Investigation of Coupling Reactions for the Synthesis of Valienamine Pseudodisaccharides

Abstract

Amine-linked pseudodisaccharides based on vali­enamine were synthesised by C-N bond-forming reactions between valienol-derived C-1 electrophiles and carbohydrate nitrogen nucleophiles. Palladium-catalysed coupling with trichloroacetimidate leaving groups, Mitsunobu reactions with a nosylamide nucleophile, and alkylation of amines by C-1 bromides were investigated.

amination - carbohydrates - carbocycles - pseudodisaccharides - valienamine

References and Notes

1 Chen X. Fan Y. Zheng Y. Shen Y. Chem. Rev.  2003,  103:  1955 

2

The lack of a stereogenic centre at C-5 means that the stereochemistry of valienamine is described by analogy to a pentose rather than as a hexose, hence it has the α-xylo configuration. 1-epi-Valienamine has a β-xylo configuration, and 2-epi-valienamine has an α-lyxo configuration. Valienamine derivatives are numbered with carbasugar numbering to stress the homomorphic relationship with carbohydrates.

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16

Mitsunobu Coupling: α-Alcohol 1 (54 mg, 0.10 mmol) and nosylamide 4 (65 mg, 0.10 mmol) were dissolved in anhyd THF (2 mL) and the solution was cooled to 0 ˚C under N₂. PPh₃ (53 mg, 0.202 mmol) was added, then after 15 min, DIAD (39 µL, 0.198 mmol) was added dropwise. After 30 min, the ice-bath was removed, and the reaction was allowed to proceed at r.t. After TLC (pentane-EtOAc, 2:1) indicated the consumption of the alcohol (R _f 0.2) and the sulfonamide (R _f 0.1) and the formation of a product (R _f 0.15), the mixture was concentrated in vacuo. The residue was purified by flash column chromatography to give the β-linked pseudodisaccharide 9 (65 mg, 64%).

17

The stereochemistry of the bromides (7 and 8) and pseudodisaccharides (9, 10 and 12) was assigned using the J _1,2 and J _1,5a coupling constants from the ^¹H NMR spectra, in comparison with reported data.^²8 In α-xylo compounds, J _1,5a was in the range 4.4-5.8 Hz; J _1,2 was in the range 3.5-4.4 Hz. In β-xylo compounds, H-5a appeared as a singlet; J _1,2 was between 7.1-9.2 Hz (not determined for 9). These J _1,2 values are consistent with the ^² H ₃ half-chair conformation expected for both diastereomers. For the nosylated pseudodisaccharide 9, many of the NMR resonances were broad, possibly resulting from steric crowding and conformational change, which weakens an argument for configurational assignment of this compound based on coupling constants, but its configuration was confirmed by its deprotection (PhSH, K₂CO₃, DMF, 83%) to give 12.

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20

Palladium-Catalysed Coupling: β-Imidate 6 (94 mg, 0.14 mmol), trimethylolpropane phosphite (TMPP; 5 mg, 0.028 mmol) and Pd₂(dba)₃ (7 mg, 0.014 mmol) were placed in a round-bottomed flask with a magnetic stirrer bar. The flask was evacuated, then placed under Ar. Amine 3 (194 mg, 0.42 mmol) was suspended in MeCN (it was partially soluble), the solvent was degassed and the mixture was placed under Ar. The amine suspension was transferred to the reaction vessel by syringe. Et₃N (0.09 mL, 0.63 mmol) was added, and the mixture colour changed from a purple/brown suspension to a pale yellow solution. The reaction mixture was stirred at r.t. under Ar. After 15 h, TLC (pentane-EtOAc, 3:1) showed complete consumption of the imidate (R _f 0.8), amine remaining (R _f 0), and the formation of a major product (R _f 0.1). The mixture was concentrated in vacuo and the residue was purified by flash column chromatography to give the β-linked pseudodisaccharide 12 (115 mg, 85%).

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23

Coupling with C-1 Bromides: β-Bromide 8 (42 mg, 0.070 mmol) and amine 3 (80 mg, 0.17 mmol) were dissolved in MeCN (1 mL) under Ar. N,N′-Diisopropylethylamine (35 µL, 0.20 mmol) was added and the reaction mixture was heated to 50 ˚C. After 24 h, TLC (pentane-EtOAc, 2:1) indicated the formation of a major product (R _f 0.3). The mixture was concentrated in vacuo, and the residue was purified by flash column chromatography to give the α-linked pseudodisaccharide 10 (46 mg, 67%).

24

The β-bromide 8 does react at a higher rate with the amine 3 (reacting slowly at r.t.) than does its α epimer 7 (which needed heating for any reaction to take place).

