WO2003048089A1 - Ring expansion of ketocyclopropanes - Google Patents

Ring expansion of ketocyclopropanes Download PDF

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WO2003048089A1
WO2003048089A1 PCT/AU2002/001626 AU0201626W WO03048089A1 WO 2003048089 A1 WO2003048089 A1 WO 2003048089A1 AU 0201626 W AU0201626 W AU 0201626W WO 03048089 A1 WO03048089 A1 WO 03048089A1
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radical
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Dennis Taylor
Ben Greatrex
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Adelaide Research And Innovation
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/45—Carboxylic acid nitriles having cyano groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C255/46—Carboxylic acid nitriles having cyano groups bound to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of non-condensed rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/10—Systems containing only non-condensed rings with a five-membered ring the ring being unsaturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/56—Ring systems containing bridged rings
    • C07C2603/58—Ring systems containing bridged rings containing three rings
    • C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
    • C07C2603/74—Adamantanes

Definitions

  • the cyclopropane to cyclopentene C 3 -C 5 ring reaction expansion has been used as a synthetic tool in the construction of a number of natural products.
  • Reviews of the C 3 -C 5 ring expansion reactions include Salun, J. Rearrangements involving the cyclopropyl group; from The Chemistry of the cyclopropyl group; Ed. S Patai, Z. R.; Wiley: Toronto, 1987; and Comprehensive Organic Synthesis, Eds. Trost, B. M. and Fleming, I. Pergamon, Oxford, 1991, Vol. 5, 8.1 p899
  • the reaction usually utilizes vinyl cyclopropanes as precursors and requires high temperatures but may be promoted by transition metals (see Hudlicky, T.; Kutchan, T. M.; Naqvi, S. M. Org React. 1985, 33, 247 and references cited therein), base (see Danheiser, R. L.; Martinez- Davila, C; Morin, J. M. J. Org. Chem. 1980, 45, 1340-1341. Danheiser, R. L.; Bronson, J. L.; Okano, K. J. Am Chem. Soc. 1985, 107, 4579-4581) and light (see Jorgensen, M. J.; Heathcock, C. H. J. Am. Chem. Soc. 1965, 87, 5264).
  • transition metals see Hudlicky, T.; Kutchan, T. M.; Naqvi, S. M. Org React. 1985, 33, 247 and references cited therein
  • base see Danheiser
  • Natural products and the starting reactants from which synthetic natural products might be synthesised are not generally suited to reactive manipulation at high temperatures. Existing processes for the synthetic production of natural products based on cyclopentenes is thus constrained by the reaction conditions.
  • the present invention is concerned with an alternative to known methods of producing cyclopentenols.
  • the present invention concerns the base-catalysed C 3 -C 5 ring expansion of cyclopropanes to cyclopentenols.
  • the process of the invention produces cyclopentenols in high yield and excellent diastereoselectivity. Therefore according the a first aspect of the present invention there is provided a process for the production of cyclopentenols (2) from cyclopropanes including the steps of reacting a cyclopropane of the type (1) shown above together with a base in the presence of tetrahydrofuran, according to Scheme 1, wherein R], R 2 and R 3 may be the same or different and are each a hydrogen atom, an alkyl radical, an alkenyl radical, an allynyl radical, a cycloalkyl radical, an aralkyl radical, an aryl radical, an alkoxy radical, alkenyloxy radical, an alkoxy carbonyl radical, alkenyloxycarbonyl radical, alkylthio radical, or alken
  • the reaction of Scheme 1 may be conducted at ambient temperatures and is thus suited to the reactive manipulation of natural products or reactants easily degraded at higher temperatures.
  • the base is selected from the group consisting of alkali metal hydrides and hydroxides and alkali metal alkyl silazanes.
  • the base is lithium hexamethyldisilazane.
  • the cyclopropane starting material is a ⁇ -ketocyclopropylcarboxylate and may be used as a racemic mixture or as an optically pure compound. Where an optically pure starting material is required the relevant cyclopropane starting material may be prepared by the reaction of 1,2- dioxines and stabilized phosphorus ylides as shown in Scheme 2 (A very, T. A.; Hasel grove, T. D.; Rathbone, T. J.; Taylor, D. K.; Tiekink, E. R. T. J. Chem. Soc. Chem. Comm. 1998, 333. Avery, T.D.; Taylor, D.K.; Tiekink, E.R.T. J. Org. Chem. 2000, 65, 5531-5546).
  • the first base tested with cyclopropanes of type 1 was sodium hydride (Table 1, entries 1,4 and 9). Although a small amount of the ring-closed cyclopentenol 3 was found in each case, the major product were the trans ring-opened products 5 and 6. When a mixture of 3a and 5a was allowed to react with an additional portion of sodium hydride, no increase in 3a was observed. Instead 5a rearranged to the more thermodynamically stable styryl isomer 6.
