Natural product synthesis carbonylation

Chemoselective reduction of a,(3-epoxy carbonyl compounds to aldols and their analogs by organoseleniums and its application to natural product synthesis 98YGK736. 

Officially, the history of MCRs dates back to the year 1850, with the introduction of the Strecker reaction (S-3CR) describing the formation of a-aminocyanides from ammonia, carbonyl compounds, and hydrogen cyanide [4]. In 1882, the reaction progressed to the Hantzsch synthesis (H-4CR) of 1,4-dihydropyridines by the reaction of amines, aldehydes, and 1,3-dicarbonyl compounds [5], Some 25 years later, in 1917, Robinson achieved the total synthesis of the alkaloid tropinone by using a three-component strategy based on Mannich-type reactions (M-3CR) [6]. In fact, this was the earliest application of MCRs in natural product synthesis [7]. 

The [2+2]-photocycloaddition of carbonyl groups with olefins (Paterno-Buchi reaction) is one of the oldest known photochemical reactions and has become increasingly important for the synthesis of complex molecules. Existing reviews have summarized the mechanistic considerations and defined the scope and limitations of this photocycloaddition73. Although this reaction likely proceeds via initial excitation of the carbonyl compound and not the excited state of the diene, the many examples of this reaction in natural product synthesis justify inclusion in this chapter. 

The asymmetric arylation of ketone enolates represents an attractive method for the preparation of optically active carbonyl compounds with a stereogenic quaternary center at the a-position to the carbonyl group. Such types of compounds are important intermediates for natural product synthesis. Replacement of BINAP by 109 provides... 

In conclusion, the ene reaction has undergone a synthetic renaissance with the advent of Lewis acid and transition metal-catalyzed protocols. The carbonyl-ene, imino-ene, and Alder-ene reactions have all experienced tremendous growth due to the mild conditions in which these reactions can be performed, the high functional group compatibility and high stereoselectivity. As a confirmation of the synthetic utility of the ene reaction, there are many applications to natural product synthesis, and some of these are highlighted in Section 10.12.6. Finally, it should be mentioned that these catalyzed ene reactions are still in their infancy, so much remains to be learned. 

The facile conversion of carbonyl groups into lactones via cyclobutanones offers many opportunities for synthetic applications considering the importance of butanol-ides in natural products synthesis. The iridoids vividly illustrate this potential. Allamandin (163) 135 c) and its dehydrated relative plumericin (164) 135 d), compounds possessing antifungal, antibacterial, and antitumor activity, pack a great deal of... 

Since the pioneering work by Sarel and co-workers on the iron carbonyl promoted transformation of vinylcyclopropanes and related compounds [1], a variety of transition metal complexes have been examined to achieve effective activation of the vinylcyclopropane-cyclopentene rearrangement which usually requires pyrolytic conditions. These reactions have been applied to natural product synthesis in some cases and have already been reviewed in several excellent articles [2-4]. 

The vast majority of the work described in this chapter was reported since 1995. Rho-dium( I)-catalyzed hydroformylation and silylformylation reactions have only very recently been adapted and developed for use in the efficient synthesis of stereochemi-cally complex natural products. In addition, the recent development of tandem reactions that take advantage of the direct production of aldehydes in these carbonylation reactions have only begun to demonstrate the versatility of this chemistry. Rhodium(I)-catalyzed hydroformylation and silylformylation, venerable reactions that have primarily been associated with organometaUic chemistry, must now be considered important tools for natural product synthesis. The continued development of these methodologies for that purpose may be expected. 

Iron carbonyls also mediate the cycloaddition reaction of allyl equivalents and dienes. In the presence of nonacarbonyldiiron a,a -dihaloketones and 1,3-dienes provide cycloheptenes (Scheme 1.5) [14,15]. Two initial dehalogenation steps afford a reactive oxoallyliron complex which undergoes a thermally allowed concerted [4 + 31-cycloaddition with 1,3-dienes. The 1,3-diene system can be incorporated in cyclic or heterocyclic systems (furans, cyclopentadienes and, less frequently, pyrroles). Noyori and coworkers applied this strategy to natural product synthesis, e.g. a-thujaplicin and P-thujaplicin [14, 16]. 

Are the above DreM tactics feasible in tandem A preliminary but affirmative answer is possible. Thus, the biaryl O-carbamate migration-amide cydization sequence 166 —> 167 —> 168 (Scheme 43), which conceptually constitutes a reaction of a biaryl 2,2 -dianion with a carbonyl dication equivalent (169), has found application in natural product synthesis [65, 72]. 

