Asymmetric copper-catalyzed alkylations and autocatalysis Pellegrini, Tilde
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Chapter 5
Design of an asymmetric organic autocatalytic reaction: the
reduction of ketones and imines with borane
After an overview regarding asymmetric autocatalysis, in this chapter the design of an organic autocatalytic reaction is discussed. Our approach is inspired by Corey-Bakshi-Shibata reduction of ketones and imines with borane. The syntheses of substrates and (auto)catalysts are reported and the potential of this reaction for asymmetric autocatalysis is evaluated.
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5.1. Introduction
How was life originated in the prebiotic world? The way life was formed from animated matter is one of the most intriguing mysteries that scientists are trying to solve. The key resides in the feature of living beings to make exact copies of themselves, called self-replication. Over the past fifty years, scientists aimed to build artificial systems able to mimic the self-reproduction observed in living systems.[1] RNA and DNA are
able to replicate themselves, acting as templates for new ribonucleotide chains. This feature appeared at first to be a unique feature of enzymatic catalysis,[2,3] but in 1986
examples of enzyme-free replication of hexadeoxynucleotides from trideoxynucleotides was achieved by von Kiedrowski et al..[1,4] In this system, the
self-replication was based on the recognition via H-bond of trideoxynucleotides by the template, that could facilitate the formation of the hexamer. The strong interaction between template and product was facilitating the formation of the product but, on the other hand, impeding the turnover of the template/catalyst. The low reaction rate through the linkage of the two trimers via the formation of a phosphoroamidate in the presence of a condensing agent to achieve the typical autocatalytic kinetic pattern.[5]
Later, various examples of self-replicating systems were reported[1,6,7].
5.1.1. Autocatalysis
Autocatalysis is the easiest form of molecular self-replication and this concerns a reaction where the products acts as catalyst for its own synthesis (Scheme 1a).[7] In
fact, reactions with this behavior are characterized by a typical sigmoidal kinetic curve (time vs. product), caused by the dependence of the reaction rate on the concentration of the product/catalyst (Scheme 1b, source of the plots: review of Bissette and Fletcher)[7]. After an initial induction period, where the concentration of the
product/catalyst is low, the reaction rate dramatically increases as an effect of the autocatalysis. If the product is an efficient catalyst for its own production, the kinetic curve will be exponential, while a more sluggish autocatalysis will result in a parabolic curve.[7] Consequently, the presence of autocatalysis can be detected by two features:
A sigmoidal curve time/product
An acceleration of the reaction by initial addition of the product to avoid the initial induction period.
115
Scheme 49 Source of the plots: review of Bissette and Fletcher.[7]
Autocatalysis is only the simplest case of how a product can affect its own synthesis. Blackmond offers a precise classification of the cases and the implications on the kinetics.[8] Autocatalysis is the simplest case, where in a system there is only one
catalytic cycle. However there is the possibility that the product of a reaction can act as catalyst for a second reaction, and that the product of the second reaction works as catalyst for the first one, and this can potentially occur also for a larger number of catalytic reactions. We refer to a cycle of two (or more) reactions related because the product of one can catalyzed the other, as cross catalysis.[6] This phenomenon has been
proposed to be a valid explanation of the origin of life.[9,10] Another case is
autoinduction, which is extensively discussed in the Chapter 4 of this thesis. The following pages will focus on autocatalysis of small molecules.
Several efforts were made toward the design of a non-enzymatic autocatalytic reaction involving small molecules, to achieve a simple artificial self-replicating system. Many examples involve template based autocatalysis.[7,11,12] For this purpose, the following
aspects must be kept into account:
The binding of the template must be specific for the couple of reagents rather than for the product or molecules of the same species. The interaction of the substrates with the template has to be sufficiently strong, in order to catalyze efficiently their reaction.
116
The interaction of the template with the product (himself) must be weak to guarantee the release of the catalyst
The recognition sites must be sufficiently far from each other to avoid self binding[7]
These factors make the design of an autocatalytic reaction quite challenging. Nevertheless, besides providing a feasible explanation for the emergence of life, this peculiar type of catalysis has some intrinsic advantages: [13]
The efficiency of the process is high, as it is an automultiplication
The amount of catalyst increases during the course of the reaction and, for this reason, the rate of the reaction drastically increases with the conversion.
As product and catalyst coincide, no separation of the product from the catalyst is needed.
In the 90s, the group of Rebek designed an autocatalytic reaction involving nitrogeneous bases.[11] The replication involved recognition of an ester (1) and an
amine (2) by adenine-[11,14] or thymine like moieties[15] and the subsequent linkage
through transamidation (Scheme 2a). The length of the spacers between these two recognition sites is critical for the autocatalytic mechanism as it could influence the non-catalyzed association of the two reagents (Scheme 2b). The addition of further functional groups cause an excessive strength of ligation between two molecule of the templates, poisoning of the catalyst.[16] The hypothesis of template catalysis was then
117
Scheme 50 Autocatalysis in Rebek’s system. [11,14]
Inspired by the recognition by H-bonding, autocatalytic cycloadditions, including Diels-Alder reaction and addition of azides to maleimide have been developed by the groups of Sutherland[17] and Philp[18]. The complexity of these reactions, where
multiple diastereomers of the products can be formed (therefore multiple feasible catalytic cycles), required thorough kinetic analyzes to be rationalized.[19]
Autocatalysis was detected also in organometallic reactions: Collum et al. noticed a rate enhancement by the product in the ortho-lithiation of phenyl amides and other arenes. This effect was most important at high concentration, where the formation of aggregates affects the rate limiting step of the catalytic cycle. [20,21]
118
More recent studies on autocatalysis concern the use of organometallic reagents and physical autocatalysis proceeding via the formation of micelles.[7,22,23]
5.1.2. Asymmetric autocatalysis
If the product of an autocatalytic reaction is chiral and enantiomerically enriched, it is possible that it transfers this chiral information to the new molecules formed. This event, called asymmetric autocatalysis, has been adopted as one of the feasible explanations for homochirality on Earth (the consistency of configuration between natural amino acids (L), sugars (D) and other natural molecules)[24], via the
enhancement of a small imbalance between the two enantiomers. However, autocatalysis is not sufficient to explain how a small imbalance of two enantiomers can be amplified to obtain one pure enantatiomer. It was hypothesized that the major enantiomer must inhibit the synthesis of its antipode to allow the propagation of chirality.[25]
In this Chapter, we will focus on the ability of the product alone to induce asymmetry in its own production. We will include both asymmetric autocatalysis and those cases of asymmetric autoinduction where the product is the only chiral auxiliary in the reaction (the catalyst is achiral). Instead, the cases of autoinduction where the product interact with a chiral catalyst to improve his own production has been discussed in
Chapter 4.
The first example of a chiral molecule inducing enantioselectivity in its own production dates back to 1989 and is described by Alberts and Wynberg.[26] In both addition of
ethyllithium or diethylzinc to benzaldehyde catalyzed by Ti(IV), the (+)-product-alkoxide can favor the synthesis of the same enantiomer (Scheme 3) with significant enantioselectivity.
Scheme 51 Asymmetric induction in addition of ethyllithium to benzaldehyde by Alberts and
Wynberg.[26]
Few years later, Soai and coworkers also reported asymmetric autocatalysis in a similar way in the addition of diethylzinc to ferrocenylcarboxaldehyde.[27] Simultaneously,
they discovered an autocatalyic system that represents until now a unique example of asymmetric autocatalysis: the asymmetric addition of diethylzinc to pyrimidinaldehyde.
119 At first, it was reported that 7 can favor its own formation with a moderate ee (Scheme
4a).[28] But in 1995, Soai described that a highly enantioenriched product could be
obtained, utilizing almost racemic 9 (ee ~ 0.00005%) as chiral initiator[29]. This
phenomenon was consequently named asymmetric amplification. Moreover, also small amounts of other chiral organic molecules[30,31], circularly polarized light
(CPL)[32], chiral inorganic[33–35] and organic crystals[36] could be used as chiral source.
