Biocatalytic Strategies towards [4++2] Cycloadditions

Biocatalysis and synthetic organic chemistry play by the same physicochemical rules, but their strong suits are fundamentally different. A case in point are cycloaddition reactions: their wide use in synthetic organic chemistry contrasts with their scarcity in biological systems. When Diels and Alder first discovered synthetic [4+2] cycloadditions they proposed that these reactions may be responsible for the formation of natural products; this prediction was accurate, but enzymes performing cycloadditions remained elusive for many decades.

 

Remarkably, Diels-Alderases raised from antibodies in the laboratory preceded isolation of natural enzymes by several years. Although Diels–Alder reactions had been implicated in biosynthetic pathways since at least the 1970s, it took until the mid-1990s for the first observation of natural enzymatic activity catalysing a Diels–Alder reaction. In recent years, a“gold rush” for enzymatic cycloadditions has unveiled a number of these biosynthetic transformations. However, the natural reactions play a different role to those employed by synthetic chemists. While synthetic chemists often harness intermolecular cycloadditions as a retrosynthetic disconnection, the natural examples tend to happen intramolecularly and occur late in the biosynthetic pathway.

 

In this review, we will explore the catalytic mechanisms of natural and unnatural [4+2] cyclases and compare them to chemical strategies. Determining accurate mechanisms of enzyme catalysed cycloadditions has proved to be challenging. The atom connectivity of reactants and products can readily be used to qualify a reaction as a formal [4+2] cycloaddition, but considerable debate concerns the degree of synchronicity[5] which is often taken as a criterium for “true” Diels–Alder reactions. As intriguing and important as the mechanistic study of enzymatic cycloadditions is, knowing the synchronicity of bond-formation events is not a priority for biocatalytic applications. Hence, we will cover enzymes catalysing formal [4+2] cycloadditions whether or not the detailed mechanism is known.

 

This includes Diels–Alderases catalysing a concerted [4+2] cycloaddition and enzymes employing stepwise Michaelaldol mechanisms. We will consider [4+2] cyclases to be any enzyme catalysing a reaction in which reactants with four and two atoms are connected to form a cycle of six while undergoing a reduction in bond multiplicity. Compared to the excellent reviews of the past years covering pericyclases, here we also highlight the newest discoveries in plants and focus particularly on the catalytic devices of the natural enzymes, designer enzymes and small molecule catalysts.

2. How chemists accelerate [4+2] cycloadditions
Although chemists have often turned to nature for inspiration, small-molecules catalysing cycloadditions were synthesised long before biocatalysts for these reactions were designed or discovered. Chemical catalysis of Diels–Alder reactions, for example, with simple Lewis acids such as aluminum trichloride, can achieve rate accelerations of 105 fold; the same range as typical, moderately efficient enzyme catalysts. This spectacular effect powers asymmetric catalysts that accelerate and direct the Diels–Alder reaction into a single stereochemical outcome. The Lewis acid metal centre of these catalysts
provides the core catalytic effect, whilst sterically demanding ligands close off undesired routes by favouring specific orientations of the reactants. Electronically, cycloaddition catalysis has been explained by a narrowing of the energy gap between the frontier orbitals of the diene and, through binding of the Lewis acid, the more electron-depleted dienophile.

 

For biological cyclases to become relevant in industrial biocatalysis, they must be able to compete with enantioselective chemical catalysts. These chemical catalysts have been meticulously designed for high catalytic efficiency and enantioselectivity and thus provide a rigorous reference point for discussing their biological counterparts (Scheme 1). Corey’s C2 symmetric aluminum diamine 1 is illustrative of the chemo-catalytic approach.[19] Here, the aluminum metal centre is coordinated by the dienophile with the less hindered lone pair opposite the oxazolidinone moiety. p–p interactions likely govern the preference of the vinyl residue to point towards the phenyl group of the catalyst and the cyclopentadiene attacks with endo preference from the less shielded face. As a result, the cycloaddition product 2, an intermediate in the total synthesis of prostaglandin, is formed with 96% enantiomeric excess.

 

Conformational restriction of the dienophile is crucial for the success of enantioselective catalysts that use only monodentate coordination, such as the aluminum diamines. In Corey’s oxazaborolidine ligand complex 3, a weak interaction with the C-alpha hydrogen of the ketone ligand has been proposed to account for this restriction, furnishing excellent enantioselectivities up to 99% ee.[19] Evan’s cationic copper(II) bisoxazolines are noteworthy because copper(II) complexes are relevant for the construction of artificial metalloenzymes. Due to the bidentate coordination of the dienophile and the C2 symmetry at the distorted square-planar copper centre in complex 4, predictions of the transition state are straightforward, and it follows that facial selectivity of the dienophile is controlled by
the bulky tert-butyl groups.

