Enantioselective ethylation of aldehydes with 1,3-N-donor ligands derived from (+)-camphoric acid

Tetrahedron: Asymmetry 21 (2010) 62–68

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Enantioselective ethylation of aldehydes with 1,3-N-donor ligands derived from (+)-camphoric acid Dina Murtinho *, M. Elisa Silva Serra, A. M. d’A. Rocha Gonsalves Departamento de Química, Faculdade de Ciências e Tecnologia, Universidade de Coimbra, 3004-535 Coimbra, Portugal

a r t i c l e

i n f o

Article history: Received 5 November 2009 Accepted 21 December 2009 Available online 11 January 2010

a b s t r a c t Derivatives of (+)-camphoric acid were prepared by a short and simple synthetic sequence and proved to be excellent ligands for the enantioselective ethylation of benzaldehyde with diethylzinc, with ees of up to 96% being obtained. The most efficient ligand was tested with several aromatic aldehydes and ees of up to 99% were observed. Structural features of the ligands are determinant for achieving high enantioselectivities. Ó 2009 Elsevier Ltd. All rights reserved.

1. Introduction The alkylation of aldehydes with dialkylzinc allows for the synthesis of chiral secondary alcohols, essential components in the preparation of pharmaceuticals, agrochemicals and perfumes, amongst others.1–3 Although many types of ligands have been used for the enantioselective alkylation of aldehydes, amino alcohols are the most currently used. Diamine ligands and derivatives have received less attention, although there are various examples of good ees obtained with this type of ligands.4–9 A considerable amount of work has been reported in the literature on the use of 1,2-bidentate ligands, while 1,3- and 1,4-bidentate ligands have been less used and studied.10–12 In contrast to 1,2-ligands, which form a five-membered chelate with the zinc atom in the transition state, 1,3- and 1,4-ligands form conformationally flexible six- or seven-membered catalytic chelates with the Zn atom. In these types of ligands, the rigidity of the structure is of particular importance in order to limit the conformational freedom of the catalytic species.12,13 Ligands with rigid skeletons, such as cyclic or bicyclic structures, are good candidates to be used. Our approach to the development of new ligands for asymmetric catalysis, namely for the enantioselective alkylation and trimethylsilylcyanation of aromatic aldehydes,14,15 was based on the use of (+)-camphoric acid as the source of chirality for the synthesis of salen ligands for the trimethylsilylcyanation of benzaldehyde.16 (+)-Camphoric acid allows the preparation of a 1,3-diamine directly in one step, by the Schmidt reaction. This diamine can easily be converted into several derivatives, namely sulfonamide and

* Corresponding author. Tel.: +351 239854478; fax: +351 239827703. E-mail address: [email protected] (D. Murtinho). 0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetasy.2009.12.012

amide type ligands, via one or two additional steps. Synthetic procedures leading to chiral ligands are often laborious, hence the development of short and simple synthetic sequences is of added value in the design of new ligands. Although a great number of N,N0 -disulfonated and diacylated chiral amines have been tested in the enantioselective alkylation with diethylzinc, especially in the presence of Ti(OiPr)4,17–20 there are fewer reports in the literature on the use of monosulfonated or monoacylated amines.1,7,21,22 Urabe et al.23 reported the use of a dialkylated diamine, a diamide and some dialkylaminoamides derived from (+)-camphoric acid in the reaction of benzaldehyde with several organometallic reagents, including diethylzinc. The best result (81% yield, 93% ee) was obtained with ligand 9, in the alkylation of benzaldehyde with diethylzinc, at 0 °C, using toluene as a solvent. To the best of our knowledge this is the only study that reports the use of diamine type (+)-camphoric acid derivatives in the enantioselective alkylation of aldehydes with diethylzinc. 2. Results and discussion 2.1. Ligands synthesis Diamine 1 [(1R,3S)-1,3-diamino-1,2,2-trimethylcyclopentane] was prepared from commercial (+)-camphoric acid, according to a previously described procedure.24 Monosulfonamides 2 and 3 were obtained by the reaction of 1 equiv of tosyl chloride or (+)-camphorsulfonyl chloride, respectively, with an excess of diamine 1, in ethanol, at room temperature. Aminoamide 4 and aminocarbamate 5 were synthesized in an analogous way, using benzoyl chloride and benzyl chloroformate, respectively (Scheme 1). The substitution occurs preferentially at the amine group with less steric hindrance, which allows for the introduction of different substituents at the two amino groups.

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NaN3/H2SO4

COOH

HOOC

H2 N

CHCl3 55-60 ºC

NH2

(1R ,3 S )-1 R= RCl H3C

EtOH, rt

SO 2

2

3

O SO 2

RHN

O

NH2

O

(1S,3R)-2-5

O

4

5 Scheme 1. Synthesis of chiral ligands.

Disulfonamides 6 and 7 were prepared by the reaction of diamine 1 with 2.2 equiv of the corresponding sulfonyl chloride, in the presence of triethylamine, Scheme 2.

RCl, NEt3

NH2

H2 N

RHN

CH2Cl2, rt

NHR

(1R,3S)-6-7

(1R,3S)-1

R=

2.2. Enantioselective alkylations

H3C

SO2

7 O

6

SO 2

Scheme 2. Synthesis of chiral disulfonamides.

Dimethylation of compounds 2, 4 and 5, with formic acid and formaldehyde, according to a described procedure,23 gave ligands 8–10, Scheme 3.

