Lawrence Berkeley National Laboratory Recent Work Title A NEW AND CONVENIENT SYNTHESIS OF 2-DEOXY-D-RIBOSE FROM 2 ,4-O-ETHYLIDENE-D- ERYTHROSE Permalink https://escholarship.org/uc/item/2sj58133 Author Hauske, J.R. Publication Date 1979 eScholarship.org Powered by the California Digital Library University of California Submitted to Journal of Organic Chemistry LBL-8641 1". / , Prepri nt' " A NEW AND CONVENIENT SYNTHESIS OF 2-DEOXY-D-RIBOSE FROM 2,4-0-ETHYLIDENE-D-ERYTHROSE. James R. Hauske and Henry Rapoport January 1979 Prepared for the U. S. Department of Energy under Contract W-7405-ENG-48 TWO-WEEK LOAN COpy lc",ECEIVED k.AWRENCE BERKSl.~:'{ LABORATORY This is a Library Circulating Copy ;,cr 281979 which may be borr()wed for two weeks. LIBRARY AND For a personal retention copy, call OOCUMENYS se:CYION Tech. Info. Division, Ext. 6782 ,. \ \. -. DISCLAIMER This document was prepared as an account of work sponsored by the United States Government. 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The views and opinions of authors expressed herein do not necessarily state or reflect those of the United States Government or any agency thereof or the Regents of the University of California. 2 A NEW AND CONVENIENT SYNTHESIS OF 2-DEOXY-D-RIBOSE 5 FROM 2,4-0-ETHYLIDENE-D-ERYTHROSE. 6 7 James R. Hauske and Henry Rapoport* e 9 Department of Chemistry and Lawrence Berkeley Laboratory University of California, Berkeley, California 94720 1 0 1 1 1 2 Abstract: A new synthesis is described of 2-deoxy-D-erythro- 1 3 pentose [2-deoxy~D-ribose, 2-deoxy-D-arabinose (!)], starting 1 1+ from D-glucose. ,The synthesis proceeds through directolefination 1 5 of 2,4-Q-ethylidene-D-erythrose (~) by addition of the stabilized 1 6 ylides generated from dimethylphosphorylmethyl phenyl sulfide 1 7 (~) and the corresponding sulfoxide ~. These afford the key 1 e intermediates, thio-enol ether 7' and (l,S-unsaturated sulfoxide ~, 1 9 which when .subjected to mercuric ion-assisted hydrolysis gave 20 high yields of' 2-deoxy-D-ribose 0). This facil-e chain extension 2 1 ,of 2 required its existance as a monomer, and conditions effective 2 i for obtaining the mOnomer have been developed .. Detailed lH_ and 2 3 13 ' C-NMR studies of these compounds are presented. 21+ 25 26 27 2 1 !1lt.~9.<!'*-~t.:h9.11 2 The synthesis of 2-deoxy sugars is an active area of 3 investigation, since these compounds are frequent constituents of q biologically important molecules. Specif~cally, our attention 5 was drawn to the synthesis of 2-deoxy-D-ribose (!), a necessary' 6 intermediate in nucleoside synthesis. Previously reported 7 syntheses of ! appeared unattractive due to relatively poor yields 8 (10-35%) as well as numerous and tedious purifications. The 9 strategies cortunon to essentially all these methods was either a I fn I 10 one-carbon degradation of D-glucose, or deoxygenation of an fn 2 2 1 1 appropriately substituted sugar derivative that.is less accessible 1 2 than glucose. An elegant example of the latter strategy is the 3 fn 3 1.3 ,recent synthesis ,. which proceeds via the deoxygenation of. the 1 q pentose arabinose. It occurred to us that a more convenierit l.5:I?fo~edure might be evolved from a two-carbon degradation of " ,~lucose ':;,16 with. subsequent chain elongation. 1 7 A useful intermediate readily applicable to this approach is fn 4 1 8 2,4-0-ethylidene-D-erythrose (2).4 However, since it has,been . 5 6 fn 5;6 1 9 reported' that 2 exists primarily as a dimer 3, its usefulness for 20 chain elongation was in doubt. Thus, f~r 2 to 'serve as an efficient 2 1 intermediate for the synthesis of 1, two questions had to be answered: (1) is it possible to. prepare monomer 2; (2) would 2 be amenable to 2 2 nucleophilic addition and chain elongation via reaction with an ylide 2 3 2q in view of the free hydroxyl group, or would an attenuating blocking-deblocking routine be necessary? 25 2 6 Although we were unable to find' any reports which unequivocally detail the preparation of monomer 2, a mixture of monomer 2 and 27 - 3 1 dimer 3 has been reported to react with certain nucleophilic reagents 2 under carefully controlled conditions of solvent and temperature. 