An Efficient and General Route to Reduced Polypropionates Via Zr-Catalyzed Asymmetric COC Bond Formation

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 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 (Et3Al) or n tripropylaluminum ( 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 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 polypropionates. 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 absent though there do not appear to be any that do: (i) high efficiency in methylalumination (27). in terms of the number of steps and overall yield, (ii) high It has recently been shown that the addition of water (28), selectivity, especially in terms of absolute and relative stereo- methylaluminoxane (MAO) (28), or isobutylaluminoxane chemistry, (iii) general applicability and synthetic flexibility, (iv) (IBAO) (29) can significantly accelerate the Zr-catalyzed asym- overall high economy involving those processes that are catalytic, metric carboalumination, especially in the otherwise sluggish especially in chiral auxiliaries, and (v) high levels of safety, reactions of styrene and proximally heterosubstituted alkenes. especially against chemical toxicity and explosiveness. Although the enantioselectivity figures appear to be basically We describe below the results obtained in attempts directed unaffected, their rate-acceleration effect, which permits the use toward the development of an ultimately satisfactory method (as of lower reaction temperatures, has led to moderate increases in defined above) for the synthesis of reduced polypropionates enantioselectivity. With more reactive alkenes, however, their through the use of Zr-catalyzed asymmetric carboalumination of dimerization and oligomerization have been potentially trouble- alkenes that we reported in 1995–1996 (22, 23). some side reactions to be suppressed (29). A later report (30) on Design of Protocols a closely related reaction with ‘‘cationic’’ chiral zirconocene derivatives should be noted. Clearly, from the results presented Profile of Zr-Catalyzed Asymmetric Carboalumination. Because it is above, the Zr-catalyzed carbometallation is multimechanistic germane to later discussions, a brief summary of the relatively (23, 31–36) and sensitive to several critical factors including unfamiliar Zr-catalyzed asymmetric carboalumination of alk- ligands (22), solvents (23), and metal countercations of alkyl- enes is presented. Since the discovery of Zr-catalyzed car- metals. With respect to metal countercations, the following boalumination of alkynes in 1978 (24), attempts have been generalizations may be presented as useful guidelines (36). made to realize a related carboalumination of alkenes with trimethylaluminum and dichlorobis(cyclopentadienyl)- zirconium, but they led to disappointingly low (Ͻ5–10%) yields of the desired products. A recent investigation (22) has indicated that the desired reaction did take place in good yields but that the products were competitively consumed through ␤-dehydrometallation to give monomeric and dimeric 1,1- dialkyl-1-alkenes. However, the use of bulky chiral zirconocene derivatives, especially dichlorobis(1-neomenthylindenyl)- zirconium, (NMI)2ZrCl2 (25), led to the discovery of the desired methylalumination in good yields and 70–80% enantiomeric excess (ee) (ref. 22; Scheme 1). Because bis(indenyl)- zirconocene dichloride, (Ind)2ZrCl2, is similarly satisfactory in inducing the Zr-catalyzed racemic methylalumination of Scheme 2.

Negishi et al. PNAS ͉ April 20, 2004 ͉ vol. 101 ͉ no. 16 ͉ 5783 Downloaded by guest on September 25, 2021 Table 1. Statistical asymmetric ampliﬁcation ee in step ee in step Max. yield of major or species I or species II stereoisomer Overall ee

70 70 74.5 94.0 80 80 82.0 97.6 90 80 86.0 98.8 90 90 90.5 99.4 99 99 99.0 99.995

Values shown are percentages. Max., maximum.

