Asymmetric synthesis of (1R,2S)-1-amino-2-vinylcyclopropanecarboxylic acid by sequential S_N2–S_N2′ dialkylation of (R)-N-(benzyl)proline-derived glycine Schiff base Ni(II) complex

Abstract

This work describes a new process for the asymmetric synthesis of (1R,2S)-1-amino-2-vinylcyclopropanecarboxylic acid of high pharmaceutical importance. The sequence of the reactions includes PTC alkylation (S_N2), homogeneous S_N2′ cyclization followed by disassembly of the resultant Ni(II) complex. All reactions are conducted under operationally convenient conditions and suitably scaled up to 6 g of the starting Ni(II) complex.

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Introduction

Tailor-made α-amino acids¹ are of vital importance in the development of modern pharmaceuticals.² In particular, sterically constrained amino acids³ are key structural units in the design of peptidic derivatives with a limited and rationally controllable number of conformations.⁴ In this line, so called α,β-methano-α-amino acids or methanologs of α-amino acids represent an extreme case of compounds containing a severely conformationally restricted cyclopropane ring.⁵ Interestingly, several cyclopropyl-group-containing amino acids are naturally occurring compounds and were isolated from some higher plants.⁶ For example, 1-aminocyclopropanecarboxylic acid 1 (ref. 6a) and a series of its 2-alkyl substituted derivatives, such as coronamic 2,^7a norcoronamic 3,^7b allo-coronamic 4,^7c and allo-norcoronamic 5 (ref. 7d) acids are found in proteins involved in various plants' defensive functions (Fig. 1).

Fig. 1 Some naturally occurring methanologs of α-amino acids 1–5 and synthetic derivative 6.

The recent upsurge of interest in methanologs of α-amino acids is related to the discovery of a novel and very potent class of hepatitis C virus (HCV) NS3/4A protease inhibitors⁸ containing (1R,2S)-1-amino-2-vinylcyclopropanecarboxylic acid 6 as a key structural feature. Quite remarkably, at least six different drugs containing amino acid 6 are currently being developed for the treatment of hepatitis C. For example, simeprevir,⁹ danoprevir,¹⁰ asunaprevir,¹¹ faldaprevir,¹² ciluprevir¹³ and grazoprevir,¹⁴ all have acid 6 as a fragment, usually as its C-sulfonamide derivative. Consequently, several approaches were developed for preparation of amino acid 6 in enantiomerically pure form. The majority of the literature methods includes multiple reaction sequences and functional group transformations, but can be applied for synthesis of various types of methanologs of α-amino acids 1–6.¹⁵ More focused and straightforward protocols rely on the sequential S_N2–S_N2′ dialkylation of glycine Schiff bases using trans-1,4-dibromobut-2-ene 7 as a source of cyclopropane ring and vinyl group.¹⁶ However, considering the current exceptional pharmacological potential of amino acid 6 and its derivatives, the relevant methodology is surprisingly understudied leaving room for alternative synthetic solutions. Taking into account our longstanding interest in the development of new methods for preparation of tailor-made amino acids¹⁷ and in particular sterically constrained structures,¹⁸ we turned our attention to Ni(II) complexes of chiral glycine Schiff bases (S)- and (R)-8 (ref. 19 and 20) (Fig. 2) to explore the possibility of their application for the asymmetric synthesis of amino acid 6. Here we report rather successful results, demonstrating that the target acid (1R,2S)-6 can be conveniently prepared via sequential S_N2–S_N2′ dialkylation of Schiff base (R)-8 with a synthetically attractive stereochemical outcome.

Fig. 2 Structures of (S)- and (R)-proline derived Ni(II) complexes of glycine Schiff base 8.

