A stereodivergent access to naturally occurring aminocarbasugars from (Phenylsulfonyl)-7 -oxa-bicyclo[2.2.1 ]heptane derivatives. Total synthesis of ( + )-Validamine and its CI and C2 stereoisomers

A stereodivergent access to naturally occurring aminocarbasugars from (Phenylsulfonyl)-7 -oxa-bicyclo[2.2.1 ]heptane derivatives. Total synthesis of ( + )- Validamine and its CI and C2 stereoisomers Un ruta de acceso estereodivergente a carbaazúcares naturales a partir de derivados (Fenilsulfonil)-7 -oxabiciclo[2.2.1 ]heptane. Síntesis total de ( ± )- V alidarnina y de sus C I y C2 estereoisómeros AIuONA, O. and PLUMET , J. Departamento de Química Orgánica, Facultad de Química, Universidad Complutense, 28040 Madrid, España. ABSTRACT The total syntheses of the antibiotic validamine an its three diastereomers have been acomplished and their racemic penta-N-O-acetates via stereocontrolled nucleophilic epoxidation of polihydroxylated cyclohexenyl sulfones, obtained from (phenylsulphonyl)-7- oxabicyclo[2,2, l ]heptanes. The diastereoselectivity of the epoxidation can be readily controlled by careful choice of the hydroxyl protecting group. Ring opening of the resulting epoxisulfones followed by stereocontrolled introduction of an amine precursor led to the four C-l and C-2 diastereomers of the I-aminocarbasugars. Key words: carbasugars, stereocontrolled epoxidation, validamine. RESUMEN La epoxidación nucleofilica estereocontrolada de ciclohexenil sulfonas polidroxiladas, obtenidas a partir de (fenilsulfonil)-7-oxabiciclo[2,2, l ] heptano s conduce a la síntesis total del antibiótico validarnina y sus tres diastereoisómeros. La diastereoselectividad de la epoxidación puede controlarse facilrnente mediante la elección del grupo protector del hidroxilo. La apertura del anillo de las epoxisulfonas resultantes, seguida de la introducción estereocontrolada de un precursor del grupo amino, conduce a los cuatro diastereosiómeros en C-l y C-2 de l-aminocarbaazúcares. Palabras clave: Carbaazúcares, pseudoazúcares, epoxidación estéreocontrolada, validamina. Recibido: 5-4-1995. Aceptado: 28-4-1995. BIBLID [0004-2927(1995) 36:3; 445-454] Ar s Pharmaceutica, 36:3; 445-454, 1995 446 A RJON A, O. and PL UMET , J. INTRODUCTION Carbasugars (ofien called pseudosugars) and re1ated compounds are products of biological relevance because they may act as enzyme inhibitors, sweeteners , antibiotics, etc. (1). Considerable efforts directed towards the development of syntheses ofthese compounds have be en made (1, 2). l-Aminocarbasugars like validamine 13 (Figure 1) are sorne ofthe most important and attractive members of the carbasugars farnily due to its enzymatic inhibitory activity against various glucose hydrolases (4). 1-Aminocarbasugars are also constituents ofthe antibiotic validarnycin complex (5), isolated from the fermentation broth of streptom yce s hygroscopicus subsp. limonenus, which shows growth inhibition activity against bacterial diseases of rice plants (6). Figure 1 NH 2 :::Q·'.-OH OH 1 ~H2 HO"Q: HO'::"'-OH OH 3 ~H2 HO ' HO:Q···.