Total Synthesis of ent-Ascospiroketal B - The Journal of Organic

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Total Synthesis of ent-Ascospiroketal B Yoshiyori Hara, Tatsuya Honda, Kazuto Arakawa, Koichiro Ota, Kazuo Kamaike, and Hiroaki Miyaoka J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02925 • Publication Date (Web): 01 Feb 2018 Downloaded from http://pubs.acs.org on February 2, 2018

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The Journal of Organic Chemistry

Total Synthesis of ent-Ascospiroketal B

Yoshiyori Hara, Tatsuya Honda, Kazuto Arakawa, Koichiro Ota, Kazuo Kamaike, and Hiroaki Miyaoka*

School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan

E-mail: [email protected]

Tel: +81-42-676-3080

Fax: +81-42-676-3073

ACS Paragon Plus Environment

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ABSTRACT: Ascospiroketal B was isolated from a marine-derived fungus as a structurally unique polyketide possessing a rare tricyclic core including 5,5-spiroketal-γ-lactone. Asymmetric total synthesis of ent-ascospiroketal B was achieved using an original synthetic route. The synthesis included stereoselective construction of 5,5-spiroketal for ascospiroketal B and stereocontrolled construction of a quaternary asymmetric carbon by rearrangement of a trisubstituted epoxide.


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INTRODUCTION Ascospiroketals A and B were isolated from the marine-derived fungus Ascochyta salicorniae by König and co-workers in 2007 as unusual polyketides possessing rare tricyclic cores including 5,5-spiroketal (Figure 1).1 The relative configurations of the tricyclic cores in 1 and 2 were determined by analysis of 1D and 2D NOE spectroscopy, respectively. However, the relative configuration at C-15, C-2’, and C-3’ of the side chain and relative relationship between the tricyclic core and side chain remained unknown. Furthermore, the absolute configuration of these compounds was not determined at that time.

Figure 1. König's structures of ascospiroketals A and B.

The unique structural features of ascospiroketals A and B prompted synthetic chemists to undertake synthetic studies of these compounds. In 2015, Britton and co-workers reported the total synthesis of ascospiroketal A using an elegant Ag-promoted cyclization cascade.2,3 The complete relative and absolute configuration of ascospiroketal A were determined by this synthesis as 3 (Figure 2). In 2016, Tong and co-worker reported the total synthesis of ent-ascospiroketals A and B using an efficient tricyclic ring-core construction employing a 10-membered ketolactone as part ACS Paragon Plus Environment

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of the key step.4 The complete relative and absolute configuration of ascospiroketal B were determined by this synthesis as 4 (Figure 2). On the other hand, Lee and co-workers reported on a synthetic study of ascospiroketal B, but did not achieve a total synthesis.5

Figure 2. Structures of ascospiroketals A and B.

The authors were interested in the unique structure of the 5,5-spiroketal-cis-fused-γ-lactone moiety of ascospiroketal B. Natural products such as cephalosporolides and penisporolides have the 5,5spiroketal-cis-fused-γ-lactone moiety as part of the structure (Figure 3). Cephalosporolides E and F, which were first isolated from the fungus Cephalosporium aphidicola by Hanson and coworkers,

are

polyketides

possessing

a

5,5-spiroketal-cis-fused-γ-lactone

moiety.6

Cephalosporolides H and I7 and penisporolides A and B8 were isolated by Li and co-workers from the lyophilized culture broth of the marine-derived fungus Penicillium sp. Among these natural products, cephalosporolides H and I are known to have inhibitory activities against xanthine oxidase and 3α-hydroxysteroid dehydrogenase. However, no biological activity has been reported for ascospiroketal B. Since cephalosporolides H and I show bioactivity and share a similar structure, the authors expect that ascospiroketal B would show some kind of bioactivity. In this ACS Paragon Plus Environment

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paper, the authors wish to report on the total synthesis of ent-ascospiroketal B.

Figure 3. Structures of natural products containing a 5,5-spiroketal-cis-fused-γ-lactone moiety.

In the synthesis of ascospiroketal B, stereoselective construction of the tricyclic core (5,5spiroketal-cis-fused-γ-lactone moiety) is important. Tong and co-workers reported on the efficient ring construction rearrangement of 10-membered ketolactone I to tricyclic compound II and 6epi-compound III (Figure 4). Ent-ascospiroketal A was synthesized from compound II and entascospiroketal B was synthesized from compound III. Unfortunately, the ratio of II and III (2 : 3) is unsuitable for the appreciable synthesis of ent-ascospiroketal B. ACS Paragon Plus Environment

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Figure 4. Total synthesis of ent-ascospiroketals A and B by Tong et al.

RESULTS AND DISCUSSION Our synthetic strategy for ent-ascospiroketal B is presented in Scheme 1. When we began this synthetic study, the absolute configuration of ascospiroketal B had not been determined. Therefore, we decided to synthesize the compound (ent-4) having the same absolute configuration described in König’s paper.1 Ent-ascospiroketal B (ent-4) would be obtained from side chain segment A and tricyclic core segment B by Sonogashira coupling. Side chain segment A would be obtained by condensation of the chiral carboxylic acid and chiral alcohol. Tricyclic core segment B would be obtained from spiroketal C by construction of γ-lactone and iodovinyl moieties. The quaternary asymmetric carbon at C-2 in spiroketal C would be constructed by stereoselective rearrangement of the epoxide in spiroketal D. Spiroketal D would be obtained from segment E by construction of a spiroketal and epoxidation. Segment E would be obtained by connection of segment F and segment G. Segment F would be prepared from D-(+)-malic acid. Segment G ACS Paragon Plus Environment

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would be prepared from L-(+)-tartaric acid. Scheme 1. Retrosynthetic Analysis for ent-Ascospiroketal B (ent-4)

Thioacetal 7 corresponding to segment F was synthesized from diol 59 prepared by a known method from D-(+)-malic acid (Scheme 2). Selective protection of the primary hydroxy group in diol 5 was carried out as a Bn ether10 (80% yield) and the secondary hydroxy group was protected as a THP ether. The TBDPS group was removed by treatment of TBAF to give the alcohol in 86% yield (2 steps). Iodination of the hydroxy group by conversion to iodide 6 was achieved in 98% yield. Iodide 6 was treated with lithiated 1,3-dithiane to afford thioacetal 7 in 91% yield.


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Scheme 2. Synthesis of Segment Fa

a

Reagents and conditions: (a) Bu2SnO, toluene, reflux, then BnBr, TBAB, 80 °C, 80%; (b) 3,4-

dihydro-2H-pyran, TsOH·H2O, Et2O, rt; (c) TBAF, THF, rt, 86% (2 steps); (d) I2, Ph3P, imidazole, benzene, rt, 98%; (e) 1,3-dithiane, BuLi, THF, −20 °C, 91%.

Iodide 12 corresponding to segment G was synthesized from known diol 811 prepared from L-(+)tartaric acid (Scheme 3). Selective mono protection of the hydroxy group in diol 8 was carried out to give mono TBS ether in 98% yield.12 The primary alcohol was oxidized using Swern oxidation13 to give the aldehyde, methylated using methyl magnesium bromide, and subsequent Swern oxidation13 of the secondary alcohol gave methyl ketone 9 in 66% yield (3 steps). Methyl ketone 9 was treated with ethyl 2-(diethoxyphosphoryl)acetate and NaH in THF to afford (E)-α,βunsaturated ester 10 (76% yield) and its (Z)-isomer (5% yield).14 Ester 10 was reduced with DIBALH to give allylic alcohol in 94% yield. Protection of the hydroxy group using pmethoxyphenylmethyl

trichloroacetimidate

(MPM-TCAI)15

and

La(OTf)3

as

p-

methoxyphenylmethyl (MPM) ether and deprotection of the TBS ether using TBAF gave alcohol 11 in 81% yield (2 steps), and subsequent iodination of the resulting hydroxy group furnished


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iodide 12 in 98% yield. Given that segments F and G were synthesized, connection with segments F and G was then carried out. Scheme 3. Synthesis of Segment Ga

a

Reagents and conditions: (a) TBSCl, NaH, THF, 0 °C to rt, 98%; (b) DMSO, (COCl)2, Et3N,

−78 °C to rt; (c) MeMgBr, THF, 0 °C; (d) DMSO, (COCl)2, Et3N, −78 °C to rt, 66% (3 steps); (e) (EtO)2P(O)CH2CO2Et, NaH, THF, 0 °C to rt, 76%, (Z)-isomer 5%; (f) DIBALH, CH2Cl2, −78 °C, 94%; (g) MPM-TCAI, La(OTf)3, CH3CN, rt; (h) TBAF, THF, rt, 81% (2 steps); (i) I2, Ph3P, imidazole, benzene, rt, 98%.

Thioacetal 7 was treated with t-BuLi in the presence of HMPA and then iodide 12 was added at −78 °C to give thioketal 13 corresponding to segment E in 88% yield (Scheme 4). Thioketal 13


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was treated with phenyliodine bis(trifluoroacetate) (PIFA) in CH3CN/buffer (pH 8) to give the ketone in 80% yield.16 Methanolysis of cyclopentylidene and THP ether and formation of 5,5spiroketal were carried out by treatment with TsOH in MeOH/THF to afford spiroketal 14 as a mixture of two diastereomers (3 : 1) at C-6 in 66% yield. Since initial efforts to separate these diastereomers was difficult, the separation was carried out at a later stage. The secondary hydroxy group in 14 was protected as a pivaloyl group and the MPM group was removed by treatment with CAN to give spiroketals 15a and 15b in 75% yield (2 steps) and 11% yield (2 steps), respectively.17 These spiroketals were easily separated by silica gel chromatography. Spiroketal 15a having the same stereochemistry as ent-ascospiroketal B could be obtained as the major product (15a : 15b = 7 : 1). Since spiroketal 15a is more thermodynamically stable than spiroketal 15b, spiroketal 15a was presumed to be obtained preferentially. Scheme 4. Synthesis of 5,5-Spiroketala


11


a

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Reagents and conditions: (a) t-BuLi, HMPA, THF, −78 °C, then 12, −78 °C, 88%; (b) PIFA,

CH3CN/buffer (pH 8), 0 °C, 80%; (c) TsOH·H2O, MeOH/THF, rt, 66% (dr = 3 : 1); (d) PivCl, Py, 40 °C; (e) CAN, CH3CN/H2O, rt, 15a, 75% (2 steps), 15b, 11% (2 steps).

The relative configurations of 15a and 15b were determined by NOESY analysis (Figure 5). The relative configuration of 15a was determined by NOE correlation between the sp2 methine proton at C-1 and the methylene protons at C-7. The relative configuration of 15b was determined by NOE correlations between the methylene protons at C-5 and one of the methylene protons at C-7, between one of the methylene protons at C-7 and the methine proton at C-9, and between another methylene proton at C-7 and the methylene protons at C-10.

Figure 5. Selected NOE correlations of 5,5-spiroketals 15a and 15b.

The pivaloyl group in spiroketal 15a was removed by treatment with MeLi to afford diol 16 in quantitative yield (Scheme 5). Epoxidation of allylic alcohol 16 under Sharpless conditions18 gave the epoxy alcohol in 78% yield as a diastereomeric ratio 8 : 1. The primary hydroxy group was protected as a TBS ether in 86% yield and the secondary hydroxy group was protected as a Bn ether to α-epoxide 17 in 84% yield. Next, construction of a quaternary asymmetric carbon at C-2 ACS Paragon Plus Environment

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was achieved by a rearrangement reaction of the epoxide. α-Epoxide 17 was treated with TBSOTf and iPr2NEt to afford the aldehyde including the desired quaternary asymmetric carbon.19 As the aldehyde was unstable, the aldehyde was immediately reduced with NaBH4 to give alcohol 18 as a sole isolable product in 9% yield (2 steps). The relative configuration of the quaternary asymmetric carbon at C-2 was confirmed at a later stage. Although the desired compound could be obtained, the chemical yield was low. Even when other Lewis acids such as methylaluminum bis(4-bromo-2,6-di-tert-butylphenoxide) (MABR)20 and SnCl421 were used, the chemical yield could not be improved. Therefore, a diastereomer at the epoxide of 17 was synthesized and a rearrangement reaction of the diastereomer was investigated. Scheme 5. Synthesis of Segment C (1)a

a

Reagents and conditions: (a) MeLi, Et2O, 0 °C, quant.; (b) TBHP, D-(−)-DIPT, Ti(OiPr)4, CH2Cl2,

−20 °C, 78% (dr = 8 : 1); (c) TBSCl, imidazole, CH2Cl2, rt, 86%; (d) BnBr, NaH, tetrabutylammonium iodide (TBAI), THF, rt, 84%; (e) TBSOTf, iPr2NEt, CH2Cl2, −78 °C; (f) NaBH4, THF/MeOH, 0 °C, 9% (2 steps).


