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Cyclopropanation of glycals: Application to the synthesis of 2-deoxy-2-vinyl glycosides
Terrahedron
larrers.
Vol. 36, No. 49, pp 8901-8904, 1995 Elsevier Science Ltd Printed in Great Britain 0040-4039/95 $9.50+0.00
0040-4039(95)01926-X
Cyclopropanation
of Glycals:
Application to the Synthesis of 2-Deoxy-ZVinyl Glycosidesl
Kenneth J. Henry Jr.,2 and Bert Fraser-Reid* Paul M. Gross Chemical
Laboratory.
D&t
University.
Durham,
North
Carolina
27708
Appropriatelyprotectedderivatrvesof glucal and galactalhave been found to undergoefticient cyclopropanation withethoxycarbonyl carbenewithexcellentfacialselectivity. whiledi-0-acetyl-L-rhamnal exhibits lnwv facialselectivity.The cyclopropane glycalsderivedfrom glucalandgala& havebeentransformedinto 2deoxy-Zvinyl mannasides andgalactosides. whicharepotentiallyvaluablebranched-chain sugars.
Absfract:
More than two decadesago, contributions from this researchgroup described the cyclopropanation of 2.3~unsaturatedsugars (i.e. pseudo glycals), and rearrangements of the derived products that afforded highly functionalized 2-deoxy-C-branched pyranoses.’ Conversely, there have been few reports in the literature concerning cycloptopanation reactionsof the more readily available parent glycals themselves4 Among these is a recent paper which describes efficient cyclopropanation of appropriately protected glycals with the Simmons-Smith reagent, or with dichlorocarbene; but the resulting 1,2-cyclopropano sugars offer limited opportunity for further elaboration or derivitization. 4c An earlier report in the Russian literature detailed the reaction of tti-0-acetyl-D-glucal (1, R=Ac) with ethoxycarbonyl carbene to give low yields of a cyclopropane whose stereochemistrywas not determined.4b Our interest in this area arose from the possibility that modified sugars such as 2 might react comparably to the above described pseudo glycal analogs,3 leading to 2-deoxy-(X-branched pyranosides which are of current interest in our laboratory.5 We now wish to report that suitably protected glycalscan be efficiently cyclopropanated with ethoxycarbonyl carbene with high stereoselectivity, and that the resulting Scheme 1 EDA, Cue --r-+
R
q--&&-?-CO,,~
(1)
3
1
3
2
1
8902
carboethoxy cyclopropanescan be used in direct synthesesof 2-deoxy-2-vinyl glycosides. In an attempt to improve upon the literature n~port,~~a suspensionof tri-O-acetyl-D-glucal (1, R=Ac) and copper powder in cyclohexane at reflux was treated with ethyl diazoacetate (EDA), but the yield of the cyclopropanated sugar 2 (R=Ac) was low (Scheme 1). Similar treatment of tri-O-rerl-butyldimethylsilyl-Dglucal (1, R=TBS) gave a clean reaction, but very low conversion to the cyclopropano glycal, most of the EDA having been converted into ethyl fumarate and ethyl maleate. This problem was overcome by adding a solution of EDA i.n cyclohexane to the refluxing solution (0.3M glycal in cyclohexane. with 5 equiv of suspendedcopper powder) at a very slow rate (-0.2 equiv/h) for 12h, or until consumption of the glycal was complete. However, under these conditions appreciable amounts of ethyl cyclohexylacetate were formed. This by-product was averted by switching from cyclohexane to methyl rerr-butyl ether as solvent.6 In this way, a 92% yield of 2 (R=TBS) could be realized.‘.* Attempts to use benzyl protecting groups gave unsatisfactory results. For example, the reaction of l(R=Bn) gave only 34% yield of a single major cyclopropanated sugar, along with several more polar by-products (possibly the result of carbenoid insertion into the aromatic rings of the benzyl groups). The procedure was extended to the galactal derivative 3, which afforded a 3.3:1 mixture of the epimeric esters 4 and 5 in 90% yield. This transformation was better accomplished in cyclohexane than in methyl terr-butyl ether.6 Stereochemical assignments for 4 and 5 could not be made on the basis of the coupling between H2 and H3 as had ken done by Nagarajan er al. 4c However, the stereochemistryof 4 was revealed by nOe enhancementsbetween H7 and both H3 and H5, which establishedthe exo nature of the ester moiety as well as the a orientation of the cyclopropane ring. With respect to 5, H7 exhibited no large Scheme 2
(R=TBS)
6
THF, RT X 4 or 5 X-COzEt 9 or 10 X=CH20H
11
8903
nOe enhancements. Furthermore, J1.7was 6.6 Hz (in comparison to 2.5 Hz for J1.7for compound 4), which is consistentwith a cis relationship between Hl and H7.9 These assignments were confirmed by the subsequent transformations
(vi& infra).