-OH OH 4 Although there are several syntheses of 1-aminocarbasugars (7) , in many cases these methods suffer from a lack of versatility in terms of both regio- and stereocontrol. One of the most widely used intermediates in the syntheses of carbasugars are 7-oxanorbomenic systems (1 , 8, 9), which are readily available even enantiomerically pure (10). A crucial transformation in these synthetic sequences employing oxabicyclic intermediates is the c1eavage of the ox yg en bridge to produce highly functionalized cyc1ohexenols derivatives (11). In this paper, we describe a short and stereodivergent route of validamine 1 and its el and C2 stereoisomers 2-4 from the cyc10hexenyl sulfones 7 (Scheme 1) . These compounds are available by our previously described methodology based on the strain-directed bridge c1eavage of 7-oxanorbomanic sulfones 6 with n-BuLi and Ars Ph armaceutica, 36:3; 445-454, 19 95 A STEREODIVERGENT ACCESS TO NATURALLY OCCURRING AMlNOCARBASUGARS FROM. .. 447 they have been employed in the total synthesis of carba-a.-DL-glucopyranose (8). Sulfones 6 are readily available in four steps from acid 512. Scheme 1 PhS0 2 XV B L' • O n-UI ,.... ", RO "-OR 5 6a R = Bn 6b R =TBDMS O PhS0 2;t) --------~ --------".. RO'" "'~-OR LiOOt-Bu OR P .. hS0 2 }1. RO"'Y ""-OR OH 7a R = Bn 7b R=TBDMS NH 2 ::X>"'-OH OH 1-4 The key step of our synthetic plan involves the diastereoselective nucleophilic epoxidation of sulfones 7. This kind of epoxidation is a well-known process (13). The reaction has been studied in terms of diastereoselectivity on acyclic (14) and cyclic (15) oxygenated vinyl sulfones. Coordination andlor conformational effects have been invoked in order to explain the diastereoselectivity of the process. With the appropiate a.,~-epoxysulfone in our hands, the stereoselective introduction of an amine group precursor by epoxide cleavage would produce the l-aminocarbasugars 1-4. RESULTS AND DISCUSSION We [¡rst examined methylene acetal 7e, obtained by reaction of sulfone 7a with (MeO)2 CH } (Scheme 2). This compound, which presents a flxed conformation, by treatment with LiOOt-BuJ3b afforded a 60:40 mixture of epoxides 8e and ge (Table 1, entry 3). In contrast with this disappointing result, dibenzyl ether 7a, under identical reaction conditions, gave a single a. , ~-epoxysulfone 8a (entry 1). In the case of disilyl sulfone 7b, a high diastereoselectivity (95:5) in the same sense was observed (entry 2) (16). In contrast, sulfones 7d and 7e, obtained by silylation (TBDMSOTf, Et 3N, THF, - 78 o C) of7a and 7b respectively, displayed high or total diastereoselectivity, but in the opposite direction (entries 4 and 5). Ars Pharmaceuti ca, 36:3; 445-454, 1995 448 ARJONA, o, .n d PLUMET, J, Thus, the diastereciselectivity of the nucleophilic epoxidation of our polyhydroxycyclohexenyI sulfones can be controlled by the choice of the protecting groups. Scheme 2 6 • PhS0 2 ;Q LiOOt-Bu PhS0 2 ,,?y 1 ,, ' 1 ". THF 1 "~o ", R O -'-OR 3 o R O "'-OR 3 OR2 -78 C to rt OR2 7a R1 = R3 = Bn, R2 = H 7b R1 = R3 = TBDMS, R2 = H 7e R1 = Bn. R2 = R3 = -CH2- 7d R1 = R3 = Bn. R2 = TBDMS 7e Rl= R2 = R3 = TBDMS Sa-d Table I .- Nucleophilic epoxidation of vinyl sulfones 7a-e. entry substrate JI / J/,/ 8 9 1 7a 6.8 9.8 8a 27b 4.9 7.4 8b 9b 3 7e 7.6 11 .0 8e ge 4 7d 2.9 2.9 8d 9d 5 7e 2.7 2.7 ge + 91Ht 8:9 ratiob yieldC 100:0 92% 95 :5 85 % 60:40 82 % 10 :90 88 % 0:100 80% "In Hz. bMeasured by integration of the IH NMR spectra of the crude reaction mixtures. COverall yield of pure products. The stereochemistry of the resulting epoxides was tentatively established from their IH NMR spectra. The crucial data was the chemicaI shift of the proton linked at the ~-alkoxy substituent to the phenylsulfonyl group, which is more deshielded for compounds 9b-d due to the syn effect of the