Asymmetric Total Synthesis of Lancifodilactone G Acetate. 1

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Asymmetric Total Synthesis of Lancifodilactone G Acetate, Part 1: Diastereoselective Synthesis of CDEFGH Ring System Tian-Wen Sun, Dong-Dong Liu, Kuang-Yu Wang, Bingqi Tong, Jia-Xin Xie, Yanlong Jiang, Yong Li, Bo Zhang, Yi-Fan Liu, Yuan-Xian Wang, Jia-Jun Zhang, Jia-Hua Chen, and Zhen Yang J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02915 • 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 1: Diastereoselective Synthesis of CDEFGH Ring System

Tian-Wen Sun,† Dong-Dong Liu,†Kuang-Yu Wang,†Bing-Qi Tong,† Jia-Xin Xie,† Yan-Long Jiang,† Yong Li,† Bo Zhang,†Yi-Fan Liu, † Yuan-Xian Wang, †Jia-Jun Zhang, †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

H O H BnO

13

O Me

H

H O OBn

12

O

O H OBn

Me

Me

O

O OH

Me

H OH

CHO

10

C

E O D HO

O Me F HG O

H O H

O

8

ABSTRACT: The stereoselective construction of the CDEFGH ring system of lancifodilactone G is described. The key steps in this synthesis are i) ring-closing metathesis for formation of the oxa-bridged eight-membered ring; ii) an intramolecular Pauson–Khand reaction for construction of the sterically congested F ring; and iii) sequential cross-metathesis, hydrogenation, and lactonization reactions for installation of the anomerically stabilized bis-spiro ketal fragment of lancifodilactone G.

ACS Paragon Plus Environment

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Introduction Wuweizi, the Chinese name for Schisandraceae, literally means “five-flavor berry” and refers to the fact that the berry has all five basic flavors: salty, sweet, sour, spicy, and bitter. Records show that for over 2000 years these “five-flavor berries” have been used as sedatives and tonics, and for the treatment of rheumatic lumbago and related diseases.1a In addition to their use in traditional Chinese medicines, certain species of the Schisandraceae family have been used in food, jellies, wine, and fruit juices.2 Plants in the Schisandraceae family are well-known traditional Chinese herbal medicines and have been targeted for medicinal chemistry leads and drug discovery. Considerable progress has been made in the discovery of bioactive and novel triterpenoids from the Schisandraceae family in the past two decades. Notably, Sun and co-workers successfully isolated over 100 nortriterpenoids from Schisandraceae,1b including lancifodilactone G (1) and the related compounds 2–61 (Fig. 1).

Figure 1: Structures of nortriterpenoids isolated from schisandraceae ACS Paragon Plus Environment

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Preliminary biological assays indicated that some of thesenortriterpenoids have inhibitory activities toward hepatitis, tumors, and HIV-1.1 Natural sources of these compounds are scarce, and this hampers systematic studies of their biological activities. Methods for synthesizing these products are needed to enable biomedical research to continue, and intensive efforts have been devoted to the total syntheses of these nortriterpenoids,3-5 recently culminating in the total syntheses of 2–6.6 Lancifodilactone G7 (1 in Fig. 1) was isolated from the medicinal plant Schisandra lancifolia by Sun and co-workers in 2005, and reported to show modest anti-HIV activity. The structure and relative stereochemistry of 1 were determined using NMR spectroscopy and X-ray crystallographic analysis.7 Unlike other family members (such as 2–6), 1 has both a CDE ring system (a 7–5–7 tricyclic core) bearing a non-resonance-stabilized aliphatic enol group (C-18)8 and an EGH ring system bearing an unprecedented two-fold anomerically stabilized bis-spiro ketal fragment.9 This aliphatic enol moiety is rare in natural products,10 and unstable because of steric and geometric constraints.11 From the perspective of synthetic view point, mapping out the fragments which contribute to the formation of the rigidity-derived aliphatic enol is critical in our design synthetic strategy toward total synthesis of 1, and such studies could help us to design synthetic strategies by puting the more rigid fragments at the later stage of our total synthesis, in consideration of the notion that more rigid molecule has a tendency to decompose during the synthesis. Therefore, study of the fragment rigidity of the target molecule 1 is critical to ensure our total synthesis. Since the CDEFGH ring system 8 (Scheme 1) bearing a bis-spiro ketal fragment represents a majority of the scaffold of 1, and we believed that both its medium-sized ring based 7-8 bicyclic ring system and its bis-spiro ketal fragment could provide enough ring rigidity to facilitate conversion of ketone 8 to its enol form 7. Herein, we report our effort for the construction of the CDEFGH ring


3


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system bearing a bis-spiro ketal fragment, and the key steps are 1) a ring-closing metathesis (RCM) reaction for synthesis of the oxa-bridged eight-membered ring (DE ring); 2) an intramolecular Pauson– Khand reaction (PKR) for formation of the sterically congested F ring; 3) sequential cross-metathesis, hydrogenation, and lactonization reactions for construction of the two-fold anomerically stabilized bis-spiro ketal moiety (GH ring) as illustrated in Scheme 1.

Scheme 1: Retrosynthetic analysis Results and discussion Synthesis of CDEFGH ring system.Scheme 1 shows our retrosynthetic analysis for this synthesis. We envisaged that the non-resonance-stabilized enol in the model molecule 7 could be derived from ketone 8 via an acid- or base-mediated ketone/enol equilibrium. We also expected that the methyl group in 7 could be installed via a regio- and stereo-selective methylation.12 Ketone 8 in turn could be made from benzyl ether 9 via a Pd-catalyzed hydrogenative debenzylation, followed by oxidation. The lactone group in compound 9 was expected to be generated from 10 via a


4

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cross-metathesis reaction with methyl acrylate,13 followed by lactonization. Our retrosynthetic analysis therefore traces back to the construction of intermediate 11, which could be prepared from ketal 13 using the chemistry involved in our total synthesis of schindilactone A.8a The key steps in this transformation are i) RCM for the formation of the eight-membered ring and ii) a PKR for construction of the sterically congested cyclopentenone fragment. Scheme 2: Synthesis of intermediate 12

Reaction conditions: a) LDA (1.2 equiv)，BrCH2COOEt (1.1 equiv), THF, -78 °C, 0.5 h, then rt, 8 h, 90%. b) Grignard reagent (2.0 equiv), Et2O, -78 °C, 1 h, then 0 oC 3 h, 75%. c) KHMDS (2.5 equiv), -78 °C, 1 h, then MoOPH(1. 5 equiv), -78 oC, 2 h, 85%. d) BnOC(= NH)CCl3 (2.0 equiv), Et2O, TfOH (cat.), 0 oC then 30 oC, 1h, 80%. e) vinylmagnesium bromide (2.0 equiv), THF, -20 °C, 0.5 h. f) Grubbs II catalyst (10 mol%), Ti(Oi-Pr)4 (1.5 equiv), CH2Cl2, 35 oC, 8 h, 55% for 2 steps. g) KHMDS (3.0 equiv), but-2-ynoic pivalic anhydride (5.0 equiv), THF, 0 oC, 3 h, 65%. h) [Co2(CO)8] (0.4 equiv), TMTU (2.4 equiv), benzene, 70 oC, 4 h, 75%. LDA = lithium diisopropylamide, KHMDS = potassium hexamethyldisilazide, Bn = benzyl, MoOPH = oxodiperoxomolybdenum(pyridine)(hexamethyl

phosphorictriamide),

THF

=

tetrahydrofuran, Tf = trifluoromethanesulfonyl, TMTU = tetramethyl thiourea.

