressure. The residue was purified by column chromatography (SiO2, pentane:EtOAc = 20:1) to afford three distinct fractions. The 1H NMR specra of all the species were still displaying the typical absorptions of both MOM-protecting groups. The spectrum of the early fraction (Rf = 0.6, pentane:EtOAc = 20:1, ca. 12 mg) displayed two sets of
absorptions in a 75:25 ratio which were lacking the typical pattern of the overcrowded alkene functionality. The spectrum of the middle fraction (Rf = 0.45, pentane:EtOAc = 20:1) displayed two sets of absorptions in
a 85:15 ratio. Consistency with the structure of product (S,M,Ra)-9 (7 mg, 0.011mmol, 21% yield) was hypothesized upon analysis of the gCOSY spectrum (see main text). 1H NMR (400 MHz, CDCl3, major species) δ 7.64 (d, J = 7.4 Hz, 1H), 7.41–7.38 (m, 1H), 7.35 (d, J = 7.5 Hz, 1H), 7.14 (td, J = 5.5, 2.7 Hz, 1H), 7.05 (t, J = 7.4 Hz, 1H), 6.90 (t, J = 7.5 Hz, 1H), 6.62 (t, J = 7.6 Hz, 1H), 6.55 (d, J = 7.3 Hz, 1H), 6.54 (d, J = 7.3 Hz, 1H), 6.41 (d, J = 8.2 Hz, 1H), 6.26 (t, J = 7.5 Hz, 1H), 5.01 (d, J = 6.3 Hz, 1H), 4.82 (d,
J = 6.3 Hz, 1H), 4.33 (d, J = 4.2 Hz, 1H), 3.88 (p, J = 6.7 Hz, 1H), 3.80 (d, J = 4.3 Hz, 1H), 3.20 (s, 3H),
2.99 (s, 3H), 2.81 (t, J = 13.8 Hz, 1H), 2.58 (d, J = 14.7 Hz, 1H), 1.85 (d, J = 12.6 Hz, 1H), 1.75–1.65 (m, 1H), 1.38 (d, J = 6.7 Hz, 3H). Note: one expected absorption peak (s, 1H) was missing and hypothesized to be hidden underneath the residual solvent peak. 13C NMR (101 MHz, CDCl3) δ 152.7, 152.7, 146.0, 144.6, 141.7, 140.0, 139.0, 139.0, 138.6, 136.9, 136.8, 133.7, 133.4, 127.2, 127.0, 126.1, 126.1, 125.9, 124.8, 124.6, 123.1, 120.4, 118.7, 118.4, 113.1, 97.9, 94.9, 57.1, 55.8, 35.3, 33.1, 29.7, 27.3, 20.8. HRMS (ESI, m/z): calcd for C34H30O4 [M-2HBr]
+
: 502.2139, found: 502.2195. The unidentified minor species was hypothesized to be assigned to either the opposite anti-conformer (S,M,Sa)-9 or the mono-halogenated intermediates 10 or 11. 1H NMR (400 MHz, CDCl3, minor unknown species, partial spectrum) δ 7.68 (t, J = 7.7 Hz, 1H), 7.61 (d, J = 7.6 Hz, 1H), 7.30–7.10 (m, 1H), 6.95 (d, J = 7.8 Hz, 1H), 5.07 (d, J = 6.8 Hz, 1H), 4.89 (d, J = 6.8 Hz, 1H), 4.43 (s, 2H), 3.32 (s, 3H), 3.04 (d, J = 2.3 Hz, 3H), 1.13 (d, J = 6.9 Hz, 3H). The later fraction (Rf = 0.25, pentane:EtOAc = 20:1) was mainly composed of unreacted substrate 7 (6 mg,
0.011 mmol, 26% recover).
7.4.3 1H NMR spectroscopy.
