WO2003031425A1

WO2003031425A1 - Diastereomerically or enantiomerically selective lactonisation

Info

Publication number: WO2003031425A1
Application number: PCT/AU2002/001351
Authority: WO
Inventors: Dennis Dr. Taylor; Mark Kimber
Original assignee: Adelaide Research And Innovation Pty. Ltd.
Priority date: 2001-10-05
Filing date: 2002-10-04
Publication date: 2003-04-17
Also published as: AUPR812901A0

Abstract

A method of forming a η-lactone said method characterized by reacting together a symmetrical or a non-symmetrical 1,2-dioxine of the formula (1), wherein R?1 and R2¿ are the same or different and are groups in which a carbon atom is bonded to the dioxine backbone; and a doubly stabilised ester nucleophile. The nucleophile is a stabilized enolate nucleophile generated from reaction of an ester, ketone or nitrile in the presence of a base. Conducting the reaction in the presence of a cobalt catalyst a chiral ligand results in a η-lactone.

Description

Diastereomerically or Enantiomerically Selective Lactonisation

FIELD OF THE INVENTION

The present invention relates to a process for introducing a γ-lactone group into a molecule.

BACKGROUND OF THE INVENTION

γ-Lactone containing natural and non-natural products have received considerable attention as synthetic targets since the incorporation of the rigidified lactone skeleton into bioactive analogues leads to conformationally constrained molecules. Such modifications often have significant effects on bioactivities with concomitant medical implications. Additionally, the chemical composition of the lactone ring represents a unique site of chemical reactivity, which can undergo many other chemical transformations to generate a host of unique chemical structures. Lactones are also generated as transient species in primary and secondary metabolisms in man, plants and microorganisms. Thus, the great importance of functionalised lactones in organic synthesis spurs a continuing search for efficient stereo controlled lactonisation methodologies. Of particular importance is the deficiency in methods for the construction of diversely functionalised lactones especially those that contain greater than di-substitution. Chemicals containing the lactone moiety may be used inter alia: in the preparation of lactone containing amino acids; the preparation of lactone containing pharmaceuticals; the preparation of new lactone containing products for further biological evaluation by chemistry / biochemistry laboratories.

γ-Lactones may be synthesised by a number of techniques including (i) intramolecular cyclisations and (ii) carbonylation type processes. Such methods, employing as they do, difficult to prepare starting materials or requiring reaction mixtures that are highly sensitive to moisture have certain practical drawbacks.

The present invention is directed to a synthetic route for the preparation of optically enriched or racemic γ-lactone compounds. SUMMARY OF THE INVENTION

Therefore according to a first aspect of the invention, although this need not be the broadest nor indeed the only aspect of the invention there is provided method of forming a γ-lactone said method characterized by reacting together:

(i) a symmetrical or a non-symmetrical 1,2-dioxine of the formula (1),

R1

wherein R¹ and R² are the same or different and are groups in which a carbon atom is bonded to the dioxine backbone; and

(ii) a doubly stabilised ester nucleophile.

There are two approaches depending that may be taken depending on whether a racemic mixture or an optically enriched γ-lactone is the preferred end result of the reaction. Thus, if racemic γ-lactones are wanted then a 1,2-dioxine, which may be symmetrical, or non-symmetrical may be used along with the double stabilized ester nucleophile.

Alternatively, if the desired products are optically enriched lactones then a symmetrical 1,2-dioxine together with a selected chiral cobalt catalyst is used along with a doubly stabilized ester nucleophile would be used in the reaction.

Therefore according to a second aspect of the invention, although this need not be the broadest nor indeed the only aspect of the invention there is provided a method of forming a γ-lactone having enhanced chirality said method comprising reacting together:

(i) a symmetrical 1,2-dioxine of the formula (1), wherein R¹ and R² are the same and are groups in which a carbon atom is bonded to the dioxine backbone; and

(ii) a doubly stabilised ester nucleophile precursor; in the presence of (iii) a cobalt catalyst containing a chiral ligand.

A reaction scheme for the synthesis of γ-lactones according to the process of the invention is illustrated below as scheme 1.

Scheme 1

Major Minor

7 8

It is suggested that the enolate anion generated from (2) (also referred to as a doubly stabilised ester nucleophile) acts as a mild base inducing the ring opening of the 1,2- dioxine (1) to their isomeric cis y-hydroxy enones (3) followed by Michael addition of the nucleophile on the less hindered face as determined by R² to afford the intermediate enolate (4). This intermediate, (4), then undergoes a proton transfer and the subsequent alkoxy intermediate, (5), cyclizes to the lactone, (6) as shown. The lactone exists as the anion until it is quenched with acid or an electrophile, with quenching of the anion presumably occurring on the less hindered face to give γ-lactone (7) in excellent yield. The small amounts of the other diastereomer, (8), detected by !H NMR, presumably result from quenching of this intermediate, (7), from the more hindered face. The γ- lactone products emerging from this reaction scheme can be prepared as racemic mixtures or if a chiral cobalt catalyst is utilised then they may be prepared in high optical purity.

In the context of the present invention a doubly stabilised ester nucleophile may be taken to mean a stabilized enolate nucleophile generated from reaction of an ester of type (2) in the presence of a base. Preferably, the doubly stabilised ester nucleophile precursor (2) is a compound of the formula

(i) R³CH₂CO₂X; wherein R³ must be a group which helps stabilise the generated enolate. For example, R can be groups such as esters, ketones or nitriles. In addition, the ester grouping X may be alkyl, substituted alkyl, aryl, substituted aryl.

In the case where a γ-lactone having enhanced chirality is produced the cobalt catalyst preferably has one of the structures shown below

or

In accordance with a further aspect of the invention there is provided a chiral lactonisation catalyst of the formulae shown in Table 1

Catalysts according to the invention in the forms a to h may be prepared by reaction of Cobalt acetoacetate with the relevant SALEN ligand. SALEN

Table 1

Chiral Cobalt Based SALEN catalysts

9a: R4,R5 = -(CH₂) -, R8 = t-Bu, R7 = H, R6 = t-Bu (R,R isomer) 9b: R4,R5 = -(CH₂)₄-, R8 = R7 = R6 = H (R,R isomer) 9c: R4,R5 = -(CH₂)₄-, R8 = t-Bu, R7 = R6 = H (R,R isomer) 9d: R4,R5 = Ph, R8 = R7 = R6 = H (R,R isomer) 9e: R4,R5 = Ph, R8 = t-Bu, R7 = R6 = H (R,R isomer) 9f : R4,R5 = -(CH₂)₄-, R8 = 5-PhEtCH-, R7 = R6 = H (R,R isomer) 9g: R4,R5 = Ph, R8 = S-PhEtCH-, R7 = R6 = H (R,R isomer) 9h: R4,R5 = Ph, R8 = S-PhEtCH-, R7 = R6 = H (S,S isomer) Beta-Ketoiminato Cobalt Based Catalysts

