Nicolaou oxidation

The first total synthesis of the marine polycyclic ether toxin (-)-gambierol was accomplished in the laboratory of M. Sasaki. The introduction of the a,(3-unsaturation into the seven-membered H ring of the FGH tricyclic subunit proved to be problematic, because both the conventional selenium-based method and the Nicolaou oxidation with IBX failed. However, when the seven-membered ketone was treated with LiHMDS in the presence of TMSCI and EtsN, the corresponding silyl enol ether was formed, which was oxidized under Saegusa conditions to give the desired cyclic enone in high yield. Because of the small scale of the reaction, a large excess of Pd(OAc)2 was used in acetonitrile so the presence of a co-oxidant was not necessary. 

Nicolaou and co-workers established the severely strained A-ring oxazole (21) in their total synthesis of antitumor agent diazonamide A through initial oxidation of the hindered alcohol of intermediate 20 with TPAP and subsequent Robinson-Gabriel cyclodehydration of the resultant ketoamide with a mixture of POCI3 and pyridine (1 2) at 70°C. ... 

Nicolaou in his model system for an approach to the thiopeptide antibiotic thiostrepton, in particular, the elaboration of the quinaldic acid moiety. The tetrahydroquinoline 21 was converted to the A-oxide by /n-CPBA oxidation. Subsequent treatment with TFAA, to carry out the Boekelheide reaction, was followed by hydrolysis of the resultant ester to produce 22 as a mixture of alcohols. 

Bunnage M. E. Nicolaou K. C. The Oxide Anion Accelerated Retro-Diels-Alder... 

The late functionalization included the introduction of the C(10) and C(13) oxygens, which was done by phenylselenenic anhydride oxidation of the enolate in Step 1-5 and by allylic oxidation at C(13) in Step J-l. These oxidative steps are similar to transformations in the Holton and Nicolaou syntheses. 

The retrosynthetic concept of the Nicolaou group is shown in Scheme 22. The target molecule 36 is disconnected via an IMDA cyclization of the diene quinone precursor 138, which would be generated from the tetraline derivative 139 using Wittig chemistry followed by aromatic oxidation. A Claisen-type rearrangement would provide access to 139 whereby the side chain required for the rearrangement of 140 would be introduced by 0-acylation. The core of 141 would be formed via an intermolecular Diels-Alder reaction between diene 142 andp-benzoquinone 130 [42]. 

Figure 7.2 Some further examples of the product of oxidation (after Nicolaou et...

Fused ring 7-lactones may also be formed by cyclizations of l-cycloalkeneacetic acids under equilibrating conditions. Nicolaou obtained evidence for the presence of an unstable -lactone in the phenyl-selenolactonization of 1-cyclohexeneacetic acid, but rearrangement occured readily at room temperature to the more stable 7-lactone (equation 12).32 An example of a one-step conversion of a 2-methyl-1-cyclohexeneacetic acid to a fused butenolide by use of diphenyldiselenide and electrochemical oxidation has been reported.47 Recent studies by Rutledge showed that simultaneous addition of bromine and thallium carbonate to 1-cyclohexeneacetic acid gave the 7-lactone as the exclusive product (compare to Table 2) however, the mechanism of this reaction may differ from other cyclofunctionalizations.21... 

Iodine(V) reagents such as Dess-Martin periodinane (DMP) and o-iodoxyben-zoic acid (IBX) are known as general reagents for oxidation of alcohols and have been utilized widely for natural product syntheses. Besides their general use for alcoholic oxidation, recently, the active studies on novel utilization of iodine( V) reagents such as DMP and IBX have been pursued mainly by Nicolaou and coworkers [26]. In particular, the versatile reactivities of anilides (62) with IBX or DMP are interesting and involve unprecedented features as follows. o-Imido-quinones (63) are prepared from 62 by the action of DMP and water. This reaction has been investigated extensively and was found to lead to p-quinones (64)... 

Cyclization of hydroxy dithioketals. Nicolaou et al.1 have used this reaction for construction of oxocenes. The most satisfactory method involves activation of the sulfur of the starting material (1) with AgC104 to produce an oxocene derivative (2), followed by C-S cleavage. This second step can be effected with (C6H5)3SnH (AIBN) or by oxidation to the corresponding sulfoxide or sulfone, which then is cleaved with... 

A more advanced, direct route to the core structure of CP-263,114 (me-1) has recently been published by Wood et al., who used carbon-based fragmentation after a phenolic oxidation/ intramolecular Diels-Alder sequence [10], In addition, various cycloadditions for the synthesis of the central bicyclic skeleton have been established [11], Further methods to construct the bicyclic backbone by means of a Diels-Alder reaction [12] and by an exciting multi-step domino reaction [13] are introduced in the next sections, in the context of the total syntheses of the phomoidrides by Nicolaou and Shair, respectively [14]. 

Fig. 7. Nicolaou s total synthesis oxidation to the y-hydroxy lactol. PDC = pyridinium dichromate, DMP = Dess-Martin periodinane.

Paquette et al. start with the bis-vinylogation of the same compound 29 [14], by Wittig-Horner reaction, reduction, and oxidation (Scheme 5). For the formation of the C17-C16 bond, the onti-aldol 41 (ds not reported) is obtained by treatment of the aldehyde 39 with the (Z)-boron enolate 40, bearing a dithioketal moiety that is later to be the C51-C54 side chain. 3-Hydroxy-assisted, diastereoselective reduction of the keto group at C15 gives 41, which is converted into intermediate 42 in five more steps. The dethioketalization of 41 is achieved with phenyliodine(m) bis(trifluoroacetate) [16], As in Nicolaou s synthesis, the N12-C13 amide bond is formed first, followed by a low-yielding (21%, even at a concentration of 1 him) macrolactonization to 3. Table 1 summarizes the benchmark data of the two total syntheses of sanglifehrin A (1). 

It turned out that mCPBA is the least selective reagent drs from 2.8 1 [20] to 4 1 [23]), also giving rise to many side products e.g. by oxidation of the side chain double bond and of the aromatic system, depending on the conditions [26]. Nicolaou et al. used the alternative H2O2/ MeCN-system with KHCO3 in methanol to epoxidize desoxyepothilone E (2e, Scheme 13) derivatives with good yields and selectivities [18]. 

While the sultame and the oxazolidinone auxiliaries represent carboxylate equivalents, which have to be reduced (and sometimes re-oxidized) to the required aldehyde function at C7, the strength of Enders SAMP and RAMP auxiliaries is their direct use as aldehyde and ketone equivalents. However, Nicolaou et al. [13, 16] for the synthesis of the protected building blocks 17a-c had to give up the correct oxidation state in order to allow necessary later manipulations. Considering the necessity of reduction, the cheaper and recoverable Evans-oxazolidinones 18 appear to be the auxiliaries of choice, as demonstrated by Schinzer et al. [21, 22, 36]. A similar methylation is described in an early publication of De Brabander et al. [38] where sultame 21 was methylated and reduced to the a-methylaldehyde 20b in only two steps in good yield and enantiomeric excess. 

Compound 25, if not used in the RCM strategy, can be converted to aldehydes 26 by protection of the alcohol group and oxidative double bond cleavage (Scheme 7) [11, 13]. It is interesting to note that Schinzer et al. go the opposite way and synthesize alkene 25 from this aldehyde 26a obtained via a different route [olefination of protected (2S)-2-hydroxybutyrolactone with ArCH2P(0)(0Et)2 (3b) [21, 22] or ArCHjPBu +Cf (3c) [23]]. Nicolaou then transformed aldehyde 26b to the phosphonium salt 27 in three steps. 

---