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

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Total Synthesis of (-)-Peniphenone A Mathilde Pantin, Margaret A. Brimble, and Daniel P. Furkert J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b03231 • Publication Date (Web): 26 Feb 2018 Downloaded from http://pubs.acs.org on February 26, 2018

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The Journal of Organic Chemistry

Total Synthesis of (–)-Peniphenone A

Mathilde Pantin, Margaret A. Brimble,* Daniel P. Furkert* School of Chemical Sciences, The University of Auckland, 23 Symonds Street, Auckland 1010, New Zealand Email: [email protected], [email protected]

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 crosscoupling 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 2,4dihydroxybenzaldehyde, 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 aryl lithium, for assembly of the polyketide domain. These studies provide a useful foundation for further work towards 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.

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 co-isolated with other non-spiroketal metabolites including peniphenone 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 1 ACS Paragon Plus Environment

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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 µM and 1.37 µM, respectively).

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

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 7 steps (longest linear sequence), as an 18:1 ratio of C8 diastereoisomers (dr 95%). Our investigations towards 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, identification of general and efficient

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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. 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.

Scheme 2. Retrosynthetic analysis of (+)-1 via two possible approaches; (A) sp3-sp2 cross-coupling, or (B) oxetane opening approaches.

O

OH

sp3-sp2 cross-coupling

8

O

13

RO

O

O O

A (-)-1

13

OR aldol O

OR

OR

10

O

O

O

OR 13

8

R

17

OR

OR

14 oxetane opening

O

LnM

8 10

16

15

Br

OP1

O 10

B OR 18

8

13

19

Retrosynthetically, peniphenone (–)-(1) was expected to be accessible by deprotection and acidpromoted spiroketalisation of linear precursor 14. Based on our previous work towards 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 3 ACS Paragon Plus Environment


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 centres. At the outset it was expected that the acidic proton at C1011 would be highly prone to epimerisation, 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 centre stereochemistry would be directed by pre-installed chirality at both C8 and C13, although this remained to be established in practice as we began our investigations. 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-n-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. Scheme 3. Synthesis of the aromatic nucleus 24a,b.a


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a

Reagents and conditions: (i) NaBH3CN, 1M 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%).

Based on earlier 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; temperature (40-125 °C, MW), ligand (RuPhos, iPr-PEPPSI, DtBPF), base (K2CO3, DBU) and solvent (dioxane, toluene, water) no coupling products (26a,b) were able to be 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 coupling, a point highlighted by Molander in discussion of the reaction scope in the original disclosure of this methodology.

To address the reactivity issue, an alternative Negshi cross-coupling was investigated.14 This approach required the generation of a Reformatsky-type coordination-stabilised zinc reagent, by zinc insertion into the carbon-iodine bond of α-chiral 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-o-tolyl 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 cross-coupling step from 70 °C 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 5 ACS Paragon Plus Environment


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. Table 1. Key sp3-sp2 cross-coupling for assembly of the α-methyl β-aryl ketone motif.

entry

RX

ArBr

conditions

product

yield

1

27

24a

Pd(OAc)2, RuPhos K2CO3, aq.toluene, 70°C

-a

-

2

27

24b

Pd(OAc)2, DtBPF DBU, aq.dioxane, 125°C

-a

-

3

25

24b

Cu/Zn, PhH/DMA, rt, 40 min;b Pd2(dba)3, P(o-tol)3, 55°C

-

trace

4

25

24b

Cu/Zn, PhH/DMA, 60°C, 3 h; Pd2(dba)3, P(o-tol)3, 100°C

26b

trace

5

25

24b

Cu/Zn, PhH/DMA, 60°C, 3 h; Pd2(dba)3, RuPhos, 70°C

26b

21

6

25

24b

Cu/Zn, PhH/DMA, 60°C, 3 h; Pd2(dba)3, RuPhos, 100°C

26b

29

7

25

24a

(as per entry 6)

26a

69

8

28

24b

(as per entry 6)

-

-

9

29

24b

(as per entry 6)

-

-

a

Dehalogenation observed; b Under sonication.

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 conditions. Use of the boron enolate prepared from B-chlorodiisopinocampheylborane (DIPCl), or 6 ACS Paragon Plus Environment

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scandium triflate gave no reaction (Table 2, entries 1 & 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 PMBprotected 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 able to be 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.

