DSpace at VNU: Total synthesis of gabosines

Job/Unit: O20477 /KAP1 Date: 04-07-12 16:28:55 Pages: 16 MICROREVIEW DOI: 10.1002/ejoc.201200477 Total Synthesis of Gabosines Dinh Hung Mac,[a,b] Srivari Chandrasekhar,[c] and René Grée*[a] Keywords: Natural products / Total synthesis / Secondary metabolites / Carbocycles / Cyclohexanones / Cyclohexenones / Carbasugars / Chiral pool / Stereoselective synthesis This review reports on the total synthesis of gabosines, a family of secondary metabolites containing trihydroxylated cyclohexanone or cyclohexenone cores Analysis of the different stategies used to prepare these natural products and their stereoisomers has been carried out with special atten- tion paid to the methods employed for the formation of the carbocyclic ring The different methods are compared in a table, and a discussion of future directions of research in this area is presented Introduction Gabosines are a family of secondary metabolites isolated from various Streptomyces strains The first compounds – KD16-U1 (identical to gabosine C)[1a] and COTC[1b] – were [a] Université de Rennes 1, Institut des Sciences Chimiques de Rennes CNRS UMR 6226, Avenue du Général Leclerc, 35042 Rennes Cedex, France Fax: +33-2-23236978 E-mail: rene.gree@univ-rennes1.fr [b] Hanoi University of Sciences, Medicinal Chemistry Laboratory, 19 Le Thanh Tong, Ha Noi, Viet Nam [c] Indian Institute of Chemical Technology, Division of Natural Products Chemistry, Hyderabad 500607, India isolated by Umezawa’s group in the early 1970s Gabosine B was isolated about ten years later from Actinomycetes strains.[1c] Since then, extensive studies have been performed by Thiericke, Zeeck and co-workers, starting from 1993,[2] and to date 15 gabosine derivatives have been characterised; their structures are given in Figure These natural products can be classified into the family of carbasugars.[3] These base-sensitive ketocarbasugars each contain a trihydroxylated cyclohexanone or cyclohexenone core with a methyl or hydroxymethyl substituent Their structural diversity is due to variations of relative and absolute configuration at their two to four asymmetric centres and/or the Dinh Hung Mac born in Hai Phong, Viet Nam, in 1982, graduated (BSc degree in Chemistry) at the Hanoi University of Science, VNU, Viet Nam in 2004 and obtained his Master’s degree in Molecular Chemistry at the Université du Maine, France in 2006 He did his doctoral studies on the tandem isomerisation/aldolisation of allylic alcohol in the presence of pentacarbonyliron as catalyst under the supervision of Dr René Grée at the University of Rennes (2006–2009) After postdoctoral work at the University of Paris-Sud in 2010 in the group of Prof Jean-Daniel Brion, he came back to HUS as lecturer in Medicinal Chemistry, faculty of Chemistry Srivari Chandrasekhar was born in 1964 in Hyderabad, India He underwent all his primary education in Hyderabad After obtaining his PhD under the supervision of Dr A V Ramarao at IICT, he moved to the University of Texas Southwestern Medical School for postdoctoral study with Prof J R Falck and then to the University of Göttingen, Germany as Alexander von Humboldt fellow in the group of Prof L F Tietze His research interests include total synthesis of marine natural products, new solvent media for organic synthesis and process development of APIs He is a recipient of the NASI-Reliance Platinum Jubilee award and Ranbaxy Research award and a Fellow of the Indian Academy of Sciences René Grée graduated from ENSCR in 1970, and after a PhD with Prof R Carrié at the University of Rennes, he moved to Ohio State University for postdoctoral study with Prof L A Paquette He holds a position as Directeur de Recherche Classe Exceptionelle CNRS The major research interests of his group are organometallic catalysis and asymmetric synthesis, fluorine chemistry, chemistry in and with ionic liquids and total synthesis of bioactive natural products and structural analogues for applications in medicinal chemistry He won the award of the Organic Chemistry Division of the French Chemical Society in 1985, and from 1990 to 2002 he also held a part-time professor position at the Ecole Polytechnique (Paris) Eur J Org Chem 0000, 0–0 © 0000 Wiley-VCH Verlag GmbH & Co KGaA, Weinheim Job/Unit: O20477 /KAP1 Date: 04-07-12 16:28:55 Pages: 16 D H Mac, S Chandrasekhar, R Grée MICROREVIEW nature of substituents on the carbon chain (Me, CH2OH or substituted hydroxymethyl) one.[14] Later, it was demonstrated that COTC acts as a prodrug and that the active inhibitor was the corresponding glutathionyl-substituted derivative.[15] The use of COTC to reverse anticancer drug resistance has also been described.[16] It inhibits alkaline phosphodiesterase and DNA polymerase α.[17] It acts synergistically with aclarubicine as an anticancer drug.[1b,13,17] Total Synthesis of Gabosines Figure Gabosine family of secondary metabolites The stereochemical configurations of natural gabosines, including their absolute configurations, were first established mainly on the basis of spectroscopic methods for gabosines A,[2] B,[1c] C,[1] D,[2] E,[2] F,[2] G,[2] H,[2] I,[2,4] J,[2] K,[2] L,[5] N,[5] and O.[5] These assignments were confirmed later by total syntheses except in the case of gabosine K, in which a first synthesis indicated that the originally assigned structure needed to be corrected,[6] which was achieved through a new total synthesis.[7] On the other hand, gabosine I was found to be identical to valienone, an intermediate in the biosynthesis of validamycin A.[8] Interestingly, gabosine-type metabolites have been detected in a large number of Streptomycetes strains Their biosynthesis has been studied in detail by Thiericke, Zeeck and co-workers.[9] Although their structures seem to be related to that of shikimic acid, they are obtained in a process different from the shikimate pathway These secondary metabolites are formed by a pentose phosphate pathway through cyclisation of heptulose phosphate intermediates Further, it is worthy of note that enantiomeric gabosines can be obtained from different strains and that gabosine B is the enantiomer of gabosine F Up to now, most of the gabosines have not shown very significant biological activities They have so far displayed no antibacterial, antifungal, antiviral, herbicidal or insecticidal properties but have exhibited weak antiprotozoal activity, and gabosine E is also a weak inhibitor of de novo cholesterol biosynthesis.[2] Furthermore, gabosines A, B, F, N and O, but not gabosines E, H and J, exhibit weak DNAbinding properties.[10] Plant growth regulating effects[11] and inhibition of glycosidases[12] have also been reported Gabosine C and its crotonyl ester (COTC) were envisaged as potential anticancer agents, because they exhibit cytotoxic and cancerostatic activities with low toxicities.[13] In this context COTC was established to be an inhibitor of glyoxalase I, but only in the presence of reduced glutathi2 www.eurjoc.org Several strategies for elegant total synthesis of gabosines have been designed The most obvious way to access these carbasugars is to start from carbohydrates This so-called “sugars-to-carbasugars” strategy has been the most commonly used approach and is therefore presented first The emphasis here is on the key reaction(s) employed to build the carbocycle In the second part, use of other molecules from the chiral pool – essentially quinic and tartaric acids – is discussed Asymmetric syntheses from non-natural chiral starting materials are then reviewed, followed by very interesting examples of chemoenzymatic approaches Finally, a table reporting all syntheses of gabosines and their stereoisomers is presented and used for analysis of these synthetic efforts as well as possible directions for future research Total Synthesis of Gabosines Starting from Carbohydrates Intramolecular 1,2-addition to a carbonyl group, in an acyclic system, is the first possibility for building the carbocycle This strategy was used by Lubineau and Billaut for the synthesis of gabosine I (Scheme 1).