Unified Strategy for 1,5,9- and 1,5,7-Triols via Configuration-Encoded

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Cite This: J. Org. Chem. 2018, 83, 13650−13669

Unified Strategy for 1,5,9- and 1,5,7-Triols via ConfigurationEncoded 1,5-Polyol Synthesis: Preparation and Coupling of C15− C25 and C26−C40 Fragments of Tetrafibricin Ryan M. Friedrich, Jay Q. Bell, Alfredo Garcia, Zican Shen, and Gregory K. Friestad* Department of Chemistry, University of Iowa, Iowa City, Iowa 52242, United States

J. Org. Chem. 2018.83:13650-13669. Downloaded from pubs.acs.org by KAOHSIUNG MEDICAL UNIV on 11/16/18. For personal use only.

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ABSTRACT: Diverse classes of natural products contain chiral 1,5,9- and 1,5,7-triol stereotriads, including the novel fibrinogen receptor antagonist tetrafibricin. Biological activities associated with compounds containing these motifs warrant targeted synthetic strategies to 1,5-polyol families from cheap and easily accessible reagents while avoiding the need to determine configurations at each alcohol stereocenter. In the accompanying paper, we present a solution to these problems via an iterative configuration-encoded strategy that exploits Julia−Kocienski couplings of enantiopure α-silyloxy-γ-sulfononitrile building blocks. The stereocontrol is unambiguous, and the building blocks are available in multigram quantities via asymmetric catalysis. This approach efficiently accessed a C26−C40 subunit of tetrafibricin that contains a syn,syn-1,5,9-triol and all of the stereochemistry and functionality needed to advance toward tetrafibricin. A modification afforded the anti,syn-1,5,7-triol within the C15−C25 fragment of tetrafibricin by merging 1,5-polyol synthesis with diastereoselective intramolecular conjugate addition. The union of the C15−C25 and C26−C40 fragments was achieved via a BF3·OEt2-mediated Mukaiyama aldol construction with high 1,3-anti stereoinduction, revealing some unexpected insights on the impact of silyl protecting groups on 1,3-anti diastereocontrol by a β-siloxyaldehyde aldol acceptor. Directed 1,3-anti reduction completed the stereostructure of the C15−C40 portion of tetrafibricin, with configurations established by a combination of NMR experiments.

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INTRODUCTION The fibrinogen receptor, an integrin glycoprotein also known as αIIbβ3 or GPIIb/IIIa, holds a position of importance in the cascade of events leading to platelet aggregation and blood clotting, and hence has been a target for development of antithrombotic agents.1 Few fibrinogen receptor antagonists have proceeded to clinical development; among these are abciximab (a 47.6 kDa mouse−human chimeric antibody), eptifibitide (a cyclic hexapeptide), and tirofiban (a tyrosine derivative that is a nonpeptide mimic of the Arg-Gly-Asp or RGD tripeptide).2 Tetrafibricin (Figure 1) is also a GPIIb/IIIa antagonist of high potency (IC50 46 nM) yet is quite different in structure from each of the aforementioned drugs; it is a polyketide bearing 1,3- and 1,5-polyol motifs, along with polyene and amine functionality. This compound was isolated from Streptomyces neyagawaensis strain NR0577 from a soil sample collected in Kiinagashima, Mie Prefecture, Japan.3 Tetrafibricin was found to interact with the fibrinogen © 2018 American Chemical Society

receptors GPIIb/IIIa on platelet membranes with a high degree of specificity, inducing conformational changes in the glycoprotein that are associated with its high-affinity binding of fibrinogen.4 It inhibited the aggregation of human platelets induced by ADP (IC50 of 5.6 μM), collagen (IC50 of 11.0 μM), and thrombin (IC50 of 7.6 μM). Additionally, when added to platelets previously aggregated by stimulation from ADP, tetrafibricin caused rapid and complete deaggregation.5 Despite the important drug discovery potential suggested by the aforementioned biological activities, synthetic efforts toward tetrafibricin did not appear in the literature until the complete stereostructure of tetrafibricin was reported. In 2003, Kishi applied a Universal NMR Database approach to characterize the configurations in tetrafibricin using the more stable N-acetyldihydrotetrafibricin methyl ester as a proxy for Received: August 6, 2018 Published: October 29, 2018 13650

DOI: 10.1021/acs.joc.8b02034 J. Org. Chem. 2018, 83, 13650−13669

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via asymmetric catalysis. In an iterative sequence, each coupling product contains a nitrile that serves as the latent aldehyde to be revealed by reduction, preparing the terminus for the next Julia−Kocienski olefination with another unit of 1. Our approach is a strategy level innovation that allows for the efficient and rapid access to all stereoisomers of a 1,5-polyol family from cheap and easily accessible reagents, without the need to determine the configuration of each alcohol stereocenter in the growing polyol chain. The accompanying paper details the development of building blocks for this approach and their implementation in iterative coupling reactions en route to 1,5-polyols. Here, we provide a full account of the iterative configuration-encoded synthesis approach to tetrafibricin, including a modification for access to 1,5,7-triols, strategic application to synthesize the C15−C25 and C26− C40 subunits of tetrafibricin, and endgame coupling studies leading to the stereoselective union of these two key fragments.

Figure 1. Complete stereochemical structure of tetrafibricin and key 1,5-polyol substructures.

the natural compound.6 Database comparisons of NMR spectra acquired in achiral and chiral solvents allowed for determination of relative and absolute stereochemistry in four isolated stereoclusters (C11−C19, C23−C29, C33, and C37) without chemical degradation of the structure. Tetrafibricin contains 1,5,9-triol and 1,5,7-triol motifs embedded within its polyketide structure (Figure 1). In the past few years, several strategies have emerged to specifically target the chiral 1,5-diols present in tetrafibricin, amphidinols, and related targets.7 However, there are a variety of limitations inherent to existing approaches. These include the use of undesirable reaction conditions (e.g., toxicity or high pressures), expensive chiral reagents used in stoichiometric quantities, problems with redox and step economies, and requirements of specialized reagents to access different diastereomeric relationships. Moreover, for strategies that generate 1,5-diol stereochemistry in coupling events, there is a significant analytical problem associated with determining the configuration of each newly generated stereogenic center. Despite these hurdles, several notable synthetic efforts toward tetrafibricin have led to a synthesis of N-acetyldihydrotetrafibricin methyl ester (Roush8), methods to prepare various polyol subunits (Krische9 and Cossy10), and synthetic studies advancing to late-stage fragment coupling (Curran11). We previously reported12 an iterative configuration-encoded strategy to access 1,5-polyols with unambiguous stereocontrol by exploiting Julia−Kocienski couplings13 of enantiopure αsiloxy-γ-sulfononitriles. These building blocks (R)-1 and (S)-1 (Scheme 1) contain an aldehyde in latent form (masked as a nitrile) along with alcohol stereocenters previously established

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RESULTS AND DISCUSSION Design and feasibility studies of the general strategy outlined in Scheme 1 are provided in the accompanying paper. With that solid foundation in place, application of the configurationencoded strategy to complex synthesis targets remained to be tested. Thus, a retrosynthetic analysis of tetrafibricin emerged (Scheme 2). Initial disconnections of a C15−C40 portion AB Scheme 2

Scheme 1

from two smaller subunits C and D14 would correspond to Pdcatalyzed alkene σ bond construction between two sp2 carbons at C7 and C8 and boron enolate aldol reaction15 to link C14 and C15. Along with the target’s bioactivity, the synthetic challenges posed by subunit AB attracted our attention and motivated the studies described herein. These challenges are (a) stereoselective aldol coupling to link fragments A and B, (b) application of configuration-encoded 1,5-polyol synthesis to fragment A, and (c) modification of the 1,5-polyol synthesis to access a 1,5,7-triol as found in fragment B. Preparation of Fragment A. Previously, we identified a C27−C40 analogue of fragment A (2, Scheme 3) as a 13651



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Scheme 3

Scheme 4

constants (13.2, 11.6, and 11.1 Hz) at the axial methylene proton, diagnostic for the indicated syn configuration.20 Next, we sought to establish the 1,5,9-triol stereochemistry of the C26−C40 fragment using our iterative configurationencoded 1,5-polyol strategy (Scheme 5). Silylation of

subtarget en route to tetrafibricin; this was reported in a preliminary communication and is briefly summarized here.12 Access to 2 began with implementation of the iterative configuration-encoded 1,5-polyol synthesis in two iterations from (S)-1 and aldehyde 3, prepared from 3-(pmethoxybenzyloxy)propanal.16 Each iteration entails Julia− Kocienski olefination followed by DIBAL-H reduction of the nitrile (4a or 5a) to the corresponding aldehyde (4b or 5b); the configurations of the hydroxyl groups within each subunit defined their syn-1,5-diol relationships after assembly. A Wittig reaction employing a stabilized ylide added two more carbons to construct the C27−C40 chain with all stereochemistry defined in enal (E,E,E)-6. Further advancement of 6 required adjustment of the C38− C40 functionality via a two-stage reduction. For this purpose, we employed an in situ generated copper hydride reagent for conjugate reduction of the enal,17 followed by typical aluminum hydride reduction conditions to furnish the corresponding primary alcohol 2. This sequence assembled a 1,5-polyol in very rapid fashion and also established a sequence to manage the functionality at the C40 terminus as needed for the synthetic route to tetrafibricin. The developments of Scheme 3 proved valuable information after a revision to the fragment coupling plans dictated that we would employ a C26−C40 fragment, i.e., a homologue of 2, as represented by fragment A (Scheme 2). The revised route would require a methyl ketone at one terminus in order to prepare a silyl enol ether for Mukaiyama aldol coupling; this extra carbon was introduced at the beginning of the sequence. Asymmetric cyanation of known enantiopure 3-hydroxybutanal derivative 718 (Scheme 4) with Me3SiCN catalyzed by Ti(O-iPr)4 (10 mol %) and ligand (R)-819 (10 mol %) afforded cyanohydrin 9 in 77% yield with high diastereoselectivity (dr 90:10 by 1H NMR); 75% recovery of ligand (R)-8 enabled recycling. In order to determine configuration, the diastereomers of 9 were separately subjected to oxidative cyclizations with DDQ under anhydrous conditions, generating PMP acetals (S,S)-9a and (R,S)-9b in 83% and 60% yields, respectively. The acetal (S,S)-9a that had been obtained from the major diastereomer exhibited three large coupling

Scheme 5

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cyanohydrin 9 (TBSCl and imidazole, 95% yield) and nitrile reduction with DIBAL-H furnished aldehyde 10b, setting the stage. The first Julia−Kocienski coupling with α-siloxy-γsulfononitrile building block (S)-1 afforded olefin 11a in 76% yield with E/Z > 95:5 as judged by 1H NMR. Next, DIBAL-H reduction to aldehyde 11b and a second iteration of the Julia− Kocienski olefination with (S)-1 afforded diene 12a in 79% yield and E/Z > 95:5. Another DIBAL-H reduction afforded the aldehyde 12b in 63% yield. An unusual finding on workup procedures in the DIBAL-H reduction of the α-silyloxynitriles in Schemes 4 and 5 is important to note here. During workup of the crude product from reduction of α-siloxynitrile 10a (1.5 equiv DIBAL-H, PhMe, 0 °C), the intermediate N-aluminoimine is hydrolyzed to the desired α-silyloxyaldehyde 10b.21 In the particular examples of Schemes 4 and 5, the N-aluminoimine was surprisingly difficult to hydrolyze without epimerization; we had not encountered this problem in the preliminary studies.12 After screening various conditions, we found that rapidly passing an ethereal solution of the crude material through a column of silica gel achieved the N-aluminoimine hydrolysis without epimerization (dr >95:5). Interestingly, with less polar eluent such as 1:3 diethyl ether/petroleum ether, this column workup led to significant epimerization (dr 76:24). On the other hand, in the DIBAL-H reduction of α-siloxynitrile 11a, hydrolysis was incomplete when eluting through silica gel with diethyl ether alone, but with 1:2 Et2O/petroleum ether there was complete hydrolysis without epimerization. Similar workup in the DIBAL-H reduction of α-silyloxynitrile 12a was best achieved with 1:4 Et2O/petroleum ether as the eluent. These eluent polarity changes appear to manipulate a delicate balance between rates of aluminoimine hydrolysis and αepimerization. Both the solvent polarity itself as well as its role in the retention time of the substrate on silica gel may impact this scenario. From a practical standpoint, once this convenient chromatographic workup was identified, it reproducibly achieved complete hydrolysis without epimerization, affording each of the α-silyloxyaldehydes 10b−12b with high diastereomeric purity (dr >95:5). With the C26−C38 α-silyloxyaldehyde 12b in hand, stabilized ylide Wittig olefination (Scheme 5) afforded enal 13 (68%, E/Z > 95:5). This enal was subjected to a two-stage reduction without impacting the other alkenes. First, Stryker’s (Ph3PCuH)6 reagent22 reduced the enal to a mixture of saturated aldehyde 14 (70% yield) and the desired saturated alcohol 15 (21% yield); in the presence of deoxygenated water, complications from Cu-enolate side reactions were minimized. The aldehyde was further reduced by DIBAL-H, furnishing the saturated alcohol 15 in a total amount of 76% yield. Successive tosylation (TsCl, pyridine) and treatment with NaN3 in DMF then placed the required nitrogen at the C40 terminus. At the other terminus, oxidative cleavage of the PMB ether (DDQ) and Swern oxidation smoothly produced methyl ketone 16, the C26−C40 fragment of tetrafibricin. Adaptation to the 1,5,7-Triol. Preparation of Fragment B. Next, we sought to expand the repertoire of our configuration-encoded 1,5-polyol synthesis strategy for application to 1,5,7-triol systems that appear not only in tetrafibricin but also in a variety of other bioactive natural products such as bastimolide A23 (Figure 2a, antimalarial) and marinomycin A24 (antitumor, antimicrobial). We noted that two iterations of our polyol synthesis approach furnish a 1,5,9-triol complemented by two alkene functionalities and hypothesized that one of the

Figure 2. (a) Representative natural product with the 1,5,7-triol motif. (b) Strategy for 1,5,7-triol synthesis.

alkenes might be engaged regioselectively for the subsequent delivery of an additional hydroxyl equivalent, as implied in structures B and C (Figure 2b). Importantly, the configurationencoded approach allows for equally facile access to B in either the syn-1,5 relative configuration (as required for bastimolide) or the anti-1,5 relationship needed for tetrafibricin. To introduce the third hydroxyl, the Evans tactic of benzylidene acetal construction25 appeared well-suited, exploiting a free hydroxyl group to direct intramolecular conjugate addition upon an unsaturated ester. In the plan for the 1,5,7-triol synthesis, two configurationencoded building blocks with differentially protected hydroxyl groups were required in order to permit regioselectivity in hydroxyl-directed benzylidene acetal construction (see structure B, Figure 2b). We opted for selective desilylation, exploiting the differential reactivity of tert-butyldimethylsilyl (TBS) and tert-butyldiphenylsilyl (TBDPS) groups. The 1,5,9triol precursor 17a for such a substrate was available via a three-step sequence from O-(p-methoxybenzyl)glycolaldehyde, (S)-1a, and (R)-1b, as discussed in the accompanying paper (Scheme 6).26 The nitrile of 17a was reduced by DIBAL-H to the corresponding aldehyde 17b (Scheme 7), and methylenation with 5-(methylsulfonyl)-1-phenyl-1H-tetrazole (MeSO2PT)27 then provided terminal alkene 18. Oxidative hydrolysis of the Scheme 6

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Scheme 7

PMB ether of 18 and oxidation of the resulting allylic alcohol under Corey’s conditions provided methyl ester 19a (80% yield).28 Selective desilylation of the TBS ether with HCl furnished 19b (96% yield) with functionality in place for the intramolecular conjugate addition. The conditions described by Evans et al. entailed additions of benzaldehyde and t-BuOK in three portions at 0 °C; in the case at hand, this led to the desired reactivity, but only in 17% yield and with 58% recovery of alcohol 19b. Experimentation with altering the base, temperatures, and addition intervals led to improved results with a portionwise addition of both benzaldehyde and KHMDS at −50 °C with warming to 0 °C between additions. Under these conditions, construction of acetal 20 proceeded in 63% yield with excellent diastereoselectivity at the syn-1,3-diol moiety (syn/anti > 95:5) and 15% recovery of unreacted alcohol 19b. The syn-1,3 configuration of 20 was confirmed by two large vicinal coupling constants observed for the axial proton at C18 (Jgeminal = 13.1 Hz, Jvicinal = 11.3, 11.3 Hz), consistent with precedent for similar compounds.25 Thus, the anti,syn-1,5,7-triol stereochemistry was secured. Aldehyde functionality was needed at C25 for fragmentcoupling studies, as indicated in the retrosynthetic analysis (Scheme 2). Selective hydroboration at the terminal alkene (9BBN, then H2O2 and NaOAc) led to primary alcohol 21 in 68% yield with 7% recovery of unreacted olefin, after which Swern oxidation smoothly furnished aldehyde 22a, ready for application in the Mukaiyama aldol fragment coupling. Fragment Coupling Studies. In the proposed stereoselective coupling of 16 and 22a, the C15−C25 and C26−C40 fragments of tetrafibricin, the desired 1,3-anti induction was expected to be feasible via Mukaiyama aldol addition based on a variety of literature precedents both in methodology studies29,30 and in applications to more complex coupling reactions in natural product synthesis.31,32 Stereocontrol in such reactions has been explained in the context of electrostatic repulsion via the Reetz model (Figure 3a), although a more refined analysis later emerged in order to consider torsional strain effects, as indicated by the Evans model (Figure 3b). On the basis of our own experimental evidence, we suggest further refinements herein. Studies of the fragment coupling via Mukaiyama aldol with the expected 1,3-anti stereocontrol began with a model ketone 24, which was prepared from 1,12-dibromododecane (23) via

Figure 3. Two prominent stereocontrol models to rationalize 1,3-anti induction in nucleophilic additions in the presence of nonchelating Lewis acids.

successive Cu-catalyzed monoallylation,33 azide substitution,34 and Wacker oxidation35 (eq 1).

