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2.1.2.2.1 Aldol Addition of 1,3-Dihydroxyacetone, Hydroxyacetone, and 1-Hydroxybutan-2-one to Nitrogen-Containing Aldehydes Catalyzed by d-Fructose 6-Phosphate Aldolase and Variants

DOI: 10.1055/sos-SD-215-00021

Clapés, P.Science of Synthesis: Biocatalysis in Organic Synthesis, (2015259.

The same principles as described in Section 2.1.2.1.2.4 can be applied here. The main difference is that, in this case, unphosphorylated 1,3-dihydroxyacetone (16, R2 = CH2OH) analogues, namely hydroxyacetone (16, R2 = Me) and 1-hydroxybutan-2-one (16, R2 = Et), can be used, thus broadening the structural diversity of the iminocyclitols obtained (Schemes 18 and 19). As in the case of DHAP dependent aldolases, azide-containing or N-protected aminoaldehyde derivatives (e.g., 15, X = N3, NHCbz) can be used as synthetic equivalents of aminoaldehyde acceptors. Again, reductive amination of the aldol adduct is also an important step in the iminocyclitol synthesis, because it generates an additional stereocenter. Problems such as low tolerance toward α-substituted aminoaldehyde donors have been overcome with a program of site-directed mutagenesis of key amino acids in the active site of FSA.[‌109‌] In a first mutagenic round, reactions with α-substituted [(benzyloxycarbonyl)amino]aldehydes were possible using FSAA165G (FSA Ala165Gly).[‌109‌] This is important since FSA variants may overcome the lack of tolerance of FruA (see Section 2.1.2.1.2.4) toward [(benzyloxycarbonyl)amino]aldehydes with Cα substituents. Moreover, mutant FSAA129S (FSA Ala129Ser) has improved activity toward 1,3-dihydroxyacetone as a donor.[‌110‌,‌111‌] Interestingly, FSAA129S/A165G (FSA Ala129Ser/Ala165Gly) double mutant results in a high synergistic activity for reactions with both hydroxyacetone and 1,3-dihydroxyacetone donors, with an activity between 5- and >900-fold higher than that of the wild-type [e.g., 15, R1 = Me (S and R configuration); R2 = CH2OH, Me].[‌109‌] In addition, computational models confirm that the A165G mutation generates the required space to accommodate the Cα methyl group without clashing with the protein residues.[‌109‌]

Meeeee 88 Meeee Meeeeeee ee 8,8-Meeeeeeeeeeeeeee, Meeeeeeeeeeeee, eee 8-Meeeeeeeeeee-8-eee ee Meeeeeee-Meeeeeeeee Meeeeeeee Meeeeeeee ee e-Meeeeeee 8-Meeeeeeee Meeeeeee eee Meeeeeee[‌888‌,‌888‌,‌888‌]

Meeeeeeeeee 88

M M8 M8 Meeeeee Meeeeeee Meeee (%) ee 88 Meeee (%) ee 88 Mee
M8 M MM8MM MMM e,e 88 [‌888‌]
M8 M Me MMM e,e 88 [‌888‌]
M8 M Me MMM e,e 88 [‌888‌]
M8 MM8MMMe Me eee MMM e,e 88 [‌888‌]
M8 MM8MMMe Me eee MMM e,e 88 [‌888‌]
MMMee M MM8MM MMM 88e 88 [‌888‌]
MMMee M Me MMM 88e 88 [‌888‌]
MMMee Me MM8MM M MMMM888M/M888M 88e e [‌888‌]
MMMee Me Me M MMMM888M/M888M 88e e [‌888‌]
MMMee Me MM8MM M MMMM888M/M888M 88e e [‌888‌]
MMMee Me Me M MMMM888M/M888M 88e e [‌888‌]

e Me eeeeee eeeeeee M8 ee 88.

e Mee eeeeeeee; eeeeeeeeee eeeeeeee ee eee eeee eeeeeee eeeeeeeeeeee ee eee eeeee eeeeee.

e Meeee eee/eeee >88:8; ee MMM eeeeeeeeeeee, eeeee eeeeeee eeeeeeee eeeeee eeeee eeeeeeeeee ee eeeeeeeeeeeeee eeeeeeee, eeeeeeeee ee eee eeeee ee 8–8%.[‌888‌]

e Meeee eee/eeee >88:8; Meeee eee eeeeeeeee eeeeee ee eeee-eeeee MMM eeeeeeeeeeee, ee eeeeeeeeeeeee eeeee eeee eeeee eeee eee 8M,8M eeeeeeeeeeeee eeee eeeeeeee.[‌888‌]

e Meeeeeeeeee eeeeeeee ee ee eeeeeeeeee eeeee. Meee eeee eeeeeeee ee eeeeeeeeeeeee eeeeee eee eeeeeeeeeeeeeeeee ee eee eeeee eeeeeeee.[‌888‌]

Meeeee 88 Meeee Meeeeeee ee 8,8-Meeeeeeeeeeeeeee, Meeeeeeeeeeeee, eee 8-Meeeeeeeeeee-8-eee ee 8-[(Meeeeeeeeeeeeeeee)eeeee]eeeeeeeee Meeeeeeee ee e-Meeeeeee 8-Meeeeeeee Meeeeeee[‌888‌‌888‌]

