A Short Route to the Ester (±) HomoSarkomycin via Johnson-Claisen Rearrangement.

BACKGROUND: α-Methylene cycloalkanones are considered of interest because of their biological activity. Herein, in this paper the synthesis of (±) HomoSarkomycine Esters was described and characterized.
METHODS: Using Bylis-Hillman adducts, triethlorthoacetate and propanoic acid, (±) HomoSarkomycine Esters could be synthesized by smoothly Johnson-Claisen rearrangement.
RESULTS: A small library of target compounds was prepared under optimized reaction conditions in moderate yields. The reaction mechanism and the DFT study have been investigated.
CONCLUSION: This methodology provides ready access to 2-hydroxymethyl-2-cyclopentenone 1a which can be served as the raw materials of the synthesis of (±) HomoSarkomycine Ester.

INTRODUCTION

α-Methylene cycloalkanones [1-12] (Fig. ) are considered as versatile intermediates to natural products [13-15] and are of current interest because of their anti-tumor activity [16, 17]. Some examples of active compounds are presented below [18-20]. Smith III, A.B. et al. prepared (±)HomoSarkomycin Ester 2a by the Johnson-Claisen rearrangement of the ketal of 1a, after hydrolysis of the ester and ketal functionalities [16].

In continuation of our interest in the synthesis of biological compounds [21-23], we established an efficient synthesis of the (±) HomoSarkomycin Ester 2a via a Johnson-Claisen rearrangement using the Baylis-Hillman adduct 1a (Scheme ), that was prepared (in our laboratory) [24] in one step from 2-cyclopentenone in high yield and in relatively high scale.

RESULTS AND DISCUSSIONS

The Baylis-Hillman reaction produces highly functionalized adducts such as 1a [24] which may serve as the startingmaterials for the synthesis of useful targets. We envisaged that the Johnson-Claisen rearrangement [25] would be a powerful and practical route to the (±) HomoSarkomycine Ester 2a (Scheme ).

The reaction between 2-hydroxymethyl-2-cyclopentenone (1a) [24] and triethyl orthoacetate in the presence of propanoic acid at 150°C leads to (±) HomoSarkomycine Ester (2a) via a [3, 3] sigma-tropic rearrangement (Scheme , Table 1).

In a second step, we studied if this Johnson-Claisen rearrangement can be generalized in order to access to α-alkylidene-β-methylethoxycarbonyl cyclopentanones 2b-d [24] (Scheme , Table 1). The corresponding α-alkylidene cyclopentanone adducts were obtained in moderate yield in all the cases.

It should be noted that the reaction with 1e results in the esterification product 2e instead of the rearrangement (Scheme ).

A plausible mechanism for the formation of compounds 2a-d and 2e is depicted in Scheme .

These mechanisms are supported by the following calculations.

Computational Details

The geometries of the CH3-C(OC2H5)3, CH3CH2-COOH, 2-(1-hydroxyethyl)cyclopentenone 1b and 2-(phenyl-hydroxymethyl)cyclopentenone 1e are optimized by Density Functional Theory calculations applying the functional B3LYP and the 6-31G (d) basis set and using the GAUSSIAN 09 program [26-28]. To characterize the reactivity, we used Fukui function, defined as the differential change in electron density due to an infinitesimal change in the number of electrons. The condensed Fukui functions of an atom, say k, in a molecule with N electrons are defined for nucleophilic and electrophilic attack, respectively as:

Where q is the electronic population of atom k in a molecule. The corresponding local softness parameters can be defined as [29-31]:

The global softness is defined as .

The hardness is given by η = .

Results of local reactivity properties of the selected molecules are summarized in Table 2 and Fig. (.

Fig. (2)

The 4 atoms O1, O2, C3 and H4.

In this study, we have presented the reactivity parameters, the local softness and of the corresponding propanoic acid, orthoester and the two Baylis-Hillman adducts (1b and 1e) and the most reactive sites for nucleophilic and electrophilic attack were derived. If we match the values of the C3 and H4 atoms of the orthoester and propanoic acid, respectively with values of the oxygen O1 and O2 in the OH group of the Bayliss-Hillman adducts 1b and 1e, respectively, one finds clearly that the of the O1 atom match better with the values of the of C3 atom, whereas the of the O2 atom match better with the H4 atom (Fig. ). Thus the local HSAB principle also predicts the reaction in accordance with the experimentally proved evidence.

