GB2280677A - Total synthesis of discodermolide - Google Patents

Total synthesis of discodermolide Download PDF

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GB2280677A
GB2280677A GB9415399A GB9415399A GB2280677A GB 2280677 A GB2280677 A GB 2280677A GB 9415399 A GB9415399 A GB 9415399A GB 9415399 A GB9415399 A GB 9415399A GB 2280677 A GB2280677 A GB 2280677A
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Julian Marian Charles Golec
Stuart Donald Jones
Roger John Gillespie
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Roussel Laboratories Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • C07F7/1872—Preparation; Treatments not provided for in C07F7/20
    • C07F7/1892—Preparation; Treatments not provided for in C07F7/20 by reactions not provided for in C07F7/1876 - C07F7/1888
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/007—Esters of unsaturated alcohols having the esterified hydroxy group bound to an acyclic carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2
    • C07D263/22—Oxygen atoms attached in position 2 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to other ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D309/28—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/30—Oxygen atoms, e.g. delta-lactones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/32—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages

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Abstract

Novel compounds of formulae (2) and (13> <IMAGE> and the enantiomeric and diastereoisomeric forms thereof are disclosed as are methods for their preparation and novel intermediates used in such methods. Their use in the total synthesis of a compound of formula (1> <IMAGE> and enantiomeric and diastereoismeric forms thereof is disclosed. Also claimed are various intermediates prepared in synthesising (1) from (2) and (13).

Description

Chemical Compounds The present invention relates to the synthesis of discodermolide and to novel intermediate compounds for use in such synthesis.
Discodermolide has recently been isolated from the marine sponge Discodermia dissoluta (US 4939168) and has been characterised (S.P. Gunasekera et al, J. Org.
Chem., 1990, 55, p 4912; ibid, 1991, off5, p 1346).
Discodermolide has been shown to possess exceptional immunosuppressant activity (R.E. Longley et al, Transplantation, 1991, 52, p 650 and p 656).
The scarcity of naturally occurring discodermolide and its potential usefulness in therapy, including transplantation therapy, means that there is a need for a synthetic method for its preparation.
The relative, but not the absolute, stereochemistry of discodermolide has been reported and discodermolide has been shown to be a lactone of formula (1)
or the enantiomeric form thereof.
We have now prepared the intermediate compounds of formula (2) (in which R1 represents a protecting group) and formula -(13) (in which R1 and R4 each represents a protecting group) which are of potential value in the total synthesis of the compound of formula (1) -
The compounds of formulae (2) and (13) and the enantiomers and diastereoisomers thereof are novel and constitute aspects of the present invention.
The protecting groups R1 and R4 may be selected from a wide range of hydroxy protecting groups known to the man skilled in the art. Such protection may be achieved by formation of an ether linkage and, for example, the groups C16-alkyl (including substituted alkyl, e.g.
methoxymethyl and benzyloxymethyl), benzyl (including substituted benzyl), allyl, trityl and tetrahydropyranyl are suitable in this regard. Preferred are trialkylsilyl ether protecting groups, for example triisopropylsilyl (TIPS) and t-butyldimethylsilyl (TBDMS). Alternatively, such protection may be achieved by reaction with a suitable acyl derivative, preferably a carboxylic acyl derivative. Further details of suitable hydroxy protecting groups and the methods for their introduction and removal are given in "Protective Groups in Organic Synthesis (2nd edn., Theodora t.
Greene and Peter G.M. Wuts, John Wiley & Sons Inc., 1991).
Although the synthetic methods outlined herein are directed towards the preparation of the particular stereoisomers of the compounds of formulae (2) and (13) (and ultimately the compound of formula (1)) depicted above, the methodology is equally applicable to the preparation of the enantiomers and diastereoisomers thereof by using enantiomers or diastereoisomers of the various chiral reagents mentioned below.
According to a further aspect of the present invention there is provided a process for the preparation of the compounds of formula (2). The compounds of formula (2) may be prepared by the synthetic method set out in Scheme 1 hereafter. The individual steps in Scheme 1 either alone or in combination with previous and/or subsequent steps constitute further aspects of the present invention.
The reaction of the compound of formula (8) to form the compound of formula (2) is preferably performed by treatment with ozone and subsequent treatment of the ozonolysis product with triphenyl phosphine at low temperature, preferably between -70 C and -80 C, in the presence of an organic solvent, preferably dichloromethane.
The lactonisation reaction of the compound of formula (7) to prepare the compound of formula (8) may be carried out by treatment with lithium hydroxide in the presence of aqueous hydrogen peroxide in a suitable solvent, preferably tetrahydrofuran/water, followed by acid treatment.
The partial reduction of the compound of formula (6) to form the compound of formula (7) is preferably carried out by treatment with zinc borohydride in an organic solvent or mixtures thereof, preferably ether and/or dichloromethane, at low temperature.
The compound of formula (6) may be prepared by the aldol condensation of the compounds of formulae (4) and (5). This condensation reaction is preferably mediated by dicyclohexylboron chloride according to the method developed by Evans et al (Tetrahedron, 1992, 48, p 2127).
The compound of formula (4) is known (Evans et al, Tetrahedron, 1992, 48, p 2127). The compound of formula (5) may be prepared by the synthetic method outlined in Scheme 2 hereafter, which method constitutes a further aspect of the present invention.
The reduction of the compound of formula (10) to prepare the compound of formula (5) is preferably carried out by DIBAL-H (diisobutylaluminium hydride) in the presence of an organic solvent, preferably dichloromethane, at low temperature, preferably in the region of -70 C.
The known compound of formula (9) (Y. Nagao et al J. Org. Chem., 1986, 51, p 2391) may be converted to its protected derivative of formula (10) by conventional protection methods. The preferred protecting group Rl is the TIPS group (triisopropylsilyl). This group may be introduced by treatment of the compound to be protected with triisopropylsilyl triflate and 2,6-lutidine.
For complete characterisation purposes the compound of formula (2) was converted to the compound of formula (11) and subsequently to the compound of formula (12) according to the synthetic method outlined in Scheme 3 hereafter, which method also constitutes a further aspect of the present invention.
The compound of formula (12) may be obtained by standard deprotection of the compound of formula (11), in the case of the TIPS group preferably by treatment with fluorosilicic acid.
The compound of formula (11) may be obtained either by the reduction of the compound of formula (2), preferably by treatment with zinc borohydride, or by the reduction of the ozonide derived from the compound of formula (8), again preferably by treatment with zinc borohydride.
The compounds of formulae (5), (6), (7), (8) , (10), (11) and (12) and the enantiomers and diastereoisomers thereof are also novel and constitute yet further aspects of the present invention.
According to a yet further aspect of the present invention there is a provided a process for the preparation of the compounds of formula (13). The compounds of formula (13) may be prepared by the synthetic method outlined in Scheme 4 hereafter. The individual steps given in Scheme 4 either alone or in combination with previous and/or subsequent steps constitute further aspects of the present invention.
The reduction of the compound of formula (14) to the compound of formula (13) is preferably carried out by treatment with DIBAL-H in the presence of an organic solvent, preferably dichloromethane, and preferably at temperatures between -70 and -80 C.
The conversion of the compound of formula (15) to the compound of formula (14) may be carried out by treatment with benzyl mercaptan and n-butyl lithium.
The preparation of the compound of formula (15) may be carried out by reacting the compound of formula (16) with the chiral auxiliary oxazolidinone of formula (17) according to the procedure developed by Evans et al (J.
Am. Chem. Soc., 1982, 104, p 1737).
The compound of formula (16) may be obtained by reacting the alcohol of formula (18c) with a suitable reagent to introduce a labile group R3. The group R3 may be selected from a variety of groups well known by the man skilled in the art to be good leaving groups in nucleophilic substitution reactions. Preferred are halogen atoms and sulfonic ester groups, e.g. tosylate and mesylate. Especially preferred for the group R3 is iodine, introduced by means of a suitable iodination reagent, preferably methyltriphenoxyphosphonium iodide.
The compound of formula (18c) may be prepared by the following processes, which processes constitute further aspects of the present invention.
According to one process the compound of formula (18c) may be prepared by the synthetic method outlined in Scheme 5 hereafter. The individual steps given in Scheme 5 either alone or in combination with previous and/or subsequent steps constitute further aspects of the present invention.
The conversion of the compound of formula (19) to the compound of formula (18c) is carried out by a suitable selective protection/deprotection sequence.
This may, for example, be achieved by reacting the compound of formula (19) with a suitable reagent to protect the primary hydroxyl group by the group R2 to yield the compound of formula (18a). The group R2 may be selected from a wide range of hydroxy protecting groups as discussed earlier in respect of the groups R1 and R4.
The protecting group R2 is preferably a pivaloyl group which may be introduced by treatment with pivaloyl chloride. Subsequent treatment of the compound of formula (18a) with a suitable reagent results in the introduction of the protecting group R1 for the secondary hydroxyl group to yield the compound of formula (18b).
This protecting group Rl is preferably the TIPS group, which may be introduced by treatment with triisopropylsilyl triflate. Subsequent selective deprotection of the primary hydroxyl group by standard methods, which in the case of the pivaloyl group is preferably by treatment with DIBAL-H or by basecatalysed hydrolysis, yields the desired compound of formula (18c). An alternative protection/deprotection sequence makes use of techniques for selective cleavage of primary protecting groups. Thus, for example, each of the primary and secondary hydroxyl groups in the compound of formula (19) may be protected by a group such as t-butyldimethylsilyl, following which the primary t-butyldimethylsilyl group denoted R2 may be selectively cleaved.
The reaction of the compound of formula (20) to prepare the compound of formula (19) is preferably carried out by treatment with DIBAL-H in the presence of an organic solvent or mixtures thereof, preferably ether and/or dichloromethane, at low temperature, preferably in the region of 0 C.
The lactonisation and subsequent elimination of the compound of formula (21) to prepare the compound of formula (20) may be carried out by use of the following three-step procedure which does not involve the need for isolation of any intermediates: (i) removal of the chiral auxiliary, preferably by treatment with lithium hydroxide and aqueous hydrogen peroxide, also resulting in lactonisation, (ii) conversion of the free hydroxyl group to a suitable leaving group, preferably a mesyl group which may be introduced by treatment with methanesulphonyl chloride, and (iii) base-catalysed elimination, preferably by treatment with triethylamine.
The reduction of the compound of formula (22) to the compound of formula (21) is preferably carried out by treatment with DIBAL-H in the presence of an organic solvent, preferably diethyl ether, at low temperature, preferably in the region of -70 C.
The compounds of formulae (23) and (24) are both known (A. Meyers et al, J.Am. Chem. Soc., 1983, 105, p 5015 and Evans et al, Tetrahedron, 1992, 48, p 2127 respectively) and undergo an aldol condensation to produce the compound of formula (22). This aldol condensation is preferably mediated by tin (II) triflate according to the method developed by Evans et al (J. Am.
Chem. Soc., 1990, 112, p 866).
According to a second process, the compound of formula (18c) may be prepared by the synthetic method outlined in Scheme 6 hereafter, which method also constitutes a further aspect of the present invention.
The individual steps in Scheme 6 either alone or in combination with previous and/or subsequent steps constitute further aspects of the present invention.