In an effort to use these annulated sugars as precursors for modified glycosides, we chose to take advantage of the unusual substitution pattern on the cyclopropane ring to perform a highly selective cyclopmpyicarbinyl-homoallyl rearrangement.IL To this end, the ester functionality in 2 (R = TBS), 4, or 5 was reduced (LiAN-4 in diethyl ether) in high yield to give the corresponding primary alcohol 69, or 10 respectively (Scheme 2). Attempts to open these cyclopropyl carbinols under mildly acidic conditions met with limited success.Furthermore, spontaneousrearrangement of cyclopropylcarbinyl estersobtained from 6, 9, or 10 was not observed for the acetate, benzoate, or even the p-nitrobenzoate derivatives; thesecompounds were even stable on silica gel. However, treatment of 6 (R = TBS) under standard Mitsunobu conditions12 employing benzoic acid as nucleophile gave a 66% yield of a 2.6: 1 anomeric mixture of the benzoyl2-deoxy2-vinyl mannosides 7 (At=Ph), along with a 17% yield of the cyclopropylcarbinyl benzoate 8 (Ar=Ph). Substituting p-nitrobenzoic acid as the nucleophile in this reaction favored the SN~ type reaction product, and the p-nitrobenzoyl2-deoxy-2-vinyl mannosideswere isolated in 93% yield (a 2.7: 1 anomeric mixture), along with a 7% yield of the cyclopropylcarbinyl p-nitrobenzoate. In both cases, only trace amounts of the corresponding 2-vinyl glycal were observed. Both 9 and 10 could be used in a similar fashion to give a mixture of p-nitrobenzoyl-2-deoxy-2-vinyl galactosides lla and llg, (a 1:l mixture) in >90% yield. These experiments substantiate the assignments made in Scheme 1 for 4 and 5, since both must have the same configurations at C2, and therefore at Cl, and must thence differ only at C7. Scheme 3 ,C02Et
,Jjee
EDA, CuowAC%*> 4
AC0
s
12
15exo
A<$ 13
*msMo
T
C02Et 4S:l. 86%
t3) 14
OPNB 0
TBSO
We now extended our studies to commercially available di-0-acetyl-L-rhamnal 12 (Scheme 3). Surprisingly, in light of the result with tri-0-acetyl-D-glucal (vide supru), the diacetate 12 was efficiently cyclopropanated in cyclohexane under conditions similar to those used for 1 (R=TBS), except that a faster rate of addition of EDA (=1 equiv/h for 5 h) had a salutary effect. Slower rates of addition (e.g. 0.2 equiv/h) were found to give diminished yields. to The reaction product obtained in 86% yield, was composed of three isomers in an 8:2:1 ratio (‘H NMR estimate), the two major being assigned as exo on the basis of the J1.7 values 2.1 Hz and 2.0 Hz respectively. The minor product was deduced to be an endo isomer on the basisof the Jt.7 value of 6.5 Hz. For further definitive assignment, the protocol in Scheme 2 was followed. Semi-
8904
preparative HPLC afforded a pure sample of the major isomer 13-exo which, after protecting group manipulation, reduction, and ring opening afforded a 2S:l mixture of anomeric p-nitrobenzoates whose rhamno con&urations followed from the Jt.2 values6.0 and 3.2 Hz respectively. The two major products of the cyclopropanation reaction are therefore 13-exo and 14ex0, and the minor isomer is tentatively assignedas 13-endo. The ease with which these transformations may be carried out make these cyclopropane derivatives valuable tools for the production of C2 branched sugars. Efforts are underway to expand the utility of cyclopropanated glycals for the synthesisof sugarderivatives. References and Notes
1. 2. 3.
4.
5.
