Carbocycles from carbohydrates via free radical cyclizations new synthetic approaches to glycomimetics Angeles Mart�ýnez-Graua and Jos�e Marco-Contelles*,b a anica Facultad de Qu Departamento de Qu�ýmica Org� �ýmica Ciudad Universitaria s/n 28040-Madrid Spain b anica Juan de la Cierva 3 28006-Madrid Spain Instituto de Qu�ýmica Org� Free radical cyclization of enantiomerically pure acyclic presursors derived from carbohydrates is an excellent method for the synthesis of complex densely functionalized chiral carbohydrate mimics (‘glycomimetics’). The extent of the acyclic diastereoselection can be modulated and is closely associated with the structure rigidity and conformational aspects of the radical precursors. General models for a rationale of the stereochemical outcome of the cyclizations are shown.1 Introduction Carbohydrates are readily available and inexpensive building blocks for the synthesis of natural products.1 In the last decade particular emphasis has been devoted to the preparation of polyfunctionalized carbocycles from sugars.2 Carbocyclization based on free radical chemistry has been recognized as an efficient tool because radical cyclization methods tolerate high levels of substrate functionalization.3 The general process includes monosaccharide protection opening functionalization and finally cyclization to a carbocyclic ring of five or six carbons. These efforts have culminated in the design of some new free radical based methodologies for the synthesis of mimetics of natural sugars (‘glycomimetics’) such as aminocyclopentitols inositols branched chain cyclitols or carbasugars.Glycomimetics play critical roles in biological systems and by Angeles Mart�ýnez-Grau was born in Madrid (Spain) in 1966. She received her BSc degree in chemistry from the Universidad Complutense of Madrid in 1990. She obtained her MSc at Instituto de Qu�ýmica Org�anica of Madrid (CSIC) in 1990 and her PhD in organic chemisry at the Universidad Complutense in 1994. She was a postdoctoral fellow with Professor Dennis P. Curran at the University of Pittsburgh (USA) from 1995 to 1996. Her research has focussed on free radical chemistry and stereoselective synthesis. In 1996 she was awarded a Spanish Royal Society of Chemistry Prize for young scientists.She joined the faculty in the Department of Organic Chemistry at the Universidad Complutense of Madrid in 1996. Angeles Mart�ýnez-Grau • RO RO I a O O c controlling cell–cell interactions or interfering with carbohydrate metabolic processes are potential candidates for new pharmaceutical drugs.4 In the last nine years our group has been actively working in this area. In this review we present the most relevant results for the synthesis of aminocyclopentitols and cyclitols by free radical cyclization of acyclic monosaccharide derivatives. Particular emphasis is placed on the stereochemical aspects of these reactions. Most of the conversions are straightforward examples that illustrate the utility scope and generality of this strategy for the synthesis of enantiomerically pure carbocycles.2 Aminocyclopentitols via cyclization of d-functionalized O-alkyl oxime ethers derived from carbohydrates The aminocyclopentitol nucleus is present in a wide variety of natural products. The synthesis of these polyhydroxylated cyclopentylamines has been an area of growing interest due to the discovery of their potent biological properties. For example allosamidin (1) trehazolin (3) mannostatins (4) and Merrel Dow’s cyclopentylamine (5) have been found to have powerful and specific inhibitory activity against glycosidases. As a consequence they have attracted the interest of organic chemists and many synthetic approaches have been reported.5 Another important group of aminocyclopentitols the 4-amino- 1,2,3-cyclopentanetriols are also versatile and valuable inter- Born in 1956 Jos�e Marco-Contelles received his BSc in chemistry from the Universidad Complutense of Madrid (Spain).He obained his PhD at the Instituto de Qu�ýmica Org�anica of Madrid (CSIC) and did his postdoctoral studies at Gif-sur-Yvette (Institute de Substances Naturelles CNRS France) in H.