We first synthesized the key intermediate 12 (Scheme 2) as follows. Commercially available cycloheptanone 14 was treated with lithium diisopropylamide (LDA) in tetrahydrofuran (THF) at ACS Paragon Plus Environment

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−78 °C, and the resultant enolate was reacted with ethyl 2-bromoacetate to give the mono-alkylated ketone 15 in 90% yield. The reaction of ketone 15 with but-3-enylmagnesium bromide in Et2O at −78 °C and then at room temperature, Grignard reagent chemoselectively attacked the ketone group and then in situ lactonization to give the 5-7 cis-fused lactone compound 16 in 75% yield as a single isomer. The chemo- and diastereo-selective formation of 16 could be a result in which the Grignard reagent approached the ketone moiety from its less hindered side (cis-configurated to the proton at C8), and resultant alkoxide then underwent and intramolecular lactonization to afford the 5-7 cis-fused lactone compound 16. The enolate obtained by treatment of lactone 16 with potassium hexamethyldisilazide (KHMDS) reacted with oxodiperoxomolybdenum -(pyridine)-(hexamethylphosphoric triamide)14 to afford α-hydroxy lactone 17 stereoselectively. The good diastereoselectivity observed in this reaction presumably was attributed to the hindered cycloheptane ring in substrate 16, which might direct the attack of oxidative reagent to approach the enolate from the less hinderedface (see the three-dimensional (3D) structure; Scheme 2). Thus, benzylation of 17 by reaction with BnOC(=NH)CCl3 in the presence of TfOH (Tf = trifluoromethanesulfony)15 gave lactone 18 in 80% yield, the reaction conditions prevented epimerization of 18 at C-16. The cyclooctene ring in compound 13 was formed by reacting lactone 18 with vinylmagnesium bromide in THF at −20 °C to give a hemi-ketal as a 1:1 mixture of diastereomers, which was directly treated, without separation, with a second-generation Grubbs catalyst (3 mol%) in the presence of Ti(Oi-Pr)416 in CH2Cl2 at 35 °C for 9 h to give hemi-ketal 13 as a single isomer. The observed in situ epimerization17 was in line with our earlier observation. 8a To install the fully functionalized F ring in 12, the hemi-ketal 13 was treated with KHMDS, and the resultant alkoxide was reacted with but-2-ynoic


6

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pivalic anhydride to form ester 19, which then underwent a Co-catalyzed intramolecular PKR in the presence of tetramethylthiourea to give cyclopentenone 12 in 75% yield. Scheme 3: Synthesis of intermediate 10 H

O F

a. MeONa, MeOH

O H OBn

H

Me

H O

O

12

b. TMS-imid. CH2Cl2 (93% in 2 steps)

13

O 20

Me

F

O

22

H COOMe H OBn OTMS

20

c. KHMDS, MeI, THF -78 oC (92%) Me O

13

O Me F 23

H CHO H OBn OTMS

10

Me d. DIBAL-H CH2Cl2, -78 oC e. DMP, NaHCO3 CH2Cl2 (91% in 2 steps)

13

O Me F

O H COOMe H OBn OTMS

11

Reaction conditions: a) MeONa (0.1 equiv), MeOH, rt. 0.5 h. b) TMS-imidazole (10 equiv), CH2Cl2, rt, 12 h, 93% for 2 steps. c) KHMDS (2.0 equiv), THF, -78 °C then MeI (3.0 equiv), -78 °C, 1 h, 92%. d) DIBAL (6.0 equiv), CH2Cl2, -78 °C, 1 h. e) DMP (2.0 equiv), NaHCO3 (5.0 equiv), CH2Cl2, rt, 91% for 2 steps. DIBAL = diisobutylaluminum hydride, DMP = Dess–Martin periodinate, TMS = trimethylsilyl.

Having secured a method for the synthesis of the key intermediate 12, we turned our attention to the preparation of aldehyde 10. As shown in Scheme 3, a two-step reaction involving generation of the methyl ester followed by trimethylsilyl (TMS) protection efficiently yielded keto ester 20. Stereoselective installation of the C-13 methyl group was achieved using the method developed in our total synthesis of schindilactone A (2). 8a Keto ester 20 was treated with KHMDS in THF at −78 °C, and the resultant enolate reacted with MeI at the same temperature to afford product 11 as a single diastereoisomer, presumably because the bulky TMS ether covers the concave face of 11, leading MeI to approach the enolate from the convex face. Further treatment of 11 involving reduction with diisobutylaluminum hydride (DIBAL-H) at −78 °C in CH2Cl2 gave a primary alcohol, which was oxidized with Dess–Martin periodinate (DMP) to afford aldehyde 10 in 91% overall yield.


7


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At the same time, we also investigated more challenged RCM reaction for construction of the medium-ring-based tri-substituted cyclooctene in compound 23. Through the similar chemistry in scheme 2, ketoester 15 underwent a regio- and stereo-selective Grignard reaction to afford lactone 21 in 89% yield. Lactone 21 was first subjected to the treatment with KHMDS in THF at −78 °C, and the resultant enolate then underwent an oxidative hydroxylation by reaction with the oxidant MoOPH, and the newly generated secondary alcohol was protected as its benzyl ether by treatment with BnBr/Ag2O18 to give lactone 22 in 77% yield in two steps. To prepare the tri-substituted cyclooctene 23, lactone 22 was first reacted with a vinyl Grignard reagent, and the resultant hemi-acetal-based diene as a pair of diastereoisomers at C-15 then underwent RCM on treatment with a Hoveyda-Grubbs II catalyst to afford 23 in 54% overall yield as a single diastereoisomer through dynamic epimerization.19 Further treatment of 23 with KHMDS in THF gave an alkoxide, which was reacted with but-2-ynoic pivalic anhydride to give ester 24 in 76% yield, the synthetic route was showed in Scheme 4. Scheme 4: Synthesis of compound 24

Reaction conditions: a) Grignard reagent (3.0 equiv), Et2O, -78 °C to rt., 89%; b) KHMDS (2.5 equiv), MoOPH (2.0 equiv), THF, -78 °C, 2 h, 86%; c) Ag2O (2.0 equiv), BnBr (2.0 equiv), TBAI (0.05 equiv), rt., 12 h, 90%; d) vinylmagnesium bromide (3.0 equiv), THF, -23 °C, 1 h; e) Hoveyda-Grubbs II catalyst (3 mol%), toluene, 80 °C, 24 h, 54% for two steps; f) KHMDS (2.0 equiv), but-2-ynoic pivalic anhydride (5.0 equiv), THF, 0 °C, 1 h, 76%.


8

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With the model enyne 24 in hand, we then began to explore its PK reaction for the stereoselective formation of compound 25 bearing an all-carbon quaternary chiral center at C-13. Various typical PK reaction conditions were profiled, the details are listed in Table 1. Table 1: Optimization of Pauson-Khand reaction Me O Me

13 14

O 16

Me O

Me

16

H BnO

24

H BnO

O

1

metal complex

H O

25

O

+ Me

O

O

H BnO

additive

15

solvent

Me

16

16

H O

26 entry

15

Me

solvent temp.

