An efficient and general route to reduced polypropionates via Zr-catalyzed asymmetric C—C bond formation

Abstract

An efficient and general method for the synthesis of reduced polypropionates has been developed through the application of asymmetric carboalumination of alkenes catalyzed by dichlorobis(1-neomenthylindenyl)zirconium [(NMI) 2ZrCl2]. In this investigation, attention has been focused on those reduced polypropionates that are ␣-monoheterofunctional and either -ethyl or -n-propyl. The reaction of 3-buten-1-ol with triethylaluminum (Et 3 Al) or tripropylaluminum ( n Pr3Al) in the presence of (NMI)2ZrCl2 and isobutylaluminoxane gave, after protonolysis, (R)-3-methyl-1-pentanol as well as (R)-and (S)-3-methyl-1-hexanols in 88 -92% yield in 90 -92% enantiomeric excess in one step. These 3-monomethyl-1-alkanols were then converted to two stereoisomers each of 2,4-dimethyl-1-hexanols and 2,4-dimethyl-1-heptanols via methylalumination catalyzed by (NMI) 2ZrCl2 and methylaluminoxane followed by oxidation with O 2. The four-step (or three-isolation-step) protocol provided syn-2,4-dimethyl-1-alkanols of >98% stereoisomeric purity in Ϸ50% overall yields, whereas (2S,4R)-2,4-dimethyl-1-hexanol of comparable purity was obtained in 40% overall yield. Commercial availability of (S)-2-methyl-1-butanol as a relatively inexpensive material suggested its use in the synthesis of (2S,4S)-and (2R,4S)-2,4-dimethyl-1-hexanols via a three-step protocol consisting of (i) iodination, (ii) zincation followed by Pd-catalyzed vinylation, and (iii) Zr-catalyzed methylalumination followed by oxidation with O 2. This three-step protocol is iterative and applicable to the synthesis of reduced polypropionates containing three or more branching methyl groups, rendering this method for the synthesis of reduced polypropionates generally applicable. Its synthetic utility has been demonstrated by preparing the side chain of zaragozic acid A and the C11-C20 fragment of antibiotics TMC-151 A-F. O ligo-and poly(alkene)s with methyl groups bonded to alternating carbon atoms in the main chain (compound 1 in Fig. 1) are important structural units in both polymer materials chemistry (1) and natural products chemistry. The latter includes those reduced polypropionates that contain (i) two methylbranched asymmetric carbon centers, such as zaragozic acid A (compound 2 in Fig. 1) (2), and (ii) three methyl-branched asymmetric carbon centers, such as antibiotics TMC-151 A-F (compound 3 in Fig. 1) (3). The degree of polymerization of poly(propylene) usually exceeds 10 3 . As a consequence, most of the methyl-branched carbon centers may be considered to be ''virtually achiral,'' rendering their absolute configuration practically insignificant. On the other hand, their relative stereochemistry, termed tacticity, is of crucial importance in various respects. In the cases of reduced polypropionates, where the degree of polymerization is mostly Ͻ10, typically 2-4, both absolute and relative configurations of compound 1 (Fig. 1) are critically important. It is therefore essential to construct each methyl-bearing asymmetric carbon center with the correct absolute configurati...

Expanding metabolism for biosynthesis of nonnatural alcohols

“…4B). These enantiomerically pure alcohols may be useful chiral synthons for chemical synthesis (25).…”

Discovery of ZACA reaction − Zr-catalyzed asymmetric carboalumination of alkenes

“…(2) There are a few or possibly more alternate and mutually complementary procedures to choose from, allowing highly flexible designs for the syntheses of chiral organic compounds 33,35 (Scheme 7).…”

“…34,35 The only remaining task for preparing ultra-pure deoxypolypropionates is ordinary and very facile chromatographic purification of newly formed 2,4-dimethyl-1-hydroxybutyl moiety one at a time. [34][35][36]38,39 We believe that the ZACA reaction is a widely applicable, high-yielding, efficient and selective method for asymmetric C-C bond formation that is potentially economical. As of today, however, it has not yet been widely embraced by the organic synthetic community, although its application to natural products synthesis by other workers is known.…”

Die magische Kraft der Übergangsmetalle: Vergangenheit, Gegenwart und Zukunft (Nobel‐Aufsatz)

“…[98,100] 3) In Fällen, in denen die ZACA-Produkte als 2-chirale verzweigte 1-Alkohole durch einfache Oxidation von Alanen, normalerweise mit O 2 , erhalten werden, bietet die Lipasekatalysierte Acetylierung mit anschließender einfacher Säu-lenchromatographie eine allgemein anwendbare und bequeme Reinigungsmethode, wobei der in der ZACA-Reaktion gebildete ausreichend hohe Enantiomerenüberschuss (70-95 %) der Rohprodukte genutzt wird. [106] [99,111] Seitenkette [99] und Totalsynthese [111] 5…”

“…TMC-151A-F, Fragment C11-C20 (2004) [100] Fragment C11-C20 [101] Fragment C9-C18 10 6,7-Dehydrostipiamid (2004) [102] Totalsynthese 11 Ionomycin, Fragment C1-C10 (2005) [103] Fragment C1-C10…”