1
Short and stereoselective synthesis of C-glycosylated glycine derivatives from glycals by radical addition and reduction

Type: Method | Advantage: None | Novelty: New | ConceptID: Met1

2
Only three steps are required for the convenient synthesis of 2-C-branched glyco-amino acids from glycals with good yields and stereoselectivities.

Type: Conclusion | Advantage: None | Novelty: None | ConceptID: Con1

3
Glycopeptides and glycoproteins are an important family of compounds, which contain a carbohydrate and a peptide domain and are of current interest in bioorganic chemistry, due to their biological functions.1,2

Type: Background | Advantage: None | Novelty: None | ConceptID: Bac1

4
Recent research activities were especially focused on modified glycopeptides, where the common O- or N-glycosidic bond linkages were replaced by a carbon-based unit of greater stability and resistance towards enzymatic deglycosylation.

Type: Method | Advantage: None | Novelty: Old | ConceptID: Met2

5
Indeed, during the last decade several syntheses of such C-glycopeptides were reported in the literature.2,3

Type: Method | Advantage: None | Novelty: Old | ConceptID: Met2

6
Furthermore, glycine derivatives directly linked to carbohydrates are constituents of natural products and possess remarkable antibiotic activities.4

Type: Background | Advantage: None | Novelty: None | ConceptID: Bac2

7
However, many synthesis of C-glycosyl amino acids focused on the linkage at the anomeric position and required many reaction steps.

Type: Method | Advantage: No | Novelty: Old | ConceptID: Met2

8
Only very recently, Chandrasekaran and coworkers developed an elegant entry to 2-C-branched glyco-amino acids by the ring opening of 1,2-cyclopropanated sugars.5

Type: Method | Advantage: None | Novelty: Old | ConceptID: Met3

9
Herein we describe our approach for the synthesis of such C-glycosylated glycine derivatives in only three steps from commercially available glycals.

Type: Method | Advantage: None | Novelty: New | ConceptID: Met4

10
The reaction sequence involves a radical addition and the reduction of CN double bonds, which both proceed with good yields and stereoselectivities.

Type: Method | Advantage: Yes | Novelty: New | ConceptID: Met4

11
During the course of our investigations on transition-metal-mediated radical reactions, we developed a simple one-step entry to 2-C-branched carbohydrates by the addition of dimethyl malonate to various glycals in the presence of ceric(iv) ammonium nitrate (CAN).6

Type: Method | Advantage: None | Novelty: Old | ConceptID: Met5

12
Thus, the gluco isomer 2 was obtained in 62% yield from tri-O-acetyl-d-glucal (1a) and was chosen as the precursor for the synthesis of the desired C-glycosylated glycine derivatives.

Type: Method | Advantage: None | Novelty: Old | ConceptID: Met5

13
The transformation of malonates into α-amino acids via the corresponding oximes is known since many years.7

Type: Method | Advantage: None | Novelty: Old | ConceptID: Met6

14
However, applications in carbohydrate chemistry were hitherto unknown, due to the drastic basic conditions.

Type: Method | Advantage: No | Novelty: Old | ConceptID: Met6

15
After careful optimization of the reaction, isoamyl nitrite was found as the reagent of choice for the introduction of the nitrogen functionality.

Type: Method | Advantage: None | Novelty: New | ConceptID: Met7

16
Thus, the oxime ester 3 was isolated in excellent yield after acetylation (Scheme 1).

Type: Method | Advantage: Yes | Novelty: New | ConceptID: Met7

17
NOE experiments indicated the exclusive formation of the Z-configured diastereomer, which can be rationalized in terms of steric repulsion between the N-O-acetyl group and the carbohydrate residue.

Type: Method | Advantage: None | Novelty: Old | ConceptID: Met8

18
Unfortunately, due to the drastic reaction conditions the transformation of other malonyl-substituted saccharides 2 into the corresponding oximes failed.

Type: Method | Advantage: No | Novelty: Old | ConceptID: Met8

19
To overcome this problem and to develop a general entry to 2-C-branched glyco-amino acids, we became interested in the introduction of the nitrogen functionality by the radical reaction in the first step.

Type: Method | Advantage: None | Novelty: New | ConceptID: Met9

20
Due to its CH acidity, the nitroacetate 4 seemed to be an ideal precursor for such a transition-metal-mediated radical reaction.

Type: Method | Advantage: None | Novelty: New | ConceptID: Met9

21
Indeed, the addition of nitroacetates to alkenes and arenes in the presence of Mn(OAc)3 was reported in the literature,8 but applications in carbohydrate chemistry were hitherto unknown.

Type: Background | Advantage: None | Novelty: None | ConceptID: Bac3

22
However, under the mild ceric(iv) ammonium nitrate (CAN) conditions, the addition of nitroacetate 4 to various glycals 1 proceeds smoothly, to afford the bicyclic isoxazoline N-oxides 5 in only one step in moderate yields and high diastereoselectivities (Scheme 2).

Type: Method | Advantage: Yes | Novelty: New | ConceptID: Met9

23
Furthermore, compared to the synthesis via the malonate 2, the addition of nitro acetate 4 requires only one reaction step for the introduction of the nitrogen functionality from glycals.

Type: Method | Advantage: Yes | Novelty: New | ConceptID: Met9

24
From the mechanistic point of view, CAN oxidizes the intermediary formed anomeric radical to a cation, which is intramolecularly trapped by the nitro group to afford the cis-bicyclic isoxazoline N-oxides 5.

