Recent progress in the synthesis of six-membered aminocyclitols (2008-2017)

Aminocyclitols are of interest as glucosidase inhibitors, as probes for the study of pseudoglycosyltransferases, and as potential therapeutics for the treatment of Gaucher’s disease. The synthesis of these targets was reviewed in early 2008


Introduction
As defined by Delgado, 1 aminocyclitols are "cycloalkanes containing at least one free or one substituted amino group and three additional hydroxyl groups on ring atoms".Examples of naturally occurring C7N aminocyclitols include validamine, valienamine, and valiolamine (1, 2, and 3 respectively, Fig. 1) which exhibit -glucosidase inhibitory activity.Validamine and valienamine both appear as subunits within the anti-fungal antibiotic N-linked pseudo saccharide validamycin A (5).Likewise, aminocyclitols lacking the hydroxymethylene sidechain, such as 2-deoxy-scyllo-inosamine (DOIA, 6), are known biosynthetic intermediates in the production of 2-deoxystreptamine (2-DOS, 7), a subunit of streptamine antibiotics such as kanamycin A (8). New aminocyclitols continue to be isolated, including kirkamide (9), 2 a positional isomer of valienamine, and nabscessins A and B (10 and 11). 3 There are several excellent reviews 1,[4][5][6][7] concerning aminocyclitols covering the literature through 2007 and a recent review reports on polyhydroxylated medium-ring carbocycles including larger ring aminocyclitols; 8,9 the reader is directed to these for literature prior to 2008.The present review will cover synthetic efforts toward six-membered aminocyclitols, excluding dihydroconduramines (4-amino-1,2,3-cyclohexanetriols), from 2008 to present.While not a focus of this review, biological evaluation of compounds will be presented where it is recorded in the literature.

Preparation from 6-Membered Carbocycles 2.1 Degradation/semi-synthesis
As part of studies on validamycin A biosynthesis, Mahmud's group required validamine 7-phosphate (12, Scheme 1) as a substrate for pseudoglycosyltransferases. 10 To this end, they utilized the Ogawa NBS oxidative cleavage reaction 11 on perbenzylated validoxylamine A (13) to afford a mixture of ketones 14/15 and amines 16/17, where the mixture of amines was separable from the ketones.Generation of the benzyloxycarbonyl protected amines allowed for their chromatographic separation.The minor product (19) could be further elaborated to (+)-1 or to the desired 7-phosphonate (+)-12.Chen and co-workers reported a semi-synthesis of valiolamine from more abundant valienamine (Scheme 2). 12Epoxidation of the tetraacetate amide (+)-20 with mCPBA gave (-)-21.The yield of this reaction was nearly doubled with 2% of radical inhibitor [4,4'-thiobis(6-t-butyl-m-cresol)].The authors propose that the stereoselectivity for this epoxidation is directed by hydrogen bonding between the acetamido substituent and mCPBA.While attempted reduction of the epoxide was not productive, ring opening with potassium halides proceeded regioselectively to give the chloride, bromide or iodide 22a, b, or c respectively.Reductive dehalogenation afforded protected valiolamine, which upon hydrolysis with Ba(OH) 2 afforded (+)-3 (5 steps, 80.6% overall yield).

Chiral pool precursors
(+)-proto-Quercitol (23, Scheme 3) is a cyclohexanepentaol isolated from the stems of Arfeuillea arborescens (ca.0.6 weight %).A racemic synthesis of (±)-23 from the simple hydrocarbon 1,4-cyclohexadiene was reported in 1997. 13Phuwapraisirisan and co-workers accomplished the synthesis of aminocyclitols from naturally occurring material (+)-23. 14Selective bis-ketalization of 23 gave 24, which also allowed for determination of its absolute configuration by NMR analysis of the R-and S-Mosher's esters.Generation of 28a relies on S N 2 displacement of mesylate 25 by azide, followed by reduction and hydrolysis.Oxidation of 24 followed by stereocontrolled reduction gave the diastereomeric alcohol 30, which was transformed into the diastereomeric aminocyclitol 34a by a similar sequence of reactions.This group also prepared 2 o and 3 o amine derivatives 28b/c and 34b/c from the stereoisomeric protected aminocyclitols 27 and 33, using standard reductive amination methodology. 15The aminocyclitols 28a and 34a exhibit dramatically different inhibitory activity against -glucosidase from Baker's yeast (28a, IC 50 = 2890 M; 34a, IC 50 = 12.5 M), suggesting that the orientation of the amino functionality was essential for mimicking the oxocarbenium ion intermediate involved in the enzyme active site.The most potent 2 o and 3 o amines are 34b, R = n-pentyl (IC 50 = 0.24 M) and 34c, R = methyl (IC 50 = 5.0 M) and these were identified as competitive inhibitors.Scheme 3. Phuwapraisirisan synthesis of aminocyclitols.
