An enantiodivergent synthesis of N-Boc-protected (R)- and (S)-4-amino cyclopent-2-en-1-one

Routes are reported for the synthesis of both (1R)- and (1S)-tert-butyl-(4-oxocyclopent-2-en-1-yl)carbamate 2. Featuring Mitsunobu reactions with di-tert-butyl iminodicarbonate, both syntheses begin from (S)-4-[(tert-butyldimethylsilyl)oxy]cyclopent-2-en-1-one (3) and take advantage of the 1,4-cyclopentenyl dioxygenation pattern of this optically active starting material. Thus both (−)- and (+)-2 have been accessed from 3 in an enantiodivergent manner in 11% and 10% overall yield over five and seven reaction steps, respectively.


Introduction
Substituted cyclopentyl and cyclopentenyl compounds are useful building blocks for the construction of natural products and other compounds of interest: many of which feature heteroatom substituents. 1 In relation to this, we have recently reported the preparation of aza-analogues of the unsaturated prostaglandin Δ 12,14 -15-deoxy-PGJ 2 (Scheme 1). 2 This type of prostaglandin possesses an interesting biological profile and attempts to explore how the structure of this compound affects its activity are hampered because it is not amenable to ready synthetic divergence from an advanced intermediate. [3][4][5][6][7][8][9][10] In relation to this point, we demonstrated that incorporation of a nitrogen atom at the 4-position in the cyclopentenone enabled ready modification of the α-prostanoid side chain. 2 In addition, alkylidination/arylidination was successfully used to instal the unsaturated exocyclic side chain present in the natural product analogue 1.
This enables 1 to be traced to the optically active N-Bocprotected functionalised cyclopentenone 2. Since some compounds of the type 1 demonstrated comparable activities to Δ 12,14 -15-deoxy-PGJ 2 in assays relevant to inflammation and anticancer activity, 2 a robust supply of optically active compound (R)-2 was required. In addition, we were also interested to explore how the stereogenicity of the α-side chain affected biological action, and consequently also required access to the (S)-enantiomer of compound 2. It should be noted that several methods for the synthesis of optically active forms of 2 have been reported, [11][12][13][14][15] and in this article, we show how (S)-4-[(tert-butyldimethylsilyl)oxy]cyclopent-2en-1-one (3) [16][17][18][19][20] can be used to prepare both (R)-and (S)-2.
ways. [16][17][18][19][20] Since the direct nucleophilic displacement of an activated form of 4-hydroxycyclopentenone is problematic and has scarce literature precedence 21,22 alternative methods for the stereocontrolled construction of 2 were considered. From 3, the ketone was initially converted into alcohol 4 via a Luche reduction. As described in the literature, 23 following this reaction, an 85:15 mixture of diastereomers (4a:4b) was formed and these isomers proved not to be chromatographically separable. Therefore, this mixture was directly converted, in moderate yield, into compound 5 by a Mitsunobu reaction involving di-tert-butyl iminodicarbonate. 24,25 Again, the mixture of the minor cisand major trans-1,4-difunctionalised cyclopentenyl compounds proved inseparable. However, on removal of the silyl protecting group (under typical conditions), the more polar alcohol 6 was separable from its minor cis-isomer by flash column chromatography. Oxidation using Dess-Martin periodinane (DMP) then gave cyclopentenone (−)-7, which subsequently could be readily mono-Boc deprotected to provide N-Boc-protected cyclopentenone (−)-2 in 11% overall yield over the five reaction steps (Scheme 2). The specific rotation of the synthetic material obtained over this sequence {[α] D = -75.5 (c = 0.1, CHCl 3 )} is consistent with reported values. 11,12 Based on the successful synthesis described in Scheme 2, attention next focused on the related preparation of (+)-2. In a first attempt, we envisaged, that a double inversion of the alcohol present in the major isomer from the Luche reduction (compound 4a in Scheme 2) would provide material that could be converted through to the target (+)-2. As shown in Scheme 3, 4a was inverted into the minor diastereomer from the Luche reduction (4b) via a classic Mitsunobu ester formation with benzoic acid, followed by hydrolysis.
Although this sequence was successful, in our hands the yield (12%) for this two-step process was unacceptably low. Consequently, an alternative approach was employed which takes advantage of the symmetrical 1,4-cis-dioxygenation pattern in compound 4a. As shown in Scheme 4, compound 4 (4a:4b = 85:15) was converted into compound 8. 26 The two alcohol functionalities are now orthogonally protected meaning that treatment of 8 with fluoride gave alcohol 9. Mitsunobu reaction of 9 with di-tert-butyl iminodicarbonate gave compound 10, which could be isolated as a single stereoisomer in moderate yield. This reaction sets the stereogenic centre bearing the nitrogen substituent required in target (+)-2. From 10, ester cleavage, oxidation with Dess-Martin periodinane and mono-N-Boc deprotection gave compound (+)-2.