Results and discussion

The chemistry of Ni(II) complexes of glycine and higher amino acids is a well established methodology for generalized and practical preparation of α-²⁰ and β-amino acids²¹ in enantiomerically pure form.²² For example, homologation of complex 8 can be conducted under operationally convenient conditions²³ and on a relatively large-scale,²⁴ usually with practically useful results. Transformation of the glycine moiety in 8 can be performed via alkyl halide alkylations,²⁵ aldol,²⁶ Michael²⁷ and Mannich²⁸ addition reactions, affording structurally varied types of α-amino acids. In particular, there are two published examples of application of complex (S)-8 for preparation of cyclopropyl-group-containing α-amino acids. The first approach includes Michael addition of (S)-8 to ethyl-2-bromoacrylate, followed by the intramolecular substitution of the ω-bromine atom and eventually leading to (2S,3R)-2,3-methano-aspartic acid.²⁹ The second report deals with dialkylation of (S)-8 with chiral (S)-4-methyl-1,3,2-dioxathiolane 2,2-dioxide (cyclic dialkyl sulfate) to afford allo-norcoronamic acid (1S,2R)-5 (ref. 30) (Fig. 1). Obviously, these procedures cannot be used for preparation of our target vinylcyclopropanecarboxylic acid 6. However, both methods report high yields and diastereoselectivity suggesting that the rigid structure of the Ni(II)-coordinated glycine Schiff base presents no problem for the formation of highly sterically congested cyclopropane rings. Furthermore, these results are agreeable with the general stereochemical trend observed in the synthesis of quaternary α-amino acids³¹ as the (S)-configured complex 8 gives preference for the α-(S) absolute configuration of the dialkylation products.

Drawing from these data and our own experience in the reactions of (S)- and (R)-8 with α,ω-dihaloalkanes,³² we initiated our study trying first the direct preparation of the target product by alkylation of (S)-8 with dibromide 7 under homogeneous conditions.^32a The reaction conducted in DMF at room temperature turned out to be very messy producing numerous products. Application of acetonitrile as solvent or lowering the reaction temperature did not improve much the outcome suggesting that the homogeneous conditions are too harsh for the reagents and intermediates with multiple reaction centers. Therefore, we decided to proceed stepwise, separating the S_N2 and S_N2′ alkylation procedures.

As presented in Scheme 1 and Table 1, phase-transfer catalysis (PTC) conditions were quite successful for preparation of monoalkylated products (S)(2S)-9 and (S)(2R)-10. For the purpose of the present work, the kinetic^25a,33 ratio (about 80 : 20) of diastereomers (S)(2S)-9 and (S)(2R)-10 had no importance as the second S_N2′ alkylation step was expected to proceed via the same intermediate enolate. Therefore, we focused on the chemical yield and purity of the products. Application of only 1.5 equivalents of dibromide 7 (Table 1, entry 1) under liquid–liquid PTC resulted in a moderate yield along with incomplete conversion of the starting complex (S)-8 and, probably, formation of binuclear Ni(II) species, complicating the purification of the target products. Gradual increase in the excess of alkylating reagent 7 allowed to improve the yield of (S)(2S)-9 and (S)(2R)-10 and reduce the number of by-products (entries 2 and 3). Scaling the reaction up under these conditions gave rather good results as a mixture of (S)(2S)-9 and (S)(2R)-10 was prepared in 77.8% isolated yield (entry 4). However, slightly better results were obtained using solid NaOH as a base (solid–liquid PTC, entries 5–8). In this case, the yield was improved and successfully reproduced on 5 g scale of starting complex (S)-8 (entry 8).

Scheme 1 Sequential S_N2–S_N2′ dialkylation of (S)-8 with dibromide 7.