ARKAT USA, Inc Kuno, et al., also utilized the bis-acetonide ketone 29, derived from proto-quercitol, for the preparation of an N-octyl valienamine stereoisomer (35, Scheme 4). 16,17Partial deprotection of the trans-acetonide, followed by treatment with benzyl chloride gave the enol benzoate (-)-36.Treatment of 36 with excess methylene ylide afforded the exocyclic diene (+)-37.The authors propose 17 that this proceeds via addition-elimination at the enol benzoate carbonyl to generate the enolate anion 38 (see insert), which undergoes -elimination to generate the enone 39. 1,4-Addition of bromine to 37, followed by displacement of the 1 o bromide gave a separable mixture of allyl bromide epimers -40 and -40; each epimer was separately transformed into the -N-octylamine (+)-35 by varying the equivalents of sodium methoxide.A similar strategy was used for the synthesis of N-octyl--valienamine (42) from (-)-vibo-quercitol (41) (Scheme 5). 16Biooxidation of 41 with Glactonobacter sp.AB10277 was previously reported by Ogawa's group to afford (-)-43. 18Acetylation of 43 proceeded with -elimination to give the cyclohexenone 44.While reaction of 44 with Wittig ylide lead to further elimination, reaction with the Nysted reagent gave the exocyclic diene 45, albeit in attenuated yield.Transformation of 45 into 42 followed in a fashion similar to the preparation of 35-HCl from 37. The hydrochloride salt (+)-35-HCl exhibited inhibitory activity against bovine liver -galactosidase, green coffee bean -galactosidase, and almond -glucosidase (IC 50 = 4.5 M, 4.5 M and 8.1 M respectively) but was relatively inactive toward -and -mannosidase and -fucosidase (IC 50 > 1 mM).In comparison, (+)-42 was a more potent inhibitor of -galactosidase (IC 50 = 2.9 M) than for -glucosidase (IC 50 = 47 M).Shikimic acid (46), isolated from Illicium verum (Chinese star anise, 3-7%) or Liquidambar styraciflua (sweetgum fruit, 1.5%), has been used as a chiral pool precursor for the synthesis of a variety of targets, most notably the antiviral agent oseltamivir (tamiflu).Xiao-Xin Shi and co-workers utilized 46 for the synthesis of (+)-valiolamine (3, Scheme 6). 19This sequence requires two inversions, at the C3 and C5 hydroxyl groups.The first inversion is achieved by hydrolysis of the epoxide 47 under acidic conditions to generate 48.Regioselective nucleophilic attack of water occurs at the C3 position of the protonated epoxide due to allylic stabilization of the partial positive charge.The second inversion proceeds via S N 2 displacement by azide ion of the C5 mesylate present in 48.After reduction of the ethyl ester and hydroxyl group protection, the C1 and C2 hydroxyl groups were introduced by Ru catalyzed oxidation.This occurred stereoselectively on the olefin face opposite to the sterically bulky TBDPS ether group.Further functional group manipulation and deprotection afforded (+)-3.Shi's group also utilized shikimic acid as a precursor for the preparation of (+)-valienamine (Scheme 7). 20n a fashion similar to their synthesis of valiolamine, hydrolysis of the epoxide 47 and S N 2 displacement by azide generate the required C3 and C1 stereocenters respectively (valienamine numbering).Furthermore, asymmetric Ru-catalyzed dihydroxylation establishes the C-4 alcohol functionality.Finally, dehydration of the tertiary alcohol of 52 was achieved using thionyl chloride to give 53.

