Approaches to the Total Synthesis of Conduramines: A Review

Abstract

This review reports on the total synthesis of conduramines, which are formally derived from conduritols, mainly containing a trihydroxy aminocyclohexene core. Analysis of the different strategies developed to prepare these aminocyclohexene triols and their derivatives has been carried out with special attention paid to the methods employed for the insertion of the chiral amine moiety.

Key words

conduritols - conduramines - aminocyclitols - total synthesis - cyclohexenes

Biographical Sketches

Dr. B. Venkateswara Rao was born in 1960 in Nellore, Andhra Pradesh, India. He graduated in Chemistry (1981) from Sri Venkateswara University, Tirupati­, India and obtained his M.Sc. degree (1983) from Sri Krishna Devaraya University, Anantapur, India. He received his Ph.D. in Chemistry (1990) under the supervision of Dr. A. V. Rama Rao from Osmania University. He joined as a Scientist in 1992 at the Indian Institute of Chemical Technology (CSIR-IICT), Hyderabad, and also worked as postdoctoral fellow under the guidance of Prof. Bert Fraser Reid from 1990 to 1992 at Duke University, Durham, USA. His research interests are in the areas of development of new synthetic routes, methodologies and their application in the synthesis of natural and unnatural products and carbohydrate mimics and process development under the principles of green chemistry. He has published more than 120 publications and filed 12 patents to his credit. He recently retired as a Chief Scientist from CSIR-IICT in 2020 and is currently working as CSIR-Emeritus Scientist at CSIR-IICT, Hyderabad.

Dr. H. Bharathkumar was born in 1988 Anantapur, Andhra Pradesh, India. He graduated in Chemistry (2009) from Sri Venkateswara University and obtained his M.Sc. degree (2011) from Sri Venkateswara University. He also received his Ph.D. in Chemistry (2016) under the supervision of Professor Basappa from Bangalore University. Later he worked at Indian Pharmacopoeia as a Research Associate. Recently he joined as a Research Associate at the CSIR-Indian Institute of Chemical Technology under the leadership of Dr. B. Venkateswara Rao working on sugar chemistry.

Dr. J. Siva Krishna, was born in 1992, in Bhimavaram, Andhra Pradesh, India. He graduated in chemistry (2012) from Andhra University and obtained his M.Sc degree (2014) from Andhra University. He received his PhD under the supervision of Dr. B. Venkateswara Rao from the Indian Institute of Chemical Technology, Hyderabad. Currently he is working at GVK biosciences, Hyderabad.

Dr. B. Surender was born in 1990 Mahabubabad, Telangana, India. He graduated in Chemistry (2010) from Kakatiya University and obtained his M.Sc. degree (2013) from Osmania University. He received his Ph.D. in Chemistry (2021) under the supervision of Dr. B. Venkateswara Rao from the Indian institute of Chemical Technology, Hyderabad. Currently he is working at IIT Hyderabad as a member of the Technical Staff.

Conduramines are aminocyclohexenetriols formally derived from conduritols, in which one of the hydroxyl groups is exchanged with an amino group.[1] Many of these conduramines exhibit significant glycosidase inhibitory activity. The conduramines are also chiral building blocks for natural products such as (+)-narciclasine, (+)-valienamine, and (+)-lycoricidine.[2] They are also important as synthetic precursors of amino cyclitols and many of these constitute the aglycon portion of therapeutically useful aminoglycoside antibiotics.[3] In addition, the conduramines are used as intermediates in the synthesis of aminosugars, sphingosines, azasugars, and narcissus alkaloids.[4] Conduramines are classified into different types, based on the position of the amino group on the cyclohexene ring. The group in which the amino group occupies an allylic position on the ring comprises conduramines A, A-1, B-1, ent-C-1, D-1, E-1, F-1, C-4, E-4, ent-F, and F-4 and when the amino group is sandwiched between two hydroxyl groups, conduramine B-2 and F-2 (Figure [1]).

Different methods have been designed for the synthesis of conduramines starting from carbohydrate and non-carbohydrates precursors. In this review article we described the total syntheses of conduramines that have been published since 2006.

Figure 1 The conduramine family

Earlier approaches have been covered in review articles published by Vogel et al., in 2006[5] and enzymatic methods of synthesis by Hudlicky et al., in 2011.[6] In this review, most of the reported approaches have focused on conduramines with an allylic amine moiety.

Vogel et al., in 2006,[7] reported the synthesis of (–)-conduramine F-1 from (±)-7-oxabicyclo[2.2.1]hept-5-en-2-one 1 (compound 1 was prepared by using their earlier protocol[8]). Reduction of cyclohexenone 4 (which was obtained from 1 via 2 and 3 [9]) using NaBH₄/CeCl₃ in aqueous methanol gave a mixture of compounds 5 and 6, respectively (Scheme [1]).

Scheme 1 Synthesis of conduramine F-1

This mixture was treated with diethyl azodicarboxylate, phthalimide 7, and triphenylphosphine in anhydrous toluene to give a mixture of N-substituted phthalimides 8 and 9 (1:2.5), which were separated by flash chromatography. Racemic 9 was subjected to desilylation, followed by aminolysis with 40% aq. CH₃NH₂, to give pure conduramine F-1 (Scheme [1]).

Pandey et al., in 2008,[10] reported the synthesis of dihydro­conduramine E-1 and ent-conduramine F-1 from 7-azabicyclo[2.2.1]heptane-2-ol 11 (Scheme [2]). Asymmetric desymmetrization of meso-compound 11 gave the desymmetrized compound 12 in 80% yield (99% de) using a reported protocol.[11] The ketal moiety was removed from 12 by hydrogenation to give 13, which, on reduction with lithium borohydride, afforded a mixture of diastereomeric alcohols 14 and 15 (1:9). Ring opening of 15 with excess of MeMgBr in THF at room temperature gave compound 16, which was treated with 6% Na/Hg in CH₃OH to furnish 17. Compound 17 was subjected to oxidation with OsO₄ and N-methylmorpholine N-oxide (NMO) to give 18, and subsequent Boc deprotection gave dihydroconduramine E-1.

