Synthesis of 2-Azabicyclo[n.2.0]alkane-Derived Building Blocks

Abstract

An approach to 2-azabicyclo[n.2.0]alkane derivatives (n = 1, 2), which relies on a tandem Strecker reaction–intramolecular nucleophilic cyclization (STRINC) sequence of the corresponding 2-(ω-chloroalkyl)cyclobutanones (in turn prepared by [2+2] cycloaddition of keteniminium salts and ethylene) is described. The utility of the method is demonstrated by multigram syntheses of bicyclic proline analogues, monoprotected diamines, as well as parent 2-azabicyclo[4.2.0]octane.

Key words

cycloaddition - bicyclic compounds - amino acids - conformational restriction - cyclobutanes - nitrogen heterocycles - keteniminium salts - Strecker reaction

Bicyclic cyclobutane-derived heteroaliphatic scaffolds have recently attracted attention in synthetic organic and medicinal chemistry as versatile sp³-rich low-molecular-weight hydrophilic conformationally restricted templates which comply with requirements of lead-oriented synthesis.[1] [2] In particular, belaperidone (1)[3] and ecenofloxacin (2)[4] (derived from 3-azabicyclo[3.2.0]heptane) have reached clinical trials as an antipsychotic and antibacterial agent, respectively (Figure [1]). Derivatives of the isomeric 2-azabicyclo[3.2.0]heptane scaffold were evaluated as inhibitors of dipeptidyl peptidase-4 (DPP-4) (3),[5] complement factor D (4),[6] or nonstructural protein 5A (NS5A).[7]

Figure 1 Biologically active azabicyclo[3.2.0]alkanes

Scheme 1 Known methods for the synthesis of 2-azabicyclo[3.2.0]heptanes and 2-azabicyclo[4.2.0]octanes

Despite these promising examples, derivatives of azabicyclo[n.2.0]alkanes remain quite rare in drug discovery.[8] In our opinion, the main reason behind this is the low synthetic accessibility of such structures. A number of papers have appeared describing the synthesis of various C-substituted 2-azabicyclo[3.2.0]heptanes and 2-azabicyclo[4.2.0]octanes. In most cases, intermolecular [2+2] cycloadditions of cyclic enamines or enecarbamates and in situ generated ketenes[5] ^, [9] [10] [11] [12] [13] [14] or other 2π-components[15–17] were used (Scheme [1], A). Other methods include intramolecular [2+2] photocycloaddition (Scheme [1], B[18] and F[19]), gold- or platinum-catalyzed cycloisomerization of ene-ynamides (Scheme [1], C),[20] [21] palladium-catalyzed carboamination of alkylidenecyclopropanes, followed by acid-catalyzed rearrangement (Scheme [1], D),[22] and intramolecular [2+2] cycloaddition involving keteniminium salt intermediates (Scheme [1], E).[23]

All of the above-mentioned methods rely on the annulation of the cyclobutane ring to the pyrrolidine/piperidine moiety, or simultaneous construction of both rings. In this work, we describe an alternative approach to 2-azabi­cyclo[n.2.0]alkanes, which relies on the formation of the heteroaliphatic ring as the key step. To achieve this, we projected using a one-pot tandem Strecker reaction–intramolecular nucleophilic cyclization (STRINC) sequence (Scheme [2]), which had been used previously by our group[24] [25] [26] [27] [28] and others[29–33] for the synthesis of various bicyclic ring systems, including bicyclic α-amino acids.[34] [35] [36] [37] [38] [39] [40] [41] [42] [43] Application of this retrosynthetic disconnection to 2-azabicyclo[3.2.0]heptane and 2-azabicyclo[4.2.0]octane systems led to 2-(ω-halo­alkyl)cyclobutanones 5 (Scheme [3]). These ω-halo ketones were not known in the literature; their further retro­synthetic analysis proposed by us relied on [2+2] cycloaddition of keteniminium salts 6 and ethylene.

Scheme 2 STRINC sequence

Scheme 3 Retrosynthetic disconnection of 2-azabicyclo[n.2.0]alkanes (n = 1, 2) used in this work

Notably, keteniminium salts 6 [44] [45] and ethylene[46] have rarely been used in previous analogous transformations, and, to the best of our knowledge, no examples of their mutual [2+2] cycloaddition have been reported to date. We found that the keteniminium salts 6a and 6b (generated in situ from amides 7a and 7b) reacted with ethylene at 75 °C at atmospheric pressure to give the corresponding cycloadducts, which provided the target ketones 5a and 5b after hydrolysis (Scheme [4]). Although the yields of products 5a and 5b were moderate (52 and 58%, respectively), they could be obtained on a scale up to 80 grams, since the starting materials are easily accessible. It should be stressed that these novel cyclobutane-derived ω-chloro ketones are versatile sp³-rich bifunctional building blocks of low molecular weight, which is fully compatible with the lead-oriented synthesis criteria.[1] Since these building blocks have become readily available now, their wide use in medicinal chemistry programs might be anticipated.