[4] Intermediate was easily prepared in five steps and 67 % yield from d-glucose Scheme Synthesis of gabosine I with an intramolecular Nozaki– Kishi reaction as key step (a) PCC, AcONa, MS (4 Å), CH2Cl2, 90 %; (b) Ph3PCHBr, THF, 74 %; (c) (i) TBAF, THF, 80 %, (ii) Swern oxidation, 89 %; (d) CrCl2, NiCl2 (0.1 %), DMF, 61 %; (e) (i) PCC, AcONa, MS (4 Å), CH2Cl2, 76 %, (ii) BCl3, CH2Cl2, 74 % Oxidation to 2, followed by a Wittig reaction, gave the (Z)-vinyl bromide with high stereoselectivity After alcohol deprotection and oxidation, key aldehyde intermediate was obtained Although the cyclisation of the derived organomagnesium reagent under Barbier’s conditions failed, a Nozaki–Kishi reaction gave the desired cyclohexenols as a 1:1 mixture of stereoisomers Oxidation with PCC/AcONa, followed by a final deprotection step with BCl3, afforded gabosine I in 12 steps and 10.8 % overall yield from d-glucose © 0000 Wiley-VCH Verlag GmbH & Co KGaA, Weinheim Eur J Org Chem 0000, 0–0 Job/Unit: O20477 /KAP1 Date: 04-07-12 16:28:55 Pages: 16 Total Synthesis of Gabosines A second useful strategy for the preparation of such cyclohexenones is intramolecular aldolisation followed by dehydration A first example was described by Corsaro et al in the synthesis of 2-epi-3-epigabosine B and di-O-benzylprotected ent-gabosine A (Scheme 2).[18] Scheme Synthesis of di-OBn-ent-gabosine A and 2-epi-3-epigabosine B with use of an intramolecular aldol reaction as key step (a) CH2I2, Et2Zn, Et2O, quantitative; (b) Hg(OCOCF3)2, anhydrous MeOH, room temp., then NaCl/H2O, 98 %; (c) NaBH4, THF, room temp., 71 % from 6; (d) CF3CO2H, CH3CN/H2O, room temp., 20 % (9) and 65 % (10); (e) Pd/C, H2, MeOH, 92 % The starting sugar derivative was prepared in two steps and 26 % yield from d-galactose The first key point in this strategy was the introduction of the methyl group necessary for gabosines This was done in two steps Firstly, cyclopropanation was performed on to afford in high yield and with excellent stereocontrol Mercury-mediated ring opening, followed by reductive demercuration with NaBH4 then gave intermediate Hydrolysis to the bis(carbonyl) intermediate, followed by the key intramolecular aldol and dehydration reactions, gave a mixture of di-O-benzyl-entgabosine A (9) and its diastereoisomer 10, which were separated by chromatography Stereoselective hydrogenation of 10 afforded 2-epi-3-epigabosine B (11, 11 % overall yield in seven steps from d-galactose) Other examples of intramolecular aldol condensations for the synthesis of ent-gabosine A and of gabosines D and E were reported by Shing’s group.[19] These derivatives have the same trihydroxycyclohexenone framework and so could be obtained from the same sugar, d-glucose (Scheme 3) Diketone 12, prepared in six steps and 37 % yield, was subjected to the key l-proline-mediated intramolecular aldol reaction, followed by dehydration to afford the first important intermediate: enone 13 With such a mixed acetal as protective group, this molecule seems best suited for the preparation of gabosines with allylic CH2OH (R) groups, but it can also be used for molecules with methyl groups in those positions Stereoselective reduction of 13 with K-selectride, followed by alcohol protection to afford 14 and removal of the isopropylidene protective group, gave the second key intermediate 15 Simple functional-group transformations then afforded the target molecules Mesylation of the primary alcohol and subsequent reduction gave derivative 16 with the required allylic methyl group Oxidation followed by deprotections gave ent-gabosine A (15 steps and 14.4 % overall yield from d-glucose) Eur J Org Chem 0000, 0–0 Scheme Synthesis of ent-gabosine A and of gabosines D and E through the use of an intramolecular aldolisation reaction as key step (a) (i) l-Proline, DMSO, 82 %, (ii) POCl3, pyridine, 99 %; (b) (i) K-Selectride, THF, –78 °C, 99 %, (ii) TBSCl, imidazole, DMF, 95 %; (c) AcOH (80 %), 88 %; (d) (i) MsCl, 2,4,6-collidine, CH2Cl2, –78 °C, (ii) LiEt3BH, THF, –78 °C, 84 % for two steps; (e) (i) PDC, MS (3 Å), CH2Cl2, 92 %, (ii) TFA, H2O, CH2Cl2, 90 %; (f) TBSCl, imidazole, CH2Cl2, 97 %; (g) (i) PDC, MS (3 Å), CH2Cl2, 100 %, (ii) TFA, H2O, CH2Cl2, 87 %; (h) AcCl, 2,4,6-collidine, CH2Cl2, –78 °C, 94 %; (i) (i) PDC, MS (3 Å), CH2Cl2, 91 %, (ii) TFA, H2O, CH2Cl2, 89 % On the other hand, gabosine D was obtained from 15 after three steps: acetylation, oxidation and deprotections (14 steps and 15.8 % overall yield from d-glucose) Similarly, gabosine E was prepared in three further steps from 15 and obtained in 14 steps and 17.5 % overall yield from d-glucose The synthesis of gabosine K, a diastereoisomer of gabosine D, was performed by starting from the same intermediate 13 (Scheme 4).[7] Reduction of 13, under Luche conditions gave (after alcohol protection) silyl ether 19 The same reactions as described above then afforded gabosine K in 15 steps and 13.5 % overall yield from d-glucose Scheme Synthesis of gabosine K through the use of an intramolecular aldolisation reaction as key step (a) (i) NaBH4, MeOH, CeCl3·7H2O, (ii) Ac2O, DMAP, Et3N, CH2Cl2, (iii) K2CO3, MeOH, (iv) TBSCl, imidazole, CH2Cl2, 81 % for four steps; (b) AcOH (80 %), 84 %, (c) (i) AcCl, 2,4,6-collidine, CH2Cl2, –30 °C, (ii) TFA, H2O, CH2Cl2, 79 % for two steps Another fruitful alternative for the preparation of desired cyclohexenones is the intramolecular Horner–Wadsworth– Emmons (HWE) reaction, developed mainly by Shing’s group Their starting material was δ-d-gluconolactone (21, Scheme 5), an industrial product obtained from d-glucose © 0000 Wiley-VCH Verlag GmbH & Co KGaA, Weinheim www.eurjoc.org Job/Unit: O20477 /KAP1 Date: 04-07-12 16:28:55 Pages: 16 D H Mac, S Chandrasekhar, R Grée MICROREVIEW by bio-oxidation Different protective groups were used for the alcohol functions Firstly, the synthesis of gabosines G and I was described.[20] Lactone 22, obtained by treatment of 21 with 2-methoxypropene, was first treated with the lithium derivative of diethyl methylphosphonate to afford 23 A one-pot oxidation/cyclisation sequence gave the desired enone 24 in 43 % yield, after optimisation of conditions for this key reaction Deprotection afforded gabosine I (four steps, 20.3 %), and regioselective acetylation gave gabosine G (five steps, 13.2 %) from d-glucolactone HWE reaction gave enone 28 and, after deprotection, gabosine I in a higher yield (five steps and 65 % overall yield from d-glucose) than in the previous synthesis On the other hand, reduction of 28 under Luche’s conditions gave 29 with a high stereoselectivity (82:9) Subsequent deprotection, followed by selective acetylation, gave gabosine K in seven steps and 40 % overall yield from δ-d-gluconolactone 21 A third variant, with a combination of protective groups, was proposed by the same group and used for another synthesis of gabosine I, as shown in Scheme 7.[22] A mixed acetal was employed to protect the OH groups in the 2- and the 3-positions in glucose, together with an EOM group to protect that in the 4-position Intermediate 30 and lactone 31 were obtained from d-glucose through selective protection steps The same sequence of reactions as described above was then used to prepare hydroxyphosphonates 32 and 33 The same key one-pot oxidation/HWE reaction procedure was used to obtain enone 34, and a final deprotection step afforded gabosine I in 10 steps and 27 % overall yield from d-glucose Scheme Synthesis of gabosines G and I through the use of an intramolecular HWE reaction as key step (a) 2-methoxypropene, CSA, DMF, 72 %; (b) (i) LDA, THF, (EtO)2POCH3, (ii) H3O+, 78 % for two steps; (c) TPAP, NMO, MS (3 Å), CH3CN, K2CO3, 43 %; (d) TFA, H2O, CH2Cl2, 95 %; (e) AcCl, collidine, –40 °C to room temp., 65 % Gabosine I and gabosine K were prepared by same strategy but with different protection – the EOM group – on the gluconolactone (Scheme 6).[21] Scheme Alternative synthesis of gabosine I through the use of an intramolecular HWE reaction as key step (a) (i) EOMCl, DIPEA, CH2Cl2, r.t., 16 h, 99 %, (ii) H2, Pd/C, EtOH, r.t., 12 h, 94 %, (iii) PDC, MS (3 Å), CH2Cl2, h, room temp., 92 %; (b) LDA, THF, CH3PO(OMe)2 –78 °C, 15 min, 96 %; (c) NaBH4, MeOH, °C, r.t., 15 min, 96 %; (d) (i) TFAA, DMSO, CH2Cl2, –78 °C, h, (ii) DIPEA, –78 °C, 15 min, (iii) TEA, LiCl, r.t., 15 min, 78 % for three steps; (e) TFA, H2O, r.t., min, 96 % A synthesis of gabosine C and COTC by Vasella’s group was also based on an intramolecular HWE reaction to build the carbocycle (Scheme 8).