Asymmetric Total Synthesis of Lancifodilactone G Acetate, Part 2: Final

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Asymmetric Total Synthesis of Lancifodilactone G Acetate, Part 2: Final Phase and Completion of the Total Synthesis Kuang-Yu Wang, Dong-Dong Liu, Tian-Wen Sun, Yong Lu, Su-Lei Zhang, Yuan-He Li, YiXin Han, Hao-Yuan Liu, Cheng Peng, Qin-Yang Wang, Jia-Hua Chen, and Zhen Yang J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02917 • Publication Date (Web): 06 Mar 2018 Downloaded from http://pubs.acs.org on March 6, 2018

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The Journal of Organic Chemistry

Asymmetric Total Synthesis of Lancifodilactone G Acetate, Part 2: Final Phase and Completion of the Total Synthesis Kuang-Yu Wang,† Dong-Dong Liu,† Tian-Wen Sun,† Yong Lu,† Su-Lei Zhang,† Yuan-He Li,† Yi-Xin Han,† Hao-Yuan Liu,† Cheng Peng,† Qin-Yang Wang,† Jia-Hua Chen,*,† Zhen Yang*,†,‡ †

State Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education and Beijing National Laboratory for Molecular Science (BNLMS), College of Chemistry and the Peking University, Beijing 100871

‡

Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Shenzhen Graduate School of Peking University, Shenzhen, China, 518055

[email protected], [email protected] RECEIVED DATE

ABSTRACT: The asymmetric total synthesis of lancifodilactone G acetate was accomplished in 28 steps. The key steps in this synthesis include :i) an asymmetric Diels–Alder reaction for formation of the scaffold of the BC ring; ii) an intramolecular ring-closing metathesis reaction for the formation of the tri-substituted cyclooctene using a Hoveyda–Grubbs II catalyst; iii) an intramolecular Pauson–Khand reaction for construction of the sterically congested F ring; iv) sequential cross-metathesis, hydrogenation, and lactonization reactions for installation of the anomerically stabilized bis-spiro ketal fragment of lancifodilactone G; and v) a Dieckmann-type condensation reaction for installation of the A ring. The strategy and chemistry developed for the total synthesis will be useful in the synthesis of other natural products and complex molecules. ACS Paragon Plus Environment

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Introduction In a previous article,1 we reported the diastereoselective synthesis of a model of lancifodilactone G (1),2 which contains a CDEFGH ring system. On the basis of the developed chemistry, we initiated a program for the asymmetric total synthesis of 1. Because of the anticipated sensitivity of the highly rigid bis-spiro system3 to both acidic and basic conditions, this segment should be installed at a late stage of the total synthesis. With this in mind, intermediate A was identified as a potential precursor of our target 1 (Fig. 1). In this article, we first describe chemistry for the asymmetric synthesis of intermediate A, and then present our effort to the asymmetric total synthesis of lancifodilactone G acetate (1a in Fig. 1)

Figure 1: Strategic bond disconnections of 1. As shown in Figure 1, intermediate A was expected to generated from intermediate B via a Pauson–Khand (PK) reaction4 for the formation of its FG ring. As the chemistry in our previous model study,1 in planning our current total synthesis of lancifodilactone G (1), to make the total synthesis more concise, we wished to use the tri-substituted olefin B as a substrate in the PK reaction, to enable generation of the intermediate A bearing a C-13 methyl group from substrate B in one step. In addition, ACS Paragon Plus Environment

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this PK reaction could be diastereoselective with regard to the formation of the two contiguous stereogenic centers at C-13 and C-14 because of the defined favorable conformation of enyne, dictated by the linking ester. In line with this analysis, our synthetic analysis was traced back to the synthesis of the tri-substituted cyclooctene ring in intermediate B via a ring-closing metathesis (RCM) reaction5 from diene C. Such a type of RCM reaction has been realized in our model study of 11 as well as in our previous synthetic study towards the total synthesis of Arisandilactone A.6 Diene C in turn was expected to made using the chemistry developed for the total synthesis of schindilactone A7 from lactone D, which was expected to be derived from ketoester E, an asymmetric Diels-Alder8 product being made from diene F and dienophile G via a modified9 Corey’s CBS catalysts.10 Herein, we report our effort toward the asymmetric construction of the core structure of BC ring, include: 1) chiral pool approach from the commercially available (R)-(–)-carvone as the starting material; 2) concise and efficient Diels-Alder reaction for the BC ring in the presence of a modified Corey’s cationic oxazaborolidine catalysts, and the details of our designed synthesis are also discussed, featuring 1) an intramolecular PK reaction to diastereoselectively form the highly rigid F ring bearing the C-13 all-carbon quaternary chiral center in intermediate A; 2) an intramolecular RCM reaction for construction of the tri-substituted cyclooctene intermediate B; 3) sequential cross-metathesis, hydrogenation, and lactonization reactions for installation of the anomerically stabilized bis-spiro ketal fragment G; and 4) a Dieckmann-type condensation reaction for installation of the A ring. Results and Discussion

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Synthesis of BC ring system. We then turned our attention to the asymmetric synthesis of lactone D, which is a corner stone in our asymmetric total synthesis of 1. Our initial effort toward asymmetric synthesis of the intermediate lactone D relayed on the chiral pool approach,11 and we selected the commercially available (R)-(–)-carvone (2) as the starting material, because 2 is an abundant naturally occurring secondary metabolite which has been widely used as the starting material in total synthesis of numerous natural products,12 and the built-in chirality of 2 could be used to induce the formation of other chiral centers in 1, leading to the asymmetric total synthesis of the target molecule. Scheme 1: Attempt for the synthesis of intermediate D O

OtBu OH

a. LiHMDS Boc-imid.

Me

Me

Me H

Me

3

(R)-(-)-carvone (2)

O

O

O O

c. 4 , oxone MeCN/H2 O (dr = 5:1)

O

4

O

e. TBSCl imid. CH2 Cl2 , rt

O

H 9

O

(43% in 3 steps)

H

HO

7

H

O

O

Me Me

TBSO

O

Me

O

O Me

O

b. Et2Zn HCO2H, CH2I 2 (68% in 2 steps)

Me

OtBu

OtBu d. H2SO4 MeOH/H2O O rt Me Me O

H

O Me

H

5

6

f. (CH2OTMS)2 , TMSOTf CH2Cl2 (61%) O H 10

O

TBSO

Me

O

O O Me

low yield O B

H

8

TBSO

Me

OTES

O

10

C

Me

H

D

Reaction conditions: a) LiHMDS (2.0 equiv), THF, -78 °C to 0 °C, 0.5 h, then Boc-imid. (1.4 equiv), -78 °C, 2 h, 90%; b) Et2Zn (2.3 equiv), CH2I2 (2.3 equiv), HCO2H (2.3 equiv), DCM, 0 °C, 75%; c) Shi’s catalyst A (0.3 equiv), oxone (1.3 equiv), MeCN/H2O (1:1), rt., 70%; d) H2SO4 (2.0 equiv), MeOH/H2O (10:1), rt.; e) TBSCl (2.2 equiv), imidazole (4.5 equiv), CH2Cl2, rt., 61% for two steps; f) TMSOCH2CH2OTMS (2.4 equiv), TMSOTf (0.1 equiv), DCM, -78 °C to -20 °C, 61%.

Scheme 1 shows our asymmetric synthesis of lactone 8 from 2. A two-step procedure for the conversion of 2 to cycloheptenone was accomplished using a modification of Mander’s method13


4

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followed by a sequence of cyclopropanation/ring-expansion reactions14 to afford olefin 3 in 68% yield. 3 was first subjected to Shi’s epoxidation15 at room temperature using catalyst 4 in the presence of oxone, and the resultant epoxides 5 (obtained as a pair of diastereoisomers in a ratio of 5:1) were subjected to an acid-mediated cascade epoxide hydroxylation/lactonization to afford alcohol 6, which without purification was reacted with TBSCl/imid. to give silyl ether 7 in 43% yield in three steps. The relative stereochemistry of 7 was confirmed by X-ray crystallographic analysis. Thus, further treatment of 7 with TMSOCH2CH2OTMS in the presence of TMSOTf in CH2Cl2, ketal 8 was obtained in 61% yield. However, when we attempted to insert the C-10 hydroxyl group in ketal 8 to form the intermediate D (Fig. 1) via the chemistry applied in our total synthesis of schindilactone A,7 the overall yield was low, which led us to explore the asymmetric Diels–Alder reaction as an alternative pathway toward the synthesis of intermediate D. Figure 2: Diels–Alder reactions of (E)-4-oxopent-2-enoates H with F

According to our retrosynthetic analysis, we selected dienophile H bearing two different electron-with drawing groups16 as a partner in the proposed Diels–Alder reaction for the synthesis of ACS Paragon Plus Environment

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ketoester E (Fig. 1), and we expected that this type of dienophile was effective in consideration of the fact that the ability of two electron-withdrawing groups could lower the level of the lowest unoccupied molecular orbital.17 However, further literature searching indicated that the low site-selective coordination of the two carbonyl groups in (E)-4-oxopent-2-enoate H with Lewis acids18 (eq. 1 in Fig. 2) would diminish its usefulness in asymmetric Diels–Alder reactions. In addition, the selectivity of Lewis acid coordination with the ketone moiety is also low because the ketone is in a similar steric environment19 (eq. 2 in Fig. 2). With this chemistry in mind, we began to systematically evaluate several well-known ligands and catalysts20 to promote our desired asymmetric Diels–Alder reaction for the synthesis of our key intermediate E. Table 1: Diels-Alder reactions in the presence of Macmillan catalysts


6

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The Journal of Organic Chemistry Me O

N R2

R1

O OTIPS +

O

(10 mol%)

