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DOI: 10.1055/s-0032-1318344
A Mild Multistep Conversion of N-Protected α-Amino Acids into N-Protected β3-Amino Acids Utilizing the Nef Reaction
Publication History
Received: 19 October 2012
Accepted after revision: 12 February 2013
Publication Date:
06 March 2013 (online)
Abstract
Current methods of homologation of α-amino acids to β-amino acids have limitations. To overcome these shortfalls the Nef reaction has been utilized in the multistep synthesis of β3-amino acids from α-amino acids. In this approach, N-protected amino aldehydes, easily accessed from α-amino acids, were transformed into the N-protected γ-amino nitroalkanes. The Nef reaction was then used to smoothly convert the nitroalkanes into the corresponding N-protected β3-amino acids without notable racemization.
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Key words
amino acids - amino alcohols - amino aldehydes - nucleophilic addition - enantioselectivityThe popularity of applications of β-amino acids as either synthons in organic chemistry or in peptidomimetics in bioorganic and medicinal chemistry is increasing. As a result a plethora of syntheses exist.[ 1 ] Of these syntheses a limited number of examples exist for the direct homologation of α-amino acids to β3-amino acids. The use of a homologation allows the chirality to be transferred to the β3-amino acid product, and does not have the requirement to use expensive, and sometimes toxic, chiral transfer reagents to install chirality in the final product.
The most well-known procedure to perform the homologation of α-amino acids to β3-amino acids is the Arndt–Eistert homologation (method A, Scheme [1]).[2] [3] However, this two-step transformation has limitations in the toxicity and safe generation of diazomethane. As a result many alternative procedures have appeared (Scheme [1]). These procedures have advantages and disadvantages. As a result there is still an unmet need to develop a novel strategy that is mild, inexpensive, safe, possesses a limited number of synthetic steps, and transfers the chirality of the α-amino acid to the β3-amino acid product faithfully. The protocol of Caputo[ 4 ] (method C, Scheme [1]) has gone a long way to achieving these idealities; however, the method requires the use of cyanide. Further, hydrolysis of the nitrile also results in loss of the N-protective group. An alternative to the use of diazomethane in the Arndt–Eistert homologation is the procedure by Bio et al.[ 5 ] that utilizes N-isocyano iminotriphenylphosphorane to produce diazoketones in three steps. More recently, this method has been applied to the homologation of N-Fmoc α-amino acids by Perlmutter.[ 6 ] The limitation of this method is the phosphorane reagent is relatively expensive and an N-Fmoc acid chloride is required for the method to be viable (method B, Scheme [1]). And finally, Temperini et al.[ 7 ] developed a synthetic sequence using inexpensive reagents, via an alkyne to produce β3-amino acids (method D, Scheme [1]). However, eight synthetic steps were required.
There are numerous other homologation procedures,[ 8 ] however, most are not applicable to β-amino acid synthesis. The methods that are, produce substituted β2, β2,3 or β2,2,3-amino acids,[ 9 ] not β3-amino acids, the focus of the work described here. One such example that produces a hydroxy-substituted β2,3-amino acid is a method that incorporates the use of the Nef reaction (Scheme [2]).[ 10 ] To the best of our knowledge the Nef reaction has not been used in the production of β3-amino acids. It is proposed to perform a Henry reaction on an α-amino aldehyde. The hydroxyl group present on the Henry reaction product will then be reductively eliminated, so a Nef reaction can be exploited to enable the synthesis of β3-amino acids from α-amino acids without racemization (Scheme [2]). Preliminary results investigating the use and scope of the Nef reaction in the production of β3-amino acids are described herein.
To demonstrate the scope of the proposed synthetic route, a small number of α-amino acid residues were selected with different side-chain functionalities, N-nonmethylated and N-methylated, and in the presence of a few common N-protecting groups, such as Cbz, Boc, and Ts.
To enable the exploitation of the Nef reaction, the γ-amino nitroalkane was required as a key synthon. It was proposed this intermediate would be accessed from an elimination of the product obtained from the Henry reaction of nitromethane with the α-amino aldehyde. The amino aldehyde will be accessed via a two-step process from the N-protected α-amino acid (Scheme [2]).
