915
J. Org. Chem. 1992,57,91&922 C, 56.66; H, 5.17; N,8.62. Found C, 56.46; H, 5.19; N, 8.69. Compound 11: yield 0.127 g (29%); mp 91 O C (4MO OC petroleum ether); ‘HNMR (DMSO-de) 6 1.20 (t,3J = 7.0 Hz, 3 H, CH2CHJ, 1.30 (br s , 3 H, CH2CHS),4.24 (m, 2 H, CH2CHS), 4.35 (br s,2 H, CH2CHJ, 6.61 (br d, 3J = 6.3 Hz,1 H, C4H), 7.06 (br 8, 1 H, C3-H), 7.47 (mc, 6 Hk), 7.97 (br d, 3J = 8.0 Hz, 2 H, phnyl-SOrC2/CH), 8.08 (d, 3J = 8.4 Hz,1 H, Cs-H); EIMS (m/z, re1 intensity) 455 (M+, l),310 (31), 169 (100). Anal. Calcd for
W a N 3 O & (455.49): C, 58.01; H, 4.65, N, 9.26. Found: C, H, 4.61; N, 9.06.
68.n
SupplementaryMaterial Availablec N details of the X-ray analysis of compound 8 and 400-MHz ‘H NMR spectra of a mixture of h a n d 7 (from (ID-la)and a ” e of 6b and 7 (from (Z)-lb)(9 pagea). Ordering information is given on any current masthead page.
Synthesis of a-Methyl 1’,2’-Dideoxycellobioside: A Novel C-Disaccharide Robert W.Armstrong* and Bradley R. Teegarden’ Department of Chemistry and Biochemistry, University of California at Los Angeles, Los Angeles, California 90024-1569 Received M a y 13,1991 Bromonium ion induced Cendo-trig cyclizations of E olefm derived from &arabinose provide a stereoeelective route to 2’-deoxyglucono-~-C-glycosides. Use of 6-alkenola containing allylic isopropylidenes (i.e., 1) prevents formation of furan producta due to the highly strained transition state 7for formation of the trans [3.3.0] bicyclic systems. Because the exo-anomeric carbon is not involved m the cyclization, previously established stereocentera at this carbon are left intact. Application of this methodology to the synthesis of a-methyl 1’,2’-dideoxycellobioeide (22) is presented. The restricted rotation about the bond connecting the two sugars affords a unique staggared conformation of the disaccharide. Because of the ubiquitous r o b carbohydrates play in biology, carbohydrate analogues are valuable tools for the study of biochemical systems. Since the chemistry of sugars is dominated by the reactivity of the glycosidic bond, a great deal of effort has gone into the synthesis and study of C-glycosides in which the acetal linkage has been replaced by a hydrolytically stable carbon-carbon bond. The best understood C-glycosides are a series of C-disaccharides synthesized and studied by Kishi2 and coworkers in which the bridging oxygen of the glycosidic linkage is replaced by a methylene group. They found that the solution conformations of these molecules are similar to those of the corresponding O-disaccharides. A general model baaed on a diamond-lattice analysis3has since been developed to predict solution conformations of disaccharides. We became interested in developing a series of C-oligosaccharides in which the “floppy” glycosidic linkage has been reengineered to produce a linkage with a predictable restricted conformation. Analysis of molecular models showed that direct connectivity of the two rings (to form a @-l’-deoxydisaccharide)should result in restricted rotation about the connecting bond, due to steric interaction between substituents on the two rings. We therefore set out to synthesize a-methyl l’,2’-dideoxycellobioaide (22) which can be considered a prototype for this class of compounds. Methodology for the generation of C-glycosides has found wide application in natural products synthesis4and (1) Taken from the PhD. thesis of B.R.T. (2) (a) Babirad, S. k,Wang, Y.; Kishi, Y. J. Org. Chem. 1987,52,1370. (b) Wu, T.-C.; Goekjii, P. G., Kishi, Y. J. Org. Chem. 1987,52,4819. (c) Goekjinu,P. G.; Wu, T.-C.; Kang, H.-Y.; Kiehi, Y. J. Org. Chem. 1987, 52,4823. (d) Babirad, S. A; Waug, Y.; Goekjii, P. G.; Kiehi, Y. J. Org. Chem. 1987,52,4826. (e) Wang, Y.; Goekjian, P. G.; Ryckman, D. M.; Kiehi, Y. J. Org. Chem. 19&3,53,4151. (3) Miller, W. H.; Ryckman, D. M.; Goekjian, P. G.; Wang, Y.; Kiehi, Y.J. Org. Chem. 1988,53,6580. (4) Examplea include showdomycin: Barton, D. H. R.; Ramesh, M. J. Am. Chem. Soc. 1990,112,891 and references therein. Palytoxh Arm-