EtO OTBS

10

9

N H

O

H

OTIPS

EtO

HClO4- (10 mol%) TBSO solvent 0 oC, 48 h

O

H 11

entry

R1

R2

solvent

acid

temperature

result

1

Ph

Ph

H2 O

HClO4-

0 oC

45% yield, 0% eea

0 oC

70% yield, 0% eeb

2

Bn

5-Me-furyl

H2 O

HClO4-

3

Bn

Ph

H2 O

HClO4-

0 oC

50% yield, 0% ee c

4

Bn

Ph

none

HClO4-

0 oC

decomposed d

0 C o

0 C o

reagents and conditions: (a) diene 9 (338 mg, 1.5 mol), dienophile 10 (272 mg, 1.0mol), H2O (0.3 mL). (b) dienophile was decomposed from the TLC, and no desired product was formed. Me O

Me

N

O

Me O

N

N

Ph Ph

N H

catalyst I

Ph Ph

N H

O

Me

Ph

catalyst II

N H

catalyst III

Initially, we attempted to use a Macmillan catalyst21 to promote the asymmetric Diels–Alder reaction of diene 9 and dienophile 10 to give product 11; the results are shown in Table 1. Under typical Macmillan catalytic conditions, the reaction between diene 9 and dienophile 10 in HClO4− in water in the presence of catalyst I at 0 °C was complete in 48 h, and the desired product 11 was obtained in 45% yield; however, no enantiomeric excess was observed (entry 1). We then performed the reaction using the Macmillan catalysts II and III (entries 2 and 3) under identical conditions. The yields of product 11 increased, but still no enantiomeric excess was observed. We also performed the reaction with catalyst III in the absence of solvent. The desired product 11 was not formed, and 9 and 10 decomposed. Table 2: Diels-Alder reactions in the presence of Corey’s catalysts


7


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We next used Corey’s cationic oxazaborolidines22 as catalysts in our Diels–Alder reaction for the asymmetric synthesis of product 11. We selected four Corey’s CBS catalysts; the results are shown in Table 2. Catalysts A, B, and C (entries 1–3) catalyzed Diels–Alder reactions of diene 9 with dienophile 10, giving product 11 in good to excellent yields with medium enantiomeric excesses. The reaction performed using catalyst D (entry 4) gave product 11 in good yield; no enantiomeric excess was observed. We then used modified Corey’s cationic oxazaborolidine catalysts to improve the ee value of the Diels–Alder reaction for the asymmetric synthesis of product 11 (Table 3). Table 3: Diels-Alder reactions in the presence of CBS-E to CBS-H


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We envisioned that electron-deficient substituents on the aryl ring of the Corey’s CBS catalysts could enhance coordination between the boron atom and the carbonyl group in dienophile 10, resulting in an improvement in the enantiomeric excess of the Diels–Alder reaction of dienophile 10 with diene 9. We therefore synthesized catalysts CBS-E, CBS-F, CBS-G, and CBS-H,23 and used them in Diels– Alder reactions under the conditions listed in Table 3. When the CBS-H catalyst was used, the Diels– Alder reaction of diene 9 with dienophile 10 was complete within 1 h and the desired product 11 was obtained in 95% yield with 96% ee.9 With compound 11 in hand, we started to plan the synthesis of compound 60. Because of the structural similarity of the BC ring in 60 to the BC ring in schindilactone A (2), we based the synthesis on the chemistry used in the total synthesis of schindilactone A.7 The reaction of keto ester 56 with MeMgBr in tetrahydrofuran (THF) gave lactone 12 as a pair of diastereoisomers (in a ratio of 1.7:1). Lactone 12 was treated, without separation, with KHMDS in the presence of P(OMe)3 under O2, followed by reaction with TESCl to give lactone 13 in 42% yield, together with its C-4 diastereoisomer ACS Paragon Plus Environment

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in 38% yield. Lactone 15 was synthesized by treating 13 with CHBr3/t-BuOK in petroleum ether, and the resultant 1,1-dibromocyclo-propane 14 was directly treated with AgClO4·H2O and CaCO3 in acetone at room temperature in 49% yield in two steps (Scheme 2). The ee value of 15 after recrystallization was 99%. At this stage, the asymmetric version of the key intermediate A can be obtained with good ee value through the same chemistry in scheme 1. Scheme 2: Synthesis of compound 15 O OTIPS a. MeMgCl THF

EtO O

11 OTBS

O

H

OTIPS

O

OTES

O B

C

O Br

O

OTES

OTIPS

O

∗ -78 oC o to -20 C Me H 12 (85%) OTBS (d.r. =1.7:1)

O

b. KHMDS P(OMe)3

O2, THF -78 oC to 0 oC Me H 13 then TESCl OTBS c. tBuOK (42%) CHBr3 PE, -20 oC d. AgClO4•H2O Ca(CO3)2, acetone (49% in 2 steps)

4

Me H 15 TBSO (> 99% ee after recrystallization)

TBSO

O

OTES

O

OTIPS Br Br

Me H 14

Reaction conditions: a) MeMgCl (2.0 equiv.), THF, -78 °C to -20 °C, 0.5 h, 85% (dr = 1.7:1); b) KHMDS (2.0 equiv.), THF, -78 °C to 0 °C followed by addition of P(OMe)3 (2.0 equiv.), O2, 0 °C, 1 h; then TESCl (1.5 equiv.), 42% and 38% C-4 isomer; c) KOtBu (6.0 equiv.), CHBr3 (6.0 equiv.), petroleum ether, -20 °C, 2 h; d) AgClO4▪H2O (2.0 equiv.), acetone, rt, 12 h, 49% for two steps.

Synthesis of BCDEFG ring system. Our study began with the synthesis of enyne 22 using the chemistry developed in the total synthesis of(+)-19-dehydroxyarisandilactone A.6 The Pd-catalyzed cross-coupling of copper enolate24 and vinyl bromide 15 was achieved by exposure of 15 and (1-tert-butoxyvinyloxy)-(tert-butyl)dimethylsilane to [PdCl2{P(o-tol)3}2] (5 mol%) in the presence of CuF2 (2.0 equiv) in THF at 75 °C; the desired product 16 was obtained in 77% yield (Scheme 3). Scheme 3: Synthesis of compound 22


10

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Reaction conditions: a): (1-tert-butoxyvinyloxy)-(tert-butyl)dimethylsilane (3.0 equiv), PdCl2/[P(o-tol)3]2 (0.1 equiv), CuF2 (3.0 equiv.), THF, reflux, 12 h, 77%; b) Pd/C (10 wt%), H2, EtOAc, 50 °C, 1 h, 97%; c) Grignard reagent (5.0 equiv), THF, -78 °C to 0 °C, 84%; d) LiHMDS (3.5 equiv), LiCl (5.0 equiv), THF, -78 oC, MoOPH (3.5 equiv), 2h; 85%; e) Ag2O (2.0 equiv), BnBr (2.0 equiv), 35 °C, 12 h, 94%; f) vinylmagnesium bromide (3.0 equiv), THF, 0 °C, 1 h; g) Hoveyda-Grubbs II catalyst (8 mol%), toluene, 85 °C, 12 h, 75% for two steps; h) KHMDS (2.0 equiv), but-2-ynoic pivalic anhydride (5.0 equiv), THF, 0 °C, 1 h, 86%.


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Diastereoselective hydrogenation was achieved using Pd/C under a balloon pressure of H2, giving product 17 in 85% yield as a single isomer. A chemoselective Grignard reaction was performed by treating 17 with 3-methylbut-3-en-1-ylmagnesium bromide in THF at 0 °C, affording lactone18 in 83% yield as a single isomer. The relative stereochemistry of 18 was confirmed by X-ray crystallographic analysis. The observed diastereoselective hydrogenation of 16 and Grignard reaction of 17 can be attributed to the steric bulk of the triethylsilyloxy group in substrates 16 and 17, which results in reagents accessing the substrates at their less-hindered faces (see three-dimensional structure of 17 in Scheme 3). To achieve facially selective α-hydroxylation, bis-lactone 18 was treated with LiHMDS in the presence of LiCl25 in THF at −78 °C. The resulting enolate complex was oxidized with MoOPH26 to afford a secondary alcohol, which was then treated with BnBr/Ag2O27 to give benzyl ether 19 in 58% overall yield as a single diastereoisomer. We then investigated our proposed RCM reaction for construction of the medium-ring-based28 tri-substituted cyclooctene in compound 21. Because of the feasibility of the hemi-ketal epimerization in diene 20 during the RCM reaction, 7,29 we decided to react bis-lactone 19 with vinylmagnesium bromide,30 and the resultant diene 20 as a pair of diastereoisomers of hemi-acetal, without separation, were tested their RCM reaction. The chemo-selective Grignard reaction for the formation of diene 20 is presumably because the carbonyl group at C15 in bis-lactone 19 is less sterically hindered compared with the carbonyl group at C1, which links to sterically bulky TES protected tertiary. As a result, even a large excess of Grignard reagent could not attack the C1 carbonyl group. Thus, after screening of various catalysts, solvents, additives, and reaction temperatures, we found that the expected RCM reaction could be achieved using a second-generation Hoveyda–Grubbs


12

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catalyst,31 and the desired product 21 was obtained as a single diastereoisomer in an overall yield of 75% for the two steps. Thus, further treatment of compound 21 with KHMDS in THF at 0 °C, and the resultant alkoxide was then reacted with but-2-ynoic pivalic anhydride32 to give ester 22 in 85% yield. We then move to the stage to explore chemistry for the construction of the cyclopentenone moiety bearing an all-carbon quaternary chiral center at C-13 in the critical intermediate 23 (Fig. 1) via the PK reaction.33 On the basis of model study1 and our group’s previous total syntheses in which PK reaction was used,34 as well as other group’s synthetic progress based on PK reaction,35 we performed the PK reaction for the stereoselective synthesis of 23 from enyne22. The reaction of 22 with Co2(CO)8 and TMTU in toluene at 95 °C for 6 h, gave product 23 in 80% as a single diastereoisomer (Scheme 4). The stereochemistry of 23 was confirmed by X-ray crystallographic analysis. Scheme 4: Synthesis of cyclopentenone 23 via PK reaction

Reaction conditions: Co2(CO)8 (0.2 equiv), TMTU (1.2 equiv, toluene, under a balloon pressure of CO, toluene, 95 °C, 8 h, 80%.

