Propose a mechanism problem for the multicomponent reaction transformation shown below.

Propose a mechanism for the following transformations.

[also discuss the origin of stereoselectivity favoring 6 over 7]

Propose a mechanism for the following transformation.
 

Consider the following observations:

The chiral amine 10 (99% ee) is converted into the stable nitroxide radical 11 with 2 equivalents of m-chloroperbenzoic acid (m-CPBA) in CH2Cl2, but this product is found to be racemic. Compound 11 was eventually prepared in chiral non-racemic form using another method, and does not racemize on standing for weeks at room temperature, either in solution or neat. Compound 11 also does not racemize in the presence of m-chlorobenzoic acid, acetic acid, or even camphorsulfonic acid. However, exposure of 11 to m-CPBA in CH2Cl2 causes complete racemization within one hour at room temperature. Reaction of compound 11 with one equivalent of bromine in CH2Cl2 for two minutes (to N-oxoammonium salt 12) followed by quenching with excess isopropanol / aqueous saturated NaHCO3 also returns racemic 11.

 
 

Provide a mechanism for m-CPBA-promoted conversion of 10 into 11.
 

Provide a mechanism for formation of racemic 11 under any one of the conditions described above for racemization.
 

Propose plausible mechanisms for each of the transformations shown below:

Provide a mechanism for conversion of enone 26 to acyclic keto-acid 27.

Provide a mechanism for conversion of enoate 28 to benzofuran-acid 29.

Provide a mechanism for conversion of 2-butanone (30) to dibromoketone 31, and for the subsequent rearrangement to cis-2-butenoic acid 32.

Reaction of ketone 33 with bromine in the presence of chlorosulfonic acid affords primarily monobromoketone 34 when the reaction is stopped after one hour, whereas slightly longer reaction times in the presence of excess bromide give dibromide 35. Tribromide 36 is produced as the major product upon reaction for five days. Provide a mechanism for the formation of each compound 34, 35, and 36.

2,2-Dialkylated 1,3-cyclopentanediones undergo facile b-dicarbonyl cleavage upon treatment with aqueous alkali, constituting an excellent synthesis of 5-substituted 4-oxoalkanoic acids. The conversion of 37 into 38 was presumed to proceed in this way for more than ten years. However, closer examination of this transformation revealed the situation to be more complex. When 1 was treated with one equivalent of sodium hydroxide in water at room temperature and the reaction was stopped after two minutes, compound 39 was obtained in ca. 50% yield. Treatment of 39 with excess sodium hydroxide solution gave a good yield of 38.

(1) Propose a mechanism for the conversion of compound 37 into intermediate 39.

(2) Propose a mechanism for conversion of 39 into product 38.

(3) Then provide a plausible mechanism for the originally presumed direct transformation of 37 to 38 (without the intermediacy of 39).

6-Substituted uracils 41 are of interest due to their possible use as anticancer and anti-AIDS drugs. Both 2,4-dimethoxy-6-iodopyrimidine (40, X = I) and 1,3-dimethyl-6-iodouracil (41, X = I) were required as starting materials for the synthesis of a variety of uracils by palladium-catalyzed C-C bond formation (41, X = various unsaturated carbon functional groups). An early report claimed that treatment of 6-chloro-2,4-dimethoxypyrimidine (40, X = Cl) with sodium iodide in refluxing DMF gave a 42% yield of 2,4-dimethoxy-6-iodopyrimidine (4, X = I), but a more recent study of this reaction clearly established that the product was in fact the isomeric 1,3-dimethyl-6-iodouracil (41, X = I).

(1) Propose a mechanism to account for the transformation of 40 (X = Cl) to 41 (X = I).

(2) Why is the presumed transformation of 6-chloro-2,4-dimethoxypyrimidine (40, X = Cl) to the iodide (40, X = I) unlikely under the reaction conditions described?

