Total Synthesis of Sekothrixide Strategically Utilizing Regioselective

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Total Synthesis of Sekothrixide Strategically Utilizing Regioselective Coupling of TMS-Protected Epoxy sec-Alcohol with Gilman Reagent Daisuke Katsumi, Kazuki Nakasone, Naoki Terayama, Eiko Yasui, Megumi Mizukami, Masaaki Miyashita, and Shinji Nagumo J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b03006 • Publication Date (Web): 04 Jan 2019 Downloaded from http://pubs.acs.org on January 7, 2019

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is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

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The Journal of Organic Chemistry

Total Synthesis of Sekothrixide Strategically Utilizing Regioselective Coupling of TMS-Protected Epoxy sec-Alcohol with Gilman Reagent Daisuke Katsumi,a Kazuki Nakasone,a Naoki Terayama,a Eiko Yasui,a,b Megumi Mizukami,c Masaaki Miyashita,a Shinji Nagumoa,b* a) Department of Applied Chemistry, Kogakuin University, Nakano 2665-1, Hachioji, Tokyo 192-0015, Japan. b) Department of Chemistry and Life Science, Kogakuin University, Nakano 2665-1, Hachioji, Tokyo 192-0015, Japan. c) Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Hokkaido University of Science, Maeda 7-15-4-1, Teine, Sapporo, Hokkaido 006-8585, Japan. [email protected]

first second

OH

OH

OP

OH

19

O

sekothrixide

O

O

inversion of configuration at the C13

OP 17

16

OP

OP

15

13

This process is applicable to stereocontrolled construction of two parts (C13-C15 and C17-C19). OTMS O O R R R' R' D

Me2CuLi

E

side chain part

ABSTRACT: A new efficient synthesis of sekothrixide was established on the basis of our developed regioselective coupling of epoxy sec-alcohol with Gilman reagent guided by a TMS group. The new synthetic route allowed overall yield of 6.3% (26 steps) from optically active 3-silyloxy-2-methylaldehyde.

INTRODUCTION Fourteen-membered macrolides continue to be attractive synthetic targets 1 ACS Paragon Plus Environment

The Journal of Organic Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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because most of them have remarkable and diverse biological activities.1 Sekothrixide has been isolated from Saccharothrixide sp. CF24 by Seto et al. during the course of their exploratory research into new agents that would conquer a multidrug resistance (Figure 1).2 The natural product exhibits cytocidal activity against colchicine-resistant KB cells (KB-C2), especially when used with colchicine. The structure has a hydrophobic 14-membered ketolide and a long side chain containing seven consecutive asymmetric centers. Three chiral methyl groups present in the lactone ring were first proposed to have (4R, 6S, 8R) configurations.2b,2c Thereafter, we succeeded in the first total synthesis of sekothrixide.3 The synthetic study also revised the absolute configurations to be (4S, 6R, 8S), which are notably against Celmer’s rule.4 Unfortunately, the amount of the target molecule obtained in the synthesis was only a few milligrams because a large number of steps was necessary. Therefore, we decided to establish a more practical and shorter synthesis which allows us to obtain a larger amount of sekothrixide. The key to success is a simple and systematic stereocontrolled construction of seven consecutive asymmetric centers present in its long side chain.

Figure 1. Sekothrixide 10 8 (s)

21

OH

OH

11

OH

6 (R) 13

O

17

4 (s) 3

O

1

O

Incidentally, ring opening of epoxides linked to a primary alcohol with organocopper reagents has been widely applied to the construction of consecutive 2 ACS Paragon Plus Environment

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asymmetric centers because it proceeds with a complete steric inversion. Furthermore, the reagent attacks at the C2 position to give 1,3-diol selectively in the case of using substrates with alkyl substituents at the opposite site to the alcohol group.5 On the other hand, we recently obtained unique regiochemical findings regarding the coupling of epoxides linked to the sec-alcohol protected by a TMS group.6 Treatment of an anti-epoxy sec-alcohol with Me2CuLi resulted in selective formation of 1,2-dihydroxy product (Scheme 1, eq. 1). However, protection of the secondary alcohol by TMS group reversed the regioselectivity to give 1.3-dihydroxy product mainly (eq. 2). We report here a new efficient synthesis of sekothrixide strategically utilizing the above regioselective coupling of epoxy sec-alcohol with Gilman reagent guided by TMS group.7

Scheme 1. Effect of the TMS group on the regiochemical course for coupling of anti-epoxy-sec-alcohol with Me2CuLi O Ph

Ph

OH

OH

Me2CuLi, Et2O Ph

OH 75% 1,3-diol : 1,2-diol = 1 : 3 OH OH OTMS 1) Me2CuLi, Et2O O Ph 2) TBAF 86% 1,3-diol : 1,2-diol = 9 : 1

(1)

(2)

RESULTS AND DISCUSSION Scheme 2 shows a new synthetic plan for sekothrixide. The final stage follows a method used in the first synthesis,3 which is connecting the C1-C10 segment A and

3 ACS Paragon Plus Environment


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C11-C21 segment B by the sequence of esterification and ring-closing metathesis (RCM).8 Inverting the configuration at the C13 position of B leads to C of which the arrangement of stereogenic centers is symmetrically centered on a methyl group at the C16 position. The segment C has two sets of 2-methyl-1,3-diol moiety with a syn-anti relative configuration. Each moiety is retrosynthetically traced back to TMS-protected anti-epoxy-secondary alcohol D by assuming the coupling with an organocopper reagent. The key intermediate D could be synthesized from the enone E by Corey-Itsuno reduction using Corey-Bakshi-Shibata (CBS) catalyst9 and subsequent Katsuki-Sharpless epoxidation.10

Scheme 2. New synthetic plan of sekothrixide 10

sekothrixide

21

OP

OP

11

OP

16 13

inversion of configuration at the C13 position first

second

OP 19

OP 17

OP

OP

15

13

16

OH

+

1

HO2C A

B

3

OP

This process is applicable to stereocontrolled construction of two parts (C13-C15 and C17-C19). OTMS O O R R R' R' D

C

Me2CuLi

E

The new synthesis was started with Wittig reaction of aldehyde 111 with stabilized ylide 2 (Scheme 3). The resulting ,-unsaturated Weinreb amide 3 was converted to allylvinylketone 4 upon treatment with allyl Grignard reagent.12,13 Compound 4 was immediately subjected to stereoselective reduction using 4 ACS Paragon Plus Environment

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(S)-2-methyl-CBS-oxazaborolidine/BH3·THF to give allylalcohol 5 in 89% yield with a diastereomeric ratio of 14:1. Katsuki-Sharpless epoxidation of 5 using D-DIPT proceeded smoothly with an almost complete kinetic resolution to afford 6 in 88% yield as a single isomer. After protection of the secondary alcohol with a TMS group, the key coupling of the resulting 7 with Me2CuLi followed by treatment with citric acid furnished 1,3-diol 8 in 80% yield. Diol 8 was protected by benzylidene acetal to afford 9 as a epimeric mixture with a ratio of 1 : 2.4, of which a portion was separated to 9a and 9b by carefully performing chromatography on silica gel. Respective relative configurations were determined by NOE correlations shown in Figure 2.

Scheme 3. Synthesis of C11-C17 segment OTBDPS

O

CHO

+

Ph3P

1

OTBDPS

a N

OMe

O

b N

OMe

3

2

OTBDPS

O

OTBDPS

c

OH

d-e

OTBDPS OP O

5

4

PMP f-g

TBDPSO

OH

OH

h

TBDPSO 17

8

O

6 (P = H) 7 (P = TMS)

O

16 13

11

9a (-PMP) 9b (-PMP)

Reagents and conditions: (a) THF, 93%; (b) CH2=CHCH2MgBr, THF, -78

oC,

86%; (c)

(S)-2-methyl-CBS-oxazaborolidine, BH3·THF, THF, -35 oC, 89% (dr = 14 : 1); (d) D-DIPT, Ti(OiPr)4, TBHP, MS4A, CH2Cl2, -30 oC, 88%; (e) TMSCl, Et3N, THF; (f) Me2CuLi, Et2O, -30 oC to 0 oC; (g) Citric acid, H2O, THF, 80% from 6; (h) p-MeOC6H4CH(OMe)2, TsOH, CH2Cl2, 97% (9a : 9b = 1 : 2.4).



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Figure 2. Stereochemical determination of 9a and 9b by NOE 6.6% TBDPSO

TBDPSO H H O

10.5%

H

O H

H H 5.6%

OMe

O

OMe

O

4.6%

9a

9b

Next, a mixture of 9a and 9b was subjected to the second constructing process of 2-methyl-1,3-diol moiety with a syn-anti relative configuration (Scheme 4). After desilylation of 9, the resulting alcohol 10 was converted to enone 12 by the sequence of IBX oxidation14 and Horner-Wadsworth-Emmons reaction.15 Reduction of 12 with (R)-2-methyl-CBS-oxazaborolidine/BH3·THF

gave

13

in

94%

yield

with

a

diastereomeric ratio of 9:1. Katsuki-Sharpless epoxidation of 13 containing a small amount of epimer using L-DIPT proceeded with a kinetic resolution to afford 14 in 89% yield, which was quantitatively converted to the key intermediate 15 by protection with a TMS group. The key coupling of 15 with Me2CuLi followed by removal of the TMS group resulted in the regioselective formation of diol 17, which was immediately subjected to acetal protection in order to avoid a transacetalization affording more stable acetal 18. 6 ACS Paragon Plus Environment

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Scheme 4. Synthesis of C11-C21 segment PMP TBDPSO

O

PMP

PMP

O

a

9

OH

O

O

O

b

OHC 11 PMP

10 PMP O

O

c

O

O

OH

d

12

OP O

O

O

PMP g-h

OP

14 (P = H) 15 (P = TMS)

OH

O

O 16

21

O

O

i

16 (P = TMS) 17 (P = H) PMP

PMP O

O

13 PMP

e-f

O

OH

O

O

O

OH

11

18

19

Reagents and conditions: (a) TBAF, THF, quant.; (b) IBX, DMSO, 96%; (c) EtCOCH2P(O)(OEt)2, LiCl, DIPEA, THF, 85%; (d) (R)-2-methyl-CBS-oxazaborolidine, BH3·THF, THF, -40 oC, 94% (dr = 9 : 1); (e) L-DIPT, Ti(OiPr)4, TBHP, MS4A, CH2Cl2, -30 oC, 89%; (f) TMSCl, Et3N, THF, quant.; (g) Me2CuLi, Et2O, -30 oC to 0 oC; (h) TBAF, THF; (i) DMP, TsOH, 65% (3 steps).