Attempts towards the asymmetric total synthesis of lancifodilactone G (1). The completion of asymmetric synthesis of compound 23 bearing the BCDEFG ring system of lancifodilactone G (1) set the stage for us to achieve the challenging asymmetric total synthesis of this complex natural product. ACS Paragon Plus Environment

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To this end, we first identify a suitable method for generating the stereogenic centers at C-20 and C-22 in 23 (Scheme 5). In our model study of the CDEFG ring system,1 we used LiAlH2(OMe)2 as an effective reducing agent for generating such stereogenic centers, but we could not use this reagent in the reaction with substrate 23 because there are two lactone groups in its scaffold. Inspection of the three-dimensional structure of 23 showed that its convex face is less sterically hindered than its concave face (Scheme 5). We therefore speculated that direct hydrogenation of 23 would afford product 24a with the opposite stereochemistry at C-20, which could be inverted to the desired stereochemistry by base-mediated epimerization because the β-face methyl group at C-20 is more stable than its counterpart α-face methyl group. With this chemistry in mind, we performed Pd-catalyzed hydrogenation of 23 under a balloon pressure of H2, followed by treatment with DBU. The expected product 24 was obtained in 78% yield in two steps. Scheme 5: Stereoselective synthesis of compound 24 O

Me

OTES

20

O

TBSO

O

Me H

H

23

Pd/C, H2 then Me DBU, 40 oC

O

O

OBn

(78%) one-pot TBSO

a. Pd/C, H2

O

Me

Me H

H

24

H H O

OBn

O

O 20

O

TBSO

Me O

b. DBU

OTES

Me H

O

OTES

O

22

H O

Me

O

O H

OBn

Me H

H O

22

O

24a 3D structure of compound 23 Reaction conditions: a) Pd/C (0.5 equiv), EtOAc, rt. 0.5 h. b) DBU (2.0 equiv), CH2Cl2, 40 °C, 12 h, 78% for 2 steps. DBU = 1, 8-diazabicyclo[5.4.0]undec-7-ene.

We next focused on formation of the H ring in 28 (Scheme 6). Our model study of the CDEFGH ring system1 showed that the H ring could be installed via a Grignard/cross-metathesis/hydrogenation/ lactonization reaction sequence. We therefore used this method for formation of the H ring in 28. When ACS Paragon Plus Environment

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lactone 24 was reacted with vinylmagnesium bromide at −15 °C, product 25a was formed as a pair of diastereoisomers. When we purified these compounds via flash column chromatography on silica gel, interestingly, we only got compound 25 as a single diastereoisomer. NOE experiments indicated that the stereochemistry at the newly generated chiral center at C-23 in 25 matched that in the natural product 1. The observed epimerization presumably occurred because the silica gel, which acted as an acid, mediated hemi-ketal epimerization to afford compound 25. Scheme 6: Synthesis of compound 28

Reaction conditions: a) vinylmagnesium bromide (3.0 equiv), THF, -15 °C, 0.5 h, 78%; b) methyl acrylate (20 equiv), Hoveyda-Grubbs II catalyst (5 mol %), toluene, 88 °C, 12 h, 66%; c) Pd/C (10 wt%), H2, EtOAc, rt, 1 h; d) Sodium hydride (10 equiv), THF, 40 °C, 72% for two steps.

A cross-metathesis reaction of 25 with methyl acrylate in the presence of a second-generation Hoveyda–Grubbs catalyst in toluene at 85 °C for 10 h gave product 26 in 66% yield. Selective ACS Paragon Plus Environment

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hydrogenation of 26 to remove its double bond by treatment with Pd/C under a balloon pressure of H2, followed by NaH-mediated intramolecular lactonization,36 gave the desired product 28 in 72% yield in two steps (Scheme 6). We next focused on installation of the C-25 methyl group and A-ring. Scheme 7 shows our initial attempt to synthesize 30, a potential precursor for installation of the A ring (Scheme 7). Scheme 7: Synthesis of compound 30 and 30a

Reaction conditions: a) TBAF (2.0 equiv), THF; TBSCI (5.0 equiv), 40 °C, 6 h, 74%; b) LiHMDS (2.0 equiv), MeI (3.0 equiv), THF, −78 °C, 76%.


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Initial effort to selective desilylation of TES group from 28 failed to afford 29 under various conditions, e.g., TBAF, CSA/MeOH, and CSA/t-BuOH, presumably because this tertiary alcohol-based silyl ether is too stable to be removed. We therefore decided to take off both the silyl groups in substrate 28, and the resultant diol was then selectively protected the primary alcohol as its TBS silyl ether. To this end, compound 28 was first desilylated by treatment with TBAF in THF, and the resultant diol then treated with TBSCl/imidazole at 40 °C to selectively protected its primary alcohol, and resulted in product 29 in 74% yield in two steps. Compound 29 was treated with LiHMDS (5.0equiv) in THF at – 78 °C, and the resultant enolate derived from the H-ring lactone was reacted with MeI at the same temperature to give products 30 and 30a in a 1:1 ratio in 76% yield. The structure of 30, which has an undesired chiral center at C-25, was confirmed by X-ray crystallographic analysis. Although we attempted to improve yield for the formation of product 30a by quenching the reaction with various proton sources, however, in all the cases 30 was always the major product. On the basis of these results, we decided to use 30 as the substrate for A-ring formation and invert the chiral center at C-25 at a later stage. However, when we treated alcohol 30 with various acetylating agents such as Ac2O/Et3N/DAMP in toluene at 60 oC, product 31 could not be formed (Scheme 8). Examining the X-ray structure of 30, we speculated that both the methyl group at C-25 and benzyl group at C16 in 30 might induce the substrate to adopt an unfavorable conformation to proceed the acetylation of its C-10 hydroxyl group. Thus, removal of the benzyl group would allow the acetylation of the C-10 hydroxyl group to occur. Since the natural product 1 has a ketone-derived enol group at C-16. We therefore decided to convert the benzoxyl group C-16 in 30 to its corresponding enol moiety followed by installation of its A ring. To achieve this, substrate 30 was first subjected to Pd-catalyzed hydrogenation to afford 32 in 80% yield, and the resultant alcohol was first oxidized to ketone 33, followed by reaction with


17


Ac2O/Et3N/DMAP at room temperature for 2 h to afford the enol acetate 34in 75% yield in two steps. Because of the steric hindrance of the hydroxyl group at C-10 in 34, its acetylation was carried out at room temperature for 3 days to completion, the desired product 35 could be obtained in 78% yield.

Scheme 8: Synthesis of compound 35 O O

TBSO

O

Me

OAc

Me H O

O

Me H

H

H O

OBn

O 25

31

Me toluene, 80 oC

a. Ac2O, TEA, DMAP O

O

Me

OH

O

O

Me H TBSO

b. Pd(OH)2, H2 EtOAc

Me

H

H O

H O

OBn

O

10

Me H O

O 16

MeH

TBSO

O

Me

OH

(80%) 25

30

O

O

H

OH

H O

32

Me

O

Me

c. NaHCO3, DMP O

Me

O OH O

O

Me H TBSO

OAc

d. Ac2O, TEA DMAP

Me H O

H O

O O

Me H TBSO

H

TBSO

O

O O Me

O

O 16

Me H

OAc

H O

H O

35

O

O

TBSO

Me H

O

16

H O

O

O

-

O

THF -78 oC TBSO MeH

O

36a

Me

O

Me

Me

O

base

O HO

O

33

Me e. Ac2O, TEA, DMAP, DCM 3 d (78%)

Me

Me H O

O

34

O OAc

O

Me

OH

(75%) O

x

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

Page 18 of 43

H O

Me H O O

OH Me

O Me

O

O OAc

37

H O

O Me H O 25

+

H

O

O

O O TBSO

Me H

O

36b

Me

O

H O O

Me H O

O

25

Me

Reaction conditions: (a) Pd(OH)2 (10 wt%), EA, rt, 1 h, 80%; (b) DMP (3.0 equiv), NaHCO3 (5.0 equiv), CH2Cl2, rt, 20 min; (c) Ac2O (8.0 equiv), DMAP (1.5 equiv), Et3N (10 equiv), 75% for two steps; d) Ac2O (8.0 equiv), DMAP (1.5 equiv), Et3N (10 equiv), 78%.


18

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With diacetate 35 in hand, we imagined that if diacetate 35 were treated with excess base, the resultant enolate 36a could proceed an intramolecular Dieckmann condensation to afford product 37 through intermediate 36b with in situ epimerization of its C-25 chiral center. To make the proposed chemistry into practice, substrate 35 was treated with various bases (such as LiHMDS, LDA, KHMDS, and NaHMDS) in different solvents at various temperatures, however, the proposed transformation did not occur, and in most cases 35 was subjected to decomposition (Scheme 8). The issues that arose in our investigation of A-ring formation and C-25 methylation led us to explore alternative pathways for the A-ring formation and the diastereoselective installation of C-25 methyl group. Realizing the fact that acetylation of the C-10 hydroxyl group in 29 could be achieved by treatment with Ac2O/Et3N/DMAP for longer time (Scheme 9), we then tested the acetylation of 29 at high temperature using the same acetylating agent. To this end, 29 was reacted with Ac2O in the presence of Et3N and DMAP at 60 °C overnight, to our delight, acetate 38 was formed in 75% yield (Scheme 9). Scheme 9: Synthesis of acetate 38

Reaction conditions: Ac2O (8 equiv), DMAP (1.5 equiv), Et3N (10 equiv), 75%.