RHN

NH2

HCOOH/HCHO RHN

reflux

(1S,3R)-2,4,5

N(CH3)2

(1S,3R)-8,9,10 O

O O

SO 2

R= 8

Ligand 11 was obtained from compound 4 by alkylation with ethyl iodide in refluxing ethanol, using potassium carbonate as a base (Scheme 4). The corresponding diethylated ligand 12 proved more difficult to synthesize: the resulting product was always a mixture of mono and diethylated compounds. Attempts to improve the yield of the diethylated compound by using a large excess of ethyl iodide or dimethylformamide as a solvent did not lead to a significant improvement in yield. Therefore, this compound was prepared in refluxing ethanol using a 10-fold excess of ethyl iodide. Ligand 7 was reduced with L-selectrideÒ, using a described procedure,20 in order to obtain the exo compound 13, Scheme 5. Our first attempt to prepare ligand 14, by reaction of 3 and ethyl iodide, always gave low yields and a mixture of product and reagent, which were difficult to separate by column chromatography on silica gel. We therefore decided to prepare this ligand starting from compound 11. Hydrolysis of the benzoyl group followed by reaction with (1S)-(+)-10-camphorsulfonyl chloride allowed us to obtain the desired product 15 (Scheme 6). Ligands 4 and 9 are known compounds, prepared by Urabe et al.23 Ligand 4, as far as we know, has not been tested in the enantioselective alkylation of benzaldehyde; ligand 9 was used for comparative purposes. All ligands were obtained with moderate to good yields.

9

10

Scheme 3. Synthesis of the dimethylated ligands.

We began to test our ligands in the enantioselective alkylation of benzaldehyde with diethylzinc, using our previously optimized conditions.25 The reactions were carried out in dry cyclohexane at 0 °C in the presence of 15% chiral ligand (Scheme 7). The results obtained are shown in Table 1. All ligands tested proved to be efficient in promoting the ethylation reaction, with conversions ranging from 34% to 98%. For some ligands, in addition to the desired chiral alcohol, 1-phenyl1-propanol, benzyl alcohol was formed as a by-product. The formation of benzyl alcohol has been observed by others and is the result of a secondary process in which benzaldehyde is reduced by the zinc alkoxide of the ethylation product, 1-phenyl-1-propanoxide.26 The results shown in Table 1, with respect to ligands 2–4 with only one substituted amine group, suggest that higher conversions and low reactions times are obtained when an amido rather than a sulfonyl group is present in the ligand. An improved enantiomeric excess (75%) was obtained with ligand 3, due to the two additional stereogenic centres from the camphorsulfonyl moiety. Lower conversions and ee were obtained with disulfonamides 6 and 7 due to the presence of two bulky substituent groups. The presence of a less sterically demanding dimethyl substituent, as in ligands 8– 10, allows for an improvement in conversions, amount of chiral product and ee. The presence of a carbamate group is more bene-

O N H

NHEt

O N H

NH2

EtI, K2CO3 EtOH, reflux

(1S,3R)-4

(1S,3R)-11 O

N H

(1S,3R)-12 Scheme 4. Synthesis of the ethylated ligands.

NEt2

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D. Murtinho et al. / Tetrahedron: Asymmetry 21 (2010) 62–68

O O

O S N O H

NH

S O O

(1R,3S)-7

-78º C (1h), rt (2h)

L-Selectride®

HO O

O S N O H

NH

S O OH

(1R,3S)-13

Scheme 5. Synthesis of disulfonamide 13.

O

HCl/H2O N H

NHEt

reflux

H2N

(1S,3R)-11

NHEt

(1R,3S)-14 SO2Cl

K2CO3, EtOH

O O

O S

NHEt

N O H

(1S,3R)-15 Scheme 6. Synthesis of ligand 15.

OH

O H

+

15 mol% ligand

Et2Zn

Cyclohexane, 0 ºC

Scheme 7. Asymmetric addition of diethylzinc to benzaldehyde.

Table 1 Enantioselective alkylation of benzaldehyde catalyzed by 2–4, 6–13, 15a Ligand

Time (h)

2 3 4 6 7 8 9 10 11 12 13 15

24 24 6 24 24 24 6 6 6 24 24 6

Conversionb (%)

1-Phenyl-1-propanolc (%)

52 48 90 49 52 72 98 97 95 34 57 90

53 89 100 64 90 78 96 100 100 52 67 100

eed (%) 41 75 68 21 62 57 90 76 96 37 21 92

(S) (S) (S) (S) (S) (S) (S)e (S) (S) (S) (S) (S)

a Reactions were carried out in cyclohexane, at 0 °C, using 0.15 mmol of chiral ligand, 1 mmol of benzaldehyde and 2 mmol of diethylzinc (1 M in hexane). b Determined by GC. c Relative to converted benzaldehyde. d Determined by GC on a chiral column; the major enantiomer is indicated in parentheses. e Ligand described by Urabe et al. (under their conditions 81% yield, 93% ee).