Impressively, even in the absence of any chiral entity, the synthesis of 7 still occurred with enantioselectivity, which indicates that the amplification is so efficient that even small statistical imbalances between the enantiomers can be enhanced thus leading to absolute enantioselective synthesis.[37]
The non-linear correlation between the ee of the catalyst and of the product ((+)-NLE), is due to the aggregation of the catalyst. Molecules of the minor enantiomer of the catalyst are inactivated by the formation of inactive oligomers with stoichiometric amount of the major enantiomer. In this way, the excess of major enantiomer is able to catalyze the reaction towards its own synthesis.[29,38,39] Numerous studies aimed to
explain the mechanism of this amplification[40] and the nature of the aggregates formed
in the reaction. The isolation of tetramers or higher oligomeric aggregates aggregates[41] suggested, multiple oligomeric species participate to the amplification
mechanism. Kinetic studies confirmed this hypothesis.[42] The understanding of the
mechanism behind absolute asymmetric synthesis in Soai’s reactions paves the way to the design of further autocatalytic reactions whit amplification of chirality.
120
Soai’s asymmetric autocatalytic system has been included in more complicated cross-catalytic cycles by the group of Amedjkouh. Soai’s autocatalyst 9 can serve as a asymmetric catalyst for the addition of diisopropylzinc reagents to a second aldehyde and the product of this reaction would simultaneously enhance the chiral amplification of Soai’s reaction (Scheme 5).[43,44]
Scheme 53 Amedjkouh’s cross catalytic system.[45]
Carreira and coworkers also described asymmetric autoinduction in synthesis of the Efavirenz intermediate 15 via the addition of a diorganozinc reagent to the trifluoromethyl ketone 13.[46] By the simple use of (S)-15 from the beginning of the
reaction, further product is obtained with 76% ee. The use of the chiral ligand L1 in combination with the product increased the ee to 91% (Scheme 6).
Scheme 54 Autocatalysis in the synthesis of (S)-15.[46]
When designing an asymmetric autocatalytic cycle it is convenient to involve organometallic reactions that are generally characterized by high rates and high turnover of the catalyst. Furthermore, metallic catalyst, having multiple coordination
121 sites, can easily form aggregates and give rise to propagation of chirality. However, when it comes to explaining the origin of life and of homochirality on earth, it is hard to find an explanation involving artificial water- and air-sensitive reagents, such as dialkyl zinc.
Mauksch and Tsogoeva were the first to report asymmetric autocatalysis and (+)-NLE in the Mannich reaction between α-immino esters and acetone.[47] The authors claim
that, in the presence of 1-5 mol% of enantiopure 19, ee values up to 27% can be obtained, but with higher catalytic loading the enantioselectivity improves up to 96% ee (Scheme 7a). The recognition of the two reactants by the template occurs via H-bonding. However, few controversies arose about the determination of the mechanism of autocatalytic and asymmetric amplification: while the authors proposed that heterodimers of 19 are labile and regenerate the reactants,[48,49] Blackmond et al. argue
that this concept violates the principle of microscopic reversibility[50]. Moreover, in the
original study, the enantioenriched product used as catalyst was prepared via natural proline catalyzed Mannich reaction. The group of Feringa decribes that 17, synthesized in an alternative way, has no catalytic activity and they question if residual proline can act as real catalyst for this reaction.[51] Mauksch and Tsogoeva also report spontaneous
symmetry breaking in this reaction (Scheme 7b).[52]
Scheme 55 Aymmetric autocatalysis in Mannich condensation.[52]
Asymmetric autocatalysis in the Mannich reactions attracted interest by several groups in the last years,[53,54] as the development of a purely organic reaction would constitute
a valuable proof for the origin of homochirality, while Soai’s reaction can only be referred to as a proof of concept for an autocatalytic mechanism. Mannich reaction can be performed autocatalytically using a limited scope of ketones and it can occur also in
122
water[53], but the mechanism must be clarified further to understand if this can be
called proper autocatalysis.
5.1.3. Corey-Bakshi-Shibata reduction and feasibility of asymmetric autocatalysis
Our group aims to develop a novel asymmetric autocatalytic reaction. We chose Corey-Bakshi-Shibata reduction as possible target for our design, that concerns the reduction of ketones or imines with borane by mean of a chiral oxazaborolidine.[55,56]
In 1981 Itsuno et al. reported the reduction of ketones using stoichiometric amounts of oxazaborolidine derived from (L)-valine (20, Scheme 8).[57] Depending on the
difference between the steric hindrances of the two substituents, optical yields up to 79% could be achieved with this methodology. The selectivity could be improved further with the use of 21 as precursor for the reagent.[58]
Scheme 56 Itsuno’s reduction of ketones.[57,58]
In 1987 Corey, Bakshi and Shibata published a highly enantioselective methodology for the reduction of ketones with borane, upon use of catalytic amounts of the oxazaborolidine 24, prepared from the natural amino acid (L)-proline.[55,56,59]
Generally, this reactions requires moderately low temperatures (0-25°C) and short reaction times (0.5-3h). With only 10 mol% catalytic loading, excellent enantioselectivities were achieved in the asymmetric reduction of acetylbenzene 22 (Scheme 9). As the oxazaborolidine was air and moisture sensitive, the use of its more stable analog, B-Me-24, has become more frequent.[59]
Scheme 57 CBS reduction of acetylbenzene 22.[56]
The ketone scope of the CBS reduction is broad and the difference in the steric bulk of the two substituents plays an important role in the enantiodiscrimination. The mechanism involves the formation of a complex between the oxazaborolidine and the borane, where the nitrogen atom coordinates the borane activating it towards the donation of hydride. The ketone instead coordinates to the boron atom of 24, in such
123 a way to minimize the steric repulsions between the more hindered substituents and the catalyst (Figure 1).[56] However, electronic factors also play a role, as it was
demonstrated by Corey via the reduction of substituted benzophenones.[60]
Figure 18 Transition state of CBS-reduction.[56]
Similarly to ketones, also imines can be reduced, but necessitate longer reaction times and higher temperatures (Scheme 10).[61] In this case, the oxazaborolidine formed
from 21 assures the best enantioselectivity, but requires higher catalytic loadings than
24.
Scheme 58 CBS-reduction of imines.[61]
The group of Feringa inquired whether the reduction of ketones with borane can undergo with an asymmetric autocatalytic mechanism. They used (S)-28 having an enantiomeric excess of 10% in the reduction of 27, hypothesizing that the oxaborolidine 29 can be formed in situ (Scheme 11). The reaction, even in the absence of 28, proceeded fast but unfortunately the product had an ee of 5.8% which is within the error margin of the chiral HPLC.[62]
Scheme 59 Reduction of 27 in the presence of its enantioenriched product 28.[62]
Using CBS-reduction, optically active alcohols and amines can be prepared. Alcohol and amines are functional groups that can form the catalyst oxazaborolidine upon reaction with borane. For this reason, this reaction has a good potential to become the next example of asymmetric autocatalysis.
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5.2. Aim
As discussed in the introduction, asymmetric autocatalysis is a rare event and concerns metal-catalyzed reactions. The development of an organic asymmetric autocatalytic reaction would shed light on the way homochirality on Earth was originated. Therefore, the aim of this chapter is to develop an organic autocatalytic and enantioselective reaction. Our design of such a reaction is based on the modification of the Corey-Bakshi-Shibata reduction of ketones and imines with borane, where the organocatalyst is the oxazaborolidine 24 derived from diphenylprolinol 31. With the idea of attaining asymmetric autocatalysis in mind, we hypothesised that diphenylprolinol (31) could be obtained by CBS-reduction of the iminoalcohol 30 (Scheme 12). Furthermore, we expected that the phenylprolinol 35 is a potential catalyst for the CBS reduction and can function as autocatalyst in the reduction of the ketone 33 or the imine 34 with borane (Scheme 12). Herein we describe our efforts to to test this hypothesis.