Scheme 4 Synthesis of 2-azabicyclo[n.2.0]alkane-derived proline analogues

First of all, we introduced ω-chloro ketones 5a and 5b into the STRINC reaction sequence. Under the standard reaction conditions (benzylamine, acetone cyanohydrin as the cyanide source, MeOH, reflux, 72 h), the target bicyclic nitrile 8a was obtained from 5a in 55% yield. In the case of 5b, a higher reaction temperature was required, so that product 8b was obtained in 64% yield when n-butanol was used as the solvent.

Hydrolysis of nitrile 8a, followed by catalytic debenzylation, proceeded smoothly and gave the target amino acid 9a, a bicyclic proline analogue, in 76% overall yield (as a hydrochloride­).[47] On the other hand, analogous transformations of 8b gave the product 10b·HCl (53% yield) without the carboxylic acid function. Obviously, decyanation occurred at the hydrolysis step, so that iminium intermediate 11b was initially formed; we were able to isolate amino ketone­ 12b (47% yield, as N-Boc derivative) from the reaction mixture. Formation of analogous products was observed by us previously for 2-azabicyclo[3.3.0]octane derivatives;[28] it is interesting, however, to outline how subtle conformational differences lead to different reaction outcomes in the following series: bridged bicyclic systems – 2-azabicyclo[3.2.0]heptane – 2-azabicyclo[4.2.0]octane – 2-azabicyclo[3.3.0]octane. It is apparent that the observed regularity can be explained by ring system strain caused by the presence of a bridgehead sp²-hybridized carbon atom in the corresponding iminium intermediates (such as 11b).

Hydrolysis of the nitrile moiety in 8b was accomplished by using 75% aq H₂SO₄. Under these conditions, amide 13b formed, and was isolated in 67% yield. Further hydrolysis of 13b, followed by catalytic hydrogenolysis gave the target amino acid 9b (81% yield, as hydrochloride).

Alternatively, nitriles 8a and 8b were reduced with LiAlH₄ to give diamines 14a and 14b (98 and 91% yield, respectively) (Scheme [5]). Orthogonally protected Boc derivatives 15a and 15b were also obtained by using standard protecting group manipulations (68 and 73% yield from 14a and 14b, respectively). Compounds 14 and 15 fall into the class of monoprotected bicyclic conformationally restricted diamines, which have proven their utility in drug discovery and other areas.[48]

Scheme 5 Synthesis of monoprotected diamine derivatives 14 and 15

In conclusion, the tandem Strecker reaction–intramolecular nucleophilic cyclization (STRINC) sequence is an efficient method for the construction of 2-azabicyclo[3.2.0]heptane and 2-azabicyclo[4.2.0]octane systems, which was demonstrated by synthesis of bicyclic conformationally restricted proline analogues and monoprotected diamines on a multigram scale. It was shown that subtle differences in conformational behavior of these bicyclic systems lead to different chemical reactivity (i.e., in hydrolysis of the corresponding α-amino nitriles). Other properties including potential biological activity could also be affected; therefore, series of building blocks derived from 2-azabicyclo[n.2.0]octanes are of special interest for application in drug discovery.

Solvents were purified according to standard procedures.[49] Compounds 7a [50] and 7b [51] were obtained by using previously reported methods. All other starting materials were purchased from commercial sources. Melting points were measured on an MPA100 OptiMelt automated melting point system. Analytical TLC was performed on Polychrom SI F254 plates. Column chromatography was performed by using Kieselgel Merck 60 (230–400 mesh) as the stationary phase. ¹H and ¹³C NMR spectra were recorded on a Bruker 170 Avance 500 spectrometer (¹H: 500 MHz, ¹³C: 126 MHz) and a Varian Unity Plus 400 spectrometer (¹H: 400 MHz, ¹³C: 101 MHz). Chemical shifts are reported in ppm downfield from TMS as an internal standard. Elemental analyses were performed at the Laboratory of Organic Analysis, Department of Chemistry, National Taras Shevchenko University of Kyiv. Mass spectra were recorded on an Agilent 1100 LCMSD SL instrument (chemical ionization, APCI) and an Agilent 5890 Series II 5972 GCMS instrument (electron impact ionization, EI). Preparative flash chromatography was performed on a Combiflash Companion chromatograph using 40 g RediSep columns.

2-(2-Chloroethyl)cyclobutanone (5a)

To a solution of amide 7a (157 g, 1.05 mol) in 1,2-dichloroethane (2.5 L), Tf₂O (355 g, 1.26 mol) was added below 0 °C upon vigorous stirring. The reaction mixture was stirred for 15 min and then heated to 75 °C. At this temperature, collidine (165 g, 1.36 mol) was added dropwise with stirring over 20–30 min; ethylene was bubbled intensively through the reaction mixture during addition. After the addition was complete, ethylene was bubbled at 75 °C for an additional 2 h. The resulting mixture was stirred at this temperature overnight, then cooled to r.t. and evaporated in vacuo. The residue was diluted with H₂O (700 mL), and Na₂CO₃ was added in portions upon stirring to pH 8–9. Hexanes (0.5 L) were added, and the mixture was stirred overnight. Concd aq HCl was added to pH 1, and the organic phase was separated. The aqueous phase was washed with hexanes (2 × 0.5 L), dried over MgSO₄, and evaporated in vacuo. The residue was distilled at 1 mmHg to give product 5a.