-P. Husson’s laboratory (1984–1985). In 1986 he was a postdoctoral fellow with Professor W. Oppolzer at Geneva University (Switzerland). From 1988 to 1989 he was an Associate Researcher at Duke University (USA) working with Professor B. Fraser-Reid. In 1985 he was appointed as Associate Researcher at the Instituto de Qu�ýmica Org�anica of Madrid (CSIC) and promoted to Scientific Researcher in 1992.His current research areas include the development of new synthetic methodologies in free radical chemistry carbohydrate chemistry asymmetric synthesis and synthesis of new heterocycles. He is the author of more than 100 papers and reviews. Jos�e Marco-Contelles 155 Chemical Society Reviews 1998 volume 27 mediates for the synthesis of cyclopentane-type glycosidase inhibitors and carbocyclic nucleosides.6 The 5-exo radical cyclization reaction of acyclic carbohydrate derivatives has been applied to the synthesis of a broad range of polyhydroxylated cyclopentanes using different types of radical acceptors olefins and enol ethers,7 unsaturated esters,8 alkynes,9 imines,10 oxime ethers11 and hydrazones.12 In this section we present a range of free radical cyclizations of acyclic d-functionalized O-alkyl oxime ethers derived from carbohydrates to obtain different aminocyclopentitols.OH RO O CH3 N N HO CH3 (–)-Allosamidin (1) OH OH O O HO R = O NHAc ) NHAc OH OH (–)-Allosamizoline (2 R = H) NH2 X HO OH HO Mannostatin A (4a X = SCH3) Mannostatin B [4b X = S(O)CH3] 2.1 Bu3SnH-mediated 5-exo radical cyclizations The ability of O-alkylaldoximes to act as intramolecular radical traps is well known. Bartlett was the first to synthesize aminocyclopentitols by cyclization of 5-oximinoalkyl radicals derived from d-glucose (Scheme 1).11 Four stereoisomers can arise in the cyclization of radical precursor 6; however only carbocycles 7 and 8 were obtained in a 62 38 ratio respectively.The 1,5-cis product is the major one and this result can be explained by assuming that the intermediate radical preferentially adopts a chair-like conformation with the substituents at C2 C3 and C4 in pseudoequatorial positions.13 NOBn S OBn PhO O Bu3SnH AIBN OBn OBn BnO 6 Scheme 1 Following a similar strategy Simpkins designed a short enantiospecific route to allosamizoline (2) the aminocy- Chemical Society Reviews 1998 volume 27 156 OH OH HO OH HO O N OH N O HO H OH Trehazolin (3) OH NHCH HO 3 OH HO Merrel Dow¢s cyclopentylamine (5) NHOBn 1 5 OBn BnO OBn BnO 7 (62:38) + NHOBn 1 5 OBn BnO OBn BnO 8 NOBn S NHCbz Im O OAc OAc AcO 9 2 X R1O NOR O O 12a-f Br O NOBn Ph O OTBS 15 clopentitol aglycon of allosamidin (1) starting from d-glucosamine (Scheme 2).14 The cyclization of radical precursor 9 showed poor diastereoselectivity; three compounds were obtained the minor 10 and the major 11 isolated as a mixture of epimers in C1.In our group we carried out a new synthesis of enantiomerically pure 4-amino-1,2,3-cyclopentanetriols15 via free radical cyclization of a series of oxime ethers 12a–f (Scheme 3) and 15 (Scheme 4); these compounds were easily prepared from d-ribono-g-lactone. All precursors were obtained and used as inseparable mixtures of E and Z oxime isomers (7 3 ratio respectively) and were submitted together to typical conditions for radical cyclization promoted by tributyltin hydride or samarium diiodide.