Scheme 2 Synthesis of dihydro conduramine E-1 and ent-conduramine F-1. ^a Neither yield nor time were mentioned in reference paper.

Compound 17 was also subjected to TBS protection to give 19, allylic oxidation of which with Pd/C and tert-butyl hydroperoxide in dichloromethane at 0 °C gave enone 20 (Scheme [2]). This was subjected to nucleophilic epoxidation using Triton-B and tert-butyl hydroperoxide in THF at 0 °C to give the single product 21 due to facial selectivity. Compound 21 was treated with KHMDS/ Comins’ reagent to yield the enol triflate, which was further treated with Pd(PPh₃)₄ and triethylsilane to afford the corresponding olefin derivative. Epoxide ring opening and deprotection with 0.1 M H₂SO₄ and 10 M HCl in dioxane under reflux conditions afforded ent-conduramine F-1.

Chang et al., in 2009,[12] synthesized conduramines A-1 and E from l-tartaric acid 22 (Scheme [3]). Treatment of 22 with 2,2-dimethoxypropane gave dimethyl 2,3-O-isopropylidenetartrate 23, which was subjected to reduction with DIBAL-H, followed by diastereoselective divinyl zinc addition to the in situ generated dialdehyde to furnish the desired vinyl carbinol 24. RCM of compound 24 afforded the corresponding cyclic diol 25; subsequent epoxidation, followed by heating with azide at different temperatures gave the allylic azides 27a and 27b. Compounds 27a and 27b, on treatment with LAH and then quenching with H₂O/AcOH, gave conduramines A-1 and E, respectively.

Scheme 3 Synthesis of conduramine A-1 and conduramine E

Jana et al., in 2009,[13] reported the synthesis of (–)-peracetylated conduramine A-1 from diene 28 and 2-nitrosopyridine (Scheme [4]). They achieved good diastereoselectivity and enantioselectivity in the Diels–Alder reaction (29, 99%, d.r. >99:1, 93% ee). This nitroso-Diels–Alder product 29 was then used to synthesize peracetylated conduramine A1. In compound 29, the N–O bond was cleaved with Mo(CO)₆/NaBH₄ followed by silylation to give the protected alcohol 30. The amine group of compound 30 was subjected to carbamoylation by treatment of the corresponding magnesium amide with methyl chloroformate to give 31 (96%), which was subjected to N-methylation and removal of the pyridyl group by hydrolysis of the pyridinium salt to give compound 32. Finally, removal of the carbamate and acetal groups and peracetylation using AcCl in combination with sodium iodide in CH₃CN, gave protected (–)-conduramine A-1 in a one-pot conversion.

Scheme 4 Synthesis of (–)-peracetylated conduramine A-1

Lu et al., in 2010,[14] reported the synthesis of (+)-ent conduramines F-1 and E-1, (–)-conduramine A-1 and A-1-tetraacetate from masked O-benzoquinones with enantiomerically pure nitroso dienophiles (Scheme [5]). The nitroso compound 34 was prepared from the chiral auxiliary A1 (prepared from (1S)-(+)-10-camphorsulfonic acid) and 2-methoxyphenol 33. Then compound 34 was treated with DIBAL-H to give hydroxy-compound 35, which was treated with LAH to give oxazine 36. Subjecting 36 to reductive cleavage of the N–O bond in the presence of Mo(CO)₆/NaBH₄ afforded the amino alcohol 37. The amine group in compound 37 was converted into azide 38 using trifluoromethanesulfonylazide and CuSO₄ and this was subjected to ketal hydrolysis with TFA to afford enone 39. Enone 39 was reduced using Luche’s reagent to furnish an inseparable mixture of alcohols 40 and 41 (53:33). This alcoholic mixture was treated with DMP to give the protected cis-diol 42. Alcohol 40 was treated with trimethylphospine in THF/H₂O to give the (+)-ent-conduramine F-1. A similar strategy was applied to prepare 43 from 42 and subsequent ketal deprotection gave (+)-conduramine E-1.

Scheme 5 Total synthesis of (+)-ent-conduramine F-1 and conduramine E-1

Scheme 6 Syntheses of (–)-conduramine A-1 and A-1 tetraacetate

For the synthesis of conduramine A-1, the MOM protected compound 44 was treated with chiral auxiliary A2, derivative of (1R)-(–)-10-camphorsulfonic acid to give an inseparable mixture of compounds 45a and 45b (Scheme [6]). These compounds further reacted with DIBAL-H to afford 46a and 46b. Compounds 46a and 46b were subjected to hydrolysis with TFA to give hemiketal 47, and was subjected to reduction by NaBH₄ to give diol 48. Compound 48 was further reacted with DMP to afford ketal 49 and this was reacted with LiAlH₄ and Mo(CO)₆ to give amino alcohol 50. Deprotection of 50 gave the target (–)-conduramine A-1 and further acetylation gave (–)-conduramine A-1 acetate.

Russell et al., in 2010,[15] reported the synthesis of conduramine E. Compound 52 was obtained by using a reported procedure[16] from benzene 51 (Scheme [7]). Treatment of 52 with two equivalents of NBS gave the oxazolidinone 53 in 49% yield, and treatment of this with DBU gave the diene 54 in 90% yield. Compound 54 was subjected to regio- and stereoselective dihydroxylation with ADmix-β for 5 hours between 0 °C and –5 °C, furnishing 55 as a single region- and stereoisomer in 76% yield, or with K₂OsO₄·2H₂O, NMO, H₂O, acetone, t-BuOH (55%, 55/56 = 4:1). Deprotection of compound 55 with TFA followed by hydrolysis with Ba(OH)₂ gave conduramine E.

