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 α-monoheterofunctional and either ω-ethyl or ω-n-propyl. The reaction of 3-buten-1-ol with triethylaluminum (Et₃Al) or tripropylaluminum (ⁿPr₃Al) 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) protocol provided syn-2,4-dimethyl-1-alkanols of ≥98% stereoisomeric purity in ≈50% 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 O₂. 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.

Oligo- 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 methyl-branched 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 10³. 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 <10, 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 configuration. Yet another notable difference between poly(propylene) and reduced polypropionates is that, whereas the former is invariably a mixture of poly(propylene)s of different degrees of polymerization, each reduced polypropionate has just one well defined degree of polymerization. These differences alone make it impractical to apply the Ziegler–Natta polymerization (1) and Kaminsky modification (4) with zirconocene catalysts to the synthesis of reduced polypropionates, despite the fact that these polymerization reactions permit (i) one-pot construction of poly(propylene) (compound 1 in Fig. 1), (ii) high product yield, and (iii) catalysis.

Fig. 1.

Structures of poly(propylene) and some naturally occurring reduced polypropionates are shown.

Currently, satisfactory synthesis of reduced polypropionates must be achieved stepwise. Furthermore, the 1,3-relationship between any two adjacent methyl groups at asymmetric carbon centers is such that it has been difficult to construct them in a convergent manner. Indeed, most of the known and comparatively satisfactory routes are linear, as briefly discussed below. The use of terminally differentiated 2,4-dimethyl-1,5-pentane derivatives can, in principle, provide convergent routes to reduced polypropionates containing more than three or four methyl-branched asymmetric carbon centers. One of the earliest methods for the preparation of terminally differentiated 2,4-dimethyl-1,5-pentane derivatives involves enzyme-catalyzed desymmetrization of 2,4-dimethyl-1,5-pentanediols (5). At the current level of development, however, the method suffers from low overall yields and long procedures for the synthesis of α-activated and ω-protected 2,4-dimethyl-1,5-pentanediols, which reportedly require six to eight steps and lead to 6–8% overall yields from diethyl α-methylmalonate and ethyl 2-bromo-2-methylpropionate for preparing the syn-dimethyl isomers (6, 7). The preparation of the anti-dimethyl isomers is even less satisfactory, proceeding in seven to eight steps and leading to <2% overall yields (7). Another earlier asymmetric route to reduced polypropionates involved diastereoselective conversion of chirons derived from natural sources (8). However, the methods most frequently used now involve either α-alkylation of chiral enolates (2, 9–12) and related nucleophiles (13) or conjugate addition to chiral α,β-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 α-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 asymmetric C—C 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 (–)-doliculide (16) makes use of Charette and Juteau's asymmetric cyclopropanation (17) and subsequent ring opening (18), but it requires a seven-step sequence for iteration. Another involves asymmetric dimerization of methylketene in the presence of 0.3 mol% of quinidine, permitting a four-step synthesis of (S)-2-methylpentanol, which is then converted to (2S,4S,6S)-2,4,6-trimethyl-1-nonanol in four additional steps, with a total yield over eight steps of 10% (19, 20). Although catalytic asymmetric C—C bond formation is not involved, catalytic hydrogenation of oxygenated alkene derivatives (9) is noteworthy. Noyori and colleagues' (21) catalytic hydrogenation of allylic alcohols has been applied to the synthesis of vitamin E, and its application to the asymmetric synthesis of reduced polypropionates should be eminently feasible. It should be noted, however, that catalytic asymmetric hydrogenation of alkenols often requires stereodefined and isomerically pure alkenols, i.e., two stereoselective processes for the generation of each asymmetric carbon center.

As in any other case of asymmetric synthesis, ultimately desirable methods should provide the following features, although there do not appear to be any that do: (i) high efficiency in terms of the number of steps and overall yield, (ii) high selectivity, especially in terms of absolute and relative stereochemistry, (iii) general applicability and synthetic flexibility, (iv) overall high economy involving those processes that are catalytic, especially in chiral auxiliaries, and (v) high levels of safety, especially against chemical toxicity and explosiveness.

We describe below the results obtained in attempts directed toward the development of an ultimately satisfactory method (as defined above) for the synthesis of reduced polypropionates through the use of Zr-catalyzed asymmetric carboalumination of alkenes that we reported in 1995–1996 (22, 23).