+ NHOBn 1 11 O O O O NHOBn OAc NHCbz OAc AcO 10 OAc NHCbz OAc AcO Scheme 2 4 NHOR R1O Bu3SnH or SmI2 O 13a-f + NHOR R1O O 14a-f Scheme 3 NHOBn Bu3SnH or SmI2 Ph O OTBS 16 + NHOBn Ph O OTBS 17 Scheme 4 From precursors 12a–f (Scheme 3) using tributyltin hydride all the cyclizations showed good yields and high sterethe formation of the exo products 13a–f. When samarium diiodide was used the yields were lower due to several competititve processes epoxide ring formation and/or elimination; however compounds 13a–f were the only diastereomers obtained.15 Table 1 Free radical cyclization of precursors 12 using Bu3SnH Total yield (%) 13/14 R1 12 R X H ButMe2Si 75 53 52 58 71 85 100/0 100/0 100/0 89/11 80/20 100/0 Bn Bn Bn Bn Me Bn Ac Bz Bz H Br Br Br Br Br I a bc def The cyclization of precursor 15 (Scheme 4) using the tin hydride method provided a mixture of 16 and 17 in a 1.8 1.0 ratio and 80% total yield.The samarium diiodide ring closure gave the major product 16 in 40% yield with traces of 17.15 The stereochemical outcome of these free radical cyclizations is consistent with the transition state model proposed by Beckwith,13 in which the radical species is in a chair-like conformation having most of the substituents in the preferred pseudo-equatorial positions.This is in agreement with the results reported by Wilcox for the cylization of analogous a,bunsaturated esters.8 In Scheme 5 hypothetical lowest energy transition states for the intermediate radicals are presented. In conformation B the unfavourable 1,3-diaxial interaction between the substituents at C2 and C4 (radical numbering) destabilizes the transition state leading to the endo product. We have not found a satisfactory explanation for the formation of small amounts of the endo product during the cyclization of precursors 12d–e (Table 1) with a benzoyl group at R1 (compare with the results obtained in the cyclization of precursors 12a–c,f with different protecting groups at this position).The higher diastereoselectivity observed in samarium-mediated carbocyclization compared with tributyltin hydride cyclization is difficult to rationalize at this moment. We can hypothesize that a chelated samarium–ligand transition state12 should impose some limits to the conformational freedom in the reactive species leading to higher stereochemical control. OR 2 N • • R1O 4 O N OR OR1 O O O B A 1 4 NHOR R1O NHOR R1O 3 2 O O O O 14a-f 13a-f Scheme 5 In summary the free radical cyclization of d-functionalized O-alkyl oxime ethers derived from d-ribose is a good method for the synthesis of (1R,2R,3S,4R)-4-amino-1,2,3-cyclopentanetriol derivatives in terms of chemical yield and acyclic diastereoselection.Major trans (C1–C4 and C3–C4) isomers are formed (Scheme 5). Comparing both cyclizations methods the tin-mediated cyclization of 5-oximinoalkyl radicals derived from monosaccharides is clearly superior to the corresponding SmI2-mediated reaction in terms of chemical yield and experimental manipulation. The use of dithioketals as a radical precursor in this type of cyclization has also been studied. Roberts was the first to use as a key step to prepare new mannostatin analogues a free radical carbocyclization of an a-sulfenyl radical on oxime ethers starting from d-allose (Scheme 6).16 The cyclization of radical precursor 18 occurs in high yield (80%) but the stereoselectivity was moderate (3 1) and unfortunately both isomers 19 and 20 were obtained as an inseparable mixture.MeON H OAc SEt Bu3SnH SEt AIBN BnO 18 Scheme 6 In parallel work we reported the synthesis of new mannostatin A analogues by free radical cyclization of precursor 21 prepared from d-ribose via a shorter route (Scheme 7).17 The yield was also high (80%) and although the stereoselectivity was only slightly better (4 1) the major compound 22 was 20 NHOBn BnO Bu3SnH OAc isolated in almost pure form. SEt AIBN BnO NOBn SEt 21 Scheme 7 OBn N BnO The cis stereochemistry at the new stereocenters (C1 and C5) in the major compound can be explained by assuming a chairlike conformation in the transition state of the 5-exo-trig ring closure (Scheme 8) with the oxime ether and most of the substituents in the preferred pseudo-equatorial positions (conformation C) to avoid 1,3-diaxial interactions in other possible conformers.23 NHOBn 1 2 BnO C Scheme 8 OBn SEt • OBn Chemical Society Reviews 1998 volume 27 NHOMe SEt AcO OAc BnO (3:1) 19 + NHOMe SEt AcO OAc BnO SEt BnO OBn BnO (4:1) 22 + NHOBn SEt BnO OBn BnO 5 4 SEt BnO 3 OBn BnO 22 157 R3SnH OR R 1 2 3 4 O O 