3 Unfortunately, olefination proceeded in only about 30% yield. The .. limited nucleophilic additions were rationalized by presuming that 5 some concentration of monomer ~ existed, however, no spectroscopic 7 8 fn 7,8 6 evidence for monomer formation was presented.' Despite poor over- 7 all yield of olefin, these results are significant, since they 8 illustrate that 2,4-0-ethylidene-D-erythrose (~) is a potentially 9 suitable substrate for nucleophilic additions. Its potential i 10 rests on the ability to prepare essentially pure monomer and its 11 reaction with an appropriately substituted ylide, which upon 12 hydrolysis would directly afford!.. This report details the 13 successful implementation of this strategy. 1 .. 1 5 Results and Discussion 1 6 Preparation of 2,4-0-Ethylidene-D-erythrose and Its NMR 17 Evaluation. The synthesis of 2,4-0-ethylidene~D-erythrose (3) 18 proceeded via the very efficient periodate degradation of 4,6-0- 19 ethylidene-D-glucose 4.4 Rec~ystallization of the crude residue afforded crystalline material which exhibited the l3 and IH-NMR 2 0 c_ spectra shown in Figures I and 2, respectively. 2 1 No aldehydic , 2 i resonance appears in either Figures 1 or 2, which is consistent with earlier reports of no aldehydic absorption either in its 2 3 , fn 9 l.n. f rare'd' spectrum 9 or l.n. 'ht e 1 H-NMR spectrum ofl.ts. acetates. 7 2 .. This lack of aldehydic resonance as well as the complexity of the 2 5 13 26 C-NMR spectrum, leaves no doubt that the product initially isolated is essentially 3. 2 7 4 Place structures 2, 3, 9 here 2 3 Presumably, there is an equilibrium between dimer ~ and ~ monomer 2,- and one might expect ylide addition. to shift the equili- 5 brium as monomer is consumed. However, addition of the ylides 6 generated from either phosphonium ,salt ~ or phosphonates ~ and 5 7 did not afford olefin, but rather resulted for the most part in the .. 8 recovery of starting material 3. Although the ethylidene erythrose 9 (~/~) has not previously served as a substrate for the synthesis of 5 10 2-deoxy-D-ribose (!), it has been reported ,6 to afford low yields 11 of ole fins upon treatment with certain phosphonate Ylides. In a 12 parallel fashion, we also obtained ole fins 7_ and 8_ in poor yield 13 upon treatment of the ethylidene erythrose with the phosphonate 1~ ylides 4y and 5y. In contrast, treatment of crystalline 3 with ethyl acetate 1 5 containing a catalytic amount of anhydrous afforded, after fn 10 1 6 aci~lO solvent removal, a solid residue which underwent olefin formation 1 7 in. excellent yield. Thus exposure of 3 to catalytic, anhydrous acid 1 8 resulted in transformation to the monomeric ethylidene erythrose, ~. 1 9 Removal of all traces of acid by continuous azeotropic distillation 20 with either benzene or toluene restored the original dimeric ·2 1 structure, 3. When this material was then resubmitted to the ylide 2 i reaction, it was e~sentially inactive. Although ylide would be 2 3 expected to destroy the residual acid and re-establishdimer 3, 2~ dimerization under these conditions is much slower than re~ction of 25 . the ylide with the monomer aldehyde 2 and high yields of olefins 26 result. 27 5 The ,13c_ and lH-NHR'spectra of monomeric 2,4-Q-ethylidene-D- 2 erythrose (~) are shown in Figures 3 and 4. The aldehydic resonance 13 . 3 now is clearly evident in both spectra. The C-Nr-1R spectrum is ~ much simpler and indicates that less than 5% of dimer 3 is 5 present. However, it is complicated by an extra absorption, seven 6 carbon resonances appearing instead of the anticipated six. This 7 cannot be due to any diastereomers since such an explanation would 8 result in nonequivalence for more than one carbon resonance. We 9 attempted, therefore, to resolve this apparent anomaly by first 10 reducing 2 with sodium borohydride to the crystalline diol ~, 4 11 obtained in 96% yield. ,6 13 . 12 The C-NMR spectrum of diol 9 appears in Figure 5. Along with 13 the lack of an aldehydic resonance one sees the appearance of the 1~ newexocyclic hydroxymethyl absorption at 62.4ppm. More significant, 15 however, is the absence of the extra resonance which is present in 16 the spectrum of £ (Fig. 3)'. The six signals corresponding to the 1 7 six carbon nuclei were readily assigned as shown on the basis of 18 . chemical shift correlations as well as off-resonance decoupling 19 experiments.