Scheme 7 Synthesis of conduramine E. ^a Reaction yield was not noted in the reference paper.

Kelebekli et al., in 2010,[17] reported the synthesis of N-tosyldihydroconduramine E-2 from diene 58 (Scheme [8]). Compound 58 was subjected to photochemical peroxidation using rose bengal in MeOH followed by treatment with thiourea to give the allylic cis-diol 59. Diol 59 was reacted with p-TsNCO in THF to obtain the bis-carbamate 60, then the reaction mixture was heated to 65 °C and the resulting solution was treated with 15 mol% triisopropyl phosphate and 5 mol% of tris(dibenzylideneacetone) dipalladium chloroform complex at the same temperature to give oxazolidinone 61. The latter was subjected to dihydroxylation with KMnO₄ to give oxazolidinone cis-diol 62. Compound 62 was treated with acetyl chloride in dichloromethane to give oxazolidin-2-one diacetate 63 and hydrolysis of 63 with K₂CO₃ in CH₃OH at room temperature and then treatment with acetyl chloride gave compound 64. Finally, global deprotection of all the acetate groups with K₂CO₃ in methanol gave the N-tosyldihydroconduramine E-2.

Scheme 8 Synthesis of (±)-N-tosyldihydroconduramine E-2

Chang et al.,[18] in 2010, reported the synthesis of (+)-conduramine A-1 starting from l-tartaric acid 22, forming compound 26 using the procedure outlined in Scheme [3]. Epoxide 26 was treated with ammonium hydroxide (25%) followed by acetal deprotection to afford conduramine A-1 (Scheme [9]).

Scheme 9 Synthesis of conduramine A-1

Norsikian et al., in 2012,[4] synthesized ent-conduramine A-1 and conduramine C-4 from d-ribose (Scheme [10]). The d-ribofuranose derivative 65 was treated with dimethyl(1-diazo-2-oxopropyl) phosphonate 66 under Demailly’s conditions to give compound 67. The secondary alcohol of 67 was subjected to TBS protection and subsequent trityl group removal with iron trichloride gave intermediate 68. The primary alcoholic group of 68 was subjected to DMP oxidation followed by trimethylorthoformate treatment to form acetal 70. Compound 72 was directly prepared from 70, using triethyl borane induced hydrometallation followed by iodolysis of the corresponding Z-alkenylindium species. Bromide 71 and iodide 72 were also synthesized in two steps by halogenation of the alkyne with NBS or NIS in the presence of silver nitrate followed by diimide cis-hydrogenation. The alkenyl bromide 71 underwent palladium-catalyzed cross coupling with bis(pinacolato)diboron to give the alkenyl boronic acid pinacol ester 73 in a Z/E ratio of 70:30. Alternatively, compound 72 was subjected to halogen–metal exchange followed by treatment with trimethyl borate and pinacol to give the boronic ester 73.

Scheme 10 Preparation of boronic ester 73

A large excess of trimethyl borate (20 equiv) was required to obtain boronic ester 73 in a good yield. Treatment of boronic ester 73 with NaIO₄ afforded the corresponding boronic acid 74. Removal of all the protecting groups with 6 M HCl in THF followed by treatment with excess of diallylamine in EtOH/H₂O at 80 °C for 19 hours gave the cyclized product 77. Deprotection of the allyl group in compound 77 gave ent-conduramine A-1 (Scheme [11]).

Scheme 11 Synthesis of ent-conduramine A-1

In their synthesis of conduramine C4, oxidation of β-d-ribofuranoside derivative 78 gave the aldehyde moiety and the resultant aldehyde was treated with PPh₃ and CBr₄ in the presence of activated Zn to give the dibromalkene 79 (Scheme [12]). Pd-catalyzed hydrogenolysis of 79 with n-Bu₃SnH afforded 80, which was subjected to boronic acid exchange to give compound 81. Complete deprotection of 81 with TFA and treatment with diallylamine in EtOH/H₂O or in CH₂Cl₂/hexafluoroisopropanol afforded compound 82, and deprotection of allyl group using palladium tetrakis(triphenylphosphine) gave conduramine C-4.

Scheme 12 Synthesis of conduramine C-4

Ghosal et al., in 2012,[19] reported the synthesis of (–)- and (+)-conduramine E. 1,2,3,4-Di-O-isopropylidine-α-d-galactopyranoside 84, gave the iodo compound 85 on iodination, which was treated with zinc dust and catalytic cyanocobalamine to give hemiacetal 86 (Scheme [13]). This was treated with tert-butylamine and trans-phenylvinyl boronic acid to give erythro-1,2-amino alcohol 87 exclusively. The amino alcohol 87 was reacted with Boc anhydride in the presence of DMAP/TEA in THF to give oxazolidinone 88 and this was subjected to RCM in the presence of Grubbs’ 2nd generation catalyst to give the conduramine core moiety 89. Deprotection of the acetonide group with TFA gave the diol 90, which is a known intermediate for (±)-conduramine E synthesis. Deprotection of the tert-butyl group in compound 90 using TFA gave oxazolidinone 91 and basic hydrolysis of 91 using Ba(OH)₂ gave (+)-conduramine E.

Scheme 13 Synthesis of (+)-conduramine E

2,3,5,6-Di-O-isopropylidine-α-d-mannofuranose hemiacetal 93 was synthesized from d-mannose 92 by the standard procedure (I₂/acetone). The anomeric carbon of compound 93 was subjected to Wittig methylenation to give the alkene 94, and the free hydroxy group of 94 was protected with TBDPSCl to give compound 95 (Scheme [14]). Selective deprotection of the terminal acetonide in 95 with 80% aq. acetic acid gave diol 96. Oxidative cleavage of the diol fragment in compound 96 using NaIO₄ gave aldehyde 97, and removal of the silyl group from aldehyde 97 with TBAF yielded the α-hydroxy aldehyde intermediate 98. Subsequently, aldehyde 98 was subjected to Petasis borono-Mannich­ reaction with trans-2-phenylvinyl boronic acid and tert-butylamine under reflux to give the desired amine 99, which was protected with Boc anhydride in the presence of base to give oxazolidinone 100. RCM of diene compound 100 using Grubbs’ 2nd generation catalyst gave the carbocyclic moiety of (–)-conduramine E 101. Conversion of 101 into (–) conduramine E was carried out by a similar set of reactions to those detailed in Scheme [13].

