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Catalytic Enantioselective Addition of Organozirconium Reagents to Aldehydes Ricard Solà 1 , Marcos Veguillas 1 ID , María José González-Soria 1 , Nicholas Carter 1 , M. Angeles Fernández-Ibáñez 2, * and Beatriz Maciá 1, * ID 1
2
*
Division of Chemistry & Environmental Science, Manchester Metropolitan University, Oxford Road, Manchester M1 5GD, UK;
[email protected] (R.S.);
[email protected] (M.V.);
[email protected] (M.J.G.-S.);
[email protected] (N.C.) Van ’t Hoff Institute for Molecular Sciences, Science Park 904, Amsterdam 1090 GS, The Netherlands Correspondence:
[email protected] (M.A.F.-I.);
[email protected] (B.M.); Tel.: +31-(0)205-258-753 (M.A.F.-I.); Tel.: +44-(0)161-247-1416 (B.M.)
Received: 6 April 2018; Accepted: 17 April 2018; Published: 20 April 2018
Abstract: A catalytic enantioselective addition reaction of alkylzirconium species to aromatic aldehydes is reported. The reaction, facilitated by a chiral nonracemic diol ligand complex with Ti(Oi Pr)4 , proceeds under mild and convenient conditions, and no premade organometallic reagents are required since the alkylzirconium nucleophiles are generated in situ by hydrozirconation of alkenes with the Schwartz reagent. The methodology is compatible with functionalized nucleophiles and a broad range of aromatic aldehydes. Keywords: alkenes; asymmetric catalysis; titanium; addition to aldehydes; Schwartz reagent
1. Introduction Chiral alcohol-containing molecules are recurrent, high-value targets in the pharmaceutical, agricultural, and material science sectors, amongst others; the development of efficient methods for their construction remains a high priority in organic synthesis [1]. The catalytic enantioselective 1,2-addition reaction of organometallic reagents to carbonyl compounds is one of the most efficient approaches to chiral alcohols. This transformation has been extensively studied with dialkylzinc [2–17] and trialkylaluminium [18–20] reagents; more recently, excellent results with Grignard [21–35] and organolithium [36–38] reagents have also been reported. The high reactivity and sometimes pyrophoric character of these premade, non-stabilized organometallic nucleophiles, however, restricts the implementation of these methodologies in industrial processes and large-scale reactions [39]. Other complicating factors are the frequent requirement for cryogenic temperatures (necessary in order to obtain high levels of enantioselectivity but often prohibitively expensive at large scale) and incompatibilities with several functional groups [40,41]. The use of less reactive nucleophiles circumvents some of these issues. Organozirconium reagents [42–48] are relatively inert toward carbonyl compounds [49], but the use of catalysts or a stoichiometric mediator [50–60] enables the nucleophilic attack and subsequent carbon-carbon bond formation. Thus, in the presence of Ag(I), ZnBr2 , or Me2 Zn, organozirconium reagents can readily be added to aldehydes [61–68], ketones [69,70], and also enones [71–74], epoxides [75], and isocyanates [76], although enantioselective protocols have been rare so far [77–92]. In 1994, Wipf reported [63,64] a high-yielding protocol for the in situ transmetalation of alkenylzirconocenes to alkenylzinc species with stoichiometric amounts of Me2 Zn, and succeeded in developing a catalytic asymmetric methodology for their subsequent additions to aldehydes [93,94]. A similar strategy was adopted by Walsh et al. for the addition of alkenylzirconocenes to ketones Molecules 2018, 23, 961; doi:10.3390/molecules23040961
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catalysed by a bis-(sulphonamide) diol ligand in the presence of stoichiometric Ti(Oi Pr)4 [95]. We are not aware, however, of any successful report addressing the catalytic asymmetric addition of alkylzirconocene nucleophiles to carbonyls [14,31,96]. The use of alkylzirconocene reagents in synthesis is greatly facilitated by their ready accessibility via (in situ) hydrozirconation of alkenes using Schwartz reagent [97–99] (Cp2 ZrHCl). This offers two key advantages: (i) alkenes, as starting materials, are inexpensive, abundant, and easy to handle [100]; (ii) hydrozirconation reaction conditions are compatible with many functional groups [101]. Here, we report the first enantioselective catalytic 1,2-addition of alkylzirconium reagents to aldehydes, based on a titanium-Ar-BINMOL complex. This methodology affords high levels of enantioselectivity at industrially relevant temperatures and the reaction tolerates functional groups that are not compatible with other organometallic reagents. 2. Results and Discussion Provided with both axial and tetrahedral chirality, 1,1-binaphthalene-2-α-arylmethan-2-ols (Ar-BINMOLs)—developed by Kiyooka, Lai, and Xu [102–105]—have recently emerged as very efficient ligands for the titanium-assisted catalytic addition of organometallic reagents to carbonyl compounds [21,23,30,36,37]. Here, we started our investigations by evaluating the use of the very versatile Ph-BINMOL [23,102–105] ligand in the addition of 1-hexene to benzaldehyde (Table 1). Following known procedures [97–99], the treatment of 1-hexene with 2.0 eq. of Schwartz reagent (Cp2 ZrHCl) provided the corresponding organozirconium reagent, which was then added to a solution of benzaldehyde (1.0 eq., 0.125 M) and Ph-BINMOL (20 mol%) in DCM at RT (Table 1). As expected, very low conversion to the desired alcohol 3aa was observed (13%, entry 1). Under similar conditions (0.125 M in benzaldehyde), the reaction was attempted in the presence of 2.5–2.8 eq. of various additives (AgOTs, Ti(Oi Pr)4 , TiCl(Oi Pr)3 , CuI, and Et2 Zn) in DCM at RT. No conversion was observed except in the presence of 2.0 eq. of Et2 Zn (19% conversion to racemic 3aa; entry 2). In accordance with Srebnik’s observations [62], more concentrated reaction conditions (0.5 M benzaldehyde in DCM) provided higher conversion to the desired product 3aa (44%, entry 3), although the enantioselectivity of the process remained zero. An extensive screening of zinc additives revealed that the use of ZnBr2 (0.5 eq.) in combination with Ti(Oi Pr)4 (1.5 eq.) provides the desired alcohol 3aa in 83% isolated yield and 80% ee, using only 1.4 eq. of the alkene and 1.2 eq. of the Schwartz reagent, in DCM (0.5 M benzaldehyde) at RT (entry 4). It is important to mention that the reaction proved to be very sensitive to the concentration and no conversion was observed under more diluted conditions (0.11 M benzaldehyde in DCM, entry 5). Working at the preferred 0.5 M concentration of substrate in DCM, variation of the titanium source (TiCl(Oi Pr)3 instead of Ti(Oi Pr)4 ), however, resulted in increased reduction of the starting material to phenylmethanol, whilst the desired product 3aa was obtained in a racemic form (entry 6). Co-solvents—tert-butylmethyl ether, THF, toluene, and diethyl ether—were also assayed in combination with DCM, which we found to be optimal for the hydrozirconation step; all attempts provided lower conversion and enantioselectivity than the use of DCM alone. Changes in the titanium loading (entries 7–8) or the amount of ZnBr2 (entries 9–10), only afforded increased amounts of the undesired reduced product and lower enantioselectivities. To our surprise, when the reaction was carried out at lower temperature (0 ◦ C, overnight), lower enantioselectivity was observed (35% ee, entry 11), whilst higher temperatures (35 ◦ C) provided slightly higher enantioselectivity than RT (82% ee, compare entries 12 and 4), but lower conversion (51%). By way of comparison, the reaction was assessed using (R)-BINOL (20 mol %) as ligand; 9% conversion to the desired product 3aa was obtained in 56% ee (entry 13).