Conclusion
In conclusion, routes are described for the synthesis of both enantiomers of tert-butyl-(4-oxocyclopent-2-en-1-yl)carbamate (2). These optically active compounds are of broad utility for the synthesis of 1,4-difunctionalised cyclopentenyl compounds which are of synthetic and biological interest. It should be noted again that the direct nucleophilic attack on activated forms of 3 has been infrequently reported due to competitive formation of cyclopentadienone (which subsequently undergoes cycloaddition chemistry). 21,22,27

General directions
Starting materials were obtained from commercial suppliers and were used without further purification unless otherwise stated. CAS number for (S)-4-[(tert-butyldimethylsilyl) oxy]cyclopent-2-en-1-one (3): 61305-36-0. All commercially available solvents were used as supplied unless otherwise stated. All 'dry' solvents were dried and distilled by standard procedures. Glassware was either dried in an oven, or flame-dried with a Bunsen burner before use and assembled hot then cooled to room temperature under a stream of nitrogen. Oxygen-free, anhydrous nitrogen was obtained from BOC. Thin-layer chromatography (TLC) was carried out on Merck silica gel aluminium sheets (60 F254). Ultraviolet (UV) light and a mixture of KMnO 4 (1.5 g), K 2 CO 3 (10 g), 10% NaOH (1.25 mL) in water (200 mL) was used to visualise spots. Merck silica 60 Å (230-400 mesh) 9385 was used for flash column chromatography. Nuclear magnetic resonance (NMR) spectra were recorded on Varian Unit 300, 400 or 500 MHz spectrometers as specified. Spectra were calibrated using trimethylsilane (TMS) or the residual protiated solvent. Coupling constants (J) are quoted in Hertz. 1 H and 13 C NMR chemical shift assignments are based on two-dimensional NMR techniques, including 1 H-1 H-gCOSY and heteronuclear single quantum coherence (HSQC) experiments. All values are reported in parts per million (ppm). Infrared (IR) spectra were recorded on a Bruker Alpha Fourier-transform infrared (FTIR) spectrometer. High-resolution mass spectrometry (HRMS) was Scheme 1. Structure of the cross-conjugated cyclopentenone prostaglandin Δ 12,14 -15-deoxy-PGJ 2 , its 4-aza analogue 1 and its retrosynthesis to optically active 4-substituted cyclopentenones 2 and 3 [Boc = tert-butyloxycarbonyl; performed using a Waters Crop, Micromass LCT, electrospray ionisation (ESI) spectrometer. Melting points were determined in an open capillary on a Gallenkamp melting point apparatus and are uncorrected. Compound names were generated using ChemDraw software. Known compounds are referenced accordingly.

(1S,4S)-4-((tert-Butyldimethylsilyl)oxy) cyclopent-2-enol (4b)
Alcohol 4 (100 mg, 0.47 mmol, 1.0 equiv.) was added to a solution of triphenylphosphine (241 mg, 0.92 mmol, 2.0 equiv.) and benzoic acid (88 mg, 0.71 mmol, 1.5 equiv.) in dry THF (5 mL). The solution was cooled to 0 °C and DIAD (0.2 mL, 0.94 mmol, 2.0 equiv.) was added. Following this, the reaction was allowed to warm to room temperature and stirred for 16 h under an inert atmosphere. After this time, the solvent was removed under a flow of air and the residue was diluted with Et 2 O (10 mL) and washed with NaHCO 3 (3 × 10 mL). The organic phase was dried over MgSO 4 and the solvent removed in vacuo. The intermediate was then diluted in methanol (5 mL) and K 2 CO 3 (326 mg, 2.35 mmol, 5.0 equiv.) was added. The resulting suspension was stirred under an inert atmosphere for 4 h, after which the suspension was filtered and concentrated in vacuo. The resulting residue was dissolved in Et 2 O (10 mL) and water (10 mL) and washed with water (3 × 10 mL) and brine (10 mL). The organic phase was dried over MgSO 4 and the solvent removed in vacuo. Purification by column chromatography (c-Hex/EtOAc; 3:1) afforded the desired product 4b (12 mg, 12%) with data as reported. 23

Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.

Funding
The author(s) disclosed receipt of the following financial support for the research, authorship and/or publication of this article: The Irish Research Council is acknowledged for the provision of a postgraduate scholarship (grant no. GOIPG/2017/1702).