  • the first base tested with cyclopropanes of type 2 was sodium hydride (Table 1, entries 1,4 and 9). Although a small amount of the ring-closed cyclopentenol 3 was found in each case, the major product was the trans ring-opened products 5 and 6. When a mixture of 3a and 5a was allowed to react with an additional portion of sodium hydride, no increase in 3a was observed. Instead 5a rearranged to the more thermodynamically stable styryl isomer 6.
  • ⁇ and 13 C NMR was performed using a Varian Gemini-200, Bruker ACP-300 or a Varian Innova-600 spectrometer operating at 200, 300 and 600 MHz respectively for ⁇ and 50, 75 and 150 MHz for 13 C in CDC1 3 .
  • 1H NMR were referenced to internal trimethylsilane ( ⁇ 0.00).
  • 13 C NMR were referenced to CDC1 3 ( ⁇ 77.0).
  • Multiplicities are assigned as s: singlet, d: doublet, t: triplet, q: quartet, p: pentet, and br: broad denotes broadened signals. All coupling constants are reported in Hz.
  • IR Spectra were recorded using a Perkin Elmer spectrometer BX FT-IR system as either nujol mulls or in the neat form as denoted. Melting points were determined on a Reichert hot stage apparatus and are uncorrected. Mass spectra were acquired using a VG ZAB 2HF spectrometer and HRMS were performed by the Organic Mass Spectrometry Facility, Central Science Laboratory, University of Kenya. Microanalysis was performed at the University of Otago.
  • the structure was solved by direct-methods (A. Altomare, M.C. Burla, M. Camalli, G.L. Cascarano, C. Giacovazzo, A. Guagliardi, A.G.G. Moliterni, G. Polidori and R. Spagna,

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  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The present invention concerns the base-catalysed C3-C5 ring expansion of cyclopropanes to cyclopentenols. A process for the production of cyclopentenols (2) from cyclopropanes characterized by the steps of reacting a cyclopropane of the type (1) together with a base in the presence of tetrahydrofuran, according to Scheme 1, wherein R1, R2 and R3 may be the same or different and are each a hydrogen atom, an alkyl radical, an alkenyl radical, an allynyl radical, a cycloalkyl radical, an aralkyl radical, an aryl radical, an alkoxy radical, alkenyloxy radical, an alkoxy carbonyl radical, alkenyloxycarbonyl radical, alkylthio radical, or alkenylthio radical; Formula (1),(2). The process of the invention produces cyclopentenols in high yield and excellent diastereoselectivity.

Description

Ring Expansion of Ketocycloprαpanes
BACKGROUND OF THE INVENTION
The cyclopropane to cyclopentene C3-C5 ring reaction expansion has been used as a synthetic tool in the construction of a number of natural products. Reviews of the C3-C5 ring expansion reactions include Salun, J. Rearrangements involving the cyclopropyl group; from The Chemistry of the cyclopropyl group; Ed. S Patai, Z. R.; Wiley: Toronto, 1987; and Comprehensive Organic Synthesis, Eds. Trost, B. M. and Fleming, I. Pergamon, Oxford, 1991, Vol. 5, 8.1 p899
The reaction usually utilizes vinyl cyclopropanes as precursors and requires high temperatures but may be promoted by transition metals (see Hudlicky, T.; Kutchan, T. M.; Naqvi, S. M. Org React. 1985, 33, 247 and references cited therein), base (see Danheiser, R. L.; Martinez- Davila, C; Morin, J. M. J. Org. Chem. 1980, 45, 1340-1341. Danheiser, R. L.; Bronson, J. L.; Okano, K. J. Am Chem. Soc. 1985, 107, 4579-4581) and light (see Jorgensen, M. J.; Heathcock, C. H. J. Am. Chem. Soc. 1965, 87, 5264).
Natural products and the starting reactants from which synthetic natural products might be synthesised are not generally suited to reactive manipulation at high temperatures. Existing processes for the synthetic production of natural products based on cyclopentenes is thus constrained by the reaction conditions.
The present invention is concerned with an alternative to known methods of producing cyclopentenols.
SUMMARY OF THE INVENTION
The present invention concerns the base-catalysed C3-C5 ring expansion of cyclopropanes to cyclopentenols. The process of the invention produces cyclopentenols in high yield and excellent diastereoselectivity. Therefore according the a first aspect of the present invention there is provided a process for the production of cyclopentenols (2) from cyclopropanes including the steps of reacting a cyclopropane of the type (1) shown above together with a base in the presence of tetrahydrofuran, according to Scheme 1, wherein R], R2 and R3 may be the same or different and are each a hydrogen atom, an alkyl radical, an alkenyl radical, an allynyl radical, a cycloalkyl radical, an aralkyl radical, an aryl radical, an alkoxy radical, alkenyloxy radical, an alkoxy carbonyl radical, alkenyloxycarbonyl radical, alkylthio radical, or alkenylthio radical.
Figure imgf000003_0001
Scheme 1
The reaction of Scheme 1 may be conducted at ambient temperatures and is thus suited to the reactive manipulation of natural products or reactants easily degraded at higher temperatures.
