Stereoselective Access to Polypropionates Expedited by the Double Hydroboration of Allenes: Total Synthesis of Antitumor (−)-Pironetin

Open AccessCCS ChemistryRESEARCH ARTICLE1 Feb 2021Stereoselective Access to Polypropionates Expedited by the Double Hydroboration of Allenes: Total Synthesis of Antitumor (−)-Pironetin Lin Yang†, Luyao Kong†, Qi Gu†, Shunjie Shao, Guo-Qiang Lin and Ran Hong Lin Yang† CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032 University of Chinese Academy of Sciences, Beijing 100049 , Luyao Kong† CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032 University of Chinese Academy of Sciences, Beijing 100049 , Qi Gu† CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032 University of Chinese Academy of Sciences, Beijing 100049 , Shunjie Shao CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032 University of Chinese Academy of Sciences, Beijing 100049 , Guo-Qiang Lin CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032 and Ran Hong *Corresponding author: E-mail Address: [email protected] CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032 https://doi.org/10.31635/ccschem.020.202000217 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookTwitterLinked InEmail Polyketides, a large class of secondary metabolites, have been of long-standing interest to the synthetic community due to their intriguing biological activities and structural versatility and complexity. A typical structural unit of various natural products, polypropionate, has prompted enormous efforts in the development of novel synthetic methods and strategies in the past five decades. In this study, a non-aldol-type approach based on double hydroboration of allenes has been developed to provide a powerful method for the stereodivergent construction of various polyol stereotriads and stereotetrads that are amenable for synthesizing polypropionates. The stereochemical control is possibly attributable to the boronate complex that aligned itself as a rigid conformation for the second stereoselective hydroboration reaction by suppressing the barotropic rearrangement of allylborane intermediates. The feasibility of preparing the key polypropionate motif facilitates the efficient synthesis of (-)-pironetin, a potent α-tubulin inhibitor halting the cell cycle at M phase. Download figure Download PowerPoint Introduction The polypropionate structural motif is widely distributed in bioactive complex polyketides, a class of essential natural products that are currently being investigated extensively and developed as chemotherapeutic agents, such as antibiotics, anticancer agents, immunosuppressants, and cholesterol-lowering drugs.1 Their structural complexity and important bioactivities have resulted in numerous total synthesis approaches and the development of novel synthetic methods in the past few decades.2 For the de novo chemical synthesis of complex polyketides with multiple hydroxy groups, conventional wisdom introduced nonskeleton-forming steps to ensure that only the requisite functional group reacts.3 Generally, the widely adapted aldol and allylation reactions require additional redox manipulations and protection/deprotection steps that might result in diminished efficiency of the synthesis.4 Therefore, for the development of an efficient approach to access the polypropionate motif, minimizing the concession steps is a very important criterium when committing to a new synthetic method. In contrast to the significant progress devoted to allylation with various borane reagents and catalyst systems, the hydroboration of allylboranes has attracted much less attention (Scheme 1). The early results from the Mikhailov, Cadiot, and Brown laboratories5–7 revealed little success in the regioselective control of hydroboration reactions and in decreasing the levels of the contaminating polyhydroboranes. The sporadic examples documented in the literature were mainly associated with specific