ficial than a sulfonyl group, but the ee is lower in comparison to when an amide group is present. With these results in hand, we decided to prepare ligands 11 and 12 with one amide moiety and one or two ethyl substituent groups in order to introduce a slightly more bulky group than methyl to determine if the enantioselectivity of the process could be improved upon. The presence of one ethyl group turned out to be beneficial in terms of ee. With this ligand the reaction is very fast, with a conversion of 95% after 6 h, no formation of the benzyl alcohol and an ee of 96%. The presence of two ethyl groups seems detrimental. The conversion is very low, indicating that the zinc does not coordinate properly with the ligand, possibly due to its excessive steric bulk. Moreover, compound 13, a tetradentate ligand obtained by reduction of the carbonyl groups of ligand 7, showed low enantioselectivity, probably because it requires the presence of titanium. Similarly to ligand 11, the presence of an ethyl group in ligand 15 reduces the reaction time and drastically improves the conversion, chiral product formation and enantiomeric excess (90%, 100% and 92%, respectively) of the catalytic process. Consequently, it seems that the presence of one ethyl group is highly advantageous for this type of ligand. Using our best ligand, 11, we tested other reaction solvents: toluene, ethyl ether and dichloromethane. The catalyst loading was also studied. The results are summarized in Table 2. The best solvent for ligand 11 was found to be cyclohexane, as shown in Table 2. The best results in terms of conversion and ee were obtained with non-coordinating solvents, cyclohexane and toluene. Decreasing the ligand loading resulted in a slight decrease in reaction conversion. With 5 mol % ligand 11, an ee of 95% and a conversion of 90% were obtained. The good results obtained with ligand 11 led us to examine its efficiency with a series of other aldehydes using our best reaction conditions (0 °C, 15 mol % catalyst and cyclohexane as solvent). The results are shown in Table 3. All aldehydes showed good conversions. With the exception of o-chlorobenzaldehyde, all of the ee were excellent. In all cases, the absolute configuration of the major enantiomer was assigned as (S) by comparison of the retention times with reported values or by determining the sign of the specific rotation of the isolated reaction.27–29 Even bulky substrates, such as 1- and 2-naphthaldehyde gave excellent ee, 96% and 92%, respectively. The best ee was obtained for m-methylbenzaldehyde, 99%. Attempts to alkylate aliphatic aldehydes, such as dodecanal in the presence of ligand 11 were unsuccessful. Only 16% conversion was obtained after a reaction time of 24 h.

3. Conclusion A new series of 1,3-chiral ligands has been easily prepared from natural (+)-camphoric acid, in a two- or three-step sequence. The ligands were tested in the enantioselective ethylation of benzaldehyde, showing excellent enantioselectivities (up to 96%). Some structural features of the ligands are determinant in order to achieve high enantioselectivities, namely the presence of a bulky substituent in the amine group with less steric hindrance, at the 3-position of the cyclopentane ring, and an ethyl substituent in the amino group with more steric hindrance. The use of our best ligand, 11, for the alkylation of other aromatic aldehydes with diethylzinc showed excellent ee (up to 99% for m-methylbenzaldehyde). Further studies are currently in progress in order to extend the application of these and other (+)-camphoric acid derived ligands to other useful asymmetric transformations.

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D. Murtinho et al. / Tetrahedron: Asymmetry 21 (2010) 62–68 Table 2 Asymmetric ethylation of benzaldehyde catalyzed by 11, with various solvents and catalyst loadingsa Solvent Cyclohexane Diethyl ether Dichloromethane Toluene Cyclohexane Cyclohexane a b c d

Catalyst (mol %)

Conversionb (%)

1-Phenyl-1-propanolc (%)

15 15 15 15 10 5

95 40 55 76 91 90

100 99 100 100 100 100

eed (%) 96 92 91 95 95 95

(S) (S) (S) (S) (S) (S)

Reactions were carried out at 0 °C for 6 h, using 1 mmol of benzaldehyde and 2 mmol of diethylzinc (1 M in hexane). Determined by GC. Relative to converted benzaldehyde. Determined by GC on a chiral column; the major enantiomer is indicated in parentheses.

reported values and by determining the sign of the specific rotation of the isolated reaction.

Table 3 Asymmetric ethylation of different aldehydes catalyzed by 11a Aldehyde o-Methylbenzaldehyde m-Methylbenzaldehyde p-Methylbenzaldehyde m-Methoxybenzaldehyde o-Chlorobenzaldehyde p-Chlorobenzaldehyde p-Nitrobenzaldehyde 1-Naphthaldehyde 2-Naphthaldehyde

Conversionb (%) 73 88 87 82 95 100 92 70 71

eec (%) 92 99 95 92 72 93 90 96 92

(S) (S) (S) (S) (S) (S) (S) (S) (S)

a Reactions were carried out at 0 °C for 6 h, using 1 mmol of aldehyde and 2 mmol of diethylzinc (1 M in hexane). b Determined by GC. c Determined by GC on a chiral column.

4. Experimental 4.1. General Commercially available compounds were used without further purification. All solvents were dried prior to use following standard procedures. Diethylzinc (Aldrich) was used as a 1 M solution in hexane. Benzaldehyde was distilled prior to use and stored over 4 Å molecular sieves. Melting points were determined using a Electrothermal Melting Point Apparatus (values are uncorrected). Optical rotations were measured with an Optical Activity AA-5 polarimeter. NMR spectra were recorded on a Bruker AMX 300 (300 and 75.5 MHz for 1H and 13C, respectively) or a Bruker Avance III 400 MHz (100 MHz for 13C). TMS was used as the internal standard and chemical shifts are given in ppm. Elemental analyses were carried out on a Fisons Instruments EA 1108 CHNS-O elemental analyzer. GC analyses were recorded on an HP 5890A instrument coupled to an HP 3396A integrator using a capillary column (Supelcowax 10, 30 m, 0.25 i.d., 0.25 lm). Infrared spectra were recorded on a Thermo Scientific Nicolet 6700 FTIR. Mass spectra were recorded on an HP 5973 MSD chromatograph with 70 eV (EI), Agilent 6890 series, equipped with an HP-5MS column (30 m d 0.25 mm d 0.25 lm) or on a Fisons Instruments-Platform with an APCI probe coupled to a Thermo Separation Spectra Series P200 chromatograph. Alkylation reactions were carried out under an inert atmosphere using standard Schlenk-type techniques. Reaction products were identified by comparison with authentic commercially acquired samples and by GC/MS analysis. Catalytic experiments were repeated in order to confirm the results. Enantiomeric excesses were determined by using a chiral c-cyclodextrin capillary column (FS-Lipodex-E, 25 m, 0.25 i.d.) from Machery-Nagel using hydrogen as carrier gas, on an HP 5890A instrument coupled to an HP 3396A integrator. The absolute configuration of the major enantiomers was determined by comparison of the retention times with

