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Synlett 2013; 24(7): 823-826
DOI: 10.1055/s-0032-1318345
letter
© Georg Thieme Verlag Stuttgart · New York

Synthesis of N-Cbz-Substituted β3-Amino Ketones Utilizing 4-Substituted 1,3-Oxazinan-6-ones

Brad E. Sleebs
a   The Walter and Eliza Hall Institute of Medical Research, Parkville 3010, Australia
b   Department of Medical Biology, The University of Melbourne, Parkville 3010, Australia
,
Nghi H. Nguyen
c   Department of Chemistry, La Trobe University, Victoria 3086, Australia   Fax: +61(3)94791266   Email: tahughes@optusnet.com.au
,
Andrew B. Hughes*
c   Department of Chemistry, La Trobe University, Victoria 3086, Australia   Fax: +61(3)94791266   Email: tahughes@optusnet.com.au
› Author Affiliations
Further Information

Publication History

Received: 07 February 2013

Accepted after revision: 12 February 2013

Publication Date:
14 March 2013 (online)

 
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Abstract

Stereoselective synthesis of N-Cbz-substituted β-amino ketones exploiting the versatile 1,3-oxazin-6-one scaffold is reported. The 4-substituted 1,3-oxazinan-6-ones were enolized and acylated diastereoselectively by addition of various acyl halides. Acidic decarboxylation was then employed to smoothly transform the 5-acylated products to chiral β-amino ketones. This methodology further highlights the utility of the 1,3-oxazinan-6-one as a scaffold to access valuable synthons that are used in the peptidomimetic field.


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Key words

ketones - amino acids - acylation - ring opening - oxazinanones

β-Amino ketones are important synthetic precursors for many syntheses[1] [2] and also have demonstrated biological activity.[ 3 ] There are numerous methods to gain access to β-amino ketones, such as Michael addition of an amine surrogate to an α,β-unsaturated ketone,[ 4 ] via a Mannich reaction,[2] [5] or by reduction of α,β-unsaturated ketones.[ 6 ] However, many of these methods are limited in their use and a large proportion do not produce chiral β-amino ketones. To overcome the shortcomings of previous syntheses, a stereoselective synthesis of β-amino ketones was devised, starting from 1,3-oxazinan-6-ones.

1,3-Oxazinan-6-ones have previously been utilized to ­produce a variety of different β-amino acid derivatives.[7] [8] [9] [10] The versatility of the 1,3-oxazinan-6-one scaffold has been shown to produce N-methyl β3-amino acids, 2-hydroxy,[ 9 ] 2-alkyl,[ 9 ] and 2,2-dialkyl β3-amino acids,[ 7 ] and recently β2,3-cyclic amino acids[ 10 ] (Scheme [1]). Ring opening of the 1,3-oxazinan-6-one has also been shown to produce a variety of carboxylic acids, esters, and amides.[7] [8] [9] [10] Herein the versatility of the 1,3-oxazinan-6-one is further ­exploited to produce chiral substituted β3-amino ketones.

It was proposed to produce the N-protected β3-amino ketones in two steps from the 1,3-oxazinan-6-one. Firstly, the 1,3-oxazinan-6-one would be enolized and then acylated by addition of an acyl halide. The 5-acylated oxazinanone would then be subjected to an acid-mediated ring opening followed by an in situ decarboxylation to produce the N-protected β-amino ketone (Scheme [2]).

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Scheme 1 Transformations of the 1,3-oxazinan-6-one to produce stereopure β-amino acid derivatives

The starting 1,3-oxazinan-6-ones 1–4 were easily prepared in three steps from the parent N-protected α-amino acids via the Arndt–Eistert homologation to produce the corresponding β-amino acids. The β-amino acids were then cyclized using a previously described method[7] [8] [9] [10] to afford the N-protected 4-substituted 1,3-oxazinan-6-ones 1–4.

The 5-position of the 1,3-oxazinan-6-one was then acylated using enolate chemistry.[ 11 ] Enolization of the 1,3-oxazinan-6-ones 1–4 was performed using LiHMDS as the base at –78 °C. The acyl halide was then added at –78 °C. The reaction was maintained at –78 °C for three hours before warming to –50 °C and quenching with an ammonium chloride solution (Table [1]).[ 11 ] A combination of the 4-substituted 1,3-oxazinan-6-ones 1–4 and various acyl halides were subjected to these conditions, and the results are shown in Table [1]. Moderate to good yields were obtained across a range of different substrates, however, the pivaloyl chloride used in entries 3, 6, and 9 consistently gave the lowest yields (30%, 43%, and 28%, respectively). Although the stereoselectivity of the 5-acylation reaction is not of relevance, because the stereocenter is removed in the next transformation to give the β-amino ketone, in all cases the trans isomer was produced with high diastereoselectivity (>95% dr, Table [1]). The trans selectivity was determined using coupling constants observed in the 1H NMR spectra. The trans selectivity has also been observed with both 5-alkylations and 5-hydroxylations of numerous 4-substituted 1,3-oxazinan-6-ones.[7] [9] [10]