Design of Protocols

Profile of Zr-Catalyzed Asymmetric Carboalumination. Because it is germane to later discussions, a brief summary of the relatively unfamiliar Zr-catalyzed asymmetric carboalumination of alkenes is presented. Since the discovery of Zr-catalyzed carboalumination of alkynes in 1978 (24), attempts have been made to realize a related carboalumination of alkenes with trimethylaluminum and dichlorobis(cyclopentadienyl)-zirconium, but they led to disappointingly low (<5–10%) 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 β-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 alkenes in good yields, the dramatic increase in product yield is due to the fused benzene ring, which appears to exert mostly steric retardation of undesirable β-dehydrometallation.

Scheme 1.

The subsequent discovery of Zr-catalyzed asymmetric ethylalumination and higher alkylalumination also required another unexpected finding. A clean and high-yielding reaction of 1-alkenes with triethylaluminum and (NMI)₂ZrCl₂ in hexanes was shown to proceed by a cyclic process, producing, after oxidation, 2-alkyl-1,4-butanediols in good yields but only in 33% ee (23). However, the course of the reaction was dramatically changed by the use of CH₂Cl₂, ClCH₂CH₂Cl, or CH₃CHCl₂ in place of hexanes to produce the desired isoalkyl alcohols in good yields and in 90–95% ee (23) (Scheme 2). The results strongly suggest that a total or nearly total mechanistic switch from cyclic to acyclic must have taken place. The uniquely lower enantio-selectivity figures for the singularly important cases of methylalumination are frustrating and puzzling. The observed difference in enantioselectivity may be rationalized in terms of an auxiliary chirality induced through α-agostic interaction (26) under the influence of a chiral ligand, e.g., 1-neomenthyindenyl, in the cases of ethyl- and higher alkylalumination, which is absent in methylalumination (27).

Scheme 2.

It has recently been shown that the addition of water (28), methylaluminoxane (MAO) (28), or isobutylaluminoxane (IBAO) (29) can significantly accelerate the Zr-catalyzed asymmetric carboalumination, especially in the otherwise sluggish reactions of styrene and proximally heterosubstituted alkenes. Although the enantioselectivity figures appear to be basically unaffected, their rate-acceleration effect, which permits the use of lower reaction temperatures, has led to moderate increases in enantioselectivity. With more reactive alkenes, however, their dimerization and oligomerization have been potentially troublesome side reactions to be suppressed (29). A later report (30) on a closely related reaction with “cationic” chiral zirconocene derivatives should be noted. Clearly, from the results presented above, the Zr-catalyzed carbometallation is multimechanistic (23, 31–36) and sensitive to several critical factors including ligands (22), solvents (23), and metal countercations of alkylmetals. With respect to metal countercations, the following generalizations may be presented as useful guidelines (36).

1. Alkylmagnesium derivatives readily dialkylate dihalozirconium derivatives, leading to the formation of zirconacyclopropanes (or alkenezirconocenes) that can undergo cyclic carbozirconation (32). It should be noted here that others (37–40) have developed mutually related Zr-catalyzed asymmetric C—C bond-forming reactions that are thought to involve cyclic carbozirconation (32). However, respectable ees of ≥90% have been reported only with allylically heterosubstituted alkenes (37–40). Methylmagnesium derivatives lacking a β-H atom apparently fail to undergo the reaction, and alkyl groups higher than ethyl generally lead to significantly lower product yields and various unwanted side reactions, such as alkyl isomerization (37, 38). Thus, these reactions are fundamentally discrete from the Zr-catalyzed asymmetric carboalumination discussed here.

2. The corresponding reactions of alkyllithiums proceed similarly under the stoichiometric conditions, but it has been difficult to induce their reactions, which are catalytic in Zr. Alkyllithiums have been shown to readily trialkylate zirconocene derivatives (41).

3. Apparently, metals that are significantly less electropositive than Al, such as B, Si, and Sn, do not readily alkylate zirconocene derivatives, and Zr-catalyzed carbometallation reactions do not seem to have been observed.