15

O

catalyst additive CO

H BnO

O

temp (oC)

H O

27 time (h)

26

56%

12%

Co2(CO)8

DME

Co2(CO)8

BuSMe

DCE

25 to 85 0.5+1.25 46%

3

Co2(CO)8

CyNH2

DCE

25 to 85 0.5+1.25

4

Co2(CO)8

TMANO

DCE

25 to 35

8+13

28%

5

Co2(CO)8

TMANO

toluene

25 to 35

9

45%

6

Co2(CO)8

TMTU

benzene

70

4.5

72%

7

CoBr2, Zn

TMTU o 4A MS

toluene

70

20

62%

6%

8

Co2(CO)8

hv

DME

50

10

55%

9%

9

[Rh(CO)2Cl]2

toluene

120

16

6%

DME

85

11

10

10

25

2

o

70

15

O

27

13%

4A MS

30% 30%

reagent and conditions: a Co2(CO)8 (0.5 eq.) under CO. b Co2(CO)8 (1.0 eq.) with BuSMe (3.5 eq.). c Co2(CO)8 (1.0 eq.) with CyNH 2 (5.0 eq.). d Co2(CO)8 (1.0 eq.) with TMANO (5.0 eq.). e Co2(CO)8 (1.0 eq.) with TMANO (5.0 eq.) and 4A MS(2.0 wt%). f Co2(CO)8 (0.5 eq.) with TMTU (3.0 eq.) under CO. g CoBr2 (0.2 eq.) with Zn (4.0 eq.) and TMTU (1.2 eq.) under CO. h Co2(CO)8 (0.2 eq.) under CO. i Rh(CO) 2Cl2 (0.05 eq.) with CO. j under CO.

Initially, the PK reaction was performed in the presence of Co2(CO)8 without any additive, and the desired annulated product 25 was obtained in 56% yield, together with the monocyclic product 26 in 12% yield (entry 1). We then tested this reaction in the presence of various additives, namely BuSMe,20 CyNH2,21 TMANO,22 TMANO/4Å molecular sieves,23 TMTU,24 and TMTU/4Å molecular sieves24


9


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(entries 2–7), and the yield of product 25 could be increased to 72% when TMTU was used as an additive in benzene at 70 °C for 12 h. It has been reported that irradiation with UV light promotes the PK reaction,25 therefore we performed the reaction under irradiation with UV light. Product 25 was obtained in 55% yield, together with 26 in 9% yield (entry 8). We also tested the PK reaction with [Rh(CO)2Cl]2 as a catalyst (entry 9),26 under this condition, product 25 was formed in only 6% yield, together with the formation of 27in 30% yield. When the reaction was performed in DME at 85 °C for 11 h without any additive, product 26 was obtained in 30% yield, together with recovered starting material 24 in ca. 60% yield. Table 2: Co2(CO)8/TMTU catalyzed Pauson-Khand reactions

According to these studies listed in Table 1, the Co2(CO)8/TMTU-catalyzed PK reaction gave the best result for formation of product 25, therefore we decided to use this catalyst in our future PK reaction, and profiled the effects of the catalyst ratio, solvent, reaction temperature, and reaction time on the outcome of the PK reaction; the results are given in Table 2. According to the results, we can make


10

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the following observations: 1) all the reactions gave product 25 as a single diastereoisomer, indicating that the butynoic ester was an effective linker, and could complement and reinforce the regio- and stereo-selectivity of the PK reaction, leading to formation of the cyclopentenone ring system bearing cis-fused C-13 and C-14 chiral centers; 2) the best result, i.e., a 70% yield of 25, was achieved when the reaction was performed using Co2(CO)8/TMTU in a ratio of 1:6 in toluene at 95 °C for 6 h (entry 7). As shown in Scheme 5, compound 11 can also be obtained in good yield from PK product 25 via a two-step reaction involving generation of the methyl ester in the presence of CH3ONa/CH3OH, then followed by trimethylsilyl (TMS) protection, as a result, one step was saved than the original approach. Scheme 5: Synthesis of compound 11 from compound 25

Reaction conditions: a) MeONa (0.1 equiv), MeOH, rt. 0.5 h. b) TMS-imidazole (10 equiv), CH2Cl2, rt, 12 h, 91% for 2 steps.

With these results in hand, we then turned our attention to stereoselective formation of the GH ring system in model 7; three possible synthetic pathways were proposed, as shown in Scheme 6. Scheme 6: Designed chemistry for the synthesis of model 7


11


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We then began to explore the feasibilities of these syntheses. For the chemistry associated with path a, we initially attempted to use a Stetter reaction27 for the synthesis of compound 28 from aldehyde 10. To achieve this transformation, we systematically profiled the Stetter reaction by treatment of aldehyde 10 and methyl acrylate at room temperature in the presence of thiazolium salt catalyst C and various bases [N,N-Diisopropylethylamine, Et3N, 1,8-diazabicyclo-[5.4.0]undec-7-ene (DBU), and Cs2CO3] in different solvents (benzene, toluene, THF, CH2Cl2, and CHCl3).28 However, the desired product 28 was not obtained under these conditions. We attribute this to the presence of an equilibrium between intermediates A and B (Scheme 7), which could reduce the nucleophilicity of intermediate A toward methyl acrylate. Scheme 7: The proposed equilibrium between A and B in the Stetter reaction for the synthesis of 28


12

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According to the proposed mechanism, a substrate without a double bond at C-20 and C-22 could avoid this equilibrium, therefore we prepared aldehyde 34 for use in the Stetter reaction (Scheme 8). Lactone 25 was subjected selective Pd-catalyzed hydrogenation to remove the double bond at C-20/C-22, and the resultant ketone 32, obtained as a pair of diastereoisomers at C-20, was treated with DBU in CH2Cl2 at 40 °C to afford product 31 as a single diastereoisomer in 70% yield in two steps. Further low-temperature reduction of 31 with DIBAl-H in THF afforded lactal 33. We believed that lactal 33 could be in equilibrium with aldehyde 34, which could undergo the Stetter reaction to form keto ester 28. However, the expected coupling reaction did not occur under various reaction conditions. Scheme 8: Attempted to synthesize 28 via Stetter reaction


13


Me

O

Me

Page 14 of 42 O 20

Me a. Pd/C, H2, EA

O H O

H

O

O H

OBn

H O

OH

O

OBn

Me Me

O

c. DIBAl-H, THF -78 oC to -20 oC

H H O

OH

H

OBn

Me

20

Me H

H O

O

OBn

31

OH

+

Me

Bn N Cl

Me

Me

H OH

H O

OH Me

S

HO

O

OBn

O

O

(80%)

33

34

H

b. DBU, CH2Cl2, 40 oC (60% in 2 steps) Me

H

Me

32

25

H

22

C X

O H

O OMe

base, solvent

H OBn OH O 28 MeOOC

Reaction conditions: a) Pd/C (0.5 equiv), EtOAc, rt. 0.5 h. b) DBU (2.0 equiv), CH2Cl2, 40 °C, 12 h, 60% for 2 steps. d) DIBAL (2.5 equiv), CH2Cl2, -78 °C, 1 h, 75%. DBU = 1, 8-diazabicyclo[5.4.0]undec-7-ene.

We then began to explore the proposed path b for the synthesis of model 7. In the past two decades, Au catalysts have become the popular catalysts for cycloisomerizations because they have high activities and require mild reaction conditions, and a wide variety of organic scaffolds have been made using this powerful method.29 Au complexes are soft Lewis acids and can therefore selectively activate alkynes and promote nucleophilic addition.30 The intramolecular nucleophilic addition of a hydroxyl group to an Au-activated carbon–carbon triple bond is a powerful method for the synthesis of structurally diverse scaffolds.31 In 2012, Ye and co-workers developed an efficient method for the synthesis of structurally diverse γ-lactones from their corresponding homopropargyl alcohols via Au-catalyzed tandem cycloisomerization /oxidation. 32 On the basis of this chemistry, we attempted to form the GH ring in 9 (Scheme 9) via an Au-catalyzed tandem reaction. Scheme 9: Attempt to synthesize compound 9 ACS Paragon Plus Environment

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Reaction conditions: a) Propargylmagnesium bromide (1.1 equiv), THF, -78 °C, 0.5 h, 88%. b) LiAlH2(OMe)2 (10 equiv), THF, -78 °C, 3 h. c) TBAF (3.0 equiv), THF, rt, 10 min. d) DBU (2.0 equiv), CH2Cl2, 40 °C, 3 h, 75% for 3 steps. e) TPAP (0.1 equiv), NMO (3.0 equiv), CH2Cl2, rt, 20 min, 60%. f) Ph3PAuCl (5 mol%), mCPBA (1.5 equiv), MsOH (1.0 equiv), DCE, rt, 5 h, trace. TBAF = Tetrabutyl-ammonium fluoride, TPAP = Tetrapropylammonium perruthenate, NMO = 4-Methylmorpholine, mCPBA = 3-Chloroperbenzoic acid. DCE = Dichloroethane.