The reduction of the compound of formula (25) to produce the desired compound of formula (18c) is preferably carried out by treatment with DIBAL-H ih the presence of an organic solvent, preferably dichloromethane, at room temperature.
The conversion of the compound of formula (26) to the compound of formula (25) may be carried out by treatment with ethyl 2-[bis(trifluoroethyI)lphospono- propionate according to the method developed by Still et al (Tetrahedron Lett., 1983, 24, p 4405).
The reduction of the compound of formula (27) to the compound of formula (26) is preferably carried out by treatment with DIBAL-H in the presence of an organic solvent, preferably dichloromethane, at low temperature, preferably in the region of -70 C.
The conversion of the compound of formula (28) to the compound of formula (27) may be carried out by treatment with benzyl mercaptan and n-butyl lithium.
The compound of formula (29) may be protected by the group R1 by standard methods, preferably by means of the TIPS protecting group by reaction with triisopropylsilyl triflate, to form the compound of formula (28).
The compound of formula (29) may be prepared by the aldol condensation of the compound of formula (30) (A.
Meyers et al, ibid) and the chiral auxiliary oxazolidinone of formula (17). This condensation reaction is preferably mediated by dibutylboron triflate according to the method developed by Evans et al (Organic Syntheses, 1990, off6, p 83).
The compounds of formulae (14) to (16), (18) to (22) and (25) to (29) and the enantiomers and diastereoisomers thereof are also novel and constitute yet further aspects of the present invention.
The total synthesis of the compound of formula (1) may be completed by the synthetic method outlined in Scheme 7 hereafter. The enantiomeric and diastereoisomeric forms thereof may be synthesised analogously by using appropriate reagents. The individual steps given in Scheme 7 either alone or in combination with previous and/or subsequent steps constitute further aspects of the present invention.
The compound of formula (13) undergoes an aldol condensation with the compound of formula (24) to produce the compound of formula (31). This aldol condensation is preferably mediated by tin (II) triflate (as in the reaction of the compounds of formulae (23) and (24) discussed hereinbefore). Subsequent reduction yields the compound of formula (32) and removal of the chiral auxiliary by reaction with benzyl mercaptan and n-butyl lithium yields the compound of formula (33) which may be lactonised and then reduced with DIBAL-H to produce the lactol of formula (34). Alternatively, the compound of formula 33 may be reduced to give the compound of formula 34 directly.The steps from the compound of formula (13) to the compound of formula (34) can be seen to be analogous to those discussed earlier from Scheme 1 (compound of formula (4) to the compound of formula (8)) and from Scheme 5 (compound of formula (23) to the compound of formula (20)).
Selective formation of the carbamate at position C19 yields the compound of formula (35) and the lactol may then be protected, for example as the methyl ether of formula (36). The benzyl group is then removed and the resulting alcohol of formula (37) may be converted to the Wittig reagent of formula (39) via the iodide of formula (38).
The stereospecific Wittig reaction between the compound of formula (38) and the compound of formula (2) yields the compound of formula (40). Deprotection of the lactol functionality yields the compound of formula (41). The subsequent Wittig reaction between the compound of formula (41) and the compound of (42), (cf.
Nicolaou et al (J. Am. Chem. Soc. 1993, 115, 3558) followed by elimination of the phenylseleno group yields the compound of formula (43). Removal of the TIPS protecting group by standard methods results in the desired compound of formula (1).
The reagents illustrated in Scheme 7 are the preferred reagents for the steps indicated; these may, however, be replaced with other suitable reagents apparent to the man skilled in the art.
The compound of formula (13) is illustrated in Scheme 7 with R4 representing a benzyl group and R1 representing a TIPS group. The compound of formula (2) is illustrated in Scheme 7 with R1 representing a TIPS group. These groups may be replaced by suitable alternative hydroxy protecting groups known to the man skilled in the art as discussed hereinbefore. For example, the benzyl group in the compound of formula (13) may be replaced by the TBDMS group. This would remove the need for Step G in Scheme 7 since the TBDMS group would be removed by the conditions employed in step F. Alternatively, the benzyl group in the compound of formula (13) may be replaced by a para-methoxybenzyl group. In this case deprotection step G could be carried out by treatment with DDQ (2,3-dichloro-5,6dicyano-1,4-benzoquinone).Alternatively, the benzyl group in the compound of formula (13) may be replaced by the TIPS group. Step G would then involve selective primary TIPS removal, although the conditions in step F may be sufficient for this removal. Other possibilities for alternative protecting groups for the compounds of formulae (13) and (2) would be apparent to the man skilled in the art.
Alternatively, the compounds of formulae (2) and (13) may be combined to form the Cl-Cl7 fragment of the compound of formula (1). This may, for example, be achieved by suitable protection of the aldehyde functionality of the compound of formula (13) and formation of a phosphorus ylid, for example the compound of formula (44) (by an analogous route to steps H and I of Scheme 7). The reaction of. the compounds of formulae (2) and (44) may then be carried out by means of a stereospecific Horner-Emmons reaction to produce the corresponding compound of formula (45) in which R represents a protecting group.
The synthesis of the compound of formula (1) could then be completed by carbonyl deprotection of the compound of formula (45) and the subsequent reaction with a suitable intermediate compound corresponding to the C18-C24 fragment of discodermolide and removal of the R1 protecting group.
Alternatively, the suitable intermediate compound corresponding to the Cl8-C24 fragment of discodermolide could be reacted with the compound of formula (13) or a suitable protected derivative thereof and the product then converted to a phosphorus ylid, for example the compound of formula (46), which compound may then undergo a stereospecific Horner-Emmons reaction with the compound of formula (2) followed by deprotection of the Rl protecting group to form the compound of formula (1)
The invention also extends to compositions for use in therapy comprising a compound of formula (1) or the enantiomeric and diastereoisomeric forms thereof produced by a method as described herein.
SCHEME 1
SCHEME 2
SCHEME 3
SCHEME 4
SCHEME 5
SCHEME 6
SCHEME 7
The following non-limiting Examples serve to further illustrate the present invention and describe the experimental methods of the aforementioned Schemes 1 to 6.
SCHEME 1 (3(2S,4R,5R,7R,8H),4S]-3(2,4-Dimethyl-5-hydro-3-oxo-9-he nyl-7-triisopropypylsilyloxy-non-8-en-1-oyl)-4-phenylmethyl -1,3-oxazolidin-2-one (6): Dicyclohexylboron chloride (2.65 g, 12.42 mmol) followed by dimethylethylamine (1.15 ml, 12.42 mmol) was added to a stirred mixture of the oxazolidinone (4) (2.99 g, 10.35 mmol) and dry ether (90 ml) at OOC. The mixture was kept at this temperature for 2 h. then cooled to -450C. A solution of the aldehyde (5) (3.43 g, 10.35 mmol) in ether (30 ml) was added to the stirred mixture while maintaining the temperature. The mixture was allowed to warm to -200C during 3 h. then quenched by the addition of a mixture of methanol (40 ml) and saturated ammonium chloride (20 ml). The mixture was stirred at 0 C for 10 min. then water (50 ml) and dichloromethane (300 ml) were added.The organic layer was separated and the aqueous layer was extracted with dichloromethane (50 ml). The combined organic extracts were dried (MgSO4) and concentrated. The resulting oil was dissolved in dichloromethane (200 ml) and stirred with Amberlite IRA743 (80 ml) for 16 h.. The Amberlite was removed by filtration and the mixture was concentrated to leave a pale yellow oil which was purified by flash chromatography (15-50% ether/ hexane) to give 3.85 g (60%) of the aldol product (6) as a colourless oil: [a] D21 +94.9" (c 0.509, CH2Cl2);IR (film) 3497, 2944, 2867, 1782, 1718, 1389, 1361, 1214, 1054, 735; 1H NMR (CDCl3) 6 7.3 (10H, m, Ar), 6.58 (lH, d J= 15.9, C8aH), 6.30 (lH, dd J= 15.9 J= 6.4, C8H), 4.86 (1H, q, C2H), 4.82(lH, m, C7H), 4.72 (lH, m, C4H) , 4.19 (3H, m, C5H, QH2) , 3.70 (1H, d, CsOH) , 3.27 (111, dd, C4aH), 2.87 (1H, m, C4H), 2.75 (1H, m, C4aH), 1.80 (2H, t, C6H2) , 1.46 (3H, d, C2aH3) , 1.14 (3H, d, C4aH3) , 1.08 (21H); 13C NMR (CDCl3) 6 210.4, 170.7, 153.3, 136.5, 135.1, 131.5, 130.0, 129.3, 128.5, 128.3, 127.5, 127.3, 126.4, 72.8, 70.4, 66.2, 55.2, 52.6, 50.4, 40.7, 37.8, 17.9, 13.0, 12.6, 12.2.
[3(25,3R,4R,5R,7R,8E) ,4S]-3-(3,5-dihvdrozy-2,4-dimethyl-9-p henyl-7-triisoroylsilyloxy-non-8-en-1-oy1) -4-phenylmethyl -1,3-oxazolidin-2-one (7): A 0.2M solution of zinc borohydride in ether (36 ml, 7.2 mmol) was added to a stirred mixture of the aldol product (6) (3.21g, 5.17 mmol) and dichloromethane (100 ml) at -700C. The mixture was kept at this temperature for 30 min. then at -30 to -400C for 2.5 h. The mixture was quenched by the addition of 1M hydrochloric acid (25 ml). The organic phase was separated and the aqueous phase was extracted with dichloromethane (30 ml). The combined extracts were washed with saturated sodium hydrogencarbonate (30 ml). The mixture was concentrated and the resulting oil redissolved in dichloromethane (100 ml) and stirred for 18 h. with Amberlite IRA 743 (35 g).The resin was removed by filtration and the mixture was concentrated. The residue was purified by flash chromatography (9:1 to 7:3 hexane/ ethyl acetate) to give 2.27 g (70.5%) of the diol as a colourless oil: [0L3D21 +79.5 (c 0.751, CH2Cl2); IR (film) 3440, 2940, 2860, 1778, 1697, 1383, 1237, 1206, 1090, 694; 1H NMR (CDCl3) 6 7.3 (10H, m, Ar), 6.59 (1H, d J= 16, C8aH), 6.30 (1H, dd, J= 16 J= 6.3, C8H), 4.86 (lH, q, C7H), 4.78 (1H, s, OH), 4.70 (1H, s, OH), 4.63 (1H, m, C4H), 4.19-3.93 (5H, m, C2H, C3H, CH, C5H2) , 3.34 (1H, dd, C4aH) , 2.75 (1H, dd, C4aH), 1.90 (2H, t, C6H2), 1.76 (1H, m, C4H), 1.23 (3H, d,C2aH3) 1.06 (21H), 0.83 (3H, d, C4aH3) ; 13C NMR (CDCl3) 6 176.1, 153.2, 136.5, 135.4, 131.0, 130.2, 129.4, 128.9, 128.6, 127.7, 127.3, 126.5, 75.3, 74.0, 73.5, 66.1, 55.9, 41.2, 41.0, 40.7, 37.7, 18.0, 12.53, 12.2, 8.5. Anal.
Calcd. for C36H53NO6Si: C, 69.30; H, 8.56; N, 2.25. Found: C, 68.95; H, 8.66; N, 2.01.
