Total Synthesis of (−)-Peniphenone A - The Journal of Organic

Feb 26, 2018 - This article is part of the Synthesis of Antibiotics and Related Molecules special issue. Cite this:J. Org. Chem. 83, 13, 7049-7059 ...
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Cite This: J. Org. Chem. 2018, 83, 7049−7059

Total Synthesis of (−)-Peniphenone A Mathilde Pantin, Margaret A. Brimble,* and Daniel P. Furkert* School of Chemical Sciences, The University of Auckland, 23 Symonds Street, Auckland 1010, New Zealand

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ABSTRACT: The asymmetric total synthesis of the polyketide benzannulated spiroketal natural product, (−)-peniphenone A, is reported. The key reaction in the synthesis involved sp3−sp2 Negishi cross-coupling between a chiral organozinc species and an aryl bromide to construct the challenging αchiral β-aryl carbonyl motif present in the natural product. Access to the spiroketal possessing the correct stereochemistry was facilitated by an unusual thermodynamic resolution at C10. The synthesis was achieved in 14 steps (longest linear sequence) from commercially available 2,4-dihydroxybenzaldehyde in 6% overall yield. Investigations into a parallel approach required extension of Krische’s enantioselective hydrogen-mediated C−C coupling to α-substituted alcohols and oxetane ring-opening with an aryllithium for assembly of the polyketide domain. These studies provide a useful foundation for further work toward the natural product family, members of which demonstrate significant activity against M. tuberculosis and offer continuing inspiration for the development of efficient new chemical methods.

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INTRODUCTION Peniphenone A (1) belongs to the family of benzannulated spiroketal natural products,1 exemplified in Figure 1 by virgatolide B (2),2 chaetoquadrin A (3),3 citreoviranol (4),4 penicophenone A (5),5 and peniciketal (6).6 Racemic (±)-1 was coisolated with other nonspiroketal metabolites including peniphenones B (7) and C (8) during investigation of cultures of the mangrove fungus Penicilium dipodomycola (strain HN4− 3A), isolated from the stem of the mangrove plant Acanthus ilicifolius from the South China Sea region.7 Although the limited quantities obtained from the natural source did not permit evaluation of the biological activity of (±)-1, peniphenones B (7) and C (8) exhibited strong antibiotic inhibitory activity against M. tuberculosis protein tyrosine phosphate B (IC50 0.16 and 1.37 μM, respectively). The structure of spiroketal-containing peniphenone A (1) was established by NMR and the relative stereochemistry unambiguously determined by X-ray crystallography. The absolute stereochemistry of (−)-1 was additionally predicted to be 8R,9R,10R,13R at the time of isolation by proposed agreement of the experimental CD spectrum with a calculated CD spectrum (DTF, B3LYP). During the course of our work, a total synthesis of (−)-peniphenone A (1) and other peniphenone family members, including 7 and 8, was reported by George in 2015 using an elegant direct biomimetic approach based on the intermediacy of an o-quinone methide (Scheme 1).8 This work led to revision of the absolute stereochemistry, instead assigning the 8R,9R,10R,13R enantiomer as (+)-1. The synthesis afforded (+)-1 in 6.9% overall yield over seven steps (longest linear sequence) as an 18:1 ratio of C8 diastereoisomers (dr 95%). Our investigations toward the synthesis of 1 form part of our ongoing interest in the asymmetric synthesis and medicinal chemistry of benzannulated spiroketals, e.g., virgatolide B (2)9 and chaetoquadrin A (3).10 In particular, © 2018 American Chemical Society

identification of general and efficient methods for asymmetric installation of the α-methyl, β-aryl ketone motif (Figure 1, blue) embedded in 1, 2, 3, and 5 formed a key objective of these investigations. Retrosynthetically, peniphenone (−)-(1) was expected to be accessible by deprotection and acid-promoted spiroketalization of linear precursor 14. Based on our previous work toward virgatolide B,9 it appeared that 14 could be assembled from an aldol reaction of advanced ketone 15 in which the acetophenone has been masked as an olefin and α-chiral ester 16 (Scheme 2, disconnection A). Ketone 15 would in turn be prepared from sp3−sp2 cross-coupling of a homochiral organometallic derivative (17) and the aromatic nucleus (18). The chirality present in both 16 and 17 would be derived from the respective enantiomers of the Roche ester. Alternatively, a second strategy was also considered (Scheme 2, disconnection B) in which fragment coupling would be effected between an organometallic reagent derived from aromatic nucleus 18 and complex oxetane 19 containing four stereogenic centers. At the outset, it was expected that the acidic proton at C1011 would be highly prone to epimerization and also that the configuration of the adjacent stereocenters resulting from the proposed aldol reactions would be rendered inconsequential by later oxidation. It therefore seemed likely that the final C10 and spiroketal center stereochemistry would be directed by preinstalled chirality at both C8 and C13, although this remained to be established in practice as we began our investigations. Special Issue: Synthesis of Antibiotics and Related Molecules Received: December 21, 2017 Published: February 26, 2018 7049

DOI: 10.1021/acs.joc.7b03231 J. Org. Chem. 2018, 83, 7049−7059

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The Journal of Organic Chemistry

Figure 1. Peniphenone A (1) and related benzannulated spiroketal natural products (left) and coisolated resorcinol derivatives (right).

Scheme 3. Synthesis of the Aromatic Nucleus 24a,ba

Scheme 1. Key Alkylation of the Lithium Enolate of 11 with in Situ Generated o-Quinone Methide 10 for Fragment Coupling and Establishment of C8 Stereochemistry in George’s 2015 Total Synthesis of Peniphenone A (+)-1

a

Reagents and conditions: (i) NaBH3CN, 1 M HCl, THF, rt, 3 h, 87%; (ii) AcOH, BF3·OEt2, 90 °C, 16 h, 89%; (iii) TBATB, CH2Cl2, rt, 16 h, 99%; (iv) K2CO3, MeI (for 23a) or PMBCl (for 23b), DMF, 60 °C, 2−7 h, sealed tube, 23a (94%), 23b (86%); (v) (a) Ph3PCH3Br, n-BuLi, THF, rt, 1 h, (b) THF, 60 °C, 5 h, 24a (80%), 24b (82%).

butylammonium tribromide (TBATB). Dimethylation of 22 to give 23a proceeded readily; however, installation of the more synthetically useful BOM or PMB protecting groups proved unexpectedly challenging, giving low conversion or monoprotected products. These issues were eventually resolved through heating the reaction mixture in a sealed tube to give the bis-PMB ether 23b in high yield. Finally, the ketone was masked as an alkene under standard Wittig conditions to give the required aromatic nucleus 24a,b. On the basis of previous work in our group leading to the total synthesis of virgatolide B (2), it appeared likely that Suzuki coupling of a suitable alkyltrifluoroborate (e.g., 27, Table 1), an approach pioneered by Molander,13 would be similarly applicable to the assembly of the peniphenone A carbon framework. Accordingly, a range of conditions were investigated in order to carry out this step. Disappointingly, despite a thorough survey of coupling conditions including temperature (40−125 °C, MW), ligand (RuPhos, iPr-PEPPSI, DtBPF), base (K2CO3, DBU), and solvent (dioxane, toluene, water), no coupling products (26a,b) were isolated (Table 1, entries 1 and 2), although molecular ions corresponding to the correct m/z could be detected in the mass spectra of crude reaction mixtures. The dehalogenation products of 24a and 24b were the predominant species obtained from these reactions. Potentially, the electron-rich nature of aryl bromides 24a,b was responsible for the observed lack of reactivity in the Suzuki

Scheme 2. Retrosynthetic Analysis of (+)-1 via Two Possible Approaches: (A) sp3-sp2 Cross-Coupling or (B) Oxetane Opening Approaches

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RESULTS AND DISCUSSION Synthetic investigations began with reduction of commercially available 2,4-dihydroxybenzaldehyde (20) and subsequent Friedel−Crafts acylation to give 21 (Scheme 3), according to known methods.8b,12 Initial attempts to brominate resorcinol 21 using NBS or molecular bromine were low yielding, but nearly quantitative conversion to 22 was achieved with tetra-n7050

DOI: 10.1021/acs.joc.7b03231 J. Org. Chem. 2018, 83, 7049−7059

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The Journal of Organic Chemistry Table 1. Key sp3−sp2 Cross-Coupling for Assembly of the αMethyl β-Aryl Ketone Motif

entry

RX

ArBr

conditions

1

27

24a

2

27

24b

3

25

24b

Pd(OAc)2, RuPhos K2CO3, aq toluene, 70 °C Pd(OAc)2, DtBPF DBU, aq dioxane, 125 °C Cu/Zn, PhH/DMA, rt, 40 minb Pd2(dba)3, P(o-tol)3, 55 °C Cu/Zn, PhH/DMA, 60 °C, 3 h Pd2(dba)3, P(o-tol)3, 100 °C Cu/Zn, PhH/DMA, 60 °C, 3 h Pd2(dba)3, RuPhos, 70 °C Cu/Zn, PhH/DMA, 60 °C, 3 h Pd2(dba)3, RuPhos, 100 °C (as per entry 6) (as per entry 6) (as per entry 6)

a

4

25

24b

5

25

24b

6

25

24b

7 8 9

25 28 29

24a 24b 24b

product

Scheme 4. Assembly of the Spiroketalization Precursor 34a,ba,b

yield (%)

a a trace

Reagents and conditions: (i) LiAlH4, Et2O, 0 °C, 15 min, quant; (ii) IBX, DMSO, 16 h, quant; (iii) EtMgBr, Et2O, 0 °C, 2 h, 66% (dr 1:1); (iv) IBX, DMSO, rt, 16 h, 92%; (v) see Table 2. For 32a,b: cHex2BCl, Et3N, Et2O, 30b, 0 °C, 30 min then 31b, −80 °C, 7 h then to rt, 16 h, 81% from 31b (100% brsm, dr 1:1); vi) O3, CH2Cl2−MeOH, −78 °C, 15 min then Me2S, −78 °C to rt, 2 h, 60%. bPeniphenone numbering. a