4.2. Synthesis of chiral ligands The syntheses of compounds 1, 4 and 9 have already been described.23,24 4.2.1. General procedure for the synthesis of compounds 2–5 To a stirred solution of diamine 1 (1.42 g, 10 mmol) in dry ethanol (25 mL) was added, at 0 °C under an inert atmosphere, a solution of the sulfonyl chloride, benzoyl chloride or benzyl chloroformate (4 mmol) in dry ethanol (20 mL). The reaction mixture was stirred overnight at room temperature. The solvent was evaporated and the reaction mixture was treated with NaHCO3 (saturated solution) to basic pH. The aqueous phase was extracted three times with dichloromethane and the joint organic phases were washed with water, brine and dried over anhydrous Na2SO4. After evaporating the solvent, the product was purified as described below. 4.2.1.1. N-((1S,3R)-3-Amino-2,2,3-trimethylcyclopentyl)-4methylbenzenesulfonamide 2. The product was purified by silica gel column chromatography (dichloromethane/methanol 90:10) to afford a white solid, which was recrystallized from CH2Cl2/hexane (56%). Mp 59–61 °C; ½a25 D ¼ þ15 (c 1.0, CH2Cl2). IR (KBr, cm1): 3125, 2958, 2925, 1400, 1315, 1154, 1094, 664, 559. 1 H NMR (400 MHz, CDCl3) d: 0.81 (s, 3H), 0.91 (s, 3H), 1.07 (s, 3H), 1.39–1.51 (m, 2H), 1.62–1.70 (m, 1H), 1.90–1.94 (m, 1H), 2.41 (s, 3H), 3.35–3.39 (m, 1H), 7.26 (d, 2H, J 8.1), 7.73 (d, 2H, J 8.1). 13C NMR (100 MHz, CDCl3) d: 17.13, 21.50, 24.63, 26.14, 37.84, 47.53, 61.88, 63.92, 126.85, 129.44, 139.46, 142.49. GC–MS (EI) m/z: 296 (M+, 1%), 225 (5), 155 (8), 126 (100), 110 (24), 91 (27), 70 (35), 57 (11). HRMS (EI+, [M+H]+) m/z: calcd for (C15H25N2O2S) 297.1637; found 297.1639. 4.2.1.2. N-((1S,3R)-3-Amino-2,2,3-trimethylcyclopentyl)-1((1S)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonamide 3. The product was purified by silica gel column chromatography (dichloromethane/methanol 95:5) to afford a white solid (63%). Mp 170 °C (sublimes); ½a25 D ¼ þ45 (c 1.0, CH2Cl2). IR (KBr, cm1): 3377, 3303, 2962, 1738, 1722, 1456, 1419, 1333, 1321, 1150, 1095, 1055, 888, 569, 529. 1H NMR (400 MHz, CDCl3) d: 0.89 (s, 3H), 0.90 (s, 3H), 1.00 (s, 3H), 1.11 (s, 3H), 1.12 (s, 3H), 1.38–1.50 (m, 3H), 1.56–1.64 (m, 1H), 1.68– 1.84 (m, 3H); 2.00–2.10 (m, 2H), 2.23–2.32 (m, 1H), 2.35–2.42 (m, 1H), 2.47–2.55 (m, 1H), 2.90 (d, 1H, J 14.8) 3.45 (d, 1H, J 14.8), 3.54 (d, 1H, J 6.8). 13C NMR (100 MHz, CDCl3) d: 17.39, 19.85, 20.00, 24.38, 25.27, 26.16, 26.94, 30.76, 37.83, 42.72, 42.79, 47.30, 47.94, 51.03, 58.79, 61.86, 63.97, 215.76. GC–MS (EI) m/z: 356 (M+, 2%), 339 (14), 215 (70), 151 (26), 124 (100), 108 (85), 93 (18), 81 (27), 67 (18), 55 (16). HRMS (EI+, [M+H]+) m/z: calcd for (C18H33N2O3S) 357.2212; found 357.2209.