EXPERIMENTAL

Proton (1H) and carbon (13C) nuclear magnetic resonance (NMR) spectra were recorded on a Bruker AC-300 MHz spectrometer as a solution in deuterochloroform. Infrared (IR) spectra were recorded on a Perkin–Elmer Spectrum (FT_IR specter Pargon 1000 PC). The products are dosed on an automatic analyzer type SCA-CHN with detector of thermal conductivity-meter: catharometer (INRAP, Tunisia). The plates used for thin-layer chromatography (TLC) were E. Merck silica gel 60F254 (0.25 mm thickness) precoated on aluminum plates, and they were visualized under both long (365 nm) and short (254 nm) UV light. All compounds were purified by column chromatography (Silica gel 60, 70-230 mesh ASTM). Mass Spectra (MS) were carried out on a Hewlett-Packard 5890 (70 ev) by the staff of Medicine Faculty of Monastir, Tunisia, under electronic impact (EI) using NH3 as the carrier gas.

Representative Procedure for the Synthesis of 2a-e

A 25 mL round bottomed flask was charged with 2-hydroxymethyl-2-cyclopentenone 1a (3 mmol, 336 mg), triethylorthoacetate (3.6 mmol, 583 mg) and propionic acid (3 mmol, 222 mg). The resulting mixture was stirred at reflux for 4 hours. When the reaction was completed, the mixture was basified by 5 mL of saturated solution of NaHCO3 and extracted with 40 mL of ethyl acetate. After the usual work, the crude product was purified by column chromatography on silica gel using Diethyl ether/Petroleum ether (1:9) as eluent, gave pure 2a in 70% yield.

3-Ethoxycarbonylmethyl-2-methylenecyclopentan-1-one (2a)

IR (CHCl3) cm-1: 1727 (C=O, ester), 1708 (C=O, ketone). 1H NMR (300 MHz, CDCl3): 6.05-5.28 (AA’, J = 2.9 Hz, 2H), 4.19 (q, J = 6.9 Hz, 2H,), 3.20 (m, 1H), 2.73-2.66 (d, 1H), 2.47-2.17 (m, 4H), 1.58 (m, 1H), 1.30 (t, J = 6.9 Hz, 3H). 13C NMR (75 MHz, CDCl3): 206.1, 171.8, 147.6, 117.1, 60.6, 38.9; 37.5, 36.9, 26.5, 14.2. MS (m/z): 41(39), 53 (88), 67 (71), 79 (64), 98 (73), 108 (100), 125 (46), 137 (57), 154 (86), 182 (M+; 65). Elemental Analysis for C10H14O3 calcld: C, 65.91 H, 7.74 found: C, 65.98; H, 7.86.

3-Ethoxycarbonylmethyl-2-ethylidenecyclopentan-1-one (2b)

IR (CHCl3) cm-1: 1715 (C=O, ester), 1698 (C=O, ketone). 1H NMR (300 MHz, CDCl3): 6.66 et 6.03 (q, J = 2.9 Hz, 1H), 4.17 (q, J = 6.9 Hz, 2H), 3.48 (m, 1H), 2.38-2.05 (m, 6H), 1.88 (d, J = 2.9 Hz, 3H), 1.27 (t, J = 6.9 Hz, 3H). 13C NMR (75 MHz, CDCl3): 206.0, 171.5, 147.1, 125.2, 60.4, 38.6, 37.3, 35.9, 26.4, 24.3, 14.1. MS (m/z): 41 (27), 67 (21), 79 (43), 109 (100), 123 (39), 151 (19) 196 (M+; 65). Elemental Analysis for C11H16O3 calcld: C, 67.32; H, 8.22 found: C, 67.40; H, 8.33.

