Catalytic Enantioselective Addition of Organozirconium Reagents to

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Apr 20, 2018 - are required since the alkylzirconium nucleophiles are generated in situ by ... via (in situ) hydrozirconation of alkenes using Schwartz reagent ...

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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



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). 

Molecules 2018, 23, 961 Molecules 2018, 23, x FOR PEER REVIEW   

Molecules 2018, 23, x FOR PEER REVIEW    Molecules 2018, 23, x FOR PEER REVIEW    Molecules 2018, 23, x FOR PEER REVIEW    Molecules 2018, 23, x FOR PEER REVIEW    Molecules 2018, 23, x FOR PEER REVIEW   

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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. 

Molecules 2018, 23, 961

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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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