Ruthenium is not an effective catalyst in many catalytic reactions however, it is becoming one of the most novel and promising metals with respect to organic synthesis. The recent discovery of C-H bond activation reactions [38] and alkene metathesis reactions [54] catalyzed by ruthenium complexes has had a significant impact on organic chemistry as well as other chemically related fields, such as natural product synthesis, polymer science, and material sciences. Similarly, carbonylation reactions catalyzed by ruthenium complexes have also been extensively developed. Compared with other transition-metal-catalyzed carbonylation reactions, ruthenium complexes are known to catalyze a few carbonylation reactions, such as hydroformylation or the reductive carbonylation of nitro compounds. In the last 10 years, a number of new carbonylation reactions have been discovered, as described in this chapter. We ex-... 

The formation of /3-hydroxyselenides through the reaction of a selenium-stabilized carbanion with carbonyl compounds has been extensively used also in the context of natural product synthesis. The phenylselenoalkyllithium compound 115 was reacted with aldehyde 116 to afford /3-hydroxyselenide 117. In a radical cyclization cascade the tricyclic molecule 118 was generated in good yields and subsequent transformations led to the synthesis of pentalenene 119 (Scheme 28).1 9 Also other natural products like zizaene and khusimone have been synthesized via a similar route.200... 

Biologically Significant Reactions of Co2(CO)6 (li2-RC=CR). Many dicobalt carbonyls with complexed alkynes have been used in natural product synthesis. In one... 

Treatment of a, -unsaturated carbonyl compounds 18 with nucleophilic selenium species affords -seleno carbonyl compounds 19 in good yields via Michael addition (Scheme 27) [46]. This reaction has been applied to protect a, -unsa-turated lactones [47], in natural product synthesis [48], and in asymmetric Michael additions in the presence of an alkaloid [49]. Michael addition also proceeds with selenolates that are prepared from diphenyl diselenide by cathodic reduction [22], reduction with the Sm-Me3SiCl-H20 system [19], and reduction with tributyl phosphine [25]. 

In a second part, the reactivity of a-phenylselanyl enolates, derived from ketones, esters, lactones and a,/i-unsatm ated carbonyl compounds, is discussed. Alkylation, aldolisation and Michael reactions are considered as the use of selenium-stabilized carbanions in the natural product synthesis. Others a-fimctionalyzed species are also presented. 

Alkoxycyclopropanes are commonly prepared from alkyl enol ethers by one of the Simmons-Smith modifications (see Chapter 7). According to Wenkert and coworkers they are cleaved by strong acids to the a-methylated carbonyl compound, thus establishing an overall a-methylation of a ketone or an aldehyde (equation 64). This method has often been used for natural product synthesis (e.g. valerane " ). 

Nogano and co-workers [3] reported similar examples of asymmetric induction for natural product synthesis using protected sugars and a variety of R MgX, where X = C1, Br, or 1. In Table 2, entries 3 and 4, the tetralose carbonyl can also contain in the Ri position an ether, ester, urethane, alkyl, or aryl group [13]. The authors reported the diastereometer ratio from the R substrate and the labeled carbon-2 varied from 80 20 to 10 90 (2S/2R). The variability was controlled by the nature of the nucleophile, the solvent, and the temperature. The authors rationalized the product distribution based on chelation of the metal and steric bulk of the reactants, favoring the R-isom.er. 

Typically, nonstabilized ylides are utilized for the synthesis of (Z)-alkenes. In 1986, Schlosser published a paper summarizing the factors that enhance (Z)-selectivity. Salt effects have historically been defined as the response to the presence of soluble lithium salts. Any soluble salt will compromise the (Z)-selectivity of the reaction, and typically this issue has been resolved by the use of sodium amide or sodium or potassium hexamethyldisilazane (NaHMDS or KHMDS) as the base. Solvent effects are also vital to the stereoselectivity. In general, ethereal solvents such as THF, diethyl ether, DME and t-butyl methyl ether are the solvents of choice." In cases where competitive enolate fomnation is problematic, toluene may be utilized. Protic solvents, such as alcohols, as well as DMSO, should be avoided in attempts to maximize (Z)-selectivity. Finally, the dropwise addition of the carbonyl to the ylide should be carried out at low temperature (-78 C). Recent applications of phosphonium ylides in natural product synthesis have been extensively reviewed by Maryanoff and Reitz. 

The aprotic Bamford-Stevens reaction has been utilized for the development of a methodology towards 1,2-carbonyl transposition in natural product synthesis. The example in Scheme 8 illustrates the regiocontrolled alkene formation for the synthesis of hirsutic acid. ... 

The reagents 128—130 are stable crystalline compounds which form anions easily with BuLi. Addition to aldehydes or ketones give protected (3,7-unsaturated carbonyl compounds, e. g. 131, after completion of the Homer-Wittig reaction, and hence the ketones 132 themselves. These methods have not yet been used in natural product synthesis. 

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