The two most widely used of the ~-phenylethyl-bearing alkylating agents are ~-phenylethyl bromide (1) and. By following the progress of the reaction by gas chromatography, it was possible to conclude. This process appears to be simply a variation of the normal reductive alkylation reaction in which an amine is combined with an aldehyde or ketone i.
The presence of a very weak carbonyl absorption in the infrared spectra of the crude mixtures indicated that there had been.
This alkylation hydrolysis sequence showed that the yield of monoalkylated hydroxyenone F-3 was generally within the range. As shown in Graph G, the dialkylated product £;;;3.& is formed when bromide Ia previously attacks the intermediate anion G-3. The extensive work of Ringold and Malhotra (34b-e), involving both protonation and alkylation of these enone systems, gives some idea of the relative importance of the steps in this scheme.
Based on the work of Stork and Schulenberg (37) in the synthesis of dehydroabietic acid, it is believed that the introduction of the benzisothiazolyl moiety occurred from the underside of the tricyclic enolate, giving the stereochemistry indicated for H-1.
CHART H
Second, we predicted, from the work of Evans, that a tetrahedral center would be necessary at C-2 to achieve stereospecific hydrogenation of the C-10 double bond. Separation of the two components was performed by thin-layer chromatography using deoxygenated solvents under a nitrogen atmosphere. The results obtained when each of the pure alcohols, as well as the mixture, were subjected to the degrading sequence of nickel treatment and Raney hydrogenolysis were discouraging at best.
In parallel with most of the previous work involving benzisothiazole bromide Ia, we developed synthetics.
CHART I
The catalyst was removed by filtration through celite and the filter cake was washed with 100 ml of hot methanol. The mixture was heated on a steam bath for 1 hour, cooled and most of the acetone was removed under reduced pressure on a rotary evaporator. The catalyst is removed by filtration and the alcoholic solution is concentrated under reduced pressure on a rotary evaporator.
The catalyst was removed by filtration through Celite and the alcoholic solution was concentrated on a rotary evaporator at reduced pressure. The catalyst was removed by filtration, the filter pad was washed with hot ethanol, and the ethanol was removed under reduced pressure on a rotary evaporator. The acid was neutralized with saturated aqueous sodium bicarbonate and the methanol was removed under reduced pressure on a rotary evaporator.
The reaction mixture was taken up in ether and the ethereal solution was washed successively with saturated aqueous sodium bicarbonate, water and brine. The catalyst was allowed to settle and the supernatant ethanol was drawn off with a pipette. Most of the acetone was removed under reduced pressure on a rotary evaporator and the residue was partitioned between ether.
The catalyst was removed by filtration through a pad of Celite and the alcoholic solution was concentrated on a rotary evaporator at reduced pressure. The combined alcoholic solution was concentrated under reduced pressure on a rotary evaporator and the residue taken up in ether-benzene (911).
- A. Evans, unpublished results
- Meerwein, Org, Syn, 46, 113 (1966)
Further elution with 500 mL of 2% ether in benzene gave 250 mL of yellow crystals identified by vpc as a mixture of the two nitrated products. Preparation of the aluminum amalgam.--Commercial aluminum foil (2.0 g), in a loose ball .of 1 inch strips, was. Recrystallization of a portion of the above material from ether gave the analytical sample as pale yellow crystals, mp 110-111°.
The mixture was cooled and most of the carbon tetrachloride was removed under reduced pressure on a rotary evaporator. Isolation of the slower motion of the two bands increased the yield of Ib to 560 mg (49%). The mixture was cooled, most of the carbon tetrachloride was removed on a rotary evaporator at reduced pressure.
Continued elution of the silica gel column with 450 mL of benzene ether (Sal) yielded 1.28 g (68%) of monobromide Ic. Furthermore, a portion of the product enriched with authentic material showed a single peak in the vpc (conditions as above). After removal of the alcohol on a rotary evaporator, the residue was diluted with water and basified with 7 ml of 10% aqueous sodium hydroxide.
Concentration of the filtrate from above gave 300 mg of a yellow oil which was purified by ptlc [ether-. The bulk of the ethanol was removed under reduced pressure on a rotary evaporator at room temperature.
OCH3
The basic model of bond cleavage and bond formation is necessary to arrive at the appropriate. That an alkaloid containing a quinoline system can derive that moiety from tryptophan (VI) is not a new idea. Moreover, the rearrangement of the indole system into the quinoline system involves cleavage of the N1-C2 bond with the subsequent formation of a new bond between N1 and c5 • However, in the case of camptothecin (I) (Chart A), the proposed inter- .
There is indirect evidence to suggest that the proposed cleavage of the C2-C3 bond of tryptophan (VI) or trypt-,.,.,.,. There appears to be no precedent for the formation of a quinoline system from N-formylkynurenine (A-1), but it is. In any case, the existence of the cyclopentanoid intermediate A-4 was substantiated by extensive labeling experience.