Table 1 Monoalkylation of Ni complex (S)-8

Entry	Scale (g)	PTC	7 (equiv.)	Base	Yield^a (%)	9 : 10 ratio^b
a Overall yield of isolated pure products.b Determined by ^1H NMR integration.
1	0.1	L/L	1.5	NaOH	58.0	80 : 20
2	0.1	L/L	2.5	NaOH	67.4	78 : 22
3	0.1	L/L	3.5	NaOH	77.5	79 : 21
4	1.0	L/L	3.5	NaOH	77.8	80 : 20
5	0.1	S/L	2.5	NaOH	75.5	79 : 21
6	0.1	S/L	2.5	KOH	75.0	80 : 20
7	0.1	S/L	3.5	NaOH	80.7	79 : 21
8	5.0	S/L	3.5	NaOH	81.3	78 : 22

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With these results in hand, we proceeded next to study the second S_N2′ alkylation step. It should be noted that under the PTC conditions the S_N2′ alkylation products were never observed as the synthesis of quaternary α-amino acids via Ni(II) chemistry requires relatively strong bases.³¹ After some preliminary experimentation we found that successful cyclization of products (S)(2S)-9 and (S)(2R)-10 could be achieved under homogeneous conditions using strong inorganic bases. The representative results are collected in Table 2.

Table 2 S_N2′ cyclization of (S)(2S)-9 and (S)(2R)-10 under homogeneous conditions

Entry	Scale (g)	Solvent	Base (equiv.)	Temp. (°C)	Time (h)	Yield^a (%)	11 : 12 ratio^b
a Overall yield of isolated pure products.b Determined by ^1H NMR integration.c The reaction was performed using pure (S)(2R)-10 as starting material.
1	0.1	DMF	NaOH (5)	0 to 25	1	44.5	79 : 21
2	0.1	DMF	KOH (5)	0 to 25	1	41.2	80 : 20
3	0.1	DMF	NaOH (5)	−15 to 25	3	48.0	85 : 15
4	0.1	MeCN	NaOH (5)	−15 to 25	7	51.7	87 : 13
5	0.1	THF	NaOH (5)	−15 to 25	7	34.3	90 : 10
6	0.1	THF	NaOt-Bu (3)	−15 to 25	2	65.1	91 : 9
7	0.1	THF	NaOt-Bu (4)	0 to 25	1	70.0	90 : 10
8	0.1	THF	NaOt-Bu (2 + 2)	0 to 25	1	75.1	91 : 9
9^c	0.05	THF	NaOt-Bu (2 + 2)	0 to 25	1	73.6	90 : 10
10	5.0	THF	NaOt-Bu (2 + 2)	0 to 25	1	75.8	90 : 10

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The reactions conducted in DMF, using NaOH (entry 1) or KOH (entry 2) as a base, resulted in rather low yields of complexes (S)(2S,3R)-11 and (S)(2R,3S)-12 due to a noticeable amount of some by-products. Lowering the reaction temperature allowed to improve the stereochemical outcome (entry 3), however, not to a satisfactory level. Application of acetonitrile (entry 4) or THF (entry 5) did not give the desired results either. We reasoned that NaOH or KOH are rather strong nucleophilic bases and could react with the ω-bromide of the starting compounds (S)(2S)-9 and (S)(2R)-10 leading to undesired substitution and/or elimination side-reactions. Further experimentation revealed that THF as a solvent and NaOt-Bu as a base can provide for a synthetically suitable stereochemical outcome. Eventually, optimal results were achieved starting the reaction at 0 °C (entry 6 vs. 7) and adding the base in two portions: at the beginning and at a point of about 50% conversion of the starting (S)(2S)-9 and (S)(2R)-10 mixture (entry 8). In this case, the target products (S)(2S,3R)-11 and (S)(2R,3S)-12 were obtained in 75.1% yield and 91 : 9 ratio. Out of stereochemical curiosity, we conducted the reaction using diastereomerically pure complex (S)(2R)-10 as a single starting compound. Quite expectedly, the diastereomeric ratio and yield of (S)(2S,3R)-11 and (S)(2R,3S)-12 were virtually the same as compared with the reactions initiated using the mixture of (S)(2S)-9 and (S)(2R)-10 (entry 8 vs. 9). Finally, we reproduced this procedure on 5 g scale; the result was rather satisfactory (entry 10) allowing preparation and purification of the major diastereomer (S)(2S,3R)-11 in good yield. Considering the chiroptical properties of compound 11, in particular the strong positive optical rotation ([α]²⁵_D = +866), its absolute configuration was assigned as (S)(2S,3R).^20,29,30