N-Protected amino alcohols 8–14 can be obtained using a number of approaches. The approach used involved activating the N-protected α-amino acid 1–6 using N-methylmorpholine and ethyl chloroformate at –15 °C, followed by the addition of sodium borohydride (Scheme [3]).[ 11 ] This gave the N-protected amino alcohols 8–13 in good to excellent yields (76–86%, Table [1]). The N-tosyl analogue 7 was converted into the amino alcohol 14 using LiAlH4.
a Yield calcd from the starting amino alcohol.
α-Amino aldehydes 15–21 can also be obtained by a variety of different methods,[ 12 ] however, a Swern oxidation of the amino alcohols 8–14 at low temperature was chosen (Scheme [3]), in order to minimize racemization.[ 13 ] Racemization of α-amino aldehydes can occur at room temperature in a short period, and to minimize racemization they were used immediately in the next transformation. The Swern reaction products 15–21 were immediately subjected to a modified Henry reaction, using nitromethane in the presence of potassium fluoride (Scheme [4]).[ 14 ] The use of potassium fluoride, in place of a strong base usually used in the Henry reaction, also minimized the risk of racemizing the α-amino aldehydes 15–21. The level of racemization was monitored only in the final β3-amino acid product. The intermediate γ-amino β-hydroxy nitroalkanes 22–28 were obtained in mediocre to good yields [37–70% (calculated from the starting amino alcohols 8 – 14), Table [1]].[ 21 ] The β-hydroxy nitroalkanes 22–28 were obtained as a mixture of diastereoisomers, and thus were not characterized at this stage, but used directly in the next transformation. The diastereoselectivity of the Henry reaction was thus not important as the β-hydroxy stereocenter was removed in the next step.
In a one-pot process the β-hydroxy functionality on nitroalkanes 22–28 was reductively eliminated using the conditions of Wollenberg et al.[ 14 ] The hydroxy group was first converted into an O-acetate, using acetic anhydride and 4-dimethylamino pyridine, and then in the same pot the O-acetate was reduced using sodium borohydride (Scheme [4]). The one-pot procedure proceeded smoothly giving good yields (48–70%) of the nitroalkanes 29–35 (Table [2]) after purification by column chromatography.[ 22 ]
|
Entry |
PG |
R1 |
R2 |
Nitro alkane |
Yield of product (%) |
Found [α] (c) |
Lit. [α] (c, solvent) |
|
1 |
Cbz |
Me |
H |
29 |
36 75 |
–12.5 (1.04) |
–15.7 (1.04, CHCl3)[ 17 ] |
|
2 |
Cbz |
Bn |
H |
30 |
37 67 |
–30.0 (1.0) |
–36.0 (1.0, CHCl3)[ 18 ] |
|
3 |
Boc |
CH2OBn |
H |
31 |
38 60 |
+16.6 (1.05) |
+15.1 (1.05, CHCl3)[ 19 ] |
|
4 |
Boc |
i-Pr |
H |
32 |
39 67 |
–20.0 (1.0) |
–20.3 (1.0, CHCl3)[ 20 ] |
|
5 |
Cbz |
Bu |
Me |
33 |
40 69 |
+6.4 (3.1) |
+5.5 (3.1, MeOH)[ 3 ] |
|
6 |
Cbz |
CH2CO2Bn |
Me |
34 |
41 70 |
+2.0 (1.0) |
+0.7 (1.0, MeOH)[ 3 ] |
|
7 |
Ts |
i-Bu |
H |
35 |
42 76 |
–30.5 (2.4) |
–12.5 (2.4, CH2Cl2)[ 16 ] |
The nitroalkanes 29–35 were then converted into the β3-amino acids using the Nef reaction carried out using the conditions of Mioskowski et al.[ 15 ] These conditions involve the use of three equivalents of sodium nitrite and ten equivalents of acetic acid in DMSO at 40 °C (Scheme [5]).[ 23 ] These conditions were applied to all residues and produced the β3-amino acids 36–42 in good yields (60–70%, Table [2]). The enantiomeric purities of the β3-amino acid products 36–42 obtained via the multistep sequence were compared to literature optical rotation values (Table [2]). The values for compounds 36–42 (Table [2], entries 1–6) compared well. However, the N-tosyl analogue 42 (Table [2], entry 7) did not compare well with the literature value.[ 16 ] The optical rotation value for 42 is significantly higher than that quoted in the literature. To prove unequivocally that 42 was enantiopure, chiral HPLC was performed. The N-tosyl analogue 42 possessed 99% enantiomeric excess.