The next task was regioselective cleavage of benzylidene acetal and inversion of configuration of the resulting hydroxyl group at the C13 position (Scheme 5). Treatment of 19 with DIBAH (4.5 equiv.) at 0 oC for 10 min resulted in selective bond cleavage to form 20 along with a small amount of the starting material,16 which interestingly was only -isomer 19a. When 19a was subjected again to reduction with DIBAH (6 equiv.) for 1h, 20 was obtained in 65% yield along with regioisomer 21 (10%) and recovered 19a (9%). Meanwhile, we synthesized a single epimer 19b from 9b that had been separated from a mixture with 9a by column chromatography. Reduction of 19b with DIBAH (2 equiv.) proceeded more smoothly to give 20 in high yield after 10 min, probably due to easier coordination of aluminum to ether oxygen at the C13 position. Next, we tried to invert the stereochemistry at the C13 postion. IBX oxidation of 20 followed by CBS reduction with (R)-2-methyl-CBS-oxazaborolidine/ BH3·THF afforded 23 having seven continuous asymmetric centers. Construction of the lactone was carried out by esterification and subsequent RCM as used for the first synthesis. Treatment of alcohol 23 and carboxylic acid 24, which previously was synthesized,3 with 2-methyl-6-nitrobenzoic anhydride, Et3N, and DMAP generated 25 in 91% yield.17 RCM of 25 with Grubbs 2nd generation catalyst in refluxing CH2Cl2 followed by removal of TBS group afforded E-alkene 26 selectively in 70% yield. Oxidation of 26 with TPAP afforded ketolide 27 in 89% yield. Finally, 27 was converted into sekothrixide by removal of the PMB group and the subsequent hydrolysis of acetonide. All spectral data of the current synthetic sample were in good agreement with those of the natural product and the previous synthetic sample.


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Scheme 5. Synthesis of sekothrixide



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PMP O

O

O

O

O

a

OPMB OH

O

+ 19a (-PMP, 18%) 19

20 (70%)

R a

O O

20 (65%)

O

OH

OPMB

19a (9%)

19a R

+

+

OMe

O

21 (10%)

OMe

O O

a 20 (87%)

Al H i Bu iBu 19b (-PMP) O

b

O

OPMB O

O

c

O

OPMB OH

20 22

23

O

d 23

OPMB

O

O

+ HO2C

O OTBS

24

O

e, f

O

OPMB

h, i sekothrixide

O R1 R2

O 26 (R1 = OH, R2 = H) 27 (R1, R2 = O)

Reagents

and

conditions:

(a)

OTBS

25

DIBAH,

g

THF,

0

oC;

(b)

IBX,

DMSO,

99%;

(c)

(R)-2-methyl-CBS-oxazaborolidine, BH3·THF, THF, -35 oC, 96%; (d) MNBA, Et3N, DMAP, CH2Cl2, 91%; (e) Grubbs 2nd., CH2Cl2, reflux; (f) TBAF, THF, 70% (2 steps); (g) TPAP, NMO, MS4A, CH2Cl2, 89%; (h) DDQ, CH2Cl2, H2O, 86%; (i) TsOH, iPrOH, H2O, 50 oC, 90%


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CONCLUSION We have succeeded in the new efficient synthesis of sekothrixide. Seven consecutive asymmetric centers present in the side chain were strategically constructed by using regioselective coupling of Me2CuLi with TMS-protected epoxy sec-alcohols 7 and 15, which were prepared from the corresponding conjugated enones 4 and 12 by the three-step sequence of CBS reduction, Katsuki-Sharpless epoxidation and silylation. After protection of diol 17 by acetonide, the resulting 19 was transformed to 23 by the sequence of regioselective cleavage of benzylidene acetal, oxidation of the generated hydroxyl

group,

and

stereoselective

reduction

using

(R)-2-methyl-CBS-oxazaborolidine/BH3·THF. Ring formation of 14-membered lactone was carried out by Siina’s esterification of 23 with carboxylic acid 24 and the subsequent RCM reaction using Grubbs 2nd catalyst. Oxidation forming ketolide and several deprotections at the last stage proceeded efficiently to generate sekothrixide. Both total yield and the number of steps (6.3%, 26 steps from optically active aldehyde 1) significantly improved from the previous synthesis3 (0.5%, 32 steps from the known compound). The establishment of an improved synthetic route would advance studies on biological activity of sekothrixide.

EXPERIMENTAL SECTION General. Melting points were determined on a Yanagimoto MP-S3 micro melting point apparatus and were uncorrected. IR spectra were recorded on a JASCO FT/IR-4100. 1H and

13C

NMR spectra were recorded on a JEOL JNN-ECX-400 or JNM-ECZ400S/L1

spectrometer at 400 and 100 MHz, respectively. Chemical shifts were expressed in  parts per million with tetramethylsilane as internal standard ( = 0 ppm) for 1H NMR. 11 ACS Paragon Plus Environment


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Chemical shifts of carbon signals were referenced to CDCl3 (C = 77.0 ppm), The following abbreviations are used: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, and br = broad. EI-mass spectra were recorded on a JEOL JMS-GCmate II. FAB-mass spectra were recorded on a JEOL JMS-700. Column chromatography was carried out on Merck’s Silica gel 60 (70-230 mesh ASTM).

(R,E)-5-((tert-butyldiphenylsilyl)oxy)-N-methoxy-N,4-dimethylpent-2-enamide (3): To a solution of 1 (3.62 g, 11.1 mmol) in THF (30 mL) was added 2 (6.17 g, 17.0 mmol) at room temperature. After being stirred for 12 h, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane : AcOEt = 7 : 1) to give 3 (4.24 g, 10.3 mmol, 93%) as a colorless oil. []D28 = +9.11° (c 1.12, CHCl3); IR (neat) 3071, 3017, 2963, 2862, 1659, 1628 cm-1; HRMS (FAB/magnetic sector) m/z Calcd for C24H34NO3Si [M+H]+ 412.2308, found 412.2327; 1H NMR (400 MHz, CDCl3)  7.67-7.63 (m, 4H), 7.45-7.34 (m, 6H), 6.94 (dd, J = 15.6, 8.0 Hz, 1H), 6.43 (d, J = 15.6 Hz, 1H), 3.66 (s, 3H), 3.63 (dd, J = 10.0, 6.8 Hz, 1H), 3.57 (dd, J = 10.0, 5.6 Hz, 1H), 3.24 (s, 3H), 2.65-2.53 (m, 1H), 1.09 (d, J = 7.2 Hz, 3H), 1.05 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3)  166.9 (C), 149.8 (CH), 135.6 (CH X 4), 133.6 (C X 2), 129.6 (CH X 2), 127.6 (CH X 4), 118.4 (CH), 67.7 (CH2), 61.6 (CH3), 39.4 (CH), 32.4 (CH3), 26.8 (CH3 X 3), 19.3 (C), 16.0 (CH3). (4R,7R,E)-8-((tert-butyldiphenylsilyl)oxy)-7-methylocta-1,5-dien-4-ol

(5):

To

a

solution of 3 (4.03 g, 9.79 mmol) in Et2O (90 mL) was added dropwise a solution of CH2=CHCH2MgBr (1M in Et2O, 20.1 mL, 20.1 mmol) at -78 oC. After being stirred for 3 min, the reaction mixture was quenched with saturated aqueous NH4Cl and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated under reduced 12 ACS Paragon Plus Environment

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pressure. The residue was purified by column chromatography on silica gel (hexane : AcOEt = 40 : 1) to give 4 (3.29 g, 8.38 mmol, 86%) as a pale yellow oil. 1H NMR (400 MHz, CDCl3)  7.68-7.63 (m, 4H), 7.45-7.34 (m, 6H), 6.86 (dd, J = 16.0, 7.6 Hz, 1H), 6.13 (d, J = 16.0 Hz, 1H), 5.95 (tqt, J = 7.2, 6.8, 6.8 Hz, 1H), 5.16 (dd, J = 19.2, 8.8 Hz, 2H), 3.64-3.57 (m, 2H), 3.31 (d, J = 6.8 Hz, 2H), 2.61-2.52 (m, 1H), 1.07 (d, J = 6.8 Hz, 3H), 1.05 (s, 9H). To a solution of 4 (3.29 g, 8.38 mmol) in THF (80 mL) was added (S)-(-)-2-methyl-CBS-oxazaborolidine (1M in toluene, 7.6 mL, 7.60 mmol) at room temperature under Ar atomosphere. After being strirred for 10 min at room temperature, BH3·THF (0.92 M in THF, 10.1 mL, 9.29 mmol) was added to the reaction mixture at -35 oC. After being further stirred for 1.5 h, the reaction mixture was quenched with saturated aqueous NaHCO3 and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane : AcOEt = 19 : 1) to give 5 (2.95 g, 7.48 mmol, 89%) with a diastereomeric ratio of 14 : 1 as a colorless oil. []D28 = +12.19° (c 1.15, CHCl3); IR (neat) 3372, 3071, 2862, 1643 cm-1; HRMS (ESI/magnetic sector) m/z Calcd for C25H34O2SiNa [M+Na]+ 417.2226, found 417.2253; 1H NMR (400 MHz, CDCl3)  7.68-7.63 (m, 4H), 7.45-7.34 (m, 6H), 5.80 (ddt, J = 17.6, 10.0, 7.2 Hz, 1H), 5.62 (ddd, J = 15.6, 6.8, 0.8 Hz, 1H), 5.50 (ddd, J = 15.6, 6.4, 0.8 Hz, 1H), 5.16-5.07 (m, 2H), 4.14-4.05 (m, 1H), 3.56 (dd, J = 9.6, 6.4 Hz, 1H), 3.50 (dd, J = 9.6, 6.4 Hz, 1H), 2.46-2.20 (m, 3H), 1.05 (s, 9H), 1.02 (d, J = 6.8 Hz, 3H);

13C{1H}

NMR (100

MHz, CDCl3)  135.6 (CH X 4), 134.4 (CH X 2), 133.9 (C X 2), 131.8 (CH), 129.5 (CH X 2), 127.6 (CH X 4), 118.0 (CH2), 71.8 (CH), 68.5 (CH2), 41.9 (CH2), 38.9 (CH), 26.8 (CH3 X 3), 19.3 (C), 16.5 (CH3). (R)-1-((2R,3R)-3-((S)-1-((tert-butyldiphenylsilyl)oxy)propan-2-yl)oxiran-2-yl)but-3 13 ACS Paragon Plus Environment


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-en-1-ol (6): To a mixture of MS4Å (2.79 g) and CH2Cl2 (30 mL) was successively added D-DIPT (0.49 mL, 2.29 mmol), Ti(Oi-Pr)4 (0.55 mL, 1.85 mmol) and TBHP (2.37 M in CH2Cl2, 5.5 mL, 13.0 mmol) at -30 oC under Ar atmosphere. After being stirred for 20 min, a solution of 5 (1.68 g, 4.26 mmol) in CH2Cl2 (20 mL) was added to the resulting mixture at -30 oC. After being stirred for 13 h at -30 oC, the reaction mixture was quenched with saturated aqueous NaSO3. After addition of saturated aqueous Rochelle salt, the mixture was filtered with celite pad. The filtrate was extracted with Et2O. The organic layer was dried over MgSO4 and concentrated. The residue was purified by column chromatography on silica gel (hexane : AcOEt = 9 : 1) to give 6 (1.53 g, 3.73 mmol, 88%) as a colorless oil. []D24 = +8.76° (c 1.10, CHCl3); IR (neat) 3456, 3071, 2932, 2862 cm-1; HRMS (FAB/magnetic sector) m/z Calcd for C25H35O3Si [M+H]+ 411.2355, found 411.2342;