We are grateful to the National Institutes of Health (GM 51237) for financial support of this work. Presentaddress,Abbott Laboratories, One Abbott Park Road, Abbott Park, IL 60064-3500. a) Radatus, B.K.; Fraser-Reid, B. Can. J. Chem.. 1969,47, 4095. b) Radatus. B.K.; Fraser-Reid, B. Can. J. Chem.. 1970,48, 2146. c) Fraser-Reid, B.; Carthy, B.J. Can. J. Chem., 1972,50,2928. d) Radatus, B.; Fraser-Reid, B. Can. J. Chem., 1972,50, 2909. e) Fraser-Reid, B.; Radatus, B. Can. J. Chem., 1972,50,2919. a) Brimacombe, J.S.; Evans, M.E.; Forbes, E.J.; Foster, A.B.; Webber, J.M. Carbohydr. Res., 1967.4, 239. b) Baidzhigitova, E.A.; Afanas’ev. V.A.; Dolgii, I.E. fzv. Akud. Nauk Kirg. SSR, 1981, (l), 50, (CA 95:98188b). c) Murali, R.; Ramana. C. V.; Nagarajan, M. J. Chem. Sot., Chem. Common., 1995, 217. d) Hoberg, J. 0.; Bozell, J. J.; Claffey, D. J.; National Organic Symposium, 1995, Abstract #36. a) Wang. G.; Fraser-Reid, B. Can. J. Gem., 1994, 72, 69. Friedrich, K.; Fraser-Reid, B. J. Curb. Gem.,
1994,13,631.
6.
Choice of cyclohexane or methyl rerr-butyl ether as solvent actually has little or no effect on selectivity or yield of the cyclopropanation reactions. At issueis the choice of which carbenoid by-products (ethyl cyclohexyl acetateor the fumarate/maJeateesters)are more easily separatedfrom the desiredproducts. 7. A small amount of another isomer was observed (tH NMR), but could not be separatedor assignedas a result of the extremely nonpolar nature of the compounds. AU new compounds exhibited satisfactory spectraland analytical properties, including proton and carbon 8. NMR, FITS, high resolution mass spectraand /or elemental analyses. 9. Williamson, K.L.; Lanford, C.A.; Nicholson, C.R. J. Am. Chem. Sot., 1964,86,762. 10. The lower yields of cyclopropano glycals under extended reaction times for 3-acetyl glycals is possibly related to the fragmentation shown below (a o-Ferrier rearrangement?), which is describedin reference 4d. Note also that in reference 4b mention is made of unidentified olefinic by-products from the cyclopropanation of tri-O-acctyl glucal.
11. Mehta, G.; Acharyulu, P. V. R. J. Chem. Sot., Chem. Commun., 1994,2759. 12. Mitsunobu, 0. Synthesis, 1981.1.
(Received in USA 28 August 1995; uccepted 29 September 1995)
larrers.
Vol. 36, No. 49, pp 8901-8904, 1995 Elsevier Science Ltd Printed in Great Britain 0040-4039/95 $9.50+0.00
0040-4039(95)01926-X
Cyclopropanation
of Glycals:
Application to the Synthesis of 2-Deoxy-ZVinyl Glycosidesl
Kenneth J. Henry Jr.,2 and Bert Fraser-Reid* Paul M. Gross Chemical
Laboratory.
D&t
University.
Durham,
North
Carolina
27708
Appropriatelyprotectedderivatrvesof glucal and galactalhave been found to undergoefticient cyclopropanation withethoxycarbonyl carbenewithexcellentfacialselectivity. whiledi-0-acetyl-L-rhamnal exhibits lnwv facialselectivity.The cyclopropane glycalsderivedfrom glucalandgala& havebeentransformedinto 2deoxy-Zvinyl mannasides andgalactosides. whicharepotentiallyvaluablebranched-chain sugars.