critical methyl group is derived from the terminal methylene Scheme 3. group. None of the three processes in Scheme 3, however, displays ees of Ն98–99%. Thus, the preparation of monomethyl-branched (i) Alkylmagnesium derivatives readily dialkylate dihalozirco- nium derivatives, leading to the formation of zirconacyclo- alkanols as the final products by these processes will require propanes (or alkenezirconocenes) that can undergo cyclic separation of undesirable enantiomers by optical resolution and carbozirconation (32). It should be noted here that others other methods (27, 29). On the other hand, the synthesis of (37–40) have developed mutually related Zr-catalyzed reduced polypropionates, in which there are two or more branch- asymmetric COC bond-forming reactions that are thought ing methyl groups at asymmetric carbon centers, is significantly to involve cyclic carbozirconation (32). However, respect- facilitated by what might be conveniently termed ‘‘statistical able ees of Ն90% have been reported only with allylically enantiomeric amplification’’ by virtue of the presence of not one heterosubstituted alkenes (37–40). Methylmagnesium de- but two or more chiral centers. In the absence of ‘‘internal rivatives lacking a ␤-H atom apparently fail to undergo the asymmetric induction’’ caused by the preexistence of chiral reaction, and alkyl groups higher than ethyl generally lead centers in the substrates, the stereochemical outcome of com- to significantly lower product yields and various unwanted bining two chiral species and͞or asymmetric reactions may be side reactions, such as alkyl isomerization (37, 38). Thus, predicted by resorting to the mass action law, as indicated for these reactions are fundamentally discrete from the Zr- some representative cases in Table 1. For example, a process III catalyzed asymmetric carboalumination discussed here. of 90% ee followed by a process I of 80% ee would produce the (ii) The corresponding reactions of alkyllithiums proceed sim- desired product of Ϸ99% ee in a maximum 86% yield. ilarly under the stoichiometric conditions, but it has been difficult to induce their reactions, which are catalytic in Zr. Experimental Procedures Alkyllithiums have been shown to readily trialkylate zir- Supporting Information. Details of the experimental procedures conocene derivatives (41). Supporting Text (iii) Apparently, metals that are significantly less electropositive can be found in , which is published as supporting than Al, such as B, Si, and Sn, do not readily alkylate information on the PNAS web site. zirconocene derivatives, and Zr-catalyzed carbometallation reactions do not seem to have been observed. Zr-Catalyzed Enantioselective Carboalumination of 3-Buten-1-ol: (3S)- (iv) Some other metals of intermediate electronegativity seem 3-methyl-1-hexanol (45). To 1.50 g (20 mmol, 96%) of 3-buten-1-ol n capable of undergoing Zr-catalyzed carbometallation, and in 20 ml of CH2Cl2 was added 9.5 ml (50 mmol) of Pr3Al at 0°C, Zn has indeed been shown to participate in the reaction (42, and the resultant mixture was warmed to 23°C. After 2 h, this ϩ 43). At present, however, only a cyclic version of Zr- mixture was added to 0.667 g (1 mmol) of ( )-(NMI)2ZrCl2 in catalyzed ethylzincation of alkenes, similar to the Dzhemi- 20 ml of CH2Cl2 at 0°C, followed by the dropwise addition of 20 lev ethylmagnesation (44), is known (43). mlofa1Msolution of IBAO in CH2Cl2. The resultant mixture was stirred for1hat0°C and then for 12 h at 23°C. The reaction Practical and Realistic Protocols for the Synthesis of Reduced Polypro- mixture was cooled to 0°C, treated with 3 M HCl, extracted with pionates. Although attempts to develop chiral ligands that are ether, washed with NaHCO3 and brine, and dried over MgSO4. superior to NMI are being made, we have also sought some After evaporation of the volatiles, the residue was purified by practical and realistic protocols for the synthesis of reduced flash chromatography (silica gel, CH Cl ) to give 2.04 g (88%) polypropionates through the use of Zr-catalyzed carboalumina- 2 2 of the title compound as a colorless oil: purity by 13C NMR, tion in its current stage of development. The goal of this Ն ␣ D ϭϪ 1 99%; [ ] 23 0.5° (c 0.67, CHCl3); H NMR (300 MHz, investigation is to develop one or more protocols that can ␦ potentially fulfill the five goals listed earlier. One specific point CDCl3), 0.8–1.0 (m, 6 H), 1.1–1.5 (m, 5 H), 1.55–1.7 (m, 2 H), 13 ␦ of special attention is to avoid undesirable enantiomeric sepa- 2.53 (s, 1 H), 3.5–3.7 (m, 2 H); C NMR (75 MHz, CDCl3) ration for high efficiency in preparing reduced polypropionates 14.19, 19.46, 19.92, 29.16, 39.36, 39.79, 60.84; IR (neat) 3,339, Ϫ1 of Ն98–99% ee. There are basically three Zr-catalyzed carboalu- 2,925, 1,456, 1,056 cm . mination processes that can be used for the synthesis of methyl- branched 1-alkanols (Scheme 3). In process I, the critical methyl Determination of ee (46). (3S)-3-methyl-1-hexanol was converted group at an asymmetric carbon center is supplied by Me3Al. The to the corresponding carboxylic acid by Jones oxidation and then reaction generally proceeds in high yields but only in 70–80% ee to the amide by treating the acid with (S)-1-(1-naphthyl)ethyl- (22). Process II involves the Zr-catalyzed alkylalumination of amine. HPLC analysis of the amide [CHIRALCEL OD-H propene, and the critical methyl group is supplied by propene. (DAICEL, Tokyo), 4.6 mm ϫ 250 mm, 95:5 hexane͞isopropyl ͞ This reaction has so far exhibited ees of 70–80% and is under alcohol, 1 ml min] showed two peaks [retention time (tr) 50.1 further investigation. On the other hand, process III has led to and 79.6 min, 95:5 ratio] assignable to the S,S and R,S diaste- good yields and an ee range of 90–95%. In this reaction, the reomers, respectively, 90% ee.

