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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
Org Lett. Author manuscript; available in PMC 2010 August 20.
Published in final edited form as:
PMCID: PMC2751794
NIHMSID: NIHMS135261

A Sequential Indium-Mediated Aldehyde Allylation/Palladium-Catalyzed Cross-Coupling Reaction in the Synthesis of 2-Deoxy-β-C-Aryl Glycosides

Abstract

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Indium-mediated allylation of aldehydes with 2-chloro-3-iodopropene, followed by a palladium-catalyzed cross-coupling reaction with triarylindium reagents or arylboronic acids, leads to aryl-substituted homoallylic alcohols in good to excellent yields and diastereoselectivities. The products obtained from reactions conducted with D-glyceraldehyde acetonide can be transformed into 2-deoxy-β-C-aryl ribofuranosides in high overall yields. Similarly, 2-deoxy-β-C-aryl allopyranosides may be prepared efficiently from 2,4-O-benzylidene erythrose.

C-Aryl glycosides are an important class of naturally occurring compounds with unique chemical and biological properties.1 Possessing a carbon-carbon bond between aromatic and carbohydrate moieties, these substances are endowed with remarkable stability toward acid and enzymatic hydrolysis; this affords them a sufficient intracellular lifetime to allow trafficking to the nucleus, where they bind DNA to form stable complexes.2 Indeed, numerous members of the glycosyl arene family have been shown to possess antibacterial, antitumor, and antifungal activities. These characteristics, in addition to limited availability from natural resources, mark these compounds as intriguing and timely targets for total synthesis.

Many previous approaches to the synthesis of C-aryl glycosides focus on achieving efficient formation of the aryl-glycosidic carbon-carbon bond.3 Refinement of activating groups,4 the use of lanthanide Lewis acids as promoters,5 and improvements in transition metal-mediated couplings6 have now made possible the total synthesis of complex natural products possessing the C-aryl glycoside functional group. Despite this progress, concerns about the use and disposal of environmentally hazardous reagents, solvents, and heavy metals have motivated chemists to investigate alternative “green” methods for forming carbon-carbon bonds, the backbone of all organic compounds.

Organoindium compounds have been shown to participate in a wide range of transition-metal mediated processes for carbon-carbon bond-formation.7 These environmentally benign reagents are air and moisture-stable, and can undergo cross-coupling reactions in an atom-efficient manner.8 Furthermore, the indium-mediated allylation of aldehydes and ketones in aqueous media is a powerful and stereoselective process that has been applied to the synthesis of a variey of complex natural products.9 In this letter we detail our findings on a sequential indium-mediated carbon-carbon bond-forming process that efficiently establishes the carbon backbone of 2-deoxy-C-aryl glycosides.

Motivated by the studies of Otera and Alcaide10 and others11 on the tin-mediated Barbier-type allylation of aldehydes with 2,3-dibromopropene, and hoping to avoid the use of toxic metals and acidic conditions required for such couplings, our initial investigations centered around the indium-mediated allylation of readily available D-glyceraldehyde acetonide (1a) with 2,3-dihalopropenes. Stirring a DMF (or 1:1 DMF:H2O) solution of 1a with 1.5 equiv of 2,3-dibromopropene 2a and 1 equiv of indium metal led to the desired homoallylic alcohol product in a disappointing 20% yield (Scheme 1). Careful study of the reaction revealed that addition of the indium metal to 2a in the presence or absence of glyceraldehyde acetonide led to a vigorous exothermic reaction and the visible production of gas. We reasoned that, upon formation, the 2-bromoallylindium reagent undergoes a rapid decomposition to indium bromide and allene. In contrast, Li has previously reported the high- yielding allylation of aldehydes with 3-bromo-2-chloropropene in water.12 Since 2,3-dichloropropene is commercially available and inexpensive, we decided to investigate the allylation of D-glyceraldehyde acetonide with this reagent in the presence of an iodide source to generate the more reactive 3-iodo-2-chloropropene in situ. Indeed, addition of indium metal (1 equiv) and TBAI (1 equiv) to a 2 M DMF solution of glyceraldehyde and 2,3-dichloropropene (2b, 1.5 equiv) led to homoallylic alcohol 4 in 92% yield and 7:1 diastereoselectivity; the major diastereomer was assigned the anti stereochemistry in analogy with previously reported indium allylations of glyceraldehyde.13 The allylation reaction takes place with similar efficiency (89% yield) and diastereoselectivity (dr=6.5:1) in 1:1 DMF:H2O when 2-chloro-3-iodopropene14 is employed as the allyl source. Subsequent cross-coupling of 4 with 1 equiv Ph3In in the presence of Pd(dppf)Cl2 (5 mol %) at 80 °C for 18 hours proceeded uneventfully,7j providing an 83% yield of 5a, the spectral data of which matched closely those reported for the same compound by Wang et al.13 Similarly, treatment of Garner’s aldehyde 1d with 2b in the presence of indium metal led to anti vinyl chloride 6c in 62% yield and 2.5:1 diastereoselectivity, in line with the previous allylation studies of Paquette;15 palladium-catalyzed cross-coupling of 6c with Ph3In furnished alcohol 7 in 71% yield. However, allylation of either 2-O-benzyl-L-glyceraldehyde16a (1b) or 2-O-triisopropylsilyl-L-glyceraldehyde16b (1c) was essentially non-diastereoselective (dr=1.2-1.5:1), producing vinyl chlorides 6a and 6b, respectively, in moderate yields.