Achiral/meso precursors
The van Delft group reported the synthesis of an optically active, orthogonally protected 2-deoxystreptamine synthon which utilized an enzymic desymmetrization (Scheme 8). 21The meso diacetate 55 was obtained by degradation of kanamycin A (8).This involved diazotransfer using triflyl azide, exhaustive allylation of the free hydroxyl groups, and acidic methanolysis of the glucoside linkages.Chromatographic separation of the desired 1,3-diazido-1,3-dideamino-5-O-allyl-2-deoxyptreptamine (54) and the resultant methyl glucosides was challenging.However reaction with TMS and HMDS afforded the bis-TMS derivative of 54, the chromatographic separation of which from the methyl glucosides was considerably easier.Acidic hydrolysis of the bis-TMS derivative regenerated pure 54 in 36% overall yield from kanamycin A. Desymmetrization of the meso diacetate (55) proved elusive using commercially available esterases, however use of Verenium esterase 5 (Venerium Corporation), an esterase specifically engineered for sterically hindered substrates, in acetonitrile and pH 7.5 phosphate buffer, gave the mono acetate 56 in high yield and with excellent enantioselectivity.Staudinger mono-reduction and Boc protection gave 57.More recently, Trost and Molhotra reported a synthesis of the optically active mono-protected 2-DOS derivative 58 (Scheme 9). 22Their route relied on a desymmetrization of meso-dibenzoate 59 with 1.2 equivalents of trimethylsilyl azide, using Pd-catalysis with the chiral bis-phosphine ligand S,S-60.Staudinger reduction of the resultant allylic azide, followed by Boc protection gave 61 with excellent enantioselectivity.Methanolysis of the optically active benzoate, followed by hydroxyl directed stereoselective epoxidation, and Ley oxidation gave the epoxyketone 62. Generation of the enolate from 62 and reaction with iso-amyl nitrite gave the oxime 63, which was stereoselectively reduced and benzoylated at both the 2 o alcohol and the oxime.Nickel-boride reduction of the benzoyl oxime was followed by migration of the O-benzoyl group to nitrogen to afford 64.Acidic hydrolysis of the epoxide was accompanied by cleavage of the Boc carbamate to afford the optically active benzoylated 2-DOS derivative 58.Scheme 9. Pd-catalyzed desymmetrization of meso dibenzoate 59.
Shashidhar's group reported a formal synthesis of racemic valiolamine from relatively abundant myoinositol 65 (Scheme 10). 22Several steps transform the precursor into axial tosylate 66. Reduction of meso 66 with lithium triethylborohydride gave diol (±)-67.The authors propose a hydride migration from the bis-boryl ether 68 which displaces the axial tosylate group (see insert, Scheme 10).The ketone 69 thus formed then undergoes reduction with LiBHEt 3 to generate racemic 2,3,4-tribenzyl vibo-quercitol 67.The hydroxymethyl substituent is introduced by reaction of dichloromethyl lithium with ketone 70 to give 71.Hydrolysis of the dichloromethyl group, reduction of the resultant aldehyde, benzyl protection and oxidation of the remaining More recently, this group utilized myo-inositol (65) in the synthesis of the aminocyclitol portion of hygromycin A, a peptidyl transferase inhibitor and broad-spectrum antibiotic (Scheme 11). 25Regioselective reduction of the tetracyclic orthoester 74 gave alcohol 75.The authors rationalized this regioselectivity on the basis of complexation of DIBAL with the OPMB ether.Triflation and azide substitution gave 76 in excellent yield (94%) from 73.Methanolysis of the methylidene acetal and the p-methoxybenzyl groups was accomplished with concentrated HCl to afford the meso triol 77.