Scheme 14 Synthesis of (–)-conduramine E

Scheme 15 Synthesis of conduramine D-1 and conduramine C-1

Rao et al., in 2013,[1] reported the synthesis of conduramine C-1 and conduramine D-1 from d-ribofuranose (Scheme [15]). The derivative 104 was reacted with vinyl magnesium bromide at –78 °C in anhydrous THF to give triol 105. The 1,2-diol was subjected to oxidative cleavage using NaIO₄ in THF/H₂O (4:1) to afford the lactol 106, which underwent condensation with benzylamine in MeOH under reflux to give the glycosylamine. Stereoselective Grignard addition of the glycosylamine with vinyl magnesium bromide gave the anti-amino alcohol 107 exclusively. Amino alcohol 107 was subjected to Cbz protection to yield the diene compound 108 and this was subjected to RCM in the presence of 10 mol% Grubbs’ 2nd generation catalyst at reflux in toluene to afford the desired cyclohexeneamine compound 109. Compound 109 was then subjected to deprotection with Na/liq. NH₃, followed by protection with Boc anhydride to give 110, which then underwent global deprotection with TFA in dichloromethane to afford conduramine D-1. The free hydroxyl group of compound 110 underwent inversion under Mitsunobu conditions to yield the epimer 111, and then deprotection gave conduramine C-1.

Scheme 16 Synthesis of conduramine A

Trost and Malhotra, in 2014,[20] reported the preparation of conduramine A, through palladium-catalyzed asymmetric allylic azidation for the desymmetrization of meso-dibenzoate 112; a procedure developed earlier to synthesize enantiomerically pure amino alcohols. The carbamate 113 was prepared from dibenzoate 112 by using a similar strategy (Scheme [16]). Compound 113 then underwent benzoate hydrolysis to give allylic alcohol 114, and diastereoselective OsO₄ catalyzed cis-dihydroxylation of 114 gave the triol, with subsequent protection with acetone giving the acetonide 115. Treatment of alcohol 115 with mesyl chloride gave mesylate 116 and elimination under microwave conditions gave the alkene 117. Epoxidation of 117 gave the epoxide 118 as a single isomer, which was treated with Li-phenyl selenide to give 119. The product was further subjected to selenoxide cycloelimination to obtain conduramine A derivative 120. Removal of protecting groups gave conduramine A.

Scheme 17 Synthesis of (–)-conduramine F-1

Ham et al., in 2015,[21] reported the synthesis of conduramine F-1. The N-benzoyl serine methyl ester 122 was prepared from serine 121 by using a reported procedure (Scheme [17]).[22] The serine derivative 122 was then treated with N,O-dimethylhydroxylamine in the presence of Al(CH₃)₃ to give the corresponding Weinreb amide that was reacted with vinyl tin and CH₃Li at –78 °C in THF to give α,β-unsaturated ketone 123. Compound 123 was subjected to reduction using Li-tri t-butoxyaluminohydride to give the anti-aminoalcohol, and subsequent TBSCl protection gave compound 124. The latter was subjected to stereoselective intramolecular cyclization in the presence of Pd(PPh₃)₄, NaH, and TBAI in THF at 0 °C to give the syn,syn-oxazine 125 and syn,anti-oxazine 126 in a 9.5:1 mixture. Interestingly, when the authors increased the reaction temperature to 50 °C, the diastereoselectivity of the reaction was changed and the major isomer was syn,anti-oxazine 126 (1:9 mixture), in 73% yield. Ozonolysis of 126 gave the aldehyde, which was treated with vinylmagnesium bromide in the presence of ZnCl₂ in THF to give the allylic alcohols 127 and 128 in a ratio of 8:1 with 71% yield. The alcohol group in compound 127 was protected with acetic anhydride and treated with Cbz-Cl in the presence of aq. NaHCO₃ to generate carbamate 129. TBS protection of the primary alcoholic group was removed with HF-Py complex, and the resultant alcohol group, on oxidation with DMP followed by treatment with triphenylphosphonium benzyl iodide, gave the phenyl-substituted diene 130, and subsequent ring-closing metathesis gave 131. Finally, global deprotection with 6N·HCl in MeOH gave the (–)-conduramine F-1.

Ogawa et al.,[23] in 2015, reported the synthesis of N-substituted conduramine F-4 derivatives (Scheme [18]). Initially the (+)-proto-quercitol 132 was treated with 2,2-dimethoxy­propane in DMF to afford diacetonide 133. The hydroxy group on compound 133 was subjected to sulfonylation to give the mesylate 134. Treatment of compound 134 with excess DBU under reflux conditions in toluene gave the cyclohexene compound 135. The trans-isopropylidene group of compound 135 was then removed selectively by using a catalytic amount of pyridinium-p-toluenesulfonate (PPTS) in MeOH to give the diol compound 136. Subsequent epoxidation of compound 136 with a slight excess of Martin sulfurane afforded the epoxide compound 137. Finally, incorporation of various amine groups at the C-1 position of compound 137 via simple addition reactions with alkylamines and treatment with HCl/aq. THF afforded the N-substituted (+)-conduramine F-4 derivatives as HCl salts.