Zoom Image
Scheme 2 Proposed route to access β-amino ketones from 1,3-oxazinan-6-ones

Table 1 Acylation of the 1,3-Oxazinan-6-ones 1–4 and β-Amino Ketone Formation 15–24

Entry

Oxazinanone

R1

R2

Product (yield, %)

Product (yield, %)

ee (%)

 1

1

i-Pr

Et

 5 (80)

15 (91)

 97

 2

1

i-Pr

Ph

 6 (71)

16 (89)

100

 3

1

i-Pr

t-Bu

 7 (30)

17 (70)

 99

 4

2

n-Bu

Et

 8 (79)

18 (82)

 97

 5

2

n-Bu

Ph

 9 (65)

19 (66)

 99

 6

2

n-Bu

t-Bu

10 (43)

20 (90)

100

 7

3

s-Bu

Et

11 (79)

21 (63)

 98

 8

3

s-Bu

Ph

12 (78)

22 (75)

100

 9

3

s-Bu

t-Bu

13 (28)

23 (87)

 98

10

4

Bn

Et

14 (66)

24 (85)

100

a Reaction conditions: (a) 1. LiHMDS, THF, –78 °C, 40 min; 2. R2COCl, –78 °C to –50 °C, 3 h; 3. NH4Cl; (b) 2 M HCl, THF, 50 °C, 4–6 h.

The 5-acylated 1,3-oxazinan-6-ones 5–14 were then transformed into the β-amino ketones under mild acidic conditions (Table [1]).[ 12 ] The 5-acylated 1,3-oxazinan-6-ones 5–14 were dissolved in a mixture of THF and 2 M HCl, and the mixture was heated at 50 °C for 4–6 h. Under the acidic conditions the 1,3-oxazinan-6-one ring opens to produce the corresponding carboxylic acid. In situ decarboxylation of the β-keto carboxylic acid and hydrolysis of the iminium species then occurs to produce the β-amino ketone (Scheme [3]). The substituted β3-amino ketones 15–24 were all prepared in high yields (Table [1]).[12] [13]

Zoom Image
Scheme 3 Mechanism of the β-amino ketone formation

In an extension of this work, it was proposed that an N-methyl β-amino ketone could also be produced using acidic conditions. It has been established that reductive cleavage of the 1,3-oxazinan-6-one ring employing BF3·OEt2 or TFA and triethylsilane produces N-methyl β-amino acids.[7] [8] [9] [10] It was proposed to use the same acidic reductive cleavage conditions to transform the 5-acylated 1,3-oxazinan-6-one 5 into the N-methyl β-amino ketone 25 (Scheme [4]). However, when this reaction was attempted the desired N-methyl β-amino ketone 25 was not obtained. The only product observed was the Cbz derivative of a secondary amine 27. This was formed via an iminium species 26 which is intercepted by a hydride anion from triethylsilane. Possible uses of this unexpected reaction are now being investigated.

Zoom Image
Scheme 4 Attempted formation of the N-methyl β-amino ketone 25 and the mechanism of formation of the unexpected byproduct 27

To further elaborate the methodology demonstrated here to produce β-amino ketones, a 5-methylated 1,3-oxazinan-6-one 28 would be 5-acylated and then subsequently subjected to acidic conditions to produce a disubstituted β2,3-amino ketone. The previously synthesized 5-methyl 1,3-oxazinan-6-one 28 was produced using enolate chemistry and quenching with methyl triflate using established conditions.[7] [9] [10] The 5-methyl 1,3-oxazinan-6-one 28 was then enolized and 5-acylated using benzoyl chloride to afford 29 in moderate yield (40%). The 5,5-disubstituted 1,3-oxazinan-6-one 29 was then subjected to acidic conditions to produce the β-amino ketone as a mixture of diastereoisomers 30 and 31 in a good yield (82%, Scheme [5]). Although the stereochemistry was not the focus of this transformation, because the stereocenter is epimerized under the decarboxylation conditions, a sample of the trans isomer was obtained during purification. This transformation further demonstrates the capacity of this methodology to produce highly functionalized substituted β2,3-amino ketones.