substrates that were generally not designed for synthetic applications.8,9 Given the various methods for accessing allylboranes from readily available compounds,10 we envisioned that the development of a method for the regio- and stereoselective hydroboration of allylboranes and subsequent oxidative deboronation would provide novel synthetic techniques for the construction of a variety of polyol or polypropionate subunits. Here, we report the first example of the highly regio- and stereoselective hydroboration of allylboranes and their subsequent oxidation to deliver versatile polyol subunits. Scheme 1 | Allylboranes: allylation versus hydroboration. Download figure Download PowerPoint Experimental Methods The representative procedures related to the preparations of 2-Z-1,4-diol, 10, syn, anti-triol, 12, and syn, syn-triol, 13, are described here. Detailed information is available in the Supporting Information. Preparation of diol 10 To a solution of allene 9 (0.485 mmol) in tetrahydrofuran (THF; 1.0 mL) was added dropwise to the freshly prepared solution of disiamylborane (Sia2BH) at –78 °C. After 30 min, the resulting mixture was warmed up to –50 °C. After another 1 h, the reaction mixture was warmed up to –30 °C and stirred for an additional 1 h. MeOH (30 µL) was added slowly ( Caution: gas evolution), followed by nBu4NOH (40% in H2O, 1.0 mL), with subsequent stirring of the mixture for 20 min and slow addition of H2O2 (30% in H2O, 1.0 mL). The resulting mixture was stirred vigorously at –30 °C for 1 h, warmed up to room temperature, and stirred for another 1 h. Then ethyl acetate (10 mL) was added, and the organic layer was separated, followed by extraction of the aqueous layer with ethyl acetate (3 × 10 mL). The combined organic extracts were washed by water and brine solution and then dried over anhydrous Na2SO4. Afterward, the solvent was removed under vacuum, followed by purification by flash column chromatography using silica gel (PE/EA: 4/1-2/1) to afford the diol, 10. Preparation of syn, anti-12 To a solution of allene 9 (0.485 mmol) in THF (1.0 mL) was added dropwise the freshly prepared solution of Sia2BH at –78 °C. After 30 min, the resulting mixture was warmed up to –50 °C. After another 1 h, the reaction mixture was warmed up to –30 °C and stirred for an additional 1 h. A freshly prepared solution of thexyl borane (ThexBH2) was added and then warmed up to room temperature and stirred for 20 h. The reaction mixture was quenched by the addition of MeOH (150 µL) at 0 °C ( Caution: gas evolution), followed by the slow addition of NaOH (3 N in H2O, 2.0 mL) and H2O2 (30% in H2O, 2.0 mL). Then the mixture was warmed up to room temperature and stirred for another 3 h. Ethyl acetate (10 mL) was added, and the resulting mixture was filtered by Celite®. The organic layer of the filtrate was separated, and then the aqueous layer was extracted with ethyl acetate (3 × 15 mL). The combined organic extracts were washed by water and brine and dried over anhydrous Na2SO4. The solvent was removed under vacuum, followed by purification by flash column chromatography using silica gel (PE/EA/EtOH: 20/1/1-10/1/1) to afford the triol, 12. Preparation of syn, syn-13 To a solution of diol (R)- 10 (0.485 mmol) in THF (2.0 mL) was added dropwise 9-BBN (0.5 M in THF, 1.0 mL, 0.52 mmol) at –30 °C. After 5 min, the resulting mixture was warmed up to 0 °C over 15 min and stirred for 30 min. Then the reaction mixture was cooled down to –30 °C. Next, the freshly prepared solution of monoisopinocampheylborane [(−)-IpcBH2] was added and then stirred for 10 h (20 h for 13e). The reaction mixture was quenched by an addition of MeOH (100 µL) ( Caution: gas evolution), followed by slow addition of NaOH (3 N in H2O, 1.5 mL) and H2O2 (30% in H2O, 1.5 mL). Subsequently, the mixture was warmed up to room temperature and stirred for another 3 h. Ethyl acetate (10 mL) was added, and the resulting mixture was filtered by