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Epoxidation of allylic alcohol 16 was carried out using L-(+)-diisopropyl tartrate (DIPT) to give epoxy alcohol in 89% yield as a diastereomeric ratio >20 : 1 (Scheme 6). The primary and secondary hydroxy groups were in turn protected as TBS (98% yield) and Bn (96% yield) ethers, respectively, to give β-epoxide 19. β-Epoxide 19 was treated with TBSOTf and iPr2NEt in CH2Cl2 at −78 °C to afford the aldehyde followed by reduction with NaBH4 to give alcohol 18 as a sole isolable product in 54% yield (2 steps). The desired same compound could also be obtained from β-epoxide 19. Even when other Lewis acids such as MABR and SnCl4 were used, the chemical yield could not be improved to greater than 54%. Therefore, alcohol 18 was synthesized from βepoxide 19 using TBSOTf as a Lewis acid. Scheme 6. Synthesis of Segment C (2)a

a

Reagents and conditions: (a) TBHP, L-(+)-DIPT, Ti(OiPr)4, CH2Cl2, −20 °C, 89% (dr = > 20 : 1);

(b) TBSCl, imidazole, CH2Cl2, rt, 98%; (c) BnBr, NaH, TBAI, THF, rt, 96%; (d) TBSOTf, iPr2NEt, CH2Cl2, −78 °C; (e) NaBH4, THF/MeOH, 0 °C, 54% (2 steps).

It is presumed that the same alcohol 18 was obtained as a single product from each of α-epoxide 17 and β-epoxide 19 for the following reasons (Figure 6). Trisubstituted α-epoxide 17 is treated with Lewis acid to give tertiary carbocation 17b via 17a by C-O bond cleavage. Migration of the


14

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siloxymethyl group to the carbocation affords aldehyde 18’. Aldehyde 18’ was reduced to afford alcohol 18. Since carbocation 17b possesses steric hindrance between the siloxymethyl and Bn groups, orientation of the siloxymethyl group as further away as possible from the Bn group is advantageous. With that conformation, migration of the siloxymethyl group occurs, and so it is presumed that aldehyde 18’ was stereoselectively obtained. Similarly, since carbocation 19b formed from β-epoxide 19 via 19a possesses steric hindrance between the siloxymethyl and Bn groups, the siloxymethyl group is located farther away from the Bn group. Since the siloxymethyl group migrates with this conformation, the same aldehyde 18' is selectively obtained.

Figure 6. A plausible mechanism for stereoselective rearrangement reaction of epoxides 17 and 19.

Alcohol 18 was converted to mesylate (98% yield), followed by treatment with Na in liquid NH3 at −78 °C, removal of the Bn group and formation of the tetrahydrofuran ring were achieved to


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give tricyclic compound 20 in 85% yield (Scheme 7). The absolute configuration at C-2 was determined by ROESY analysis of tricyclic compound 20 (Figure 7). The NOE correlations of 20 between methine proton at C-3 and methine proton at C-4, methine proton at C-4 and methylene protons at C-16, suggested that these protons were oriented in the same face. Therefore, the configuration at C-2 in 20 was found to adopt the S configuration. Primary protection of the hydroxy group in 20 as the acetate, oxidation of tetrahydrofuran to γ-lactone with RuCl3/NaIO422 and methanolysis of the acetate with K2CO3 in MeOH gave γ-lactone 21 in 64% yield (3 steps). Oxidation of alcohol 21 with Dess-Martin periodinane (DMP)23 followed by treatment with OhiraBestmann reagent (diethyl (1-diazo-2-oxopropyl)phosphonate)24 and K2CO3 gave alkyne 22 in 70% yield (2 steps). Alkyne 22 was treated with Schwartz's reagent25 and the iodine to give (E)iodoalkene 23 which corresponded to segment B in 63% yield.

Scheme 7. Synthesis of Segment Ba OH

H O

18

a, b

O

H

c-e

2

O H

OTBS

20

OH

H O

O

H

O

f, g

O H 21 H O

OTBS I H

O O h

H O

O

H

O O

H 22

O

OTBS

H 23


OTBS 16

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a

Reagents and conditions: (a) MsCl, Et3N, CH2Cl2, rt, 98%; (b) Na, liq. NH3, THF, −78 °C, 85%; (c) Ac2O,

Py, DMAP, rt; (d) RuCl3·nH2O, NaIO4, NaHCO3, CCl4/CH3CN/H2O, rt to 35 °C; (e) K2CO3, MeOH, rt, 64% (3 steps); (f) DMP, NaHCO3, CH2Cl2, rt; (g) Ohira-Bestmann reagent, K2CO3. MeOH, rt, 70% (2 steps); (h) Cp2ZrHCl, THF, 0 °C, then I2, −78 °C, 63%.

Figure 7. Selected NOE correlations of tricyclic compound 20.

Side chain segment A was obtained by condensation of known alcohol 2426 and known carboxylic acid 252,3 (Scheme 8). Alcohol 24 was synthesized from (R)-propylene oxide and TMS-acetylene and carboxylic acid 25 was synthesized from (R)-malic acid. Condensation of alcohol 24 and carboxylic acid 25 was carried out according to the Shiina method.27 After adding 2-methyl-6nitrobenzoic anhydride (MNBA), DMAP and Et3N to carboxylic acid 25 in CH2Cl2, alcohol 24 reacted to obtain ester 26 which corresponded to segment A in 90% yield. Since segments A and B could be synthesized, ent-ascospiroketal B (ent-4) was synthesized by coupling both segments. Scheme 8. Synthesis of Segment Aa


17


a

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Reagents and condition: (a) MNBA, DMAP, Et3N, CH2Cl2, rt, 90%.

Sonogashira coupling28 of 26 corresponded to segment A with vinyl (E)-iodoalkene 23 to afford the full carbon skeleton of ascospiroketal B, followed by Lindlar reduction29 of the coupling enyne to give (E,Z)-diene in 47% yield (2 steps) (Scheme 9). Removal of the TBS group with TBAF gave ent-ascospiroketal B (ent-4) in quantitative yield. There was excellent correlation of 1H- and 13

C-NMR data between synthetic ent-4 and the reported natural product. The specific rotation of

ent-4 ([α]D23 −9.33 (c 0.24, MeOH)) differed in sign and absolute value from that of the reported natural product ([α]D23 +3 (c 0.33, MeOH)).1 However, since the specific rotation of synthesized ent-4 was consistent with that of synthesized ent-ascospiroketal B ([α]D25 −10.6 (c 0.33, MeOH)) by Tong et al,4 total synthesis of ent-ascospiroketal B was achieved.

Scheme 9. Total Synthesis of ent-Ascospiroketal B (ent-4)a

a

Reagents and conditions: (a) 26, Pd(PPh3)4, CuI, Et3N, rt; (b) H2, Lindlar catalyst, quinoline,

MeOH, 0 °C, 47% (2 steps); (c) TBAF, THF, rt, quant.


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CONCLUSION In conclusion, the asymmetric total synthesis of the structurally unique polyketide entascospiroketal B by our original synthetic route was reported. This synthesis included stereoselective construction of 5,5-spiroketal for ascospiroketal B and stereocontrolled construction of a quaternary asymmetric carbon by rearrangement of the trisubstituted epoxide. The biological activity of the synthesized compound is currently under investigation.

EXPERIMENTAL SECTION

General Experimental Procedures. Optical rotations were measured with a JASCO P-1030 polarimeter. IR spectra were recorded with a JASCO FT-IR/620 spectrometer. 1H and

13

C NMR

spectra were recorded on a Bruker Biospin AVANCE III HD 400 Nanobay (400 MHz for 1H, 100 MHz for

13

C), and the reported chemical shifts in parts per million (ppm) are relative to the

internal CHCl3 (7.26 ppm for 1H and 77.0 ppm for and 128.4 ppm for

13

13

C) and the internal C6H6 (7.16 ppm for 1H

C) and the internal (CH3)2CO (2.04 ppm for 1H and 29.8 ppm for

13

C), J

values were measured in Hertz.. The coupling patterns are denoted as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad). HR-ESI-MS spectra were obtained using a Micromass LCT spectrometer with time-of-flight (TOF) analyzer. Elemental analysis data were obtained using an Elementar Vario EL. Pre-coated silica gel plates with a fluorescent indicator (Merck 60 F254) were used for analytical and preparative thin layer chromatography (TLC). Flash column chromatography was performed using Kanto Chemical Silica Gel 60N (spherical, natural) ACS Paragon Plus Environment

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40−50 µm. All reagents (Aldrich, Kanto, TCI, and Wako) and solvents were of commercial quality and were used as received.

2-(((R)-1-(Benzyloxy)-4-iodobutan-2-yl)oxy)tetrahydro-2H-pyran (6). To a solution of diol 5 (6.07 g, 17.6 mmol) in toluene (88.0 mL) was added dibutyltin oxide at rt and stirred under reflux for 4 h in a Dean-Stark apparatus with removal of water. After being cooled to rt, the mixture was evaporated to 44.0 mL and added benzyl bromide (6.30 mL, 52.8 mmol), TBAB (2.80 g, 8.80 mmol). The mixture was heated at 80 ˚C and stirred at for 14 h. The mixture was cooled, added water and diluted with Et2O. The organic layer was washed with water, saturated aqueous NaCl. The organic layer was dried over Na2SO4 and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane : EtOAc = 8 : 1) to afford benzyl ether (6.16 g, 80% yield) as colorless oil. Rf 0.50 (hexane : EtOAc = 8 : 1); [α]D25 +0.95 (c 0.84, CHCl3); IR (neat) νmax = 3471, 3070, 2928, 2857, 1589 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.70–7.63 (4H, m), 7.46–7.24 (11H, m), 4.56 (2H, s), 4.10 (1H, m), 3.91–3.78 (2H, m), 3.51 (1H, dd, J = 4.2, 9.5 Hz), 3.43 (1H, dd, J = 6.9, 9.5 Hz), 3.03 (1H, d, J = 3.0 Hz), 1.81–1.67 (2H, m), 1.04 (9H, s);

13

C NMR (100 MHz, CDCl3) δ 138.1 (C), 135.54 (CH)×2, 135.53 (CH)×2, 133.3

(C), 133.2 (C), 129.7 (CH)×2, 128.4 (CH)×2, 127.71 (CH)×6, 127.68 (CH), 74.4 (CH2), 73.4 (CH2), 69.4 (CH), 62.0 (CH2), 35.4 (CH2), 26.8 (CH3)×3, 19.0 (C); LRMS (ESI-TOF) m/z: 457 [M+Na]+ (100); HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C27H34O3SiNa 457.2175; Found 457.2179; Anal. Calcd for C27H34O3Si: C, 74.61; H, 7.88. Found: C, 74.44; H, 7.95.


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To a solution of benzyl ether (23.5 g, 54.1 mmol) in Et2O were added p-toluenesulfonic acid monohydrate (1.03 g, 5.41 mmol) and 3,4-dihydro-2H-pyran (12.3 mL, 135 mmol) at rt and stirred for 1.5 h. The mixture was quenched with saturated aqueous NaHCO3 and diluted with Et2O. The organic layer was washed with water, saturated aqueous NaCl and dried over Na2SO4 and then concentrated under reduced pressure. The crude ether was used for the next step without further purification.

To a solution of the above ether in THF (270 mL) was added TBAF (108 mL, 108 mmol, 1.0 M in THF) at rt and stirred for 4 h. The mixture was quenched with saturated aqueous NH4Cl and diluted with Et2O. The organic layer was washed with water, saturated aqueous NaCl and dried over Na2SO4 and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane : EtOAc = 2 : 1) to afford alcohol (13.0 g, 86 % yield for 2 steps) as colorless oil. Rf 0.40 (hexane : EtOAc = 1 : 1); IR (neat) νmax = 3463, 2938, 1496 cm−1; 1

H NMR (400 MHz, CDCl3) δ 7.38–7.24 (5H, m), 4.75–4.66 (1H, m), 4.61–4.47 (2H, m), 4.10

(0.5H, m), 4.02–3.80 (2H, m), 3.76–3.64 (2H, m), 3.56 (0.5H, dd, J = 6.4, 9.6 Hz), 3.54–3.42 (2H, m), 2.01–1.41 (9H, m); 13C NMR (100 MHz, CDCl3) δ 138.2 (C), 138.1 (C), 128.5 (CH), 128.4 (CH)×2, 128.3 (CH)×2, 127.74 (CH), 127.71 (CH), 127.63 (CH), 127.60 (CH), 127.5 (CH), 100.9 (CH), 99.1 (CH), 75.3 (CH), 73.8 (CH), 73.5 (CH2), 73.4 (CH2), 73.3 (CH2), 72.6 (CH2), 65.1 (CH2), 62.9 (CH2), 59.8 (CH2), 58.9 (CH2), 34.6 (CH2), 34.2 (CH2), 31.3 (CH2), 31.0 (CH2), 25.3 (CH2), 25.1 (CH2), 21.4 (CH2), 19.8 (CH2); LRMS (ESI-TOF) m/z: 281 [M+H]+ (100); HRMS


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(ESI-TOF) m/z: [M+H]+ Calcd for C16H25O4 281.1753; Found 281.1749; Anal. Calcd for C16H24O4: C, 68.55; H, 8.63. Found: C, 68.30; H, 8.48.