5784 ͉ www.pnas.org͞cgi͞doi͞10.1073͞pnas.0307514101 Negishi et al. Downloaded by guest on September 25, 2021 SPECIAL FEATURE

Scheme 4.

Zr-Catalyzed Enantioselective Carboalumination of 4-Methyl-1- Alkenes: (2S,4S)-2,4-dimethyl-1-heptanol (7). To 0.42 g (0.6 mmol) of ϩ ( )-(NMI)2ZrCl2 in 20 ml of CH2Cl2 was added consecutively 1.8 ml (19 mmol) of Me3Al and 2.4 ml of a 10 wt% solution of MAO in toluene. After 5 min, 1.55 g (12 mmol; purity by GC was 91%) of (4S)-4-methyl-1-heptene in 10 ml of CH2Cl2 was added at 0°C. The reaction mixture was stirred for 24 h at 23°C, treated with a vigorous stream of oxygen bubbled through it for1hat 0°C, then stirred for 5 h under oxygen atmosphere at 23°C. The CHEMISTRY resultant mixture was diluted with CH2Cl2, washed with 2 M Scheme 5. aqueous NaOH and brine, and dried over MgSO4. After evaporation of the solvents in vacuo, the residue was purified by column chromatography (silica gel, CH2Cl2) to give 1.5 g (86%) of the crude product as a colorless oil [diastereomeric ratio (dr) as a relatively inexpensive material (20 g for $39.10 from TCI by 13C NMR, 6.7:1]. The product was further purified by column America, Portland, OR), it will be used as one of the mono- ͞ methyl-branched ␻-ethyl starting compounds. To develop a chromatography (silica gel, eluted with 50:1 hexane ethyl ace- ␻ ␻ n tate) to give 1.2 g (68%) of the title compound: dr by 13C NMR, generally applicable method for the synthesis of -ethyl or - Pr Ͼ40:1; enantiomeric purity at C2 by Mosher ester analysis (for methyl-branched reduced polypropionates, however, it is desir- Ͼ Ͼ ␣ D ϭϪ able to develop one or more efficient and selective synthetic a fraction with dr of 100:1), 99%; [ ] 23 13.5° (c 0.8, 1 ␦ routes to other suitable monomethyl-substituted 1-alkanols or CHCl3); H NMR (300 MHz, CDCl3) 0.85–1.0 (m, 9 H), 1.0–1.6 (m, 6 H), 1.7–1.8 (m, 2 H), 1.95 (s, 1 H), 3.3–3.6 (m, 2 H); 13C their synthetic equivalents. To this end, (R)-3-methyl-1-pentanol ␦ (compound 5 in Scheme 4) and (R)- and (S)-3-methyl-1-hexanols NMR (75 MHz, CDCl3) 14.34, 17.25, 19.89, 20.28, 29.74, 33.07, 38.93, 41.03, and 68.33; IR (neat) 3,332, 2,962, and 1,037 cmϪ1; (compound 6 in Scheme 4) were chosen as potentially attractive ϩ ϩ monomethyl-branched intermediates. We initially envisioned high-resolution MS calculated for C9H20O[M H] , 145.1583; found, 145.1581. their synthesis by means of a recently reported procedure (29) t using TBS-protected 3-buten-1-ol, where TBS is BuMe2Si. With Conversion of 4,6-Dimethyl-1-Alkenes into 2,4,6-Trimethyl-1-Alkanols: the hope of eliminating two steps needed for protection