Scheme 1
Glyceraldehyde allylation with 2,3-dihalopropenes

Ultimately it was revealed that both the allylation and cross-coupling reactions could be performed sequentially without purification of the intermediate homoallylic alcohol: crude 4 obtained from a simple extractive work up of the allylation reaction was directly treated with the reagents for cross-coupling and the reaction was heated for 16-36 hours. To explore the scope of this process, we tested cross-coupling with a variety of aryl- and heteroarylindium reagents. Both electron rich (Table 1, entries 2 and 6) and electron deficient (entries 4, 5, and 7) arylindiums cross-couple efficiently. However, sterically hindered arylindiums (entries 11 and 12) such as tris-2-tolylindium or tris-1-naphthylindium provided negligible yields (<10%) of coupled products even at elevated temperatures (100 °C) and with extended reaction times (48 h). The use of alternative catalyst systems, such as Fu’s P(t-Bu)3/Pd2(dba)3, PCy3/Pd(OAc)2 systems, 17a or Nolan’s NHC/Pd(OAc)2 complexes,17b afforded no significant improvement in the yields of 5k and 5l obtained (~10-20%). Employing tributylindium (entry 13) in the cross-coupling led to the formation of reduced products due to a facile β-hydride elimination/reductive elimination sequence. However, arylboronic acids could be efficiently used in place of arylindium reagents (entries 8-10) when slightly modified reaction conditions were employed for the cross-coupling (1.5 equiv ArB(OH)2, 3 equiv Na2CO3 (2 M), 3:1 toluene:EtOH, 90 °C, 18-21 h). Optimal yields were obtained with 1 equiv of triarylindium reagent or 1.5 equiv of arylboronic acid; employing decreased amounts of these reagents led to significantly increased reaction times and lower overall yields.

Table 1
Scope of the Sequential Glyceraldehyde Allylation / Arylindium Cross-Coupling Reactiona

Although this method did not furnish products containing sterically encumbered, ortho-substituted aryl groups, these substrates could be prepared by an alternate route involving Xiao’s α-regioselctive Heck arylation of allyl alcohol,18 allylic iodide formation, and indium-mediated glyceraldehyde allylation in aqueous media (Scheme 2). This procedure afforded alcohols 5k,l in ~40% overall yield and 3:1 diastereoselectivity.