Zoom Image
Scheme 5Acylation of the 1,3-oxazinan-6-one 28 and β-amino ketone (30 and 31) formation. Reagents and conditions: (a) 1. LiHMDS, THF, –78 °C, 40 min; 2. PhCOCl, –78 °C to –50 °C, 3 h; 3. NH4Cl (40%); (b) 2 M HCl, THF, 50 °C, 4–6 h (82%).

In summary, the synthesis of chiral substituted β3-amino ketones 15–24 has been described starting from 4-substituted 1,3-oxazinan-6-ones 1–4. The 1,3-oxazinan-6-ones 1–4 were acylated using enolate chemistry to afford the 5-acylated 1,3-oxazinan-6-ones 5–14 in moderate to high yields. The 5-acylated products 5–14 were then smoothly transformed into the corresponding β-amino ketones 15–24, under acidic conditions. This methodology was further expanded to demonstrate that a disubstituted β2,3-amino ketone (30 and 31) could also be produced starting from the 5-methyl 4-substituted 1,3-oxazinan-6-one 28. The methodology described again highlights the versatility of the 1,3-oxazinan-6-one as a useful scaffold to access a diverse assortment of β-amino acids and β-amino ketones for use in the peptidomimetic field.


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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

  • 2 Webster SP, Binnie M, McConnell KM. M, Sooy K, Ward P, Greaney MF, Vinter A, Pallin TD, Dyke HJ, Gill MI. A, Warner I, Seckl JR, Walker BR. Bioorg. Med. Chem. Lett. 2010; 20: 3265
    CrossrefSearch in Google Scholar
  • 6 Geng H, Huang K, Sun T, Li W, Zhang X, Zhou L, Wu W, Zhang X. J. Org. Chem. 2011; 76: 332
    CrossrefSearch in Google Scholar
  • 7 Nguyen NH, Sleebs BE, Hughes AB. Tetrahedron 2012; 68: 4745
    CrossrefSearch in Google Scholar
  • 9 Sleebs BE, Hughes AB. J. Org. Chem. 2007; 72: 3340
    CrossrefSearch in Google Scholar
  • 10 Sleebs BE, Nguyen NH, Hughes AB. Tetrahedron 2013; 69: in press
    Search in Google Scholar
  • 11 General Procedure 1 5-Acylation of 1,3-Oxazinan-6-ones A solution of the 1,3-oxazinan-6-one 1–4 (0.1 M in dry freshly distilled THF) was cooled to –78 °C under an argon atmosphere. Then LiHMDS (1.1 equiv of a 1.0 M solution in THF) was added dropwise, and the solution was left to stir at –78 °C for 40 min. The acylating agent (3.0 equiv) was then added dropwise and stirring was continued for 3 h at –78 °C. The solution was then allowed to warm to –50 °C, and the reaction was then quenched with sat. NH4Cl solution (5 mL). The solution was diluted with EtOAc (20 mL) and washed with H2O (20 mL). The organic layer was dried (MgSO4) and concentrated in vacuo to give an oil. The oil was subjected to flash