R. W.; Beau,J. M.; C h , s. H.; Christ, W. J.; Fujioka, H.; Ham, W. H.; Hawkins, L. D.; K i , Y.;Jm,H.; Kang,5.H.; Tino, J. A.; Taniguchi, M.;Uenishi, J.; Ueda, K.; Talamaa, F. X.;Stutz, A. E.;White,J. B.; Yonaga, W, Mcwhorter, W. W.; Nakata, Martinelli,M. J.; Mizuno, M.J. Am. Chem. SOC. 1989,111,7525. strong,
0022-3263/92/1957-0915$03.00/0
in the synthesis of biologically active carbohydrate anal o g u e ~ . ~Methods which exploit the steric and/or stereoelectronic effects of pyranose or furanose substrates involve the intermediacy of cations, radicals, anions, or organometallic reagents at the anomeric carbon! Equally productive approaches make use of the de novo synthesis of furanose or pyranose rings via cycloaddition or cyclization reactions on cyclic7 or acyclic intermediates? We desired a pyranose &C-glycoside synthesis that would allow coupling of preformed glycoside units without disrupting the stereochemistry at the exo carbon adjacent to the anomeric position? The extensive literature describing the electrophile-induced cyclization of carbohydrate-derived alkenolslO encouraged us to pursue this methodology for the generation of the acyclic precursors. However, we realized that attaining selective 6-endo (versus 5-exo)” cyclization would be a problem. Both steric and electronic (inductive) effects can influence the stereo- and regiochemical outcome of the cyclization reaction. For example, ~~
~~
(5) (a) Peseke, K.; Abroei, H. D.; Michalik, M. Carbohydr. Res. 1989, 194, 87. (b) Bamford, M. J.; Coe, P. L.; Walker, R. T. J. Med. Chem. 1990,33,2494. (c) Related compounde: Daniehefsky, S. J.; Pearson, W. H.; Harvey, D. F.; Maring, C. J.; Spring, J. P. J. Am. Chem. SOC. 1986, 107,1256. (6) For a comprehensive listing of methods for C-glycoeidation, see:
Herscovici, J.; Muleka, K.; Boumaiza, L.; Antonakis, K. J. Chem. SOC., Perkin Tram. 1 1990,1995. (7) Ireland, R. E.; Thaisrivongs, S.; Wilcox, C. S. J. Am. Chem. SOC. 1980,102,1155. Burke, S. D.; Armistead, D. M.; Schoenen, F. J. J. Org. Chem. 1984,49,4320. Curran, D. P.; Suh, Y. G. Carbohydr. Res. 1987, 171, 161. (8) Myles, D. C.; Danishefsky, S. J.; Schulte, G. J. Org. Chem. 1990, 55, 1636 and references cited therein. (9) In general, many previously developed methods meet thie criteria (i.e., Diela-Alder reactions, Claissen rearrangements, any Cendo cycli-
zation). However, construction of C-oligoaaccharidea using carbohydrate precursors provides a complementary route to these targets (vide infra). (10) S i provided one of the ffit examplea of a Cexo-trig cycbtion of a glucose-derivedb-hydroxyalkene, with predominant formation of the a-anomer. In general, the directing effect of allylic hydroxy groups in 6and 6-ex0 cyclizationa result in products with cis relationship between the alcohol and the carbon on the newly formed stereocenter: Pougny, J. R.; Neser, M. A. M.; Sinay, P. J. Chem. SOC.,Chem. Commun. 1981, 375. For comprehensivestudies on carbohydrate subatratea, we: Reitz, A. B.; Nortey, 5.0.;Maryanoff, B. E.; Liotta, D.; Monahan, R.J. Org. Chem. 1987,52,4191 and references cited therein. (11) Baldwin, J. E. J. Chem. SOC.,Chem. Comm. 1976,734.
0 1992 American Chemical Society
916 J. Org. Chem., Vol. 57, No.3,1992
Armstrong and Teegarden
A,/
Scheme I l.TPSCI,DMF. imid.