We then used 38 as a substrate to investigate the reaction conditions of Dieckmann reaction for the synthesis of lactone 39. As shown in Table 4, various reaction conditions were tested, but none of them gave the desired annulated product 39, and the substrate was either recovered or decomposed. Table 4: Tested reaction conditions for synthesis of 39


19


Page 20 of 43

In our total synthesis of schindilactone A,7 A-ring could be formed after removal of the C-16 benzyl group. With this chemistry in mind, we then removed the benzyl group of 38 via Pd(OH)2-catalyzed hydrogenation under a balloon pressure of hydrogen, and the resultant acetate 40 was then treated with LiHMDS in THF at −78 °C to afford diol 41 in 78% yield in two steps (Scheme 10). Treatment of diol 41 with a slight excess of Martin’s sulfurane37 could proceed a regioselective dehydration38 of C-1 tertiary hydroxyl group to afford product 42 in 80% yield. It is worthwhile to mention that the reaction time was critical in this dehydration for obtaining a high yield; if the reaction was performed for more than 10 min, side reactions occurred, which significantly decreased the yield. We then turned our attention to developing an appropriate method for diastereoselective installation of the C-25 methyl group. In view of our previous failure to achieve this, we decided to explore alternative approaches. The methylation results shown in Scheme 7 show that the undesired diastereoisomer 30 bearing an α-methyl group at C-25 was the major product in the majority of cases. ACS Paragon Plus Environment

20

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This can be attributed to the lower steric hindrance at the α-face of 29, which could guide MeI to approach the enolate via the α-face. We therefore envisaged that if the Pd-catalyzed hydrogenation of enone 44 occurred via the catalyst approaching the enone moiety from the less-hindered α-face, product 45 bearing the desired β-methyl group at C-25 could be obtained (Scheme 10). In addition, this hydrogenation might also saturate the A-ring double bond in 44 in a diastereoselective manner. To explore this approach, enone44 initially attempted to be made from lactone 42 using Eschenmoser’s salt39 as the methylenation agent, however, under typical conditions the reaction was slow, and the yields of 44 were 20% to 50%. We later found that the yield could be significantly improved by addition of 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT)40 to the reaction, giving enone 44 in 50% to 60% yields in two steps. Thus, further treatment of 44 under the typical hydrogenation condition using Pd/C as a catalyst, product 45 was obtained in 80% yield as the sole product, realizing the proposed diastereoselective installation of both stereogenic centers at C-1 and C-25 in a single step. Scheme 10: Synthesis of compound 45


21


Page 22 of 43

Reaction conditions: a) Pd(OH)2/C (10 wt %), EtOAc, rt, 1 h; b) LiHMDS (5.0 equiv), THF, −78 °C to −20 °C, 78% for two steps; c) Martin’s sulfurane (1.2 equiv), CH2Cl2, rt, 5 min, 80%; d) LiHMDS (5.0 equiv), THF, −78 °C, then Eschenmoser’s salt (6.0 equiv), −78 to 0 °C; e) CDMT (5.0 equiv), Et3N (10.0 equiv), CH2Cl2, 0.5 h, 60% for 2 steps; f) Pd/C (100 wt %), EtOAc, rt, 3 h, 80%.

We then moved to the final stages of the total synthesis of lancifodilactone G (1). To make our total synthesis more concise, we envisaged that the hydroxyl group at C-16 in substrate 44 could be oxidized to give the corresponding ketone 46, which could undergo Pd-catalyzed hydrogenation to saturate the double bonds at C-1 and C-25, leading to stereoselective formation of the chiral centers at C-1 and C-25 in ketone 47. Ketone 47 could be converted to 1 through a ketone–enol equilibrium. Scheme 11: Synthesis of the ketone form 47 of lancifodialctone G (1)


22

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Reaction conditions:(a) DMP (3 equiv), NaHCO3 (5 equiv), CH2Cl2, rt, 20 min; (b) Pd/C (100 wt%), MeOH, rt, 3 h, 60%

In the event, alcohol 44 was oxidized with DMP to afford 46, which then underwent Pd-catalyzed hydrogenation in MeOH under a balloon pressure of H2, as previously demonstrated, to give ketone 47 in 60% yield in two steps. The TBS group in 46 was also removed under these conditions (Scheme 11).41 However, conversion of the keto moiety in 47 to its enol form in lancifodilactone G (1) proved to be difficult. Various conditions (either acidic or basic) were tested, but in most cases, a mixture of 1, 47, and 47a was formed, according to a crude proton NMR spectroscopic study. Isolation of pure lancifodilactone G (1) from the mixture failed. We therefore had to redesign our synthetic pathway to achieve our final goal. We previously observed that ketone 33 could be converted to its enol acetate 34 in 75% yield by treatment with Ac2O/Et3N in the presence of DMAP (Scheme 8), and we used this route for the synthesis of enol acetate 48 (Scheme 12). When ketone 44 was treated with DMP/NaHCO3, then


23


Page 24 of 43

Ac2O/Et3N/DMAP in CH2Cl2 at room temperature for 1 h, enol acetate 48 was obtained in 62% yield; 48 was then subjected to Pd-catalyzed hydrogenation under a balloon pressure of H2, giving lancifodilactone G acetate (1a) in 80% yield. The structure of 1a was confirmed by single-crystal X-ray analysis. Scheme 12: Synthesis of lancifordilactone G acetate (1a)

Reaction conditions:(a) DMP (3.0 equiv), NaHCO3 (5.0 equiv), CH2Cl2, rt, 20 min; then, Ac2O (8.0 equiv), DMAP (1.5 equiv), Et3N (10 equiv), 62%; (b) Pd/C (100 wt%), MeOH, rt, 3 h, 80%.

We then investigated methods for removal of the acetate group in 1a to achieve the total synthesis of lancifodilactone G (1). However, acetate removal failed under typical deacetylation conditions, and in most cases 1a decomposed, as shown in Table 5.

Table 5: Attempt to synthesis of lancifodilactone G (1)


24

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This apparently easy deacetylation turned out to be challenging. We performed computational experiments to improve our understanding of the reaction and clarify the reasons for the observed difficulties.

The

computational

study

was

performed

at

the

PWPB95-D3/def2-QZVPP(-g,-f)//M06-2X-D3/def-TZVP level with SMD solvation in chloroform. The obtained thermodynamic data are shown in Scheme 13. The results provided insights that helped us to understand these issues, and the following observations were made. 1) The stability of the enol form in the central core slowly builds up as the structure becomes increasingly like the scaffold of lancifodilactone G (1), and the enol form is the thermodynamically stable form of 1; 2) The difference between the enolization free energies (∆G) of isomer 47 and 1 is −0.7 kcal mol−1, and the enolization ∆G between isomer 47a and 1 is −0.8 kcal mol−1. Because the energy differences among these three compounds are so small, all of them could exist under hydrolytic reaction conditions, which could account for the observed reaction mixture generated during hydrolysis. Scheme 13: The thermodynamic data of enolization of S1-S4


25


Page 26 of 43

CONCLUSION In summary, the asymmetric total synthesis of lancifodilactone G acetate (1a)42 was completed in 28 steps. The salient features of this work are (1) development of a highly enantioselective oxazaborolidine-catalyzed Diels–Alder reaction to build up the initial chiral centers, ensuring that asymmetric total synthesis is achieved; (2) demonstration of the efficiency of the RCM approach for


26

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accessing an oxabicyclo[4.2.1]nonene core bearing a sterically hindered tri-substitutedolefin; and (3) use of our Co/TMTU-catalyzed Pauson–Khand reaction for the stereoselective synthesis of the highly congested F ring, which bears an all-carbon quaternary chiral center at C-13. EXPERIMENTAL SECTION General Information: Unless otherwise mentioned, all reactions were carried out under a nitrogen atmosphere under anhydrous conditions and all reagents were purchased from commercial suppliers without further purification. Solvent purification was conducted according to Purification of Laboratory Chemicals (Peerrin, D. D.; Armarego, W. L. and Perrins, D. R., Pergamon Press: Oxford, 1980). Yields refer to chromatographically and spectroscopically (1H NMR) homogeneous materials. Reactions were monitored by Thin Layer Chromatography on plates (GF254) supplied by Yantai Chemicals (China) visualized by UV or stained with ethanolic solution of phosphomolybdic acid and cerium sulfate, basic solution of KMnO4, and iodine vapor. If not specially mentioned, flash column chromatography was performed using E. Merck silica gel (60, particle size 0.040–0.063 mm).

NMR spectra were recorded on

Bruker AV400, Bruker AV500 instruments and calibrated by using residual undeuterated chloroform (δH = 7.26 ppm) and CDCl3 (δC = 77.0 ppm), or undeuterated pyridine (δH= 8.71 ppm) and pyridine-d5 (δC = 150.1 ppm) as internal references. The following abbreviations were used to explain the multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, b = broad, td = triple doublet, dt = double triplet, dq = double quartet, m = multiplet. Infrared (IR) spectra were recorded on a Thermo Nicolet Avatar 330 FT-IR spectrometer. High-resolution mass spectra (HRMS) were recorded on a Bruker Apex IV FTMS mass spectrometer using ESI-TOF (electrospray ionization) as ionization method.