Enolsilane preparation from ketone 24 led to a regioisomer mixture 25a/25b (70:30) favoring the isomer derived from the kinetic enolate (Scheme 8).36 Aldol reaction of 25 with aldehyde 22a in the presence of BF3·OEt2 at low temperature furnished an excellent yield, but unfortunately, the fraction of 26 derived from the kinetic enolate exhibited a very disappointing diastereomer ratio (dr 57:43). After separation of the major diastereomer of 26a, directed reduction with triacetoxyborohydride37 furnished the anti-1,3-diol 27a, and removal of the silyl group (HF·pyr) gave triol 28. At this point, the relative configuration was confirmed by two independent methods. First, on treatment with acid and 2,2-dimethoxypropane, triol 28 gave two regioisomeric acetonide derivatives, both exhibiting methyl resonances at ca. 25 ppm in the 13 C NMR spectrum, consistent with anti,anti relative stereochemistry.38 A single syn relationship would be expected to give predominantly one syn acetonide derivative. Second, the 13 C NMR spectrum of triol 28 showed a peak at 63.8 ppm (DMSO-d6) for the central CHOH carbon of the 1,3,5stereotriad, confirming the anti,anti assignment by comparison with data from the Kishi Universal NMR Database.39 This confirmed that the aldol reaction had proceeded with the desired 1,3-anti stereoselectivity. However, the 57:43 ratio was 13654



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theoretical standpoint, Evans examined stereocontrol models A−F (Figure 4b, R = t-Bu, PG = Me) via semiempirical (AM1) computation and concluded that stereocontrol model A was favored by minimizing a combination of electrostatic repulsions and torsional strain. Branched alkyl groups were present in both the experimental and computational aspects of Evans’ analysis. In contrast, in our aldehyde substrate 22a the analogous substituent is unbranched at the point of attachment (R = CH2-alkyl). We suggest that this scenario should make models B and E more competitive with A because the indicated steric repulsion (red arrows in Figure 4b) is diminished when R is small. Because E leads to the syn diastereomer, its participation (or participation of both B and E) when R is small would produce lower 1,3-anti selectivity, consistent with our observations. Increasing the steric bulk of the group R to destabilize conformers B and E was not an option in the context of tetrafibricin, so we considered the alternative hypothesis that decreasing the steric bulk of the β-silyloxy substituent (OPG in Figure 4) could stabilize conformer A and bias the reaction toward the desired 1,3-anti-selective pathway. This could be tested simply by use of a smaller silyl protecting group. Toward this end, we made use of already available primary alcohol 21 (Scheme 9). Removal of the TBDPS group and replacement with TBS was followed by Swern oxidation to furnish aldehyde 22b, bearing a less sterically demanding β-silyloxy group. Mukaiyama aldol reaction with enolsilane 2536 then provided the desired adduct 26b with an improved diasteromer ratio of 71:29.40 This ratio, while still costly in a fragment coupling reaction, is a significant qualitative improvement, supporting the hypothesized role of conformer E in diminished stereocontrol. With improved selectivity at hand, the Mukaiyama aldol reaction was applied for coupling of the fully functionalized C15−C25 and C26−C40 fragments of tetrafibricin (Scheme 10). Enolization of azidoketone 16 and trapping with Me3SiCl proceeded with excellent selectivity at the terminal carbon (i.e., the kinetic enolate), providing the requisite enolsilane (fragment A). Then reaction of this enolsilane with aldehyde 22b (fragment B) in the presence of BF3·OEt2 produced a 71% yield of aldol adduct 33. Gratifyingly, the 1,3-anti selectivity was much improved (dr 87:13) relative to the exploratory reactions. Structural confirmation was achieved by anti-selective reduction with triacetoxyborohydride to give 34 and desilylation, yielding polyol 35 containing a 1,3,5,7-tetraol stereotetrad. This type of system can be subjected to comparative analysis with the Kishi Universal NMR Database, treating the 1,3,5,7-tetraol as two overlapping 1,3,5-triols. The two CHOH methines at C25 and C27 were found to have 13C NMR resonances at 63.8 ppm, diagnostic for the anti,anti,anti configuration. Thus, the C15−C40 portion of tetrafibricin was assembled with eight secondary alcohols correctly configured and with termini appropriately functionalized for further synthetic elaboration.

Scheme 8

clearly unsuitable for further progress in the synthesis of tetrafibricin. To understand and correct this unfortunate outcome, we revisited the aforementioned analysis by Evans et al. of 1,3-anti induction in the BF3·OEt2 -mediated Mukaiyama aldol reactions.30 On the experimental side, Evans reported coupling of enolsilane 29 with chiral β-silyloxy (PG = TBS) or β-alkoxy (PG = PMB) aldehydes 30a and 30b (Figure 4a) to afford aldols 31 with good 1,3-anti diastereoselectivities. From a

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CONCLUSION In conclusion, preparation of the C15−C25 and C26−C40 subunits of tetrafibricin was achieved using configurationencoded 1,5-polyol synthesis strategy. From a 3-hydroxybutyrate precursor, cyanation and two iterations of the 1,5-diol synthesis led to C26−C40 fragment 16. A new modification was introduced to allow for hydroxyl group addition to convert

Figure 4. (a) Typical examples of 1,3-anti selectivity in Lewis acid promoted Mukaiyama aldol additions to β-alkoxy- and β-silyloxyaldehydes. (b) Stereocontrol models presented by Evans et al. with branched substituents (R = i-Pr or t-Bu); red arrows indicate steric interactions disfavoring B and E. Evans attributed high anti selectivity to addition via model A. 13655



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Scheme 9

Scheme 10

The resulting C15−C40 portion of tetrafibricin contains all of the 1,5-diol units of the target and, therefore, constitutes a significant advance in validating the synthetic utility of our configuration-encoded 1,5-polyol synthesis strategy.

a 1,5-diol to a 1,5,7-triol; this tactic is addressable to a specific location in a polyol via selective deprotection of silyl ethers of modulated reactivity and was a key step en route to the C15− C25 fragment 22b. Coupling of these two fragments via nonchelating Mukaiama aldol reaction conditions gave new insights about the roles of β-silyloxy groups in 1,3-diastereocontrol in these reactions. Reducing the steric demand of a β-silyloxy substituent allowed for substantial improvement in stereocontrol, from dr 57:43 to >71:29 in a model compound, and dr 87:13 for fragment coupling to yield aldol 33 in the fully functionalized series. Notably, Wender’s scalable synthesis of bryostatin was hampered by poor 1,3-anti diastereocontrol in numerous attempts at aldol reactions of aldehyde acceptor 36 (eq 2);

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EXPERIMENTAL SECTION

Materials and Methods. Reactions employed oven- or flamedried glassware under nitrogen unless otherwise noted. THF, diethyl ether, CH2Cl2, benzene, and toluene were purchased inhibitor-free, sparged with argon, and passed through columns of activated alumina prior to use (dropwise addition of blue benzophenone ketyl solution revealed the THF purified in this manner sustained the blue color more readily than the control sample purified by distillation). Nitrogen was passed successively through columns of anhydrous CaSO4 and R3−11 catalyst for removal of water and oxygen, respectively. All other materials were used as received from commercial sources unless otherwise noted. Thin-layer chromatography (TLC) employed glass 0.25 mm silica gel plates with UV indicator. Flash chromatography columns were packed with 230−400 mesh silica gel as a slurry in the initial elution solvent. Gradient flash chromatography was conducted by adsorption of product mixtures on silica gel, packing over a short pad of clean silica gel as a slurry in hexane, and eluting with a continuous gradient from hexane to the indicated solvent. Radial chromatography refers to centrifugally accelerated thin-layer chromatography performed with a Chromatotron using commercially supplied rotors. Melting points are uncorrected. Nuclear magnetic resonance (NMR) data were obtained

Mukaiyama conditions gave “at best ∼1:1 dr”.41 Our results suggest that the bulky β-OTBDPS group may be responsible for this unfortunate outcome; further data and analysis are warranted on how the identity of a β-alkoxy or β-silyloxy group may impact the roles of various 1,3-diastereocontrol models in Figure 4. 13656



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at operating frequencies of 600, 500, 400, or 300 MHz for 1H and 150, 125, 100, or 75 MHz for 13C, respectively. Infrared spectra were recorded using a single beam FT-IR spectrophotometer by standard transmission methods or by use of an attenuated total reflectance (ATR) probe. Optical rotations were determined using a digital polarimeter operating at ambient temperature. Low- and highresolution mass spectra were obtained using sample introduction by dip, liquid chromatography, or gas chromatography. Combustion analyses were obtained from external commercial services. Chromatographic diastereomer ratio analyses employed GCMS with 15 mL × 0.25 mm i.d. × 0.25 μm F.T. 5% Phenyl−95% dimethylsiloxane column and helium as mobile phase or HPLC with Microsorb-MV Si 8 μm 100A or Chiralcel OD columns (2-propanol/hexane as mobile phase) or Chirex 3014 column (chloroform/hexane as mobile phase). In infrared spectra of cyanohydrins, nitrile peaks may be weak or absent if electronegative substituents are present at the α position.42 General Procedure A: Julia−Kocienski Reactions. To a solution of sulfononitrile (R)-1 or (S)-1 (1 equiv) in THF (0.03 M) was added NaHMDS or KHMDS (1 M in THF, 1.2 equiv) at −78 °C. After 45 min, the requisite aldehyde (1 equiv) in THF (0.2 M) was added to the reaction mixture at −78 °C. After 3 h at −78 °C, the reaction mixture was quenched with aqueous NH4Cl solution, allowed to warm to room temperature, and then extracted with EtOAc. The organic phase was washed with water and brine and then dried over Na2SO4. Concentration and gradient flash chromatography (petroleum ether to 50% EtOAc in petroleum ether) or radial chromatography (10−50% EtOAc in petroleum ether) afforded the alkene products. General Procedure B: DIBAL-H Reductions. The α-silyloxynitrile (1 equiv) was dissolved in toluene (0.04 M) and cooled to −78 °C. To this solution was added DIBAL-H (1 M in heptane, 1.5 equiv) at −78 °C. After 4 h, the reaction mixture was warmed slowly to −10 °C over period of 5 h, quenched with methanol (2 mL), and warmed to room temperature. A saturated solution of sodium potassium tartrate (Rochelle’s salt, 15 volumes) was added. After 12 h, the mixture was filtered over Celite, and the organic phase was washed with brine, dried over Na2SO4, and concentrated. Products were used directly without purification unless otherwise noted. (S)-4-(4-Methoxybenzyloxy)-2-hydroxybutanenitrile (43). A mixture of ligand (R)-3-(1H-imidazol-1-yl)-1,1′-bi-2-naphthol43 ((R)-8, 1.09 g, 3.09 mmol) and Ti(O-i-Pr)4 (0.88 g, 3.1 mmol) in CH2Cl2 (35 mL) was stirred for 1 h at room temperature and then cooled to −50 °C. TMSCN (8.25 mL, 61.9 mmol) was added at −50 °C. After 10 min, a solution of 3-(4-methoxybenzyloxy)propanal44 (6 g, 0.03 mol) in CH2Cl2 (100 mL) was added over 40 min. After 48 h at −50 °C, aq HCl (2 N, 400 mL) and EtOAc (200 mL) were added [CAUTION: hydrogen cyanide may be evolved from acidified reaction mixtures and extraction fractions; these should be handled in a hood], and the mixture was allowed to warm to room temperature. After 3 h, the mixture was partitioned between EtOAc (400 mL) and brine, and the organic phase was dried over Na2SO4. Concentration and gradient flash chromatography (petroleum ether to 50% EtOAc in petroleum ether) afforded the binaphthol ligand (90% recovery) and (S)-4-(4-methoxybenzyloxy)-2-hydroxybutanenitrile (43, 6.48 g, 95.5% yield) as a pale yellow oil: IR (film) 3426, 2936, 2869, 2238, 1613, 1514, 1249, 1105 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.25−7.20 (m, 2H), 6.89−6.84 (m, 2H), 4.65 (ddd, J = 7.7, 6.0, 4.2 Hz, 1H), 4.46 (ABq, Δν = 16.0 Hz, J = 11.3 Hz, 2H), 4.03 (d, J = 7.7 Hz, 1H), 3.86 (ddd, J = 9.7, 9.7, 3.5 Hz, 1H), 3.78 (s, 3H), 3.71 (ddd, J = 9.3, 4.6, 4.6 Hz, 1H), 2.20 (dddd, J = 14.7, 9.4, 4.3, 4.3 Hz, 1H), 1.98 (dddd, J = 14.6, 5.9, 5.0, 3.5 Hz, 1H); 13C{1H} NMR (75 MHz, CDCl3) δ 159.6, 129.7, 129.2, 119.6, 114.1, 73.5, 67.0, 61.1, 55.4, 34.1; MS (ESI) m/z (relative intensity) 239.0 [M + NH4]+, 12). Anal. Calcd for C12H15NO3: C, 65.14; H, 6.83; N, 6.33. Found: C, 64.84; H, 7.00; N, 6.36. Optical rotation was measured after the following step to avoid racemization. (S)-4-(4-Methoxybenzyloxy)-2-(tert-butyldimethylsilyloxy)butanenitrile (44). To a solution of the cyanohydrin prepared as described above (6.48 g, 29.3 mmol) in CH2Cl2 (350 mL) were added imidazole (5.5 g, 80 mmol) and tert-butyldimethylsilyl chloride

(6.6 g, 44 mmol) at room temperature. After 24 h, the reaction mixture was partitioned between water (150 mL) and CH2Cl2 (400 mL). The organic phase was washed with brine and dried over Na2SO4. Concentration and gradient flash chromatography (petroleum ether to 50% EtOAc in petroleum ether) afforded the title αsilyloxynitrile (44, 9.19 g, 93.7% yield, 80%ee) as a pale yellow viscous oil: [α]D26 −14.1 (c 17.5, CHCl3); IR (film) 2956, 2932, 2859, 2238, 1613, 1513, 1251, 1122 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.27− 7.23 (m, 2H), 6.91−6.86 (m, 2H), 4.67 (dd, J = 6.9, 6.7 Hz, 1H), 4.42 (s, 2H), 3.81 (s, 3H), 3.63−3.52 (m, 2H), 2.10−2.04 (m, 2H), 0.91 (s, 9H), 0.19 (s, 3H), 0.14 (s, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ 159.4, 130.1, 129.5, 120.3, 114.0, 73.1, 64.5, 59.0, 55.4, 36.8, 25.7, 18.2, −5.1, −5.3; MS (ESI) m/z (relative intensity) 335.1 (M+, 4), 336.1 ([M + H]+, 30), 353 ([M + NH4]+, 100). Anal. Calcd for C18H29NO 3Si: C, 64.44; H, 8.71; N, 4.17. Found: C, 64.58; H, 8.83; N, 4.21. HPLC retention times (Chiralcel OD-H, hexane/0.3% i-PrOH, 0.45 mL/min): tR 57.2 min (major), tR 80.4 min (minor).

(S)-4-(4-Methoxybenzyloxy)-2-(tert-butyldimethylsilyloxy)butanal (3). From the α-silyloxynitrile prepared as described above (380 mg, 1.13 mmol) via general procedure B was obtained unreacted α-silyloxynitrile (23 mg, 6% recovery) and 3 (313 mg, 82% yield) as a pale yellow viscous liquid: IR (film) 2954, 2930, 2857, 1737, 1514, 1250, 1096 cm−1; 1H NMR (300 MHz, CDCl3) δ 9.60 (d, J = 1.3 Hz, 1H), 7.25−7.22 (m, 2H), 6.89−6.84 (m, 2H), 4.40 (ABq, Δν = 13.9 Hz, J = 11.4 Hz, 2H), 4.18 (ddd, J = 5.9, 5.9, 1.3 Hz, 1H), 3.79 (s, 3H), 3.61 (ddd, J = 9.4, 6.1, 6.1, 1H), 3. 52 (ddd, J = 9.4, 5.9, 5.9 Hz, 1H), 2.01−1.86 (m, 2H), 0.92 (s, 9H), 0.09 (s, 3H), 0.06 (s, 3H); 13 C{1H} NMR (75 MHz, CDCl3) δ 204.1, 159.3, 130.4, 129.5, 113.9, 75.1, 72.8, 64.7, 55.4, 33.5, 25.9, 18.3, −4.5, −4.9; MS (ESI) m/ z (relative intensity) 338.1 (M+, 5), 361.1 ([M + Na]+, 18); HRMS (ESI-TOF) calcd for C18H 30O4NaSi ([M + Na]+) 361.1811, found 361.1818. This material was not sufficiently stable for combustion analysis or precise measurement of optical rotation.

(E,2S,6S)-8-(4-Methoxybenzyloxy)-2,6-di(tertbutyldimethylsilyloxy)oct-4-enenitrile (4a). From (S)-1 (260 mg, 0.645 mmol) and 3 (213 mg, 0.625 mmol) via general procedure A was obtained 4a (280 mg, 85% yield, E/Z 95:5) as a pale yellow viscous liquid: [α]D25 −0.80 (c 1.2, CHCl3); IR (film) 2955, 2930, 2857, 2067, 1641, 1631, 1513, 1361, 1250, 1111 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.29−7.25 (m, 2H), 6.90−6.85 (m, 2H), 5.69−5.60 (m, 1H), 5.57 (ddd, J = 15.6, 6.3, 6.3 Hz, 1H), 4.41 (ABq, Δν = 15.4 Hz, J = 11.1 Hz, 2H), 4.41 (m, 1H), 4.34−4.27 (m, 1H), 3.80 (s, 3H), 3.59−3.44 (m, 2H), 2.55−2.40 (m, 2H), 1.76 (m, apparent q, J = 6.3 Hz, 2H), 0.91 (s, 9H), 0.89 (s, 9H), 0.18 (s, 3H), 0.14 (s, 3H), 0.06 (s, 3H), 0.04 (s, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ 159.3, 139.2, 130.8, 129.6, 121.9, 119.8, 113.9, 72.9, 69.9, 66.5, 62.4, 55.5, 39.4, 38.4, 26.1, 25.7, 18.4, 18.3, −4.0, −4.7, −4.9, −5.1; MS (ESI) m/z (relative intensity) 519.8 (M+, 32), 536.9 ([M + NH4]+, 100); HRMS (ESI-TOF) calcd for C28H49NNaO4Si 2 ([M + Na]+) 542.3098, found 542.3115. For (Z)-4a: 1H NMR (300 MHz, CDCl3) δ 5.39 (ddd, J = 10.8, 6.9, 6.9 Hz, 1H), 4.63−4.51 (m, 1H), other peaks were not resolved.

(2S,4E,6S,8E,10S)-12-(4-Methoxybenzyloxy)-2,6,10-tri(tertbutyldimethylsilyloxy)dodeca-4,8-dienenitrile (5a). From 4a (215 mg, 0.414 mmol) via general procedure B was obtained unreacted 4a (30 mg, 14% recovery) and aldehyde 4b (168 mg, 78% yield) as a pale yellow viscous oil that was used directly in the subsequent step. 13657



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From (S)-1 (75 mg, 0.18 mmol) and aldehyde 4b (95 mg, 0.18 mmol) via general procedure A was obtained 5a (109.6 mg, 86% yield) as a pale yellow viscous oil: [α]D26 −4.9 (c 3.6, CHCl3); IR (film) 2956, 2895, 2857, 2226, 1613, 1514, 1463, 1362, 1257, 1113 cm−1; 1H NMR (300 MHz, CDCl3) δ7.27−7.24 (m, 2H), 6.89−6.86 (m, 2H), 5.68−5.47 (m, 3H), 5.44 (dd, J = 15.6, 6.0 Hz, 1H), 4.41 (ABq, Δν = 15.1 Hz, J = 11.4 Hz, 2H), 4.41 (dd, J = 6.3, 6.0 Hz, 1H), 4.28−4.20 (m, 1H), 4.13−4.09 (m, 1H), 3.80 (s, 3H), 3.57−3.42 (m, 2H), 2.56−2.40 (m, 2H), 2.29−2.16 (m, 2H), 1.74 (m, apparent q, J = 6.4 Hz, 2H), 0.91 (s, 9H), 0.89 (s, 9H), 0.88 (s, 9H), 0.18 (s, 3H), 0.14 (s, 3H), 0.05 (s, 3H), 0.04 (s, 6H), 0.02 (s, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ 159.3, 138.9, 138.8, 138.6, 136.4, 136.2, 130.9, 129.5, 125.9, 122.0, 119.8, 113.9, 72.9, 72.8, 70.7, 70.6, 66.8, 62.4, 62.3, 55.5, 41.6, 41.5, 39.4, 38.6, 26.1, 25.7, 18.4, 18.3, −3.9, −4.1, −4.6, −4.9, −5.1; MS (ESI) m/z (relative intensity) 721 ([M + NH4]+, 84), 354.11 (100). Anal. Calcd for C38H69NO5Si3: C, 64.81; H, 9.88; N, 1.99. Found: C, 65.07; H, 10.10; N, 2.06.