Scheme 2
Synthesis of substrates containing sterically-hindered aryl moieties

2-Deoxy-β-C-aryl glycofuranosides have recently gained heightened importance as non-natural nucleoside analogs.19,20 Given that our arylated products contain the carbon backbone of 2-deoxyribose, we envisioned that they could be transformed into C-aryl ribofuranosides in a straightforward manner. Benzylation of 5a, acetonide deprotection, and regioselective silylation of the primary hydroxyl group took place in 80% overall yield. Oxidative cleavage of the alkene (cat. OsO4, NMO, acetone/H2O; KIO4, pH 6.5 buffer) gave 9a as a mixture of C.1 anomers; stereoselective ketol reduction (Et3SiH, TESOTf, CH2Cl2, -78 °C) then provided the target 1-phenyl-2-deoxyribofuranoside 10a with >10:1 β:α stereoselectivity. The undesired diastereomer at C.3 formed in the allylation step could be easily separated at this stage by silica gel chromatography; the overall yield of 10a from compound 5a was 58% (Scheme 3). Compounds 5e, 5g, 5h, and 5i can be transformed into C-aryl glycosides 10e, 10g, 10h, and 10i in an analogous manner in 51-70% overall yields. The stereochemistry of the products was confirmed by analysis of crosspeaks observed in the NOESY spectrum of 10h (see Supporting Information for details).

Scheme 3
Synthesis of 2-deoxy-C-arylfuranosides 10 from 5

To extend this process to the synthesis of C-aryl pyranosides, we investigated allylation reactions of glucose-derived aldehyde 1121 wih 2,3-dichloropropene under our standard conditions. Vinyl chloride 12 was obtained in low (30%) yield; however, when 2-chloro-3-iodopropene 2c was used as the allyl source and the reaction was conducted under aqueous conditions (1:1 DMF:H2O), a 78% yield of 12 was obtained. In both cases, only a single diastereomer was evident by 1H NMR, indicating <95:5 diastereoselectivity for the reactions. We suspect that a highly organized transition state, such as that represented by structure A in Scheme 4, is responsible for the high level of diastereoselection observed in this process.13d The resulting 2,3-anti, 3,4 anti stereorelationship was deduced by analysis of the NOESY spectrum of acetonide derivative 16a (vide infra, Scheme 5). Subsequent palladium-catalyzed cross-coupling of 12 with triphenylindium led to styrene 13a in 70% yield; Suzuki coupling of 12 with 3-fluorophenylboronic acid or 2-naphthaleneboronic acid gave rise to 13b and 13c in 56% and 88% yields, respectively.

Scheme 4
Diastereoselective allylation of 2,4-O-benzylidene erythrose 11
Scheme 5
Synthesis of 2-deoxy β-C-aryl glycosides 15a-c

Compound 13a, containing the carbon backbone of 2-deoxyallose, was then subjected to standard olefin oxidative cleavage conditions; subsequent silyl protection of the C.3 alcohol produced ketol 14a. Treatment with excess Et3SiH and TESOTf at -78 °C led to reduction of the C.1 ketol and opening of the benzylidene acetal in a regioselective fashion to provide β-C-aryl glycoside 15a in 80% overall yield from 13a (Scheme 5). Compounds 13b and 13c could be similarly transformed into C-glycosides 15b and 15c in 69-90% overall yields. The 11.2 Hz coupling constant observed for the anomeric protons in 15a-c confirmed the β-orientation of the aryl groups at C.1 of the carbohydrates. Importantly, the differential protection of the three hydroxyl groups on glycosides 15a-c allows for regioselective unmasking for subsequent O-glycosylation reactions.

The sequential indium-mediated aldehyde allylation/palladium-catalyzed cross-coupling process efficiently established the carbon backbone of 2-deoxy-C-aryl ribofuranosides and allopyranosides; subsequent transformations stereoselectively furnish glycosides with differential hydroxyl protection. We are currently exploring the utility of this method in the context of natural product synthesis.

Supplementary Material

1_si_001

Acknowledgments

We thank the National Institutes of Health (SC2 GM081064-01), the ACS Petroleum Research Fund (No. PRF 45277-B1) and the Henry Dreyfus Teacher-Scholar Award for their generous support of our research program.

Footnotes

Supporting Information Available Detailed experimental procedures, spectroscopic data, and 1H and 13C NMR spectra for all compounds in Table 1 and Schemes 1--5,5, as well as NOESY spectra for compounds 10h and 16a. This material is available free of charge on the Internet at http://pubs.acs.org.