The reaction of aldehyde 10 with prop-2-yn-1-ylmagnesium bromide in THF gave homopropargyl alcohol 35 as a single isomer in 88% yield. The excellent diastereoselectivity is likely attributed to both the defined orientation of the aldehyde (resulting from the dipole interaction of the oxygen atom in the aldehyde with the oxygen atom in OTMS), and a steric shielding of the concave face by the OTMS of the substrate 10.6a Regioselective reduction of its α,β-unsaturated double bond was achieved via a sequence consisting of LiAlH4/MeOH-mediated reduction,33 desilylation, and DBU-mediated epimerization to afford ketone 36 in 75% overall yield. The observed stereoselective reduction of the C-20 and C-22 double bond is attributed to complexation between the substrate propargyl alcohol at C-23 and the reducing agent (LiAlH4/MeOH), which could guide the hydride to ACS Paragon Plus Environment

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approach the double bond from its upper face. The precursor 29 for formation of the GH bicyclic ring in 9 was prepared by oxidizing 36 with tetrapropylammonium perruthenate/4-methylmorpholine (TPAP/NMO); however, under the reaction conditions, products 29a and 29b were obtained in 60% yield in ratio of 1:1. The formation of 29a presumably occurred because 29b can undergo alkyne/allene isomerization during the reaction or chromatography on silica gel.34 With 29b in hand, we investigated its Au-catalyzed tandem reaction. When 29b was treated with Ph3PAuCl in the presence of 3-chloroperbenzoic acid in dichloroethane,32 only a trace amount of the desired annulated product 9 was observed, and lactone 31 was obtained in over 60% yield via releasing an allene group from 29a under acid activation. To improve the yield, we screened other Au catalysts for this reaction, but no improvement was obtained. Scheme 10: Attempt to synthesize compound 37

Although the above reaction did not give the desired product 9, the formed lactone 31 was used as a starting material to test the feasibility of formation of the GH bicyclic ring system in 37 via a Reformatsky reaction.35 Lactone 31 was reacted with ethyl 3-(bromomethyl)-2-oxobut-3-enoate in the presence of various Zn agents under the conditions listed in Scheme 10, however, none of them gave the expected annulated product 37.


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Because the three proposed synthetic pathways failed to achieve construction of the GH ring system, we considered use of a step-wise method for its formation. Aldehyde 10 was selected as the substrate; it was reacted with vinylmagnesium bromide in THF at −78 °C, and the resultant product was subjected to desilylation by treatment with tetrabutylammonium fluoride in THF to give allylic alcohol 38 in 89% yield in two steps (Scheme 11). Scheme 11: Synthesis of ketal 40 O

Me

Me O

a. vinyl magnesium bromide

23

H CHO OBn

OTMS

13

F

O

23

OH

H

THF, -78 oC (88%)

H

10

OTMS OBn

38 b. TBAF, THF

d. DBU, CH2Cl 2

c. LiAlH2(OMe)2 THF, -78 oC

(70% in 3 steps)

O

Me

Me

Me F

13

H

O H

Me

Me F

13

H

O

OBn

H 23 O OH

e. MnO2, CH 2Cl2 (90%, dr = 5:1)

13

O H

40

OBn

O 20

F 22

H OH

Me H 23

OH

39

Reaction conditions: a) vinylmagnesium bromide (1.1 equiv), THF, -78 oC, 0.5 h, 88%. b) TBAF (3.0 equiv), THF, rt, 10 min. c) LiAlH2(OMe)2 (10 equiv), THF, -78 o

C, 3 h. d) DBU (2 equiv), CH2Cl2, 40 oC, 3 h, 70% for 3 steps. e) MnO2(10 equiv),

CH2Cl2, 40 oC, 36 h, 90%.

To achieve regio- and stereo-selective reduction of its α,β-unsaturated double bond, 38 was subjected to a red-Al-mediated reduction,33 and the resultant ketone was treated with DBU to epimerize its C-20 stereogenic center to give ketone 39 with high stereoselectivity. For synthesis of hemi-ketal 40, several oxidants (i.e., DMP, PCC, PDC, TPAP, and MnO2) were tested, but only oxidation with MnO2 gave the desired product 40, in 90% yield as a pair of diastereoisomers (dr = 5:1) at the newly generated C-23 chiral center. We later found out that this transformation could also be achieved in 86% yield via TEMPO/Fe(NO3)3-catalyzed36 oxidation in the presence of oxygen as an oxidant. Scheme 12: Synthesis of model 8 ACS Paragon Plus Environment

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Reaction conditions: a) Et3N (3.0 equiv), DMAP (1.0 equiv), methacrylic anhydrate (2.2 equiv), CH2Cl2, 30 oC, 1 h, 87%. b) methyl methacrylate (10.0 equiv), benzene, 80 oC, 4 h. c) methyl acrylate (10.0 equiv), Grubbs II catalyst (10 mol%), benzene, 80 o

C, 4 h, 50%, 80% brsm. or methyl acrylate (10.0 equiv), Hoveyda-Grubbs II catalyst

(10 mol%), toluene, 100 oC, 4 h, 84%. d) Pd/C (1.0 equiv), EtOAc, rt. 0.5 h, 95%. e) KHMDS (2.0 equiv), THF, -20 oC, 0.5 h, 85%. f) Pd(OH)2 (1.0 equiv), EtOAc, rt. 0.5 h, 95%. g) DMP (2.0 equiv), NaHCO3 (5.0 equiv), CH2Cl2, rt, 85%. DMAP = 4-dimethylaminopyridine.

With 40 in hand, we were at the stage for construction of the H ring of our target molecule 1; lactone 42 was selected as the first model to be prepared. Substrate 40was reacted with methacrylic anhydride in the presence of DMAP and Et3N, and the resultant diene 41 was treated with metathesis ACS Paragon Plus Environment

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catalysts such as Grubbs I, Grubbs II, and Hoveyda–Grubbs II catalysts, but none of these reactions afforded the desired lactone 42. We then attempted to use an intermolecular cross-metathesis reaction for the formation of intermediate 43, which was expected to proceed via double-bond isomerization and lactonization to generate the H ring of lactone 42. However, this transformation did not occurre due to the low reactivity of 1,1-disubstituted alkene. We then decided to form the H ring without the methyl group at C-25. Hemi-ketal 40 was reacted with methyl acrylate in benzene at 80 °C in the presence of a Grubbs II or Hoveyda–Grubbs II catalyst.37 The expected product 44 was obtained in 50% yield and 84% yield, respectively (Scheme 12). After saturation of the C-23/C-24 double bond by Pd/C-catalyzed hydrogenation, followed by treatment with KHMDS at −20 °C in THF, lactone 9 was obtained as a single diastereoisomer in 81% yield in two steps. To complete synthesis of model compound 7, lactone 9 was subjected to Pd(OH)2-catalyzed debenzylation, and oxidation of the resultant alcohol 45 with DMP afforded product 8 in 81% yield in two steps. The relative stereochemistry of 45 was unambiguously confirmed by X-ray crystallographic analysis. It is worth mentioning that compound 8 existed in its ketone form, and none of the enol isomer 7 was observed, indicating that an additional driving force might be needed to drive the equilibrium from the ketone form to the enol form. CONCLUSION The stereoselective synthesis of the CDEFGH ring system of lancifodilactone G was achieved. The key steps in this synthesis are i) a RCM reaction for construction of the oxa-bridged eight-membered ring; ii) an intramolecular PKR for formation of the sterically congested F ring; and iii) a cross-metathesis, hydrogenation, and lactonization reaction sequence for construction of the FGH ring bearing an anomerically stabilized bis-spiro ketal. The observed form of compound 8, i.e., the ketone


