Process for the synthesis of inhibitors of E1 activating enzyme

A process for forming a compound of formula (I): ** ** Formula or a salt thereof; wherein: the asterisk positions illustrated in stereochemical configurations indicate relative stereochemistry; Ra is hydrogen or a hydroxyl protecting group selected from silyl protecting group, aliphatic group, optionally substituted -C (O) -Raa and -C (O) -ORaa; or Ra and Rj taken together with the intervening atoms forms a cyclic diol protecting group -C (Raa) (Rbb); or Ra taken together with Rm and the intervening atoms forms a cyclic diol protecting group -C (Raa) (Rbb); Rb is hydrogen, fluoro, C1-4 aliphatic or C1-4 fluoroaliphatic; Rc is hydrogen, fluoro, chloro, -OH, -O-Rm or optionally substituted C1-4 aliphatic; Rd is hydrogen, fluoro, C1-4 aliphatic or C1-4 fluoroaliphatic; Re is hydrogen or C1-4 aliphatic; Re 'is hydrogen or C1-4 aliphatic; each Rf is independently hydrogen, fluoro, C1-4 aliphatic or C1-4 fluoroaliphatic; Rg is chloro, fluoro, iodo or bromo; Rh is hydrogen, fluoro, C1-4 aliphatic or C1-4 fluoroaliphatic; Rh is hydrogen, fluoro, C1-4 aliphatic or C1-4 fluoroaliphatic; Rj is hydrogen or a hydroxyl protecting group selected from silyl protecting group, aliphatic group, optionally substituted -C (O) -Raa and -C (O) -ORaa; or Rj and Ra taken together with the intervening atoms forms a cyclic diol protecting group -C (Raa) (Rbb); Rk is hydrogen or C1-4 aliphatic; Rm is a hydroxyl protecting group selected from silyl protecting group, aliphatic group, optionally substituted -C (O) -Raa and -C (O) -ORaa; or Rm and Ra taken together with the intervening atoms forms a cyclic diol protecting group -C (Raa) (Rbb); Raa is optionally substituted C1-4 aliphatic or optionally substituted aryl; and Rbb is hydrogen or C1-4 aliphatic optionally substituted; aliphatic is a hydrocarbon straight, branched or cyclic chain that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, where, unless defined ora way, an aliphatic straight or branched chain is a C1-12 hydrocarbon and a cyclic aliphatic ring system is a cyclic hydrocarbon C3-14 optionally wherein two adjacent substituents on a cycloaliphatic ring, taken together with the intervening ring atoms, form an aromatic 5- to 6-membered optionally substituted or a non-aromatic ring of 3 to 8 membered ring having 0-3 ring heteroatoms selected from the group consisting of O, N and S condensate; aryl is an aromatic hydrocarbon C6 to C14, comprising one to three rings, optionally wherein two adjacent substituents on an aryl ring, taken together with the ring atoms involved, form an aromatic ring 5 to 6 condensed membered ring optionally substituted or nonaromatic ring of 4 to 8 membered ring having 0-3 ring heteroatoms selected from the group consisting of O, N and S; heteroaryl is a group having 5 to 14 ring atoms having 6, 10 or 14 π electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to four heteroatoms selected from the group consisting of O, N and S, including any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen, optionally wherein two substituents adjacent a heteroaryl, taken together with the intervening ring atoms, form an aromatic ring optionally substituted 5 to 6 membered ring or a condensed non-aromatic ring 4 to 8 membered ring having 0-3 ring heteroatoms selected from the group consisting O, N and S; a heterocyclic group is a monocyclic heterocyclic radical having 3 to 7 members, or one bicyclic condensed 7 to 10-membered or bridged 6-10 membered ring which is either saturated or partially unsaturated, and having, in addition to carbon atoms , one or more, preferably one to four, heteroatoms selected from the group consisting of O, N and S, optionally wherein two adjacent substituents on a cycloaliphatic ring, taken together with the ring atoms involved, form an aromatic 5- optionally substituted fused 6 membered ring or a nonaromatic ring of 3 to 8 membered ring having 0-3 