To a solution of alcohol (8.45 g, 30.1 mmol) in benzene (300 mL) were added imidazole (7.14 g, 105 mmol), triphenylphosphine (15.7 g, 59.9 mmol), and iodine (15.2 g, 59.9 mmol) at 0 ˚C. After being stirred at the same temperature for 15 min, the mixture was warmed to rt and stirred for 12 h. The mixture was quenched with aqueous Na2S2O3 and diluted with Et2O. The organic layer was washed with water, saturated aqueous NaCl and dried over Na2SO4 and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane : EtOAc = 15 : 1) to afford iodide 6 (11.5 g, 98% yield) as colorless oil. Rf 0.40 (hexane : EtOAc = 15 : 1); IR (neat) νmax = 2940, 2857, 1453 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.38–7.25 (5H, m), 4.80–4.69 (1H, m), 4.56 (0.5H, s), 4.55 (0.5H, s), 4.53 (1H, s), 3.96–3.80 (2H, m), 3.66 (0.5H, dd, J = 4.2, 9.8 Hz), 3.58–3.41 (2.5H, m), 3.36–3.19 (2H, m), 2.22–2.05 (2H, m), 1.88–1.67 (2H, m), 1.66–1.45 (4H, m);

13

C NMR (100 MHz, CDCl3) δ 138.2 (C), 138.1 (C), 128.4 (CH)×2, 128.3

(CH)×2, 127.7 (CH)×2, 127.6 (CH), 127.54 (CH), 127.53 (CH)×2, 100.0 (CH), 97.8 (CH), 76.9 (CH), 74.8 (CH), 73.3 (CH2)×2, 72.1 (CH2), 71.3 (CH2), 63.1 (CH2), 62.8 (CH2), 37.1 (CH2), 36.2 (CH2), 30.9 (CH2)×2, 25.34 (CH2), 25.31 (CH2), 19.9 (CH2), 19.8 (CH2), 2.7 (CH2), 2.6 (CH2); LRMS (ESI-TOF) m/z: 391 [M+H]+ (100); HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C16H24O3I 391.0770; Found 391.0784; Anal. Calcd for C16H23O3I: C, 49.24; H, 5.94. Found: C, 49.20; H, 6.03.


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2-(((R)-1-(Benzyloxy)-4-(1,3-dithian-2-yl)butan-2-yl)oxy)tetrahydro-2H-pyran

(7).

To

a

solution of 1,3-dithiane (4.57 g, 38.0 mmol) in THF (100 mL) was slowly added BuLi (14.7 mL, 39.0 mmol, 2.65 M in hexane) at −20 ˚C under Ar. After being stirred at the same temperature for 30 min, the mixture was warmed to 0 ˚C and slowly added a solution of iodide 6 (7.41 g, 19.0 mmol) in THF (90.0 mL) and stirred at the same temperature for 30 min. The mixture was quenched with saturated aqueous NH4Cl and diluted with Et2O. The organic layer was washed with water, saturated aqueous NaCl and dried over Na2SO4 and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane : EtOAc = 8 : 1) to afford thioacetal 7 (6.57 g, 91% yield) as colorless oil. Rf 0.51 (hexane : EtOAc = 6 : 1); IR (neat) νmax = 2940, 2854, 1450 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.39–7.22 (5H, m), 4.82 (0.4H, dd, J = 3.0, 4.0 Hz), 4.66 (0.6H, dd, J = 3.0, 4.0 Hz), 4.60–4.48 (2H, m), 4.07 (0.4H, t, J = 6.8 Hz), 4.02 (0.6H, t, J = 6.1 Hz), 3.95–3.74 (2H, m), 3.62 (0.6H, dd, J = 4.9, 9.8 Hz), 3.52–3.40 (2.4H, m), 2.91–2.77 (4H, m), 2.15–2.05 (1H, m), 2.02–1.63 (7H, m), 1.62–1.44 (4H, m);

13

C

NMR (100 MHz, CDCl3) δ 138.4 (C), 138.3 (C), 128.31 (CH)×2, 128.25 (CH)×2, 127.6 (CH)×2, 127.49 (CH), 127.48 (CH)×2, 127.4 (CH), 98.6 (CH), 97.5 (CH), 75.7 (CH), 74.0 (CH), 73.2 (CH2)×2, 72.41 (CH2), 72.39 (CH2), 62.51 (CH2), 62.48 (CH2), 47.6 (CH), 47.5 (CH), 31.3 (CH2), 31.0 (CH2), 30.9 (CH2)×2, 30.34 (CH2)×2, 30.32 (CH2), 30.26 (CH2), 29.5 (CH2), 28.7 (CH2), 26.0 (CH2), 25.9 (CH2), 25.5 (CH2), 25.4 (CH2), 19.64 (CH2), 19.55 (CH2); LRMS (ESI-TOF) m/z: 405 [M+Na]+ (100); HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C20H30O3S2Na 405.1534; Found 405.1531; Anal. Calcd for C20H30O3S2: C, 62.79; H, 7.90. Found: C, 62.94; H, 8.02. ACS Paragon Plus Environment

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1-((2R,3S)-3-(((tert-Butyldimethylsilyl)oxy)methyl)-1,4-dioxaspiro[4.4]nonan-2-yl)ethan-1one (9). To a suspension of NaH (2.80 g, 64.0 mmol, 55% in oil) in THF (305 mL) was slowly added a solution of diol 8 (11.5 g, 61.0 mmol) in THF (305 mL) at 0 ˚C and stirred for 30 min. The mixture was slowly added TBSCl (9.60 g, 64.0 mmol) at 0 ˚C and then warmed to rt and stirred for 1 h. The mixture was quenched with saturated aqueous NH4Cl and diluted with Et2O. The organic layer was washed with water, saturated aqueous NaCl and dried over Na2SO4 and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:EtOAc = 6 : 1) to afford silyl ether (18.1 g, 98% yield) as colorless oil. Rf 0.55 (hexane : EtOAc = 5 : 1); [α]D25 +11.5 (c 1.16, CHCl3); IR (neat) νmax = 3465, 2954 cm−1; 1H NMR (400 MHz, CDCl3) δ 3.93 (1H, dt, J = 4.8, 7.2 Hz), 3.89–3.79 (2H, m), 3.75 (1H, dd, J = 4.8, 11.4 Hz), 3.70 (1H, dd, J = 4.8, 11.4 Hz), 3.64 (1H, dd, J = 7.1, 9.8 Hz), 2.34 (1H, brs), 1.89– 1.56 (8H, m), 0.89 (9H, s), 0.08 (6H, s);

13

C NMR (100 MHz, CDCl3) δ 119.2 (C), 80.2 (CH),

78.0 (CH), 63.8 (CH2), 63.0 (CH2), 37.3 (CH2), 37.2 (CH2), 25.8 (CH3)×3, 23.5 (CH2), 23.4 (CH2), 18.3 (C), −5.5 (CH3)×2; LRMS (ESI-TOF) m/z: 303 [M+H]+ (100); HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C15H31O4Si 303.1992; Found 303.2003; Anal. Calcd for C15H30O4Si: C, 59.56; H, 10.00. Found: C, 59.42; H, 9.86.

To a solution of oxalyl chloride (0.900 mL, 10.5 mmol) in CH2Cl2 (9.00 mL) was slowly added DMSO (1.00 mL, 14.0 mmol) at −78 ˚C and stirred for 40 min and then slowly added a solution of silyl ether (1.06 g, 3.51 mmol) in CH2Cl2 (9.00 mL). After being stirred at the same temperature for 90 min, the mixture was slowly added Et3N (2.45 mL, 17.6 mmol) and then warmed to rt and ACS Paragon Plus Environment

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stirred for 9 h. The mixture was quenched with saturated aqueous NaHCO3 and diluted with Et2O. The organic layer was washed with saturated aqueous NaHCO3, water, saturated aqueous NaCl and dried over Na2SO4 and then concentrated under reduced pressure. The crude aldehyde was used for the next step without further purification.

To a solution of the above aldehyde in THF (17.6 mL) was slowly added methylmagnesium bromide (8.30 mL, 8.80 mmol, 1.06 M in THF) at 0 ˚C and stirred for 6 h. The mixture was quenched with saturated aqueous NH4Cl, and diluted with Et2O. The organic layer was washed with water, saturated aqueous NaCl and dried over Na2SO4 and then concentrated under reduced pressure. The crude alcohol was used for the next step without further purification.

To a solution of oxalyl chloride (0.900 mL, 10.5 mmol) in CH2Cl2 (9.00 mL) was slowly added DMSO (1.00 mL, 14.0 mmol) at −78 ˚C and stirred for 45 min and then slowly added a solution of the above alcohol in CH2Cl2 (9.00 mL). After being stirred at the same temperature for 4 h, the mixture was slowly added Et3N (2.50 mL, 17.6 mmol) and then warmed to rt and stirred for 2 h. The mixture was quenched with saturated aqueous NaHCO3 and diluted with Et2O. The organic layer was washed with saturated aqueous NaHCO3, water, saturated aqueous NaCl and dried over Na2SO4 and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane : EtOAc = 20 : 1) to afford ketone 9 (724 mg, 66% yield for 3 steps) as colorless oil. Rf 0.61 (hexane : EtOAc = 10 : 1); [α]D25 +11.4 (c 1.65, CHCl3); IR (neat) νmax = 2956, 2858, 1720 cm−1; 1H NMR (400 MHz, CDCl3) δ 4.25 (1H, d, J = 7.1 Hz), 4.00 (1H,


25


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ddd, J = 4.1, 4.3, 7.1 Hz), 3.84 (1H, dd, J = 4.1, 11.1 Hz), 3.75 (1H, dd, J = 4.3, 11.1 Hz), 2.26 (3H, s), 1.90–1.60 (8H, m), 0.89 (9H, s), 0.07 (6H, s); 13C NMR (100 MHz, CDCl3) δ 208.4 (C), 120.7 (C), 81.6 (CH), 78.7 (CH), 63.2 (CH2), 37.0 (CH2), 36.7 (CH2), 26.4 (CH3), 25.9 (CH3)×3, 23.5 (CH2), 23.2 (CH2), 18.4 (C), −5.3 (CH3), −5.4 (CH3); LRMS (ESI-TOF) m/z: 337 [M+Na]+ (100); HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C16H30O4SiNa 337.1811; Found 337.1800; Anal. Calcd for C16H30O4Si: C, 61.11; H, 9.61. Found: C, 61.01; H, 9.46.

Ethyl

(E)-3-((2S,3S)-3-(((tert-butyldimethylsilyl)oxy)methyl)-1,4-dioxaspiro[4.4]-nonan-2-

yl)but-2-enoate (10). To a suspension of NaH (5.14 g, 118 mmol, 55% in oil) in THF (150 mL) was slowly added ethyl 2-(diethoxyphosphoryl)acetate (19.7 mL, 98.5 mmol) at 0 ˚C and stirred for 1 h. The mixture was slowly added a solution of ketone 9 (12.4 g, 39.4 mmol) in THF (50.0 mL) at the same temperature and then warmed to rt and stirred for 1.5 h. The mixture was quenched with saturated aqueous NH4Cl and diluted with Et2O. The organic layer was washed with water, saturated aqueous NaCl and dried over Na2SO4 and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane : EtOAc = 20 : 1) to afford ester 10 (11.5 g, 76% yield) and Z-isomer (758 mg, 5% yield) as colorless oil. Rf 0.62 (hexane : EtOAc = 10 : 1); [α]D25 −13.3 (c 0.81, CHCl3); IR (neat) νmax = 2956, 2931, 2858, 1719, 1657 cm−1; 1H NMR (400 MHz, CDCl3) δ 5.98 (1H, m), 4.33 (1H, d, J = 6.8 Hz), 4.16 (2H, dq, J = 1.2, 7.2 Hz), 3.83–3.69 (3H, m), 2.15 (3H, d, J = 1.3 Hz), 1.93–1.52 (8H, m), 1.27 (3H, t, J = 7.2 Hz), 0.89 (9H, s), 0.07 (3H, s), 0.07 (3H, s); 13C NMR (100 MHz, CDCl3) δ 166.4 (C), 154.9 (C), 119.8 (C), 116.9 (CH), 81.8 (CH), 80.5 (CH), 63.2 (CH2), 59.8 (CH2), 37.5 (CH2), 37.0 (CH2), ACS Paragon Plus Environment

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25.8 (CH3)×3, 23.4 (CH2), 23.3 (CH2), 18.3 (C), 14.6 (CH3), 14.3 (CH3), −5.3 (CH3), −5.4 (CH3); LRMS (ESI-TOF) m/z: 407 [M+Na]+ (100); HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C20H36O5SiNa 407.2230; Found 407.2220; Anal. Calcd for C20H36O5Si: C, 62.46; H, 9.44. Found: C, 62.21; H, 9.42. Z-isomer: Rf 0.63 (hexane : EtOAc = 10 : 1); [α]D25 +9.20 (c 0.41, CHCl3); IR (neat) νmax = 2956, 2929, 2857, 1716, 1650 cm−1; 1H NMR (400 MHz, CDCl3) δ 5.82 (1H, m), 5.60 (1H, d, J = 7.1 Hz), 4.12 (2H, q, J = 7.1 Hz), 3.86–3.74 (3H, m), 1.95–1.78 (7H, m), 1.71– 1.58 (4H, m), 1.26 (3H, t, J = 7.1 Hz), 0.88 (9H, s), 0.06 (3H, s), 0.05 (3H, s);

13

C NMR (100

MHz, CDCl3) δ 165.4 (C), 154.9 (C), 120.0 (C), 119.9 (CH), 81.2 (CH), 74.8 (CH), 64.6 (CH2), 59.9 (CH2), 37.7 (CH2), 36.9 (CH2), 25.9 (CH3)×3, 23.7 (CH2), 23.2 (CH2), 19.1 (CH3), 18.4 (C), 14.2 (CH3), −5.2 (CH3), −5.3 (CH3); LRMS (ESI-TOF) m/z: 407 [M+Na]+ (100); HRMS (ESITOF) m/z: [M+Na]+ Calcd for C20H36O5SiNa 407.2230; Found 407.2197; Anal. Calcd for C20H36O5Si: C, 62.46; H, 9.44. Found: C, 62.24; H, 9.28.