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form, indicates that a substrate bearing an additional ring, might provide the additional driving force to achieve formation of the non-resonance-stabilized aliphatic enol form.The information generated from this model study guided us in the development of synthetic strategies and tactics for the asymmetric total synthesis of lancifodilactone G (1).38 EXPERIMENTAL SECTION Synthesis ofethyl 2-(2-oxocycloheptyl)acetate(15). To a stirred solution of the diisopropylamine (7.7 mL, 55.0 mmol) in THF (25 mL) was added n-BuLi (20.0 mL, 2.5 M, 50.0 mmol) at -78 oC under N2 atmosphere, and the mixture was stirred at 0 oC for 30 min. To this solution was added a solution of cycloheptanone 14 (5.3 mL, 44.6 mmol) in THF (50 mL) at -78 oC, and the formed mixture was stirred at the same temperature for 1 h. To this solution was added a solution of ethyl bromoacetate (5.4 mL, 49.1 mmol) in THF (10 mL) at -78 oC for 30 min slowly, the resultant mixture was then warmed up to room temperature, and stirred for 8 h. The reaction mixture was quenched carefully with a saturated solution of NH4Cl (50 mL), and the mixture was extracted with ethyl acetate (3 × 100 mL). The combined organic layers were washed with brine, and ried over Na2SO4. The solvent was removed under vacuum, and the residue was purified by a flash column chromatography on silica gel (eluting with petroleum ether/ethyl acetate = 10:1) to give product 15 as yellow oil (8.0 g, 90% yield). Data for compound 15: Rf = 0.7 (silica gel, EtOAc: petroleum ether 1:2); FT-IR (neat) νmax 2827, 1800, 1705, 1185 cm-1; 1HNMR (400 MHz, CDCl3) δ 4.13-4.11 (q, J = 7.1 Hz, 2H), 3.11-3.09 (m, 1H), 2.84-2.77 (dd, J = 8.4, 16.7 Hz, 1H), 2.66-2.61 (m, 1H), 2.49-2.45 (m, 1H), 2.32-2.26 (dd, J = 5.7, 16.7 Hz, 1H), 1.87-1.72 (m, 5H), 1.57-1.38 (m, 1H), 1.37-1.27 (m, 2H),1.26-1.22 (t, J = 7.2 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ 214.2, 172.5, 60.4, 47.4, 43.3, 36.7, 31.2, 29.3, 28.9, 23.5, 14.1 ppm; HRMS(ESI): calcd for C11H18O3Na [M + Na]+ 221.1148, found 221.1144.


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Synthesis of (3aS,8aR)-8a-(but-3-en-1-yl)octahydro-2H-cyclohepta[b]furan-2-one(16). To a mixture of Mg turning (0.3 g, 12.5 mmol) in ether (2 mL) was added 4-bromo-1- butene (1.0 mL, 10.0 mmol) slowly under N2 atmosphere, and the resultant mixture was stirred at room temperature for 1 h. To a solution of compound 15 (1.0 g, 5.0 mmol) in ether (20 mL) was added the Grignard reagent made above at -78 oC slowly, and the mixture was first kept at this temperature for 1 h, and then warmed up to room temperature for another 3 h. The reaction was quenched by addition of a saturated solution of NH4Cl (20 mL), and the mixture was extracted with ethyl acetate (3 × 40 mL). The combined organic extracts were 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 (eluting with petroleum ether/ethyl acetate = 20:1) to give product 16 as yellow oil (0.8 g, 75% yield). Data for compound 16: Rf = 0.5 (silica gel, EtOAc: petroleum ether 1:4); FT-IR (neat) νmax 2929, 2853, 1761, 1460, 1187 cm-1; 1H NMR (400 MHz, CDCl3) δ 5.85-5.75 (m, 1H), 5.07-5.02 (m, 1H), 4.99-4.96 (m,1H), 2.93-2.86 (dd, J = 17.9, 9.7 Hz, 1H), 2.40-2.25 (m, 2H), 2.22-2.06 (m, 2H), 2.00-1.97 (dd, J = 14.5, 8.7 Hz, 1H), 1.85-1.57 (m, 7 H), 1.53-1.20 (m, 4H) ppm;

13

CNMR (100 MHz, CDCl3) δ 176.2,

137.6, 114.9, 91.7, 43.8, 40.4, 36.8, 34.8, 31.8,30.4, 27.5, 27.2, 23.0 ppm; HRMS(ESI) calcd for C13H20O2Na [M + Na]+ 231.1356, found 231.1354. Synthesis of (3S,3aS,8aR)-8a-(but-3-en-1-yl)-3-hydroxyoctahydro-2H-cyclohepta[b]furan-2-one (17). To a solution of compound 16 (4.0 g, 19.2 mmol) in THF (100 mL) was added a solution of KHMDS (1 M in THF, 48.0 mL, 48.0 mmol) at -78 oC slowly, and the resultant mixture was stirred at the same temperature for 1 h. To this solution was added MoOPH (12.4 g, 28.8 mmol) in 2 portions, and the reaction mixture was stirred at -78 oC for 2 h. The reaction was quenched by addition of a saturated


21


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solution of Na2SO3 (40 mL), and the mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were 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 = 5:1) to give product 17 (3.7 g, 85% yield) as a yellow oil. Data for 17: Rf = 0.2 (silica gel, petroleum ether/ethyl acetate = 4:1); FT-IR (neat) νmax: 2929, 2862, 1759, 1629, 1449, 1201 cm-1; 1H NMR (400 MHz, CDCl3) δ: 5.85-5.75 (m, 1H), 5.07-5.03 (d, J = 17.2 Hz, 1H), 4.99-4.96 (d, J = 10 Hz, 1H), 4.47-4.43 (m, 1H), 3.19-3.18 (d, J = 3.2 Hz, 1H), 2.40-2.37 (m, 1H), 2.23-2.13 (m, 2H), 1.95-1.74 (m, 7H), 1.60-1.50 (m, 5H) ppm;