Synthesis of tert-butyl (1R,2R)-5-methyl-6-oxo-2-(prop-1-en-2-yl)cyclohept-4-ene-1-carboxylate (3):


27


Page 28 of 43

To a solution of LiHMDS (1.0 L, 1.0 mol/L in THF, 1.0 mol) was added a solution of R-(-)-carvone (2, 71.5 g,0.5mol) in THF (150 mL) at -78 oC during 15 min, and the resultant mixture was slowly warmed to 0 oC during a period of 1 h. The mixture was then cooled to -78 oC, and stirred 30 min. To this solution was added a solution of Boc-imidazole (67.5 g, 0.7mol) in THF (400 mL) slowly via cannular in 2 h, and the resultant mixture was stirred at the same temperature for 15 min. The reaction mixture was quenched by addition of a saturated solution of NH4Cl (400 mL) at -78 oC, and the mixture was extracted with dichloromethane (500 mL×3). The combined organic phase was washed by brine (500 mL), and dried over Na2SO4. The solvent was removed under vacuum, and the residue was purified by a flash column chromatography on silica gel (petroleum ether/ethyl acetate = 50:1) to give a ketoester(107.3 g, 90%) as a yellowish oil. Rf = 0.3 (silica gel, petroleum ether/ethyl acetate = 4:1); -1 1 [] = - 11.3 (c = 0.40 in CH2Cl2); IR (neat)νmax: 2976, 2924, 1734, 1674, 1367, 1149, 1083 cm ; H

NMR (400 MHz, chloroform-d): δ 6.73 (m, 1H), 4.90 – 4.78 (m, 2H), 3.35 (d, J = 12.8 Hz, 1H), 3.07 (ddd, J = 12.9, 10.8, 4.9 Hz, 1H), 2.51 – 2.38 (m, 1H), 2.32 (m, 1H), 1.79 (dt, J = 2.7, 1.4 Hz, 3H), 1.76 (t, J = 1.1 Hz, 3H), 1.45 (s, 9H) ppm; 13C NMR (100 MHz, CDCl3) δ 195.5, 169.1, 144.9, 144.3, 135.0, 112.8, 81.4, 59.3, 45.9, 31.0, 28.1, 19.9, 15.9 ppm; HRMS (ESI): m/z calcd for C15H22O3Na [M+Na]+: 273.1461, found 273.1462. To a solution of Et2Zn (288.0 mL, 2.0 mol/L in hexane, 0.6mol) in a three-way flask, which connected a drying tube, a condenser and a stir bar, was added a solution of HCO2H (26.5 g, 0.6 mol) in dichloromethane (500 mL) at 0 oC in 2 h, and the resultant mixture was stirred at the same temperature for 10 min. During this period of time, a large amount of gas was released (make sure the drying tube didn’t block). To this solution was added a solution of CH2I2 (154.1 g, 0.6 mol) in dichloromethane (150 mL) at 0 oC in a drop-wise manner over 15 min, and the resultant mixture was then stirred at the same


28

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temperature for 1 h. To this solution was added a solution of the ketoester made above (62.5 g, 0.25 mol) in dichloromethane (150 mL) at 0 oC within 10 min (CAUTION: this reaction is exothermic and gas-releasing, and needs stirring vigorously under cooling conditions). After addition, the resultant mixture was stirred at 0 oC for 2 h, and then quenched by addition of a saturated solution of NH4Cl (300 mL). The mixture was extracted with dichloromethane (500 mL×3), and the combined organic phases were washed with brine (200 mL), and dried over Na2SO4. The solvent was removed under vacuum, and the residue was purified by a flash column chromatography on silica gel (petroleum ether/ethyl acetate = 50:1) to give product 3 (49.5 g, 75%) as a yellowish oil. Rf = 0.70 (silica gel, petroleum ether/ethyl acetate = 4:1); [] = - 4.2 (c = 0.55 in CH2Cl2); IR (neat) νmax: = 2975, 2931, 1723, 1667, 1367, 1149 cm-1; 1H NMR (400 MHz, chloroform-d): δ = 6.54 (ddq, J = 7.8, 6.4, 1.6 Hz, 1H), 4.77-4.75 (m, 2H), 2.92 (td, J = 7.6, 5.0 Hz, 1H), 2.81 (dd, J = 16.2, 7.6 Hz, 1H), 2.75-2.68 (m, 2H), 2.45-2.39 (m, 2H), 1.81 (d, J = 1.4 Hz, 3H), 1.73 (d, J = 1.2 Hz, 3H), 1.40 (s, 9H) ppm;

13

CNMR (100 MHz, CDCl3) δ

201.5, 173.1, 146.9, 140.0, 139.7, 111.3, 81.1, 46.3, 43.9, 43.6, 30.7, 27.9, 20.5, 18.6 ppm; HRMS (ESI): m/z calcd for C16H24O3Na [M+Na]+: 287.1618, found 287.1615. Synthesis

of

tert-butyl

(1R,2R)-5-methyl-2-((S)-2-methyloxiran-2-yl)-6-oxocyclohept-4-ene-1-carboxylate (5): To a solution of compound 3 (527.0 mg, 2.1 mmol) in MeCN (20 mL) was added buffer (0.05 M Na2B4O7·10H2O in 4×10-4 M aqueous Na2(EDTA), 20 mL), tetrabutylammonium hydrogen sulfate (27.2 g, 0.08 mmol), and catalyst 4 (155.2 mg, 0.6 mmol). To this solution was simultaneously added a solution of Oxone (1.6 g, 2.6 mmol) in aqueous Na2(EDTA) (4 ×10-4 M, 13 mL) and a solution of K2CO3 (1.9 g, 13.4 mmol) in water (13 mL) through two additional funnels at room temperature over a period of 0.5 h. After addition, the reaction was immediately quenched by addition of water (50 mL),


29


Page 30 of 43

and resultant mixture was extracted with ethyl acetate (3 × 30 mL). The combined organic phase was washed with brine, and dried over Na2SO4. The solvent was removed under vacuum, and the residue was purified by a flash column chromatography on silica gel (petroleum ether/ethyl acetate = 50:1) to give product 5 (376 mg, 70% yield) as yellowish oil; Rf= 0.30 (silica gel, petroleum ether/ethyl acetate = 1 4:1); [] = + 14.7 (c = 1.00 in CH2Cl2) IR (neat) νmax: 2976, 2925, 1724, 1667, 1367, 1151 cm-1; H

NMR (400 MHz, chloroform-d): δ 6.57 (ddq, J = 7.7, 6.2, 1.5 Hz, 1H), 2.83 (dd, J = 15.6, 6.6 Hz, 1H), 2.74-2.62 (m, 3H), 2.59-2.51 (m, 2H), 2.47-2.39 (m, 1H), 2.17 (td, J = 8.4, 4.5 Hz, 1H) 1.81 (d, J = 1.2 Hz, 3H), 1.43 (s, 9H), 1.32 (s, 3H) ppm;

13

CNMR (100 MHz, CDCl3): δ 200.8, 172.8, 140.0, 139.8,

81.5, 58.5, 45.6, 43.6, 42.0, 27.9, 27.9, 18.6, 18.4 ppm; HRMS (ESI): m/z calcd for C16H24O4Na [M+Na]+: 303.1567, found 303.1563. Synthesis

of

(3R,3aR,8aR)-3-(((tert-butyldimethylsilyl)oxy)methyl)-3,6-dimethyl-3a,4,8,8a-tetrahydro-1H-cyclo hepta[c]furan-1,7(3H)-dione (7): To a solution of compound 5 (376 mg, 1.3 mmol) in methanol (20 mL) was added H2SO4 (2.2 mL, 1 M, 2.2 mmol) at 0 oC, and the resultant mixture was then warmed up to room temperature, and stirred for 2h. The reaction mixture was quenched by addition of water (20 mL), and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed by brine (50 mL), and dried over Na2SO4. The solvent was removed under vacuum to give a crude product 6 as a yellowish oil. To a solution of the crude product made above in THF (10 mL) was added imidazole (408 mg, 6.0 mmol) and TBSCl (452.1 mg, 3.0 mmol) at room temperature, and the resultant mixture was then stirred at the same temperature for 30 min. The reaction mixture was quenched by addition of a


30

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saturated solution of NaHCO3 (10 mL), and resultant mixture was then extracted with ethyl acetate (3 × 10 mL). The combined organic layers were washed with brine (50 mL), and dried over Na2SO4. The solvent was removed under vacuum, and the residue was purified by a flash column chromatography on silica gel (petroleum ether/ethyl acetate = 20:1) to give product 7 (276 mg, 61% yield) as white solid; Rf = 0.55 (silica gel, petroleum ether/ethyl acetate = 2:1); [] = - 55.8 (c = 1.00 in CH2Cl2) IR (neat)νmax: 2953, 2928, 2890, 2856, 1770, 1656, 1251, 1109, 838 cm-1; 1H NMR (400 MHz, Chloroform-d): δ 6.33 (ddq, J = 6.4, 3.3, 1.6 Hz, 1H), 3.69 (d, J = 10.8 Hz, 1H), 3.61 (d, J = 10.8 Hz, 1H), 3.21 (dd, J = 16.9, 4.2 Hz, 1H), 2.82 (td, J = 11.9, 4.2 Hz, 1H), 2.70 (dd, J = 11.8, 3.7 Hz, 1H), 2.67- 2.51 (m, 2H), 2.41-2.30 (m, 1H), 1.91 (d, J = 1.3 Hz, 3H), 1.27 (s, 3H), 0.89 (s, 9H), 0.08 (s, 3H), 0.07 (s, 3H) ppm;