26b

trace

26b

21

26b

29

26a

69

conditions. Use of the boron enolate prepared from Bchlorodiisopinocampheylborane (DIPCl) or scandium triflate gave no reaction (Table 2, entries 1 and 2). Use of the lithium enolate of 30a prepared using lithium hexamethydisilazide gave a 21% combined yield of two diastereoisomers (dr 1:1.2) (Table 2, entry 3), while the boron enolate derived from cyclohexyl boron chloride19 was more effective, giving a mixture of 32a and 32b in 49% yield (dr 1.3:1) (Table 2, entry 4). The best results for the aldol coupling were eventually obtained by reaction of the boron enolate of 30b with PMB-protected aldehyde 31b, affording 33a and 33b in a combined yield of 81% (dr 1:1) with the remaining balance of ketone 30b recovered after chromatography (Table 2, entry 5). Although these reagents are usually expected to deliver anti-aldol products, 32a,b and 33a,b appeared most likely to be C10 epimeric pairs, a supposition later borne out by subsequent stereochemical elucidation. Interestingly, no coupling products were isolated from reactions of aldehyde 31b with enolates derived from dimethyl-protected ketone 30a (Table 2, entry 6). Finally, oxidative cleavage of the olefin in 33a,b using ozonolysis then afforded the corresponding ketones 34a and 34b, required for investigation of the spiroketal formation sequence. With the carbon framework in hand, epimeric ketones 34a and 34b were individually submitted to hydrogenolytic deprotection of the PMB groups (Scheme 5). Somewhat remarkably, both epimers furnished the same spiroketal 35 in both cases in 93% and 94% yield, respectively. The 1H NMR spectrum indicated that spiroketal 35 was nonidentical to the corresponding penultimate intermediate 36 prepared by George et al. in their total synthesis of (+)-1,8a notably differing in the shifts observed for H10 and H11. Additionally, a sharp doublet at δ 3.45 ppm was observed due to the C11 hydroxy proton, suggesting the presence of a hydrogen bond to the phenolic oxygen of the spiroketal. Taken together, these data suggested that the relative stereochemistry of 35

Dehalogenation observed. bUnder sonication.

coupling, a point highlighted by Molander in a discussion of the reaction scope in the original disclosure of this methodology. To address the reactivity issue, an alternative Negshi crosscoupling was investigated.14 This approach required the generation of a Reformatsky-type coordination-stabilized zinc reagent by zinc insertion into the carbon−iodine bond of αchiral ester (R)-25.15 Initial forays using zinc insertion conditions reported by Yoshida (Table 1, entry 3)16 or Schiller (Table 1, entry 4), followed by Negishi coupling using tri-otolyl phosphine/Pd2(dba)3 were disappointing. Application of a variety of zinc activation methods failed to offer any improvement. Some success was finally achieved by the use of RuPhos/Pd2(dba)3 as reported by Buchwald,17 affording the desired Negishi coupling product 26b in 21% yield (Table 1, entry 5). A slight increase in the temperature of the crosscoupling step from 70 to 100 °C did afford a minor yield improvement to 29% (Table 1, entry 6), and the dimethylprotected aryl bromide 24a was pleasingly found to give a 69% yield of the corresponding coupling product 26a under the same conditions. Attempts to improve the synthetic efficiency of the overall route using alternative iodides, Weinreb amide 28 or ketone 29, were not successful. Although after extensive investigation the best yield for 26b remained 29%, this proved to be reliable and scalable and was accordingly used to support ongoing synthetic studies. Methyl esters 26a,b were next converted to ethyl ketones 30a,b in high yield over four steps using standard chemistry (Scheme 4). The key aldol reaction of aldehyde 31a, derived from commercially available ethyl (S)-3-hydroxybutanoate,18 and ethyl ketone 30a was then investigated under a variety of 7051

DOI: 10.1021/acs.joc.7b03231 J. Org. Chem. 2018, 83, 7049−7059

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The Journal of Organic Chemistry Table 2. Optimization of the Key Aldol Reaction between 30 and 31a,b

a

entry

RCHO

ketone

conditions

1

31a

30a

2

31a

30a

3

31a

30a

4

31a

30a

5

31b

30b

9

31b

30a

Sn(OTf)2, Et3N CH2Cl2, −80 to −20 °C (+)-DIPCl, Et3N Et2O, −80 to −50 °C LHMDS, Et2O, − 30 °C then ZnCl2, −80 to −20 °C, 16 h (chex)2BCl, Et3N Et2O, −80 to −20 °C, 16 h (chex)2BCl, Et3N Et2O, −80 °C to rt, 16 h various

product

% yield

a a 32a,b

21a (73)b

32a,b

49 (9)b

33a,b

81 (19)b

b

Combined yield (dr 1:1). Ketone 30a or 30b recovered.

species such as 35*. It is possible that upon oxonium formation deprotonation at C10 is effected by the phenoxide leaving group. Concurrent with the successfully completed total synthesis, parallel investigations had also been undertaken into accessing the α-methyl, β-aryl ketone motif required for natural products such as peniphenone A (Scheme 1, 1), virgatolide B (2), chaetoquadrin A (3), and penicophenone (5) via an alternative oxetane opening approach. Based upon a small amount of related literature precedent for nucleophilic oxetane opening with alkynes, allyl silanes, and organometallic species,21 it seemed likely that intermediate 14 (Scheme 6) containing the carbon framework of peniphenone A (1) could also be assembled by ring opening of oxetane 19 with an aryllithium reagent (18·Li).

Scheme 5. Spirocyclization and Synthesis of Peniphenone A (−)-1

Scheme 6. Retrosynthetic Analysis of the Peniphenone A Framework 14 via Oxetane Opening

a

Note the C10,C11 relative stereochemistry. Compound 36 belongs to the enantiomeric series leading to (+)-1. Reagents and conditions: (i) 10 wt % Pd/C, EtOAc, H2, rt, 16 h, 94%; (ii) IBX, DMSO, rt, 5.5 h, 94%.

corresponded to the C11 epimer of 36. Calculation of relative energies for the most stable conformers of 35 and 36 suggested that these were of very similar relative energy (±0.5 kcal/mol) and that both of these were significantly lower in energy than their C10 Me epimers by approximately 9 kcal/mol).20 In confirmation of the stereochemical assignment of 35, oxidation of the C11 alcohol to the ketone proceeded smoothly, using IBX in DMSO, to afford the natural product target, peniphenone A (−)-1, in nearly quantitative yield. We were pleased to observe that the spectral data for (−)-1 closely matched that reported for the isolated racemic natural product and the synthetic sample of (+)-1 prepared by George et al. The respective optical rotations were also in good agreement; (−)-1: [α]D22 −81.0 (c 0.20, MeOH),8a lit. (+)-1: [α]D22 +85.6 (c 0.88, MeOH). In our original plan, we had anticipated that the C10 methyl group would readily epimerise in the natural product, via oxonium species (−)-1*. Our observations indicated that epimerization to give the thermodynamically favored C10 epimer of 35 also occurred readily at the alcohol oxidation state, presumably via the intermediacy of an oxonium

The realization of this approach would require the development of several challenging transformations that were not well precedented at the outset of our studies. Despite some closely related examples,22 the opening of 2-alkyloxetanes with aryllithium reagents required to access 14 was not well established. Further, our retrosynthesis suggested that a novel Brook-type rearrangement to generate a vinylic organometallic species from 38 to introduce the right-hand three-carbon fragment in 37 would potentially offer an efficient solution to this disconnection. Finally, vinylsilane 38 itself was envisaged to arise from Krische-type hydrogen-mediated coupling of monoprotected diol 39 with 2-silyl-1,4-butadiene 40. This latter methodology has seen rapid development in very recent years; however, the use of α-substituted primary alcohols had 7052

DOI: 10.1021/acs.joc.7b03231 J. Org. Chem. 2018, 83, 7049−7059

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The Journal of Organic Chemistry not been investigated and the influence of the α-substituent on the crucial stereochemical outcome in the formation of the contiguous stereotriad present in 38 remained uncertain. Given that access to 38 would underpin the remainder of this proposed approach, it formed the target of our initial investigations. The Krische group has recently established new methods for hydrogen-mediated carbon−carbon bond formation, avoiding preformed organometallic reagents or carbonyl compounds.23 In particular, methods for direct asymmetric formyl anticrotylation of alcohols using allylic acetates24 and syncrotylation of alcohols using 2-phenyldimethylsilyl-1,4-butadiene (40) have been reported (Scheme 7).25 Of particular

Scheme 8. Oxetane 45 Ring Opening with Aryllithium 24b

type rearrangement step required to piece together the planned synthetic route. The Takeda group has reported the use of copper(I) tertbutoxide to promote the generation of vinyl copper species from hydroxyl vinyl silanes of general structure 47 via 1,4 C-toO silyl migration or Brooke-type rearrangement to give products of general structure 48 (Scheme 9).28 A small number

Scheme 7. Direct Access to the Defined Stereotriad in anti,syn-43 by Krische-Type Hydrogen-Mediated C−C Coupling of Protected Diol 4226

Scheme 9. Attempted Brooke-Type Rearrangement of 43b or Diol 49

relevance to the current study, in the presence of a ruthenium catalyst and a chiral ligand based on SEGPHOS, the syn products (41) were obtained in high yield with excellent enantio- and diastereoselectivity. A detailed stereochemical study was therefore undertaken by our group,26 extending these conditions to the α-substituted diol substrates 42a,b required for the current synthesis. This study revealed that, remarkably, the introduction of the two new syn stereocenters in 43a,c was completely controlled by the enantiomer of the DMSEGPHOS ligand used, giving the products in high yield as essentially single diastereoisomers. These findings provided the first step toward the peniphenone A (1) framework via this second approach, providing synthetically useful quantities of enantiomerically pure anti,syn-43b for ongoing studies. With access to 43b secured, the feasibility of oxetane opening with aryllithium reagents in our system was next investigated. As an exemplar, known oxetane 45 (Scheme 8) was accordingly prepared according to reported procedures.27 Treatment of 45 with the aryllithium reagent derived from lithium−halogen exchange of aryl bromide 24b, in the presence of boron trifluoride etherate, pleasingly afforded the desired secondary alcohol 46 in a moderate yield of 47%. This represents one of the first examples of 2-alkyl oxetane opening by an aryl organometallic reagent. Encouraged by this result involving the aryl system required for peniphenone A, we next proceeded to investigate the possibility of effecting the Brooke-

of examples have also been reported on the application of related methodology to the synthesis of complex natural product fragments.29 On the basis of this precedent, it appeared possible that carbon−carbon bond formation might be possible via a vinyl cuprate species derived from 43b and a suitable three-carbon electrophile such as epoxide 50 or chloride 51.30 Although 43b contains an additional silyl protecting group, it was hoped that the steric, electronic, and transition-state ring size (5 vs 6) differences between them would allow formation of the desired vinyl metal intermediate. In the event, however, these hopes were frustrated, as despite a number of attempts only starting material was recovered from either TBDPS-protected 43b or diol 49, with no evidence of silyl transfer or cleavage of the sp2 carbon−silicon bond. Although this result was disappointing, further transformations of vinyl silane diol 49 were investigated (Scheme 10) to determine other possibilities for achieving the necessary carbon−carbon bond formation for peniphenone A via vinyl silane 43b. It was established that cyclization of diol 49 to oxetane 54 occurred in almost quantitative yield. The preparation of potential precursors to vinyl organometallic reagents was also examined, demonstrating that vinyl bromide 55 was readily available from oxetane 54 but that its use was hampered by problematic volatility. It appeared that analogous 7053

DOI: 10.1021/acs.joc.7b03231 J. Org. Chem. 2018, 83, 7049−7059

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alcohols and investigation of challenging Brooke-type rearrangement and oxetane ring-opening transformations. Although eventually unsuccessful, these latter studies lay a strong foundation for future synthetic studies toward the natural product family and related compounds and have inspired the exploration of new reaction pathways for novel method development. The successful total synthesis afforded enantio- and diastereoisomerically pure peniphenone A (−)-1 and was achieved in similar overall yield to the o-quinone methide route recently reported by George et al.8 Facile epimerization of the C10 methyl group upon spiroketalization was found to occur, allowing the use of both diastereoisomers of the preceding aldol coupling for preparation of the natural product.