M in heptane, 0.1 mL, 0.1 mmol). After 10 h, the reaction mixture was quenched with saturated sodium potassium tartrate solution (12 mL). Concentration of the organic phase and radial chromatography (10% EtOAc in petroleum ether) afforded 2 (45.0 mg, 90% yield) as a colorless oil; IR (film) 2954, 2929, 2857, 1514, 1463, 1361, 1251, 1082 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.25−7.23 (m, 2H), 6.88−6.85 (m, 2H), 5.56−5.37 (m, 4H), 4.34 (ABq, Δν = 15.6 Hz, J = 11.4 Hz, 2H), 4.25−4.19 (m, 1H), 4.09−4.03 (m, 1H), 3.79 (s, 3H), 3.73−3.70 (m, 1H), 3.61−3.42 (m, 4H), 2.22−2.13 (m, 4H), 1.73 (m, apparent q, J = 6.3 Hz, 2H), 1.64−1.56 (m, 2H), 1.54−1.45 (m, 2H) 0.88 (s, 9H), 0.87 (s, 18H), 0.05 (s, 3H), 0.03 (s, 9H), 0.01 (s, 6H); 13C{1H} NMR (75 MHz, CDCl3) δ 159.4, 136.1, 136.0, 135.8, 130.9, 129.5, 126.4, 114.0, 73.5, 72.9, 72.1, 70.8, 70.7, 66.9, 63.2, 55.5, 41.8, 40.1, 38.7, 33.1, 32.9, 28.6, 26.1, 18.5, 18.3, −3.9, −4.1, −4.2, −4.5, −4.6; HRMS (EI-TOF) Calcd for C36H67O6Si3 ([M−t-Bu]+): 679.4246, found 679.4260. The [M − 57]+ peak is a diagnostic proxy for molecular weight in mass spectrometry of TBS ethers.45

(2E,4S,6E,8S,10E,12S)-14-(4-Methoxybenzyloxy)-4,8,12-tri(tertbutyldimethylsilyloxy)tetradeca-2,6,10-trienal (6). From 5a (92 mg, 0.13 mmol) via general procedure B was obtained aldehyde 5b (76 mg, 82% yield) as a colorless oil which was used directly in the subsequent step. To a solution of aldehyde 5b (50 mg, 0.071 mmol) in benzene (3 mL) was added (triphenylphosphoranylidene)acetaldehyde (35 mg, 0.11 mmol). The reaction mixture was heated at 80 °C for 14 h. Concentration and radial chromatography (5% EtOAc in petroleum ether) afforded an inseparable mixture of minor isomers (2.5 mg, 4.8%) and isomerically pure 6 (46.0 mg, 89% yield): [α]D23 +3.8 (c 0.98, CHCl3); IR (film) 2955, 2928, 2856, 1693, 1613, 1514, 1462, 1361, 1250, 1087 cm−1; 1H NMR (300 MHz, CDCl3) δ 9.55 (d, J = 8.0 Hz, 1H), 7.26−7.24 (m, 2H), 6.89−6.85 (m, 2H), 6.78 (dd, J = 15.5, 4.2 Hz, 1H), 6.26 (ddd, J = 15.5, 8.0, 1.5 Hz, 1H), 5.60−5.47 (m, 3H), 5.43 (dd, J = 15.2, 6.1 Hz, 1H), 4.49−4.40 (m, 1H), 4.40 (ABq, Δν = 15.6 Hz, J = 11.4 Hz, 1H), 4.23 (dddd, J = 6.2, 6.2, 6.2, 3.8 Hz, 1H), 4.11−4.02 (m, 1H), 3.79 (s, 3H), 3.58−3.42 (m, 2H), 2.40−2.28 (m, 2H), 2.25−2.10 (m, 2H), 1.73 (m, apparent q, J = 6.3 Hz, 2H), 0.90 (s, 9H), 0.87 (s, 18H), 0.07 (s, 3H), 0.04 (s, 3H), 0.031 (s, 3H), 0.026 (s, 3H), 0.01 (s, 3H), −0.01 (s, 3H); 13 C{1H} NMR (75 MHz, CDCl3) δ 193.8, 159.7, 159.3, 136.1, 132.2, 130.9, 129.5, 126.0, 124.3, 113.9, 72.8, 71.7, 70.5, 66.8, 55.5, 41.6, 40.4, 38.6, 29.9, 26.1, 26.0, 18.4, 1.2, −3.9, −4.2, −4.5, −4.6; MS (ESI) m/ z (relative intensity) 750.02 ([M + NH4] +, 100%); HRMS (ESI-TOF) calcd for C40H72NaO6Si3 ([M + Na]+) 755.4534, found 755.4537.

(2S,4S)-2-Hydroxy-4-((4-methoxybenzyl)oxy)pentanenitrile (9). A mixture of ligand (R)-819 (0.501 g, 1.42 mmol) and Ti(O-i-Pr)4 (0.42 mL, 1.42 mmol) in CH2Cl2 (19 mL) was stirred for 1 h at room temperature. TMSCN (3.56 mL, 28.48 mmol) was added at −50 °C, and after 10 min, aldehyde 746 (2.965 g, 14.24 mmol) in CH2Cl2 (57 mL) was slowly added by cannula over 25 min. After 51 h at −50 °C, aq HCl (2 M, 150 mL) and EtOAc (75 mL) were added at −50 °C [CAUTION: hydrogen cyanide may be evolved from acidified reaction mixtures and extraction fractions; these should be handled in a hood], and the mixture was allowed to warm to room temperature. After 15 h, the mixture was extracted with EtOAc (3 × 100 mL). The organic phase was washed with brine (25 mL) and dried over anhydrous Na2SO4. Concentration and gradient flash chromatography (petroleum ether to 25% EtOAc in petroleum ether) afforded cyanohydrin 9 (2.575 g, 77% yield, dr 90:10) as a yellow oil, and elution with MeOH provided ligand (R)-8 (75% recovery). The S,S/R,S diastereomers of 9 were separated by flash chromatography (1% MeOH in CHCl3) with the minor (R,S)-diastereomer eluting before the major (S,S)-diastereomer, and their ratios were determined by 1H NMR. For (S,S)-9: [α]D21 +76.1 (c 1.96, CHCl3); IR (film) 3429, 2971, 2934, 2838, 1613, 1559, 1540, 1514, 1466, 1377, 1303, 1250, 1176, 1142, 1033 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.24 (d, J = 8.6 Hz, 2H), 6.89 (d, J = 8.6 Hz, 2H), 4.65 (ddd, J = 8.9, 5.4, 3.8 Hz, 1H), 4.59 (d, J = 11.0 Hz, 1H), 4.33 (d, J = 11.0 Hz, 1H), 3.89−3.82 (m, 1H), 3.81 (s, 3H), 3.72−3.69 (m, 1H), 2.10 (ddd, J = 14.4, 9.7, 8.1 Hz, 1H), 1.98 (ddd, J = 14.4, 5.4, 3.3 Hz, 1H), 1.30 (d, J = 6.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 159.6, 129.7, 129.6, 119.6, 114.2, 73.4, 70.4, 60.6, 55.4, 41.8, 19.4; HRMS (ESITOF) m/z [M + Na]+ calcd for C13H17NO3Na 258.1106, found 258.1108. Anal. Calcd for C13H17NO3: C, 66.36; H, 7.28; N, 5.95. Found: C, 66.07; H, 7.39; N, 5.93. For (R,S)-9: 1H NMR (400 MHz, CDCl3) δ 7.33 (d, J = 8.7 Hz, 2H), 6.94 (d, J = 8.7 Hz, 2H), 4.68− 4.64 (m, 2H), 4.46 (d, J = 10.2 Hz, 1H), 4.24−4.16 (m, 1H), 3.85 (s, 3H), 3.83−3.82 (m, 1H), 2.08 (ddd, J = 14.9, 10.3, 3.2 Hz, 1H), 1.97 (ddd, J = 14.9, 5.8, 3.2 Hz, 1H), 1.34 (d, J = 6.1 Hz, 3H). The configurations of the S,S and R,S-9 diastereomers were determined by conversion to their corresponding PMP-acetals.

(4R,6E,8S,10E,12S)-14-(4-Methoxybenzyloxy)-4,8,12-tri(tertbutyldimethylsilyloxy)tetradeca-6,10-dien-1-ol (2). To a solution of CuI (18 mg, 0.092 mmol) and HMPA (0.81 mL, 4.3 mmol) in THF (2 mL) at 0 °C was added DIBALH (1.5 mL, 1.5 mmol). After 20 min, α,β-unsaturated aldehyde 6 (60 mg, 0.31 mmol) was added at 0 °C. After 2 h, the reaction mixture was quenched with saturated sodium potassium tartrate solution (10 mL) and filtered through Celite pad. Concentration of the organic phase yielded the corresponding saturated aldehyde (45, 54.0 mg, 90% yield) as a colorless oil used without further purification; 1H NMR (300 MHz, CDCl3) δ 9.75 (t, J = 1.8 Hz, 1H), 7.26−7.23 (m, 2H), 6.88−6.85 (m, 2H), 5.57−5.38 (m, 4H), 4.40 (ABq, Δν = 15.6 Hz, J = 11.4 Hz, 2H), 4.23 (dddd, J = 6.2, 6.2, 6.2, 3.8 Hz, 1H), 4.09−4.06 (m, 1H), 3.80 (s, 3H), 3.78−3.53 (m, 1H), 3.52−3.45 (m, 2H), 2.48−2.43 (m, 2H), 2.23−2.18 (m, 4H), 1.80−1.65 (m, 4H), 0.88 (s, 9H), 0.87 (s, 18H), 0.09 (s, 3H), 0.05 (s, 3H), 0.03 (s, 9H), 0.01 (s, 3H). To a solution of aldehyde prepared as described above (50 mg, 0.068 mmol) in CH2Cl2 (10 mL) at −78 °C was added DIBALH (1

(2S,4S,6S)-2-(4-Methoxyphenyl)-6-methyl-1,3-dioxane-4-carbonitrile ((S,S)-9a). To a solution of cyanohydrin (S,S)-9 (84.8 mg, 0.360 mmol) in CH2Cl2 (1.2 mL) at 0 °C was added DDQ (81.7 mg, 0.360 mmol). After 2.5 h, the reaction mixture was partitioned between saturated aq NaHCO3 (2 mL), H2O (5 mL), and CH2Cl2 (3 13658



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× 5 mL). The organic phase was then washed with brine (1 mL) and dried over anhydrous Na2SO4. Concentration and radial chromatography (17% EtOAc in petroleum ether) afforded (S,S)-9a (69.7 mg, 83% yield) as a colorless solid: mp 79−81 °C; [α]D22 −34.5 (c 1.58, CHCl3); IR (film) 2977, 2935, 2871, 2840, 1615, 1589, 1518, 1457, 1404, 1381, 1330, 1305, 1256, 1174, 1137, 1108, 1074, 1031 cm−1; 1 H NMR (400 MHz, CDCl3) δ 7.42 (d, J = 8.8 Hz, 2H), 6.90 (d, J = 8.8 Hz, 2H), 5.47 (s, 1H), 4.74 (dd, J = 11.5, 3.2 Hz, 1H), 4.00−3.92 (m, 1H), 3.81 (s, 3H), 2.00 (ddd, J = 13.2, 11.6, 11.1 Hz, 1H), 1.92 (ddd, J = 13.2, 2.8, 2.8 Hz, 1H), 1.35 (d, J = 6.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 160.5, 129.4, 127.7, 117.2, 113.9, 101.5, 72.5, 64.7, 55.4, 36.1, 21.3; HRMS (ESI-TOF) m/z [M + H]+ calcd for C13H16NO3 234.1130, found 234.1135. Anal. Calcd for C13H15NO3: C, 66.94; H, 6.48; N, 6.00. Found: C, 66.75; H, 6.44; N, 5.94.

(2S,6S,8S,E)-2,6-Bis((tert-butyldimethylsilyl)oxy)-8-((4methoxybenzyl)oxy)non-4-enenitrile (10b). To a solution of nitrile 10a (0.640 g, 1.83 mmol) in toluene (46 mL) at 0 °C was added DIBAL-H (1 M in heptane, 2.75 mL, 2.75 mmol) dropwise. After 6 h, MeOH (6 mL) was slowly added to quench the remaining DIBAL-H, and the reaction mixture was allowed to warm to room temperature. After 1 h, the reaction mixture was diluted with Et2O (46 mL) and washed with saturated aq Rochelle’s salt (sodium potassium tartrate, 92 mL). The mixture was then filtered through Celite and extracted with Et2O (2 × 46 mL). The organic phase was dried over anhydrous Na2SO4. Concentration and passage through SiO2 (35 × 5 cm, Et2O) afforded the crude aldehyde 10b (0.383 g, 59% yield, S,S/R,S = 98:2 by 1H NMR integration) as a pale yellow oil: 1H NMR (300 MHz, CDCl3) δ 9.54 (s, 1H), 7.23 (d, J = 8.8 Hz, 2H), 6.86 (d, J = 8.8 Hz, 2H), 4.44 (d, J = 11.1 Hz, 1H), 4.32 (d, J = 11.1 Hz, 1H), 4.08 (dd, J = 6.3, 3.4 Hz, 1H), 3.83−3.75 (m, 1H), 3.79 (s, 3H), 2.07 (ddd, J = 14.2, 9.6, 3.4 Hz, 1H), 1.81 (ddd, J = 14.2, 6.3, 3.6 Hz, 1H), 1.18 (d, J = 6.2 Hz, 3H), 0.93 (s, 9H), 0.10 (s, 3H), 0.06 (s, 3H). The aldehyde 10b was used immediately in the subsequent step without further purification. Using an alternative purification method, the undesired epimerization product (R,S)-10b was observed: The reaction mixture from DIBAL-H reduction of 10a was purified by flash chromatography (3:1 petroleum ether/Et2O) to afford aldehyde 10b (33% yield, S,S/R,S 76:24). For minor (R,S)-10b, 1H NMR (300 MHz, CDCl3) δ 9.57 (d, J = 1.6 Hz, 1H), 4.52 (d, J = 10.8 Hz, 1H), 3.80 (s, 3H), 1.94 (ddd, J = 14.1, 9.2, 3.9 Hz, 1H), 0.08 (s, 3H), other peaks were not resolved.

(2S,4R,6S)-2-(4-Methoxyphenyl)-6-methyl-1,3-dioxane-4-carbonitrile ((R,S)-9b). To a solution of cyanohydrin (R,S)-9 (80.5 mg, 0.342 mmol) in CH2Cl2 (1.1 mL) at 0 °C was added DDQ (77.7 mg, 0.342 mmol). After 2.5 h, the reaction mixture was partitioned between saturated aq NaHCO3 (2 mL), H2O (5 mL), and CH2Cl2 (3 × 5 mL). The organic phase was then washed with brine (1 mL) and dried over anhydrous Na2SO4. Concentration and radial chromatography (17% EtOAc in petroleum ether) afforded (R,S)-9b (47.6 mg, 60% yield) as a colorless oil: [α]D21 +8.11 (c 0.950, CHCl3); IR (film) 2976, 2935, 2872, 2839, 1615, 1590, 1519, 1457, 1402, 1380, 1306, 1252, 1174, 1127, 1111, 1065, 1033 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.42 (d, J = 8.9 Hz, 2H), 6.91 (d, J = 8.9 Hz, 2H), 5.91 (s, 1H), 5.10−5.08 (m, 1H), 4.34−4.26 (m, 1H), 3.81 (s, 3H), 2.06 (ddd, J = 13.8, 11.4, 5.8 Hz, 1H), 1.82 (ddd, J = 13.8, 2.2, 1.5 Hz, 1H), 1.36 (d, J = 6.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 160.5, 129.6, 127.7, 117.5, 113.9, 98.4, 70.2, 63.7, 55.5, 34.7, 21.3; HRMS (ESI-TOF) m/z [M + H]+ calcd for C13H16NO3 234.1130, found 234.1137. Anal. Calcd for C13H15NO3: C, 66.94; H, 6.48; N, 6.00. Found: C, 66.69; H, 6.68; N, 5.94.

(2S,6S,8S,E)-2,6-Bis((tert-butyldimethylsilyl)oxy)-8-((4methoxybenzyl)oxy)non-4-enenitrile (11a). To a solution of sulfone (S)-1 (0.886 g, 2.17 mmol) in THF (44 mL) at −78 °C was slowly added KHMDS (0.5 M in toluene, 4.13 mL, 2.06 mmol) by syringe over 10 min. After 1 h, a solution of aldehyde 10b (0.383 g, 1.09 mmol) in THF (5.4 mL) was slowly added by syringe over 10 min. After 4 h, the reaction was quenched with saturated aq NH4Cl (8 mL) and H2O (8 mL), allowed to warm to room temperature over 30 min, and extracted with EtOAc (3 × 25 mL). The organic phase was washed with brine (5 mL) and dried over anhydrous Na2SO4. Concentration and gradient flash chromatography (petroleum ether to Et2O) afforded unreacted sulfone (S)-1 (58% recovery without loss of enantiopurity as judged by optical rotation measurement) and 11a (0.439 g, 45% yield over two steps, E/Z > 95:5, S,S,S/S,R,S > 95:5) as a colorless oil: [α]D22 +7.30 (c 1.15, CHCl3); IR (film) 2956, 2931, 2886, 2858, 1614, 1559, 1514, 1463, 1362, 1302, 1250, 1111, 1040 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.26 (d, J = 8.7 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H), 5.59 (dd, J = 15.3, 6.6 Hz, 1H), 5.45 (dddd, J = 15.2, 7.0, 7.0, 0.7 Hz, 1H), 4.49 (d, J = 11.4 Hz, 1H), 4.38 (dd, J = 6.3, 6.3 Hz, 1H), 4.34 (d, J = 11.4 Hz, 1H), 4.25 (ddd, J = 6.5, 6.5, 6.5 Hz, 1H), 3.80 (s, 3H), 3.61−3.53 (m, 1H), 2.47−2.43 (m, 2H), 1.91 (ddd, J = 13.6, 7.5, 6.1 Hz, 1H), 1.49 (ddd, J = 13.6, 7.1, 5.4 Hz, 1H), 1.19 (d, J = 6.1 Hz, 3H), 0.91 (s, 9H), 0.87 (s, 9H), 0.18 (s, 3H), 0.14 (s, 3H), 0.04 (s, 3H), 0.03 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 159.2, 139.3, 131.3, 129.4, 122.2, 119.7, 113.8, 71.4, 70.6, 69.8, 62.1, 55.4, 45.7, 39.3, 26.0, 25.6, 19.9, 18.3, 18.2, −4.0, −4.7, −5.0, −5.2; HRMS (EI-TOF) m/z [M]+ calcd for C29H51NO4Si2 533.3357, found 533.3378. Anal. Calcd for C29H51NO4Si2: C, 65.24; H, 9.63; N, 2.62. Found: C, 65.50; H, 9.76; N, 2.70.