13

C NMR (100 MHz, CHCl3): δ 200.0, 175.3, 137.8, 136.0, 85.5, 68.0, 44.4, 44.3,

40.2, 31.1, 25.8, 22.4, 18.3, 18.2, -5.4, -5.5 ppm; HRMS (ESI): m/z calcd for C18H30O4SiNa [M + Na]+: 361.1806, found 361.1803. Synthesis of (1R,3aR,8aR)-1-(((tert-butyldimethylsilyl)oxy)methyl)-1,6-dimethyl-3a,4,8,8a-tetrahydro-1H,3H-spiro[cyclohepta[c]furan-5,2'-[1,3]dioxolan]-3-one (8): To a solution of compound 7 (220 mg, 0.7 mmol) in CH2Cl2 (10 mL) was added (CH2OTMS)2 (384.2 mg, 1.9mol) in one portion followed by addition of TMSOTf (11.1 mg, 0.06 mmol) in a drop-wise manner at -78 oC under N2 protection. The mixture was then warmed up to -20 oC, and stirred at the same temperature for 12 h. The reaction was quenched by addition of a saturated solution of NaHCO3 (10 mL), and mixture was extracted with CH2Cl2 (3 × 10 mL). The combined organic layers were washed with brine (50 mL), and dried over Na2SO4. The solvent was removed under vacuum, and the residue was purified by a flash column chromatography on silica gel (petroleum ether/ethyl acetate = 20:1) to give product 8 (276.1 mg, 61% yield) as an colorless oil; Rf = 0.60 (silica gel, petroleum


31


Page 32 of 43

ether/ethyl acetate = 2:1); [] = + 39.9 (c = 1.00 in CH2Cl2); IR (neat)νmax: 2952, 2927, 2884, 2856, 1773, 1254, 1120, 1062 cm-1; 1H NMR (400 MHz, chloroform-d): δ 5.69 (ddq, J = 7.6, 3.7, 1.8 Hz, 1H), 4.04-3.92 (m, 4H), 3.65 (d, J = 10.9 Hz, 1H), 3.60 (d, J = 10.9 Hz, 1H), 2.89 (td, J = 12.3, 2.8 Hz, 1H), 2.36 (dd, J = 13.7, 2.8 Hz, 1H), 2.22-2.11 (m, 3H), 1.78 (d, J = 1.6 Hz, 3H), 1.66 (dd, J = 13.7, 12.1 Hz, 1H), 1.22 (s, 3H), 0.89 (s, 9H), 0.07 (s, 3H), 0.06 (s, 3H) ppm; 13C NMR (100 MHz, CHCl3): δ 176.9, 141.8, 125.2, 108.6, 86.0, 67.8, 65.0, 64.4, 45.0, 42.2, 36.1, 27.2, 25.8, 22.1, 18.2, 16.8, -5.4, -5.5 ppm; HRMS (ESI): m/z calcd for C20H34O5SiNa [M + Na]+: 405.2068, found 405.2070. Synthesis

of

ethyl

(1R,6R)-6-(2-((tert-butyldimethylsilyl)oxy)acetyl)-3-((triisopropylsilyl)oxy-

cyclohex-3-ene-1-carboxylate (11): To a solution of CBS-D (40 mmol) in CH2Cl2 (700 mL) was added a solution of Tf2NH (15.5 g, 55 mmol) in CH2Cl2 (50 mL) at -25 oC. The resultant mixture was first stirred at the same temperature for 30 min, and then cooled back to -78 oC. To this solution was added a solution of diene 9 (66.2 g, 82 mL, 294 mmol) and dienophile 10 (53.3 g, 196 mmol) in CH2Cl2 (200 mL), and the resultant mixture was then stirred at the same temperature for 12 h. The reaction mixture was quenched by addition of a saturated solution of NaHCO3 (500 mL), and the mixture was extracted with CH2Cl2 (3 × 250 mL). The combined organic layers were washed with brine (500 mL), and dried over Na2SO4. The solvent was removed under vacuum, and the residue was purified by a flash column chromatography on silica gel (petroleum ether/ethyl acetate = 100:1) to give product 11(93.2 g, 95% yield, 87% e.e.) as colorless oil; Rf = 0.4 (silica gel, petroleum ether/ethyl acetate = 16:1); [] = - 24.8 (c = 0.7 in CHCl3); IR (neat)νmax: 2944, 2866, 1732, 1673, 1463, 1202, 882, 837, 779 cm-1; 1H NMR (400 MHz, chloroform-d): δ 4.85 (dd, J = 5.3, 2.5 Hz, 1H), 4.35 (s, 2H), 4.10 (qd, J = 7.2, 2.0 Hz, 2H), 3.19 – 2.92 (m, 2H), 2.50 – 2.40 (m, 1H), 2.40 – 2.32 (m, 1H), 2.21 (dddd, J = 17.0, 9.9, 3.9, 1.9 Hz, 1H), 2.06 – 1.88 (m, 1H), 1.24


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(t, J = 7.1 Hz, 3H), 1.19 – 1.11 (m, 3H), 1.07 (dd, J = 7.3, 1.4 Hz, 18H), 0.92 (s, 9H), 0.10 (s, 6H) ppm; 13

C NMR (125 MHz, CDCl3): δ 212.9, 174.5, 149.0, 100.9, 69.2, 60.9, 43.4, 41.9, 32.5, 26.8, 25.9, 18.5,

18.1, 14.3, 12.7, -5.3, -5.4ppm; HRMS (ESI): m/z calcd for C26H51O5Si2 [M + H]+: 499.3269, found 499.3258. Synthesis of (3aR,7aR)-3-(((tert-butyldimethylsilyl)oxy)methyl)-3-methyl-6-((triisopropylsilyl)oxy) -3a,4,7,7a-tetrahydroisobenzofuran-1(3H)-one (12): To a solution of compound 11 (57.0 g,114.4 mmol) in THF (700 mL) was added methyl magnesium chloride (76.0 mL, 3.0 M, 228.9 mmol) slowly at -78 °C during 30 min, and the resultant mixture was then warmed up to -20 °C, and stirred at the same temperature for 30 min. The reaction was quenched by addition of a saturated solution of NH4Cl (500 mL), and the resultant mixture was extracted with EtOAc (3 × 250 mL). The combined organic extract was washed with brine (500 mL), and dried over Na2SO4. The solvent was removed under vacuum, and the residue was purified by a flash column chromatography on silica gel (petroleum ether/ethyl acetate = 50:1) to give product 12 (45.5g, 85% yield, dr = 1.7 : 1 at C4) as yellowish oil; Rf = 0.35 (silica gel, petroleum ether/ethyl acetate = 16:1); [] = - 42.9 (c = 0.45 in CHCl3); IR (neat) νmax: 2944, 2865, 1782, 1648, 1463, 1324, 1257, 1192, 1106, 863, 837 cm-1;1H NMR (400 MHz, CDCl3): δ 4.98 – 4.92 (m, 1H), 3.73 (d, J = 11.3 Hz, 1H), 3.68 (d, J = 10.7 Hz, 1H),, 3.62 (d, J = 10.7 Hz, 1H), 3.12 (ddd, J = 13.7, 11.6, 5.5 Hz, 1H), 2.59 (ddd, J = 14.0, 11.3, 5.6 Hz, 1H), 2.51 – 2.35 (m, 1H), 2.34 – 2.19 (m, 2H), 2.18 – 1.95 (m, 2H), 1.25 (s, 3H), 1.20 – 1.08 (m, 3H), 1.07 (d, J = 7.0 Hz, 18H), 0.88 (s, 9H), 0.08 – 0.03 (m, 6H) ppm; 13C NMR (100 MHz, CDCl3): δ 177.1, 176.0, 151.1, 150.6, 103.5, 103.1, 87.1, 86.5, 68.4, 66.8, 48.0, 42.6, 42.3, 41.1, 31.4, 30.6, 25.9, 25.9, 24.1, 23.4, 23.3, 18.4, 18.2, 18.1, 17.1, 12.7, -5.3, -5.4, -5.6, -5.7. ppm; HRMS (ESI): m/z calcd for C25H49O4Si2 [M + H]+: 469.3164, found 469.3177.


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Synthesis of (3R,3aS,7aR)-3-(((tert-butyldimethylsilyl)oxy)methyl)-3-methyl-7a-((triethylsilyl)oxy) -6-((triiso-propylsilyl)oxy)-3a,4,7,7a-tetrahydroisobenzofuran-1(3H)-one (13): To a solution of compound 12 (1.4 g, 3.0 mmol) in THF (50 mL) was added potassium bis(trimethylsilyl)amide (1.0 M solution in THF, 6.0 mL, 6.0 mmol) at -78 °C in drop-wise manner under nitrogen atmosphere, and the resultant mixture was then stirred at the same temperature for 10 min. After warming up to 0 °C, the reaction mixture was first stirred for 30 min, and then cooled back to -78 °C. To this solution was added P(OMe)3 (0.75 mL, 6.0 mmol) in one portion, and the resultant mixture was degassed at -78 °C with O2 for 3 times under a balloon pressure of oxygen. The resultant mixture was first stirred at -78 °C for 20 min, and then at 0 °C for 1 h. After changing the reaction atmosphere from oxygen to nitrogen, the reaction mixture was treated with TESCl (0.9 ml, 4.5 mmol), and the formed mixture was stirred at the same temperature for 1 h. The reaction mixture was quenched by addition of a saturated solution of NH4Cl (50 mL), and the mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (50 mL), and dried over Na2SO4. The solvent was removed under vacuum [warning: the remaining P(OMe)3 is poisonous], and the residue was purified by a flash column chromatography on silica gel (petroleum ether/ethyl acetate = 200:1-120:1) to give product 13 (720 mg, 42% yield) as a clear colorless oil and its C4 epimer (650 mg, 38% yield). Rf = 0.8 (silica gel, petroleum ether/ethyl acetate = 8:1); [] = + 27.1 (c = 0.45 in CHCl3); IR (neat) νmax: 2948, 2891, 2867, 1782, 1681, 1463, 1257, 1209, 1134, 1098, 1015, 836, 745 cm-1; 1H NMR (400 MHz, CDCl3): δ 4.86 (td, J = 3.2, 1.6 Hz, 1H), 3.59 (d, J = 10.7 Hz, 1H), 3.49 (d, J = 10.8 Hz, 1H), 2.68 (d, J = 8.1 Hz, 1H), 2.47 – 2.36 (m, 3H), 2.03 (dd, J = 17.7, 3.8 Hz, 1H), 1.22 (s, 3H), 1.22 – 1.08 (m, 3H), 1.07 (d, J = 6.6 Hz, 18H), 0.94 (t, J = 7.9 Hz, 9H), 0.90 (s, 9H), 0.71 – 0.60 (m, 6H), 0.08 (s, 3H), 0.07 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ 177.0, 146.7, 100.0, 84.7, 76.7,