Celite. The organic layer of the filtrate was separated, and the aqueous layer was extracted with ethyl acetate (6 × 5 mL). The combined organic extracts were dried over anhydrous Na2SO4. The solvent was removed under vacuum, followed by purification by flash column chromatography using silica gel (PE/EA: 1/1-1/3) to afford the triol, 13. Results and Discussion The weak electronic directing inducing effect of boron on allylborane and the sensitivity of hydroboration to steric hindrance render poor regioselectivity of the second hydroboration except for simple B-allyl-9-BBN Moreover, a common boratropic rearrangement associated with a rapid [1,3]-boron shift might be rigorous and resulted in E/Z isomerization prior to the second hydroboration, even for trisubstituted alkenes.12 This result was indeed observed when a model substrate, 1,1-dialkyl-substituted allene, 4, was subjected to the first hydroboration using 9-borabicyclo[3.3.1]nonane (9-BBN) or disiamylborane (Sia2BH) to form the corresponding allylborane intermediate, which was followed by the second hydroboration with thexylborane (ThexBH2).13 Upon oxidation, a mixture of 1,2- and 1,3-diols ( 5a/b) was generated (Scheme 2a). An unsatisfactory regio- and stereoselectivity were obtained, attributable to the barotropic rearrangement, which scrambled the distribution of allylboranes 6 and 7, and thus, resulted in the generation of various stereoisomers of 1,2- or 1,3-diborane, 8. Although more sterically hindered Sia2BH prevented this rearrangement and favored the formation of Z-allylborane, 6, after the first hydroboration (Z/E > 5/1), determined by oxidative deboronation, as shown in the Supporting Information Table S1, the second hydroboration was sluggish due to steric hindrance and only traced amounts of compounds 5a/b were detected after oxidation. Scheme 2 | The initial attempt of hydroboration and oxidation of allylboranes (a) and chelation-effect-guided design (b). TBDPS = tert-butyldiphenylsilyl. Download figure Download PowerPoint To circumvent the barotropic rearrangement, we presumed that intramolecular chelation via a boronate complex would be an instrumental research suggestion, as the previous proposal of stereoselectivity origin from an "ate" complex via S-B or F-B interaction.14–16 Accordingly, the hydroboration of 2,3-allenol 9a with Sia2BH and the subsequent oxidation resulted in diol 10a (67% yield) and diene 11 (20–30%) after treatment of the conventional NaOH–H2O2 reaction system17 (Scheme 2b). Although the selectivity of 10a was excellent (Z/E > 98/2), the considerable amount of diene generated still could not rule out plausible contamination with 1,4- or 1,2-borono-Peterson elimination reaction18,19 (Scheme 2b, transition state inset), and thus, the possibility of chelation in Z- Ia is not conclusive. The unprecedented excellent Z-selectivity and potential synthetic applications 20–24 of 10a motivated us to optimize further the conditions to suppress the elimination pathway. In the proposed borono-Peterson elimination reaction, an increase in the concentration of the hydroperoxide anion (HO2−) in the organic phase might facilitate the requisite 1,2-alkyl migration of the allyl group (B→O), thus, inhibiting the proposed borono-Peterson elimination. After optimization, tetrabutylammonium hydroxide (nBu4NOH) proved to be effective in suppressing the side elimination pathway, and the Z-1,4-diol 10a was isolated with an excellent 92% yield and high stereoselectivity (Z/E > 98/2). We believed the free hydroxyl group (–OH) served a dual function; to facilitate the maintenance of the Z-configuration in allylborane (i.e., Z- Ia) and to deter the barotropic rearrangement via a chelation effect. This approach was amenable to an 11-gram-scale synthesis of compound 10a, and also, applicable to a variety of allenes bearing an adjacent free hydroxy group (Scheme 3). The replacement of tert-Butyldiphenylsilyl (TBDPS) with the benzyl group