((2S,3S)-3-((E)-4-((4-Methoxybenzyl)oxy)but-2-en-2-yl)-1,4-dioxaspiro[4.4]nonan-2yl)methanol (11). To a solution of ester 10 (21.1 g, 54.9 mmol) in CH2Cl2 (270 mL) was slowly added DIBALH (113 mL, 116 mmol, 1.02 M in hexane) at −78 ˚C under Ar and stirred at the same temperature for 30 min. The mixture was diluted with Et2O and added Na2SO4·10H2O, stirred at rt for 12 h. The suspension was added MgSO4 and stirred for 30 min. The suspension was filtered through Na2SO4 and then concentrated under pressure. The residue was purified by column chromatography on silica gel (hexane : EtOAc = 4 : 1) to afford allylic alcohol (17.0 g, 94% yield) as colorless oil. Rf 0.45 (hexane : EtOAc = 4 : 1); [α]D25 −9.03 (c 2.32, CHCl3); IR ACS Paragon Plus Environment

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(neat) νmax = 3417, 2955, 2858 cm−1; 1H NMR (400 MHz, CDCl3) δ 5.74 (1H, t, J = 6.6 Hz), 4.30– 4.12 (3H, m), 3.82–3.66 (3H, m), 1.95–1.59 (11H, m), 1.42 (1H, brs), 0.89 (9H, s), 0.06 (6H, s); 13

C NMR (100 MHz, CDCl3) δ 135.3 (C), 127.9 (CH), 119.1 (C), 82.6 (CH), 79.6 (CH), 63.1

(CH2), 59.2 (CH2), 37.6 (CH2), 37.1 (CH2), 25.9 (CH3)×3, 23.5 (CH2), 23.2 (CH2), 18.3 (C), 11.8 (CH3), −5.3 (CH3), −5.4 (CH3); LRMS (ESI-TOF) m/z: 365 [M+Na]+ (100); HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C18H34O4SiNa 365.2124; Found 365.2105; Anal. Calcd for C18H34O4Si: C, 63.11; H, 10.00. Found: C, 62.81; H, 9.91.

To a solution of allylic alcohol (20.0 g, 58.4 mmol) in CH3CN (150 mL) were added La(OTf)3 (855 mg, 1.46 mmol) and MPM-TCAI (24.0 mL, 115 mmol) at rt and stirred for 4 h. The mixture was concentrated under reduced pressure. After the residue was purified by column chromatography on silica gel (hexane : EtOAc = 4 : 1), the crude ether was used for the next reaction.

To a solution of the above ether in THF (120 mL) was added TBAF (87.6 mL, 87.6 mmol, 1.0 M in THF) at rt and stirred for 12 h. The mixture was quenched with saturated aqueous NH4Cl and diluted with Et2O. The organic layer was washed with water, saturated aqueous NaCl and dried over Na2SO4 and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane : EtOAc = 2:1) to afford alcohol 11 (16.5 g, 81% yield for 2 steps) as colorless oil. Rf 0.25 (hexane : EtOAc = 2:1); [α]D25 −12.9 (c 0.89, CHCl3); IR (neat) νmax = 3455, 2954, 1612, 1513 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.29–7.23 (2H, m), 6.90–6.85 (2H,


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m), 5.73 (1H, t, J = 6.2 Hz), 4.43 (2H, s), 4.21 (1H, d, J = 8.4 Hz), 4.06 (2H, d, J = 6.2 Hz), 3.85– 3.75 (5H, m), 3.60 (1H, m), 1.91–1.50 (12H, m); 13C NMR (100 MHz, CDCl3) δ 159.2 (C), 135.1 (C), 130.3 (C), 129.4 (CH)×2, 126.2 (CH), 119.2 (C), 113.8 (CH)×2, 81.7 (CH), 79.3 (CH), 71.9 (CH2), 65.9 (CH2), 61.8 (CH2), 55.3 (CH3), 37.5 (CH2), 37.2 (CH2), 23.4 (CH2), 23.3 (CH2), 11.9 (CH3); LRMS (ESI-TOF) m/z: 371 [M+Na]+ (100); HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C20H28O5Na 371.1834; Found 371.1820; Anal. Calcd for C20H28O5: C, 68.94; H, 8.10. Found: C, 68.71; H, 8.08.

(2R,3S)-2-(Iodomethyl)-3-((E)-4-((4-methoxybenzyl)oxy)but-2-en-2-yl)-1,4-dioxaspiro[4.4]nonane (12). To a solution of alcohol 11 (7.73 g, 22.2 mmol) in benzene (222 mL) were added imidazole (3.78 g, 55.5 mmol), triphenylphosphine (8.16 g, 31.1 mmol), and iodine (7.89 g, 31.1 mmol) at 0 ˚C. After being stirred at the same temperature for 15 min, the mixture was warmed to rt and stirred for 12 h. The mixture was quenched with saturated aqueous Na2S2O3 and diluted with Et2O. The organic layer was washed with water, saturated aqueous NaCl and dried over Na2SO4 and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane : EtOAc = 15 : 1) to afford iodide 12 (9.97 g, 98% yield) as colorless oil. Rf 0.51 (hexane : EtOAc = 15 : 1); [α]D25 −19.4 (c 0.71, CHCl3); IR (neat) νmax = 2956, 2871, 1612, 1513 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.30–7.23 (2H, m), 6.92–6.85 (2H, m), 5.76 (1H, m), 4.44 (2H, s), 4.09 (1H, d, J = 7.4 Hz), 4.06 (2H, d, J = 6.8 Hz), 3.80 (3H, s), 3.69 (1H, ddd, J = 4.7, 5.5, 7.4 Hz), 3.31 (1H, dd, J = 4.6, 10.7 Hz), 3.21 (1H, dd, J = 5.5, 10.7 Hz), 1.93–1.80 (4H, m), 1.76–1.62 (7H, m); 13C NMR (100 MHz, CDCl3) δ 159.2 (C), 134.6 (C), ACS Paragon Plus Environment

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130.2 (C), 129.4 (CH)×2, 127.2 (CH), 119.4 (C), 113.8 (CH)×2, 86.2 (CH), 77.4 (CH), 72.0 (CH2), 66.0 (CH2), 55.3 (CH3), 37.9 (CH2), 37.3 (CH2), 23.6 (CH2), 23.2 (CH2), 12.0 (CH3), 5.8 (CH2); LRMS (ESI-TOF) m/z: 481 [M+Na]+ (100); HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C20H27O4INa 481.0852; Found 481.0815; Anal. Calcd for C20H27O4I: C, 52.41; H, 5.94. Found: C, 52.48; H, 6.00.

(2S,3S)-2-((2-((3R)-4-(Benzyloxy)-3-((tetrahydro-2H-pyran-2-yl)oxy)butyl)-1,3-dithian-2yl)methyl)-3-((E)-4-((4-methoxybenzyl)oxy)but-2-en-2-yl)-1,4-dioxaspiro[4.4]nonane (13). To a solution of thioacetal 7 (28.6 g, 74.8 mmol) in THF (150 mL)/HMPA (15.2 mL) was slowly added t-BuLi (37.4 mL, 59.8 mmol, 1.60 M in pentane) at −78 ˚C under Ar. After being stirred at the same temperature for 40 min, the mixture was slowly added iodide 12 (13.7 g, 29.9 mmol) in THF (150 mL) and stirred for 30 min. The mixture was quenched with saturated aqueous NH4Cl and diluted with Et2O. The organic layer was washed with water, saturated aqueous NaCl and dried over Na2SO4 and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane : EtOAc = 6 : 1) to afford thioacetal 13 (18.7 g, 88% yield) as colorless oil. Rf 0.25 (hexane : EtOAc = 4 : 1); IR (neat) νmax = 2940, 2865, 1612, 1512 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.40–7.24 (7H, m), 6.91–6.86 (2H, m), 5.75 (1H, m), 4.89 (0.4H, t, J = 3.5 Hz), 4.73 (0.6H, t, J = 3.5 Hz), 4.63–4.50 (2H, m), 4.48–4.41 (2H, m), 4.12–3.84 (6H, m), 3.81 (3H, s), 3.64 (0.6H, dd, J = 5.6, 10.1 Hz), 3.56–3.42 (2.4H, m), 2.87–2.61 (4H, m), 2.25–1.44 (25H, m);

13

C NMR (100 MHz, CDCl3) δ 159.2 (C)×2, 138.6 (C), 138.4 (C), 134.84

(C), 134.83 (C), 130.4 (C), 130.3 (C), 129.3 (CH)×4, 128.3 (CH)×2, 128.2 (CH)×2, 127.6 (CH)×2, ACS Paragon Plus Environment

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127.5 (CH), 127.44 (CH)×2, 127.37 (CH)×3, 119.0 (C)×2, 113.7 (CH)×4, 97.6 (CH)×2, 86.41 (CH), 86.37 (CH), 75.5 (CH), 74.93 (CH), 74.91 (CH), 74.7 (CH), 73.20 (CH2), 73.16 (CH2), 72.8 (CH2), 72.6 (CH2), 71.80 (CH2), 71.77 (CH2), 66.0 (CH2)×2, 62.3 (CH2), 62.2 (CH2), 55.3 (CH3)×2, 52.5 (C), 52.3 (C), 40.2 (CH2), 40.2 (CH2), 37.4 (CH2)×2, 37.3 (CH2)×2, 34.4 (CH2), 34.0 (CH2), 31.0 (CH2)×2, 30.9 (CH2)×2, 27.3 (CH2), 26.0 (CH2)×2, 25.81 (CH2), 25.79 (CH2), 25.6 (CH2), 25.5 (CH2)×2, 25.2 (CH2)×2, 23.4 (CH2)×2, 19.54 (CH2), 19.48 (CH2), 11.7 (CH3)×2; LRMS (ESI-TOF) m/z: 735 [M+Na]+ (100); HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C40H56O7S2Na 735.3365; Found 735.3346; Anal. Calcd for C40H56O7S2: C, 67.38; H, 7.92. Found: C, 67.33; H, 8.01.

(2S,3S,7R)-7-((Benzyloxy)methyl)-2-((E)-4-((4-methoxybenzyl)oxy)but-2-en-2-yl)-1,6dioxaspiro[4.4]nonan-3-ol (14). To a solution of thioacetal 13 (193 mg, 271 µmol) in CH3CN (2.30 mL)/buffer (pH 8) (0.400 mL) was added PIFA (350 mg, 813 µmol) at 0 ˚C and stirred for 1 h. The mixture was quenched saturated aqueous NaHCO3 and diluted with Et2O. The organic layer was washed with water, saturated aqueous NaCl and dried over Na2SO4 and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane : EtOAc = 4 : 1) to afford ketone (135 mg, 80% yield) as colorless oil. Rf 0.43 (hexane : EtOAc = 2 : 1); IR (neat) νmax = 2938, 1716, 1613, 1513 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.37–7.22 (7H, m), 6.90–6.84 (2H, m), 5.66 (1H, m), 4.69 (0.6H, dd, J = 2.6, 4.9 Hz), 4.63 (0.4H, dd, J = 2.8, 4.3 Hz), 4.53 (0.8H, s), 4.51 (1.2H, s), 4.45–4.39 (2H, m), 4.21–4.10 (1H, m), 4.08–4.00 (2H, m), 3.96–3.76 (6H, m), 3.61 (0.4H, dd, J = 4.6, 9.8 Hz), 3.50–3.40 (2.6H, m), 2.74–2.45 (4H, m), ACS Paragon Plus Environment

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2.01–1.41 (19H, m); 13C NMR (100 MHz, CDCl3) δ 207.9 (C), 207.8 (C), 159.2 (C)×2, 138.3 (C), 138.2 (C), 134.5 (C), 134.4 (C), 130.23 (C), 130.20 (C), 129.3 (CH)×4, 128.30 (CH)×2, 128.26 (CH)×2, 127.6 (CH)×2, 127.52 (CH)×2, 127.47 (CH)×2, 127.1 (CH), 127.0 (CH), 119.0 (C), 118.9 (C), 113.8 (CH)×4, 98.8 (CH), 98.7 (CH), 86.03 (CH), 85.98 (CH), 75.2 (CH), 74.2 (CH)×2, 74.1 (CH), 73.2 (CH2)×2, 72.6 (CH2), 72.3 (CH2), 71.94 (CH2), 71.90 (CH2), 66.0 (CH2)×2, 63.5 (CH2), 62.6 (CH2), 55.2 (CH3)×2, 45.3 (CH2), 45.1 (CH2), 39.4 (CH2), 39.1 (CH2), 37.5 (CH2)×2, 37.2 (CH2)×2, 31.1 (CH2), 30.9 (CH2), 25.9 (CH2), 25.4 (CH2), 25.3 (CH2), 25.2 (CH2), 23.5 (CH2)×2, 23.3 (CH2)×2, 20.4 (CH2), 19.7 (CH2), 11.7 (CH3)×2; LRMS (ESI-TOF) m/z: 645 [M+Na]+ (100); HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C37H50O8Na 645.3403; Found 645.3384; Anal. Calcd for C37H50O8: C, 71.36; H, 8.09. Found: C, 71.11; H, 8.00.