1H

NMR (400 MHz, CDCl3)

 7.69-7.62 (m, 4H), 7.47-7.35 (m, 6H), 5.84 (ddt, J = 17.2, 10.4, 6.8 Hz, 1H), 5.14-5.05 (m, 2H), 3.84-3.77 (m, 1H), 3.64 (dd, J = 10.0, 6.4 Hz, 1H), 3.59 (dd, J = 10.0, 5.2 Hz, 1H), 2.99 (dd, J = 6.8, 2.4 Hz, 1H), 2.91 (dd, J = 3.6, 2.4 Hz, 1H), 2.39-2.22 (m, 2H), 1.83 (d, J = 2.8 Hz, 1H), 1.72-1.60 (m, 1H), 1.06 (s, 9H), 1.01 (d, J = 6.8 Hz, 3H); 13C{1H}

NMR (400 MHz, CDCl3)  135.6 (CH X 4), 133.7 (CH), 133.5 (C X 2), 129.7

(CH X 2), 127.7 (CH X 4), 118.1 (CH2), 68.3 (CH), 66.1 (CH2), 59.7 (CH), 57.8 (CH), 38.04 (CH2), 38.01 (CH), 26.9 (CH3 X 3), 19.2 (C), 13.4 (CH3). (2S,3R,4S,5R)-1-((tert-butyldiphenylsilyl)oxy)-2,4-dimethyloct-7-ene-3,5-diol

(8):

To a solution of 6 (3.54 g, 8.60 mmol) in THF (60 mL) was added Et3N (12.0 mL, 85.0 mmol) and TMSCl (5.5 mL, 42.7 mmol) at room temperature. After being stirred for 2.5 h, the reaction mixture was quenched with saturated aqueous NaHCO3 under ice cooling and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated 14 ACS Paragon Plus Environment

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under reduced pressure. The residue was purified by column chromatography on silica gel (hexane : AcOEt = 24 : 1) to give 7 (4.18 g) as a colorless oil. 1H NMR (400 MHz, CDCl3)  7.66 (d, J = 8.0 Hz, 4H), 7.45-7.36 (m, 6H), 5.82 (tqt, J = 7.6, 6.8, 6.8 Hz, 1H), 5.07 (d, J = 13.6 Hz, 1H),5.03 (d, J = 6.4 Hz, 1H), 3.65 (dd,J = 10.0, 6.4 Hz,1H), 3.61-3.55 (m, 1H), 3.56 (dd, J = 10.0, 6.4 Hz, 1H), 2.92 (dd, J = 5.6, 2.0 Hz, 1H), 2.79 (dd, J = 4.4, 2.4 Hz, 1H), 2.35-2.21 (m, 2H), 1.77-1.67 (m, 1H), 1.07 (s, 9H), 0.96 (d, J = 6.8 Hz, 3H). To a suspension of CuI (8.31 g, 43.2 mmol) in dried Et2O (30 mL) was added dropwise MeLi (1.16 M in Et2O, 75.0 mL, 87.0 mmol) at -30 oC under Ar atmosphere. After being stirred for 30 min, a solution of 7 (4.15 g, 8.60 mmol) in Et2O (30 mL) was added to the mixture at -30 oC. The reaction mixture was stirred for 10 h, allowing temperature to rise gradually to 0 oC. After being further stirred for 11 h at 0 oC,

the reaction mixture was quenched with saturated aqueous NaHCO3 and saturated

aqueous NH4Cl and extracted with AcOEt. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give crude (4.20 g). To a solution of the crude in THF (50 mL) was added saturated aqueous citric acid (10 mL). After being stirred for 3 h at room temperature, the mixture was neutrized with saturated aqueous NaHCO3 and extracted with AcOEt. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane : AcOEt = 7 : 1) to give 8 (2.93 g, 6.87 mmol, 80% from 6) as a colorless oil. []D26 = +13.3° (c 1.18, CHCl3); IR (neat) 3449, 3071, 2932, 2862 cm-1; HRMS (FAB/magnetic sector) m/z Calcd for C26H39O3Si [M+H]+ 427.2669, found 427.2693; 1H NMR (400 MHz, CDCl3)  7.69-7.64 (m, 4H), 7.49-7.37 (m, 6H), 5.89 (ddt, J = 17.2, 10.0, 7.2 Hz, 1H), 5.18-5.07 (m, 2H), 3.95-3.87 (m, 2H), 3.81 (dd, J = 10.0, 3.6 Hz, 1H), 3.69 (dd, J = 10.0, 4.4 Hz, 1H), 3.40 (d, J = 2.4 Hz, 15 ACS Paragon Plus Environment


Page 16 of 38

1H), 2.78 (d, J = 6.0 Hz, 1H), 2.37-2.17 (m, 2H), 1.89-1.70 (m, 2H), 1.07 (s, 9H), 0.99 (d, J = 6.8 Hz, 3H), 0.81 (d, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3)  136.1 (CH), 135.7 (CH X 2), 135.5 (CH X 2), 133.0 (C), 132.8 (C), 129.86 (CH), 129.81 (CH), 127.8 (CH X 4), 117.0 (CH2), 76.3 (CH), 72.7 (CH), 69.2 (CH2), 39.3 (CH), 38.0 (CH2), 36.5 (CH), 26.8 (CH3 X 3), 19.2 (C), 11.6 (CH3), 9.6 (CH3). (2R,4R,5S,6R)-4-[[(1S)-2-tert-Butyldiphenylsilyloxy]-1-methylethyl]-2-(4-methoxyp henyl)-5-methyl-6-(2-propen-1-yl)-1,3-dioxane

(9a)

and

(2S,4R,5S,6R)-4-

[[(1S)-2-tert-Butyldiphenylsilyloxy]-1-methylethyl]-2-(4-methoxyphenyl)-5-methyl6-(2-propen-1-yl)-1,3-dioxane (9b): To a solution of 8 (1.10 g, 2.58 mmol) in CH2Cl2 (25 mL) was added p-anisaldehyde dimethyl acetal (1.40 mL, 7.81 mmol) and TsOH·H2O (50.1 mg, 0.266 mmol) at room temperature. After being further stirred for 4 h, the reaction mixture was quenched with saturated aqueous NaHCO3 and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane : AcOEt = 5 : 1) to give 9 (1.36 g, 2.50 mmol, 97%) with a diastereomeric ratio of 1 : 2.4 (9a : 9b) as a colorless oil. A portion of the diastereomeric mixture was separated to 9a and 9b by column chromatography on silica gel (hexane : AcOEt = 49 : 1). 9a: []D25 = +31.6° (c 1.06, CHCl3); IR (neat) 3071, 2931, 2862, 1612 cm-1; HRMS (ESI/magnetic sector) m/z Calcd for C34H44O4SiNa [M+Na]+ 567.2907, found 567.2916; 1H NMR (400 MHz, CDCl3)  7.68-7.62 (m, 4H), 7.47-7.35 (m, 8H), 6.88 (d, J = 8.8 Hz, 2H), 5.80-5.67 (m, 1H), 5.61 (s, 1H), 5.14-4.99 (m, 2H), 4.03-3.97 (m, 1H), 3.79 (s, 3H), 3.73 (d, J = 10.8 Hz, 1H), 3.64-3.55 (m, 2H), 2.56-2.44 (m, 1H), 2.44-2.34 (m, 1H), 2.16-2.05 (m, 1H), 1.74-1.65 (m, 1H), 1.20 (d, J = 7.2 Hz, 3H), 1.12 (d, J = 6.8 Hz, 3H), 1.05 (s, 9H);

13C{1H}

NMR (100 MHz, CDCl3)  159.8 (C), 135.6 (CH X 4), 134.4 16 ACS Paragon Plus Environment

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(CH), 133.4 (C X 2), 131.8 (C), 129.7 (CH X 2), 127.7 (CH X 4), 127.3 (CH X 2), 117.0 (CH2), 113.6 (CH X 2), 95.3 (CH), 82.1 (CH) 74.7 (CH), 66.5 (CH2), 55.2 (CH3), 37.1 (CH2), 34.0 (CH), 31.3 (CH), 26.8 (CH3 X 3), 19.2 (C), 14.2 (CH3), 13.1 (CH3). 9b: []D25 = +29.3° (c 0.96, CHCl3); IR (neat) 3071, 2932, 2862, 1612 cm-1; HRMS (ESI/magnetic sector) m/z Calcd for C34H44O4SiNa [M+Na]+ 567.2907, found 567.2909; 1H NMR (400 MHz, CDCl3)  7.68-7.60 (m, 4H), 7.44-7.30 (m, 6H), 7.21 (t, J = 8.0 Hz, 2H), 6.86 (d, J = 9.2 Hz, 2H), 6.00-5.87 (m, 1H), 5.67 (s, 1H), 5.20-5.09 (m, 2H), 4.18-4.09 (m, 2H), 3.80 (s, 3H), 3.78 (t, J = 9.6 Hz, 1H), 3.56 (dd, J = 9.6, 6.0 Hz, 1H), 2.88-2.76 (m, 1H), 2.43-2.31 (m, 1H), 2.31-2.22 (m, 1H), 2.05-1.94 (m, 1H), 1.06 (s, 9H), 0.87 (d, J = 7.6 Hz, 3H), 0.79 (d, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3)  159.6 (C), 135.5 (CH X 4), 135.4 (CH), 133.9 (C), 133.8 (C), 132.0 (C), 129.53 (CH), 129.47 (CH), 127.60 (CH X 2), 127.56 (CH X 2), 127.3 (CH X 2), 116.6 (CH2), 113.4 (CH X 2), 93.3 (CH), 76.7 (CH), 74.8 (CH), 65.3 (CH2), 55.3 (CH3), 36.5 (CH), 33.2 (CH), 30.1 (CH2), 26.9 (CH3 X 3), 19.3 (C), 12.5 (CH3), 9.1 (CH3). (S)-2-((2R,4R,5S,6R)-6-allyl-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl)propan -1-ol (10a) and 　 (S)-2-((2S,4R,5S,6R)-6-allyl-2-(4-methoxyphenyl)-5-methyl1,3-dioxan-4-yl)propan-1-ol (10b): To a solution of 9 (1.02 g, 1.87 mmol, 9a : 9b = 1 : 2.4) in THF (20 mL) was added TBAF (1.0 M in THF, 3.80 mL, 3.80 mmol) at room temperature. After being stirred for 9 h, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexanes / AcOEt = 5 :1) to give 10 (578 mg, 1.89 mmol, quant.) as a white solid. Also separated 9a and 9b were subjected to the same procedure to give 10a and 10b in 100% and 99%, respectively. 10a: m.p. 68.5-68.7 oC (white cotton, Hexane / Et2O); []D27 = +60.87° (c 1.61, CHCl3); IR (neat) 3325, 2970, 2932, 2878, 1612 cm-1; HRMS 17 ACS Paragon Plus Environment