4(2S,4S)-2-((tert-Butyldimethylsilyl)oxy)-4-((4-methoxybenzyl)oxy)pentanenitrile (10a). To a solution of cyanohydrin (S,S)-9 (1.52 g, 6.47 mmol) in CH2Cl2 (72 mL) were added imidazole (1.10 g, 16.18 mmol) and tert-butyldimethylsilyl chloride (1.46 g, 9.70 mmol). After 42 h, the reaction mixture was partitioned between H2O (75 mL) and CH2Cl2 (3 × 50 mL). The organic phase was washed with brine (10 mL) and dried over anhydrous Na2SO4. Concentration and gradient flash chromatography (petroleum ether to 20% EtOAc in petroleum ether) afforded 10a (2.32 g, quantitative yield) as a colorless oil: [α]D21 +29.2 (c 1.22, CHCl3); IR (film) 2956, 2932, 2886, 2859, 1614, 1559, 1514, 1467, 1376, 1340, 1303, 1250, 1174, 1119, 1037 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.27 (d, J = 8.7 Hz, 2H), 6.89 (d, J = 8.7 Hz, 2H), 4.64 (dd, J = 9.0, 5.6 Hz, 1H), 4.54 (d, J = 11.0 Hz, 1H), 4.36 (d, J = 11.0 Hz, 1H), 3.83−3.74 (m, 1H), 3.81 (s, 3H), 2.02 (ddd, J = 13.8, 9.3, 5.6 Hz, 1H), 1.92 (ddd, J = 13.7, 9.0, 3.9 Hz, 1H), 1.25 (d, J = 6.1 Hz, 3H), 0.90 (s, 9H), 0.18 (s, 3H), 0.12 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 159.4, 130.5, 129.5, 120.2, 114.0, 71.0, 70.7, 60.0, 55.4, 43.8, 25.6, 19.7, 18.1, −5.0, −5.2; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C19H31NO3SiNa 372.1971, found 372.1984. Anal. Calcd for C19H31NO3Si: C, 65.29; H, 8.94; N, 4.01. Found: C, 65.57; H, 8.94; N, 4.04.

(2S,6S,8S,E)-2,6-Bis((tert-butyldimethylsilyl)oxy)-8-((4methoxybenzyl)oxy)non-4-enal (11b). To a solution of nitrile 11a (0.529 g, 0.992 mmol) in toluene (25 mL) at 0 °C was added DIBALH (1 M in heptane, 1.49 mL, 1.49 mmol) dropwise. After 5 h, MeOH (3 mL) was slowly added to quench the remaining DIBAL-H, and the 13659



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6.86 (d, J = 8.6 Hz, 2H), 5.58−5.49 (m, 2H), 5.47−5.36 (m, 2H), 4.46 (d, J = 11.3 Hz, 1H), 4.34 (d, J = 11.3 Hz, 1H), 4.19 (ddd, J = 6.4, 6.4, 6.4 Hz, 1H), 4.10−4.04 (m, 1H), 4.00 (ddd, J = 5.9, 5.9, 1.5 Hz, 1H), 3.80 (s, 3H), 3.60−3.54 (m, 1H), 2.39−2.36 (m, 2H), 2.24−2.13 (m, 2H), 1.92 (ddd, J = 13.6, 6.8, 6.8 Hz, 1H), 1.49−1.41 (m, 1H), 1.18 (d, J = 6.1 Hz, 3H), 0.92 (s, 9H), 0.87 (s, 9H), 0.86 (s, 9H), 0.08 (s, 3H), 0.07 (s, 3H), 0.03 (s, 3H), 0.02 (s, 3H), 0.01 (s, 6H). The aldehyde 12b was used immediately in the subsequent step without further purification.

reaction mixture was allowed to warm to room temperature. After 1 h, the reaction mixture was diluted with Et2O (25 mL) and washed with saturated aq Rochelle’s salt (sodium potassium tartrate, 50 mL). The mixture was then filtered through Celite and extracted with Et2O (2 × 25 mL). The organic phase was dried over anhydrous Na2SO4. Concentration and passage through SiO2 (30 × 4 cm, 2:1 petroleum ether/Et2O) afforded the crude aldehyde 11b (0.316 g, 59% yield) as a pale yellow oil: 1H NMR (300 MHz, CDCl3) δ 9.57 (d, J = 1.5 Hz, 1H), 7.25 (d, J = 8.6 Hz, 2H), 6.87 (d, J = 8.6 Hz, 2H), 5.59−5.38 (m, 2H), 4.48 (d, J = 11.3 Hz, 1H), 4.33 (d, J = 11.3 Hz, 1H), 4.23− 4.17 (m, 1H), 4.00 (ddd, J = 5.9, 5.9, 1.5 Hz, 1H), 3.80 (s, 3H), 3.58−3.52 (m, 1H), 2.45−2.31 (m, 2H), 1.90 (ddd, J = 13.5, 7.1, 6.4 Hz, 1H), 1.46 (ddd, J = 13.4, 6.9, 6.0 Hz, 1H), 1.19 (d, J = 6.1 Hz, 3H), 0.92 (s, 9H), 0.86 (s, 9H), 0.09 (s, 3H), 0.08 (s, 3H), 0.02 (s, 3H), 0.01 (s, 3H). The aldehyde 11b was used immediately in the subsequent step without further purification.

(2E,4S,6E,8S,10E,12S,14S)-4,8,12-Tris((tert-butyldimethylsilyl)oxy)-14-((4-methoxybenzyl)oxy)pentadeca-2,6,10-trienal (13). To a solution of aldehyde 12b (0.284 g, 0.394 mmol) in benzene (20 mL) was added (triphenylphosphoranylidene)acetaldehyde (0.240 g, 0.788 mmol). The reaction mixture was then heated at reflux for 41 h and cooled to room temperature. After 20 h, the reaction mixture was concentrated, and gradient flash chromatography (petroleum ether to Et2O) afforded unreacted aldehyde 12b (9% recovery) and trienal 13 (0.200 g, 43% yield over two steps, E,E,E/Z,E,E > 95:5, S,S,S,S/ R,S,S,S > 95:5) as a yellow oil: [α]D21 +38.3 (c 1.73, CHCl3); IR (film) 2955, 2930, 2895, 2857, 1693, 1514, 1462, 1361, 1250, 1080 cm−1; 1H NMR (400 MHz, CDCl3) δ 9.54 (d, J = 8.0 Hz, 1H), 7.24 (d, J = 8.6 Hz, 2H), 6.86 (d, J = 8.6 Hz, 2H), 6.76 (dd, J = 15.5, 4.3 Hz, 1H), 6.26 (ddd, J = 15.5, 8.0, 1.6 Hz, 1H), 5.56−5.47 (m, 2H), 5.47−5.38 (m, 2H), 4.48−4.43 (m, 1H), 4.46 (d, J = 11.3 Hz, 1H), 4.34 (d, J = 11.3 Hz, 1H), 4.19 (ddd, J = 6.4, 6.4, 6.4 Hz, 1H), 4.11− 4.07 (m, 1H), 3.79 (s, 3H), 3.61−3.53 (m, 1H), 2.38−2.28 (m, 2H), 2.26−2.13 (m, 2H), 1.92 (ddd, J = 13.5, 6.7, 6.7 Hz, 1H), 1.45 (ddd, J = 13.3, 6.3, 6.3 Hz, 1H), 1.18 (d, J = 6.1 Hz, 3H), 0.91 (s, 9H), 0.87 (s, 9H), 0.86 (s, 9H), 0.07 (s, 3H), 0.04 (s, 3H), 0.03 (s, 3H), 0.02 (s, 3H), 0.01 (s, 3H), 0.00 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 193.5, 159.3, 159.1, 136.9, 136.1, 131.3, 131.2, 129.2, 126.3, 124.2, 113.8, 72.9, 71.9, 71.5, 71.3, 69.9, 55.4, 45.8, 41.5, 40.3, 26.04, 25.98, 25.9, 19.9, 18.4, 18.30, 18.29, −3.9, −4.2, −4.61, −4.62, −4.65, −4.71; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C41H74O6Si3Na 769.4691, found 769.4709. Anal. Calcd for C41H74O6Si3: C, 65.90; H, 9.98. Found: C, 66.00; H, 10.01.

(2S,4E,6S,8E,10S,12S)-2,6,10-Tris((tert-butyldimethylsilyl)oxy)12-((4-methoxybenzyl)oxy)trideca-4,8-dienenitrile (12a). To a solution of sulfone (S)-1 (0.480 g, 1.18 mmol) in THF (24 mL) at −78 °C was slowly added KHMDS (0.5 M in toluene, 2.24 mL, 1.12 mmol) by syringe over 5 min. After 1 h, a solution of aldehyde 11b (0.316 g, 0.588 mmol) in THF (2.9 mL) was slowly added by syringe over 5 min. After 5 h, the reaction was quenched with saturated aq NH4Cl (5 mL) and H2O (5 mL), allowed to warm to room temperature over 30 min, and extracted with EtOAc (3 × 30 mL). The organic phase was washed with brine (5 mL) and dried over anhydrous Na2SO4. Concentration and gradient flash chromatography (petroleum ether to Et2O) afforded unreacted sulfone (S)-1 (50% recovery without loss of enantiopurity) and 12a (0.335 g, 47% yield over two steps, E,E/Z,E > 95:5, S,S,S,S/S,R,S,S > 95:5) as a colorless oil: [α]D21 +6.77 (c 1.55, CHCl3); IR (film) 2955, 2930, 2896, 2857, 1614, 1559, 1513, 1463, 1362, 1302, 1255, 1116 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.25 (d, J = 8.5 Hz, 2H), 6.86 (d, J = 8.6 Hz, 2H), 5.67−5.54 (m, 2H), 5.51−5.39 (m, 2H), 4.47 (d, J = 11.3 Hz, 1H), 4.40 (dd, J = 6.3, 6.3 Hz, 1H), 4.35 (d, J = 11.3 Hz, 1H), 4.20 (ddd, J = 6.4, 6.4, 6.4 Hz, 1H), 4.12−4.11 (m, 1H), 3.80 (s, 3H), 3.62−3.54 (m, 1H), 2.52−2.41 (m, 2H), 2.28−2.16 (m, 2H), 1.93 (ddd, J = 13.5, 6.7, 6.7 Hz, 1H), 1.46 (ddd, J = 13.4, 6.3, 6.3 Hz, 1H), 1.19 (d, J = 6.1 Hz, 3H), 0.91 (s, 9H), 0.89 (s, 9H), 0.87 (s, 9H), 0.18 (s, 3H), 0.14 (s, 3H), 0.05 (s, 3H), 0.04 (s, 3H), 0.03 (s, 3H), 0.02 (s, 3H); 13 C{1H} NMR (100 MHz, CDCl3) δ 159.1, 138.7, 136.3, 131.4, 129.2, 126.2, 122.1, 119.6, 113.9, 72.7, 71.9, 71.3, 69.9, 62.2, 55.4, 45.8, 41.4, 39.3, 26.05, 26.01, 25.7, 19.9, 18.4, 18.3, 18.2, −3.9, −4.3, −4.62, −4.65, −5.0, −5.2; HRMS (EI-TOF) m/z [M]+ calcd for C 39 H 71 NO 5 Si 3 717.4640, found 717.4626. Anal. Calcd for C39H71NO5Si3: C, 65.22; H, 9.96; N, 1.95. Found: C, 65.34; H, 10.02; N, 1.99.

(4R,6E,8S,10E,12S,14S)-4,8,12-Tris((tert-butyldimethylsilyl)oxy)14-((4-methoxybenzyl)oxy)pentadeca-6,10-dienal (14). To a solution of enal 13 (0.180 g, 0.241 mmol) in THF (2.4 mL) were added deoxygenated H2O (0.09 mL) and (triphenylphosphine)copper hydride hexamer (0.236 g, 0.120 mmol). After 20 h, the reaction mixture was exposed to air for 30 min and petroleum ether (10 mL) added to precipitate copper byproducts. The mixture was then filtered through Celite. Concentration and radial chromatography (gradient, petroleum ether to Et2O) afforded the saturated alcohol 15 (21% yield) and saturated aldehyde 14 (0.126 g, 70% yield) as a pale yellow oil: 1H NMR (300 MHz, CDCl3) δ 9.75 (t, J = 1.6 Hz, 1H), 7.25 (d, J = 8.1 Hz, 2H), 6.86 (d, J = 8.1 Hz, 2H), 5.57−5.37 (m, 4H), 4.46 (d, J = 11.3 Hz, 1H), 4.34 (d, J = 11.3 Hz, 1H), 4.19 (ddd, J = 6.4, 6.4, 6.4 Hz, 1H), 4.08 (ddd, J = 5.7, 5.7, 5.7 Hz, 1H), 3.80 (s, 3H), 3.77− 3.69 (m, 1H), 3.63−3.52 (m, 1H), 2.52−2.39 (m, 2H), 2.28−2.11 (m, 4H), 1.92 (ddd, J = 13.6, 6.8, 6.8 Hz, 1H), 1.86−1.75 (m, 1H), 1.74−1.65 (m, 1H), 1.50−1.41 (m, 1H), 1.18 (d, J = 6.1 Hz, 3H), 0.88 (s, 18H), 0.86 (s, 9H), 0.05 (s, 3H), 0.04 (s, 6H), 0.02 (s, 6H), 0.01 (s, 3H). The aldehyde 14 was used immediately in the subsequent step.

(2S,4E,6S,8E,10S,12S)-2,6,10-Tris((tert-butyldimethylsilyl)oxy)12-((4-methoxybenzyl)oxy)trideca-4,8-dienal (12b). To a solution of nitrile 12a (0.451 g, 0.628 mmol) in toluene (16 mL) at 0 °C was added DIBAL-H (1 M in heptane, 0.94 mL, 0.94 mmol) dropwise. After 6 h, MeOH (2 mL) was slowly added to quench the remaining DIBAL-H, and the reaction mixture was allowed to warm to room temperature. After 1 h, the reaction mixture was diluted with Et2O (16 mL) and washed with saturated aq Rochelle’s salt (sodium potassium tartrate, 32 mL). The mixture was then filtered through Celite and extracted with Et2O (2 × 32 mL). The organic phase was dried over anhydrous Na2SO4. Concentration and passage through SiO2 (30 × 4 cm, 4:1 petroleum ether/Et2O) afforded the crude aldehyde 12b (0.284 g, 63% yield) as a pale yellow oil: 1H NMR (300 MHz, CDCl3) δ 9.57 (d, J = 1.6 Hz, 1H), 7.25 (d, J = 8.6 Hz, 2H), 13660



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(4R,6E,8S,10E,12S,14S)-4,8,12-Tris((tert-butyldimethylsilyl)oxy)14-((4-methoxybenzyl)oxy)pentadeca-6,10-dien-1-ol (15). To a solution of aldehyde 14 (0.126 g, 0.168 mmol) in toluene (4.2 mL) at −78 °C was added DIBAL-H (1 M in heptane, 0.50 mL, 0.50 mmol) dropwise. After 10 h, saturated aq NH4Cl (5 mL) was slowly added, and the reaction mixture was allowed to warm to room temperature. After 1 h, the reaction mixture was diluted with Et2O (5 mL), filtered through Celite, and dried over anhydrous Na2SO4. Concentration and radial chromatography (gradient, petroleum ether to EtOAc) afforded 15 (0.101 g, 80% yield) as a colorless oil: [α]D21 +17.0 (c 1.21, CHCl3); IR (film) 3454, 2954, 2929, 2856, 1613, 1514, 1462, 1360, 1250, 1059 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.25 (d, J = 8.7 Hz, 2H), 6.86 (d, J = 8.6 Hz, 2H), 5.55−5.38 (m, 4H), 4.46 (d, J = 11.3 Hz, 1H), 4.34 (d, J = 11.3 Hz, 1H), 4.19 (ddd, J = 6.5, 6.5, 6.5 Hz, 1H), 4.10−4.06 (m, 1H), 3.80 (s, 3H), 3.76−3.70 (m, 1H), 3.64−3.54 (m, 3H), 2.26−2.14 (m, 4H), 1.99 (br s, 1H), 1.92 (ddd, J = 13.6, 6.8, 6.8 Hz, 1H), 1.64−1.55 (m, 2H), 1.54−1.42 (m, 3H), 1.18 (d, J = 6.1 Hz, 3H), 0.89 (s, 9H), 0.88 (s, 9H), 0.86 (s, 9H), 0.061 (s, 3H), 0.058 (s, 3H), 0.04 (s, 3H), 0.02 (s, 6H), 0.01 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 159.2, 136.0, 135.7, 131.3, 129.3, 126.6, 126.3, 113.9, 73.4, 72.0, 71.9, 71.4, 69.9, 63.2, 55.4, 45.7, 41.6, 39.9, 32.9, 28.5, 26.1, 26.03, 26.01, 19.9, 18.4, 18.3, 18.2, −3.8, −4.2, −4.3, −4.5, −4.56, −4.62; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C41H78O6Si3Na 773.5004, found 773.5020. Anal. Calcd for C41H78O6Si3: C, 65.54; H, 10.46. Found: C, 65.72; H, 10.38.

55.4, 51.8, 45.8, 41.6, 40.3, 33.5, 26.1, 26.03, 26.01, 25.0, 19.9, 18.4, 18.3, 18.2, −3.8, −4.18, −4.21, −4.5, −4.56, −4.62; HRMS (ESITOF) m/z [M + Na]+ calcd for C41H77N3O5Si3Na 798.5069, found 798.5070.

(2S,4S,5E,8S,9E,12R)-15-Azido-4,8,12-tris((tertbutyldimethylsilyl)oxy)pentadeca-5,9-dien-2-ol (37). To a solution of p-methoxybenzyl ether 37 (80.3 mg, 0.103 mmol) in CH2Cl2 (3.2 mL) and H2O (0.18 mL) was added DDQ (35.2 mg, 0.155 mmol). After 1 h, the reaction mixture was filtered through Celite. The filtrate was washed with saturated aq NaHCO3 (10 mL) and extracted with CH2Cl2 (3 × 15 mL). The organic phase was dried over anhydrous Na2SO4. Concentration and radial chromatography (gradient, petroleum ether to Et2O) afforded 38 (55.1 mg, 82% yield) as a colorless oil: [α]D21 +3.18 (c 1.98, CHCl3); IR (film) 3452, 2956, 2930, 2896, 2857, 2096, 1462, 1360, 1255, 1073 cm−1; 1H NMR (400 MHz, CDCl3) δ 5.58−5.50 (m, 2H), 5.46−5.40 (m, 2H), 4.33−4.28 (m, 1H), 4.09 (ddd, J = 6.0, 6.0, 6.0 Hz, 1H), 4.01−3.93 (m, 1H), 3.73−3.67 (m, 1H), 3.39 (br s, 1H), 3.25 (m, apparent t, J = 6.8 Hz, 2H), 2.27−2.14 (m, 4H), 1.74−1.40 (m, 6H), 1.15 (d, J = 6.2 Hz, 3H), 0.89 (s, 9H), 0.88 (s, 18H), 0.09 (s, 3H), 0.05 (s, 3H), 0.042 (s, 6H), 0.035 (s, 3H), 0.02 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 135.74, 135.68, 127.2, 126.2, 75.3, 73.2, 71.6, 67.3, 51.8, 46.5, 41.4, 40.3, 33.5, 26.00, 25.99 (2 × 3C), 25.0, 23.7, 18.4, 18.2, 18.1, −3.4, −4.20, −4.23, −4.5, −4.61, −4.63; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C33H69N3O4Si3Na 678.4494, found 678.4496. Anal. Calcd for C33H69N 3O4Si3: C, 60.40; H, 10.60; N, 6.40. Found: C, 60.68; H, 10.61; N, 6.35.