Chemistry of cinchona alkaloids:

The reaction of quinine (42) with thionyl chloride affords the corresponding secondary chloride (43), commonly known as 9-epi-chloroquinine. This chloride was originally reported to undergo rearrangement upon reaction with silver benzoate in refluxing methanol to afford a product assigned as structure 44. Several decades later, the structure of this rearrangement product was reexplored with the aid of NMR spectroscopy and single crystal X-ray diffractometry, and was corrected to structure 45. Quinidine (46), which is a diastereomer of quinine, underwent a similar series of transformations via 9-epi-chloroquinidine to afford structure 47, which is an isomer of compound 45.

 

Propose a mechanism for the conversion of 43 into structure 45. Propose a complete stereostructure for compound 45.

Propose a complete stereostructure for compound 47, based on a plausible mechanism for the rearrangement from 46.

Propose a plausible mechanism for the hypothetical conversion of 43 into the originally misassigned structure 44, and propose a likely stereostructure for 44 based on your mechanism.

Is "the well-known diminished basicity of hetero-cinchona alkaloids..." more consistent with structure 44, or with structure 45? Explain with a scheme and/or a few words.

Synthesis of Aspidosperma alkaloids:

Propose plausible mechanisms for each transformations shown below. Describe why phenylphosphoryl dichloride at 105oC gives a 4 : 1 ratio of 8 : 9, whereas reaction with trifluoroacetic acid at 60oC gives a 3.6 : 1 ratio favoring epimer 50.

Both epimers 49 and 50 were transformed via a few straightforward steps into compound 51, produced as a mixture of epimers. Each epimer of 51 underwent cyclodehydration upon brief heating with toluenesulfonic acid to give pentacyclic product 52. Propose a mechanism for the conversion of either epimer of 51 into product 52.

In the course of characterizing product 52, the authors discovered that their synthetic material exhibited an optical rotation which was nearly zero, even though both epimers of precursor 51 were determined to be > 95% enantiomerically pure, having been ultimately derived from the chiral amino acid L-aspartic acid. If necessary, modify your mechanism to accomodate the formation of racemic 52 from either epimer of 51.

Provide detailed mechanisms for the transformations shown below. Is product 53 chiral or achiral?

Propose mechanisms for the conversion of 54 into 55, and then for the stereochemically different conversion of 56 into product 57. Also assign the probable stereochemistry for any unassigned stereocenters in each product 55 and 57.

Propose a mechanism for the conversion of 58 into product 59. Is product 59 chiral or achiral?

However, attempted conversion of the isomer 60 under identical conditions gave only fragmentation at the carbon-carbon bond indicated. Propose structures for the fragments produced, as well as a reasonable mechanism for the fragmentation.

The investigators evantually found that 60 could be converted into 61 upon heating with methanol. Is product 61 chiral or achiral?

Propose a mechanism for the conversion of 62 into product 63. Is this product chiral or achiral?

Draw the structure of the product obtained from similar treatment of isomeric compound 64.

Provide a detailed mechanism for each transformation:

Provide plausible mechanisms for each transformation shown below in a short synthesis of benzanthracenedione 85:

Propose a detailed mechanism for each multicomponent transformation. Discuss the origin of stereoselectivity of the first and third reactions:

Propose a mechanism for the hypothetical prebiotic synthesis of adenine from five units of hydrocyanic acid. Assume that dilute aqueous acid and / or base is available, with heat, sunlight, and probably lightning (electricity) available as energy sources.

Propose a detailed mechanism for each multicomponent transformation. Discuss the origin of stereoselectivity in the last three transformations:


Scientists at a major pharmaceutical company have studied the iron porphyrin-catalyzed oxidation of various drugs, as a mimic for oxidative metabolic processes that occur in the liver. For instance, reaction of many organic compounds with an iron porphyrin catalyst in the presence of hydrogen peroxide or bleach has been shown to carry out reactions as disparate as anti-dihydroxylation of alkenes, benzylic hydroxylation, and amine demethylation.