3-Ethoxycarbonylmethyl-2-butylidenecyclopentan-1-one (2c)

IR (CHCl3) cm-1: 1717 (C=O, ester), 1695 (C=O, ketone). 1H NMR (300 MHz, CDCl3): 6.64 and 5.56 (t, J = 2.9 Hz, 1H), 4.22 (q, J = 6.9 Hz, 2H), 2.58 (m, 4H), 2.44-2.34 (m, 4H), 2.05-1.71 (m, 4H), 1.25 (m, 2H), 1.15 (t, J = 6.9 Hz, 3H), 0.91 (m, 3H). 13C NMR (75 MHz, CDCl3): 207.3, 173.6, 158.3, 145.6, 69.2, 35.3, 35.1, 29.7, 27.7, 26.5, 18.5, 13.7, 9.2. MS (m/z): 41 (13), 55 (15), 67 (18), 79 (21), 95 (21), 107 (11), 121 (11), 137 (100), 224 (M+; 29). Elemental Analysis for C13H20O3 calcd: C, 69.61; H, 8.99, found: C, 69.55; H, 9.12.

3-Ethoxycarbonylmethyl-2-(2-methylpropylidene) cyclopentan-1-one (2d)

IR (CHCl3) cm-1: 1722 (C=O, ester), 1703 (C=O, ketone). 1H NMR (300 MHz, CDCl3): 6.41 (d, J = 2.9 Hz, 1H), 4.17 (q, J = 6.9 Hz, 2H), 3.74 (m, 1H), 2.44-1.85 (m, 7H), 1.25 (t, J = 6.9 Hz, 3H), 1.04 (m, 6H). 13C NMR (75 MHz, CDCl3): 207.0, 171.8, 144.2, 137.4, 60.7, 39.4, 35.8, 34.8, 29.7, 28.7 25.2, 22.1, 14.2. MS (m/z): 41 (13), 55 (14), 67 (17), 79 (23) 95 (18), 109 (16), 121 (10), 137 (100), 179 (8), 224 (M+; 30). Elemental Analysis for C13H20O3 calcd: C, 69.61; H, 8.99, found: C, 69.54; H, 9.12.

2-(1-Phenyl-propanoyloxyméthyl)cyclopent-2-en-1-one (2e)

IR (CHCl3) cm-1: 1743 (C=O, ester), 1701 (C=O, ketone). 1H NMR (300 MHz, CDCl3): 7.48 (m, 1H), 7.37-7.18 (m, 5H), 6.54 (s, 1H), 2.58 (m, 2H), 2.45-2.29 (m, 4H), 1.17 (t, J = 7.3 Hz, 3H). 13C NMR (75 MHz, CDCl3): 206.5, 171.9, 159.2, 145.4, 138.2, 128.4, 128.3, 127.2, 70.2, 34.9, 27.6, 26.6, 9.0. MS (m/z): 57(98), 77(28), 109(55), 128 (97), 141(16), 141(16), 159(14), 171(20), 187(100), 244 (M+; 2). Elemental Analysis for C15H16O3 calcd: C, 73.75; H, 6.60, found: C, 73.78; H, 6.71.

CONCLUSION

In the present study, we have reported the preparation of the (±) HomoSarkomycine Ester 2a in one step from 2-hydroxymethl-2-cyclopentenone 1a. We have succeeded to generalize this process with Baylis-Hillman adducts 1b-e. Local reactivity descriptors are shown to be very powerful in predicting the reactivity of Baylis-Hillman adducts 1a-e, propanoic acid and triethylorthoester.

Table 1

Synthesis of 2a-d from 1a-d with Johnson-Claisen rearrangement.

2	a	b	c	d
R	H	Me	n-Pr	i-Pr
Time	4 h	4 h	5h 30 mn	6h
Z/E*	-	20/80	30/70	10/90
Yield (%)	70	60	58	64

* The proportion is calculated from the 1H NMR.

Table 2

Calculated local reactivity properties of the selected molecules using BLYP/6-31g(d) method for NBO derived charges.

Entry	O1	O2	C3	H4
	0.177	0.046
			0.423	0.116
ELUMO - EHOMO	0.19458	0.17922	0.28787	0.27589
η	0.09729	0.08961	0.14393	0.13794
S	5.1390	5.5797	3.47380	3.6250
	0.9096	0.2567
			1.4660	0.4205