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Table 1. Optimisation of reaction conditions for the addition of 1‐hexene (2a) to benzaldehyde (1a) aa. Table 1. Optimisation of reaction conditions for the addition of 1-hexene (2a) to benzaldehyde (1a) .
Ti(OiiPr)4 ZnBr2 Conv. Cp2ZrHCl 1‐hexene Undesired Cp2 ZrHCl 1-hexene ZnBr2 Undesired Ti(O Pr)4 Entry ee (%) c b b b ee (%) c Entry (%) (eq.) (eq.) (eq.) (eq.) (eq.) Conv. (%) Phenylmethanol (%) (eq.) (eq.) Phenylmethanol (%) b (eq.) 1 d d 2 2 2 2 ‐ ‐ 13 0 0 13 0 0 1 e 2 d 2 d 2 2 2 2 ‐ 19 - e‐ 19 0 0 0 0 44 3 3 2 2 2 2 ‐ - e‐ e 44 0.0. 4 1.2 1.4 1.5 0.5 1010 8080 n.d. (83) f f 4 1.2 1.4 1.5 0.5 n.d. (83) 5g 1.2 1.4 1.5 0.5 1 n.d. 0 5 g 1.2 1.4 1.5 0.5 1 n.d. 0 6 1.2 1.4 0.5 22 78 0 -h h 22 6 7 1.2 1.2 1.4 1.4 ‐ 1.0 0.50.5 43 5778 35 0 7 8 1.2 1.2 1.4 1.4 1.0 2.0 0.50.5 543 8957 6235 1.5 0.20.5 185 7389 8062 8 9 1.2 1.2 1.4 1.4 2.0 10 1.2 1.4 1.5 0.7 20 74 66 9 i 1.2 1.4 1.5 0.2 18 73 80 1.2 1.4 1.5 0.5 6 67 35 11 10 12 j 1.2 1.2 1.4 1.4 1.5 0.7 20 74 1.5 0.5 51 36 8266 k 1.2 1.2 1.4 1.4 1.5 11 i13 1.5 0.50.5 96 8367 5635 1.5 0.50.5 11 5936 9082 1.2 1.0 1.4 1.2 1.5 51 12 j 14 j f l 1.5 0.5 5 99 (87) 93 (R) 13 k15 1.2 2.0 1.4 2.2 1.5 0.5 9 83 56 a i conditions: 1a1.2 (0.15 mmol, 1.0 1.5 eq.), (Ra ,S)-Ph-BINMOL (0.2 eq.), DCM (0.5 M), room 14 Reaction1.0 0.5 11 Ti(O Pr)4 (1.5 eq.), 59 90 b Determined by CG-MS. c Determined by Chiral GC (see supplementary material for temperature, overnight. j f l 2.0 d 2.2 1.5 0.5 99 (87) 5 93 (R) 15 e f further details). 0.125 M in benzaldehyde. Reaction carried out with Et2 Zn instead of ZnBr2 . Isolated yield after Reaction conditions: 1a (0.15 mmol, 1.0 eq.), (R a,S)‐Ph‐BINMOL (0.2 eq.), Ti(OiPr) i flash chromatography. g 0.11 M 1a in DCM. h Reaction carried out with 1.5 eq. of TiCl(Oi Pr)4 (1.5 eq.), DCM (0.5 3 instead of Ti(O Pr)4 . b c Determined by Chiral iM), ◦ j k (R)-BINOL room temperature, Determined CG‐MS. (20 GC (see Reaction carried out at 0 C. overnight. Reaction carried out at 35 ◦ C. by mol %) used as ligand. l Configuration determined based on the optical rotation, by comparison with literature. d 0.125 M in benzaldehyde. e Reaction carried out with supplementary material for further details). a
Et2Zn instead of ZnBr2. f Isolated yield after flash chromatography. g 0.11 M 1a in DCM. h Reaction iPr)3 instead of Ti(O iPr) j Reaction Lowering the amounts of the Schwartz reagent and the alkene provided higher enantioselectivity carried out with 1.5 eq. of TiCl(O 4. i Reaction carried out at 0 °C. k l (R)‐BINOL (20 mol %) used as ligand. Configuration determined based on the (90%)carried out at 35 °C. but lower conversion to the desired 3aa, due to a substantial increase in the reduction by-product optical rotation, by comparison with literature. (entry 14). Fortunately, improved results were obtained with increased amounts of Schwartz reagent
and the alkene, and, after fine adjustments, 99% conversion and 93% ee could be reached in 5 h when ◦ C (entryThe Regarding the reagent mechanism of the reaction, a number of pathways are 2.0 eq. of Schwartz were used inaddition combination with 2.2 eq. of alkene in DCM at 35possible. 15). transmetallation of mechanism the organozirconium reagent with ZnBr 2 [106–108], followed are by possible. second Regarding the of the addition reaction, a number of pathways transmetallation with of the organotitanium species is 2 a [106–108], very plausible route The transmetallation theappropriate organozirconium reagent with ZnBr followed by [97–99]. second However, the activation of aldehydes by complexation with zinc halides [109] is a well‐known transmetallation with the appropriate organotitanium species is a very plausible route [97–99]. process that be discarded at this of our investigations. It is worth out the However, thecannot activation of aldehydes bystage complexation with zinc halides [109] pointing is a well-known versatility of Ar‐BINMOL ligands, in particular the simple and readily available Ph‐BINMOL, which process that cannot be discarded at this stage of our investigations. It is worth pointing out the is able to catalyse the carbonyl addition of a broad spectrum of organometallic reagents, including versatility of Ar-BINMOL ligands, in particular the simple and readily available Ph-BINMOL, which is organozinc [110], [21,23,30], organolithium [36–38], organoaluminum [20], able to catalyse theorganomagnesium carbonyl addition of a broad spectrum of organometallic reagents, including organotitanium [111], and, now, organozirconium reagents. As far as we know, this catalytic system organozinc [110], organomagnesium [21,23,30], organolithium [36–38], organoaluminum [20], allows the broadest variety of organometallic reagents in enantioselective 1,2‐addition to carbonyl organotitanium [111], and, now, organozirconium reagents. As far as we know, this catalytic groups. system allows the broadest variety of organometallic reagents in enantioselective 1,2-addition to With groups. the optimised conditions in hand, we tested the scope of the reaction with different carbonyl aromatic (Table 2). Thus, the reaction of the 1‐hexene with p‐tolualdehyde With aldehydes the optimised conditions in hand, we tested scope of(2a) the reaction with different afforded aromatic product 3ba with good yield (74%) and excellent enantioselectivity (91%, entry 1). In the case of m‐ aldehydes (Table 2). Thus, the reaction of 1-hexene (2a) with p-tolualdehyde afforded product 3ba with and o‐tolualdehyde (entries 2 and 3), where the methyl substituent in the aromatic ring is closer to good yield (74%) and excellent enantioselectivity (91%, entry 1). In the case of m- and o-tolualdehyde the reactive site, higher percentages of the corresponding aryl methanol (reduction of the aldehyde) (entries 2 and 3), where the methyl substituent in the aromatic ring is closer to the reactive site, higher and dehydration products 4 (Figure 1) were obtained, as well as lower enantioselectivity (89% and percentages of the corresponding aryl methanol (reduction of the aldehyde) and dehydration products 76%, respectively); this is probably due to increased steric hindrance close to the carbonyl group. The 4 (Figure 1) were obtained, as well as lower enantioselectivity (89% and 76%, respectively); this is reaction p‐bromo and p‐chlorobenzaldehyde afforded (56% and 59%) and probably with due to increased steric hindrance close to the carbonylmoderated group. Theyields reaction with p-bromo and excellent enantioselectivities (91% and 90%, entries 4 and 5, respectively). The use of p‐ p-chlorobenzaldehyde afforded moderated yields (56% and 59%) and excellent enantioselectivities acetylbenzaldehyde as starting material (entry 6), provided the corresponding alcohol 3ga in excellent enantioselectivity (94%) but lower yield (32%). This is probably due to the reduction of the