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(EI/magnetic sector) m/z Calcd for C18H26O4 [M]+ 306.1831, found 306.1827; 1H NMR (400 MHz, CDCl3)  7.43 (d, J = 8.8 Hz, 2H), 6.89 (d, J = 8.8 Hz, 2H), 5.89-5.76 (m, 1H), 5.67 (s, 1H), 5.18-5.04 (m, 2H), 4.11 (td, J = 7.2, 2.4 Hz, 1H), 3.79 (s, 3H), 3.67-3.49 (m, 3H), 2.54-2.39 (m, 2H), 2.25-2.15 (m, 1H), 1.86-1.78 (m, 1H), 1.50 (br, 1H), 1.22 (d, J = 7.6 Hz, 3H), 1.09 (d, J = 6.8 Hz, 3H);

13C{1H}

NMR (100 MHz,

CDCl3)  159.8 (C), 134.3 (CH), 131.6 (C), 127.3 (CH X 2), 117.1 (CH2), 113.6 (CH X 2), 95.5 (CH), 81.7 (CH), 74.6 (CH), 65.7 (CH2), 55.3 (CH3), 36.9 (CH2), 34.3 (CH), 31.6 (CH), 13.7 (CH3), 13.1 (CH3). 10b: m.p. 90.1-90.5 oC (White cotton, Hexane / Et2O); []D27 = +65.86° (c 0.97, CHCl3); IR (neat) 3256, 2963, 2916, 2878, 1612 cm-1; HRMS (EI/magnetic sector) m/z Calcd for C18H26O4 [M]+ 306.1831, found 306.1828; 1H

NMR (400 MHz, CDCl3)  7.35 (d, J = 8.8 Hz, 2H), 6.86 (d, J = 8.8 Hz, 2H),

5.97-5.85 (m, 1H), 5.76 (s, 1H), 5.22-5.09 (m, 2H), 4.15 (dt, J = 11.6, 5.6 Hz, 1H), 4.03 (dd, J = 10.8, 2.0 Hz, 1H), 3.79 (s, 3H), 3.76-3.69 (m, 2H), 2.93-2.81 (m, 1H), 2.47-2.35 (m, 1H), 2.33-2.22 (m, 1H), 2.07 (br, 1H), 1.96-1.85 (m, 1H), 1.04 (d, J = 6.8 Hz, 3H), 0.80 (d, J = 7.6 Hz, 3H);

13C{1H}

NMR (100 MHz, CDCl3)  159.7 (C), 135.0 (CH),

131.4 (C), 127.2 (CH X 2), 116.7 (CH2), 113.5 (CH X 2), 93.4 (CH), 78.2 (CH), 76.3 (CH), 66.6 (CH2), 55.2 (CH3), 35.7 (CH), 33.3 (CH), 30.0 (CH2), 12.3 (CH3), 9.2 (CH3). (S,E)-6-((2R,4R,5S,6R)-6-allyl-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl)hept4-en-3-one

(12a)

and

(S,E)-6-((2S,4R,5S,6R)-6-allyl-2-(4-methoxyphenyl)-

5-methyl-1,3-dioxan-4-yl)hept-4-en-3-one (12b): To a solution of 10 (244 mg, 0.796 mmol, 10a : 10b = 1 : 2.4) in DMSO (10 mL) was added 2-iodoxybenzoic acid (330 mg, 1.18 mmol) at room temperature. After being stirred for 1 h, the reaction mixture was quenched with saturated aqueous NaHCO3 under ice cooling and filtered with celite pad. The filtrate was extracted with AcOEt. The organic layer was dried over MgSO4 18 ACS Paragon Plus Environment

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and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane : AcOEt = 3 : 1) to give 11 (233 mg, 0.766 mmol, 96%) as colorless oil. 11a: 1H NMR (400 MHz, CDCl3)  9.64 (d, J = 2.8 Hz, 1H), 7.42 (d, J = 9.2 Hz, 2H), 6.90 (d, J = 9.2 Hz, 2H), 5.86-5.73 (m, 1H), 5.58 (s, 1H), 5.18-5.04 (m, 2H), 4.14-4.07 (m, 1H), 3.98 (d, J = 11.2 Hz, 1H), 3.80 (s, 3H), 3.37-3.26 (m, 1H), 2.49-2.39 (m, 1H), 2.23-2.14 (m, 1H), 1.63-1.55 (m, 1H), 1.27 (d, J = 6.8 Hz, 3H), 1.25 (d, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3)   CH 160.0 (C), 133.9 (CH), 131.1 (C), 127.3 (CH X 2), 117.4 (CH2), 113.7 (CH X 2), 95.8 (CH), 78.6 (CH), 74.7 (CH), 55.3 (CH3), 46.1 (CH), 36.9 (CH2), 32.7 (CH), 13.0 (CH3), 10.8 (CH3). 11b: 1H

NMR (400 MHz, CDCl3)  9.77 (s, 1H), 7.31 (d, J = 9.2 Hz, 2H), 6.84 (d, J = 9.2

Hz, 2H), 5.98-5.85 (m, 1H), 5.77 (s, 1H), 5.23-5.11 (m, 2H), 4.39 (dd, J = 10.8, 2.8 Hz, 1H), 4.18 (dt, J = 11.6, 5.2 Hz, 1H), 3.78 (s, 3H), 2.96-2.84 (m, 1H), 2.55-2.37 (m, 2H), 2.36-2.27 (m, 1H), 1.25 (d, J = 6.8 Hz, 3H), 0.85 (d, J = 7.2 Hz, 3H);

13C{1H}

NMR

(100 MHz, CDCl3)   CH 159.8 (C), 134.8 (CH), 131.0 (C), 127.2 (CH X 2), 117.0 (CH2), 113.5 (CH X 2), 93.3 (CH), 76.1 (CH), 75.9 (CH), 55.3 (CH3), 47.5 (CH), 33.2 (CH), 30.0 (CH2), 12.4 (CH3), 6.7 (CH3). To a solution of diethyl (2-oxobutyl)phosphonate (0.23 mL, 1.14 mmol) and LiCl (101.1 mg, 2.36 mmol) in THF (4 mL) was added dropwise diisopropylethylamine (0.27 mL, 1.53 mmol) at room temperature under Ar atmosphere. After being stirred for 20 min, a solution of 11 (233 mg, 0.766 mmol) in THF (4 mL) was added to the mixture at room temperature. After being further stirred for 38 h at 0 oC, the reaction mixture was quenched with saturated aqueous NH4Cl and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane : AcOEt = 9 : 1) to give 12 (234 mg, 0.653 mmol, 19 ACS Paragon Plus Environment


85%) as a light yellow oil. Also separated 10a and 10b were subjected to the same procedure to give 12a and 12b in 85% and 80%, respectively. 12a: []D28 = -3.29° (c 1.02, CHCl3); IR(neat) 3017, 2978, 2940, 1674, 1620 cm-1; HRMS (EI/magnetic sector) m/z Calcd for C22H30O4 [M]+. 358.2144, found 358.2149; 1H NMR (400 MHz, CDCl3)

 7.43 (d, J = 8.4 Hz, 2H), 6.90 (d, J = 8.4 Hz, 2H), 6.61 (dd, J = 16.0, 8.8 Hz, 1H), 6.18 (d, J = 16.0 Hz, 1H), 5.84-5.71 (m, 1H), 5.66 (s, 1H), 5.17-5.03 (m, 2H), 4.08 (td, J = 7.2, 2.4 Hz, 1H), 3.80 (s, 3H), 3.58 (d, J = 11.2 Hz, 1H), 3.33-3.20 (m, 1H), 2.58 (q, J = 7.2 Hz, 2H), 2.47-2.37 (m, 1H), 2.21-2.11 (m, 1H), 1.63-1.54 (m, 1H), 1.20 (d, J = 7.2 Hz, 3H), 1.19 (d, J = 6.4 Hz, 3H), 1.11 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 200.7 (C), 160.0 (C), 147.7 (CH), 133.9 (CH), 131.3 (C), 130.4 (CH), 127.3 (CH X 2), 117.3 (CH2), 113.7 (CH X 2), 95.2 (CH), 82.9 (CH), 74.4 (CH), 55.3 (CH3), 36.9 (CH2), 36.3 (CH), 33.7 (CH2), 31.4 (CH),16.8 (CH3), 13.1 (CH3), 8.0 (CH3). 12b: []D28 = -101.83° (c 1.01, CHCl3); IR(neat) 3017, 2978, 2940, 1667, 1620 cm-1; HRMS (EI/magnetic sector) m/z Calcd for C22H30O4 [M]+ 358.2144, found 358.2138; 1H NMR (400 MHz, CDCl3) δ 7.37 (d, J = 8.8 Hz, 2H), 6.96 (dd, J = 16.4, 7.6 Hz, 1H), 6.87 (d, J = 8.8 Hz, 2H), 6.14 (d, J = 16.4 Hz, 1H), 5.97-5.83 (m, 1H), 5.72 (s, 1H), 5.20-5.09 (m, 2H), 4.14 (dt, J = 10.8, 5.2 Hz, 1H), 3.84-3.77 (m, 1H), 3.79 (s, 3H), 2.87-2.74 (m, 1H), 2.64-2.53 (m, 3H), 2.43-2.21 (m, 2H), 1.16 (d, J = 6.8 Hz, 3H), 1.09 (t, J = 7.2 Hz, 3H), 0.84 (d, J = 7.2 Hz, 3H);

13C{1H}

NMR (100 MHz, CDCl3)  201.4 (C), 159.7 (C),

149.7 (CH), 134.9 (CH), 131.4 (C), 129.5 (CH), 127.2 (CH X 2), 116.9 (CH2), 113.5 (CH X 2), 93.6 (CH), 79.1 (CH), 75.9 (CH), 55.2 (CH3), 38.0 (CH), 33.8 (CH), 33.0 (CH2), 30.2 (CH2), 12.5 (CH3), 12.2 (CH3), 8.1 (CH3). (3S,6S,E)-6-((2R,4R,5S,6R)-6-allyl-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl) hept-4-en-3-ol (13a) and (3S,6S,E)-6-((2S,4R,5S,6R)-6-allyl-2-(4-methoxyphenyl)20 ACS Paragon Plus Environment