In conclusion, a preliminary study converting α-amino acids via a mild multistep synthesis, utilizing the Nef reaction, into β3-amino acids has been described. To obtain the Nef reaction synthon, γ-amino nitroalkanes 29–35, N-protected α-amino aldehydes 15–21 were converted into the β-hydroxy-nitroalkanes 22–28 using the Henry reaction. The hydroxyl functionality was then reductively eliminated in a two-step process, to obtain the Nef synthons 29–35. And finally the Nef reaction proceeded smoothly to obtain a small selection of NH- and N-methyl N-protected β3-amino acids 36–42. Residues were obtained without racemization of the chiral center. The overall conversion from N-protected α-amino acids into the desired β3-amino acids occurs in five steps. Although the number of synthetic steps used here is greater than earlier methods, this approach only requires the use of inexpensive and nontoxic reagents. Table [3] helps to facilitate comparison of the current work with previous methods. Future studies will focus on shortening the synthetic sequence and improving synthetic yields, to further highlight that the Nef reaction in the production of β3-amino acids is a viable alternative to current homologation methods.
|
Residues |
Homologation Methods |
|||
|
Arndt–Eistert |
Caputo |
Temperini |
Current method |
|
|
Cbz-β3-Ala |
72% (2 steps) |
40%[ 24 ] (5 steps) |
– |
26% |
|
Cbz-β3-Val |
63%[ 25 ] (2 steps) |
28%[ 24 ] (5 steps) |
19%[ 7 ] (8 steps) |
22% |
|
Cbz-β3-Phe |
77%[ 26 ] (2 steps) |
35%[ 24 ] (5 steps) |
– |
20% |
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Acknowledgment
We thank La Trobe University for the provision of a postgraduate scholarship awarded to N.H.N. and the NHMRC (App. 1010326) for funding B.E.S.
Supporting Information
- for this article is available online at http://www.thieme-connect.com.accesdistant.sorbonne-universite.fr/ejournals/toc/synlett.
- Supporting Information
-
References and Notes
- 1a Sleebs BE, Van Nguyen TT, Hughes AB. Org. Prep. Proced. Int. 2009; 41: 429
- 1b Juaristi E. Enantioselective Synthesis of β-Amino Acids . Wiley-VCH; Weinheim: 2005. 2nd ed.
- 1c Liu M, Sibi MP. Tetrahedron 2002; 58: 7991
- 1d Juaristi E, Lopez-Ruiz H. Curr. Med. Chem. 1999; 6: 983
- 1e Cole DC. Tetrahedron 1994; 50: 9517
- 2a Hughes AB, Sleebs BE. Aust. J. Chem. 2008; 61: 131
- 2b Müller A, Vogt C, Sewald N. Synthesis 1998; 837
- 2c Plucinska K, Liberek B. Tetrahedron 1987; 43: 3509
- 2d Seebach D, Kimmerlin T. Helv. Chim. Acta 2003; 86: 2098
- 2e Seebach D, Overhand M, Matinoni B, Oberer L, Hommel U, Widmer H. Helv. Chim. Acta 1996; 79: 913
- 2f Seebach D, Podlech J. Angew. Chem., Int. Ed. Engl. 1995; 34: 471
- 2g Seebach D, Podlech J. Liebigs Ann. 1995; 1217
- 2h Sleebs BE, Hughes AB. Aust. J. Chem. 2006; 58: 778
- 2i Sleebs BE, Hughes AB. Synth. Commun. 2009; 39: 48
- 3 Sleebs BE, Hughes AB. Helv. Chim. Acta 2006; 89: 2611
- 4 Caputo R, Cassano E, Longobardo L, Palumbo G. Tetrahedron 1995; 51: 12337
- 5 Bio MM, Javadi G, Song ZJ. Synthesis 2005; 19
- 6 Perlmutter, P.; Poster at the Univeristy of Melbourne Organic Synthesis Symposium, 2011.