D-Arabinose
2. NBS, CH&N 66%
MF
,ms
15%
1. DIBALH, M F , 0%
TP
dh\d
H-
6
2. TPSU, hid. DMF H
Yoshida12 has found that iodoetherification of some substituted 4-pentene-l,3-diols affords a predominance of tetrahydropyran (over tetrahydrofuran) products when all substituents in the former are equatorial. More predictable and regiospecific 6-endo cyclization of y-hydroxyalkenes and hydroxy epoxides13 has been achieved by inductive stabilization of the developing positive charge in the transition state. These elegant approaches unfortunately place constraints on the nature of the substituents a t the exo anomeric carbon. For our purposes, a modification of the cyclization event was necessary to avoid involvement of this atom. We reasoned that electrophile-induced cyclization~’~ of trans-acetonide olefins of the type shown in structure 1should yield exclusively the desired pyranose
product 2, because the competing 5-exo-trig cyclization to the trans-fused [3.3.0] bicyclic structure 3 requires a highly strained transition state. Olefins of type 1 are readily available through the Wittig condensation, avoiding perturbation of stereoGentere contiguous to C1. Furthermore, anomeric configuration can potentially be controlled by the choice of Z (to give a) or E (to give /3)1 as the cyclization precursor. We wish to report the successful application of this strategy to the synthesis of a-methyl 1’,2’-dideoxycellobioside (22) via bromonium ion induced cyclization of olefin 17.16
Results and Discussion Initial cyclization models were generated from D arabinose since it contains the required stereochemical (12) Tamaru, T.; Hojo, M.; Kawamaura, SA.;Sawada, S.; Yoshida, 2.4. J. Org. Chem. 1987, 52, 4062. (13) A systematic study of acid-catalyzedcyclizations of hydroxy epoxides resulting in stereoselective synthesis of tetrahydrofuranand tetrahydropyran system has recently appeared, including a thorough citation of previous work Nimlaou, K. C.; Prasad, C. V. C.; Somers, P. K.; Hwang, C.-K. J. Am. Chem. SOC.1989,111,6330. (14) Brominative cyclizations to pyran derivatives directed by inductive stabilization of transition states have been previously reported: (a) Kato, T.; Ichinose, I.; Hosogai, T.;Kitahara, Y. Chem. Lett. 1976,1187. (b) Ting, P. C.; Bartlett, P. A. J. Am. Chem. SOC.1984,106,2668. (c) Jung, M.E.; Lew, W. J. Org. Chem. lSSl,56, 1347. (16) Carbohydrate-relatedpyran dimers which are C1 linked have been reported aa byproduds: Dubois, E.: Beau, J.-M. J. Chem. SOC., Chem. Commun. 1990,1191.
DTPS
relationship a t C2 and C3. The one-carbon transposition of stereocenters upon homologation affords D-glucose stereochemistry a t C3, C4, and C5. Thus, arabinose derivative 416was converted to cyclization precursor 7 in 42% overall yield using standard techniques (Scheme I). When an acetonitrile solution of 7 was exposed to N-bromosuccinimide, only starting material was recovered. However, addition of catalytic Br2 to the NBS/CH3CN solution resulted in a 52% yield of a single diastereomer 9,with an equatorial bromine at C2 and the /3-confiiation at the anomeric p0siti0n.l~ The ‘H NMR spectrum of 9 shows large Hl-H2 and H4-H5 coupling constants (9.7 and 9.1 Hz,respectively), confirming the trans diaxial relationship of these seta of hydrogens. Diastereomer 9 is presumably formed via the six-membered-ring transition state 8. Extension of this cyclization strategy to the synthesis of 1,4C-dieaccharidescontaining no glymidic oxygen was then investigated (Scheme 11). Aldehyde 12 was generated from D-arabinose in five steps in 43% overall yield. Conversion of 10l8to the phosphonium salt 11 and condensation with aldehyde 12 afforded a 67% combined yield of 13 and 14 (1:3 E/Z). The mixture of olefins was photochemically isomerizedl9to a 2:3 E / Z mixture and then deprotected to the C5’/C6’ diols 15 and 16, which were readily separated by silica gel chromatography. Reprotection of the primary hydroxyl group afforded cyclization precursore 17 and 18 in 81% and 89% yield, respectively. Cyclization studies were initially undertaken on the cisalkenol 18. Assuming a similar transition state as that proposed for the formation of 9, the cis isomer should afford the a-anomer a t C1’ and an equatorial bromide at C2’. AU attempts at cyclization were unsuccessful, p:ob ably due to the substantial allylic strain (C3’/C4) r e q d in the transition state. The stereochemical outcome in the cyclization of the trans isomer 17 was predicted to be the same as for model alkenol7 due to the conformational rigidity facilitated by the isopropylidene group. However, construction of models indicated that formation of the initial bromonium ion intermediate might be difficult because of steric crowding a t C4 by the C3 and C5 substituents on the pyran. We were pleased to find that cyclization of 17 with NBS/Br2 in CH3CN resulted in the formation of disaccharide 19 as a single diastereomer in 32% yield. Other products obtained included the noncyclized mixture of isomeric dibromides (-30%) and several compounds resulting from debenzylation at C6 of the benzyl ether (-20%). (16) Fried, J.; Walz, D. E. J. Am. Chem. SOC.1949, 71,140. h e r , H.; Temban, G.; Klocking, H. P. Chem. Ber. 1957,90,2688. (17) Addition of bromine vapor to a stirring solution of NBS/CH&N waa the most reproducible protocol. Slow addition of bromine resulted mostly in dibromide biproducta. (18) Daly, S.M.; h t r o n g , R.W. Tetrahedron Lett. 1989,30,6713. (19) Lorem, K.; Lichtenthaler, F. W. TetrahedronLett. 1987,28,6437.