Yield: 82.3 g (52%); colorless liquid; bp 41 °C/1 mmHg.

¹H NMR (500 MHz, CDCl₃): δ = 3.63–3.51 (m, 2 H), 3.51–3.40 (m, 1 H), 3.12–2.97 (m, 1 H), 2.94–2.82 (m, 1 H), 2.28–2.16 (m, 1 H), 2.16–2.05 (m, 1 H), 1.96–1.83 (m, 1 H), 1.71–1.58 (m, 1 H).

¹³C NMR (126 MHz, CDCl₃): δ = 209.8, 57.0, 44.2, 42.0, 31.9, 16.3.

MS (EI): m/z = 132/134 [M⁺], 104/106 [M⁺ – C₂H₄].

Anal. Calcd for C₆H₉ClO: C, 54.35; H, 6.84; Cl, 26.74. Found: C, 54.34; H, 7.05; Cl, 26.80.

2-(3-Chloropropyl)cyclobutanone (5b)

Prepared from 7b using the procedure described above for 5a.

Yield: 77.6 g (58%); yellowish liquid; bp 54 °C/1 mmHg.

¹H NMR (500 MHz, CDCl₃): δ = 3.57–3.44 (m, 2 H), 3.32–3.18 (m, 1 H), 3.07–2.94 (m, 1 H), 2.94–2.82 (m, 1 H), 2.24–2.11 (m, 1 H), 1.93–1.70 (m, 3 H), 1.70–1.56 (m, 2 H).

¹³C NMR (126 MHz, CDCl₃): δ = 210.7, 59.0, 44.1, 44.0, 29.6, 26.4, 16.4.

MS (EI): m/z = 146/148 [M⁺], 118/120 [M⁺ – C₂H₄].

Anal. Calcd for C₇H₁₁ClO: C, 57.35; H, 7.56; Cl, 24.18. Found: C, 57.02; H, 7.70; Cl, 23.78.

2-Benzyl-2-azabicyclo[3.2.0]heptane-1-carbonitrile (8a)

To a solution of acetone cyanohydrin (159 g, 1.87 mol) in anhyd MeOH (1.8 L), benzylamine (67.9 g, 0.634 mol) was added under an argon atmosphere, and the resulting mixture was left at r.t. for 30 min. Ketone 11 (80.0 g, 0.603 mol) was added, and the mixture was refluxed for 72 h and then evaporated in vacuo. A solution of 5% aq NaOH was added to pH 12, the mixture was stirred vigorously for 30 min, and then extracted with t-BuOMe (2 × 0.5 L). The organic extracts were washed with 2 M aq HCl (1 L) and H₂O (0.5 L). The combined aqueous phases were made alkaline with 25% aq NaOH (to pH 12) and extracted with t-BuOMe (2 × 0.5 L). The organic extracts were dried over Na₂SO₄ and evaporated in vacuo. The crude product was purified by column chromatography (silica gel, hexanes–t-BuOMe–Et₃N, 10:3:1) to give 8a.

Yield: 70.4 g (55%); yellowish oil.

¹H NMR (500 MHz, CDCl₃): δ = 7.44–7.32 (m, 4 H), 7.29 (t, J = 7.0 Hz, 1 H), 3.95 (d, J = 13.0 Hz, 1 H), 3.60 (d, J = 13.0 Hz, 1 H), 3.38–3.29 (m, 1 H), 2.98–2.88 (m, 1 H), 2.75 (td, J = 9.3, 6.2 Hz, 1 H), 2.39–2.19 (m, 3 H), 2.03–1.92 (m, 1 H), 1.66–1.55 (m, 2 H).

¹³C NMR (126 MHz, CDCl₃): δ = 137.9, 128.3, 127.9, 126.9, 120.7, 59.5, 52.7, 50.3, 44.2, 30.1, 23.6, 21.6.

MS (CI): m/z = 213 [MH⁺].

Anal. Calcd for C₁₄H₁₆N₂: C, 79.21; H, 7.6; N, 13.20. Found: C, 79.53; H, 7.39; N, 13.06.

2-Benzyl-2-azabicyclo[4.2.0]octane-1-carbonitrile (8b)

Prepared from 5b using the procedure described above for 8a and purified by chromatography (hexanes–t-BuOMe–Et₃N, 10:1:1).

Yield: 59.2 g (64%); yellowish oil.