- 7 Temperini A, Capperucci A, Degl’Innocenti A, Terlizzi R, Tiecco M. Tetrahedron Lett. 2010; 51: 4121
- 8a Li J. Name Reactions for Homologation . Wiley-VCH; Weinheim: 2009. Parts 1 and 2
- 8b Katritzky AR, Bobrov S. ARKIVOC 2005; (x): 174
- 9a Boto A, Hernández R, Saavedra CJ. Synlett 2010; 659
- 9b Moumne R, Lavielle S, Karoyan P. J. Org. Chem. 2006; 71: 3332
- 9c Moumne R, Lavielle S, Karoyan P, Curie M, Jussieu P, Cedex P. Tetrahedron 2006; 21
- 9d Saavedra C, Hernandez R, Boto A, Alvarez E. J. Org. Chem. 2009; 74: 4655
- 9e Saavedra CJ, Boto A, Hernandez R. Org. Biomol. Chem. 2012; 10: 4448
- 9f Saavedra CJ, Hernández R, Boto A, Álvarez E. Tetrahedron Lett. 2006; 47: 8757
- 10a Lei LJ, He XC. Org. Prep. Proced. Int. 2005; 37: 555
- 10b Sasai H, Kim W.-S, Suzuki T, Shibasaki M, Mitsuda M, Hasegawa J, Ohashi T. Tetrahedron Lett. 1994; 35: 6123
- 11a Kokotos G. Synthesis 1990; 299
- 11b Rodriguez M, Llinares M, Doulut S, lleitr A, Mwtmez J. Tetrahedron Lett. 1991; 32: 923
- 12 Hili R, Baktharaman S, Yudin A. Eur. J. Org. Chem. 2008; 5201
- 13 Konradi AW, Kemp SJ, Pedersen SF. J. Am. Chem. Soc. 1994; 116: 1316
- 14 Wollenberg RH, Miller SJ. Tetrahedron Lett. 1978; 19: 3219
- 15 Matt C, Wagner A, Mioskowski C. J. Org. Chem. 1997; 62: 234
- 16 Howson W, Osborn HM. I, Sweeney J. J. Chem. Soc., Perkin Trans. 1 1995; 19: 2439
- 17 Arvidsson PI, Frackenpohl J, Seebach D. Helv. Chim. Acta 2003; 86: 1522
- 18 Patil BS, Vasanthakumar G.-R, Suresh Babu VV. Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem. 2005; 12: 2611
- 19 Matthews JL, Gademann K, Jaun B, Seebach D. J. Chem. Soc., Perkin Trans. 1 1998; 20: 3331
- 20 Patil BS, Suresh Babu VV. Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem. 2005; 12: 2611
- 21 General Procedure B: Preparation of N-Protected β-Hydroxy Nitroalkanes 22–28 Oxalyl chloride (9.56 mmol) was dissolved in CH2Cl2 (20 mL), the mixture was cooled to –78 °C, and a solution of dry DMSO (19.1 mmol) in CH2Cl2 (5 mL) was added dropwise during 15 min. The N-protected amino alcohol 8–14 (4.78 mmol) in CH2Cl2 (15 mL) was added dropwise during 10 min, the resulting solution was stirred for 10 min at –78 °C, and a solution of Et3N (28.7 mmol) in CH2Cl2 (20 mL) was added dropwise during 15 min. After 20 min, H2O (5.0 mL) was added to the vigorously stirred solution at –78 °C. The resulting slurry was poured in Et2O (50 mL) and washed with 20% aq KHSO4 (2 × 30 mL), the layers were separated, and the aqueous layer was back-extracted with Et2O (2 × 50 mL). The combined organic layers were washed with brine (2 × 50 mL), dried (MgSO4), and the solvent was removed under reduced pressure (at <20 °C) to afford the crude aldehyde 15–21, which was immediately used in the next reaction without any further purification. To a solution of crude aldehyde 15–21 and nitromethane (19.1 mmol, 4 equiv) in i-PrOH (30 mL), cooling to 0 °C, was added KF (4.78 mmol, 1 equiv). The reaction mixture was warmed to r.t. and stirred for 8 h, H2O (50 mL) was added, and the aqueous layer was extracted with Et2O (3 × 20 mL). The organic layers were washed with H2O (50 mL), dried (MgSO4), and concentrated in vacuo. The crude product was subjected to flash column chromatography, eluting with 10–35% EtOAc–hexane to give a diastereomeric mixture of nitro alcohols 22–28. The diastereomeric mixture of β-hydroxy nitroalkanes 22–28 were not characterized and were used directly in the next reaction.