Absfract:
More than two decadesago, contributions from this researchgroup described the cyclopropanation of 2.3~unsaturatedsugars (i.e. pseudo glycals), and rearrangements of the derived products that afforded highly functionalized 2-deoxy-C-branched pyranoses.’ Conversely, there have been few reports in the literature concerning cycloptopanation reactionsof the more readily available parent glycals themselves4 Among these is a recent paper which describes efficient cyclopropanation of appropriately protected glycals with the Simmons-Smith reagent, or with dichlorocarbene; but the resulting 1,2-cyclopropano sugars offer limited opportunity for further elaboration or derivitization. 4c An earlier report in the Russian literature detailed the reaction of tti-0-acetyl-D-glucal (1, R=Ac) with ethoxycarbonyl carbene to give low yields of a cyclopropane whose stereochemistrywas not determined.4b Our interest in this area arose from the possibility that modified sugars such as 2 might react comparably to the above described pseudo glycal analogs,3 leading to 2-deoxy-(X-branched pyranosides which are of current interest in our laboratory.5 We now wish to report that suitably protected glycalscan be efficiently cyclopropanated with ethoxycarbonyl carbene with high stereoselectivity, and that the resulting Scheme 1 EDA, Cue --r-+
R
q--&&-?-CO,,~
(1)
3
1
3
2
1
8902
carboethoxy cyclopropanescan be used in direct synthesesof 2-deoxy-2-vinyl glycosides. In an attempt to improve upon the literature n~port,~~a suspensionof tri-O-acetyl-D-glucal (1, R=Ac) and copper powder in cyclohexane at reflux was treated with ethyl diazoacetate (EDA), but the yield of the cyclopropanated sugar 2 (R=Ac) was low (Scheme 1). Similar treatment of tri-O-rerl-butyldimethylsilyl-Dglucal (1, R=TBS) gave a clean reaction, but very low conversion to the cyclopropano glycal, most of the EDA having been converted into ethyl fumarate and ethyl maleate. This problem was overcome by adding a solution of EDA i.n cyclohexane to the refluxing solution (0.3M glycal in cyclohexane. with 5 equiv of suspendedcopper powder) at a very slow rate (-0.2 equiv/h) for 12h, or until consumption of the glycal was complete. However, under these conditions appreciable amounts of ethyl cyclohexylacetate were formed. This by-product was averted by switching from cyclohexane to methyl rerr-butyl ether as solvent.6 In this way, a 92% yield of 2 (R=TBS) could be realized.‘.* Attempts to use benzyl protecting groups gave unsatisfactory results. For example, the reaction of l(R=Bn) gave only 34% yield of a single major cyclopropanated sugar, along with several more polar by-products (possibly the result of carbenoid insertion into the aromatic rings of the benzyl groups). The procedure was extended to the galactal derivative 3, which afforded a 3.3:1 mixture of the epimeric esters 4 and 5 in 90% yield. This transformation was better accomplished in cyclohexane than in methyl terr-butyl ether.6 Stereochemical assignments for 4 and 5 could not be made on the basis of the coupling between H2 and H3 as had ken done by Nagarajan er al. 4c However, the stereochemistryof 4 was revealed by nOe enhancementsbetween H7 and both H3 and H5, which establishedthe exo nature of the ester moiety as well as the a orientation of the cyclopropane ring. With respect to 5, H7 exhibited no large Scheme 2
(R=TBS)
6
THF, RT X 4 or 5 X-COzEt 9 or 10 X=CH20H
11
8903
nOe enhancements. Furthermore, J1.7was 6.6 Hz (in comparison to 2.5 Hz for J1.7for compound 4), which is consistentwith a cis relationship between Hl and H7.9 These assignments were confirmed by the subsequent transformations
(vi& infra).
In an effort to use these annulated sugars as precursors for modified glycosides, we chose to take advantage of the unusual substitution pattern on the cyclopropane ring to perform a highly selective cyclopmpyicarbinyl-homoallyl rearrangement.IL To this end, the ester functionality in 2 (R = TBS), 4, or 5 was reduced (LiAN-4 in diethyl ether) in high yield to give the corresponding primary alcohol 69, or 10 respectively (Scheme 2). Attempts to open these cyclopropyl carbinols under mildly acidic conditions met with limited success.Furthermore, spontaneousrearrangement of cyclopropylcarbinyl estersobtained from 6, 9, or 10 was not observed for the acetate, benzoate, or even the p-nitrobenzoate derivatives; thesecompounds were even stable on silica gel. However, treatment of 6 (R = TBS) under standard Mitsunobu conditions12 employing benzoic acid as nucleophile gave a 66% yield of a 2.6: 1 anomeric mixture of the benzoyl2-deoxy2-vinyl mannosides 7 (At=Ph), along with a 17% yield of the