Scheme 60 Design of asymmetric autocatalytic CBS-reduction.
5.3. Results and discussion
Using CBS-reductions, it is possible to reduce ketones to alcohols or imines to amines. In our proposed system, two pathways are outlined. The first involves the reduction of the prochiral imine 30, bearing an alcoholic functionality. The catalyst 34 can be obtained from the product 31 (Scheme 13a). In the following pages, we will refer to this pathway as the imine pathway. The second possibility is that the oxazaborolidine
35 is obtained from the amino alcohol 35, that is the product of either reduction of
imine 33 or ketone 34 (Scheme 13b). Both of these starting materials bear a chiral center, meaning that the diastereoselectivity of their reduction should be evaluated in place of the enatioselectivity. This second pathway will be called the ketone pathway.
125
Scheme 61 Syntheses of 24 and 35.
With this in mind, we proceeded towards the synthesis of the substrates required for our designed autocatalytic reactions
5.3.1. The Imine Pathway
First, we focused on the synthesis of the iminoalcohol 30 (Scheme 14) that could be obtained upon addition of an organometallic reagent to the iminoketone 36.[63] The
aminoketone 33, when exposed to the air, easily oxidizes to 36, because of the stabilization of the product by conjugation.[63,64] We planned to prepare 33 from the
natural amino acid proline (37).
Scheme 62 Retrosynthesis of 30.
At first, we attempted the arylation of a Boc-protected proline (N-Boc-37) with PhLi in the presence of HMPA but Boc-33 was not formed under these conditions (Scheme
15a). Then, we tried to obtain Boc-33 by formation of a mixed anhydride with
diphenylchlorophosphite and subsequent reaction with PhMgBr but unfortunately, this strategy did not lead to the formation of the product either (Scheme 15b). Therefore, we decided to synthesize 33 by Friedel-Craft alkylation (Scheme 16a).
126
Scheme 63 Attempts towards the preparation of N-Boc-33.
The proline was converted in the acylchloride 38·HCl by using PCl5 as chlorinating
agent. Upon addition of AlCl3 and benzene 33·HCl was formed. Even if this salt does
not undergo oxidation as fast as the free ketoamine 33, its purification revealed to be tedious and we could not isolate the pure compound. We decided therefore to subject the crude to oxidation by oxygen in a basic environment directly after the reaction. In this way, the product 36 was obtained in poor yield (6%) (Scheme 16a). This compound is relatively unstable and undergoes radical polymerization; it must be isolated rapidly, stored at 4oC and used within few weeks.
To improve the efficiency of this synthesis, we protected the amine as carbamate (Boc and Fmoc). The chlorination of N-Boc-37 using SOCl2 or PCl5 did not afford the
corresponding acyl chloride (Scheme 16b): we attributed the unsuccessful result to the limited stability of the Boc to the acidic conditions. For this reason, we changed the proline protecting group to Fmoc. In this case, it was possible to obtain N-Fmoc-38 with SOCl2 in toluene (Scheme 16c). Unfortunately, after Friedel-Craft acylation, no
product was isolated, probably due to the acylation of the aromatic rings on the Fmoc moiety. Our last approach concerned the reaction of the Fmoc-38 with PhMgBr[65]. In
127
Scheme 64 Attempts towards the preparation of N-protected-33.
From these results, we envisioned that the unprotected amine 33 is considerably unstable and we concentrated our efforts on the direct preparation of the imino-ketone
36. Helquist et al. reported an elegant procedure for the synthesis of this
compound[66], which involves the silver-catalyzed hydroamination and benzylic
oxidation of compound 39. The reported synthesis of the precursor requires two synthetic steps[67] from compound 42, prepared from lithium phenyl acetylide (40)
and 1-bromo-3-chloropropane (41)[68]. In our hands, this procedure resulted on a yield
of 50% of 42 and 15% in the preparation of 39. Compound 36 was obtained in 13% yield (Scheme 17a).a *Experiments performed by Dr. Francesco Lanza. NMR-Spectra
match with the reported.[66–68] Convenient procedure reported in 2017 by Cheng et
128
In 2018, 36 was obtained by Yu et al. by acyl migration of α-azidyl tertiary ketones with excellent yield (Scheme 17b).[70] Because this methodology was published very
recently, this synthetic route was not explored further.
Scheme 65 Alternative methodologies for the syntheses of 36.
Given that 33 is oxidized by oxygen to imino-ketone, we decided to prepare first the amino alcohol 35 and subsequently treat it with a classic oxidizing agent for secondary alcohols. Starting the ortho lithiation of the N-Boc-pyrroliyne (44) with s-BuLi and TMEDA and condensation with benzaldehyde, we obtained N-Boc-35 as a mixture of the syn and anti diastereomer in 79%.[71] The product was removed in acidic conditions
to afford 35 in 92% yield (Scheme 18a). The Swern oxidation afforded pure 36 in 22% yield. The low yield is due to the difficulty to remove the Et3N avoiding any acidic
workup that could hydrolize the imine. Using the Dess-Martin oxidation with hypervalent-iodine as oxidizing agent (45), the starting material was converted completely to an unidentified product.
129
Scheme 66 Synthesis of 36 by oxidation of 35.
With 36 in our hands, we could prepare 30 by simple addition of PhLi that afforded the product of addition to the ketone at -78 oC. The chemoselective addition of the less
reactive MeLi was reported on 2-acetyl-2,4-dihydropyrrol is described in literature;[63]
it is remarkable that the addition of a more reactive organolithium reagent also proceeds with an elevated chemoselectivity (Scheme 19).
Scheme 67 Synthesis of the imino-alcohol 30.
Once 30 became available, the moment had come to test the potential for autocatalysis in its reduction. The reduction of 30 with borane in the presence of the catalyst
B-Me-24 took place to afford 31 in toluene as solvent (entries 1 and 2, Table 1), while only
a dirty crude was obtained in THF. The imino alcohol 30 could be reduced also in the absence of catalyst. The reduction rates with or without catalyst are comparable. It is feasible that the alcohol functional group can activate the borane towards the hydride transfer, as hypothesized by the group of Feringa in the reduction of 27[62]. The amine
was subsequently protected with Boc to allow the separation of the two enantiomers on the chiral HPLC. Unfortunately, we discovered that the reduction occurs with low
130
or no enantioselectivity (Table 1). This fact, together with the nearly similar rates of the catalyzed and uncatalyzed reduction pathways, leave few hopes for a successful asymmetric autocatalysis. Consequently, this research line was abandoned.
Table 15 CBS reduction of 30.
Entry Solvent (x mol%) yield Boc-31 (%) ee (%)a
1 Toluene 25 78 13
2 Toluene 40 38 racemic
3 THF 25 n.d. b n.d.
a Calculated with the formula eeprod = eemeas-(eecat*x/100). eemeas was determined via
CSP-HPLC b Dirty crude, no Boc-2 could be isolated.
5.3.2. The Ketone Pathway
At this point of our travel towards the design of an asymmetric auto-organocatalyzed reaction, we concentrated our efforts on the second pathway. Here we planned to achieve asymmetric induction in the reduction of 33 or 34 catalyzed by 35 (Scheme
12). As discussed in Paragraph 5.3.1., the amino ketone 33 is an unstable compound
that spontaneously oxidizes to 36. A comparable behavior can be expected for compound 34, and to the best of our knowledge, no synthesis of the latter has been reported so far. Moreover, both compound 33 and 34 bear a preformed stereogenic center and therefore, they cannot be employed for the evaluation of the enantioselectivity of their reduction. Then we planned to submit 36 directly to the CBS-reduction with syn-35 or anti-35 as catalyst.
131
Scheme 68 Asymmetric synthesis of syn- and anti-phenylprolinol (35).