24 O O R Et3B Scheme 9 R1 H Ph H Bu Ac Ph TBDMS Ph Scheme 10 O Entry D Table 2 Free radical cyclization of precursor 24 BnOHN H BnOHN O 2.2 R3SnH-mediated 5-exo cyclization of d-alkyne tethered O-alkyl oxime ethers The intramolecular coupling of oxime ethers tethered to terminal alkynes to prepare acyclic sugar derivatives has been carried out using a hydrostannylation reaction.18 Derived from d-mannose the radical precursor 24 (Scheme 9) was cyclized using tributyltin or triphenyltin hydride plus Et3B to give the vinyl stannanes 25 as a mixture of the separable Z/E isomers (Table 2).Each geometric isomer was diastereomerically pure at the new stereocenter (C4) with the absolute configuration shown in Scheme 9. The synthesis and cyclization of a similar radical precursor prepared from d-ribose leads to enantiomers of compounds 25Z/E in good yield and complete diastereoselection at the newly formed stereocenter.The diastereoselectivity observed in the cyclization can be explained according to Beckwith’s guidelines,13 assuming that in the early transition state the favoured intermediate vinyl radical is in a chair-like conformation D with most of the substituents in the preferred pseudoequatorial orientation (Scheme 10). As in the cyclization of precursors 12 (Scheme 3) major isomers having a trans relationship between C1/C4 and C3/C4 are obtained. 25E 25Z (%) 25E (%) SnR1 3 1 2 O 25 BnON H 158 SnR3 • N OBn 2.3 SmI2-mediated intramolecular reductive coupling of d-carbonyl tethered O-alkyl oxime ethers In 1989 Enholm was the first to describe the samariummediated intramolecular cyclization of aldehydes tethered to Chemical Society Reviews 1998 volume 27 H SnR1 3 4 OR BnOHN O O 25Z + H OR O O 3 69 78 (4.5 1 ratio) — 14 70 45 OR R1 3Sn 4 3 a,b-unsaturated esters in substrates derived from carbohydrates.19 Our group has recently developed the samarium-mediated intramolecular reductive coupling of carbonyl-tethered O-alkyl oxime ethers to provide a new and synthetically useful method for the construction of aminocyclopentitols.15 This procedure was applied to the synthesis of trehazolamine analogous 26 (Scheme 11) by reductive coupling of d-carbonyl tethered O-alkyl oxime ethers derived from d-glucose. Reaction of precursor 27 using samarium iodide gave only isomer 28 in 80% yield. Simultaneously Naito also analyzed this protocol using Bu3SnH as a reagent for carbocyclization.20 Reaction of 27 (Scheme 11) with tributyltin hydride gave a 1.0 1.4 mixture of 28 and 29 respectively in 68% overall yield.This reaction using samarium diiodide was also carried out with precursors obtained from d-mannose and d-galactose.15 Ketone 30 derived from d-mannose afforded a mixture of three aminocyclopentitols 31–33 (Scheme 11) in a ratio 15 3 1 respectively. The reductive coupling of precursor 34 obtained from d-galactose gave only compound 35. In all cases the cyclization gave major compounds showing a trans relationship between the hydroxy at C1 and the benzyloxyamino group at C5 and between C4 and C5. There is also a trans relationship between the hydroxy at C1 and the benzyloxy group at C2 (except for the cyclization of the d-glucose derivative 27 that led to isomer 28).The stereochemistry obtained was independent of the geometry of the starting oxime ether. Surprisingly no additives such as HMPA were necessary. These results can be rationalized in terms of a ninemembered ring chelate12 as shown in Scheme 12. The anion radical species adopt chair-like conformations in which the O-alkyl oxime ether at C5 (radical numbering) is in the preferred pseudoequatorial position. In order to explore the scope of the method related aldehydes were also studied.15 To this end alcohol 36 prepared from d-arabinose was submitted to a one-pot sequence of Swern oxidation and reductive coupling promoted by SmI2 (Scheme 13).A mixture of 37a and 37b was obtained in a 8 1 ratio respectively. Following the same procedure appropriate and conveniently functionalized alcohols