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4.2.1.3. N-((1S,3R)-3-Amino-2,2,3-trimethylcyclopentyl)benzamide 4. The product was purified by silica gel column chromatography (diethyl ether/triethylamine 80:2) to afford a low 1 H NMR melting solid (90%). ½a25 D ¼ þ80 (c 1.5, CH2Cl2). (400 MHz, CDCl3) d: 0.95 (s, 3H), 0.96 (s, 3H), 1.16 (s, 3H), 1.54– 1.65 (m, 2H), 1.82–1.89 (m, 1H), 2.25–2.34 (m, 1H), 4.36 (approx. t, 1H, J 8.4), 7.38–7.45 (m, 3H), 7.78–7.80 (m, 2H), 8.75 (d, 1H, J 7.8). 4.2.1.4. Benzyl (1S,3R)-3-amino-2,2,3-trimethylcyclopentylcarbamate 5. The product was purified by silica gel column chromatography (dichloromethane/methanol 95:5) to afford an oil (81%). The product was used directly in the next step. 1H NMR (400 MHz, CDCl3) d: 0.88 (s, 6H), 1.09 (s, 3H), 1.49–1.60 (m, 2H), 1.66–1.78 (m, 1H), 2.15–2.25 (m, 1H), 3.82–3.87 (m, 1H), 5.06 (d, 1H, J 12.6), 5.10 (d, 1H, J 12.6), 6.57 (d, 1H, J 9.2), 7.26–7.35 (m, 5H). 4.2.2. General procedure for the synthesis of compounds 6 and 7 To a stirred solution of diamine 1 (0.71 g, 5 mmol) in dry dichloromethane (50 mL) and triethylamine (1.53 mL, 11 mmol) was added, at 0 °C in an inert atmosphere, a solution of the sulfonyl chloride (11 mmol) in dry dichloromethane (20 mL). The reaction mixture was stirred overnight at room temperature. The reaction mixture was extracted with HCl 2 M and water. The organic phase was dried over anhydrous Na2SO4. After evaporating the solvent, the product was purified as described below. 4.2.2.1. N,N0 -((1R,3S)-1,2,2-Trimethylcyclopentane-1,3-diyl)bis(4-methylbenzene-sulfonamide) 6. The product was recrystallized in CHCl3/hexane to give a white solid (35%). Mp 1 ): 3585, 205–206 °C; ½a25 D ¼ þ30 (c 0.5, CHCl3). IR (KBr, cm 3501, 3246, 2973, 2590, 1455, 1318, 1303, 1160, 1134, 1094, 1079, 816, 708. 1H NMR (300 MHz, CDCl3) d: 0.79 (s, 3H), 0.88 (s, 3H), 0.92–1.04 (m, 1H), 1.09 (s, 3H), 1.47–1.57 (m, 1H), 1.64–1.77 (m, 1H), 2.05–2.15 (m, 1H), 2.41 (s, 3H), 2.43 (s, 3H), 3.25–3.34 (m, 1H), 4.49 (s, 1H), 5.50 (d, 1H, J 10.0), 7.25–7.31 (m, 4H), 7.66 (d, 2H, J 8.3), 7.74 (d, 2H, J 8.3). 13C NMR (75.5 MHz, CDCl3) d: 17.61, 21.47, 21.69, 23.06, 28.45, 33.04, 48.42, 60.81, 68.39, 76.68, 126.98, 127.01, 129.62, 129.71, 138.22, 140.06, 143.26, 143.30. LC–MS (ES+) m/z: 451 [(M+1)+, 100%], 434 (37), 375 (38), 345 (27). Anal. Calcd for C22H30N2S2O41/2H2O: C, 57.49; H, 6.80; N, 6.09; S, 13.95. Found: C, 57.12; H, 6.54; N, 6.41; S, 13.40. 4.2.2.2. N,N0 -((1R,3S)-1,2,2-Trimethylcyclopentan-1,3-diyl)-bis((1S)-(7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonamide 7. The product was recrystallized in CH2Cl2/ hexane to give a white solid (48%). Mp 184 °C (sublimes); 1 ): 3244, 2968, 1732, ½a25 D ¼ þ40 (c 1.0, CH2Cl2). IR (KBr, cm 1456, 1418, 1395, 1328, 1146, 1080, 1052, 1017, 594, 577. 1H NMR (300 MHz, CDCl3) d: 0.90 (s, 3H), 0.92 (s, 3H), 1.00 (s, 3H), 1.02 (s, 3H), 1.04 (s, 3H), 1,07 (s, 3H), 1.43 (s, 3H) 1.90–2.18 (m, 12H), 2.29–2.47 (m, 6H), 2.92 (d, 1H, J 6.2), 2.97 (d, 1H, J 6.2), 3.44 (d, 1H, J 15.0), 3.55 (d, 1H, J 15.0), 3.61–3.70 (m, 1H), 5.35 (d, 1H, J 9.2), 5.71 (s, 1H). 13C NMR (100 MHz, CDCl3) d: 17.77, 19.48, 19.73, 19.93, 19.97, 22.18, 23.12, 26.21, 26.33, 26.97, 27.02, 29.72, 34.27, 42.70, 42.78, 42.84, 42.94, 48.42, 48.66, 49.03, 51.38, 53.93, 59.10, 59.37, 61.11, 67.33, 216.26, 218.07. Anal. Calcd for C28H46N2O6S2: C, 58.92; H, 8.12; N, 4.91. Found: C, 58.75; H, 8.27; N, 4.72. 4.2.3. General procedure for the synthesis of compounds 8–10 To 2 mL (50 mmol) of 98% formic acid, cooled in an ice bath, was slowly added compound 2, 4 or 5 (10 mmol). To the resulting mixture were added 2.5 mL (30 mmol) of a formaldehyde solution (34%) and was stirred at reflux overnight. The solution was cooled,