10a: R4 = R5 = H, R9 = (-)-bornoxy 10b: R4 = R5 = Ph, R9 = (-)-bornoxy (S,S isomer) 10c: R4 = R5 = Ph, R9 = (-)-bornoxy (R,R isomer) lOd: R4 = R5 = -(CH₂)₄-, R9 = (-)-bornoxy (R,R isomer) lOe: R4 = R5 = Ph, R9 = (-)-menthoxy (S,S isomer) lOf: R4 = R5 = Ph, R9 = (-)-menthoxy (R,R isomer) lOg: R4 = R5 = Ph, R9 = (+)-menthoxy (S,S isomer) lOh: R4 = R5 = Ph, R9 = (+)-menthoxy (R,R isomer) lOi: R4 = R5 = Ph, R9 = ethoxy (S,S isomer) lOj: R4 = R5 = Ph, ethoxy (R,R isomer) 10k: R4 = R5 = -(CH₂)₄-, R9 = ethoxy (R,R isomer) 101: R4 = R5 = Ph, R9 = methyl (S,S isomer)

Preferably, the γ-lactones of the invention are prepared in a solvent such as tetrahydrofuran, ether, toluene, carbon tetrachloride, alcohols and dichloromethane or mixtures thereof. In a particularly preferred form of the invention the cyclopropanes of the invention are prepared in tetrahydrofuran. It will be appreciated by those skilled in the art that a range of solvents would in fact be suitable for use in conducting the reaction of the invention. In any specific case an optimum solvent can be identified by trail and experiment using the above solvents and others.

The enantiomerically enhanced γ-lactones of the invention are preferably prepared with catalyst concentration of up to 50 mol% catalyst relative to the 1,2-dioxine, and more preferably still a catalyst concentration of 5-15 mol%.

The optically enriched γ-lactones prepared in accordance with the invention may be further enriched by conventional techniques. For example, by recrystallization or conversion to diastereoisomers which can be separated by conventional techniques, e.g. recrystallization of column chromatography.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention will now be described by way of a number of non limiting examples. It should be noted that the invention presents a synthetic route for racemic or optically enhanced γ-lactones and that the range of structures capable of synthesis according to the process of the invention is not to be taken as being limited to those structures described herein. An extremely wide range of γ-lactone structures may be manufactured according to the process of the invention

Initial demonstration of methodology. Preparation of γ-lactones 7a-c.

The initial investigations centred on the use of β-stabilised enolate esters such as the enolate of diethyl malonate, with the 3-phenyl-6-phenyl dioxine la chosen as the model 1,2-dioxine. The results are summarised below within Scheme 2 and Table 2.

1a 2 R = CO;>Et 7a-c

2b: R = C(0)Me 2c R= CN

Scheme 2

Table 2. Synthesis of lactones 7a-c, utilising 1,2-dioxine la and esters 2a-c.

entry R Lactone Yield (%)

1 CO Et 7a 93

2 CN 7b 93 3* C(O)Me 7c 45 4c C(O)Me 7c 70 ^General reaction conditions contained in experimental. ^bl equivalent of ester. ^c2 equivalents of ester.

The enolates of the di -substituted esters 2a-c reacted with dioxine la to afford the lactones 7a-c in excellent yield. However, two equivalents of ester 2c were required to generate the lactone 7c in high yield (entry 4). Each reaction was highly diastereoselective (>85%), with the stereochemistry about the lactone ring system determined by 2-D ^H and ^C NMR techniques and further confirmed by a single crystal analysis of 7c. A small amount of a minor lactone isomer (8) could be seen by

1H NMR but no attempt was made to isolate this minor isomer.

Each reaction required acidic work-up due to the basicity of the proton at C3 and this therefore allowed for alkylation at this position prior to work-up. Hence the anion of (6) was readily alkylated with Mel to give lactone 11, which was decarboxylated to afford lactones 12a and 12b in a 65:35 ratio, epimeric at C3. Similarly, 6 could be alkylated with BnBr to afford lactone 13, exclusively, which, after decarboxylation gave lactone 14, (Scheme 3).

65 35

12a 12b

13 F COaEt

1₄ R = H I ^{C (85%)}

Scheme 3 (a) R-X; (b) 50%AcOH, reflux, 16h; (c) (i) KOH (2M), EtOH; (ii) toluene, reflux.

Further scope of reaction.

To highlight the potential of this process ester nucleophiles 2a-c were reacted with a range of acyclic and cyclic 1,2- dioxines to test the scope of the reaction. The results are summarised below in Table 3. The diagrams of the 1,2-dioxines and the formed lactones are numbered below.

15c

PH' <y 'C₈H 16c

8^π17

21

Table 3. Reaction of diester nucleophiles 2a-c with a range of 1,2-dioxines.

entry 1,2-dioxine lactone Yield (%)

1 lb 15a 97

2 15b 78

3 15c 85

4 lc 16a 92

5 16b 65

6 16c 74

7 Id 17a 65

8 le 18 93

9 If 19 84

10 ig 20 95

11 lh 21 56

Yields were good to excellent for all of the lactones and the diastereoselectivity for the lactones was also excellent, de 85-95%. As described previously, two equivalents of ethyl acetoacetate were required for complete conversion of the 1,2-dioxines to lactones (entries 3 and 6). The 3-substituted cyano lactones, 15b and 16b were also obtained in high yield. As well as acyclic 1,2-dioxines, bicyclic dioxine Id gave an excellent yield of the cis fused lactone 17a (entry 7) as confirmed by 2-D ^lH and ¹³C NMR techniques. Additionally, long chain alkyl chained dioxine le was tolerant of the reaction conditions as seen in entry 8. 3,5-Disubstituited dioxine, If, gave a high yield of the lactone 19 as a 1 : 1 mixture, epimeric at C3 (entry 9). 5-Dimethyl dioxine lg also gave the desired lactone 20 in excellent yield and de (entry 10). The results shown in Table 2 indicate that this reaction is general for a range of 1,2-dioxines and could be conceivably be applied to many other novel 1,2-dioxines.

Preparation of optically-enriched γ-lactones.

Therefore, when the dioxine la was reacted with optically pure cobalt(II) catalysts (10b and 10g,f) optically pure enone is formed which can then be expediently converted to the subsequent lactone (Scheme 4 and Table 4) when treated with the anions of 2a-c. 22

Scheme 4

1a 7a-c

Table 4. Formation of Optically enriched lactones 7a-c using Chiral Co(II) catalysts 10b, lOg and lOf and meso- 1,2-dioxine la.^α

entry 1,2-dioxine lactone ratio ee^ύ

1 la 7a 90 : 10 80

2^C 7b - -

3 7c 91 : 9 82

₄d 7a 88.5 : 11.5 77

5^e 11 : 89 78 ^αSee experimental for reaction conditions. Reaction carried out using chiral Co(TJ) catalyst 10b unless otherwise stated. ^bt determined by chiral shift. ^cee could not be determined due to insolubility of 7b in chiral shift solvent. ^Reaction carried out using chiral Co(H) catalyst lOg. ^Reaction carried out using chiral Co(H) catalyst lOf.