Accordingly, the synthesis of the pharmacologically important enantiomeric compound of (2R,3S) absolute configuration would require the use of glycine Schiff base (R)-8. With this in mind, we decided to repeat the whole sequence of the reactions based on (R)-8 as the starting compound (Scheme 2). Taking into account that all reactions involved had already been optimized, we readily reproduced the process starting with 6 g of (R)-8. The first PTC alkylation step proceeded quite smoothly affording a mixture of (R)(2R)-9 and (R)(2S)-10 in about 80 : 20 ratio and 78.5% yield. Without additional purification, this mixture was subjected to the second alkylation (S_N2′) step giving rise to cyclized products (R)(2R,3S)-11 and (R)(2S,3R)-12 in 90 : 10 ratio and 73.4% yield.

Scheme 2 Preparation of amino acid (1R,2S)-6 and its derivative (1R,2S)-15 from glycine Schiff base (R)-8.

Having thus prepared complex (R)(2R,3S)-11, our next goal was its disassembly and isolation of the target vinylcyclopropanecarboxylic acid 6. As shown in Scheme 2, treatment of diastereomerically pure (R)(2R,3S)-11 with aq. 1 N HCl in methanol at 50 °C resulted in complete disassembly of the Ni(II)-complex structure and the formation of chiral ligand (R)-13 along with amino acid (1R,2S)-6. Ligand (R)-13 was recovered in 92.8% yield by extraction and amino acid (1S,2R)-6 was isolated by using a cation exchange resin.

In view of the fact that the physicochemical properties of amino acid (1R,2S)-6 render its proper characterization rather difficult, we followed the literature suggestion^16a and prepared its derivatized form 15. The amino functionality was protected with a Boc group and the resulting compound (1R,2S)-14 was best isolated as its dicyclohexylammonium salt. Finally, esterification with TMSCHN₂ afforded the fully protected derivative (1R,2S)-15. Thus prepared (1R,2S)-15 was found to possess spectral and chiroptical properties matching those of the literature data.^16a Furthermore, we confirmed its optical purity by HPLC on a chiral stationary phase.

With these experimental data in hand, we are in position to discuss the stereochemical aspects of these sequential S_N2–S_N2′ dialkylation reactions. First of all, we have determined that application of the (S)-configured starting Ni(II) complex of glycine Schiff base (S)-8 gives preference for the α-(S) products 11 and (R)-8 leads to α-(R) derivatives. Second, we should emphasize the very high level of relative stereochemistry control observed in these reactions (S_N2′). Thus, only pairs of (S)(2S,3R)-11 and (S)(2R,3S)-12 [starting from (S)-8] and (R)(2R,3S)-11 and (R)(2S,3R)-12 [starting from (R)-8] were observed in the reaction mixtures, while other theoretically possible (2S,3S) and (2R,3R) diastereomers were never detected. The first trend, the preference for the α-stereochemistry on the alkylation products, is rather expected and well established in the numerous literature examples.²⁰ On the other hand, the excellent relative stereocontrol is quite unexpected and deserves a particular discussion.

First of all, we would like to note that due to the conformational homogeneity of both (Z)-enolate and trans-olefin moieties, one can build only two possible TS B and B′.³⁴ As presented in Fig. 3, the S_N2′ cyclization of the (R)-enolate A might proceed by way of TS B giving rise to the product C of (2R,3S) absolute configuration. On the other hand formation of the other possible diastereomeric product (2R,2R)-C′ can be anticipated via TS B′. Considering likelihood of these two situations, one might agree that TS B′ is significantly disadvantaged due to the apparently sterically crowded position of the whole CH=CH–CH₂Br group “inside” the Ni(II)-coordinated enolate, while in the TS B the only unfavorable steric interactions are between the enolate oxygen and the CH₂Br moiety. Furthermore, the formation of TS B′ requires a sterically unfavourable “folded” conformation of the side chain in enolate A′ generating an increase of allylic strain, as compared with the “extended” and much more probable conformation in enolate A, leading to the TS B. Considering these modes of steric interactions, and consistent with the experimental results, one may assume that formation of TS B′ is greatly improbable rendering the second S_N2′ alkylation step of very high relative stereochemical control.