- 22 General Procedure C: Preparation of N-Protected γ-Amino Nitroalkanes 29–35 To the β-hydroxy nitroalkane 22–28 (1.79 mmol) was added dry Et2O (20 mL), followed by Ac2O (3.58 mmol) and DMAP (0.18 mmol). The reaction mixture was stirred at 25 °C for 2 h, and the solvent was evaporated in vacuo. To the resulting crude residue was added 1 N ethanolic NaBH4 (4 mL) at 0 °C with stirring for 2 h (monitored by TLC). The mixture was acidified with 0.5 N HCl and extracted with Et2O (3 × 20 mL), and the organic layers were washed with H2O (1 × 20 mL). The crude was subjected to flash column chromatography, eluting with 10–30% EtOAc–hexane to give the nitroalkanes 29–35. (3S)-N-Benzyloxycarbonyl-3-amino-1-nitrobutane (29) The β-hydroxy nitroalkane 22 (0.48 g, 1.79 mmol) was transformed according to the General Procedure C, which afforded the desired nitro alkane 29 as a clear oil (crystallized on standing; 0.31 g, 70%); mp 45–48 °C; [α]D 29 +9.2, (c 2.71, MeOH). HRMS (ESI+): m/z calcd for C12H16N2O4 [M + H]+: 253.1183; found: 253.1184. IR (NaCl): νmax = 3392 (NH), 3349, 3336 (CH), 1680 (CO), 1550 (NO2), 1242, 1064, 897 cm–1. 1H NMR (300 MHz, CDCl3, 300 K): δ = 7.32 (5 H, s, ArH), 5.06 (2 H, s, ArCH2O), 4.78 (1 H, d, J = 7.3 Hz, NH), 4.43–4.37 (2 H, m, CH2NO2), 3.82 (1 H, br s, NCH), 2.19–2.08 (2 H, m, CH 2CH2NO2), 1.20 (3 H, d, J = 6.6 Hz, CHCH 3). 13C NMR (75 MHz, CDCl3, 300 K): δ = 155.9 (CO), 136.2, 136.2 (aryl C), 128.6, 128.2, 128.1 (aryl CH), 72.7 (CH2NO2) 66.9 (ArCH2O), 45.1 (NCH), 34.4 (CH2CH2NO2), 21.2 (CHCH3).