Scheme 18 Total synthesis of N-substituted (+)-conduramine F-4 derivatives

Maji and Yamamoto,[24] in 2015, reported the synthesis of conduramine A-1 (Scheme [19]). The acetal protected meso-cyclohexa-3,5-diene-1,2-diol 138 was treated with 139 in the presence of a Cu catalyst to afford 140 with excellent enantio- and diastereoselectivity (d.r. >99:1 and >99% ee). Compound 140 was treated with Mo(CO)₆ to mediate reductive N–O bond cleavage, and O and N protection afforded 141. Subsequent removal of the pyridazyl group by quaternization with 3-iodopropyl triflate, reduction with NaBH₄, and then a second quaternization and hydrolysis using NaOH in one pot, afforded 142. Deprotection and acylation of 142 using the procedure described in Scheme [4[13] gave tetraacetyl conduramine A-1.

Scheme 19 Total synthesis of tetraacetyl conduramine A-1

Harit and Ramesh, in 2016,[25] reported the synthesis of conduramine F-4 from d-glucose derived 1,6-diol 144 (3,4,5-tri-O-benzyl-2-deoxy-2-(N-benzyl-N-p-toluenesulfonyl)-amino-d-glucitol), prepared by using a reported procedure.[26] Selective debenzylative acetylation was carried out with zinc chloride in acetic acid–acetic anhydride in a ratio of 1:5 to give the 1,6-O-diacetate 145, which was then treated with an excess of LAH to furnish triol 146 (Scheme [20]). The primary alcohol groups in compound 146 were protected with TBS to give compound 147, then benzylation of the secondary alcoholic group with benzyl bromide gave the fully protected compound 148. Deprotection of compound 148 with camphorsulfonic acid gave the 1,6-diol 149.

Scheme 20 Synthesis of conduramine F-4

The diol 149 underwent Swern oxidation followed by Wittig reaction to furnish diene 151. The ring closing of diene 151 with Grubbs’ 2nd generation catalyst furnished protected (–)-conduramine F-4 152. N-Detosylation of 152 with Na-Hg gave the amino derivative 153, which was subjected to acylation followed by deprotection using Na/liq. NH₃ to afford (–)-conduramine F-4 (Scheme [20]).

Ham et al., in 2016,[27] reported the synthesis of (–)-conduramine A-1 from d-serine by using the series of reactions shown in Scheme [17[21] (Scheme [21] and Scheme [22]).

Scheme 21 syn,anti,syn-Oxazine approach

Scheme 22 Total synthesis of (–) conduramine A-1

Raghavan et al., in 2016,[28] reported the synthesis of (–)-conduramine B (Scheme [23]). Initially compound 166 was treated with LDA and the anion was treated with ethyl sorbate 167 to give the β-keto sulfoxide 168, which was subjected to diastereoselective reduction using DIBAL-H in the presence of anhydrous ZnCl₂ to give the diene alcohol 169. Diene 169 was then treated with N-bromosuccinimide in dichloromethane to give the bromodiol 170. The hydroxyl groups of 170 were protected as TBS ethers to give 171, and reduction of the sulfinyl group using TFAA and NaI gave sulfide 172. Treatment of 172 with N-chlorosuccinimide gave the α-chlorosulfide, which, on treatment with vinyl zinc bromide, gave diene sulfide 173 as the sole product. The silyl protecting groups of 173 were removed to give the bromodiol, which, on acetylation, afforded diacetate 174. The crude diacetate was then treated with acetic anhydride to give the triacetate compound 175. RCM of 175 using Grubbs’ 2nd generation catalyst gave the allylic sulfide 176. The acetate groups in 176 were subsequently hydrolyzed and the resultant product was protected by benzylation to give 177. Treatment of 177 with N-chloro N-tert-butyloxy carbamate at 0 °C and heating the reaction mixture to room temperature gave the allylic amino derivative, which, upon treatment with NaBH₄ in CH₃OH, gave the (–)-conduramine-B derivative.

Scheme 23 Synthesis of conduramine (–)-B

Sarlah et al.,[29] in 2016, reported the application of dearomative dihydroxylation for the synthesis of conduramine A via the corresponding 1,2,4-triazoline-3,5-dione-benzene adduct 178 through a modified hydrolysis oxidation that installed an additional 1,4-syn-aminohydroxy functionality via successive urazole hydrolysis, hydrazine/oxamic acid oxidation in one pot, and subsequent hetero-Diels–Alder reaction to afford the bicyclic product 179 in 83% yield. Subsequent N–O cleavage and removal of the trichloroethoxycarbonyl group, followed by acid-mediated deprotection of the acetonide, afforded conduramine A (Scheme [24]).

Rao et al., in 2017,[30] reported the synthesis of N-benzyl conduramine F-1, N-benzyl ent-conduramine E-1, dihydroconduramine F-1 and ent-dihydroconduramine E-1 from d-mannitol (Scheme [25]). Initially they prepared diol 182 using a described protocol from d-mannitol. Aldehyde 183 was prepared using NaIO₄ via oxidative cleavage and was treated with vinyl magnesium bromide to give separable diastereomeric mixture of 184 and 185 (1:1.3). Deprotection of the primary acetonide and oxidative cleavage of compound 184 using H₅IO₆ gave aldehyde 186, which was subsequently treated with benzylamine to give aldimine 187. Nucleophilic addition on 187 using vinyl magnesium bromide in THF at –10 °C gave the anti product 188 exclusively. Amine 188 was subjected to Boc protection using (Boc)₂O in the presence of sodium bicarbonate in CH₃OH to give 189, which, on ring-closing metathesis using Grubbs’ 2nd generation catalyst in dichloromethane, gave the cyclized product 190. Treatment with 6 M HCl to give N-benzyl conduramine F-1, and reduction of the alkene and complete deprotection yielded dihydroconduramine F-1.

Scheme 24 Synthesis of conduramine A

A similar sequence of reactions was carried out for the synthesis of N-benzyl ent-conduramine E-1 and ent-dihydroconduramine E-1 from compound 185 (Scheme [26]).