To a solution of ketone (181 mg, 291 µmol) in MeOH (2.10 mL)/THF (0.700 mL) was added ptoluenesulfonic acid monohydrate (5.50 mg, 29.0 µmol) at rt and stirred for 5 h. The mixture was quenched with saturated aqueous NaHCO3 and diluted with Et2O. The organic layer was washed with water, saturated aqueous NaCl and dried over Na2SO4 and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane : EtOAc = 1 : 1) to afford spiroketal 14 (87.7 mg, 66% yield, dr 3 : 1) as colorless oil. Rf 0.34 (hexane : EtOAc = 1 : 1); IR (neat) νmax = 3455, 2856, 1612, 1513 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.36–7.23 (7H, m), 6.90–6.83 (2H, m), 5.90–5.81 (1H, m), 4.62–4.41 (5H, m), 4.38–4.24 (2H, m), 4.16–4.05 (2H, m), 3.80 (2.3H, s), 3.77 (0.7H, s), 3.65 (0.2H, dd, J = 6.8, 9.8 Hz), 3.57 (0.2H, dd, J = 4.8, 9.8 Hz), 3.46 (1.6H, d, J = 5.0 Hz), 2.52 (0.7H, dd, J = 5.8, 14.4 Hz), 2.23–1.62 (9.3H, m); 13C ACS Paragon Plus Environment

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NMR (100 MHz, CDCl3) δ 159.1 (C), 159.0 (C), 138.3 (C), 138.2 (C), 135.7 (C), 134.1 (C), 130.6 (C), 130.3 (C), 129.6 (CH)×2, 129.3 (CH)×2, 128.3 (CH)×4, 127.6 (CH)×2, 127.53 (CH)×2, 127.47 (CH)×2, 123.6 (CH), 122.0 (CH), 114.9 (C), 114.2 (C), 113.7 (CH)×2, 113.6 (CH)×2, 87.8 (CH), 84.4 (CH), 79.5 (CH), 77.1 (CH), 74.4 (CH2), 73.3 (CH2), 73.2 (CH2), 72.5 (CH), 72.4 (CH2), 72.0 (CH2), 71.5 (CH), 71.4 (CH2), 65.8 (CH2)×2, 55.2 (CH), 55.1 (CH), 45.0 (CH2), 43.6 (CH2), 36.0 (CH2), 35.5 (CH2), 27.4 (CH2), 27.0 (CH2), 14.4 (CH3), 14.2 (CH3); LRMS (ESITOF) m/z: 477 [M+Na]+ (100); HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C27H34O6Na 477.2253; Found 477.2268; Anal. Calcd for C27H34O6: C, 71.34; H, 7.54. Found: C, 71.43; H, 7.69.

(2S,3S,5R,7R)-7-((Benzyloxy)methyl)-2-((E)-4-hydroxybut-2-en-2-yl)-1,6dioxaspiro[4.4]nonan-3-yl pivalate (15a) and (2S,3S,5S,7R)-7-((benzyloxy)methyl)-2-((E)-4hydroxybut-2-en-2-yl)-1,6-dioxaspiro[4.4]nonan-3-yl pivalate (15b). To a solution of spiroketal 14 (4.12 g, 9.06 mmol) in Py (45.0 mL) was added PivCl (3.30 mL, 26.8 mmol) at 40 ˚C and stirred for 21 h. The mixture was added toluene and concentrated under reduced pressure. After the residue was purified by column chromatography on silica gel (hexane : EtOAc = 2 : 1), the crude ester was used for the next reaction.

To a solution of the above ester in CH3CN (82.0 mL)/H2O (8.00 mL) was added CAN (12.4 g, 22.6 mmol) at 0 ˚C and stirred for 1.5 h. The mixture was quenched with saturated aqueous NaHCO3 and diluted with Et2O. The suspension was filtered through celite. The organic layer was washed with water, saturated aqueous NaCl and dried over Na2SO4 and then concentrated under


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reduced pressure. The residue was purified by column chromatography on silica gel (hexane : EtOAc = 1 : 1) to afford spiroketal 15a (2.85 g, 75% yield for 2 steps) as colorless oil and spiroketal 15b (420 mg, 11% yield for 2 steps) as colorless oil. Spiroketal 15a: Rf 0.47 (hexane : EtOAc = 1 : 1); [α]D25 −17.4 (c 0.53, CHCl3); IR (neat) νmax = 3487, 2974, 1727 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.73–7.23 (5H, m), 5.76 (1H, m), 5.42 (1H, ddd, J = 2.9, 4.5, 6.4 Hz), 4.61– 4.51 (3H, m), 4.31 (1H, ddd, J = 5.0, 7.3, 10.3 Hz), 4.24–4.13 (2H, m), 3.46 (2H, d, J = 5.0 Hz), 2.62 (1H, dd, J = 6.4, 14.5 Hz), 2.25–2.14 (2H, m), 2.07 (1H, dd, J = 2.9, 14.5 Hz), 2.00 (1H, m), 1.81–1.69 (2H, m), 1.62 (3H, d, J = 0.6 Hz), 1.13 (9H, s); 13C NMR (100 MHz, CDCl3) δ 177.6 (C), 138.2 (C), 133.0 (C), 128.3 (CH)×2, 127.6 (CH)×2, 127.5 (CH), 125.6 (CH), 114.0 (C), 83.0 (CH), 77.4 (CH), 73.9 (CH), 73.3 (CH2), 72.4 (CH2), 59.0 (CH2), 42.7 (CH2), 38.7 (C), 35.7 (CH2), 27.0 (CH3)×3, 26.8 (CH2), 14.0 (CH3); LRMS (ESI-TOF) m/z: 441 [M+Na]+ (100); HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C24H34O6Na 441.2253; Found 441.2212; Anal. Calcd for C24H34O6: C, 68.88; H, 8.19. Found: C, 68.65; H, 8.12. Spiroketal 15b: Rf 0.32 (hexane : EtOAc = 1 : 1) [α]D25 +55.0 (c 0.47, CHCl3); IR (neat) νmax = 3449, 2971, 2928, 1724 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.40–7.22 (5H, m), 5.79 (1H, m), 5.27 (1H, ddd, J = 1.6, 4.6, 5.9 Hz), 4.64 (1H, d, J = 12.0 Hz), 4.57 (1H, d, J = 12.0 Hz), 4.40 (1H, d, J = 4.3 Hz), 4.27 (1H, m), 4.16 (2H, t, J = 7.0 Hz), 3.65 (1H, dd, J = 6.7, 10.1 Hz), 3.56 (1H, dd, J = 4.6, 10.1 Hz), 2.34 (1H, dd, J = 5.4, 14.4 Hz), 2.23 (1H, dd, J = 1.5, 14.4 Hz), 2.13–1.99 (2H, m), 1.96–1.79 (2H, m), 1.65 (3H, s), 1.14 (9H, s);

13

C NMR (100 MHz, CDCl3) δ 178.1 (C), 138.6 (C), 134.1 (C), 128.3 (CH)×2, 127.6

(CH)×2, 127.5 (CH), 125.8 (CH), 114.2 (C), 85.1 (CH), 79.5 (CH), 74.7 (CH2), 73.6 (CH), 73.3 ACS Paragon Plus Environment

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(CH2), 59.1 (CH2), 41.7 (CH2), 38.8 (C), 37.2 (CH2), 27.4 (CH2), 27.0 (CH3)×3, 14.1 (CH3); LRMS (ESI-TOF) m/z: 441 [M+Na]+ (100); HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C24H34O6Na 441.2253; Found 441.2212; Anal. Calcd for C24H34O6: C, 68.88; H, 8.19. Found: C, 68.92; H, 8.22.

(2S,3S,5R,7R)-7-((Benzyloxy)methyl)-2-((E)-4-hydroxybut-2-en-2-yl)-1,6dioxaspiro[4.4]nonan-3-ol (16). To a solution of spiroketal 15a (914 mg, 2.18 mmol) in Et2O (2.18 mL) was added MeLi (5.84 mL, 6.54 mmol, 1.16 M in Et2O) at 0 ˚C and stirred for 1 h under Ar. The mixture was quenched with saturated aqueous NH4Cl and diluted with Et2O. The organic layer was washed with water, saturated aqueous NaCl and dried over Na2SO4, and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane : acetone = 1 : 1) to afford diol 16 (730 mg, quant.) as colorless oil. Rf 0.42 (hexane : acetone = 1 : 1); [α]D25 +7.81 (c 0.91, MeOH); IR (neat) νmax = 3399, 2922, 1453 cm−1; 1

H NMR (400 MHz, CDCl3) δ 7.39–7.23 (5H, m), 5.81 (1H, m), 4.56 (1H, s), 4.55 (1H, s), 4.44

(1H, d, J = 3.6 Hz), 4.36 (1H, ddd, J = 2.0, 3.8, 5.8 Hz), 4.32–4.08 (3H, m), 3.45 (2H, d, J = 5.1 Hz), 2.66 (2H, brs), 2.51 (1H, dd, J = 5.8, 14.3 Hz), 2.21–2.20 (3H, m), 2.02 (1H, m), 1.72 (1H, m), 1.69 (3H, s);

13

C NMR (100 MHz, CDCl3) δ 138.2 (C), 134.1 (C), 128.3 (CH)×2, 127.6

(CH)×2, 127.5 (CH), 127.2 (CH), 114.2 (C), 84.3 (CH), 77.1 (CH), 73.2 (CH2), 72.4 (CH2), 71.7 (CH), 58.3 (CH2), 44.9 (CH2), 35.9 (CH2), 27.0 (CH2), 14.3 (CH3); LRMS (ESI-TOF) m/z: 357 [M+Na]+ (100); HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C19H26O5Na 357.1678; Found 357.1668; Anal. Calcd for C19H26O5: C, 68.24; H, 7.84. Found: C, 68.00; H, 7.95. ACS Paragon Plus Environment

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(((2R,3S)-3-((2R,3S,5R,7R)-3-(Benzyloxy)-7-((benzyloxy)methyl)-1,6-dioxaspiro[4.4]nonan-2yl)-3-methyloxiran-2-yl)methoxy)(tert-butyl)dimethylsilane (17). To a suspension of molecular sieves 4Å (430 mg) in CH2Cl2 (15.0 mL) was added D-(−)-diisopropyl tartrate (DIPT) (90.7 mg, 387 µmol), Ti(OiPr)4 (76.0 µL, 258 µmol) at −20 ˚C. After being stirred at the same temperature for 20 min, the mixture was added TBHP (645 µL, 3.87 mmol, 6.00 M in CH2Cl2). After being stirred at the same temperature for 20 min, the mixture was slowly added diol 16 (430 mg, 1.29 mmol) over 12 h. The mixture was added NaOH (450 µL, 30% in brine) and diluted with Et2O. After being stirred at rt for 30 min, the mixture was added MgSO4 (50 mg), celite (400 mg) and stirred for 30 min. The suspension was passed through a pad of celite and then concentrated under reduced pressure. The residue was purified with flash column chromatography on silica gel (hexane : acetone = 2 : 1) to afford α-epoxyalcohol (310 mg, 69% yield) as a colorless oil and βepoxyalcohol (38.9 mg, 9% yield) as a colorless oil. α-Epoxyalcohol: Rf 0.57 (hexane : acetone = 1 : 2); [α]D25 −20.7 (c 0.50, CHCl3); IR (neat) νmax = 3433, 2928, 2868, 1644, 1454 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.38–7.24 (5H, m), 4.57 (1H, s), 4.55 (1H, s), 4.46 (1H, m), 4.29 (1H, m), 4.08 (1H, d, J = 3.6 Hz), 3.81 (2H, t, J = 5.0 Hz), 3.51–3.40 (2H, m), 3.36 (1H, t, J = 5.7 Hz), 2.74 (1H, d, J = 3.4 Hz), 2.53 (1H, dd, J = 5.9, 14.4 Hz), 2.21–1.95 (5H, m), 1.70 (1H, m), 1.42 (3H, s); 13

C NMR (100 MHz, CDCl3) δ 138.2 (C), 128.3 (CH)×2, 127.58 (CH)×2, 127.55 (CH), 114.6 (C),

81.2 (CH), 77.2 (CH), 73.2 (CH2), 72.5 (CH), 72.3 (CH2), 60.5 (CH2), 60.5 (C), 59.1 (CH), 45.5 (CH2), 35.9 (CH2), 26.8 (CH2), 15.1 (CH3); LRMS (ESI-TOF) m/z: 373 [M+Na]+ (100); HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C19H26O6Na 373.1627; Found 373.1619; Anal. Calcd for ACS Paragon Plus Environment

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C19H26O6: C, 65.13; H, 7.48. Found: C, 64.95; H, 7.62. β-Epoxyalcohol: Rf 0.38 (hexane : acetone = 1 : 1); [α]D25 −35.1 (c 0.62, CHCl3); IR (neat) νmax = 3420, 2925, 1454 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.37–7.23 (5H, m), 4.63 (1H, m), 4.55 (1H, s), 4.54 (1H, s), 4.25 (1H, ddd, J = 5.1, 7.3, 10.8 Hz), 3.99 (1H, d, J = 4.7 Hz), 3.81 (1H, dd, J = 4.7, 12.0 Hz), 3.71 (1H, dd, J = 6.4, 12.0 Hz), 3.43 (2H, d, J = 5.1 Hz), 3.28 (1H, dd, J = 4.7, 6.4 Hz), 3.25 (1H, brs), 2.71 (1H, brs), 2.46 (1H, dd, J = 6.3, 14.0 Hz), 2.19–1.92 (4H, m), 1.69 (1H, m), 1.39 (3H, s);

13

C NMR (100

MHz, CDCl3) δ 138.2 (C), 128.3 (CH)×2, 127.60 (CH)×2, 127.57 (CH), 114.2 (C), 80.5 (CH), 77.3 (CH), 73.3 (CH2), 73.0 (CH), 72.4 (CH2), 60.63 (CH2), 60.57 (C), 57.9 (CH), 45.4 (CH2), 35.4 (CH2), 26.9 (CH2), 14.9 (CH3); LRMS (ESI-TOF) m/z: 373 [M+Na]+ (100); HRMS (ESITOF) m/z: [M+Na]+ Calcd for C19H26O6Na 373.1627; Found 373.1593; Anal. Calcd for C19H26O6: C, 65.13; H, 7.48. Found: C, 65.08; H, 7.65.