[23] Scheme Synthesis of gabosines I and K through the use of an intramolecular HWE reaction as key step (a) EOMCl, 2,6-lutidine, 93 %; (b) (MeO)2POCH2Li, THF, –78 °C, 15 min, 95 %; (c) NaBH4, MeOH, 96 %; (d) (i) TFAA, DMSO, CH2Cl2, –78 °C, (ii) Et3N, –78 °C to room temp., 80 % for two steps; (e) TFA, H2O, room temp., min, 96 %; (f) NaBH4, MeOH, CeCl3·7H2O, 82 %; (g) (i) TFA, H2O, 89 %, (ii) AcCl, 2,4,6-collidine, CH2Cl2, –30 °C, 80 % Addition of phosphonate anion to 25 afforded 26 in excellent yield A two-step reduction/oxidation protocol was found to afford ketophosphonate 27 in best yields The www.eurjoc.org Scheme Synthesis of gabosine C and COTC through the use of an intramolecular HWE reaction as key step (a) (i) PDC, MS (3 Å), CH2Cl2, (ii) Et3N, CH2Cl2, (iii) NaBH4, iPrOH, (iv) O3, –78 °C, CH2Cl2; (b) TBSCl, DMF, imidazole, 72 % from 35; (c) CH3PO(OMe)2, nBuLi, THF, –78 °C, 62 %; (d) Me3Al, HSPh, CH2Cl2, –78 °C, then HCHOgas bubbled through mixture at –50 °C, NH4Claq, 66 % of a mixture of diastereoisomers, (e) mCPBA, CH2Cl2, °C, 91 %; (f) TFA (60 %), 100 %; (g) crotonic acid, BF3·Et2O, MS (4 Å), CH3CN, 48 % © 0000 Wiley-VCH Verlag GmbH & Co KGaA, Weinheim Eur J Org Chem 0000, 0–0 Job/Unit: O20477 /KAP1 Date: 04-07-12 16:28:55 Pages: 16 Total Synthesis of Gabosines Benzoate 35 was obtained in three steps and 78 % yield from d-mannose It was converted into 36 by treatment with Et3N to perform β-elimination and subsequent reduction with NaBH4 and ozonolysis Protection afforded silyl ether 37 in 72 % yield from 35 without isolation of unstable intermediates The first key step was treatment with the anion of dimethyl methylphosphonate to give cyclohexenone 38 directly The second key step, the introduction of the CH2OH chain, was then carried out by treatment with Me2AlSPh, followed by trapping with formaldehyde to give 39 The corresponding sulfoxide underwent β-elimination to afford 40 Deprotection afforded gabosine C (21 % overall yield in 11 steps from d-mannose), and COTC was then obtained by esterification with crotonic acid Ring closing metathesis (RCM) is another very fruitful strategy for accessing carbocycles It has been successfully used to prepare some gabosines, starting from different sugars The first examples were described by Rao’s group, in preparations of gabosine C, ent-gabosine N and ent-gabosine O with use of d-ribose as starting material (Scheme and Scheme 10, below) Scheme Synthesis of gabosine C and COTC through the use of a ring closing metathesis reaction as key step (a) Vinylmagnesium bromide, THF, –78 °C to °C, h, 70 %; (b) (i) Piv-Cl, 2,6-lutidine, DMAP, CH2Cl2, °C to room temp., 12 h, 74 %, (ii) MOMCl, DIPEA, TBAI, CH2Cl2, °C to room temp., 24 h, 83 %, (iii) NaOMe, MeOH, °C to room temp., h, 75 %; (c) (i) Swern oxidation, (ii) A, CrCl2, NiCl2, DMF, room temp., 24 h, 84 % for two steps; (d) second-generation Grubbs catalyst (10 mol-%), CH2Cl2, 80 °C, 48 h, 56 %; (e) PDC, CH2Cl2, °C to room temp., 24 h, 78 %; (f) Amberlyst®15, THF/H2O (2:1), 70 °C, h, 50 % Lactol 41, easily obtained in three steps and 74 % yield from d-ribose, gave diol 42 after treatment with a vinyl Grignard reagent After protection and deprotection steps, followed by oxidation, a Nozaki–Kishi reaction was performed on the intermediate aldehyde to give diene 44 The key RCM reaction, in the presence of the second-generation Grubbs catalyst, afforded cyclohexenone 45 in 86 % yield Oxidation to 46, followed by deprotection reactions, afforded gabosine C in 12 steps and 4.4 % overall yield from d-ribose.[24] ent-Gabosine N and ent-gabosine O were prepared by a similar strategy, as indicated in Scheme 10.[25] Protected lactol 47 was easily prepared in two steps from d-ribose (61 % yield) A Wittig reaction gave 48, and in three classical steps intermediate aldehyde 49 was obtained Eur J Org Chem 0000, 0–0 Scheme 10 Synthesis of ent-gabosines N and O through the use of a ring closing metathesis reaction as key step (a) (i) Ph3P=CH2, THF, –78 °C to room temp., h, (ii) MOMCl, DIPEA, DMAP (cat.), CH2Cl2, –15 °C to room temp., 12 h, 71 % for two steps; (b) (i) TBAF, THF, h, 95 %, (ii) Swern oxidation; (c) 2-bromopropene, CrCl2, NiCl2, 12 h, 72 %; (d) second-generation Grubbs catalyst, toluene, reflux, 12 h, 85 %; (e) PDC, CH2Cl2, MS (4 Å), 12 h, 82 %; (f) Amberlyst®15, THF/H2O (2:1), 70 °C, h, 75 %; (g) H2, Pd/C, MeOH, h, 95 %; (h) Amberlyst®15, THF/H2O (2:1), 70 °C, h, 85 % This was submitted to a Nozaki–Kishi reaction to afford allylic alcohols 50 (3.8:1 mixture of stereoisomers) Under the same conditions as above, the key RCM reaction yielded cyclohexenols 51 in 85 % yield Oxidation to 52, followed by deprotection, afforded ent-gabosine N in 10 steps and 18.2 % overall yield from d-ribose On the other hand, hydrogenation of 52 was fully stereoselective (reaction occurring from the face anti to the bulky protecting groups), affording 53 and, after deprotection, ent-gabosine O (11 steps and 19.5 % overall yield from d-ribose) RCM was also employed by Madsen’s group for the synthesis of gabosines A and N (Scheme 11).[26] Iodo derivative 54 was prepared from d-ribose in two steps and 78 % yield On treatment of 54 with zinc, an interesting tandem reaction occurred, affording an intermediate aldehyde, which was trapped by an allylmetal reagent derived from 55 This sequence afforded a 2:1 mixture of alcohol 56 and its diastereoisomers, which were separated by chromatography The sequence was continued with 56 RCM in the presence of the second-generation Grubbs catalyst afforded 57 in excellent yield, and two protection/deprotection steps yielded 58 Oxidation, followed by a final deprotection, gave gabosine N (eight steps and 17.1 % yield from d-ribose) On the other hand, inversion of the configuration in 57 was performed on the free alcohol, and the same reaction sequence afforded gabosine A in nine steps and 18.5 % overall yield from d-ribose Ferrier carbocyclisation (also known as Ferrier II rearrangement) is a widely used method for transformation of pyranoses into six-membered carbocycles It was used by Shaw’s group to prepare four examples of gabosines (Scheme 12 and Scheme 13, below).[27] Iodo derivative 61, obtained from d-glucose in four steps and 62 % yield, was © 0000 Wiley-VCH Verlag GmbH & Co KGaA, Weinheim www.eurjoc.org Job/Unit: O20477 /KAP1 Date: 04-07-12 16:28:55 Pages: 16 D H Mac, S Chandrasekhar, R Grée MICROREVIEW Scheme 11 Synthesis of gabosines A and N through the use of a ring closing metathesis reaction as key step (a) Zn, THF, H2O, 40 °C, sonication 58 %; (b) second-generation Grubbs catalyst, CH2Cl2, 40 °C, 97 %; (c) (i) DHP, PPTS, CH2Cl2, room temp 75 %, (ii) NaOMe, MeOH, room temp., 83 %; (d) PDC, CH2Cl2, room temp., 71 %; (e) AcOH, H2O, room temp to 40 °C, 88 %; (f) (i) Tf2O, pyridine, CH2Cl2, –20 °C to room temp., then NaNO2, DMF, room temp., (ii) DHP, PPTS, CH2Cl2, room temp 85 %; (g) (i) NaOMe, MeOH, room temp., (ii) PDC, CH2Cl2, room temp., (iii) AcOH, H2O, 40 °C, 40 % for three steps subjected to dehydrohalogenation followed by protection of the free hydroxy group to afford exopyranoside 62 This intermediate was ready for the key Ferrier carbocyclisation in the presence of mercury(II) trifluoroacetate, followed by mesylation to afford enone 63 in 70 % yield To introduce the required methyl group on the double bond, a two-step sequence was then employed: iodination to 64, followed by a Stille cross-coupling reaction with Me4Sn to give 65 A final deprotection step gave 4-epigabosine A in 11 steps and 12.9 % yield from d-glucose The same sequence of reac- Scheme 12 Synthesis of gabosine A and 4-epigabosine A through the use of a Ferrier carbocyclisation reaction as key step (a) (i) tBuOK, THF, °C to room temp., 24 h, (ii) BnBr, NaH, DMF, °C to room temp., h, 64 % for two steps; (b) (i) Hg(OCOCF3)2, (CH3)2CO/H2O (1:1), h, (ii) MsCl, CH2Cl2, Et3N, °C to room temp., h, 70 % for two steps; (c) I2, DMAP, CCl4/pyridine (1:1), °C to room temp., h, 90 %; (d) Me4Sn, AsPh3, Pd2(dba)3, CuI, sealed tube, THF, 80 °C, 36 h, 72 %; (e) BCl3, CH2Cl2, °C, h, 64 % www.eurjoc.org tions was followed starting from d-mannose, affording gabosine A in 11 