and (2R,4R,6R)-2,4,6-trimethyl-1-nonanol (19). The title compound was deprotection of alcohols, however, we directly subjected unpro- synthesized from (4R,6R)-2,4-dimethyl-1-nonene (1.07 g, 7.0 tected 3-buten-1-ol to the Zr-catalyzed alkylalumination with 2.5 n mmol) according to the procedure described in the preceding equivalents of Et3Al or Pr3Al in the presence of 5 mol% of Ϫ experiment, with ( )-(NMI)2ZrCl2 (0.20 g, 0.3 mmol). After (NMI)2ZrCl2 and 1 equivalent of IBAO in CH2Cl2 at 23°C. concentration, 1.07 g (82%) of the crude product obtained (dr Under these conditions, the reactions were essentially complete by 13C NMR, 8:1) was further purified by column chromatog- within 12 h. As shown in Scheme 4, the desired compounds (5 raphy (silica gel, eluted with 50:1 hexane͞ethyl acetate) to give and 6) were obtained in 88–92% yields in 90–91% ee. 0.85 g (67%) of the title compound: dr by 13C NMR, Ն50:1; [␣] Even at this enantioselectivity level, the results shown in 23 ϭϪ 1 ␦ D 3.4° (c 0.8, CHCl3); H NMR (300 MHz, CDCl3) Scheme 4 may well represent the currently most efficient and 0.8–1.1 (m, 15 H), 1.1–1.4 (m, 5 H), 1.4–1.8 (m, 4 H), 3.3–3.6 (m, potentially satisfactory method for the preparation of com- 13 ␦ 2 H); C NMR (75 MHz, CDCl3) 14.39, 17.51, 19.90, 20.40, pounds 5 and 6 as intermediates for the preparation of reduced 20.87, 27.47, 29.70, 33.04, 38.78, 41.25, 45.14, and 68.19; IR polypropionates. Although examination by 1H NMR spectros- (neat) 3,339 cmϪ1. copy of the Mosher esters (47) of 2-methyl-1-alkanols has been generally satisfactory, it was not reliable for determining the Results and Discussion enantiomeric purity of 3-methyl-1-alkanols, such as compounds Asymmetric Synthesis of 3-Methyl-1-Pentanol and 3-Methyl-1-Hexanols. 5 and 6. Therefore, they were converted to the corresponding Synthesis of many natural products containing reduced polypro- carboxylic acids and then to carboxamides by amidation with pionate fragments, such as compounds 2 and 3 (Fig. 1), can be 1-(1-naphthyl)ethylamine, and analyzed by HPLC (46). achieved through asymmetric synthesis of terminally monoheterofunctional, reduced polypropionates containing either an Synthesis of 2,4-Dimethyl-1-Hexanols and 2,4-Dimethyl-1-Heptanols. ␻-ethyl or an ␻-nPr group. Because (S)-2-methyl-1-butanol Because most, if not all, of the possible stereoisomers of reduced (compound 4 in Scheme 4) of Ͼ98% ee is commercially available polypropionate fragments are present in various natural prod-

Negishi et al. PNAS ͉ April 20, 2004 ͉ vol. 101 ͉ no. 16 ͉ 5785 Downloaded by guest on September 25, 2021 Scheme 6.