4. Some other metals of intermediate electronegativity seem capable of undergoing Zr-catalyzed carbometallation, and Zn has indeed been shown to participate in the reaction (42, 43). At present, however, only a cyclic version of Zr-catalyzed ethylzincation of alkenes, similar to the Dzhemilev ethylmagnesation (44), is known (43).

Practical and Realistic Protocols for the Synthesis of Reduced Polypropionates. Although attempts to develop chiral ligands that are superior to NMI are being made, we have also sought some practical and realistic protocols for the synthesis of reduced polypropionates through the use of Zr-catalyzed carboalumination in its current stage of development. The goal of this investigation is to develop one or more protocols that can potentially fulfill the five goals listed earlier. One specific point of special attention is to avoid undesirable enantiomeric separation for high efficiency in preparing reduced polypropionates of ≥98–99% ee. There are basically three Zr-catalyzed carboalumination processes that can be used for the synthesis of methyl-branched 1-alkanols (Scheme 3). In process I, the critical methyl group at an asymmetric carbon center is supplied by Me₃Al. The reaction generally proceeds in high yields but only in 70–80% ee (22). Process II involves the Zr-catalyzed alkylalumination of propene, and the critical methyl group is supplied by propene. This reaction has so far exhibited ees of 70–80% and is under further investigation. On the other hand, process III has led to good yields and an ee range of 90–95%. In this reaction, the critical methyl group is derived from the terminal methylene group.

Scheme 3.

None of the three processes in Scheme 3, however, displays ees of ≥98–99%. Thus, the preparation of monomethyl-branched alkanols as the final products by these processes will require separation of undesirable enantiomers by optical resolution and other methods (27, 29). On the other hand, the synthesis of reduced polypropionates, in which there are two or more branching methyl groups at asymmetric carbon centers, is significantly facilitated by what might be conveniently termed “statistical enantiomeric amplification” by virtue of the presence of not one but two or more chiral centers. In the absence of “internal asymmetric induction” caused by the preexistence of chiral centers in the substrates, the stereochemical outcome of combining two chiral species and/or asymmetric reactions may be predicted by resorting to the mass action law, as indicated for some representative cases in Table 1. For example, a process III of 90% ee followed by a process I of 80% ee would produce the desired product of ≈99% ee in a maximum 86% yield.

Table 1. Statistical asymmetric amplification.

ee in step or species I	ee in step or species II	Max. yield of major 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.

Experimental Procedures

Supporting Information. Details of the experimental procedures can be found in Supporting Text, which is published as supporting information on the PNAS web site.

Zr-Catalyzed Enantioselective Carboalumination of 3-Buten-1-ol: (3S)-3-methyl-1-hexanol (45). To 1.50 g (20 mmol, 96%) of 3-buten-1-ol in 20 ml of CH₂Cl₂ was added 9.5 ml (50 mmol) of ⁿPr₃Al at 0°C, and the resultant mixture was warmed to 23°C. After 2 h, this mixture was added to 0.667 g (1 mmol) of (+)-(NMI)₂ZrCl₂ in 20 ml of CH₂Cl₂ at 0°C, followed by the dropwise addition of 20 ml of a 1 M solution of IBAO in CH₂Cl₂. The resultant mixture was stirred for 1 h at 0°C and then for 12 h at 23°C. The reaction mixture was cooled to 0°C, treated with 3 M HCl, extracted with ether, washed with NaHCO₃ and brine, and dried over MgSO₄. After evaporation of the volatiles, the residue was purified by flash chromatography (silica gel, CH₂Cl₂) to give 2.04 g (88%) of the title compound as a colorless oil: purity by ¹³C NMR, ≥99%; [α]^D₂₃ = –0.5° (c 0.67, CHCl₃); ¹H NMR (300 MHz, CDCl₃), δ 0.8–1.0 (m, 6 H), 1.1–1.5 (m, 5 H), 1.55–1.7 (m, 2 H), 2.53 (s, 1 H), 3.5–3.7 (m, 2 H); ¹³C NMR (75 MHz, CDCl₃) δ 14.19, 19.46, 19.92, 29.16, 39.36, 39.79, 60.84; IR (neat) 3,339, 2,925, 1,456, 1,056 cm^–1.