steps and 10.8 % overall yield A similar approach was followed for the synthesis of two other derivatives, 2-epi-3-epigabosine E and ent-gabosine E In that case, however, a CH2OH group had to be introduced on the double bond, and the authors considered the possible use of a Morita–Baylis–Hillman reaction (Scheme 13) However, this reaction did not work when starting from the above benzyl-protected intermediate 63, affording only an aromatised product, so a change to an acetate-protected derivative was considered Enone 69, prepared by same route as described above, reacted with formaldehyde in the presence of DMAP to give the desired adduct 70 After deprotection steps, 2-epi-3-epigabosine E was obtained in 11 steps and 6.4 % overall yield from glucose Similar reactions gave ent-gabosine E in 11 steps and 6.5 % overall yield from d-mannose Scheme 13 Synthesis of ent-gabosine E and 2-epi-3-epigabosine E through the use of a Ferrier carbocyclisation reaction as key step (a) (i) tBuOK, THF, 24 h, °C to room temp., (ii) Ac2O, pyridine, °C, h, 64 %; (b) (i) Hg(OCOCF3)2, (CH3)2CO/H2O (1:1), h, (ii) MsCl, CH2Cl2, Et3N, °C to room temp., h, 72 % for two steps, (c) HCHO, DMAP, THF, –10 °C, d, 49 %; (d) (i) pTsOH·H2O, CH2Cl2/MeOH (9:1), (ii) BCl3, CH2Cl2, °C, h, 46 % for two steps A new iron-catalysed reaction, complementary to the Ferrier carbocyclisation, was developed by us to prepare six gabosine derivatives.[28,29] It was first demonstrated by the synthesis of 4-epigabosine A and 4-epigabosine B, starting from d-glucose (Scheme 14) Vinylic pyranoside 73 was prepared from glucose by known reactions in six steps and 26 % overall yield The key carbonyliron-catalysed tandem isomerisation/aldolisation sequence produced aldols 74, as a mixture of stereoisomers, in 95 % yield Treatment of this mixture with MsCl and Et3N gave enone 75 One of the interesting aspects of this approach is that it directly introduces the required methyl group in the appropriate position on the carbocycle Deprotection of 75 afforded 4-epigabosine A, whereas hydrogenation gave 76 and then 4-epigabosine B These two target molecules were obtained in nine and ten steps and 9.4 % and 14.5 % overall yields, respectively, from d-glucose.[28] Similar reactions were performed from mannose to afford gabosine A and 6-epigabosine O in nine steps and in 5.7 % and 6.9 % overall yields, respectively, from d-mannose 4-Epigabosine N and 4-epi-6-epigabosine B were similarly prepared in nine steps and 8.8 % and 5.5 % overall yields, respectively, from d-galactose.[29] © 0000 Wiley-VCH Verlag GmbH & Co KGaA, Weinheim Eur J Org Chem 0000, 0–0 Job/Unit: O20477 /KAP1 Date: 04-07-12 16:28:55 Pages: 16 Total Synthesis of Gabosines first involved the preparation of ent-gabosine C and gabosine E from d-ribose (Scheme 16).[31] Scheme 14 Synthesis of six gabosine derivatives through the use of an iron-catalysed carbocyclisation reaction as key step (a) Fe(CO)5 (10 mol-%), THF, hν, h, 95 %; (b) MsCl, Et3N, CH2Cl2; (c) FeCl3, CH2Cl2, °C, 15 min; (d) H2, Pd/C, EtOH, h; (e) H2, Pd/C, EtOH, d Another aldol-like condensation was used for the preparation of gabosine C and COTC (Scheme 15).[30] Scheme 15 Synthesis of gabosine C and COTC through the use of a SnCl4-mediated aldol-like cyclisation as key step (a) (i) TBSOTf, 2,6-lutidine, (ii) H2, Pd/C, (iii) DCC Py·TFA, DMSO/Et2O, (iv) HC(OMe)3, CSA/MeOH, 64 % for four steps; (b) MeSO3Ph, nBuLi/THF, 90 %; (c) TBSOTf, 2,6-lutidine, 74 %; (d) SnCl4, CH2Cl2, 85 %; (e) (i) Bu3SnLi, THF then HCHOgas bubbling through mixture, (ii) SiO2/PhH, 70 % for two steps; (f) 90 % TFA, 86 %; (g) crotonic acid, BF3·Et2O, MeCN, 71 % The trityl-protected lactone 77, easily obtained from dribose in two steps and 81 % yield, was transformed in a few classical steps [bis(silylation), deprotection of the primary alcohol followed by oxidation and acetal formation] into intermediate 78 Addition of lithiated methyl sulfone afforded 79, which, after silylation, gave the labile silyl enol ether 80 In the key step, an SnCl4-induced aldol-like cyclisation yielded cyclohexenone 81 The sulfonyl group was used again to solve the second problem, the introduction of the CH2OH group Treatment with (tributylstannyl)lithium, followed by trapping with formaldehyde, afforded (after treatment with silica gel) the protected gabosine derivative 82 Deprotection gave gabosine C in 11 steps and 19.8 % overall yield from ribose The use of intramolecular 1,3-dipolar cycloadditions was another very attractive strategy to access gabosines Three syntheses have been reported; the first two used nitrile oxides as 1,3-dipoles, whereas the last employed nitrones The Eur J Org Chem 0000, 0–0 Scheme 16 Synthesis of ent-gabosine C and gabosine E through the use of an intramolecular nitrile oxide cycloaddition reaction as key step (a) Vinylmagnesium bromide (10 equiv.), THF, room temp., 90 %; (b) (i) TBSCl, pyridine, DMAP, (ii) BzCl, pyridine, (c) (i) 2,3-dihydrofuran, PPTS, CH2Cl2, (ii) TBAF, THF, room temp., (iii) Swern oxidation, (iv) HCl·H2NOH, pyridine, MeOH, room temp., 59 % from 84; (d) NaOCl, Et3N, CH2Cl2, 60 %; (e) H2, Raney-Ni, EtOH, AcOH, 89 %; (f) DABCO, THF, 80 % (mixture 2:1 of 89/90); (g) TFA, CH2Cl2 (95 % from 89, 100 % from 90) Lactol 83 was prepared from d-ribose in one step and 70 % yield Treatment with vinyl Grignard reagent gave allylic alcohol 84 Selective protections of the three alcohols (TBS, benzoate and tetrahydrofuranyl) gave the key intermediate 85 In particular, the benzoate protection in the allylic position proved to be important for the success of the next steps From oxime 86, the key intramolecular nitrile oxide cycloaddition (INOC) gave isoxazoline 87 in 60 % yield Hydrogenolysis then afforded ketone 88 in 89 % yield The next step, elimination of benzoic acid, was not straightforward because of possible aromatisation, as well as epimerisation reactions A DABCO-mediated reaction gave mixtures of 90 (formed first) and 89 with a 2:1 ratio at equilibrium After separation, treatment with trifluoroacetic acid yielded ent-gabosine C (12 steps and 10 % overall yield from d-ribose) and gabosine E (12 steps and 5.4 % overall yield from d-ribose), respectively A second example of the use of INOC reactions was developed by Shing’s group for the preparation of gabosine O and 4-epigabosine O from d-mannose, as well as of gabosine F from l-arabinose (Scheme 17 and Scheme 18, below).[32] The oxime 92 was easily prepared from d-mannose in four steps and 60 % yield The key INOC reaction, mediated by silica gel/chloramine, then afforded a mixture of isoxazolines 93α (65 %) and 93β (14 %) Mitsunobu inversion of configuration afforded alcohols 94α and 94β Hydrogenolysis of 94α or 94β (or mixtures of both) with Raney-nickel/acetic acid yielded the same 6:1 mixture of 95α/95β, due to equilibrium under the reaction conditions Water elimination could be performed with Martin’s sulfurane, under carefully controlled conditions, to give enone 96, which was hydrogenated from the less hindered face to 97 A final deprotection afforded 4-epigabosine O in 11 steps and 38 % yield from d-mannose © 0000 Wiley-VCH Verlag GmbH & Co KGaA, Weinheim www.eurjoc.org Job/Unit: O20477 /KAP1 Date: 04-07-12 16:28:55 Pages: 16 D H Mac, S Chandrasekhar, R Grée MICROREVIEW densation with methylhydroxylamine the intermediate nitrone underwent the desired 1,3-dipolar cycloaddition to afford isoxazolidine 106 plus its diastereoisomer at position C2 in a 2:1 ratio After separation by chromatography, the N–O bond of 106 was cleaved by hydrogenolysis to afford 107, and the primary alcohol was selectively protected to give 108 The final steps included quaternarisation of the amine, followed by oxidative elimination and deprotection By this route, ent-gabosine E was obtained in 11 steps and 12 % overall yield from d-mannose Scheme 17 Synthesis of 4-epigabosine O and gabosine O through the use of an intramolecular nitrile oxide cycloaddition reaction as key step (a) (i) H5IO6, Et2O, room temp., 18 h, 79 %, (ii) NH2OH, MeOH, room temp., d, 100 %; (b) chloramine-T, silica gel, EtOH, room temp., 15 min, 79 %, α/β = 4.6:1; (c) (i) PPh3, DIAD, pNO2BzOH, room temp., 15 h; (ii) LiOH (aq), 98 %; (d) H2, RaneyNi, AcOH, EtOH/H2O/1,4-dioxane (8:2:1), room temp., 12 h, 93 %, α/β = 6:1; (e) Martin’s sulfurane, THF, –78 °C, 10 min; (f) H2, Raney-Ni, AcOH, EtOH/H2O/1,4-dioxane (8:2:1), –78 °C, 10 h, 88 % from 95; (g) TFA, H2O, CH2Cl2, room temp., min, 100 %; (h) H2, Raney-Ni, AcOH, EtOH/H2O/1,4-dioxane (8:2:1), room temp., 12 h, 97 %, α/β = 5:1 By the same series of reactions, gabosine O was prepared from the 93α/93β mixture (nine steps, 41 % overall yield from d-mannose) On the other hand, the same strategy was also followed for the preparation of gabosine F (Scheme 18) Scheme 19 Synthesis of ent-gabosine E through the use of an intramolecular nitrone cycloaddition reaction as key step (a) MeNHOH·HCl, EtONa, EtOH then 20 °C, 24 h, 80 % (mixture of isomers); (b) Zn, AcOH, reflux, h; (c) TBSOTf, 2,6-lutidine, CH2Cl2, –78 °C, 45 min, 77 % from 106; (d) (i) MeI (excess), K2CO3, THF, 24 h, (ii) DMP oxidation, CH2Cl2, 20 °C, 30 min, 80 % for two steps; (e) BBr3, CH2Cl2, –78 °C, 45 min, 85 % Total Synthesis of Gabosines Starting from Other Natural Products Several gabosines have been prepared from quinic acid, whereas gabosine H has been obtained by starting from tartaric acid In the first case, a large proportion of the gabosine skeleton is already present in the starting material, but functional modifications have to be performed selectively Ganem’s group has described the synthesis of gabosine C and COTC (Scheme 20).[34] Scheme 18 Synthesis of gabosine F through the use of an intramolecular nitrile oxide cycloaddition reaction as key step (a) Chloramine-T, silica gel, EtOH, room temp., min, 94 %; (b) H2, RaneyNi, AcOH, EtOH/H2O/1,4-dioxane (8:2:1), room temp., 12 h, 90 %; (c) AcCl, 2,4,6-collidine, CH2Cl2, –78 °C, 12 h, 87 %; (d) Et3N, CH2Cl2, reflux, 11 h; (e) H2, Raney-Ni, AcOH, EtOH/H2O/1,4-dioxane (8:2:1), room temp., 12 h, 97 % from 102; (f) TFA, H2O, CH2Cl2, room temp., h, 100 % The oxime 99 was prepared from l-arabinose by known procedures in six steps and 34 % yield INOC afforded isoxazoline 100 in 94 % yield Ring opening to give 101, followed by regioselective acetylation to afford 102 and elimination, gave enone 103 Stereoselective hydrogenation, possibly directed by the free OH group, followed by deprotection, afforded gabosine F in 12 steps and 23 % overall yield from l-arabinose An intramolecular nitrone cycloaddition as a key step for the synthesis of ent-gabosine E from d-mannose was also reported by the group of Gallos (Scheme 19).[33] The vinylic derivative 105 was prepared from methyl d-mannoside by known procedures in six steps and 41.6 % yield Upon con8 www.eurjoc.org Scheme 20 Synthesis of gabosine C and COTC starting from quinic acid (a) Tf2O (2.2 equiv.), pyridine, CH2Cl2, 65 %; (b) CsOAc, DMF; (c) (i) NBS/H2O, DMF, (ii) Dibal-H, benzene/ toluene, 47 % from 112; (d) LiN(TMS)2, THF, –78 °C, 87 %; (e) MeSO3H, DMSO, room temp., 1.5 h, then Et3N, room temp., min, 71 %; (f) TFA/H2O (1:1), 88 % They started from acetonide 110, obtained in two steps and 77 % yield from quinic acid On treatment with triflic anhydride and base the intermediate bis(triflate) first spontaneously eliminated mol-equiv of triflic acid to give 111, © 0000 Wiley-VCH Verlag GmbH & Co KGaA, Weinheim Eur J Org Chem 0000, 0–0 Job/Unit: O20477 /KAP1 Date: 04-07-12 16:28:55 Pages: 16 Total Synthesis of Gabosines followed on treatment with a second base with a second, affording conjugated diene 112 The bromohydrin 113 was obtained in a two-step sequence: formation of a bromo formate by treatment with NBS in a mixture of DMF and water, followed by reduction of ester groups with DibalH Cyclisation to epoxide 114 was performed under basic conditions in good yield The desired opening of this epoxide was not straightforward but could be achieved under carefully controlled conditions (MeSO3H/DMSO and then Et3N) to give 115 Deprotection gave gabosine C in nine steps and 12.7 % overall yield from quinic acid Other examples were reported later by Ohfune’s group (Scheme 21).[35] Scheme 21 Synthesis of gabosines A and B and of ent-gabosines D and E starting from quinic acid (a) (i) (EtO)3P, EtOH, reflux, 16 h, 98 %, (ii) MOMCl (2 equiv.), iPr2NEt, CH2Cl2, 16 h, 90 %: (b) SeO2 (1 equiv.), pyridine N-oxide (0.5 equiv.), 1,4-dioxane, reflux, 16 h, 54 %; (c) Ac2O, DMSO (3:2), 18 h, 65 %; (d) NaOH (0.1 n)/THF (1:9), 40 min, 68 %; (e) AcONa, AcOH, 110 °C, 2.5 h, 71 %; (f) TFA/H2O (1:20), CH2Cl2, 2–4 h, 59 % from 120, 62 % from 121; (g) Pd/C (10 %, 50 % w/w), H2, MeOH, h, 60 %; (h) DMP (1.2 equiv.), CH2Cl2, 67 %; (i) NaOH (0.1 n), THF, h, 81 %; (k) TFA/H2O (1:20), CH2Cl2, 0.5 h, 90 %; (l) Pd/C (10 %, 50 % w/ w), H2, MeOH, h, 80 % (1:1 mixture of isomers); (m) DBU (0.5 equiv.), benzene, reflux, 16 h, 89 % The synthesis started from sulfoxide 116, prepared in four steps and 40 % overall yield from quinic acid Thermolysis in the presence of P(OEt)3 afforded the allylic alcohol in excellent yield, and this was protected as the MOM ether 117 After allylic oxidation, the alcohols 118 were oxidised to give the ketone 119 The next step, conjugate addition of water, followed by β-elimination of the MOM group, could be performed with NaOH solution (0.1 n) to afford 120 in 68 % yield On the other hand, addition of an acetoxy group yielded 121 Final deprotection steps gave ent-gabosine E and ent-gabosine D in 11 steps and 11.7 % and 13.3 % yields respectively from quinic acid Eur J Org Chem 0000, 0–0 Ketone intermediate 119 was considered as a possible precursor for gabosines A and B but all investigated methods for 1,4-addition of hydride were unsuccessful, so an alternative strategy was used Catalytic hydrogenation of 118 to afford 122 and subsequent oxidation gave 123 as a mixture of stereoisomers On treatment with NaOH, β-elimination occurred to give 124 Hydrogenation of 124 gave 125 in 80 % yield but as a 1:1 mixture of α- and β-stereoisomers However, DBU-mediated epimerisation afforded the desired molecule 125β Final deprotection steps afforded the desired gabosines A and B in 11 and 13 steps, respectively, in 8.3 % and 4.5 % overall yields from quinic acid Another useful chiral pool molecule is tartaric acid, employed by Prasad’s group for a short synthesis of gabosine H (Scheme 22).[36] The bis(amide) 126 was obtained from tartaric acid in two steps and 27 % overall yield A first selective addition of a Grignard reagent gave the monoketo monoamide 127 in good yield Reduction under Luche’s conditions gave the allylic alcohol 128 with good stereocontrol (9:1), and the major isomer was isolated by crystallisation Scheme 22 Synthesis of gabosine H starting from tartaric acid (a) CH2=CMeMgBr, THF, –15 °C, 0.5 h, 84 %; (b) NaBH4, CeCl3, MeOH, –78 °C, 1.5 h, 93 % (dr = 9:1), 83 % after recrystallisation; (c) CH2=CHMgBr, THF, –15 °C, 0.5 h, 65 %; (d) second-generation Grubbs catalyst (5 mol-%), CH2Cl2 (0.03 m), 50 °C, h, 62 %; (e) PPTS, MeOH, r.t., h, 92 % Addition of a second Grignard reagent afforded the ketone 129 in 65 % yield Ring closing metathesis in the presence of the second-generation Grubbs catalyst gave the desired cyclohexenone 130 in 62 % yield Final deprotection gave gabosine H in seven steps and % overall yield from tartaric acid A very recent synthesis of three gabosine derivatives by Krishna’s group started from 2,3-O-isopropylidene-l-threitol (131, Scheme 23), available from different sources, including from tartaric acid (two steps and 82 % yield).