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(91% and 90%, entries 4 and 5, respectively). The use of p-acetylbenzaldehyde as starting material (entry group 6), provided the corresponding alcohol in excellent reagent enantioselectivity (94%) but lower acetyl by β‐hydride transfer from the 3ga organometallic (by‐product 5, Figure 1). Molecules 2018, 23, x FOR PEER REVIEW 4 of 11 yield (32%). This is probably due to the reduction of the acetyl group by β-hydride transfer from Molecules 2018, 23, x FOR PEER REVIEW 4 of 11 Gratifyingly, the methodology proved to be compatible with other functional groups such as p‐CN Molecules 2018, 23, x FOR PEER REVIEW 4 of 11 Molecules 2018, 23, x FOR PEER REVIEW 4 of 11 the organometallic3 (entry 8), leading to good yield (55–58%) and high enantioselectivity (87% ee). reagent (by-product 5, Figure 1). Gratifyingly, the methodology proved to be Molecules 2018, 23, x FOR PEER REVIEW (entry 7) and p‐CF acetyl group by β‐hydride transfer from the organometallic reagent (by‐product 5, Figure 4 of 11 1). Molecules 2018, 23, x FOR PEER REVIEW 4 of 11 acetyl group by with β‐hydride transfer from the organometallic reagent (by‐product 5, Figure 1). Molecules 2018, 23, x FOR PEER REVIEW 4 of 11 compatible other functional groups such as p-CN (entry 7) and p-CF (entry 8), leading to these good acetyl group by β‐hydride transfer from the organometallic reagent (by‐product 5, 3Figure 1). Gratifyingly, the methodology proved to be compatible with other functional groups such as p‐CN Molecules 2018, 23, x FOR PEER REVIEW 4 of 11 Unfortunately, aliphatic and α,β‐unsaturated aldehydes gave very low under acetyl group by β‐hydride transfer from the organometallic reagent (by‐product 5, conversions Figure 1). Gratifyingly, the methodology proved to be compatible with other functional groups such as p‐CN acetyl group by β‐hydride transfer from the organometallic reagent (by‐product 5, Figure 1). yieldgroup (55–58%) and high enantioselectivity (87% ee). Unfortunately, aliphatic and1). α,β-unsaturated Gratifyingly, the methodology proved to be compatible with other functional groups such as p‐CN (entry 7) and p‐CF (entry 8), leading to good yield (55–58%) and high enantioselectivity (87% ee). acetyl by 3β‐hydride from the organometallic reagent (by‐product 5, Figure reaction conditions. transfer Gratifyingly, the methodology proved to be compatible with other functional groups such as p‐CN (entry 7) and p‐CF acetyl group by 3 (entry 8), leading to good yield (55–58%) and high enantioselectivity (87% ee). β‐hydride transfer from the organometallic reagent (by‐product 5, Figure 1). Gratifyingly, the methodology proved to be compatible with other functional groups such as p‐CN (entry 7) and p‐CF 3β‐hydride (entry 8), leading to good yield (55–58%) and high enantioselectivity (87% ee). acetyl group by transfer from the organometallic reagent (by‐product 5, Figure 1). Unfortunately, aliphatic and α,β‐unsaturated aldehydes gave very low conversions under these aldehydes gave very low conversions under these reaction conditions. Gratifyingly, the methodology proved to be compatible with other functional groups such as p‐CN (entry 7) and p‐CF 3 (entry 8), leading to good yield (55–58%) and high enantioselectivity (87% ee). Unfortunately, aliphatic and α,β‐unsaturated aldehydes gave very low conversions under these Gratifyingly, the methodology proved to be compatible with other functional groups such as p‐CN (entry 7) and p‐CF 3 (entry 8), leading to good yield (55–58%) and high enantioselectivity (87% ee). Unfortunately, aliphatic and α,β‐unsaturated aldehydes gave very low conversions under these Gratifyingly, the methodology proved to be compatible with other functional groups such as p‐CN reaction conditions. (entry 7) and p‐CF 3 (entry 8), leading to good yield (55–58%) and high enantioselectivity (87% ee). Unfortunately, and α,β‐unsaturated aldehydes very (2a) low to conversions under these reaction conditions. Table 2. aliphatic Enantioselective catalysed addition of gave 1‐hexene aromatic aldehydes—Scope of the (entry 7) and p‐CF 3 (entry 8), leading to good yield (55–58%) and high enantioselectivity (87% ee). Unfortunately, aliphatic and α,β‐unsaturated aldehydes gave very low conversions under these reaction conditions. (entry 7) and p‐CF 3 (entry 8), leading to good yield (55–58%) and high enantioselectivity (87% ee). Unfortunately, aliphatic and α,β‐unsaturated aldehydes gave very (2a) low toconversions under these Table 2. Enantioselective catalysed addition of 1-hexene aromatic aldehydes—Scope of the reaction conditions. a Unfortunately, aliphatic and α,β‐unsaturated aldehydes gave very low conversions under these reaction . reaction conditions. Table 2. Enantioselective catalysed addition of aldehydes 1‐hexene (2a) to aromatic aldehydes—Scope of the these Unfortunately, aliphatic and α,β‐unsaturated gave very low conversions under a reaction conditions. Table 2. Enantioselective catalysed addition of 1‐hexene (2a) to aromatic aldehydes—Scope of the reaction . reaction conditions. Table 2. aEnantioselective catalysed addition of 1‐hexene (2a) to aromatic aldehydes—Scope of the reaction . reaction conditions. a Enantioselective Table 2. catalysed addition of 1‐hexene (2a) to aromatic aldehydes—Scope of the reaction . a. Enantioselective catalysed addition of 1‐hexene (2a) to aromatic aldehydes—Scope of the Table 2. reaction a. Enantioselective catalysed addition of 1‐hexene (2a) to aromatic aldehydes—Scope of the Table 2. reaction a. Table 2. Enantioselective catalysed addition of 1‐hexene (2a) to aromatic aldehydes—Scope of the reaction a. Table 2. Enantioselective catalysed addition of 1‐hexene (2a) to aromatic aldehydes—Scope of the reaction reaction a a. reaction .
