Glycals as Ambident Electrophiles Towards Organometallic Nucleophiles. Stereoselective Synthesis of C(3)-Branched Carbohydrates

Simon N. Thorn and Timothy Gallagher

School of Chemistry, University of Bristol, Bristol, BS8 1TS, UK

Abstract: Reaction of glycals with simple and functionalised alkyl Zn/Cu reagents in the presence of BF₃.OEt₂ leads to C(3)-branched carbohydrates with complete control of stereochemistry at C(3).

The reaction of organozinc nucleophiles (R₂Zn or RZnX) with O-acetyl and O-benzyl-protected glycals provides a useful entry to C-glycosides (Eq. 1).¹ Glycals are, however, only modest electrophiles, with the transformation shown in Eq. 1 requiring activation with an appropriate Lewis acid (BF₃.OEt₂ or TMSOTf). In order to extend the utility of this process we have sought to enhance the reactivity of the nucleophilic component by evaluating the corresponding Zn/Cu species.² While these reagents retain much of the versatility associated with conventional organozinc nucleophiles, notably the ability to tolerate a spectrum of useful functional groups, a quite different pattern of reactivity towards glycals has emerged.

In earlier studies, our attempts to add (2-cyanoethyl)zinc iodide (2)³ to 3,4,6-tri-O-acetyl-D-glucal (1a) to give the C(1)-glycoside (3) were unsuccessful, a problem that has been associated with stabilisation of the organozinc species in THF solution; this reaction is successful if CH₂Cl₂ is used as solvent.^1c However, when the corresponding Zn/Cu reagent (4)⁴ was employed, in the presence of up to 3 equivalents of BF₃.OEt₂, the C(3)adduct (5) was isolated in 91% yield (Scheme 1). Under the same conditions, the corresponding O-benzyl glucal (1b) gave adduct (6) in 51% yield. In both of these cases the new C-C bond was formed at C(3) rather than at C(1) (none of the C(1) adduct was detected) and, furthermore, C(3)-substitution occurred with net retention of configuration (see below). The scope of this process has been evaluated using both simple and synthetically more useful Zn/Cu reagents, in combination with a representative series of glycals: (1a), (1b), 3,4-di-O-acetyl-6-deoxy-L-glucal (7), 3,4-di-O-acetyl-D-xylal (8) and hepta-O-acetyl maltal (9). The results of this study are summarised in Table 1.⁴

Although small amounts of C(1)-adducts (cf. (3)) were isolated, generally the C(3)-branched glycal (10-16) was the major product. An exception to this was 3,4-di-O-acetyl-D-xylal (8) which underwent addition of BuCu(CN)ZnI to give approximately equal quantities of the C(3) adduct (15) and the corresponding C(1) derivative.⁵

The stereochemical course of the C(3) substitution appeared, based on ¹H NMR correlations, to be consistent for all of the systems studied in Scheme 1 and Table 1.⁶ However, in the absence of an additional conformational constraint to provide more rigidity to the dihydropyran ring, stereochemical assignments by ¹H NMR are less clear cut. As a consequence, the configuration at C(3) of the newly-formed C-C bond has been assigned in a more rigorous fashion. This is illustrated in Scheme 2 for two representative examples. Hydrogenation of (5) gave tetrahydropyran (17) (74% yield) and the trans relationship between H(3) and H(4) (pyran numbering) was characterised by ¹H NMR.⁷ A similar sequence was carried out with the D-xylal-derived adduct (15) to give tetrahydropyran (18) in 62% yield.

Glycals are ambident electrophiles capable of reacting at either C(1) or C(3) with nucleophiles either directly or via the intermediacy of a Ferrier rearrangement product (a ^2,3 glycal).⁸ Nucleophilic displacement of a C(3)-mesylate glucal derivative has been reported by Mitsunobu using either a Cu/Li or Cu/Mg reagent.^9,10 Use of these more reactive organocopper reagents does limit the range of useful functional groups that can be carried within the nucleophilic component, however, Mitsunobu also observed inversion, rather than retention of configuration at C(3) of the D-glucal used in his study.

In summary, reaction of glycals, in the presence of Lewis acid activation, with Zn/Cu nucleophiles leads predominantly to the formation of C(3)-branched carbohydrate derivatives in a stereoselective fashion. This complements the regiochemical preference previously observed with conventional zinc reagents which provides an efficient and equally versatile entry to the C(1)-substituted isomers.^1c

Acknowledgement. We thank EPSRC (Grant No. GR/H92142) for financial support and Professor R. F. W. Jackson for discussions.

References

1. (a) Orsini, F.; Pelizzoni, F. Carbohydr. Res. 1993, 243, 183; (b) Dunkerton, L.V.; Euske, J.M.; Serino, A.J. Carbohydr. Res. 1987, 171, 89; (c) Thorn, S. N.; Gallagher, T. Synlett 1996, 185.

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

3. Yeh, M. C. P.; Knochel, P. Tetrahedron Lett. 1988, 29,2395

4. General Experimental Procedure: To a cold (-25 C) solution of NCCH₂CH₂Cu(CN)ZnI (4)³ (prepared from 7.4 mmol of 3-iodopropionitrile) in THF (10 mL) was added a solution of glucal (1a) (2.5 mmol) in THF (3 mL) followed, after 10 min, by BF₃.OEt₂ (7.4 mmol). The reaction mixture was allowed to warm to r.t. over 1.5 h after which time TLC showed complete conversion to a slightly less polar product. The mixture was diluted with H₂O and CH₂Cl₂, filtered (to remove solids) and the organic phase was separated, dried (MgSO₄) and concentrated in vacuo. The product was purified by chromatography (eluting with 25% EtOAc - 75% hexanes) to give adduct (5) in 91% yield as a pale yellow oil.