 

For cycloadditions featuring hydrophobic reactants, for example, the Diels–Alder reaction of methylvinylketone and cyclopentadiene, solvent selection can be influential. In a polar solvent like water, greasy reactants will associate with each other, and this hydrophobic proximity effect can accelerate the Diels–Alder reaction by two to three orders of magnitude. To achieve rate accelerations, an enzyme in aqueous solution must therefore provide more than the hydrophobic effect in solvent alone. A more exotic catalytic device not directly available to enzymes are high pressures of several thousand atmospheres, which have been useful in mechanistic studies and total synthesis. High pressures drive formation of the, relative to the reactants, more compact Diels–Alder transition state.

 

Enantioselective catalysts often show high stereoselectivity like enzymes but compare poorly in terms of catalytic efficiency: reactions typically take days to reach completion. For copper bisoxazolinones, dissociation constants in the high millimolar range have been reported. Given the open and solvent exposed arrangement of substrates on the metal centre of a small molecule chiral catalyst, weak binding and a generally large substrate scope are unsurprising. Currently, although cyclases are not able to supplant small molecule catalysts, with further optimisation they may provide stronger binding and
higher catalytic efficiencies.

 

3. Metals for speed, protein for selectivity
Artificial metalloenzymes hold great promise as designer biocatalysts with bespoke binding pockets, superior selectivities to small molecule catalysts and, perhaps, additional catalytic groups for faster reaction rates. Several exquisite examples have been created in the laboratory. Metallo-cyclases require the anchoring of the catalytic metal complex inside a proteinaceous pocket whilst also accommodating the substrates in the correct orientation for selective catalysis. For instance, Reetz and co-workers have bound a Cu II-phthalocyanine complex to bovine serum albumin (BSA), a protein with a universal ten dency to accommodate hydrophobic molecules on its surface (Scheme 1 B). Upon protein addition, the high endo/exo selectivity of the catalyst (96:4) was maintained while the chiral
protein environment conferred a 93% enantiomeric excess.

 

The catalytic rate, however, dropped slightly compared to the free ligand. With 2 mol% catalyst loading of a 66 kDa protein, the protein exceeded the product mass by far, underlining the challenge to create designer biocatalysts with fast catalytic rates (i.e. kcat) and high turnover numbers (TON). With protein catalysts comes the promise of genetic fine tuning and metalloenzymes are no exception to this. Enzyme binding pockets enclose substrates with a shell of protein side-chains that can be mutated to a vast variety of shapes and decorated with charges and H-bonding donors and acceptors. Bos and colleagues installed a conjugation site for bromoacetamide ligands by introducing the mutation Met89Cys into the small, homodimeric Lactococcal multidrug resistance Regulator (LmrR) protein (Scheme 1 B).[30] By conjugating a phenanthroline ligand and adding copper, an enantioselective catalyst was created reaching a good enantiomeric excess of 97% (endo/exo=95:5). In this case, conjugation to
LmrR not only rendered the reaction enantioselective but also accelerated it, as indicated by a 4.7-fold increase in yield after three days reaction time. The active site was responsive to mutation which could perhaps be exploited by more comprehensive mutational screens.

 

Metallo-cyclases appear to provide the best of both worlds for catalyst design: catalysis is provided by the metal centre and selectivity by the protein. This separation of roles may ultimately make these systems easier to control and modify than natural cyclases, in which catalysis and selectivity are intimately coupled within the protein structure. The presence of a protein scaffold, amenable to mutation and directed evolution, makes these synthetic enzymes a promising prospect for industrial biocatalysis. Despite the abundance of natural enzymes with catalytic metal centres, and the utility of metals in
cycloaddition catalysis, natural [4+2] cyclases utilising metal catalysis have not been observed. Instead, enzymes using other catalytic strategies have been discovered.