To a solution of α-epoxyalcohol (90.1 mg, 257 µmol) in CH2Cl2 (5.10 mL) was added imidazole (52.5 mg, 771 µmol), TBSCl (50.3 mg, 334 µmol) at rt and stirred for 15 min. The mixture was quenched with saturated aqueous NH4Cl and diluted with Et2O. The organic layer was washed with water, saturated aqueous NaCl and dried over Na2SO4 and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane : EtOAc = 1 : 1) to afford silyl ether (102 mg, 86% yield) as colorless oil. Rf 0.43 (hexane : EtOAc = 1 : 1); [α]D25 −17.4 (c 0.54, CHCl3); IR (neat) νmax = 3466, 2954, 2929, 2855, 1461 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.38–7.23 (5H, m), 4.57 (1H, s), 4.56 (1H, s), 4.42 (1H, ddd, J = 2.0, 3.4, 5.6 Hz), 4.29 (1H, m), 4.08 (1H, d, J = 3.4 Hz), 3.84 (1H, dd, J = 5.6, 11.3 Hz), 3.75 (1H, dd, J = 5.7, 11.3 ACS Paragon Plus Environment

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Hz), 3.45 (2H, d, J = 5.0 Hz), 3.29 (1H, t, J = 5.6 Hz), 2.85 (1H, d, J = 3.2 Hz), 2.47 (1H, dd, J = 5.6, 14.2 Hz), 2.21–1.98 (4H, m), 1.70 (1H, m), 1.40 (3H, s), 0.90 (9H, s), 0.09 (3H, s), 0.08 (3H, s);

13

C NMR (100 MHz, CDCl3) δ 138.3 (C), 128.3 (CH)×2, 127.6 (CH)×2, 127.5 (CH), 114.8

(C), 81.0 (CH), 77.2 (CH), 73.3 (CH2), 72.6 (CH), 72.5 (CH2), 61.6 (CH2), 60.3 (C), 59.7 (CH), 45.3 (CH2), 36.1 (CH2), 27.0 (CH2), 25.8 (CH3)×3, 18.3 (C), 15.2 (CH3), −5.3 (CH3), −5.5 (CH3); LRMS (ESI-TOF) m/z: 465 [M+H]+ (100); HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C25H41O6Si 465.2672; Found 465.2669; Anal. Calcd for C25H40O6Si: C, 64.62; H, 8.68. Found: C, 64.52; H, 8.57.

To a solution of silyl ether (296 mg, 638 µmol) in THF (3.20 mL) was added NaH (83.4 mg, 1.91 mmol, 55% in oil), BnBr (152 µL, 1.28 mmol), TBAI (23.6 mg, 63.8 µmol) at rt and stirred for 3 h. The mixture was quenched with saturated aqueous NH4Cl and diluted with Et2O. The organic layer was washed with water, saturated aqueous NaCl and dried over Na2SO4 and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane : EtOAc = 6 : 1) to afford benzyl ether 17 (297 mg, 84% yield) as colorless oil. Rf 0.67 (hexane : EtOAc = 3 : 1); [α]D25 −1.01 (c 0.53, CHCl3); IR (neat) νmax = 2954, 2928, 2884, 2856, 1496, 1455 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.40–7.22 (10H, m), 4.60–4.49 (3H, m), 4.42 (1H, d, J = 11.7 Hz), 4.34–4.23 (2H, m), 4.06 (1H, d, J = 5.0 Hz), 3.87 (1H, dd, J = 3.1, 11.9 Hz), 3.62 (1H, dd, J = 6.8, 11.9 Hz), 3.44 (1H, s), 3.43 (1H, d, J = 0.9 Hz), 3.32 (1H, dd, J = 3.1, 6.8 Hz), 2.42 (1H, dd, J = 6.2, 13.9 Hz), 2.23–2.09 (3H, m), 1.98 (1H, m), 1.69 (1H, m), 1.29 (3H, s), 0.89 (9H, s), 0.06 (3H, s), 0.05 (3H, s); 13C NMR (100 MHz, CDCl3) δ 138.4 (C), 138.1 (C), ACS Paragon Plus Environment

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128.3 (CH)×4, 127.6 (CH)×3, 127.5 (CH)×3, 114.7 (C), 81.9 (CH), 79.3 (CH), 77.3 (CH), 73.2 (CH2), 72.4 (CH2), 71.3 (CH2), 62.6 (CH2), 61.0 (C), 59.0 (CH), 41.9 (CH2), 35.5 (CH2), 26.7 (CH2), 25.9 (CH3)×3, 18.4 (C), 15.1 (CH3), −5.2 (CH3), −5.4 (CH3); LRMS (ESI-TOF) m/z: 577 [M+Na]+ (100); HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C32H46O6SiNa 577.2961; Found 577.2962; Anal. Calcd for C32H46O6Si: C, 69.28; H, 8.36. Found: C, 68.99; H, 8.23.

(S)-2-((2S,3S,5R,7R)-3-(Benzyloxy)-7-((benzyloxy)methyl)-1,6-dioxaspiro[4.4]nonan-2-yl)-3((tert-butyldimethylsilyl)oxy)-2-methylpropan-1-ol (18). To a solution of benzyl ether 17 (85.1 mg, 153 µmol) in CH2Cl2 (3.10 mL) was added iPrNEt2 (215 µL, 153 mmol), TBSOTf (62.0 µL, 230 µmol) at −78 ˚C and stirred for 5 h under Ar. The mixture was quenched with saturated aqueous NaHCO3 and diluted with Et2O. The organic layer was washed with water, saturated aqueous NaCl and dried over Na2SO4 and then concentrated under reduced pressure. After the residue was purified by column chromatography on silica gel (hexane : EtOAc = 8 : 1), the crude aldehyde was used for the next reaction.

To a solution of the above aldehyde in THF (2.30 mL)/MeOH (0.800 mL) was added NaBH4 (14.4 mg, 383 µmol) at 0 ˚C and stirred for 30 min. The mixture was quenched with saturated aqueous NH4Cl and diluted with Et2O. The organic layer was washed with water, saturated aqueous NaCl and dried over Na2SO4 and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane : EtOAc = 4 : 1) to afford alcohol 18 (8.10 mg, 9% yield for 2 steps) as colorless oil. Rf 0.32 (hexane : EtOAc = 4 : 1); [α]D25 +2.42 (c 0.15, CHCl3);


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IR (neat) νmax = 3511, 2928, 2856, 1456 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.42–7.22 (10H, m), 4.58 (1H, s), 4.57 (1H, s), 4.51 (1H, d, J = 11.5 Hz), 4.50 (1H, d, J = 11.5 Hz), 4.29–4.20 (2H, m), 4.10 (1H, d, J = 3.9 Hz), 3.76–3.59 (4H, m), 3.50–3.42 (2H, m), 2.41 (1H, dd, J = 5.6, 14.2 Hz), 2.22 (1H, dd, J = 1.6, 14.2 Hz), 2.17–2.07 (2H, m), 1.95 (1H, m), 1.72 (1H, m), 0.97 (3H, s), 0.88 (9H, s), 0.04 (3H, s), 0.02 (3H, s);

13

C NMR (100 MHz, CDCl3) δ 138.4 (C), 137.8 (C), 128.4

(CH)×2, 128.3 (CH)×2, 127.7 (CH)×3, 127.6 (CH)×2, 127.5 (CH), 113.6 (C), 82.3 (CH), 80.3 (CH), 76.7 (CH), 73.3 (CH2), 72.5 (CH2), 71.0 (CH2), 68.9 (CH2), 68.8 (CH2), 42.1 (C), 41.6 (CH2), 36.1 (CH2), 27.0 (CH2), 25.9 (CH3)×3, 18.2 (C), 17.1 (CH3), −5.65 (CH3), −5.68 (CH3); LRMS (ESI-TOF) m/z: 579 [M+Na]+ (100); HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C32H48O6SiNa 579.3118; Found 579.3104; Anal. Calcd for C32H48O6Si: C, 69.03; H, 8.69. Found: C, 68.86; H, 8.85.

(((2S,3R)-3-((2R,3S,5R,7R)-3-(Benzyloxy)-7-((benzyloxy)methyl)-1,6-dioxaspiro[4.4]nonan-2yl)-3-methyloxiran-2-yl)methoxy)(tert-butyl)dimethylsilane (19). To a suspension of molecular sieves 4Å (2.40 g) in CH2Cl2 (40 mL) was added L-(+)-DIPT (253 mg, 1.08 mmol), Ti(OiPr)4 (212 µL, 718 µmol) at −20 ˚C. After being stirred at the same temperature for 20 min, the mixture was added TBHP (2.73 mL, 21.5 mmol, 7.89 M in CH2Cl2). After being stirred at the same temperature for 20 min, the mixture was slowly added the diol 16 (2.40 g, 7.18 mmol) over 5 h. The mixture was added NaOH (550 µL, 30% in brine) and diluted with Et2O. After being stirred at rt for 30 min, the mixture was added MgSO4 (60 mg), celite (490 mg) and stirred for 30 min. The mixture was passed through a pad of celite and then concentrated under reduced pressure. The ACS Paragon Plus Environment

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residue was purified with flash column chromatography on silica gel (hexane : acetone = 1 : 1) to afford α-epoxyalcohol 87.5 mg, 3% yield) as a colorless oil and β-epoxyalcohol (2.17 g, 86% yield) as a colorless oil.

To a solution of the β-epoxyalcohol (2.54 g, 7.25 mmol) in CH2Cl2 (73.0 mL) was added imidazole (1.47 g, 21.6 mmol), TBSCl (2.19 g, 14.5 mmol) at rt and stirred for 15 min. The mixture was quenched with saturated aqueous NH4Cl and diluted with Et2O. The organic layer was washed with water, saturated aqueous NaCl and dried over Na2SO4 and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane : EtOAc = 1 : 1) to afford silyl ether (3.29 g, 98% yield) as colorless oil. Rf 0.76 (hexane : EtOAc = 1 : 1); [α]D25 −32.0 (c 0.87, CHCl3); IR (neat) νmax = 3466, 2953, 2929, 2856, 1460 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.36–7.22 (5H, m), 4.67–4.48 (3H, m), 4.26 (1H, ddd, J = 5.1, 7.2, 11.0 Hz), 4.02 (1H, d, J = 4.4 Hz), 3.77 (2H, d, J = 5.5 Hz), 3.44 (2H, d, J = 5.1 Hz), 3.25 (1H, t, J = 5.5 Hz), 2.89 (1H, d, J = 6.5 Hz), 2.46 (1H, dd, J = 6.2, 14.0 Hz), 2.18–1.93 (4H, m), 1.69 (1H, m), 1.38 (3H, s), 0.91 (9H, s), 0.10 (3H, s), 0.09 (3H, s); 13C NMR (100 MHz, CDCl3) δ 138.2 (C), 128.3 (CH)×2, 127.6 (CH)×2, 127.5 (CH), 114.3 (C), 80.5 (CH), 77.2 (CH), 73.26 (CH2), 73.25 (CH), 72.4 (CH2), 61.7 (CH2), 59.9 (C), 57.9 (CH), 45.3 (CH2), 35.4 (CH2), 26.9 (CH2), 25.9 (CH3)×3, 18.3 (C), 15.0 (CH3), −5.3 (CH3), −5.4 (CH3); LRMS (ESI-TOF) m/z: 487 [M+Na]+ (100); HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C25H40O6SiNa 487.2492; Found 487.2489; Anal. Calcd for C25H40O6Si: C, 64.62; H, 8.68. Found: C, 64.67; H, 8.65.