Page 20 of 38

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5-methyl-1,3-dioxan-4-yl)hept-4-en-3-ol (13b): To a solution of 12 (184 mg, 0.513 mmol) in THF (7 mL) was added (R)-(+)-2-methyl-CBS-oxazaborolidine (1M in toluene, 0.64 mL, 0.640 mmol) at room temperature under Ar atomosphere. After being strirred for 10 min at room temperature, BH3·THF (0.95 M in THF, 0.65 mL, 0.684 mmol) was added to the reaction mixture at -40 oC. After being further stirred for 3 h at -40 oC, the reaction mixture was quenched with saturated aqueous NaHCO3 and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane : AcOEt = 6 : 1) to give 13 (173 mg, 0.480 mmol, 94%) with a diastereomeric ratio of 9 : 1 as a colorless oil. Also separated 12a and 12b were subjected to the same procedure to give 13a and 13b in 95% and 97%, respectively. 13a; []D29 = +10.01° (c 1.18, CHCl3); IR (neat) 3464, 2970, 2932, 1612 cm-1; HRMS (EI/magnetic sector) m/z Calcd for C22H32O4 [M]+ 360.2301, found 360.2280; 1H NMR (400 MHz, CDCl3) δ 7.45-7.41 (m, 2H), 6.91-6.87 (m, 2H), 5.84-5.74 (m, 1H), 5.66 (s, 1H), 5.54 (dd, J = 15.6, 6.4 Hz, 1H), 5.42 (dd, J = 15.2, 8.8 Hz, 1H), 5.15-5.05 (m, 2H), 4.10 (td, J = 7.2, 2.4 Hz, 1H), 4.00 (td, J = 12.8, 6.4 Hz, 1H), 3.79 (s, 3H), 3.47 (d, J = 11.2 Hz, 1H), 3.15-3.05 (m, 1H), 2.45-2.38 (m, 1H), 2.22-2.14 (m, 1H), 1.77-1.72 (m, 1H), 1.63-1.46 (m, 2H), 1.19 (d, J = 6.8 Hz, 3H), 1.12 (d, J = 6.4 Hz, 3H), 0.91 (t, J = 7.6 Hz, 3H); 13C{1H}

NMR (100 MHz, CDCl3) δ 159.8 (C), 134.1 (CH), 133.4 (CH), 131.6 (C),

127.3 (CH), 117.1 (CH2), 113.6 (CH), 95.1 (CH), 83.1 (CH), 74.4 (CH), 73.8 (CH), 55.3 (CH3), 36.9 (CH2), 35.8 (CH), 30.6 (CH), 30.1(CH2), 17.7 (CH3), 13.1 (CH3), 9.6 (CH3). 13b; []D27 = +60.70° (c 1.17, CHCl3); IR (neat) 3449, 2970, 2932, 1612 cm-1; HRMS (EI/magnetic sector) m/z Calcd for C22H32O4 [M]+ 360.2301, found 360.2283; 1H

NMR (400 MHz, CDCl3) δ 7.40-7.36 (m, 2H), 6.88-6.85 (m, 2H), 5.96-5.80 (m, 21 ACS Paragon Plus Environment


Page 22 of 38

2H), 5.71(s, 1H), 5.49 (dd, J = 15.6, 7.6 Hz, 1H), 5.18-5.10 (m, 2H), 4.11 (td, J = 11.2, 5.2 Hz, 1H),3.99-3.94 (m, 1H), 3.78 (s, 3H), 3.72 (dd, J = 6.4, 2.8 Hz, 1H), 3.84-2.76 (m, 1H), 2.47-2.39 (m, 1H), 2.37-2.22 (m, 2H), 1.64-1.44 (m, 2H), 1.08 (d, J = 7.2 Hz, 3H), 0.88 (t, J = 3.2 Hz, 3H), 0.82 (d, J = 7.2 Hz, 3H);

13C{1H}

NMR (100 MHz,

CDCl3) δ 159.8 (C), 135.6 (CH), 135.3 (CH), 132.3 (CH), 127.4 (C), 116.8 (CH2), 113.6 (CH), 93.7 (CH), 80.1 (CH), 76.0 (CH), 74.7 (CH), 55.4 (CH3), 37.9 (CH), 34.0 (CH), 30.5 (CH2), 30.3 (CH2), 13.3 (CH3), 12.7 (CH3), 9.9 (CH3). (S)-1-((2S,3S)-3-((R)-1-((2R,4S,5S,6R)-6-allyl-2-(4-methoxyphenyl)-5-methyl-1,3-di oxan-4-yl)ethyl)oxiran-2-yl)propan-1-ol

(14a)

and

(S)-1-((2S,3S)-3-((R)-1-

((2S,4S,5S,6R)-6-allyl-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl)ethyl)oxiran2-yl)propan-1-ol (14b): To a mixture of MS4Å (403 mg) and CH2Cl2 (6 mL) was successively added L-DIPT (0.1 mL, 0.461 mmol), Ti(Oi-Pr)4 (0.1 mL, 0.335 mmol) and TBHP (2.75 M in CH2Cl2, 1.0 mL, 2.75 mmol) at -30 oC under Ar atmosphere. After being stirred for 30 min, a solution of 13 (299 mg, 0.829 mmol) in CH2Cl2 (4 mL) was added to the resulting mixture at -30 oC. After being stirred for 14 h at -30 oC, the reaction mixture was quenched with saturated aqueous Na2SO3. After addition of saturated aqueous Rochelle salt, the mixture was filtered with celite pad. The filtrate was extracted with Et2O. The organic layer was dried over MgSO4 and concentrated. Next, to a solution of crude residue (672.5 mg) in MeOH (5 mL) and H2O (5 mL) was added NaIO4 (191.9 mg, 0.897 mmol) at room temperature. After being stirred for 3 h, the reaction mixture was quenched with saturated aqueous Na2SO3 while ice cooling and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane : AcOEt = 5 : 1) to give 14 (277 mg, 0.736 mmol, 89%) as a colorless oil. 22 ACS Paragon Plus Environment

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Also separated 13a and 13b were subjected to the same procedure to give 14a and 14b in 88% and 85%, respectively. 14a; []D28= +12.65° (c 1.02, CHCl3); IR (neat) 3472, 3009, 2970, 1612 cm-1; HRMS (EI/magnetic sector) m/z Calcd for C22H32O5 [M]+ 376.2250, found 376.2248; 1H NMR (400 MHz, CDCl3) δ 7.41 (d, J = 8.8 Hz, 2H), 6.89 (d, J = 8.8 Hz, 2H), 5.85-5.74 (m, 1H), 5.59 (s, 1H), 5.18-5.08 (m, 2H), 4.07-4.03 (m, 1H), 3.80 (s, 3H), 3.71-3.63 (m, 2H), 2.84-2.78 (m, 2H), 2.48-2.41 (m, 1H), 2.32-2.18 (m, 2H), 1.81-1.77 (m, 2H), 1.66-1.56 (m, 1H), 1.53-1.42 (m, 1H), 1.25 (d, J = 6.8 Hz, 3H), 1.17 (d, J = 6.8 Hz, 3H), 1.04 (t, J = 7.2 Hz,3H);

13C{1H}

NMR (100 MHz,

CDCl3) δ 160.0 (C), 133.9 (CH), 131.3 (C), 127.3 (CH), 117.6 (CH2), 113.7 (CH), 95.5 (CH), 81.6 (CH), 74.6 (CH), 70.1 (CH), 61.5 (CH), 57.4 (CH), 55.3 (CH3), 37.0 (CH2), 34.5(CH), 31.6 (CH), 26.6 (CH2), 13.9 (CH3), 13.0 (CH3), 10.0 (CH3). 14b; []D25 = +64.67° (c 1.10, CHCl3); IR (neat) 3480, 3017, 2970, 1612 cm-1; HRMS (EI/magnetic sector) m/z Calcd for C22H32O5 [M]+ 376.2250, found 376.2267; 1H NMR (400 MHz, CDCl3) δ 7.37-7.34 (m, 2H), 6.89-6.85 (m, 2H), 5.96-5.86 (m, 1H), 5.71 (s, 1H), 5.19-5.11 (m, 2H), 4.14 (td, J = 11.6, 4.8 Hz, 1H), 3.82 (dd, J = 10.8, 2.0 Hz, 1H), 3.79 (s, 3H), 3.72 (br, 1H), 3.13 (dd, J = 7.2, 2.4 Hz, 1H), 2.94 (dd, J = 3.2, 2.0 Hz, 1H), 2.86-2.78 (m, 1H), 2.43-2.34 (m, 1H), 2.29-2.22 (m, 1H), 1.84 (br, 1H), 1.69-1.49 (m, 2H), 1.18 (d, J = 7.6 Hz, 3H), 1.00 (t, J = 7.6 Hz, 3H), 0.78 (d, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 159.8 (C), 134.0 (CH), 131.4 (C), 127.2 (CH), 116.9 (CH2), 113.5 (CH), 93.4 (CH), 77.7 (CH), 76.0 (CH), 69.7 (CH), 60.2 (CH), 58.1 (CH), 55.3 (CH3), 36.9 (CH), 33.1(CH), 30.1 (CH2), 26.5(CH2), 12.4 (CH3), 10.3 (CH3), 9.4 (CH3). ((S)-1-((2R,3S)-3-((R)-1-((2R,4S,5S,6R)-6-allyl-2-(4-methoxyphenyl)-5-methyl-1,3-d ioxan-4-yl)ethyl)oxiran-2-yl)propoxy)trimethylsilane (15a) and ((S)-1-((2R,3S)-3((R)-1-((2S,4S,5S,6R)-6-allyl-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl)ethyl)o 23 ACS Paragon Plus Environment


xiran-2-yl)propoxy)trimethylsilane (15b): To a solution of 14 (146 mg, 0.388 mmol) in THF (4 mL) was added Et3N (0.56 mL, 3.97 mmol) and TMSCl (0.26 mL, 2.04 mmol) at room temperature. After being stirred for 2 h, the reaction mixture was quenched with saturated aqueous NaHCO3 while ice cooling and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane : AcOEt = 10 : 1) to give 15 (176 mg, 0.392 mmol, quant.) as a colorless oil. Also separated 14a and 14b were subjected to the same procedure to give 15a and 15b in 98% and 97%, respectively. 15a; []D27 = +3.05° (c 1.02, CHCl3); IR (neat) 3009, 2970, 1612 cm-1; HRMS (EI/magnetic sector) m/z Calcd for C25H40O5Si [M]+ 448.2645, found 448.2641; 1H

NMR (400 MHz, CDCl3) δ 7.41 (d, J = 8.4 Hz, 2H), 6.89 (d, J = 8.8 Hz, 2H),

5.85-5.75 (m, 1H), 5.58 (s, 1H), 5.18-5.08 (m, 2H), 4.07-4.03 (m, 1H), 3.79 (s, 3H), 3.64 (d, J = 11.6 Hz, 1H), 3.40 (td, J = 11.6, 5.6 Hz, 1H), 2.74-2.72 (m, 2H), 2.59 (d, J = 8.0 Hz, 1H), 2.47-2.40 (m, 1H), 2.29-2.18 (m, 2H), 1.94-1.89 (m, 1H), 1.67-1.47 (m, 2H), 1.26 (d, J = 6.8 Hz, 3H), 1.16 (d, J = 6.4 Hz, 3H), 0.97 (t, J = 7.6 Hz, 3H), 0.10 (s, 9H) ;