Reaction of the antibiotic clarithromycin (93) with 0.1 % iron porphyrin (95) and 1.1 equiv of bleach (NaOCl) gives three products A (21% yield), B (45% yield), and ketone 94 (20% yield), in which the macrolide and cladinose portions of the drug are unchanged. Compound A is the major product when a large excess of bleach is used, whereas B is produced in approximately 90% yield upon reaction of clarithromycin with m-chloroperbenzoic acid (m-CPBA). Compound B is inert upon further reaction with catalyst 95 and bleach.

 

partial characterization data, incl. NMR data for desosamine of (93) and the corresponding region of A, B, and 94:

93: 1H NMR (CDCl3) d 4.44 (d, 1H), 3.48 (m, 1H), 3.40 (s, 1H, exch. w/ D2O), 3.20 (dd, 1H), 2.41 (m, 1H), 2.29 (s, 6H), 1.66 (m, 1H), 1.22 (m, 1H), 1.21 (d, 3H); 13C NMR (CDCl3) d 102.9, 71.0, 68.7, 65.6, 40.2, 28.7, 21.4.

A: 1H NMR (CDCl3) d 4.47 (d, 1H), 3.55 (dqd, 1H), 3.43 (dd, 1H), 2.98 (s, 3H), 2.75 (ddd, 1H), 1.89 (ddd, 1H), 1.55 (dd, 1H), 1.26 (d, 3H); 13C NMR (CDCl3) d 102.2, 72.2, 70.3, 67.8, 48.7, 30.5, 21.3; FAB MS (m/z): 768, 734, 610, 178, 78; FAB HRMS (m/z) 768.4302; Elemental analysis: C, 58.07%; H, 8.71%; N, 1.66%; Cl, 4.31%.

B: 1H NMR (CDCl3) d 4.57 (d, 1H), 3.70 (m, 1H), 3.66 (m, 1H), 3.51 (m, 1H), 3.30 (s, 3H), 3.22 (s, 3H), 2.05 (br d, 1H), 1.34 (br d, 1H), 1.27 (d, 3H); 13C NMR (CDCl3) d 102.3, 76.3, 72.6, 66.9, 58.1, 52.7, 34.9, 21.4; FAB MS (m/z): 764, 606, 174; FAB HRMS (m/z) 764.4797.

94: 1H NMR (CDCl3) d 4.51 (d, 1H), 3.99 (ddd, 1H), 3.69 (dqd, 1H), 3.60 (s, 1H, exch. w/ D2O), 2.55 (dd, 1H), 2.40 (ddd, 1H), 1.21 (d, 3H); 13C NMR (CDCl3) d 206.0, 103.4, 78.8, 67.3, 47.2, 21.6; FAB MS (M+KI, m/z): 757, 657; FAB HRMS (M+KI, m/z) 757.3790; Elemental analysis: C, 59.98%; H, 8.74%.

The iron porphyrin catalyst is activated by reaction with bleach, and the reactive intermediate is thought to be iron oxo 96.

 

Compound A was originally reported to be structure 97 in which the dimethylamino substituent was substituted by a methoxy group, which was particularly surprising in that the authors noted that "this unprecedented reaction occurs in the absence of added methanol." This report was later retracted and the structural assignment for compound A was eventually corrected.

Please answer the following questions:

Propose a structure for compound A, and propose the mechanism for the formation of this compound from iron-catalyzed bleach oxidation of clarithromycin (93).

Propose a structure for compound B, and propose the mechanism for the formation of this compound from oxidation of clarithromycin (93).

Propose a mechanism for the formation of 94 from oxidation of clarithromycin (93).

Can you explain how the original assignment of structure 97 might have been rationalized?
 

Researchers at Yale have prepared the highly unsaturated acyclic compound 98, and subjected this substance to refluxing benzene in the presence of a radical inhibitor. Under these reaction conditions, one major product 99 was produced in 66% yield, which was determined to be an isomer of compound 98.