sulfone. Anyway, to further prove our assignment, we carried out chemical correlations of our sulfonyl oxiranes with the known tribenzyl epoxides 10 and 11 17 (Figure 2), and thus, the previously proposed stereochemistry was confmned. Figure 2 o Bno,J:~)""-OBn O, Bno,J) " "'-OBn OBn OBn 10 11 Ar s Pharmaceutica, 36:3; 445-454, 1995 A STEREODlVE RG ENT ACCESS TO NATURALLY OCCURRING A MI NOCARBASUGARS FROM... 449 The stereochemical outcome of the nucleophilic epoxidation of our substrates can be rationalized on the basis of the conformational behaviour of the starting polyoxygenated cyclohexenyl sulfones along with coordinative effects of the remote hydroxyl group. Inspection on the J1,2 and J1,6 coupling constant data (Table 1) shows that 7a-c present similar ground state conformational equilibria; however, the selectivity ofthe process is clearly controlled by the free homoallylic hydroxyl group. Finally, the striking reversal of diastereoselectivity found for 7d and 7e presumably reflects the intrinsic steric bias of the molecule (15) as a result of its very different conformation (see J1,2 and J1,6 in Table 1) probably due to the dissappearance of an hydrogen bonding. The epoxide ring opening with concomitant loss of the phenylsulfonyl group was the next step of our synthetic plan. The introduction of an azide group in the epoxide ge would produce an a-azidoketone with the same configuration on the azide group as in validamine. Unfortunately, when ge was treated with NaN3 in DMF at re flux (18), we did not obtain the desired a-azidoketone (19). Therefore, the approach to this product was performed indirectly by means of the reaction of 8a with MgBr2-OEt lO (Scheme 3) affording a-bromoketone 12 along with its epimer in 89: 11 ratio (90% overall yield). After chromatographic separation, 12 was transformed into the related a-azidoketone 13 21 by halogen displacement with NaN3 (88% yield). This reaction occured at room temperature and with retention of configuration (22). Compound 13 could be the intermediate precursor of compounds 3 and 4, by reduction of the carbonyl group followed by azide hydrogenation. At this 8a 12 Scheme 3 ~r ~3 O ' O ~ MgBr2 • OEt2 :Q NaN3":Q .. . , DMF " ' 0, Et20~HF BnO" oOI/_OBn rt BnO' 1/-OBn (80%) OH (88%) OH [H] .. 12 Br HO/,O: BnO"" 'o"/-OBn + OH 14 13 Br HO : 9no:Q ""'-09n OH 15 Ars Pharmaceut ica, 36:3; 445-454, 1995 450 ARJONA , O. and PLUMET , J. point, we reasoned that stereocontrolled reduction of the carbonyl group in 12 would produce both diols 14 and 15. Azide displacement in each case with inversion of configuration and subsequent reduction of the azide to amine would afford validamine 1 and its epimer 2. Thus, the stereochemistry of the reduction of carbonyl group of 12 was considered. A wide range of reagents and temperatures were tested for the reduction of ketone 12 (Table 2). Treatment of 12 with LiAI(t-BuO)3H at -78 oC gave axial alcohol 14 as single diastereomer (85% yield). Other reducing agents (NaBH", LiAlH4, DIBAL-H, NaBHJCeC13) afforded mixtures of both diastereomers, but 14 was always the major product due to preferential equatorial atlack. Finally , reduction with BH3 -SMe2 at room temperature yielded the desired equatorial alcohol 15 as the major diastereomer in a 82: 18 ratio (94% overall yield). These diols were easily separated by colurnn chromatography. Table 2. -Stereochemistry of the reduction of ketone 12. reagent temperature 