- 23 General Procedure D – Preparation of the N-Protected β-Amino Acids 36–42 To a solution of nitroalkane 29–35 (0.79 mmol) in DMSO (2 mL) was added NaNO2 (2.37 mmol) and AcOH (7.9 mmol), and the reaction was heated to 40 °C for 20 h. After cooling to r.t., 1 N HCl was added to the yellow solution, stirring for another 15 min, and the aqueous was extracted with Et2O (3 × 15 mL). The organic layers were washed with H2O (2 × 20 mL) and extracted with sat. NaHCO3 solution (3 × 15 mL). The aqueous layers were acidified to pH 2 with 2 N HCl and then re-extracted with EtOAc (3 × 15 mL). The organic extracts were dried (MgSO4) and evaporated in vacuo. The residue was subjected to flash column chromatography, gradient eluting with 10–40% EtOAc–hexane to afford the N-protected β-amino acids 36–42. (3S)-N-Benzyloxycarbonyl-3-aminobutanoic Acid 36 Nitroalkane 29 (199 mg, 0.79 mmol) was transformed according to the General Procedure D, and afforded the desired β-amino acid 36 as a white solid (140 mg, 75%); [α]D 24 –12.5 (c 1.0, CHCl3); lit. [α]D 27 –15.7 (c 1.0, CHCl3).17 1H NMR (300 MHz, CDCl3, 300 K): δ = 7.33–7.29 (5 H, m, ArH), 5.32 (1 H, NH), 5.08 (2 H, s, ArCH2O), 4.10 (1 H, HNCH), 2.57 (2 H, s, CH2), 1.26 (3 H, d, J = 6.7 Hz, CH3).
- 24 Sutherland A, Willis CL. J. Org. Chem. 1998; 63: 7764
- 25 Gopi HN, Roy RS, Raghothama S, Karle IL, Balaaram P. Helv. Chim. Acta 2002; 85: 3313
- 26 Patil BS, Vasanthakumar G.-R, Babu VV. S. Synth. Commun. 2003; 33: 3089
-
References and Notes
- 1a Sleebs BE, Van Nguyen TT, Hughes AB. Org. Prep. Proced. Int. 2009; 41: 429
- 1b Juaristi E. Enantioselective Synthesis of β-Amino Acids . Wiley-VCH; Weinheim: 2005. 2nd ed.
- 1c Liu M, Sibi MP. Tetrahedron 2002; 58: 7991
- 1d Juaristi E, Lopez-Ruiz H. Curr. Med. Chem. 1999; 6: 983
- 1e Cole DC. Tetrahedron 1994; 50: 9517
- 2a Hughes AB, Sleebs BE. Aust. J. Chem. 2008; 61: 131
- 2b Müller A, Vogt C, Sewald N. Synthesis 1998; 837
- 2c Plucinska K, Liberek B. Tetrahedron 1987; 43: 3509
- 2d Seebach D, Kimmerlin T. Helv. Chim. Acta 2003; 86: 2098
- 2e Seebach D, Overhand M, Matinoni B, Oberer L, Hommel U, Widmer H. Helv. Chim. Acta 1996; 79: 913
- 2f Seebach D, Podlech J. Angew. Chem., Int. Ed. Engl. 1995; 34: 471
- 2g Seebach D, Podlech J. Liebigs Ann. 1995; 1217
- 2h Sleebs BE, Hughes AB. Aust. J. Chem. 2006; 58: 778
- 2i Sleebs BE, Hughes AB. Synth. Commun. 2009; 39: 48
- 3 Sleebs BE, Hughes AB. Helv. Chim. Acta 2006; 89: 2611
- 4 Caputo R, Cassano E, Longobardo L, Palumbo G. Tetrahedron 1995; 51: 12337
- 5 Bio MM, Javadi G, Song ZJ. Synthesis 2005; 19
- 6 Perlmutter, P.; Poster at the Univeristy of Melbourne Organic Synthesis Symposium, 2011.