Preferably, the base is selected from the group consisting of alkali metal hydrides and hydroxides and alkali metal alkyl silazanes. In a preferred embodiment the base is lithium hexamethyldisilazane.
Figure imgf000003_0002
Scheme 2 The cyclopropane starting material is a β-ketocyclopropylcarboxylate and may be used as a racemic mixture or as an optically pure compound. Where an optically pure starting material is required the relevant cyclopropane starting material may be prepared by the reaction of 1,2- dioxines and stabilized phosphorus ylides as shown in Scheme 2 (A very, T. A.; Hasel grove, T. D.; Rathbone, T. J.; Taylor, D. K.; Tiekink, E. R. T. J. Chem. Soc. Chem. Comm. 1998, 333. Avery, T.D.; Taylor, D.K.; Tiekink, E.R.T. J. Org. Chem. 2000, 65, 5531-5546).
It has been established that the preferred β-ketocyclopropylcarboxylate starting compound can be generated by the use of bulky ylides, LiBr and the adoption of dilute solutions.
DESCRIPTION OF THE PREFERRED EMBODIMENT
A variety of cyclopentenols were prepared using β-keto-cyclopropanes with various bases. The results are tabulated in table 1 giving yields for various reaction products identified from the reaction
ii
Figure imgf000004_0001
Scheme 3
The first base tested with cyclopropanes of type 1 was sodium hydride (Table 1, entries 1,4 and 9). Although a small amount of the ring-closed cyclopentenol 3 was found in each case, the major product were the trans ring-opened products 5 and 6. When a mixture of 3a and 5a was allowed to react with an additional portion of sodium hydride, no increase in 3a was observed. Instead 5a rearranged to the more thermodynamically stable styryl isomer 6.
The isolation of the trans ring-opened products 5b and 5c indicated competitive cis and trans ring-opening. Of the two product enolates 7a and 7b, only cis 7a could undergo an intramolecular aldol yielding the observed cyclopentenol, Scheme 3. Higher temperatures failed to cleanly afford cyclopentenol (entry 2) whilst changing counter ions from sodium to lithium using lithium hydride gave a multi component reaction mixture. Table 1. The Reaction of β-keto-cyclopropanes with base.
Entry'1 2 R1 R: R3 Base Temp Yield"
3 8 5 6
1 a Ph Ph C02l-Ad NaH RT a 18 (23) - a - 35 (77)
2C a Ph Ph C02l-Ad LiOH 110 a 38 - a - 8
3 a Ph Ph C02l-Ad LHMDS RT a 83 - - -
4d b Ph Me C02Bu' NaH RT b - (23) - b - (77) -
5d b Ph Me C02Bu' LHMDS -78 b - (6) - b - (94) -
6 b Ph Me CO-Bu1 LHMDS RT b 78 - - -
7 c Ph Ph C02Bu' LHMDS RT c 80 - - -
8 d Ph H C02l-Ad LHMDS RT d 85 - - -
9 e n-Pr n-Pr C02Bu' NaH RT e -d (10) - c 59 (90) -
10 e n-Pr n-Pr C02Bu' LHMDS RT e 84 - - -
1 1 f Ph Ph CN LHMDS RT f 45 - - -
12e b Ph Me C02Bu' KHMDS RT b 80 (86) 8(14) - - a Typically reactions were performed on a 50mg scale by addition of a solution of cyclopropane in THF or ether to 1.5-2.0 equivalents of base in THF and worked up after 15 mins.
b Yield refers to isolated product. Parentheses indicate product ratio determined by *H NMR.
c Reaction time was 3 hours.
d Isolation not attempted. e Reaction performed in a 4:1 ether/toluene mixture (toluene was present from the solution of base).
The first base tested with cyclopropanes of type 2 was sodium hydride (Table 1, entries 1,4 and 9). Although a small amount of the ring-closed cyclopentenol 3 was found in each case, the major product was the trans ring-opened products 5 and 6. When a mixture of 3a and 5a was allowed to react with an additional portion of sodium hydride, no increase in 3a was observed. Instead 5a rearranged to the more thermodynamically stable styryl isomer 6.
The isolation of the trans ring-opened products 5b and 5c indicated competitive cis and trans ring-opening. Of the two product enolates 7a and 7b, only cis 7a could undergo an intramolecular aldol yielding the observed cyclopentenol, Scheme 3. Higher temperatures failed to cleanly afford cyclopentenol (entry 2) whilst changing counter ions from sodium to lithium using lithium hydride gave a multi component reaction mixture.
As two cyclopropyl keto-enolates are possible, it was thought that each enolate could lead to the formation of a specific ring-opened geometric isomer. Lithium hexamethyldisilazide (LHMDS) gives exclusively Z-ketoenolates at -72° C. The reaction of 2b with LHMDS at - 78°C gave nearly exclusively trans ring-opening (entry 5), however, the addition of 2b to 1.5 equivalents of LHMDS in THF at 25° afforded cyclopentenol 3b in 78% yield (entry 6). The order of addition was found to be important, as the dropwise addition of base to cyclopropane reduced the yield to only 17%.