[37] Selective protection gave 132, which upon oxidation, followed by a Morita–Baylis–Hilman reaction under optimised conditions, afforded 133 as an inseparable mixture of stereoisomers Reduction of the ester to afford alcohol 134, followed by acetonide formation, gave 135 Deprotection of the primary alcohol afforded isomers 136 and 137, which were separated by chromatography The next reactions were performed independently on each stereoisomer Firstly, from minor isomer 137, oxidation of the primary alcohol and subsequent addition of © 0000 Wiley-VCH Verlag GmbH & Co KGaA, Weinheim www.eurjoc.org Job/Unit: O20477 /KAP1 Date: 04-07-12 16:28:55 Pages: 16 D H Mac, S Chandrasekhar, R Grée MICROREVIEW Scheme 23 Synthesis of gabosines I and G and of 4-epigabosine I starting from tartaric acid (a) TBDPSCl, imidazole, CH2Cl2, 79 %; (b) (i) Swern oxidation, 96 %, (ii) ethyl acrylate, DABCO, DMSO, 85 % (30 % de); (c) Dibal-H, CH2Cl2, –20 °C, 91 %; (d) 2,2-DMP, PTSA, CH2Cl2, °C, 94 %; (e) TBAF, THF, room temp (57.8 % for 136 and 31.2 % for 137); (f) (i) Swern oxidation, (ii) vinylMgBr, –20 °C, 87 % for two steps; (i) second-generation Grubbs catalyst, toluene, reflux, h, 83 %; (k) DMP oxidation, CH2Cl2, °C, 96 %; (l) TFA, CH2Cl2, °C, h vinyl Grignard reagent gave 138, as a mixture of isomers, but that was of no consequence, because the corresponding alcohol was to be oxidised later A ring closing metathesis was then performed, yielding 139 and, after oxidation, the desired enone 140 Final deprotection gave gabosine I in 11 steps and 11.8 % yield from 131 Gabosine G was also prepared from gabosine I, by literature procedures The same sequence of reactions starting from diastereoisomer 136 was followed, affording 4-epigabosine I in 11 steps and 21.8 % yield from 131 Total Synthesis of Gabosines Starting from Non-Natural Products Several gabosines have also been prepared by starting from non-natural products The first two examples used bicyclic systems obtained through Diels–Alder cycloaddition reactions The first, shown in Scheme 24, was described by Mehta’s group.[6] It started from bicyclic derivative 144, obtained in five steps and 60 % overall yield from 1,2,3,4-tetrachloro-5,5-dimethoxycyclopentadiene A key Grob-type fragmentation furnished the cyclohexene 145, which was transformed into 146 by a four-step sequence (dihydroxylation followed by protection as acetonide, reduction of the ester and tosylation) Elimination via the corresponding iodide gave the key intermediate alkene 147 Rhodium trichloride mediated isomerisation of the double bond then gave cyclohexene 148, which on hydrolysis afforded gabosine F, in racemic 10 www.eurjoc.org Scheme 24 Synthesis of gabosine F and 1-epi-4-epigabosine K starting from 1,2,3,4-tetrachloro-5,5-dimethoxycyclopentadiene (a) MeONa, MeOH, h, 70°%; (b) (i) LAH, THF, °C, 90 %, (ii) TsCl, pyridine, CH2Cl2, 94 %; (c) NaI, acetone, Δ, 30 h, 92 %, (ii) tBuOK, Δ, 20 h, 70 %; (d) RhCl3, NaHCO3, EtOH, Δ, 20 h, 60 %; (e) HCl (5 %), H2O/Et2O (4:1), room temp., 90 %; (f) OsO4, NMO, acetone/H2O (4:1), room temp., d, 95 %; (g) Ac2O, DMAP, °C, 30 min, SOCl2, pyridine, CH2Cl2, room temp., h, 45 % (mixture of isomers); (h) Amberlyst®15, THF/H2O (2:3), room temp., 48 h, 85 % from 150 form The stereoselectivity of the protonation step in this reaction is remarkable On the other hand, dihydroxylation of 147 gave diol 149 in a 70:30 ratio with its diastereoisomer After separation by chromatography, 149 was subjected to selective acetylation of the primary alcohol, followed by dehydration, to yield a mixture of alkenes 150 and 151 in a 2:1 ratio Acetonide deprotection, under controlled conditions, then afforded a compound with spectral properties that did not match those of the natural product These results led to revision of the structure of gabosine K; the compound obtained in this synthesis was (Ϯ)-1-epi-4-epigabosine K These syntheses were later extended to optically active derivatives,[38a] because very efficient resolution processes (Ͼ48 % yield for each enantiomer) to obtain the starting Diels–Alder adducts in optically active form have been described.[38b] The second example, by Koizumi’s group, used chiral sulfinylacrylate 152 (Scheme 25) as a dienophile.[39] This optically active alkene 152 was prepared in four steps and 14 % overall yield from (+)-camphor The first key step was a high-pressure Diels–Alder reaction, at 1.2 GPa It was stereoselective with regard to the sulfur stereocentre, with additions on the face anti to the bulky R group, but gave a 71:29 mixture of endo isomer 153 and the corresponding exo derivative After dihydroxylation of the mixture, diol 154, now containing a sulfonyl group, was isolated in 53 % overall yield from 152 Acetonide formation to provide 155 was followed by reduction to alcohol 156 Treatment with aqueous trifluoroacetic acid then directly afforded gabosine C by removal of the acetonide, opening of the bicyclic system and hydrolysis to the keto group On © 0000 Wiley-VCH Verlag GmbH & Co KGaA, Weinheim Eur J Org Chem 0000, 0–0 Job/Unit: O20477 /KAP1 Date: 04-07-12 16:28:55 Pages: 16 Total Synthesis of Gabosines Scheme 25 Synthesis of gabosine C and COTC starting from a chiral sulfinylacrylate (a) Room temp., CH2Cl2, d (71:29 endo/exo); (b) OsO4 (cat.), Me3NO, acetone, °C then room temp., 53 % from 152; (c) 2,2-dimethoxypropane, pTsOH, acetone, reflux, 64 %; (d) LiAlH4, THF, room temp.; (e) 80 % TFA, –20 °C, gabosine C (51 % from 155) the other hand, esterification of 156 with crotonic anhydride, followed by the same reaction with trifluoroacetic acid, yielded COTC in nine steps and 2.4 % overall yield from (+)-camphor Other chiral sulfoxides have proved to be useful starting materials for the synthesis of gabosines The chiral quinone 159 (Scheme 26) was used by Carreno’s group for the synthesis of gabosine O and 4-epigabosine A.[40] They started from chiral sulfoxide 157, easily available in two steps and 48 % yield from menthol Treatment of the lithium anion of 157 with the benzoquinone monoketal 158, followed by hydrolysis, gave 159 An interesting desymmetrisation process was then performed by treatment of this quinone with AlMe3 (4 equiv.), affording enone 160 This compound was the result of an exclusive addition on the pro-S carbon Scheme 26 Synthesis of gabosine O and 4-epigabosine A starting from a chiral sulfoxide (a) (i) (S,S)-157, LDA, THF, –78 °C, (ii) oxalic acid, THF, H2O, room temp., 78 % for two steps; (b) AlMe3 (4 equiv.), CH2Cl2, –78 °C, 76 %; (c) mCPBA, CH2Cl2, °C, h, 98 %; (d) Dibal-H, THF, –78 °C, 30 min, 95 %; (e) TBSOTf, 2,6lutidine, CH2Cl2, °C, 93 %; (f) Cs2CO3, CH3CN, room temp., 89 %; (g) TBAF, THF, °C, 80 %; (h) OsO4 (1 equiv.), TMEDA, CH2Cl2, –78 °C, 60 %; (i) (i) (S,R)-131, LDA, THF, –78 °C, (ii) oxalic acid, THF, H2O, room temp., 76 % for two steps; (j) (i) mCPBA, CH2Cl2, °C, (ii) TBHP, Triton B, THF, °C, 72 % for two steps; (k) Dibal-H, THF, –78 °C, 67 % (de Ͼ 98 %); (l) Cs2CO3, CH3CN, room temp., 54 %; (m) NaOAc, H2O, reflux, 45 % Eur J Org Chem 0000, 0–0 atom of quinone 159 In order to provide a better leaving group, quinone 160 was oxidised to the sulfone 161 Selective reduction to alcohol 162 was then achieved with DibalH After protection of the secondary alcohol to give 163, a retroaddition process was performed with Cs2CO3 to give enone 164 From this compound, RuCl3/OsO4-mediated dihydroxylation occurred but only with a moderate yield (31 %) and a low diastereoselectivity (58:42) Deprotection to afford alcohol 165 was therefore carried out, and treatment with OsO4 (1 equiv.) gave gabosine O in a fully stereocontrolled manner On the other hand, a one-pot, three-step sequence (1,4addition of AlMe3, followed by trapping of the resulting enolate by NBS and then a base-mediated HBr elimination) starting from 159 was used to prepare 166 Oxidation followed by epoxidation stereoselectively gave 167 Dibal-H reduction gave a 77:23 mixture of 168 plus its diastereoisomer, and these were separated by chromatography Treatment of 168 with Cs2CO3 gave 169, a natural product known as epiepoformin Finally, heating of this compound with aqueous NaOAc gave 4-epigabosine A in 45 % yield This strategy thus afforded gabosine O and 4epigabosine A in eight and ten steps, respectively, and in 21.8 and % overall yields from menthol Another series of masked p-benzoquinones was used by Figueredo’s group for the preparation of several gabosine derivatives (Scheme 27).