The stable form of phosphoric acid (S,M,Ra)-2 (~4.0 mg) was dissolved in CDCl3 (0.65 mL). The sample was placed in an NMR tube and irradiated towards the metastable state (S,P,Sa)-2 with UV light at 365 nm at a distance of ca. 2 cm from the LED source. 1H NMR spectra of the sample were taken before, during and after irradiation at rt. No further changes were observed after 60 min of irradiation. The relative integration of the absorptions in 1H NMR spectra revealed a PSS365 mixture of (S,M,Ra)-2: (S,P,Sa)-2 = 20:80. The sample was subsequently irradiated towards the stable state (S,P,Sa)-2 with visible light at 420 nm at a distance of ca. 2 cm from the LED source. 1H NMR spectra of the sample were taken before, during and after irradiation at rt. No further changes were observed after 180 min of irradiation. The relative integration of the absorptions in 1H NMR spectra revealed a PSS420 mixture of (S,M,Ra)-2: (S,P,Sa)-2 = 85:15. 1H NMR of the starting solution of stable state, PSS365 and PSS420 and intermediate state are reported in Figure 7. of the main text with assignment of main distinctive peaks.
7.4.4 UV-vis and CD spectroscopy.
A solution of stable form of phosphoric acid (S,M,Ra)-2 in spectroscopic grade chloroform (6.2·10 -5
M) was transferred in a fluorescence quartz cuvette with magnetic stirrer and degassed with argon under stirring for 5 min. The forward and backward irradiation process from the stable isomer to the metastable isomer was monitored by UV-vis absorption spectroscopy time-course measurement (wavelength range 300–650 nm, scan periods of 20 s). After starting the time-course measurements, the sample was irradiated under stirring with the proper LED source perpendicularly to the analysis path of the spectrophotometer (3 min at 365 nm, 3 min at 420 nm). To ensure that the PSS was reached, irradiations were continued until no further changes in the absorption spectra were observed. CD spectra were recorded for the same starting solution of stable form of (S,M,Ra)-2 and after reaching the photostationary state at 365 nm and 420 nm (mixture of stable form (S,M,Ra)-2 and metastable form (S,P,Sa)-2). UV-vis and CD spectra are reported in main text (Figure 7.).
7.4.5 Catalysis tests
Brønsted acid catalyzed asymmetric aldol reaction
The aldol reaction was attempted by a modified procedure previously reported.45 A flame-dried Schlenk tube was equipped with vacuum/nitrogen stopcock and a magnetic stirring bar. The tube was charged with phosphoric acid (S,M,Ra)-2 (2.4 mg, 0.005 mmol, 0.05 eq, 90% ee), ethyl glyoxalate (50% in toluene) (20 mg, 0.1 mmol, 1 equiv) and cyclohexanone (98 mg, 1 mmol, 10 equiv). The reaction mixture was stirred at 0 °C over 7 d. The volatiles were removed under reduced pressure and the crude was purified by flash column chromatography (SiO2, pentane:EtOAc= 3:1). No trace of the expected product ethyl 2-hydroxy-2-(2-oxocyclohexyl)acetate was detected by 1H NMR, as compared with the previously reported physical data.45 Major syn-isomer. Rf = 0.2 in cyclohexane:EtOAc, 70:30.
1
H NMR (400 MHz, CDCl3) δ 4.61 (d, J = 1.6 Hz, 1H, CHOH), 4.19 (q, J = 7.0 Hz, 2H), 2.91 (s, 1H, OH), 2.78–2.70 (m, 1H), 2.44–2.38 (m, 1H), 2.34–2.20 (m, 1H), 2.06–1.97 (m, 1H), 1.92–1.78 (m, 3H), 1.65–1.53 (m, 2H), 1.23 (t, J = 7.0 Hz, 3H). Minor anti–isomer: 1H NMR (400 MHz, CDCl3) δ 4.18 (qd, J = 7.0 and 2 Hz, 2H), 3.95 (d, J = 3.2 Hz, 1H), 3.08 (s, 1H), 2.92–2.85 (m, 1H), 2.39–2.31 (m, 1H), 2.28–2.17 (m, 1H), 2.10–1.95 (m, 2H), 1.93–1.79 (m, 2H), 1.71–1.52 (m, 2H), 1.21 (t, J = 7.0 Hz, 3H).