Scheme 10. Further Transformations of Diol 49

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EXPERIMENTAL SECTION

General Methods. All reactions were performed under a nitrogen or argon atmosphere in oven-dried glassware. Toluene was purified on alumina oxide activated basic Brockmann grade 1, 58 Å, then dried over 4 Å molecular sieves. Chromatography was carried out using 0.063−0.1 mm silica gel (Davisil LC60A 40-63 Micron) or alumina oxide activated neutral Brockmann grade 1, 58 Å. Optical rotations were measured on a Rudolph Research Analytical - Autopol IV polarimeter. HRMS were recorded using a Bruker micrOTOF-QII mass spectrometer. NMR spectra were recorded at 21 °C in CDCl3 on a Bruker DRX400 spectrometer operating at 400 MHz for 1H nuclei and 100 MHz for 13C nuclei or on a Bruker Ascend 500 spectrometer operating at 500 MHz for 1H nuclei and 125 MHz for 13C nuclei. Chemical shifts are reported in parts per million (ppm) from tetramethylsilane (δ = 0 ppm) and measured relatively to the solvent in which the sample was analyzed (CDCl3 δ = 7.26 ppm for 1H NMR and δ = 77.16 ppm for 13C NMR). Assignments were made with the aid of 2D spectra (COSY, HSQC, HMBC, NOESY, and 1D-TOCSYHOHAHA) where necessary. Coupling constants (J) are reported in Hertz (Hz). 1H NMR data is reported as chemical shift in ppm, followed by multiplicity (“s” singlet, “d” doublet, “dd” doublet of doublet, “ddd” doublet of doublet of doublet, “t” triplet, “m” multiplet, “b” broad), coupling constant where applicable, relative integral. 13C spectra are reported as chemical shift in ppm followed by degree of hybridization. Bromoresorcinol 22. A solution of TBATB (2.62 g, 5.42 mmol, 1.0 equiv) in CH2Cl2 (60 mL) was slowly added to a solution of acetyl resorcinol 21 (0.90 g, 5.42 mmol, 1.0 equiv) in CH2Cl2 (60 mL) at rt. After the reaction mixture was stirred at rt for 18 h, water was added. The organic layer was dried over anhydrous Na2SO4 and concentrated. Purification by chromatography (hexanes−EtOAc, 19:1−9:1) afforded 22 (1.31 g, 99%) as a pale yellow solid: 1H NMR (CDCl3, 400 MHz) δ 13.33 (s, 1H), 7.47 (s, 1H), 6.27 (s, 1H), 2.58 (s, 3H), 2.27 (d, J = 0.9 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 202.6, 159.3, 157.3, 131.5, 116.5, 114.1, 99.2, 26.4, 16.1; HRMS (ESI) m/z calcd for C9H9BrNaO3 [(M + Na)+] 266.9627, found 266.9627; mp 131−133 °C; Rf 0.65 (hexanes−EtOAc, 9:1); IR νmax (neat) 3200, 1844, 1594, 1294, 1175, 870, 801 cm−1. Dimethylbromoresorcinol 23a. K2CO3 (586 mg, 4.24 mmol, 4.0 equiv) and iodomethane (0.66 mL, 10.6 mmol, 10.0 equiv) were added to a solution of bromide 22 (250 mg, 1.06 mmol, 1.0 equiv) in DMF (2 mL) at rt. After being stirred at 60 °C for 7 h in a sealed tube, the reaction mixture was diluted with EtOAc and water. The organic layer was washed with a saturated aqueous LiCl solution, dried over anhydrous Na2SO4, and concentrated. Purification by chromatography (hexanes−EtOAc, 9:1−4:1) afforded 23a (272 mg, 94%) as a white solid: 1H NMR (CDCl3, 400 MHz) δ 7.45 (s, 1H), 3.84 (s, 3H), 3.82 (s, 3H), 2.61 (s, 3H), 2.29 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 198.7, 159.9, 156.1, 131.1, 130.1, 129.0, 114.0, 62.4, 60.3, 30.5, 16.3; HRMS (ESI) m/z calcd for C11H13BrNaO3 [(M + Na)+] 294.9940, found 294.9934; mp 43−45 °C; Rf 0.60 (hexanes−EtOAc, 9:1); IR νmax (neat) 3650, 2979, 1666, 1385, 1254, 1152, 1069, 952 cm−1.

conversion to iodide 56 was also possible from TLC evidence; however, the instability of this compound prevented its characterization. The vinyl silane function could readily be converted into a methyl ketone, affording 57, via cobaltmediated conditions identified by Herzon.31 Alternatively, cyclic acetal formation proceeded in high yield from diol 49 to give 58 in which the relative stereochemistry of the phenyl group was able to be determined by a NOESY correlation observed between the indicated 1,3-diaxial protons. Again, conversion of the vinyl silane function to give the corresponding vinyl bromide 59 occurred in high yield. Finally, an attempt to effect carbon−carbon bond formation via lithium−halogen exchange and treatment with propylene oxide was unsuccessful. In this case, only the oxidative dimerization product 60 was isolated in low yield. Despite the failure to identify a productive route toward peniphenone A (1), these studies have provided a significant foundation of established transformations upon which to build future synthetic studies toward this family of antimicrobial polyketide natural product targets and clearly demonstrated the power of natural products to inspire new developments in chemical methodology.

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CONCLUSION The asymmetric total synthesis of (−)-peniphenone A (1) is reported. The synthesis was pursued by two parallel approaches, the first of which accomplished the key carbon− carbon coupling to form the polyketide domain containing an α-chiral β-aryl carbonyl motif using an sp3−sp2 Negishi crosscoupling between a chiral organozinc species and an aryl bromide, and eventually led to the successful total synthesis of 1. The second approach aimed to assemble the same key polyketide domain via oxetane ring-opening with an aryl lithium reagent. Synthesis of the necessary intermediates for the latter route required extension of Krische’s enantioselective hydrogen-mediated C−C coupling to include α-substituted 7054

DOI: 10.1021/acs.joc.7b03231 J. Org. Chem. 2018, 83, 7049−7059

Article

The Journal of Organic Chemistry PMB-Protected Bromoresorcinol 23b. Using the method described for 23a above, 23b (539 mg, 86%) was obtained as white crystals: 1H NMR (CDCl3, 400 MHz) δ 7.43−7.40 (m, 5H), 6.96− 6.89 (m, 4H), 4.93 (s, 2H), 4.92 (s, 2H), 3.84 (s, 3H), 3.83 (s, 3H), 2.56 (s, 3H), 2.27 (d, J = 0.9 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 199.4, 160.1, 160.0, 158.5, 154.3, 131.3, 130.8, 130.5 (2), 130.3 (2), 129.6, 128.8, 128.3, 115.0, 114.1, 77.1, 74.6, 55.5 (2), 30.7, 16.6; HRMS (ESI) m/z calcd for C25H25BrNaO5 [(M + Na)+] 507.0783, found 507.0778; mp 117−119 °C; Rf 0.25 (hexanes−EtOAc, 9:1); IR νmax (neat) 2940, 1663, 1515, 1250, 1158, 821 cm−1. Bromoalkene 24a. n-Butyllithium (1.6 M in hexanes, 6.18 mL, 9.89 mmol, 10.0 equiv) was added dropwise to a suspension of methyl triphenylphosphonium bromide (3.53 g, 9.89 mmol, 10.0 equiv) in THF (35 mL) at rt. After being stirred at rt for 1 h, a solution of 23a (270 mg, 1.00 mmol, 1.0 equiv) in THF (5 mL) was added, and the reaction mixture was heated at 60 °C for 16 h and then cooled to rt. Et2O was added, and the reaction mixture was filtered then concentrated. Purification by chromatography (hexanes−Et2O, 49:1) afforded 24a (214 mg, 80%) as a colorless oil: 1H NMR (CDCl3, 400 MHz) δ 6.96 (d, J = 0.9 Hz, 1H, H6), 5.16−5.15 (m, 1H, CCH2a), 5.10−5.09 (m, 1H, CCH2b), 3.81 (s, 3H, OCH3), 3.74 (s, 3H, OCH3), 2.23 (d, J = 0.9 Hz, 3H, C1-CH3), 2.09 (s, 3H, CO-CH3); 13C NMR (CDCl3, 100 MHz) δ 155.4 (C2), 153.3 (C4), 143.2 (C5-C), 134.2 (C5), 130.4 (C6), 128.0 (C1), 115.9 (CH2), 113.3 (C3), 60.8 (OCH3), 60.3 (OCH3), 23.2 (C-CH3), 16.2 (C1-CH3); HRMS (ESI) m/z calcd for C12H15BrNaO2 [(M + Na)+] 293.0157, found 293.0148; Rf 0.48 (hexanes−Et2O, 19:1); IR νmax (neat) 2936, 1470, 1415, 1311, 1223, 1081, 1005, 841 cm−1. Bromoalkene 24b. n-Butyllithium (1.6 M in hexanes, 5.5 mL, 8.82 mmol, 20.0 equiv) was added dropwise to suspension of methyl triphenylphosphonium bromide (3.15 g, 8.82 mmol, 20.0 equiv) in THF (30 mL) at rt. After the reaction mixture was stirred at rt for 1 h, a solution of 23b (214 mg, 0.44 mmol, 1.0 equiv) in THF (2 mL) was added, and the mixture was heated at 60 °C for 5 h. Et2O (30 mL) was added and the reaction mixture filtered then concentrated. Purification by chromatography (hexanes−EtOAc, 19:1) afforded 24b (174 mg, 82%) as a colorless oil: 1H NMR (CDCl3, 400 MHz) δ 7.46−7.43 (m, 4H), 7.01 (s, 1H), 6.96−6.91 (m, 4H), 5.21−5.20 (m, 1H), 5.18−5.17 (m, 1H), 4.89 (s, 2H), 4.82 (s, 2H), 3.84 (s, 3H), 3.83 (s, 3H), 2.28 (s, 3H), 2.15 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 159.8, 159.7, 154.1, 151.9, 143.4, 134.7, 130.4 (2), 130.1 (2), 129.3, 128.6, 116.1, 114.3, 114.0 (2), 113.9 (2), 74.8, 74.3, 55.4 (2), 23.4, 15.6; HRMS (ESI) m/z calcd for C26H27BrNaO4 [(M + Na)+] 505.0990, found 505.0968; Rf 0.43 (hexanes−EtOAc, 9:1); IR νmax (neat) 2955, 1612, 1513, 1242, 1168, 1074, 820 cm−1. (S)-2-Methyl-3-aryl Propionate 26a. In an argon-purged Schlenk tube, alkyl iodide 25 (0.78 mL, 5.52 mmol, 3.0 equiv) was added to a suspension of Zn/Cu couple (1.20 g, 18.4 mmol, 10.0 equiv) in a mixture of benzene/DMA (7.5 mL/1.9 mL). After being stirred at 60 °C for 3 h, the supernatant was transferred in a previously purged Schlenk charged with Pd(dba)2 (211 mg, 0.37 mmol, 0.2 equiv), RuPhos (361 mg, 0.74 mmol, 0.4 equiv), and aryl bromide 24a (500 mg, 1.84 mmol, 1.0 equiv). After being stirred at 100 °C for 16 h, the reaction mixture was cooled to rt and quenched with water. The reaction mixture was filtered through a pad of Celite and then extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4 and then concentrated. Purification by chromatography (petroleum ether−EtOAc, 9:1) afforded 26a (372 mg, 69%) as a yellow oil: 1H NMR (CDCl3, 400 MHz) δ 6.89 (s, 1H), 5.12−5.10 (m, 1H), 5.09−5.08 (m, 1H), 3.72 (s, 3H), 3.66 (s, 3H), 3.65 (s, 3H), 3.03−2.94 (m, 1H), 2.88−2.77 (m, 1H), 2.82−2.75 (m, 1H), 2.24 (s, 3H), 2.11 (s, 3H), 1.11 (d, J = 6.8 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 177.3, 157.1, 155.1, 144.2, 132.5, 130.1, 126.0, 125.9, 115.0, 60.6, 60.4, 51.7, 39.8, 28.5, 23.1, 16.8, 16.1; HRMS (ESI) m/z calcd for C17H24NaO4 [(M + Na)+] 315.1567, found 315.1555; Rf 0.28 (petroleum ether−EtOAc, 9:1); IR νmax (neat) 2963, 1641, 1501, 1262, 1166, 1058, 1022, 827 cm−1; [α]22 D +10.5 (c 0.19 in CHCl3). (S)-2-Methyl-3-aryl Propionate 26b. Using the method described for 26a above, 24b afforded 26b (15 mg, 29%) as a colorless oil: 1H NMR (CDCl3, 400 MHz) δ 7.42−7.33 (m, 4H), 6.96