does not attenuate the stereoselectivity and isolated yield of diol 10b. Aryl and simple alkyl substitutions at C(4) ( 9c–i) proceeded smoothly to deliver diols with excellent yields and stereoselectivities. For the long-chain-derived allenol 9e, the previously known protocol using NaOH as the base afforded 10e at a yield of only 49%.25 Notably, some functional groups, such as alkenes ( 10j) and esters ( 10k), were also tolerated. When a thioether was introduced into substrate 9l, overoxidized products such as sulfones and sulfoxides were detected upon oxidation and reduced the isolated yield of diol 10l. With the additional stereocenters in substrates 9m–p, high stereoselectivity was retained, while the selectivity for the ω-chlorinated allenic alcohol 9p was slightly decreased (dr 18/1). The monohydroboration of allenol 9q, in which the methyl group at C(3) was depleted, remained effective, and a high yield of 10q was achieved with remarkable stereoselectivity. Interestingly, substrate 9r also produced a high yield of alcohol 10r. However, the labile acetyl group in substrate 9s was deprotected partially under the optimal conditions, and Brown's method, using NaOH-based alkaline hydroperoxide,17 was resumed to afford alcohol 10s in 89% yield. Scheme 3 | Substrate scope for the hydroboration–oxidation of allenes. aThe stereoselectivity of the alkene is typically ds >98/2, unless indicated otherwise (18/1 for compound 10p); boxidation at –30 °C; coxidation using NaOH (3 N, 1 mL) and H2O2 (30% in H2O, 1.0 mL). TBS = tert-butyldimethylsilyl; Bn = benzyl. Download figure Download PowerPoint The confinement of Z-stereoselectivity in the hydroboration of allenic alcohol 9a allowed us to investigate the second stereoselective hydroboration reaction. To examine the effect of the inherent stereocenter in the possible chelated Z- Ia, optically pure allenol 9a (> 99% ee)26 was subjected to the hydroboration. Thus, Z-allylborane Ia generated in situ with Sia2BH was examined by a second hydroboration reaction with various borane reagents. For dialkylboranes such as 9-BBN and Sia2BH, the required transformation did not proceed . When simple borane BH3•Me2S was executed, substantial alkene isomerization was observed and the desired triol 12a was only detected in a trace amount due to the low reactivity of E-allylborane (entry 1, Table 1). Gratifyingly, when [(−)-IpcBH2]27 was used, the second hydroboration reaction proceeded smoothly, and 2,3-syn-3,4-anti-isomer 12a was isolated in 79% yield with modest diastereoselectivity (ds 5/1, entry 2). Remarkably, the diastereoselectivity was improved to a higher level (ds 17/1) when the antipode of borane [(+)-IpcBH2] was applied (entry 3). No appreciable alkene isomerization was observed during the second hydroboration reaction (entries 2 and 3). When another sterically bulky borane, ThexBH2, was used, the selectivity (dr) was improved further to > 20/1, and the triol 12a was obtained in 89% NMR yield (entry 4). Table 1 | Optimization of the Second Hydroboration (Hydroboration of the Proposed Z-Allylborane)a,b Entry R′BH2 (equiv.) Time (h)c Isomerization (Z/E)d Yield of 12a (ds)e 1 BH3•Me2 S (3) 8 1/4 <10 (n.d.)f 2 (−)-IpcBH2 (3.5) 5 no 79 (5/1) 3 (+)-IpcBH2 (3.5) 5 no 83 (17/1) 4 ThexBH2 (3.5) 20 no 89 (> 20/1) Note: aReaction conditions: (R)- 9a (0.5 mmol), THF (2.5 mL), and Sia2BH (3.5 equiv.), −78 °C to −30 °C; then borane (3–3.5 equiv.) bThe diastereoselectivity and yield were determined using 1H NMR (400 MHz, CD3OD). cThe reaction time refers to the second hydroboration reaction. dIsomerization of the alkene occurred due to a barotropic rearrangement, and the Z/E-selectivity was based on the ratio of Z- 10a. dThe diastereoselectivity (ds) in parentheses is presented as the ratio of the major isomer (syn, anti- 12a) to the sum (Σ) of other isomers. e 10a obtained after oxidation. fn.d. = not determined. After determining the optimal conditions, we then exploited