- 7 Temperini A, Capperucci A, Degl’Innocenti A, Terlizzi R, Tiecco M. Tetrahedron Lett. 2010; 51: 4121
- 8a Li J. Name Reactions for Homologation . Wiley-VCH; Weinheim: 2009. Parts 1 and 2
- 8b Katritzky AR, Bobrov S. ARKIVOC 2005; (x): 174
- 9a Boto A, Hernández R, Saavedra CJ. Synlett 2010; 659
- 9b Moumne R, Lavielle S, Karoyan P. J. Org. Chem. 2006; 71: 3332
- 9c Moumne R, Lavielle S, Karoyan P, Curie M, Jussieu P, Cedex P. Tetrahedron 2006; 21
- 9d Saavedra C, Hernandez R, Boto A, Alvarez E. J. Org. Chem. 2009; 74: 4655
- 9e Saavedra CJ, Boto A, Hernandez R. Org. Biomol. Chem. 2012; 10: 4448
- 9f Saavedra CJ, Hernández R, Boto A, Álvarez E. Tetrahedron Lett. 2006; 47: 8757
- 10a Lei LJ, He XC. Org. Prep. Proced. Int. 2005; 37: 555
- 10b Sasai H, Kim W.-S, Suzuki T, Shibasaki M, Mitsuda M, Hasegawa J, Ohashi T. Tetrahedron Lett. 1994; 35: 6123
- 11a Kokotos G. Synthesis 1990; 299
- 11b Rodriguez M, Llinares M, Doulut S, lleitr A, Mwtmez J. Tetrahedron Lett. 1991; 32: 923
- 12 Hili R, Baktharaman S, Yudin A. Eur. J. Org. Chem. 2008; 5201
- 13 Konradi AW, Kemp SJ, Pedersen SF. J. Am. Chem. Soc. 1994; 116: 1316
- 14 Wollenberg RH, Miller SJ. Tetrahedron Lett. 1978; 19: 3219
- 15 Matt C, Wagner A, Mioskowski C. J. Org. Chem. 1997; 62: 234
- 16 Howson W, Osborn HM. I, Sweeney J. J. Chem. Soc., Perkin Trans. 1 1995; 19: 2439
- 17 Arvidsson PI, Frackenpohl J, Seebach D. Helv. Chim. Acta 2003; 86: 1522
- 18 Patil BS, Vasanthakumar G.-R, Suresh Babu VV. Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem. 2005; 12: 2611
- 19 Matthews JL, Gademann K, Jaun B, Seebach D. J. Chem. Soc., Perkin Trans. 1 1998; 20: 3331
- 20 Patil BS, Suresh Babu VV. Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem. 2005; 12: 2611
- 21 General Procedure B: Preparation of N-Protected β-Hydroxy Nitroalkanes 22–28 Oxalyl chloride (9.56 mmol) was dissolved in CH2Cl2 (20 mL), the mixture was cooled to –78 °C, and a solution of dry DMSO (19.1 mmol) in CH2Cl2 (5 mL) was added dropwise during 15 min. The N-protected amino alcohol 8–14 (4.78 mmol) in CH2Cl2 (15 mL) was added dropwise during 10 min, the resulting solution was stirred for 10 min at –78 °C, and a solution of Et3N (28.7 mmol) in CH2Cl2 (20 mL) was added dropwise during 15 min. After 20 min, H2O (5.0 mL) was added to the vigorously stirred solution at –78 °C. The resulting slurry was poured in Et2O (50 mL) and washed with 20% aq KHSO4 (2 × 30 mL), the layers were separated, and the aqueous layer was back-extracted with Et2O (2 × 50 mL). The combined organic layers were washed with brine (2 × 50 mL), dried (MgSO4), and the solvent was removed under reduced pressure (at <20 °C) to afford the crude aldehyde 15–21, which was immediately used in the next reaction without any further purification. To a solution of crude aldehyde 15–21 and nitromethane (19.1 mmol, 4 equiv) in i-PrOH (30 mL), cooling to 0 °C, was added KF (4.78 mmol, 1 equiv). The reaction mixture was warmed to r.t. and stirred for 8 h, H2O (50 mL) was added, and the aqueous layer was extracted with Et2O (3 × 20 mL). The organic layers were washed with H2O (50 mL), dried (MgSO4), and concentrated in vacuo. The crude product was subjected to flash column chromatography, eluting with 10–35% EtOAc–hexane to give a diastereomeric mixture of nitro alcohols 22–28. The diastereomeric mixture of β-hydroxy nitroalkanes 22–28 were not characterized and were used directly in the next reaction.
