An efficient and general route to reduced polypropionates via Zr-catalyzed asymmetric COC bond formation Ei-ichi Negishi*, Ze Tan, Bo Liang, and Tibor Novak H. C. Brown Laboratories of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, IN 47907-2084 Edited by Barry M. Trost, Stanford University, Stanford, CA, and approved February 6, 2004 (received for review November 13, 2003) An efficient and general method for the synthesis of reduced polypropionates has been developed through the application of asymmetric carboalumination of alkenes catalyzed by dichloro- bis(1-neomenthylindenyl)zirconium [(NMI)2ZrCl2]. In this investiga- tion, 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 (Et3Al) or n tripropylaluminum ( Pr3Al) in the presence of (NMI)2ZrCl2 and isobutylaluminoxane gave, after protonolysis, (R)-3-methyl-1-pen- tanol 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 methyl- alumination catalyzed by (NMI)2ZrCl2 and methylaluminoxane fol- lowed by oxidation with O2. The four-step (or three-isolation-step) Fig. 1. Structures of poly(propylene) and some naturally occurring reduced protocol provided syn-2,4-dimethyl-1-alkanols of >98% stereoiso- polypropionates are shown. meric 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 just one well defined degree of polymerization. These differ- inexpensive material suggested its use in the synthesis of (2S,4S)- ences alone make it impractical to apply the Ziegler–Natta and (2R,4S)-2,4-dimethyl-1-hexanols via a three-step protocol con- polymerization (1) and Kaminsky modification (4) with zircono- sisting of (i) iodination, (ii) zincation followed by Pd-catalyzed cene catalysts to the synthesis of reduced polypropionates, vinylation, and (iii) Zr-catalyzed methylalumination followed by despite the fact that these polymerization reactions permit (i) oxidation with O2. This three-step protocol is iterative and appli- one-pot construction of poly(propylene) (compound 1 in Fig. 1), cable to the synthesis of reduced polypropionates containing three (ii) high product yield, and (iii) catalysis. or more branching methyl groups, rendering this method for the Currently, satisfactory synthesis of reduced polypropionates synthesis of reduced polypropionates generally applicable. Its must be achieved stepwise. Furthermore, the 1,3-relationship synthetic utility has been demonstrated by preparing the side between any two adjacent methyl groups at asymmetric carbon chain of zaragozic acid A and the C11–C20 fragment of antibiotics centers is such that it has been difficult to construct them in a TMC-151 A–F. convergent manner. Indeed, most of the known and compara- tively satisfactory routes are linear, as briefly discussed below. The use of terminally differentiated 2,4-dimethyl-1,5-pentane ligo- and poly(alkene)s with methyl groups bonded to derivatives can, in principle, provide convergent routes to re- 1 Oalternating carbon atoms in the main chain (compound in duced polypropionates containing more than three or four Fig. 1) are important structural units in both polymer materials methyl-branched asymmetric carbon centers. One of the earliest chemistry (1) and natural products chemistry. The latter includes methods for the preparation of terminally differentiated 2,4- those reduced polypropionates that contain (i) two methyl- dimethyl-1,5-pentane derivatives involves enzyme-catalyzed de- branched asymmetric carbon centers, such as zaragozic acid A symmetrization of 2,4-dimethyl-1,5-pentanediols (5). At the (compound 2 in Fig. 1) (2), and (ii) three methyl-branched current level of development, however, the method suffers from asymmetric carbon centers, such as antibiotics TMC-151 A–F low overall yields and long procedures for the synthesis of (compound 3 in Fig. 1) (3). The degree of polymerization of ␣ ␻ 3 -activated and -protected 2,4-dimethyl-1,5-pentanediols, poly(propylene) usually exceeds 10 . As a consequence, most of which reportedly require six to eight steps and lead to 6–8% the methyl-branched carbon centers may be considered to be overall yields from diethyl ␣-methylmalonate and ethyl 2-bromo- ‘‘virtually achiral,’’ rendering their absolute configuration prac- 2-methylpropionate for preparing the syn-dimethyl isomers (6, tically insignificant. On the other hand, their relative stereo- 7). The preparation of the anti-dimethyl isomers is even less chemistry, termed tacticity, is of crucial importance in various satisfactory, proceeding in seven to eight steps and