Reaction of 77 with dimethoxymethane/TMSOTf, followed by hydrolysis of the methoxymethyl ether generated a racemic monoalcohol.Coupling with the racemate with (R)-O-acetylmandelic acid gave a mixture of diastereomeric esters (-)-78 and (+)-79, which could be separated by flash chromatography on a >1 g scale.Methanolysis of the individual diastereomers and subsequent azide reduction gave the enantiomeric aminocyclitols (-)-80 and (+)-80.Sureshan's group also utilized myo-inositol in the synthesis of a variety of racemic cyclitol natural products, including valienamine (±)-2 (Scheme 12). 26A series of protection and oxidation steps afforded the mesoketone 81, 27 which underwent Wittig olefination to give the methyl vinyl ether 82.Treatment with 0.1N HCl, led to hydrolysis of both the cyclic ortho ester and the enol ether and -elimination to yield the enal (±)-83.The allylic alcohol 84, derived from 83, underwent Mitsunobu inversion in the presence of diphenylphosphoryl azide and sodium azide.Treatment with BCl 3 afforded (±)-2.Sar and Donaldson prepared a library of eight protected stereoisomeric aminocyclitols 85-92 from racemic (2,4-cyclohexadien-1-yl)phthalimide (93, Scheme 13). 28The precursor could be prepared in two steps from (cyclohexadienyl)Fe(CO) 3 + cation.Cycloaddition of 93 with singlet oxygen gave a separable mixture of endoperoxides 94 and 95; the stereochemistry of each was confirmed by X-ray crystallography.Further transformation by endoperoxide cleavage, Kornblum-DeLaMare rearrangement, dihydroxylation or epoxidation/hydrolysis generated the hydroxyl substituents in a stereocontrolled fashion.The relative stereochemistries of these products was tentatively assigned on the basis of 3 J H-H coupling constants; the assignments for 85, 88, 91 and 92 were eventually corroborated by X-ray crystal structures.Sengul and co-workers reported the synthesis of a unique trio of bicyclic aminocyclitols 96-98 from methyl 1,3,5-cycloheptatriene-7-carboxylate (99, Scheme 14). 29Photooxygenation of 99 is known to proceed via the norcaradiene to generate meso tricyclic endoperoxide 100. 30Reduction of 100 with triethylphosphite yields the racemic epoxide (±)-101 in good yield.Ring opening of 101 with sodium azide proceeds selectively at the allylic epoxide carbon.Epoxidation/hydrolysis and azide reduction led to (±)-96 while osmium catalyzed dihydroxylation and azide reduction led to (±)-97.Alternatively, methanolysis of epoxide 101 followed by acetylation gave a separable mixture of acetates 103-105.Reaction of 105 with mCPBA gave a single epoxide 106, which underwent regioselective opening with azide ion.Reduction gave aminocyclitol (±)-98.Scheme 14. Sengul synthesis of bicyclic aminocyclitols.

Intramolecular aldol condensation
Two syntheses reported during this period feature generation of the cyclohexyl ring of aminocyclitols via intramolecular aldol condensation.This reaction results in the desirable -hydroxycarbonyl functionality present within the carbocyclic ring.The Li group began their synthesis with addition of the alkenyl zirconium reagent derived from alkyne 107 to Garner's aldehyde 108, in the presence of zinc bromide, to afford the allylic alcohol 109 with excellent diastereoselectivity thus establishing the required C5 stereocenter (Scheme 15). 31A sequence of dihydroxylation, protection, deprotection and primary alcohol oxidation gave the 1,7-dial 111.Intramolecular aldol condensation with piperidine followed by mesylation-elimination afforded 112.Reduction of 112 under Luche conditions, and global deprotection gave (+)-2.

Scheme 15. The Li group synthesis of peracetylated valienamine (EOM = ethoxymethyl).
Shing's group at the University of Hong Kong utilized an intramolecular aldol condensation for the synthesis of valiolamine (Scheme 16). 32,33D-Glucose was transformed into the differentially protected lactol 113 via a 4 step procedure. 28Methyl Grignard addition followed by oxidation afforded the diketone 114.Extensive experimentation revealed that aldol condensation using potassium hexamethyldisilazane led to the formation of the -hydroxyketone 115.Imine formation, catalytic reduction and global deprotection completed the synthesis of (+)-3.

Ring-closing metathesis
Ring-closing metathesis (RCM) has played a prominent role in the synthesis of aminocyclitols, and the reader is directed to earlier reviews for prior examples. 1,6RCM is particularly attractive since the product possesses an olefin that can serve as a handle for the introduction of further hydroxyl groups.