Yields for each transformation were good to excellent (65-95%) and the ee introduced into each lactone was also excellent (77-82%). Bornoxy Co(H) catalyst 10b introduced similar ee's into each lactone, irrespective of which ester nucleophile was utilised. Menthoxy catalysts lOg and lOf are matched enantiomers and consequently they generated lactones of opposite absolute configuration. These results therefore suggest that ee is being introduced into the cis γ-hydroxy enone, subsequent to the syn 1,4- addition of the ester nucleophiles.

General experimental for the above transformations.

General Lactonization procedure using diethyl malonate. To a solution of sodium ethoxide (0.5 M, 2.2 ml) and THF (4 ml) was added diethyl malonate, 2a (1 mmol), and the reaction allowed to stir for 15 min. under an N2 atmosphere. To this solution was added the 1,2-dioxine (1 mmol) and the reaction left to stir for 16hr. After this period the reaction was quenched by the addition of 1M HC1 (2 ml) and the mixture partitioned between dichloromethane (50 ml) and 1M HC1 (50 ml). The aqueous layer was then extracted and the organic layers dried, filtered and the solvent removed under reduced pressure. Column chromatography (60 : 40, hexane : ethyl acetate) yielded the following substituted lactones:

(±)-Ethyl 2-oxo-4-(2-oxo-2-phenylethyl)-5-phenyltetrahydro-3-furancarboxylate,

7a. As a colourless oil (Rf 0.62, 60 : 40, hexanes : ethyl acetate). BR (oil): 2983, 1782,

1732, 1683, 1597, 1581, 1497, 1449, 1371, 1341 cm"¹; lH NMR (CDCI3, 200 MHz) 5 1.34 (t, J = 7.2 Hz, 3H), 2.63 (dd, 7 = 8.4, 18.3 Hz, IH), 2.91 (dd, 7 = 6.0, 18.3 Hz, IH), 3.54 (d, J = 9.6 Hz, IH), 3.90 (dddd, J = 6.0, 7.5, 8.4, 9.6 Hz, IH), 4.30 (q, J = 7.2 Hz, 2H), 6.04 (d, J = 7.5 Hz, IH), 7.11 - 7.14 (m, 2H), 7.26 - 7.30 (m, 3H), 7.36 - 7.42 (m, 2H), 7.51 - 7.54 (m, IH), 7.68 - 7.71 (m, 2H); ¹³C NMR (CDCI3, 75 MHz) 6 14.0, 38.3, 39.9, 50.9, 62.3, 82.2, 125.7, 127.7, 128.4, 128.5, 128.7, 128.8, 133.4, 135.2, 167.1, 171.3, 197.3. MS (M+, %) 353 (M^*+> 20), 232 (72), 186 (32), 159 (26), 105 (100), 77 (52). Anal. Calcd. for C₂ιH₂oO₅: C, 71.58; H, 5.72 %. Found C, 71.32, H, 5.81 %.

(±)-Ethyl 5-methyl-2-oxo-4-(2-oxo-2-phenylethyI)-tetrahydro-3-furancarboxylate, 7b. As a clear oil (R_f 0.55, 60 : 40, hexanes : ethyl acetate). IR (oil) 2983, 1778, 1732,

1685, 1597, 1581, 1449, 1373, 1275 cm"¹; lH NMR (CDC1₃, 300 MHz) δ 1.24 (d, J = 6.6 Hz, IH), 1.34 (t, J = 7.2 Hz, 3H), 3.14-3.31 (m, 2H), 3.40 (d, J = 9.9 Hz, IH), 3.60 (m, IH), 4.29 (q, J = 7.2 Hz, 2H), 5.14 - 5.17 (m, IH), 7.46 - 7.52 (m, 2H), 7.58 - 7.64 (m, IH), 7.93 - 7.97 (m, 2H); ¹³C NMR (CDCI3, 150 MHz) δ 14.0, 15.8, 37.5, 38.5, 51.1, 62.2, 77.6, 127.9, 128.8, 133.7, 135.9, 167.2, 170.8, 196.9. MS (M+ %) 290 (M^,+J5), 245 (38), 226 (31), 200 (12), 105 (100), 77 (21). Anal. Calcd. for Cι₆Hι₈O₅: C, 66.20; H, 6.25 %. Found C, 65.95, H, 6.22 %.

(±)-Ethyl 2-oxo-4-(2-oxo-2-phenylethyl)-tetrahydro-3-furancarboxylate, 7c. As white plates, m.p. 67.5 - 69.5°C (Rf 0.42, 60 : 40, hexanes : ethyl acetate). IR (nujol)

2984, 1778, 1731, 1684, 1596, 1449, 1372, 1225 cm"¹; ^lH NMR (CDCI3, 300 MHz) δ

1.31 (t, 7 = 7.1 Hz, 3H), 3.18 (dd, J = 8.4, 18.0 Hz, IH), 3.39 (dd, J = 5.1, 18.0 Hz, IH), 3.40 (d, J = 8.7 Hz, IH), 3.53 (ddddd, J = 5.1, 7.8, 7.8, 8.4, 8.7 Hz, IH), 4.01 (dd, J = 7.8, 9.0 Hz, IH), 4.30 (q, J =7.8 Hz, 2H), 4.81 (dd, J = 7.8, 9.0 Hz, IH), 7.48 - 7.51 (m, 2H), 7.58 - 7.64 (m, IH), 7.91 - 7.94 (m, 2H); 13c NMR (CDCI3, 75 MHz) δ 14.0, 35.7, 40.9, 51.8, 62.3, 71.9, 128.0, 128.8, 131.4, 133.8, 167.2, 171.4, 197.8. MS (M+, %) 277 (M^*+. 100), 231 (10), 145 (63), 105 (22). Anal. Calcd. for Cι₅Hι₆O₅: C, 65.21; H, 5.84 %. Found C, 65.03; H, 5.90 %.

General procedure for alkylation of lactone 6a. To a solution of sodium ethoxide (0.5 M, 2.2 ml) and THF (4 ml) was added diethyl malonate, 2a (1 mmol), and the reaction allowed to stir for 15 min. under an N₂ atmosphere. To this solution was added the 1,2-dioxine (1 mmol) and the reaction left to stir for 16hr. After this period alkyl halide (1.05mmol) was added and the reaction stirred overnight (16 h) at room temperature. The reaction was quenched by the addition of 1M HC1 (2 ml) and the mixture partitioned between dichloromethane (50 ml) and 1M HC1 (50 ml). The aqueous layer was then extracted and the subsequent organic layers dried, filtered and the solvent removed under reduced pressure. Column chromatography (60 : 40, hexane : ethyl acetate) yielded the following lactones.