Fig. 3 Mechanistic consideration of the reactions under study.

Conclusions

To conclude, we have developed a new process for asymmetric synthesis of 1-amino-2-vinylcyclopropanecarboxylic acid 6 via sequential S_N2–S_N2′ dialkylation of chiral Ni(II) complex of glycine Schiff base 8. We found that application of complex (S)-8 leads predominantly to the formation of amino acid 6 with (1S,2R) absolute configuration, while the enantiomeric and pharmaceutically important (1R,2S)-6 can be obtained using (R)-8 as the starting glycine derivative. The sequence of the reactions includes PTC alkylation (S_N2), homogeneous S_N2′ cyclization followed by disassembly of the resultant Ni(II) complex. All reactions are conducted under operationally convenient conditions³⁵ and therefore can be reasonably (6 g) scaled up rendering the presented method practically useful for preparation of amino acid (1R,2S)-6 of high pharmaceutical importance.

Experimental

Synthesis of Ni(II) complexes of the Schiff base of (S)-N-(benzylprolyl)-2-aminobenzophenone and trans-2-amino-6-bromohex-4-enoic acid, (S)(2S)-9 and (S)(2R)-10

NaOH (16.06 g, 401 mmol) was added to a mixture of (S)-8 (ref. 19b) (5.0 g, 10.04 mmol), trans-1,4-dibromo-2-butene (7.51 g, 35.10 mmol) and n-Bu₄NI (927 mg, 2.51 mmol) in (CH₂Cl)₂ (100 mL). The reaction was monitored by TLC (CH₂Cl₂–acetone, 4 : 1). After stirring at room temperature for 30 min, the mixture was diluted with H₂O and extracted with CH₂Cl₂. The organic phases were then dried over Na₂SO₄ and concentrated at reduced pressure. Purification by column chromatography on silica (CH₂Cl₂–acetone, 4 : 1) afforded a diastereomeric mixture (78 : 22 ratio) of (S)(2S)-9 and (S)(2R)-10 (5.15 g, 81.3% yield). A pure fraction of (S)(2S)-9 was isolated for characterization purposes by further purification by column chromatography on silica (hexane–acetone, 1 : 1). [α]²⁵_D = +1875 (c 0.033, CHCl₃). ¹H NMR (300 MHz, CDCl₃) δ 8.17–8.04 (m, 1H), 7.95 (d, J = 7.1 Hz, 2H), 7.56–7.35 (m, 3H), 7.27 (t, J = 7.6 Hz, 2H), 7.20–7.03 (m, 3H), 6.87 (d, J = 6.3 Hz, 1H), 6.67–6.49 (m, 2H), 6.06 (dt, J = 15.0, 7.4 Hz, 1H), 5.60 (dt, J = 15.1, 7.5 Hz, 1H), 4.35 (d, J = 12.6 Hz, 1H), 3.98–3.76 (m, 3H), 3.59–3.32 (m, 4H), 2.67 (d, J = 6.2 Hz, 1H), 2.61–2.31 (m, 3H), 2.09–1.91 (m, 2H). ¹³C NMR (75 MHz, CDCl₃) δ 180.8, 178.9, 171.6, 142.9, 134.3, 133.8, 133.5, 132.8, 132.0, 130.8, 130.3, 129.5, 129.3, 129.3, 128.1, 127.5, 126.7, 124.1, 121.2, 70.6, 63.5, 57.4, 37.9, 32.4, 31.2, 24.3. HRMS calcd for C₃₁H₃₁BrN₃NiO₃ [M + H]⁺ 630.0902, found 630.0915.