13

C NMR (100 MHz, CDCl3) δ 177.5, 137.6, 115.0, 90.7,

72.5, 50.5, 41.4, 35.4, 30.6, 28.0, 27.3, 24.3, 22.9 ppm; HRMS (ESI): calcd for C13H20O3Na [M + Na]+ 247.1305, found 247.1299. Synthesis

of

(3S,3aS,8aR)-3-(benzyloxy)-8a-(but-3-en-1-yl)octahydro-2H-cyclohepta[b]furan-2-one (18). To a solution of compound 17 (1.3 g, 5.9 mmol) in Et2O (30 mL) was added benzyl 2,2,2-trichloroacetimidate (2.2 mL, 12.0 mmol) and TfOH (0.03 mL, 0.03 mmol) at 0 oC, and the resultant mixture was stirred at 30 oC for 1 h. The reaction was quenched by addition of silica gel (5.0 g) and solid NaHCO3 (1.0 g), the mixture was concentrated under vacuum. The residue was purified by a flash column chromatography on silica gel (petroleum ether/ethyl acetate = 25:1) to give product 18 (1.5 g, 80% yield) as a yellow solid. Data for 18: Rf = 0.8 (silica gel, petroleum ether/ethyl acetate = 4:1); FT-IR (neat) νmax: 2929, 2856, 1761, 1638, 14511 1193 cm-1; 1H NMR (400 MHz, CDCl3) δ: 7.39-7.26 （m, 5H）, 5.84-5.74 (m, 1H), 5.06-5.02 (m, 2H), 4.98-4.96 (m, 1H), 4.79-4.76 (d, J = 12 Hz, 1H), 4.05-4.03 (d, J = 8 Hz, 1H), 2.42-2.37 (m, 1H), 2.23-2.11 (m, 2H), 1.89-1.74 (m, 5H), 1.66-1.61 (m, 1H), 1.47-1.37 (m, 6H) ppm; 13C NMR (100 MHz, CDCl3) δ: 174.7, 137.7, 137.4, 128.5, 128.2, 128.0,


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127.8, 115.0, 89.9, 78.2, 72.3, 50.0, 41.4, 35.5, 30.5, 28.3, 27.4, 25.1, 22.9 ppm; HRMS (ESI): calcd for C20H27O3 [M + H]+ 315.1955, found 315.1955. Synthesis of (5aR,10S,11S,11aS)-11-(benzyloxy)-2,3,4,5,6,7,11,11a-octahydro-5a,10-epoxycyclohepta[8] annulen-10(1H)-ol(13). To a solution of compound 18 (1.6 g, 5.0 mmol) in THF (25 mL) was added vinyl magnesium bromide (14.4 mL, 0.7 M, 10 mmol) at -20 oC slowly, and the resultant mixture was then stirred at the same temperature for 30 min. The reaction was quenched by addition of a saturated solution of NH4Cl (30 mL) at 0 oC, and the mixture was then extracted with EtOAc (3 × 30 mL). The combined organic extracts were washed with brine, and dried over Na2SO4. The solvent was removed under vacuum to give the diene. To a solution of the diene made above in CH2Cl2 (180 mL) was added Ti(Oi-Pr)4 (2.2 g，7.5 mmol) at 0 oC, and the resultant mixture was stirred at the same temperature for 30 min. To this solution was added Grubbs’ II catalyst (470.0 mg, 0.55 mmol), and the mixture was then stirred at 35 oC for 8 h. The reaction was quenched by addition of silica gel (100 mg), and the mixture was concentrated under vacuum. The residue was purified by a flash column chromatography on silica gel (petroleum ether/ethyl acetate = 10:1) to give product 13 (865.0 mg, 55% yield in 2 steps) as a yellowish oil. Data for 13: Rf = 0.4 (silica gel, petroleum ether/ethyl acetate = 4:1); FT-IR (neat) νmax: 2918, 2850, 1452, 1350, 1130, 1092 cm-1; 1H NMR (400 MHz, CDCl3) δ: 7.34-7.26 (m, 5H),5.98-5.92 (m, 1H), 5.83-5.80 (d, J = 11.6 Hz，1H), 4.80-4.77 (d, J = 12 Hz, 1H), 4.57-4.54 (d, J = 12 Hz, 1H), 3.63-3.61 (d, J = 8 Hz, 1H), 3.18 (s, 1H), 2.55-2.48 (m, 1H), 2.34-2.23 (m, 1H), 2.19-2.16 (m, 1H), 1.98-1.93 (m, 1H), 1.85-1.56 (m, 8H), 1.45-1.34 (m, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ: 138.4, 132.6, 131.9, 128.4,


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128.3, 127.9, 127.6, 104.5, 91.1, 83.7, 71.9, 50.8, 40.3, 39.9, 31.4, 30.1, 27.3, 24.7, 24.3 ppm; HRMS (ESI): calcd for C20H30NO3 [M + NH4]+ 332.2220, found 332.2224. Synthesis of (5aR,10R,11S,11aS)-11-(benzyloxy)-2,3,4,5,6,7,11,11a-octahydro-5a,10-epoxycyclohepta[8]annulen-10(1H)-yl but-2-ynoate(19). To a solution of 2-butynoic acid (640.2 mg, 7.6 mmol) in THF (16 mL) was added NaH (273.6 mg, 11.4 mmol) at 0 oC, and the mixture was stirred at the same temperature for 25 min. To this solution was added PivCl (0.9 mL, 7.6 mmol), and the formed mixture was stirred at 0 oC for 50 min. To a solution of compound 13 (0.5 g, 1.6 mmol) in THF (6 mL) was added KHMDS (6.9 mL, 0.7 M, 4.8 mmol) at 0 oC, and the mixture was stirred at the same temperature for 20 min. To this solution was added the solution of the mixed anhydride made above at 0 oC, and the resultant mixture was then stirred at same temperature for 3 h. The reaction was quenched by addition of a saturated solution of NH4Cl (30 mL), and the mixture was extracted with EtOAc (3 × 50 mL). The combined organic extracts were 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 = 6:1) to give product 19 (395.2 mg, 65% yield) as yellow oil. Data for compound 19: Rf = 0.6 (silica gel, petroleum ether/ethyl acetate = 4:1); FT-IR (neat) νmax: 2921, 2853, 2236, 1730, 1455, 1245 cm-1; 1H NMR (400 MHz, CDCl3) δ: 7.35-7.27 (m, 5H), 5.99-5.94 (m, 1H), 5.87-5.84 (d, J = 12 Hz，1H), 4.72-4.70 (d, J = 11.6 Hz, 1H), 4.54-4.51 (d, J = 11.6 Hz, 1H), 4.00-3.98 (d, J = 7.6 Hz, 1H), 2.57-2.51 (m, 1H), 2.35-2.30 (m, 1H), 2.14-2.09 (m, 1H), 1.99 (s, 3H), 1.86-1.83 (m, 1H), 1.76-1.73 (m, 2H), 1.73-1.69 (m, 1H), 1.71-1.63 (m, 4H), 1.53-1.44 (m, 1H), 1.35-1.28 (m, 1H), 1.27-1.21 (m, 2H) ppm; 13

C NMR (100 MHz, CDCl3) δ: 151.1, 138.1, 131.9, 129.7, 128.5, 128.4, 128.0, 127.8, 109.1, 90.4,