7.5 mL of HCl 2 M were added and the solution was evaporated under reduced pressure. The residue was dissolved in water and NaOH 15% was added to basic pH. The resulting mixture was extracted several times with dichloromethane. The joint organic phases were dried over anhydrous Na2SO4. After evaporating the solvent, the product was purified as described below. 4.2.3.1. N-((1S,3R)-3-(Dimethylamino)-2,2,3-trimethylcyclopentyl)-4-methylbenzene-sulfonamide 8. The product was recrystallized in CH2Cl2/hexane. A white solid was obtained (44%). Mp 191 °C (sublimes); ½a25 D ¼ þ20 (c 1.0, CH2Cl2). IR (KBr, cm1): 3292, 3251, 2969, 2820, 2777, 1438, 1345, 1323, 1161, 1077, 914, 817, 667, 566, 550. 1H NMR (300 MHz, CDCl3) d: 0.84 (s, 3H), 0.89 (s, 3H), 0.95 (s, 3H), 1.38–1.47 (m, 1H), 1.61–1.80 (m, 3H), 2.16 (s, 6H), 2.42 (s, 3H), 3.35–3.38 (m, 1H), 4.60 (d, 1H, J 10.1), 7.29 (d, 2H, J 8.2), 7.75 (d, 2H, J 8.2). 13C NMR (100 MHz, CDCl3) d: 11.21, 17.18, 21.54, 22.43, 27.55, 36.53, 40.14, 47.25, 62.46, 66.18, 126.99, 129.63, 138.41, 143.17. GC–MS (EI) m/z: 324 (M+, 2%), 169 (6), 154 (100), 98 (21), 86 (13), 69 (7), 56 (6). Anal. Calcd for C17H28N2O2S: C, 62.93; H, 8.70; N, 8.63; S, 9.88. Found: C, 62.76; H, 9.08; N, 8.37; S, 10.38. 4.2.3.2. N-((1S,3R)-3-(Dimethylamino)-2,2,3-trimethylcyclopentyl)benzamide 9. The product was recrystallized in CH2Cl2/ hexane to give a white solid (96%). Mp 141–143 °C (lit. 135– 23 1 H 137 °C); ½a25 D ¼ þ25 (c 1.0, CH2Cl2); [lit. +30 (c 0.6, CHCl3)]. NMR (300 MHz, CDCl3) d: 1.02 (s, 3H), 1.03 (s, 3H), 1.06 (s, 3H), 1.40–1.50 (m, 1H), 1.60–1.69 (m, 1H), 1.91–1.97 (m, 1H), 2.10– 2.23 (m, 1H), 2.25 (s, 6H), 4.47 (q, 1H, J 9.4), 6.48 (d, 1H, J 9.4), 7.41–7.50 (m, 3H), 7.75–7.78 (m, 2H). 4.2.3.3. Benzyl (1S,3R)-3-(dimethylamino)-2,2,3-trimethylcyclopentylcarbamate 10. The product was purified by silica gel column chromatography (diethyl ether/triethylamine 80:2) to afford the product as an oil (55%). ½a25 D ¼ þ20 (c 1.0, CH2Cl2). IR (KBr, cm1): 2966, 1702, 1535, 1396, 1243, 1221, 1049, 1028, 737, 697. 1H NMR (400 MHz, CDCl3) d: 0.89 (s, 3H), 0.96 (s, 3H), 1.02 (s, 3H) 1.27–1.36 (m, 1H), 1.52–1.59 (m, 1H), 1.80–1.88 (m, 1H), 1.90–2.10 (m, 1H), 2.20 (s, 6H), 3.96 (q, 1H, J 9.6), 4.75 (d, 1H, J 9.6), 5.06 (d, 1H, J 12.4), 5.12 (d, 1H, J 12.4), 7.33–7.37 (m, 5H). 13C NMR (100 MHz, CDCl3) d: 11.14, 14.14, 17.06, 22.66, 26.85, 36.65, 40.11, 47.14, 59.59, 66.52, 66.70, 128.13, 128.16, 128.54, 136.58, 156.35. GC–MS (EI) m/z: 304 (M+, 8%), 289 (3), 154 (87), 98 (100), 91 (37), 85 (43), 56 (10). HRMS (EI+, [M]+) m/ z: calcd for (C18H28N2O2) 304.2151; found 304.2137. 4.2.4. General procedure for the synthesis of compounds 11–12 A mixture of compound 4 (2.46 g, 10 mmol), K2CO3 (5.5 g, 40 mmol) and ethyl iodide (3.23 mL, 40 mmol for compound 11 and 8.12 mL, 100 mmol for compound 12), in dry ethanol (60 mL) was refluxed for 24 h. The resulting solution was cooled to room temperature and the solvent evaporated under reduced pressure. Water and dichloromethane were added and the aqueous phase was extracted several times with dichloromethane. The combined organic phases were dried over anhydrous Na2SO4. The products were purified as described below. 4.2.4.1. N-((1S,3R)-3-(Ethylamino)-2,2,3-trimethylcyclopentyl)benzamide 11. The product was purified by silica gel column chromatography using diethyl ether as eluent to give a white solid (67%). Mp 128–129 °C; ½a25 D ¼ þ60 (c 1.0, CH2Cl2). IR (KBr, cm1): 3293, 2960, 2868, 1650, 1579, 1520, 1483, 1351, 703. 1H NMR (400 MHz, CDCl3) d: 0.95 (s, 3H), 0.99 (s, 3H), 1.08 (s, 3H), 1.16 (t, 3H, J 7.1), 1.51–1.60 (m, 2H), 1.68–1.71 (m, 1H), 1.94– 2.06 (m, 1H), 2.27–2.34 (m, 1H), 2.56–2.61 (m, 1H), 2.65–2.71 (m, 1H), 4.30 (approx. t, 1H, J 8.4), 7.39–7.51 (m, 3H), 7.78–7.80