The Boc-protected amino alcohols were prepared with the procedure reported by Gilday et al.[72], that involves the enantioelective α-deprotonation of the
Boc-pyrrolidine (44) with catalytic (+)-sparteine (46) and the subsequent trapping of the lithiated 44 with benzaldehyde (Scheme 20a). This reaction proceeds with syn-diastereoselectivity and (S,S)-syn-N-Boc-35 and (S,R)-anti-N-Boc-35 were obtained with respective ees of 76% and 68%. The amino alcohol 35 was recovered after deprotonation with TFA (Scheme 20b).
The catalytic activity of (S,S)-syn-35 and (R,S)-anti-35 was tested in the CBS reduction, taking the acetyl ferrocene (47) as model ketone molecule. Both of the diastereoisomers of 35 were found to be active as asymmetric catalysts, even though their performance doesn't match to that of Me-34 in terms of enantioselectivity (entry
1, Table 2). Interestingly, anti-35 (with configuration R,S) provided (R)-48 in 97%
yield and an enantiomeric excess of 86% (when normalized with respect to one of the catalyst; entry 3, Table 2). On the contrary, syn-35 afforded the opposite enantiomer of the product with a lower enantioselectivity in 77% yield (entry 2, Table 2), demonstrating that it’s the configuration of the alcohol that directs the hydride trasfer. In anti-35, the stereocenters are favorably combined and form the matched catalyst. The syn is instead the mismatched catalyst.
132
Table 16 Asymmetric reduction of 47
Entry Catalyst Yield (%)a ee (%)b
1 c B-Me-24 96 98, (R)
2 d (S,S)-syn-35/BH3·SMe2 (ee 78%) 77 31 (40e), (S)f
3 d (R,S)-anti-35/BH3·SMe2 (ee 66%) 97 57 (86e), (R)f
a Isolated yield b Determined via CSP-HPLC. c reaction was performed following the
literature procedure.[73]d 35 and BH3·SMe2 (0.5 equiv.) were stirred at 40oC for 45 min
prior to the addition of 47. e ee of the product normalized with the ee of the catalyst.
Calculated with the formula eemeas/eecat = eeeff.f Configuration assigned by comparison
with the literature.[73]
At this point, the anti-diastereomer of 35 should have been tested in the asymmetric reduction of 36. Unfortunately, due to the instability of the imino-ketone 36 and the tedious synthesis, it was not possible for us to perform further studies concerning its autocatalytic reduction and we renounced to this research line.
5.3.4. Reduction of the phenyl-(2-pyridyl)-ketone
Our last effort towards the design of asymmetric autocatalysis inspired by CBS-reduction concerned the CBS-reduction of the phenyl 2-pyridyl ketone (49). We imagined that pyridine moiety could substitute the pyrroldine moiety of 34 and coordinate to the borane (Scheme 21). A catalyst where the nitrogen does not form covalent bonds with the borane can be generated faster than the oxazaborolidine and therefore is a better candidate for an autocatalytic reaction. Nevertheless the reduction of 49 by the Me-24 and borane proceeded with a complete lack of enantioselectivity due to the poor differentiation in the steric bulk between the two substituents of the ketone, so we cannot expect any asymmetric autocatalysis using CBS method to reduce this substrate.
133
Scheme 69 Autocatalysis in the reduction of phenyl-(2-pyridyl)-ketone.
5.4. Conclusions
We discussed the design of an asymmetric autocatalytic reaction inspired by CBS-reduction of ketones and imines. Two possible autocatalytic cycles were envisioned: the first concerning the reduction of an imine, the second of a ketone. The starting material for both pathways towards autocatalysis were prepared, with low yields due to the instability of one of the intermediates.
For what concerned the reduction of the imine, the reaction rate in the presence of the autocatalyst shows no significant improvement with respect to the not catalyzed one. Moreover we observed no clear influence of the product on the enantioselectivity. For the pathway involving the reduction of the ketone, two diastereomeic (syn and anti) enantioeriched precursors for the catalyst were prepared. They were tested in the reduction of a model ketone. The catalyst generated from the anti diastereomer showed good performance (matched catalyst). However, we did not evaluate the potential of this reaction for the autocatalysis because the substrate could only be obtained in low yields and is unstable.
Our a posteriori considerations about the possibility of autocatalysis on this system are:
In both pathways, the product of the reaction is an amino alcohol, which is the precursor of the catalyst (oxazaborolidine). Consequently, the rate of formation of the oxazaborolidine is crucial for an efficient autocatalysis.
134
In an efficient asymmetric CBS reduction, the difference between the dimensions of the substituents of the ketone or imine is important. In the case of autocatalysis, a less hindered substrate would generate a less hindered product that would be a worst catalyst for this reaction. The similarity of the product/catalyst with the starting material constitutes a limitation for the chiral induction.
As in CBS reduction, the product has no possibility to form oligomeric species, this reaction has no potential for asymmetric amplification.
5.5. Experimental section
5.5.1. General information
All reactions using oxygen- and/or moisture-sensitive materials were carried out with anhydrous solvents (vide infra) under a nitrogen atmosphere using oven dried glassware and standard Schlenk techniques. Reactions were monitored by 1H NMR.
Purification of the products, when necessary, was performed by flash-column chromatography using Merck 60 Å 230-400 mesh silica gel or VWR AnalaR NORMAPUR aluminum oxide basic. NMR data was collected on Bruker Avance NEO 600 (1H at 600.0 MHz; 13C at 150.87MHz), equipped with a Prodigy Cryo-probe and
Varian VXR400 (1H at 400.0 MHz; 13C at 100.58 MHz), equipped with a 5 mm
z-gradient broadband probe. Chemical shifts are reported in parts per million (ppm) relative to residual solvent peak (CDCl3, 1H: 7.26 ppm; 13C: 77.16 ppm). Coupling
constants are reported in Hertz. Multiplicity is reported with the usual abbreviations (s: singlet, bs: broad singlet, d: doublet, dd: doublet of doublets, t: triplet, , q: quartet, m: multiplet). Exact mass spectra were recorded on a LTQ Orbitrap XL apparatus with ESI ionization. Enantiomeric excesses (ees) were determined by Chiral HPLC analysis using a Shimadzu LC-10ADVP HPLC equipped with a Shimadzu SPD-M10AVP diode array detector and by Waters Acquity UPC2 system with PDA detector and QDA mass detector.
Unless otherwise indicated, reagents and substrates were purchased from commercial sources and used as received. Solvents not required to be dry were purchased as technical grade and used as received. Dry solvents were freshly collected from a dry solvent purification system prior to use. The DMAE was distilled on KOH and stored on MS4A. Inert atmosphere experiments were performed with standard Schlenk techniques with dried (P2O5) nitrogen gas. All reported compounds were characterized
by 1H and 13C NMR and compared with literature data. All new compounds were fully
characterized by 1H and 13C NMR and HRMS techniques. The absolute configurations
135
5.5.2. Synthesis of N-Fmoc-38
(9H-fluoren-9-yl)-methyl (S)-2-(chlorocarbonyl)pyrrolidine-1-carboxylate
Under inert atmosphere, 0.26 mL of SOCl2 (3.5 mmol, 1.3 equiv.) were
added dropwise at 70°C to a suspension of N-Fmoc-37 (1.0 g, 2.7 mmol, 1.0 equiv.). The reaction was stirred at 70°C for 8 h. Dry toluene (6 mL) were added and the azeotrope SOCl2/toluene was distilled under reduced
pressure (procedure repeated 3 times). When about 2 mL of toluene were left, the solution was cooled to -20°C. The crystals were filtered and dried under reduced pressure an pale yellow crystals of N-Fmoc-38 were obtained (0.66 g, 1.9 mmol, 69% yield). The NMR data are in agreement with the ones present in literature[74]. 1H NMR (400 MHz, Chloroform-d) δ 7.77 (dd, J = 7.6, 3.4 Hz, 4H), 7.60 (t, J = 7.8 Hz, 1H), 7.55 (d, J = 7.5 Hz, 1H), 7.41 (t, J = 7.4 Hz, 2H), 7.37 – 7.23 (m, 2H), 4.69 (dd, J = 8.8, 4.0 Hz, 1H), 4.60 – 4.32 (m, 2H), 4.23 (dt, J = 29.9, 6.5 Hz, 1H), 3.70 – 3.48 (m, 2H), 2.40 – 2.18 (m, 2H), 2.10 – 1.85 (m, 2H). 13C NMR (101 MHz, Chloroform-d) δ 174.4, 155.4, 143.9, 143.8, 143.5, 141.4, 127.8, 127.7, 127.2, 127.1, 127.0, 125.1, 125.0, 124.8, 124.7, 120.1, 120.0, 67.9, 67.8, 67.6, 67.3, 47.2, 47.1, 46.6, 30.5, 29.3, 24.1, 23.0.