References

1. Hansen MR, Hurley LH. Acc Chem Res. 1996;29:249., and references therein.
2. Hacksell U, Daves GD. Prog Med Chem. 1985;22:1. [PubMed]
3. (a) Jaramillo C, Knapp S. Synthesis. 1994;1:1. (b) Levy DE, Tang C. The Chemistry of C-glycosides. Elsevier Science; Tarrytown, NY: 1995. (c) Postema MHD. In: C-Glycoside Synthesis. Rees CW, editor. CRC Press; Boca Raton, FL: 1995. (d) Nicotra F. Top Corr Chem. 1997;187:55. (e) Du Y, Linhardt RJ. Tetrahedron. 1998;54:9913.
4. (a) Matsumoto T, Katsuki M, Suzuki K. Tetrahedron Lett. 1988;29:6935. (b) Matsumoto T, Katsuki M, Jona H, Suzuki K. Tetrahedron Lett. 1989;30:6185. (c) Matsumoto T, Hosoya T, Suzuki K. Tetrahedron Lett. 1990;31:4629. (d) Matsumoto T, Katsuki M, Jona H, Suzuki K. J Am Chem Soc. 1991;113:6982.
5. (a) Sharma GVM, Raman KK, Sreenivas P, Radha Krishna P, Chorghade MS. Tetrahedron: Asym. 2002;13:687. (b) Hosoya T, Takashiro E, Matsumoto T, Suzuki K. J Am Chem Soc. 1994;116:1004.
6. Palladium, Tin: (a) Parker KA, Koh Y. J Am Chem Soc. 1994;116:11149. (b) Parker KA, Coburn CA, Koh Y. J Org Chem. 1995;60:2938. (c) Apsel B, Bender JA, Escobar M, Kaelin DE, Lopez OD, Martin SF. Tetrahedron Lett. 2003;44:1075. (d) Kaelin DE, Jr, Sparks SM, Plake HR, Martin SF. J Am Chem Soc. 2003;125:12994. [PubMed] (e) Kaelin DE, Lopez OD, Martin SF. J Am Chem Soc. 2001;123:6937. [PubMed] (f) McDonald FE, Zhu HYH, Holmquist CR. J Am Chem Soc. 1995;117:6605. Ruthenium: (g) Schmidt B, Settelkau T. Tetrahedron. 1997;53:12991. (h) Schmidt B. Org Lett. 2000;2:791. [PubMed] Chromium: (i) Pulley SR, Carey JP. J Org Chem. 1999;63:5275. (j) Fuganti C, Serra S. Synlett. 1999;8:1241. Nickel: (k) Moineau C, Bolitt V, Sinou D. J Org Chem. 1998;63:582–591. [PubMed] (l) Sinou D, Moineau C. Recent Res Dev Org Chem. 1999;3:1. (m) Bertini B, Moineau C, Sinou D, Gesekus G, Vill V. Eur J Org Chem. 2001;2:375. Explosive Lewis acids such as AgClO4 have also been successfully used to promote C-aryl glycosidations. See: (n) Toshima K, Matsuo G, Tatsuta K. Tetrahedron Lett. 1992;33:2175.
7. (a) Perez I, Perez Sestelo J, Sarandeses LA. Org Lett. 1999;1:1267. (b) Perez I, Perez-Sestelo J, Sarandeses LA. J Am Chem Soc. 2001;123:4155. [PubMed] (c) Lee PH, Sung S-Y, Lee K. Org Lett. 2001;3:3201. [PubMed] (d) Lee K, Lee J, Lee PH. J Org Chem. 2002;67:8265. [PubMed] (e) Lehmann U, Awasthi S, Minehan T. Org Lett. 2003;5:2405. [PubMed] (f) Rodriguez D, Perez Sestelo J, Sarandeses LA. J Org Chem. 2003;68:2518. [PubMed] (g) Baker L, Minehan T. J Org Chem. 2004;69:3957. [PubMed] (h) Rodriguez D, Perez Sestelo J, Sarandeses LA. J Org Chem. 2004;69:8136. [PubMed] (i) Riveiros R, Rodriguez D, Perez Sestelo J, Sarandeses LA. Org Lett. 2006;8:1403. [PubMed] (j) Rivieros R, Saya L, Perez Sestelo J, Sarandeses LA. Eur J Org Chem. 2008;11:1959.