Brønsted acid catalyzed asymmetric Friedel-Crafts alkylation
The Friedel-Crafts alkylation was attempted by a modified procedure previously reported.12 A flame-dried Schlenk tube was equipped with vacuum/nitrogen stopcock and a magnetic stirring bar. The tube was charged with phosphoric acid (S,M,Ra)-2 (3.0 mg, 0.0063 mmol, 0.05 eq, 90% ee), powdered 4Å molecular sieves (15 mg), and trans-2-nitrostyrene (37.3 mg, 0.25 mmol, 2 equiv). Dry benzene (0.3 mL) and dry dichloroethane (0.3 mL) were added. The mixture was cooled at -30 °C. At this temperature, indole (14.6 mg, 0.125 mmol, 1 equiv) was added to the mixture. After being stirred at this temperature for 7d, the reaction mixture was poured on silica gel column and purified by flash column chromatography (SiO2, pentane:EtOAc= 20:1 to 5:1) to yield racemic 3-(2-nitro-1-phenylethyl)-1H-indole (22 mg, 0.082 mmol, 65%) as a yellow solid. The physical data of the product were identical in all respects to those previously reported.12 1H NMR (400 MHz, CDCl3) δ 8.09 (br s, 1H), 7.44 (d, J = 7.9 Hz, 1H), 7.37–7.18 (m, 7H), 7.09–7.03 (m, 2H), 5.19 (t, J = 8.0 Hz, 1H), 5.07 (dd, J = 12.5, 7.5 Hz, 1H), 4.94 (dd, J = 12.5, 8.2 Hz, 1H). 13
C NMR (100 MHz, CDCl3) δ 139.1, 136.4, 128.9, 127.7, 127.5, 126.6, 122.7, 121.6, 119.9, 118.9, 114.4, 111.3, 79.5, 41.5. GC-MS (EI, m/z): calcd for C16H15N2O4 [M+H]
+
: 267.11, found: 267.12. Chiral separation was achieved by chiral HPLC analysis (Chiralpak AD-H, hept:2-propanol = 90:10, flow 0.75 mL/min, 40 °C, Rt: 32.9 min (1
st
Brønsted acid catalyzed asymmetric three-component Strecker reaction
The Strecker reaction was attempted by a modified procedure previously reported.46 In a Glove-box, a screw capped vial was charged with a magnetic stir bar, phosphoric acid (S,M,Ra)-2 (7.1 mg, 0.015 mmol, 0.1 eq, 90% ee), powdered 4Å molecular sieves (25 mg), 4-methoxylaniline (18.5 mg, 0.25 mmol, 1 equiv), phenol (14.1 mg, 0.15 mmol, 1 equiv), toluene (0.5 mL), acetophenone (19.8 mg, 0.019 mL, 0.165 mmol, 1.1 equiv) and TMSCN (22.3 mg, 0.030 mL, 0.225 mmol, 1.5 equiv). The resulting mixture was stirred at 40 °C during 7 d. However, TLC showed incomplete conversion. The reaction solution was concentrated under vacuum, and the residue was purified by flash column chromatography (SiO2, pentane:EtOAc= 20:1 to 10:1) to yield racemic 2-(4-methoxyphenylamino)-2-phenylpropanenitrile (12 mg, 0.045 mmol, 30%) as a white solid. The phosphoric acid 2 (6.7 mg, 0.014 mmol, 92%) was recovered by further flushing the column (eluent: CH2Cl2:MeOH = 1:1). The physical data of the product were identical in all respects to those previously reported.[461H NMR (400 MHz, CDCl3) δ 7.65–7.36 (m, 5H), 6.71–6.55 (m, 4H), 3.70 (s, 3H), 1.92 (s, 3H). 13C NMR (100 MHz, CDCl3) δ154.2, 140.3, 137.4, 129.4, 128.8, 125.3, 121.2, 118.5, 114.6, 58.4, 55.7, 33.2. GC-MS (EI, m/z): calcd for C16H17N2O[M+H]+: 253.13, found: 254.11; calcd for C16H16NO [M-CN]
+
: 226.12, found: 226.31. Chiral separation was achieved by chiral HPLC analysis (Chiralpak AD-H, hept:2-propanol = 85:15, flow 0.5 mL/min, 40 °C, Rt: 19.3 min (1
st
) and 24.0 min (2nd)). Brønsted acid catalyzed asymmetric reductive amination