Synthesis of Ni(II) complexes of the Schiff base of (R)-N-(benzylprolyl)-2-aminobenzophenone and trans-2-amino-6-bromohex-4-enoic acid, (R)(2R)-9 and (R)(2S)-10

The above procedure was performed starting from (R)-8 (ref. 36) (6.0 g, 12.04 mmol) to give a 80 : 20 mixture of (R)(2R)-9 and (R)(2S)-10 (5.97 g, 78.5% yield).

Synthesis of Ni(II) complexes of the Schiff base of (S)-N-(benzylprolyl)-2-aminobenzophenone and 1-amino-2-vinylcyclopropanecarboxylic acid, (S)(2S,3R)-11 and (S)(2R,3S)-12)

NaOt-Bu (1.52 g, 15.84 mmol) was added to a solution of a mixture of (S)(2S)-9 and (S)(2R)-10 (5.0 g, 7.92 mmol) in THF (100 mL) at 0 °C. The reaction was monitored by TLC (hexane–acetone, 1 : 1). After stirring at room temperature for 0.5 h, a second portion of NaOt-Bu (1.52 g, 15.84 mmol) was added. After 1 h, the mixture was poured into H₂O and extracted with CH₂Cl₂. The organic phases were then dried over Na₂SO₄ and concentrated at reduced pressure. Purification by column chromatography on silica (hexane–acetone, 1 : 1) afforded a diastereomeric mixture (90 : 10 ratio) of (S)(2S,3R)-11 and (S)(2R,3S)-12 (3.30 g, 75.8% yield). Further purification by column chromatography on silica (CH₂Cl₂–acetone, 10 : 1) was carried out to isolate the pure products. Data of (S)(2S,3R)-11: [α]²⁵_D = +866 (c 0.021, CHCl₃). ¹H NMR (400 MHz, CDCl₃) δ 8.03 (d, J = 7.4 Hz, 2H), 7.94 (d, J = 8.6 Hz, 1H), 7.43 (t, J = 7.2 Hz, 2H), 7.35 (t, J = 7.0 Hz, 1H), 7.27–7.19 (m, 3H), 7.08 (t, J = 7.4 Hz, 1H), 7.05–6.99 (m, 1H), 6.77 (d, J = 7.3 Hz, 1H), 6.57 (s, 2H), 5.71–5.56 (m, 1H), 5.49 (d, J = 16.8 Hz, 1H), 5.21 (d, J = 12.3 Hz, 1H), 4.25 (d, J = 12.6 Hz, 1H), 3.78 (s, 1H), 3.41 (d, J = 12.7 Hz, 1H), 3.38–3.30 (m, 2H), 2.75 (s, 1H), 2.54–2.40 (m, 1H), 2.04 (s, 1H), 1.91 (dd, J = 18.4, 9.6 Hz, 2H), 1.50–1.40 (m, 1H), 0.38–0.24 (m, 1H). ¹³C NMR (75 MHz, CDCl₃) δ 180.0, 174.1, 165.9, 142.0, 135.1, 134.9, 133.4, 132.0, 131.3, 130.0, 129.4, 129.0, 128.9, 128.8, 128.5, 127.6, 127.4, 127.0, 126.2, 123.2, 122.0, 120.6, 118.2, 70.8, 62.9, 60.8, 56.9, 39.3, 30.6, 25.4, 23.5. HRMS calcd for C₃₁H₃₀ClN₃NiO₃ [M + H]⁺ 550.1641, found 550.1640. Data of (S)(2R,3S)-12: [α]²⁵_D = −669 (c 0.034, CHCl₃). ¹H NMR (300 MHz, CDCl₃) δ 8.35 (dd, J = 8.7, 0.9 Hz, 1H), 8.10 (d, J = 6.7 Hz, 2H), 7.51–7.30 (m, 7H), 7.12 (ddd, J = 8.7, 6.8, 1.8 Hz, 2H), 6.93 (s, 1H), 6.67 (dd, J = 8.4, 1.7 Hz, 1H), 6.59 (ddd, J = 8.3, 6.8, 1.2 Hz, 1H), 5.83–5.63 (m, 1H), 5.32 (dd, J = 17.1, 1.6 Hz, 1H), 5.13 (dd, J = 10.3, 1.7 Hz, 1H), 4.50 (d, J = 12.9 Hz, 1H), 4.19–4.05 (m, 1H), 3.47 (dd, J = 9.4, 4.3 Hz, 1H), 3.18 (d, J = 12.9 Hz, 1H), 2.68–2.44 (m, 2H), 2.20–2.02 (m, 2H), 1.97–1.80 (m, 2H), 1.50–1.43 (m, 1H), 0.48 (dd, J = 9.9, 6.7 Hz, 1H). ¹³C NMR (75 MHz, CDCl₃) δ 182.1, 175.4, 167.4, 143.2, 136.0, 135.1, 134.3, 134.0, 132.8, 132.0, 130.3, 129.5, 129.0, 127.8, 127.3, 123.3, 120.8, 118.1, 69.0, 61.7, 60.8, 59.0, 39.2, 30.8, 26.7, 23.8. HRMS calcd for C₃₁H₃₀ClN₃NiO₃ [M + H]⁺ 550.1641, found 550.1652.