(s, 1H), 6.94−6.89 (m, 4H), 5.20−5.15 (m, 2H), 4.73 (s, 4H), 3.83 (s, 3H), 3.82 (s, 3H), 3.57 (s, 3H), 2.99 (dd, J = 12.4, 5.4 Hz, 1H), 2.91− 2.83 (m, 1H), 2.78 (dd, J = 12.4, 8.5 Hz, 1H), 2.29 (s, 3H), 2.15 (s, 3H), 1.05 (d, J = 6.9 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 177.2, 159.6, 159.5, 155.9, 153.5, 144.4, 133.2 (2), 130.2, 130.0, 129.8 (2), 129.6 (2), 126.9, 126.6, 115.3, 114.0 (2), 113.9 (2), 74.7, 74.5, 55.4 (2), 51.6, 39.9, 29.0, 23.3, 16.6, 16.4; HRMS (ESI) m/z calcd for C31H36NaO6 [(M + Na)+] 527.2404, found 527.2420; Rf 0.22 (hexanes−EtOAc, 9:1); IR νmax (neat) 2965, 1640, 1511, 1257, 1176, 1058, 1021, 825 cm−1; [α]24 D +3.0 (c 1.00 in CHCl3). Iodide 29. Ethyl magnesium bromide (3 M in Et2O, 1.09 mL, 3.27 mmol, 2.0 equiv) was added dropwise to a solution of Weinreb amide 2832 (420 mg, 1.63 mmol, 1.0 equiv) in Et2O (10 mL) at 0 °C. After being stirred at rt for 1 h, water was added, and the organic layer was dried over anhydrous Na2SO4 and concentrated. Purification by chromatography (pentane−Et2O, 9:1) afforded the iodide 29 (84 mg, 23%) as a highly volatile pale yellow liquid: 1H NMR (CDCl3, 400 MHz) δ 3.38 (dd, J = 9.8, 7.3 Hz, 1H), 3.12 (dd, J = 9.8, 6.2 Hz, 1H), 2.96−2.87 (m, 1H), 2.61−2.43 (m, 2H), 1.20 (d, J = 7.0 Hz, 3H), 1.08 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 211.9, 48.5, 34.9, 18.4, 7.7, 6.4; HRMS (ESI) m/z calcd for C6H11INaO [(M + Na)+] 248.9752, found 248.9754; IR νmax (neat) 2923, 1715, 1459, 1364, 1271, 1027, 724 cm−1; [α]22 D +1.4 (c 0.60 in CHCl3). Ethyl Ketone 30a. LiAlH4 (48 mg, 1.27 mmol, 1.0 equiv) was added to a solution of ester 26a (372 mg, 1.27 mmol, 1.0 equiv) in Et2O (10 mL) at 0 °C. After the reaction mixture was stirred at rt for 30 min, Et2O was added, and the reaction mixture was filtered through a pad of Celite and then concentrated. Purification by chromatography (petroleum ether−EtOAc, 4:1) afforded the corresponding alcohol (335 mg, quant) as a pale yellow oil: 1H NMR (CDCl3, 400 MHz) δ 6.88 (s, 1H), 5.14−5.11 (m, 1), 5.11−5.07 (m, 1H), 3.75 (s, 3H), 3.69 (s, 3H), 3.40−3.24 (m, 2H), 2.81 (s, 1H), 2.64 (dd, J = 12.9, 5.6 Hz, 1H), 2.59 (dd, J = 12.9, 9.0 Hz, 1H), 2.25 (s, 3H), 2.11 (t, J = 1.2 Hz), 1.94−1.81 (m, 1H), 1.07 (d, J = 6.8 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 156.8, 154.7, 144.0, 132.7, 129.9, 126.9, 126.3, 115.3, 65.9, 60.9, 60.7, 36.9, 27.6, 23.1, 18.1, 16.1; HRMS (ESI) m/z calcd for C16H24NaO3 [(M + Na)+] 287.1618, found 287.1622; Rf 0.19 (petroleum ether−EtOAc, 9:1); IR νmax (neat) 2975, 1513, 1267, 1174, 1058, 1020, 824 cm−1; [α]22 D +13.4 (c 0.56 in CHCl3). IBX (222 mg, 0.80 mmol, 2.0 equiv) was added to a solution of the above alcohol (105 mg, 0.40 mmol, 1.0 equiv) in DMSO (10 mL) at rt. After the reaction mixture was stirred at rt for 3 h, Et2O and brine were added. The organic layer was dried over anhydrous Na2SO4 then concentrated. Purification by chromatography (petroleum ether− EtOAc, 19:1) afforded the expected aldehyde (87 mg, 84%) as a pale yellow oil: 1H NMR (CDCl3, 400 MHz) δ 9.68 (t, J = 1.5 Hz, 1H), 6.90 (s, 1H), 5.13−5.10 (m, 1H), 5.10−5.07 (m, 1H), 3.72 (s, 3H), 3.66 (s, 3H), 3.03−2.93 (m, 1H), 2.77−2.65 (m, 2H), 2.24 (s, 3H), 2.10 (s, 3H), 1.08 (d, J = 7.0 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 205.4, 156.9, 154.8, 144.0, 132.6, 130.3, 126.5, 125.5, 115.2, 60.6, 60.5, 47.2, 25.8, 23.0, 16.1, 13.7 ; HRMS (ESI) m/z calcd for C16H22NaO3 [(M + Na)+] 285.1461, found 285.1467; Rf 0.48 (petroleum ether− EtOAc, 9:1); IR νmax (neat) 2965, 1640, 1511, 1257, 1176, 1058, 1021, 825 cm−1; [α]19 D −0.5 (c 0.39 in CHCl3). Ethylmagnesium bromide (3 M in Et2O, 0.70 mL, 2.10 mmol, 2.0 equiv) was added dropwise to a solution of the above aldehyde (276 mg, 1.05 mmol, 1.0 equiv) in Et2O (5 mL) at rt. After the reaction mixture was stirred at rt for 2 h, water was added, and the organic layer was dried over anhydrous Na2SO4 and then concentrated. Purification by chromatography (petroleum ether/EtOAc 9:1) afforded an inconsequential 1:1 mixture of alcohol epimers (294 mg, 96%) as yellow oils. Diastereoisomer A: 1H NMR (CDCl3, 400 MHz) δ 6.89 (s, 1H), 5.15−5.12 (m, 1H), 5.12−5.09 (m, 1H), 3.75 (s, 3H), 3.69 (s, 3H), 3.17−3.11 (m, 2H), 2.64 (dd, J = 12.9, 5.9 Hz, 1H), 2.59 (dd, J = 12.9, 10.4 Hz, 1H), 2.25 (s, 3H), 2.12 (t, J = 1.1 Hz, 3H), 1.86−1.71 (m, 1H), 1.60−1.43 (m, 1H), 1.36−1.17 (m, 1H), 0.97 (d, J = 7.0 Hz, 3H), 0.85 (t, J = 7.4 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 156.8, 154.8, 144.0, 132.7, 129.9, 126.9, 126.2, 115.3, 72.9, 60.9, 60.7, 38.6, 29.1, 27.0, 23.1, 16.1, 13.7, 11.1; HRMS (ESI) m/z calcd for C18H28NaO3 [(M + Na)+] 315.1931, found 315.1928; Rf 0.11 7055