leading to respects. In the cases of reduced polypropionates, where the Ͻ2% overall yields (7). Another earlier asymmetric route to Ͻ degree of polymerization is mostly 10, typically 2–4, both reduced polypropionates involved diastereoselective conversion 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 ab- This paper was submitted directly (Track II) to the PNAS office. solute configuration. Yet another notable difference between Abbreviations: dr, diastereomeric ratio; ee, enantiomeric excess; IBAO, isobutylaluminox- poly(propylene) and reduced polypropionates is that, whereas ane; MAO, methylaluminoxane. the former is invariably a mixture of poly(propylene)s of differ- *To whom correspondence should be addressed. E-mail: [email protected]. ent degrees of polymerization, each reduced polypropionate has © 2004 by The National Academy of Sciences of the USA 5782–5787 ͉ PNAS ͉ April 20, 2004 ͉ vol. 101 ͉ no. 16 www.pnas.org͞cgi͞doi͞10.1073͞pnas.0307514101 Downloaded by guest on September 25, 2021 of chirons derived from natural sources (8). However, the ␣ methods most frequently used now involve either -alkylation of SPECIAL FEATURE chiral enolates (2, 9–12) and related nucleophiles (13) or con- jugate addition to chiral ␣,␤-unsaturated carboxamides (14, 15). Despite the fact that these methods require at least one, and often more than one, equivalent of chiral reagents, some of them, in particular the protocol of Myers et al.(11, 12), may be viewed as the current benchmarks. These methods typically require three steps involving (i) asymmetric ␣-alkylation, (ii) reduction of amides to alcohols, and (iii) iodination or similar activation toward enolates for iterative construction of reduced polypro- pionates. Less well developed are methods that involve asym- Scheme 1. metric COC bond formation in the presence of chiral catalysts. Over the last few years, however, at least two such methods have been reported. One that has been used for the synthesis of alkenes in good yields, the dramatic increase in product yield (Ϫ)-doliculide (16) makes use of Charette and Juteau’s asym- is due to the fused benzene ring, which appears to exert mostly metric cyclopropanation (17) and subsequent ring opening (18), steric retardation of undesirable ␤-dehydrometallation. but it requires a seven-step sequence for iteration. Another The subsequent discovery of Zr-catalyzed asymmetric ethyl- involves asymmetric dimerization of methylketene in the pres- alumination and higher alkylalumination also required another ence of 0.3 mol% of quinidine, permitting a four-step synthesis unexpected finding. A clean and high-yielding reaction of 1- of (S)-2-methylpentanol, which is then converted to (2S,4S,6S)- alkenes with triethylaluminum and (NMI)2ZrCl2 in hexanes was 2,4,6-trimethyl-1-nonanol in four additional steps, with a total shown to proceed by a cyclic process, producing, after oxidation, yield over eight steps of 10% (19, 20). Although catalytic 2-alkyl-1,4-butanediols in good yields but only in 33% ee (23). asymmetric COC bond formation is not involved, catalytic However, the course of the reaction was dramatically changed by hydrogenation of oxygenated alkene derivatives (9) is notewor- the use of CH2Cl2, ClCH2CH2Cl, or CH3CHCl2 in place of thy. Noyori and colleagues’ (21) catalytic hydrogenation of allylic hexanes to produce the desired isoalkyl alcohols in good yields alcohols has been applied to the synthesis of vitamin E, and its and in 90–95% ee (23) (Scheme 2). The results strongly suggest CHEMISTRY application to the asymmetric synthesis of reduced polypropi- that a total or nearly total mechanistic switch from cyclic to onates should be eminently feasible. It should be noted, however, acyclic must have taken place. The uniquely lower enantio- that catalytic asymmetric hydrogenation of alkenols often re- selectivity figures for the singularly important cases of methyl- quires stereodefined and isomerically pure alkenols, i.e., two alumination are frustrating and puzzling. The observed differ- stereoselective processes for the generation of each asymmetric ence in enantioselectivity may be rationalized in terms of an carbon center. auxiliary chirality induced through ␣-agostic interaction (26) As in any other case of asymmetric synthesis, ultimately under the influence of a chiral ligand, e.g., 1-neomenthyindenyl, desirable methods should provide the following features, al- in the cases of ethyl- and higher alkylalumination, which is