the substrate scope to access various stereodefined chiral building blocks (Scheme 4). Thus, allenic alcohols 9a–i were smoothly converted to stereotriads 12a–i at good-to-excellent isolated yields with high diastereoselectivities (ds > 20/1). The isolated yield of the thioether syn, anti-triol 12l was attenuated due to the overoxidized side products (such as sulfoxide and sulfone) produced during the oxidation step. Notably, the adjacent stereocenter at C(5) will require a delicate choice of the alkylborane for the second hydroboration reaction. For instance, triol 12m was obtained with excellent selectivity, while the selectivity of 12n decreased in the reaction using the standard conditions with ThexBH2. The sterically demanding (+)-IpcBH2 was superior (ds > 20/1). However, for the substrate anti- 9o, only (−)-IpcBH2 produced an excellent ratio of syn, anti, anti- 12o with excellent diastereoselectivity, while (+)-IpcBH2 only generated ds of 3/1 of the same stereoisomer (see the Supporting Information for details). Based on this phenomenon, the absolute configuration of the secondary alcohol at C(4) exerts a match-and-mismatch effect with the antipodes of IpcBH2. This one-pot protocol was even more intriguing to access the densely functionalized polyol 12p in good isolated yield with high diastereoselectivity (ds 15/1); otherwise, a multiple-step sequence must be devised. Crystalline compounds 12c and 12h were both suitable for X-ray analysis, and the corresponding stereochemistry was consistent with the primary compound 12a.a Scheme 4 | Hydroboration–oxidation of allylborane (the numbering of product 12 was based on allenol 9). aThe diastereoselectivity of 12 is typically, ds > 20/1, unless indicated otherwise. bAll yields are reported as the isolated yield of the major isomer. Download figure Download PowerPoint For allenol 9k, the ester group was not tolerable due to the superior reducing ability of the monoalkylboranes ThexBH2 and IpcBH2. Substantial elimination occurred in substrate 9q, and the product was contaminated with diene and unidentified diols due to the poor regioselectivity and barotropic rearrangement in the second hydroboration reaction of 1,3-diene. For protected allenic alcohols 9r and 9s, the second hydroboration was sluggish due to combined electronic and steric interactions, and only diols 10r and 10s (cf. Scheme 3) were generated after the oxidative reaction. These results indicated a crucial role of the possible boronate complex without the loss of configurational integrity involved in the second hydroboration reaction. Complementary to the construction of syn, anti-triol 12via the double hydroboration of allenol, the hydroboration of Z-1,4-diol 10, and subsequent oxidation was resumed to produce the syn, syn-diastereoisomer 13. The dehydrocoupling of diol (R)- 10 with 9-BBN and subsequent treatment with sterically demanding (−)-IpcBH2 afforded syn, syn-triol 13a with increased diastereoselectivity (ds 7.5/1 at –30 °C; ds > 10/1 at –78°C), compared to the previous ratio obtained at –20 °C (ds 6.4/1)28 (Scheme 5). This protocol readily produced the desired triols 13b, 13c, and 13d with good diastereoselectivity.b Notably, stereotetrad 13d contained identical stereogenetic centers to the C18–C21 fragment in actinoallolide B,29 which was a potent antitrypanosomal macrolide, recently synthesized by the Paterson group.30 For the polyoxygenated substrate 10m, a synthetically useful 60% yield of triol 13e was obtained, although the diastereoselectivity was attenuated (ds 4.3/1) due to the detrimental effect of the competitive coordination of ketal oxygen to boron. Scheme 5 | Hydroboration–oxidation to prepare syn, syn-13. Download figure Download PowerPoint From the mechanistic perspective, the syn, anti-selectivity of stereotriads and stereotetrads derived from the simple allenol 9 renders this stereochemical control intriguing. In the Still–Houk model,31,32 a σ-donor (i.e., the R group instead of OH or OR) was proposed to be antiperiplanar to the approaching borane and thus, second hydroboration reaction would favor the production of a syn, anti-isomer (Scheme 6a). A supporting experiment in the study by Still and colleagues revealed that the hydroboration of a structurally closed Z-2-ene-allylic alcohol indeed generated a syn, anti-isomer.31 However, based on Still's original descriptionc and our observations, the rapid reaction of borane with alcohol33 (gas release) reminded us to adjust the original H-eclipsed projection32 with a possible chelation model (Scheme 6b), in which a half-chair conformation allowed an incoming sterically bulky borane (ThexBH2 or IpcBH2) to form a syn, anti-triol with excellent facial selectivity. Moreover, the origin of the stereochemistry in triol 13 also, possibly arose from a chelation model34 (Scheme 6c). The borinate group [–OB(Ipc)H or –BBN] might be responsible for the formation of the seven-membered ring to rigidify the conformation, and thus, the excess (−)-IpcBH2 approached the less sterically hindered face to generate syn, syn-triol 13 after oxidative deboronation. Scheme 6 | Proposed mechanism for the double hydroboration of allenol 9 (a: Still–Houk model; b: chelation model for triol 12) and hydroboration of diol 10 (c: chelation model for triol 13). Download figure Download PowerPoint With a sufficient amount of polyol 12n available, we devised a concise route for synthesizing the antitumor polyketide (−)-pironetin. Originally identified as a plant growth regulator,35–37 this soil-borne bacteria-producing polyketide was characterized recently as a potent antitumor agent that exclusively binds to α-tubulin.38–40 Its mode of action (MoA) is distinct from other well-known anticancer drugs targeting β-tubulin (e.g., epothilone and paclitaxel), indicating its potential as a promising lead compound for the treatment of multidrug resistance genes and mutations related to β-tubulin. Therefore, pironetin has been the focus of considerable synthetic efforts, as evidenced by the 12 total syntheses reported in the past two decades.37 However, the lengthy synthetic routes underline the challenge in its preparation when a sufficient quantity is required for biological evaluations. The total synthesis commenced from the (S)-Roche ester to provide the (S)-tertiary chirality at C10. After protection with the TBDPS group, the corresponding ester 1441 was subjected to diisobutylaluminium hydride (DIBAL-H) reduction and a subsequent reaction with in situ generated propargylborane42 to produce syn-allenol 9n in 62% yield, with an excellent diastereoselectivity ratio (dr) of 13/1 (Scheme 7). Under the optimal conditions, the aforementioned stereotetrad polyol 12n was obtained in 72% yield and dr > 20/1 on a 5-gram scale. After confirming of the stereochemistry of compound 12n further (see crystalline derivative 15),d regioselective epoxide formation from the vicinal diols was challenging due to the interference of C9–OH (see the Supporting Information for details). A Mitsunobu reaction using diisopropyl azodicarboxylate/ triphenylphosphine (DIAD/PPh3)43 in refluxed toluene was optimal for achieving a high yield (81%) and excellent selectivity (ds 12/1) of the requisite epoxide, which was converted further to methyl ether 16. The copper-catalyzed vinylation44 and immediate protection of the resulting alcohol with a tert-butyldimethylsilyl (TBS) group were conducted in the one-pot protocol to generate alkene 17 at a 95% yield. After the oxidative cleavage of the terminal alkene, asymmetric pentenylation45–49 was achieved with high diastereoselectivity (ds 15/1), and subsequent acryloylation provided ester 19 at a good yield. At this stage, a common strategy of ring-closing metathesis (RCM) was adopted to obtain the requisite pentenolide moiety. However, substantial epimerization at C4 of the preinstalled pentenolide occurred during the