[41] They started from 171, easily prepared in three steps and 50 % yield from 170 The first key step was the efficient enzymatic resolution of 171, affording alcohol 172 in 45 % yield and 98 % ee together with acetate 173 in 48 % yield and 90 % ee From the acetate 173, ent-172 was obtained in 75 % yield and 97 % ee after saponification and crystallisation After protection of ent-172 as 174, alkylation mediated by potassium tert-butoxide afforded a mixture of 175 (67 %) and 176 (30 %), which were separated by chromatography Dihydroxylation of major isomer 175 gave diol 177 with full stereocontrol Desulfurisation gave 178, and after deprotection 4-epigabosine O was obtained On the other hand, again starting from 177, oxidation followed by pyrolysis gave 179, which was deprotected to afford 2-epi-3-epigabosine N Further, dihydroxylation of 176 gave a 2.8:1 mixture of 180 and its diastereoisomer They could not easily be isolated in pure form by chromatography, so the next reaction was performed with this mixture Desulfurisation gave 181 in 53 % yield together with a small amount (11 %) of its diastereoisomer After deprotection, ent-gabosine O was obtained On the other hand, the same oxidation/pyrolysis protocol as above gave 182 in 60 % yield, with a small amount (8 %) of its diastereoisomer A final deprotection step afforded ent-gabosine N in ten steps and 2.8 % overall yield The enantiomers of these gabosines were obtained in the same way, by starting from 172 This group completed these studies by also preparing ent-gabosine A, 4-epigabosine A and gabosine F by use of these versatile masked benzoquinone intermediates © 0000 Wiley-VCH Verlag GmbH & Co KGaA, Weinheim www.eurjoc.org 11 Job/Unit: O20477 /KAP1 Date: 04-07-12 16:28:55 Pages: 16 D H Mac, S Chandrasekhar, R Grée MICROREVIEW Scheme 27 Synthesis of ent-gabosines N and O and of epigabosines N and O starting from a masked p-benzoquinone (a) AcOCH=CH2, Novozyme®435, iPr2O, 32 °C, h (45 % for 172 and 48 % for 173); (b) MeONa, MeOH, room temp., 30 min, then recrystallisation, 75 %; (c) TBSCl, imidazole, CH2Cl2, room temp., d, then montmorillonite K10, CH2Cl2, room temp., 18 h, 62 %; (d) (i) tBuOK, THF, –78 °C, 15 min, (ii) MeI, –78 °C to room temp., h (67 % for 175 and 30 % for 176); (e) OsO4/NMO, H2O/ acetone, room temp., h (70 % for 177 and 62 % for a mixture of diastereoisomers for 180); (f) Bu3SnH/AIBN, toluene, reflux, h, 83 %; (g) TBAF, THF, room temp., d, 66 %; (h) (i) mCPBA, CHCl3, °C, h then reflux in h, (ii) TFA, CHCl3, room temp., h, 84 %; (i) TBAF, THF, room temp., h, 73 %; (j) Bu3SnH/ AIBN, toluene, reflux, h, 53 %; (k) TBAF, THF, room temp., 30 min, 51 %; (l) mCPBA, CHCl3, °C, h then reflux in h, 60 %; (m) TBAF, THF, room temp., 30 min, 83 % (Scheme 28).[42] The synthesis started from enones 175 and 176; epoxidation with potassium tert-butyl hydroperoxide was fully stereocontrolled, affording the epoxides 183 and 184, respectively, in excellent yields The same oxidation/ thermolysis protocol as above was followed to give a mixture of 185 and 186 Desilylation of this mixture with Et3N·3HF directly gave epiepoformin 169, a known precursor of 4-epigabosine A ent-Gabosine A could be also prepared from this versatile intermediate in a few steps; acetylation to 187 followed by BF3·Et2O-induced ring opening afforded a mixture of regioisomers 188 and 189 On treatment with MeONa, this mixture gave ent-gabosine A in excellent yield The same sequence of reactions starting from ent-175 and ent-176 gave gabosine B in 14 steps and 23.7 % yield from p-methoxyphenol Finally, a synthesis of gabosine F starting from intermediates 183 and 184 was described (Scheme 28) Bu3SnH-mediated desulfonylation of either isomer, or of the mixture of 12 www.eurjoc.org Scheme 28 Synthesis of gabosines B and F and of ent-gabosine A and 4-epigabosine A starting from a masked p-benzoquinone (a) tBuOOH/Triton B, THF (96 % for 157, 98 % for 158); (b) mCPBA, CHCl3, Δ, 87 %; (c) Et3N·3HF, THF, 86 %; (d) NaOAc, H2O reflux, 45 %; (e) Ac2O, DMAP, CH3CN; (f) BF3·Et2O toluene; (g) MeONa, MeOH, 77 % from 187; (h) Bu3SnH, AIBN, toluene (80 % for 190, 90 % for 191); (i) (i) Et3N·3HF, THF, (ii) Ac2O, DMAP, CH3CN, 65 % for two steps; (k) (i) BF3·Et2O, toluene, (ii) MeONa/MeOH, 88 % both, gave the same 6.6:1 mixture of epoxides 190 and 191 Desilylation followed by acetylation gave acetates 192 and 193 The same two-step protocol as described above for gabosine A then gave gabosine F in 13 steps and 13.9 % overall yield The enantiomer, gabosine B, was prepared similarly Total Synthesis of Gabosines by Chemoenzymatic Methods Two innovative syntheses of gabosine A using biotransformation of aromatic systems have been reported The first, from Banwell’s group, used the dihydroxylation of iodobenzene, mediated by toluene dioxygenase, as the key step (Scheme 29).[43] This reaction afforded a cyclohexadienediol, which was immediately selectively protected on the less hindered alcohol to give silyl ether 194 Dihydroxylation of this iodo derivative was achieved in a regiocontrolled and stereoselective fashion on the face anti to the two substituents to give 195 After protection to afford acetonide 196, oxidation was performed to give enone 197 The last key step was the introduction of the desired methyl group After several unsuccessful attempts, the authors found that the coupling of 197 with methylmagnesium © 0000 Wiley-VCH Verlag GmbH & Co KGaA, Weinheim Eur J Org Chem 0000, 0–0 Job/Unit: O20477 /KAP1 Date: 04-07-12 16:28:55 Pages: 16 Total Synthesis of Gabosines chloride in the presence of FeCl3 was very efficient, affording 198 in 93 % yield Final deprotection gave gabosine A in six steps and 42.3 % overall yield from iodobenzene Table lists the different syntheses that have been reported We have indicated the yields and the number of steps starting from similar structures, such as the different sugars in the chiral-pool approaches Conclusions Scheme 29 Synthesis of gabosine A using the dihydroxylation of iodobenzene mediated by toluene dioxygenase as a key step (a) (i) Pseudomonas putida UV4, 80 % (ee Ͼ 98 %), (ii) TBDPSCl (1.1 equiv.), imidazole, CH2Cl2, 18 °C, 1.5 h; (b) OsO4 (cat.), NMO (1.5 equiv.), acetone/H2O (1:1), 60 °C, h; (c) 2,2-dimethoxypropane (neat), pTsOH (cat.), 18 °C, h, then Et3N (0.27 equiv.); (d) Swern oxidation; (e) MeMgCl (2.2 equiv.), FeCl3 (10 mol-%), NMP (9 equiv.), THF, °C, 0.5 h; (f) HCl (trace of a m solution), MeOH, 18 °C, 96 h, then (Me2N)3S+F2SiMe3– (4.8 equiv.) A similar approach was followed more recently by Pandolfi’s group, starting from toluene in order to avoid the iodo to methyl group transformation (Scheme 30).[44] Scheme 30 Synthesis of gabosine A using the dihydroxylation of toluene mediated by Pseudomonas putida as a key step (a) Pseudomonas putida F39/D, 60 % (ee Ͼ 99 %); (b) DMP, acetone, pTsOH, °C, 80 %; (c) OsO4 (cat.), NMO, H2O/acetone (1:5), room temp., 70 % (7:3 ratio of 201/202); (d) BzCl, Et3N, CH2Cl2, quant.; (e) CuCl2·H2O, CH3CN, quant.; (f) IBX, DMF, 92 %; (g) K2CO3, MeOH, 54 % The known dihydroxylation of toluene mediated by Pseudomonas putida afforded enantiopure cis-diol 199 in 60 % yield and acetonide 200 after protection As already mentioned by Banwell et al.,[43] the key step was the non-selective dihydroxylation of this intermediate, affording a 70:30 mixture of the two regioisomers 201/202 After separation by chromatography, the minor isomer 202 was dibenzoylated to give 203 After deprotection to provide diol 204, oxidation of the allylic alcohol afforded enone 205 and after final deprotection gabosine A This compound was obtained in seven steps and % overall yield from toluene It appears interesting to compare the different approaches to gabosines and their isomers To this end, Eur J Org Chem 0000, 0–0 The fifteen natural gabosines have been synthesised, as well as some of their enantiomers and various diastereoisomers Many elegant strategies for the total synthesis of these derivatives have been developed From the analysis of literature data several aspects are worthy of note: – Although these natural products have relatively simple structures, the numbers of steps required to prepare them are still high (around 10), and the overall yields for the syntheses are in general only moderate (around 4–20 %) Direct comparison between the different syntheses is, of course, extremely difficult, because it would require taking into account a number of other factors such as availability and cost of starting materials and reagents, time to perform the total synthesis and so on Furthermore, the versatility of an approach to obtain other isomers and/or chemical libraries could be an important point, for study of structure/ activity relationships, for instance In any case, it is clear that new synthetic strategies to improve access to these molecules still need to be designed – The first total syntheses were