This optimised methodology was then applied to a series of cyclopropanes with various substitution patterns (entries 3, 6-8, 10-12). All cyclopropanes with bulky ester groups afforded high yields of cyclopentenols; most of the products being highly crystalline. Entry 11 demonstrates that the reaction is applicable with electron acceptors other than ester groups. Stereochemistry was assigned on the basis of the 2D ROES Y NMR spectra and all products were found to have trans stereochemistry between groups attached to C-l and C-5 of the cyclopentenol ring. Further evidence for the conserved syn relationship between the group attached to Cl and the OH on C2 of the cyclopentene ring comes from the x-ray structure of cyclopentenol 3d.
The reaction of 2b with potassium hexamethyldisilazide (KHMDS) in toluene/ether yielded two cyclopentenol products (entry 12) arising from competing transition states in the intramolecular aldol addition. The structure of the minor isomer 8 was deduced by 2D Η NMR. Attempts at increasing the yield of cyclopentenol 8 by performing the reaction in toluene were unsuccessful as the yield of cyclopentenol decreased in favour of the trans ring- opened product 5b.
General Experimental
Η and 13C NMR was performed using a Varian Gemini-200, Bruker ACP-300 or a Varian Innova-600 spectrometer operating at 200, 300 and 600 MHz respectively for Η and 50, 75 and 150 MHz for 13C in CDC13. 1H NMR were referenced to internal trimethylsilane (δ 0.00). 13C NMR were referenced to CDC13 (δ 77.0). Multiplicities are assigned as s: singlet, d: doublet, t: triplet, q: quartet, p: pentet, and br: broad denotes broadened signals. All coupling constants are reported in Hz.
IR Spectra were recorded using a Perkin Elmer spectrometer BX FT-IR system as either nujol mulls or in the neat form as denoted. Melting points were determined on a Reichert hot stage apparatus and are uncorrected. Mass spectra were acquired using a VG ZAB 2HF spectrometer and HRMS were performed by the Organic Mass Spectrometry Facility, Central Science Laboratory, University of Tasmania. Microanalysis was performed at the University of Otago.
Thin layer chromatography was performed using Merck silica gel 60 F25 aluminium backed silica sheets. Flash chromatography were performed using Merck silica gel 60 (230-400 mesh). Et2O and THF were distilled from sodium/benzophenone ketyl. All cyclopropanes were prepared using the protocol outlined in reference 5. 2-(2-oxo-2-phenylethyl)-3-phenylcyclopropyl cyanide 2f. To a solution of 3,6-diphenyl-3,6- dihydro-l,2-dioxine (100 mg, 0.41 mmol)) in dichloromethane (9 ml) was added LiBr (37 mg, 0.50 mmol), 2-(l,l,l-triphenyl-λ5-phosphanylidene)acetonitrile (152 mg, 0.50 mmol), and Co(II) Salen (5 mg) and the reaction left to stir for 1 week at ambient temperature. The mixture was evaporated and product purified by flash chromatography to give a colourless oil (35 mg, 32%); Rf 0.25 (80 : 20, hexane : ethyl acetate); IR (neat) 3085, 3060, 3029, 1668, 1598, 1450 cm'1; 1H NMR (CDC13, 600 MHz) δ 1.80 (dd, 7= 8.4, 4.8 Hz, IH), 2.10 (ddd, 7 = 6.0, 6.0, 4.8 Hz, IH), 2.35 (dd, 7= 6.0, 4.8 Hz, IH), 3.24 (dd, 7 = 18.6, 6.0 Hz, IH), 3.42 (dd, 7 = 18.6, 6.0 Hz, IH), 7.15-7.25 (m, 5H), 7.40 (m, 2H), 7.52 (m, IH), 7.93 (m, 2H); 13C NMR (CDCI3, 150 MHz) δ 11.7, 21.6, 31.5, 39.4, 119.3, 126.9, 127.5, 128.0, 128.1, 128.6, 128.7, 128.8,129.3, 133.6, 136.2, 137.1, 197.1 (one aromatic signal masked). MS m/z (%) 261 (M+, 20), 120 (21), 105 (100), 77 (62), 51 (21).