Scheme 4. Assembly of the spiroketalisation precursor 34a,b.a,b

a

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%;

b

Peniphenone numbering.



Table 2. Optimisation of the key aldol reaction between 30 and 31.a,b entry

RCHO

ketone

conditions

product

%

1

31a

30a

Sn(OTf)2, Et3N CH2Cl2, –80 to –20 °C

-a

-

2

31a

30a

(+)-DIPCl, Et3N Et2O, –80 to –50 °C

-a

-

3

31a

30a

LHMDS, Et2O, –30 °C then ZnCl2, –80 to –20 °C, 16 h

32a,b

21a (73)b

4

31a

30a

(chex)2BCl, Et3N Et2O, –80 °C to –20 °C, 16 h

32a,b

49 (9)b

5

31b

30b

(chex)2BCl, Et3N Et2O, –80 °C to rt, 16 h

33a,b

81 (19)b

9

31b

30a

various

-

-

a

Combined yield (dr 1:1). b Ketone 188a or 188b recovered.

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 non-identical 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 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


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would readily epimerise in the natural product, via oxonium species (–)-1*. Our observations indicated that epimerisation to give the thermodynamically favoured C10 epimer of 35 also occurred readily at the alcohol oxidation state, presumably via the intermediacy of an oxonium species such as 35*. It is possible that upon oxonium formation, deprotonation at C10 is effected by the phenoxide leaving group.

Scheme 5. Spirocyclization and synthesis of peniphenone A (–)-1.

a

Note 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%.

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 aryl lithium reagent (18·Li).



Scheme 6. Retrosynthetic analysis of the peniphenone A framework 14 via oxetane opening.

The realisation 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-alkyl oxetanes with aryl lithium 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, vinyl silane 38 itself was envisaged to arise from Krische-type hydrogen-mediated coupling of monoprotected diol 39 with 2silyl-1,4-butadiene 40. This latter methodology has seen rapid development in very recent years, however the use of α-substituted primary alcohols had 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 anti-crotylation of alcohols using allylic acetates,24 and syn10 ACS Paragon Plus Environment

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crotylation of alcohols using 2-phenyldimethylsilyl-1,4-butadiene (40) have been reported (Scheme 7).25 Of particular relevance to the current study, in the presence of a ruthenium catalyst and a chiral ligand based on SEGPHOS, the syn products (41) were able to be 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 DM-SEGPHOS ligand used, giving the products in high yield as essentially single diastereoisomers. These findings provided the first step towards 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 aryl lithium reagents in our system was next investigated.

Scheme 7. Direct access to the defined stereotriad in anti,syn-43 by Krische-type hydrogen mediated C-C coupling of protected diol 42.26



Scheme 8. Oxetane 45 ring-opening with aryl lithium 24b.

As an exemplar, known oxetane 45 (Scheme 8) was accordingly prepared according to reported procedures.27 Treatment of 45 with the aryl lithium 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-type rearrangement step required to piece together the planned synthetic route. The Takeda group has reported the use of copper(I) tert-butoxide to promote the generation of vinyl copper species from hydroxyl vinyl silanes of general structure 47 via 1,4 C-to-O silyl migration or Brooke-type rearrangement to give products of general structure 48 (Scheme 9).28 A small number of examples have also been reported on the application of related methodology to the synthesis of complex natural product fragments.29 Based on this precedent it appeared possible that carbon-carbon bond formation might be possible via a vinyl cuprate species derived from 43b, and a suitable threecarbon 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.


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Scheme 9. Attempted Brooke-type rearrangement of 43b or diol 49.

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.

Scheme 10. Further transformations of diol 49.



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 cyclisation 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 conversion to iodide 56 was also possible from TLC evidence, however the instability of this compound prevented its characterisation. The vinyl silane function could readily be converted into a methyl ketone, affording 57, via cobalt-mediated 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 carboncarbon 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.


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Despite the failure to identify a productive route towards peniphenone A (1), these studies have provided a significant foundation of established transformations upon which to build future synthetic studies towards this family of antimicrobial polyketide natural product targets, and clearly demonstrated the power of natural products to inspire new developments in chemical methodology.

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 a 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 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 towards 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. Facile epimerisation of the C10 methyl group upon spiroketalisation was found to occur, allowing the use of both diastereoisomers of the preceding aldol coupling for preparation of the natural product.