(5S,6E,9S,10E,13R)-13-(3-Azidopropyl)-9-((tertbutyldimethylsilyl)oxy)-5-((S)-2-((4-methoxybenzyl)oxy)propyl)2,2,3,3,15,15,16,16-octamethyl-4,14-dioxa-3,15-disilaheptadeca6,10-diene (37). To a solution of alcohol 15 (0.105 g, 0.140 mmol) in pyridine (0.28 mL) at 0 °C was added p-toluenesulfonyl chloride (0.053 g, 0.280 mmol). After 6 h, the reaction mixture was partitioned between aq HCl (1 M, 1 mL) and Et2O (3 × 5 mL). The organic phase was washed with saturated aq NaHCO3 (1 mL) and dried over anhydrous Na2SO4. Filtration and concentration afforded the crude tosylate derivative (46, 0.130g, quantitative yield) as a pale yellow oil; 1 H NMR (300 MHz, CDCl3) δ 7.78 (d, J = 8.2 Hz, 2H), 7.33 (d, J = 8.2 Hz, 2H), 7.24 (d, J = 8.6 Hz, 2H), 6.85 (d, J = 8.6 Hz, 2H), 5.53− 5.36 (m, 4H), 4.46 (d, J = 11.3 Hz, 1H), 4.34 (d, J = 11.3 Hz, 1H), 4.18 (ddd, J = 6.3, 6.3, 6.3 Hz, 1H), 4.09−4.04 (m, 1H), 3.99 (m, apparent t, J = 6.6 Hz, 2H), 3.79 (s, 3H), 3.66−3.52 (m, 2H), 2.44 (s, 3H), 2.27−2.04 (m, 4H), 1.92 (ddd, J = 13.5, 6.7, 6.7 Hz, 1H), 1.79− 1.54 (m, 2H), 1.49−1.34 (m, 3H), 1.18 (d, J = 6.1 Hz, 3H), 0.87 (s, 9H), 0.86 (s, 9H), 0.85 (s, 9H), 0.03 (s, 3H), 0.02 (s, 6H), 0.01 (s, 3H), 0.00 (s, 3H), −0.02 (s, 3H). The tosylate was used in the subsequent step without further purification. To a solution of tosylate 46 prepared as described above (0.130 g, 0.140 mmol) in DMF (distilled over 3 Å molecular sieves, 4.7 mL) was added sodium azide (0.046 g, 0.700 mmol). The reaction mixture was then heated at 50 °C. After 19 h, the reaction mixture was diluted with EtOAc (30 mL) and washed repeatedly with H2O (5 × 10 mL). The organic phase was washed with brine (3 mL) and dried over anhydrous Na2SO4. Concentration and radial chromatography (gradient, petroleum ether to EtOAc) afforded alcohol 15 (13% recovery) and azide 37 (0.080 g, 74% yield over two steps) as a colorless oil: [α]D21 +18.7 (c 0.795, CHCl3); IR (film) 2955, 2930, 2857, 2097, 1614, 1559, 1514, 1462, 1361, 1302, 1250, 1079 cm−1; 1 H NMR (400 MHz, CDCl3) δ 7.25 (d, J = 8.7 Hz, 2H), 6.86 (d, J = 8.7 Hz, 2H), 5.57−5.39 (m, 4H), 4.46 (d, J = 11.3 Hz, 1H), 4.35 (d, J = 11.3 Hz, 1H), 4.19 (ddd, J = 6.5, 6.5, 6.5 Hz, 1H), 4.09 (ddd, J = 6.0, 6.0, 6.0 Hz, 1H), 3.80 (s, 3H), 3.73−3.67 (m, 1H), 3.62−3.54 (m, 1H), 3.24 (m, apparent t, J = 6.9 Hz, 2H), 2.27−2.15 (m, 4H), 1.93 (ddd, J = 13.5, 6.8, 6.8 Hz, 1H), 1.74−1.62 (m, 1H), 1.62−1.53 (m, 1H), 1.51−1.39 (m, 3H), 1.19 (d, J = 6.1 Hz, 3H), 0.89 (s, 18H), 0.87 (s, 9H), 0.06 (s, 3H), 0.05 (s, 6H), 0.031 (s, 3H), 0.027 (s, 3H), 0.02 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 159.2, 136.0, 135.8, 131.4, 129.2, 126.6, 126.1, 113.9, 73.3, 71.9, 71.6, 71.4, 70.0,

(4S,5E,8S,9E,12R)-15-Azido-4,8,12-tris((tert-butyldimethylsilyl)oxy)pentadeca-5,9-dien-2-one (16). To a solution of oxalyl chloride (1.0 M in CH2Cl2, 0.77 mL, 0.77 mmol) at −78 °C was added DMSO (>99%, anhydrous, 1.5 M in CH2Cl2, 0.77 mL, 1.16 mmol) dropwise. After 30 min, alcohol 38 (50.6 mg, 0.077 mmol) in CH2Cl2 (0.77 mL) was added dropwise at −78 °C. After 6 h, Et3N (2.5 M in CH2Cl2, 0.77 mL, 1.93 mmol) was added at −78 °C. The reaction mixture was allowed to warm to room temperature over 1 h and then partitioned between H2O (10 mL) and CH2Cl2 (3 × 25 mL). The organic phase was washed with brine (5 mL) and dried over anhydrous Na2SO4. Concentration and radial chromatography (gradient, petroleum ether to Et2O) afforded 16 (42.8 mg, 85% yield) as a colorless oil: [α]D21 +6.99 (c 1.25, CHCl3); IR (film) 2955, 2929, 2895, 2857, 2096, 1722, 1472, 1462, 1360, 1255, 1074 cm−1; 1 H NMR (400 MHz, CDCl3) δ 5.62−5.49 (m, 2H), 5.47−5.41 (m, 2H), 4.57−4.52 (m, 1H), 4.08 (ddd, J = 6.0, 6.0, 6.0 Hz, 1H), 3.72− 3.67 (m, 1H), 3.25 (m, apparent t, J = 6.8 Hz, 2H), 2.67 (dd, J = 14.6, 8.0 Hz, 1H), 2.42 (dd, J = 14.6, 4.7 Hz, 1H), 2.26−2.14 (m, 4H), 2.15 (s, 3H), 1.74−1.62 (m, 1H), 1.61−1.39 (m, 3H), 0.89 (s, 9H), 0.88 (s, 9H), 0.86 (s, 9H), 0.06 (s, 3H), 0.05 (s, 3H), 0.04 (s, 3H), 0.03 (s, 3H), 0.02 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 207.5, 135.7, 134.8, 127.1, 126.2, 73.2, 71.6, 70.6, 52.2, 51.8, 41.5, 40.3, 33.5, 31.9, 26.02, 26.00, 25.97, 25.0, 18.4, 18.23, 18.21, −4.0, −4.19, −4.21, −4.5, −4.6, −4.8; HRMS (ESI-TOF) m/z [M + Na]+ Calcd for C33H67N3O4Si3Na 676.4337, found 676.4350. Anal. Calcd for C33H67N 3O4Si3: C, 60.59; H, 10.32; N, 6.42. Found: C, 60.88; H, 10.33; N, 6.52.

(5S,9R,E)-5-((E)-4-((4-Methoxybenzyl)oxy)but-2-en-1-yl)-2,2,3,3,12,12-hexamethyl-11,11-diphenyl-9-vinyl-4,10-dioxa-3,11-disilatridec-6-ene (18). To a solution of nitrile 17a (0.900 g, 1.34 mmol, E,E/ 13661



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E,Z 90:10, R,S/R,R > 95:5) in toluene (34 mL) at −78 °C was added DIBAL-H (1 M in heptane, 2.02 mL, 2.02 mmol) dropwise. After 5 h, MeOH (4 mL) was slowly added to quench remaining DIBAL-H, and the reaction mixture was allowed to warm to room temperature. After 1 h, the reaction mixture was washed with aq tartaric acid (0.5 M, 130 mL) and extracted with Et2O (3 × 50 mL). The organic phase was washed with brine (20 mL) and dried over anhydrous Na2SO4. Concentration afforded the crude aldehyde 17b (0.921 g, quantitative yield) as a pale yellow oil: 1H NMR (300 MHz, CDCl3) δ 9.54 (d, J = 1.5 Hz, 1H), 7.66−7.61 (m, 4H), 7.47−7.34 (m, 6H), 7.26 (d, J = 8.6 Hz, 2H), 6.87 (d, J = 8.6 Hz, 2H), 5.71−5.41 (m, 4H), 4.41 (s, 2H), 4.09−4.00 (m, 2H), 3.93 (m, apparent d, J = 5.0 Hz, 2H), 3.80 (s, 3H), 2.39−2.35 (m, 2H), 2.27−2.14 (m, 2H), 1.11 (s, 9H), 0.88 (s, 9H), 0.02 (s, 3H), 0.01 (s, 3H). This material was stored frozen in benzene (ca. −5 °C) and used in the subsequent step without further purification. To a solution of 5-(methylsulfonyl)-1-phenyl-1H-tetrazole (MeSO2PT)47 (0.614 g, 2.74 mmol) in THF (61 mL) at −78 °C was slowly added KHMDS (0.5 M in toluene, 5.20 mL, 2.60 mmol). After 1 h, aldehyde 17b (0.921 g, 1.37 mmol) in THF (7 mL) was slowly added. After 5 h, the reaction was quenched with saturated aq NH4Cl (10 mL) and H2O (10 mL), allowed to warm to room temperature over 30 min, and extracted with EtOAc (3 × 30 mL). The organic phase was washed with brine (20 mL) and dried over anhydrous Na2SO4. Concentration and gradient flash chromatography (petroleum ether to Et2O) afforded 18 (0.750 g, 83% yield over two steps E,E/E,Z 90:10, R,S/R,R > 95:5) as a colorless oil. The E,E/E,Z isomers and R,S/R,R diastereomers were inseparable by radial/flash chromatography and their ratios were determined by 1H NMR: [α]D22 −23.0 (c 1.35, CHCl3); IR (film) 3072, 3048, 2999, 2931, 2895, 2856, 1613, 1513, 1472, 1427, 1361, 1302, 1248, 1173, 1112 cm−1; HRMS (ES-TOF) m/z [M + Na]+ calcd for C41H58O4Si2Na 693.3771, found 693.3781. Anal. Calcd for C41H58O4Si2: C, 73.38; H, 8.71. Found: C, 73.66; H, 8.91. For (R,E,S,E)-18: 1H NMR (400 MHz, CDCl3) δ 7.70 (d, J = 7.2 Hz, 2H), 7.66 (d, J = 7.2 Hz, 2H), 7.44−7.40 (m, 2H), 7.39−7.34 (m, 4H), 7.27 (d, J = 8.4 Hz, 2H), 6.88 (d, J = 8.4 Hz, 2H), 5.78 (ddd, J = 16.8, 10.4, 6.0 Hz, 1H), 5.70− 5.55 (m, 2H), 5.47 (ddd, J = 15.2, 7.2, 7.2 Hz, 1H), 5.33 (dd, J = 15.3, 6.2 Hz, 1H), 5.04−4.96 (m, 2H), 4.42 (s, 2H), 4.18 (ddd, apparent q, J = 5.9 Hz, 1H), 4.04 (ddd, apparent q, J = 6.0 Hz, 1H), 3.94 (m, apparent d, J = 5.3 Hz, 2H), 3.81 (s, 3H), 2.26−2.14 (m, 4H), 1.08 (s, 9H), 0.88 (s, 9H), 0.02 (s, 3H), −0.01 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 159.3, 140.3, 136.1, 136.0, 135.7, 134.5, 134.2, 131.0, 130.7, 129.7, 129.6, 129.5, 128.8, 127.6, 127.5, 125.6, 114.7, 113.9, 74.4, 73.2, 71.6, 70.7, 55.4, 41.7, 40.8, 27.2, 26.0, 19.5, 18.4, −4.2, −4.6.

7.45−7.33 (m, 6H), 5.78 (ddd, J = 16.8, 10.4, 6.1 Hz, 1H), 5.64−5.62 (m, 2H), 5.46 (ddd, J = 14.8, 6.8, 6.8 Hz, 1H), 5.31 (dd, J = 15.4, 6.2 Hz, 1H), 5.04−4.97 (m, 2H), 4.17 (ddd, apparent q, J = 5.9 Hz, 1H), 4.08−4.05 (m, 2H), 4.03 (ddd, apparent q, J = 6.2 Hz, 1H), 2.23− 2.13 (m, 4H), 1.20−1.40 (br s, 1H), 1.08 (s, 9H), 0.87 (s, 9H), 0.01 (s, 3H), −0.01 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 140.3, 136.09, 136.05, 135.7, 134.5, 134.2, 131.3, 129.75, 129.66, 129.6, 127.6, 127.5, 125.7, 114.7, 74.4, 73.2, 63.9, 41.5, 40.7, 27.2, 26.0, 19.5, 18.4, −4.1, −4.6. For (R,E,S,Z)-39: 1H NMR (400 MHz, CDCl3) δ 4.11 (apparent d, J = 6.1 Hz, 2H), other peaks were not resolved. (2E,5S,6E,9R)-Methyl 5-((tert-Butyldimethylsilyl)oxy)-9-((tertbutyldiphenylsilyl)oxy)undeca-2,6,10-trienoate (19a). To a solution of alcohol 39 (58.4 mg, 0.106 mmol, E,E/E,Z 89:11) in petroleum ether (5.3 mL) was added activated MnO2 (184.0 mg, 2.120 mmol). After 19 h, the petroleum ether was removed by rotary evaporation, and another portion of activated MnO2 (184.0 mg, 2.120 mmol) was added along with KCN (36.6 mg, 0.562 mmol), acetic acid (glacial, 9.8 μL, 0.170 mmol), and MeOH (5.3 mL). [CAUTION: Acidified reaction mixtures and extraction fractions should be handled in a fume hood]. After 25 h, the reaction mixture was filtered through Celite. Concentration and radial chromatography (CH2Cl2) afforded 19a (48.9 mg, 80% yield, E,E/E,Z 94:6, R,S/R,R > 95:5) as a colorless oil. The isomers could be enriched by careful radial chromatography (CH2Cl2) with the minor (E,Z)-isomer eluting before the major (E,E)-isomer, and their ratios were determined by 1H NMR: [α]D22 −33.3 (c 1.27, CHCl3); IR (film) 3072, 2955, 2931, 2895, 2857, 1727, 1653, 1462, 1427, 1258, 1168, 1112, 1072 cm−1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C34H50O4Si2Na 601.3145, found 601.3148. Anal. Calcd for C34H50O4Si2: C, 70.54; H, 8.71. Found: C, 70.54; H, 8.81. For (R,E,S,E)-19a: 1H NMR (400 MHz, CDCl3) δ 7.70−7.64 (m, 4H), 7.45−7.33 (m, 6H), 6.90 (ddd, J = 15.7, 7.4, 7.4 Hz, 1H), 5.80 (d, J = 15.6 Hz, 1H), 5.77 (ddd, J = 16.8, 10.4, 6.1 Hz, 1H), 5.49 (ddd, J = 15.2, 7.2, 7.2 Hz, 1H), 5.30 (dd, J = 15.4, 6.3 Hz, 1H), 5.02 (ddd, apparent dt, J = 17.3, 1.4 Hz, 1H), 4.98 (ddd, apparent dt, J = 10.4, 1.3 Hz, 1H), 4.17 (ddd, apparent q, J = 5.9 Hz, 1H), 4.11 (ddd, apparent q, J = 6.1 Hz, 1H), 3.72 (s, 3H), 2.37−2.24 (m, 2H), 2.24− 2.12 (m, 2H), 1.07 (s, 9H), 0.87 (s, 9H), 0.01 (s, 3H), −0.02 (s, 3H); 13 C{1H} NMR (100 MHz, CDCl3) δ 167.0, 146.1, 140.2, 136.1, 136.0, 135.1, 134.5, 134.2, 129.8, 129.7, 127.7, 127.5, 126.4, 123.0, 114.8, 74.4, 72.4, 51.5, 41.5, 40.7, 27.2, 26.0, 19.5, 18.3, −4.2, −4.7. For (R,E,S,Z)-19a: 1H NMR (300 MHz, CDCl3) δ 6.28 (ddd, J = 11.6, 7.1, 7.1 Hz, 1H), 2.81 (ddd, J = 7.2, 5.7, 1.5 Hz, 2H), other peaks were not resolved.

