Nicolaou method

Scheme 12. Generation of an epothilone library on solid-phase using SMART microreactors and the pool and split method (Nicolaou et al.) [25c]...

The polyether natural products have provided an excellent testing ground for oxygen heterocyclic synthesis, and have also inspired many new methods. Nicolaou s group has shown that in contrast to the usual mode of cyclization onto an epoxide, the... 

The generality of the dioxahorolane method makes it well-suited for synthesis of complex natural products. For example, Nicolaou et al. have successfully used... 

Nicolaou and coworkers reported a new method for preparing glyco-syl fluorides (38) from phenyl thioglycosides (37) by treatment with di-ethylaminosulfur trifluoride (DAST)-A -bromosuccinimide (NBS), or HF-pyridine-NBS, the phenylthio group of the thioglycosides being initially activated by NBS. Thus prepared were compounds 39, 40, and 42 (see Table I) and 3,4-C)-carbonyl-2,6-dideoxy-3-C-methyl-L-n Z)ohexo-pyranosyl, 2-azido-2,6-dideoxy-3,4-0-isopropylidene-D-altropyranosyl,... 

K. C. Nicolaou and E. J. Sorensen, in Classics in Total Synthesis, Targets, Strategies, and Methods, VCH, Weinheim, 1996. 

Nicolaou and coworkers used this approach also for the synthesis of hamigerans A and B [30], as well as of several of their epimers [29, 31]. The group of Kraus succeeded in a formal total synthesis of the anticancer agent podophyllotoxin 5-103 from 5-100 [32] (Scheme 5.19) [33]. The method allows a rapid access to the central core 5-102 via 5-101. 

In connection with the synthetic work directed towards the total synthesis of polyene macrolide antibiotics -such as amphotericin B (i)- Sharpless and Masamune [1] on one hand, and Nicolaou and Uenishi on the other [2], have developed alternative methods for the enantioselective synthesis of 1,3-diols and, in general, 1, 3, 5...(2n + 1) polyols. One of these methods is based on the Sharpless asymmetric epoxidation of allylic alcohols [3] and regioselective reductive ring opening of epoxides by metal hydrides, such as Red-Al and DIBAL. The second method uses available monosaccharides from the "chiral pool" [4], such as D-glucose. 

We will describe here the first method as developed by Nicolaou [2] which has recently been applied to the synthesis and stereochemical assignment of the C(l)-C(10) fragment of nystatin Aj (2) [5]. 

Macrolactonization of CD-hydroxyl-acid using 2,2 -dipyridyl disulfide. Also known as Corey-Nicolaou double activation method. 

Nicolaou reported a novel method for the synthesis of polycychc compounds in which the six-membered ring of polycyclic compound 32 was constructed by RCM [Eq. (6.23)1 25... 

Another example in which literature results were reanalyzed in view of the PSSC concept concerns the development of ligands for the farnesoid X receptor. The farnesoid X receptor is a transcriptional sensor for bile acids, the primary products of cholesterol metabolism, and plays an important role in lipid homeostasis. The farnesoid X receptor was, until recently, an orphan receptor, which means that no specific ligands existed for this receptor. Selective ligands for this receptor have been found in natural product libraries described by Nicolaou et al. The group of Nicolaou developed solid phase synthesis methods to make combinatorial libraries based on a benzopyran core structure. " A 10,000-membered combinatorial library based on the benzopyran core structure was synthesized and screened for activity on the farnesoid X receptor. The first specific ligands for the... 

It is interesting to note that the oxa-analogous Michael addition was reported for the first time in 1878 by Loydl et al. [19] in their work on the synthesis of artificial malic acid, which was five years ahead of the discovery of the actual Michael reaction described first by Komnenos [20], Claisen [21], and later Michael in 1887 [22] as one of the most important methods for C—C bond formation. In continuation of the early work on the oxa-Michael addition [23], the inter- and intramolecular additions of alkoxides to enantiopure Michael acceptors has been investigated, leading to the diastereo- and enantioselective synthesis of the corresponding Michael adducts [24]. The intramolecular reaction has often been used as a key step in natural product synthesis, for example as by Nicolaou et al. in the synthesis of Brevetoxin B in 1989 [25]. The addition of oxygen nucleophiles to nitro-alkenes was described by Barrett et al. [26], Kamimura et al. [27], and Brade and Vasella [28]. 

The usefulness of this method is further exemplified by the synthesis of the products shown is figure 7.2 that were reported by Nicolaou et al. ... 

Nicolaou, C. A., Brown, N., Pattichis, C. S. (2007) Molecular optimization using computational multi-objective methods. Curr Opin Drug Discov Dev 10, 316-324. 

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