Compound 99 was oxidized with ceric ammonium nitrate to give a synthetic intermediate 100 (C21H28O4Si), followed by a second oxidation which was accomplished with equal facility with either manganese dioxide or catalytic tetrapropylammonium perruthenate / N-methylmorpholine N-oxide to give compound 101.

characterization data:

99: 1H NMR (CDCl3) d 7.26 (d, J = 8.6 Hz, 2H), 6.85 (d, J = 8.6 Hz, 2H), 5.85 (dd, J= 9.7, 2.4 Hz, 1H), 5.74 (dd, J = 9.7, 0.8 Hz, 1H), 5.54 (br s, 1H), 5.20 (br s, 1H), 4.59 (d, J = 11.9 Hz, 1H), 4.51 (d, J = 11.9 Hz, 1H), 3.93 (br s, 1H), 3.78 (s, 3H), 3.60 (s, 3H), 3.60 (m, 1H), 2.96 (m, 2H), 2.65 (m, 1H), 0.89 (s, 9H), 0.12 (s, 3H), 0.10 (s, 3H). 13C NMR (CDCl3) d 172.8, 159.3, 142.1, 129.9, 129.4, 124.3, 122.5, 121.3, 113.7, 102.3, 96.5, 85.7, 82.4, 71.1, 70.2, 69.0, 55.2, 51.9, 40.0, 33.9, 25.7, 22.7, 18.1, -5.1. IR (film) 2201 (w), 1738 (s) cm-1. MS (EI, 20eV) 492.3 (2%), 435.2 (20%), 121.1 (100%).

101: 1H NMR (CDCl3) d 5.85 (br s, 1H), 5.81 (dd, J = 10.0, 2.7 Hz, 1H), 5.74 (dd, J = 10.0, 1.0 Hz, 1H), 5.28 (d, J = 1.0 Hz, 1H), 3.68 (s, 3H), 3.62 (m, 1H), 3.58 (m, 1H), 3.25 (dd, J = 6.9, 2.7 Hz, 1H), 3.06 (d, J = 20.5 Hz, 1H), 0.91 (s, 9H), 0.15 (s, 3H), 0.12 (s, 3H). Irradiation of d 5.81 simplifies d 3.58 without changing d 3.25. 13C NMR (CDCl3) d 193.3, 172.1, 160.7, 124.0, 121.6, 118.7, 99.4, 93.5, 52.4, 42.3, 39.3, 25.6, 18.1, -4.9, -5.1. IR (film) 1738 (s), 1731 (m), 1694 (s) cm-1. MS (EI, 20eV) 370.2 (100%).
 

(a) Propose a structure for compound 99.

(b) Propose a structure for compound 100.

(c) Propose a structure for compound 101.
 
 

Researchers at UCLA reported that photolysis of diazomalonate (102) in the presence of cyclohexene (103) afforded one new compound in excellent yield. This product was originally assigned as cyclopropyl diester product 104, but this assignment was later shown to be incorrect.

Spectroscopic data for the new product: 1H NMR (CDCl3) d 3.08 (br s, 1), 1.60 (s, 3H), 1.55 (s, 3H), 1.39 (s, 3H), 1.02-1.68 (m, 6H), 1.20 (s, 3H), 0.95 (s, 3H). Partial 13C NMR (CDCl3) d 202, 168, 111, 94. IR (CCl4) 1798 (s), 1770 (s) cm-1. HRMS 266.1510.

Propose the correct structure for the photoproduct of 102 and 103. Also propose a reasonable mechanism for the formation of this photoproduct.

A researcher claiming to be at Johns Hopkins reported the condensation of 105 and enamine 106 to give compound 107. Jones oxidation of 107 and treatment of the oxidation product with diazomethane was claimed to give compound 108. Subsequent addition of aryl Grignard reagent followed by reaction with phosphorus oxychloride and pyridine was reported to give 109 as a cis / trans mixture.