ucts, any general methods for their synthesis must be capable of producing all possible stereoisomers with comparable ease and without extensive procedural modifications. To this end, two synthetic protocols for the conversion of monomethyl- substituted 1-alkanols into 2,4-dimethyl-1-alkanols have been devised. One (shown in Scheme 5) is a three-step process involving (i) oxidation of alcohols to aldehydes, (ii) olefination Scheme 7. by Wittig or other related reactions, and (iii) Zr-catalyzed methylalumination for converting 3-methyl-1-alkanols (compounds 5 and 6) into 2,4-dimethyl-1-alkanols (compounds 7 and 1.10:1.0 ratios with a slight preference for the formation of 8 in Scheme 5). Because the aldehydes generated via oxidation (2S,4S)-7. In any event, (2S,4S)-7 and (2R,4S)-7 obtained via are subjected to Wittig olefination without isolation, it is, in fact, asymmetric methylalumination are estimated to be in Ն99.8% a two-isolation-step protocol. It should be clearly noted here that and Ն99.6% ee, respectively, on the basis of the observed purity process III in Scheme 3 used for the preparation of compounds of Ն98% ee for compound 4. The main task remaining was to 5 and 6 cannot be iterated for the synthesis of reduced polypro- purify the products through diastereomeric separation, and this pionates and that process III must therefore be followed by was achieved by single chromatographic operation (230–400 process I of 85–90% stereoselectivity. mesh silica gel, 1:50 EtOAc͞hexanes). In the case of (2S,4S)-7, The other protocol for chain elongation shown in Scheme 6 81% of the crude product was converted into the final product also involves a three-step process consisting of (i) iodination of of Ն50:1 dr. Purification of (2R,4S)-7, which eluted slower than alcohols, (ii) zincation followed by Pd-catalyzed vinylation (43, the other isomer, was somewhat less efficient, leading to 62% 48, 49), and (iii) Zr-catalyzed asymmetric methylalumination recovery of the final product of Ն40:1 dr. followed by oxidation with O2 (22). This protocol is iterative, and Stereoisomers of 2,4-dimethyl-1-hexanols (compound 7) have it should be applicable to the synthesis of reduced polypropi- been used for the syntheses of some natural products, such as onates containing any number of branching methyl groups. zaragozic acid A (compound 2) (2) and sambutoxin (15). In one Specifically, (S)-2-methyl-1-butanol (compound 4) was iodin- synthesis of compound 2,(2S,4S)-7 was prepared from com- Ϸ ated in 91% yield with I2 and PPh3 in the presence of imidazole. pound 4 in 40% yield in six to seven steps via stoichiometric t ␣ Successive treatment of the iodide with BuLi (2.1 eq), dry ZnBr2 -methylation of a chiral amide (2). Thus, even at the current (0.6 molar eq), and vinyl bromide (2 eq) in the presence of 5 stage of development, the three-step synthesis of (2S,4S)-7 via mol% of Pd(PPh3)4 produced (S)-4-methyl-1-hexene in 75% Zr-catalyzed asymmetric methylalumination offers a higher level yield. Full retention of the S configuration (Ն99%) was con- of efficiency and catalysis in chiral auxiliary as advantageous firmed by HPLC analysis of the carboxamide obtained via features. Further improvements of product yields (unoptimized), oxidation and amidation, as described earlier (46). The reaction stereoselectivity, and overall economy are desirable, and they Ͼ of isomerically pure (S)-4-methyl-1-hexene with Me3Al (1.5 appear to be eminently feasible. Similarly, (2S,4R)-7 of 40:1 dr molar eq), MAO (30 mol% based on Al), and 5 mol% of prepared in 40% overall yield in four (three isolation) steps (NMI)2ZrCl2 gave, after oxidation with O2, the expected 2,4- (Scheme 5) may be compared with its multistep synthesis used dimethyl-1-hexanols. The two reactions run with (ϩ)- and for the synthesis of (ϩ)-sambutoxin, which appears to involve Ϫ ( )-(NMI)2ZrCl2 as catalysts gave (2S,4S)-7 and (2R,4S)-7, nine steps from methyl 3-hydroxy-2-methylpropionate (15). respectively, in 78–79% yields. The drs determined by 13C NMR spectroscopy were 9:1 (or 90:10) and 6:1 (86:14), respectively, Synthesis of 2,4,6-Trimethyl-1-Octanols and 2,4,6-Trimethyl-1-Nonanols. and these figures agreed very well with those obtained by Mosher The iterative three-step protocol established in the previous ester analysis of (2S,4S)-7 and (2R,4S)-7, respectively. The section has proved to be readily applicable to the conversion of results suggested that the formation of (2S,4S)-7 is mildly 2,4-dimethyl-1-alkanols to 2,4,6-trimethyl-1-alkanols, as indi- favored by the preexisting 4-methyl group, whereas that of cated by the synthesis of three all-syn isomers of compounds 9 (2R,4S)-7 is either essentially unaffected or slightly disfavored. and 10, summarized in Scheme 7. For these presumably favor- To probe the extent of internal asymmetric induction, (S)-4- able cases, drs of 8:1 to 8.5:1, corresponding to 89–89.5% methyl-1-hexene was methylaluminated by using 5 mol% of stereoselectivity at C2, have been consistently observed. As (Ind)2ZrCl2 or (2-MeInd)2ZrCl2, where Ind is indenyl and discussed earlier, the overall enantiomeric excess for these 2-MeInd is 2-methylindenyl. These reactions produced nearly trimethyl derivatives may safely be estimated to be racemic mixtures of (2S,4S)-7 and (2R,4S)-7 in 1.03:1.0 to Ϸ99.8–99.9%.

