Organozinc Reagents for the Nucleophilic C-Glycosylation of Glycals

Simon N. Thorn and Timothy Gallagher

School of Chemistry, University of Bristol, Bristol, BS8 1TS, United Kingdom

Abstract: Addition of a variety of simple and functionalised organozinc reagents (R₂Zn or RZnX) to a structurally diverse range of glycals takes place in the presence of either BF₃.OEt₂ or TMSOTf and efficiently leads to C(1)-glycosides with selectivity for the alpha-isomer.

The electrophilic reactivity of glycals 1 towards carbon nucleophiles provides a versatile entry into C(1)-glycosides 2 via the carbon-Ferrier reaction.^1,2 Of the organometallic nucleophiles (RMetal) available, zinc-based reagents (e.g. R₂Zn, RZnX) are particularly attractive as vehicles for this transformation being readily generated and, more importantly, tolerant of a spectrum of functionality, both within the zinc reagent itself as well as in the electrophilic glycosyl component.³

The reaction of organozincs with glycals to give C-glycosides 2 has been reported, but this has only been achieved using a simple Reformatsky reagent.⁴ C-Aryl variants of 2 have also been prepared via ArZnX in the presence of Pd(0), but this is based on a stereospecific displacement of 1-O-acetyl-2,3-dideoxyhex-2-enopyranosides - the DELTA²-isomer of glycal 1.⁵

The more general aspects of this zinc-mediated approach to C-glycoside synthesis remain to be defined and in this paper we describe the reaction of alkyl organozinc nucleophiles towards a series of glycal derivatives. This process requires Lewis acid activation, but will permit the presence of acetate and benzyl O-protecting groups, as well as an interglycosidic linkage within the glycosyl electrophile, and flexibility within the organozinc component.

The results of this study are presented in two parts. Table 1 illustrates the scope of the chemistry available in terms of the glycal substrates that have been utilised with Et₂Zn acting as a prototypical organozinc nucleophile. In Table 2, the ability to vary the functional groups associated with the organozinc nucleophile is displayed based on employing 3,4,6-tri-O-acetyl-DELTA-glucal as the electrophilic component.

The results shown in Table 1 show that good yields of C-glycoside products are available, but it is important to appreciate that the order of addition of reagents was crucial; exposure of the glycal to BF₃.OEt₂ prior to addition of Et₂Zn resulted in poor yields. Usually only one equivalent of BF₃.OEt₂ was needed, except for substrates containing either O-benzyl units (entry 5, Table 1) or a high degree of oxygenation, as with hepta-O-acetylmaltal (entry 7, Table 1) where up to 5 equivalents of the Lewis acid were employed. In all cases, including the examples shown in Table 2, the alpha-C(1)-glycoside was the predominant product. The configuration at C(1) (alpha vs. beta) was based primarily on ¹³C NMR analysis in accordance with earlier studies; the chemical shift of C(5) is diagnostic and in the alpha-isomer is shielded relative to the corresponding beta-isomer.⁶ With the pentose-derived products (entries 1 and 2, Table 1), ¹³C NMR was less useful and, as a consequence, assignments in these two cases are viewed as tentative, but parallel the course of related C-glycosylation reactions.⁷

The ability to utilise zinc reagents that introduce useful functionality within the C-glycoside product was important to our longer term goals and variation in the structure of the organozinc reagent has been examined using 3,4,6-tri-O-acetyl-D-glucal 3. This led to C-glycosides 4 and the range of products available, together with yields and C(1)-isomer ratios, are presented in Table 2.

In the course of these studies two specific problems were encountered. The pivaloyl-based reagent (t-BuOCOCH₂ZnI)⁸, which is equivalent to "·CH₂OH", was less stable than the other alkyl zinc reagents used and C-glycoside 4e was obtained in only 29% yield. With the nitrile-containing reagent NCCH₂CH₂CH₂ZnI,¹⁰ the zinc species was essentially insoluble (and unreactive) in CH₂Cl₂ and this reagent was also inert towards 3 in ether-based solvents. This difficulty was overcome by careful isolation of NCCH₂CH₂CH₂ZnI from THF solution, followed by suspension in CH₂Cl₂ containing glucal 3 and BF₃.Et₂O, and the reaction mixture was then placed in a ultrasound bath. Not only was the carbon-Ferrier displacement observed using sonication, but the rate of this process to give 4f was also very substantially increased (10 min. vs. 3-8 h. for reactions of 3 with other alkyl organozinc reagents). In the other cases shown in Table 2, solubility and stability of the organozinc species was not a significant barrier and the successful incorporation of useful residues at C(1) illustrates an advantage of using organozinc reagents over a host of other metal-based nucleophiles.

The balance between reactivity and tolerance of functionality is an essential feature of this approach to C-glycoside synthesis. Glycals are relatively unreactive electrophiles and, by necessity, will often contain protecting groups that preclude the use of more nucleophilic, but acid-sensitive organometallic reagents. Zinc-based methodology offers a flexible and direct entry into functionalised C-glycosides and further development of this chemistry, including the use of sonication to enhance reactivity, is underway.