5.5.3. Synthesis of the imino-ketone 36
(3,4-dihydro-2H-pyrrol-5-yl)(phenyl)methanone
Under inert atmosphere, 2.0 g of (L)-proline (9) (17.4 mmol, 1.0 equiv.) were added to a suspension of 3.6 g of PCl5 (17.4 mmol, 1.0
equiv.)in CH2Cl2 (100 mL) at 0oC. the reaction was allowed to warm
to rt and stir for 2h. The solvent was removed under reduced pressure, then the crude was dissolved in benzene (70 mL) and 6.9 g of AlCl3
were added to the reaction mixture (52 mmol, 3.0 equiv.), the reaction was warmed up to 60oC. After 3 h, the reaction mixture was quenched into crushed ice and a 1M HCl
aqueous solution. The organic phase was separated and the acqueous phase was washed with 20 mL of AcOEt. The organic phase was neutralized with NaHCO3 sat in
H2O and aluminates were filtrated. The aqueous phase was extracted with CH2Cl2 (3 x
20 mL). 1.5 mL of HCl (37% in H2O) were added and the solvent was removed under
reduced pressure. The crude was dissolved in H2O (100mL) and the pH was adjusted
to ~7 with NaHCO3. A balloon containing O2 was attached to the reaction vessel.
Subsequently, the reaction was warmed to 50oC and stirred for 1h. The water phase
was extracted with CH2Cl2 (3 x 20 mL). The joint organic phases where dried on
Na2SO4, filtered and the solvent was removed under reduced pressure. The crude was
stored under inert atmosphere at 4oC and cleaned the day after by column
136
mg, 0.68 mmol, yield 4%) and stored under inert atmosphere at 4oC for a maximum
time of 4 weeks. The spectral data match those reported in literature[75]
1H NMR (400 MHz, Chloroform-d) δ 8.17 (d, J = 8.2, 1.1 Hz, 2H), 7.62 – 7.50 (m, 1H),
7.46 (t, J = 7.6 Hz, 2H), 4.23 (tt, J = 7.6, 2.5 Hz, 2H), 2.96 (tt, 2H), 2.01 (p, 2H).
13C NMR (101 MHz, Chloroform-d) δ 191.1, 174.3, 135.7, 133.5, 130.6, 128.4, 63.4, 35.8,
21.8.
5.5.4. Procedure for the synthesis of 30
(3,4-dihydro-2H-pyrrol-5-yl)diphenylmethanol
In a heat dried Schlenk under inert atmosphere, 116.5 mg (0.67 mmol, 1.0 equiv.) of 36 were dissolved in 10 mL of Et2O and the solution was
cooled to -60oC. 0.35 mL of a solution of s-BuLi in n-Bu2O (1.9 M,
0.67 mmol, 1.0 equiv.) were added over 1h. The solution was allowed to warm to -15oC over 3h. The reaction was quenched after 2.5 hours
with 0.7 mL of MeOH and 4 mL saturated aqueous NH4Cl solution and extracted with
Et2O (3 x 5mL). The combined organic phases were dried on MgSO4, filtrated and the
solvent was removed under reduced pressure. The product was purified by column chromatography (SiO2, pentane : EtOAc, 9:1 -> 8:2) obtained as a colorless solid (129
mg, 0.51 mmol, 77% yield)
1H NMR (400 MHz, Chloroform-d) δ 7.41 – 7.21 (m, 10H), 5.67 (broad s, 1H), 3.93 (t,
J = 7.4 Hz, 2H), 2.50 (t, J = 8.2 Hz, 2H), 2.05 (p, J = 7.7 Hz, 2H).
13C NMR (101 MHz, Chloroform-d) δ 181.4, 143.8, 128.3, 127.9, 127.7, 80.2, 59.6, 35.1,
24.5.
HRMS (ESI+): m/z calcd. for C16H23NO2Na ([M+Na+]) 250.12264, found 250.12385
5.5.5. Procedure for the reduction of 30
N-Boc-diphenylprolinol (Boc-31)
In a heat dried Schlenk maintained under inert atmosphere, 10.2 mg of B-Me-CBS-oxazaborolidine (B-Me-24) (0.045 mmol, 0.25 equiv.) were dissolved in toluene (0.6 mL) and 0.05 mL of BH3.SMe2 (2M in
THF, 0.10 mmol, 0.7 equiv.) were added and allowed to stir at rt for 15 min. 0.065 mL of BH3.SMe2 (2M in THF, 0.13 mmol, 0.9 equiv.)
were added amd a solution of imine (37.7 mg, 0.15 mmol, 1.0 equiv.) in 0.4 mL of toluene was added over 20 min. The reaction was stirred at 45oC for 17
hours, monitored by TLC (SiO2, pentane:AcOEt, 4:1) and quenched with MeOH (0.5
mL). The crude was dissolved in CH2Cl2 (4.5mL) and 105 mg of Boc2O (0.48 mmol, 1.1
equiv.) were added at 0oC. After stirring at rt for 3h, the solvent was removed under
reduced pressure and the crude was purified by column chromatography (SiO2,
pentane:AcOEt, 9:1). N-Boc-31 was obtained as a white solid (151 mg, 35.1 mmol, 78% yield).
137
1H NMR (400 MHz, Chloroform-d) δ 7.42 – 7.34 (m, 4H), 7.34 – 7.22 (m, 6H), 4.89
(dd, J = 8.9, 3.7 Hz, 1H), 3.35 (q, J = 9.3 Hz, 1H), 2.86 (m, 1H), 2.09 (dq, J = 13.3, 8.8 Hz, 1H), 1.92 (m, 1H),1.51-1.37 (m, 2H), 1.43 (s, 9H), 0.78 (broad s, 1H).
13C NMR (101 MHz, Chloroform-d) δ 146.6 (quaternary), 143.9 (quaternary), 128.4,
128.0, 127.8, 127.5, 127.2, 127.2, 81.9, 80.8, 48.0, 29.9, 28.5, 23.1.
HRMS (ESI+): m/z calcd. for C22H26NO3 ([M+H+]) 352.19072, found 352.19161
CSP-HPLC: (254nm, Chiralcel OD-H, n-heptane:i-PrOH = 99:1, 40 °C, 0.5 ml/min.),
tR = 33.20 min, tR = 26.74 min
5.5.6. Racemic synthesis of the tert-butyl (S)-2-((R)-hydroxy(phenyl)methyl)pyrrolidine-1-carboxylate
tert-butyl pyrrolidine-1-carboxylate (N-Boc-44)
In a 100 mL round bottom flask, 2.0 g of Boc2O (9.16 mmol, 1.0 equiv.)
were dissolved in 30 mL of CH2Cl2 at 0oC. To the solution, 0.96 mL of
pyrrolidine (44) (11.5 mmol, 1.26 equiv.) were added dropwise. The reaction was allowed to warm up to rt and stirred for 2h. The solvent and the residual pyrrolidine were removed under reduced pressure.