J. Org. Chem., Vol. 57, No. 3, 1992 917
Synthesis of a-Methyl 1’,2’-Dideoxycellobioside Scheme I1 OBn
OBn
11
+ 12
I
OBn
13 R=TBSJEF 15 R=H
8996
OCH,
14 R = T B Z & Y F , 10 R=H
Chart I
(P
In an attempt to increase the efficiency of cyclization and minimize the formation of byproducts, we investigated other conditions with varying success. For instance, 2,4,4,6-tetrabromocycIohe~a-2,5-dienone~~ afforded 19 in acetonitrile (3448%)and nitromethane (19%) only in the presence of catalytic Br2 N-Bromosuccinimide in methylene chloride or acetonitrile gave no reaction. The effect of the C6’ blocking group on the cyclization efficiency was also investigated. Exchange of the TPS protecting group for benzyl or benzoyl resulted in low yields ( e l l % ) even under the best cyclization conditions. Deprotection of silyl ether 19 afforded bromide 20 which could be directly reduced with sodium in liquid a”onia/THF to tetrol 21.20 Acid hydrolysis of the isopropylidene group afforded the a-methyl glycoside of 1’,2’-dideoxycellobiose 22 in 45 % yield from 19. The stereochemistry of the C-disaccharide intermediates 19-22 was unambiguously established by IH NMR analysis (Table I). The coupling constant between H1’ and H4 in 19,20, and 21 (in CDCI3)is zero, suggesting that the dihedral angle about Cl’/C4 is near 90” in the (20) A small quantity (10%)of reductive elimination products were observed. (21) Compounds 9,19, and 20 are at a field strength of 360 MHz; 21 and 22 are at 500 MHz.
preferred conformation. As a consequence, H1’ is an apparent doublet with a large coupling constant (19: J1t,2ta = 10.3 Hz; 20: J1f,2fa = 9.7 Hz; 21: J1f,2fa = 10.5 Hz) reflecting the diaxial relationship to H2’, and confjming the 6 stereochemistry at the anomeric carbon. Similarly, the H4 hydrogen is an apparent triplet as a result of the near-identical trans diaxial couplings to H3 and H5. All disaccharides show strong nuclear Overhauser enhancements (NOE) between H1’ and H4. Unlike intermediates 19-21 (in CDCI3), poly01 22 (in CD30D) exhibits a 2.5-Hz coupling constant between H1’ and H4. Solvent effects play a role in this observation, since comparison of this same coupling constant for 21 in CD30D reveals a value of 1.7 Hz. Conformational changes induced by removal of the isopropylidine might also influence this value. The Karplus relation22can be used to correlate the H1’ to H4 coupling constant with the interring conformation of the preferred rotamer. The contribution to the coupling constant should be large for rotamer A because of the anti relationship between these two hydrogens and small for gauche rotamers B and C (60’).The observation of a zero coupling constant for compounds 19-21 in a wide tem(22) Karplus, M. J. Chem. Phys. 1959, 30, 11. Karplue, M. J. Am. Chem. SOC.1963,85,2870.