(±)-Ethyl 3-Methyl-2-oxo-4-(2-oxo-2-phenyIethyl)-5-phenyltetrahydro-3- furancarboxylate, 11. Obtained as a mixture of isomers epimeric at C3 (as determined by *H NMR) , which were not separated, but decarboxylated. Hence, 11 was refluxed in 50% AcOH (5 ml) for 16h and the resultant mixture cooled and basified. The aqueous layer was then extracted with dichloromethane (20 ml) and the resultant organic layer dried, filtered and the solvent removed under reduced pressure. This yielded two products (65 : 35 mixture by *H NMR), which were separated by chromatography (70 : 30, hexanes : ethyl acetate) and identified as the following;

(±)-(3S, 4S, 5S)-3-Methyl-4-(2-oxo-2-phenylethyl)-5-phenyltetrahydro-3-furanone, 12a, as colourless plates, m.p. 147-149°C (Rf 0.53, 60 : 40, hexanes : ethyl acetate). IR (nujol) 1758, 1683, 1376, 1349, 1163 cm"¹; ^lH NMR (CDCI3, 600 MHz) d 1.28 (d, J = 7.2 Hz, 3H), 2.61 - 2.66 (dq, J = 7.2, 7.2 Hz, IH), 2J0 - 2J5 (dddd, J = 4.8, 7.2, 7.2, 9.0 Hz, IH), 3.11 - 3.15 (dd, J = 7.2, 16.8 Hz, IH), 3.20 - 3.23 (dd, 7 = 4.8, 16.8 Hz, IH), 5.12 (d, J = 9.0 Hz, IH), 7.32 - 7.43 (m, 7H), 7.54 - 7.57 (m, IH), 7.79 - 7.81 (m, 2H). ¹³C NMR (CDCI3, 75 MHz). 14.5, 38.7, 41.9, 48.1, 83.8, 126.6, 128.0, 128.8, 129.1, 133.6, 136.5, 170.2, 197.3, one carbon masked. MS (M+, %) 295 (M«+, 100), 174 (25), 105 (20). Anal. Calcd. for Cι₉Hι₈O₃: C, 77.53; H: 6.16 %. Found: C, 77.88 ; H, 6.08%.

(±)-(3S, 4R, 5S)-3-Methyl-4-(2-oxo-2-phenylethyl)-5-phenyltetrahydro-3-furanone 12b, as colourless prisms, m.p. 158-160°C (Rf 0.68, 60 : 40, hexanes : ethyl acetate). IR (nujol) 1755, 1679, 1376, 1350, 1165 cnrl. ^lR NMR (CDCI3, 600 MHz) d 1.18 (d, J = 7.8 Hz, 3H), 3.03 (dq, J = 7.2, 7.8 Hz, IH), 3.09 - 3.20 (m, 3H), 5.22 (d, J = 4.8 Hz, IH), 7.32 - 7.35 (m, IH), 7.38 - 7.40 (m, 2H), 7.45 - 7.48 (m, 4H), 7.57 - 7.60 ( , IH), 7.93 - 7.95 (m, 2H); MS (M⁺, %) 295 (M-+, 30), 175 (15), 174 (62), 105 (100), 77 (25). (±)-Ethyl 3-Methyl-2-oxo-4-(2-oxo-2-phenylethyl)-5-phenyltetrahydro-3- furancarboxylate, 13. Obtained as a colourless oil (Rf 0.53, 60 : 40, hexanes : ethyl acetate). lH NMR (CDC1₃, 300 MHz) δ 1.23 (t, J = 7.2 Hz, 3H), 2.62 - 2.71 (dd, J = 9.0, 18.9 Hz, IH), 2.95 - 3.03 (dd, J = 5.1, 18.9 Hz, IH), 3.35 (d, J = 13.8 Hz, IH), 3.53 (d, J = 13.8 Hz, IH), 3.80 - 3.88 (ddd, J = 5J, 9.0, 9.3 Hz, IH), 4.12 (q, J = 7.2 Hz, 2H), 5.21 (d, J = 9.3 Hz, IH), 7.08 - 7.21 (m, 5H), 7.30 - 7.40 (m, 7H), 7.50 - 7.55 (m, IH), 7.62 - 7.66 (m, 2H). MS (M+, %) 443.4 (M'⁺ 100), 221 J (38), 105,1 (25). 12 was decarboxylated under basic conditions. Hence, 12 was stirred in a mixture of ethanol (10 ml) and KOH (2M, 10 ml) for 16 h. After this period the mixture was acidified and the aqueous layer extracted with dichloromethane (20 ml) and the resultant organic layer dried, filtered and the solvent removed under reduced pressure. The residue was then dissolved in toluene (10 ml) and refluxed overnight. The toluene was then removed under reduced pressure and the residue purified by chromatography to yield the following;

(±)-3-Benzyl-4-(2-oxo-2-phenylethyl)-5-phenyltetrahydro-3-furanone, 14. White solid, m.p. 96-97.5°C (Rf 0.65, 60 : 40, hexanes : ethyl acetate). IR (nujol) 1776, 1679,

1340, 1164 cm-¹; H NMR (CDCI3, 300 MHz) δ 2.75 (dddd, J = 5.4, 6.3, 8.1, 9.3 Hz, IH), 2.88 (dd, J = 5.4, 17.1 Hz, IH), 2.94 (dd, J = 7.8, 13.8 Hz, IH), 2.97 (dd, J = 6.3,

17.1 Hz, IH), 3.14 (ddd, J - 4.8, 7.8, 9.3 Hz, IH), 3.24 (dd, J - 4.8, 13.8 Hz, IH), 5.25 (d, 7 = 8.1 Hz, IH), 7.10 - 7.20 ( , 8H), 7.28 - 7.30 (m, 2H), 7.35 - 7.40 (m, 2H), 7.51 -

7.57 (m, IH), 7.63 - 7.66 (m, 2H); ¹³C NMR (CDCI3, 100 MHz) δ 35.5, 38.6, 44.6, 47.0, 83.6, 126.3, 126.7, 127.8, 128.5, 128.6, 128.7, 129.2, 131.0, 133.3, 136.3, 137.7, 137.9, 177.3, 197.6. MS (M+, %) 371 (M^*+, 28), 250 (29), 159 (82), 105 (100), 77 (35). Anal. Calcd. for C25H22O3: C, 81.06; H: 5.99 %. Found; C.80.78 ;H,5.98%.