N-Boc-44 was obtained after a short column chromatography (SiO2, pentane : AcOEt, 4.1) as
transparent oil (1.42 g, yield 91%). The NMR data are in agreement with the ones present in literature. [76] 1H NMR (400 MHz, Chloroform-d) δ 3.43 – 3.27 (d, 4H), 1.88 (t, J = 4.5, 2.2 Hz, 4H), 1.50 (s, 9H). 13C NMR (101 MHz, Chloroform-d) δ 193.9, 79.0, 46.1, 45.8, 28.7, 25.9, 25.1. (Rac)-tert-butyl-2-(hydroxy(phenyl)methyl)pyrrolidine-1-carboxylate (N-Boc-35)
In a heat dried 50 mL Schlenk kept undert inhert and anhydrous atmosphere, 5.57 mL of a 1.4 M solution of s-BuLi in cyclohexane (7.8 mmol, 1.3 equiv.) were added to a solution of 5.57 mL of anhydrous TMEDA (7.8 mmol, 1.3 equiv.) in 12 mL of Et2O at -78oC. The solution was stirred at
-78oC for 30 min and a solution of 1.04g of N-Boc-44 (6.0
mmol, 1.0 equiv.) in 1 mL of Et2O was added over 15 min. the
reaction was stirred for 4 h and 0.81 mL of benzaldehyde (849 mg, 8.0 mmol, 2.0 equiv.) in 1 mL of Et2O was added dropwise. The reaction was allowed to warm up to
rt and stir overnight. It was quenched with 5 mL of a saturated aqueous NH4Cl solution
and extracted with Et2O (3 x 10 mL) and the combined organic phases were dried on
Na2SO4, filtrated and the solvent was removed under reduced pressure. The crude was
purified by column chromatography (SiO2, CH2Cl2 : acetone = 97:3) and the product
138
combined yield of 79% (4.8 mmol). The spectral data match those reported in literature[71,72]
syn-tert-butyl-2-(hydroxy(phenyl)methyl)pyrrolidine-1-carboxylate (syn-N-Boc-35)
Pale yellow oil, 709 mg (3,69 mmol, 61% yield). The NMR data are in agreement with the ones present in literature [71,72]
1H NMR (400 MHz, Chloroform-d) δ 7.43 – 7.25 (m, 5H), 5.80 (broad
s, 1H), 4.53 (d, 1H), 4.09 (td, 1H), 3.56 – 3.15 (m, 2H), 1.79 – 1.55 (m, 1H), 1.46 (s, 1H).
13C NMR (151 MHz, Chloroform-d) δ 154.9, 141.0, 128.7, 128.5, 127.8,
127.1, 80.9, 65.5, 45.9, 28.7, 25.5.
HRMS (ESI+): m/z calcd. for C16H23NO2Na ([M+Na+]) 300.15822, found 300.15823
anti-tert-butyl-2-(hydroxy(phenyl)methyl)pyrrolidine-1-carboxylate
(anti-N-Boc-35)
Pale yellow oil, 294 mg (1.06 mmol, 18% yield). The NMR data are in agreement with the ones present in literature. [71,72]
1H NMR (600 MHz, Chloroform-d) δ 7.41 – 7.19 (m, 5H), 4.95 (broad
s, 1H), 4.24 (broad s, 1H), 3.37 (broad s, 1H), 2.93 (broad s, 1H), 1.83 (s, 3H), 1.52 (s, 10H), 1.48 – 1.38 (m, 1H).
13C NMR (151 MHz, Chloroform-d) δ 141.4, 128.2, 127.4, 126.9, 80.4,
63.5, 47.95, 28.7, 28.6, 28.6, 27.1, 23.7. Quaternary signals of the Boc-group were not detected.
HRMS (ESI+): m/z calcd. for C16H23NO2Na ([M+Na+]) 300.15823, found 300.15823
5.5.7. Asymmetric synthesis of the tert-butyl-2-((R)-hydroxy(phenyl)methyl)pyrrolidine-1-carboxylate
In a heat dried 50 mL Schlenk, kept undert inhert and anhydrous atmosphere, 9.6 mL of a 1.4 M solution of s-BuLi in cyclohexane (13.5 mmol, 2.3 equiv.) were added to 17 mL of Et2O at -78oC. A
solution of 0.42 mL of (+)-sparteine (423 mg, 1.8 mmol, 0.3 equiv.) in 1 mL of Et2O was added
dropwise, followed by a solution of 0.60 mL of DMAE (535 mg, 6 mmol, 1.0 equiv.) in 1 mL of Et2O. The solution was stirred at -78oC
for 10 min and a solution of 0.98 mg of N-Boc-44 (6.0 mmol, 1.0 equiv.) in 1.0 mL of Et2O was added over 15 min. the reaction was stirred for 3h and 0.81 mL of
benzaldehyde (849 mg, 8.0 mmol, 2.7 equiv.) in 1 mL of Et2O was added dropwise. The
139 of a saturated aqueous NH4Cl solution and extracted with Et2O (3 x 10 mL) and the
combined organic phases were dried on Na2SO4, filtrated and the solvent was removed
under reduced pressure. The crude was purified by column chromatography (SiO2,
CH2Cl2 : acetone = 97:3) and the product was obtained as a colorless oil as a mixture of
syn and anti isomer (10:1) with a combine yield of 59% (3.5 mmol).
tert-butyl-(S)-2-((S)-hydroxy(phenyl)methyl)pyrrolidine-1-carboxylate
((S,S)-syn-N-Boc-35)
Pale yellow oil, 709 mg (2.56 mmol, 43% yield, 76% ee). The NMR data are in agreement with the ones present in literature [71,72] 1H NMR (400 MHz, Chloroform-d) δ 7.43 – 7.25 (m, 5H), 5.80
(broad s, 1H), 4.53 (d, 1H), 4.09 (td, 1H), 3.56 – 3.15 (m, 2H), 1.79 – 1.55 (m, 1H), 1.46 (s, 1H).
13C NMR (151 MHz, Chloroform-d) δ 154.9, 141.0, 128.7, 128.5,
127.8, 127.1, 80.9, 65.5, 45.9, 28.7, 25.5.
HRMS (ESI+): m/z calcd. for C16H23NO2Na ([M+Na+]) 300.15822, found 300.15823
CSP-HPLC: (190 nm, Chiralcel OD-H, n-heptane/i-PrOH = 90:10, 40 °C, 0.5
ml/min.), tR = 13.83 min (major), tR = 12.38 min (minor)
tert-butyl-(S)-2-((R)-hydroxy(phenyl)methyl)pyrrolidine-1-carboxylate
((S,R)-anti-N-Boc-35)
Pale yellow oil, 260 mg (0.94 mmol, 16% yield, 68% ee) The NMR data are in agreement with the ones present in literature. [71,72] 1H NMR (600 MHz, Chloroform-d) δ 7.41 – 7.19 (m, 5H), 4.95
(broad s, 1H), 4.24 (broad s, 1H), 3.37 (broad s, 1H), 2.93 (broad s, 1H), 1.83 (s, 3H), 1.52 (s, 10H), 1.48 – 1.38 (m, 1H).
13C NMR (151 MHz, Chloroform-d) δ 141.4, 128.2, 127.4, 126.9,
80.4, 63.5, 47.95, 28.7, 28.6, 28.6, 27.1, 23.7. Quaternary signals of the Boc-group were not detected.