(2E,5S,6E,9R)-Methyl 9-((tert-Butyldiphenylsilyl)oxy)-5-hydroxyundeca-2,6,10-trienoate (19b). To a solution of silyl ether 19a (0.444 g, 0.767 mmol, E,E/E,Z 97:3) in THF (7.7 mL) was added HCl (2 M, 2.57 mL, 5.14 mmol). After 46 h, the reaction mixture was partitioned between saturated aq NaHCO3 (25 mL) and EtOAc (3 × 25 mL). The organic phase was washed with brine (5 mL) and dried over anhydrous Na2SO4. Concentration and flash chromatography (CH2Cl2/MeOH) afforded 19b (0.341 g, 96% yield, E,E/E,Z 95:5) as a pale yellow oil. The isomers could be enriched by careful radial chromatography (5% MeOH in CH2Cl2) with the minor (E,Z)isomer eluting before the major (E,E)-isomer, and their ratios were determined by 1H NMR: [α]D21 −36.9 (c 0.870, CHCl3); IR (film) 3436, 3072, 3049, 3013, 2998, 2932, 2895, 2858, 1726, 1710, 1659, 1472, 1428, 1320, 1277, 1210, 1169, 1112 cm−1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C28H36O4SiNa 487.2281, found 487.2294. Anal. Calcd for C28H36O4Si: C, 72.37; H, 7.81. Found: C, 72.55; H, 7.97. For (R,E,S,E)-19b: 1H NMR (400 MHz, CDCl3) δ 7.70−7.68 (m, 2H), 7.65−7.63 (m, 2H), 7.45−7.33 (m, 6H), 6.91 (ddd, J = 15.7, 7.4, 7.4 Hz, 1H), 5.87 (ddd, J = 15.8, 1.4, 1.4 Hz, 1H), 5.80 (ddd, J = 16.8, 10.4, 6.1 Hz, 1H), 5.52 (ddd, J = 14.4, 7.2, 6.8 Hz, 1H), 5.34 (dd, J = 15.4, 6.8 Hz, 1H), 5.06 (ddd, J = 17.2, 1.4, 1.4 Hz, 1H), 5.02 (ddd, J = 10.4, 1.4, 1.4 Hz, 1H), 4.21 (ddd, apparent q, J = 5.8 Hz, 1H), 4.09 (ddd, apparent q, J = 6.3 Hz, 1H), 3.72 (s, 3H),

(2E,5S,6E,9R)-5-((tert-Butyldimethylsilyl)oxy)-9-((tertbutyldiphenylsilyl)oxy)undeca-2,6,10-trien-1-ol (38). To a solution of benzyl ether 18 (54.0 mg, 0.080 mmol, E,E/E,Z 90:10, R,S/R,R > 95:5) in CH2Cl2 (2.6 mL) and H2O (0.14 mL) was added DDQ (27.0 mg, 0.120 mmol) with vigorous stirring. After 1.5 h, the reaction mixture was filtered through Celite. The filtrate was washed with saturated aq NaHCO3 (10 mL) and brine (20 mL) and extracted with CH2Cl2 (3 × 10 mL). The organic phase was then washed with brine (5 mL) and dried over anhydrous Na2SO4. Concentration and radial chromatography (5% MeOH in CH2Cl2) afforded the corresponding primary alcohol 39 (38.4 mg, 87% yield, E,E/E,Z 90:10) as a pale yellow oil. The isomers could be enriched by careful radial chromatography (CH2Cl2/MeOH) with the minor (E,Z)-isomer eluting before the major (E,E)-isomer, and their ratios were determined by 1H NMR: [α]D22 −28.8 (c 1.50, CHCl3); IR (film) 3345, 3072, 3049, 2999, 2930, 2894, 2857, 1590, 1472, 1427, 1389, 1362, 1256, 1112, 1006 cm−1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C33H50O3Si2Na 573.3196, found 573.3200. Anal. Calcd for C33H50O3Si2: C, 71.94; H, 9.15. Found: C, 71.95; H, 9.28. For (R,E,S,E)-39: 1H NMR (400 MHz, CDCl3) δ 7.71−7.65 (m, 4H), 13662



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1H), 3.70 (s, 3H), 3.65 (ddd, J = 11.0, 5.5, 5.5 Hz, 1H), 2.73 (dd, J = 15.8, 6.9 Hz, 1H), 2.50 (dd, J = 15.8, 6.3 Hz, 1H), 2.28 (ddd, J = 14.3, 7.2, 7.2 Hz, 1H), 2.21−2.15 (m, 1H), 1.80 (dddd, J = 13.9, 8.2, 5.5, 4.6 Hz, 1H), 1.73 (br s, 1H), 1.69−1.62 (m, 2H), 1.45 (ddd, J = 13.1, 11.3, 11.3 Hz, 1H), 1.07 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 171.2, 138.4, 136.1, 136.0, 134.1, 133.7, 132.3, 130.0, 129.9, 128.9, 128.32, 128.30, 127.9, 127.8, 126.3, 100.8, 76.9, 73.1, 71.7, 59.8, 51.9, 40.8, 39.8, 38.0, 36.6, 27.2, 19.4; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C35H44O6SiNa 611.2805, found 611.2803. Anal. Calcd for C35H44O6Si: C, 71.39; H, 7.53. Found: C, 71.20; H, 7.58.

2.36−2.32 (m, 2H), 2.20−2.16 (m, 2H), 1.38 (br s, 1H), 1.07 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 166.8, 145.1, 140.3, 136.12, 136.06, 134.5, 134.4, 134.1, 129.8, 129.7, 128.4, 127.7, 127.6, 123.5, 114.7, 74.2, 71.5, 51.6, 40.7, 40.0, 27.2, 19.5. For (R,E,S,Z)19b: 1H NMR (400 MHz, CDCl3) δ 6.28 (ddd, J = 11.5, 7.5, 7.5 Hz, 1H), 2.83−2.79 (m, 2H), other peaks were not resolved.

Methyl 2-((2S,4R,6S)-6-((R,E)-4-((tert-Butyldiphenylsilyl)oxy)hexa-1,5-dien-1-yl)-2-phenyl-1,3-dioxan-4-yl)acetate (20). To a solution of alcohol 19b (0.107 g, 0.229 mmol, E,E/E,Z 95:5) in THF (2.3 mL) at −50 °C was added benzaldehyde (0.5 M in THF, 0.51 mL, 0.253 mmol), followed by KHMDS (0.05 M in 9:1 THF/ toluene, 0.46 mL, 0.023 mmol). The reaction mixture was then slowly warmed to 0 °C over 1 h. The cooling/addition/warming procedure was repeated two additional times, with warming to 0 °C over 2 h on third iteration. The reaction mixture was partitioned between saturated aq NH4Cl (5 mL) and EtOAc (3 × 10 mL). The organic phase was washed with brine (5 mL) and dried over anhydrous Na2SO4. Concentration and radial chromatography (gradient, petroleum ether to Et2O) afforded unreacted alcohol 19b (15% recovery) and 20 (0.082 g, 63% yield, R,S,R/R,R,S > 95:5) as a colorless oil: [α]D22 −30.1 (c 2.01, CHCl3); IR (film) 3071, 3047, 3013, 2999, 2953, 2857, 1738, 1728, 1589, 1472, 1428, 1339, 1264, 1216, 1112 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.75−7.68 (m, 4H), 7.54−7.51 (m, 2H), 7.47−7.34 (m, 9H), 5.85 (ddd, J = 16.9, 10.4, 6.2 Hz, 1H), 5.70 (ddd, J = 14.4, 7.2, 6.4 Hz, 1H), 5.62 (s, 1H), 5.50 (dd, J = 15.6. 6.1 Hz, 1H), 5.07 (ddd, J = 17.2, 1.4, 1.4 Hz, 1H), 5.03 (ddd, J = 10.4, 1.3, 1.3 Hz, 1H), 4.35 (dddd, J = 11.2, 6.6, 6.6, 2.3 Hz, 1H), 4.31−4.24 (m, 2H), 3.73 (s, 3H), 2.77 (dd, J = 15.8, 7.0 Hz, 1H), 2.55 (dd, J = 15.8, 6.2 Hz, 1H), 2.30−2.20 (m, 2H), 1.70 (ddd, J = 13.1, 2.4, 2.4 Hz, 1H), 1.52 (ddd, J = 13.1, 11.3, 11.3 Hz, 1H), 1.12 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 171.2, 140.3, 138.5, 136.1, 136.0, 134.4, 134.1, 132.0, 129.7, 129.6, 128.8, 128.5, 128.2, 127.6, 127.5, 126.3, 114.6, 100.7, 77.0, 74.2, 73.1, 51.8, 40.9, 40.8, 36.6, 27.1, 19.5; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C 35 H 42 O 5 SiNa 593.2699, found 593.2702. Anal. Calcd for C35H42O5Si: C, 73.65; H, 7.42. Found: C, 73.91; H, 7.53. Syn-1,3diol coupling constant peak assignments were confirmed by 1H−1H COSY NMR (600 MHz, CDCl3). The minor anti-1,3-diols (R,S,S and R,R,R) were not observed.

Methyl 2-((2S,4R,6S)-6-((R,E)-4-((tert-Butyldiphenylsilyl)oxy)-6oxohex-1-en-1-yl)-2-phenyl-1,3-dioxan-4-yl)acetate (22a). To a solution of oxalyl chloride (0.4 M in CH2Cl2, 1.24 mL, 0.496 mmol) at −78 °C was added DMSO (>99%, anhydrous, 0.6 M in CH2Cl2, 1.24 mL, 0.744 mmol) dropwise. After 30 min, alcohol 21 (73.0 mg, 0.124 mmol) in CH2Cl2 (0.62 mL) was added dropwise at −78 °C. After 3 h, Et3N (1.0 M in CH2Cl2, 1.24 mL, 1.24 mmol) was added at −78 °C. The reaction mixture was allowed to warm to room temperature over 1 h and then partitioned between H2O (10 mL) and CH2Cl2 (3 × 20 mL). The organic phase was washed with brine (5 mL) and dried over anhydrous Na2SO4. Concentration and radial chromatography (gradient, petroleum ether to Et2O) afforded 22a (61.9 mg, 85% yield) as a colorless oil: [α]D22 −18.9 (c 1.05, CHCl3); IR (film) 3070, 2930, 2857, 2752, 1738, 1728, 1428, 1364, 1340, 1310, 1262, 1215, 1162, 1111, 1010 cm−1; 1H NMR (400 MHz, CDCl3) δ 9.68 (t, J = 2.3 Hz, 1H), 7.68−7.65 (m, 4H), 7.48−7.32 (m, 11H), 5.65 (ddd, J = 14.8, 7.2, 6.4 Hz, 1H), 5.58 (s, 1H), 5.48 (dd, J = 15.5, 5.8 Hz, 1H), 4.35−4.25 (m, 3H), 3.71 (s, 3H), 2.74 (dd, J = 15.8, 6.9 Hz, 1H), 2.54−2.49 (m, 3H), 2.29−2.26 (m, 2H), 1.69 (ddd, J = 13.1, 2.4, 2.4 Hz, 1H), 1.46 (ddd, J = 13.1, 11.3, 11.3 Hz, 1H), 1.05 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 201.7, 171.2, 138.4, 136.0 (2 × 2C), 133.8, 133.5, 133.2, 130.1, 130.0, 128.9, 128.3, 127.9, 127.8, 127.4, 126.3, 100.8, 76.7, 73.1, 68.9, 51.9, 50.2, 40.8, 40.5, 36.6, 27.1, 19.4; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C35H42O6SiNa 609.2648, found 609.2647.

15-Azidopentadec-1-ene (40). To a solution of CuCl2 (2.11 g, 15.2 mmol) in THF (70 mL) was added a solution of LiCl (1.33 g, 31.1 mmol) in THF (55 mL) via cannula. After 20 h at rt, 1,12dibromododecane (25.4 g, 76 mmol) was added in one portion. The solution was cooled to 0 °C, and a solution of allylmagnesium chloride (2.0 M in THF, 57.6 mL, 115.2 mmol) was added dropwise over 65 min. After another 60 min at 0 °C, the mixture was partitioned between 1.0 M aq HCl (192 mL) and Et2O (250 mL), and the aqueous phase was extracted with Et2O (3 × 75 mL). The organic phase was washed with brine (3 × 200 mL) and dried over Na2SO4. Concentration and flash chromatography (petroleum ether) afforded 15-bromopentadec-1-ene (6.67 g) of >95% purity and a fraction (7.00 g) containing a mixture of 15-bromopentadec-1-ene and 1,17-octadecadiene (76:24 w/w, 5.31 g of 15-bromopentadec-1ene). The total amount of 15-bromopentadec-1-ene was 11.98 g (54% yield). Colorless wax: 1H NMR (400 MHz, CDCl3) δ 5.81 (ddt, J = 17.1, 10.2, 6.7 Hz, 1H), 4.99 (br d, J = 17.1 Hz, 1H), 4.94−4.91 (m, 1H), 3.41 (t, J = 6.9 Hz, 2H), 2.04 (q, J = 7.1 Hz, 2H), 1.85 (quintet, J = 7.2 Hz, 2H), 1.26−1.25 (m, 20H). Data were consistent with those previously reported.48 A suspension of 15-bromopentadec-1-ene (7.00 g, 76% w/w with 1,17-octadecadiene, 18.3 mmol) and NaN3 (4.73 g, 72.0 mmol) in DMF (100 mL) was stirred at 60 °C for 75 min. The suspension was diluted with Et2O (100 mL) and filtered through Celite employing Et2O to rinse the filter cake. Concentration and flash chromatography

Methyl 2-((2S,4R,6S)-6-((R,E)-4-((tert-Butyldiphenylsilyl)oxy)-6hydroxyhex-1-en-1-yl)-2-phenyl-1,3-dioxan-4-yl)acetate (21). To a solution of olefin 20 (81.6 mg, 0.143 mmol) in THF (0.7 mL) was added 9-BBN (0.5 M in THF, 0.43 mL, 0.214 mmol). The reaction mixture was then heated at reflux for 5 h, cooled to room temperature, treated with H2O (0.2 mL), aq NaOAc (3M, 0.22 mL, 0.66 mmol), and H2O2 (30% wt. aq, 0.08 mL, 0.69 mmol), and heated at reflux for 1 h. The reaction mixture was partitioned between saturated aq NH4Cl (1 mL), brine (1 mL), and EtOAc (3 × 5 mL). The organic phase was washed with brine (1 mL) and dried over anhydrous Na2SO4. Concentration and radial chromatography (gradient, petroleum ether to Et2O) afforded unreacted olefin 20 (7% recovery) and 21 (56.9 mg, 68% yield) as a colorless oil: [α]D21 −28.0 (c 0.725, CHCl3); IR (film) 3459, 3070, 3046, 2931, 2857, 1738, 1472, 1457, 1428, 1389, 1363, 1340, 1311, 1260, 1215, 1162, 1111, 1012 cm−1; 1 H NMR (400 MHz, CDCl3) δ 7.71−7.67 (m, 4H), 7.47−7.31 (m, 11H), 5.61−5.54 (m, 1H), 5.56 (s, 1H), 5.41 (dd, J = 15.5, 5.9 Hz, 1H), 4.30 (dddd, J = 11.2, 6.6, 6.6, 2.3 Hz, 1H), 4.23 (ddd, J = 10.4, 6.0, 1.6 Hz, 1H), 4.02−3.96 (m, 1H), 3.75 (ddd, J = 11.0, 8.2, 4.9 Hz, 13663



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(petroleum ether) afforded azide 40 (4.61 g, 99% yield) as a colorless wax: 1H NMR (400 MHz, CDCl3) δ 5.81 (ddt, J = 17.0, 10.2, 6.7 Hz, 1H), 4.99 (br d, J = 17.1 Hz, 1H), 4.94−4.91 (br d, J = 10.0 Hz, 1H), 3.25 (t, J = 7.0 Hz, 2H), 2.04 (q, J = 7.1 Hz, 2H), 1.60 (quintet, J = 7.2 Hz, 2H), 1.26 (m, 20H); 13C{1H} NMR (100 MHz, CDCl3) δ 139.3, 114.1, 51.5, 33.9, 29.74, 29.66, 29.64, 29.57, 29.54, 29.52, 29.2, 29.0, 28.9, 26.8. Data were consistent with those previously reported.49

product ratio of 62:38, a thermodynamic enolsilane-derived aldol product diastereomeric ratio of 66:34, and a kinetic enolsilane-derived aldol product diastereomeric ratio of 57:43, as determined by 1H NMR. The kinetic/thermodynamic enolsilane-derived aldol products were separable by further radial chromatography (2:1 petroleum ether/Et2O) to give the thermodynamic enolsilane-derived aldol diastereomers (28 mg, dr 71:29) and the kinetic enolsilane-derived aldol diastereomers (47 mg, dr 57:43). Careful radial chromatography (2:1 petroleum ether/Et2O) afforded an enriched ratio of the desired major kinetic enolsilane-derived aldol diastereomer 26a (19.8 mg, S,R,S,R/R,R,S,R > 90:10): [α]D21 −11.0 (c 0.710, CHCl3); IR (film) 3400, 2927, 2855, 2095, 1742, 1711, 1457, 1428, 1376, 1306, 1215, 1163, 1111, 1027 cm−1; HRMS (ES-TOF) m/z [M + Na]+ calcd for C50H71N3O7SiNa 876.4959, found 876.4965. For major kinetic enolsilane-derived aldol diastereomer (S,R,S,R)-26a: 1H NMR (500 MHz, CDCl3) δ 7.71−7.67 (m, 4H), 7.47−7.31 (m, 11H), 5.60−5.56 (m, 1H), 5.50 (s, 1H), 5.39 (dd, J = 15.5, 6.0 Hz, 1H), 4.32−4.20 (m, 3H), 4.04−4.00 (m, 1H), 3.70 (s, 3H), 3.25 (m, apparent t, J = 7.0 Hz, 2H), 3.04 (br s, 1H), 2.72 (dd, J = 15.8, 6.9 Hz, 1H), 2.50 (dd, J = 15.8, 6.2 Hz, 1H), 2.47−2.42 (m, 1H), 2.39−2.33 (m, 3H), 2.31− 2.25 (m, 1H), 2.21−2.16 (m, 1H), 1.64 (ddd, J = 13.2, 2.3, 2.3 Hz, 1H), 1.61−1.42 (m, 7H), 1.40−1.33 (m, 2H), 1.32−1.22 (m, 16H), 1.06 (s, 9H); 13C{1H} NMR (125 MHz, CDCl3) δ 211.3, 171.2, 138.5, 136.1 (2 × 2C), 134.2, 133.8, 132.4, 130.0, 129.9, 128.8, 128.33, 128.28, 127.8, 127.7, 126.4, 100.8, 77.0, 73.2, 71.1, 64.6, 51.9, 51.7, 49.8, 43.7, 42.5, 40.9, 40.2, 36.6, 29.73 (2 × C), 29.67, 29.62, 29.61, 29.55, 29.34, 29.30, 29.0, 27.2, 26.9, 23.8, 19.5. For minor kinetic enolsilane-derived aldol diastereomer (R,R,S,R)-26a: 1H NMR (500 MHz, CDCl3) δ 5.56 (s, 1H), 3.99−3.95 (m, 1H), 3.15 (br s, 1H), 1.05 (s, 9H), other peaks were not resolved. For major thermodynamic enolsilane-derived aldol diastereomer: 1H NMR (500 MHz, CDCl3) δ 3.18 (d, J = 2.0 Hz, 1H), 2.11 (s, 3H), other peaks were not resolved. For minor thermodynamic enolsilane-derived aldol diastereomer: 1H NMR (500 MHz, CDCl3) δ 2.90 (d, J = 2.5 Hz, 1H), 2.12 (s, 3H), other peaks were not resolved. The configuration of the major kinetic enolsilane-derived aldol diastereomer 26a was determined after subsequent steps.

15-Azidopentadecan-2-one (24). To a solution of 40 (4.342 g, 17.3 mmol) in 7:1 N,N-dimethylacetamide/H2O (80 mL) were added PdCl2 (310.5 mg, 1.7 mmol) and Cu(OAc)2·H2O (703.6 mg, 3.5 mmol). After the atmosphere in the flask was replaced with O2, the suspension was stirred at 50 °C under O2 (balloon) for 18 h. The mixture was allowed to cool to rt, diluted with Et2O (200 mL), and filtered through Celite, employing Et2O (5 × 25 mL) to rinse the filter cake. The filtrate was partitioned between H2O (150 mL) and Et2O (3 × 100 mL), and the organic phase was washed with brine (5 × 100 mL) and dried over Na2SO4. Concentration and gradient flash chromatography (10:1 petroleum ether/EtOAc to EtOAc) afforded 24 (1.55 g, 34%) as a yellow oil: TLC (SiO2, 10:1 petroleum ether/ EtOAc) Rf = 0.38; IR (neat) 2925, 2854, 2096, 1720, 1712, 1466, 1358, 1257, 1165 cm−1; 1H NMR (400 MHz, CDCl3) δ 3.25 (t, J = 6.9 Hz, 2H), 2.41 (t, J = 7.4 Hz, 2H), 2.12 (s, 3H), 1.61−1.56 (m, 4H), 1.34−1.27 (m, 18H); 13C{1H} NMR (100 MHz, CDCl3) δ 208.6, 51.1, 43.4, 29.4, 29.3 (2C), 29.23, 29.18, 29.16, 29.12, 28.87, 28.86, 28.5, 26.4, 23.5; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C15H29N3ONa, 290.2208, found 290.2206.