5. Usually small amounts of addition reaction at C(1) were observed. Generally the beta-anomer of the C(1) adducts predominated and were assigned using ¹³C NMR spectroscopy as described earlier.^1c Tri-O-acetyl-D-galactal did not undergo C(3) substitution with BuCu(CN)ZnI, and, in this example, the C(1) adduct was only obtained in 10% yield.
   Attempts to add Bu^tCO.OCH₂Cu(CN)ZnI to (1a) were also unsuccessful.

6. The C(3)-adducts (5, 6, 10-16) all showed essentially the same coupling constant (³J_3,4 9.3±0.3 Hz) between H(3) and H(4). In addition, H(2) appeared as a doublet of doublets (J 6, 2 Hz) which is also consistent with the C(3) stereochemistry indicated. For ¹H NMR data for 3-substituted glycals see Fraser-Reid, B.; Carthy, B. J.; Radatus, B. Tetrahedron 1972, 28, 2741; Greenspoon, N.; Keinan, E. J. Org. Chem. 1988, 53, 3723; Marco-Contelles, J. L.; Fernández, C.; Gómez, A.; Martín-León, N. Tetrahedron Lett. 1990, 31, 1467.

7. The saturated tetrahydropyrans (17) and (18) showed coupling constants consistent with the trans configuration shown - note that pyran numbering is used: (17): delta_H 4.68 (1 H, t, J 9.8 Hz, H(3)); (18): delta_H 4.58 (1 H, t d, J 9.3, 4.4 Hz, H(3)). Glycals (11) and (13) were also subjected to the reduction sequence shown in Scheme 2 and ¹H NMR analysis was consistent with the stereochemical assignments shown. See also Kelly, M. J.; Roberts, S. M. J. Chem. Soc., Perkin Trans. 1 1991,787.

8. The intermediacy of a Ferrier rearrangement product/oxonium species is likely in the systems discussed in this paper. In support of this, substitution of 3,4,6-tri-O-acetyl-D-allal (19) led to adduct (5) in 59% isolated yield, a process that proceeds with inversion of configuration at C(3).

   

9. Mitsunobu, O.; Yoshida, M.; Takayi, M.; Kubo, K.; Maruyama, S.; Satoh, I.; Iwami, H. Chemistry Lett. 1989, 809. Ogihara. T.; Mitsunobu, O. Tetrahedron Lett. 1983, 24, 3505.

10. Dorgan, B. J.; Jackson, R. F. W. Synlett, accompanying manuscript.

    

Scheme 1. Reagents: i, NCCH₂CH₂ZnI (2), BF₃.OEt₂, THF, -25°C to r.t; ii, NCCH₂CH₂Cu(CN)ZnI (4), BF₃.OEt₂,THF, -25 °C to r.t.

Scheme 2. Reagents: i, H₂, 10% Pd on C, EtOH

Table 1

Glycal	Zn/Cu Reagent	C(3) Adduct	C(1) Adduct	% (alpha:beta)
(1a)	BuCu(CNZn)I		(10) 63%	8% (1:1.4)
(1a)	NC(CH2)3Cu(CN)ZnI		(11) 91% R=(CH2)3CN	none
(1a)	Cl(CH2)4Cu(CN)ZnI		(12) 42% R=(CH2)4Cl	4% beta only)
(1a)	EtO2C(CH2)3Cu(CN)ZnI		(13) 32% R=(CH2)3CO2Et	none
(7)	BuCu(CN)ZnI		(14) 48%	10% (beta only)
(8)	BuCu(CN)ZnI		(15) 21%	20% (1:1.2)
Hepta-O-acetyl maltal (9)	NC(CH2) 2Cu(CN)ZnI			10% (beta only)

Glycals as Ambident Electrophiles Towards Organometallic Nucleophiles. Stereoselective Synthesis of C(3)-Branched Carbohydrates

Simon N. Thorn and Timothy Gallagher

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

Glycals as Ambident Electrophiles Towards Organometallic Nucleophiles. Stereoselective Synthesis of C(3)-Branched Carbohydrates Simon N. Thorn and Timothy Gallagher C(3)-branched glycals, Zn/Cu nucleophiles

Table 1

Glycal Zn/Cu Reagent	C(3) Adduct	[C(1) Adduct % (alpha:beta)]
(1a) BuCu(CNZn)I		(10) 63% [8 %; 1:1.4]
(1a) NC(CH2)3Cu(CN)ZnI	R=(CH2)3CN	(11) 91% [no C(1) adduct]
(1a) Cl(CH2)4Cu(CN)ZnI	R=(CH2)4Cl	(12) 42% [4% (beta only)]
(1a) EtO2C(CH2)3Cu(CN)ZnI	R=(CH2)3CO2Et	(13) 32% [no C(1) aduct]
(7) BuCu(CN)ZnI		(14) 48% [10% beta only)]
(8) BuCu(CN)ZnI		(15) 21% [20% 1:1.2]
Hepta-O-acetyl maltal (9) NC(CH2) 2Cu(CN)ZnI		(16) 67% [10% beta only)]