A Nobel Laureate questioned the validity of this work shortly after its publication, and subsequently demonstrated that the synthesis of 109 could not work as reported.

 

Identify at least three things which are chemically inconsistent in this scheme.

Propose a realistic, alternative synthesis of compound 108.
 
 

The pyrone natural product, kojic acid (110), was reported to undergo base-catalyzed conjugate addition to acrylonitrile, and after acidic hydrolysis a product was claimed as yellow crystals with m.p. 155o (analysis C, 50.63; H, 4.43) and this product was assigned as structure 111. The same researcher later claimed that compound 111 was also obtained upon reaction of kojic acid (110) with 3-bromopropionic acid in the presence of sodium bicarbonate and refluxing ethanol; this product was white crystals with m.p. 152o (analysis C, 50.78; H, 4.82).

Another laboratory tried to repeat this work, but found that under the first set of reported reaction conditions only a black tarry product was obtained even upon "following his directions as carefully as possible". This laboratory did obtain white crystals melting at 152o under the second set of reaction conditions, but determined that this material was recovered kojic acid (110, lit. m.p. 152 - 155o; analysis calculated for C6H6O4, C, 50.71; H, 4.26) rather than compound (111). These workers were successful in preparing compound 112 (m.p. 168 - 168.5o, analysis C, 47.76, H, 4.08) from bromoacetic acid and kojic acid in the presence of sodium methoxide, but these conditions failed to give 111 with 3-bromopropionic acid.

Explain why the reaction of bromoacetic acid with kojic acid gives a new pyrone product (compound 112), but the analogous reaction of bromopropionic acid fails to give a new pyrone product.

B: Further studies on the base-catalyzed reaction of kojic acid and acrylonitrile in refluxing methanol solvent followed by acidification at room temperature resulted in formation of a major product, compound A (m.p. 261-262o). This reaction was found to be critically dependent on the amount of base catalyst (either sodium methoxide or trimethylbenzylammonium hydroxide, ideally 0.5 equivalents), and when one full equivalent of base was used, the only effect was prompt precipitation of the sodium salt of kojic acid, and compound A was not formed.

Careful monitoring of the reaction of kojic acid and acrylonitrile in the presence of approximately 0.05 equivalents of KOH in refluxing methanol resulted in the formation of a small amount of precipitate, which was filtered off and briefly acidified at room temperature. After evaporation of the solvent, a black tar was obtained (compound B) which contained nitrogen (by sodium fusion test). When compound B was dissolved in concentrated hydrochloric acid (36% HCl in water), compound A was produced. Compound A was analyzed by elemental analysis (C, 52.97; H, 4.34) and was judged to have molecular formula C15H14O9. Compound A gave a positive ferric chloride enolic test and could be titrated as a weak monobasic acid.

alpha-Deoxykojic acid (4) was similarly reacted with acrylonitrile to give a good yield of a product C (m.p. 262 - 264o) after acidification at room temperature. Compound C gave analysis (C, 59.02; H, 4.77; N, 4.88) and was judged to have molecular formula C15H15NO6. Compound C gave a positive ferric chloride enolic test and was also a weak monobasic acid.

Products A and C were originally analyzed by what was then the relatively new technique of infrared spectroscopy. This problem was reexplored two decades later with the additional techniques of 1H and 13C NMR spectroscopy.

compound A: IR (KBr pellet, m) 2.94 (s), 5.63 (s), 5.78 (s), 6.02 (s), 6.18 (s), 6.36 (s); 1H NMR (CDCl3, d) 6.90 (s, 1H), 5.60 (br d, J= 7 Hz, 1H), 4.77 (s, 2H), 4.70 (d, J= 10 Hz, 1H), 4.40 (d, J= 10 Hz, 1H), 3.67 (d, J= 14 Hz, 1H), 3.51 (dd, J= 10, 4 Hz, 1H), 3.13 (d, J= 14 Hz, 1H), 2.90 (m, J = 14, 10, 1.5 Hz, 1H), 2.62 (m, J = 14, 7, 4 Hz, 1H); 13C NMR with 13C-1H coupling (CDCl3, d) 201.8 (s), 177.9 (s), 174.4 (s), 168.3 (s), 146.5 (s), 142.4 (s), 109.0 (d), 88.7 (s), 80.1 (s), 80.0 (d), 71.6 (t), 60.0 (t), 47.3 (d), 46.5 (t), 28.2 (t).