DOI: 10.1021/acs.joc.7b03231 J. Org. Chem. 2018, 83, 7049−7059

Article

The Journal of Organic Chemistry (petroleum ether−EtOAc, 9:1); IR νmax (neat) 2962, 1541, 1260, 1176, 1048, 1022, 827 cm−1; [α]23 D +26.0 (c 0.20 in CHCl3). Diastereoisomer B: 1H NMR (CDCl3, 400 MHz) δ 6.87 (s, 1H), 5.14−5.10 (m, 1H), 5.10−5.07 (m, 1H), 3.74 (s, 3H), 3.67 (s, 3H), 3.38−3.27 (m, 1H), 2.75 (dd, J = 13.0, 5.5 Hz, 1H), 2.57 (dd, J = 13.0, 7.4 Hz, 1H), 2.24 (s, 3H), 2.11 (t, J = 1.2 Hz, 3H), 1.94−1.83 (m, 1H), 1.59−1.49 (m, 1H), 1.42−1.30 (m, 1H), 0.95 (t, J = 7.4 Hz, 3H), 0.90 (d, J = 7.0 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 156.8, 154.8, 144.2, 132.6, 129.7, 127.7, 126.1, 115.1, 77.7, 60.7, 60.5, 40.1, 27.2, 27.0, 23.1, 17.1, 16.1, 10.5; HRMS (ESI) m/z calcd for C18H28NaO3 [(M + Na)+] 315.1931, found 315.1928; Rf 0.06 (petroleum ether− EtOAc, 9:1); IR νmax (neat) 2965, 1544, 1260, 1177, 1048, 1023, 827 cm−1; [α]23 D −9.4 (c 0.35 in CHCl3). IBX (588 mg, 2.10 mmol, 2.1 equiv) was added to a solution of the above alcohol epimers (294 mg, 1.01 mmol, 1.0 equiv) in DMSO (10 mL) at rt. After the reaction mixure was stirred at rt for 16 h, Et2O and brine were added. The organic layer was dried over anhydrous Na2SO4 and then concentrated. Purification by chromatography (petroleum ether−EtOAc, 9:1) afforded ethyl ketone 30a (258 mg, 85%) as a colorless oil: 1H NMR (CDCl3, 400 MHz) δ 6.88 (s, 1H), 5.13−5.10 (m, 1H), 5.09−5.07 (m, 1H), 3.71 (s, 3H), 3.64 (s, 3H), 2.97−2.83 (m, 2H), 2.75−2.64 (m, 1H), 2.54−2.36 (m, 2H), 2.24 (s, 3H), 2.11 (t, J = 1.2 Hz, 3H), 1.07−1.00 (m, 6H); 13C NMR (CDCl3, 100 MHz) δ 215.5, 157.0, 154.9, 144.1, 132.6, 130.0, 126.5, 126.1, 115.1, 60.6, 60.4, 46.5, 34.8, 27.9, 23.1, 16.5, 16.1, 8.0; HRMS (ESI) m/z calcd for C18H26NaO3 [(M + Na)+] 313.1774, found 313.1786; Rf 0.71 (petroleum ether−EtOAc, 9:1); IR νmax (neat) 2962, 1670, 1544, 1260, 1186, 1049, 821 cm−1; [α]18 D +28.0 (c 0.38 in CHCl3). Ethyl Ketone 30b. An analogous sequence of transformations beginning from 26b afforded initially the corresponding alcohol: 1H NMR (CDCl3, 400 MHz) δ 7.43−7.30 (m, 4H), 6.95 (s, 1H), 6.98− 6.88 (m, 4H), 5.22−5.17 (m, 2H), 4.83−4.66 (s, 4H), 3.83 (s, 3H), 3.82 (s, 3H), 3.30 (dd, J = 11.6, 3.5 Hz, 1H), 3.19 (dd, J = 11.7, 4.1 Hz, 1H), 2.65−2.54 (m, 2H), 2.32 (s, 3H), 2.17 (s, 3H), 1.87−1.81 (m, 2H), 0.97 (d, J = 6.9 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 159.8, 159.7, 155.7, 153.2, 144.2, 133.3, 129.9, 129.9 (2), 129.7 (2), 129.5, 129.4, 127.8, 126.8, 115.5, 114.2 (2), 114.1 (2), 75.2, 74.9, 65.5, 55.5, 55.4, 36.9, 28.0, 23.3, 18.0, 16.5; HRMS (ESI) m/z calcd for C30H36NaO5 [(M + Na)+] 499.2460, found 499.2462; Rf 0.20 (petroleum ether−EtOAc, 4:1); IR νmax (neat) 2922, 2161, 1716, 1513, 1364, 1513, 1364, 1267, 1031, 761, 740 cm−1; [α]20 D +5.3 (c 0.43 in CHCl3). Oxidation of the above alcohol with IBX afforded the aldehyde: 1H NMR (CDCl3, 400 MHz) δ 9.56 (d, J = 1.4 Hz, 1H), 7.38−7.26 (m, 4H), 6.97 (s, 1H), 6.95−6.86 (m, 4H), 5.21−5.15 (m, 2H), 4.74 (dd, 4H, J = 13.2, 11.2 Hz), 3.83 (s, 3H), 3.82 (s, 3H), 2.92 (dd, J = 12.2, 5.7 Hz, 1H), 2.74−2.65 (m, 1H), 2.64 (dd, J = 12.2, 7.7 Hz, 1H), 2.30 (s, 3H), 2.15 (s, 3H), 0.98 (d, J = 6.8 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 205.4, 159.7, 159.6, 155.7, 153.3, 144.2, 133.3, 130.3, 129.8 (2), 129.7 (2), 129.5 (2), 126.7, 126.5, 115.5, 114.1 (2), 114.0 (2), 74.7 (2), 55.5, 55.4, 47.2, 26.2, 23.3, 16.5, 13.7; HRMS (ESI) m/z calcd for C30H34NaO5 [(M + Na)+] 497.2298, found 497.2285; Rf 0.52 (petroleum ether−EtOAc, 4:1); IR νmax (neat) 2938, 1715, 1612, 1515, 1370, 1249, 1034, 912, 823, 737 cm−1; [α]19 D +10.0 (c 0.45 in CHCl3). Reaction of the above aldehyde with ethylmagnesium bromide gave a 1:1 mixture of alcohol diastereoisomers: 1H NMR (CDCl3, 400 MHz) δ 7.42−7.30 (m, 4H), 6.98−6.86 (m, 5H), 5.23−5.14 (m, 2H), 4.84−4.64 (m, 4H), 3.83 (s, 3H), 3.82 (s, 3H), 3.23−3.06 (m, 1H), 2.77−2.50 (m, 2H), 2.35−2.28 (m, 3H), 2.19−2.12 (m, 3H), 1.96− 1.70 (m, 1H), 1.70−1.51 (m, 1H), 1.51−1.33 (m, 1H), 1.23−1.133 (m, 1H), 0.90−0.73 (m, 6H); 13C NMR (CDCl3, 100 MHz) δ 159.8, 159.7, 155.8 and 158.7, 153.4, 144.5, 144.2, 133.3, 129.9, 129.8 (2), 129.7 (2), 129.5, 129.3, 128.4 (2), 127.8, 126.7, 126.6, 115.5, 115.3, 114.3, 114.1 (2), 114.0 (2), 75.2, 75.1, 74.9, 74.7, 72.5, 55.5, 55.4, 40.0, 38.5, 36.9, 29.6, 27.6, 26.9, 23.3, 16.9, 16.5, 13.6, 11.2, 10.5; HRMS (ESI) m/z calcd for C32H40NaO5 [(M + Na)+] 527.2768, found 527.2764; Rf 0.48 and 0.62 (petroleum ether−EtOAc, 4:1); IR νmax (neat) 2963, 1714, 1612, 1514, 1250, 1174, 1035, 911, 823, 739 cm−1.

Oxidation of the above mixture of alcohols with IBX afforded ethyl ketone 30b: 1H NMR (CDCl3, 400 MHz) δ 7.41−7.29 (m, 4H), 6.95 (s, 1H), 6.95−6.86 (m, 4H), 5.20−5.15 (m, 2H), 4.72 (dd, 4H, J = 17.2, 10.8 Hz), 3.83 (s, 3H), 3.82 (s, 3H), 2.99−2.87 (m, 1H), 2.84 (dd, J = 12.8, 5.1 Hz, 1H), 2.67 (dd, J = 12.9, 8.7 Hz, 1H), 2.30 (s, 3H), 2.28−2.17 (m, 2H), 2.15 (s, 3H), 0.96 (d, J = 6.9 Hz, 3H), 0.91 (t, J = 14.6 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 215.5, 159.7, 159.6, 155.8, 153.5, 144.4, 133.2, 130.0, 130.0, 129.8, 129.8 (2), 129.7 (2), 127.4, 126.6, 115.3, 114.1 (2), 113.9 (2), 74.7, 74.6, 55.5, 55.4, 46.4, 34.6, 28.3, 23.3, 16.5, 13.3, 7.9; HRMS (ESI) m/z calcd for C32H38NaO5 [(M + Na)+] 525.2611, found 525.2605; Rf 0.74 (petroleum ether:EtOAc, 4:1); IR νmax (neat) 2936, 1711, 1612, 1514, 1247, 1174, 1100, 1034, 976, 822, 738 cm−1; [α]19 D −9.0 (c 0.30 in CHCl3). Aldol Adducts 32a and 32b. Method A. Triethylamine (0.22 mL, 1.66 mmol, 2.4 equiv) was added to a solution of chlorodicyclohexyl borane (1 M in hexanes, 1.50 mL, 1.50 mmol, 2.0 equiv) in Et2O (1 mL) at 0 °C. After the reaction mixture was stirred at 0 °C for 10 min, a solution of ketone 30a (197 mg, 0.75 mmol, 1.0 equiv) in Et2O (1 mL) was added. After being stirred at 0 °C for 30 min, the reaction mixture was cooled to −80 °C, and a solution of aldehyde 31a (240 mg, 0.83 mmol, 1.1 equiv) in Et2O (1 mL) was added. The reaction mixture was stirred at −80 °C for 1 h then at −20 °C for 12 h. Water was added, and the organic layer dried over anhydrous Na2SO4 then concentrated. Purification by chromatography (petroleum ether/EtOAc, 9:1) afforded diastereoisomers 32a (102 mg, 28%) and 32b (76 mg, 21%) as colorless oils. A small amount of starting material ethyl ketone 30a was also recovered (17 mg, 9%). Method B. LHMDS (1 M in hexanes, 0.19 mL, 0.19 mmol, 1.5 equiv) was added to a solution of ketone 30a (50 mg, 0.19 mmol, 1.5 equiv) in Et2O (0.7 mL) at −80 °C. After being stirred at −80 °C for 30 min, a solution of aldehyde 61 (38 mg, 0.13 mmol, 1.0 equiv) in Et2O (0.3 mL) was added. After being stirred at −80 °C for 1 h and at −20 °C for 16 h, water and EtOAc were added. The organic layer was dried over anhydrous Na2SO4 and then concentrated. Purification by chromatography (petroleum ether−EtOAc, 9:1) afforded diastereoisomers 32a (6 mg, 9%) and 32b (9 mg, 12%) as colorless oils. A small amount of starting material ethyl ketone 30a was also recovered (25 mg, 73%). Data for 32a: 1H NMR (CDCl3, 400 MHz) δ 6.88 (s, 1H), 5.13− 5.10 (m, 1H), 5.10−5.06 (m, 1H), 4.24−4.13 (m, 1H), 4.09−3.93 (m, 1H), 3.71 (s, 3H), 3.65 (s, 3H), 3.14−3.02 (m, 1H), 2.96 (dd, J = 13.1, 4.1 Hz, 1H), 2.80−2.80 (m, 1H), 2.62 (dd, J = 13.0, 9.4 Hz, 1H), 2.23 (s, 3H), 2.11 (s, 3H), 1.65−1.46 (m, 2H), 1.20 (d, J = 6.3 Hz, 3H), 1.09 (d, J = 7.0 Hz, 3H), 1.01 (d, J = 7.0 Hz, 3H), 0.89 (s, 9H), 0.09 (s, 3H), 0.08 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 219.3, 157.0, 155.0, 144.1, 132.7, 130.0, 126.5, 126.2, 115.2, 70.5, 66.7, 60.6, 60.4, 51.2, 46.8, 42.8, 27.0, 26.0, 23.6, 23.2, 18.1, 16.1, 15.7, 13.9, −4.3, −4.8; HRMS (ESI) m/z calcd for C28H48NaO5Si [(M + Na)+] 515.3163, found 515.3163; Rf 0.48 (petroleum ether:EtOAc, 9:1); IR νmax (neat) 2931, 1969, 1713, 1457, 1422, 1373, 1223, 1091, 1009, 777, 741 cm−1; [α]20 D +47.4 (c 0.70 in CHCl3). Data for 32b: 1H NMR (CDCl3, 400 MHz) δ 6.87 (s, 1H), 5.11− 5.10 (m, 1H), 5.19−5.07 (m, 1H), 4.12−4.00 (m, 1H), 3.91−3.82 (m, 1H), 3.71 (s, 3H), 3.65 (s, 3H), 3.16−3.03 (m, 1H), 2.88 (dd, J = 13.0, 5.0 Hz, 1H), 2.83−2.73 (m, 1H), 2.67 (dd, J = 13.0, 8.8 Hz, 1H), 2.50 (s, 1H), 2.23 (s, 3H), 2.10 (s, 3H), 1.60−1.52 (m, 2H), 1.18 (d, J = 6.1 Hz, 3H), 1.04 (d, J = 7.2 Hz, 3H), 1.02 (d, J = 7.3 Hz, 3H), 0.88 (s, 9H), 0.09 (s, 3H), 0.08 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 219.0, 157.0, 155.0, 144.1, 132.6, 130.1, 126.4, 126.1, 115.1, 72.3, 68.9, 60.6, 60.4, 51.0, 46.3, 43.3, 27.5, 26.0, 24.2, 23.1, 18.1, 16.2, 16.1, 12.7, −3.9, −4.6; HRMS (ESI) m/z calcd for C28H48NaO5Si [(M + Na)+] 515.3163, found 515.3161; Rf 0.43 (petroleum ether-EtOAc, 9:1); IR νmax (neat) 2934, 1972, 1713, 1457, 1424, 1375, 1223, 1097, 1011, 778, 741 cm−1; [α]20 D +37.4 (c 2.00 in CHCl3). Aldol Adducts 33a and 33b. Using method A described above, ketone 30b (150 mg, 0.30 mmol, 1.0 equiv) and aldehyde 31b (94 mg, 0.45 mmol, 1.5 equiv) afforded diastereoisomers 33a (89 mg, 42%) and 33b (84 mg, 39%) as colorless oils. A small amount of starting 7056