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2-Chloro-N,N-diethylbenzamide Catalog No.:AA007GFO CAS No.:10345-79-6 MDL No.:MFCD00018262 MF:C11H14ClNO MW:211.6880	3-Phenylcyclohex-2-en-1-one Catalog No.:AA00922Y CAS No.:10345-87-6 MDL No.:MFCD00029515 MF:C12H12O MW:172.2231
ClarithroMycin 9-OxiMe Catalog No.:AA008WTW CAS No.:103450-87-9 MDL No.:MFCD29060002 MF:C38H70N2O13 MW:762.9680	Tris(N,N'-di-i-propylformamidinato)lanthanum(III) Catalog No.:AA01FOZQ CAS No.:1034537-36-4 MDL No.:MFCD28411663 MF:C21H45LaN6 MW:520.5277
1-(TERT-BUTOXYCARBONYL)-5-(TRIFLUOROMETHOXY)INDOLE-2-BORONIC ACID Catalog No.:AA008V5S CAS No.:1034566-16-9 MDL No.:MFCD11109337 MF:C14H15BF3NO4 MW:329.0794	ERBIUM TRIS[BIS(TRIMETHYLSILYL)AMIDE] Catalog No.:AA003PV5 CAS No.:103457-72-3 MDL No.:MFCD00271002 MF:C6H19ErNSi2 MW:328.6518
(S)-1-N-Boc-4-N-Fmoc-piperazine-2-carboxylic acid Catalog No.:AA007GFQ CAS No.:1034574-30-5 MDL No.:MFCD02179101 MF:C25H28N2O6 MW:452.4996	1-Cyclopropyl-6,8-difluoro-7-(3-methylpiperazin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid Catalog No.:AA007XFH CAS No.:103460-89-5 MDL No.:MFCD18379316 MF:C18H19F2N3O3 MW:363.3586
Nms-1286937 Catalog No.:AA008TFS CAS No.:1034616-18-6 MDL No.:MFCD26793840 MF:C24H27F3N8O3 MW:532.5182	2-Bromo-4-iodopyrimidine Catalog No.:AA00HA04 CAS No.:1034619-55-0 MDL No.:MFCD11847633 MF:C4H2BrIN2 MW:284.8805
(4-Methoxybenzyl)(2-methoxyethyl)amine Catalog No.:AA0085LE CAS No.:103464-79-5 MDL No.:MFCD01655155 MF:C11H17NO2 MW:195.2582	(5-Chloro-2-fluoropyridin-4-yl)boronic acid Catalog No.:AA003MJX CAS No.:1034659-38-5 MDL No.:MFCD05662405 MF:C5H4BClFNO2 MW:175.3532
3-Amino-5-fluoro-1h-pyrazolo[3,4-b]pyridine Catalog No.:AA008TUP CAS No.:1034667-22-5 MDL No.:MFCD15526909 MF:C6H5FN4 MW:152.1291	2,2,3,3-Tetrafluoro-6-hydroxybenzodioxene Catalog No.:AA008SGX CAS No.:103467-50-1 MDL No.:MFCD00190145 MF:C8H4F4O3 MW:224.1092
GSK2018682 Catalog No.:AA01EOJO CAS No.:1034688-30-6 MDL No.:MFCD18633078 MF:C22H21ClN4O4 MW:440.8795	3-Iodo-4-(trifluoromethyl)benzoic acid Catalog No.:AA0096H1 CAS No.:1034690-61-3 MDL No.:MFCD18398157 MF:C8H4F3IO2 MW:316.0158
4-Bromo-3-(trifluoromethyl)benzamide Catalog No.:AA00HA06 CAS No.:1034690-74-8 MDL No.:MFCD18089254 MF:C8H5BrF3NO MW:268.0306	Maprotiline, HCl Catalog No.:AA007XEC CAS No.:10347-81-6 MDL No.:MFCD00079464 MF:C20H24ClN MW:313.8643
3-tert-Butyladipic acid Catalog No.:AA007GFF CAS No.:10347-88-3 MDL No.:MFCD00020550 MF:C10H18O4 MW:202.2475	Yttrium(III) 2-ethylhexanoate Catalog No.:AA003VA7 CAS No.:103470-68-4 MDL No.:MFCD00070441 MF:C24H45O6Y MW:518.5163
1-Boc-azepane-2-carboxylic acid Catalog No.:AA008S0X CAS No.:1034708-26-3 MDL No.:MFCD03790979 MF:C12H21NO4 MW:243.2994	N-(1-cyano-1-methylethyl)methanesulfonamide Catalog No.:AA01A41U CAS No.:103472-14-6 MDL No.:MFCD12792027 MF:C5H10N2O2S MW:162.2101
Ethyl 3-(chlorosulfonyl)propanoate Catalog No.:AA007GFM CAS No.:103472-25-9 MDL No.:MFCD07186267 MF:C5H9ClO4S MW:200.6406	3-(2-Bromophenyl)-4-methyl-4h-1,2,4-triazole Catalog No.:AA00HA07 CAS No.:1034734-64-9 MDL No.:MFCD11983291 MF:C9H8BrN3 MW:238.0839