Experimental Section



General. 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, 58Ă, then dried over 4Ă 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 Ă. 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 analysed (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-TOCSY-HOHAHA) 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 hybridisation. 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 stirring 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 to 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);

13

C 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. Dimethyl Bromoresorcinol 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 stirring 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 to 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);

13

C 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. 16 ACS Paragon Plus Environment

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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 ºC; Rf 0.25 (hexanes-EtOAc, 9:1); IR νmax (neat) 2940, 1663, 1515, 1250, 1158, 821 cm-1. Bromo Alkene 24a. n-Butyllithium (1.6M in hexanes, 6.18 mL, 9.89 mmol, 10.0 equiv) was added dropwise to suspension of methyl triphenylphosphonium bromide (3.53 g, 9.89 mmol, 10.0 equiv) in THF (35 mL) at rt. After stirring 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 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);

13

C 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. Bromo Alkene 24b. n-Butyllithium (1.6M 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 stirring 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);

13

C 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 stirring at 60 °C for 3 h, the supernatant was 17 ACS Paragon Plus Environment


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 stirring 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® then extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4 then concentrated. Purification by chromatography (pet. EtherEtOAc, 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 (pet. Ether-EtOAc, 9:1); IR νmax (neat) 2963, 1641, 1501, 1262, 1166, 1058, 1022, 827 cm-1; [α] +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), 6.946.89 (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] +3.0 (c 1.00 in CHCl3). Iodide 29. Ethyl magnesium bromide (3M 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 ºC. After stirring 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] +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 stirring at rt for 30 min, Et2O was added and the reaction mixture was filtered through a pad of Celite® then concentrated. Purification by chromatography (pet. ether-EtOAc, 4:1) afforded the corresponding alcohol (335 mg, quant.) as a pale


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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 (pet. ether-EtOAc, 9:1); IR νmax (neat) 2975, 1513, 1267, 1174, 1058, 1020, 824 cm-1; [α] +13.4 (c 0.56 in CHCl3). IBX (222 mg, 0.80 mmol, 2.0 equiv) was added to a solution the above alcohol (105 mg, 0.40 mmol, 1.0 equiv) in DMSO (10 mL) at rt. After stirring at rt for 3 h, Et2O and brine were added. The organic layer was dried over anhydrous Na2SO4 then concentrated. Purification by chromatography (pet. 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);

13

C 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 (pet. Ether-EtOAc, 9:1); IR νmax (neat) 2965, 1640, 1511, 1257, 1176, 1058, 1021, 825 cm-1; [α] -0.5 (c 0.39 in CHCl3). Ethylmagnesium bromide (3M 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 stirring at rt for 2 h, water was added and the organic layer was dried over anhydrous Na2SO4 then concentrated. Purification by chromatography (Pet. Ether:EtOAc 9:1) afforded an inconsequential 1:1 mixture of alcohol epimers (294 mg, 96%) as yellow oils: Diastereoiosmer A:

1

H 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);

13

C 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 (pet. Ether-EtOAc, 9:1); IR νmax (neat) 2962, 1541, 1260, 1176, 1048, 1022, 827 cm-1; [α] +26.0 (c 0.20 in CHCl3). Diastereoiosmer B:

1

H 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 (pet. Ether-EtOAc, 9:1); IR νmax (neat) 2965, 1544, 1260, 1177, 1048, 1023, 827 cm-1; [α] -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 stirring at rt for 16 h, Et2O and brine were added. The organic layer was dried over anhydrous Na2SO4 then concentrated. Purification by chromatography (pet. ether-EtOAc ,9:1) afforded ethyl ketone 30a (258 mg, 85%) as a colourless oil. 1

H 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);

13

C 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 (pet. Ether-EtOAc, 9:1); IR νmax (neat) 2962, 1670, 1544, 1260, 1186, 1049, 821 cm-1; [α]

+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 (pet. Ether-EtOAc, 4:1); IR νmax (neat) 2922, 2161, 1716, 1513, 1364, 1513, 1364, 1267, 1031, 761, 740 cm-1; [α] +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 (pet. Ether-EtOAc, 4:1); IR νmax (neat) 2938, 1715, 1612, 1515, 1370, 1249, 1034, 912, 823, 737 cm-1; [ ]