Scheme 25 Synthesis of N-benzyl-conduramine F-1 and dihydroconduramine F-1

Scheme 26 Synthesis of N-benzyl ent-conduramine E-1 and ent-dihydroconduramine E-1

Prasad and Rangari, in 2018,[31] reported the synthesis of ent-conduramine F-1 from tartaric acid (Scheme [27]). Vinyl magnesium bromide was added to the bis-Weinreb amide 194 to give the mono ketoamide 195. The carbonyl group of compound 195 was subjected to stereoselective Luche reduction to give the alcohol 196 (de 99:1). The hydroxyl group of 196 was then protected as its tert-butyldimethylsilyl ether to give 197. Treatment of 197 with DIBAL-H gave the corresponding aldehyde, and further reaction with (S)-tert-butylsulfinamide gave the sulfinimine 198. Addition of vinyl magnesium bromide to 198 gave the sulfonamide 199 and TBS deprotection of 199 gave the diene 200. Treatment of intermediate 200 with Grubbs’ 2nd generation catalyst gave the cyclized product 201. Removal of the sulfinyl and acetonide groups in 201 using HCl in methanol, followed by NaHCO₃ treatment gave ent-conduramine F-1.

Scheme 27 Synthesis of ent-conduramine F-1

Da Silva Pinto et al., in 2019,[32] reported the synthesis of (–)-conduramines A-1, A-2, and E-2 (Scheme [28]). Initially, 202 was subjected to oxidation in the presence of peracetic acid in dichloromethane to give the cyclohexa-1,4-diene monoepoxide 203. Compound 203 was then subjected to bromination in a mixture of dichloromethane and chloroform to give the corresponding dibromide, which, on treatment with DBU, gave the benzene oxide 204. The latter underwent ring opening with enantiopure (R)-α-methyl-p-methoxybenzylamine to afford a mixture of two compounds, 205 and 206. Treatment of 205 with 40% aqueous HBF₄ and then m-CPBA gave a mixture of four compounds in a ratio of 17:37:32:14. These compounds were separated using preparative TLC and identified as N-α-methyl-p-methoxybenzyl derivatives of conduramine A1 (209), A2 (210), E2 (211), and F2 (212), respectively. Finally, removal of the α-methyl-p-methoxybenzyl fragment from 209–211 with Et₃SiH in the presence of TFA gave (–)-conduramine A-1, A-2, and E-2, respectively.

Scheme 28 Synthesis of (–)-conduramines A-1, A-2, and E-2

Harit and Ramesh,[33] in 2019, reported the synthesis of ent-conduramine F-2 and conduramine B-2 from precursor 143 (Scheme [29]). Initially, intermediate 213 was prepared from compound 143 using a reported procedure.[29] Compound 213 was then heated at 50 °C with 1 equiv of NaBH₄ in THF and MeOH (1:1) to give 214. Compound 214 was then subjected to chemoselective debenzylation and acetylation of the primary benzyloxy group at C-6 with ZnCl₂ in an acetic acid acetic anhydride mixture to furnish 6-O-acetate 215, which was then hydrolyzed to alcohol 216 with sodium carbonate in methanol. Compound 216 was then converted into iodo compound 217 using PPh₃, I₂ and imidazole, and 217, under sonication with Zn at 40 °C, underwent Vasella reductive elimination to give the formyl-alkene 218. Subsequently, 218 was treated with vinyl magnesium bromide in THF at 0–35 °C to give the dienes 219a and 219b as a separable mixture of diastereomers, in a ratio of 1:2.5, respectively.

The dienes 219a and 219b were independently subjected to RCM in the presence of Grubbs’ 1st generation catalyst to give 220a (79%) and 220b (78%), respectively. Global removal of the benzyloxy and tosyl protecting groups in compounds 220a and 220b with Na/liq. NH₃ afforded ent-conduramine F-2 and conduramine B-2 in 77 and 76% yield, respectively (Scheme [29]).

Scheme 29 Total synthesis of conduramine B-2 and ent-conduramine F-2

Yan et al.,[34] in 2019, reported the synthesis of tetra­acetyl conduramines B‑1, ent-C-1, C‑4, D‑1, ent-F-1, and ent-F-4. Initially compound 27a was prepared from l-tartaric acid 22 using a reported procedure (Scheme [3]).[12] The azido alcohol 27a was treated with trifluoroacetic acid (TFA) and oxidation of the allylic alcohol with DMP gave enone 221 (Scheme [30]). Treatment of enone 221 with DIBAL-H at –78 °C afforded 222 in good yield with good selectivity (68%, S/R = 1:8.5). Treatment of compound 222 with LAH and subsequent acetonide deprotection and peracylation afforded the desired tetraacetyl conduramine C-4. The 1,4-anti-azido alcohol compound 27b was synthesized from cyclic diol 25 (for details, see Scheme [3]). Subsequently, treatment of 27b with DEAD, benzyl alcohol, and PPh₃ in THF for 2 h afforded the 1,4-syn-azido alcohol 223. Reduction of compound 223 with LAH, followed by acetonide removal and peracylation, yielded tetraacetyl ent-conduramine F-1 (Scheme [30]).

Scheme 30 Total synthesis of conduramine C‑4 and tetra-acetyl conduramine F-1

Bromohydrin 224 was prepared from allylic epoxide 26 in a regioselective manner (see Scheme [3])[12] [35] and was subjected to nucleophilic substitution with sodium azide to give azido alcohol 225 (Scheme [31]). Compound 225 underwent TFA-catalyzed rearrangement to give the thermodynamically preferred cis-fused acetonide, and oxidation with DMP gave enone 226. Luche reduction of enone 226 afforded the 1,4-cis-azido alcohol 227. Subsequent acetonide removal and peracylation of compound 227 resulted in conduramine D-1 tetraacetate. Treatment of compound 225 with LAH and subsequent acetonide deprotection and peracylation yielded the tetraacetyl ent-conduramine C-1.