Methyl 2-amino-5-bromopyrimidine-4-carboxylate Catalog No.:AA0085LB CAS No.:1034737-23-9 MDL No.:MFCD09966084 MF:C6H6BrN3O2 MW:232.0347	Tepoxalin Catalog No.:AA008R7B CAS No.:103475-41-8 MDL No.:MFCD00866620 MF:C20H20ClN3O3 MW:385.8441
D-Myo-Inositol-1,4,5-trisphosphate tripotassium salt Catalog No.:AA019FSV CAS No.:103476-24-0 MDL No.:MFCD00077799 MF:C6H9K6O15P3 MW:648.6377	Leupeptin hemisulfate Catalog No.:AA00ILGI CAS No.:103476-89-7 MDL No.:MFCD00198027 MF:C20H38N6O4 MW:426.5535
{4-[4-(Dimethylsilyl)benzyl]phenyl}(dimethyl)-silane Catalog No.:AA007GFJ CAS No.:1034767-18-4 MDL No.:MFCD08056689 MF:C17H22Si2 MW:282.5276	Benzyl (s)-(2-oxoazepan-3-yl)carbamate Catalog No.:AA003CIO CAS No.:103478-12-2 MDL No.:MFCD08060107 MF:C14H18N2O3 MW:262.3043
[rac-(1R,5S)-5-(hydroxymethyl)bicyclo[3.1.0]hexan-1-yl]methanol, cis Catalog No.:AA01EHOL CAS No.:103478-23-5 MDL No.:MFCD30164747 MF:C8H14O2 MW:142.1956	Fmoc-n-methyl-d-valine Catalog No.:AA003QKZ CAS No.:103478-58-6 MDL No.:MFCD00153396 MF:C21H23NO4 MW:353.4116
Fmoc-N-Me-Leu-OH Catalog No.:AA007GFH CAS No.:103478-62-2 MDL No.:MFCD00151933 MF:C22H25NO4 MW:367.4382	Fmoc-N-Me-D-Leu-OH Catalog No.:AA003QKY CAS No.:103478-63-3 MDL No.:MFCD00235877 MF:C22H25NO4 MW:367.4382
Ethyl dl-leucate Catalog No.:AA003Q1H CAS No.:10348-47-7 MDL No.:MFCD11975417 MF:C8H16O3 MW:160.2108	Methyl 5-amino-2-phenyl-1,3-oxazole-4-carboxylate Catalog No.:AA00VV5N CAS No.:1034889-77-4 MDL No.:MFCD13187386 MF:C11H10N2O3 MW:218.2087
3-(4-Azidophenyl)propionic acid Catalog No.:AA003I09 CAS No.:103489-31-2 MDL No.:MFCD00798799 MF:C9H9N3O2 MW:191.1867	4-(4-AZIDOPHENYL)BUTYRIC ACID Catalog No.:AA008XCJ CAS No.:103489-33-4 MDL No.:MFCD00798800 MF:C10H11N3O2 MW:205.2132
1-(4-Bromo-2-chlorophenyl)hydrazine, HCl Catalog No.:AA00HA08 CAS No.:1034891-38-7 MDL No.:MFCD05256438 MF:C6H7BrCl2N2 MW:257.9432	3-methyl-4-phenyl-1,2,5-oxadiazole Catalog No.:AA01A272 CAS No.:10349-09-4 MDL No.:MFCD01201489 MF:C9H8N2O MW:160.1726
1,2,5-Oxadiazol-3-amine,4-phenyl- Catalog No.:AA007XE8 CAS No.:10349-14-1 MDL No.:MFCD00124949 MF:C8H7N3O MW:161.1607	Quinoline-6-carboxylic acid Catalog No.:AA0034AT CAS No.:10349-57-2 MDL No.:MFCD00047613 MF:C10H7NO2 MW:173.1681
Spiro[cyclobutane-1,3'-indolin]-2'-one Catalog No.:AA00HA09 CAS No.:103490-52-4 MDL No.:MFCD24552851 MF:C11H11NO MW:173.2111	Methyl 1-benzylazetidine-3-carboxylate Catalog No.:AA007GF6 CAS No.:103491-29-8 MDL No.:MFCD11111578 MF:C12H15NO2 MW:205.2530
O-(2-Methoxyisopropyl)hydroxylamine Catalog No.:AA003TC2 CAS No.:103491-33-4 MDL No.:MFCD20265597 MF:C4H11NO2 MW:105.1356	(1R,4S)-tert-Butyl 2-azabicyclo[2.2.1]heptane-2-carboxylate Catalog No.:AA0093MC CAS No.:1034912-28-1 MDL No.:MFCD13152026 MF:C11H19NO2 MW:197.2741
methyl 2-phenyl-2-(piperidin-1-yl)propanoate Catalog No.:AA019EY3 CAS No.:1034912-50-9 MDL No.:MFCD22421119 MF:C15H21NO2 MW:247.3327	Methyl 4-chloro-3-fluoropyridine-2-carboxylate Catalog No.:AA0095D5 CAS No.:1034921-05-5 MDL No.:MFCD16293406 MF:C7H5ClFNO2 MW:189.5715
2-Methylpyrimidine-5-boronic acid Catalog No.:AA0037YT CAS No.:1034924-06-5 MDL No.:MFCD07375144 MF:C5H7BN2O2 MW:137.9323	tert-Butyl 2-amino-4-(4-methylpiperazin-1-yl)benzoate Catalog No.:AA01DF3J CAS No.:1034975-35-3 MDL No.:MFCD26384463 MF:C16H25N3O2 MW:291.3886