The reductive amination was attempted by a modified procedure previously reported.[6 In a Glove-box, a screw capped vial was charged with a magnetic stir bar, phosphoric acid (S,M,Ra)-2 (4.8 mg, 0.01 mmol, 0.1 eq, 90% ee), powdered 4Å molecular sieves (20 mg), 4-methoxylaniline (12.3 mg, 0.10 mmol, 1 equiv) and Hantzsch ester (30.4 mg, 0.12 mmol, 1.2 equiv). Dry benzene (0.5 mL) was added, followed by acetophenone (36.0 mg, 0.30 mmol, 3 equiv). The reaction mixture was heated with stirring to 50 °C. After 4 d, the reaction mixture was filtered through a plug of silica, eluting with Et2O to remove the molecular sieves and unreacted Hantzsch ester, then concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO2, pentane:Et2O= 10:1 to 5:1) to yield racemic methoxy-N-(1-phenylethyl)aniline (12 mg, 0.045 mmol, 30%) as a white solid. The non-reduced imine intermediate 4-methoxy-N-(1-phenylethylidene)aniline was isolated as major product (12 mg, 0.053 mmol, 52%). The phosphoric acid 2 (4.3 mg, 0.009 mmol, 90%) was recovered by further flushing the column (eluent: CH2Cl2:MeOH = 1:1). The physical data of the product were identical in all respects to those previously reported.[61H NMR (300 MHz, CDCl3) δ 6.70–6.67 (m, 2H), 7.38–7.26 (m, 4H), 7.26–7.22 (m, 1H), 6.50– 6.47 (m, 2H), 4.41 (q, J = 6.9 Hz, 1H), 3.69 (s, 3H), 1.51 (d, J = 6.6 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 151.9, 145.5, 128.7, 126.9, 125.9, 114.8, 114.6, 55.8, 25.2. GC-MS (EI, m/z): calcd for C15H17NO[M+H]
+ : 227.13, found: 227.13. Chiral separation was achieved by chiral GC analysis (Chirasil-Dex-CB, 150 °C isotherm for 150 min, 1 mL/min, Rt: 79.91 min (1
st
) and 81.43 min (2nd)).
Chiral Brønsted acid-catalyzed allylboration of aldehydes
The allylboration of aldehydes was attempted by a modified procedure previously reported.[8 A flame-dried Schlenk tube was equipped with vacuum/nitrogen stopcock and a magnetic stirring bar. The tube was charged with phosphoric acid (S,M,Ra)-2 (4.8 mg, 0.010 mmol, 0.1 eq, 90% ee), freshly distilled benzaldehyde (10.6 mg, 0.011 mL, 0.10 mmol, 1 equiv) and dry toluene (1.5 ml). The reaction mixture was then cooled to -30 °C followed by the addition of allyl boronic acid pinacol ester (20.0 mg, 22 µL, 0.12 mmol, 1.2 equiv). The mixture was stirred over 3 d at this temperature. Aq. 1M HCl (3 mL) was added and the reaction mixture was stirred for 15 min, then extracted with Et2O (3 x 3 mL). The collected organic fractions were washed with water (5 mL), brine (5 mL), dried over Na2SO4, filtered and the solvent was removed under reduces pressure. The residue was purified by flash column chromatography (SiO2, pentane:EtOAc= 10:1) to yield racemic 1-phenylbut-3-en-1-ol (13.5 mg, 0.09 mmol, 90%) as a white solid. The phosphoric acid 2 (4.2 mg, 0.009 mmol, 88%) was recovered by further flushing the column (eluent:
CH2Cl2:MeOH = 1:1). The physical data of the product were identical in all respects to those previously reported.[81H NMR (400 MHz, CDCl3) δ 7.35–7.20 (m, 5H), 5.85–5.71 (m, 1H), 5.16–5.10 (m, 2H), 4.72 (dd, J = 7.6, 5.6 Hz, 1H), 2.54–2.43 (m, 2H), 2.00 (br s, 1H). 13C NMR (50 MHz, CDCl3) δ 144.6, 135.2, 129.1, 128.2, 126.5, 119.0, 74.0, 44.5. GC-MS (EI, m/z): calcd for C10H13O [M+H]
+
: 149.09, found: 149.18. Chiral separation was achieved by chiral HPLC analysis (Chiralpak OD-H, hept:2-propanol = 98:2, flow 0.7 mL/min, 40 °C, Rt: 20.2 min (1
st
) and 21.9 min (2nd)).
7.5
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