(38,4R,5S,16R,6(2R,3E)]-3,5-Dimethyl-4-hydroxy-6-(4-henyl-2 - triisopropyllsilyloxy-but-3-en-1-yl)tetrahydro(2H)pyran-2-o ne (8): 30% Aqueous hydrogen peroxide (2.6 ml, 23 mmol) and lithium hydroxide (300 mg, 12.5 mmol) were added to a stirred solution of the diol (7) (2g, 3.21 mmol) in a 4:1 mixture of tetrahydrofuran and water (31 ml) at OOC. The mixture was stirred for 1 h. at this temperature then sodium bisulphite (5.6g, 53.8 mmol) and 1M hydrochloric acid (19 mlj 19 mmol) were added. The resulting mixture was stirred for 15 min. before being diluted with ethyl acetate (50 ml) and water (25 ml). The mixture was stirred for a further 45 min. before the organic layer was removed. The aqueous layer was extracted with ethyl acetate (2x30 ml).
The combined organic extracts were washed with saturated sodium hydrogen carbonate then saturated brine. They were dried (MgSO4) and concentrated. The residue was purified by flash chromatography (10% ether in dichloromethane) to give 1.26 g (88%) of the lactone (8) as an oil. An analytical sample crystallised from an ether pentane mixture: m.p.
89-90"C; [a]D21 +81.8 (c 0.5, CH2Cl2); IR 3440, 2942, 2866, 1708, 1462, 1389, 1238, 1125, 1102, 1086, 988, 969; 1H NMR (CDCl3) 6 7.3 (5H, m, Ar), 6.54 (lH, d J= 16, QaH), 6.19 (1H, dd J= 16 J= 7.6, C8H), 4.73 (2H, m, QH, C7H), 3.74 (lH, t, C3H), 2.65 (2H, m, C2H, OH), 1.96 (2H, m, C6H2), 1.67 (1H, m, C4H) , 1.31 (3H, d, C2aH3) , 1.07 (24H); 13C NMR (CDCl3) 6 174.1, 136.7, 133.2, 129.6, 128.5, 127.5, 126.3, 76.8, 72.9, 69.8, 43.1, 35.8, 18.0, 15.3, 12.4. Anal. Calcd. for C26H42O4Si: C, 69.91; H, 9.48. Found: C, 69.79; H, 9.43.
(2R13 (3S, 4R, 5S, 6R) 1-3- (3,5-Dimetyl-4-hydroxytetrahydro(2H) pyran-2-one-6-yl)-2-triisopropylsilyloxypropanal (2): Ozone was bubbled through a solution of the olefin (8) (93.2 mg, 0.209 mmol) in dichloromethane (3ml) at -780C until a blue colour persisted. The mixture was kept for 5 min. then triphenyl phosphine (140 mg, 0.53 mmol) was added. ~The mixture was kept stirring at -780C for 30 min. then allowed to warm to room temperature.The mixture was concentrated and the residue purified by flash chromatography (10% ether/dichloromethane) to give 60.9 mg (78%) of aldehyde (2) as a colourless oil: IR (film) 3460, 2945, 2875, 1732, 1460, 1240, 1130, 1092, 1000, 884; 1H NMR (CDC13) 6 9.7 (lH, d, J= 1.4, C8H), 4.62 (2H, m, CsH, C7H), 3.76 (lH, t, C3H), 2.67 (lH, m, C2H), 1.89 (3H, m, C4H, C6H2), 1.37 (3H, d, C2aH3) , 1.10 (24H, m, C4aH3, Si(CH(CH3)2)3) SCHEME 2 (3 (3R,4H) 481 -4-Isorov1-3- (5-heny1-triisoroy1silvloz ent-4-en-loyl)-1,3-thiazolidin-2-thione (10):: 2,6-Lutidine (11.5 ml, 98 mmol) and triisopropylsilyl trifluoromethanesulphonate (15.9 ml, 59.2 mmol) were added to a stirred mixture of the alcohol (9) (14.6 g, 43.6 mmol) and dichloromethane (250 ml) while maintaining the temperature at OOC. The mixture was kept stirring at this temperature for 2 h. then quenched with 0.5M potassium hydrogen sulphate (330 ml). The organic layer was removed and the aqueous layer was extracted with dichloromethane (2x60 ml).The combined organic extracts were washed with water (2x60 ml) and saturated brine (60 ml) then dried (MgSO4) . The solution was concentrated and the residue was purified by flash chromatography (0-50W dichloromethane in hexane) to give 18.96 g (89%) of the product as an oil: [a1D21 +236.9 (c 1.025, CH2Cl2);IR (film) 2950, 2930, 2855, 1682, 1455, 1355, 1297, 1238, 1152, 1102, 1078, 1057, 1030, 872, 637; 1H NMR (CDCl3) 6 7.13 (5H, m, Ar), 6.68 (1H, dd J= 16 J= 1.1, C8aH), 6.27 (1H, dd J= 16 J= 5.9, C8H), 5.20 (1H, dt, C4H), 4.85 (1H, m, C7H), 3.74 (1H, dd J= 17.5, 3, C6H), 3.46 (2H, m, C6H, C5H), 3.02 (lH, dd J= 11.5, 1.0, CsH), 2.37 (1H, m, C4aH) , 1.07 (3H, d, C4'bH3), 0.99 (3H, d, C4,bH3); 13C NMR (CDC) 6 202.8, 171.1, 136.7, 132.1, 129.9, 128.5, 127.6, 126.4, 71.7, 70.8, 46.9, 30.7, 30.6, 19.1, 18.1, 17.1, 12.4. Anal. Calcd. for C26E41NO2S2Si: C, 63.49; H, 8.40; N, 2.85; S, 13.04.Found: C, 63.25; H, 8.36; N, 2.76; S, 12.87.
[3R,4E]-5-Phenyl-3-triisopropylsilyloxypent-4-enal (5): A 1M solution of DIBAL-H in dichloromethane (26 ml, 26 mmol) was added during 15 min. to a stirred solution of the thiazolidinethione (10) (6.44g, 13.1 mmol) in dichloromethane (130ml) at -700C. Care was taken to keep the temperature below -650C. The mixture was kept at -700C for 30 min. then poured into a stirred solution of tartaric acid (3.9g, 26 mmol) in 1M potassium tartrate (250ml). The organic layer was removed and the aqueous layer was extracted with dichloromethane (2x50 ml).The combined organic extracts were washed with water (50 ml) then dried (MgSO4) . The mixture was concentrated and the residue purified by flash chromatography (30 dichloromethane/ hexane) to yield 3.94 g (91%) of the aldehyde (5) as a colourless oil: [a]D21 +68.50 (c 1.004, CH2Cl2); IR (film) 2930, 2855, 1720, 1458, 1115, 1080, 963, 877, 714; 1H NMR (CDCl3) 6 9.85 (1H, t J= 2.4, QH), 7.31 (5H, m, Ar), 6.60 (1H, dd J= 0.7 J= 15.9, C8aH),6.25 (1H, dd, J=15.9, 6.5,C8H), 4.94 (1H, m, C7H), 2.71 (2H, m, C6H2), 1.06 (21H); 13C NMR (CDC13) 6 201.5, 136.4, 131.5, 130.1, 128.6, 127.8, 126.5, 69.6, 52.0, 18.0, 12.3;MS (CI, isobutane) 333, 0.71% (M+1)+, 289, 100%. Anal. Calcd. for C20H32O2Si: C, 72.24; H, 9.70. Found: C, 72.12; H, 9.71.
SCHEME 3 (3S,4R,5S,6R,6(2R)]-3,5-Dimethyl-4-hydrozy-6-(3-hydrozy-2-t riisopropylsilyloxo-Pent-l-yl)-tetrahodro(2H)PYran-2-one (11): Ozone was bubbled through a stirred solution of the lactone (8) (123 mg, 0.276 mmol) in methylene chloride (3 ml) at -78 C until a pale blue colour remained. At this point a 0.2M solution of zinc borohydride in ether (2.76 ml, 0.552 mmol) was added and the mixture stirred at - 780C for 1 h. and at -30 C for 1 h. Acetone (2 ml) was added and the mixture allowed to warm to room temperature and kept for 0.5 h. The mixture was quenched with 1M potassium sodium tartrate (10 ml). The mixture was extracted three times with dichloromethane and the combined extracts were dried (MgSO4) and concentrated.The residue was purified by flash chromatography (25% ether in dichloromethane) to give 76.8 mg (74%) of the product as an oil which crystallised from an ether/ pentane mixture: m.p. 81-81.50C; [&alpha;]D21+59.0 (c 0.25, CH2Cl2); IR (KBr disc) 3430, 3325, 2945, 2870, 1685, 1468, 1460, 1250, 1130, 1097, 1054, 983; 1H NMR (CDCl3) 6 4.57 (1H, t, C5H), 4.27 (1H, m, C7H), 3.76 (2H, m, C3H, C8H), 3.53 (1H, m, C8H), 2.64 (1H, m, C2H), 2.06-1.75 (5H, m, C4H-, C6H2, 20H), 1.66 (3H, d, C2aH3), 1.19 (21H), 1.08 (3H, d, C4aH3); 13C NMR (CDCl3) 6 174.2 (C1), 77.2(C5), 73.4(C3), 69.3(C7), 67.2(C8), 43.3(C2), 38.45 (C6), 35.85 (C4), 18.1, 15.6 (C2a), 12.6. Anal.Calcd. for C19H38O5Si: C, 60.92; H, 10.23. Found: C, 60.88; H, 10.13.
(3S,4R,5B,6R,6(2R)]-3,5-Dimethyl-4-hydrozy-6-(2,3-dihydroxy Pent-l-vl)-tetrahvdro(2#)pvran-2-one (12): 25% Aqueous fluorosilicic acid (5 drops) was added to a stirred solution of the diol (11) (74.2 mg, 0.198 mmol) in acetonitrile (1.5 ml). The mixture was stirred at room temperature for 3.5 h. then quenched with solid sodium hydrogencarbonate. The mixture was stirred for a further 30 min. then filtered and concentrated at room temperature.
The residue was purified by flash chromatography (0-10W methanol in dichloromethane) to give 35.1 mg (81%) of an oil which crystallised on standing: mp 105-1070C; [aiD20 +810 (c 0.237, CH3OH); IR (KBr disc) 3496, 3433, 3320, 2950, 1720, 1461, 1400, 1389, 1226, 1096, 1060, 1002; 1H NMR (CDCl3) 6 4.66 (1H, dt, C5H), 4.13 (1H, m, C7H), 3.75-3.44 (3H, m, C3H, C8H2), 2.94 (1H, bs, OH), 2.72 (1H, m, C2H), 2.29 (1H, bs, OH), 1.90-1.50 (3H, m, C4H, C6H2), 1.32 (3H, d, C2aH3), 0.89 (3H, d, C4aH3). 13C NMR (CDCl3) 6 174, 73.4, 67.9, 67.0, 43.3, 36.7, 35.7, 18.1, 15.7.Anal. Calcd. for C10H18Os : C, 55.03; H, 8.31. Found: C, 54.87; H, 8.25.