HRMS (ESI+): m/z calcd. for C16H23NO2Na ([M+Na+]) 300.15823, found 300.15823
CSP-HPLC: (190 nm, Chiralcel OD-H, n-heptane/i-PrOH = 99:1, 40 °C, 0.5 ml/min.),
tR = 47.10 min (major), tR = 44.24 min (minor)
5.5.8. General procedure for the deprotection of Boc-pyrroldines
Under inert atmosphere, Boc-35 (1.0 equiv.) was dissolved in CH2Cl2 and TFA (4.0-4.1
equiv.) was added dropwise at 0oC. The reaction was allowed to stir for 20h at rt and
was quenched with NH3 (25% in H2O). The organic layer was separated and the
aqueous phase was extracted with CH2Cl2 (3 x 5 mL). The joined organic phases were
dried with MgSO4, filtered and the solvent was removed under reduced pressure. The
product was purified with a short column chromatography (SiO2, pentane:AcOEt, 9:1
140
(S)-phenyl((S)-pyrrolidin-2-yl)methanol ((S,S)-syn-35)
Reaction performed on 400 mg (1.44 mmol, 1.0 equiv.) of (S,S)-syn-N-Boc-35 and 0.85 mL of TFA (6.32 mmol, 4.4 equiv.). The (S,S)-syn-35 was obtained as a yellow oil (101 mg, 0.97 mmol, yield 67%). The NMR data are in agreement with the ones present in literature.[71]
1H NMR (400 MHz, Chloroform-d) δ 7.43 – 7.28 (m, 4H), 7.29 – 7.18 (m, 1H), 4.34 (d, J = 6.8 Hz, 1H), 3.85 (broad s, 2H), 3.42-3.30 (m, 1H), 2.99 (t, 2H), 1.98 – 1.34 (m, 4H). 13C NMR (101 MHz, Chloroform-d) δ 142.8, 128.5, 127.7, 126.7, 75.5, 65.1, 46.3, 28.4, 26.0. (R)-phenyl((S)-pyrrolidin-2-yl)methanol ((R,S)-anti-35)
Reaction performed on 177 mg (0.64 mmol, 1.0 equiv.) of (S,R)-anti-N-Boc-35 and 0.20 mL of TFA (2.60, 4.1 equiv.). (R,S)-anti-35 was obtained as a yellow oil (78.1 mg, 0.44 mmol, yield 66%). The NMR data are in agreement with the ones present in literature.[71]
1H NMR (400 MHz, Chloroform-d) δ 7.48 – 6.91 (m, 5H), 4.78 (d,
1H), 3.56 (broad s, 2H), 3.41 (m, 1H), 3.11 – 2.79 (m, 2H), 1.82 – 1.52 (m, 3H), 1.52 – 1.34 (m, 1H).
13C NMR (101 MHz, Chloroform-d) δ 142.1, 128.4, 127.3, 126.0, 73.7, 64.2, 46.8, 25.5,
24.9.
5.5.9. General procedure for the reduction of 47
(R)-2-ferrocenyl-ethanol (48)
In a heat dried Schlenk maintained under inert atmosphere, 0.09 mL of a solution of BH3.SMe2 (2M in THF, 0.18 mmol, 0.6 equiv.) were
added at rt to 15.9 mg of (R,S)-anti-35 (0.09 mmol, 0.25 equiv.) dissolved in 1 mL THF. The solution was stirred at 40oC for 40 min and
subsequently it was allowed to cool to rt in 20 min. A solution of 68 mg of 47 (0.3 mmol, 1 equiv.) in 0.3 mL of THF and 0.11 mL of a solution of BH3.SMe2 (2M
in THF, 0.21 mmol, 0.7 equiv.) were added simultaneously at rt over 15 minutes. The reaction was quenched after 1h with MeOH (0.3 mL). The solvent was removed under reduced pressure and the crude was purified by column chromatography (SiO2,
pentane:AcOEt, 4:1) to obtain the alcohol 48 as an orange solid (66 mg, 0.29 mmol, yield 97%, ee 57%). Spectral data match with the ones reported in literature[77].
1H NMR (400 MHz, Chloroform-d) δ 4.55 (qd, J = 6.4, 4.7 Hz, 1H), 4.31 – 4.01 (m,
9H), 1.90 – 1.78 (m, 1H), 1.44 (d, J = 6.4 Hz, 3H).
13C NMR (101 MHz, Chloroform-d) δ 95.0, 71.0, 68.4, 68.1, 68.0, 66.3, 66.2, 65.7,
23.9.
CSP-HPLC: (254 nm, Chiralcel AD-H, n-heptane/i-PrOH = 95:5, 40 °C, 0.5 ml/min.),
141
5.5.10. CBS-Reduction of 49
Phenyl-(2-pyridyl)-methanol (51)
Product 51 was obtained following the literature procedure[73] from 49
(183 mg, 1 mmol, 1.0 equiv.), Me-1 (45 mg, 0.2 mmol, 20 mol%), BH3.SMe2 (0.73, 2M in THF, 0.15 mmol, 1.5 equiv.) in 1 ml THF, as a
white solid (123mg, 0.66 mmol, yield 66%, racemic). Spectral data match with the ones reported in literature.[78]
1H NMR (400 MHz, Chloroform-d) δ 8.56 (d, J = 4.9, 1H), 7.61 (td, J = 7.7, 1.7 Hz,
1H), 7.42 – 7.34 (m, 2H), 7.39 – 7.25 (m, 3H), 7.29 – 7.12 (m, 2H), 5.75 (s, 1H).
13C NMR (101 MHz, Chloroform-d) δ 161.0, 147.9, 143.3, 137.0, 128.7, 128.0, 127.2,
122.6, 121.5, 75.1.
CSP-HPLC: (254 nm, Chiralcel AD-H, n-heptane/i-PrOH = 95:5, 40 °C, 0.5 ml/min.),
tR = 28.65 min, tR = 34.86 min
5.6. Bibliography
[1] D. H. Lee, K. Severin, M. R. Ghadiri, Curr. Opin. Chem. Biol. 1997, 1, 491–496. [2] G. F. Joyce, Nature 1989, 338, 217–224.
[3] L. E. Orgel, Crit. Rev. Biochem. Mol. Biol. 2004, 39, 99–123.
[4] B. G. Bag, G. von Kiedrowski, Pure Appl. Chem. 1996, 68, 2145–2152. [5] G. von Kiedrowski, B. Wlotzka, J. Helbing, M. Matzen, S. Jordan, Angew.
Chemie - Int. Ed. 1991, 30, 423–426.
[6] H. Duim, S. Otto, Beilstein J. Org. Chem 2017, 13, 1189–1203.
[7] A. J. Bissette, S. P. Fletcher, Angew. Chemie - Int. Ed. 2013, 52, 12800–12826. [8] D. G. Blackmond, Angew. Chemie - Int. Ed. 2009, 48, 386–390.
[9] V. Vasas, C. Fernando, M. Santos, S. Kauffman, E. Szathmáry, Biol. Direct
2012, 7, 1.
[10] O. Markovitch, D. Lancet, Artif. Life 2012, 18, 243–266.
[11] T. Tjivikua, P. Ballester, J. Rebek, J. Am. Chem. Soc. 1990, 112, 1249–1250. [12] D. N. Reinhoudt, D. M. Rudkevich, F. de Jong, J. Am. Chem. Soc. 1996, 118,
6880–6889.
[13] K. Soai, T. Kawasaki, Chirality 2006, 26, 469–478.
[14] J. S. Nowick, Q. Feng, T. Tjivikua, P. Ballester, J. Rebek, J. Am. Chem. Soc.
1991, 113, 8831–8839.
[15] T. K. Park, Q. Feng, J. J. Rebek, J. Am. Chem. Soc. 1992, 114, 4529–4532. [16] E. A. Wintner, M. M. Conn, J. Rebek, J. Am. Chem. Soc 1994, 116, 8877–8884. [17] B. Wang, I. O. Sutherland, Chem. Commun 1997, 1495–1496.
[18] A. Vidonne, D. Philp, European J. Org. Chem. 2009, 2009, 593–610. [19] I. Stahl, G. von Kiedrowski, J. Am. Chem. Soc. 2006, 128, 14014–14015. [20] A. C. Hoepker, L. Gupta, Y. Ma, M. F. Faggin, D. B. Collum, J. Am. Chem. Soc.
142
[21] K. J. Singh, A. C. Hoepker, D. B. Collum, J. Am. Chem. Soc. 2008, 130, 18008–18017.
[22] A. J. Bissette, S. P. Fletcher, Orig. Life Evol. Biosph. 2015, 45, 21–30.
[23] J. Ortega-Arroyo, A. J. Bissette, P. Kukura, S. P. Fletcher, Proc. Natl. Acad. Sci. U. S. A. 2016, 113, 11122–11126.