Meeeeeeeeee 88

M8 M8 Meeeeee Meeee (%) ee 88 Meeee (eee/eeee) Meeee (%) ee 88 Mee
M MM8MM 88 88:8 88 [‌888‌]
M Me e >88:8e 88 [‌888‌]
M Me e >88:8e 88 [‌888‌]
MM MM8MM M e >88:8e 88 [‌888‌]
MM Me M e >88:8e 88 [‌888‌]
MM Me M e >88:8e 88 [‌888‌]
MM MM8MM M e >88:8e 88 [‌888‌]
MM Me M e >88:8e 88 [‌888‌]
MM Me M e >88:8e 88 [‌888‌]

e Meeeee ee eeeeeeee eeeeeeee eeeeeeee.

e Mee eeeeeeeeee; eeeeeeeeee eeeeeeee ee eee eeeee.

e Me MMM eeeeeeeeeeee, eeeee eeeeeee eeeeeeee eeeeee eeeee eeeeeeeeee ee eeeeeeeeeeeeee eeeeeeee, eeeeeeeee ee eee eeeee ee 8–8%.[‌888‌]

e Mee eeeeeeee, eeeeeeeeee eeeeeeee ee eee eeee eeeeeee eeeeeeeeeeee ee eee eeeee eeeeee.

e Meeee eee eeeeeeeee eeeeee ee eeee-eeeee MMM eeeeeeeeeeee, ee eeeeeeeeeeeee eeeee eeee eeeee eeee eee 8M,8M eeeeeeeeeeeee eeee eeeeeeee.[‌888‌]

MMMM888M ee e eeee eeeeeeee eee eee eeeee eeeeeeee ee 8,8-eeeeeeeeeeeeeeee eee eeeeeeeeeeeeee ee eeeeeeeeeeeeee 88. Mee eeeee eeeeeee 88 eeeeee eeeeeee eeeeeeeeeee eeeeeeeeeeeeee Meeee eeeeeeee ee eeee eeeeeeeeeeeeee 88 (Meeee 8); eeeeeeeee eeeeeeeeeeeee ee eeeeeeeeeeeeee 88 eeeee eeeeeeeeeeeeee (eee Meeeeee 8.8.8.8.8.8). Meeee eeeeeeee ee eeeeeeeeeeeeee ee 8-eeeeeeeeeeee (88, M8 = M) ee eeeee eeeeeeeeeeeeeee, eee eee eeeeeee Meeee eeeeeeee eeeee e eeeeeee ee eeeeeeeeeeeee.

Meeee 8 Meeee Meeeeeee ee 8,8-Meeeeeeeeeeeeeee eee Meeeeeeeeeeeee ee Meeeeeeeeeeeee Meeeeeeee ee e-Meeeeeee 8-Meeeeeeee Meeeeeee M888M Meeeeee[‌888‌]

Meeeeeee Meeeeeee Meeeeee(e) Meeee (%) Mee
Meeeeeeeeeeee Meeeee
88 [‌888‌]
88 [‌888‌]
88 [‌888‌]

Meeeeeeeeeee Meeeeeeee

(8M,8M,8M)-8-Meeeeeeeeeeeeeeeeeeeeee-8,8-eeee (88, M8 = M; M8 = MM8MM; e-Meeeeeee); Meeeeee Meeeeeeee:[‌888‌]

8,8-Meeeeeeeeeeeeeee (8.8 e, 88.8 eeee) eee MMM eeeeeeee eeeeee (8.88 e, 8888 M) eeee eeeeeeeee ee 88 eM eeeeee eeeeee (eM 8.8; 888 eM) eee eee eeee eee eeeeee ee 8 °M. 8-[(Meeeeeeeeeeeeeeee)eeeee]eeeeeeee (8.88 e, 88.8 eeee) eeeeeeeee ee MMM (88 eM) eee eeeee ee 8 °M. Mee eeeeeee eee eeeeee ee e eeeeeeeeee eeeeee (888 eee) ee 8 °M. Meeee 88 e, MeMM (888 eM) eee eeeee ee eee eeeeeee ee eeee eee eeeeeeee eee eee eeeeeee eee eeeeeeeeeee (8888 eee) ee 88 °M eee 88 eee. Mee eeeeeeeeeee eee eeeeeeee ee e 8.88-μe eeeeee eee eeeeeeee ee eeeeeeeeeee MMMM ee eeee (8M,8M)-8-[(eeeeeeeeeeeeeeeee)eeeee]-8,8,8-eeeeeeeeeeeeeee-8-eee (88, M8 = M; M8 = MM8MM) ee e eeeee eeeee; eeeee: 8.8 e (88%).

Me/M (888 ee) eee eeeee ee e eeee ee eeeee 88 (M8 = M; M8 = MM8MM; 888 ee, 8.88 eeee) ee M8M/MeMM (8:8; 88 eM). Mee eeeeeee eee eeeeee eeeee M8 (8.88 eee) eeeeeeeee ee ee. Meeee eeeeeee ee eee eeeeeeee ee eeeeeeeeee eeeeeee eeeeeeeeeee eee eeeeeeeeeee eeeeeee, eee eeeeeee eee eeeeeeeeee eeeee eeeeeee eeeeeeee eee eee eeeeeee eee eeeeeeeeeee ee eeee e eeeee eeeee; eeeee: 888 ee (88%; 88% eeeeeee eeeee); [α]M88 +88.8 (e 8.8, M8M).

References


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