cyclopropylcarbinyl benzoate 8 (Ar=Ph). Substituting p-nitrobenzoic acid as the nucleophile in this reaction favored the SN~ type reaction product, and the p-nitrobenzoyl2-deoxy-2-vinyl mannosideswere isolated in 93% yield (a 2.7: 1 anomeric mixture), along with a 7% yield of the cyclopropylcarbinyl p-nitrobenzoate. In both cases, only trace amounts of the corresponding 2-vinyl glycal were observed. Both 9 and 10 could be used in a similar fashion to give a mixture of p-nitrobenzoyl-2-deoxy-2-vinyl galactosides lla and llg, (a 1:l mixture) in >90% yield. These experiments substantiate the assignments made in Scheme 1 for 4 and 5, since both must have the same configurations at C2, and therefore at Cl, and must thence differ only at C7. Scheme 3 ,C02Et
,Jjee
EDA, CuowAC%*> 4
AC0
s
12
15exo
A<$ 13
*msMo
T
C02Et 4S:l. 86%
t3) 14
OPNB 0
TBSO
We now extended our studies to commercially available di-0-acetyl-L-rhamnal 12 (Scheme 3). Surprisingly, in light of the result with tri-0-acetyl-D-glucal (vide supru), the diacetate 12 was efficiently cyclopropanated in cyclohexane under conditions similar to those used for 1 (R=TBS), except that a faster rate of addition of EDA (=1 equiv/h for 5 h) had a salutary effect. Slower rates of addition (e.g. 0.2 equiv/h) were found to give diminished yields. to The reaction product obtained in 86% yield, was composed of three isomers in an 8:2:1 ratio (‘H NMR estimate), the two major being assigned as exo on the basis of the J1.7 values 2.1 Hz and 2.0 Hz respectively. The minor product was deduced to be an endo isomer on the basisof the Jt.7 value of 6.5 Hz. For further definitive assignment, the protocol in Scheme 2 was followed. Semi-
8904
preparative HPLC afforded a pure sample of the major isomer 13-exo which, after protecting group manipulation, reduction, and ring opening afforded a 2S:l mixture of anomeric p-nitrobenzoates whose rhamno con&urations followed from the Jt.2 values6.0 and 3.2 Hz respectively. The two major products of the cyclopropanation reaction are therefore 13-exo and 14ex0, and the minor isomer is tentatively assignedas 13-endo. The ease with which these transformations may be carried out make these cyclopropane derivatives valuable tools for the production of C2 branched sugars. Efforts are underway to expand the utility of cyclopropanated glycals for the synthesisof sugarderivatives. References and Notes
1. 2. 3.
4.
5.
We are grateful to the National Institutes of Health (GM 51237) for financial support of this work. Presentaddress,Abbott Laboratories, One Abbott Park Road, Abbott Park, IL 60064-3500. a) Radatus, B.K.; Fraser-Reid, B. Can. J. Chem.. 1969,47, 4095. b) Radatus. B.K.; Fraser-Reid, B. Can. J. Chem.. 1970,48, 2146. c) Fraser-Reid, B.; Carthy, B.J. Can. J. Chem., 1972,50,2928. d) Radatus, B.; Fraser-Reid, B. Can. J. Chem., 1972,50, 2909. e) Fraser-Reid, B.; Radatus, B. Can. J. Chem., 1972,50,2919. a) Brimacombe, J.S.; Evans, M.E.; Forbes, E.J.; Foster, A.B.; Webber, J.M. Carbohydr. Res., 1967.4, 239. b) Baidzhigitova, E.A.; Afanas’ev. V.A.; Dolgii, I.E. fzv. Akud. Nauk Kirg. SSR, 1981, (l), 50, (CA 95:98188b). c) Murali, R.; Ramana. C. V.; Nagarajan, M. J. Chem. Sot., Chem. Common., 1995, 217. d) Hoberg, J. 0.; Bozell, J. J.; Claffey, D. J.; National Organic Symposium, 1995, Abstract #36. a) Wang. G.; Fraser-Reid, B. Can. J. Gem., 1994, 72, 69. Friedrich, K.; Fraser-Reid, B. J. Curb. Gem.,
1994,13,631.
6.
Choice of cyclohexane or methyl rerr-butyl ether as solvent actually has little or no effect on selectivity or yield of the cyclopropanation reactions. At issueis the choice of which carbenoid by-products (ethyl cyclohexyl acetateor the fumarate/maJeateesters)are more easily separatedfrom the desiredproducts. 7. A small amount of another isomer was observed (tH NMR), but could not be separatedor assignedas a result of the extremely nonpolar nature of the compounds. AU new compounds exhibited satisfactory spectraland analytical properties, including proton and carbon 8. NMR, FITS, high resolution mass spectraand /or elemental analyses. 9. Williamson, K.L.; Lanford, C.A.; Nicholson, C.R. J. Am. Chem. Sot., 1964,86,762. 10. The lower yields of cyclopropano glycals under extended reaction times for 3-acetyl glycals is possibly related to the fragmentation shown below (a o-Ferrier rearrangement?), which is describedin reference 4d. Note also that in reference 4b mention is made of unidentified olefinic by-products from the cyclopropanation of tri-O-acctyl glucal.
11. Mehta, G.; Acharyulu, P. V. R. J. Chem. Sot., Chem. Commun., 1994,2759. 12. Mitsunobu, 0. Synthesis, 1981.1.
(Received in USA 28 August 1995; uccepted 29 September 1995)