[24] B. Feringa, R. A. van Delden, Angew. Chem. Int. Ed. Engl. 1999, 38, 3418– 3438.
[25] D. G. Blackmond, Proc. Natl. Acad. Sci. U. S. A. 2004, 101, 5732–5736. [26] A. H. Alberts, H. Wynberg, J. Am. Chem. Soc 1989, 111, 7265–7266. [27] K. Soai, T. Hayase, K. Takai, Tetrahedron: Asymmetry 1995, 6, 637–638. [28] K. Soai, S. Niwa, H. Hori, J. Chem. Soc. Chem. Commun. 1990, 982–983. [29] K. Soai, T. Shibata, H. Morioka, K. Choji, Nature 1995, 378, 767–768.
[30] I. Sato, S. Osanai, K. Kadowaki, T. Sugiyama, T. Shibata, K. Soai, Chem. Lett.
2002, 31, 168–169.
[31] S. Tanji, A. Ohno, I. Sato, K. Soai, Org. Lett. 2001, 3, 287–289.
[32] T. Kawasaki, M. Sato, S. Ishiguro, T. Saito, Y. Morishita, I. Sato, H. Nishino, Y. Inoue, K. Soai, J. Am. Chem. Soc. 2005, 127, 3274–3275.
[33] K. Soai, S. Osanai, K. Kadowaki, S. Yonekubo, T. Shibata, I. Sato, J. Am. Chem. Soc. 1999, 11235–11236.
[34] I. Sato, K. Kadowaki, K. Soai, Angew. Chemie - Int. Ed. 2000, 39, 1510–1512. [35] I. Sato, K. Kadowaki, H. Urabe, J. H. Jung, Y. Ono, S. Shinkai, K. Soai,
Tetrahedron Lett. 2003, 44, 721–724.
[36] T. Kawasaki, K. Jo, H. Igarashi, I. Sato, M. Nagano, H. Koshima, K. Soai, Angew. Chemie - Int. Ed. 2005, 44, 2774–2777.
[37] K. Soai, I. Sato, T. Shibata, S. Komiya, M. Hayashi, Y. Matsueda, H. Imamura, T. Hayase, H. Morioka, H. Tabira, et al., Tetrahedron: Asymmetry 2003, 14, 185–188.
[38] C. Girard, H. B. Kagan, Angew. Chemie - Int. Ed. 1998, 37, 2922–2959. [39] T. Shibata, T. Hayase, J. Yamamoto, K. Soai, Tetrahedron: Asymmetry 1997,
8, 1717–1719.
[40] T. Gehring, M. Quaranta, B. Odell, D. G. Blackmond, J. M. Brown, Angew. Chemie - Int. Ed. 2012, 51, 9539–9542.
[41] A. Matsumoto, T. Abe, A. Hara, T. Tobita, T. Sasagawa, T. Kawasaki, K. Soai, Angew. Chemie - Int. Ed. 2015, 54, 15218–15221.
[42] M. N. Oble-Terán, J.-M. Cruz, J.-C. Micheau, T. Buhse, Chem. Cat. Chem.
2018, 10, 642–648.
[43] C. Romagnoli, B. Sieng, M. Amedjkouh, European J. Org. Chem. 2015, 2015, 4087–4092.
[44] M. Funes-Maldonado, B. Sieng, M. Amedjkouh, Org. Lett. 2016, 18, 2536– 2539.
143 4081–4086.
[46] N. Chinkov, A. Warm, E. M. Carreira, Angew. Chemie - Int. Ed. 2011, 50, 2957–2961.
[47] M. Mauksch, S. B. Tsogoeva, I. M. Martynova, S. Wei, Angew. Chemie - Int. Ed.
2007, 46, 393–396.
[48] M. Mauksch, S. B. Tsogoeva, ChemPhysChem 2008, 9, 2359–2371.
[49] M. Mauksch, S. Wei, M. Freund, A. Zamfir, S. B. Tsogoeva, Orig. Life Evol. Biosph. 2010, 40, 79–91.
[50] D. G. Blackmond, Angew. Chemie - Int. Ed. 2009, 48, 2648–2654.
[51] P. H. Bos, Novel Asymmetric Copper-Catalyzed Transformations, University of Groningen, 2012.
[52] M. Mauksch, S. B. Tsogoeva, S. Wei, I. m. Martynova, Chirality 2007, 19, 816– 825.
[53] M. Amedjkouh, M. Brandberg, Chem. Commun. 2008, 3043–3045.
[54] X. Wang, Y. Zhang, H. Tan, Y. Wang, P. Han, D. Z. Wang, J. Org. Chem 2010, 75, 2403–2406.
[55] E. J. Corey, C. J. Helal, Angew. Chemie - Int. Ed. 1998, 37, 1986–2012. [56] E. J. Corey, R. K. Bakshi, S. Shibata, J. Am. Chem. Soc 1987, 109, 5551–5553. [57] A. Hirao, S. Itsuno, S. Nakahama, N. Yamazaki, J. Chem. Soc. Chem. Commun.
1981, 315.
[58] S. Itsuno, Y. Sakurai, K. Ito, A. Hirao, S. Nakahama, Bull. Chem. Soc. Jpn.
1987, 60, 395–396.
[59] E. J. Corey, R. K. Bakshi, S. Shibata, C.-P. Chen, V. K. Singh, J. Am. Chem. Soc
1987, 109, 7925–7926.
[60] E. J. Corey, C. J. Helal, Tetrahedron Lett. 1995, 36, 9153–9156. [61] B. T. Cho, Y. S. Chun, Tetrahedron: Asymmetry 1992, 3, 1583–1590.
[62] S. Guduguntla, Exploring Asymmetric Catalytic Transformations, University of Groningen, 2017.
[63] N. G. De Kimpe, C. V. Stevens, M. A. Keppens, J. Agric. Food Chem. 1993, 41, 1458–1461.
[64] J. Deblander, S. Van Aeken, A. Adams, N. De Kimpe, K. A. Tehrani, FOOD Chem. 2015, 168, 327–331.
[65] R. Vícha, M. Potáček, Tetrahedron 2005, 61, 83–88.
[66] J. M. Carney, P. J. Donoghue, W. M. Wuest, O. Wiest, P. Helquist, Org. Lett.
2008, 10, 3903–3906.
[67] T. E. Mü, M. Grosche, E. Herdtweck, A.-K. Pleier, E. Walter, Y.-K. Yan, Organometallics 2000, 19, 170–183.
[68] Y. Ashikari, T. Nokami, J.-I. Yoshida, Org. Lett. 2012, 14, 938–941.
[69] N. S. Upadhyay, J. Jayakumar, C.-H. Cheng, Chem. Commun. 2017, 53, 2491– 2494.
144
[70] T. Yang, X. Fan, X. Zhao, W. Yu, n.d., DOI 10.1021/acs.orglett.8b00409. [71] F. Bächle, I. Fleischer, A. Pfaltz, Adv. Synth. Catal. 2015, 357, 2247–2254. [72] J. L. Bilke, S. P. Moore, P. O’Brien, J. Gilday, Org. Lett. 2009, 11, 1935–1938. [73] M. Woltersdorf, R. Kranich, H. G. Schmalz, Tetrahedron 1997, 53, 7219–7230. [74] J. Cianci, J. B. Baell, A. J. Harvey, Tetrahedron Lett. 2007, 48, 5973–5975. [75] T. Yang, X. Fan, X. Zhao, W. Yu, Org. Lett. 2018, 20, 1875–1879.
[76] M. Liniger, K. Estermann, K.-H. Altmann, J. Org. Chem. 2013, 78, 11066– 11070.
[77] M. Noji, Y. Konno, K. Ishii, J. Org. Chem. 2007, 72, 5161–5167.
[78] H. Yang, N. Huo, P. Yang, H. Pei, H. Lv, X. Zhang, Org. Lett. 2015, 17, 4144– 4147.