SCHEME 4 Benzyl[(2R,3S,4R,5Z]-7-iodo-3-triisopropylsilyloxy-2,4,6-tr imethylhept-5-en-1-yl) ether (16): A solution of methyl triphenoxyphosphonium iodide (1.76 g, 3.9 mmol) in DMF (5 ml) was added to a stirred mixture of alcohol (18c) (1.06 g, 2.44 mmol) and DMF (25 ml) at OOC. The mixture was stirred at this temperature for 5 min. then at room temperature for 20 min.. The mixture was diluted with hexane and then stirred with ice cold 1M sodium hydroxide.
The organic phase was separated and washed once with 1M sodium hydroxide and twice with water, dried (MgSO4) and concentrated. The residue was purified by flash chromatography (0-258 dichloromethane/ hexane) to give 1.22g (92%) of product which was used in the next stage immediately: 1H NMR (CDC13) 6 7.3 (5H, m, Ar), 5.26 (1H, m, Cl3H), 4.47 (2H, s), 3.94 (1H, d J= 9, C15H), 3.81 (1H, m, CllH), 3.78 (1H, d J= 9, Cl5H), 3.47 (1H, dd J= 9.2, 6.5, C9H), 3.29 (1H, dd J= 9.1, 7.2, C8H), 2.59 (1H, m, Cl2H), 2.09 (1H, m, C10H) 1.77 (3H, d J= 1.3, Cl4aH3), 1.07 (21H, s), 1.01 (3H, d J= 7.2, C10aH3), 1.00 (3H, d J= 6.7, C12aH3); 13C NMR (CDCl3) 6 138.7, 134.8 (C12), 130.2 (Cl4), 128.2, 127.5, 127.4, 77.1 (C11), 73.0, 72.8 (C11), 39.8 (Cl0), 36.2 (Cl2), 22.3 (C14a) , 18.3, 15.6, 13.4, 13.3, 7.0 (C15).
[3 (2R,4Z,61R,7S,8R) ,4S]-4-Benzyl-3-(9-benzyloxy-1-oxo-2,4,6, 8-tetramethyl-7-triisopropylsilyloxynon- oxazolidin- 2-one (15): A 1M solution of sodium bis(trimethylsilyl)amide in THF (1.24 ml, 1.24 mmol) was added to a stirred mixture of (S)-3-propionyl-4-benzyl-2-oxazolidinone (17) (257 mg, 1.1 mmol) in THF (5ml) at -700C. The mixture was kept at this temperature for 30 min. then treated with a solution of the iodide (16) (200 mg, 0.367 mmol) in THF (1.5 ml).
The mixture was stirred at -50 C to -40 C for 2 h. then at -20 C for 4 h. The mixture was poured into a cold saturated aqueous ammonium chloride and extracted twice with ether.
The combined organic extracts were washed once with 1M hydrochloric acid and twice with water, dried (MgSO4) and concentrated. The residue was purified by flash ~ chromatography (0-20W ethyl acetate / hexane) to give 175 mg (73%) of the product: [aiD21 +27.34 (c 1.3, CH2Cl2);IR (film) 2964, 2943, 2867, 1783, 1702, 1455, 1385, 1350, 1241, 1210, 1096, 1058, 1028, 1015, 735, 699, 678; 1H NMR (CDCl3) 6 7.15-7.34 (10, m, Ar), 5.17 (1H, d J= 10.2, C13H), 4.6-4.74 (1H, m), 4.45 (2H, s), 4.09-4.23 (2H, m), 3.81-3.96 (1H, m, C16H), 3.74 (1H, dd J= 5.8, 4.4, C11H), 3.48 (1H, dd J= 9, 5.9, C9H), 3.17-3.32 (2H, m), 2.70 (1H, dd), 2.55-2.7 (1H, m, C12H), 2.17-2.44 (2H, m, C15H2), 2.02-2.15 (1H, m, C10H), 1.67 (3H, t J= 0.5, Cl4aH3), 1.07 (21H), 1.00 (3H, d) , 0.99 (3H, d) ; 13C NMR (CDCl3) 8 177.1 (C1,), 153.0, 138.8, 135.2, 133.0 (C13), 129.8, 129.4, 128.9, 128.2, 127.4, 127.3, 77.9 (C11), 73.3 (C9), 72.8, 66.0, 55.3, 39.9 (C1O), 38.0, 35.6 (C16), 35.3, 22.6 (Cl4a), 18.4, 17.3, 15.6, 13.4. Anal. Calcd. for C39H59NO5Si: C, 72.07; H, 9.15; N, 2.15. Found: C, 72.07; H, 9.16; N, 2.07.
S-Benzyl[2R,4Z,6R,7S,8R]-9-benzyloxy-2,4,6,8-tetramethyl-7- triisopropylsilyloxynon-4-enthioate (14): 1. 45M n-Butyl lithium in hexane (175 l, 0.245 mmol) was added to a stirred mixture of benzyl mercaptan (53 mg, 0.424 mmol) and THF (5 ml) at -700C. The mixture was kept at -20 C for 10 min. then cooled to -70 C before a solution of the compound (15) (138 mg, 0.212 mmol) in THF (2 ml) was added. The resulting mixture was stirred at -70 C for 5 min. and at -10 C for 1.75 h. The mixture was poured into cold saturated aqueous ammonium chloride then extracted three times with ether. The combined extracts were washed with cold 1M sodium hydroxide then water, dried (MgSO4) and concentrated.The residue was purified by flash chromatography (0-50k dichloromethane/hexane) to give 102 mg (81%) of the thioester: [&alpha;]D21 -30.44 (c 0.338, CH2C12); IR (film) 2965, 2944, 2866, 1690, 1497, 1454, 1379, 1246, 1092, 1028, 1015, 966, 883, 735, 698, 679; 1H NMR (CDC13) 6 7.28 (10H, m, Ar), 5.14 (1H, d J= 10, C13H), 4.45 (2H, s), 4.09 (2H, s), 3.71 (1H, dd J= 5, CllH), 3.45(1H, dd J= 9, 5.9, C9H), 3.25 (1H, m, C9H), 2.76 (1H, m, C16H), 2.54 (1H, m, C12H), 2.34 (1H, dd J= 13.5, 9.3, C15H), 2.18 (lH, dd J= 13.5, 5.5, C15H), 2.06 (1H, m, C10H), 1.57 (3H, s, C14aH3), 1.09 (3H, d, 016aH3), 1.07 (21H, s), 0.98 (3H, d J= 6.8, C10aH3) a 0.96 (3H, d J= 6.5, C12aH3);; 13C NMR (CDCl3) 6 202.7 (C17), 138.8, 137.6, 133.1(C13), 129.5 (C14), 128.8, 128.6, 128.2, 127.5, 127.3, 127.2, 77.9 (C1l), 73.2 (C9), 72.9, 46.4 (C16), 39.8 (C10), 35.9 (C15), 35.3 (C12), 33.1, 23.1(C14a), 18.4, 17.1 (C12a), 16.7 (016a), 13.5 (C10a), 13.4.
Anal. Calcd. for C36H5603SSi: C, 72.43; H, 9.46; S, 5.37.
Found: C, 72.39; H, 9.43; S, 5.31.
(2R,4Z,6R,7S,8R]-9-Benzyloxy-2,4,6,8-tetramethyl-7-triisopr opylsilyloxynon-4-en-1-al (13): A 1M solution of DIBAL-H in dichloromethane (410 l, 410 M) was added dropwise to a stirred mixture of the thioester (14) (61 mg, 0.102 mmol) and dichloromethane (3 ml) at -700C. The mixture was kept at this temperature for 1 h. then poured into 1M aqueous tartaric acid at 0 C. The mixture was stirred at 0 C for 25 min. then extracted three times with ether. The combined extracts were washed with water, dried (MgSO4) and concentrated.The residue was purified by flash chromatography (0-60t dichloromethane in hexane) to give 42 mg (88%) of a colourless oil: [a]D21 -12.79 (c 0.9, CH2Cl2); IR (film) 3031, 2962, 2943, 2867 1728, 1455, 1092, 1028, 1014, 883, 697, 678, 651; 1H NMR (CDCl3) 6 9.62 (1H, d J= 1.6, C17H), 7.29 (5H, m, Ar), 5.17 (1H, d J= 10, C13H), 4.46 (2H, s), 3.72 (1H, dd J= 5.7 J=4.3, C1lH), 3.46 (1H, dd, J= 9 J=6, C9H), 3.26 (1H, dd J= 9 J= 7.6, C9H), 2.52 (1H, m, C12H), 2.5 (1H, m, C16H), 2.18 (2H, d J= 7.7, C15H2), 2.08 (1H, m, C10H), 1.61 (3H, d J= 1.2, C14aH3), 1.08 (21H), 1.01 (3H, d J= 7, 016aH3), 0.97 (3H, d J= 7.1, C10aH3), 0.96 (3H, d J= 6.7, C12aH3); 13C NMR (CDCl3) 6 204.7 (C17), 138.8, 133.2 (Cl3), 129.3 (C14), 128.2, 127.5, 127.4, 78.0 (C1l), 73.1 (C9), 73.0, 44.5 (C16), 39.8 (C10), 35.4 (C12), 32.4 (C15), 23.0 (C14a), 18.4, 17.1, 13.6, 13.4, 12.9. Anal. Calcd. for C29H5003Si: C, 73.36; H, 10.61. Found: C, 73.34; H, 10.47.
SCHEME 5 (3(2R,4S,5R,6R),4R]-4-Benzyl-3-(7-benzyloxv-1,3-dioxo-5-hyd- roxy-2,4,6-trimethylhetyl)oxazolidin-2-one (22): Triethylamine (5.08g, 50.1 mmol) was added to a stirred mixture of tin(II) triflate (21.22g, 50.9 mmol) and dichloromethane (200 ml). The mixture was cooled to -200C and stirred for 10 min. before a solution of the ss-ketoimide (24) (11.16 g, 36.6 mmol) in dichloromethane (40 ml) was added dropwise during 15 min. The mixture was stirred at -20 C for 2 h. then cooled to -78 C whereupon a solution of the aldehyde (23) (10.31g, 57.9 mmol) in dichloromethane (20 ml) was added dropwise during 40 min., while maintaining the temperature. The mixture was stirred at -780C for 2.5 h. then quenched by the addition of 1M sodium hydrogensulphate (800 ml) and dichloromethane (500 ml) at 0 C.After stirring for 10 min. the organic phase was separated and the aqueous phase reextracted with dichloromethane (2x250 ml). The combined organic extracts were washed with saturated sodium hydrogencarbonate, dried (MgSO4) and concentrated. The residue was purified by flash chromatography (25-37.5 ethyl acetate/hexane) to give 9.72g (94%) of a solid: m.p. 93-95 C; [&alpha;]D21-60.02 (c 0.58, CH2Cl2);IR (film) 3480, 2980, 2940, 2870, 1775, 1715, 1455, 1385, 1360, 1225, 1100, 1045, 1005, 980; 1H NMR (CDCl3) 6 7.29 (10H, m, Ar), 4.93 (1H, q, J= 7.2, C14H), 4.71 (1H, m), 4.52 (2H, s), 4.20 (2H, m), 3.92 (1H, dd J= 8.7 J= 2.6, C1lH), 3.58 (2H, d J= 5.6, C9H2), 3.40 (1H, s, OH), 3.30 (1H, dd), 2.92 (1H, m, Cl2H), 2.76 (1H, dd), 1.92 (1H, m, C10H), 1.47 (3H, d J= 7.2, C14aH3), 1.19 (3H, d J= 7, Cl2aH3), 0.92 (3H, d J= 6.9, C10aH3); 13C NMR (CDCl3) 6 210.4(C13), 170.3, 153.5 (C15), 137.9, 135.0, 129.3, 128.9, 128.4, 127.6, 127.4, 74.2 (C9), 74.2 (C11) , 73-.4, 66.3, 55.3, 50.9 (Cl4), 47.2 (C12), 37.8, 36.0 (C10), 13.9 (Cioa), 13.4 (C14a), 9.0 (C12a). Anal. Calcd. for C27H33NO6: C, 69.36; H, 7.11; N, 3.00. Found: C, 69.33; H, 7.21; N, 3.00.