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To a solution of silyl ether (5.18 g, 11.2 mmol) in THF (110 mL) was added NaH (1.71 g, 39.2 mmol, 55% in oil), BnBr (2.70 mL, 22.7 mmol), TBAI (2.10 g, 5.69 mmol) at rt and stirred for 16 h. The mixture was quenched with saturated aqueous NH4Cl and diluted with Et2O. The organic layer was washed with water, saturated aqueous NaCl and dried over Na2SO4 and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane : EtOAc = 10 : 1) to afford benzyl ether 19 (5.94 g, 96% yield) as colorless oil. Rf 0.57 (hexane : EtOAc = 4 : 1); [α]D25 −13.2 (c 0.28, CHCl3); IR (neat) νmax = 2928, 2856, 1455 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.37–7.22 (10H, m), 4.60–4.50 (3H, m), 4.47 (1H, d, J = 12.0 Hz), 4.41 (1H, m), 4.30 (1H, ddd, J = 5.3, 7.6, 11.0 Hz), 3.85 (1H, dd, J = 4.0, 11.7 Hz), 3.80 (1H, d, J = 6.7 Hz), 3.71 (1H, dd, J = 6.1, 13.2 Hz), 3.44 (2H, d, J = 5.0 Hz), 3.00 (1H, dd, J = 4.0, 6.1 Hz), 2.38 (1H, dd, J = 6.9, 13.2 Hz), 2.23–2.13 (2H, m), 2.07 (1H, dd, J = 6.3, 13.2 Hz), 2.00 (1H, m), 1.71 (1H, m), 1.35 (3H, s), 0.90 (9H, s), 0.07 (3H, s), 0.06 (3H, s);

13

C NMR (100 MHz,

CDCl3) δ 138.3 (C), 138.1 (C), 128.32 (CH)×2, 128.30 (CH)×2, 127.57 (CH)×2, 127.55 (CH), 127.5 (CH), 127.3 (CH)×2, 114.1 (C), 84.2 (CH), 79.2 (CH), 77.2 (CH), 73.2 (CH2), 72.4 (CH2), 71.9 (CH2), 62.2 (CH2), 59.8 (CH), 59.7 (C), 41.3 (CH2), 34.5 (CH2), 26.5 (CH2), 25.9 (CH3)×3, 18.3 (C), 13.9 (CH3), −5.2 (CH3), −5.4 (CH3); LRMS (ESI-TOF) m/z: 577 [M+Na]+ (100); HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C32H46O6SiNa 577.2961; Found 577.2983; Anal. Calcd for C32H46O6Si: C, 69.28; H, 8.36. Found: C, 69.15; H, 8.35.

(S)-2-((2S,3S,5R,7R)-3-(Benzyloxy)-7-((benzyloxy)methyl)-1,6-dioxaspiro[4.4]nonan-2-yl)-3((tert-butyldimethylsilyl)oxy)-2-methylpropan-1-ol (18). To a solution of benzyl ether 19 (5.75 ACS Paragon Plus Environment

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g, 10.4 mmol) in CH2Cl2 (210 mL) was added N,N-diisopropylethylamine (14.6 mL, 104 mmol), TBSOTf (4.20 mL, 15.6 mmol) at −78 ˚C and stirred for 6 h under Ar. The mixture was quenched with saturated aqueous NaHCO3 and diluted with Et2O. The organic layer was washed with water, saturated aqueous NaCl and dried over Na2SO4 and then concentrated under reduced pressure. After the residue was purified by column chromatography on silica gel (hexane:EtOAc = 8:1), the crude aldehyde was used for the next reaction.

To a solution of the above aldehyde in THF (79.0 mL)/MeOH (26.0 mL) was added NaBH4 (984 mg, 26.0 mmol) at 0 ˚C and stirred for 15 min. The mixture was quenched with saturated aqueous NH4Cl and diluted with Et2O. The organic layer was washed with water, saturated aqueous NaCl and dried over Na2SO4 and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane : EtOAc = 4 : 1) to afford alcohol 18 (3.14 g, 54% yield for 2 steps) as colorless oil.

((2R,3a'S,5R,6'S,6a'S)-6'-(((tert-Butyldimethylsilyl)oxy)methyl)-6'-methylhexahydro-3H,3'Hspiro[furan-2,2'-furo[3,2-b]furan]-5-yl)methanol (20). To a solution of alcohol 18 (1.34 g, 2.41 mmol) in CH2Cl2 (48.2 mL) was added MsCl (467 µL, 6.03 mmol), Et3N (1.00 mL, 7.23 mmol) at rt and stirred for 15 min. The mixture was quenched with saturated aqueous NH4Cl and diluted with Et2O. The organic layer was washed with water, saturated aqueous NaCl and dried over Na2SO4 and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane : EtOAc = 5 : 1) to afford mesylate (1.50 g, 98% yield) as


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colorless oil. Rf 0.33 (hexane : EtOAc = 4 : 1); [α]D25 +1.66 (c 0.71, CHCl3); IR (neat) νmax = 2952, 2927, 2856, 1496, 1359 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.41–7.23 (10H, m), 4.61 (1H, s), 4.58 (1H, s), 4.49 (1H, d, J = 11.4 Hz), 4.39 (1H, d, J = 9.0 Hz), 4.34–4.27 (2H, m), 4.26–4.20 (2H, m), 3.97 (1H, d, J = 4.2 Hz), 3.67 (1H, d, J = 9.8 Hz), 3.56 (1H, d, J = 9.7 Hz), 3.46 (2H, d, J = 5.0 Hz), 2.87 (3H, s), 2.40 (1H, dd, J = 5.7, 14.2 Hz), 2.19 (1H, dd, J = 2.0, 14.2 Hz), 2.16–2.06 (2H, m), 1.96 (1H, m), 1.72 (1H, m), 1.09 (3H, s), 0.87 (9H, s), 0.02 (3H, s), 0.00 (3H, s);

13

C

NMR (100 MHz, CDCl3) δ 138.3 (C), 137.8 (C), 128.4 (CH)×2, 128.3 (CH)×2, 127.73 (CH)×2, 127.68 (CH), 127.6 (CH)×2, 127.5 (CH), 113.6 (C), 80.5 (CH), 80.2 (CH), 77.0 (CH), 73.3 (CH2), 72.5 (CH2), 72.3 (CH2), 71.1 (CH2), 65.2 (CH2), 42.0 (C), 41.7 (CH2), 36.5 (CH2), 35.8 (CH2), 27.0 (CH2), 25.9 (CH3)×3, 18.2 (C), 15.8 (CH3), −5.57 (CH3), −5.59 (CH3); LRMS (ESI-TOF) m/z: 657 [M+Na]+ (100); HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C33H50O8SiSNa 657.2893; Found 657.2885; Anal. Calcd for C33H50O8SiS: C, 62.43; H, 7.94. Found: C, 62.42; H, 7.95.

To a solution of mesylate (1.18 g, 1.86 mmol) in liq. NH3 (30.0 mL)/THF (18.6 mL) was added Na (200 mg, 8.68 mmol) at −78 ˚C and stirred for 10 min. The mixture was quenched with NH4Cl and diluted with Et2O. The organic layer was washed with water, saturated aqueous NaCl and dried over Na2SO4 and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane : EtOAc = 2 : 1) to afford alcohol 20 (570 mg, 85% yield) as colorless oil. Rf 0.39 (hexane : EtOAc = 1 : 1); [α]D25 −74.9 (c 1.08, CHCl3); IR (neat) νmax = 3450, 2954, 2932, 2893, 2857 cm−1; 1H NMR (400 MHz, C6D6) δ 4.87 (1H, ddd, J = 3.9, 5.0, 7.6 Hz), 4.31 (1H, d, J = 5.0 Hz), 4.06 (1H, m), 3.79 (1H, d, J = 8.5 Hz), 3.53 (1H, d, J = 8.4 Hz), 3.41 ACS Paragon Plus Environment

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(1H, m), 3.36 (1H, s), 3.34 (1H, s), 3.23 (1H, m), 2.27 (1H, dd, J = 7.6, 13.9 Hz), 2.06–1.92 (2H, m), 1.83 (1H, ddd, J = 8.0, 12.0, 16.6 Hz), 1.68 (1H, m), 1.44 (1H, m), 1.33 (1H, t, J = 5.7 Hz), 1.20 (3H, s), 0.94 (9H, s), 0.02 (3H, s), 0.02 (3H, s); 13C NMR (100 MHz, C6D6) δ 117.0 (C), 85.9 (CH), 83.6 (CH), 79.5 (CH), 73.7 (CH2), 67.5 (CH2), 65.2 (CH2), 49.6 (C), 43.3 (CH2), 34.9 (CH2), 26.6 (CH2), 26.5 (CH3)×3, 18.9 (C), 14.8 (CH3), −5.1 (CH3)×2; LRMS (ESI-TOF) m/z: 359 [M+H]+ (100); HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C18H35O5Si 359.2254; Found 359.2223; Anal. Calcd for C18H34O5Si: C, 60.30; H, 9.56. Found: C, 60.35; H, 9.69.

(2R,3a'S,5R,6'S,6a'S)-6'-(((tert-Butyldimethylsilyl)oxy)methyl)-5-(hydroxymethyl)-6'methylhexahydro-3H,5'H-spiro[furan-2,2'-furo[3,2-b]furan]-5'-one (21). To a solution of alcohol 20 (1.33 g, 3.71 mmol) in Py (18.6 mL) was added Ac2O (18.6 mL), DMAP (90.7 mg, 742 µmol) at rt and stirred for 15 min. The mixture was added toluene and concentrated under reduced pressure. After the residue was purified by column chromatography on silica gel (hexane : EtOAc = 4 : 1), the crude ester was used for the next reaction.

To a solution of the above ester in CCl4 (43.0 mL)/H2O (21.0 mL)/CH3CN (10.5 mL) was added NaHCO3 (3.12 g, 37.1 mmol), NaIO4 (3.17 g, 14.8 mmol), RuCl3·nH2O (306 mg, 1.48 mmol) at rt and stirred for 1 day. The mixture was filtered through silica gel pad. The filtrate was diluted with EtOAc. The organic layer was washed with saturated aqueous Na2S2O3, water, saturated aqueous NaCl and dried over Na2SO4 and then concentrated under reduced pressure. After the residue was


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purified by column chromatography on silica gel (hexane : EtOAc = 5 : 1), the crude γ-lactone was used for the next reaction.

To a solution of the above γ-lactone in MeOH (37.0 mL) was added K2CO3 (2.04 g, 14.8 mmol) at rt and stirred for 1 h. The suspension was filtered through silica gel pad and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane : EtOAc = 1 : 1) to afford alcohol 21 (891 mg, 64% yield for 3 steps) as colorless oil. Rf 0.38 (hexane : EtOAc = 1 : 1); [α]D25 −76.3 (c 0.66, CHCl3); IR (neat) νmax = 3484, 2950, 2931, 2857, 1776 cm−1; 1H NMR (400 MHz, CDCl3) δ 5.05 (1H, ddd, J = 2.2, 4.5, 6.9 Hz), 4.59 (1H, d, J = 4.5 Hz), 4.22 (1H, m), 3.74 (1H, d, J = 9.5 Hz), 3.70 (1H, dd, J = 3.2, 11.6 Hz), 3.62 (1H, d, J = 9.5 Hz), 3.52 (1H, dd, J = 5.8, 11.6 Hz), 2.56 (1H, dd, J = 7.0, 14.9 Hz), 2.31 (1H, dd, J = 2.2, 14.9 Hz), 2.18–1.97 (3H, m), 1.78–1.57 (2H, m), 1.13 (3H, s), 0.87 (9H, s), 0.04 (6H, s);

13

C NMR

(100 MHz, CDCl3) δ 180.3 (C), 115.4 (C), 83.7 (CH), 81.9 (CH), 78.9 (CH), 69.2 (CH2), 64.9 (CH2), 51.1 (C), 41.9 (CH2), 35.1 (CH2), 25.9 (CH2), 25.8 (CH3)×3, 18.1 (C), 13.5 (CH3), −5.7 (CH3), −5.8 (CH3); LRMS (ESI-TOF) m/z: 373 [M+H]+ (100); HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C18H33O6Si 373.2046; Found 373.2044; Anal. Calcd for C18H32O6Si: C, 58.03; H, 8.66. Found: C, 57.91; H, 8.77.

(2R,3a'S,5R,6'S,6a'S)-6'-(((tert-Butyldimethylsilyl)oxy)methyl)-5-ethynyl-6'methylhexahydro-3H,5'H-spiro[furan-2,2'-furo[3,2-b]furan]-5'-one (22). To a solution of alcohol 21 (172 mg, 461 µmol) in CH2Cl2 (9.20 mL) was added NaHCO3 (387 mg, 4.61 mmol),


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Dess-Martin periodinane (391 mg, 922 µmol) at 0 ˚C and stirred for 4 h. The mixture was quenched with saturated aqueous NaHCO3/Na2S2O3 (1 : 1) and diluted with Et2O. The organic layer was washed with water, saturated aqueous NaCl and dried over Na2SO4 and then concentrated under reduced pressure. After the residue was purified by column chromatography on silica gel (hexane : EtOAc = 1 : 1), the crude aldehyde was used for the next reaction.