Yield Undesired Undesired Yield d b Yield Undesired Entry Product Conv. (%) c ee (%) b Arylmethanol Entry Product Yieldd (%) (%) b Conv. (%) (%) ee (%)dd b Entry Product Conv. ee (%) Yield Undesired Entry Product Conv. (%) Undesired (%) cc ee (%) Arylmethanol (%) b d (%) c b Arylmethanol (%) Yield Undesired Entry Product Conv. (%) ee (%) (%) Arylmethanol (%) d c Yield Undesired bb Entry Product Conv. (%) b Arylmethanol (%) ee (%) c Yield Undesired b (%) Entry Product Conv. (%) b Arylmethanol (%) ee (%) dd (%) c Yield Undesired Entry Product Conv. (%) ee (%) Yield (%) Arylmethanol (%) 1 1 6 6 74 91 (R) 94 94 74 d 91 (R) b b c Undesired Entry Product Conv. (%) ee (%) (%) Arylmethanol (%) 1 94 6 74 91 (R) b b 94 6 74 91 (R) Entry Product Conv. (%) ee (%) d 74 (%) c c Arylmethanol (%) 1 1 94 6 91 (R) b (%) Arylmethanol (%) 1 94 6 74 91 (R) 1 6 74 91 (R) 94 1 94 6 74 91 (R) 1 94 6 74 91 (R) e 1 94 6 74 91 (R) 2 77 15 e e 54 89 (R) 2 2 15 e 15 54 89 (R) 77 77 54 89 (R) 2 2 77 15 e 89 (R) 54 e 89 (R) 77 15 54 2 77 15 e 54 89 (R) 2 77 15 e 54 89 (R) 2 77 15 e 54 89 (R) 2 77 15 54 89 (R) f e 77 15 54 89 (R) 3 2 49 76 (R) 54 28 f 3 49 76 (R) 54 28 f f 3 3 49 76 (R) 28 f 28 54 54 49 76 (R) 3 49 76 (R) 54 28 f 3 3 76 (R) 49 54 28 f 76 (R) 54 28 f 49 3 49 76 (R) 54 28 49 76 (R) 54 28 f 87 10 56 91 (R) 4 3 49 76 (R) 54 28 f 87 10 56 91 (R) 4 3 87 10 56 91 (R) 4 10 10 56 91 (R) 4 4 87 87 56 91 (R) 87 10 56 91 (R) 4 87 10 91 (R) 56 4 4 87 10 56 91 (R) 87 10 56 91 (R) 4 g 92 6 59 90 (R) 5 4 87 10 56 91 (R) 6 59 90 (R) 5 gg 92 92 6 59 90 (R) 5 g 92 6 59 90 (R) 5 gg 6 6 59 90 (R) 5 55 g 92 92 59 90 (R) OH 92 6 59 90 (R) OH 92 6 59 90 (R) 59 5 gg5 g OH 92 6 90 (R) 92 6 59 90 (R) 5 OH 6 32 94 (R) 76 4 h OH 3ga 6 32 94 (R) 4 hh OH 76 3ga 6 32 94 (R) 76 4 h OH 3ga OH 6 32 94 (R) 76 4 h OH O 3ga 6 32 94 (R) 76 4 h h O 3ga 6 32 94 (R) 76 4 h4 6 76 32 94 (R) O 6 32 94 (R) 76 4 h 3ga O 3ga 6 32 94 (R) 76 4 h O 32 94 (R) 76 4 3ga 81 19 58 87 (R) 7 f f 6 O 3ga 81 19 58 87 (R) 7 f O 81 19 58 87 (R) 7 f O 81 19 58 87 (R) 7 f O 19 58 87 (R) 7 f 81 81 19 58 87 (R) 7 f 81 19 58 87 (R) 7 81 19 58 87 (R) 7 f i (R) 81 19 58 87 (R) 7 69 28 55 87 8 i (R) 69 28 55 87 8 i (R) 69 28 55 87 8 7 f 81 19 58 87 (R) 69 28 55 87 i (R) 8 69 28 55 87 ii (R) 8 a Reaction conditions: 3 (0.15 mmol, 1.0 eq.), (R iPr)4 (1.5 eq.), 1‐hexene a69 ,S)‐Ph‐BINMOL (0.2 eq.), Ti(O 28 55 87 i (R) 8 a Reaction conditions: 3 (0.15 mmol, 1.0 eq.), (R i a69 ,S)‐Ph‐BINMOL (0.2 eq.), Ti(O Pr)4 (1.5 eq.), 1‐hexene 28 55 87 (R) 8 a Reaction conditions: 3 (0.15 mmol, 1.0 eq.), (R i a,S)‐Ph‐BINMOL (0.2 eq.), Ti(O Pr) 4 (1.5 eq.), 1‐hexene 28 28 bb Determined by GC‐MS. 55 87 i (R) 8 8 69 69 55cc (2.2 eq.), Cp 2ZrHCl (2.0 eq.), ZnBr2 (0.5 eq.), DCM (0.375 M), 35 °C, 5–12 h. 87 i (R) a Reaction conditions: 3 (0.15 mmol, 1.0 eq.), (R iPr)4 (1.5 eq.), 1‐hexene a,S)‐Ph‐BINMOL (0.2 eq.), Ti(O (2.2 eq.), Cp 2 ZrHCl (2.0 eq.), ZnBr 2 (0.5 eq.), DCM (0.375 M), 35 °C, 5–12 h. Determined by GC‐MS. a Reaction conditions: 3 (0.15 mmol, 1.0 eq.), (R iPr)4 (1.5 eq.), 1‐hexene b c a ,S)‐Ph‐BINMOL (0.2 eq.), Ti(O d (2.2 eq.), Cp 2ZrHCl (2.0 eq.), ZnBr 2 (0.5 eq.), DCM (0.375 M), 35 °C, 5–12 h. a Reaction conditions: 3 (0.15 mmol, 1.0 eq.), (R iPr)4 (1.5 eq.), 1‐hexene Isolated yield after flash chromatography. Determined by Chiral GC. Determined by GC‐MS. Configuration based on a,S)‐Ph‐BINMOL (0.2 eq.), Ti(O d Determined (2.2 eq.), Cp 2ZrHCl (2.0 eq.), ZnBr 2 (0.5 eq.), DCM (0.375 M), 35 °C, 5–12 h. Determined by GC‐MS. a Reaction conditions: 3 (0.15 mmol, 1.0 eq.), (R iPr) Isolated after flash chromatography. based on c55 69 by Chiral GC. bConfiguration 28 87 i (R) 8 yield b Determined by GC‐MS. a,S)‐Ph‐BINMOL (0.2 eq.), Ti(O 4 (1.5 eq.), 1‐hexene d Determined 2 (0.5 eq.), DCM (0.375 M), 35 °C, 5–12 h. e 8% of dehydration product 4 was observed a(2.2 eq.), Cp iPr)4 (1.5 eq.), 1‐hexene Isolated yield 22ZrHCl (2.0 eq.), ZnBr after flash chromatography. by Chiral GC. Configuration on cc b Determined by GC‐MS. literature data (see supplementary material for details). Reaction conditions: 3 (0.15 mmol, 1.0 eq.), (R a,S)‐Ph‐BINMOL (0.2 eq.), Ti(O a Reaction i Pr)based d (2.2 eq.), Cp ZrHCl (2.0 eq.), ZnBr 2 (0.5 eq.), DCM (0.375 M), 35 °C, 5–12 h. e conditions: 3 (0.15 mmol, 1.0 eq.), (R ,S)-Ph-BINMOL (0.2 eq.), Ti(O (1.5 eq.), 1-hexene (2.2 eq.), Isolated yield after flash chromatography. Determined by Chiral GC. bConfiguration based on c a 8% of dehydration product 4 was observed literature data (see supplementary material for details). (2.2 eq.), Cp 2ZrHCl (2.0 eq.), ZnBr 2 (0.5 eq.), DCM (0.375 M), 35 °C, 5–12 h. Determined by GC‐MS. e 8% of dehydration product 4 was observed Isolated yield after flash chromatography. Determined by Chiral GC. Configuration 4based on f 18% of dehydration product 4 was observed by GC‐MS. g The reaction was carried out cc dd (0.375 literature data (see supplementary material for details). by GC‐MS. ◦by b bDetermined (2.2 eq.), Cp 2ZrHCl (2.0 eq.), ZnBr 2 (0.5 eq.), DCM (0.375 M), 35 °C, 5–12 h. Determined by GC‐MS. e 8% of dehydration product 4 was observed Isolated yield after flash chromatography. Determined Chiral GC. Configuration based on f g Cp ZrHCl (2.0 eq.), ZnBr (0.5 eq.), DCM M), 35 C, 5–12 h. by GC-MS. Isolated yield after literature data (see supplementary material for details). d 2 2 18% of dehydration product 4 was observed by GC‐MS. The reaction was carried out by GC‐MS. e Isolated yield after flash chromatography. d Determined by Chiral GC. Configuration based a Reaction conditions: 3 (0.15 mmol, 1.0 eq.), (R iPr)4on f 18% of dehydration product 4 was observed by GC‐MS. g The reaction was carried out literature data (see supplementary material for details). h 19% i e 8% of dehydration product 4 was observed by GC‐MS. a,S)‐Ph‐BINMOL (0.2 eq.), Ti(O (1.5 eq.), 1‐hexene in DCM (0.3 M). of chromatography. 5 dwas observed by by Chiral GC‐MS. Determined the corresponding acetate Isolated yield after flash Determined by Chiral GC. Configuration based on f 18% of dehydration product 4 was observed by GC‐MS. gon literature data (see supplementary material for details). 8% of dehydration product 4 was observed flash(0.3 chromatography. Determined GC. Configuration based on literature data (see supplementary h 19% of 5 was i Determined The reaction was carried out by GC‐MS. e in DCM M). observed by GC‐MS. on the corresponding acetate g The reaction was carried out literature data (see supplementary material for details). 