[3(2R,3R,4S,5R,6R),4R]-4-Benzyl-3-(7-benzyloxy-3,5-dihydrox y-1-oxo-2,4,6-trimetholheptyl)oxazolidin-2-one (21): A 1M solution of DIBAL-H in methylene chloride (4.3 ml,A.3 mmol) was added dropwise during 5 min. to a stirred solution of the aldol product (22) (500 mg, 1.07 mmol) in ether (50 ml) at -700C. The mixture was stirred at -70 C for 15 min. then quickly added to rapidly stirred 1M hydrochloric acid (80 ml) at O C. The mixture was stirred for 5 min then extracted with dichloromethane (3x50 ml).
The combined extracts were washed with saturated sodium hydrogencarbonate (50 ml), dried (MgSO4), and concentrated.
The residue was purified by flash chromatography (20% ethyl acetate/ dichloromethane) to give 499 mg (99%) of the diol as a colourless oil: [aiD21 -78.160 (c 0.403, CH2Cl2) IR (CHCl3) 3450, 2980, 2930, 2870, 1780, 1690, 1455, 1385, 1350, 1290, 1260, 1215, 1105, 1045, 1015, 970, 910; 1H NMR (CDCl3) 6 7.3 (10H, m, Ar), 4.71 (1H, m), 4.53 (2H, s), 4.38 (1H, s, OH), 4.1 (1H, s, OH), 4.12 (2H, m), 4.11 (1H, m, Cl3H), 4.07 (1H, m, C14H), 3.76 (1H, dd J= 9.2 J= 1.9, C11H), 3.62 (1H, dd J= 9.1, J= 4.2, C9H), 3.48 (1H, dd J= 9.1, C9H), 3.29 (1H, dd), 2.78 (1H, dd), 2.02 (1H, m, C10H), 1.75 (1H, m, C12H), 1.14 (3H, d J= 6.3, C14aH3), 0.95 (3H, d J= 7, 012aH3), 0.79 (3H, d J= 6.9, C10aH3); 13C NMR (CDC13) 6 176.4, 153.24 (C15), 137.31, 135.34, 129.3, 128.7, 128.38, 127.56, 127.76, 127.08, 82.00 (C1l), 78.90 (C13), 76.16 (C9), 73.37, 65.92, 55.31, 40.26 (C14), 37.82, 35.85 (C10), 34.58 (C12), 14.12 (C14a), 12.97 (C10a), 4.22 (C12a). Anal. Calcd. for C27H3sNO6: C, 69.06; H, 7.51; N, 2.98. Found: C, 69.06; H, 7.59; N, 2.96.
[5R,6S,6(2R)]-6-(Benzyloxoprop-2-yl)-5,6-dihydro-3,5-dimeth yl(2H)pyran-2-one (20): 30% Aqueous hydrogen peroxide (5.46 ml) then lithium hydroxide monohydrate (1.01 g, 24.1 mmol) were added to a stirred mixture of the diol (21) (5.65g, 12 mmol), tetrahydrofuran (250 ml) and water (70 ml) at 0 C.
The mixture was kept stirring at this temperature for 2.5 h. then a saturated solution sodium sulphite (170 ml) was added dropwise. The mixture was stirred vigorously for 30 min then the mixture was brought to pH 3 by the addition of sodium hydrogensulphate. The mixture was diluted with water (11) then extracted with dichloromethane (500 ml then 3x250 ml). The combined extracts were washed with water (11), dried (MgSO4) and concentrated to leave an oily residue.
The residue was dissolved in dichloromethane (40 ml) and cooled to -10 C. To this mixture were added triethylamine (1.86 ml, 36.1 mmol) followed by the dropwise addition of methanesulphonyl chloride (1.86 ml, 24.1 mmol) during 15 min.. The resulting suspension was stirred at 0 C for 2h.
then poured into stirred aqueous 1M sodium hydrogensulphate (150 ml) at OOC. The mixture was extracted with ether (3x100ml). The combined extracts were washed with water (100 ml), dried (MgSO4) and concentrated to leave a pale yellow oil (6.4 g).
The oil was dissolved in dichloromethane (50 ml) and treated with triethylamine (8.06 ml, 60.2 mmol). The resulting mixture was stirred at 350C for 1.75h., cooled to room temperature and diluted with dichloromethane (200 ml).
The mixture was washed with water (2x200 ml), dried (MgSO4) and concentrated. The residue was purified by flash chromatography (10-25% ethyl acetate in hexane) to give 2.36g (72%) of a pale orange oil: [aiD2i -85.9 (c 1.09, CH2Cl2); IR (film) 2970, 2920, 2870, 2850, 1724, 1708, 1446, 1362, 1218, 1126, 1092, 1074, 1046, 986, 734, 694; 1H NMR (CDCl3) 6 7.22-7.36 (5H, m, Ar), 6.68 (1H, dd J= 6.6 J= 1.4, C1sH), 4.51 (2H, s), 4.25 (111, dd J= 10.6 J= 3.1, C11H), 3.62-3.69 (2H, m, C9H2)r 2.33-2.42 (111, m, C12H), 2.08 (1H, m, C10H), 1.9 (3H, br s, C14aH3), 1.01 (3H, d J= 7, 010aH3), 0.99 (3H, d J=7, C12aH3); 13C NMR (CDC13) 6 166.03 (C15), 145.82 (C13) 138.53 (Cl4), 128.2, 127.37, 126.93, 80.24 (C11), 73.08, 71.09 (C9), 34.75 (Cio), 30.20 (Cl2), 16.78 (Cl4a), 12.95 (Cioa), 10.74 (C12a). Anal. Calcd. for Cl7H22O3: C, 74.42; H, 8.08. Found: C, 74.33; H, 8.09.
(2Z,4R,5S,6R]-7-Benzyloxy-2,4,6-trimethylhet-2-ene-1,5- diol (19): A solution of DIBAL-H in 1M in dichloromethane (0.8 ml, 0.8 mmol) was added dropwise to a stirred mixture of the lactone (20) (55 mg, 0.2 mmol) and dichloromethane (1 ml) at -700C. The mixture was kept at this temperature for 2 h. and at 0 C for 1 h.. The mixture was cooled to -70 C and another addition of the DIBAL-H solution (0.4 ml) was made. The mixture was kept at 0 C for 2 days then poured into ice cold 1M tartaric acid. The mixture was stirred for 5 min. then extracted twice with ether. The combined extracts were washed with saturated sodium- hydrogencarbonate then water, dried (MgSO4), and concentrated.
The residue was purified by flash chromatography (0-100% ethyl acetate/ hexane) to give 35 mg (63%) of the product: [&alpha;]D2l +7.94 (c 1.16, CH2Cl2); IR (film) 3403, 2965, 2932, 2917, 1454, 1366, 1089, 1076, 1009, 739, 698; 1H NMR (CDCl3) 6 7.35 (5H, m, Ar), 5.22 (111, d J= 9.8, C13H), 4.50 (2H, dd), 4.10 (111, d J= 11.8, C15H), 3.92 (111, d J= 11.8, C15H), 3.56 (111, dd J= 9.2, 4.1, C,H), 3.45 (1H, dd J= 9.2, 6.5, C,H), 3.31 (1H, m,C11H), 2.65 (1H, m, Cl2H), 1.94 (1H, m, C10H)r 1.79 (3H, d J= 1.4, Cl4aH3), 1.01 (3H, d J= 6.7, C12H3), 0.97 (3H, d J= 7, C1oaH3);; 13C NMR (CDCl3) 6 137.5, 134.3, 131.4 (Cl3), 128.5, 127.9, 80.3 (Cii), 74.3 (C9), 73.6, 61.7 (Cl5), 36.2 (Cl2), 35.4 (Cio), 21.8 (C14a), 16.4 (012a), 15.2 (C10a). Anal. Calcd. for C17H26O3: C, 73.35; H, 9.41. Found: C, 73.72; H, 9.74.
(2Z,4R,5S,6R]-7-Benzyloxy-5-hydroxy-2,4,6-trimethylhept- 2-enyl 2,2-dimethylpropionate (18a): Pivaloyl chloride (395 l, 3.2 mmol) was added dropwise to a stirred mixture of the diol (19) (811 mg, 2.91 mmol) and pyridine (10 ml) at 0 C. The mixture was stirred at 0 C for 1 h. then at room temperature for 20.5 h.. The reaction was completed by the further addition of pivaloyl chloride (143 ,il) and stirred for 2.75 h.. The mixture was quenched by the addition of water (50 ml) and extracted with ether (3x 50 ml). The combined extracts were washed with aqueous copper(II) sulphate (2x 50 ml), water (50 ml), and brine (50 ml).
They were dried (MgSO4) and concentrated. The residue was purified by flash chromatography (10-30% ethyl acetate/ hexane) to give 962.4 mg (91%) of a colourless oil: [&alpha;]D21-14.73 (c 1.09, CH2Cl2); IR (film) 3505, 2971, 2934, 2913, 2874, 1728, 1480, 1454, 1398, 1366, 1283, 1155, 1092, 1030; 1H NMR (CDCl3) 6 7.31 (5H, m, Ar), 5.38 (1H, d J= 9.8, C13H), 4.53 (2H, s, C15H2), 4.50 (2H, s), 3.63(1H, dd J= 9.1, 3.9, C9H), 3.43 (lH, dd J= 9.1, 6.4, C9H), 3.31 (1H, t, J= 6, C11H), 2.58 (1H, m, C12H), 1.90 (1H, m, C10H), 1.73 (3H, d J= 1.4, C14aH3), 1.20 (9H, s), 1.00 (3H, d J= 6.7), 0.98 (3H, d J= 7.1); 13C NMR (CDCl3) 6 178.3, 137.5, 133.8, 129.1, 128.4, 127.7, 127.6, 80.0 (C11), 74.5 (C9), 73.5, 63.0 (Cl5), 38.7, 35.7 (C12), 35.6 (C10), 27.1, 21.4 (C14a), 15.3 (C12a), 14.6 (C10a) . Anal. Calcd. for C22H3404: C, 72.89; H, 9.45.
Found: C, 72.71; H, 9.46.