13C{1H}

NMR (100 MHz, CDCl3) δ 160.0 (C), 133.9 (CH), 131.4 (C), 127.3

(CH), 117.5 (CH2), 113.7 (CH), 95.3 (CH), 81.9 (CH), 74.8 (CH), 73.1 (CH), 61.6 (CH), 58.8 (CH), 55.3 (CH3), 37.0 (CH2), 34.7(CH), 31.6 (CH), 28.2 (CH2), 14.0 (CH3), 13.2 (CH3), 9.5 (CH3), 0.2 (CH3). 15b; []D24 = +52.43° (c 1.01, CHCl3); IR (neat) 3009, 2967, 1616 cm-1; HRMS (EI/magnetic sector) m/z Calcd for C25H40O5Si [M]+ 448.2645, found 448.2635; 1H NMR (400 MHz, CDCl3) δ 7.38-7.35 (m, 2H), 6.88-6.85 (m, 2H), 5.96-5.86 (m, 1H), 5.72 (s, 1H), 5.18-5.11 (m, 2H), 4.14 (dt, J = 11.6, 5.2 Hz, 1H), 3.87 (dd, J = 11.2, 2.0 Hz, 1H), 3.80 (s, 3H), 3.36-3.31 (m, 1H), 3.01 (dd, J = 7.6, 2.0 Hz, 1H), 2.86-2.77 (m, 2H), 2.43-2.34 (m, 1H), 2.30-2.23 (m, 1H), 1.69-1.47 (m, 24 ACS Paragon Plus Environment

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2H), 1.16 (d, J = 6.8 Hz, 3H), 0.94 (t, J = 7.6 Hz, 3H), 0.77 (d, J = 6.8 Hz, 3H), 0.08 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 159.8 (C), 135.1 (CH), 131.6 (C), 127.4 (CH), 116.9 (CH2), 113.5 (CH), 93.3 (CH), 77.4 (CH), 76.1 (CH), 73.3 (CH), 61.1 (CH), 60.3 (CH), 55.4 (CH3), 37.3 (CH), 33.2 (CH), 30.2 (CH2), 28.3 (CH2), 12.5 (CH3), 10.1 (CH3), 9.6 (CH3), 0.4 (CH3). (4R,5R,6S)-4-((R)-1-((2R,4S,5S,6R)-6-allyl-2-(4-methoxyphenyl)-5-methyl-1,3-diox an-4-yl)ethyl)-6-ethyl-2,2,5-trimethyl-1,3-dioxane (19a) and (4R,5R,6S)-4-((R)-1((2S,4S,5S,6R)-6-allyl-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl)ethyl)-6-ethyl -2,2,5-trimethyl-1,3-dioxane (19b): To a suspension of CuI (1.58 g, 8.25 mmol) in dried Et2O (4 mL) was added dropwise MeLi (1.08 M in Et2O, 15.0 mL, 16.2 mmol) at -30 oC under Ar atmosphere. After being stirred for 30 min, a solution of 15 (704 mg, 1.57 mmol) in Et2O (6 mL) was added to the mixture at -30 oC. The reaction mixture was stirred for 4h while gradually rising temperature to 0 oC. After being further stirred for 5 h at 0 oC, the reaction mixture was quenched with saturated aqueous NaHCO3 and saturated aqueous NH4Cl and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated under reduced pressure to give crude 16 (678 mg). To a solution of the crude in THF (16 mL) was added TBAF (1.0 M in THF, 3.2 mL, 3.20 mmol). After being stirred for 45 min, the mixture was concentrated under reduced pressure. The residue was roughly purified by short column chromatography on silica gel (hexane : AcOEt = 3 : 1) to give 17 (558 mg) as a colorless oil. To a solution of 17 in 2,2-Dimethoxypropane (30 mL) was added TsOH·H2O (11.9 mg, 61.7 µmol) at room temperature. After being further stirred for 40 min, the reaction mixture was quenched with saturated aqueous NaHCO3 and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by 25 ACS Paragon Plus Environment


column chromatography on silica gel (hexane : AcOEt = 20 : 1) to give 19 (442 mg, 1.02 mmol, 65% from 15) as a colorless oil. Also separated 15a and 15b were subjected to the same procedure to give 19a and 19b in 63% and 71%, respectively. 19a; []D28 = +24.03° (c 1.18, CHCl3); IR (neat) 3009, 2978, 2940, 1612 cm-1; HRMS (EI/magnetic sector) m/z Calcd for C26H40O5 [M]+ 432.2876, found 432.2900; 1H NMR (400 MHz, CDCl3)  7.43 (d, J = 8.8 Hz, 2H), 6.88 (d, J = 8.8 Hz, 2H), 5.85-5.75 (m, 1H), 5.61 (s, 1H), 4.04 (td, J = 9.2, 1.6 Hz, 2H), 3.80 (s, 3H), 3.76 (d, J = 10.8 Hz,2H), 3.67-3.62 (m, 1H), 3.22 (d, J = 8.0 Hz, 1H), 2.48-2.32 (m, 2H), 2.26-2.19 (m, 1H), 1.94-1.86 (m, 1H), 1.77-1.72 (m, 1H), 1.51-1.33 (m, 2H),1.29 (s, 3H), 1.27 (s, 3H), 1.23 (d, J = 6.8 Hz, 3H), 1.06 (d, J = 7.2 Hz, 3H), 0.93 (t, J = 3.6 Hz, 3H), 0.81 (d, J = 6.8 Hz,3H); 13C{1H} NMR (100 MHz, CDCl3)  159.8 (C), 134.0 (CH), 131.8 (C), 127.3 (CH), 117.2 (CH2), 113.6 (CH), 100.3 (C), 95.3 (CH), 81.1 (CH), 74.6 (CH), 73.9 (CH), 71.2 (CH), 55.3 (CH3), 36.9 (CH2), 36.3(CH), 33.8 (CH), 30.5 (CH), 24.7 (CH3), 23.6 (CH2), 23.5 (CH3), 13.1 (CH3), 11.7 (CH3), 10.6 (CH3), 10.0 (CH3). 19b; []D33 = +48.81° (c 1.17, CHCl3); IR (neat) 3017, 2970, 2940, 1612 cm-1; HRMS (EI/magnetic sector) m/z Calcd for C26H40O5 [M]+ 432.2876, found 432.2861; 1H NMR (400 MHz, CDCl3)  7.39-7.36 (m, 2H), 6.89-6.86 (m, 2H), 5.97-5.87 (m, 1H), 5.69 (s, 1H), 5.19-5.11 (m, 2H), 4.14 (td, J = 11.2, 4.8 Hz, 1H), 3.85 (dd, J = 10.4, 2.0 Hz, 1H), 3.80 (s, 3H), 3.72-3.68 (m, 1H), 3.38 (dd, J = 7.6 Hz, 1H), 2.86-2.78 (m, 1H), 2.48-2.38(m, 1H), 2.29-2.22 (m, 1H), 1.86-1.72 (m, 2H), 1.51-1.29 (m, 8H), 1.08 (d, J = 6.8 Hz, 3H), 0.93-0.86 (m, 6H), 0.81 (d, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3)  159.7 (C), 135.2 (CH), 131.7 (C), 127.2 (CH), 116.7 (CH2), 113.4 (CH), 100.2 (C), 93.2 (CH), 76.1 (CH), 76.0 (CH), 75.8 (CH), 70.9 (CH), 55.2 (CH3), 39.8 (CH), 37.7 (CH), 33.6 (CH), 30.2 (CH2), 25.6 (CH3), 23.6 (CH2), 23.6 (CH3), 12.7 (CH3), 12.2 (CH3), 10.5 (CH3), 9.8 (CH3). 26 ACS Paragon Plus Environment

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(4R,5S,6S,7R)-7-((4R,5R,6S)-6-ethyl-2,2,5-trimethyl-1,3-dioxan-4-yl)-6-((4-methox ybenzyl)oxy)-5-methyloct-1-en-4-ol (20): To a solution of 19 (79.5 mg, 0.183 mmol) in CH2Cl2 (2 mL) was DIBAH (1.02 M in hexane, 0.80 mL, 0.816 mmol) at 0 oC under Ar atomosphere. After being stirred for 10 min, the reaction mixture was quenched with saturated aqueous NH4Cl and saturated aqueous Rochelle salt and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane : AcOEt = 12 : 1) to give 20 (55.5 mg, 0.128 mmol, 70%) as a colorless oil along with recovered 19a (13.9 mg, 0.0321 mmol, 18%). []D24 = +18.32° (c 0.98, CHCl3); IR (neat) 3472, 2978, 2940, 1612 cm-1; HRMS (FAB/magnetic sector) m/z Calcd for C26H43O5 [M+H]+ 435.3110, found 435.3100; 1H NMR (400 MHz, CDCl3)  7.27-7.24 (m, 2H), 6.87-6.85 (m, 2H), 5.81-5.70 (m, 1H), 5.13-5.04 (m, 2H), 4.60 (d, J = 10.4 Hz, 1H), 4.50 (d, J = 10.4 Hz, 1H), 4.00 (t, J = 7.2 Hz, 1H), 3.79 (s, 3H), 3.65-3.61 (m, 2H), 3.45 (dd, J = 8.4, 2.8 Hz, 1H), 3.18 (dd, J = 8.0, 1.6 Hz, 1H), 2.37-2.30 (m, 1H), 2.17-2.09 (m, 1H), 1.95-1.80 (m, 3H), 1.51-1.26 (m, 8H), 1.11 (d, J = 7.2 Hz, 3H), 1.10 (d, J = 7.2 Hz, 3H), 0.93 (t, J = 7.2 Hz, 3H), 0.78 (d, J = 6.8 Hz, 3H);

13C{1H}

NMR (100 MHz, CDCl3)

 159.3 (C), 135.2 (CH), 130.3 (C), 129.3 (CH), 117.1 (CH2), 113.9 (CH), 100.2 (C), 88.1 (CH), 75.8 (CH2), 74.7 (CH), 71.1 (CH), 70.0 (CH), 55.2 (CH3), 39.0 (CH), 39.0 (CH2), 36.6 (CH), 36.2 (CH), 24.9 (CH3), 23.8 (CH3), 23.6 (CH2), 11.9 (CH3), 11.4 (CH3), 10.5 (CH3), 10.4 (CH3). (5R,6R,7R)-7-((4R,5R,6S)-6-ethyl-2,2,5-trimethyl-1,3-dioxan-4-yl)-6-((4-methoxybe nzyl)oxy)-5-methyloct-1-en-4-one (22): To a solution of 20 (83.4 mg, 0.192 mmol) in DMSO (2.5 mL) was added 2-iodoxybenzoic acid (54.1 mg, 1.93 mmol) at room temperature. After being stirred for 1.5 h, the reaction mixture was quenched with 27 ACS Paragon Plus Environment


saturated aqueous NaHCO3 while ice cooling and filtered with celite pad. The filtrate was extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane : AcOEt = 8 : 1) to give 22 (82.1 mg, 0.190 mmol, 99%) as colorless oil. []D25 = -33.57° (c 0.68, CHCl3); IR (neat) 3017, 2970, 2940, 1713, 1612 cm-1; HRMS (ESI/magnetic sector) m/z Calcd for C26H40O5Na [M+Na]+ 455.2774, found 455.2761; 1H