DOI: 10.1021/acs.joc.7b03231 J. Org. Chem. 2018, 83, 7049−7059

Article

The Journal of Organic Chemistry

(m, 1H), 2.59 (s, 3H), 2.30 (s, 3H), 1.55−1.46 (m, 2H), 1.21 (d, J = 6.1 Hz, 3H), 0.94 (d, J = 7.0 Hz, 3H), 0.91 (d, J = 7.0 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 218.1, 200.7, 160.0, 159.85, 159.83, 159.4, 156.0, 130.6, 130.3, 130.2, 130.1, 130.0, 129.9, 129.5, 129.1 (2), 128.8 (2), 128.5, 127.6, 114.1 (2), 114.0 (2), 113.7 (2), 77.8, 75.4, 74.8, 73.1, 70.2, 55.4, 50.6, 46.5, 40.8, 30.4, 27.5, 19.8, 16.6, 15.7, 12.9; HRMS (ESI) m/z calcd for C43H52NaO9 [(M + Na)+] 735.3504, found 735.3488; Rf 0.36 (petroleum ether−EtOAc, 2:1); IR νmax (neat) 2938, 1932, 1714, 1622, 1529, 1231, 1175, 1105, 1029, 974, 820, 738 cm−1; [α]23 D +39.3 (c 2.00 in CHCl3). Spiroketal Alcohol 35. Pd/C (0.25 mg) was added to a solution of ketone 34b (25 mg, 35 μmol, 1.0 equiv) in EtOAc (3 mL) at rt. The flask was purged with nitrogen and then allowed to stir at rt under an H2 atmosphere. After being stirred at rt for 20 h, the reaction mixture was filtered through a pad of Celite and then concentrated. Purification by preparative TLC (petroleum ether−EtOAc, 4:1) afforded spiroketal alcohol 35 (11 mg, 94%) as a colorless oil: 1H NMR (CDCl3, 400 MHz) δ 12.81 (s, 1H), 7.36 (s, 1H), 4.01−3.90 (m, 2H), 3.45 (d, J = 10.1 Hz, 1H), 2.67 (dd, J = 16.5, 5.6 Hz, 1H), 2.55 (s, 3H), 2.47 (dd, J = 16.5, 12.6 Hz, 1H), 2.18 (s, 3H), 2.16−2.07 (m, 1H), 2.08−2.01 (m, 1H), 1.94 (dt, J = 13.8, 2.8 Hz, 1H), 1.59−1.52 (m, 1H), 1.18 (d, J = 7.2 Hz, 3H), 1.10 (d, J = 6.6 Hz, 3H), 1.07 (d, J = 6.3 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 203.0, 160.3, 156.0, 129.6, 116.2, 113.3, 111.6, 105.0, 70.0, 62.0, 41.1, 36.5, 30.9, 26.4, 23.0, 21.3, 16.3, 15.4, 12.3; HRMS (ESI) m/z calcd for C19H26NaO5 [(M + Na)+] 357.1672, found 357.1666; Rf 0.46 (petroleum ether−EtOAc, 2:1); IR νmax (neat) 3386, 2974, 2939, 1622, 1476, 1331, 1280, 1189, 1062, 924 cm−1; [α]20 D −34.6 (c 0.50 in CDCl3). (−)-Peniphenone A ((−)-1). IBX (4.2 mg, 15 μmol, 1.0 equiv) was added to a solution of spiroketal alcohol 35 (5 mg, 15 μmol, 1.0 equiv) in DMSO (0.5 mL) at rt. After the reaction mixture was stirred at rt for 5.5 h, EtOAc and water were added. The organic layer was dried over anhydrous Na2SO4 and then concentrated. Purification by chromatography (petroleum ether−EtOAc, 9:1) afforded (−)-peniphenone A (1) (4.5 mg, 90%) as a colorless oil: 1H NMR (CDCl3, 500 MHz) δ 12.82 (s, 1H), 7.32 (s, 1H), 3.93 (ddq, J = 11.5, 6.1, 3.1 Hz, 1H), 2.87 (dq, J = 6.7, 1.0 Hz, 1H), 2.77 (dd, J = 16.5, 5.7 Hz, 1H), 2.54 (s, 3H), 2.51 (d, J = 16.8, 3.3 Hz, 1H), 2.49 (d, J = 13.3, 2.9 Hz, 1H), 2.34 (ddd, J = 13.9, 11.1, 1.0 Hz, 1H), 2.14−2.05 (m, 1H), 2.03 (s, 3H), 1.23 (d, J = 6.8 Hz, 3H), 1.19 (d, J = 6.2 Hz, 3H), 1.14 (d, J = 6.8 Hz, 3H); 13C NMR (CDCl3, 125 MHz) δ 206.5, 202.9, 160.0, 155.6, 129.5, 117.0, 113.2, 111.1, 105.0, 67.5, 49.2, 48.6, 30.7, 26.3, 23.4, 21.7, 15.2, 15.1, 7.5; HRMS (ESI) m/z calcd for C19H24NaO5 [(M + Na)+] 355.1516, found 355.1516; Rf 0.63 (petroleum ether−EtOAc, 2:1); IR νmax (neat) 2974, 2939, 1724, 1624, 1477, 1455, 1330, 1274, 1188, 1076, 936 cm−1; [α]22 D −81.0 (c 0.20 in MeOH), lit. [α]25 D +85.6 (c 0.88 in MeOH) for the opposite enantiomer.8a The 13C NMR spectra of (−)-1 (CDCl3) were calibrated at 77.00 ppm instead of 77.16 ppm to match the data reported by George et al.8a Alcohol 46. n-Butyllithium (1.6 M in hexanes, 80 μL, 0.12 mmol, 1.2 equiv) was added to a solution of aryl bromide 24b (50 mg, 0.10 mmol, 1.0 equiv) in Et2O (1 mL) at −80 °C. After the reaction mixture was stirred at −80 °C for 30 min, oxetane 45 (19 mg, 0.10 mmol, 1.0 equiv) and boron trifluoride diethyl etherate (13 μL, 0.10 mmol, 1.0 equiv) were added. After being stirred at −80 °C for 1 h, the reaction mixture was quenched by a saturated aqueous NH4Cl solution. EtOAc was added, and the organic layer was dried over anhydrous Na2SO4 and then concentrated. Purification by chromatography (petroleum ether−EtOAc, 9:1) afforded alcohol 46 (28 mg, 47%) as a colorless oil: 1H NMR (CDCl3, 400 MHz) δ 7.42−7.33 (m, 4H), 7.32−7.23 (m, 5H), 6.95 (s, 1H), 6.94−6.87 (m, 4H), 5.23−5.16 (m, 2H), 4.82−4.70 (m, 4H), 4.47 (d, J = 15.3, 12.0 Hz, 2H), 3.83 (s, 3H), 3.81 (s, 3H), 3.69−3.60 (m, 1H), 3.38−3.29 (m, 2H), 2.91 (br s, 1H), 2.86−2.68 (m, 2H), 2.31 (s, 3H), 2.17 (s, 3H), 1.73−1.67 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ 159.7, 159.6, 155.6, 153.2, 144.3, 138.3, 133.3 (2), 129.9, 129.8 (2), 129.7 (2), 129.6, 128.7, 128.5 (2), 127.9 (2), 127.7, 126.8, 115.4, 114.1 (2), 114.0 (2), 75.1, 74.9, 74.6, 73.4, 69.6, 55.4 (2), 34.0, 23.4, 20.9, 16.5; HRMS (ESI) m/z calcd for C37H42NaO6 [(M + Na)+] 605.2874, found 605.2856; Rf 0.19