derived from d-ribose and d-xylose were also cyclized in good yield and from excellent to moderate diastereoselectivity.15 In the SmI2-promoted cyclization of d-aldehyde O-alkyl oxime ethers we have observed a trans relationship between C1/C2 and C4/C5 in the major isomers. Collectively the experiments above suggest that the samarium diiodide mediated 5-exo intramolecular cyclization of d-carbonyl tethered O-alkyl oxime ethers derived from sugars is a good method for the synthesis of aminocyclopentitols in enantiomerically pure form. 2- 2.4 SmI2-mediated intramolecular reductive coupling of a,b-unsaturated esters tethered O-alkyl oxime ethers As a complement of the well known SmI2-mediated reductive coupling of sugar-derived a,b-unsaturated esters tethered to carbonyl groups,19 we have also described the first SmI promoted intramolecular cyclization of unsaturated esters to O-alkyl oxime ethers (Scheme 14).15 The cyclization of E-isomers 38 provided compound 39 in 52% yield as a single isomer.3 Cyclitols from sugars via free radical cyclization Cyclitols and aminocyclitols are polyhydroxylated cyclohexanes with important biological activities.4 Different methodologies have been developed for the synthesis of these compounds. 21 Sugars have been commonly used as chiral starting materials. However among the numerous methods reported for the conversion of carbohydrates into cyclitols free radical cyclization is not so frequently used when a cyclohexane is the target ring.OBn N BnO BnO 27 BnO O OBn 30 OBn BnO N BnO O 1 • 5 OBn • BnO 34 BnO BnO BnO 1 • 5 H H SmI2•(HMPA) n OBn N 30 BnO OBn SmI2•(HMPA) n OBn OBn SmI2•(HMPA) n 1 5 O Scheme 12 3.1 Bu3SnH-mediated 6-endo cyclization Hex-5-ynyl radicals cyclize preferentially via the kinetically favoured 5-exo pathway. Nevertheless the regioselectivity can be changed by structural factors.22 This feature has been used in a novel strategy for the synthesis of cyclitols.23 We thought that in the cyclization of 1-iodoalk-5-ynes of type 40 (Scheme 15) the 6-endo-dig ring closure should be preferred because the trans located 1,3-dioxolane moiety prevents the 5-exo-dig pathway leading to thermodynamically disfavoured trans fused cyclopentanes.The cyclohexenes 41 were obtained in good yield; the diastereomeric mixture of 41a was oxidized to cyclohexanone 42 a highly functionalized chiral intermediate for the synthesis of cyclitols.24 O NOR BnO BnO OBn OBn 27 HO OH NH HO 2 OH HO O NOBn BnO OBn OBn O NOBn BnO OBn 26 Trehazolamine SmI2 THF OBn 34 28 31 35 BnO OH 1 SmI2 THF NHOR BnO 2 5 ref. 15 4 OBn BnO BnO OH BnO BnO 29 BnO BnO OH OH X 1 NHOBn BnO 5 2 Y 4 OBn OBn BnO BnO 32 X = H; Y = NHOBn 33 Y = H; X = NHOBn BnO 1 NHOBn BnO 5 2 OBn BnO OH OH 1 5 2 NHOBn a) Swern oxidation O O 4 b) SmI2 ButOH 3 O O OTBS 37a 36 (8:1) + OH NHOBn O O OTBS 37b Scheme 13 CO2Et 2Et NHOBn NOBn SmI2 O O THF/HMPA O Ph O Ph OTBS 39 (52%) 38 Scheme 14 28 NHOR OBn + OH 4 35 NOBn OTBS CO OTBS Chemical Society Reviews 1998 volume 27 31 SmI2 THF Scheme 11 3.2 Bu3SnH-mediated 6-exo cyclization Most of the free radical cyclizations of acyclic carbohydrate derivatives to obtain carbocycles use hex-5-enyl radicals whereas the 6-exo closure to give cyclohexane rings has been used less frequently because the cyclization of hept-6-enyl radicals is about 40 times slower than the cyclization of the hexenyl radical.Therefore reactions competing with the 159 • RO RO RO O b I a O O O O O O 40a R = H b R = Ac 41a R = H 50 % b R = Ac 66% Scheme 15 cyclization (e.g. reduction of the initial radical) become important. Another potential problem of the heptenyl radical is due to a 1,5-hydrogen transfer that leads to allyl radicals. Nevertheless the 6-exo cyclization is a well known procedure in the synthesis of branched chain sugars where the cyclization of hept-6-enyl radicals is accelerated by the introduction of electron-withdrawing groups in the radical acceptor.25 Crich obtained a 1 1 mixture of the cyclohexanones 44 and 45 (Scheme 16) in 