(±) l-Adamantyl (lS,2R,5R)-2-hydroxy-2,5-diphenyl-3-cyclopentene-l-carboxylate 3a. To a stirred solution of hexamethyldisilazane (25 mg, 0.16 mmol) in THF (2 ml) was added methyl lithium (0.11 ml, 1.4 M, 0.16 mmol) in Et2O and stirring continued for 10 mins. 1- Adamantyl 2-(2-oxo-2-phenylethyl)-3-phenylcyclopropane-l-carboxylate 2a (42 mg, 0.10 mmol) in THF (2 ml) was added dropwise over 2 mins and the reaction mixture stirred for a further 15 mins. The reaction was quenched with methanol (0.5 ml) then volatiles removed in vacuo. The product was purified by flash chromatography (dichloromethane) then recrystallized from hot hexane to give colourless crystals (35 mg, 83%); mp = 180-182°C (hexane/ethyl acetate); R/ 0.30 (dichloromethane); IR (nujol): 3430, 1696, 1248, 1184 cm"1; 1H NMR (600 MHz) δ 1.61 (m, 6H), 2.06 (m, 6H), 2.11 (br s, 3H), 3.05 (d, 7 = 9 Hz, IH), 3.41 (br s, IH), 4.54 (ddd, 7= 9.0, 2.4, 1.8 Hz, IH), 5.98 (dd, 7= 5.4, 2.4 Hz, IH), 6.15 (dd, 7 = 5.4, 1.8 Hz, IH), 7.22-7.25 (m, 4H), 7.26-7.37 (m, 4H), 7.50-7.52 (m, 2H); 13C NMR (75 MHz) δ 30.7, 36.1, 41.2, 52.5, 65.8, 81.7, 86.6, 125.4, 126.9, 127.0, 127.5, 128.0, 128.6, 136.5, 137.9, 142.8, 145.6, 171.8; MS (El) m/z (%): 414 (10), 396 (20), 352 (40), 135 (100); Anal. Calcd for C26H30O3: C, 81.12; H, 7.29; Found: C, 81.35; H, 7.50. (±) tert-Butyl (lS,2R-5/?)-2-hydroxy-5-methyl-2-phenyl-3-cyclopenteιιe carboxylate 3b.
The reaction of LHMDS (0.5 mmol) in Et20 (2.5 ml) with tert-butyl 2-(2-oxo-2-phenylethyl 3-methylcyclopropane-l -carboxylate 2b (95 mg, 0.34 mmol) as per 3a gave colourless crystals (74 mg, 78%); mp = 85-87°C; Rf 0.25 (dichloromethane); IR (nujol): 3423, 1711,
1184, 1086 cm"1; Η NMR (300 MHz) δ 1.20 (d, 7 = 7.0 Hz, 3H), 2.41 (s, 9H), 2.65 (d, 7 = 7.4 Hz, 3H), 3.32 (dddq, 7 = 7.4, 7.0, 2.5, 1.8 Hz, IH), 3.75 (br s, IH), 5.76 (dd, 7 = 5.6, 2.5 Hz, IH), 5.98 (dd, 7= 5.6, 1.9 Hz, IH), 7.25-7.27 (m, IH), 7.32-7.37 (m, 2H), 7.43-7.46 (m, 2H); 13C NMR (75 MHz) δ 19.4, 28.0, 42.1, 64.0, 81.4, 86.5, 125.2, 126.8, 127.9, 134.2, 139.9, 146.1, 172.3; MS (El) m/z (%): 273 (M+, 3), 257 (100), 201 (50); Anal. Calcd for CπH22O3: C, 74.42; H, 8.08; Found: C, 74.53; H, 8.12
(±) tørt-Butyl (lS,2R,5R)-2-hydroxy-2,5-diphenyl-3-cyclopentene-l-carboxylate 3c. The reaction of LHMDS (2.67 mmol) in THF (10 ml) with tert-butyl 2-(2-oxo-2-phenylethyl)-3- phenylcyclopropane-1 -carboxylate 2c (600 mg, 1.78 mmol) in THF (10 ml) as per 3a gave colourless crystals (481 mg, 80%); mp = 127-128°C (hexane); R 0.26 (dichloromethane); IR (nujol): 3450, 1707, 1251, 1160 cm"1; Η NMR (300 MHz) δ 1.35 (s, 9H), 3.06 (d, 7 = 7.7, IH), 3.37 (br s, IH), 4.56 (ddd, 7 = 7.7, 2.5, 1.9 Hz, IH), 5.99 (dd, 7= 5.8, 2.5 Hz, IH), 6.17 (dd, 7 = 5.8, 1.9 Hz, IH), 7.21-7.39 (m, 8H), 7.50-7.53 (m, 2H); 13C NMR (75 MHz) δ 28.0, 52.4, 65.9, 81.5, 86.7, 125.3, 126.8, 127.0, 127.3, 128.0, 128.6, 136.5, 137.9, 142.7, 145.5, 171.3; MS (El) m/z (%): 336 (M+, trace), 318 (12), 280 (30), 218 (100); Anal. Calcd for C22H24O3: C, 78.54; H, 7.19; Found: C, 78.58; H, 7.15.