material ethyl ketone 30b was also recovered (27 mg, 18%). Data for 33a: 1H NMR (CDCl3, 400 MHz) δ 7.42−7.30 (m, 4H), 7.25−7.20 (m, 2H), 6.95 (s, 1H), 6.94−6.81 (m, 6H), 5.21−5.15 (m, 2H), 4.79− 4.67 (m, 4H), 4.49 (d, J = 11.2 Hz, 1H), 4.35 (d, J = 11.2 Hz, 1H), 3.92−3.82 (m, 1H), 3.82−3.77 (m, 1H), 3.80 (s, 3H), 3.79 (s, 3H), 3.76 (s, 3H), 3.09−2.98 (m, 2H), 2.91 (dd, J = 13.0, 4.3 Hz, 1H), 2.61 (dd, J = 13.0, 9.8 Hz, 1H), 2.51 (qt, J = 9.4 Hz, 1H), 2.29 (s, 3H), 2.16 (s, 3H), 1.45 (ddd, J = 14.3, 8.5, 2.3 Hz, 1H), 1.33 (ddd, J = 14.2, 10.0, 3.0 Hz, 1H), 1.15 (d, J = 6.2 Hz, 3H), 0.94 (d, J = 5.8 Hz, 3H), 0.92 (d, J = 5.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 219.6 (C3), 159.7 (C), 159.5 (C), 159.2 (C), 155.8 (C2′), 153.5 (C6′), 144.3 (C2″), 133.2 (C5′), 131.0 (C), 130.1 (C4′), 129.9 (C), 129.8 (Ar−CH × 2), 129.7 (C), 129.6 (Ar−CH × 2), 129.5 (Ar−CH × 2), 127.1 (C1′), 126.7 (C3′), 115.4 (C1″), 114.1 (Ar−CH × 2), 113.9 (Ar−CH × 4), 74.7 (OCH2), 74.6 (OCH2), 71.9 (C7), 70.6 (C5), 70.5 (OCH2), 55.4 (OCH3 × 3), 50.3 (C4), 46.4 (C2), 41.5 (C6), 27.7 (C1), 23.4 (C3″), 19.8 (C8), 16.5 (C3′-CH3), 15.5 (C2-CH3 and C4-CH3); HRMS (ESI) m/z calcd for C44H54NaO8 [(M + Na)+] 733.3711, found 733.3683; Rf 0.47 (petroleum ether-EtOAc, 2:1); IR νmax (neat) 2936, 1932, 1714, 1614, 1524, 1239, 1174, 1101, 1034, 976, 822, 738 cm−1; [α]24 D +19.6 (c 0.23 in CHCl3). Data for 33b: 1H NMR (CDCl3, 400 MHz) δ 7.41−7.28 (m, 4H), 7.24−7.18 (m, 2H), 6.94 (s, 1H), 6.93−6.81 (m, 6H), 5.20−5.14 (m, 2H), 4.79−4.65 (m, 4H), 4.52 (d, J = 11.0 Hz, 1H), 4.33 (d, J = 11.0 Hz, 1H), 3.82 (s, 3H), 3.81−3.80 (m, 1H), 3.80 (s, 3H), 3.77 (s, 3H), 3.75−3.69 (m, 1H), 3.60 (d, J = 3.1 Hz 1H), 3.10−2.99 (m, 1H), 2.83 (dd, J = 13.0, 4.7 Hz, 1H), 2.63 (dd, J = 13.0, 9.5 Hz, 1H), 2.58 (qt, J = 6.4 Hz, 1H), 2.29 (s, 3H), 2.15 (s, 3H), 1.57−1.47 (m, 2H), 1.20 (d, J = 6.1 Hz, 3H), 0.93 (d, J = 7.0 Hz, 3H), 0.78 (d, J = 5.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 218.6, 159.6, 159.5, 159.4, 155.8, 153.5, 144.4, 133.2, 130.4, 130.0, 129.8, 129.8 (2), 129.7 (2), 129.5 (2), 127.3, 126.6, 115.3, 114.1 (2), 114.0 (2), 113.9 (2), 75.2, 74.7, 74.6, 73.0, 70.2, 55.4 (2), 50.6, 46.9, 40.8, 27.7, 23.3, 19.7, 16.5, 15.8, 12.9; HRMS (ESI) m/z calcd for C44H54NaO8 [(M + Na)+] 733.3711, found 733.3706; Rf 0.42 (petroleum ether−EtOAc, 2:1); IR νmax (neat) 2935, 1932, 1707, 1614, 1524, 1237, 1174, 1101, 1034, 976, 822, 736 cm−1; [α]24 D +17.6 (c 0.13 in CHCl3). Ketone 34b. A solution of alkene 33b (212 mg, 0.30 mmol) in CH2Cl2−MeOH (10:2 mL) was ozonized until a blue color persisted. The reaction mixture was then purged with argon until complete disappearance of the color. Dimethyl sulfide (0.37 mL, 5.96 mmol, 20 euiv) was added, and the mixture was allowed to warm to rt over 2 h. A NaHCO3-saturated solution was added, and the aqueous phase was extracted with CH2Cl2. The combined organic layer was dried over Na2SO4, filtered, and concentrated. Purification by chromatography (petroleum ether−EtOAc, 9:1 to 7:3) afforded ketone 43b (129 mg, 60%) as a colorless oil: 1H NMR (CDCl3, 400 MHz) δ 7.36−7.30 (m, 4H), 7.25−7.19 (m, 2H), 6.94−6.81 (m, 7H), 4.81−4.68 (m, 4H), 4.50 (d, J = 11.2 Hz), 4.35 (d, J = 11.2 Hz), 3.95−3.87 (m, 1H), 3.82− 3.80 (m, 1H), 3.80 (s, 3H), 3.79 (s, 3H), 3.76 (s, 3H), 3.11−3.03 (m, 1H), 3.02 (d, J = 5.7 Hz, 1H), 2.90 (dd, J = 13.0, 4.5 Hz, 1H), 2.62 (dd, J = 13.0, 9.5 Hz, 1H), 2.58 (s, 3H), 2.55−2.46 (m, 1H), 2.04 (s, 3H), 1.48 (ddd, J = 14.5, 8.2, 2.2 Hz, 1H), 1.36 (ddd, J = 17.6, 10.0, 3.0 Hz, 1H), 1.17 (d, J = 6.1 Hz, 3H), 0.95 (d, J = 7.0 Hz, 3H), 0.91 (d, J = 7.0 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 219.0, 200.7, 160.0, 159.85, 159.83, 159.3, 156.0, 130.9, 130.6, 130.2, 130.0 (2), 129.8 (2), 129.4 (2), 128.8, 128.2, 127.6, 114.1 (2), 113.9 (2), 113.7 (2), 77.8, 74.8, 71.9, 70.7, 70.5, 55.41, 55.39, 55.3, 50.5, 46.3, 41.2, 30.5, 27.5, 19.7, 16.6, 15.5, 14.2; HRMS (ESI) m/z calcd for C43H52NaO9 [(M + Na)+] 735.3504, found 735.3488; Rf 0.43 (petroleum ether-EtOAc, 2:1); IR νmax (neat) 2938, 1940, 1725, 1614, 1522 1247, 1169, 1100, 1029, 975, 822, 736 cm−1; [α]23 D +8.5 (c 2.00 in CHCl3). Ketone 34a. Using the procedure described above, 33a (60 mg, 84 μmol) afforded ketone 34a (27 mg, 45%): 1H NMR (CDCl3, 400 MHz) δ 7.41−7.28 (m, 4H), 7.25−7.19 (m, 2H), 6.95−6.81 (m, 6H), 6.93 (s, 1H), 4.83−4.66 (m, 4H), 4.53 (d, J = 11.0 Hz, 1H), 4.33 (d, J = 11.0 Hz, 1H), 3.87−3.83 (m, 1H), 3.77−3.72 (m, 1H), 3.81 (s, 3H), 3.81 (s, 3H), 3.77 (s, 3H), 3.67 (d, J = 2.8 Hz, 1H), 3.11−2.98 (m, 1H), 2.82 (dd, J = 13.1, 4.7 Hz, 1H), 2.67−2.61 (m, 1H), 2.60−2.57 7057