90% yield after cyclization of an acyclic acyl radical.26 O SPh O SPh PhSe OTBS TBSO OTBS TBSO 44 43 + (1:1) O SPh OTBS TBSO 45 Scheme 16 Redlich carried out a very interesting study on the cyclization of 7-deoxy-7-iodohept-1-enitols of the allo- manno- galacto- Br R1O Bu3SnH OR N R2O AIBN OR2 R1O Br Bu3SnH OBn AcO N 2 AIBN O Br Bu3SnH OBn AcO N 2 AIBN O 52 46a-e AcO 3 O 49 AcO 3 O Chemical Society Reviews 1998 volume 27 160 O O and gulo-series using tributyltin hydride.27 The cyclization of radical precursors provided carba-6-deoxyhexoses in very good yield.The authors studied the effect of varying the protecting groups adjacent to the reaction centers and the influence of the stereochemistry. They rationalized the observed selectivities in terms of chair- and boat-like transition states depending on the threo or erythro disposition of the substituents contiguous to the reaction centers.42 Of particular interest has been the application of the 6-exo free radical cyclization to the synthesis of aminocyclitols. In our group we carried out the first synthesis of 5-amino-1,2,3,4-cyclohexanetetrols by 6-exo cyclization of 6-bromo-6-deoxyhexose derivatives using oxime ethers as radicals acceptors (Scheme 17).28 All the precursors were obtained as inseparable mixtures of E and Z isomers in a 70 30 ratio. The radical is generated at an appropriate distance from the double bond to give 6-exo ring closure. The precurosrs 46a–e prepared from d-glucose with different protecting groups (Table 3) and the d-manno 49 and d-gulo 52 derivatives were cyclized in moderate yield and good diastereoselectivity.The incorporation of an isopropylidenedioxy at C2 and C3 in radical precursors 49 and 52 dramatically increased the diastereoselection (Scheme 17) giving almost a single isomer at the newly formed stereocenter (C5). Table 3 Free radical cyclization of precursors 46 46 ab cd e The stereochemical outcome of the cyclizations could be justified by assuming that the major products arose via transition states in which the radical species adopts a preferred chair-like conformation with most of the substituents occupying pseudoequatorial positions to minimize unfavourable 1,3-diaxial steric interactions.28 In precursors 46 (Scheme 18) the steric interaction between the substituent at C5 and the oxime R1O NHOR R2O OR2 R1O 5 NHOBn AcO O O 97:3 (50%) 5 NHOBn AcO 47a-e AcO AcO O O 53 (50%) 50 Scheme 17 Yield (%) R2 47/48 R1 R 52 55 50 40 42 83/17 75/25 73/27 80/20 78/22 Bn Bn Me Bn Bn Ac Bz Bz H Ac Ac Bz Bz Bn Bn R1O NHOR R2O + OR2 R1O 48a-e AcO NHOBn AcO + O O 51 ether at C1 (radical numbering) displaces the equilibrium to conformer E leading predominantly to compound 47.Nevertheless this steric repulsion is not critical because the results of substrates 49 and 52 point to the significance of the gauche interaction between the C2 substituent (isopropylidenedioxy group) and the oxime ether at C1.5 • O O N OBn 1 O O H E R1O NHOR R2O R1O OR2 47 Scheme 18 This work has been extended to explore the 6-exo cyclization of several 6-bromo-6-deoxy-d-glucose derivatives by changing the nature of the radical trap.28 As expected the d-gluco derivative 54a with two isopropylidenedioxy groups at C2/C3 and C4/C5 afforded after cyclization only isomer 55a in 82% diastereomeric excess (Scheme 19). The reactions of enol ether 54b and a,b-unsaturated ester 54c with tributyltin hydride gave the major carbocycles 55b–c in high diastereomeric excess (84 and 86% respectively). This improvement in the stereoselectivity compared with that observed for the analogous precursors 46a–e confirms the influence of structural factors on the stereochemical outcome of the reaction.Br O O O X Bu3SnH AlBN O O 54a X = CH NOBn b X = CH CHOMe c X = CH CHCO 55a Y = NHOBn (d.e. 82%; 75%) b Y = CH2OMe (d.e. 84%; 60%) c Y = CH2CO2Me (d.e. 86%; 80%) 2Me Scheme 19 After our initial reports on the synthesis of branched chain cyclitols,28 several groups have successfully applied this strategy to the