[2Z,4R,5S,6R]-7-Benzyloxy-5-triisopropylsilyloxy-2,4,6-trim ethylhept-2-en-1-yl 2,2-dimethylpropionate (18b): Triisopropylsilyltrifluoromethanesulphonate (38 l, 0.14 mmol) was added to a stirred mixture of the alcohol (18a) (25 mg, 0.07 mmol), dichloromethane (0.5 ml), and 2,6-lutidine (35 yl, 0.28 mmol) at - 50C. The mixture was kept at this temperature for 5h. then quenched by the addition of water. The mixture was extracted twice with ether. The combined extracts were washed twice with aqueous copper(II) sulphate, once with water, then dried (MgSO4) and concentrated.The residue was purified by flash chromatography (0-100% dichloromethane/ hexane then 0-100% ethyl acetate/ dichloromethane) to give 32 mg (89%) of the product: [&alpha;]D21 -9.36 (c 0.75, CH2C12); IR (film) 2965, 2944, 2868, 1730, 1462, 1281, 1152, 1092, 1032, 1015, 883, 698, 679, 667, 650; 111 NMR (CDC13) 6-7.31 (5H, m, Ar), 5.26 (1H, d, C13H), 4.54 (2H, q, C15H2), 4.46 (2H, s), 3.76(1H, dd J= 5.9, 4.4, C11H), 3.46 (1H, dd J= 9.1, 6.3, C,H), 3.27 (1H, dd J= 9, 7.5, C,H), 2.64 (1H, m, C12H), 2.08 (1H, m, C10H)r 1.67 (3H, d J= 1.1, C14aH3), 1.19 (9H, s), 1.07 (21H, s), 0.99 (3H, d J= 7.1), 0.95 (3H, d J= 7.0); 13C NMR (CDCl3) 6 178.4, 138.7, 134.8, 128.2, 127.5, 127.4, 77.6 (C1l), 73.0 (Cg), 72.9, 63.2 (C15), 39.9 (C10), 38.8, 35.5 (C12), 27.2, 21.3 (C14a), 18.3, 17.4, 13.4, 13.2; MS (ci) 519 (M+1', 2.6%). [2Z,4R,5S,6R]-7-Benzyloxy-5-triisopropylsilyloxy-2,4,6-trim etholhept-2-en-1-ol (18c): A 1M solution of DIBAL-H in dichloromethane (0.24 ml, 0.24 mmol) was added to a stirred mixture of the ester (18b) (31 mg, 0.06 mmol) and dichloromethane (0.5 ml) at -400C. The mixture was stirred at room temperature for 2.5 h. then poured into ice cold 1M aqueous tartaric acid. The mixture was extracted twice with ether. The combined extracts were washed with saturated sodium hydrogencarbonate then water.They were dried (MgSO4) and concentrated. The residue was purified by flash chromatography (0-40k ethyl acetate/ hexane) to give 21 mg (81%) of the product.
SCHEME 6 [3(2S,3R,4R),4S]-4-Benzyl-3-(5-benzyloxy-2,4-dimethyl-3-hyd roxv-l-oxopentyl)-oxazolidin-2-one (29): 1M Dibutylboron triflate in dichloromethane (7.1 ml, 7.1 mmol) was added dropwise during 5 min. to a stirred solution of (4S)-4-benzyl-3-propanoyloxazolin-2-one (17) (1.5g, 6.43 mmol) at -700C. This was followed by the addition of triethylamine (1.25 ml, 9.0 mmol). The resulting mixture was kept at -700C for 1 h. and at OOC for 1 h.. The mixture was cooled to -700C then a solution of the aldehyde (30) (1.6 g, 8.98 mmol) in dichloromethane (3 ml) was added. The mixture was kept at -700C for 3.5h then at OOC for 45 min..The mixture was quenched by the addition of pH 7 phosphate buffer (20 ml), methanol (2 ml), followed by dropwise addition of 30% hydrogen peroxide (4 ml). The resulting mixture was stirred at OOC for 30 min.. The organic phase was removed and the aqueous phase was extracted twice with dichloromethane. The combined organic phases were washed with saturated sodium hydrogencarbonate then water, dried (MgSO4) and concentrated.The residue was purified by flash chromatography (0-50k ethyl acetate/ hexane) to give 2.43 g (92%) of product: [a]D21 +39.53 (c 1.872, CH2Cl2); IR (CH2Cl2) 3475, 2960, 2920, 2865, 1775, 1730, 1695, 1493, 1478, 1450, 1380, 1358, 1320, 1210, 1105, 1070, 1045, 1028, 1012, 984, 970; 1H NMR (CDCl3) 6 7.28 (10H, m, Ar), 4.66 (1H, m), 4.50 (2H, s), 4.15 (2H, m), 3.92 (1H, m, C12H), 3.88 (1H, m, C11H), 3.74 (1H, m, OH), 3.58 (2H, m, C9H2) 3.31 (1H, dd), 2.75 (1H, dd), 1.98 (1H, m, CioH), 1.26 (3H, d J= 6.8, C12aH3), 0.95 (3H, d J= 7, C10aH3) 13C NMR (CDCl3) 6 176.0, 152.9 (C13), 137.7, 135.1, 129.2, 128.7, 128.2, 127.4, 127.1, 74.9 (Cii), 74.4 (C9), 73.2, 65.9, 55.3, 40.4 (C12), 37.4, 35.8 (C10), 13.4 (C10a), 9.7 (C12a) (3(2S,3R,4R), 4S]-4-Benzyl-3-(5-benzyloxy-2,4-dimethyl-1-oxo -3-triispropylsilyloxypentyl)oxazolidin-2-one (28): Triisopropylsilyltrifluoromethanesulphonate (10.06 ml, 37.42 mmol) was added dropwise to a stirred mixture of the alcohol (29) (7.7 g, 18.71 mmol), dichloromethane (80 ml), and 2,6-lutidine (8.72 ml, 74.84 mmol) at O C.The mixture was kept at this temperature for 23 h. then poured onto cold water (250 ml). The phases were separated and the aqueous phase was extracted three times with ether. The combined organic phases were washed four times with aqueous copper(II) sulphate, once with water, then dried (MgSO4) and concentrated.The residue was purified by flash chromatography (0-100% dichloromethane/ hexane) to give 7.96 g (75%) of the product: [&alpha;]D21 +60.360 (c 0.946, CH2Cl2); IR (CH2Cl2) 2945, 2865, 1775, 1690, 1455, 1380, 1350, 1205, 1105, 1060, 1015, 970, 880, 808; 1H NMR (CDCl3) 6 7.23 (10H, m, Ar), 4.40 (2H, s), 4.37 (2H, m, 04.11, C11H), 3.50 (2H, m, C9H), 4.03 (1H, m, C12H), 3.92 (1H, dd), 3.50 (2H, m), 3.24 (1H, dd, C9H), 3.19 (1H, dd), 2.67 (1H, dd), 2.11 (1H, m, C10H), 1.29 (3H, d J= 7, C12aH3), 1.06 (3H, d J= 7, C10aH3) 1.05 (21H, s); 13C NMR (CDCl3) 6 176.1, 152.7 (C13), 138.6, 135.3, 129.4, 128.8, 128.2, 127.3, 127.1, 74.9 (Cii), 72.7, 72.3 (C9), 65.5, 55.2, 40.6 (C12), 39.9 (C10), 37.6, 18.3, 15.0 (C12a), 13.4, 13.1 (Cica) S-Benzyl [2S,3R,4R]-5-benzyloxy-2,4-dimethyl-3-triisoropyl silyloxypentanethioate (27): A 1.55M solution of n-butyl lithium (9.9 ml, 15.28 mmol) was added to a stirred mixture of benzyl mercaptan (2.99 ml, 25.46 mmol) and T11F (100 ml) at -700C. The mixture was kept at this temperature for 10 min. then at -25 C for 15 min. before being recooled. A solution of the oxazolidinone (28) (7.23 g, 12.73 mmol) in T11F was added dropwise then the mixture was allowed to warm to -10 C during 40 min.The mixture was kept at this temperature for 1 h. then poured into ice cold saturated ammonium chloride (150 ml). The mixture was extracted three times with ether. The combined extracts were washed with ice cold 1M sodium hydroxide (2x100 ml) and water (2x 100 ml), dried (MgSO4) and concentrated. The residue was purified by flash chromatography (0-40W dichloromethane/ hexane) to give 4.9 g (75%) of product: [aiD21 +5.75 (c 1.026, CH2Cl2);IR (CH2Cl2) 2940, 2865, 1680, 1495, 1455, 1385, 1365, 1100, 1030, 1012, 955, 920, 880, 835; 1H NMR (CDCl3) 6 7.27 (10H, m, Ar), 4.39 (2H, s), 4.37 (1H, m, C1lH), 4.04 (2H, s), 3.39 (1H, dd J= 9.3, 6.4, C9H), 3.24 (1H, dd J= 9.3, 6.9, C9H), 2.84 (1H, m, C12H), 2.12 (1H, m, C10H), 1.25 (3H, d J= 7), 1.05 (21H, s), 0.99 (3H, d J= 7); 13C NMR (CDCl3) 6 201.6 (Cl3), 138.6, 137.6, 128.8, 128.5, 128.2, 127.4, 127.3, 127.1, 74.2 (Cii), 73.0, 72.5 (C9), 50.9 (Cl2), 40.4 (C10), 33.2, 18.3, 13.8 (C12a), 13.2, 12.7 (C10a) . Anal. Calcd. for C30H46O3SSi: C, 69.99; H, 9.01; S, 6.23. Found: C, 69.93; H, 9.01; S, 6.16.
[2S,3R,4R]-5-Benzyloxy-2,4-dimethyl-3-triisopropylsilyloxy- Pentanal (26): A 1M solution of DIBAL in dichloromethane (7.88 ml, 7.88 mmol) was added to a stirred mixture of the thioester (27) (1.014 g, 1.97 mmol) and dichloromethane (15 ml) at -700 C. The mixture was stirred at this temperature for 1 h. then poured into ice cold 1M tartaric acid (100 ml). The mixture was extracted three times with ether, the combined extracts were washed with water, dried (MgSO4), and concentrated to give a precipitation of inorganic solids.
These were removed by filtration and the residue was redissolved in ether and stirred with 1M tartaric acid.
The extraction process was repeated and the ethereal solution concentrated. The residue was purified by flash chromatography (0-50k dichloromethane/ hexane) to give 700 mg (91%) of the product: [&alpha;]D21+27.6 (c 0.493, CH2Cl2); IR (CH2Cl2) 2945, 2870, 1720, 1455, 1380, 1365, 1100, 1052, 1028, 1012, 996, 958, 918, 880, 810; 1H NMR (CDCl3) 6 9.74 (1H, d J= 1, C13H), 7.31 (5H, m, Ar), 4.45 (2H, m), 4.45 (1H, m, C11H), 3.38 (2H, m, C9H2), 2.50 (1H, m, C12H), 2.15 (1H, m, C10H) 1.13 (3H, d J= 7.1, C12aH3), 1.06 (21H, s), 0.98 (3H, d J= 7, CloaH3); 13C NMR (CDCl3) 6 204.8 (C13), 138.3, 128.-3, 127.5, 73.0, 72.5 (Cii), 72.2 (C9), 49.9 (C12), 39.2 (C10), 18.2, 13.4 (C10a), 13.0, 9.0 (C12a)- Ethyl [2Z,4R,5S,6R]-7-benzyloxy-5-triisopropyloxy-2,4,6- trimethylhet-2-en-1-oate (25): A 0.5M solution of potassium bis(trimethylsilyl)amide in toluene (5.22 ml, 2.609 mmol) was added dropwise to a stirred mixture of ethyl 2-[bis(trifluoroethyl)phosphonopropionate (881 mg, 2.546 mmol), 18-crown-6 (1.4g, 5.296 mmol) and THF (25 ml) at -700C. The mixture was stirred at this temperature for 20 min. then treated with a solution of the aldehyde (26) (500 mg, 1.273 mmol) in THF (6 ml). The mixture was stirred at -70 C for 5 h. then at -30 C for 1.5 h. before it was poured into ice cold saturated ammonium chloride.The mixture was extracted three times with ether. The combined extracts were washed with water, dried (MgSO4) and concentrated. The residue was purified by flash chromatography (2-10k ethyl actate/ hexane) to give 562 mg (93%) of a product which was slightly contaminated. The impurities were readily removed in the next step.