25

Representative Data:
2,3,4,6-Tetra- O -benzyl-5a-carba-β- d - xylo -hex-5(5a)-enopyranosyl Trichloroacetimidate (6): colourless oil; [α]_D ^²¹ -53.9 (c = 1.0, CHCl₃). IR (film): 1662 (C=N) cm^-¹. ^¹H NMR (500 MHz, CDCl₃): δ = 3.91-4.00 (m, 3 H, H-2, H-3, H-6), 4.23 (d, J _{6,6 ′} = 12.2 Hz, 1 H, H-6′), 4.37 (d, J _3,4 = 7.5 Hz, 1 H, H-4), 4.49, 4.53 (2 × d, J = 11.9 Hz, 2 H, PhCH ₂), 4.73 (d, J = 10.9 Hz, 1 H, PhCHH′), 4.82, 5.00 (2 × d, J = 11.0 Hz, 2 H, PhCH ₂), 4.85-4.91 (m, 3 H, PhCH ₂, PhCHH′), 5.75 (d, J _1,2 = 7.1 Hz, 1 H, H-1), 5.82 (s, 1 H, H-5a), 7.26-7.35 (m, 20 H, ArH), 8.48 (s, 1 H, NH). ^¹³C NMR (125 MHz, CDCl₃): δ = 69.7, 72.5, 74.8, 75.3, 75.5, 79.5, 79.6, 81.7, 83.9, 91.4, 122.1, 127.6, 127.7, 127.7, 127.8, 127.9, 127.9, 128.3, 128.4, 128.4, 137.9, 138.2, 138.3, 138.4, 138.6, 162.1. HRMS-ESI: m/z [M + Na]⁺ calcd for C₃₇H₃₆O₅NCl₃Na: 702.1551; found: 702.1521. 2,3,4,6-Tetra- O -benzyl-5a-carba-β- d - xylo -hex-5(5a)-enopyranosyl Bromide (8): colourless oil; [α]_D ^²³ -73.3 (c = 1.0, CHCl₃). ^¹H NMR (500 MHz, CDCl₃): δ = 3.75 (dd, J _2,3 = 10.2 Hz, J _3,4 = 8.0 Hz, 1 H, H-3), 3.94-3.98 (m, 2 H, H-2, H-6), 4.23 (d, J _{6,6 ′} = 12.7 Hz, 1 H, H-6′), 4.37 (d, J _3,4 = 8.0 Hz, 1 H, H-4), 4.51, 4.54 (2 × d, J = 11.8 Hz, 2 H, PhCH ₂), 4.73 (d, J = 10.8 Hz, 1 H, PhCHH′), 4.76 (d, J _1,2 = 7.9 Hz, 1 H, H-1), 4.82 (d, J = 11.0 Hz, 1 H, PhCHH′), 4.86 (d, J = 10.9 Hz, 1 H, PhCHH′), 4.93-4.98 (m, 3 H, PhCH ₂, PhCHH′), 5.91 (s, 1 H, H-5a), 7.25-7.41 (m, 20 H, ArH). ^¹³C NMR (125 MHz, CDCl₃): δ = 51.7, 69.5, 72.6, 75.4, 75.7, 76.2, 79.8, 85.0, 85.5, 125.9, 127.9, 127.9, 127.9, 127.9, 128.0, 128.0, 128.3, 128.5, 128.5, 128.6, 137.7, 138.1, 138.1, 138.3, 138.4. HRMS-ESI: m/z [M + Na]⁺ calcd for C₃₅H₃₅O₄BrNa: 621.1611; found: 621.1610.
Methyl 6-[2,3,4,6-Tetra- O -benzyl-5a-carba-β- d - xylo -hex-5(5a)-enopyranosylamino]-2,3,4-tri- O -benzyl-6-deoxy-α- d -glucopyranoside (12): white solid; [α]_D ^²5 -21.2 (c = 1.0, CHCl₃). ^¹H NMR (500 MHz, CDCl₃): δ = 2.60 (dd, J _5,6 = 6.4 Hz, J _{6,6 ′} = 11.7 Hz, 1 H, H-6^I), 3.01 (dd, J _{5,6 ′} = 2.5 Hz, J _{6,6 ′} = 11.7 Hz, 1 H, H-6′^I), 3.29 (s, 3 H, OMe), 3.36 (m, 1 H, H-1^II), 3.46-3.51 (m, 2 H, H-2^I, H-4^I), 3.59 (at J = 9.2 Hz, 1 H, H-2^II), 3.73 (m, 1 H, H-5^I), 3.87-3.90 (m, 2 H, H-3^II, H-6^II), 3.99 (at, J = 9.3 Hz, 1 H, H-3^I), 4.26 (d, J _{6,6 ′} = 12.0 Hz, 1 H, H-6′^II), 4.33 (d, J _3,4 = 7.1 Hz, 1 H, H-4^II), 4.41-5.00 (m, 15 H, 7 × PhCH ₂, H-1^I), 5.67 (s, 1 H, H-5a^II), 7.23-7.40 (m, 35 H, ArH). ^¹³C NMR (125 MHz, CDCl₃): δ = 47.1, 55.3, 60.0, 70.3, 70.5, 72.3, 73.5, 74.7, 75.1, 75.2, 75.4, 75.9, 79.3, 80.2, 80.4, 82.0, 82.1, 85.2, 98.1, 127.2, 127.7, 127.8, 127.9, 127.9, 128.0, 128.1, 128.3, 128.5, 128.5, 128.5, 128.6, 135.6, 138.4, 138.4, 138.6. HRMS-ESI: m/z [M + Na]⁺ calcd for C₆₃H₆₇NO₉Na: 1004.4708; found: 1004.4626.

26

Acarbose is used as a diabetes type 2 drug; Validamycin A is used as an agrochemical fungicide against rice sheath blight.

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