(±) l-Adamantyl (lS,2R)-2-hydroxy-2-phenyl-3-cyclopentene carboxylate 3d. The reaction of LHMDS (0.22 mmol) in Et2O (2 ml) and l-Adamantyl 2-(2-oxo-2- phenylethyl)cyclopropane-l -carboxylate 2d (50mg, 0.15 mmol) in Et2O (2 ml) as per 3a gave colourless rods (43 mg, 85%); mp = 142-143°C (hexane); Rf 0.28 (dichloromethane); IR (nujol): 3423, 1711, 1184, 1086 cm"1; H NMR (600 MHz) δ 1.64 (br s, 6H), 2.08-2.14 (m, 6H), 2.14 (br s, 3H), 2.67 (dddd, 7 = 17.0, 8.6, 2.4, 1.8 Hz, IH), 2.92 (dddd, 7= 17.0, 7.0, 2.4, 2.2 Hz, IH), 3.17 (dd, 7 = 8.6, 7.0 Hz, IH) 3.47 (br s, IH), 5.80 (ddd, 7= 5.8, 2.4, 1.8 Hz, IH), 6.12 (ddd, 7 = 5.8, 2.4, 2.2 Hz, IH), 6.91-7.31 (m, IH), 7.33-7.43 (m, 2H), 7.43-7.47 (m, 2H); 13C NMR (75 MHz) δ 30.7, 34.7, 36.1, 41.3, 55.6, 81.4, 86.2, 125.2, 126.8, 127.9, 133.6, 136.0, 146.0, 172.2; MS (El) m/z (%): 338 (M+, 20), 320 (10), 135 (100); Anal. Calcd for C22H2603: C, 78.07; H, 7.74; Found: C, 78.13; H, 7.58.
(±) tert-Butyl (lS,2R,5R)-2-hydroxy-2,5-dipropyl-3-cyclopentene carboxylate 3e. The reaction of LHMDS (0.35 mmol) in Et2O (2 ml) and tert-butyl 2-(2-oxopentyl)-3-propyl-l- cyclopropanecarboxylate 2e (50 mg, 0.19 mmol) in Et2O (2 ml) as per 3a gave a colourless oil (42 mg, 84%); R/0.40 (dichloromethane); IR (neat): 3483, 2959, 1717, 1458, 1368 cm"1; 1H NMR (300 MHz) δ 0.91 (t, 7 = 7.2 Hz, 3H), 0.94 (t, 7 = 7.4 Hz, 3H), 1.20-1.50 (m, 6H), 1.44 (s, 9H), 2.47 (d, 7 = 8.8, IH), 2.54 (br s, IH), 3.17 (m, IH), 5.61 (dd, 7= 5.6, 2.5 Hz, IH), 5.79 (dd, 7 = 5.6, 2.5 Hz, IH); 13C NMR (75 MHz) δ 14.1, 14.5, 17.8, 20.8, 28.1, 37.2, 43.0, 47.4, 58.2, 80.9, 86.1, 134.2, 137.0, 172.8; MS (El) m/z (%): 251 (M+-OH, 10), 195 (20), 169 (50), 151 (70); Anal. Calcd for C16H28O3: C, 71.6; H, 10.51; Found: C, 71.55; H, 10.25.
(±) (lR,2R,5R)-2-Hydroxy-2,5-diphenyl-3-cyclopentene-l-carbonitrile 3f. The reaction of LHMDS (.12 mmol) in THF (1 ml) and 2-(2-oxo-2-phenylethyl)-3-phenylcyclopropyl cyanide 2f (22 mg, .08 mmol) in THF (1 ml) as per 3a gave colourless plates (10 mg, 45%); mp = 145- 146°C (hexane/dichloromethane); R/0.40 (dichloromethane); IR (nujol) 3429, 2924, 2251, 1124, 1052 cm"1; Η NMR (300 MHz) δ 2.47 (s, IH), 3.65 (d, 7 = 8.7 Hz, IH), 4.32 (d, 7 = 8.7 Hz, IH), 6.22-6.27 (m, 2H), 7.31-7.54 (m, 10H); 13C NMR (75 MHz) δ 50.1, 52.5, 85.8, 116.8, 124.7, 128.1, 128.3, 128.5, 128.8, 128.8 135.9, 136.0, 138.2, 143.3; MS (El) m/z (%): 261 (M+) (20), 233 (10), 43 (100); Anal. Calcd for C18Hι5ON: C, 82.73; H, 5.78; N, 5.35; Found: C, 82.70; H, 6.05; N, 5.43. (±) (E) tert-Butyl 3-methyl-6-phenyl-6-oxo-4-hexenoate 5b. Colourless oil; R 0.27 (dichloromethane); IR (neat): 2976, 1727, 1671, 1621, 1367, 1156 cm"1; !H NMR (300 MHz) δ 1.17 (d, 7 = 6.9 Hz, 3H), 1.43 (s, 9H), 2.32 (dd, 7 = 14.8, 7.0 Hz,lH), 2.40 (dd, 7 = 15.3, 7.0 Hz, IH), 2.93 (dddq, 7 = 7.0, 7.0, 6.9, 6.9 Hz, IH), 6.90 (d, 7 = 15.6 Hz, IH) 6.98 (dd, 7 = 15.6, 6.9 Hz, IH), 7.42-7.61 (m, 3H), 7.90-7.96 (m, 2H); 13C NMR (75 MHz) δ 19.2, 28.0, 33.8, 41.8, 80.7, 124.5, 128.5, 128.5, 132.6, 137.8, 152.5, 171.1, 190.9; MS (LSI) m/z (%): 275 (M+H, 15), 219 (100), 201(40); HRMS of 5b (+H) CI7H23O3: calcd, 275.1647; found 275.1650.