ring heteroatoms selected from the group consisting of O, N and S; an aryl optionally substituted, when substituted, is substituted by one or more substituents selected from -halo group, -NO2-, -CN, -R *, -C (R *)> = C (R *) 2 -C> = CR *, ** -SR, -S (O) R **, ** -SOSR, -SO2N (R +) 2, - N (R +) 2, -NR + C (O) R *, -NR + C (O) N (R +) S, -NR + CO2R **, -SO2N (R +) 2, -N (R +) 2, -NR + C (O) R *, -C (O) R *, - C (O) N (R +) 2, - C (O) N (R +) C2 -OC (O) R *, -CO2R *, -C (O) -C (O) R *, -C (O ) R *, -C (O) N (R +) 2, -C (O) N (R +) - N (R +) 2, -N (R +) C (> = NR +) X, - NR + SO2R ** , -NR + SO2N (R +) 2, -OP (O) -OR *, and P (O) (NR +) - N (R +) 2, an optionally substituted aliphatic group, when substituted, is substituted with one or more substituents , on a saturated carbon atom, selected from the group -NO2-, -CN, -R *, -C (R *)> = C (R *) 2 -C> = CR *, ** -SR, - S (O) R **, ** -SOSR, -SO2N (R +) 2, -N (R +) 2, -NR + C (O) R *, -NR + C (O) N (R +) S, - NR ** + CO2R, -SO2N (R +) 2, -N (R +) 2, - NR + C (O) R *, -C (O) R *, -C (O) N (R +) 2, - C (O) N (R +) C2 -OC (O) R *, -CO2R *, -C (O) -C (O) R *, -C (O) R *, -C (O) N ( R +) 2, - C (O) N (R +) - N (R +) 2, -N (R +) C (> = NR +) X, -NR + SO2R **, -NR + SO2N (R +) 2, - OP (O) -OR *, and P (O) (NR +) - N (R + ) 2,> = O,> = S,> = C (R *) 2> = NN (R *) 2> = N-OR *, -N-NHC (O) R *,> = N- NHCO2R **,> = N-NHSO 2 **, y> = NR *; an optionally substituted heteroaryl, when substituted, is substituted with one or more substituents, or an unsaturated carbon atom, selected from the group -NO2-, -CN, -R *, -C (R *)> = C (R * ) -C 2> = CR *, ** -SR, -S (O) R ** - ** SOSR, -SO2N (R +) 2, -N (R +) 2, -NR + C (O) R *, -NR + C (O) N (R +) S, -NR + CO2R **, -SO2N (R +) 2, -N (R +) 2, -NR + C (O) R *, - C (O ) R *, -C (O) N (R +) 2, -C (O) N (R +) C2 -OC (O) R *, -CO2R *, -C (O) -C (O) R * , -C (O) R *, -C (O) N (R +) 2, -C (O) N (R +) - N (R +) 2, -N (R +) C (> = NR +) X, - NR + SO2R **, -NR + SO2N (R +) 2, -OP (O) -OR *, and P (O) (NR +) - N (R +) 2; a heterocyclic group optionally substituted, when substituted, is substituted with one or more substituents, if on a saturated carbon atom, is selected from the group -NO2-, -CN, -R *, - C (R *)> = C (R *) 2 -C> = CR *, ** -SR, -S (O) R **, ** -SOSR, -SO2N (R +) 2, -N (R +) 2, -NR + C (O) R *, -NR + C (O) N (R +) S, -NR + CO2R **, -SO2N (R +) 2, -N (R +) 2, -NR + C (O) R *, -C (O) R *, -C (O) N (R +) 2, -C (O) N (R +) C2 -OC (O) R *, -CO2R *, -C (O) -C ( O) R *, - C (O) R *, -C (O) N (R +) 2, -C (O) N (R +) - N (R +) 2, -N (R +) C (> = NR + ) X, -NR + SO2R **, -NR + SO2N (R +) 2, -OP (O) -OR *, y- P (O) (NR +) - N (R +) 2,> = O,> = S,> = C (R *) 2> = NN (R *) 2> = N-OR *, -N-NHC (O) R *,> = N-NHCO2R **> = N-NHSO2R **, and> = NR *, or is on a nitrogen atom, selected from the group include -R *, -N (R *) 2, -C (O) R *, -C (O) -C (O) R * - C (O) CH2C (L) R *, -SO 2 N (R *) 2, -C (> = S) N (R *) 2, -C (> = NH) -N (R *) 2, and -NR * SO2R *, R ** is an aliphatic or aryl group; each R +, independently, is hydrogen or an aliphatic, aryl, heteroaryl or heterocyclic, or two R + on the same nitrogen atom, taken together with the nitrogen atom, form an aromatic or non-aromatic 5-8 membered ring also the nitrogen atom, 0-2 ring heteroatoms selected from N, O and S; each R * is independently hydrogen or an aliphatic, aryl, heteroaryl or heterocyclic; said process comprising the step of combining a compound of formula (II) or a salt thereof, with a compound of formula (III) to give a compound of formula (I) ** ** Formula wherein: stereochemical configurations illustrated in asterisk positions indicate relative stereochemistry; each Ra, Rb, Rc, Rd, Fe, Re ', Rf, Rg, Rh, Rh', Rj, Rk and Rm variables in formulas (II) and (III) is as defined in formula ( I); R1 is -CH2CHO; wherein said combining step comprises the step: aa) treating a compound of formula (II) or a salt thereof, with a compound of formula (III) in the presence of a base.