¹H NMR (500 MHz, CDCl₃): δ = 7.45–7.33 (m, 4 H), 7.29 (t, J = 6.7 Hz, 1 H), 3.83 (d, J = 13.9 Hz, 1 H), 3.45 (d, J = 14.0 Hz, 1 H), 2.93–2.81 (m, 1 H), 2.66–2.56 (m, 1 H), 2.51–2.40 (m, 1 H), 2.34–2.25 (m, 1 H), 2.13–2.02 (m, 2 H), 1.97 (dd, J = 17.5, 8.9 Hz, 1 H), 1.79–1.66 (m, 1 H), 1.61–1.48 (m, 3 H).

¹³C NMR (126 MHz, CDCl₃): δ = 138.2, 127.9, 126.7, 118.5, 56.4, 55.4, 44.8, 38.5, 30.1, 22.8, 21.9, 21.8.

MS (CI): m/z = 227 [MH⁺].

Anal. Calcd for C₁₅H₁₈N₂: C, 79.61; H, 8.02; N, 12.38. Found: C, 79.36; H, 7.83; N, 12.38.

2-Azabicyclo[3.2.0]heptane-1-carboxylic Acid Hydrochloride (9a·HCl)

Amino nitrile 8a (21.0 g, 99.3 mmol) was refluxed in 6 M aq HCl (300 mL) for 36 h, then cooled and evaporated in vacuo. The residue was made alkaline with 20% aq KOH (100 mL), and the resulting solution was evaporated in vacuo. H₂O (2 × 100 mL) was added, and the mixture was evaporated in vacuo twice to remove residual NH₃. The residue was acidified with 6 M aq HCl to pH 1–2 and evaporated in vacuo again. The resulting solid was triturated with anhyd EtOH (200 mL) and filtered. The filtrate was evaporated in vacuo, and the residue was dissolved in H₂O (200 mL). Then 10% Pd/C (5.02 g) was added, and the resulting mixture was hydrogenated in an autoclave at 70 °C (50 bar) for 36 h (monitored by ¹H NMR). The catalyst was filtered off and the filtrates were evaporated in vacuo. The crude product was triturated with acetone (100 mL), filtered, and dried in vacuo to give 9a·HCl.[47]

Yield: 13.4 g (76%); colorless solid; mp 213–217 °C (dec.).

¹H NMR (500 MHz, DMSO-d ₆): δ = 13.79 (br s, 1 H), 10.69 (s, 1 H), 9.05 (s, 1 H), 3.59–3.45 (m, 2 H), 3.17–3.06 (m, 1 H), 2.56–2.35 (m, 2 H), 2.25–2.09 (m, 1 H), 1.99–1.87 (m, 1 H), 1.82 (dd, J = 12.6, 4.9 Hz, 1 H), 1.76–1.63 (m, 1 H).

¹³C NMR (126 MHz, DMSO-d ₆): δ = 170.8, 67.6, 45.2, 40.4, 29.7, 24.0, 19.8.

MS (CI): m/z = 142 [MH⁺], 96 [M⁺ – COOH].

Anal. Calcd for C₇H₁₂ClNO₂: C, 47.33; H, 6.81; N, 7.89; Cl, 19.96. Found: C, 47.49; H, 6.93; N, 8.00; Cl, 19.56.

2-Benzyl-2-azabicyclo[4.2.0]octane-1-carboxamide (13b)

Nitrile 8b (10.0 g, 44.0 mmol) was dissolved in 75% aq H₂SO₄ (100 mL). The resulting solution was stirred at 85 °С for 20 h, then cooled and poured carefully into 25% aq NH₄OH (300 mL) below 25 °C. The resulting mixture was extracted with CH₂Cl₂ (2 × 200 mL). The combined extracts were washed with H₂O (200 mL), dried over Na₂SO₄, and evaporated in vacuo. Et₂O (100 mL) was added, and the mixture was stirred at 0 °С for 15 min. The precipitate was filtered, washed with Et₂O (30 mL), and dried in vacuo to give 13b.

Yield: 7.25 g (67%); yellowish solid; mp 106–109 °C.

¹H NMR (500 MHz, CDCl₃): δ = 7.33–7.26 (m, 2 H), 7.26–7.20 (m, 3 H), 7.14 (s, 1 H), 5.52 (s, 1 H), 3.48 (d, J = 13.5 Hz, 1 H), 3.16 (d, J = 13.5 Hz, 1 H), 2.75 (d, J = 10.7 Hz, 1 H), 2.44–1.97 (m, 6 H), 1.69–1.54 (m, 1 H), 1.40–1.28 (m, 3 H).

¹³C NMR (126 MHz, CDCl₃): δ = 180.2, 138.2, 128.7, 128.4, 127.1, 65.8, 56.2, 46.8, 39.4, 29.4, 23.6, 23.1, 19.4.

MS (CI): m/z = 245 [MH⁺], 200 [MH⁺ – CO – NH₃].

Anal. Calcd for C₁₅H₂₀N₂O: C, 73.74; H, 8.25; N, 11.47. Found: C, 73.34; H, 8.45; N, 11.83.

