1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) is an effective nucleophilic catalyst for carboxylic acid esterification with dimethyl carbonate (DMC). The reaction pathway of this new class of nucleophilic catalysis has been studied. A plausible, multistep mechanism is proposed, which involves an initial N-acylation of DBU with DMC to form a carbamate intermediate. Subsequent O-alkylation of the carboxylate with this intermediate generates the corresponding methyl ester in excellent yield. In the absence of DBU or in the presence of other bases, such as ammonium hydroxide or N-methylmorpholine, the same reaction affords no desired product. This method is particularly valuable for the synthesis of methyl esters that contain acid-sensitive functionality.
1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) is a novel and active catalyst in promoting the methylation reaction of phenols, indoles, and benzimidazoles with dimethyl carbonate under mild conditions. Additional rate enhancement is accomplished by applying microwave irradiation. By incorporating tetrabutylammonium iodide, the same microwave reactions can be further accelerated. By combining these acceleration strategies, very slow chemical transformations that take up to several days can be performed efficiently in high yield within minutes. [reaction: see text]
DABCO is an extremely active catalyst for the methylation of indoles in conjunction with dimethyl carbonate (DMC). This green chemistry is highly effective and produces N-methylindoles in nearly quantitative yields. The reaction sequence consists of competing alkylation and acylation pathways and involves 1,4-diazabicyclo[2.2.2]octane (DABCO) dually as a nucleophilic catalyst, ultimately resulting in a single product: the N-methylated indole.
Coupling of C9
-
14 (4) and C15
-
21 (5a) fragments to produce the
cis-trisubstituted olefin was achieved using Suzuki-type coupling
conditions employed by Marshall (5a/tert-BuLi/B-OMe-9-BBN
added to 4/Cs2CO3/Pd(dppf)2). The terminal (Z)-diene moiety
was attached to aldehyde 10 by using a sequential Nozaki−Hiyama allylation and Peterson olefination sequence; careful
monitoring of the disappearance of both diastereomeric β-hydroxysilanes was found to be essential for achieving a high yield.
In the oxidation of alcohols 12 and 16 to 13 and 7, respectively,
using iodobenzene diacetate and TEMPO, addition of a trace
of water was found to be crucial for complete conversion. The
C8
-
9 (Z)-olefin functionality was introduced on to aldehyde 13
using a Still−Gennari HWE reaction. Subsequent carbamate
installation at C-19 followed by a reduction/oxidation sequence
gave the title fragment C7
-
24 (7) ready to be coupled with the
C1
-
6 fragment, which is described in Part 2 of this series.
The synthetic strategy for producing multigram quantities of
(+)-discodermolide (1) using a hybridized Novartis−Smith−Paterson synthetic route via common precursor 3 is described.
In the first part of this five-part series, we present a multikilogram preparation of α-methyl aldehyde 10 from Roche ester,
its syn-aldol reaction with Evans boron enolate, removal of the
chiral auxiliary, and the preparation of Weinreb amide 3 (Smith
common precursor). The common precursor was produced
without any chromatography.
The matrix metalloproteinase enzyme MMP-13 plays a key role in the degradation of type II collagen in cartilage and bone in osteoarthritis (OA). An effective MMP-13 inhibitor would therefore be a novel disease modifying therapy for the treatment of arthritis. Our efforts have resulted in the discovery of a series of carboxylic acid inhibitors of MMP-13 that do not significantly inhibit the related MMP-1 (collagenase-1) or tumor necrosis factor-alpha (TNF-alpha) converting enzyme (TACE). It has previously been suggested (but not proven) that inhibition of the latter two enzymes could lead to side effects. A promising carboxylic acid lead 9 was identified and a convergent synthesis developed. This paper describes the optimization of 9 and the identification of a compound 24f for further development. Compound 24f is a subnanomolar inhibitor of MMP-13 (IC(50) value 0.5 nM and K(i) of 0.19 nM) having no activity against MMP-1 or TACE (IC(50) of >10000 nM). Furthermore, in a rat model of MMP-13-induced cartilage degradation, 24f significantly reduced proteoglycan release following oral dosing at 30 mg/kg (75% inhibition, p < 0.05) and at 10 mg/kg (40% inhibition, p < 0.05).
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