column chromatography, eluting with 5–30% EtOAc–hexane. Data for (4S,5R)-N-Benzyloxycarbonyl-4-isopropyl-5-propionyl-1,3-oxazinan-6-one (5) General Procedure 1 was followed for the acylation of oxazinanone 1 (63 mg, 0.23 mmol) with propionyl chloride (59.8 μL, 0.68 mmol), to afford the desired 5-substituted 1,3-oxazinan-6-one 5 as a clear oil (crystallized on standing; 60 mg, 80% yield); mp 82–84 °C; Rf = 0.23 (20% EtOAc–hexane); [α]D 25 +116 (c 2.17, MeOH). 1H NMR (300 MHz, CDCl3): δ = 7.33 (s, 5 H), 5.93 (d, 1 H, J = 9.9 Hz), 5.17 (s, 2 H), 4.93 (d, 1 H, J = 9.9 Hz), 4.59 (t, 1 H, J = 7.2 Hz), 3.73 (d, 1 H, J = 7.2 Hz), 2.84–2.73 (m, 1 H), 2.58–2.47 (m, 1 H), 1.88–1.77 (m, 1 H), 1.09 (t, 3 H, J = 7.2 Hz), 0.89 (d, 3 H, J = 7.2 Hz), 0.85 (d, 3 H, J = 7.2 Hz). 13C NMR (75 MHz, CDCl3): δ = 202.7 167.3, 154.5, 134.9, 128.3, 128.1, 127.8, 72.9, 68.2, 55.9, 55.1, 36.5, 31.0, 18.3, 18.1, 7.2. IR (film): νmax = 2967, 2940, 1748, 1717, 1458, 1412, 1258, 1123, 979 cm–1. HRMS (ESI–): m/z calcd for C18H23NO5 [M – H]–: 332.1503; found: 332.1496.
  • 12 General Procedure 2
    Formation of the β3-Amino Ketones     The oxazinanone 15–24 was dissolved in a mixture of THF–2 M HCl (1:1, 0.013 M solution), and the reaction mixture was gently heated to 50 °C for 4–6 h. The THF was then removed under reduced pressure. The aqueous solution was taken up EtOAc and washed with H2O (3 × 10 mL) followed by brine (1 × 10 mL). The organic layer was dried (MgSO4) and evaporated in vacuo to give an oil. The oil was subjected to flash column chromatography, eluting with 5–20% EtOAc–hexane.
  • 13 Data for (5R)-(N-Benzyloxylcarbonyl-5-amino)-6-methyl-heptan-2-one (15) General Procedure 2 was followed for the hydrolysis of the 1,3-oxazinan-6-one 5 (31 mg, 0.09 mmol), and afforded the β-amino ketone 15 as a white solid (24 mg, 92% yield); mp 75–77 °C; Rf = 0.50 (30% EtOAc–hexane); [α]D 25 –3.6 (c 1.09, MeOH). 1H NMR (300 MHz, CDCl3): δ = 7.32–7.27 (m, 5 H), 5.14 (d, 1 H, J = 8.9 Hz), 5.06 (s, 2 H), 3.83–3.76 (m, 1 H), 2.61 (br d, 2 H, J = 5.7 Hz), 2.47–2.33 (m, 2 H), 1.89–1.80 (m, 1 H), 1.00 (t, 3 H, J = 7.2 Hz), 0.89 (d, 3 H, J = 4.2 Hz), 0.87 (d, 3 H, J = 4.5 Hz). 13C NMR (75 MHz, CDCl3): δ = 210.0, 155.7, 136.3, 128.1, 127.6, 127.5, 66.2, 53.2, 43.9, 35.8, 31.2, 19.1, 18.2, 7.3. IR (film): νmax = 3325, 2940, 2878, 1709, 1682, 2539, 1454, 1416, 1308. HRMS (ESI+): m/z calcd for C16H23NO3 [M + H]+: 278.1751; found: 278.1756. HPLC [Chiralpak AD-H, PE–2-PrOH (90:10), 25 °C, 254 nm]: t R (major) = 7.1 min; t R (minor) = 6.1 min, 97% ee.