34

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69.0, 42.2, 39.0, 26.0, 21.0, 18.6, 18.1, 18.0, 12.7, 7.1, 6.2, -5.2, -5.3 ppm; HRMS (ESI): m/z calcd for C31H63O5Si3 [M + H]+: 599.3978, found 599.3976. Synthesis of (3R,3aS,8aR)-6-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-3-methyl-8a-((triethyl -silyl) oxy)-3a,4,8,8a-tetrahydro-1H-cyclohepta[c]furan-1,7(3H)-dione (15): To a solution of compound 13 (5.1 g, 8.6 mmol) in dry petroleum ether (100 mL) was added t-BuOK (5.8 g, 51.7 mmol) at -20 oC, followed by addition of a solution of CHBr3 (4.5 mL, 52 mmol) in petroleum ether (50 mL) in a dropwise manner at the same temperature for 1 h. The formed mixture was then stirred at -20 oC for 3 h. The reaction was worked up by filtration of the reaction mixture through a silica gel pad, and washed with mixed solvent (petroleum ether/ethyl acetate = 4:1), The filtrate was concentrated under vacuum afford red-brown oil, which will be used in next step without purification due to the instability of the formed product. To a solution of the oil made above in acetone (150 mL) was added CaCO3 (4.3 g, 43 mmol) and AgClO4·H2O (3.9 g, 17.2 mmol) at room temperature, and the resultant mixture was then stirred at 25 o

C for 10 h. The reaction was quenched by addition of a saturated solution of NaHCO3 (50 mL). The

resultant mixture was extracted with CH2Cl2 (3 × 150 mL), and the combined organic layers were washed with brine (100 mL), and dried over Na2SO4. The solvent was removed under vacuum, and the residue was purified by a flash column chromatography on silica gel (petroleum ether/ethyl acetate = 15:1) to give product 15 (2.2 g, 49% yield) as yellowish oil; The product was recrystallized by CH2Cl2/hexane to afford a white solid (99% ee). Rf = 0.5 (silica gel, petroleum ether/ethyl acetate = 4:1); [] = + 53.3 (c = 1.0 in CH2Cl2); IR (neat) νmax: 2954, 2929, 2878, 2857, 1757, 1681, 1257, 1101, 1073, 1013, 838, 798, 730 cm-1; 1H NMR (400 MHz, chloroform-d): δ 7.37 (dd, J = 9.7, 5.3 Hz, 1H), 3.65 (dd, J = 1.5 Hz, 2H), 3.40 (d, J = 15.3 Hz, 1H), 2.82 (d, J = 15.3 Hz, 1H), 2.77 (dd, J = 12.1, 5.3


35


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Hz, 1H), 2.61 – 2.43 (m, 2H), 1.33 (s, 3H), 0.94 – 0.86 (m, 18H), 0.65 (q, J = 8.1 Hz, 6H), 0.09 (d, J = 2.3 Hz, 6H) ppm;

13

C NMR (100 MHz, CDCl3): δ 188.7, 174.6, 143.3, 129.6, 84.5, 78.2, 70.0, 50.9,

49.4, 28.5, 26.0, 20.6, 18.5, 7.0, 5.9, -5.3, -5.3 ppm; HRMS (ESI): m/z calcd for C23H42O5Si2Br [M + H]+: 533.1749, found 533.1761. Synthesis of compound (29): To a solution of compound 28 (20 mg, 0.024 mmol) in THF (3 mL) was added anhydrous TBAF (0.048 mL, 1.0 M, 0.048 mmol) at room temperature, and the resultant mixture was stirred at the same temperature for 3 min. To this mixture was added TBSCl (18 mg, 0.12 mmol) at room temperature, and the resultant mixture was the stirred at 40 °C for 6 h. The reaction was quenched by addition of a saturated solution of NH4Cl (5 mL) at 25 °C, and the mixture was extracted with EtOAc (3 × 5 mL). The combined organic extracts were washed with brine (5 mL), and dried over Na2SO4. The solvent of the extract was removed under vacuum, and the residue was purified by a flash column chromatography on silica gel (petroleum ether/ethyl acetate = 5:1) to give product 29 (14 mg, 74% yield) as a colorless oil; Rf = 0.5 (silica gel, petroleum ether/ethyl acetate = 3:2); [] = + 17.3 (c = 1.0 in CH2Cl2); IR (neat) νmax: 2957, 2877, 1778, 1738, 1128, 920 cm-1;1H NMR (500 MHz, CDCl3): δ 7.39 – 7.29 (m, 5H), 4.94 (s, 1H), 4.86 (d, J = 12.1 Hz, 1H), 4.61 (d, J = 12.1 Hz, 1H), 4.17 (d, J = 8.0 Hz, 1H), 3.52 (d, J = 10.7 Hz, 1H), 3.47 (d, J = 10.7 Hz, 1H), 3.37 (d, J = 7.1 Hz, 1H), 2.86 (ddd, J = 17.6, 10.2, 9.2 Hz, 1H), 2.77 (dd, J = 9.9, 7.2 Hz, 1H), 2.66 (t, J = 6.5 Hz, 1H), 2.59 (ddd, J = 17.7, 9.2, 2.6 Hz, 1H), 2.56 – 2.42 (m, 2H), 2.43 – 2.35 (m, 2H), 2.17 (d, J = 15.7 Hz, 1H), 2.01 – 1.90 (m, 3H), 1.88 (d, J = 15.7 Hz, 1H), 1.85 – 1.72 (m, 3H), 1.51 – 1.42 (m, 1H), 1.37 – 1.31 (m, 1H), 1.31 (d, J = 7.3 Hz, 3H), 1.27 (s, 3H), 1.10 (s, 3H), 0.88 (s, 9H), 0.05 (s, 3H), 0.04 (s, 3H);

13

C NMR (125 MHz,

CDCl3): δ 218.7, 177.3, 174.8, 137.5, 128.5, 128.1, 128.0, 116.1, 115.6, 85.9, 84.5, 84.3, 78.5, 72.6,


36

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69.3, 53.7, 53.0, 49.9, 47.7, 45.7, 42.9, 41.2, 39.5, 29.9, 29.1, 28.2, 27.3, 25.8, 21.2, 19.4, 18.2, 17.6, -5.4, -5.5 ppm; HRMS (ESI): m/z calcd for C39H58O10SiN [M + NH4]+: 728.3824, found 728.3840. Synthesis of compounds 30 and 30a: To a solution of compound 29 (10 mg, 0.014 mmol) in THF (2 mL) was slowly added lithium bis(trimethylsilyl)amide (0.03 mL, 1.0 M, 0.03 mmol) at -78 °C, and the resultant mixture was then stirred at the same temperature for 0.5 h. To the above solution was added MeI (6 mg, 0.05 mmol), and the resultant mixture was then warmed to 0 °C slowly. The reaction mixture was quenched by addition of a saturated solution of NH4Cl (3 mL) at 0 °C, and the mixture was extracted with EtOAc (3 × 3 mL). The combined organic extracts were washed with brine (5 mL), and dried over Na2SO4. The solvent of the extract was removed under vacuum, and the residue was purified by a flash column chromatography on silica gel (petroleum ether/ethyl acetate = 3:1) to give products 30 and 30a (in a ratio of 1:1, 7.5 mg, 76% yield). Compound 30 is white semi-soild. Rf = 0.8 (silica gel, dichloromethane/acetone = 1:1); IR (neat) νmax: 3432, 2952, 2927, 2874, 1776, 1741, 1455, 1250, 1151cm-1; 1H NMR (500 MHz, chloroform-d) δ 7.44 – 7.28 (m, 5H), 4.97 (s, 1H), 4.89 – 4.75 (m, 1H), 4.59 (d, J = 12.1 Hz, 1H), 4.15 (d, J = 7.8 Hz, 1H), 3.50 (d, J = 15.2 Hz, 1H), 3.36 (d, J = 7.1 Hz, 1H), 3.02 (dq, J = 10.8, 7.3 Hz, 1H), 2.75 (td, J = 10.1, 7.1 Hz, 1H), 2.62 (dt, J = 28.7, 6.5 Hz, 1H), 2.57 – 2.49 (m, 1H), 2.49 – 2.29 (m, 2H), 2.17 (d, J = 15.7 Hz, 1H), 2.19 – 2.02 (m, 2H), 2.00 – 1.90 (m, 3H), 1.88 (d, J = 15.7 Hz, 1H), 1.85 – 1.68 (m, 3H), 1.50 – 1.42 (m, 2H), 1.33 (d, J = 6.9 Hz, 3H), 1.31 (s, 3H), 1.29 (d, J = 8.5 Hz, 3H), 1.10 (s, 3H), 0.88 (s, 9H), 0.05 (s, 3H), 0.04 (s, 3H) ppm; 13C NMR (125 MHz, CDCl3) δ 218.9, 177.9, 177.3, 137.5, 128.5, 128.1, 115.6, 113.7, 85.9, 84.3, 78.6, 72.5, 69.3, 53.6, 53.0, 49.9, 47.8, 45.7, 42.9, 41.2, 39.5, 38.5, 34.4, 29.2, 27.4, 27.4, 25.8, 25.7,21.2, 19.5, 19.4, 18.3, 17.7, 14.9, -5.4, -5.5 ppm; HRMS (ESI): m/z calcd for C40H57O10Si [M + H]+: 725.3716, found 725.3726.