The allylic epoxide 26 was treated with benzoic acid in the presence of 2 mol% Pd(PPh₃)₄, to give 1,4-syn-allylic alcohol 228. The allylic alcohol unit of compound 228 was subjected to mesylation, followed by nucleophilic displacement with sodium azide, affording allylic azide 229. Reduction of 229 with LAH, followed by acetonide removal and peracylation yielded tetraacetyl conduramine B-1. Compound 26 underwent palladium-catalyzed nucleophilic opening of the allylic epoxide with TsNH₂/TsNHNa in acetonitrile at 40 °C to give the 1,4-syn-amide 230. The amide was then treated with Na/NH₃, followed by acetonide removal and peracetylation, to give tetraacetyl ent-conduramine F-4 (Scheme [31]).

Scheme 31 Total synthesis of conduramine B‑1, ent-C-1, D‑1, and ent-F-4

Narayana et al., in 2021,[36] reported the synthesis of N-acetyl ent-conduramine B-1 from commercially available N-acetyl-d-glucosamine 231 (Scheme [32]). Initially 231 was heated to reflux in CH₃OH in the presence of Amberlite IR-120-H1 resin to give the corresponding methylglycoside and this was treated with triphenylmethyl chloride in pyridine to give 6-O-trityl derivative 232. Trityl derivative 232 was subjected to benzylation followed by removal of the trityl group to give 233, which was subjected to tosylation followed by iodination and dehydrohalogenation at room temperature to furnish 234.[37] Subsequently, 234 was subjected to HgSO₄ catalyzed Ferrier carbocyclization in 1,4-dioxane and 5 mM H₂SO₄(2:1) at 50 °C, to give cyclohexanone 235. Compound 235 was treated with excess methanesulfonyl chloride and TEA to give the α,β-unsaturated ketone 236, which underwent stereoselective Luche reduction to give a mixture of diastereomeric alcohols (α/β = 1:9). Finally, debenzylation of compound 237 using Lewis acid gave N-acetyl ent-conduramine B-1 (Scheme [32]).

Scheme 32 Synthesis of N-acetyl ent-conduramine B-1

In conclusion, a range of conduramines have been synthesized in recent years, as well as some of their enantiomers. Many elegant strategies for the total synthesis of these derivatives have been developed.

In the synthesis of conduramines, the insertion of amine moiety and extension of the corresponding substrate to different conduramines is one of the key aspects in the strategies. The amine group has been introduced at different stages of synthesis. Most approaches focus on constructing the allylic amine using benzylamine, allyl amine, NaN_3, N-tert-butylcyclohexa-2,5-dienylamine, α-methyl-p-methoxy benzyl amine, P-TsNCO, t-BuNH₂, TMSN₃, NaNBocCl, and phthalimide on appropriate precursors. Details of the amine sources are listed in Table [1] and the synthetic approaches are summarized and classified in Table [2].

Table 1 Synthesis of Conduramine Derivatives from 2007 to 2021

Entry	Conduramine derivative	Source of nitrogen	Reference
1	conduramine A	TMSN3	[20]
2	conduramine A	TrocNHOH	[29]
3	conduramine A-1	NaN3	[12]
4	conduramine A-1	3-methyl-6-nitrosopyridazine	[24]
5	conduramine A-1	NH4OH	[18]
6	(–)-conduramine A-1	(R)-α-methyl-p-methoxybenzylamine	[32]
7	peracetylated conduramine A-1	2-nitrosopyridine	[13]
8	(–)-conduramine A-1	d-serine	[27]
9	(–) conduramine A-1	Bu4NIO4	[14]
10	ent-conduramine A-1	allyl amine	[4]
11	(–)-conduramine A-2	(R)-α-methyl-p-methoxybenzylamine	[32]
12	(–)-conduramine B	N-chloro-N-tert-butyloxycarbamate	[28]
13	N-acetyl ent conduramine B-1	N-acetyl-d-glucosamine	[36]
14	tetracetyl conduramine B-1	sodium azide	[34]
15	conduramine B-2	p-toluene sulfonamide	[33]
16	conduramine C-1	benzyl amine	[1]
17	tetracetyl ent-conduramine C-1	sodium azide	[34]
18	conduramine C-4	allyl amine	[4]
19	tetraacetyl conduramine C-4	azide ion	[34]
20	conduramine D-1	benzyl amine	[1]
21	tetracetyl conduramine D-1	sodium azide	[34]
22	conduramine E	N-tert-butylcyclohexa-2,5-dienylamine	[15]
23	conduramine E	NaN3	[12]
24	(+)-conduramine E	tert-butyl amine	[19]
25	(–)-conduramine E	tert-butyl amine	[19]
26	dihydro conduramine E-1	7-azabicyclo[2.2.1]heptane-2-ol	[10]
27	ent-dihydroconduramine E-1	benzylamine	[30]
28	(+)-ent-conduramine E-1	Bu4NIO4	[14]
29	N-benzyl ent conduramine E-1	benzylamine	[30]
30	(–)-conduramine E-2	(R)-α-methyl-p-methoxybenzylamine	[32]
31	N-tosyl dihydroconduramine E-2	p-toluenesulfonyl isocyanate	[17]
32	conduramine F-1	phthalimide	[7]
33	ent-conduramine F-1	7-azabicyclo[2.2.1]heptane-2-ol	[10]
34	(+)-ent-conduramine F-1	Bu4NIO4	[14]
35	(–)-conduramine F-1	d-serine	[21]
36	N-benzyl conduramine F-1	benzylamine	[30]
37	dihydro conduramine F-1	benzylamine	[30]
38	ent-conduramine F-1	bis-Weinreb amide	[31]
39	tetraacetyl ent-conduramine F-1	azide ion	[34]
40	ent-conduramine F-2	p-toluene sulfonamide	[33]
41	(–)-conduramine F-4	p-toluene sulfonamide	[25]
42	tetracetyl ent-conduramine F-4	sodium azide	[34]
43	N-substituted conduramine F-4	alkyl amine	[23]