M e t h y l 2 - ( ( 2 S , 4 R , 6 S ) - 6 - ( ( 4 R , 6 S , E) -2 1 - A z i d o - 4 - ( ( t e r t butyldiphenylsilyl)oxy)-6-hydroxy-8-oxohenicos-1-en-1-yl)-2-phenyl-1,3-dioxan-4-yl)acetate (26a). To a solution of ketone 24 (39.0 mg, 0.146 mmol) in THF (2.9 mL) at −78 °C was added chlorotrimethylsilane (0.093 mL, 0.73 mmol) followed by LiHMDS (1.0 M in THF, 0.73 mL, 0.73 mmol) dropwise. After 5 h, the reaction mixture was partitioned between aq phosphate buffer (pH 7, 20 mL) and petroleum ether (3 × 20 mL). The organic phase was washed with brine (5 mL) and dried over anhydrous Na2SO4. Concentration afforded the crude enolsilane 25 (49.3 mg, 99% yield, kinetic/thermodynamic = 70:30, thermodynamic E/Z = 75:25) as a yellow oil. The kinetic/thermodynamic and E/Z ratios were determined by integration of the 1H NMR spectrum. For kinetic 25a: 1H NMR (300 MHz, CDCl3) δ 4.03 (s, 2H), 3.25 (t, J = 7.0 Hz, 2H), 2.02−1.97 (m, 2H), 1.64−1.55 (m, 2H), 1.48−1.39 (m, 2H), 1.38−1.25 (m, 18H), 0.20 (s, 9H). For thermodynamic (E)-25b: 1H NMR (300 MHz, CDCl3) δ 4.43 (tq, apparent dt, J = 7.0, 0.8 Hz, 1H), 1.76 (d, J = 0.9 Hz, 3H), other peaks were not resolved. For thermodynamic (Z)-25b: 1H NMR (300 MHz, CDCl3) δ 4.64 (tq, apparent dt, J = 7.6, 0.7 Hz, 1H), 1.71 (d, J = 0.7 Hz, 3H), other peaks were not resolved. The enolsilane 25 was used in the subsequent step without further purification. To a solution of enolsilane 25 (49.3 mg, 0.145 mmol) and aldehyde 22a (61.9 mg, 0.105 mmol) in CH2Cl2 (0.22 mL) at −78 °C was added BF3·OEt2 (0.018 mL, 0.145 mmol) dropwise. After 5 h, saturated aq NaHCO3 (3 mL) was added, and the reaction mixture was allowed to warm to room temperature. After 30 min, the reaction mixture was extracted with CH2Cl2 (3 × 10 mL) and the organic phase dried over anhydrous Na2SO4. Concentration and radial chromatography (gradient, petroleum ether to Et2O) afforded ketone 24 (13.9 mg, 36% recovery) and 26a (78.0 mg, 87% yield) as colorless oil with a kinetic/thermodynamic enolsilane-derived aldol

Methyl 2-((2S,4R,6S)-6-((4R,6R,8S,E)-21-Azido-4-((tertbutyldiphenylsilyl)oxy)-6,8-dihydroxyhenicos-1-en-1-yl)-2-phenyl1,3-dioxan-4-yl)acetate (27a). To a solution of tetramethylammonium triacetoxyborohydride (50.0 mg, 0.190 mmol) in MeCN (dried over 3 Å molecular sieves, 0.32 mL) at room temperature was added AcOH (glacial, 0.096 mL) dropwise. After 40 min, the reaction mixture was cooled to −40 °C, and aldol 26a (16.2 mg, 0.0190 mmol, S,R,S,R/R,R,S,R > 90:10) in a solution of MeCN (dried over 3 Å molecular sieves, 0.29 mL) and THF (0.19 mL) was added dropwise. After 48 h at −40 °C, saturated aq NaHCO3 (5 mL) was slowly added, and the reaction mixture was partitioned between brine (5 mL) and CH2Cl2 (4 × 5 mL). The organic phase was dried over anhydrous Na2SO4. Concentration and radial chromatography (gradient, petroleum ether to EtOAc) afforded unreacted aldol 26a (17% recovery) and 27a (11.1 mg, 68% yield, S,R,R,S,R/R,R,R,S,R > 95:5) as a colorless oil; [α]D21 −7.5 (c 0.38, CHCl3); IR (film) 3467, 2926, 2854, 2095, 1742, 1462, 1428, 1377, 1339, 1306, 1259, 1215, 1111, 1027 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.71−7.67 (m, 4H), 7.47−7.30 (m, 11H), 5.55−5.45 (m, 1H), 5.54 (s, 1H), 5.38 (dd, J = 15.6, 5.9 Hz, 1H), 4.32−4.18 (m, 3H), 4.05−4.00 (m, 1H), 3.84−3.78 (m, 1H), 3.70 (s, 3H), 3.25 (m, apparent t, J = 7.0 Hz, 2H), 3.10−2.60 (br s, 2H), 2.72 (dd, J = 15.8, 6.9 Hz, 1H), 2.49 (dd, J = 15.8, 6.3 Hz, 1H), 2.39−2.30 (m, 1H), 2.25−2.19 (m, 1H), 1.77 (ddd, J = 14.3, 10.5, 3.7 Hz, 1H), 1.65−1.55 (m, 3H), 1.53−1.30 (m, 10H), 1.30−1.22 (m, 16H), 1.06 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 171.2, 138.4, 136.12, 136.09, 133.6, 133.3, 132.4, 130.2, 130.1, 128.9, 128.31, 128.27, 128.0, 127.9, 126.3, 100.8, 76.9, 73.1, 13664



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5.8 Hz, 1H), 5.60 (s, 1H), 4.39−4.30 (m, 2H), 3.90−3.72 (m, 3H), 3.70 (s, 3H), 2.83−2.80 (m, 1H), 2.75 (dd, J = 15.8, 6.9 Hz, 1H), 2.69−2.62 (m, 1H), 2.53 (dd, J = 15.8, 6.2 Hz, 1H), 2.28−2.17 (m, 2H), 1.79 (ddd, J = 13.1, 2.4, 2.4 Hz, 1H), 1.72−1.62 (m, 2H), 1.56 (ddd, J = 13.0, 11.3, 11.3 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 171.2, 138.3, 132.9, 128.9, 128.4, 128.3, 126.3, 100.9, 76.8, 73.1, 71.2, 61.6, 51.9, 40.8, 40.7, 37.9, 36.7; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C19H26O6Na 373.1627, found 373.1624.

72.1, 69.2, 66.2, 51.9, 51.6, 43.1, 41.5, 40.8, 39.4, 37.7, 36.6, 29.9, 29.80 (2 × C), 29.78 (2 × C), 29.7, 29.6, 29.3, 29.0, 27.2, 26.9, 25.9, 19.4; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C50H73N3O7SiNa 878.5115, found 878.5109.

Methyl 2-((2S,4R,6S)-6-((4R,6R,8S,E)-21-Azido-4,6,8-trihydroxyhenicos-1-en-1-yl)-2-phenyl-1,3-dioxan-4-yl)acetate (28). To a solution of silyl ether 27a (7.5 mg, 8.8 μmol) in THF (0.30 mL) was added HF·pyridine (∼70% wt, 0.023 mL, 0.88 mmol). After 52 h, saturated aq NaHCO3 (5 mL) was slowly added and the reaction mixture extracted with EtOAc (4 × 5 mL). The organic phase was dried over anhydrous Na2SO4. Concentration and flash chromatography (5% MeOH in CH2Cl2) afforded 27a (4.1 mg, 76% yield) as a colorless solid: [α]D21 −7.7 (c 0.065, CHCl3); IR (film) 3361, 2924, 2853, 2096, 1738, 1659, 1552, 1437, 1388, 1337, 1250, 1095, 1013 cm−1; 1H NMR (600 MHz, DMSO-d6) δ 7.40−7.34 (m, 5H), 5.74 (ddd, J = 15.2, 7.4, 6.8 Hz, 1H), 5.61 (s, 1H), 5.51 (dd, J = 15.6, 5.9 Hz, 1H), 4.40−4.37 (m, 1H), 4.39 (d, J = 5.5 Hz, 1H), 4.31−4.27 (m, 1H), 4.20 (d, J = 6.2 Hz, 1H), 4.19 (d, J = 6.4 Hz, 1H), 3.89−3.84 (m, 1H), 3.72−3.66 (m, 1H), 3.61−3.59 (m, 1H), 3.60 (s, 3H), 3.30 (m, apparent t, J = 6.9 Hz, 2H), 2.64 (dd, J = 15.7, 4.9 Hz, 1H), 2.55 (dd, J = 15.7, 8.0 Hz, 1H), 2.10−2.08 (m, 2H), 1.73 (ddd, J = 13.1, 2.2, 2.1 Hz, 1H), 1.54−1.49 (m, 2H), 1.42 (ddd, J = 13.0, 11.3, 11.3 Hz, 1H), 1.37−1.24 (m, 26H); 13C{1H} NMR (150 MHz, DMSOd6) δ 170.7, 138.6, 131.2, 129.0, 128.6, 128.0, 126.2, 99.8, 76.1, 72.6, 66.6 (2 × C), 63.8, 51.4, 50.6, 45.6, 45.0, 40.9, 40.1, 37.9, 36.1, 29.3, 29.2, 29.1 (2 × C), 29.04, 28.96, 28.93, 28.5, 28.2, 26.1, 25.3; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C34H55N3O7Na 640.3938, found 640.3945. DQF 1H−1H COSY, HSQC, HMBC, and TOCSY spectra supported peak assignments in the NMR spectra. The anti,anti relative configurational assignment of the 1,3,5-triol substructure in 28 was supported by the formation of a mixture of two acetonides. These exhibited 13C NMR resonances in the 25 ppm region, consistent with anti-1,3-diol configurations. To a solution of alcohol 28 (1.6 mg, 2.6 μmol) in 2,2-dimethoxypropane (0.26 mL) was added camphorsulfonic acid (0.06 mg, 0.26 μmol). After 27 h, the reaction mixture was partitioned between saturated aq NaHCO3 (0.2 mL) and CH2Cl2 (3 × 5 mL). The organic phase was dried over anhydrous Na2SO4. Concentration and flash chromatography (CH2Cl2 to 5% MeOH in CH2Cl2) afforded a mixture of acetonides 41a and 41b (2.0 mg, quantitative yield) as a colorless oil: 13C{1H} DEPT NMR (150 MHz, CDCl3) δ 25.02, 24.99 (2C), 24.8; LCHRMS (ESI-TOF) m/z [M + Na]+ calcd for C37H59N3O7Na 680.4251, retention times tR 13.1 min (found 680.4259), tR 13.6 min (found 680.4259).

Methyl 2-((2S,4R,6S)-6-((R,E)-4,6-Bis((tert-butyldimethylsilyl)oxy)hex-1-en-1-yl)-2-phenyl-1,3-dioxan-4-yl)acetate (32b). To a solution of diol 32a (68.2 mg, 0.195 mmol) in CH2Cl2 (4.9 mL) were added imidazole (0.133 g, 1.95 mmol) and tert-butyldimethylsilyl chloride (0.176 g, 1.17 mmol). After 46 h, the reaction mixture was partitioned between H2O (10 mL) and CH2Cl2 (3 × 10 mL). The organic phase was washed with brine (3 mL) and dried over anhydrous Na2SO4. Concentration and gradient flash chromatography (petroleum ether to 20% EtOAc in petroleum ether) afforded 32b (0.112 g, 99% yield) as a colorless oil: [α]D21 −6.70 (c 0.880, CHCl3); IR (film) 2928, 2856, 1744, 1472, 1437, 1387, 1361, 1340, 1311, 1255, 1215, 1094, 1028 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.51− 7.48 (m, 2H), 7.37−7.29 (m, 3H), 5.83−5.76 (m, 1H), 5.61 (s, 1H), 5.58 (dd, J = 15.6, 6.1 Hz, 1H), 4.38−4.31 (m, 2H), 3.90−3.84 (m, 1H), 3.71 (s, 3H), 3.67−3.64 (m, 2H), 2.76 (dd, J = 15.7, 7.0 Hz, 1H), 2.53 (dd, J = 15.7, 6.3 Hz, 1H), 2.36−2.15 (m, 2H), 1.77 (ddd, J = 13.1, 2.4, 2.4 Hz, 1H), 1.66−1.61 (m, 2H), 1.61−1.52 (m, 1H), 0.89 (s, 18H), 0.05 (s, 6H), 0.04 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 171.3, 138.5, 131.8, 129.4, 128.8, 128.3, 126.4, 100.8, 77.2 (DEPT), 73.2, 69.0, 60.0, 51.9, 40.9, 40.7, 40.1, 36.8, 26.1, 26.0, 18.4, 18.2, −4.2, −4.5, −5.1 (2 × C); HRMS (ESI-TOF) m/z [M + Na]+ calcd for C31H54O6Si2Na 601.3357, found 601.3367. Anal. Calcd for C31H54O6Si2: C, 64.31; H, 9.40. Found: C, 64.60; H, 9.64.

Methyl 2-((2S,4R,6S)-6-((R,E)-4-((tert-Butyldimethylsilyl)oxy)-6hydroxyhex-1-en-1-yl)-2-phenyl-1,3-dioxan-4-yl)acetate (42). To a solution of silyl ether 32b (0.105 g, 0.181 mmol) in THF (6.0 mL) at 0 °C was added HF·pyridine (∼70% wt, 0.47 mL, 18.1 mmol) dropwise. After 30 min, saturated aq NaHCO3 (50 mL) was slowly added and the reaction mixture extracted with EtOAc (3 × 50 mL). The organic phase was dried over anhydrous Na2SO4. Concentration and gradient flash chromatography (petroleum ether to EtOAc) afforded unreacted silyl ether 32b (17% recovery), diol 32a (9% yield), and 42 (55.3 mg, 66% yield) as a colorless oil: [α]D21 −12.0 (c 1.60, CHCl3); IR (film) 3457, 2953, 2929, 2885, 2856, 1742, 1439, 1361, 1341, 1311, 1254, 1215, 1163, 1141, 1094, 1062, 1026 cm−1; 1 H NMR (400 MHz, CDCl3) δ 7.50−7.48 (m, 2H), 7.37−7.29 (m, 3H), 5.79−5.71 (m, 1H), 5.60 (dd, J = 15.5, 5.8 Hz, 1H), 5.60 (s, 1H), 4.37−4.31 (m, 2H), 3.99−3.93 (m, 1H), 3.80 (ddd, J = 12.4, 7.9, 4.6 Hz, 1H), 3.73−3.68 (m, 1H), 3.70 (s, 3H), 2.75 (dd, J = 15.7, 6.9 Hz, 1H), 2.53 (dd, J = 15.7, 6.3 Hz, 1H), 2.32−2.27 (m, 3H), 1.82−1.74 (m, 2H), 1.69−1.61 (m, 1H), 1.55 (ddd, J = 13.0, 11.3, 11.3 Hz, 1H), 0.90 (s, 9H), 0.09 (s, 3H), 0.08 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 171.2, 138.4, 132.3, 128.9, 128.5, 128.3, 126.3, 100.8, 76.9, 73.1, 71.2, 60.2, 51.9, 40.8, 40.3, 38.0, 36.7, 25.9, 18.1, −4.2, −4.6; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C 25 H 40 O 6 SiNa 487.2492, found 487.2494. Anal. Calcd for C25H40O6Si: C, 64.62; H, 8.68. Found: C, 64.85; H, 8.81.

Methyl 2-((2S,4R,6S)-6-((R,E)-4,6-Dihydroxyhex-1-en-1-yl)-2-phenyl-1,3-dioxan-4-yl)acetate (32a). To a solution of silyl ether 21 (0.150 g, 0.255 mmol) in THF (8.5 mL) at 0 °C was added HF· pyridine (∼70% wt., 0.66 mL, 25.5 mmol) dropwise. The reaction mixture was then allowed to warm to room temperature. After 63 h, saturated aq NaHCO3 (50 mL) was slowly added and the reaction mixture extracted with EtOAc (3 × 50 mL). The organic phase was dried over anhydrous Na2SO4. Concentration and gradient flash chromatography (50% EtOAc in petroleum ether to 5% MeOH in EtOAc) afforded unreacted silyl ether 21 (4% recovery) and 32a (76.6 mg, 86% yield) as a colorless oil: [α]D21 +2.10 (c 1.10, CHCl3); IR (film) 3400, 2923, 1738, 1439, 1405, 1341, 1313, 1217, 1163, 1094, 1060, 1011 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.50−7.47 (m, 2H), 7.37−7.31 (m, 3H), 5.82−5.74 (m, 1H), 5.65 (dd, J = 15.7, 13665



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5.78−5.73 (m, 1H), 5.60 (s, 1H), 5.59 (dd, J = 15.5, 5.9 Hz, 1H), 4.36−4.31 (m, 2H), 4.31−4.27 (m, 1H), 4.05−4.01 (m, 1H), 3.70 (s, 3H), 3.45 (br s, 1H), 3.25 (m, apparent t, J = 7.0 Hz, 2H), 2.75 (dd, J = 15.8, 6.9 Hz, 1H), 2.57−2.49 (m, 3H), 2.40 (m, apparent t, J = 7.4 Hz, 2H), 2.31−2.27 (m, 2H), 1.77 (ddd, J = 13.1, 2.3, 2.3 Hz, 1H), 1.62−1.52 (m, 6H), 1.44 (ddd, J = 14.1, 7.6, 2.3 Hz, 1H), 1.36−1.33 (m, 2H), 1.32−1.22 (m, 16H), 0.89 (s, 9H), 0.09 (s, 3H), 0.08 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 211.9, 171.2, 138.4, 132.2, 128.8, 128.5, 128.3, 126.3, 100.8, 76.9, 73.1, 69.6, 64.4, 51.9, 51.6, 49.9, 43.7, 42.3, 40.8, 40.5, 36.7, 29.8, 29.7, 29.63, 29.58, 29.55, 29.51, 29.28, 29.26, 28.9, 26.8, 26.0, 23.7, 18.1, −4.3, −4.6. For minor kinetic enolsilane-derived aldol diastereomer (R,R,S,R)-26b: 1H NMR (500 MHz, CDCl3) δ 3.38 (d, J = 2.1 Hz, 1H), 0.09 (s, 3H), other peaks were not resolved. For major thermodynamic enolsilane-derived aldol diastereomer: 1H NMR (500 MHz, CDCl3) δ 3.55 (d, J = 1.9 Hz, 1H), 2.16 (s, 3H), other peaks were not resolved. For minor thermodynamic enolsilane-derived aldol diastereomer: 1H NMR (500 MHz, CDCl3) δ 3.40−3.39 (m, 1H), 2.18 (s, 3H), other peaks were not resolved.