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(m, 2H), 8.89 (d, 1H, J 8.4). 13C NMR (100 MHz, CDCl3) d: 16.59, 16.64, 19.02, 25.31, 30.10, 31.83, 36.33, 48.56, 59.33, 65.90, 126.80, 128.35, 130.89, 135.39, 165.31. GC–MS (EI) m/z: 274 (M+, 7%), 154 (62), 115 (45), 98 (100), 84 (28), 77 (31), 70 (22). Anal. Calcd for C17H26N2O1/2H2O: C, 72.05; H, 9.60; N, 9.88. Found: C, 72.45; H, 9.95; N, 9.80. 4.2.4.2. N-((1S,3R)-3-(Diethylamino)-2,2,3-trimethylcyclopentyl)benzamide 12. The product was purified by silica gel column chromatography using diethyl ether as eluent to give 12 as a white solid (27%). Mp 119–120 °C; ½a25 D ¼ þ70 (c 1.0, CH2Cl2). IR (KBr, cm1): 3351, 2968, 1640, 1581, 1493, 1369, 1306, 1194, 1073, 1027, 691. 1H NMR (400 MHz, CDCl3) d: 1.01 (s, 3H), 1.02 (s, 3H), 1.04 (t, 6H, J 7.2), 1.04 (s, 3H), 1.42–1.51 (m, 1H), 1.61– 1.70 (m, 1H), 2.09–2.16 (m, 1H), 2.19–2.28 (m, 1H), 2.55–2.70 (m, 4H), 4.30–4.36 (m, 1H), 7.34 (d, 1H, J 8.4), 7.40–7.50 (m, 3H), 7.76–7.78 (m, 2H). 13C NMR (100 MHz, CDCl3) d: 15.18, 17.28, 19.02, 24.59, 28.77, 35.34, 43.78, 48.98, 58.69, 69.15, 126.84, 128.44, 131.10, 135.29, 166.55. GC–MS (EI) m/z: 302 (M+, 5%), 182 (55), 126 (100), 113 (44), 105 (42), 98 (50), 77 (28). HRMS (EI+, [M]+) m/z: calcd for (C19H30N2O) 302.2358; found 302.2350. 4.2.4.3. N,N0 -((1R,3S)-1,2,2-Trimethylcyclopentan-1,3-diyl)bis((1S,2R)-(7,7-dimethyl-2-hydroxybicyclo[2.2.1]heptan-1yl)methanesulfonamide 13. To a solution of 7 (0.57 g, 1 mmol) in dry THF (3 mL) at 78 °C and under an inert atmosphere was added 1 M L-selectrideÒ in THF (4.5 mL) dropwise. The reaction mixture was stirred at 78 °C for 1 h, followed by 2 h at room temperature, then cooled to 0 °C and quenched by the successive addition of water (1 mL), ethanol (3 mL), 3 M NaOH (4 mL). 30% aq H2O2 (3 mL) was added dropwise over a 30 min period. The aqueous phase was saturated with K2CO3 and extracted with CH2Cl2. The organic phase was dried with anhydrous Na2SO4, and filtered. Evaporation of the solvent followed by silica gel column chromatography using AcOEt/hexane (3:2) as eluent affords 13 as a white solid (68%). Mp 162 °C (sublimes); ½a25 D ¼ þ5 (c 2.0, CH2Cl2). IR (KBr, cm1): 3528, 3301, 3277, 2959, 2883, 1741, 1456, 1392, 1317, 1148, 1077, 1058, 1013, 579. 1H NMR (300 MHz, CDCl3) d: 0.82 (s, 3H), 0.93 (s, 3H), 0.99 (s, 3H), 1.02 (s, 3H), 1.07 (s, 6H), 1.41 (s, 3H), 1.65–2.01 (m, 12H), 2.10–2.65 (m, 6H), 2.84 (d, 1H, J 13.6), 2.92 (d, 1H, J 15.2), 3.22 (d, 1H, J 13.6), 3.49 (d, 1H, J 15.2), 3.53–3.59 (m, 2H), 4.06–4.11 (m, 1H), 4.88 (d, 1H, J 10.3), 5.91 (s, 1H). 13C NMR (100 MHz, CDCl3) d: 17.82, 19.40, 19.91, 19.94, 19.98, 20.56, 21.08, 22.88, 23.12, 23.14, 26.35, 27.02, 27.38, 30.15, 30.66, 33.69, 38.89, 42.71, 42.97, 44.39, 48.72, 49.28, 50.49, 53.62, 54.00, 59.46, 62.11, 68.03. Anal. Calcd for C28H50N2O6S21/2H2O: C, 57.60; H, 8.80; N, 4.80; S, 10.98. Found: C, 57.70; H, 8.87; N, 4.58; S, 12.97. 4.2.4.4. N-((1S,3R)-3-(Ethylamino)-2,2,3-trimethylcyclopentyl)1-((1S)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonamide 15. To compound 11 (1.27 g, 4.6 mmol) was added water (5 mL) and concd HCl (7 mL). The mixture was refluxed overnight. After cooling to room temperature, the mixture was evaporated and water and ethyl acetate were added to the residue. Next, NaOH 1 M was added to the mixture until basic and extracted several times with ethyl acetate. The combined organic phases were washed with water and brine and dried over anhydrous Na2SO4. After filtration and evaporation of the solvent, an oil, 14, was obtained and used in the next step without further purification (77%). 1H NMR (400 MHz, CDCl3) d: 0.78 (s, 3H), 0.80 (s, 3H), 0.97–1.01 (m, 6H), 1.19–1.28 (m, 1H), 1.44–1.52 (m, 1H), 1.61–1.68 (m, 4H), 1.93–2.02 (m, 1H), 2.42–2.52 (m, 1H), 2.56– 2.62 (m, 1H), 2.86–2.89 (m, 1H). To a mixture of compound 14 (0.55 g, 3.24 mmol) and K2CO3 (0.45 g, 3.24 mmol) in dry ethanol (30 mL), at 0 °C and under an