(±) (E) tert-Butyl 3-propyl-6-oxo-4-nonenoate 5c. Colourless oil; R/ 0.45 (dichloromethane); IR (neat): 2961, 1729, 1673, 1457, 1153 cm"1; 1H NMR (600 MHz) δ 0.89 (t, 7= 7.2 Hz, 3H), 0.93 (t, 7 = 7.2 Hz, 3H), 1.20-1.50 (m, 6H), 1.42 (s, 9H), 1.63 (tq, 7= 7.2, 7.2 Hz, 2H), 2.24 (dd, 7 = 15, 8.4 Hz, IH) 2.35 (d, 7= 15, 6.0 Hz, IH), 2.63-2.67 (m, IH), 6.09 (dd, 7= 16, 0.8 Hz, IH), 6.64 (dd, 7 = 16, 9.0 Hz, IH); 13C NMR (75 MHz) δ 13.7, 13.8, 17.6, 20.0, 28.0, 36.1, 38.9, 40.4, 42.1, 80.5, 130.1, 148.8, 171.0, 200.4; MS (LSI) m/z (%): 269 (M+H+, 5), 213 (100); HRMS of 5c Cι6H29O3 : calcd, 269.2116; found 269.2103.
(E) l-Adamantyl 3,6-diphenyl-6-oxo-3-hexenoate 6. Colourless oil; R 0.45 (dichloromethane); IR (neat): 3054, 2912, 1722, 1690, 1596, 1445, 1253, 1056 cm"1; 1H NMR (300 MHz) δ 1.58-1.59 (m, 6H), 2.00 (br s, 6H), 2.10 (br s, 3H), 3.48 (s, 2H), 3.98 (d, 7 = 6.6 Hz, 2H), 6.30 (d, 7= 6.6 Hz, IH) 7.24-7.58 (m, 8H), 8.00-8.03 (m, 2H); 13C NMR (75 MHz) δ 30.7, 36.1, 38.4, 38.8, 41.6, 81.1, 123.4, 126.2, 127.1, 128.2, 128.3, 128.6, 133.1, 136.1, 136.7, 142.0, 169.8, 197.3; MS (El) m/z (%): 414 (M+, 30), 413 (100); HRMS of 6 C28H30O3: calcd, 414.2194; found, 414.2181.
(.±) tørt-Butyl (lS,2S,5R)-2-hydroxy-5-methyl-2-phenyI-3-cyclopentene carboxylate 8. To a stirred solution of KHMDS (0.5 mmol) in Et2O (3 ml) and toluene (0.7 ml) was added tert- butyl 2-(2-oxo-2-phenylethyl)-3-methylcyclopropane-l -carboxylate 2b (95 mg, 0.34 mmol) in Et20 (1 ml). Purification by successive flash chromatography (dichloromethane) then recrystallization from hexane gave 3b (38 mg, 76%) and 8 as colourless crystals (4 mg, 8%); mp = 114-116°C; Rf 0.25 (dichloromethane); IR (nujol): 3472, 1686, 1162 cm"1; 'H NMR (600 MHz) δ 1.05 (s, 9H), 1.23 (d, 7= 6.9 Hz, 3H), 2.66 (br s, IH), 2.90 (d, 7 = 7.2 Hz, 3H), 3.32 (dddq, 7 = 7.2, 6.9, 2.3, 1.9 Hz, IH), 5.66 (dd, 7 = 5.5, 2.3 Hz, IH), 5.88 (dd, 7 = 5.5, 1.9 Hz, IH), 7.19-7.43 (m, 5H); 13C NMR (75 MHz) δ 20.3, 27.5, 41.7, 52.6, 67.9, 80.6, 88.9, 125.2, 127.2, 128.0, 135.4, 137.1, 141.6, 142.9, 170.3 ; MS (El) m/z (%): 274 (M+, 3), 256 (3), 218 (100), 200 (25); HRMS of 8 C17H22O3: calcd, 274.1568; found, 274.1564.