Methyl 2-((2S,4R,6S)-6-((R,E)-4-((tert-Butyldimethylsilyl)oxy)-6oxohex-1-en-1-yl)-2-phenyl-1,3-dioxan-4-yl)acetate (22b). To a solution of oxalyl chloride (0.4 M in CH2Cl2, 0.96 mL, 0.38 mmol) at −78 °C was added DMSO (>99%, anhydrous, 0.6 M in CH2Cl2, 0.96 mL, 0.58 mmol) dropwise. After 30 min, alcohol 42 (44.6 mg, 0.096 mmol) in CH2Cl2 (0.48 mL) was added dropwise at −78 °C. After 3 h, Et3N (1.0 M in CH2Cl2, 0.96 mL, 0.96 mmol) was added at −78 °C. The reaction mixture was allowed to warm to room temperature over 1 h and then partitioned between H2O (5 mL) and CH2Cl2 (3 × 10 mL). The organic phase was washed with brine (3 mL) and dried over anhydrous Na2SO4. Concentration and gradient flash chromatography (petroleum ether to Et2O) afforded 22b (32.0 mg, 72% yield) as a colorless oil: [α]D21 −7.42 (c 1.32, CHCl3); IR (film) 2955, 2927, 2855, 1742, 1729, 1462, 1438, 1362, 1340, 1310, 1254, 1215, 1163, 1141, 1095, 1010 cm−1; 1H NMR (400 MHz, CDCl3) δ 9.79 (t, J = 2.3 Hz, 1H), 7.50−7.48 (m, 2H), 7.37−7.29 (m, 3H), 5.77 (dddd, J = 15.4, 7.2, 7.2, 1.0 Hz, 1H), 5.61 (dd, J = 15.6, 5.7 Hz, 1H), 5.61 (s, 1H), 4.38−4.31 (m, 2H), 4.29−4.23 (m, 1H), 3.71 (s, 3H), 2.75 (dd, J = 15.7, 6.9 Hz, 1H), 2.56−2.51 (m, 3H), 2.32−2.28 (m, 2H), 1.78 (ddd, J = 13.0, 2.4, 2.4 Hz, 1H), 1.55 (ddd, J = 13.0, 11.3, 11.3 Hz, 1H), 0.87 (s, 9H), 0.08 (s, 3H), 0.06 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 202.0, 171.2, 138.4, 133.0, 128.9, 128.3, 127.6, 126.3, 100.8, 76.8, 73.1, 67.8, 51.9, 50.6, 40.9, 40.8, 36.7, 25.9, 18.1, −4.3, −4.6; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C25H38O6SiNa 485.2335, found 485.2338.

Methyl 2-((2S,4R,6S)-6-((1E,4R,6S,10S,11E,14S,15E,18R)-21Azido-4,10,14,18-tetrakis((tert-butyldimethylsilyl)oxy)-6-hydroxy8-oxohenicosa-1,11,15-trien-1-yl)-2-phenyl-1,3-dioxan-4-yl)acetate (33). To a solution of ketone 16 (36.7 mg, 56.1 μmol) in THF (5.6 mL) at −78 °C was added chlorotrimethylsilane (0.036 mL, 0.28 mmol) followed by LiHMDS (1.0 M in THF, 0.28 mL, 0.28 mmol) dropwise over 20 min. After 5 h, the reaction mixture was partitioned between aq phosphate buffer (pH 7, 6 mL) and petroleum ether (3 × 10 mL). The organic phase was washed with brine (3 mL) and dried over anhydrous Na2SO4. Concentration afforded the crude enolsilane (47, 39.7 mg, 97% yield) as a yellow oil: 1H NMR (300 MHz, CDCl3) δ 5.60−5.41 (m, 4H), 4.32−4.26 (m, 1H), 4.08 (ddd, J = 5.7, 5.7, 5.7 Hz, 1H), 4.04 (s, 2H), 3.73−3.66 (m, 1H), 3.25 (m, apparent t, J = 6.7 Hz, 2H), 2.27−2.15 (m, 5H), 2.09 (dd, J = 13.6, 6.4 Hz, 1H), 1.72−1.65 (m, 1H), 1.62−1.54 (m, 1H), 1.52−1.39 (m, 2H), 0.89 (m, 18H), 0.88 (s, 9H), 0.20 (s, 6H), 0.19 (s, 3H), 0.06, (s, 3H), 0.05 (m, 12H), 0.02 (s, 3H). The kinetic/thermodynamic ratio of the enolsilane was unable to be determined by 1H NMR. The enolsilane was used in the subsequent step without further purification. To a solution of enolsilane 47 prepared as described above (39.7 mg, 54.7 μmol) and aldehyde 22b (32.0 mg, 69.2 μmol) in CH2Cl2 (0.11 mL) at −78 °C was added BF3·OEt2 (9.0 μL, 69.2 μmol) dropwise. After 5 h, saturated aq NaHCO3 (3 mL) was added, and the reaction mixture was allowed to warm to room temperature. After 30 min, the reaction mixture was extracted with CH2Cl2 (3 × 10 mL), and the organic phase dried over anhydrous Na2SO4. Concentration and radial chromatography (gradient, petroleum ether to EtOAc) afforded aldehyde 22b (23% recovery), thermodynamic enolsilanederived aldol product (6.8 mg, 11% yield), and kinetic enolsilanederived aldol product 33 (43.3 mg, 71% yield, C25(S)/C25(R) 87:13) as a colorless oil: [α]D21 −1.26 (c 1.11, CHCl3); IR (film) 3512, 2929, 2857, 2096, 1744, 1710, 1472, 1437, 1406, 1361, 1301, 1254, 1216, 1079, 1007 cm−1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C58H105N3O10Si4Na 1138.6775, found 1138.6804. The kinetic enolsilane-derived aldol 33 diastereomers were inseparable by radial chromatography, and the C25(S)/C25(R) ratio was determined by 1H NMR. For major kinetic enolsilane-derived aldol diastereomer C25(S)-33: 1H NMR (500 MHz, CDCl3) δ 7.50−7.47 (m, 2H), 7.36−7.29 (m, 3H), 5.76 (ddd,, J = 14.8, 7.2, 7.2 Hz, 1H), 5.61−5.50 (m, 3H), 5.60 (s, 1H), 5.46−5.41 (m, 2H), 4.59−4.55 (m, 1H), 4.36−4.32 (m, 2H), 4.28−4.23 (m, 1H), 4.08 (ddd, J = 6.0, 6.0, 6.0 Hz, 1H), 4.05−4.01 (m, 1H), 3.72−3.68 (m, 1H), 3.71 (s, 3H), 3.38 (d, J = 2.2 Hz, 1H), 3.25 (m, apparent t, J = 6.9 Hz, 2H), 2.75 (dd, J = 15.7, 7.0 Hz, 1H), 2.67 (dd, J = 14.9, 8.3 Hz, 1H), 2.59−2.51

M e t h y l 2 - ( ( 2 S , 4 R , 6 S ) - 6 - ( ( 4 R , 6 S , E) -2 1 - A z i d o - 4 - ( ( t e r t butyldimethylsilyl)oxy)-6-hydroxy-8-oxohenicos-1-en-1-yl)-2-phenyl-1,3-dioxan-4-yl)acetate (26b). To a solution of ketone 24 (26.4 mg, 0.099 mmol) in THF (4.9 mL) at −78 °C was added chlorotrimethylsilane (0.063 mL, 0.49 mmol) followed by LiHMDS (1.0 M in THF, 0.49 mL, 0.49 mmol) dropwise over 20 min. After 5 h, the reaction mixture was partitioned between aq phosphate buffer (pH 7, 10 mL) and petroleum ether (3 × 10 mL). The organic phase was washed with brine (3 mL) and dried over anhydrous Na2SO4. Concentration afforded the crude enolsilane 25 (33.5 mg, 99% yield, kinetic/thermodynamic = 83:17, thermodynamic E/Z = 71:29) as a yellow oil. The kinetic/thermodynamic and E/Z ratios were determined by 1H NMR. The enolsilane 25 was used in the subsequent step without further purification. To a mixture of enolsilane 25 (6.8 mg, 0.020 mmol) and aldehyde 22b (8.2 mg, 0.014 mmol) at −78 °C was added BF3·OEt2 (0.66 M in CH2Cl2, 0.03 mL, 0.020 mmol) dropwise. After 5 h, saturated aq NaHCO3 (1 mL) was added, and the reaction mixture was allowed to warm to room temperature. After 30 min, the reaction mixture was extracted with CH2Cl2 (3 × 5 mL) and the organic phase dried over anhydrous Na2SO4. Concentration afforded crude aldol 26b with a kinetic/thermodynamic enolsilane-derived aldol product ratio of >57:43, a thermodynamic enolsilane-derived aldol product diastereomeric ratio of 71:29, as determined by 1H NMR. Careful radial chromatography (gradient, petroleum ether to EtOAc) afforded ketone 24 (4.1 mg, 77% recovery) and an enriched ratio of the major kinetic enolsilane-derived aldol diastereomer 26b (6.6 mg, 66% yield, estimated purity >90%, S,R,S,R/R,R,S,R 81:19) as a colorless oil: IR (film) 3506, 2927, 2855, 2096, 1742, 1710, 1462, 1437, 1372, 1341, 1301, 1254, 1216, 1163, 1093, 1027 cm−1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C40H67N3O7SiNa 752.4646, found 752.4647. For major kinetic enolsilane-derived aldol diastereomer (S,R,S,R)-26b: 1H NMR (600 MHz, CDCl3) δ 7.49−7.47 (m, 2H), 7.35−7.30 (m, 3H), 13666



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phenyl-1,3-dioxan-4-yl)acetate (35). To a solution of silyl ether 34 (3.9 mg, 3.5 μmol) was added HF·pyridine (2.9 M in THF, 0.12 mL, 0.35 mmol). After 17 h, saturated aq NaHCO3 (3 mL) was slowly added and the reaction mixture extracted with EtOAc (4 × 5 mL). The organic phase was dried over anhydrous Na2SO4. Concentration and gradient flash chromatography (petroleum ether to EtOAc to 5% MeOH in EtOAc) afforded 35 (1.7 mg, 74% yield) as a colorless solid: [α]D21 −40 (c 0.065, CHCl3); IR (film) 3356, 2923, 2852, 2097, 1738, 1552, 1378, 1311, 1252, 1163, 1092, 1027 cm−1; 1H NMR (600 MHz, DMSO-d6) δ 7.39−7.35 (m, 5H), 5.74 (ddd, J = 14.4, 7.3, 7.3 Hz, 1H), 5.61 (s, 1H), 5.57−5.48 (m, 3H), 5.46−5.40 (m, 2H), 4.63 (d, J = 4.1 Hz, 1H), 4.52 (d, J = 5.4 Hz, 1H), 4.51 (d, J = 5.4 Hz, 1H), 4.41 (d, J = 5.3 Hz, 1H), 4.41−4.36 (m, 1H), 4.31− 4.26 (m, 1H), 4.26 (d, J = 5.8 Hz, 1H), 4.23 (d, J = 5.7 Hz, 1H), 4.12−4.06 (m, 1H), 3.91−3.84 (m, 3H), 3.72−3.67 (m, 1H), 3.60 (s, 3H), 3.46−3.41 (m, 1H), 3.33−3.27 (m, 2H), 2.64 (dd, J = 15.7, 4.7 Hz, 1H), 2.55 (dd, J = 15.7, 8.0 Hz, 1H), 2.14−2.03 (m, 6H), 1.73 (d, J = 12.9 Hz, 1H), 1.69−1.62 (m, 1H), 1.57−1.48 (m, 1H), 1.47−1.39 (m, 2H), 1.38−1.25 (m, 7H); 13C{1H} NMR (150 MHz, DMSO-d6) δ 170.8, 138.7, 136.8, 135.6, 131.2, 129.1, 128.6, 128.0, 126.3, 126.2, 125.1, 99.8, 76.1, 72.7, 71.0, 69.3, 67.7, 66.7, 63.85, 63.82, 51.5, 50.9, 46.0, 45.8, 45.1, 40.9, 40.6, 40.4, 40.2, 36.1, 33.3, 24.8; HRMS (ESITOF) m/z [M + Na]+ calcd for C34H51N3O10Na 684.3472, found 684.3474. DQF 1H−1H COSY, HSQC, HMBC, and TOCSY spectra supported peak assignments in the NMR spectra.

(m, 3H), 2.40 (dd, J = 14.9, 4.4 Hz, 1H), 2.29−2.27 (m, 2H), 2.22− 2.17 (m, 4H), 1.77 (ddd, J = 13.1, 2.2, 2.2 Hz, 1H), 1.72−1.65 (m, 1H), 1.60−1.48 (m, 4H), 1.47−1.40 (m, 2H), 0.89 (s, 9H), 0.88 (m, 18H), 0.85 (s, 9H), 0.09 (s, 3H), 0.08 (s, 3H), 0.06 (s, 3H), 0.05 (s, 3H), 0.04 (s, 3H), 0.022 (s, 3H), 0.019 (s, 3H), 0.015 (s, 3H); 13 C{1H} NMR (125 MHz, CDCl3) δ 209.9, 171.2, 138.6, 135.8, 134.7, 132.2, 128.8, 128.6, 128.3, 127.2, 126.4, 126.2, 100.8, 77.0, 73.3, 73.2, 71.6, 70.4, 69.5, 64.4, 52.1, 51.9, 51.84, 51.75, 42.7, 41.5, 40.9, 40.7, 40.3, 36.8, 33.5, 26.04 (2 × 3C), 26.03 (2 × 3C), 25.0, 18.4, 18.23 (2 × C), 18.19, −4.0, −4.18 (2 × C), −4.24, −4.49, −4.54 (2 × C), −4.7. For minor kinetic enolsilane-derived aldol diastereomer C25(R)-33: 1H NMR (500 MHz, CDCl3) δ 3.33 (d, J = 2.2 Hz, 1H), other peaks were not resolved. The configuration of the major kinetic enolsilane-derived aldol diastereomer 33 was determined after subsequent steps.

Methyl 2-((2S,4R,6S)-6-((1E,4R,6R,8R,10S,11E,14S,15E,18R)-21azido-4,10,14,18-tetrakis((tert-butyldimethylsilyl)oxy)-6,8-dihydroxyhenicosa-1,11,15-trien-1-yl)-2-phenyl-1,3-dioxan-4-yl)acetate (34). To a solution of tetramethylammonium triacetoxyborohydride (89.0 mg, 0.339 mmol) in MeCN (dried over 3 Å molecular sieves, 0.56 mL) at room temperature was added AcOH (glacial, 0.17 mL) dropwise. After 40 min, the reaction mixture was cooled to −40 °C, and aldol 33 (37.8 mg, 33.9 μmol, C25(S)/C25(R) 87:13) in a solution of MeCN (dried over 3 Å molecular sieves, 0.51 mL) and THF (0.34 mL) was added dropwise. After 72 h at −40 °C, saturated aq NaHCO3 (10 mL) was slowly added, and the reaction mixture was partitioned between brine (10 mL) and CH2Cl2 (4 × 15 mL). The organic phase was dried over anhydrous Na2SO4. Concentration and radial chromatography (gradient, petroleum ether to EtOAc) afforded unreacted aldol 33 (24% recovery) and 34 (20.5 mg, 54% yield, C25(R),C27(R)/C25(S),C27(S) 85:15, C25(R),C27(R)/C25(R),C27(S) > 95:5) as a colorless oil: [α]D21 +0.67 (c 0.45, CHCl3); IR (film) 3477, 2953, 2929, 2857, 2096, 1743, 1472, 1463, 1437, 1361, 1304, 1255, 1216, 1080, 1028, 1006 cm−1; HRMS (ESITOF) m/z [M + Na]+ calcd for C58H107N3O10Si4Na 1140.6931, found 1140.6941. The diol 34 C25(R),C27(R)/C25(S),C27(S) diastereomers were inseparable by radial chromatography, and their ratio was determined by 1H NMR. For C25(R),C27(R)-34: 1H NMR (400 MHz, CDCl3) δ 7.50−7.47 (m, 2H), 7.37−7.29 (m, 3H), 5.75 (ddd, J = 15.0, 7.0, 7.0 Hz, 1H), 5.62−5.50 (m, 4H), 5.60 (s, 1H), 5.44 (dd, J = 15.3, 6.0 Hz, 1H), 4.48−4.44 (m, 1H), 4.37−4.30 (m, 2H), 4.28−4.21 (m, 2H), 4.10 (ddd, J = 5.9, 5.9, 5.9 Hz, 1H), 4.07− 4.01 (m, 1H), 3.91 (d, J = 1.7 Hz, 1H), 3.80 (d, J = 1.8 Hz, 1H), 3.73−3.67 (m, 1H), 3.71 (s, 3H), 3.25 (m, apparent t, J = 6.8 Hz, 2H), 2.75 (dd, J = 15.7, 7.0 Hz, 1H), 2.53 (dd, J = 15.7, 6.2 Hz, 1H), 2.33−2.29 (m, 2H), 2.28−2.16 (m, 4H), 1.84−1.73 (m, 2H), 1.72− 1.63 (m, 2H), 1.62−1.41 (m, 8H), 0.90−0.88 (m, 36H), 0.10 (s, 3H), 0.084 (s, 3H), 0.077 (s, 3H), 0.06 (s, 3H), 0.05 (m, 6H), 0.04 (s, 3H), 0.02 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 171.3, 138.5, 135.8, 134.5, 132.1, 128.93, 128.86, 128.3, 127.1, 126.3, 126.1, 100.8, 77.0, 73.3, 73.2, 72.7, 71.6, 70.8, 66.3, 65.5, 51.9, 51.8, 43.9, 43.7, 42.7, 41.5, 40.9, 40.3, 40.1, 36.7, 33.5, 26.0 (4 × 3C), 25.0, 18.4, 18.24, 18.22, 18.16, −4.17 (2 × C), −4.21, −4.3, −4.5, −4.6 (2 × C), −4.9. For C25(S),C27(S)-34: 1H NMR (400 MHz, CDCl3) δ 3.99 (br s, 1H), 3.96 (br s, 1H, other peaks were not resolved. The configuration of the major diol diastereomer C25(R),C27(R)-34 was determined after the following step.

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ASSOCIATED CONTENT

* Supporting Information S

1 H and 13C NMR spectra for new compounds, data on diastereomer ratios and configuration assignments. The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b02034.

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1 H and 13C NMR spectra for new compounds 43, 44, 4−6, 2, 9−15, 46, 37, 38, and 16 (PDF) 1 H and 13C NMR spectra for new compounds 17b, 18, 39, 19−24, 26−28, 32, 42, and 33−35 (PDF) 2D NMR spectra for new compounds 20, 28, and 35; diastereomer ratios and configuration assignments of 9, 26a, 28, 26b, 33, and 34 (PDF)

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Gregory K. Friestad: 0000-0001-5374-2620 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS For their gracious support of this research, we thank the University of Iowa (MPSFP award to G.K.F., SROP program funding for A.G.), the UI Department of Chemistry (Ralph Shriner Graduate Fellowship Award to R.M.F.), and the Grinnell College Internship Program (Z.S.). We thank Santhana Velupillai (University of Iowa) for assistance with 2D NMR data acquisition and analysis.

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REFERENCES

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Unified Strategy for 1,5,9- and 1,5,7-Triols via Configuration-Encoded

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