2-Azabicyclo[4.2.0]octane-1-carboxylic Acid Hydrochloride (9b·HCl)

Amide 13b (6.95 g, 28.5 mmol) was dissolved in 6 M aq HCl (70 mL). The resulting solution was refluxed for 18 h, and then evaporated in vacuo. The residue was triturated with CHCl₃ (140 mL), the precipitate was filtered off, and the filtrate was evaporated in vacuo. The crude product 13b was dissolved in H₂O (80 mL). Then 10% Pd/C (2.43 g) was added, and the mixture was hydrogenated in an autoclave at 70 °C and 50 bar for 36 h (monitored by ¹H NMR). The catalyst was filtered off, and the filtrates were evaporated in vacuo. The residue was triturated with acetone (20 mL), filtered, and dried in vacuo to give 9b as hydrochloride.

Yield: 4.42 g (81%); white solid; mp 232–236 °C (dec.).

¹H NMR (500 MHz, DMSO-d ₆): δ = 10.19 (br s, 1 H), 9.17 (br s, 1 H), 3.16 (dt, J = 12.2, 3.5 Hz, 1 H), 2.99–2.89 (m, 1 H), 2.79 (t, J = 10.9 Hz, 1 H), 2.42 (dt, J = 11.6, 8.6 Hz, 1 H), 2.30 (td, J = 18.1, 8.9 Hz, 1 H), 2.21 (ddd, J = 11.7, 8.7, 3.0 Hz, 1 H), 2.00–1.87 (m, 2 H), 1.63–1.46 (m, 3 H); COOH is exchanged with HDO.

¹³C NMR (126 MHz, DMSO-d ₆): δ = 171.2, 60.8, 40.9, 35.4, 27.1, 22.8, 20.3, 17.3.

MS (CI): m/z = 156 [MH⁺].

Anal. Calcd for C₈H₁₄ClNO₂: C, 50.13; H, 7.36; N, 7.31; Cl, 18.50. Found: C, 49.73; H, 7.31; N, 6.96; Cl, 18.90.

(2-Benzyl-2-azabicyclo[3.2.0]heptan-1-yl)methanamine (14a)

To a suspension of LiAlH₄ (7.15 g, 0.188 mol) in anhyd THF (200 mL), a solution of 8a (20.0 g, 94.3 mmol) in anhyd THF (100 mL) was added dropwise with stirring at –78 °C. The mixture was stirred at this temperature for 15 min, then allowed to warm to r.t., stirred for 18 h, and cooled to 0 °C. H₂O (7.2 mL) was added at this temperature dropwise with stirring, followed by 15% aq NaOH (7.2 mL) and H₂O (21.5 mL). The precipitate was filtered and washed with THF (100 mL). The combined filtrates were evaporated in vacuo to give the product 14a.

Yield: 20.1 g (98%); colorless oil.

¹H NMR (500 MHz, CDCl₃): δ = 7.35–7.25 (m, 4 H), 7.25–7.19 (m, 1 H), 3.65 (d, J = 13.4 Hz, 1 H), 3.25 (d, J = 13.4 Hz, 1 H), 3.03 (t, J = 8.0 Hz, 1 H), 2.78 (d, J = 13.4 Hz, 1 H), 2.69 (d, J = 13.7 Hz, 1 H), 2.67–2.60 (m, 2 H), 2.18–2.01 (m, 2 H), 1.87 (s, 2 H), 1.80–1.69 (m, 1 H), 1.50–1.38 (m, 2 H), 1.38–1.30 (m, 1 H).

¹³C NMR (126 MHz, CDCl₃): δ = 139.8, 128.0, 127.8, 126.2, 68.7, 51.4, 51.3, 45.3, 39.5, 29.8, 20.2, 19.6.

MS (CI): m/z = 217 [MH⁺].

Anal. Calcd for C₁₄H₂₀N₂: C, 77.73; H, 9.32; N, 12.95. Found: C, 77.64; H, 9.69; N, 12.66.

(2-Benzyl-2-azabicyclo[4.2.0]octan-1-yl)methanamine (14b)

Prepared from 8b using the procedure described above for 14a.

Yield: 20.4 g (91%); colorless oil.

¹H NMR (500 MHz, CDCl₃): δ = 7.36–7.24 (m, 4 H), 7.25–7.16 (m, 1 H), 3.74 (d, J = 13.9 Hz, 1 H), 3.05 (t, J = 13.9 Hz, 1 H), 2.95 (d, J = 13.4 Hz, 1 H), 2.72 (d, J = 10.8 Hz, 1 H), 2.67 (d, J = 13.5 Hz, 1 H), 2.35–2.16 (m, 2 H), 2.05–1.93 (m, 1 H), 1.92–1.82 (m, 1 H), 1.77 (s, 2 H), 1.57–1.48 (m, 1 H), 1.48–1.41 (m, 1 H), 1.41–1.29 (m, 2 H), 1.30–1.18 (m, 1 H).