8% of dehydration product 4 was observed h 19% of e5 was observed by GC‐MS. i eDetermined 18% of dehydration product 4 was observed by GC‐MS. by GC‐MS. b Determined by GC‐MS. in DCM (0.3 ffor M). on the acetate f g The reaction was carried out derivative (see supplementary material for further details). literature data (see supplementary material for details). (2.2 eq.), Cp 2ZrHCl (2.0 eq.), ZnBr 2 (0.5 eq.), DCM (0.375 M), 35 °C, 5–12 h. h 19% of 5 material 8% of observed dehydration producti 8% of dehydration product 4 was observed 4Determined was observed bycorresponding GC-MS. f 18% of dehydration product 4c by GC‐MS. in DCM (0.3 f 18% of dehydration product 4 was observed by GC‐MS. M). details). was by GC‐MS. on the corresponding acetate derivative (see supplementary material for further details). h 19% of 5 was observed by GC‐MS. i Determined gon 18% of dehydration product 4 was observed by GC‐MS. The reaction was carried out by GC‐MS. in DCM (0.3 M). the M). corresponding f g g h 19% of 5 acetate derivative (see supplementary material for further details). h 19% 18% of dehydration product 4 was observed by GC‐MS. The reaction was carried out by GC‐MS. d iDetermined was observed by GC-MS. The reaction was carried out in DCM (0.3 was observed based by GC-MS. in DCM (0.3 M). of 5 was observed by GC‐MS. Determined on the corresponding acetate Isolated yield after flash chromatography. by Chiral GC. Configuration on derivative (see supplementary material for further details). in i DCM (0.3 M). hh 19% of 5 was observed by GC‐MS. i i Determined on the corresponding acetate derivative (see supplementary material for further details). Determined the corresponding acetate derivative (see supplementary material for further in DCM (0.3 M). on 19% of 5 was observed by GC‐MS. Determined on the corresponding acetate details). derivative (see supplementary material for further details). e literature data (see supplementary material for details). 8% of dehydration product 4 was observed derivative (see supplementary material for further details). derivative (see supplementary material for further details). b b b b
by GC‐MS. f 18% of dehydration product 4 was observed by GC‐MS. g The reaction was carried out in DCM (0.3 M). h 19% of 5 was observed by GC‐MS. i Determined on the corresponding acetate derivative (see supplementary material for further details).
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Figure 1. By‐products of the reaction. Figure 1. By-products of the reaction. Figure 1. By‐products of the reaction. Figure 1. By‐products of the reaction. Figure 1. By‐products of the reaction. Next, we tested the scope of the reaction with different alkenes (Table 3). Thus, the reaction of Next, we tested the scope of the reaction with different alkenes (Table 3). Thus, the reaction of Figure 1. By‐products of the reaction. Figure 1. By‐products of the reaction. 4‐phenyl‐1‐butene (2b) with benzaldehyde (1a) provided the corresponding alcohol 3ab in excellent Next, we tested the scope of the reaction with different alkenes (Table 3). Thus, the reaction of 4-phenyl-1-butene (2b) with benzaldehyde (1a) provided the corresponding alcohol 3ab in excellent Next, we tested the scope of the reaction with different alkenes (Table 3). Thus, the reaction of Next, we tested the scope of the reaction with different alkenes (Table 3). Thus, the reaction of yield (93%) and good enantioselectivity (77% ee, entry 1). The methodology is also compatible with 4‐phenyl‐1‐butene (2b) with benzaldehyde (1a) provided the corresponding alcohol 3ab in excellent Next, we tested the scope of the reaction with different alkenes (Table 3). Thus, the reaction of yield (93%) and good enantioselectivity (77% ee, entry 1). The methodology is also compatible with 4‐phenyl‐1‐butene (2b) with benzaldehyde (1a) provided the corresponding alcohol 3ab in excellent Next, we tested the scope of the reaction with different alkenes (Table 3). Thus, the reaction of 4‐phenyl‐1‐butene (2b) with benzaldehyde (1a) provided the corresponding alcohol 3ab in excellent functionalised alkenes. The reaction of benzaldehyde with 4‐[(tert‐butyldimethylsilyl)oxy]‐1‐butene yield (93%) and good enantioselectivity (77% ee, entry 1). The methodology is also compatible with 4‐phenyl‐1‐butene (2b) with benzaldehyde (1a) provided the corresponding alcohol 3ab in excellent functionalised alkenes. The reaction of benzaldehyde with 4-[(tert-butyldimethylsilyl)oxy]-1-butene yield (93%) and good enantioselectivity (77% ee, entry 1). The methodology is also compatible with 4‐phenyl‐1‐butene (2b) with benzaldehyde (1a) provided the corresponding alcohol 3ab in excellent yield (93%) and good enantioselectivity (77% ee, entry 1). The methodology is also compatible with (2c) led to the desired alcohol 3ac in moderate yield (42%) but good enantioselectivity (88% ee, entry functionalised alkenes. The reaction of benzaldehyde with 4‐[(tert‐butyldimethylsilyl)oxy]‐1‐butene yield (93%) and good enantioselectivity (77% ee, entry 1). The methodology is also compatible with (2c) led to the desired alcohol 3ac in moderate yield (42%) but good enantioselectivity (88% ee, entry 2). functionalised alkenes. The reaction of benzaldehyde with 4‐[(tert‐butyldimethylsilyl)oxy]‐1‐butene yield (93%) and good enantioselectivity (77% ee, entry 1). The methodology is also compatible with functionalised alkenes. The reaction of benzaldehyde with 4‐[(tert‐butyldimethylsilyl)oxy]‐1‐butene 2). Similar results were obtained when 4‐halo‐1‐butenes 2d and 2e were used as nucleophiles (entries (2c) led to the desired alcohol 3ac in moderate yield (42%) but good enantioselectivity (88% ee, entry functionalised alkenes. The reaction of benzaldehyde with 4‐[(tert‐butyldimethylsilyl)oxy]‐1‐butene Similar results were obtained when 4-halo-1-butenes 2d and 2e were used as nucleophiles (entries 3 (2c) led to the desired alcohol 3ac in moderate yield (42%) but good enantioselectivity (88% ee, entry functionalised alkenes. The reaction of benzaldehyde with 4‐[(tert‐butyldimethylsilyl)oxy]‐1‐butene (2c) led to the desired alcohol 3ac in moderate yield (42%) but good enantioselectivity (88% ee, entry 3 and 4), providing 3ad and 3ae in moderate yields and 85 and 74% ee, respectively. The use of 5‐ 2). Similar results were obtained when 4‐halo‐1‐butenes 2d and 2e were used as nucleophiles (entries (2c) led to the desired alcohol 3ac in moderate yield (42%) but good enantioselectivity (88% ee, entry and 4), providing 3ad and 3ae in moderate yields and 85 and 74% ee, respectively. The use of 2). Similar results were obtained when 4‐halo‐1‐butenes 2d and 2e were used as nucleophiles (entries (2c) led to the desired alcohol 3ac in moderate yield (42%) but good enantioselectivity (88% ee, entry 2). Similar results were obtained when 4‐halo‐1‐butenes 2d and 2e were used as