+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, 20 ACS Paragon Plus Environment

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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 (pet. 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);

13

C 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 (pet. ether:EtOAc, 4:1); IR νmax (neat) 2936, 1711, 1612, 1514, 1247, 1174, 1100, 1034, 976, 822, 738 cm-1; [α] -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 (1M in hexanes, 1.50 mL, 1.50 mmol, 2.0 equiv) in Et2O (1 mL) at 0 °C. After stirring 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 stirring 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 (pet. 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 ºC. After stirring at -80 ºC for 30 min, a solution of aldehyde 61 (38 mg, 0.13 mmol, 1.0 equiv) in Et2O (0.3 mL) was added. After stirring at -80 ºC for 1 h and at -20 ºC for 16 h, water and EtOAc were added. The organic layer was dried over anhydrous Na2SO4 then concentrated. Purification by chromatography (pet. Ether-EtOAc, 9:1) afforded diastereoisomers 32a (6 mg, 9%) and 32b (9 mg, 12%) as colourless 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), 4.244.13 (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, 21 ACS Paragon Plus Environment


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 (pet. ether:EtOAc, 9:1); IR νmax (neat) 2931, 1969, 1713, 1457, 1422, 1373, 1223, 1091, 1009, 777, 741 cm-1; [α] +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), 4.124.00 (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 (pet. Ether-EtOAc, 9:1); IR νmax (neat) 2934, 1972, 1713, 1457, 1424, 1375, 1223, 1097, 1011, 778, 741 cm-1; [α] +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 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 (pet. Ether-EtOAc, 2:1); IR νmax (neat) 2936, 1932, 1714, 1614, 1524, 1239, 1174, 1101, 1034, 976, 822, 738 cm-1; [α] +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), 6.936.81 (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 22 ACS Paragon Plus Environment

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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 (pet. ether-EtOAc, 2:1); IR νmax (neat) 2935, 1932, 1707, 1614, 1524, 1237, 1174, 1101, 1034, 976, 822, 736 cm-1; [α] +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 ozonised until a blue colour 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 up 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 (pet. 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), 7.257.19 (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), 3.953.87 (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 (pet. ether-EtOAc, 2:1); IR νmax (neat) 2938, 1940, 1725, 1614, 1522 1247, 1169, 1100, 1029, 975, 822, 736 cm-1; [α] +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 (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); 13

C 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 23 ACS Paragon Plus Environment


calcd for C43H52NaO9 [(M+Na)+] 735.3504; found 735.3488; Rf 0.36 (pet. Ether-EtOAc, 2:1); IR νmax (neat) 2938, 1932, 1714, 1622, 1529, 1231, 1175, 1105, 1029, 974, 820, 738 cm-1; [α] +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 then left stirring at rt under an H2 atmosphere. After stirring at rt for 20 h, the reaction mixture was filtered through a pad of Celite® then concentrated. Purification by preparative TLC (pet. 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), 4.013.90 (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); 13

C 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 (pet. ether:EtOAc, 2:1); IR νmax (neat) 3386, 2974, 2939, 1622, 1476, 1331, 1280, 1189, 1062, 924 cm-1; [α] -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 stirring at rt for 5.5 h, EtOAc and water were added. The organic layer was dried over anhydrous Na2SO4 then concentrated. Purification by chromatography (pet. 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 (pet. Ether-EtOAc, 2:1); IR νmax (neat) 2974, 2939, 1724, 1624, 1477, 1455, 1330, 1274, 1188, 1076, 936 cm-1; [α] -81.0 (c 0.20 in MeOH), lit. [α] +85.6 (c

0.88 in MeOH) for the opposite enantiomer.9 The 13C NMR spectra of (–)-1 (CDCl3) was calibrated at 77.00 ppm instead of 77.16 ppm to match the data reported by George et al. 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 ºC. After stirring at -80 ºC 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 stirring at -80 ºC for 1 h, the reaction mixture was quenched 24 ACS Paragon Plus Environment

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by a saturated aqueous NH4Cl solution. EtOAc was added and the organic layer was dried over anhydrous Na2SO4 then concentrated. Purification by chromatography (pet. 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);