Determination of ee (46). (3S)-3-methyl-1-hexanol was converted to the corresponding carboxylic acid by Jones oxidation and then to the amide by treating the acid with (S)-1-(1-naphthyl)ethylamine. HPLC analysis of the amide [CHIRALCEL OD-H (DAICEL, Tokyo), 4.6 mm × 250 mm, 95:5 hexane/isopropyl alcohol, 1 ml/min] showed two peaks [retention time (t_r) 50.1 and 79.6 min, 95:5 ratio] assignable to the S,S and R,S diastereomers, respectively, 90% ee.

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 (+)-(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 for 1 h at 0°C, then stirred for 5 h under oxygen atmosphere at 23°C. The resultant mixture was diluted with CH₂Cl₂, washed with 2 M 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) by ¹³C NMR, 6.7:1]. The product was further purified by column chromatography (silica gel, eluted with 50:1 hexane/ethyl acetate) to give 1.2 g (68%) of the title compound: dr by ¹³C NMR, >40:1; enantiomeric purity at C2 by Mosher ester analysis (for a fraction with dr of >100:1), >99%; [α]^D₂₃ = –13.5° (c 0.8, CHCl₃); ¹H NMR (300 MHz, CDCl₃) δ 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 NMR (75 MHz, CDCl₃) δ 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 cm^–1; high-resolution MS calculated for C₉H₂₀O [M+H]⁺, 145.1583; found, 145.1581.

Conversion of 4,6-Dimethyl-1-Alkenes into 2,4,6-Trimethyl-1-Alkanols: (2R,4R,6R)-2,4,6-trimethyl-1-nonanol (19). The title compound was synthesized from (4R,6R)-2,4-dimethyl-1-nonene (1.07 g, 7.0 mmol) according to the procedure described in the preceding experiment, with (–)-(NMI)₂ZrCl₂ (0.20 g, 0.3 mmol). After concentration, 1.07 g (82%) of the crude product obtained (dr by ¹³C NMR, 8:1) was further purified by column chromatography (silica gel, eluted with 50:1 hexane/ethyl acetate) to give 0.85 g (67%) of the title compound: dr by ¹³C NMR, ≥50:1; [α]_D²³ = –3.4° (c 0.8, CHCl₃); ¹H NMR (300 MHz, CDCl₃) δ 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, 2 H); ¹³C NMR (75 MHz, CDCl₃) δ 14.39, 17.51, 19.90, 20.40, 20.87, 27.47, 29.70, 33.04, 38.78, 41.25, 45.14, and 68.19; IR (neat) 3,339 cm^–1.

Results and Discussion

Asymmetric Synthesis of 3-Methyl-1-Pentanol and 3-Methyl-1-Hexanols. Synthesis of many natural products containing reduced polypropionate fragments, such as compounds 2 and 3 (Fig. 1), can be achieved through asymmetric synthesis of terminally monoheterofunctional, reduced polypropionates containing either an ω-ethyl or an ω-ⁿPr group. Because (S)-2-methyl-1-butanol (compound 4 in Scheme 4) of >98% ee is commercially available as a relatively inexpensive material (20 g for $39.10 from TCI America, Portland, OR), it will be used as one of the monomethyl-branched ω-ethyl starting compounds. To develop a generally applicable method for the synthesis of ω-ethyl or ω-ⁿPr methyl-branched reduced polypropionates, however, it is desirable to develop one or more efficient and selective synthetic routes to other suitable monomethyl-substituted 1-alkanols or their synthetic equivalents. To this end, (R)-3-methyl-1-pentanol (compound 5 in Scheme 4) and (R)- and (S)-3-methyl-1-hexanols (compound 6 in Scheme 4) were chosen as potentially attractive monomethyl-branched intermediates. We initially envisioned their synthesis by means of a recently reported procedure (29) using TBS-protected 3-buten-1-ol, where TBS is ^tBuMe₂Si. With the hope of eliminating two steps needed for protection and deprotection of alcohols, however, we directly subjected unprotected 3-buten-1-ol to the Zr-catalyzed alkylalumination with 2.5 equivalents of Et₃Al or ⁿPr₃Al in the presence of 5 mol% of (NMI)₂ZrCl₂ and 1 equivalent of IBAO in CH₂Cl₂ at 23°C. Under these conditions, the reactions were essentially complete within 12 h. As shown in Scheme 4, the desired compounds (5 and 6) were obtained in 88–92% yields in 90–91% ee.