  • References and Notes

  • 2 Webster SP, Binnie M, McConnell KM. M, Sooy K, Ward P, Greaney MF, Vinter A, Pallin TD, Dyke HJ, Gill MI. A, Warner I, Seckl JR, Walker BR. Bioorg. Med. Chem. Lett. 2010; 20: 3265
    CrossrefSearch in Google Scholar
  • 6 Geng H, Huang K, Sun T, Li W, Zhang X, Zhou L, Wu W, Zhang X. J. Org. Chem. 2011; 76: 332
    CrossrefSearch in Google Scholar
  • 7 Nguyen NH, Sleebs BE, Hughes AB. Tetrahedron 2012; 68: 4745
    CrossrefSearch in Google Scholar
  • 9 Sleebs BE, Hughes AB. J. Org. Chem. 2007; 72: 3340
    CrossrefSearch in Google Scholar
  • 10 Sleebs BE, Nguyen NH, Hughes AB. Tetrahedron 2013; 69: in press
    Search in Google Scholar
  • 11 General Procedure 1 5-Acylation of 1,3-Oxazinan-6-ones A solution of the 1,3-oxazinan-6-one 1–4 (0.1 M in dry freshly distilled THF) was cooled to –78 °C under an argon atmosphere. Then LiHMDS (1.1 equiv of a 1.0 M solution in THF) was added dropwise, and the solution was left to stir at –78 °C for 40 min. The acylating agent (3.0 equiv) was then added dropwise and stirring was continued for 3 h at –78 °C. The solution was then allowed to warm to –50 °C, and the reaction was then quenched with sat. NH4Cl solution (5 mL). The solution was diluted with EtOAc (20 mL) and washed with H2O (20 mL). The organic layer was dried (MgSO4) and concentrated in vacuo to give an oil. The oil was subjected to flash column chromatography, eluting with 5–30% EtOAc–hexane. Data for (4S,5R)-N-Benzyloxycarbonyl-4-isopropyl-5-propionyl-1,3-oxazinan-6-one (5) General Procedure 1 was followed for the acylation of oxazinanone 1 (63 mg, 0.23 mmol) with propionyl chloride (59.8 μL, 0.68 mmol), to afford the desired 5-substituted 1,3-oxazinan-6-one 5 as a clear oil (crystallized on standing; 60 mg, 80% yield); mp 82–84 °C; Rf = 0.23 (20% EtOAc–hexane); [α]D 25 +116 (c 2.17, MeOH). 1H NMR (300 MHz, CDCl3): δ = 7.33 (s, 5 H), 5.93 (d, 1 H, J = 9.9 Hz), 5.17 (s, 2 H), 4.93 (d, 1 H, J = 9.9 Hz), 4.59 (t, 1 H, J = 7.2 Hz), 3.73 (d, 1 H, J = 7.2 Hz), 2.84–2.73 (m, 1 H), 2.58–2.47 (m, 1 H), 1.88–1.77 (m, 1 H), 1.09 (t, 3 H, J = 7.2 Hz), 0.89 (d, 3 H, J = 7.2 Hz), 0.85 (d, 3 H, J = 7.2 Hz). 13C NMR (75 MHz, CDCl3): δ = 202.7 167.3, 154.5, 134.9, 128.3, 128.1, 127.8, 72.9, 68.2, 55.9, 55.1, 36.5, 31.0, 18.3, 18.1, 7.2. IR (film): νmax = 2967, 2940, 1748, 1717, 1458, 1412, 1258, 1123, 979 cm–1. HRMS (ESI–): m/z calcd for C18H23NO5 [M – H]–: 332.1503; found: 332.1496.
  • 12 General Procedure 2
    Formation of the β3-Amino Ketones     The oxazinanone 15–24 was dissolved in a mixture of THF–2 M HCl (1:1, 0.013 M solution), and the reaction mixture was gently heated to 50 °C for 4–6 h. The THF was then removed under reduced pressure. The aqueous solution was taken up EtOAc and washed with H2O (3 × 10 mL) followed by brine (1 × 10 mL). The organic layer was dried (MgSO4) and evaporated in vacuo to give an oil. The oil was subjected to flash column chromatography, eluting with 5–20% EtOAc–hexane.
  • 13 Data for (5R)-(N-Benzyloxylcarbonyl-5-amino)-6-methyl-heptan-2-one (15) General Procedure 2 was followed for the hydrolysis of the 1,3-oxazinan-6-one 5 (31 mg, 0.09 mmol), and afforded the β-amino ketone 15 as a white solid (24 mg, 92% yield); mp 75–77 °C; Rf = 0.50 (30% EtOAc–hexane); [α]D 25 –3.6 (c 1.09, MeOH). 1H NMR (300 MHz, CDCl3): δ = 7.32–7.27 (m, 5 H), 5.14 (d, 1 H, J = 8.9 Hz), 5.06 (s, 2 H), 3.83–3.76 (m, 1 H), 2.61 (br d, 2 H, J = 5.7 Hz), 2.47–2.33 (m, 2 H), 1.89–1.80 (m, 1 H), 1.00 (t, 3 H, J = 7.2 Hz), 0.89 (d, 3 H, J = 4.2 Hz), 0.87 (d, 3 H, J = 4.5 Hz). 13C NMR (75 MHz, CDCl3): δ = 210.0, 155.7, 136.3, 128.1, 127.6, 127.5, 66.2, 53.2, 43.9, 35.8, 31.2, 19.1, 18.2, 7.3. IR (film): νmax = 3325, 2940, 2878, 1709, 1682, 2539, 1454, 1416, 1308. HRMS (ESI+): m/z calcd for C16H23NO3 [M + H]+: 278.1751; found: 278.1756. HPLC [Chiralpak AD-H, PE–2-PrOH (90:10), 25 °C, 254 nm]: t R (major) = 7.1 min; t R (minor) = 6.1 min, 97% ee.

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Zoom Image
Scheme 1 Transformations of the 1,3-oxazinan-6-one to produce stereopure β-amino acid derivatives
Zoom Image
Scheme 2 Proposed route to access β-amino ketones from 1,3-oxazinan-6-ones
Zoom Image
Scheme 3 Mechanism of the β-amino ketone formation
Zoom Image
Scheme 4 Attempted formation of the N-methyl β-amino ketone 25 and the mechanism of formation of the unexpected byproduct 27
Zoom Image
Scheme 5Acylation of the 1,3-oxazinan-6-one 28 and β-amino ketone (30 and 31) formation. Reagents and conditions: (a) 1. LiHMDS, THF, –78 °C, 40 min; 2. PhCOCl, –78 °C to –50 °C, 3 h; 3. NH4Cl (40%); (b) 2 M HCl, THF, 50 °C, 4–6 h (82%).