3-(4-Ethoxyphenyl)-2-thioxo-2,3-dihydroquinazolin-4(1H)-one Catalog No.:AA007XB0 CAS No.:1035-51-4 MDL No.:MFCD01238589 MF:C16H14N2O2S MW:298.3596	Ethyl 4-hydroxy-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate Catalog No.:AA007GEK CAS No.:10350-10-4 MDL No.:MFCD00205625 MF:C9H11NO4 MW:197.1879
2-(5-Methyl-1,2,4-oxadiazol-3-yl)pyridine Catalog No.:AA0085KP CAS No.:10350-68-2 MDL No.:MFCD20257806 MF:C8H7N3O MW:161.1607	5-Methyl-3-(pyridin-3-yl)-1,2,4-oxadiazole Catalog No.:AA009RAE CAS No.:10350-69-3 MDL No.:MFCD00264571 MF:C8H7N3O MW:161.1607
4-(5-Methyl-1,2,4-oxadiazol-3-yl)pyridine Catalog No.:AA007XE1 CAS No.:10350-70-6 MDL No.:MFCD00464110 MF:C8H7N3O MW:161.1607	Benzyl (1-(hydroxymethyl)cyclopropyl)carbamate Catalog No.:AA0038A2 CAS No.:103500-22-7 MDL No.:MFCD16294221 MF:C12H15NO3 MW:221.2524
7-Chloro-9-methyl-3,4-dihydro-2H-benzo[b]oxepin-5-one Catalog No.:AA008UQ1 CAS No.:103501-83-3 MDL No.:MFCD01648762 MF:C11H11ClO2 MW:210.6568	2-(2,2,2-Trifluoroethoxy)ethan-1-amine hydrochloride Catalog No.:AA00HA0D CAS No.:1035041-75-8 MDL No.:MFCD03196899 MF:C4H9ClF3NO MW:179.5686
(2-oxopiperidin-3-yl)methyl methanesulfonate Catalog No.:AA01C24P CAS No.:1035042-29-5 MDL No.:MFCD24566762 MF:C7H13NO4S MW:207.2474	[2,2'-Bipyridine]-6,6'(1h,1'h)-dione Catalog No.:AA0035RN CAS No.:103505-54-0 MDL No.:MFCD18452865 MF:C10H8N2O2 MW:188.1827
α-[(2-chloroacetyl)(3-chloro-4-methoxyphenyl)amino]-N-(2-phenylethyl)-2-thiopheneacetamide Catalog No.:AA01EPIA CAS No.:1035072-16-2 MDL No.:MFCD03450805 MF:C23H22Cl2N2O3S MW:477.4034	Methyl 5-aminobenzo[d]oxazole-2-carboxylate Catalog No.:AA0085KN CAS No.:1035093-77-6 MDL No.:MFCD11506182 MF:C9H8N2O3 MW:192.1714
(S)-Chroman-4-ylamine, HCl Catalog No.:AA003CJK CAS No.:1035093-81-2 MDL No.:MFCD08752571 MF:C9H12ClNO MW:185.6507	Iloprost-d4 (Major) Catalog No.:AA008W97 CAS No.:1035094-10-0 MDL No.: MF:C22H28D4O4 MW:364.5117
2,3,5,6-Tetrachloropyridine-4-thiol Catalog No.:AA007XE0 CAS No.:10351-06-1 MDL No.:MFCD00006231 MF:C5HCl4NS MW:248.9451	3-Methyl-4-pyridinethiol Catalog No.:AA019D8R CAS No.:10351-13-0 MDL No.:MFCD13175381 MF:C6H7NS MW:125.1915
(4-Pyridylthio)acetic acid Catalog No.:AA003BTY CAS No.:10351-19-6 MDL No.:MFCD00006424 MF:C7H7NO2S MW:169.2010	Benzimidazole-5,6-dicarboxylic acid Catalog No.:AA003EAO CAS No.:10351-75-4 MDL No.:MFCD03093058 MF:C9H6N2O4 MW:206.1549
7-Methylquinoxaline-6-carboxylic acid Catalog No.:AA01DUUT CAS No.:10351-82-3 MDL No.:MFCD20647506 MF:C10H8N2O2 MW:188.1827	Phyllanthin Catalog No.:AA008WF4 CAS No.:10351-88-9 MDL No.:MFCD17166965 MF:C24H34O6 MW:418.5232
3-(6-Bromopyridin-3-yl)acrylic acid Catalog No.:AA007GEE CAS No.:1035123-89-7 MDL No.:MFCD11504804 MF:C8H6BrNO2 MW:228.0427	Ethyl 4-chloro-6-nitroquinoline-3-carboxylate Catalog No.:AA00HA0E CAS No.:103514-54-1 MDL No.:MFCD02077676 MF:C12H9ClN2O4 MW:280.6639
2-Chloro-5-iodobenzyl alcohol Catalog No.:AA00HA0F CAS No.:1035155-69-1 MDL No.:MFCD18072886 MF:C7H6ClIO MW:268.4794	5-Hydrazinyl-2-(trifluoromethyl)pyridine Catalog No.:AA0038ZX CAS No.:1035173-53-5 MDL No.:MFCD11113388 MF:C6H6F3N3 MW:177.1271