DOI: 10.1021/acs.joc.7b03231 J. Org. Chem. 2018, 83, 7049−7059

Article

The Journal of Organic Chemistry (petroleum ether-EtOAc, 4:1); IR νmax (neat) 2926, 1612, 1514, 1249, 1173, 1033, 821 cm−1; [α]24 D +12.9 (c 0.07 in CHCl3). Diol 49. TBAF (1 M in THF, 0.19 mL, 0.19 mmol, 1.0 equiv) was added to a solution of vinyl silane 43b (98 mg, 0.19 mmol, 1.0 equiv) in THF (1.2 mL) at rt. After being stirred at rt for 20 min, the reaction mixture was quenched by addition of a saturated aqueous NH4Cl solution and then diluted with Et2O. The organic layer was dried over anhydrous Na2SO4 then concentrated. Purification by chromatography (petroleum ether−EtOAc, 7:3) afforded diol 49 (48 mg, 91%) as colorless crystals: 1H NMR (CDCl3, 400 MHz) δ 7.55−7.49 (m, 2H), 7.39−7.31 (m, 3H), 5.77 (dd, J = 1.9, 0.9 Hz, 1H), 5.54 (d, J = 2.4 Hz, 1H), 3.63 (dd, J = 8.3, 2.9 Hz, 1H), 3.52−3.44 (m, 2H), 2.52−2.40 (m, 1H), 1.96 (br s, 1H), 1.73−1.59 (m, 1H), 1.04 (d, J = 6.8 Hz, 3H), 0.76 (d, J = 7.1 Hz, 3H), 0.42 (s, 3H), 0.41 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 154.1, 138.2, 134.1 (2), 129.3, 128.0 (2), 127.3, 76.3, 67.8, 43.2, 36.5, 17.7, 9.8, −2.0, −2.2; HRMS (ESI) m/z calcd for C16H26NaO2Si [(M + Na)+] 301.1594, found 301.1589; Rf 0.17 (petroleum ether−EtOAc, 7:3); mp 80−82 °C; IR νmax (neat) 3365, 2959, 1737, 1427, 1248, 1109, 815, 697 cm−1; [α]25 D +19.8 (c 1.00 in CHCl3). Oxetane 54. Triethylamine (55 μL, 0.41 mmol, 2.0 equiv) and MsCl (16 μL, 0.21 mmol, 1.0 equiv) were added to a solution of diol 49 (57 mg, 0.21 mmol, 1.0 equiv) in CH2Cl2 (6 mL) at rt. After the reactionmixture was stirred at rt for 16 h, potassium tert-butoxide (173 mg, 1.72 mmol, 4.0 equiv) was added. The reaction mixture was stirred for an additional 10 min, and then water was added. The organic layer was dried over anhydrous Na2SO4 and then concentrated. Purification by chromatography (petroleum ether−EtOAc, 19:1 to 9:1) afforded the oxetane 54 (53 mg, 99%) as a yellow oil: 1H NMR (CDCl3, 400 MHz) δ 7.56−7.49 (m, 2H), 7.40−7.30 (m, 3H), 5.74−5.68 (m, 1H), 5.56−5.49 (m, 1H), 4.38 (dd, J = 8.1, 5.7 Hz, 1H), 4.26 (dd, J = 8.8, 6.4 Hz, 1H), 4.09 (dd, J = 7.0, 5.8 Hz, 1H), 2.63−2.52 (m, 1H), 2.40− 2.28 (m, 1H), 1.05 (d, J = 6.8 Hz, 3H), 0.99 (d, J = 6.7 Hz, 3H), 0.42 (s, 3H), 0.41 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 151.6, 137.9, 134.2 (2), 129.2, 127.9 (2), 127.1, 92.9, 74.5, 44.6, 34.6, 18.4, 17.5, −2.7, −2.9; HRMS (ESI) m/z calcd for C16H24NaOSi [(M + Na)+] 283.1489, found 283.1481; Rf 0.84 (petroleum ether−EtOAc, 7:3); IR νmax (neat) 2959, 2871, 1428, 1249, 1110, 970, 819, 700 cm−1; [α]21 D −1.6 (c 0.50 in CHCl3). Vinyl Bromide 55. Triethylamine (0.26 mL, 1.94 mmol, 1.2 equiv) and pyridinium tribromide (620 mg, 1.94 mmol, 1.2 equiv) were added to a solution of oxetane 54 (421 mg, 1.62 mmol, 1.0 equiv) in methylene chloride (4.7 mL) at 0 °C and then stirred at rt for 30 min. The above procedure was repeated three times, and then the reaction mixture was quenched with 4% aqueous sodium sulfite solution. The organic layer was dried over anhydrous Na 2 SO 4 and then concentrated. The crude product was dissolved in MeOH (4.7 mL), and then MeONa (306 mg, 5.67 mmol, 3.5 equiv) was added. After 20 min of stirring at rt, water was added, and the organic layer was dried over anhydrous Na2SO4 and then concentrated. Purification by chromatography (petroleum ether−Et2O, 19:1 to 9:1) afforded vinyl bromide 55 (302 mg, 91%) as a colorless oil: 1H NMR (CDCl3, 400 MHz) δ 5.71 (d, J = 1.5 Hz, 1H), 5.49 (d, J = 1.5 Hz, 1H), 4.55 (dd, J = 8.3, 5.9 Hz, 1H), 4.29 (dd, J = 8.5, 6.2 Hz, 1H), 4.22 (dd, J = 6.8, 5.9 Hz, 1H), 2.81−2.63 (m, 2H), 1.22 (d, J = 6.8 Hz, 3H), 1.16 (d, J = 6.4 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 135.0, 117.9, 91.2, 74.9, 50.8, 34.5, 18.2, 15.4; HRMS (ESI) m/z calcd for C8H13BrNaO [(M + Na)+] 227.0043, found 227.0049; Rf 0.42 (petroleum ether−EtOAc, 9:1); IR νmax (neat) 2970, 2877, 1739, 1366, 1217, 970, 887, 758 cm−1; [α]23 D +18.6 (c 1.00 in CHCl3). Methyl Ketone 57. A flask charged with vinyl silane 54 (200 mg, 0.75 mmol, 1.0 equiv), Co(acac)2 (193 mg, 0.75 mmol, 1.0 equiv), TBHP (94 μL, 0.75 mmol, 1.0 equiv), and Et3SiH (17 mg, 0.17 mmol, 0.1 equiv) in MeOH (2 mL) was purged three times with oxygen. After being stirred at rt for 16 h, the reaction mixture was purged with N2 and then concentrated. Chromatography (petroleum ether−Et2O, 7:3) afforded the methyl ketone 57 (106 mg, 99%) as a colorless oil: 1 H NMR (CDCl3, 400 MHz) δ 4.52 (dd, J = 8.2, 7.8 Hz, 1H), 4.46 (t, J = 6.8 Hz, 1H), 4.21 (dd, J = 6.7, 6.0 Hz, 1H), 2.97−2.88 (m, 1H), 2.84−2.72 (m, 1H), 2.19 (s, 3H), 1.22 (d, J = 6.8 Hz, 3H), 1.12 (d, J =

7.0 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 210.7, 90.2, 75.4, 52.7, 34.0, 30.2, 18.3, 11.8; HRMS (ESI) m/z calcd for C8H14NaO2 [(M + Na)+] 165.0886, found 165.0883; Rf 0.34 (petroleum ether−Et2O, 7:3); IR νmax (neat) 2933, 2161, 1710, 1455, 1366, 1266, 742, 705 cm−1; [α]20 D −29.5 (c 1.60 in CHCl3). Ketal 58. A mixture of trimethyl orthoformate (74 μL, 0.68 mmol, 3.0 equiv), diol 49 (63 mg, 0.23 mmol, 1.0 equiv), and 4 Å MS (20 mg) in toluene (1 mL) was stirred at 110 °C for 16 h. The reaction mixture was cooled to rt, and then benzaldehyde (23 μL, 0.23 mmol, 1.0 equiv) and CSA (5 mg, 23 μmol, 0.1 equiv) were added. After the reaction mixture was stirred at rt for 1 h, EtOAc and water were added. The organic layer was dried over anhydrous Na2SO4 and then concentrated. Purification by chromatography (petroleum ether− EtOAc, 49:1) afforded ketal 58 (80 mg, 97%) as a colorless oil: 1H NMR (CDCl3, 400 MHz) δ 7.55−7.27 (m, 10H), 6.00 (d, J = 2.4 Hz, 1H), 5.63 (d, J = 2.4 Hz, 1H), 5.08 (s, 1H), 4.01 (dd, J = 11.1, 4.7 Hz, 1H), 3.31 (t, J = 11.1 Hz, 1H), 3.25 (dd, J = 16.5, 9.9 Hz, 1H), 2.65 (bq, J = 7.0 Hz, 1H), 2.02−1.88 (m, 1H), 1.11 (d, J = 7.0 Hz, 3H), 0.59 (d, J = 6.8 Hz, 3H), 0.40 (s, 3H), 0.38 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 152.2, 139.2, 138.8, 134.1 (2), 129.1, 128.5, 128.1 (2), 127.9 (2), 127.7, 126.2 (2), 100.8, 84.2, 73.2, 37.8, 31.3, 12.9, 12.4, −2.2, −2.7; HRMS (ESI) m/z calcd for C23H30NaO2Si [(M + Na)+] 389.1907, found 389.1889; Rf 0.41 (petroleum ether:EtOAc, 19:1); IR νmax (neat) 3339, 2968, 1380, 1128, 950, 815 cm−1; [α]21 D +64.4 (c 2.00 in CHCl3). Vinyl Bromide 59. Triethylamine (18 μL, 0.13 mmol, 1.2 equiv) and pyridinium tribromide (42 mg, 0.13 mmol, 1.2 equiv) were added to a solution of vinyl silane 58 (40 mg, 0.11 mmol, 1.0 equiv) in methylene chloride (1 mL) at 0 °C. The reaction mixture was stirred at rt for 30 min and then quenched by addition of 4% aqueous sodium sulfite solution. The organic layer was dried over anhydrous Na2SO4 and then concentrated. The crude product was dissolved in MeOH (1 mL), and then MeONa (21 mg, 0.38 mmol, 3.5 equiv) was added. After being stirred at reflux for 16 h, water and EtOAc were added, and the organic layer was dried over anhydrous Na2SO4 and then concentrated. Purification by chromatography (petroleum ether− EtOAc, 49:1) afforded vinyl bromide 59 (34 mg, 100%) as a colorless oil: 1H NMR (CDCl3, 400 MHz) δ 7.56−7.43 (m, 2H), 7.40−7.26 (m, 3H), 5.76 (d, J = 1.9 Hz, 1H), 5.58 (d, J = 1.9 Hz, 1H), 5.52 (s, 1H, H2), 4.14 (dd, J = 11.1, 4.9 Hz, 1H), 3.85 (dd, J = 10.0, 2.3 Hz, 1H), 3.56 (t, J = 11.1 Hz, 1H), 2.76 (bq, J = 6.5 Hz, 1H), 2.14−1.97 (m, 1H), 1.26 (d, J = 7.0 Hz, 3H), 0.84 (d, J = 6.5 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 138.8, 137.2, 128.7, 128.2 (2), 126.1 (2), 117.4, 100.9, 82.7, 73.1, 45.5, 31.4, 13.0, 12.3; HRMS (ESI) m/z calcd for C15H19BrNaO2 [(M + Na)+] 333.0461, found 333.0453; Rf 0.37 (petroleum ether−EtOAc, 19:1); IR νmax (neat) 2971, 1628, 1393, 1118, 1027, 967 cm−1; [α]21 D +52.0 (c 1.00 in CHCl3). Oxidative Dimerization Product 60. t-Butyllithium (0.20 mL, 0.26 mmol, 2.0 equiv) was added dropwise to a solution of vinyl bromide 59 (40 mg, 0.13 mmol, 1.0 equiv) in Et2O (1 mL) at −80 °C. The reaction mixture was stirred at −80 °C and then warmed to −40 °C. CuI (24 mg, 0.26 mmol, 1.0 equiv) was added, and the reaction mixture was allowed to reach −20 °C over 2 h. The reaction mixture was cooled to −80 °C, then (S)-propylene oxide (27 μL, 0.39 mmol, 3.0 equiv) was added. The reaction mixture was allowed to reach rt over 4 h and quenched with water. The organic layer was dried over anhydrous Na2SO4 and then concentrated. Purification by preparative TLC (petroleum ether−EtOAc, 49:1) afforded the dimerization product 60 (7 mg, 11%) as white crystals: 1H NMR (CDCl3, 400 MHz) δ 7.51−7.40 (m, 4 H), 7.39−7.28 (m, 6 H), 5.29 (s, 2 H), 5.20 (d, J = 1.8 Hz, 2 H), 5.13 (d, J = 1.8 Hz, 2 H), 4.04 (dd, J = 11.1, 4.7 Hz, 2H), 3.48 (dd, J = 10.0, 1.4 Hz, 2H), 3.30 (t, J = 11.1 Hz, 2H), 2.85 (bq, J = 7.0 Hz, 2H), 2.11−1.97 (m, 2H), 1.22 (d, J = 7.0 Hz, 6H), 0.76 (d, J = 6.5 Hz, 6H); 13C NMR (CDCl3, 100 MHz) δ 150.8, 139.1, 128.6, 128.2 (2), 126.0 (2), 112.7 (2), 100.6, 82.9, 73.2, 36.2 (2), 31.2, 12.4 (2), 12.1; HRMS (ESI) m/z calcd for C30H38NaO4 [(M + Na)+] 485.2770, found 485.2660; Rf 0.44 (petroleum ether−EtOAc, 9:1); IR νmax (neat) 2968, 1625, 1387, 1117, 1027, 966 cm−1; [α]21 D +11.2 (c 0.70 in CHCl3). 7058

DOI: 10.1021/acs.joc.7b03231 J. Org. Chem. 2018, 83, 7049−7059

Article

The Journal of Organic Chemistry

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b03231. 1 H and 13C NMR spectra for novel compounds; 2D COSY and HSQC NMR spectra for (−)-peniphenone A and (−)-1 (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Margaret A. Brimble: 0000-0002-7086-4096 Daniel P. Furkert: 0000-0001-6286-9105 Notes

The authors declare no competing financial interest.

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REFERENCES

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DOI: 10.1021/acs.joc.7b03231 J. Org. Chem. 2018, 83, 7049−7059