Two groups utilized D-glucose as a precursor since the C2, C3, and C4 stereocenters present in D-glucose match those in (+)-valienamine.Cumpstey's group reported 34 a variety of routes to protected 1,7-octadienes (Scheme 17).Addition of vinyl Grignard to 2,3,4,6-tetra-O-benzyl glucose gave a separable mixture of allylic alcohols 116 and 117.Selective protection of diol 116 proved challenging, however benzylation with 3,4dimethoxybenzyl chloride (DMBCl) proceeded predominantly at the non-allylic alcohol.Protection/deprotection and subsequent Swern oxidation gave a separable mixture of the C6 ketone 120 and the regioisomeric enone.In order to avoid the problems of selective protection of diol 116 Cumpstey also reported a route from L-sorbose.Ring-closing metathesis of allylic pivalate 121, or its derived allylic alcohol 122a, proceed in good yield using Grubbs' 2 nd generation catalyst.Cumpstey's group eventually completed a synthesis of -valienamine 126 by displacement of the cyclic allylic alcohol 124a with phthalimide under Mitsunobu conditions.About 5 years later, Jung's group reported a selective route to valienamine from D-glucose. 35Olefin (+)-128 was generated via a sequence of standard transformations (Scheme 17). 34Addition of vinyl Grignard to the aldehyde generated from 128 gave an inseparable mixture of diastereomeric allylic alcohols 122a/b.Ringclosing metathesis of 122a/b gave a separable mixture of 124a (25%) and 124b (60%), which could be converted into the perbenzyl pentaol 129 via oxidation/stereoselective reduction/benzylation.Treatment of 129 with chlorosulfonyl isocyanate led to the Cbz protected amine 130, via an S N i substitution with retention of configuration.Debenzylation gave valienamine (±)-2.Krishna and Reddy utilized an enyne ring-closing metathesis for preparation of (+)-valienamine (Scheme 18). 36The C6 stereocenter (CAS numbering) was derived from Garner's aldehyde, while the C1-C3 stereocenters were respectively introduced by Sharpless asymmetric dihydroxylation of 131, and Carreira asymmetric alkynylation of aldehyde 132 in the presence of (-)-N-methylephedrine.Ring-closing metathesis of enyne 134 was accomplished using Grubbs' 2 nd generation catalyst, under an atmosphere of ethylene, to afford the vinylcyclohexene 135 in high yield.Oxidative excision of the terminal methylene carbon afforded a cyclohexenecarboxaldehyde, which after reduction and global deprotection gave (+)-2.This was characterized as its peracetylated derivative (+)-20.Use of (+)-N-methylephedrine in the Carreira alkynylation gave the diastereomer of 133, which gave peracetylated 3-epi-valienamine (CAS numbering) in a similar fashion.
Tu-Hsin Yan's group reported the synthesis of valienamine (Scheme 19). 37The precursor, L-tartaric acid, was converted into the C2 symmetric 1,7-octadiene (-)-136 which underwent RCM with Grubbs' 2 nd generation catalyst to afford the C 2 symmetric cyclohexene (+)-137, according to the procedure of Madsen, et al. 38 Activation of 137 with phenyl-bis(trifluoromethanesulfonimide) and reaction with sodium azide gave 138.This reaction is believed to proceed via generation of the epoxide 139, regioselective ring opening and a [3,3]sigmatropic rearrangement to yield 138 with apparent retention of configuration.The required hydroxymethyl substituent was introduced by oxidation of the allylic alcohol and Baylis-Hillman condensation with aqueous formaldehyde to yield 140. Luche reduction of the resultant enone, azide reduction and acetonide hydrolysis completed the synthesis of (+)-2.Scheme 18. Krishna and Reddy enyne ring-closing metathesis route to valienamine.

Scheme 19. The Yan group synthesis of valienamine.
More recently, this group completed a synthesis of (+)-valiolamine (Scheme 20). 39In this case, D-tartaric acid was transformed into (-)-141; double oxidation and semi-reduction gave acetonide protected 4,5,6trihydroxycyclohexenone 143 along with the diastereomer (13:1 dr).Methenylation of 143 required considerable experimentation.Peterson olefination or reaction with the ylide generated from methyltriphenyl phosphonium bromide proceed with partial epimerization at the -carbon.Successful olefination without epimerization was achieved by using the phosphonium iodide to afford exclusively 144, which was converted into carbonimidothioate 145.Sharpless asymmetric dihydroxylation of the exocyclic olefin of 145 proved to be the next challenging step.While the standard 1,3-phthalazinediyl (PHAL) or pyrimidine (PYR) linked biscinchona ligands gave low to modest diastereoselectivity, Yan's group found that 1% of the anthraquinone linked ligand (DHQD) 2 AQN afforded the desired 146 with >18:1 dr.Cyclization of the carbonimidothioate with iodine generated the required amine stereocenter, which was eventually transformed into (+)-3.