3-Chlorosulfonyl-pyrrolidine-1-carboxylic acid benzyl ester Catalog No.:AA007XDX CAS No.:1035173-74-0 MDL No.:MFCD11501253 MF:C12H14ClNO4S MW:303.7619	N-(2-BENZOYL-4-CHLOROPHENYL)FORMAMIDE Catalog No.:AA008SBR CAS No.:10352-28-0 MDL No.:MFCD00111034 MF:C14H10ClNO2 MW:259.6877
2,6-Dichloro-4-phenylquinoline Catalog No.:AA00VRSY CAS No.:10352-30-4 MDL No.:MFCD00436567 MF:C15H9Cl2N MW:274.1447	2,3-Dimethylquinolin-4-ol Catalog No.:AA007GCM CAS No.:10352-60-0 MDL No.:MFCD09264032 MF:C11H11NO MW:173.2111
Sodium chloromethanesulfonate Catalog No.:AA009LVT CAS No.:10352-63-3 MDL No.:MFCD00182591 MF:CH2ClNaO3S MW:152.5325	Octahydroindolizine-2-carboxylic acid Catalog No.:AA019368 CAS No.:103521-84-2 MDL No.:MFCD12546948 MF:C9H15NO2 MW:169.2209
[(2R)-2-aminopropyl](benzyl)methylamine Catalog No.:AA01BBF1 CAS No.:1035211-86-9 MDL No.:MFCD24641488 MF:C11H18N2 MW:178.2740	(75-76% POLYDIMETHYLSILOXANE)-ETHYLENE COPOLYMER, 80-120 cSt Catalog No.:AA008ZI4 CAS No.:1035218-85-9 MDL No.: MF: MW:
2-Bromo-6,7-dihydrothiazolo[5,4-c]pyridin-4(5h)-one Catalog No.:AA007GCP CAS No.:1035219-96-5 MDL No.:MFCD14706758 MF:C6H5BrN2OS MW:233.0857	(S)-1-Boc-2-methyl-[1,4]diazepane Catalog No.:AA007GCO CAS No.:1035226-84-6 MDL No.:MFCD08437660 MF:C11H22N2O2 MW:214.3046
AZ505 Catalog No.:AA008TAV CAS No.:1035227-43-0 MDL No.:MFCD28044083 MF:C29H38Cl2N4O4 MW:577.5424	Az505 ditrifluoroacetate Catalog No.:AA008TAW CAS No.:1035227-44-1 MDL No.:MFCD28137733 MF:C33H40Cl2F6N4O8 MW:805.5891
1-(4-(Benzyloxy)-2-hydroxy-3-nitrophenyl)ethanone Catalog No.:AA009KML CAS No.:1035229-31-2 MDL No.:MFCD20482501 MF:C15H13NO5 MW:287.2674	8-Acetyl-5-(benzyloxy)-2h-benzo[b][1,4]oxazin-3(4h)-one Catalog No.:AA0097M5 CAS No.:1035229-32-3 MDL No.:MFCD21607217 MF:C17H15NO4 MW:297.3053
5-(Benzyloxy)-8-(2-chloroacetyl)-2h-benzo[b][1,4]oxazin-3(4h)-one Catalog No.:AA009KMK CAS No.:1035229-33-4 MDL No.:MFCD22575152 MF:C17H14ClNO4 MW:331.7504	2-(1-Methyl-1h-pyrazol-4-yl)-1,3-thiazole-5-carboxylic acid Catalog No.:AA01AHJC CAS No.:1035235-01-8 MDL No.:MFCD11208453 MF:C8H7N3O2S MW:209.2251
methyl 5-(2-cyanophenyl)-1H-pyrazole-3-carboxylate Catalog No.:AA01A4NN CAS No.:1035235-09-6 MDL No.:MFCD23701964 MF:C12H9N3O2 MW:227.2188	Methyl 4-(2-bromophenyl)-2,4-dioxobutanoate Catalog No.:AA0095WQ CAS No.:1035235-10-9 MDL No.:MFCD11188864 MF:C11H9BrO4 MW:285.0908
Methyl 5-(2-bromophenyl)-1h-pyrazole-3-carboxylate Catalog No.:AA008SHF CAS No.:1035235-11-0 MDL No.:MFCD12400790 MF:C11H9BrN2O2 MW:281.1054	2-BROMO-5-(DIMETHYLAMINO)BENZOIC ACID Catalog No.:AA01C7HO CAS No.:1035235-21-2 MDL No.:MFCD23726327 MF:C9H10BrNO2 MW:244.0852
2(1H)-Isoquinolinecarboxylic acid, 3,4-dihydro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-, 1,1-dimethylethyl ester Catalog No.:AA007XDS CAS No.:1035235-26-7 MDL No.:MFCD11044677 MF:C20H30BNO4 MW:359.2675	tert-Butyl-4-bromoisoindoline-2-carboxylate Catalog No.:AA007XBL CAS No.:1035235-27-8 MDL No.:MFCD10700130 MF:C13H16BrNO2 MW:298.1756
N-BOC-isoindoline-4-boronic acid, pinacol ester Catalog No.:AA00944H CAS No.:1035235-28-9 MDL No.:MFCD16652360 MF:C19H28BNO4 MW:345.2409	4-Cyano-2-fluorophenylboronic acid, pinacol ester Catalog No.:AA008SDK CAS No.:1035235-29-0 MDL No.:MFCD09998162 MF:C13H15BFNO2 MW:247.0731