(±)-Ethyl 2,5-dioxoperhydrocycloocta[b]furan-3-carboxylate, 17. As a colourless oil (Rf 0.54, 60 : 40, hexanes : ethyl acetate). IR (oil) 3545, 1786, 1736, 1459, 1374,

1337, 1273 cm-1. ^lH NMR (CDCI3, 600 MHz) δ 1.32 (t, J = 7.2 Hz, 3H), 1.41 - 1.17 (m, IH), 1.73 - 1.85 (m, 3H), 1.86 - 1.92 (m, 1H), 2.16 - 2.21 (m, IH), 2.33 (dt, J = 5.4,

13.2 Hz, IH), 2.41 (dd, J = 11.4, 14.4 Hz, IH), 2.70 (dd, J = 3.6, 14.4 Hz, IH), 2.71 - 2.16 (m, IH), 3.14 - 3.21 (m, IH), 3.35 (d, J = 12.0 Hz, IH), 4.12 - 4.16 (m, IH), 4.25 - 4.30 (m, 2H). ¹³C NMR (CDC1₃, 300 MHz) δ . MS (M+, %) 255 (M^*++ H, 100), 237 (10), 208 (25), 196 (32), 141 (18), 123 (30), 105 (52). Anal. Calcd. for Cι₃Hι₈O₅: C, 61.41; H, 7.14 %. Found: C, 61.64; H, 7.40 %.

(±)-Ethyl 5-octyl-2-oxo-4-(2-oxo-2-phenylethyl)-tetrahydro-3-furancarboxylate, 18. As a viscous oil (Rf 0.55, 60 : 40, hexanes : ethyl acetate). IR (oil) 1778, 1735,

1686, 1449, 1372, 1344, 1229 cm^"1; ^lU NMR (CDCI3, 75 MHz) δ 0.86 (m, 3H), 1.17- 2.04 (m, 17H), 3.21 (d, J = 7.2 Hz, 2H), 3.38 (d, J = 9.3 Hz, IH), 3.58 (m, IH), 4.22 (q, J = 7.2 Hz, 2H), 4.93 - 4.95 (m, IH), 7.46 - 7.51 (m, 2H), 7.58 - 7.61 (m, IH), 7.92 - 7.95 (m, 2H); ¹³C NMR (CDCI3, 75 MHz) δ 14.0, 22.6, 25.7, 29.1, 29.2, 29.3, 30.3, 31.8, 37.3, 38.5, 51.8, 62.3, 81.6, 128.0, 128.8, 133.8, 135.9, 167.3, 171.4, 197.0 (two alkyl carbons masked). MS (M⁺, %) 389 (M^*+, 21), 285 (62), 257 (18), 143 (86), 105 (100), 69 (64). Anal. Calcd. for C23H32O5: C, 71.11; H, 8.30 %. Found: C, 70.80; H, 8.01 %.

(±)-Ethyl 4-methyl-2-oxo-4-(2-oxo-2-phenylethyl)-tetrahydro-3-furancarboxylate, 19. As a colourless oil (Rf 0.42, 70 : 30, hexanes : ethyl acetate). Obtained as a 1 : 1 mixture of isomers, epimeric at C3 , which were assigned by 2-D *H NMR. (A) *H NMR (CDCI3, 600 MHz) δ 1.24 (t, J = 7.2 Hz, 3H), 1.37 (s, 3H), 3.07 (d, J = 18.0 Hz, IH), 3.46 (s, IH), 3.47 (d, J = 18.0 Hz, IH), 4.18 (q, J = 7.2 Hz, 2H), 4.33 (d, J = 9.0 Hz, IH), 4.49 (d, J = 9.0 Hz, IH), 7.43 - 7.48 (m, 2H), 7.55 - 7.59 (m, IH), 7.87 - 7.89 (m, 2H); (B) ^JH NMR (CDCI3, 600 MHz) δ 1.29 (s, 3H), 1.29 (t, J = 7.2 Hz, 3H), 3.16 (d, J = 18.0 Hz, IH), 3.47 (d, J = 18.0 Hz, IH), 3.58 (s, IH), 4.25 (q, J = 7.2 Hz, 2H), 4.32 (d, J = 9.0 HzJH), 4.41 (d, J = 9.0 Hz, IH), 7.43 - 7.48 (m, 2H), 7.55 - 7.59 (m, IH), 7.91 - 7.92 (m, 2H). MS (M+, %) 291 (M^«+, 32), 245 (10), 159 (52), 120 (100), 105 (92), 77 (98). The mixture was not separated but decarboxylated as follows. The mixture was refluxed in 50% acetic acid solution (5 ml) for 16 hrs. After this period the reaction was cooled, basified and the aqueous layer extracted with dichloromethane (50 ml). The combined organic extracts were then dried, filtered and the solvent removed under reduced pressure. This yielded (±)-4-methyl-2-oxo-4-(2-oxo-2-phenylethyl)- tetrahydrofuran, as a white solid, which was purified by chromatography (Rf 0.48, 60 : 40, hexanes : ethyl acetate), m.p. 64.5 - 66°C. IR (nujol) 1760, 1681, 1454, 1419, 1372, 1307, 1291, 1194, 1167 cm-1. 1H NMR (CDC1₃, 300 MHz) δ 1.34 (s, 3H), 2.48 (d, J = 17.4 Hz, IH), 2.63 (d, J = 17.4 Hz, IH), 3.13 (d, J = 17.4 Hz, IH), 3.31 (d, J = 17.4 Hz, IH), 4.26 - 4.33 (m, 2H), 7.45 - 7.51 (m, 2H), 7.57 - 7.61 (m, IH), 7.91 - 7.95 (m, 2H). ¹³C NMR (CDCI3, 75 MHz) δ 24.1, 38.3, 42.1, 46.0, 78.3, 127.8, 128.7, 133.5, 136.8, 176.2, 197.4. MS (M⁺, %) 219 (M^*+, 92), 159 (33), 120 (100), 105 (34). Anal. Calcd. for C₁3H14O3: C, 71.54; H, 6.47 %. Found: C, 71.81; H, 6.34 %.

(±)-Ethyl 5-dimethyl-2-oxo-4-(2-oxo-2-phenylethyl)-tetrahydro-3- furancarboxylate, 20. Mp 65-67 °C (Rf 0.48, 60 : 40. hexanes : ethyl acetate). IR (oil)

3533, 3062, 2981, 1772, 1687, 1449, 1377, 1352, 1267 cm-¹. ^lH NMR (CDCI3, 300 MHz) δ 1.20 (t, J = 7.2 Hz, 3H), 1.30 (s, 3H), 1.48 (s, 3H), 3.10 - 3.17 (m, 2H), 3.21 - 3.30 (m, IH), 3.43 (d, J = 11.4 Hz, IH), 4.17 (q, J = 7.2 Hz, 2H), 7.40 - 7.45 (m, 2H), 7.53 (m, IH), 7.87 - 7.90 (m, 2H). ¹³C NMR (CDCI3, 75 MHz) δ 13.7, 22.8, 27.1, 37.9, 44.9, 53.1, 61.7, 85.3, 127.9, 128.6, 133.4, 135.9, 167.5, 170.3, 196.8. MS (M+, %) 304 (M-+, 18), 259 (30), 240 (60), 105 (100).