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Synthesis of compound 32: To a solution of compound 30 (18 mg, 0.025mmol) in EtOAc (3 mL) was added the Pd(OH)2/C (20 wt % Pd loading, 2.1 mg, 10 wt%), and the resultant mixture was degassed with H2 for times at room temperature, and the mixture was then stirred at the same temperature under a balloon pressure of H2 for 1 h. The reaction mixture was filtrated off through a celite pad. The solvent of the extract was removed under vacuum, and the residue was purified by a flash column chromatography on silica gel (petroleum ether/ethyl acetate = 3:1) to give product 32 (13 mg, 80% yield) as white semi-solid; Rf = 0.4 (silica gel, dichloromethane/acetone = 1:1); IR (neat) νmax: 3455, 2954, 2926, 1780, 1455, 1250, 980 cm-1; 1H NMR (500 MHz, chloroform-d) δ 4.85 (s, 1H), 4.43 (d, J = 9.4 Hz, 1H), 3.57 (d, J = 10.8 Hz, 1H), 3.51 (d, J = 10.8 Hz, 1H), 3.31 (d, J = 6.9 Hz, 1H), 3.12 – 2.88 (m, 1H), 2.79 (d, J = 6.0 Hz, 1H), 2.69 (dd, J = 9.9, 6.9 Hz, 1H), 2.54 (dd, J = 12.9, 8.2 Hz, 1H), 2.47 – 2.38 (m, 2H), 2.18 (d, J = 15.3 Hz, 1H), 2.15 – 1.97 (m, 4H), 1.95 (d, J = 15.6 Hz, 1H), 1.93 – 1.79 (m, 3H), 1.65 (dt, J = 13.4, 5.9 Hz, 1H), 1.39 (d, J = 8.4 Hz, 1H), 1.32 (s, 3H), 1.31 (s, 3H), 1.30 (s, 3H), 1.09 (s, 3H), 0.88 (s, 9H), 0.07 (s, 4H), 0.06 (s, 3H) ppm;

13

C NMR (125 MHz, CDCl3) δ 218.4, 178.3, 177.5,115.4, 113.4, 85.7, 84.7, 78.7,

77.6, 69.1, 54.0, 51.8, 50.3, 47.1, 44.5, 42.9, 41.5,8.7, 37.9, 34.6, 29.4, 27.6, 25.9, 24.9, 21.1, 19.4, 18.4, 17.7, 15.0, -5.3 -5.4 ppm; HRMS (ESI): m/z calcd for C33H54O10SiN [M + NH4]+: 652.3512, found 652.3513. Synthesis of compound 34: To a solution of the compound 32 (6.0 mg, 0.01mmol) in CH2Cl2 (2 mL) was added NaHCO3 (4.0 mg, 0.05 mmol) and Dess-Martin periodinane (12.0 mg, 0.03mmol) at room temperature, and the resultant mixture was then stirred at the same temperature for 20 min. To this mixture was added triethylamine (0.01 ml, 0.1 mmol), 4-(dimethylamino)pyridine (1.7 mg,0.014 mmol) and acetic


38

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anhydride (7.2 mg, 0.072 mmol) at 25 °C, and the resultant mixture was at the same temperature stirred for 1 h. The reaction was quenched by addition of a saturated solution of NH4Cl (3 mL), and the mixture was extracted with EtOAc (3×3 mL). The combined organic extracts were washed with brine (5 mL), and dried over Na2SO4. The solvent of the extract was removed under vacuum, and the residue was purified by a flash column chromatography on silica gel (petroleum ether/ethyl acetate = 1:1) to give product 34 (4.0 mg, 75% yield) as white semi-solid; Rf = 0.4 (silica gel, dichloromethane/acetone = 1:1); IR (neat) νmax: 3400, 2954, 2930, 1777, 7260, 1158, 997, 780 cm-1; 1H NMR (800 MHz, chloroform-d) δ 3.60 (d, J = 10.4 Hz, 1H), 3.57 (d, J = 10.3 Hz, 1H), 3.47 (s, 1H), 2.97 (dt, J = 11.4, 7.4 Hz, 1H), 2.80 – 2.74 (m, 1H), 2.63 (dd, J = 12.8, 8.0 Hz, 1H), 2.59 – 2.55 (m, 2H), 2.53 (dd, J = 13.4, 3.0 Hz, 1H), 2.42 – 2.35 (m, 1H), 2.35 (d, J = 16.0 Hz, 1H), 2.27 (s, 3H), 2.25 – 2.18 (m, 2H), 2.09 – 2.01 (m, 2H), 1.86 (d, J = 15.9 Hz, 1H), 1.77 (tt, J = 11.2, 3.4 Hz, 2H), 1.61 (dt, J = 14.4, 3.6 Hz, 1H), 1.32 – 1.28 (m, 1H), 1.30 (d, J = 7.3 Hz, 3H), 1.28 (d, J = 7.2 Hz, 3H), 1.23 (s, 3H), 1.02 (s, 3H), 0.88 (d, J = 2.4 Hz, 9H), 0.059 (s, 3H), 0.057 (s, 3H) ppm;

13

C NMR (200 MHz, CDCl3) δ 218.9, 178.1,

176.4, 167.9,140.2, 129.4, 114.6, 112.7, 87.0, 85.4, 78.1, 69.4, 56.7, 52.7, 48.5, 42.6, 41.6, 38.5,36.3, 34.3, 29.7, 28.3, 26.5, 25.8, 22.7, 21.8, 20.4, 19.9, 18.2, 17.9, 14.8, -5.5 ppm; HRMS (ESI): m/z calcd for C35H51O11Si [M + H]+: 675.3195, found 675.3179. Synthesis of compound 45: To a solution of compound 44 (5.0 mg, 0.012 mmol) in EtOAc (3 mL) was added the Pd/C (5%wt Pd on carbon, 5.0 mg, 100 wt%), and the mixture was degassed with H2 for three times at room temperature, and the resultant mixture was stirred at the same temperature under a balloon pressure of H2 for 1 h. The reaction mixture was worked up by filtration through a celite pad. The filtrate was concentrated under vacuum, and the residue was purified by a flash column chromatography on silica


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gel (petroleum ether/ethyl acetate = 1:10) to give product 45 (4.0 mg, 80% yield) as white semi-solid; Rf = 0.4 (silica gel, ethyl acetate); IR (neat): 3463, 2960, 1890, 1250, 1154, 960 cm-1; 1H NMR (800 MHz, Chloroform-d) δ 4.40 (d, J = 4.8 Hz, 1H), 4.03 (d, J = 9.3 Hz, 1H), 3.44 (d, J = 9.8 Hz, 1H), 3.40 (d, J = 9.7 Hz, 1H), 3.26 (d, J = 6.8 Hz, 1H), 2.75 (dp, J = 9.3, 7.3 Hz, 1H), 2.70 (dd, J = 18.1, 4.9 Hz, 1H), 2.63 – 2.59 (m, 2H), 2.59 (dd, J = 8.9, 4.1 Hz, 1H), 2.55 (dd, J = 13.4, 5.6 Hz, 1H), 2.33 (d, J = 15.5 Hz, 1H), 2.37 – 2.21 (m, 4H), 2.19 – 2.12 (m, 1H), 2.05 (dt, J = 15.3, 4.1 Hz, 1H), 1.99 – 1.92 (m, 1H), 1.83 – 1.75 (m, 2H), 1.76 (d, J = 15.4 Hz, 1H), 1.72 – 1.62 (m, 1H), 1.52 (dt, J = 13.7, 4.0 Hz, 1H), 1.39 (d, J = 7.4 Hz, 3H), 1.28 (d, J = 7.4 Hz, 3H), 1.10 (s, 6H), 0.87 (s, 9H), 0.03 (s, 3H), 0.02 (s, 3H) ppm; 13C NMR (200 MHz, CDCl3) δ 218.8, 177.5, 174.2, 114.6, 114.3, 96.7, 86.9, 81.6, 80.2, 79.6, 70.2, 54.2, 53.3, 51.2, 50.9, 45.0, 43.7, 43.0, 38.6, 36.5, 36.0, 31.9, 29.7, 29.2, 27.5, 26.6, 25.9, 24.4, 19.6, 18.2, 16.4, -5.4, -5.5 ppm; HRMS (ESI): m/z calcd for C35H53O10Si [M + H]+: 661.3403, found 661.3411. The details of 1H and 13C NMR spectra for the synthesized compound 16-48 and compound 1a are listed in the manuscript of reference 42. ASSOCIATED CONTENT Supporting Information: The Supporting Information is available free of charge on the ACS Publications website at DOI: 1 H and 13C NMR spectra of synthesized compounds (PDF) X-ray crystallographic data for 18 (CIF) X-ray crystallographic data for 23 (CIF) X-ray crystallographic data for 30 (CIF) X-ray crystallographic data for 1a (CIF) AUTHOR INFORMATION Corresponding Author [email protected] [email protected] Author Contributions The manuscript was written through contributions of all authors. / All authors have given approval to the final version of the manuscript. ACS Paragon Plus Environment

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Notes The authors declare no competing financial interests. ACKNOWLEDGMENT We thank professor Wen-Xiong Zhang and Dr. Neng-Dong Wang for their assistant for X-ray crystallographic analysis. Funding Sources: National Basic Research Program of China (Grant Nos. 21372016, 21572009, and 21472006). REFERENCES (1)

(2)

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Asymmetric Total Synthesis of Lancifodilactone G Acetate, Part 2: Final

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