Scheme 4.

Even at this enantioselectivity level, the results shown in Scheme 4 may well represent the currently most efficient and potentially satisfactory method for the preparation of compounds 5 and 6 as intermediates for the preparation of reduced polypropionates. Although examination by ¹H NMR spectroscopy of the Mosher esters (47) of 2-methyl-1-alkanols has been generally satisfactory, it was not reliable for determining the enantiomeric purity of 3-methyl-1-alkanols, such as compounds 5 and 6. Therefore, they were converted to the corresponding carboxylic acids and then to carboxamides by amidation with 1-(1-naphthyl)ethylamine, and analyzed by HPLC (46).

Synthesis of 2,4-Dimethyl-1-Hexanols and 2,4-Dimethyl-1-Heptanols. Because most, if not all, of the possible stereoisomers of reduced polypropionate fragments are present in various natural products, 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 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 8 in Scheme 5). Because the aldehydes generated via oxidation are subjected to Wittig olefination without isolation, it is, in fact, a two-isolation-step protocol. It should be clearly noted here that process III in Scheme 3 used for the preparation of compounds 5 and 6 cannot be iterated for the synthesis of reduced polypropionates and that process III must therefore be followed by process I of 85–90% stereoselectivity.

Scheme 5.

The other protocol for chain elongation shown in Scheme 6 also involves a three-step process consisting of (i) iodination of alcohols, (ii) zincation followed by Pd-catalyzed vinylation (43, 48, 49), and (iii) Zr-catalyzed asymmetric methylalumination followed by oxidation with O₂ (22). This protocol is iterative, and it should be applicable to the synthesis of reduced polypropionates containing any number of branching methyl groups. Specifically, (S)-2-methyl-1-butanol (compound 4) was iodinated in 91% yield with I₂ and PPh₃ in the presence of imidazole. Successive treatment of the iodide with ^tBuLi (2.1 eq), dry ZnBr₂ (0.6 molar eq), and vinyl bromide (2 eq) in the presence of 5 mol% of Pd(PPh₃)₄ produced (S)-4-methyl-1-hexene in 75% yield. Full retention of the S configuration (≥99%) was confirmed by HPLC analysis of the carboxamide obtained via oxidation and amidation, as described earlier (46). The reaction of isomerically pure (S)-4-methyl-1-hexene with Me₃Al (1.5 molar eq), MAO (30 mol% based on Al), and 5 mol% of (NMI)₂ZrCl₂ gave, after oxidation with O₂, the expected 2,4-dimethyl-1-hexanols. The two reactions run with (+)- and (–)-(NMI)₂ZrCl₂ as catalysts gave (2S,4S)-7 and (2R,4S)-7, respectively, in 78–79% yields. The drs determined by ¹³C NMR spectroscopy were 9:1 (or 90:10) and 6:1 (86:14), respectively, and these figures agreed very well with those obtained by Mosher ester analysis of (2S,4S)-7 and (2R,4S)-7, respectively. The results suggested that the formation of (2S,4S)-7 is mildly favored by the preexisting 4-methyl group, whereas that of (2R,4S)-7 is either essentially unaffected or slightly disfavored. To probe the extent of internal asymmetric induction, (S)-4-methyl-1-hexene was methylaluminated by using 5 mol% of (Ind)₂ZrCl₂ or (2-MeInd)₂ZrCl₂, where Ind is indenyl and 2-MeInd is 2-methylindenyl. These reactions produced nearly racemic mixtures of (2S,4S)-7 and (2R,4S)-7 in 1.03:1.0 to 1.10:1.0 ratios with a slight preference for the formation of (2S,4S)-7. In any event, (2S,4S)-7 and (2R,4S)-7 obtained via asymmetric methylalumination are estimated to be in ≥99.8% and ≥99.6% ee, respectively, on the basis of the observed purity of ≥98% ee for compound 4. The main task remaining was to purify the products through diastereomeric separation, and this was achieved by single chromatographic operation (230–400 mesh silica gel, 1:50 EtOAc/hexanes). In the case of (2S,4S)-7, 81% of the crude product was converted into the final product of ≥50:1 dr. Purification of (2R,4S)-7, which eluted slower than the other isomer, was somewhat less efficient, leading to 62% recovery of the final product of ≥40:1 dr.