(±)-Ethyl 2-oxo-4-(2-oxopentyl)-5-propyltetrahydro-3-furancarboxylate, 21. As a colourless oil (Rf 0.44; 70 : 30, hexanes : ethyl acetate). IR (oil) 2963, 2876, 1780, 1737, 1714, 1374, 1262, 1157 cm-¹. ^!H NMR (CDCI3, 300 MHz) δ θ.92 (t, /= 7.5 Hz, 3H), 0.95 (t, J = 6.9 Hz, 3H), 1.20 - 1.44 (m, 6H), 1.55 - 1.64 (m, 3H), 2.41 (t, J = 7.2 Hz, 2H), 2.55 - 2.72 (m, 2H), 3.26 (d, J = 9.3 Hz, IH), 3.35 - 3.41 (m, IH), 4.26 (q, J = 7.2 Hz, 2H), 4.80 - 4.89 (m, IH). ¹³C NMR (CDCI3, 75 MHz) δ 13.5, 13.6, 13.9, 17.1,

18.9, 32.3, 38.0, 41.1, 44.7, 51.7, 62.1, 81.1, 167.2, 170.9, 207.8. MS (M+, %) 285 (M^,+, 30), 199 (18), 153 (30), 71 (94), 43 (100). Anal. Calcd. for C15H₂₄O5: C, 63.36;

H, 8.51 %. Found C, 63.52; H, 8.66 %.

General Lactonization procedure using ethyl cyanoacetate. To a solution of sodium ethoxide (0.5 M, 2.2 ml, 1J mmol) and THF (4 ml) was added ethyl cyanoacetate, 2b (1.05 mmol), and the reaction allowed to stir for 15 min. under an N2 atmosphere. To this solution was added the 1,2-dioxine (1.0 mmol) and the reaction left to stir for 16hr. After this period the reaction was quenched by the addition of 1M HC1 (2 ml) and the mixture partitioned between dichloromethane (50 ml) and 1M HC1 (50 ml). The aqueous layer was then extracted and the subsequent organic layers dried, filtered and the solvent removed under reduced pressure. Column chromatography (60 : 40, hexane : ethyl acetate) yielded the following substituted lactones.

(±)-2-Oxo-4-(2-oxo-2-phenylethyl)-5-phenyltetrahydro-3-furancarbonitrile, 7b. As a fine white crystals, m.p. 129 - 131°C (Rf 0.54, 60 : 40, hexanes : ethyl acetate). IR

(nujol) 1774, 1675, 1369, 1340, 1322, 1282, 1182 era"¹; ^lH NMR (CDC1₃, 300 MHz) δ 3.00 (d, J = 6.9 Hz, 2H), 3.95 (ddd, J = 6.9, 6.9, 9.0 Hz, IH), 4J6 (d, J = 9.0 Hz, IH), 5.85 (d, J = 6.9 Hz, IH), 7.21 - 7.32 (m, 5H), 7.37 - 7.41 (m, 2H), 7.50 - 7.56 (m, IH), 7.67 - 7.69 (m, 2H); ¹ C NMR (CDCI3, 75 MHz) δ 36J, 37.5, 38.3, 83.0, 113.3, 125.6, 125.8, 127.8, 128.5, 128.9, 129.2, 133.6, 135.8, 167.6, 196.L MS (M+, %) 306 (M^*+. 32), 256 (10), 199 (22), 120 (48), 105 (100), 77 (32). Anal. Calcd. for C₁9H₁5N₁O3: C, 74.74; H, 4.95; N, 4.59 %. Found C, 74.47; H, 4.91; N, 4.64 %.

(±)-5-Methyl-2-Oxo-4-(2-oxo-2-phenylethyl)-tetrahydro-3-furancarbonitrile, 15b.

As a clear oil that decomposed upon standing (Rf 0.40, 60 : 40, hexanes : ethyl acetate). IR (oil) 3062, 2986, 2903, 1786, 1686, 1597, 1449, 1415, 1380, 1322, 1268 cm^{" 1}; ^lH NMR (CDCI3, 300 MHz) δ 1.25 (d, J = 6.3 Hz, 3H), 3.40 (d, J = 7.2 Hz, 2H), 3.51 - 3.54 (m, IH), 4.00 (d, J = S.l Hz, IH), 4.95 - 4.99 (m, IH), 7.48 - 7.54 (m, 2H), 7.61 - 7.65 (m, IH), 7.95 - 8.00 (m, 2H); ¹³C NMR (CDCI3, 300 MHz) δ 15J, 36.2, 36.9,

39.8, 78.5, 114.4, 128.0, 128.8, 128.9, 134.0, 166.9, 196.2. MS (M⁺, %) 243 (M'⁺, 21), 159 (18), 120 (18), 105 (100), 77 (52). HRMS Calcd. for C14H₁3NO3: 243.0895; found: 243.0905.

(±)-2-Oxo-4-(2-oxo-2-phenylethyl)-tetrahydro-3-furancarbonitrile, 16b. As a viscous oil that decomposed upon standing (Rf 0.36, 60 : 40, hexanes : ethyl acetate). IR (oil) 2924, 1799, 1682, 1596, 1451, 1376, 1162 cm"¹; Η NMR (CDCI3, 300 MHz) δ 3.21 (dd, J = 8.7, 18.0 Hz, IH), 3.46 (ddddd, J = 4.8, 6.3, 7.2, 8.7, 9.0 Hz, IH), 3.58 - 3.65 (dd, J = 4.8, 18.0 Hz, IH), 3.66 (d, J = 6.3 Hz, IH), 4.08 (dd, J = 9.0, 9.3 Hz, IH), 4.87 - 4.92 (dd, J = 7.2, 9.3 Hz, IH), 7.26 - 7.54 (m, 2H), 7.59 - 7.65 (m, IH), 7.91 - 7.94 (m, 2H); ¹³C NMR (CDCI3, 75 MHz) δ 36.9, 37.6, 39.2, 72.0, 114.1, 128.1, 129.0, 134.2, 135.6, 167.3, 196.0. MS (M+, %) 292.2 (M^,+, 28), 145 (38), 120 (32), 105 (100), 77 (50). HRMS Calcd. for C₁3H_{1 1}NO3: 229.0739; found: 229.0741.