(+/-) tert-Butyl 4-methyl-6-phenyl-6-oxo-2-hexenoate 11. White solid, mp = 35-38°C; Rf 0.53 (80 / 20 hexane / ethyl acetate); IR (nujol): cm"1; 1H NMR (600 MHz) δ 1.14 (d, 7 = 6.6 Hz, 3H), 1.47 (s, 9H), 2.94-3.12 (m, 4H), 5.78 (dd, 7= 15.6, 1.5 Hz, IH), 6.87 (dd, 7= 15.6, 6.6 Hz, IH), 7.44-7.57 (m, 3H), 7.93-7.96 (m, 2H); 13C NMR (75 MHz) δ 19.1, 28.1, 31.7, 44.2, 80.2, 121.7, 128.1, 128.6, 133.1, 137.0, 151.4, 166.1, 198.1; MS (El) m/z (%): 274 (M+, 20), 218 (50), 200 (80), 157 (50), 104, (100); Anal. Calcd for C17H22O3: C, 74.40; H, 8.08; Found: C, 74.18, 7.89.
Crystallography for 3a
Intensity data for a colourless block (0.08 x 0.24 x 0.29 mm) were collected at 173 K on a Rigaku AFC7R diffractometer employing Mo-Kα radiation (λ 0.7107 A) and the ω:2θ scan
technique such that θmax as 27.5°. Corrections were made for Lorentz and polarization
effects (teXsan, Single Crystal Structure Analysis Software, Version 1.04 (1997), Molecular Structure Corporation, The Woodlands, TX, USA.( but not for absorption. Of the 4260 reflections measured, 3811 were unique (Rint = 0.051) and of these, 2372 satisfied the I >
2.0σ(I) criterion. Crystal data: C28H30O3, M = 414.5, monoclinic, P2 ln, a = 12.757(4), b = 9.738(3), c =
17.633(5) A, β = 98.51(2)°, V= 2166(1) A3, Z = 4, Dx = 1.271 g cm"3, μ(Mo-Kα) = 0.81 cm-1,
(000) = 888, 281 refined parameters, pmax = 0.20 e A-3.
The structure was solved by direct-methods (A. Altomare, M.C. Burla, M. Camalli, G.L. Cascarano, C. Giacovazzo, A. Guagliardi, A.G.G. Moliterni, G. Polidori and R. Spagna,
S1R97, J. Appl. Crystallogr. 32 (1999) 115) and refined by a full-matrix least-squares procedure based on F2 using all reflections (G.M. Sheldrick, SHELXL-97. Program for crystal structure refinement. University of Gδttingen, Germany, 1997). The non-hydrogen atoms were refined with anisotropic displacement parameters and H atoms were included in the model at their calculated positions. A weighting scheme of the form w = l/[σ2( ) + 0.0709 2 + 0.365 ], where P = (F0 2 +2 c 2)/3, was employed and at convergence, final R = 0.096 and wR = 0.135 (all data); final R = 0.046 and wR = 0.114 (observed data). 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

Claims:
1. A process for the production of cyclopentenols (2) from cyclopropanes characterized by the steps of reacting a cyclopropane of the type (1) together with a base in the presence of tetrahydrofuran, according to Scheme 1, wherein R\, R2 and R3 may be the same or different and are each a hydrogen atom, an alkyl radical, an alkenyl radical, an allynyl radical, a cycloalkyl radical, an aralkyl radical, an aryl radical, an alkoxy radical, alkenyloxy radical, an alkoxy carbonyl radical, alkenyloxycarbonyl radical, alkyl thio radical, or alkenylthio radical.
Figure imgf000014_0001
2
Scheme 1
2. A process according to claim 1, characterized in that the reaction of Scheme 1 may be conducted at ambient temperatures
3. A process according to claim 1, characterized in that the base is selected from the group consisting of alkali metal hydrides and hydroxides and alkali metal alkyl silazanes.
4. A process according to claim 3, characterized in that the base is lithium hexamethyldisilazane.
5. A process according to claim 1, characterized in that the β-ketocyclopropylcarboxylate cyclopropane starting material may be used as a racemic mixture or as an optically pure compound.
6. A process according to claim 1, characterized in that an optically pure β- ketocyclopropylcarboxylate cyclopropane starting material is prepared by the reaction of 1,2-dioxines and stabilized phosphorus ylides as shown in Scheme 2
Figure imgf000015_0001
Scheme 2
7. A process according to claim 6, characterized in that the optically pure β- ketocyclopropylcarboxylate cyclopropane starting material 2 is prepared by the reaction as shown in Scheme 2 , the starting compound 2 being generated by the use of bulky ylides, LiBr and the use of dilute solutions.
Dated 3 December 2002
Adelaide Research and Innovation Pty Ltd
By their Patent Attorneys
Lesicar Perrin
PCT/AU2002/001626 2001-12-03 2002-12-03 Ring expansion of ketocyclopropanes WO2003048089A1 (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100374449C (en) * 2006-06-16 2008-03-12 南京大学 Asymmetric synthesizing process of chiral cyclopropane compound

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
GREATREX B.W. ET AL.: "An anionic C3-C5 ring expansion of -ketocycloprepanes to cyclopentenols", ORGANIC LETTERS, vol. 4, no. 2, 2002, pages 221 - 224 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100374449C (en) * 2006-06-16 2008-03-12 南京大学 Asymmetric synthesizing process of chiral cyclopropane compound

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