Scheme 20. The Yan group synthesis of valiolamine.
Very recently, Banwell's group reported the first synthesis of nabscessin B (Scheme 21). 40Their route uses L-tartaric acid as starting material to produce (-)-147, 41 the enantiomeric 1,2-diacetal protected analog of (+)-142.Stereoselective mono-carbonyl reduction, protection, reduction of the remaining carbonyl and stereoselective hydroxyl directed epoxidation affords the epoxy alcohol (-)-148.Lewis acid activated reduction of 148 gave a mixture of diols (-)-149 and (-)-150, which were separable on a >1 g scale.The major product arises via a diaxial epoxide ring opening (Furst-Plattner rule).Selective protection of the equatorial hydroxyl at C2 of 150, followed by activation, azide displacement and Staudinger reduction yielded the amine 151.
Ring-closing metathesis also played a prominent role in the preparation of an aminocyclitol mimic 165 of -galactosylceramide (Scheme 24). 44Precursor aldehyde 166 was prepared from D-xylose which was subjected to an Evans' chiral oxazolidinone directed anti-aldol for introduction of the C4-C5 bond.Reductive removal of the auxiliary afforded 1,7-octadiene 167.Ring closing metathesis with Grubbs' 2 nd generation catalyst and benzylation of the 1 o alcohol yielded the cyclohexene 168.Installation of the required C1 alcohol proved challenging.Unlike the Banwell synthesis of nabcessin B, epoxidation of cyclohexene 168 (or various derivatives) either failed to proceed or gave unstable products.Eventually the authors found that hydroboration-oxidation, followed by oxidation to the ketone and stereoselective reduction gave a separable mixture of 169 and the desired (+)-170.Mesylation of 170, S N 2 displacement with azide and reduction gave tetrabenzyl 4-epi-validamine 171.Conversion of 171 to the phytoceramide yielded 165 (HS161).This ARKAT USA, Inc compound proved to be a invarient Natural Killer T cell (iNKT) agonist, inducing Interferon- production in spleen cell culture, as well as by intraperitoneal administration in mice (1 g dose).Vankar's group reported the known 5-amino-5-deoxy-D-vibo-quercitol pentaacetate (+)-172 and two new positional isomers, (+)-173a and (-)-174 (Scheme 25). 45,46D-mannitol was transformed into the chiral aldehydes 175 and 176 respectively.The addition of allyl magnesium chloride or allylzinc to 175 gave an inseparable mixture of diastereomers 177/178 (~ 1:4 dr); conversion of the mixture via tosylate displacement, reduction and acetylation gave a separable mixture of 1,7-octadienes 179 and 180.After adjusting the protecting groups, ring-closing metathesis was accomplished with Grubbs' 1 st generation catalyst; stereocontrolled dihydroxylation of 181 and acetylation yielded (+)-172.In contrast, addition of allyl magnesium chloride or allylzinc to 176 proceeded with low diastereoselectivity, however in this case the derived acetates 182 and 183 were separable by chromatography.Ring closing metathesis and dihydroxylation of the individual diastereomeric cyclohexenes occurred in a stereoselective fashion rendering (+)-173a and (-)-174 respectively, after global deprotection.Chattopadhyay's group reported a route to (-)-173b (Scheme 26), 47 the N-Boc protected analog, which shares some similarity to the methodology outlined in the previous Scheme.Beginning with Garner's aldehyde, addition of vinyl magnesium bromide gave a separable mixture of allylic alcohols 184 and 185. 48he major diastereomer (184) was converted into 186 (the TBDPS protected analog of 176).Barbier reaction of 186, followed by ring-closing metathesis with Grubbs' 1 st generation catalyst gave a separable mixture of 187 and 188.While dihydroxylation of 187 proceeded in a stereoselective fashion yielding exclusively (-)-173b after desilylation, applying the same sequence to 188 gave an inseparable mixture of epimeric products.The minor aldehyde 185 was processed to diastereomeric aminocyclitols (-)-190 and (-)-191.Venkateswara Rao's group reported the synthesis of two novel aminocyclohexitols from D-glucose (Scheme 27). 49The amino chiral center was generated by addition of allyl Grignard to the imine derived from 192.Ring-closing metathesis of (+)-193 with Grubbs' 2 nd generation catalyst gave modest yields of (+)-194.Reduction or dihydroxylation, followed by cleavage of the oxazolidinone gave (+)-195 or (+)-196 respectively.The novel triol 195 inhibited yeast -glucosidase (IC 50 = 1.02 mM), while the pentaol 196 inhibited both yeast -glucosidase (IC 50 = 0.82 mM) and green coffee bean -galactosidase (IC 50 = 1. 2 mM).Neither compound inhibited -glucosidase or -galactosidase.Scheme 27.Venkateswara Rao synthesis of novel aminocyclitols.