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86.4, 85.3, 73.2, 72.3, 49.3, 39.9, 39.4, 31.4, 29.9, 27.3, 24.8, 24.1, 3.9 ppm; HRMS (ESI): calcd for C24H28NaO4 [M + Na]+ 403.1880, found 403.1878. Synthesis of (2a1R,4aS,6aR,11aS,12S,12aR)-12-(benzyloxy)-3-methyl-2a1,4a,5,6,8,9,10,11,11a,12decahydro-7H-1,13-dioxa-6a,12a-methanocyclohepta[5,6]cycloocta[1,2,3-cd]pentalene-2,4-dione (12). To a solution of the compound 19 (760 mg, 2.0 mmol) in benzene (10 mL) was added Co2(CO)8 (133.0 mg, 0.4 mmol) and TMTU (317.2 mg, 2.4 mmol) under N2 atmosphere, and the resultant mixture was degassed with CO for 3 times, and the mixture was then stirred at 70 oC for 4 h. The reaction was worked up by removal of the solvent under vacuum, and the residue was purified by a flash column chromatography on silica gel (petroleum ether/ethyl acetate = 5:1) to give product 12 (613.0 mg, 75% yield) as white solid. Data for 12: Rf = 0.3 (silica gel, petroleum ether/ethyl acetate = 4:1); FT-IR (neat) νmax: 2923, 2863, 2058, 1782, 1703, 1453, 1303 cm-1; 1H NMR (400 MHz, CDCl3) δ: 7.39-7.27 (m, 5H), 4.72-4.69 (d, J = 12 Hz, 1H), 4.64-4.61 (d, J = 11.6 Hz, 1H), 4.03-4.01 (d, J = 6.4 Hz, 1H), 3.88-3.85 (m, 1H), 2.85-2.80 (m, 1H), 2.22-2.17 (m, 1H), 2.06 (d, J = 2.8 Hz, 3H), 2.05-1.91 (m, 2H), 1.77-1.65 (m, 6H), 1.61-1.55 (m, 3H), 1.43-1.37 (m, 1H), 1.30-1.24 (m, 2H) ppm; 13C NMR (100 MHz, CDCl3) δ: 209.4, 164.5, 153.5, 144.2, 137.3, 128.6, 128.1, 127.8, 113.2, 86.2, 85.5, 73.1, 51.6, 48.5, 46.7, 39.2, 38.8, 31.1, 30.4, 27.6, 23.6, 22.0, 9.3 ppm; HRMS (ESI): calcd for C25H28NaO5 [M + Na]+ 431.1834, found 431.1836. Synthesis of methyl (3aR,4R,5S,5aS,10aR,12aS)-5-(benzyloxy)-2-methyl-1-oxo-4-((trimethylsilyl) oxy)-3a,4,5,5a,6,7,8,9,10,11,12,12a-dodecahydro-1H-4,10a-epoxycyclohepta[a]cyclopenta[e][8]-ann ulene-3-carboxylate (20).


25


Page 26 of 42

To a solution of the compound 12 (490.2 mg, 1.2 mmol) in methanol (10 mL) was added sodium methoxide (6.5 mg, 0.12 mmol) at room temperature, and the mixture was stirred at the same temperature for 30 min. The reaction was quenched by addition of a saturated solution of NH4Cl (20 mL), and the mixture was extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine, and dried over Na2SO4. The solvent was removed under vacuum to give a residue as white solids. To a solution of the white solids made above in dried DCM (10 mL) was added N-(trimethylsilyl)-imidazole (836 mg, 6.0 mmol), and the mixture was then stirred at room temperature for 12 h. The reaction was quenched by addition of a saturated solution of NH4Cl (10 mL), and the mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic layers were 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 = 10:1) to give product 20 (572.2 mg, 93% yield for 2 steps) as a white solid. Data for compound 20: Rf = 0.8 (silica gel, petroleum ether/ethyl acetate = 4:1); FT-IR (neat) νmax: 2946, 2850, 1712, 1435, 1247, 1121, 1081 cm-1; 1H NMR (400 MHz, CDCl3) δ: 7.40-7.26 (m, 5H), 4.85-4.82 (d, J = 11.6 Hz, 1H), 4.61-4.58 (d, J = 12 Hz, 1H), 4.27-4.26 (d, J = 6 Hz, 1H), 3.82 (s, 3H), 3.58-3.57 (d, J = 6 Hz, 1H), 2.59-2.56 (m, 1H), 2.27-2.23 (m, 1H), 2.15 (s, 1H), 2.11 (s, 1H), 2.03 (s, 3H), 1.83 (m, 2H), 1.80-1.74 (m, 3H), 1.73 (s, 1H), 1.65-1.63 (m, 1H), 1.57-1.56 (m, 1H), 1.53-1.50 (m, 1H), 1.27-1.11 (m, 2H), 1.06-1.03 (m, 1H) 0.00 (s, 9H) ppm; 13

C NMR (100 MHz, CDCl3) δ: 208.1, 165.1, 153.1, 144.4, 136.4, 126.9, 126.7, 107.9, 94.2, 86.8, 70.4,

49.9, 49.1, 48.5, 47.1, 37.5, 35.4, 31.4, 29.8, 27.9, 23.3, 17.9, 8.3, ppm; HRMS(ESI): calcd for C29H41O6Si [M + H]+ 513.2667, found 513.2674.


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Synthesis of methyl (3aR,4R,5S,5aS,10aR,12aS)-5-(benzyloxy)-2,12a-dimethyl-1-oxo-4-((trimethyl -silyl)oxy)-3a,4,5,5a,6,7,8,9,10,11,12,12a-dodecahydro-1H-4,10a-epoxycyclohepta[a]cyclopenta[e][8]annulene-3-carboxylate (11). To a solution of compound 20 (174.1 mg, 0.34 mmol) in THF (5 mL) was added KHMDS (0.97 mL, 0.7 M, 0.68 mmol) at -78 oC slowly, and the resultant mixture was stirred at same temperature for 1 h. To this solution was added methyl iodide (0.064 mL, 1.02 mmol) at -78 oC slowly, and the mixture was then stirred at the same temperature for 1 h. The reaction was quenched by addition of a saturated solution of NH4Cl (20 mL), and the mixture was extracted with EtOAc (3 × 40 mL). The combined organic layers were 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 = 15:1) to give product 11 (165 mg, 92% yield) as color-less oil. Data for compound 11: Rf = 0.7 (slica gel, petroleum ether/ethyl acetate = 8:1); FT-IR(neat) νmax: 2921, 2850, 1710, 1455, 1207, 1089 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.40-7.24 (m, 5H), 4.78-4.75 (d, J = 11.6 Hz, 1H), 4.60-4.57 (d, J = 12 Hz, 1H), 3.81 (s, 3H), 3.60-3.59 (d, J = 5.2 Hz, 1H), 2.17-2.10 (m, 1H), 2.08-2.02 (m, 4H), 1.94-1.91 (m, 1H), 1.84-1.73 (m, 1H), 1.74-1.53 (m, 7H), 1.48-1.40 (m, 1H), 1.23-1.11 (m, 3H), 1.11-1.02 (m, 4H), 0.00 (s, 9H) ppm; 13C NMR (100 MHz, CDCl3) δ: 211.8, 165.3, 153.1, 142.2, 136.4, 126.8, 126.5, 126.2, 107.7, 94.9, 87.1, 70.5, 57.0, 49.8, 49.7, 49.5, 37.3, 36.0, 31.5, 29.7, 29.6, 28.2, 26.5, 23.1, 8.3, 0.0 ppm; HRMS (ESI): calcd for C30H43O6Si [M + H]+ 527.2823, found 527.2813. Synthesis of (3aS,4R,5S,5aS,10aR,12aS)-5-(benzyloxy)-2,12a-dimethyl-1-oxo-4-((trimethylsilyl)oxy) -3a,4,5,5a,6,7,8,9,10,11,12,12a-dodecahydro-1H-4,10a-epoxycyclohepta[a]cyclopenta[e][8]annulene-3-carbaldehyde (10).