Experimental Procedures: General reaction conditions involved addition of the pre-formed organozinc reagent to a solution of the glycal in dry CH₂Cl₂ at -20°C followed by addition of the Lewis acid component. Et₂Zn was used in hexane solution, but in cases where the zinc reagent was prepared in THF, this solvent was removed in vacuo (see below) prior to addition of CH₂Cl₂. The reaction mixtures were allowed to warm to r.t. over 30-60 min. (for reactions involving Et₂Zn, Table 1) or 3-8 hr. (for most reagents used in Table 2) and the products were isolated after an aqueous work-up and chromatography. With NCCH₂CH₂CH₂ZnI, once halogen-zinc exchange was complete, the THF solution of the zinc reagent was evaporated in vacuo (at 30-40°C and maintaining an atmosphere of argon when appropriate) to give a viscous grey liquid which was then taken up in CH₂Cl₂ and treated with glucal 3 and BF₃.OEt₂ at r.t. The mixture was then placed in a conventional laboratory ultrasonic bath for 10 minutes after which time glucal 3 had been consumed.¹¹

Acknowledgement. We thank EPSRC (Grant No. GR/H92142) for financial support.

References

1. Postema, M.H.D. Tetrahedron 1992, 48, 8545; Postema, M.H.D. In New Directions in Organic Chemistry; Rees, C.W., Ed.; CRC, 1995.

2. Ferrier, R.J.; Prasad, N. J. Chem. Soc (C). 1969, 570.

3. Knochel, P.; Singer, R.D. Chem. Rev. 1993, 93, 2117.

4. Orsini, F.; Pelizzoni, F. Carbohydr. Res. 1993, 243, 183.

5. (a) Dunkerton, L.V.; Euske, J.M.; Serino, A.J. Carbohydr. Res. 1987, 171, 89. The use of Pd(0) involves a different mechanistic pathway. (b) For other studies involving the reactivity of organozinc reagents towards conventional O-glycosides, see Kozikowski, A.P.; Konoike, T.; Ritter, A. Carbohydr. Res. 1987, 171, 109

6. (a) Stothers, J.B. Carbon-13 NMR Spectroscopy; Academic: New York, 1973, ch. 3; Kalinowski, H.-O.; Berger S.; Braun, S. Carbon-13 NMR Spectroscopy; Wiley: New York, 1988; (b) For recent applications see: reference 4; Moineau, C.; Bolitt, V.; Sinou, D. J. Chem. Soc., Chem. Commun. 1995, 1103; Brakta, M.; Lhoste, P.; D. Sinou, J. Org. Chem. 1989, 54, 1890.

7. Sabol, J.S.; Cregge, R.J.; Tetrahedron Lett. 1989, 30, 6271.

8. Knochel, P.; Chou, T.-S.; Jubert C.; Rajagopal, D. J. Org. Chem. 1993, 58, 588.

9. Jubert, C.; Knochel, P. J. Org. Chem. 1992, 57, 5431.

10. Knochel, P.; Yeh, M.C.P.; Berk, S.C.; Talbert, J. J. Org Chem. 1988, 53, 2392.

11. Satisfactory microanalytical and/or high resolution mass and spectroscopic (IR, ¹H and ¹³C NMR) data has been obtained for all new compounds. Yields refer to isolated material and in most cases the isomeric C-glycosides shown in Tables 1 and 2 were separable by chromatography.
    

Table 1. C-Glycosylation of glycals using Et₂Zn

Entry	Glycal	C-Glycoside	alpha:beta (% yield)
1			24:1 80%
2			12:1 53%
3			1.5:1 71%
4			3.2:1 95%
5			4.1:1 87%
6			alpha only 73%
7	Maltal (R = Ac)		2:1 81%

Table 2. C-Glycosylation of glucal 3 using RZnX

C-Glycoside 4	Zinc Reagent Lewis acid	alpha:beta ratio % yield
4a	PhCH2ZnBr TMSOTf (1 equiv.)	1.7:1 57%
4b	PhCH2CH2ZnI BF3.OEt2 (1 equiv.)	7:1 53%
4c	Cl(CH2)4ZnI BF3.OEt2 (3 equiv.)	9:1 63%
4d	EtO2C(CH2)3ZnI BF3.OEt2 (6 equiv.)	5:1 87%
4e	t-BuOCOCH2ZnI BF3.OEt2 (4 equiv.)	4:1 29%
4f	NC(CH2)3ZnI BF3.OEt2 (3 equiv.)	5:1 63% (See text)

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Organozinc Reagents for the Nucleophilic C-Glycosylation of Glycals

Simon N. Thorn and Timothy Gallagher

School of Chemistry, University of Bristol, Bristol BS8 1TS, United Kingdom

Organozinc Reagents for the Nucleophilic C-Glycosylation of Glycals. S. N. Thorn and T. Gallagher C-Glycosides, organozinc reagents, ultrasound