NMR (400 MHz, CDCl3)  7.20-7.16 (m, 2H), 6.86-6.82 (m, 2H), 5.94-5.84 (m,

1H), 5.15-5.01 (m, 2H), 4.50 (d, J = 10.4 Hz, 1H), 4.21 (d, J = 10.4 Hz, 1H), 3.79 (s, 3H), 3.64 (td, J = 9.2, 4.8 Hz, 1H), 3.59 (dd, J = 8.4, 2.8 Hz, 1H), 3.41 (dd, J = 7.6, 2.4 Hz, 1H), 3.22 (d, J = 6.8 Hz, 1H), 2.95 (qd, J = 8.8, 6.8 Hz, 1H), 1.82-1.74 (m, 2H), 1.51-1.34 (m, 5H), 1.32 (s, 3H), 1.07 (d, J = 7.2 Hz, 3H), 1.04 (d, J = 7.2 Hz, 3H), 0.92 (t, J = 7.2 Hz, 3H), 0.83 (d, J = 6.8 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3)  212.0 (C), 159.0 (C), 130.9 (C), 130.8 (CH), 129.4 (CH), 118.5 (CH2), 113.6 (CH), 100.1 (C), 85.0 (CH), 75.9 (CH), 73.0 (CH2), 71.1 (CH), 55.2 (CH3), 49.0 (CH), 48.7 (CH2), 38.8 (CH), 37.1 (CH), 25.2 (CH3), 23.8 (CH3), 23.7 (CH2), 13.9 (CH3), 12.1 (CH3), 10.5 (CH3), 9.4 (CH3). (4S,5S,6S,7R)-7-((4R,5R,6S)-6-ethyl-2,2,5-trimethyl-1,3-dioxan-4-yl)-6-((4-methoxy benzyl)oxy)-5-methyloct-1-en-4-ol (23): To a solution of 22 (82.1 mg, 0.190 mmol) in THF (2.5 mL) was added (R)-(+)-2-methyl-CBS-oxazaborolidine (1.0M in toluene, 0.25 mL, 0.250 mmol) at room temperature under Ar atomosphere. After being strirred for 10 min at room temperature, BH3·THF (0.92 M in THF, 0.25 ml, 0.230 mmol) was added to the reaction mixture at -40 oC. After being further stirred for 30 min, the reaction mixture was quenched with saturated aqueous NaHCO3 and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated under reduced 28 ACS Paragon Plus Environment

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pressure. The residue was purified by column chromatography on silica gel (benzene : AcOEt = 24 : 1) to give 23 (79.7 mg, 0.183 mmol, 96%) as a colorless oil. []D24 = +39.28° (c 0.88, CHCl3); IR (neat) 3456, 2978, 2940, 1612 cm-1; HRMS (ESI/magnetic sector) m/z Calcd for C26H42O5Na [M+Na]+ 457.2930, found 457.2934; 1H NMR (400 MHz, CDCl3)  7.27-7.24 (m, 2H), 6.89-6.85 (m, 2H), 6.00-5.90 (m, 1H), 5.14-5.07 (m, 2H), 4.48 (s, 2H), 3.80 (s, 3H), 3.67 (dd, J = 5.2, 3.2 Hz, 1H), 3.65-3.62 (m, 1H), 3.61-3.55 (m, 2H), 3.33 (dd, J = 7.2, 2.4 Hz, 1H), 2.45-2.40 (m, 1H), 2.22-2.12 (m, 1H), 2.05-1.94 (m, 2H), 1.93-1.85 (m, 1H), 1.46-1.23 (m, 2H), 1.35 (s, 3H), 1.33 (s, 3H), 1.03 (d, J = 7.2 Hz, 3H), 0.894 (d, J = 7.6 Hz, 3H), 0.885 (t, J = 7.6 Hz, 3H), 0.84 (d, J = 6.8 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3)  159.3 (C), 135.6 (CH), 130.9 (C), 129.2 (CH), 116.7 (CH2), 113.7 (CH), 100.4 (C), 81.3 (CH), 77.9 (CH), 73.0 (CH), 71.9 (CH2), 71.6 (CH), 55.2 (CH3), 41.0 (CH), 38.9 (CH2), 38.4 (CH), 35.4 (CH), 25.3 (CH3), 23.8 (CH3), 23.6 (CH2), 12.9 (CH3), 12.8 (CH3), 10.9 (CH3), 10.5 (CH3). (4S,5S,6S,7R)-7-((4R,5R,6S)-6-ethyl-2,2,5-trimethyl-1,3-dioxan-4-yl)-6-((4-methoxy benzyl)oxy)-5-methyloct-1-en-4-yl

(3S,4S,6R,8S)-3-((tert-butyldimethylsilyl)oxy)-

4,6,8,10-tetramethylundec-10-enoate

and

(4S,5S,6S,7R)-7-((4R,5R,6S)-6-ethyl-2,2,5trimethyl-1,3-dioxan-4-yl)-6-((4-methoxybenzyl)oxy)-5-methyloct-1-en-4-yl (3R,4S,6R,8S)-3-((tert-butyldimethylsilyl)oxy)-4,6,8,10-tetramethylundec-10-enoat e (25): To a solution of 23 (62.9 mg, 0.145 mmol) and 24 (80.1 mg, 0.216 mmol) in CH2Cl2 (2 mL) was added Et3N (0.56 mL, 3.97 mmol), MNBA (164 mg, 2.04 mmol) and DMAP (6.0 mg, 0.0489 mmol) at room temperature. After being stirred for 4 h, the reaction mixture was quenched with saturated aqueous NaHCO3 while ice cooling and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated under 29 ACS Paragon Plus Environment


reduced pressure. The residue was purified by column chromatography on silica gel (hexane : AcOEt = 50 : 1) to give 25 (102 mg, 0.132 mmol, 91%, based on 23) with a diastereomeric ratio of 2 : 1 as a colorless oil. []D26 = -5.87° (c 0.89, CHCl3); IR (neat) 2963, 2932, 1728, 1605 cm-1; HRMS (ESI/magnetic sector) m/z Calcd for C47H82O7SiNa [M+Na]+ 809.5728, found 809.5717; 1H NMR (400 MHz, CDCl3)  7.26 (d, J = 8.4 Hz, 2H), 6.88-6.85 (m, 2H), 5.77-5.67 (m, 1H), 5.17-5.08 (m, 1H), 5.04-4.97 (m, 2H), 4.73 (s, 1H), 4.65 (s, 1H), 4.58 (dd, J = 10.8, 6.8 Hz, 1H), 4.40 (dd, J = 10.8, 8.4 Hz, 1H), 4.03-3.99 (m, 1H), 3.80 (s, 3H), 3.66-3.61 (m, 1H), 3.39-3.36 (m, 1H), 3.30 (q, J = 5.2 Hz, 1H), 2.51-2.46 (m, 1H), 2.46-2.32 (m, 2H), 2.30-2.23 (m, 1H), 2.20-2.11 (m, 1H), 2.04-1.98 (m, 1H), 1.92-1.82 (m, 2H), 1.79-1.60 (m, 3H), 1.68 (s, 3H), 1.60-1.51 (m, 1H), 1.50-1.42 (m, 1H), 1.40-1.31 (m, 1H), 1.322 (s, 3H), 1.316 (s, 3H), 1.28-1.21 (m, 1H), 1.20-0.96 (m, 4H), 1.04 (d, J = 6.8 Hz, 3H), 1.00 (d, J = 7.2 Hz, 3H) , 0.92 (t, J = 7.2 Hz, 3H), 0.87-0.86 (m, 9H), 0.86-0.80 (m, 9H), 0.056 (s, 3H), 0.024 (d, J = 5.6 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3)  171.4 (C, major), 171.0 (C, minor), 158.9 (C, both isomers), 144.8 (C, both isomers), 135.2 (CH, minor), 134.9 (CH, major), 131.4 (C, both isomers), 128.9 (CH, both isomers), 116.9 (CH2, major), 116.7 (CH2, minor), 113.6 (CH, both isomers), 111.3 (CH2, both isomers), 100.0 (C, both isomers), 84.1 (CH, minor), 83.8 (CH, major), 76.1 (CH, minor), 75.9 (CH, major), 74.1 (CH, both isomers), 73.8 (CH2, both isomers), 73.4 (CH, minor), 73.2 (CH, major), 71.3 (CH, both isomers), 55.2 (CH3, both isomers), 46.2 (CH2, major), 46.11 (CH2, major), 46.06 (CH2, minor), 46.0 (CH2, minor), 40.0 (CH2, major), 39.6 (CH2, major), 39.4 (CH, minor), 39.3 (CH, minor), 39.2 (CH2, minor), 39.10 (CH, major), 39.07 (CH, major), 38.6 (CH2, minor), 36.6 (CH, minor), 36.5 (CH, major), 36.0 (CH, minor), 35.4 (CH, major), 34.8 (CH2, minor), 34.7 (CH2, major), 27.8 (CH, minor), 27.7 (CH, 30 ACS Paragon Plus Environment

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major), 27.2 (CH, minor), 27.1 (CH, major), 25.9 (CH3, both isomers), 25.2 (CH3, both isomers), 23.84 (CH3, minor), 23.79 (CH3, major), 23.6 (CH2, both isomers), 22.2 (CH3, both isomers), 20.0 (CH3, minor), 19.9 (CH3, major), 19.8 (CH3, minor), 19.5 (CH3, major), 18.03 (C, major), 18.00 (C, minor), 14.8 (CH3, minor), 12.9 (CH3, major), 12.6 (CH3, minor), 12.5 (CH3, major), 12.1 (CH3, minor), 12.0 (CH3, major), 10.6 (CH3, both isomers), 9.8 (CH3, major), 9.7 (CH3, minor), -4.4 (CH3, major), -4.5 (CH3, minor), -4.7 (CH3, both isomers). (5S,7R,9S,14S,E)-14-((2S,3S,4R)-4-((4R,5R,6S)-6-ethyl-2,2,5-trimethyl-1,3-dioxan4-yl)-3-((4-methoxybenzyl)oxy)pentan-2-yl)-5,7,9,11-tetramethyloxacyclotetradec-1 1-ene-2,4-dione (27): A mixture of 25 (180 mg, 0.233 mmol) and Grubbs 2nd (41.4 mg, 0.0488 mmol) was stirred for 2.5 days in refluxing CH2Cl2 (400 mL, 0.6 mM) under Ar atmosphere. The reaction mixture was filtered through a short pad of silica gel (hexane : AcOEt = 7 : 1). The residue was purified by column chromatography on silica gel (hexane : AcOEt = 15 : 1) to give a ring closed compound (187 mg) as a colorless oil. To a solution of the compound in THF (3 mL) was added TBAF (1.0 M in THF, 0.25 mL, 0.250 mmol). After being stirred for 16 h, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane : AcOEt = 6 : 1) to give 26 (106 mg, 0.164 mmol, 70% from 25) with a diastereomeric ratio of 2 : 1 as a colorless oil. []D25 = +20.81° (c 0.94, CHCl3); IR (neat) 3472, 2963, 2924, 1721 cm-1; HRMS (EI/magnetic sector) m/z Calcd for C39H64O7 [M]+ 644.4652, found 644.4649; 1H NMR (400 MHz, CDCl3)  7.27-7.24 (m, 2H), 6.88-6.84 (m, 2H), 5.17-5.08 (m, 1H), 5.07-5.00 (m, 1H), 4.59 (d, J = 11.2 Hz, 1H), 4.38 (d, J = 11.2 Hz, 1H), 3.80 (m, 4H), 3.64 (td, J = 8.8, 3.6 Hz, 1H), 3.42-3.38 (m, 1H), 3.29-3.23 (m, 1H), 2.58-2.46 (m, 2H), 2.41-2.25 (m, 3H), 2.21-2.10 (m, 1H), 31 ACS Paragon Plus Environment