5786 ͉ www.pnas.org͞cgi͞doi͞10.1073͞pnas.0307514101 Negishi et al. Downloaded by guest on September 25, 2021 To demonstrate the potential applicability of (2S,4S,6S)-2,4,6- After simple chromatographic purification, syn-2,4-dimethyl- 9 Ն trimethyl-1-octanol (compound ) to the synthesis of antibiotics 1-alkanols of 40:1 dr were obtained in 78–79% recovery. SPECIAL FEATURE TMC-151 A-F (compound 3) (3), it was converted in 62% yield The combined yield of the purified products over four (three in two steps to compound 11 (shown in Scheme 7), which isolation) steps was Ϸ50%. The corresponding combined corresponds to the C11–C20 fragment of compound 3 without yield for (2S,4R)-2,4-dimethyl-1-hexanol was 40%. the sugar moiety. 3. An alternative protocol employs commercially available (S)- 2-methyl-1-butanol of Ͼ98% ee. Its two-step conversion via Conclusion iodination and Pd-catalyzed vinylation to (S)-4-methyl-1- An efficient and general method for the synthesis of reduced hexene in 69% combined yields was followed by Zr-catalyzed polypropionates has been developed through the application of methylalumination–oxidation to produce 2,4-dimethyl-1- asymmetric carboalumination of alkenes catalyzed by hexanols in 78–79% yields (Scheme 6). (NMI)2ZrCl2. Some critical components of the development are 4. This three-step protocol is iterative and is applicable, in as follows. principle, to the synthesis of higher reduced polypropionates via Zr-catalyzed asymmetric methylalumination, as exempli- 1. The reaction of 3-buten-1-ol with Et Al or nPr Al in the 3 3 fied by the synthesis of all-syn-2,4,6-trimethyl-1-nonanols presence of 5 mol% of (NMI) ZrCl and IBAO (1 eq) gave, 2 2 summarized in Scheme 7. (2S,4S,6S)-2,4,6-trimethyl-1- after protonolysis, (R)-3-methyl-1-pentanol as well as (R)- nonanol was further converted in two steps in 62% combined and (S)-3-methyl-1-dimethyl-1-hexanols in 88–92% yield in yield to compound 11, which corresponds to the C11–C20 90–92% ee in one step (Scheme 4). fragment of TMC-151 A–F (compound 3) (3). 2. Without purification, these alcohols were oxidized and ole- ϭ finated with Ph3P CH2 in 81–86% overall yields to give the We thank Drs. D. Y. Kondakov, S. Huo, and J. Shi for their contri- corresponding 4-methyl-1-alkenes. Their reactions with butions. Boulder Scientific Co. generously provided Zr compounds. Me3Al in the presence of 5 mol% of (NMI)2ZrCl2 and 30 This work was supported by National Institutes of Health Grant GM mol% of MAO, followed by oxidation with O2, produced the 36792 (to E.-i.N.), National Science Foundation Grant CHE-0309613 corresponding 2,4-dimethyl-1-heptanols in 84–89% yield. (to E.-i.N.), and Purdue University.

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