performed in order to establish the stereostructures of these derivatives unambiguously, but the corresponding molecules were later selected as excellent models to demonstrate the scopes and limitations of methodologies developed by synthetic chemists Further, these routes are also of interest for the preparation of other derivatives, especially in the carbasugar family – The chiral-pool approach has, as usual, been efficient for establishing the structures and absolute configurations of these derivatives but requires further synthetic steps, or changes in starting material, to allow access to their stereoisomers – In contrast, approaches through chiral molecules obtained by resolution processes might have lower yields due to the first resolution steps, but they are flexible and can afford the two enantiomeric series more directly – Although they have not yet been much developed, approaches based on bioconversion methodologies appear very attractive, because they are very short in terms of numbers of steps and clearly open a new avenue in this field – It is very interesting to remark that, with the exception of the bioconversions mentioned above, no synthesis of gabosine based on asymmetric catalysis, neither through organometallic nor through organocatalytic processes, has been reported to date However, these natural products would appear to be well suited for the use of the corresponding methodologies, and it can be expected that powerful developments in this direction should arise in the near future – As indicated above, these gabosines have not so far demonstrated very significant biological properties How- © 0000 Wiley-VCH Verlag GmbH & Co KGaA, Weinheim www.eurjoc.org 13 Job/Unit: O20477 /KAP1 Date: 04-07-12 16:28:55 Pages: 16 D H Mac, S Chandrasekhar, R Grée MICROREVIEW Table Synthesis of gabosine derivatives from 1994 to 2012 Gabosine derivative Starting material Gabosine A Gabosine A Gabosine A Gabosine A Gabosine A Gabosine A ent-Gabosine A ent-Gabosine A Di-OBn-ent-gabosine A 4-Epigabosine A 4-Epigabosine A 4-Epigabosine A 4-Epigabosine A Gabosine B 4-Epigabosine B 2-Epi-3-epigabosine B 4-Epi-6-epigabosine B Gabosine B Gabosine C Gabosine C Gabosine C Gabosine C Gabosine C ent-Gabosine C COTC Gabosine D ent-Gabosine D Gabosine E Gabosine E ent-Gabosine E ent-Gabosine E ent-Gabosine E 2-Epi-3-epigabosine E (Ϯ)-Gabosine F Gabosine F Gabosine F Gabosine G Gabosine G Gabosine H Gabosine I Gabosine I Gabosine I Gabosine I Gabosine I 4-Epigabosine I Gabosine K Gabosine K (Ϯ)-1-Epi-4-epigabosine K Gabosine N ent-Gabosine N ent-Gabosine N 4-Epigabosine N 2-Epi-3-epigabosine N Gabosine O Gabosine O ent-Gabosine O ent-Gabosine O 4-Epigabosine O 4-Epigabosine O 6-Epigabosine O d-ribose d-mannose d-mannose quinic acid iodobenzene toluene d-glucose p-methoxyphenol galactose d-glucose d-glucose menthol p-methoxyphenol quinic acid d-glucose d-galactose d-galactose p-methoxyphenol d-mannose d-ribose d-ribose quinic acid (+)-camphor d-ribose gabosine C d-glucose quinic acid d-glucose d-ribose d-mannose d-mannose quinic acid d-glucose cyclopentadiene derivatives l-arabinose p-methoxyphenol δ-d-gluconolactone tartaric acid tartaric acid d-glucose δ-d-gluconolactone δ-d-gluconolactone d-glucose tartaric acid tartaric acid d-glucose δ-d-gluconolactone cyclopentadiene derivatives d-ribose d-ribose p-methoxyphenol d-galactose p-methoxyphenol d-mannose menthol d-ribose p-methoxyphenol d-mannose p-methoxyphenol d-mannose ever, it would not be surprising if these molecules, or their derivatives, might be of use for some of the numerous new biological targets discovered every day This is exemplified by a recent example; it has been shown that gabosine deriv14 www.eurjoc.org Number of steps steps 11 steps steps 11 steps steps steps 15 steps 13 steps steps 11 steps steps 10 steps 11 steps 13 steps 10 steps steps steps 13 steps 11 steps 12 steps 11 steps steps steps 12 steps step 14 steps 11 steps 14 steps 12 steps 11 steps 11 steps 11 steps 11 steps steps 12 steps 13steps steps 12 steps steps 12 steps steps steps 10 steps 11 steps 11 steps 15 steps steps 11 steps steps 10 steps 10 steps steps 11 steps steps 10 steps 11 steps 11 steps 11 steps 11 steps steps Overall yield Reference 13.9 % 10.8 % 5.7 % 8.3 % 58 % 5% 14.4 % 11.6 % 3.7 % 12.9 % 9.4 % 4% 3.7 % 4.5 % 14.5 % 11 % 5.5 % 13.9 % 21 % 4.4 % 19.8 % 12.7 % 2.4 % 10 % 48–71 % 15.8 % 13.3 % 17.5 % 5.4 % 6.5 % 12 % 11.7 % 6.4 % 13.4 % 23 % 13.9 % 13.2 % 7.7 % 7% 10.8 % 20.3 % 65 % 27 % 11.8 % 21.8 % 13.5 % 40 % 8.9 % 17.1 % 18.2 % 2.8 % 8.8 % 8.6 % 41 % 13 % 19.5 % 0.9 % 38 % 4.6 % 6.9 % [26] [27] [29] [35] [43] [44] [19] [42] [18] [27] [28] [40] [42] [35] [28] [18] [29] [42] [23] [24] [30] [34] [39] [31] [23,24,30,34,39] [19] [35] [19] [31] [27] [33] [35] [27] [6] [32] [42] [20] [37] [36] [4] [20] [21] [22] [37] [37] [7] [21] [6] [26] [25] [41] [29] [41] [32] [40] [25] [41] [32] [41] [29] atives, and in particular 4-O-decyl-gabosine D, are glutathione S-transferase M1 inhibitors Through this action, they have demonstrated synergistic effects with cisplatin against a lung cancer cell line to overcome resistance.[45] © 0000 Wiley-VCH Verlag GmbH & Co KGaA, Weinheim Eur J Org Chem 0000, 0–0 Job/Unit: O20477 /KAP1 Date: 04-07-12 16:28:55 Pages: 16 Total Synthesis of Gabosines Note Added in Proof (July 3, 2012): After acceptance of this manuscript, a paper was published to describe a stereoselective synthesis of gabosine J and to correct the stereochemistry previously assigned to this molecule.[46] Acknowledgments This research has been performed as part of the project IndoFrench “Joint Laboratory for Sustainable Chemistry at Interfaces” We thank the Centre National de la Recherche Scientifique (CNRS), the University of Rennes 1, the French Ministry for Foreign Affairs and the Council of Scientific and Industrial Research (CSIR) for support of this research D H M thanks the Vietnam Nation Foundation for Science and Technology Development (NAFOSTED) (grant number 104.01-2011.52) [1] a) K Tatsuka, T Tschuyia, M Mikami, H Umezawa, H Naganawa, J Antibiot 1974, 27, 579–586; b) T Takeuchi, H Chimura, M Hamada, H Umezawa, H Yoshka, N Oguchi, Y Takahashi, A Matsuda, J Antibiot 1975, 28, 737–742; c) A Müller, W Keller-Schierlein, J Bielicki, G Rak, J Stümpfel, H Zähner, Helv Chim Acta 1986, 69, 1829–1832 [2] G Bach, S Breiding-Mack, S Grabley, P Hammam, K Hütter, R Thiericke, H Uhr, J Wink, A Zeeck, Liebigs Ann Chem 1993, 241–250 [3] For reviews on carbasugars, see: a) P Vogel, Chimia 2001, 55, 359–365; b) O Arjona, A M Gomez, 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Chem 2011, 54, 8574–8581 [46] M A Fresneda, R Alibes, J Font, P Bayon, M Figueredo, J Org Chem 2012, 77, 5030–5035 Received: April 13, 2012 Published Online: ᭿ © 0000 Wiley-VCH Verlag GmbH & Co KGaA, Weinheim www.eurjoc.org 15 Job/Unit: O20477 /KAP1 Date: 04-07-12 16:28:55 Pages: 16 D H Mac, S Chandrasekhar, R Grée MICROREVIEW Total Synthesis Gabosines are a family of bioactive secondary metabolites from various Streptomyces strains Total syntheses of carbasugars of this family reported to date are described Key aspects include control of the absolute configurations at the stereocentres, generally achieved by use of appropriate chiral optically active starting materials, and methods used for elaboration of the carbocycles 16 www.eurjoc.org D H Mac, S Chandrasekhar, R Grée* 1–16 Total Synthesis of Gabosines Keywords: Natural products / Total synthesis / Secondary metabolites / Carbocycles / Cyclohexanones / Cyclohexenones / Carbasugars / Chiral pool / Stereoselective synthesis © 0000 Wiley-VCH Verlag GmbH & Co KGaA, Weinheim Eur J Org Chem 0000, 0–0 ... strategies for the total synthesis of these derivatives have been developed From the analysis of literature data several aspects are worthy of note: – Although these natural products have relatively... /KAP1 Date: 04-07-12 16:28:55 Pages: 16 Total Synthesis of Gabosines A second useful strategy for the preparation of such cyclohexenones is intramolecular aldolisation followed by dehydration... gabosine B, was prepared similarly Total Synthesis of Gabosines by Chemoenzymatic Methods Two innovative syntheses of gabosine A using biotransformation of aromatic systems have been reported The