- 22 General Procedure C: Preparation of N-Protected γ-Amino Nitroalkanes 29–35 To the β-hydroxy nitroalkane 22–28 (1.79 mmol) was added dry Et2O (20 mL), followed by Ac2O (3.58 mmol) and DMAP (0.18 mmol). The reaction mixture was stirred at 25 °C for 2 h, and the solvent was evaporated in vacuo. To the resulting crude residue was added 1 N ethanolic NaBH4 (4 mL) at 0 °C with stirring for 2 h (monitored by TLC). The mixture was acidified with 0.5 N HCl and extracted with Et2O (3 × 20 mL), and the organic layers were washed with H2O (1 × 20 mL). The crude was subjected to flash column chromatography, eluting with 10–30% EtOAc–hexane to give the nitroalkanes 29–35. (3S)-N-Benzyloxycarbonyl-3-amino-1-nitrobutane (29) The β-hydroxy nitroalkane 22 (0.48 g, 1.79 mmol) was transformed according to the General Procedure C, which afforded the desired nitro alkane 29 as a clear oil (crystallized on standing; 0.31 g, 70%); mp 45–48 °C; [α]D 29 +9.2, (c 2.71, MeOH). HRMS (ESI+): m/z calcd for C12H16N2O4 [M + H]+: 253.1183; found: 253.1184. IR (NaCl): νmax = 3392 (NH), 3349, 3336 (CH), 1680 (CO), 1550 (NO2), 1242, 1064, 897 cm–1. 1H NMR (300 MHz, CDCl3, 300 K): δ = 7.32 (5 H, s, ArH), 5.06 (2 H, s, ArCH2O), 4.78 (1 H, d, J = 7.3 Hz, NH), 4.43–4.37 (2 H, m, CH2NO2), 3.82 (1 H, br s, NCH), 2.19–2.08 (2 H, m, CH 2CH2NO2), 1.20 (3 H, d, J = 6.6 Hz, CHCH 3). 13C NMR (75 MHz, CDCl3, 300 K): δ = 155.9 (CO), 136.2, 136.2 (aryl C), 128.6, 128.2, 128.1 (aryl CH), 72.7 (CH2NO2) 66.9 (ArCH2O), 45.1 (NCH), 34.4 (CH2CH2NO2), 21.2 (CHCH3).
- 23 General Procedure D – Preparation of the N-Protected β-Amino Acids 36–42 To a solution of nitroalkane 29–35 (0.79 mmol) in DMSO (2 mL) was added NaNO2 (2.37 mmol) and AcOH (7.9 mmol), and the reaction was heated to 40 °C for 20 h. After cooling to r.t., 1 N HCl was added to the yellow solution, stirring for another 15 min, and the aqueous was extracted with Et2O (3 × 15 mL). The organic layers were washed with H2O (2 × 20 mL) and extracted with sat. NaHCO3 solution (3 × 15 mL). The aqueous layers were acidified to pH 2 with 2 N HCl and then re-extracted with EtOAc (3 × 15 mL). The organic extracts were dried (MgSO4) and evaporated in vacuo. The residue was subjected to flash column chromatography, gradient eluting with 10–40% EtOAc–hexane to afford the N-protected β-amino acids 36–42. (3S)-N-Benzyloxycarbonyl-3-aminobutanoic Acid 36 Nitroalkane 29 (199 mg, 0.79 mmol) was transformed according to the General Procedure D, and afforded the desired β-amino acid 36 as a white solid (140 mg, 75%); [α]D 24 –12.5 (c 1.0, CHCl3); lit. [α]D 27 –15.7 (c 1.0, CHCl3).17 1H NMR (300 MHz, CDCl3, 300 K): δ = 7.33–7.29 (5 H, m, ArH), 5.32 (1 H, NH), 5.08 (2 H, s, ArCH2O), 4.10 (1 H, HNCH), 2.57 (2 H, s, CH2), 1.26 (3 H, d, J = 6.7 Hz, CH3).
- 24 Sutherland A, Willis CL. J. Org. Chem. 1998; 63: 7764
- 25 Gopi HN, Roy RS, Raghothama S, Karle IL, Balaaram P. Helv. Chim. Acta 2002; 85: 3313
- 26 Patil BS, Vasanthakumar G.-R, Babu VV. S. Synth. Commun. 2003; 33: 3089