Table 2 Synthetic Approaches to Conduramine Targets

Entry	Conduramine name	No. of synthetic routes reported	Reference
1	conduramine A and its isomers	11	[4] [12] [13] [14] [18] [20] [24] [27] [29] [32]
2	conduramine B and its isomers	4	[28] [33] [34] [36]
3	conduramine C and its isomers	3	[1] [4] [34]
4	conduramine D and its isomers	2	[1] [34]
5	conduramine E and its isomers	10	[10] [12] [14] [15] [17] [19] [30] [32]
6	conduramine F and its isomers	12	[7] [10] [14] [21] [23] [30] [31] [33] [34]

Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

IICT communication number IICT/Pubs./2022/236.
Dr. B. V. Rao thanks the Director of CSIR-IICT for constant support and encouragement.

• References

• 1 Rajender A, Rao BV. Tetrahedron Lett. 2013; 54: 2329
• 2 Kanieda Y, Asano N, Teranishi M, Matsui K. J. Antibiot. 1980; 33: 1573
• 3 Leung T.-R, Liu Y, Muchowski JM, Wu Y.-L. J. Org. Chem. 1998; 63: 3235
• 4 Norsikian S, Soulé J.-F, Cannillo A, Guillot R, Dau M.-ET. H, Beau J.-M. Org. Lett. 2012; 14: 544
• 5 Łysek R, Vogel P. Tetrahedron 2006; 62: 2733
• 6 Duchek J, Adams D.-R, Hudlicky T. Chem. Rev. 2011; 111: 4223
• 7 Lysek R, Schutz C, Favre S, O’Sullivan A.-C, Pillonel C, Krulle T, Jung PM.-J, Clotet-Codina I, Este JA, Vogel P. Bioorg. Med. Chem. 2006; 14: 6255
• 8 Forster A, Kovac T, Mosimann H, Renaud P, Vogel P. Tetrahedron: Asymmetry 1999; 10: 567
• 9 Le Drian C, Vionnet J.-P, Vogel P. Helv. Chim. Acta 1990; 73: 161
• 10 Pandey G, Tiwari KN, Puranik VG. Org. Lett. 2008; 10: 3611
• 11 Pandey G, Tiwari SK, Singh RS, Mali RS. Tetrahedron Lett. 2001; 42: 3947
• 12 Chang YK, Lo HJ, Yan TH. Org. Lett. 2009; 11: 4278
• 13 Jana CK, Grimme S, Studer A. Chem. Eur. J. 2009; 15: 9078
• 14 Lu PH, Yang CS, Devendar B, Liao CC. Org. Lett. 2010; 12: 2642
• 15 Chappell D, Drew MG. B, Gibson S, Harwood LM, Russell AT. Synlett 2010; 517
• 16 Gibson S. PhD Thesis 2004
• 17 Kelebekli L, Celik M, Kara Y. J. Chem. Res. 2010; 34: 54
• 18 Chang Y.-K, Lo H.-J, Yan T.-H. J. Chin. Chem. Soc. 2010; 57: 24
• 19 Ghosal P, Shaw AK. J. Org. Chem. 2012; 77: 7627
• 20 Trost BM, Malhotra S. Chem. Eur. J. 2014; 20: 8288
• 21 Kim JS, Kang J.-C, Yoo G.-H, Jin X, Myeong IS, Oh CY, Ham W.-H. Tetrahedron 2015; 71: 2772
• 22 Kim J.-Y, Mu Y, Jin X, Park S.-H, Pham V.-T, Song D.-K, Lee K.-Y, Ham W.-H. Tetrahedron 2011; 67: 9426
• 23 Kuno S, Higaki K, Takahashi A, Nanba E, Ogawa S. MedChemComm 2015; 6: 306
• 24 Maji B, Yamamoto H. J. Am. Chem. Soc. 2015; 137: 15957
• 25 Harit VK, Ramesh NG. J. Org. Chem. 2016; 81: 11574
• 26 Kumar V, Ramesh NG. Tetrahedron 2006; 62: 1877
• 27 Myeong I.-S, Kim J.-S, Lee Y.-T, Kang J.-C, Park S.-H, Jung C, Ham W.-H. Tetrahedron: Asymmetry 2016; 27: 823
• 28 Raghavan S, Chiluveru RK, Subramanian SG. J. Org. Chem. 2016; 81: 4252
• 29 Southgate EH, Pospech J, Fu J, Holycross DR, Sarlah D. Nat. Chem. 2016; 8: 922
• 30 Katakam R, Anugula R, Macha L, Rao BV. Tetrahedron Lett. 2017; 58: 559
• 31 Prasad KR, Rangari VA. Tetrahedron 2018; 74: 6689
• 32 Da Silva Pinto S, Davies SG, Fletcher AM, Roberts PM, Thomson JE. Org. Lett. 2019; 21: 7933
• 33a Harit VK, Ramesh NG. Org. Biomol. Chem. 2019; 17: 5951
• 33b Harit VK, Ramesh NG. Org. Biomol. Chem. 2019; 17: 6506
• 34 Lo HJ, Chang YK, Ananthan B, Lih YH, Liu KS, Yan TH. J. Org. Chem. 2019; 84: 10065
• 35 Lo HY, Chang YK, Yan TH. Org. Lett. 2012; 14: 5896
• 36 Narayana C, Khanna A, Kumari P, Sagar R. Asian J. Org. Chem. 2021; 10: 392
• 37 Narayana C, Kumari P, Ide D, Hoshino N, Kato A, Sagar R. Tetrahedron 2018; 74: 1957

Publication History

Received: 21 July 2022

Accepted after revision: 25 August 2022

Accepted Manuscript online:
29 August 2022

Article published online:
13 October 2022