To a solution of the above aldehyde in MeOH (9.20 mL) was added diethyl (1-diazo-2oxopropyl)phosphonate (152 mg, 692 µmol), K2CO3 (190 mg, 1.38 mmol) at rt and stirred for 13 h. The mixture was quenched with saturated aqueous NH4Cl and diluted with Et2O. The organic layer was washed with water, saturated aqueous NaCl and dried over Na2SO4 and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane : EtOAc = 10 : 1) to afford alkyne 22 (119 mg, 70% yield for 2 steps) as colorless oil. Rf 0.54 (hexane : EtOAc = 4 : 1); [α]D25 −63.5 (c 0.74, CHCl3); IR (neat) νmax = 2954, 2933, 2858, 1777 cm−1; 1H NMR (400 MHz, CDCl3) δ 5.06 (1H, ddd, J = 2.4, 4.5, 7.0 Hz), 4.71 (1H, ddd, J = 2.1, 5.8, 7.8 Hz), 4.59 (1H, d, J = 4.5 Hz), 3.74 (1H, d, J = 9.4 Hz), 3.61 (1H, d, J = 9.5 Hz), 2.66 (1H, dd, J = 7.1, 15.0 Hz), 2.49 (1H, d, J = 2.1 Hz), 2.44–2.30 (2H, m), 2.26–2.10 (2H, m) 2.04 (1H, m), 1.12 (3H, s), 0.86 (9H, s), 0.03 (6H, s);

13

C NMR (100 MHz, CDCl3) δ

180.2 (C), 115.2 (C), 83.8 (CH), 82.8 (C), 81.7 (CH), 73.4 (CH), 69.1 (CH2), 67.4 (CH), 51.0 (C), 42.2 (CH2), 34.6 (CH2), 32.0 (CH2), 25.7 (CH3)×3, 18.1 (C), 13.4 (CH3), −5.7 (CH3), −5.8 (CH3); LRMS (ESI-TOF) m/z: 389 [M+Na]+ (100); HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for


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C19H30O5SiNa 389.1760; Found: 389.1761; Anal. Calcd for C19H30O5Si: C, 62.26; H, 8.25. Found: C, 62.12; H, 8.20.

(2R,3a'S,5R,6'S,6a'S)-6'-(((tert-Butyldimethylsilyl)oxy)methyl)-5-((E)-2-iodovinyl)-6'methylhexahydro-3H,5'H-spiro[furan-2,2'-furo[3,2-b]furan]-5'-one (23). To a solution of alkyne 22 (151 mg, 412 µmol) in THF (10.0 mL) was added Cp2ZrHCl (212 mg, 824 µmol) at 0 ˚C and stirred for 30 min under Ar. After being cooled to −78 ˚C, the mixture was added a solution of iodine (157 mg, 618 µmol) in THF (10.0 mL) and stirred for 30 min. The mixture was quenched with saturated aqueous Na2S2O3 and diluted with Et2O. The organic layer was washed with water, saturated aqueous NaCl and dried over Na2SO4 and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane : EtOAc = 12 : 1) to afford (E)-iodoalkene 23 (129 mg, 63% yield) as colorless oil. Rf 0.55 (hexane : EtOAc = 4 : 1); [α]D25 −27.7 (c 0.42, CHCl3); IR (neat) νmax = 2954, 2931, 2858, 1776, 1463 cm−1; 1H NMR (400 MHz, CDCl3) δ 6.53 (1H, dd, J = 6.6, 14.4 Hz), 6.37 (1H, dd, J = 1.0, 14.4 Hz), 5.05 (1H, ddd, J = 2.2, 4.5, 6.8 Hz), 4.58 (1H, d, J = 4.5 Hz), 4.50 (1H, m), 3.74 (1H, d, J = 9.5 Hz), 3.62 (1H, d, J = 9.5 Hz), 2.58 (1H, dd, J = 7.0, 15.0 Hz), 2.37–2.20 (3H, m), 2.09 (1H, m), 1.71 (1H, m), 1.12 (3H, s), 0.86 (9H, s), 0.03 (6H, s); 13C NMR (100 MHz, CDCl3) δ 180.2 (C), 145.6 (C), 115.1 (C), 83.8 (CH), 81.8 (CH), 80.4 (CH), 78.1 (CH), 69.1 (CH2), 51.1 (C), 42.1 (CH2), 34.5 (CH2), 30.1 (CH2), 25.8 (CH3)×3, 18.1 (C), 13.5 (CH3), −5.7 (CH3), −5.8 (CH3); LRMS (ESITOF) m/z: 517 [M+Na]+ (100); HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C19H31O5SiINa


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517.0883; Found 517.0884; Anal. Calcd for C19H31O5SiI: C, 46.15; H, 6.32. Found: C, 46.39; H, 6.58.

(R)-Pent-4-yn-2-yl (2S,3R)-3-((tert-butyldimethylsilyl)oxy)-2-methylbutanoate (26). To a solution of the carboxylic acid 25 (59.4 mg, 256 µmol) in CH2Cl2 (2.70 mL) was added Et3N (107 µL, 824 µmol), DMAP (6.30 mg, 51.2 µmol), 2-methyl-6-nitrobenzoic anhydride (171 mg, 512 µmol) at rt under Ar. After being stirred at the same temperature for 30 min, the mixture was added a solution of alcohol 24 (32.3 mg, 384 µmol) in CH2Cl2 (2.50 mL) and stirred for 3 h. The mixture was quenched with saturated aqueous NH4Cl and diluted with Et2O. The organic layer was washed with water, saturated aqueous NaCl and dried over Na2SO4 and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane : EtOAc = 20 : 1) to afford alkyne 26 (68.6 mg, 90% yield) as colorless oil. Rf 0.70 (hexane : EtOAc = 4 : 1); [α]D25 +11.6 (c 0.47, CHCl3); IR (neat) νmax = 2959, 2933, 2888, 2857, 1733 cm−1; 1

H NMR (400 MHz, CDCl3) δ 4.99 (1H, m), 4.01 (1H, quintet, J = 6.2 Hz), 2.48–2.35 (3H, m),

1.99 (1H, t, J = 2.6 Hz), 1.33 (3H, d, J = 6.2 Hz), 1.15 (3H, d, J = 6.2 Hz), 1.15 (3H, d, J = 6.7 Hz), 0.87 (9H, s), 0.05 (3H, s), 0.04 (3H, s); 13C NMR (100 MHz, CDCl3) δ 174.4 (C), 79.8 (C), 70.4 (CH), 69.7 (CH), 68.2 (CH), 47.9 (CH), 25.8 (CH3)×3, 25.5 (CH2), 22.0 (CH3), 19.1 (CH3), 18.0 (C), 12.9 (CH3), −4.3 (CH3), −4.9 (CH3); LRMS (ESI-TOF) m/z: 321 [M+Na]+ (100); HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C16H30O3SiNa 321.1862; Found 321.1861; Anal. Calcd for C16H30O3Si: C, 64.38; H, 10.03. Found: C, 64.49; H, 10.07.


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Ent-Ascospiroketal B (ent-4). To a solution of (E)-iodoalkene 23 (15.2 mg, 30.7 µmol) and alkyne 26 (13.8 mg, 46.1 µmol) in Et3N (2.70 mL) was added Pd(PPh3)4 (1.80 mg, 1.56 µmol), CuI (0.500 mg, 2.63 µmol) at rt and stirred for 30 min under Ar. The mixture was quenched with saturated aqueous NH4Cl and diluted with Et2O. The organic layer was washed with water, saturated aqueous NaCl and dried over Na2SO4 and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane : EtOAc = 10 : 1) to afford alkyne as yellow oil.

To a solution of alkyne in MeOH (1.70 mL) was added quinoline (6.00 µL), Lindlar cat (5.10 mg) at 0 ˚C and stirred for 3 h under H2. The suspension was filtered through silica gel pad and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane : EtOAc = 10 : 1) to afford diene (9.60 mg, 47% yield for 2 steps) as colorless oil. Rf 0.55 (hexane : EtOAc = 4 : 1); [α]D25 −56.0 (c 0.18, CHCl3); IR (neat) νmax = 2954, 2931, 2884, 2857, 1778, 1729, 1462 cm−1; 1H NMR (400 MHz, CDCl3) δ 6.48 (1H, ddt, J = 1.0, 11.2, 15.0 Hz), 6.07 (1H, dd, J = 10.8, 11.2 Hz), 5.65 (1H, dd, J = 7.3, 15.0 Hz), 5.42 (1H, dt, J = 7.6, 10.8 Hz), 5.06 (1H, ddd, J = 2.2, 4.4, 6.9 Hz), 4.93 (1H, sextet, J = 6.2 Hz), 4.60 (1H, d, J = 4.4 Hz), 4.58 (1H, q, J = 6.9 Hz), 3.99 (1H, quintet, J = 6.2 Hz), 3.75 (1H, d, J = 9.5 Hz), 3.62 (1H, d, J = 9.5 Hz), 2.60 (1H, dd, J = 7.0, 14.9 Hz), 2.48 (1H, m), 2.41–2.15 (4H, m), 2.14–2.05 (2H, m), 1.69 (1H, m), 1.22 (3H, d, J = 6.4 Hz), 1.15–1.11 (9H, m), 0.87 (9H, s), 0.86 (9H, s), 0.05 (3H, s), 0.04 (3H, s), 0.03 (6H, s); 13C NMR (100 MHz, CDCl3) δ 180.3 (C), 174.6 (C), 133.6 (CH), 130.1 (CH), 127.3 (CH), 126.8 (CH), 115.1 (C), 83.7 (CH), 82.0 (CH), 79.2 (CH), 70.1 (CH), 69.7 (CH), ACS Paragon Plus Environment

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69.2 (CH2), 51.1 (C), 48.1 (CH), 42.3 (CH2), 35.1 (CH2), 34.0 (CH2), 31.1 (CH2), 25.8 (CH3)×3, 25.7 (CH3)×3, 22.0 (CH3), 19.5 (CH3), 18.1 (C), 18.0 (C), 13.5 (CH3), 13.1 (CH3), −4.3 (CH3), −4.9 (CH3), −5.7 (CH3), −5.8 (CH3); LRMS (ESI-TOF) m/z: 689 [M+Na]+ (100); HRMS (ESITOF) m/z: [M+Na]+ Calcd for C35H62O8Si2Na 689.3881; Found 689.3879; Anal. Calcd for C35H62O8Si2: C, 63.02; H, 9.37. Found: C, 63.17; H, 9.36.

To a solution of diene (9.60 mg, 14.5 µmol) in THF (1.45 mL) was added TBAF (58.0 µL, 58.0 µmol, 1.0 M in THF) at rt and stirred for 3 h. The mixture was quenched with saturated aqueous NH4Cl and diluted with EtOAc. The organic layer was washed with water, saturated aqueous NaCl and dried over Na2SO4 and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane : EtOAc = 1 : 1) to afford ent-4 (6.40 mg, quant.) as colorless oil. Rf 0.50 (hexane : EtOAc = 1 : 2); [α]D23 −9.33 (c 0.24, MeOH); IR (neat) νmax = 3458, 2976, 2927, 2854, 1771, 1725, 1457 cm−1; 1H NMR (400 MHz, (CD3)2CO) δ 6.58 (1H, ddt, J = 1.0, 11.2, 15.1 Hz), 6.10 (1H, dd, J = 10.8, 11.2 Hz), 5.71 (1H, dd, J = 6.9, 15.1 Hz), 5.45 (1H, dt, J = 7.8, 10.8 Hz), 5.10 (1H, ddd, J = 2.1, 4.4, 6.7 Hz), 4.91 (1H, sextet, J = 6.3 Hz), 4.58 (1H, d, J = 4.4 Hz), 4.53 (1H, q, J = 6.8 Hz), 4.39 (1H. t, J = 5.1 Hz), 3.87 (1H, quintet, J = 6.2 Hz), 3.70–3.59 (3H, m), 2.55 (1H, dd, J = 6.9, 14.9 Hz), 2.49 (1H, m), 2.31 (1H, m), 2.24 (1H, dd, J = 2.1, 14.9 Hz), 2.21–2.05 (3H, m), 1.67 (1H, m), 1.22 (3H, d, J = 6.3 Hz), 1.14 (3H, d, J = 7.0 Hz), 1.13 (3H, d, J = 6.2 Hz), 1.09 (3H, s); 13C NMR (100 MHz, (CD3)2CO) δ 180.1 (C), 175.0 (C), 135.4 (CH), 131.2 (CH), 127.6 (CH), 126.7 (CH), 116.0 (C), 84.1 (CH), 82.2 (CH), 79.6 (CH), 70.6 (CH), 68.9 (CH2), 68.0 (CH2), 51.6 (C), 48.1 (CH), 42.9 (CH2), 35.6 (CH2), 34.5 ACS Paragon Plus Environment

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(CH2), 31.8 (CH2), 21.7 (CH3), 19.8 (CH3), 14.0 (CH3), 12.9 (CH3); LRMS (ESI-TOF) m/z: 461 [M+Na]+ (100); HRMS (ESI-TOF), m/z: [M+Na]+ Calcd for C23H34O8Na 461.2151; Found 461.2149.

ASSOCIATED CONTENT Supporting Information Supporting Information is available free of charge on the ACS Publications website at DOI: 1

H and 13C NMR spectra of compounds 6, 7, 9−23, 26, and ent-ascospiroketal B (ent-4) (PDF)

AUTHOR INFORMATION Corresponding Author *E-mail: [email protected]. Tel: +81-42-676-3080. Fax: +81-42-676-3073. (H. Miyaoka). ORCID Koichiro Ota: 0000-0001-5618-9373 Hiroaki Miyaoka: 0000-0003-2486-0403 Notes The authors declare no competing financial interest.

ACKNOWLEDGEMENT We would like to thank Mr. Yasushi Yoshida, Mr. Ryou Osada, Mr. Yutaka Shimizu, and Mr. ACS Paragon Plus Environment

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Atsushi Kimura for their technical support. This work was supported by JSPS KAKENHI Grant Number 23590016.

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Total Synthesis of ent-Ascospiroketal B - The Journal of Organic

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