Synthesis of Ni(II) complexes of the Schiff base of (R)-N-(benzylprolyl)-2-aminobenzophenone and 1-amino-2-vinylcyclopropanecarboxylic acid, (R)(2R,3S)-11 and (R)(2S,3R)-12)

The above procedure was performed starting from a mixture of (R)(2R)-9 and (R)(2S)-10 (3.15 g, 5 mmol) to give a 90 : 10 mixture of (R)(2R,3S)-11 and (R)(2S,3R)-12 (2.57 g, 73.4% yield). NMR data of both compounds matched those obtained for their enantiomers. For (R)(2R,3S)-11: [α]²⁵_D = −930 (c 0.08, CHCl₃). For (R)(2S,3R)-12: [α]²⁵_D = +705 (c 0.08, CHCl₃).

Synthesis of (1R,2S)-1-amino-2-vinylcyclopropanecarboxylic acid, (1R,2S)-6

Aqueous 1 N HCl (20 mL) was added to a suspension of (R)(2R,3S)-11 (1.0 g, 1.82 mmol) in MeOH (20 mL) and the reaction mixture was stirred for 1 h at 50 °C. After the reaction was completed, the mixture was concentrated at reduced pressure. H₂O (50 mL) and EtOAc (50 mL) were added to the residue and then the phases were separated. The aqueous layer was washed with EtOAc (50 mL) and then concentrated at reduced pressure. The residue from the aqueous portion was dissolved in DI H₂O (100 mL), placed on a cation-exchange Dowex-50 resin column and eluted first with DI H₂O, until neutral pH, followed by 8% NH₄OH to elute the free amino acid. This solution was evaporated to afford the crude (1R,2S)-6 (186 mg, 80.5% yield). On the other hand, the organic layer was washed by H₂O (100 mL), 4% NH₄OH (20 mL, 2 times) and aq. sat. NaCl (100 mL), dried over Na₂SO₄, filtered and concentrated at reduced pressure to afford (R)-13 (0.65 g, 92.8% yield).