Analytical data is given for a purified sample. [&alpha;]D21 -31.90 (c 0.502, CH2Cl2); IR (CH2Cl2) 2940, 2860, 1700, 1455, 1370, 1300, 1220, 1175, 1160, 1095, 1030, 1015, 880, 805; 1H NMR (CDCl3) 6 7.32 (5H, m, Ar), 5.83 (1H, m, C13H), 4.46 (2H, m), 4.16 (2H, q), 3.83 (1H, t, CllH), 3.47 (1H, dd J= 9.1, 6, C9H), 3.37 (1H, m, C12H), 3.27 (1H, dd J= 9, 7.8, C9H), 2.06 (1H, m, CioH), 1.84 (3H, d J= 1.2, C14aH3) 1.27 (3H, t), 1.07 (21H, s), 1.02 (3H, d J= 6.5, C12aH3), 0.99 (3H, d J= 6.8, C10aH3) ; 13C NMR (CDC13) 6 167.9 (C15), 146.5 (C13), 138.7, 128.2, 127.4, 127.3, 125.3 (Cl4), 77.1 (C11), 73.0 (C9), 72.9, 60.0, 39.8 (C10), 36.3 (Cl2), 20.8 (C14a), 18.3, 15.9 (C12a), 14.2, 13.4 (C10a)- [2Z,4R,5S,6R]-7-Benzyloxy-5-triisoroylsilyloxy-2,4,6-trim ethylhept-2-en-1-ol (18c): A 1M solution of DIBAL in dichloromethane (10.5 ml, 10.5 mmol) was added to a stirred mixture of the ester (25) (1.254 g, 2.63 mmol) and dichloromethane (40 ml) at -70 C. The mixture was allowed to reach room temperature and kept for 2.75 h.. The mixture was poured into ice cold 1M tartaric acid (75 ml). The mixture was extracted three times with ether, the combined extracts were washed with water, dried (MgSO4), and concentrated. The residue was purified by flash chromatography (0-20W ethyl acetate/ hexane) to give 1.06g (93W) of the product: [&alpha;]D21 +3.140(c 0.51, CH2Cl2); IR (film) 3393, 2969, 2944, 2891, 2866, 1462, 1381, 1252, 1090, 1067, 1013, 883, 735, 698, 677: 1H NMR (CDCl3) 6 7.32 (5H, m Ar), 5.11 (1H, d J= 10.3, C13H), 4.48 (2H, s), 4.15 (1H, dd J= 11.8, 4.5, C15H), 3.86 (1H, dd J= 11.8, 7.4, C15H), 3.66 (1H, dd J= 6.7, 3.1 , C11H), 3.59 (1H, dd, J= 9.2, 6.6, C9H), 3.23 (1H, dd J= 9.3, 6.5, C9H), 2.73 (1H, m, C12H), 2.12 (1H, m, C10H), 2.0 (1H, m, OH), 1.75 (3H, d J= 1.4, C14aH3), 1.08 (21H, s), 0.98 (3H, d J= 6.7, C12aH3), 0.96 (3H, d J= 7.1 C10aH3) . Anal. Calcd. for C26H46O3Si: C, 71.83; H, 10.67. Found: C, 71.89; H, 10.63.

Claims (84)

Claims
1. Compounds of formula (2)
wherein R1 represents a protecting group, and enantiomeric and diastereoisomeric forms thereof.
2. Compounds of formulae (2) as claimed in claim 1 wherein R1 represents a trialkylsilyl protecting group.
3. Compounds of formula (2) as claimed in claim 1 or claim 2 as specifically described.
4. Compounds of formula (2) as claimed in claim 1 or claim 2 as specifically described with particular reference to the Examples.
5. Compounds of formula (13)
wherein R1 and R4 each represents a protecting group, and enantiomeric and diastereoisomeric forms thereof.
6. Compounds of formula (13) as claimed in claims wherein R1 represents a trialkylsilyl protecting group and R4 represents a trialkylsilyl protecting group or a benzyl group.
7. Compounds of formula (13) as claimed in claim 5 or claim 6 as specifically described.
8. Compounds of formula (13) as claimed in claim 5 or claim 6 as specifically described with particular reference to the Examples.
9. A process for the preparation of a compound of formula (2) as claimed in any one of claims 1 to 4 which comprises the reaction of a compound of formula (8)
with appropriate reagents to form the compound of formula (2).
10. A process as claimed in claim 9 wherein the compound of formula (8) is treated with ozone and subsequent the ozonolysis product is treated with triphenyl phosphine at a temperature between -70"C and -80 C in the presence of dichloromethane.
11. A process as claimed in claim 9 or claim 10 wherein the compound of formula (8) is prepared by a lactonisation reaction of the compound of formula (7)
12. A process as claimed in claim 11 wherein the lactonisation reaction is carried out by treatment of the compound of formula (7) with lithium hydroxide in the presence of aqueous hydrogen peroxide in tetrahydrofuran/water, followed by acid treatment.
13. A process as claimed in claim 11 or claim 12 wherein the compound of formula (7) is prepared by the partial reduction of the compound of formula (6)
14. A process as claimed in claim 13 wherein the partial reduction is carried out by treatment of the compound of formula (6) with zinc borohydride in ether and/or dichloromethane, at low temperature.
15. A process as claimed in claim 13 or claim 14 wherein the compound of formula (6) is prepared by the aldol condensation of the compounds of formulae (4) and (5)
16. A process as claimed in claim 15 wherein the condensation reaction is mediated by dicyclohexylboron chloride.
17. A process for the preparation of a compound of formula (5) as defined in claim 15 which comprises the reduction of the compound of formula (10)
18. A process as claimed in claim 17 wherein the reduction is carried out by treatment with DIBAL-H (diisobutylaluminium hydride) in the presence of dichloromethane, at a temperature in the region of -70oC.
19. A process as claimed in claim 17 or claim 18 wherein the compound of formula (10) is prepared by protecting the compound of formula (9)
by conventional methods.
20. A process for the preparation of a compound of formula (5) as claimed in any one of claims 17 to 19 substantially as herein described.
21. A process for the preparation of a compound of formula (5) as claimed in any one of claims 17 to 19 substantially as herein described and with particular reference to the Examples.
22. A process as claimed in claim 15 or claim 16 wherein the compound of formula (5) is prepared by a process as claimed in any one of claims 17 to 21.
23. A process for the preparation of a compound of formula (2) as claimed in any one of claims 9 to 16 and 22 substantially as herein described.
24. A process for the preparation of the compounds of formula (2) as claimed in any one of claims 9 to 16 and 22 substantially as herein described and with particular reference to the Examples.
25. A compound of formula (2) whenever prepared by a process as claimed in any one of claims 9 to 16 and 22 to 24.
26. Compounds of formulae (5), (6), (7), (8) and (10) as defined in claims 15, 13, 11, 9 and 17 respectively, and the enantiomeric and diastereoisomeric forms thereof.
27. A process for the preparation of a compound of formula (12)
which comprises the conversion of a compound of formula (2) as claimed in claim 1 to a compound of formula (11)
which is subsequently deprotected by standard methods to obtain the compound of formula (12)
28. A process as claimed in claim 27 wherein the compound of formula (11) is obtained by the reduction of the compound of formula (2).
29. A process as claimed in claim 28 wherein the reduction is carried out by treatment with zinc borohydride.
30. A process as claimed in claim 27 wherein the compound of formula (11) is prepared by reduction of the ozonide derived from the compound of formula (8) as defined in claim 9.
31. A process as claimed in claim 30 wherein the reduction is carried out by treatment with zinc borohydride.
32. A process as claimed in any one of claims 27 to 31 wherein the compound of formula (2) is prepared by a process as claimed in any one of claims 9 to 16 and.22 to 24.
33. A process as claimed in any one of claims 27 to 32 substantially as herein described.
34. A process as claimed in any one of claims 27 to 32 substantially as herein described and with particular reference to the Examples.
35. Compounds of formulae (11) and (12) as defined in claim 27 and the enantiomeric and diastereoisomeric forms thereof.
36. A process for the preparation of a compound of formula (13) as claimed in any one of claims 5 to 8 which comprises the reduction of a compound of formula (14)
37. A process as claimed in claim 36 in which the reduction is carried out by treatment of the compound of formula (14) with DIBAL-H in the presence of dichloromethane, at a temperature between -70 and -80 C.
38. A process as claimed in claim 36 or claim 37 wherein the compound of formula (14) is obtained by reacting a compound of formula (15)
with benzyl mercaptan and n-butyl lithium.
39. A process as claimed in claim 38 wherein the compound of formula (15) is prepared by reacting a compound of formula (16)
with the chiral auxiliary oxazolidinone of formula (17)
40. A process as claimed in claim 39 wherein the compound of formula (16) is obtained by reacting an alcohol of formula (18c)
with a suitable reagent to introduce a labile group R3.
41. A process as claimed in claim 40 wherein R3 is selected from a halogen atom and a sulfonic ester group,
42. A process claimed in claim 40 or claim 41 wherein R3 is iodine.
43. A process for the preparation of a compound of formula (18c)
which comprises converting a compound of formula (19)
to the compound of formula (18c) by means of a suitable selective protection/deprotection sequence.
44. A process as claimed in claim 43 which comprises reacting the compound of formula (19) with a suitable reagent to protect the primary hydroxyl group by the group R2 to yield a compound of formula (18a), subsequently treating the compound of formula (18a) with a suitable reagent resulting in the introduction of a protecting group R1 for the secondary hydroxyl group to yield a compound of formula (18b) and then subsequently selectively deprotecting a primary hydroxyl group by standard methods to yield the desired compound of formula (18c).
45. A process as claimed in claim 44 wherein the protecting group R1 is a TIPS group and the protecting group R2 is a pivaloyl group.
46. A process as claimed in 43 which comprises protecting each of the primary and secondary hydroxyl groups in the compound of formula (19) by a t-butyldimethylsilyl group, following which the primary t-butyldimethylsilyl group denoted by R2 is selectively cleaved.
47. A process as claimed in any one of claims 43 to 46 wherein the compound of formula (19) is prepared from a compound of formula (20)
48. A process as claimed in claim 47 wherein the compound of formula (19) is treated with DIBAL-H in the presence of ether and/or dichloromethane, at a temperature in the region of 000.