nucleophiles (entries bromopent‐1‐ene (2f) provided 3af in 31% yield and 81% ee. 3 and 4), providing 3ad and 3ae in moderate yields and 85 and 74% ee, respectively. The use of 5‐ 2). Similar results were obtained when 4‐halo‐1‐butenes 2d and 2e were used as nucleophiles (entries 5-bromopent-1-ene (2f) provided 3af in 31% yield and 81% ee. 3 and 4), providing 3ad and 3ae in moderate yields and 85 and 74% ee, respectively. The use of 5‐ 2). Similar results were obtained when 4‐halo‐1‐butenes 2d and 2e were used as nucleophiles (entries 3 and 4), providing 3ad and 3ae in moderate yields and 85 and 74% ee, respectively. The use of 5‐ bromopent‐1‐ene (2f) provided 3af in 31% yield and 81% ee. 3 and 4), providing 3ad and 3ae in moderate yields and 85 and 74% ee, respectively. The use of 5‐ bromopent‐1‐ene (2f) provided 3af in 31% yield and 81% ee. 3 and 4), providing 3ad and 3ae in moderate yields and 85 and 74% ee, respectively. The use of 5‐ a bromopent‐1‐ene (2f) provided 3af in 31% yield and 81% ee. Table 3. Enantioselective catalysed addition of alkenes to benzaldehyde—Scope of the reaction Table 3. Enantioselective catalysed addition of alkenes to benzaldehyde—Scope of the reaction a .. bromopent‐1‐ene (2f) provided 3af in 31% yield and 81% ee. bromopent‐1‐ene (2f) provided 3af in 31% yield and 81% ee. a Table 3. Enantioselective catalysed addition of alkenes to benzaldehyde—Scope of the reaction . a Entry Product Conv. (%) b Yield (%) c ee (%) d Table 3. Enantioselective catalysed addition of alkenes to benzaldehyde—Scope of the reaction . a. Table 3. Enantioselective catalysed addition of alkenes to benzaldehyde—Scope of the reaction c d b aee Yield (%) Entry Entry Product Table 3. Enantioselective catalysed addition of alkenes to benzaldehyde—Scope of the reaction Conv. (%) a. . (%) Product Conv. (%) b b Yield (%) c c ee (%) d d Table 3. Enantioselective catalysed addition of alkenes to benzaldehyde—Scope of the reaction Yield (%) c 93 ee (%) d 77 (R) Entry 1 e Product Conv. (%) b>99 Entry Product Conv. (%) b Yield (%) c ee (%) d Entry Product Conv. (%) b Yield (%) c ee (%) Yield (%) ee (%) d Entry Product Conv. (%) >99 93 77 (R) 1 e 1 e e >99 93 77 (R) 1 >99 93 77 (R) 1 ee >99 93 77 (R) 1 >99 93 1 e >99 n.d. 93 42 77 (R) 77 (R) 88 (R) 2 2 n.d. 42 88 (R) 2 n.d. 42 88 (R) 2 n.d. 42 88 (R) 2 n.d. 42 88 (R) 2 n.d. 42 88 (R) 2 n.d. 42 88 (R) f g 3 75 (10) 40 85 (R) f g (R) 3 75 (10) 40 85 f 3 75 (10) 40 85 gg (R) f f 3 75 (10) 40 85 40g (R) 85 g (R) 3 75 (10) f 3 75 (10) 40 85 f g (R) 3 75 (10) 40 85 (R) 4 67 41 74 (R) 4 41 74 (R) 67 4 67 41 74 (R) 4 67 41 74 (R) 4 67 41 74 (R) 4 67 41 74 (R) 4 67 61 41 31 74 (R) 81 (R) 5 31 81 (R) 5 61 61 31 81 (R) 5 a Reaction conditions: 1a (0.15 mmol, 1.0 eq.), (R iPr)4 (1.5 eq.), 2 (2.2 61 a,S)‐Ph‐BINMOL (0.2 eq.), Ti(O 31 81 (R) 5 61 31 81 (R) 5 61 31 81 (R) 5 5 61 31 81 (R) c b a Reaction conditions: 1a (0.15 mmol, 1.0 eq.), (R (0.375 M), 35 °C, 5–12 h. iPr) Determined by GC‐MS. eq.), Cp2ZrHCl (2.0 eq.), ZnBr2 (0.5 eq.), DCM 4 (1.5 eq.), 2 (2.2 a Reaction conditions: 1a (0.15 mmol, 1.0 eq.), (R a,S)‐Ph‐BINMOL (0.2 eq.), Ti(O a,S)‐Ph‐BINMOL (0.2 eq.), Ti(OiPr)4 (1.5 eq.), 2 (2.2 a Reaction conditions: 1a (0.15 mmol, 1.0 eq.), (R i d Determined by Chiral b Determined c a,S)‐Ph‐BINMOL (0.2 eq.), Ti(O Pr) 4 (1.5 eq.), 2 (2.2 GC. Configuration based on Isolated yield after flash chromatography. 2ZrHCl (2.0 eq.), ZnBr 2 (0.5 eq.), DCM (0.375 M), 35 °C, 5–12 h. by GC‐MS. eq.), Cp a Reaction conditions: 1a (0.15 mmol, 1.0 eq.), (R i a,S)‐Ph‐BINMOL (0.2 eq.), Ti(O Pr) c aeq.), iPr)44 (1.5 eq.), 2 (2.2 2ZrHCl (2.0 eq.), ZnBr2 (0.5 eq.), DCM (0.375 M), 35 e°C, 5–12 h. bb Determined by GC‐MS. Cp a Reaction i Pr) (1.5 Reaction conditions: 1a (0.15 mmol, 1.0 eq.), (R a,S)‐Ph‐BINMOL (0.2 eq.), Ti(O (1.5 eq.), 2 (2.2 conditions: 1a (0.15 mmol, eq.), (R (0.2 eq.), eq.), 2 (2.2 eq.),on Cpcc 2 ZrHCl a ,S)-Ph-BINMOL d Determined 4 2ZrHCl (2.0 eq.), ZnBr 2 (0.5 eq.), 1.0 DCM (0.375 M), 35 °C, 5–12 h. Ti(O by GC‐MS. eq.), Cpliterature data (see supplementary material for details). Reaction carried out with 3.0 eq. of 2 and 2.8 by Chiral GC. Configuration based Isolated after flash chromatography. b Determined 2yield ZrHCl (2.0 eq.), ZnBr 2 (0.5 eq.), DCM (0.375 M), 35 °C, 5–12 h. Determined by GC‐MS. eq.), Cp d ◦(0.375 b by c Isolatedbased c flash Determined Chiral GC. Configuration on Isolated yield after flash chromatography. (2.0 eq.), after ZnBr (0.5 feq.), DCM (0.375 C, 5–12M), h. 35 Determined byb Determined GC-MS. yield on after 2ZrHCl (2.0 2flash eq.), ZnBr 2 (0.5 eq.), M), DCM °C, 5–12 GC. h. by based GC‐MS. eq.), Cp d35 g Determined e Reaction carried out with 3.0 eq. of 2 and 2.8 Determined by Chiral Configuration Isolated yield chromatography. eq. of Cp 2ZrHCl. 15% of dehydration product 4 was observed by GC‐MS. on the literature data (see supplementary material for details). d d by Chiral GC. based Isolated yield flash chromatography. e Reaction carried out with 3.0 eq. of 2 and 2.8 chromatography. Determined by Chiral GC. Configuration based on literature data (see supplementary material d Determined literature data (see supplementary material for details). Determined by Chiral GC. Configuration Configuration based on on Isolated yield after after flash chromatography. e Reaction carried out with 3.0 eq. of 2 and 2.8 f 15% of dehydration product 4 was g Determined on the literature data (see supplementary material for details). e f corresponding cyclised derivative 6 (see supplementary material for details). eq. of Cp 2 ZrHCl. observed by GC‐MS. e Reaction carried out with 3.0 eq. of 2 and e2.8 eq. of Cp2by ZrHCl. 15%gof dehydration on product literature data (see supplementary material for details). Reaction carried out with 3.0 eq. of 2 and 2.8 eq. of for Cpdetails). 2ZrHCl. f 15% of dehydration product 4 was observed GC‐MS. Determined the 4 was literature data (see supplementary material for details). g Determined on the eq. of Cp 2ZrHCl. 15% of g dehydration 4 was Reaction carried out with 3.0 eq. of 2 and 2.8 observed GC‐MS. observed by fGC-MS. Determined onproduct the corresponding cyclised by derivative 6 (see supplementary material for corresponding cyclised derivative 6 (see supplementary material for details). eq. of Cp 2ZrHCl. f f 15% of dehydration product 4 was observed by GC‐MS. gg Determined on the corresponding cyclised derivative 6 (see supplementary material for details). eq. of As Cp2an ZrHCl. 15% of of dehydration product 4 product was observed by GC‐MS. Determined on the details). corresponding cyclised derivative 6 (see supplementary material for details). application this methodology, 3ad was transformed into its corresponding corresponding cyclised derivative 6 (see supplementary material for details). corresponding cyclised derivative 6 (see supplementary material for details).