Type: Method | Advantage: None | Novelty: New | ConceptID: Met9

25
The preferred formation of the depicted diastereomers can be rationalized by an anti attack of the radicals to the 3-O-acetyl group, in accordance with the addition of malonates.6

Type: Method | Advantage: None | Novelty: New | ConceptID: Met9

26
To obtain the desired glycine derivatives, the CN double bonds had to be reduced in the next step, with especial interest on the diastereoselectivity.

Type: Method | Advantage: None | Novelty: New | ConceptID: Met10

27
The hydrogenation of simple oximes is described in the literature with several palladium catalysts.9

Type: Method | Advantage: None | Novelty: Old | ConceptID: Met11

28
However, the additional ester groups in substrates 3 and 5 diminish the reactivity towards catalytic hydrogenation.

Type: Method | Advantage: No | Novelty: Old | ConceptID: Met11

29
Furthermore, the large steric demand of the carbohydrate moiety was problematic and resulted in slow heterogeneous reactions.

Type: Method | Advantage: No | Novelty: Old | ConceptID: Met11

30
Thus, some catalysts were unreactive and only palladium hydroxide at 40 bar hydrogen pressure led to 81% conversion of the oxime ester 3.

Type: Method | Advantage: None | Novelty: Old | ConceptID: Met12

31
After acetylation the desired glycine derivatives 6 were isolated in good yield and diastereoselectivity.

Type: Method | Advantage: Yes | Novelty: Old | ConceptID: Met12

32
However, the isoxazoline N-oxides 5 did not react under such conditions (Table 1).

Type: Method | Advantage: No | Novelty: Old | ConceptID: Met12

33
To overcome this problem and to develop a general entry to 2-C-branched glyco-amino acids, we investigated the reduction of the CN double bonds by aluminium amalgam,10 which mechanistically proceeds by an electron transfer.

Type: Method | Advantage: None | Novelty: New | ConceptID: Met13

34
Indeed, now the electron poor oxime 3 and isoxazoline N-oxides 5a–d did react smoothly with high conversions.

Type: Method | Advantage: Yes | Novelty: New | ConceptID: Met13

35
After acetylation the diastereomeric C-glycosylated amino acids 6 were separated by column chromatography and isolated in good overall yields.

Type: Result | Advantage: None | Novelty: None | ConceptID: Res1

36
Reduction of the bicyclic substrates 5 afforded α/β anomeric mixtures, due to the intermediary formed hemi-acetals, whereas oxime 3 gave exclusively the β-configured methyl glycoside (Table 1).

Type: Result | Advantage: None | Novelty: None | ConceptID: Res2

37
The catalytic hydrogenation and amalgam reductions proceed with moderate to high stereoselectivities, due to steric interactions with the carbohydrate residue.

Type: Result | Advantage: None | Novelty: None | ConceptID: Res3

38
All main products have the same absolute configuration at the newly formed C-7 stereogenic center, which was established by comparison of the NMR spectra.

Type: Result | Advantage: None | Novelty: None | ConceptID: Res4

39
Interestingly, the gluco (3 and 5a) and xylo (5c) isomers gave similar dr (77∶23 to 85∶15), whereas the galacto isomer 5b reacts less selectively (70∶30) and the malto isomer 5d with higher selectivity (94∶6).

Type: Result | Advantage: None | Novelty: None | ConceptID: Res5

40
This can be rationalized by a predominant attack of the reductant from the Re side, which is hindered by the axial O-acetyl group in 5b and even more preferred by the equatorial carbohydrate residue in 5d.

Type: Result | Advantage: None | Novelty: None | ConceptID: Res5

41
Thus, the main products of all reactions should have the S configuration at C-7.

Type: Result | Advantage: None | Novelty: None | ConceptID: Res5

42
However, due to the fast rotation of the C–C single bond, the determination of the configuration at the newly formed C-7 stereocenter was not possible by the coupling constants in the 1H NMR spectra.

Type: Result | Advantage: None | Novelty: None | ConceptID: Res5

43
Finally, the crystallization of the main isomer from the reduction of the gluco-oxime 3 was achieved, which was assigned unequivocally as the S-configured product by X-ray analysis (Fig. 1). Interestingly, this is the opposite configuration of Chandrasekaran’s C-glycosylated amino acids,5 which is important for future applications in glycobiology.

Type: Method | Advantage: None | Novelty: New | ConceptID: Met14

44
In conclusion, the reaction sequence, radical addition to glycals and subsequent reduction, allows the simple synthesis of various glycosylated glycine derivatives in good overall yields.

Type: Conclusion | Advantage: None | Novelty: None | ConceptID: Con2

45
The addition of nitroacetates to glycals was realized for the first time.

Type: Method | Advantage: None | Novelty: New | ConceptID: Met15

46
Both steps proceed with moderate to high stereoselectivities, affording the S-configured amino acids as the main products.

Type: Result | Advantage: None | Novelty: None | ConceptID: Res6

47
The herein described new protocol is characterized by commercially available precursors and only three reaction steps.

Type: Method | Advantage: Yes | Novelty: New | ConceptID: Met1

48
Studies of the scope and limitations of the reaction sequence and further applications for the synthesis of C-glycopeptides are in progress.

Type: Conclusion | Advantage: None | Novelty: None | ConceptID: Con3

49
This work was generously supported by the Fonds der Chemischen Industrie and the Deutsche Forschungsgemeinschaft (Li 556/7-2).

Type: Background | Advantage: None | Novelty: None | ConceptID: Bac4