removal of the TBDPS group at C11 under basic conditions. Therefore, we managed to remove the TBDPS group selectively from bisilylated ester 19 prior to lactone formation. Accordingly, the oxidative Horner–Wadsworth–Emmons (HWE) process50 was performed to generate enone 20 in a 70% yield after two steps. To our delight, the resumed RCM reaction proceeded smoothly to complete the whole carbon framework. A hydrazone–reduction–rearrangement cascade 51,52 followed by desilylation was performed to secure the trans-alkene configuration of C12–C13, and the synthetic (−)-pironetin was identical to the reported data.36,48 The target was synthesized in 13 steps from the commercially available (S)-Roche ester, which represented the shortest synthesis route reported to date37 for this potent anticancer agent. Scheme 7 | Total synthesis of (−)-pironetin (the carbon numbering was based on pironetin). Reaction and conditions: (a) DIBAL-H (1.2 equiv.), CH2Cl2, –78 °C; then nBuLi (1 equiv.), 2-butyne (1.1 equiv.), (−)-Ipc2BCl (1.8 equiv.), THF, –100 °C, 62% for two steps; (b) Sia2BH (3.5 equiv.), THF, –78 °C to –30 °C; then (+)-IpcBH2 (in situ, 3.5 equiv.),rt, NaOH (aq.), H2O2 (30%), 72%; (c) CSA (cat.), DMP (4 equiv.), 0.5 h, rt; then TBAF (1.6 equiv.), 2 h, rt, 88%; (d) DIAD (1.2 equiv), PPh3 (1.2 equiv.), toluene, reflux, 81%; (e) MeI (10 equiv.), NaH (3 equiv.), CH2Cl2, rt, 95%; (f) CuI (10 mol%), vinylmagnesium bromide (4 equiv.), THF, –20 °C to 0 °C, 2 h; then TBSOTf (8 equiv.), 2,6-lutidine (15 equiv.), 95%; (g) ozone, CH2Cl2, then PPh3 (5 equiv.), rt, 5 h, 91%; (h) cis-2-pentene (6 equiv.), tBuOK (2 equiv.), n-BuLi (2 equiv.), (−)-Ipc2BOMe (2.5 equiv.), BF3·Et2O (2.5 equiv), THF, 2 h, –45 °C; then acryloyl chloride (8 equiv.), Et3N (12 equiv.), 2 h, rt, 71%; (i) TBAF (3 equiv.), THF, rt, 12 h; (j) Dess–Martin periodinane (4 equiv.), CH2Cl2, rt, 2 h; then (MeO)2POCH2COMe (6 equiv), tBuOK (5 equiv.), 0 °C to rt, 18 h, 70% for two steps; (k) Grubbs catalyst-II (20 mol%), CH2Cl2, rt, 12 h, 93% (brsm); (l) TsNHNH2 (2 equiv.), MeOH, rt, 12 h; then NaBH4 (20 equiv.), AcOH, rt, 3 h, then HCl (aq.), 70 °C, 3 h, 76%. CSA = camphorsulfonic acid, DMP = 2,2-dimethoxypropane, TBAF = tetrabutylammonium fluoride, DIAD = diisopropyl azodicarboxylate, rt = room temperature, TBSOTf = tert-butyldimethylsilyl trifluoromethanesulfonate, THF = tetrahydrofuran, Ipc = isopinocampheyl, Dess–Martin = Dess–Martin periodinane, Ts = para-toluenesulfonyl, brsm = based on the recovered starting material. Download figure Download PowerPoint Conclusions We developed the highly stereoselective syntheses of various stereotriads and stereotetrads in a highly regio- and stereoselective manner. The free hydroxy group was crucial for achieving high selectivity in the first hydroboration reaction of allene and the completion of the second hydroboration reaction to convert the allylborane into valuable adjacent stereocenters that are key chiral motifs for synthesizing natural products. In this compelling one-pot process, dialkylborane and monoalkylborane assumed their respective roles in the sequential hydroboration reactions. The proposed boronate complex models conceivably interpreted the stereochemical control during the hydroboration of trisubstituted alkenes. Along with previous iterative hydroboration–oxidation reactions leading to the production of the syn, syn-stereotriad, the current complementary nonaldol acyclic approach is versatile for accessing chiral polyol subunits (syn, anti-stereotriad) without resorting to protecting groups that would otherwise be generated inevitably in the synthesis of complex polyketides. The application of this method for the concise and successful synthesis of (−)-pironetin has encouraged us to explore further its full potential in the construction of complex bioactive molecules. Footnotes a CCDC 1902092, 1902093, and 1902091 ( 10d, 12c, and 12h) contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Da