tetrahydropyran adduct 6. Tetrahydropyran rings are very important structural moieties, which are As an application of this methodology, product 3ad was transformed into its corresponding As an application of this methodology, product 3ad was transformed into its corresponding As an application of this product 3ad was into its corresponding As an application ofmethodology, this methodology, product 3adtransformed was transformed into its corresponding present in a large variety of natural products such as polyether antibiotics and marine macrocycles tetrahydropyran adduct 6. Tetrahydropyran rings are very important structural moieties, which are As an application of this methodology, product 3ad was transformed into its corresponding tetrahydropyran adduct 6. Tetrahydropyran rings are very important structural moieties, which are As an application of this methodology, product 3ad was transformed into its corresponding tetrahydropyran adduct 6. Tetrahydropyran rings are very important structural moieties, which are tetrahydropyran adduct 6. Tetrahydropyran rings are very important structural moieties, which [112–116]. Additionally, they are also employed in the perfume industry or as flavouring ingredients present in a large variety of natural products such as polyether antibiotics and marine macrocycles tetrahydropyran adduct 6. Tetrahydropyran rings are very important structural moieties, which are present in a large variety of natural products such as polyether antibiotics and marine macrocycles tetrahydropyran adduct 6. Tetrahydropyran rings are very important structural moieties, which are present in a large variety of natural products such as polyether antibiotics and marine macrocycles are present in a large variety of natural products such as polyether antibiotics and marine in the food industry [117]. [112–116]. Additionally, they are also employed in the perfume industry or as flavouring ingredients present in a large variety of natural products such as polyether antibiotics and marine macrocycles [112–116]. Additionally, they are also employed in the perfume industry or as flavouring ingredients present in a large variety of natural products such as polyether antibiotics and marine macrocycles [112–116]. Additionally, they are also employed in the perfume industry or as flavouring ingredients macrocycles [112–116]. Thus, following a straightforward procedure [118], alcohol 3ad was dissolved in dry THF and in the food industry [117]. Additionally, they are also employed in the perfume industry or as flavouring [112–116]. Additionally, they are also employed in the perfume industry or as flavouring ingredients in the food industry [117]. t [112–116]. Additionally, they are also employed in the perfume industry or as flavouring ingredients in the food industry [117]. industry ingredients in the food [117]. treated with 2 eq. of KO Bu at RT. Tetrahydropyran 6 was obtained in 84% yield and 85% ee after Thus, following a straightforward procedure [118], alcohol 3ad was dissolved in dry THF and in the food industry [117]. Thus, following a straightforward procedure [118], alcohol 3ad was dissolved in dry THF and in the food industry [117]. a straightforward procedure [118], alcohol 3ad was dissolved in dry THF and Thus, following a straightforward procedure [118], alcohol 3ad was dissolved in dry THF and t Thus, following purification by column chromatography (Scheme 1). It is worth pointing out that no racemization treated with 2 eq. of KO Bu at RT. Tetrahydropyran 6 was obtained in 84% yield and 85% ee after Thus, following a straightforward procedure [118], alcohol 3ad was dissolved in dry THF and tBu at RT. Tetrahydropyran 6 was obtained in 84% yield and 85% ee after treated with 2 eq. of KO Thus, following a straightforward procedure [118], alcohol 3ad was dissolved in dry THF and tBu at RT. Tetrahydropyran 6 was obtained in 84% yield and 85% ee after treated with 2 eq. of KO treated with 2 eq. KOt Bu at RT. Tetrahydropyran 6 was obtained in 84% yield and 85% ee after occurs during the cyclization [119]. This strategy constitutes a novel and straightforward method for tof purification by column chromatography (Scheme 1). It is worth pointing out that no racemization treated with 2 eq. of KO Bu at RT. Tetrahydropyran 6 was obtained in 84% yield and 85% ee after t purification by column chromatography (Scheme 1). It is worth pointing out that no racemization treated with 2 eq. of KO Bu at RT. Tetrahydropyran 6 was obtained in 84% yield and 85% ee after purification by column chromatography (Scheme 1). It is worth pointing out that no racemization purification by column chromatography (Scheme 1). It is worth pointing out that no racemization the synthesis of chiral tetrahydropyran derivatives via an enantioselective 1,2‐addition of an alkene occurs during the cyclization [119]. This strategy constitutes a novel and straightforward method for purification by column chromatography (Scheme 1). It is worth pointing out that no racemization occurs during the cyclization [119]. This strategy constitutes a novel and straightforward method for purification by column chromatography (Scheme 1). It is worth pointing out that no racemization occurs during the cyclization [119]. This strategy constitutes a novel and straightforward method for occurs during the cyclization [119]. This strategy2 reaction. constitutes a novel and straightforward method for to a carbonyl followed by an intramolecular SN the synthesis of chiral tetrahydropyran derivatives via an enantioselective 1,2‐addition of an alkene occurs during the cyclization [119]. This strategy constitutes a novel and straightforward method for the synthesis of chiral tetrahydropyran derivatives via an enantioselective 1,2‐addition of an alkene occurs during the cyclization [119]. This strategy constitutes a novel and straightforward method for the synthesis of chiral tetrahydropyran derivatives via an enantioselective 1,2‐addition of an alkene to a carbonyl followed by an intramolecular SN 2 reaction. the synthesis of chiral tetrahydropyran derivatives via an enantioselective 1,2‐addition of an alkene to a carbonyl followed by an intramolecular SN2 reaction. the synthesis of chiral tetrahydropyran derivatives via an enantioselective 1,2‐addition of an alkene to a carbonyl followed by an intramolecular SN 2 reaction. to a carbonyl followed by an intramolecular SN to a carbonyl followed by an intramolecular SN22 reaction. reaction.