¹³C NMR (126 MHz, CDCl₃): δ = 139.6, 128.1, 128.0, 127.7, 127.6, 126.1, 60.4, 52.9, 47.8, 45.3, 35.6, 28.6, 23.3, 22.1, 21.2.

MS (CI): m/z = 231 [MH⁺].

Anal. Calcd for C₁₅H₂₂N₂: C, 78.21; H, 9.63; N, 12.16. Found: C, 77.93; H, 9.31; N, 11.97.

tert-Butyl (2-Azabicyclo[3.2.0]heptan-1-ylmethyl)carbamate (15a)

To a solution of 14a (20.6 g, 95.4 mmol) in anhyd CH₂Cl₂ (200 mL), Et₃N (15.6 mL, 114 mmol) was added. The reaction mixture was cooled to 10 °C, and a solution of Boc₂O (22.8 g, 105 mmol) in anhyd CH₂Cl₂ (100 mL) was added. The resulting mixture was stirred at r.t. overnight, then washed with H₂O (2 × 500 mL). The organic phase was dried over Na₂SO₄ and evaporated in vacuo.

(NH₂)₄CO₃ (27.9 g, 0.441 mol) and MeOH (300 mL) were added to the residue, followed by 5% Pd/C (26.5 g). The mixture was refluxed for 3 h, and then cooled. The catalyst was filtered off, and the filtrates were evaporated in vacuo. Then 5% aq NaOH was added to pH 12, and the mixture was extracted with CH₂Cl₂ (2 × 100 mL). The combined organic extracts were washed with H₂O, dried over Na₂SO₄, and evaporated in vacuo to give 15a.

Yield: 14.7 g (68%); white powder; mp 75–77 °C.

¹H NMR (500 MHz, CDCl₃): δ = 4.96 (br s, 0.9 H), 4.77 (br s, 0.1 H), 3.41–3.26 (m, 1 H), 3.26–3.10 (m, 3 H), 2.55–2.43 (m, 1 H), 2.04–1.91 (m, 2 H), 1.81–1.69 (m, 1 H), 1.69–1.59 (m, 1 H), 1.52 (dd, J = 12.1, 4.3 Hz, 1 H), 1.46–1.37 (m, 1 H), 1.40 (s, 9 H), 1.35–1.25 (m, 1 H).

¹³C NMR (126 MHz, CDCl₃): δ = 156.0, 78.4, 65.3, 46.5, 45.6, 39.3, 32.5, 29.2, 27.9, 18.7.

MS (EI): m/z = 170 [M⁺ – C₄H₈], 57 [C₄H₉ ⁺].

Anal. Calcd for C₁₂H₂₂N₂O₂: C, 63.69; H, 9.80; N, 12.38. Found: C, 63.85; H, 9.69; N, 12.49.

tert-Butyl (2-Azabicyclo[4.2.0]octan-1-ylmethyl)carbamate (15b)

Prepared from 14b using the procedure described above for 15a.

Yield: 14.8 g (73%); yellowish oil.

¹H NMR (500 MHz, CDCl₃): δ = 5.02 (br s, 0.8 H), 4.83 (br s, 0.2 H), 3.13 (dd, J = 13.1, 4.4 Hz, 1 H), 3.04 (dd, J = 12.8, 6.0 Hz, 1 H), 2.82–2.70 (m, 1 H), 2.65–2.50 (m, 1 H), 2.07–1.93 (m, 1 H), 1.83–1.62 (m, 5 H), 1.55–1.42 (m, 2 H), 1.39 (s, 9 H), 1.34–1.23 (m, 2 H).

¹³C NMR (126 MHz, CDCl₃): δ = 156.1, 78.3, 56.1, 46.5, 40.6, 33.8, 28.0, 27.9, 25.3, 22.5, 20.2.

MS (EI): m/z = 184 [M⁺ – C₄H₈], 167 [M⁺ – Boc], 110 [M⁺ – CH₂NHBoc].

Anal. Calcd for C₁₃H₂₄N₂O₂: C, 64.97; H, 10.07; N, 11.66. Found: C, 64.82; H, 9.82; N, 12.03.

2-Azabicyclo[4.2.0]octane Hydrochloride (10b·HCl)

Prepared from 8b using the procedure described above for 9a·HCl.

Yield: 26.2 g (53%); colorless solid; mp 143–147 °C (dec.).

¹H NMR (500 MHz, DMSO-d ₆): δ = 9.60 (br s, 1 H), 9.22 (br s, 1 H), 3.69–3.59 (m, 1 H), 3.09–2.95 (m, 1 H), 2.86–2.72 (m, 1 H), 2.56–2.45 (m, 1 H), 2.28–2.15 (m, 1 H), 2.13–2.00 (m, 1 H), 1.94–1.66 (m, 4 H), 1.59–1.42 (m, 2 H).