Radical cyclization
A group under the direction of Ana Gomez and Cristobal Lopez explored radical addition-cyclization for the preparation of a variety of carbahexopyranones. 50D-Glucose was converted into the ynone 197; Peterson olefination gave the cyclization precursor 198 (Scheme 28).Reaction of a mixture of 198 and tributyltin hydride under standard conditions gave only addition product 199.However when the tin-hydride was added slowly via syringe pump a separable mixture of desired 200 (56%) and its C6 epimer 201 (5%), created via a 6endo-trig radical cyclization, along with minor amounts of acyclic addition product 199 (18%) was produced.The diastereomers 200 and 201 are formed by hydrogen atom abstraction from either the -or -face respectively of the 3 o radical intermediate 202 (see insert).The cyclic constraints inherent in the bis(acetonide) protected intermediate were crucial for this level of diastereoselectivity (>10:1 dr); attempted cyclization of either the tetrabenzyl-or tetraacetyl-analogues of 198 gave only modest : selectivity (ca.1.5:1 dr).Treatment of 200 with acetic acid resulted in acetonide hydrolysis and protodestannylation; the resulting tetraol was peracetylated to afford 203.The olefin was converted into azide 204 by ozonolysis, stereoselective ketone reduction, mesylation and S N 2 displacement by azide.This constituted a formal synthesis of validamine pentaacetate, as Ogawa's group 51 had previously demonstrated this transformation.Scheme 28.The Gomez/Lopez formal synthesis of validamine pentaacetate.
The Ye group reported a similar approach to the synthesis of the 2-DOS subunit of neamine (Scheme 30). 54ethyl -D-glucopyranoside was transformed into the 1 o iodide 211 by literature procedures. 55Treatment of 211 with sodium hydride and allyl iodide effected both O-allylation as well as dehydrohalogenation to afford the exocyclic enol ether 212.Carbo-Ferrier rearrangement of 212, using mercuric trifluoroacetate, gave a mixture of diastereomeric 5-hydroxycyclohexanones (5:1 ratio) with 213 as the major product.Stereoselective reduction of 213 gave the differentially protected cyclohexanediol 214.Activation with triflic anhydride, followed by double displacement with azide and Pd-catalyzed cleavage of the allyl ether generated the alcohol 215.N-Iodosuccinimide mediated coupling of thioglucoside donor 216 with 215 gave the tetraazide 217, which upon azide reduction and benzyl deprotection afforded (+)-neamine (218).The Gademann group used an NMR-guided fractionation approach to identify a new C7N aminocyclitol (9, Scheme 31) from the obligate leaf nodule symbiont bacterium Burkholderia kirkii. 2 After isolation by reverse phase HPLC and prep TLC, the structure of 9 was assigned on the basis of its on NMR and MS spectral data and eventually confirmed by single crystal X-ray diffraction.Total synthesis of 9 commenced with methyl-N-acetyl-D-glucosamine 219.Iodination, acetylation and elimination with silver fluoride gave the enol ether 220.Protecting group reorganization gave 221 which underwent a carbo-Ferrier rearrangement upon treatment with HgSO 4 and sulfuric acid to afford the cyclohexanone 222.The hydroxymethyl substituent was introduced by generation of the enol triflate 223 and Pd-catalyzed coupling with hydroxymethylstannane.Deprotection generated the natural product 9.This compound, which the authors termed kirkamide, was found to be toxic to aquatic arthropods and insects with an LD 50 = 0.48 mg/mL.