Ethyl 2-(4-fluorophenyl)-2-methylpropanoate Catalog No.:AA00HA0J CAS No.:1035261-07-4 MDL No.:MFCD16748922 MF:C12H15FO2 MW:210.2447	4-(3-Fluorophenyl)tetrahydro-2h-pyran-4-carbonitrile Catalog No.:AA00HA0K CAS No.:1035261-79-0 MDL No.:MFCD10694448 MF:C12H12FNO MW:205.2282
4-(3-(Trifluoromethyl)phenyl)tetrahydro-2H-pyran-4-carboxylic acid Catalog No.:AA019WY5 CAS No.:1035261-84-7 MDL No.:MFCD10690199 MF:C13H13F3O3 MW:274.2357	2-(3,4-Difluorophenyl)-2-methylpropanenitrile Catalog No.:AA0085KG CAS No.:1035262-16-8 MDL No.:MFCD11036569 MF:C10H9F2N MW:181.1820
2-(3-chloro-2-fluorophenyl)-2-methylpropanoic acid Catalog No.:AA01ACYL CAS No.:1035262-79-3 MDL No.:MFCD11036905 MF:C10H10ClFO2 MW:216.6366	(4-Chloro-3-fluorophenyl)acetic acid methyl ester Catalog No.:AA0093NU CAS No.:1035262-89-5 MDL No.:MFCD11110082 MF:C9H8ClFO2 MW:202.6100
3-Cyano-5-methoxyphenylboronic acid, pinacol ester Catalog No.:AA0090CB CAS No.:1035266-33-1 MDL No.:MFCD11855976 MF:C14H18BNO3 MW:259.1086	Azd4547 Catalog No.:AA008TAZ CAS No.:1035270-39-3 MDL No.:MFCD22580423 MF:C26H33N5O3 MW:463.5719
3-[3-(2-Methoxyethoxy)phenyl]propanoic acid Catalog No.:AA01BCPB CAS No.:1035271-23-8 MDL No.:MFCD28012294 MF:C12H16O4 MW:224.2530	3-Propylbenzaldehyde Catalog No.:AA00987I CAS No.:103528-31-0 MDL No.:MFCD18824427 MF:C10H12O MW:148.2017
(3-methoxy-2-methylidene-3-oxopropyl)phosphonic acid Catalog No.:AA01C4PA CAS No.:103528-51-4 MDL No.:MFCD23131401 MF:C5H9O5P MW:180.0957	1,2-Epoxy-5-hexene Catalog No.:AA003DC7 CAS No.:10353-53-4 MDL No.:MFCD00010051 MF:C6H10O MW:98.1430
Cellobiosyl fluoride Catalog No.:AA01EAX8 CAS No.:103531-01-7 MDL No.:MFCD31916316 MF:C11H19FO11 MW:346.2604	5-{[(tert-butoxy)carbonyl]amino}bicyclo[3.1.1]heptane-1-carboxylic acid Catalog No.:AA01EKCE CAS No.:1035325-28-0 MDL No.:MFCD13806407 MF:C13H21NO4 MW:255.3101
1-(tert-Butoxycarbonyl)-3-hydroxyazetidine-3-carboxylic acid Catalog No.:AA009920 CAS No.:1035351-06-4 MDL No.:MFCD24465599 MF:C9H15NO5 MW:217.2191	tert-Butyl N-[(3-hydroxyazetidin-3-yl)methyl]carbamate Catalog No.:AA00HA0P CAS No.:1035351-07-5 MDL No.:MFCD24467501 MF:C9H18N2O3 MW:202.2508
(3R,3Ar,6r,6ar)-3,6-bis(allyloxy)hexahydrofuro[3,2-b]furan Catalog No.:AA0096T1 CAS No.:103536-97-6 MDL No.:MFCD30342469 MF:C12H18O4 MW:226.2689	3-Aminocyclobutanone hydrochloride Catalog No.:AA007XBF CAS No.:1035374-20-9 MDL No.:MFCD12923220 MF:C4H8ClNO MW:121.5654
4-Bromo-6-chlorobenzoimidazol-2-one Catalog No.:AA007GCC CAS No.:1035390-48-7 MDL No.:MFCD22123612 MF:C7H4BrClN2O MW:247.4765	Dibenzosuberenol Catalog No.:AA003P8T CAS No.:10354-00-4 MDL No.:MFCD00003586 MF:C15H12O MW:208.2552
N-Phenylpicolinamide Catalog No.:AA003A1C CAS No.:10354-53-7 MDL No.:MFCD00511984 MF:C12H10N2O MW:198.2206	1,4-DIMETHYLPIPERIDIN-4-OL Catalog No.:AA008ROK CAS No.:10354-61-7 MDL No.:MFCD00101728 MF:C7H15NO MW:129.2001
(3E)-4-(dimethylamino)-1,1-diphenylbut-3-en-2-one Catalog No.:AA00INHB CAS No.:103541-08-8 MDL No.:MFCD02089618 MF:C18H19NO MW:265.3496	methyl 2-(2-amino-4,5-dihydro-1,3-thiazol-4-yl)acetate Catalog No.:AA01BAHS CAS No.:103541-12-4 MDL No.:MFCD02656566 MF:C6H10N2O2S MW:174.2208