¹³C NMR (126 MHz, DMSO-d ₆): δ = 48.3, 39.3, 31.2, 23.5, 22.7, 22.3, 18.4.

MS (CI): m/z = 112 [MH⁺].

Anal. Calcd for C₇H₁₄ClN: C, 56.94; H, 9.56; N, 9.49; Cl, 24.01. Found: C, 56.91; H, 9.91; N, 9.64; Cl, 23.77.

tert-Butyl Benzyl[3-(2-oxocyclobutyl)propyl]carbamate (N-Boc-12b)

N-Boc-12b was isolated from the crude product obtained by hydrolysis of 8b (0.500 g, 2.36 mmol) as described above (6 M aq HCl, reflux, 18 h). The residue after evaporation of the reaction mixture was dissolved in anhyd CH₂Cl₂ (30 mL), and Et₃N (2.32 mL, 16.9 mmol) was added. The reaction mixture was cooled to 10 °C, and a solution of Boc₂O (3.38 g, 15.6 mmol) in anhyd CH₂Cl₂ (15 mL) was added. The resulting mixture was stirred at r.t. overnight, then washed with H₂O (2 × 50 mL). The organic phase was dried over Na₂SO₄ and evaporated in vacuo. The crude product was purified by using flash chromatography (silica gel, hexane–t-BuOMe, 4:1).

Yield: 0.351 g (47%); yellowish oil.

¹H NMR (500 MHz, CDCl₃): δ = 7.32–7.25 (m, 2 H), 7.25–7.14 (m, 3 H), 4.38 (br s, 2 H), 3.31–3.04 (m, 3 H), 3.02–2.94 (m, 1 H), 2.91–2.79 (m, 1 H), 2.18–2.06 (m, 1 H), 1.68–1.31 (m, 14 H).

¹³C NMR (126 MHz, CDCl₃): δ = 211.8 and 211.6, 155.9 and 155.6, 138.5, 128.5, 127.7, 127.1, 79.7, 60.0, 50.4 and 49.9, 46.1, 44.4, 28.4, 26.8, 25.6 and 25.4, 16.9.

MS (CI): m/z = 218 [MH⁺ – CO₂ – C₄H₈].

Anal. Calcd for C₁₉H₂₇NO₃: C, 71.89; H, 8.57; N, 4.41. Found: C, 71.83; H, 8.89; N, 4.62.

Acknowledgment

The authors thank Prof. Andrey A. Tolmachev for his encouragement and support and UOSLab (www.en.uoslab.com) for providing high pressure reactors.