Tryptophan and geraniol tracer studies predict 100% incorporation at the carbons of interest, while mevalonic acid tracer studies predict 50% incorporation at the carbons of interest. Position of Position of Position of Carbon in 14c label in 14c label in Camptothecin Tryptophan geraniol.
XIII
Recently, Gianturco and Friedel (4) prepared several 3-alkylfurans in about 50% overall yield by applying the Bamford-Stevens reaction to the tosylhydrazones of some 3-alkyltetrahydrofuran-4-ones. As is known, 3-alkylfurans that are not substituted at the 2- and 5-positions are extremely difficult to synthesize because substitution of the furan nucleus always occurs. This order of reactivity implies that an efficient synthesis of a 3-alkylfuran must involve an indirect route in which the future 3-alkyl.
In addition to providing an efficient route to a variety of 3-alkylfurans, this scheme has an added value in that one of the intermediates is 3-alkyl-4,5-dihydrofuran A-5. In any case, partial hydrolysis at this time poses no problem since the silyl group will be hydrolyzed in the next step. The essence of the proposed synthesis, the conversion of siloxy oxirane A-3 to hydroxy tetrahydrofuran A-4, is.
Opening of epoxides with alcohols in the presence of basic catalysts requires on the order of five to six. Between the two dihydrofurans, 4,5-di-. hydrofuran should be the dominant one, since the relatively acidic C-2 hydrogens adjacent to the ether oxygen are more easily removed than the unactivated C-4 hydrogens. In fact, both dihydrofurans can be converted to the same furan by the bromination-dehydrobromination sequence described below.
Chart B avoids this shortcoming by introducing the necessary functionality before the formation of the 1,2-benzisothiazole ring system. The core of the synthetic scheme concerns the efficient, stepwise conversion of thiocyanacetate B-3 to keto-thioether B-6 under mild conditions.
CHART B
LiAlH4
The reactivity of thiocyanogen chloride was first reported by Bacon and Guy (4), who found that nuclear aromatic thiocyanations resembled the corresponding substitutions by molecular halogen in that the reaction rate was affected by both the polarity of the solvent and the nature of the activating group. The order of reactivity for thiocyanation in acetic acid was found to parallel that observed in electrophilic aromatic halogenation. In all cases, the thiocyanation of simple benzene derivatives yielded only para-substituted products and there was no concurrent chlorination.
In general, the reactions were carried out at room temperature using one to two equivalents of thiocyanogen chloride, which was generated in situ from lead. Because of the great reactivity of thiocyanogen chloride in polar solvents, acetic acid was the solvent of choice1, however, chloroform was also used with success. It was obtained as the sole product in 75% yield from alcohol B-2 by the general procedure described above and.
In this earlier work, the use of the amino or hydroxy analogue of ketone B-1 was necessary to. In our case, sodium borohydride reduction of thio- cyano acetate B-3 followed by methylation of the inter-. 1.: Since thiocyanates can also be reduced to thiols with lithium aluminum hydride (7), reduction of both the thiocyanate and acetate groups of B-3 with lithium aluminum.
Collins• procedure, a modification of the standard Sarett oxidation (9), was used to convert alcohols to.
This compound is available from Aldrich Chemical Co
However, under the same conditions it was found that ketoacid Ia gave the unexpected α-meth. Oxyketo acid Id in 80% yield, but none of the desired. α-Acetoxylation is believed to involve a mechanism in which enolization of the ketone is the rate-determining step (4,5)1. In its capacity as a Lewis acid, boron trifluoride is thought to accelerate the dissolution of the ketone: but it may also accelerate the dissolution of lead tetraacetate into +pb(OAc)3 and -oAc.
The relative amounts of reagents used in this reaction are the same as those given earlier for the conversion of Ib to Ic. Support for the formation of a seven-membered ring in A-3 can be obtained by analogy with the postulated inter-. In addition, ring formation removes the remaining acetates bound to the lead from the vicinity of the methylene group.
The preferred conformation is expected to be one in which the carboxylcarbonyl is below the plane of the molecule and the terminal methylene group is above the plane. At the heart of the proposed mechanism is the existence of the seven-membered ring intermediate A-3. the relative positions of the ketone and acid groups. one could forbid the possibility that such an intermediate could form. By lowering the acidity of the reaction medium, one could isolate the cyclic osmate ester X by allowing this.
If the reaction rate is independent of the lead tetraacetate concentration, then all that can be said is that if A-3 does form, its formation occurs. The above presentation is not intended to provide conclusive proof of the proposed mechanism: it should, however, provide insight into the operation of a rather complicated lead tetraacetate oxidation.