2.03 (d, J = 12.4 Hz, 1H), 1.95-1.81 (m, 2H), 1.74-1.57 (m, 4H), 1.56 (s, 3H), 1.52-1.26 (m, 8H), 1.31 (s, 3H), 1.05 (d, J = 7.2 Hz, 3H), 1.01-0.99 (m, 3H) , 0.94-0.84 (m, 15H) , 0.96-0.53 (m, 1H). To a mixture of 26 (106 mg, 0.164 mmol), tetrapropylammonium perruthenate (10.6 mg, 0.0302 mmol), MS4Å (166 mg) and CH2Cl2 (2 mL) was added 4-methylmorpholine N-oxide (49.0 mg, 0.418 mmol) at room temperature. After being stirred for 15 min, the reaction mixture was filtered through a short pad of silica gel (hexane : AcOEt = 4 : 1). The residue was purified by column chromatography on silica gel (hexane : AcOEt = 20 : 1) to give 27 (93.8 mg, 0.146 mmol, 89%) as a colorless oil. []D28 = -41.85° (c 0.81, CHCl3); IR (neat) 3017, 2963, 2932, 1705 cm-1; HRMS (EI/magnetic sector) m/z Calcd for C39H62O7 [M]+ 642.4496, found 642.4496; 1H NMR (400 MHz, CDCl3)  7.27-7.25 (m, 2H), 6.88-6.84 (m, 2H), 5.12-5.08 (td, J = 10.0, 3.6 Hz, 1H), 4.97-4.93 (m, 1H), 4.58 (d, J = 10.8 Hz, 1H), 4.40 (d, J = 11.2 Hz, 1H), 3.80 (s, 3H), 3.66-3.62 (m, 1H), 3.50 (d, J = 12.8 Hz, 1H), 3.43 (dd, J = 8.0, 2.0 Hz, 1H), 3.29-3.25 (m, 2H), 2.99-2.91 (m, 1H), 2.37-2.26 (m, 2H), 2.19-2.12 (m, 1H), 1.99 (d, J = 10.8 Hz, 1H), 1.95-1.81 (m, 3H), 1.72-1.52 (m, 2H), 1.54 (s, 3H), 1.50-1.25 (m, 3H), 1.31 (s, 6H), 1.29-1.24 (m, 1H), 1.10 (d, J = 7.2 Hz, 3H), 1.05 (d, J = 7.2 Hz, 3H), 1.01 (d, J = 7.2 Hz, 3H), 0.97-0.83 (m, 2H), 0.92 (t, J = 7.2 Hz, 3H), 0.89-0.86 (m, 9H), 0.54-0.47 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3)  205.6 (C), 166.4 (C), 158.9 (C), 136.6 (C), 131.3 (C), 128.9 (CH), 122.1 (CH), 113.6 (CH), 100.7 (C), 84.1 (CH), 76.7 (CH), 75.5 (CH), 74.0 (CH2), 71.3 (CH), 55.2 (CH3), 49.0 (CH2), 48.9 (CH2), 41.4 (CH2), 41.2 (CH), 39.6 (CH), 39.2 (CH), 39.1 (CH2), 36.6 (CH), 29.6 (CH), 28.6 (CH2), 28.0 (CH), 25.2 (CH3), 23.8 (CH3), 23.6 (CH2), 23.2 (CH3), 21.0 (CH3), 19.5 (CH3), 16.7 (CH3), 12.3 (CH3), 11.9 (CH3), 10.6 (CH3), 9.9 (CH3). Sekothrixide: To a solution of 27 (58.6 mg, 0.0911 mmol) in CH2Cl2 (4 mL) and H2O 32 ACS Paragon Plus Environment

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(0.7 mL) was added DDQ (32.2 mg, 0.139 mmol) at room temperature. After being stirred for 40 min, the reaction mixture was quenched with saturated aqueous NaHCO3 and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane : AcOEt = 6 : 1) to give mono-alcohol compound (40.9 mg, 0.0782 mmol, 86%) as a colorless oil. []D26 = -83.16° (c 0.16, CHCl3); IR (neat) 3503, 2970, 2924, 1713 cm-1; HRMS (EI/magnetic sector) m/z Calcd for C31H54O6 [M]+ 522.3920, found 522.3898; 1H NMR (400 MHz, CDCl3)  5.36 (ddd, J = 11.6, 3.6, 2.0 Hz, 1H), 5.10-5.07 (m, 1H), 3.65 (td, J = 9.2, 5.2 Hz, 1H), 3.57-3.53 (m, 2H), 3.54 (d, J = 12.8 Hz, 1H), 3.48 (dd, J = 8.4, 2.0 Hz, 1H), 3.28 (d, J = 12.8 Hz, 1H), 3.01-2.92 (m, 1H), 2.38-2.29 (m, 1H), 2.16-2.12 (m, 1H), 2.12-2.03 (m, 1H), 2.03-1.91 (m, 2H), 1.91-1.83 (m, 1H), 1.72-1.51 (m, 2H), 1.68 (q, J = 10.8 Hz, 3H), 1.59 (s, 3H), 1.49-1.29 (m, 3H), 1.39 (s, 3H), 1.31 (s, 3H), 1.12 (d, J = 7.2 Hz, 3H), 0.97-0.90 (m, 1H), 0.96 (d, J = 7.2 Hz, 3H), 0.92 (t, J = 7.2 Hz, 3H), 0.888 (d, J = 6.4 Hz, 3H), 0.885 (d, J = 6.8 Hz, 6H), 0.83 (d, J = 6.8 Hz, 3H), 0.53 (ddd, J = 14.0, 7.6 Hz, 1H);

13C{1H}

NMR (100 MHz,

CDCl3)  205.9 (C), 166.6 (C), 137.0 (C), 122.0 (CH), 100.7 (C), 81.1 (CH), 78.6 (CH), 76.5 (CH), 71.1 (CH), 49.34 (CH2), 49.29 (CH2), 41.3 (CH2), 41.1 (CH), 39.3 (CH), 39.0 (CH2), 36.5 (CH), 36.0 (CH), 29.8 (CH), 28.0 (CH), 26.5 (CH2), 24.8 (CH3), 24.0 (CH3), 23.5 (CH2), 23.2 (CH3), 21.1 (CH3), 19.6 (CH3), 16.4 (CH3), 12.0 (CH3), 10.5 (CH3), 10.0 (CH3), 5.1 (CH3). To a solution of 28 (40.5 mg, 0.0775 mmol) in iPrOH (5 mL) and H2O (5mL) was added TsOH·H2O (15.6 mg, 0.0812 mmol) at room temperature. After being stirred for 13 h at 50 oC, the reaction mixture was quenched with saturated aqueous NaHCO3 and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by 33 ACS Paragon Plus Environment


column chromatography on silica gel (hexane : AcOEt = 4 : 1) to give sekothrixide (33.6 mg, 0.0696 mmol, 90%) as a colorless oil. []D25 = -47.65° (c 1.54, CHCl3); IR (neat) 3426, 2970, 2924, 1705 cm-1; HRMS (EI/magnetic sector) m/z Calcd for C28H50O6 [M]+. 482.3607, found 482.3612; 1H NMR (400 MHz, CDCl3)  5.26 (ddd, J = 11.2, 3.6, 2.0 Hz, 1H), 5.06-5.03 (m, 1H), 4.14 (br, 1H), 3.84 (dd, J = 9.6, 2.0 Hz, 1H), 3.73-3.71 (m, 1H), 3.62 (d, J = 10.4 Hz, 1H), 3.55 (br, 1H), 3.53 (d, J = 12.8 Hz, 1H), 3.30 (d, J = 13.2 Hz, 1H), 2.96-2.88 (m, 1H), 2.63 (br, 1H), 2.40-2.31 (m, 1H), 2.17-2.12 (m, 1H), 2.10-1.99 (m, 1H), 2.01 (d, J = 13.6 Hz, 1H), 1.94-1.84 (m, 2H), 1.74-1.44 (m, 6H), 1.59 (s, 3H), 1.34-1.28 (m, 1H), 1.11 (d, J = 7.2 Hz, 3H), 1.01 (t, J = 7.2 Hz, 3H), 0.99-0.89 (m, 1H), 0.91-0.87 (m, 9H), 0.84 (d, J = 6.8 Hz, 3H), 0.77 (d, J = 7.2 Hz, 3H), 0.55-0.48 (m, 1H);

13C{1H}

NMR (100 MHz, CDCl3)  205.7 (C), 167.0

(C), 137.2 (C), 121.6 (CH), 79.5 (CH), 79.0 (CH), 76.7 (CH), 76.2 (CH), 49.0 (CH2), 48.9 (CH2), 41.5 (CH), 41.3 (CH2), 39.7 (CH), 39.3 (CH2), 35.1 (CH), 29.7 (CH), 28.1 (CH), 26.9 (CH2), 25.1 (CH2), 23.3 (CH3), 21.1 (CH3), 19.3 (CH3), 16.6 (CH3), 11.9 (CH3), 11.1 (CH3), 10.7 (CH3), 3.9 (CH3).

ASSOCIATED CONTENT Supporting Information The supporting Information is available free of charge on the ACS publications website at DOI Copies of the 1H/13C NMR of all new products

Acknowledgment. Financial support from the Ministry of Education, Culture, Sports, Science and Technology, Japan (a grant from the Strategic Research Foundation 34 ACS Paragon Plus Environment

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Grant-aided Project for Private Universities (S1411005), a Grant-in-Aid for Scientific Research (B) (No. 19350027) and (C) (No. 16K05782), and Advanced Promotion Research Program for Education of Graduate School) is gratefully acknowledged. We wish to dedicate this study to Dr. Kiyoshi Sakai, Professor Emeritus of Kyushu University, on the occasion of his 88th birthday (BEIJU).

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(a) Kim, Y. J.; Furihata, K.; Shimazu, A.; Furihata, K.; Seto, H. Isolation and structural elucidation of sekothrixide, a new macrolide effective to overcome drug-resistance of cancer cell. J. Antibiot., 1991, 44, 1280-1282. (b) "Studies on microbial metabolites effective against multi-drug resistant cancer cells", (Doctoral thesis, Tokyo Univ.), Kim, Y. J. (1993). (c) Tennen Yuki Kagobutsu Toronkai Koen Yoshishu 1996, 38th, 379-384. 35 ACS Paragon Plus Environment


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Total Synthesis of Sekothrixide Strategically Utilizing Regioselective

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