synthesis of some natural products.29,30 3.3 SmI2-mediated intramolecular reductive coupling of e-carbonyl tethered O-alkyl oxime ethers Continuing our interest in the synthesis of aminocyclitols we tried the intramolecular reductive coupling of a sugar-derived oxime ether e-functionalized with an aldehyde.15 In order to favor the cyclization we selected the conformationally strained d-glucose derivative 56 (Scheme 20).Dess–Martin oxidation gave the intermediate aldehyde that was submitted to reductive coupling promoted by samarium diiodide yielding the isomers 57a–c. Total yield was good but the diastereoselection was very poor. 4 Conclusions In summary we have shown that the 5-exo 6-endo and 6-exo free radical carbocyclization of acyclic conveniently functionalized radical precursors derived from sugars is a suitable method for the synthesis of polyhydroxylated carbocycles in 5 O O H O O 1 N OBn F R1O NHOR R2O OR2 R1O 48 O Y O O O OH O OH NHOBn O O NOBn O O O O 56 57a (22%) + O O OH OH NHOBn O NHOBn O O O O O 57b (24%) + Scheme 20 57c (20%) enantiomerically pure form.The type of radical trap allows us to manipulate the type of carbocycle to be prepared. The appropriate selection of radical precursor and the nature of the functional groups also determines the qualitative and quantitative course of the acyclic diastereoselection in the formation of new stereocenters. 5 References 1 P. Collins and R. R. Ferrier in Monosaccharides Wiley and Sons 2 T. V. RajanBabu in Preparative Carbohydrate Chemistry ed. S. 3 B. Giese in Radicals in Organic Synthesis Formation of Carbon- Chichester 1995. Hanessian Marcel Dekker New York 1997 p. 545. Carbon Bond Pergamon Oxford 1986. 4 A. D. Elbein Ann. Rev.Biochem. 1987 56 497. 5 See for instance B. M. Trost and D. L. V. Vranken J. Am. Chem. Soc. 1993 115 444. 6 A. D. Borthwick and K. Biggadike Tetrahedron 1992 48 571. 7 T. V. RajanBabu Acc. Chem. Res. 1991 24 139. 8 C. S. Wilcox and L. M. Thomasco J. Org. Chem. 1985 17 546. 9 J. C. Malanda and A. Doutheau J. Carbohydr. Chem. 1993 12 999. 10 M. J. Tomaszuvski J. Warkentin and N. H. Werstink Aust. J. Chem. 1995 48 291. 11 P. A. Bartlett K. L. McLaren and P. C. Ting J. Am. Chem. Soc. 1988 110 1633. 12 C. F. Sturino and A. G. Fallis J. Am. Chem. Soc. 1994 116 7447. 13 A. L. J. Beckwith Tetrahedron 1981 37 3073. 14 N. S. Simpkins S. Stokes and A. J. Whittle J. Chem. Soc. Perkin Trans. 1 1992 2471. 15 J. Marco-Contelles P. Gallego M. Rodr�ýguez-Fern�andez N. Khiar C. Destabel M. Bernab�e A. Mart�ýnez-Grau and J. L. Chiara J. Org. Chem. 1997 62 7397. 16 A. H. Ingall P. R. Moore and S. M. Roberts Tetrahedron Asymmetry 1994 5 2155. 17 J. Marco-Contelles C. Destabel and P. Gallego J. Carbohydr. Chem. 1995 14 1343. 18 J. Marco-Contelles C. Destabel P. Gallego J. L. Chiara and M. Bernab�e J. Org. Chem. 1996 61 1354. 19 E. J. Enholm and A. Trivellas J. Am. Chem. Soc. 1989 111 6463. 20 T. Kiguchi K. Tajiri I. Ninomiya T. Naito and H. Hiramatsu 21 P. Vogel D. Fatton F. Gasperini and C. Le Brian Synlett 1990 173 22 U. Albrecht R. Wartchow and H. M. R. Hoffmann Angew. Chem. Int. 23 J. Marco-Contelles M. Bernab�e D. Ayala and B. S�anchez J. Org. 24 X. Deruyttere L. Dumortier J. Van der Eycken and M. Vandewalle 25 J. Marco-Contelles A. Mart�ýnez-Grau M. Mart�ýnez-Ripoll F. H. Cano Tetrahedron Lett. 1995 36 253. and references cited therein. Ed. Engl. 1992 31 910. Chem. 1994 59 1234. Synlett 1992 51. and C. Foces-Foces J. Org. Chem. 1992 57 403. Chemical Society Reviews 1998 volume 27 161 26 D. Batty D. Crich and S. M. Fortt J. Chem. Soc. Chem. Commun. 1989 1366. 27 H. Redlich W. Sudau A. K. Szardenings and R. Vollerthun Carbohydr. Res. 1992 226 57. 28 J. L. Marco-Contelles C. Pozuelo M. L. Jimeno L. Mart�ýnez and A. Mart�ýnez-Grau J. Org. Chem. 1992 57 2625. Chemical Society Reviews 1998 volume 27 162 29 G. E. Keck S. F. McHardy and J. A. Murry J. Am. Chem. Soc. 1995 117 7289. 30 R. Clauss and R. Hunter J. Chem. Soc. Perkin Trans. 1 1997 71. Received 25th July 1997 Acce