compound C: IR (KBr pellet, m) 3.04 (s), 3.14 (s), 3.40 (w), 4.38 (s), 5.78 (s), 6.1 (br, s); 1H NMR (CDCl3, d) 6.28 (s, 1H), 5.55 (dd, J= 8, 2 Hz, 1H), 3.59 (dd, J= 10, 4 Hz, 1H), 3.40 (d, J= 14 Hz, 1H), 3.00 (d, J = 14 Hz, 1H), 2.88 (m, J = 14, 10, 2 Hz, 1H), 2.61 (m, J = 14, 8, 4 Hz, 1H), 2.10 (s, 3H), 1.72 (s, 3H); 13C NMR with 13C-1H coupling (CDCl3, d) 202.1 (s), 174.1 (s), 165.3 (s), 146.4 (s), 141.8 (s), 120.8 (s), 111.1 (d), 84.3 (s), 79.2 (s), 78.4 (d), 52.5 (t), 36.9 (d), 31.1 (t), 23.1 (q), 19.5 (q).

Please answer the following questions:

Propose the structure of compound A. Then propose a mechanism for the formation of this product from kojic acid and acrylonitrile. Your mechanism should accomodate the intermediacy of a moderately stable nitrogen-containing intermediate B.

Propose the structure of compound C (hint: many similarities to structure A).
 
 

Construction of organic nanostructures:

A wide variety of topologically interesting organic compounds can be prepared using a small number of versatile and highly chemoselective reactions. Write out the mechanism for each transformation shown below:

Propose syntheses of the following macrocyclic structures, starting only with simple difunctional aromatic compounds and monosilyl alkynes, and using only the five reactions shown in part 1. For instance,


 

Exercises in stereo induction:

Draw models explaining the stereoinduction observed for each case:

Draw models explaining the stereoinduction observed for each case:

Explain why the stereoinduction is not as high in the cases below, again drawing models:

Henbest and Wilson showed in 1958 that peracid epoxidations of alkenes are directed by allylic hydroxyl groups. This concept has been demonstrated with several other substrates and epoxidation catalysts. Explain the differences between peracid and vanadium-catalyzed epoxidations, noting the considerable differences in behavior observed upon increasing ring size from 2-cyclohexen-1-ol to 2-cycloocten-1-ol:

Draw models explaining the stereoinduction observed for each case:

Exercises in stereoinduction

Propose a mechanistic model which explains the stereochemical results observed.


 

Enzymatic mechanisms: Enzymes catalyze many reactions under physiological conditions and with rapid reaction rates; these reactions would occur much more slowly or require much harsher reaction conditions under abiological conditions. Although the active sites of enzymes localize reactants in various pockets / cavities / tunnels of the protein structure, the chemical mechanisms follow all fundamental laws of chemistry.

Many enzyme sites contain an aspartate-histidine-serine catalytic triad. For each reaction below, propose a detailed chemical mechanism. The mechanism for chymotrypsin-catalyzed amide hydrolysis (part 1a) is attached as an example.

The following reactions require a basic amino acid in the active site (histidine or lysine) for general acid/base catalysis, as well as a divalent metal ion (Mg+2 or Mn+2) to stabilize negative charges. Propose detailed chemical mechanisms for both forward and reverse equilibrium reactions for each case shown below.

 
 

More exercises in stereoinduction:

Propose a mechanistic model which explains the stereochemical results observed.