Scheme 6.

Stereoisomers of 2,4-dimethyl-1-hexanols (compound 7) have been used for the syntheses of some natural products, such as zaragozic acid A (compound 2) (2) and sambutoxin (15). In one synthesis of compound 2, (2S,4S)-7 was prepared from compound 4 in ≈40% yield in six to seven steps via stoichiometric α-methylation of a chiral amide (2). Thus, even at the current stage of development, the three-step synthesis of (2S,4S)-7 via Zr-catalyzed asymmetric methylalumination offers a higher level of efficiency and catalysis in chiral auxiliary as advantageous features. Further improvements of product yields (unoptimized), stereoselectivity, and overall economy are desirable, and they appear to be eminently feasible. Similarly, (2S,4R)-7 of >40:1 dr prepared in 40% overall yield in four (three isolation) steps (Scheme 5) may be compared with its multistep synthesis used for the synthesis of (+)-sambutoxin, which appears to involve nine steps from methyl 3-hydroxy-2-methylpropionate (15).

Synthesis of 2,4,6-Trimethyl-1-Octanols and 2,4,6-Trimethyl-1-Nonanols. The iterative three-step protocol established in the previous section has proved to be readily applicable to the conversion of 2,4-dimethyl-1-alkanols to 2,4,6-trimethyl-1-alkanols, as indicated by the synthesis of three all-syn isomers of compounds 9 and 10, summarized in Scheme 7. For these presumably favorable cases, drs of 8:1 to 8.5:1, corresponding to 89–89.5% stereoselectivity at C2, have been consistently observed. As discussed earlier, the overall enantiomeric excess for these trimethyl derivatives may safely be estimated to be ≈99.8–99.9%.

Scheme 7.

To demonstrate the potential applicability of (2S,4S,6S)-2,4,6-trimethyl-1-octanol (compound 9) to the synthesis of antibiotics TMC-151 A-F (compound 3) (3), it was converted in 62% yield in two steps to compound 11 (shown in Scheme 7), which corresponds to the C11–C20 fragment of compound 3 without the sugar moiety.

Conclusion

An efficient and general method for the synthesis of reduced polypropionates has been developed through the application of asymmetric carboalumination of alkenes catalyzed by (NMI)₂ZrCl₂. Some critical components of the development are as follows.

1. The reaction of 3-buten-1-ol with Et₃Al or ⁿPr₃Al in the presence of 5 mol% of (NMI)₂ZrCl₂ and IBAO (1 eq) gave, after protonolysis, (R)-3-methyl-1-pentanol as well as (R)- and (S)-3-methyl-1-dimethyl-1-hexanols in 88–92% yield in 90–92% ee in one step (Scheme 4).

2. Without purification, these alcohols were oxidized and olefinated with Ph₃P=CH₂ in 81–86% overall yields to give the corresponding 4-methyl-1-alkenes. Their reactions with Me₃Al in the presence of 5 mol% of (NMI)₂ZrCl₂ and 30 mol% of MAO, followed by oxidation with O₂, produced the corresponding 2,4-dimethyl-1-heptanols in 84–89% yield. After simple chromatographic purification, syn-2,4-dimethyl-1-alkanols of ≥40:1 dr were obtained in 78–79% recovery. The combined yield of the purified products over four (three isolation) steps was ≈50%. The corresponding combined yield for (2S,4R)-2,4-dimethyl-1-hexanol was 40%.

3. An alternative protocol employs commercially available (S)-2-methyl-1-butanol of >98% ee. Its two-step conversion via iodination and Pd-catalyzed vinylation to (S)-4-methyl-1-hexene in 69% combined yields was followed by Zr-catalyzed methylalumination–oxidation to produce 2,4-dimethyl-1-hexanols in 78–79% yields (Scheme 6).

4. This three-step protocol is iterative and is applicable, in principle, to the synthesis of higher reduced polypropionates via Zr-catalyzed asymmetric methylalumination, as exemplified by the synthesis of all-syn-2,4,6-trimethyl-1-nonanols summarized in Scheme 7. (2S,4S,6S)-2,4,6-trimethyl-1-nonanol was further converted in two steps in 62% combined yield to compound 11, which corresponds to the C11–C20 fragment of TMC-151 A–F (compound 3) (3).