8. Takami K, Yorimitsu H, Shinokobu H, Matsubara S, Oshima K. Org Lett. 2001;3:1997. [PubMed]
9. For reviews, see: (a) Li CJ. Chem Rev. 2005;105:3095. [PubMed] (b) Li CJ, Chan TH. Organic Reactions in Aqueous Media. Wiley; New York: 1997. (c) Li CJ, Chan TH. In: Organic Synthesis in Water. Grieco PA, editor. Thomson Science; Glasgow, Scotland: 1998. (d) Li CJ, Chan TH. Tetrahedron Lett. 1991;32:7017. (e) Chan TH, Yang Y. J Am Chem Soc. 1999;121:3228.
10. Mandai T, Nokami J, Yano T, Yoshinaga Y, Otera J. J Org Chem. 1984;49:172.
11. Alcaide B, Almendros P, Rodriguez-Acebes R. J Org Chem. 2005;70:2713. [PubMed]
12. Yi X-H, Meng Y, Li C-J. Tetrahedron Lett. 1997;38:4731.
13. (a) Pan C-F, Zhang Z-H, Sun G-J, Wang Z-Y. Org Lett. 2004;6:3059. [PubMed] (b) Cleghorn LAT, Cooper RR, Fishwick CWG, Grigg R, MacLachlan WS, Rasparini M, Sridharan V. J Organomet Chem. 2003;687:483. (c) Paquette LA, Mitzel TM. Tetrahedron Lett. 1995;36:6863. (d) Paquette LA, Mitzel TM. J Am Chem Soc. 1996;118:1931. (e) Paquette LA, Mitzel TM. J Org Chem. 1996;61:8799. [PubMed]
14. 2-Chloro-3-iodopropene was prepared by treatment of commercially available 2,3-dichloropropene with NaI in acetone at room temperature overnight: Pace V, Martinez F, Fernandez M, Sinisterra JV, Alcantara AR. Org Lett. 2008;9:2661. [PubMed]
15. Paquette LA, Mitzel TM, Isaac MB, Crasto CF, Schomer WW. J Org Chem. 1997;62:4293. [PubMed]
16. (a) Steuer B, Wehner V, Lieberknecht A, Jager V. Org Syn. 1997;71:1. (b) McNulty J, Mao J. Tetrahedron Lett. 2002;43:3857.
17. (a) Littke AF, Dai C, Fu GC. J Am Chem Soc. 2000;122:4020. (b) Singh R, Viciu MS, Kramareva N, Navarro O, Nolan SP. Org Lett. 2005;7:1829. [PubMed]
18. (a) Mo J, Xu L, Ruan J, Liu S, Xiao J. Chem Commun. 2006;34:3591. [PubMed] (b) Mo J, Xu L, Xiao J. J Am Chem Soc. 2005;127:751. [PubMed] (c) Mo J, Xiao J. Angew Chem Int Ed. 2006;45:4152. [PubMed]
19. (a) Schweitzer BA, Kool ET. J Org Chem. 1994;59:7238. [PMC free article] [PubMed] (b) Schweitzer BA, Kool ET. J Org Chem. 1995;60:8326. (c) Ren X-F, Schweitzer BA, Sheils CJ, Kool ET. Angew Chem Int Ed Engl. 1996;35:743. [PMC free article] [PubMed] (d) Ren X-F, Chaudhuri NC, Kool ET. J Am Chem Soc. 1996;118:7671. [PMC free article] [PubMed]
20. (a) Schweitzer BA, Kool ET. J Am Chem Soc. 1995;117:1863. [PMC free article] [PubMed] (b) Moran S, Rem RX-F, Rumney S, Kool ET. J Am Chem Soc. 1997;119:2056. [PMC free article] [PubMed]
21. Rhee JU, Bliss BI, RajanBabu TV. J Am Chem Soc. 2003;125:492. [PubMed]