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the synthesis of chiral tetrahydropyran derivatives via an enantioselective 1,2-addition of an alkene to a carbonyl followed by an intramolecular SN2 reaction. Molecules 2018, 23, x FOR PEER REVIEW 6 of 11
Scheme 1. Formation of the chiral tetrahydropyran 6 from chiral chloroalcohol 3ad. Scheme 1. Formation of the chiral tetrahydropyran 6 from chiral chloroalcohol 3ad.
3. Materials and Methods 3. Materials and Methods General procedure for the catalytic enantioselective 1,2‐addition of alkenes to aldehydes: To a General procedure for the catalytic enantioselective 1,2-addition of alkenes to aldehydes: To stirred 2ZrHCl (77 mg, 0.3 mmol, 2.0 eq.) in dry DCM (0.3 mL) at RT, the a stirredsuspension suspensionof ofCp Cp 2 ZrHCl (77 mg, 0.3 mmol, 2.0 eq.) in dry DCM (0.3 mL) at RT, the corresponding alkene (0.33 mmol, 2.2 eq.) was added dropwise and the solution was stirred at RT for corresponding alkene (0.33 mmol, 2.2 eq.) was added dropwise and the solution was stirred at RT for 30 min. The mixture turned into a clear yellow solution, which indicated the successful formation of 30 min. The mixture turned into a clear yellow solution, which indicated the successful formation of the the organozirconium reagent. flamed‐dried 2 (0.075 mmol, 0.5 eq.) was added into the organozirconium reagent. Next,Next, flamed-dried ZnBr2 ZnBr (0.075 mmol, 0.5 eq.) was added into the solution iPr)4 (0.225 solution and the mixture was stirred at RT for 2 min. Subsequently, a solution of Ti(O i Pr) (0.225 and the mixture was stirred at RT for 2 min. Subsequently, a solution of Ti(O mmol, 1.5 eq.) 4 mmol, 1.5 eq.) and (R a,S)‐Ph‐BINMOL (20 mol %) in dry DCM (0.1 mL) was added and stirred for and (Ra ,S)-Ph-BINMOL (20 mol %) in dry DCM (0.1 mL) was added and stirred for further 2 min at RT. further 2 min at RT. Finally, the aldehyde (0.15 mmol) was added and the solution was stirred at 35 Finally, the aldehyde (0.15 mmol) was added and the solution was stirred at 35 ◦ C for 3–18 h (reaction °C for 3–18 h (reaction was monitored by TLC). (Note that liquid aldehydes were previously distilled was monitored by TLC). (Note that liquid aldehydes were previously distilled before its addition before its addition whilst solid aldehydes were dissolved in dry DCM (0.1 or 0.2 mL depending on whilst solid aldehydes were dissolved in dry DCM (0.1 or 0.2 mL depending on its solubility) and its solubility) and added to the solution.) The reaction was quenched by the addition of water (1 mL). added to the solution.) The reaction was quenched by the addition of water (1 mL). The layers were The layers were separated, and the aqueous layer was extracted with Et O (3 × 10 mL). The combined separated, and the aqueous layer was extracted with Et2 O (3 × 10 mL). 2The combined organic layers organic layers were dried with anhydrous MgSO 4, filtered, and concentrated under vacuum. The were dried with anhydrous MgSO4 , filtered, and concentrated under vacuum. The crude reaction crude reaction product was purified by flash silica gel chromatography. product was purified by flash silica gel chromatography. 4. Conclusions 4. Conclusions In conclusion, we and efficient efficient procedure procedure for for the the titanium-assisted titanium‐assisted In conclusion, we have have developed developed a a new new and catalytic asymmetric addition of alkylzirconium reagents to aromatic aldehydes, based on the use of catalytic asymmetric addition of alkylzirconium reagents to aromatic aldehydes, based on the use of a readily available Ar‐BINMOL ligand and ZnBr a readily available Ar-BINMOL ligand and ZnBr2. The alkylzirconium nucleophiles are generated in 2 . The alkylzirconium nucleophiles are generated situ by by hydrozirconation of ofalkenes premade in situ hydrozirconation alkeneswith withSchwartz Schwartzreagent, reagent,thus thusavoiding avoidingthe the use use of of premade organometallic reagents. The reaction—which proceeds under mild conditions and industrially organometallic reagents. The reaction—which proceeds under mild conditions and industrially relevant temperatures—allows the corresponding chiral chiral secondary secondary alcohols alcohols in in relevant temperatures—allows the synthesis synthesis of of the the corresponding moderate to good yields (32–93%) and good to excellent enantioselectivities (76–91% ee). It is worth moderate to good yields (32–93%) and good to excellent enantioselectivities (76–91% ee). It is worth mentioning several functional functional groups in mentioning that that the the methodology methodology is is compatible compatible with with the the presence presence of of several groups in both the aldehyde (including halogens, ketone, cyano, and trifluoromethyl) and the alkene (including both the aldehyde (including halogens, ketone, cyano, and trifluoromethyl) and the alkene (including halogens and TBS protected alcohol). The usefulness of this novel method has been demonstrated halogens and TBS protected alcohol). The usefulness of this novel method has been demonstrated with with the enantioselective synthesis of a chiral tetrahydropyran by a subsequent intramolecular the enantioselective synthesis of a chiral tetrahydropyran by a subsequent intramolecular cyclization cyclization on a functionalised addition product. on a functionalised addition product. Supplementary Materials: Experimental Experimental methods and spectroscopic for new compounds are available Supplementary Materials: methods and spectroscopic datadata for new compounds are available online. online. Acknowledgments: B.M. thanks the European Commission for a Marie Curie Career Integration Grant, the EPSRC for a First Grant and B.M. the R.S. for a the travel grant. G.P. Howell is thanked for helpful comments on the manuscript. Acknowledgments: thanks European Commission for a Marie Curie Career Integration Grant, the EPSRC for a First Grant R.S., and M.V., the R.S. for a travel grant. conceived G.P. Howell is thanked for comments the Author Contributions: B.M., and M.A.F.-I. and designed thehelpful experiments; R.S.,on M.V., M.J.G.-S., and N.C. performed the experiments and analyzed the data; B.M. and M.A.F.-I. contributed manuscript. reagents/materials/analysis tools and wrote the paper. Author Contributions: R.S., M.V., B.M., and M.A.F.‐I. conceived and designed the experiments; R.S., M.V., Conflicts of Interest: The authors declare no conflict of interest. M.J.G.‐S., and N.C. performed the experiments and analyzed the data; B.M. and M.A.F.‐I. contributed reagents/materials/analysis tools and wrote the paper. Conflicts of Interest: The authors declare no conflict of interest.
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