49. A process as claimed in claim 47 and claim 48 in which the compound of formula (20) is prepared by the lactonisation and subsequent elimination of a compound of formula (21)
by use of the following three-step procedure: (i) removal of the chiral auxiliary, preferably by treatment with lithium hydroxide and aqueous hydrogen peroxide, also resulting in lactonisation, (ii) conversion of the free hydroxyl group to a suitable leaving group, preferably a mesyl group, and (iii) base-catalysed elimination.
50. A process as claimed in claim 49 wherein the compound of formula (21) is prepared by the reduction of a compound of formula (22)
51. A process as claimed in claim 50 wherein the reduction is carried out by treatment with DIBAL-H in the presence of diethyl ether, at a temperature in the region of -70 C.
52. A process as claimed in claim 50 and claim 51 wherein the compound of formula (22) is prepared by an aldol condensation between the compounds of formulae (23)~and (24)
53. A process as claimed in claim 52 wherein the aldol condensation is mediated by tin (II) triflate.
54. A process for the preparation of a compound of formula (18c) which comprises the reduction of a compound of formula (25)
55. A process as claimed in claim 54 in which the reduction is carried out by treatment with DIBAL-H in the presence of dichloromethane at room temperature.
56. A process as claimed in claim 54 and claim 55 wherein the compound of formula (25) is prepared from the reaction of the compound of formula (26)
with ethyl 2-[bis(trifluoroethyl)]phospono-propionate.
57. A process as claimed in claim 56 wherein the compound of formula (26) is prepared by the reduction of a compound of formula (27)
58. A process as claimed in claim 57 wherein the reduction is carried out by treatment with DIBAL-H in the presence of.dichloromethane at a temperature in the region of -70 C.
59. A process as claimed in claim 57 or claim 58 wherein the compound of formula (27) is obtained by a reaction of a compound of formula (28)
with benzyl mercaptan and n-butyl lithium.
60. A process as claimed in claim 59 wherein the compound of formula (28) is prepared by protecting a compound of formula (29)
by standard methods.
61. A process as claimed in claim 60 wherein the compound of formula (29) is prepared by the aldol condensation of a compound of formula (30)
and a chiral auxiliary oxazolidinone of formula (17) as defined in claim 39.
62. A process as claimed in claim 61 wherein the condensation reaction is mediated by dibutylboron triflate.
63. A process for the preparation of a compound of formula (18c) as claimed in any one of claims 43 to 62 substantially as herein described.
64. A process for the preparation of a compound of formula (18c) as claimed in any one of claims 43 to 62 substantially as herein described and with particular reference to the Examples.
65. A process as claimed in any one of claims 40 to 42 wherein the compound of formula (18c) is prepared by a process as claimed in any one of claims 43 to 62.
66. A process for the preparation of a compound of formula (13) as claimed in any one of claims 36 to 42 and 65 substantially as herein described.
67. A process for the preparation of a compound of formula (13) as claimed in any one of claims 36 to 42 and 65 substantially as herein described and with particular reference to the Examples.
68. A compound of formula (13) whenever prepared by a process as claimed in any one of claims 36 to 42 and 65 to 67.
69. Compounds of formulae (14) to (16), (18) to (22) and (25) to (29) as defined in claims 36 to 60 and the enantiomeric and diastereoisomeric forms thereof.
70. Use of a compound of formula (2) or an enantiomer or diastereoisomer thereof as claimed in claim 1 or of a 8 compound of formula (13) or an enantiomer or diastereoisomer thereof as claimed in claim 5 in a process for the preparation of a compound of formula (1)
or an enantiomer or diastereoisomer thereof.
71. A process as claimed in claim 70 wherein the compound of formula (2) is prepared by a process as claimed in any one of claims 9 to 16 and 22 to 24 and the compound of formula (13) is prepared by a process as claimed in any one of claims 36 to 42 and 65 to 67.
72. A process as claimed in claim 70 or claim 71 wherein the compounds of formulae (2) and (13) are reacted according to a process as set out in Scheme 7 herein or according to an analogous process in which appropriate alternative reagents for the individual steps therein and/or appropriate alternative protecting groups in the compounds of formulae (2) and (13) are used.
73. A process as claimed in claim 72 substantially as herein described.
74. A process as claimed in claim 70 or claim 71 wherein the compounds of formulae (2) and (13) are combined to form the C1-Cl7 fragment of the compound of formula (1), subsequently reacting this fragment with a suitable intermediate compound corresponding to the C18-C24 fragment of the compound of formula (1), followed by removal of the protecting groups -
75. A process as claimed in claim 74 wherein the aldehyde functionality of the compound of formula (13) is suitably protected and a phosphorus ylid is prepared, the ylid is subsequently reacted with a compound of formula (2) by means of a stereospecific Horner-Emmons reaction to produce a protected compound corresponding to the C1-Cl7 fragment of the compound of formula (1) and subsequently the carbonyl group is deprotected.
76. A process as claimed in claim 75 wherein the phosphorus ylid is a compound of formula (44)
and the protected compound corresponding to the C1-Cl7 fragment of the compound of formula (1) is a compound of formula
77. A process as claimed in claim 70 or claim 71 wherein the compound of formula (13) or a suitable protected derivative thereof is reacted with a suitable intermediate compound corresponding to the C18-C24 fragment of the compound of formula (1) followed by a process involving reaction with the compound of formula (2), followed by removal of the protecting groups.
78. A process as claimed in claim 77 wherein the reaction product of the compound of formula (13) or a suitable protected derivative thereof with a suitable intermediate compound corresponding to the C18-C24 fragment of the compound of formula (1) is converted to a phosphorus ylid which then undergoes a stereospecific Horner-Emmons reaction with the compound of formula (2) followed by removal of the protecting groups.
79. A process as claimed in claim 78 wherein the phosphorus ylid is a compound of formula (46)
80. A process as claimed in any one of claims 74 to 79 substantially as herein described.
81. Compounds of formulae (31) to (41) and (43) as defined in Scheme 7 herein and enantiomeric and diastereoisomeric forms thereof and analogous compounds carrying alternative protecting groups.
82. Compounds of formulae (44) and (45) as defined in claim 76 and enantiomeric and diastereoisomeric forms thereof.
83. A compound of formula (1) as defined in claim 70 or the enantiomeric or diastereoisomeric forms thereof whenever prepared by a process as claimed in any one of claims 70 to 80.
84. Compositions for use in therapy comprising a compound of formula (1) as defined in claim 70 or the enantiomeric or diastereoisomeric forms thereof produced by a process as claimed in any one of claims 70 to 80.
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WO1998048791A1 (en) * 1997-04-30 1998-11-05 The Regents Of The University Of California Synthesis of discodermolide and analogs
WO2000004865A2 (en) * 1998-07-23 2000-02-03 The Trustees Of The University Of Pennsylvania Synthetic techniques and intermediates for polyhydroxy, dienyl lactone derivatives
US6127406A (en) * 1998-10-09 2000-10-03 Harbor Branch Oceanographic Institution, Inc. Discodermolide compounds and methods of use
US6242616B1 (en) 1996-12-03 2001-06-05 The Trustees Of The University Of Pennsylvania Synthetic techniques and intermediates for polyhydroxy, dienyl lactone derivatives
WO2002098843A2 (en) * 2001-04-17 2002-12-12 Novartis Ag Certain salts of discodermolide acid, pharmaceutical compositions containing them and their use in treating tumors
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US7368585B2 (en) 1996-12-03 2008-05-06 The Trustees Of The University Of Pennsylvania Synthetic techniques and intermediates for polyhydroxy dienyl lactones and mimics thereof
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EP2272511A1 (en) 2006-05-09 2011-01-12 Novartis AG Combination comprising an iron chelator and an anti-neoplastic agent and use thereof
US10851121B2 (en) * 2016-12-09 2020-12-01 Akanocure Phamraceuticals, Inc. Scalable polypropionate lactone stereotetrads

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US7368585B2 (en) 1996-12-03 2008-05-06 The Trustees Of The University Of Pennsylvania Synthetic techniques and intermediates for polyhydroxy dienyl lactones and mimics thereof
US6031133A (en) * 1996-12-03 2000-02-29 The Trustees Of The University Of Pennsylvania Synthetic techniques and intermediates for polyhydroxy, dienyl lactones and mimics thereof
US6096904A (en) * 1996-12-03 2000-08-01 The Trustees Of The University Of Pennsylvania Synthetic techniques and intermediates for polyhydroxy, dienyl lactone derivatives
US5789605A (en) * 1996-12-03 1998-08-04 Trustees Of The University Of Pennsylvania Synthetic techniques and intermediates for polyhydroxy, dienyl lactones and mimics thereof
US7723536B2 (en) 1996-12-03 2010-05-25 The Trustees Of The University Of Pennsylvania Synthetic techniques and intermediates for polyhydroxy dienyl lactones and mimics thereof
US6242616B1 (en) 1996-12-03 2001-06-05 The Trustees Of The University Of Pennsylvania Synthetic techniques and intermediates for polyhydroxy, dienyl lactone derivatives
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JP2011046714A (en) * 1998-07-23 2011-03-10 Trustees Of The Univ Of Pennsylvania Synthetic method and intermediate for polyhydroxy dienyl lactone derivative
JP2002521317A (en) * 1998-07-23 2002-07-16 ザ・トラスティーズ・オブ・ザ・ユニバーシティ・オブ・ペンシルバニア Method for synthesizing polyhydroxy and dienyl lactone derivatives and intermediates
WO2000004865A3 (en) * 1998-07-23 2000-09-21 Univ Pennsylvania Synthetic techniques and intermediates for polyhydroxy, dienyl lactone derivatives
WO2000004865A2 (en) * 1998-07-23 2000-02-03 The Trustees Of The University Of Pennsylvania Synthetic techniques and intermediates for polyhydroxy, dienyl lactone derivatives
US6127406A (en) * 1998-10-09 2000-10-03 Harbor Branch Oceanographic Institution, Inc. Discodermolide compounds and methods of use
US6495594B2 (en) 2000-03-01 2002-12-17 Harbor Branch Oceanographic Institution, Inc. Biologically active analogs of discodermolide
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US6506910B1 (en) 2000-08-07 2003-01-14 Novartis Ag Process for preparing discodermolide and analogues thereof
US6974875B2 (en) 2001-01-22 2005-12-13 Novartis Ag Process for preparing intermediates for the manufacture of discodermolide and discodermolide analogues
US6734177B2 (en) 2001-04-17 2004-05-11 Novartis Ag Certain salts of discodermolide acid, pharmaceutical compositions containing them and their use in treating tumors
WO2002098843A3 (en) * 2001-04-17 2003-05-01 Novartis Ag Certain salts of discodermolide acid, pharmaceutical compositions containing them and their use in treating tumors
WO2002098843A2 (en) * 2001-04-17 2002-12-12 Novartis Ag Certain salts of discodermolide acid, pharmaceutical compositions containing them and their use in treating tumors
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EP2272511A1 (en) 2006-05-09 2011-01-12 Novartis AG Combination comprising an iron chelator and an anti-neoplastic agent and use thereof
US10851121B2 (en) * 2016-12-09 2020-12-01 Akanocure Phamraceuticals, Inc. Scalable polypropionate lactone stereotetrads
US11447509B2 (en) 2016-12-09 2022-09-20 Akanocure Pharmaceuticals, Inc. Scalable polypropionate lactone stereotetrads

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