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inert atmosphere, was added dropwise (+)-camphorsulfonyl chloride (0.81 g, 3.24 mmol) in dry ethanol (20 mL). The mixture was stirred overnight at room temperature. The solvent was evaporated, after which water and ethyl acetate were added, and the reaction mixture was extracted several times with ethyl acetate. The combined organic phases were washed with water and brine and dried over anhydrous Na2SO4. After filtration and removal of the solvent, the product was purified by silica gel column chromatography (diethyl ether/triethylamine 80:2). The product was obtained as a white solid (41%). Mp 58–60 °C; ½a25 D ¼ þ55 (c 1.0, CH2Cl2). IR (KBr, cm1): 3219, 2966, 2879, 1729, 1477, 1454, 1372, 1328, 1152, 1116, 1069, 912, 767, 572. 1H NMR (400 MHz, CDCl3) d: 0.89 (s, 3H), 0.91 (s, 3H), 0.99 (s, 3H), 1.03 (s, 3H), 1.08 (t, 3H, J 7.0), 1.13 (s, 3H), 1.38–1.52 (m, 3H), 1.63–1.73 (m, 2H), 1.90–1.96 (m, 2H), 2.00–2.09 (m, 2H), 2.23–2.32 (m, 1H), 2.34– 2.41 (m, 1H), 2.49–2.63 (3H), 2.88 (d, 1H, J 14.8), 3.44 (d, 1H, J 14.8); 3.38 (d, 1H, J 6.0), 8.82 (br s, 1H). 13C NMR (100 MHz, CDCl3) d: 16.47, 17.21, 19.01, 19.86, 20.05, 24.92, 25.23, 26.96, 31.08, 32.16, 36.43, 42.74, 42.88, 47.91, 48.29, 51.02, 58.78, 63.76, 65.41, 215.53. GC–MS (EI) m/z: 384 (M+, 1%), 249 (24), 215 (7), 154 (100), 124 (7), 108 (10), 98 (38), 84 (11), 70 (11). Anal. Calcd for C20H36N2O3S1/2H2O: C, 61.03; H, 9.48; N, 7.12; S, 8.15. Found: C, 60.97; H, 9.27; N, 6.99; S, 6.47. 4.2.5. General procedure for enantioselective alkylation reactions To the chiral ligand (0.15 mmol) and benzaldehyde (1 mmol) under an inert atmosphere, 4 mL of solvent were added. The temperature of the reaction mixture was lowered to 0 °C and diethylzinc (2 mmol, as a 1 M hexane solution) was added. The reaction was stirred at the same temperature for the appropriate time. After this time a saturated ammonium chloride solution (1 mL) followed by 2 M HCl (1 mL) were added and the reaction mixture was extracted with diethyl ether. The organic phases were washed with water and brine and dried over anhydrous magnesium sulfate. The resulting solution was analyzed by GC on a chiral column in order to determine the ee of the 1-phenyl-1-propanol. Conditions: chiral c-cyclodextrin capillary column (FS-Lipodex-E, 25 m, 0.25 i.d.) P = 20 psi; 1-phenyl-1-propanol: T = 100 °C, tR (R) = 15.8 min, tR (S) = 16.3 min; 1-o-tolyl-1-propanol: T = 100 °C, tR (R) = 32.1 min, tR (S) = 35.4 min; 1-m-tolyl-1-propanol: T = 100 °C, tR (R) = 27.4 min, tR (S) = 28.1 min; 1-p-tolyl-1-propanol: T = 100 °C, tR (R) = 27.5 min, tR (S) = 28.4 min; 1-(m-methoxyphenyl)-1-propanol: T = 110 °C, tR (R) = 53.2 min, tR (S) = 54.9 min; 1-(o-chlorophenyl)-1-propan-ol: T = 120 °C, tR (R) = 22.3 min, tR (S) = 20.3 min; 1-(p-chlorophenyl)-1-propan-ol: T = 120 °C, tR (R) = 29.3 min, tR (S) = 30.4 min; 1-(p-nitrophenyl)-1-propanol: T = 130 °C, tR (R) = 28.5 min, tR (S) = 27.9 min; 1-(1-naphthalenyl)-1-propanol: T = 140 °C, tR (R) = 61.0 min, tR (S) = 63.8 min; 1-(2-naphthalenyl)1-propanol: T = 140 °C, tR (R) = 71.3 min, tR (S) = 72.9 min. Acknowledgements The authors would like to thank Chymiotechnon for financial support. NMR data was obtained at the Nuclear Magnetic Resonance Laboratory of the Coimbra Chemistry Centre (www.nmrccc. uc.pt), Universidade de Coimbra, supported in part by Grant REEQ/ 481/QUI/2006 from FCT, POCI-2010 and FEDER, Portugal. References 1. Pu, L.; Yu, H. B. Chem. Rev. 2001, 101, 757–824. 2. Lin, G. Q.; Li, Y. M.; Chan, A. S. C. Principles and Applications of Asymmetric Synthesis; John Wiley & Sons: New York, 2001. 3. Yus, M.; Ramón, D. J. Pure Appl. Chem. 2005, 77, 2111–2119. 4. Saravanan, P.; Bisai, A.; Baktharaman, S.; Chandrasekhar, M.; Singh, V. K. Tetrahedron 2002, 58, 4693–4706.

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