General Lactonization procedure using ethyl acetoacetate. To a solution of sodium ethoxide (0.5 M, 4.4 ml, 2.2 mmol) and THF (4 ml) was added ethyl acetoacetate, 2c (2J mmol), and the reaction allowed to stir for 15 min. under an N₂ atmosphere. To this solution was added the 1,2-dioxine (1 mmol) and the reaction left to stir for 16hr. After this period the reaction was quenched by the addition of 1M HC1 (2 ml) and the mixture partitioned between dichloromethane (50 ml) and 1M HC1 (50 ml). The aqueous layer was then extracted and the subsequent organic layers dried, filtered and the solvent removed under reduced pressure. Column chromatography (60 : 40, hexane : ethyl acetate) yielded the following substituted lactones:

(±)-3-Acetyl-4-(2-oxo-2-phenylethyl)-5-phenyltetrahydro-2-furanone, 7c. As colourless needles, m.p. 113-114°C (R_f 0.25, dichloromethane). IR (nujol) 1769, 1714,

1677, 1459, 1379, 1341, 1237, 1164 cπr¹. ^lK NMR (CDCI3, 300 MHz) δ 2.52 (s, 3H), 2.59 (dd, J = 4.2, 18.3 Hz, IH), 2.85 (dd, J = 4.5, 18.3 Hz, IH), 3.71 (d, J = 7.4 Hz, IH), 3.84 (dddd, J = 4.2, 4.5, 7.4, 7.4 Hz, IH), 5.95 (d, J = 7.4 Hz, IH), 7.17 - 7.20 (m, 2H), 7.26 - 7.55 (m, 6H), 7.66 - 7.70 (m, 2H); ¹³C NMR (CDCI3, 75 MHz) δ 29.6, 38.0, 38.1, 58.6, 82.2, 125.6, 127.7, 128.2, 128.6, 128.6, 128.8, 133.5, 135.5, 136.1, 171.1, 197.6, 200.1. MS (M+, %) 323 (M'⁺ + H, 5), 202 (100), 160 (30), 105 (75). Anal. Calcd. for C₂oHι₈O₄: C, 74.52; H, 5.63 %. Found, C, 74.56; H, 5.79 %.

(±)-3-Acetyl-5-methyl-4-(2-oxo-2-phenylethyl)-tetrahydro-2-furanone, 15c. As white crystals, m.p. 80-81°C (Rf 0.23, 70 : 30, hexanes : ethyl acetate). IR (nujol)

2983, 1767, 1717, 1683, 1597, 1449, 1357 cm"¹. ^lH NMR (CDCI3, 300 MHz) δ 1.27

(d, J = 6.6 Hz, 3H), 2.47 (s, 3H), 3.10 - 3.30 (m, 2H), 3.51 - 3.57 (m, 2H), 5.06 (dq, J =

6.6, 6.6 Hz, IH), 7.45 - 7.51 (m, 2H), 7.58 - 7.63 (m, IH), 7.92 - 7.95 (m, 2H); ¹³C NMR (CDCI3, 75 MHz) δ 16.0, 29.5, 36.3, 37.2, 58.2, 77.6, 127.9, 128.7, 133.6, 136.0,

171.3, 197.4, 200.2. MS (M⁺, %) 261 (M^*+ + H, 25), 218 (10), 159 (14), 105 (100). Analysis Calcd. for Cι₅Hι₆O₄: C, 69.21. H, 6.19 %. Found, C, 69.29; H, 6.37 %.

(±)-3-Acetyl-4-(2-oxo-2-phenylethyl)-tetrahydro-2-furanone, 16c. As white plates, m.p. 114-115°C. (Rf 0.21, 70 : 30, hexanes : ethyl acetate). ER (nujol) 1769, 1713, 1676, 1597, 1580, 1012 cπr¹; ^lH NMR (CDC1₃, 300 MHz) δ 2.48 (s, 3H), 3.11 - 3.16 (m, IH), 3.31 - 3.34 ( , IH), 3.51 - 3.57 (m, 2H), 4.69 - 4.73 (m, IH), 7.47 - 7.50 (m, 2H), 7.59 - 7.61 (m,lH), 7.92 - 7.95 ( m, 2H); ¹³C NMR (CDCI3, 75 MHz) δ 29.6, 33.2, 40.8, 58.5, 71.8, 127.9, 128.8, 133.7, 136.0, 171.8, 197.2, 200.0. MS (M+, %) 247 (M^,+ +H, 10), 145 (20), 120 (50), 105 (100). Anal. Calcd. for C₁₄H₁₄O₄: C, 68.28; H, 5.73 %. Found, C, 68.35; H, 5.62 %.

General Procedure for the Synthesis of Optically Enriched Lactones 7a-c.

Catalyst Preparation

Beta Ketoiminato Catalyst Preparation - The preparation of a chiral cobalt catalyst (10b).

Preparation of (-)-Bornyl acetoacetate

To a solution of ethyl acetoacetate (4.5g, 0.0346 mol) in n-heptane (70 mL) was added (-)-borneol (5.34g, 0.0346 mol) and sodium hydride (50mg) and the reaction mixture refluxed under Deans Stark conditions for 2 days. The solvent was then removed in vacuo and the residue purified by chromatography on silica (1:9 ethyl acetate: hexanes). (6.16g, 70%) R 0.32 (1:9 ethyl acetate: hexanes) Η NMR δ 0.85 (s, 3H), 0.88 (s, 3H), 0.91 (s, 3H), 0.94 - 1.43 (m, 4H), 1.64 - 2.00 (m, 3H)2.85 (s, 3H), 3.47 (s, 2H), 4.95 (ddd, IH, J=15, 5.1, 3.3 Hz). ^I3C NMR δ 13.35, 18.71, 19.57, 26.96, 27.89, 29.99, 36.51, 44.76, 47.77, 48.76, 50.29, 81.07, 90.10, 167.30. MS m/z 238 (42%, M⁺), 154 (11%), 137 (100%), 121 (10%), 95 (23%).

(-) Bornyl 2-formyl-3-oxobutanoate

To the (-)-bornyl acetoacetate (2.0g, 8.4 x 10^"3moles) was added N,N- dimethylformamide dimethyl acetal (2g, 1.68 x 10^"2moles), the mixture stirred at room temperature for 2 hours, then cooled to 0°C and methanolic sodium hydroxide (IN, 14 mL 1:1 methanol: water) added. The reaction mixture was stirred for a further 2 hours then cooled to 0°C and hydrochloric acid (IN) added till pH 3-4. The mixture was extracted with diethyl ether, dried (Na₂SO₄) and the solvent removed in vacuo. R/ 0.6 (1:9 ethyl acetate: hexanes) Due to the instability of the aldehyde it was used directly in the next reaction to form the ligand. Η NMR δ 0.875 (s, 3H), 0.90 (s, 3H), 0.94 (s, 3H), 1.00 - 1.48 (m, IH), 1.12 - 1.48 ( , 4H), 2.32 - 2.54 (m, IH), 2.57 (s, 3H), 4.96 - 5.05 (m, IH), 9.25 (d, IH, J=9 Hz).