Boc-val-chloromethylketone Catalog No.:AA008UET CAS No.:103542-47-8 MDL No.:MFCD11113165 MF:C11H20ClNO3 MW:249.7344	ALENDRONIC-D6 ACID Catalog No.:AA008XLM CAS No.:1035437-39-8 MDL No.:MFCD08063600 MF:C4H7D6NO7P2 MW:255.1330
Risedronic Acid-d4 (Major) Catalog No.:AA01CCCG CAS No.:1035438-80-2 MDL No.: MF:C7H7D4NO7P2 MW:287.1369	3-benzyl-5H,6H,7H,8H-[1,2,4]triazolo[4,3-a]pyrazine Catalog No.:AA01AKUK CAS No.:1035454-21-7 MDL No.:MFCD11856751 MF:C12H14N4 MW:214.2664
rac-(4R,5S)-5-(aminomethyl)-N-cyclopropyl-1,3-dioxolane-4-carboxamide, trans Catalog No.:AA01EJO5 CAS No.:1035456-32-6 MDL No.:MFCD31559789 MF:C8H14N2O3 MW:186.2084	Quinoline-4-boronic acid pinacol ester Catalog No.:AA003LXY CAS No.:1035458-54-8 MDL No.:MFCD05155221 MF:C15H18BNO2 MW:255.1199
tert-butyl N-[2-(1H-indol-3-yl)ethyl]carbamate Catalog No.:AA0085JY CAS No.:103549-24-2 MDL No.:MFCD00716928 MF:C15H20N2O2 MW:260.3315	4-(4-Chlorophenoxy)phenylboronic acid Catalog No.:AA00HA0Q CAS No.:1035491-05-4 MDL No.:MFCD13182407 MF:C12H10BClO3 MW:248.4700
1-Methyl-3-(methylsulfonyl)benzene Catalog No.:AA007XB3 CAS No.:10355-06-3 MDL No.:MFCD03789191 MF:C8H10O2S MW:170.2288	4-Nitro-p-terphenyl Catalog No.:AA003LTT CAS No.:10355-53-0 MDL No.:MFCD00149860 MF:C18H13NO2 MW:275.3013
2-Azetidinemethanamine Catalog No.:AA007XB2 CAS No.:103550-76-1 MDL No.:MFCD06658334 MF:C4H10N2 MW:86.1356	methyl 2-amino-4-methylpent-4-enoate Catalog No.:AA01BE6X CAS No.:103550-87-4 MDL No.:MFCD19661114 MF:C7H13NO2 MW:143.1836
TAK-733 Catalog No.:AA008TH1 CAS No.:1035555-63-5 MDL No.:MFCD24386349 MF:C17H15F2IN4O4 MW:504.2267	A1-Phytoprostane-I Exclusive Catalog No.:AA0097C9 CAS No.:1035557-09-5 MDL No.: MF:C18H28O4 MW:308.4125
1-Bromo-3-(4-chlorophenyl)propan-2-one Catalog No.:AA0094EI CAS No.:103557-35-3 MDL No.:MFCD11847556 MF:C9H8BrClO MW:247.5162	Ethyl 4-(4-Fluorophenyl)-6-isopropyl-2-(N-methylsulfonamido)pyrimidine-5-carboxylate Catalog No.:AA007GBY CAS No.:1035595-71-1 MDL No.:MFCD09840588 MF:C17H20FN3O4S MW:381.4218
4-Amino-5-fluoro-1-((2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidin-2(1H)-one Catalog No.:AA0085JN CAS No.:10356-76-0 MDL No.:MFCD00077348 MF:C9H12FN3O4 MW:245.2077	4-ONE Catalog No.:AA008RB5 CAS No.:103560-62-9 MDL No.:MFCD08062226 MF:C9H14O2 MW:154.2063
9-Phenyl-2,7-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9H-carbazole Catalog No.:AA00IMHA CAS No.:1035631-57-2 MDL No.:MFCD31618151 MF:C30H35B2NO4 MW:495.2252	N-[4-[(3-Chloro-4-fluorophenyl)amino]-7-methoxy-6-quinazolinyl]-2-propenamide Catalog No.:AA01ENHW CAS No.:1035638-91-5 MDL No.:MFCD30182370 MF:C18H14ClFN4O2 MW:372.7808
4-[(3-methoxyphenyl)amino]butanoic acid Catalog No.:AA01AJ3K CAS No.:103565-46-4 MDL No.:MFCD09806780 MF:C11H15NO3 MW:209.2417	3-Fluoro-3'-(trifluoromethoxy)-[1,1'-biphenyl]-4-amine Catalog No.:AA01B5C9 CAS No.:1035689-62-3 MDL No.:MFCD17406621 MF:C13H9F4NO MW:271.2103
1-bromo-3-cyclopropoxybenzene Catalog No.:AA0039W8 CAS No.:1035690-22-2 MDL No.:MFCD17000487 MF:C9H9BrO MW:213.0712	3-Cyclopropoxyphenylboronic acid pinacol ester Catalog No.:AA0093H0 CAS No.:1035690-24-4 MDL No.:MFCD16994464 MF:C15H21BO3 MW:260.1364