14:15 ratio LiAl(t-BuO)3 H -78 oC 100:0 NaBH4 O oC 91:9 LiAlli4 O oC 91 :9 DIBAL-H O oC 91 :9 NaBH¡CeCI3 -78 oC 71 : 29 NaBH¡CeCI3 rt 50:50 BH3 · SMe2 -78 oC 40: 60 BH3 · SMe2 rt 18 : 82 The synthesis of validamine was then addressed from bromohydrin lS . Substitution with NaN3 gave azide 16 (77% yield) (Scheme 4). The dissappearance of the carbonyl group allowed for the reaction to occur with inversion 01 configuration. This transformation required an increase of the reaction temperature to 150 oC and the addition ofHMPA as cosolvent (23). Reduction ofthe azido group and concurrent removal of benzyl groups by catalytic hydrogenation (H 2I Pd-C, Me OH) provided (± )-validamine 1, which was fully characterized as the corresponding pentaacetate 17 (AcP, pyr, DMAP) (54% overall yield). Ita spectral features were identical to those reported in the literature (3). Similarly, we achieved the syntheses of diastereomers 2, 3 and 4. Thus, the reaction of cis-bromohydrin 14 with NaN3 afforded 18 (66% yield), followed by hydrogenation under the same conditions as before provided 2-epivalidamine (l-amino-l-deoxycarba-a.-mannopyranose) 2, that was characterized as the pentaacetate 19 (49% overall yield) (7f). On the other hand, reduction of exazidoketone 13 was carried out in the same manner as in the case of 12. Treatrnent of 13 with LiAl(t-BuO)3H at -78 oC produced 20 as a single diastereomer Ars Pharmaceutica, 36:3; 445-454, 1995 A STEREODlVERGENT ACCESS TO NATURALLY OCCURRJNG AMINOCARBASUGARS FROM... 451 15 DMFIHMPA· 150 Oc (77%) 16 N 3 Scheme 4 NHR Rol) .. RO" " · ···,-OR OR AC20, pyr I 1 R = H DMAP L-17 R =Ac (54% overall) NHR NaNa HO~:~ . . H,. Pd-C 14 DMF/HMPA· BnO" y "'-OBn • RO,. A RO""Y ""-OR OR 150 Oc OH (66%) 18 N3 AC20, pyr I 2 R = H DMAP L-19 R = Ac (49% overall) NHR ,....L_iA_I(....;..~ ___ BH U_ F O_)_3 H _ HOI" ' Q ~ H2, Pd-C -78 Oc BnO"" ·· ··,-OBn (82%) ROI"Q: .. RO"" ·· ··,-OR OR OH 20 13 N 3 AC20, pyr I 3 R = H DMAP L- 22 R =Ac (66% overall) NHR BH3· SMe2 = THF H0;Q - H2, Pd-C L- ___ 20+ (91 % ~Verall) BnO"" "" '-OBn ·:::Q".-OR OR OH 21 (48:52) AC20, pyr I . 4 R = H DMAP L-23 R =Ac (62% overall) Ars Pharmaceutica, 36:3; 445-454, 1995 452 ARJONA, O. and PLUMET, J. (82% yield), whereas in the presence of BH 3-SMe2, a 48:52 mixture of 20 and 21 was obtained (91 % overall yield). Compound 21 was easily separated by chromatography for the synthesis of 4. Catalytic hydrogenation of 20 afforded l-amino-l-deoxycarba-¡3-mannopyranose 3, and the same procedure in the case of 21 yielded the l-epivalidamine (l-amino-l-deoxycarba-¡3-glucopyranose) 4. These products were fully characterized as pentaacetates 22 (24) and 23 (25) respectively. In summary, an efficient, regio- and stereocontrolled route to naturally occurring aminocarbasugars from (phenylsulfonyl)-7-oxanorbomanic systems has been developed. Useful control ofthe diastereoselectivity ofthe nuc1eophilic epoxidation of polyoxygenated cyc10hexenyl sulfones by choosing the protecting groups, and subsequent oxirane opening with concomitant loss of the phenylsulfonyl group provided an a-bromoketone, key intermediate for the synthesis of (±)- validamine and its Cl and C2 stereoisomers. 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Soco Chim. Be lg. , 99:395-439. b) VOGEL, P .; FATTORl, D .; GASPARINI, F. and LE DRlAN, C. (1990): Synlett, pp. 173-1 85. For recents applications of these A rs Pharmaceutica, 36:3; 445-454, 1995