Armstrong and Teegarden
918 J. Org. Chem., Vol. 57, No. 3, 1992
Chart I1 H
H
Table I. Comparison of Coupling Constants (Hz) for Ring Protons of C-Disaccharides 19-22 and Monosaccharide 921
fused isoproylidene ring involving the erythro allylic and homoallylic oxygens in the starting alkenols. The required erythro relationship of these oxygen substituents limits the scope of this method to the synthesis of glucono-8-Cglycosides with the possibility of reduction to the 2'-deoxy derivatives or heteroatom substitution at C2' (Br X). Structural demands of the ylide-containing sugar fragment should be less restrictive. For instance, generation of 2'deoxy-glu-man or 2'-deoxy-glu-gal as well as 2'-deoxyglu-furan dimers should be possible. Many methods are known for stereospecific synthesis of C-glycosides, but the C5 + C7 strategy for the synthesis of C6 + C6 dimers offers a rapid entry into these interesting targets. The apparent conformational lock which compound 22 exhibits provides a unique structural motif which may prove to be useful in controlling localized conformations of larger oligosaccharides. The selective homologation of these disaccharides to oligosaccharides is the focus of current studies in our laboratories.
-
3.7 9.2 9.8 9.7 0 9.7
J1t,ya
9.7
3.8 9.4 10.6 10.4 0 10.3
J1',2'e Jya,3#
10.6
9.9
10.3
8.9 9.1
9.4 9.1
8.7 9.0
51.2 J2,3 J3,4 J4,5 J4,Y
JYe,3' J31,4!
J4t.5'
3.9 8.7 9.2 9.9 0 10.5 2.6 10.5 2.6 9.1 9.1
3.7 10.7 10.7 1.7 11.6 3.1 11.6 3.4 9.1 9.1
3.8 9.5 10.2 10.5 2.5 11.8 1.9 11.6 5.0 8.7 9.3
perature range (-40 to +25 "C) suggests that a conformation resembling structure B or C should be favored. Van der Waals contacts between the C6 and C2' hydrogens in C effectively rule out rotamers with this general conformation. NOE experiments on 20-22 provide additional support for general structure B. Enhancements between are clearly ~ b s e r v a b l e . ~The ~ H2' -H5 and H2',-H3 s m J distortion induced by the trans bicyclic nature of the sugar containing the ketal might account for a dihedral value larger than 60". In contrast, the fully deprotected poly01 22 (CD,OD) exhibits an average value more in line with a staggered conformation. When triol 21 is viewed down the C4/Cl' bond connecting the two sugars and is drawn as rotamer D (same as general structure B), the hydroxyl groups at C2, C3, and C6' are essentially planar (these groups are underlined and highlighted with arrows). This feature might explain the NMR behavior (CDC13) of 21 at low temperature. From -20 to -40 "C, the spectrum of 21 gradually converts to a new species which exhibits sharp lines and appears to be an aggregate of 21. The formation (CDC13)of hydrogen bonds in a cooperative fashion might facilitate this complexation. No substantial change was observed in the variable temperature spectra of 19 and 20 (in CDC1,) or 22 (in CD,OD).
Conclusions The synthesis of a-methyl 1',2'-dideoxycellobioside (22) has been achieved via a cyclization route which does not involve the exo anomeric carbon in the cyclization process. Regiochemical control is achieved by the use of a trans(23) NOE data has been successfully applied to the conformational analysis of carbohydrates: Williams, N. R.; Davison, B. E.; Ferrier, R. J.; Furneax, R. H. Carbohydr. Chem. 1985,17, 205 and ref 2.
Experimental Section General Information. 'H and 'Y!NMR spectra were recorded
at the field strength specified in MHz. Chemical shifts are reported in ppm with CHC13,acetone-ds, or DMSO-d6as internal standards. Tetrahydrofuran, diethyl ether, and toluene solvents were distilled from sodium benzophenone ketyl under N2. Methylene chloride was distilled from P20b Dimethylformamide, diisopropylamine, and dimethyl sulfoxide were distilled from barium oxide under N2 and stored over 4-A molecular sieves. Tetrabutylammonium fluoride (TBAF),tert-butyldimethylsilyl chloride (TBSCI), and tert-butyldiphenylsilyl chloride (TPSC1) as well as all other reagents were used as supplied. All crude organic extracts were dried with sodium sulfate unless noted otherwise. Solvents were removed under reduced pressure using a rotary evaporator. Unless otherwise noted, flash chromatography was performed on Merck silica gel 60 (230-400 mesh) usingvarious gradients of hexanes/ethyl acetate as eluants. Small-scale separations (