13

C 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 (pet. Ether-EtOAc, 4:1); IR νmax (neat) 2926, 1612, 1514, 1249, 1173, 1033, 821 cm-1; [α] +12.9 (c 0.07 in CHCl3). Diol 49. TBAF (1M 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 stirring at rt for 20 min, the reaction mixture was quenched by addition of a saturated aqueous NH4Cl solution then diluted with Et2O. The organic layer was dried over anhydrous Na2SO4 then concentrated. Purification by chromatography (pet. 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 (pet. Ether-EtOAc, 7:3); Mp 80-82 ºC; IR νmax (neat) 3365, 2959, 1737, 1427, 1248, 1109, 815, 697 cm-1; [α] +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 stirring 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 then water was added. The organic layer was dried over anhydrous Na2SO4 then concentrated. Purification by chromatography (pet. 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);

13

C 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 (pet. ether-EtOAc, 7:3); IR νmax (neat) 2959, 2871, 1428, 1249, 1110, 970, 819, 700 cm-1; [α] -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 ºC then stirred at rt for 30 min. The above procedure was repeated three times then the reaction mixture quenched with 4% aqueous sodium sulphite solution. The organic layer was dried over anhydrous Na2SO4 then concentrated. The crude product was dissolved in MeOH (4.7 mL) then MeONa (306 mg, 5.67 mmol, 3.5 equiv) was added. After 20 min stirring at rt, water was added and the organic layer was dried over anhydrous Na2SO4 then concentrated. Purification by chromatography (pet. 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), 2.812.63 (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 (pet. ether-EtOAc, 9:1); IR νmax (neat) 2970, 2877, 1739, 1366, 1217, 970, 887, 758 cm-1; 〖[α]D23 +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 stirring at rt for 16 h, the reaction mixture was purged with N2 then concentrated. Chromatography (pet. Ether-Et2O, 7:3) afforded the methyl ketone 57 (106 mg, 99%) as a colorless oil: 1H 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 (pet. ether-Et2O, 7:3); IR νmax (neat) 2933, 2161, 1710, 1455, 1366, 1266, 742, 705 cm-1; [α] -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 4Å MS (20 mg) in toluene (1 mL) was stirred at 110 ºC for 16 h. The reaction mixture was cooled down to rt then benzaldehyde (23 µL, 0.23 mmol, 1.0 equiv) and CSA (5 mg, 23 µmol, 0.1 equiv) were added. After stirring at rt for 1 h, EtOAc and water were added. The organic layer was dried over anhydrous Na2SO4 then concentrated. Purification by chromatography (pet. 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, 26 ACS Paragon Plus Environment

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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); 13

C 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 (pet. ether:EtOAc, 19:1); IR νmax (neat) 3339, 2968, 1380, 1128, 950, 815 cm-1; [α] +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 ºC. The reaction mixture was stirred at rt for 30 min then quenched by addition of 4% aqueous sodium sulphite solution. The organic layer was dried over anhydrous Na2SO4 then concentrated. The crude product was dissolved in MeOH (1 mL) then MeONa (21 mg, 0.38 mmol, 3.5 equiv) was added. After stirring at reflux for 16 h, water and EtOAc were added and the organic layer was dried over anhydrous Na2SO4 then concentrated. Purification by chromatography (pet. Ether-EtOAc, 49:1) afforded vinyl bromide 59 (34 mg, 100%) as a colorless oil: 1

H 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 (pet. Ether-EtOAc, 19:1); IR νmax (neat) 2971, 1628, 1393, 1118, 1027, 967 cm-1; [α] +52.0 (c 1.00 in CHCl3). Oxidative Dimerisation 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 ºC. The reaction mixture was stirred at -80 ºC then warmed to -40 ºC. CuI (24 mg, 0.26 mmol, 1.0 equiv) was added and the reaction mixture was allowed to reach -20 ºC over 2 h. The reaction mixture was cooled to -80 ºC 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 then concentrated. Purification by preparative TLC (pet. 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 (pet. Ether-EtOAc, 9:1); IR νmax (neat) 2968, 1625, 1387, 1117, 1027, 966 cm-1; [α] +11.2 (c 0.70 in CHCl3). 27 ACS Paragon Plus Environment


Supporting Information. Copies of 1H and 13C NMR spectra for novel compounds, 2D COSY and HSQC NMR spectra for (-)-peniphenone A, (-)-1.

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TOC Graphic 29 ACS Paragon Plus Environment



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

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