The crude (-)-bornyl 2-formyl-3-oxobutanoate (0.25g, 9.49 x 10^"4 mol) was combined in ethanol (3 mL) with (lS,2S)-l,2-diphenylethylenediamine (OJOg, 4.75 x 10^"4 mol) and allowed to react for 2 days, the solvent was then removed in vacuo and the residue purified by chromatography (1:9 acetone: dichloromethane) (290mg, 86%). R/ 0.64 (1:9 acetone: dichloromethane). 1H NMR δθ.79 (s, 6H), 0.86 (s, 6H), 0.90 (s, 6H), 0.96 - 1.32 (m, 4H), 1.60 - 1.82 (m, 6H), 2.28 - 2.49 (m, 2H), 2.51 (s, 6H), 4.67 (d, 2H, j=7.8 Hz), 4.89 (dm, 2H, j=8.2 Hz), 7J0 - 7.15 (m, 4H), 7.27 - 7.33 (m, 6H), 7.79 (d, 2H, j=12.8 Hz), 11.93 - 12.02 (m, 2H). ¹³C NMR 613.63, 18.84, 19.70, 27.64, 28.03, 31.02, 36.92, 44.84, 47.74, 48.74, 69.53, 79.48, 102.05, 135.68, 158.96, 167.09, 199.71. MS m/z 710 (M⁺, 4%), 555 (22%), 447 (19%), 354 (14%), 200 (31%), 137 (33%), 95 (100%).

Preparation of catalyst 10b

A mixture of ligand (144mg, 2.03 x 10^"4 mol) was combined with cobalt acetate tetrahydrate (50.6mg, 2.03 x 10^"4) in deaerated ethanol (4 mL) and heated under reflux for 4 hours. The solvent was then removed in vacuo till dryness of the complex resulted. The complex was used without further purification.

Each of the catalysts lOa-101 may be prepared using similar methodology and by substitution of the appropriate bornoxy, ethoxy, methoxy, ethoxy or methyl starting materials.

Preparation of Optically Enriched Lactones 7a-c. To a solution of the chiral cobalt (II) complex (10b, lOg or lOf) (0.075 mmol) in dry THF (5.0 ml) at -4°C under N was added 1,2-dioxine la (0.238 g, 1.0 mmol) and the mixture allowed to stir until complete conversion of the 1,2-dioxine to the enone (as determined by t.l.c; approx 3 hr). After this period a solution of the ester (2a and 2b 1.0 mmol; 2c 2.0 mmol) in sodium ethoxide (2a and 2b 1.05mmol; 2c 2.1 mmol) was added and the reaction stirred for a further 16 hr at room temperature. After this period 1M HC1 (2.0 ml) was added and the aqueous layer extracted with dichloromethane (20.0 ml) and the resultant organic layers dried, filtered and the solvent removed under reduced pressure and the lactone purified by chromatography (60 : 40 hexanes : ethyl acetate). The enantiomeric excess (ee) for each lactone was determined as follows; lactone (approx. 6 mg) was dissolved in a 1 : 4 dg-benzene : CCI₄ solution and chiral shift reagent europium tri[3-(heptafluoropropylhydroxymethylene)-(+)-camphorate] complex added until base line separation was attained. The following *H signals were chosen; 7a (CHPh); 7c (C(O)CH3). Enatiomeric excess could not be established for lactone 7b due to insolubility in the c?6-benzene-CCl4 solvent system.

The invention has been described by way of example. The examples are not, however, to be taken as limiting the scope of the invention in any way. Modifications and variations of the invention such as would be apparent to a skilled addressee are deemed to be within the scope of the invention.

Claims

1. A method of forming a γ-lactone said method characterized by reacting together: (i) a symmetrical or a non-symmetrical 1,2-dioxine of the formula (1),

R1

wherein R¹ and R² are the same or different and are groups in which a carbon atom is bonded to the dioxine backbone; and (ii) a doubly stabilised ester nucleophile.

2. A method according to claim 1, characterized by in that a cobalt catalyst is used to promote the reaction.

3. A method according to any one of claims 1 or 2, characterized in that a cobalt catalyst incorporating a chiral ligand is used to promote the reaction.

4. A method according to any one of claims 1 or 2, characterized in that the 1,2- dioxine is a symmetrical dioxine and that the γ-lactone product is optically enriched.

5. A method of forming a γ-lactone having enhanced chirality said method comprising reacting together:

(i) a symmetrical 1,2-dioxine of the formula (1), wherein R¹ and R² are the same and are groups in which a carbon atom is bonded to the dioxine backbone; and (ii) a doubly stabilised ester nucleophile precursor; in the presence of

(iii) a cobalt catalyst containing a chiral ligand.

6. A method according to any one of the preceding claims, characterized in that, a doubly stabilised ester nucleophile includes a stabilized enolate nucleophile generated from reaction of an ester precursor of type in the presence of a base.

7. A method according to claim 6, characterized in that the doubly stabilised ester nucleophile precursor is a compound of the formula R³CH₂CO₂X; wherein R³ is a group which helps stabilise the generated enolate nucleophile.

8. A method according to claim 7, characterized in that the R³ group is selected from esters, ketones or nitriles which may be optionally substituted.

9. A method according to any one of claims 2-8, characterized in that the cobalt catalyst preferably is based on a complex of cobalt with either a SALEN or beta- ketoiminato based ligand.

10. A method according to claim 9, characterized in that the cobalt catalyst has the following structure:

or

wherein R4 and R5 may be hydrogen, alkyl, aryl; R6 may be hydrogen, alkyl, t- alkyl, alkyl or aryl, alkoxy, aryl alkoxy; R6, R7, R8 and R9 may be independently H, alkyl, aryl, keto, or ester.

11. A method according to claim 10, in which R4 and R5 are each the same and are selected from hydrogen, (CH₂) , or benzyl.

12. A method according to claim 10, in which R6 is hydrogen, t-butyl, or benzyl ethyl, bornoxy, menthoxy, ethoxy or methyl.

13. A method according to claim 10, in which R7 and R8 may be the same or different and are selected from hydrogen, and t-butyl.

14. A method of forming a γ-lactone according to any one of claims 10-15, characterized in that the catalyst concentration is up to 50 mol% catalyst relative to the 1 ,2-dioxine.

15. A method of forming a γ-lactone according to any one of claims 10-15, characterized in that the catalyst concentration o5-15 mol% catalyst relative to the 1,2-dioxine.

Dated:4 October 2002 The University of Adelaide By their Patent Attorneys LESICAR PERRIN