Synthesis of dicyclohexylammonium (1R,2S)-N-(tert-butoxycarbonyl)-1-amino-2-vinylcyclopropanecarboxylate, (1R,2S)-14

Boc₂O (2.46 g, 0.01126 mol) and Et₃N (1.14 g, 0.1126 mol) were added to a solution of (1R,2S)-6 (0.894 g, 0.00704 mol) in H₂O (20 mL) and acetone (20 mL) and stirred for 20 h at room temperature. After the reaction was completed, the mixture was concentrated at reduced pressure to a volume under 100 mL. The solution was adjusted to pH 2–3 with solid citric acid and extracted with EtOAc (20 mL, 3 times). The organic layers were combined, washed with H₂O (20 mL) and aq. sat. NaCl (20 mL), dried over Na₂SO₄, filtered and concentrated at reduced pressure. The crude product (1.72 g, quant.) obtained as a yellow oil was dissolved in EtOAc (10 mL, 4 v/w). Dicyclohexylamine (1.28 g, 0.00704 mol) was slowly added to the mixture and stirred for 20 h at room temperature and then for 1 h at 0 °C. The resulting white crystals were filtered and washed with iced EtOAc (10 mL) to afford (1R,2S)-14 (2.3 g, 80.0% yield). Mp: 178 °C (dec.). ¹H NMR (200 MHz, CD₃OD): δ 5.88 (ddd, J = 17.3, 10.3, 9.8 Hz, 1H), 5.15 (dd, J = 17.3, 2.2 Hz, 1H), 4.92 (dd, J = 10.3, 2.2 Hz, 1H), 3.22–3.06 (m, 2H), 2.16–1.61 (m, 13H), 1.43 (s, 9H), 1.49–1.10 (m, 10H). ¹³C NMR (50.3 MHz, CD₃OD): δ 177.5, 158.1, 138.4, 115.3, 80.0, 54.4, 44.0, 33.4, 30.7, 29.0, 26.3, 25.7, 23.1.

Synthesis of methyl (1R,2S)-1-(tert-butoxycarbonylamino)-2-vinylcyclopropanecarboxylate, (1R,2S)-15

5% aq. AcOH (8 mL) was dropped to a suspension of (1R,2S)-14 (800 mg, 1.958 mmol) in EtOAc (8 mL) kept under 3 °C and the mixture was stirred for 30 minutes. After the reaction was completed the organic solvent was separated and the aqueous layer was extracted with EtOAc (25 mL, 3 times). The organic layers were combined, washed with H₂O (25 mL, 2 times), dried over Na₂SO₄, filtered and concentrated at reduced pressure affording 472 mg, of product as a colourless oil. 400 mg of this material was dissolved in a mixture of methanol (4 mL) and toluene (20 mL), and TMSCHN₂ (2 M in Et₂O, 1.144 mL, 2.288 mmol) was added. The mixture was stirred for 30 minutes at room temperature, and then it was quenched with 5% AcOH and concentrated at reduced pressure. The crude was purified by silica-gel column chromatography (hexane : EtOAc = 20 : 1) to give (1R,2S)-15 as a colorless oil (360 mg, 84% yield). Its NMR data matched those previously described.^16a [α]²⁵_D = +39.4 (c 0.45, MeOH), lit. data: [α]²⁵_D = +42.8 (c 1.00, MeOH).^16a The optical purity of (1R,2S)-15 was determined as 98.6% ee by HPLC on a ChiralCel OD-H column (5 μm, 250 × 4.6 mm i.d.), eluent: 1.0% EtOH in hexane isocratic, flow rate: 0.75 mL min⁻¹, temp.: 25 °C, detector: UV 200 nm (t = 16.64 min for (1R,2S)-15, t = 19.17 min for (1S,2R)-15).

Acknowledgements

We thank IKERBASQUE, Basque Foundation for Science; the Basque Government (SAIOTEK S-PE13UN098), the Spanish Ministry of Science and Innovation (CTQ2010-19974) and Hamari Chemicals (Osaka, Japan) for generous financial support. We also thank SGIker (UPV/EHU) for HRMS analyses.

Notes and references

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36. The synthesis of (R)-8 was carried out following the procedure described in ref. 19b starting from (R)-proline.

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Footnote

† Electronic supplementary information (ESI) available: Copies of ¹H and ¹³C NMR spectra and HPLC analysis of compound (1R,2S)-15. See DOI: 10.1039/c4ra12658k

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