• References

• 1 Nadin A. Hattotuwagama C. Churcher I. Angew. Chem. Int. Ed. 2012; 51: 1114
• 2 Doveston R. Marsden S. Nelson A. Drug Discov. Today 2014; 19: 813
• 3 Tricklebank MD. IDrugs 2000; 3: 228
• 4 Graul A. Castaer J. Drugs Future 1998; 23: 370
• 5 Tang PC. Lin ZG. Wang Y. Yang FL. Wang Q. Fu JH. Zhang L. Gong AS. Luo JJ. Dai J. She GH. Si DD. Feng J. Chin. Chem. Lett. 2010; 21: 253
• 6 Wiles JA. Phadke AS. Deshpande M. Agarwal A. Chen D. Gadhachanda VR. Hashimoto A. Pais G. Wang Q. Wang X. PCT Int. Patent WO2017035348, 2017
• 7 Tong L. Yu W. Coburn CA. Chen L. Selyutin O. Zeng Q. Dwyer MP. Nair AG. Shankar BB. Kim SH. Yang D.-Y. Rosenblum SB. Ruck RT. Davies IW. Hu B. Zhong B. Hao J. Ji T. Zan S. Liu R. Agrawal S. Carr D. Curry S. McMonagle P. Bystol K. Lahser F. Ingravallo P. Chen S. Asante-Appiah E. Kozlowski JA. Bioorg. Med. Chem. Lett. 2016; 26: 5354
• 8 Bento AP. Gaulton A. Hersey A. Bellis LJ. Chambers J. Davies M. Krüger FA. Light Y. Mak L. McGlinchey S. Nowotka M. Papadatos G. Santos R. Overington JP. Nucleic Acids Res. 2014; 42: D1083
• 9 Miranda PC. M. L. Correia CR. D. Tetrahedron Lett. 1999; 40: 7735
• 10 de Faria AR. Salvador EL. Correia CR. D. J. Org. Chem. 2002; 67: 3651
• 11 Luna A. Gutiérrez M.-C. Furstoss R. Alphand V. Tetrahedron: Asymmetry 2005; 16: 2521
• 12 Valle MS. Retailleau P. Correia CR. D. Tetrahedron Lett. 2008; 49: 1957
• 13 Gross U. Nieger M. Brase S. Chem. Eur. J. 2010; 16: 11624
• 14 Kawano M. Kiuchi T. Negishi S. Tanaka H. Hoshikawa T. Matsuo J. Ishibashi H. Angew. Chem. Int. Ed. 2013; 52: 906
• 15 Adembri G. Donati D. Fusi S. Ponticelli F. J. Chem. Soc., Perkin Trans. 1 1992; 2033
• 16 Li X.-X. Zhu L.-L. Zhou W. Chen Z. Org. Lett. 2012; 14: 436
• 17 Faustino H. Bernal P. Castedo L. López F. Mascareñas JL. Adv. Synth. Catal. 2012; 354: 1658
• 18 Basler B. Schuster O. Bach T. J. Org. Chem. 2005; 70: 9798
• 19 Druzhenko T. Skalenko Y. Samoilenko M. Denisenko A. Zozulya S. Borysko PO. Sokolenko MI. Tarasov A. Mykhailiuk PK. J. Org. Chem. 2018; 83: 1394
• 20 Couty S. Meyer C. Cossy J. Tetrahedron 2009; 65: 1809
• 21 Marion F. Coulomb J. Courillon C. Fensterbank L. Malacria M. Org. Lett. 2004; 6: 1509
• 22 Lazzara PR. Fitzpatrick KP. Eichman CC. Chem. Eur. J. 2016; 22: 16779
• 23 Kolleth A. Lumbroso A. Tanriver G. Catak S. Sulzer-Mossé S. De Mesmaeker A. Tetrahedron Lett. 2017; 58: 2904
• 24 Grygorenko OO. Artamonov OS. Palamarchuk GV. Zubatyuk RI. Shishkin OV. Komarov IV. Tetrahedron: Asymmetry 2006; 17: 252
• 25 Ivon YM. Tymtsunik AV. Komarov IV. Shishkin OV. Grygorenko OO. Synthesis 2015; 47: 1123
• 26 Radchenko DS. Kopylova N. Grygorenko OO. Komarov IV. J. Org. Chem. 2009; 74: 5541
• 27 Grygorenko OO. Kopylova NA. Mikhailiuk PK. Meißner A. Komarov IV. Tetrahedron: Asymmetry 2007; 18: 290
• 28 Kopylova NA. Grygorenko OO. Komarov IV. Groth U. Tetrahedron: Asymmetry 2010; 21: 2868
• 29 Wauters I. De Blieck A. Muylaert K. Heugebaert TS. A. Stevens CV. Eur. J. Org. Chem. 2014; 1296
• 30 Heugebaert T. Van Hevele J. Couck W. Bruggeman V. der Jeught S. Masschelein K. Stevens CV. Eur. J. Org. Chem. 2010; 1017
• 31 Rammeloo T. Stevens CV. De Kimpe N. 2002; 67: 6509
• 32 Rammeloo T. Stevens CV. Chem. Commun. 2002; 250
• 33 De Blieck A. Stevens CV. Synlett 2011; 1748
• 34 Komarov IV. Grigorenko AO. Turov AV. Khilya VP. Russ. Chem. Rev. 2004; 73
• 35 Trabocchi A. Scarpi D. Guarna A. Amino Acids 2008; 34: 1
• 36 Soloshonok VA. Curr. Org. Chem. 2002; 6: 341
• 37 Hanessian S. Auzzas L. Acc. Chem. Res. 2008; 41: 1241
• 38 Wang Y. Song X. Wang J. Moriwaki H. Soloshonok VA. Liu H. Amino Acids 2017; 49: 1487
• 39 Tanaka M. Chem. Pharm. Bull. 2007; 55: 349
• 40 Maity P. König B. Pept. Sci. 2008; 90: 8
• 41 Sorochinsky AE. Aceña JL. Moriwaki H. Sato T. Soloshonok VA. Amino Acids 2013; 45: 691
• 42 Sorochinsky AE. Aceña JL. Moriwaki H. Sato T. Soloshonok V. Amino Acids 2013; 45: 1017
• 43 Aceña JL. Sorochinsky AE. Soloshonok V. Amino Acids 2014; 46: 2047
• 44 Dowd P. Zhang W. J. Org. Chem. 1992; 57: 7163
• 45 Painter TO. Thornton PD. Orestano M. Santini C. Organ MG. Aubé J. Chem. Eur. J. 2011; 17: 9595
• 46 Falmagne J.-B. Escudero J. Taleb-Sahraoui S. Ghosez L. Angew. Chem. 1981; 93: 926
• 47 While the manuscript was in preparation, an alternative synthesis of the amino acid 9a was published; see ref. 19.
• 48 Grygorenko OO. Radchenko DS. Volochnyuk DM. Tolmachev AA. Komarov IV. Chem. Rev. 2011; 111: 5506
• 49 Armarego WL. F. Chai C. Purification of Laboratory Chemicals. 5th ed. Elsevier; Oxford: 2003
• 50 Schlesinger AH. Prill EJ. J. Am. Chem. Soc. 1956; 78: 6123
• 51 Buswell M. Fleming I. Ghosh U. Mack S. Russell M. Clark BP. Org. Biomol. Chem. 2004; 2: 3006