27


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To a solution of compound 11 (453.3 mg, 0.9 mmol) in DCM (10 mL) was added DIBAL (5.2 mL, 1.0 M, 5.2 mmol) at -78 oC slowly, and the mixture was then stirred at the same temperature for 1 h. The reaction mixture was quenched by addition of a saturated solution of potassium sodium tartrate (10 mL), followed by EtOAc (10 mL), and the resultant mixture was stirred at room temperature for 2 h. The mixture was extracted with EtOAc (3 × 10 mL), and the combined organic layers were washed with brine, and dried over Na2SO4. The solvent was removed under vacuum, and the residue was used in the next step without purification. To a solution of the alcohol made above in DCM (10 ml) was added sodium bicarbonate (361.4 mg, 4.3 mmol) and Dess-Martin periodinane (733 mg, 1.7 mmol), and the resultant mixture was stirred at room temperature for 2 h. The reaction was quenched by addition of a saturated solution of sodium thiosulphate (10 mL), and the mixture was extracted with EtOAc (3 × 30 mL). The combined organic layers were 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 = 12:1) to give product 10 (389.0 mg, 91% yield for 2 steps) as a yellowish solid. Data for compound 10: Rf = 0.7 (silica gel, petroleum ether/ethyl acetate = 4:1); FT-IR (neat) νmax: 2926, 2853, 1709, 1693, 1453, 1247, 1094 cm-1; 1H NMR (400 MHz, CDCl3) δ: 9.88 (s, 1H), 7.39-7.24 (m, 5H), 4.67-4.66 (m, 2H), 3.69-3.68 (m, 2H), 2.23-2.15 (m, 1H), 2.05-2.04 (m, 4H), 1.98-1.81 (m, 2H), 1.70-1.62 (m, 7H), 1.40-1.36 (m, 1H), 1.23-1.21 (m, 2H), 1.02 (s, 4H), 0.00 (s, 9H) ppm; 13C NMR (100 MHz, CDCl3) δ: 212.4, 190.2, 155.5, 142.8, 136.2, 126.7, 126.2, 126.1, 107.7, 95.7, 87.2, 71.0, 56.2, 49.9, 48.8, 37.2, 36.1, 31.7, 29.4, 29.0, 28.3, 26.5, 22.9, 7.8 ppm; HRMS (ESI): calcd for C29H41O5Si [M + H]+ 497.2718, found 497.2726. Synthesis of (3aS,8aR)-8a-(3-methylbut-3-en-1-yl)octahydro-2H-cyclohepta[b]furan-2-one(21):


28

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To a solution of compound 15 (2.0 g, 10.1mmol) in Et2O (6 mL) was slowly added a fresh prepared Grignard reagent (24 mL, 1.25 M, 30.0 mmol) at -78 oC, and the resultant reaction mixture was warmed up to room temperature, and stirred for another 9 h. Thereaction was quenched by addition of a saturated solution of NH4Cl (30 mL), 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, and the residue was purified by a flash column chromatography on silica gel (petroleum ether/ethyl acetate = 20:1) to give product 21 (2.0 g, 89 % yield) as a colorless oil. Rf= 0.4 (silica gel, petroleum ether/ethyl acetate = 4:1); IR (neat)νmax: 2934, 2859, 1771, 1198, 734 cm-1; 1H NMR (400 MHz, chloroform-d): δ 4.73 (s, 1H), 4.69 (s, 1H), 2.90 (dd, J = 18.0, 9.8 Hz, 1H), 2.42 – 2.33 (m, 1H), 2.34 – 2.23 (m, 1H), 2.19 – 2.06 (m, 2H), 2.01 (dd, J = 14.4, 8.6 Hz, 1H), 1.90 – 1.72 (m, 4H), 1.73 (s, 3H), 1.73 – 1.58 (m, 4H), 1.51 – 1.21 (m, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ 176.5, 145.2, 110.2, 92.1, 44.2, 39.6, 37.1, 35.1, 32.1, 31.3, 30.7, 27.5, 23.3, 22.9 ppm; HRMS (ESI): m/z calcd for C14H22O2Na [M + Na]+: 245.1512, found 245.1510. Synthesis of (3S,3aS,8aR)-3-(benzyloxy)-8a-(3-methylbut-3-en-1-yl)octahydro-2H-cyclohepta[b]furan-2-one(22): To a solution of 11 (10.1 g, 49.9 mmol) in THF (460 mL) was slowly added KHMDS (125.0 mL, 1M, 125 mmol) at -78 oC, and the resultant mixture was stirred at the same temperature for 1 h. To this solution was added MoOPH (43.4g, 100.0 mmol), and the reaction mixture was stirred at -78 oC for 2 h. The reaction was quenched by addition of a saturated solution of Na2SO3 (150 mL), and the mixture was extracted with EtOAc (3 × 150 mL). The combined organic layers were washed with brine (200 mL) and dried over Na2SO4. The solvent wad removed under vacuum, and the residue was purified by a flash column chromatography on silica gel (petroleum ether/ethyl acetate = 8:1) to give a secondary


29


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alcohol (10.2 g, 86% yield) as a white solid; Rf = 0.2 (silica gel, petroleum ether/ethyl acetate = 2:1); IR (neat) νmax: 3415, 2930, 2859, 1763, 1198, 884 cm-1; 1H NMR (400 MHz, chloroform-d): δ 4.71 (d, J = 12.5 Hz, 2H), 4.40 (dd, J = 9.3, 3.4 Hz, 1H), 3.48 (d, J = 3.6 Hz, 1H), 2.38 (td, J = 8.9, 4.2 Hz, 1H), 2.22 – 2.00 (m, 2H), 2.00 – 1.75 (m, 7H), 1.73 (s, 3H), 1.63 – 1.42 (m, 5H) ppm; 13C NMR (100 MHz, CDCl3): δ 177.2, 145.0, 110.3, 90.9, 72.7, 50.7, 40.6, 35.6, 31.1, 30.7, 28.3, 24.5, 23.1, 22.8 ppm; HRMS (ESI): m/z calcd for C14H22O3Na [M + Na]+: 261.1461, found 261.1458. To a solution of the alcohol made above (10.2 g, 42.8mmol) in CH2Cl2 (30 mL) was added Ag2O (19.4 g, 85.6 mmol), BnBr (10.3 mL, 85.6 mmol) and TBAI (0.8 g, 2.1 mmol). The reaction mixture was stirredat room temperature for 12 h. The reaction mixture was filtrated through a pad of celite, and the filtrate was removed under vacuum. The residue was purified by a flash column chromatography on silica gel (petroleum ether/ethyl acetate = 20:1) to give product 22 (12.6 g, 90% yield) as light yellow oil; Rf = 0.7 (silica gel, petroleum ether/ethyl acetate =2:1); IR (neat) νmax: 2929, 2855, 1769, 1198, 1128, 887 cm-1; 1H NMR (400 MHz, chloroform-d): δ 7.39-7.31 (m, 5H), 5.05 (d, J = 12.0 Hz, 1H), 4.78 (d, J = 12.0 Hz, 1H), 4.72 (s, 1H), 4.69 (s, 1H), 4.05 (d, J = 8.0 Hz, 1H), 2.41 (dt, J = 3.2, 8.0 Hz, 2H), 2.17 (ddd, J = 14.0, 12.4, 4.8 Hz, 1H), 2.07 (dt, J = 4.4, 12.8 Hz, 1H), 1.95-1.81 (m, 4H), 1.73 (s, 3H), 1.64 (dt, J = 14.8, 8.8 Hz, 1H), 1.57-1.36 (m, 7H); 13C NMR (100 MHz, CDCl3): δ 174.8, 145.0, 137.4, 128.5, 128.2, 128.0, 110.1, 90.0, 78.2, 72.3, 50.0, 40.3, 35.5, 31.0, 30.5, 28.3, 25.1, 22.9, 22.7 ppm; HRMS (ESI): m/z calcd for C21H32O3N, [M + NH4]+: 346.2377, found 346.2375. Synthesis

of

(5aR,10S,11S,11aS)-11-(benzyloxy)-8-methyl-2,3,4,5,6,7,11,11a-octahydro-5a,10-epoxycyclohepta[ 8]annulen-10(1H)-ol (23):


30

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To a solution of compound 22 (5.0 g, 15.1 mmol) in THF (80 mL) was added vinyl magnesium bromide (64.0 mL, 0.7 M, 45.0 mmol) slowly at -23 oC, and the resultant mixture was stirred at the same temperature for 1h. The reaction was quenched by addition of a saturated solution of NH4Cl (50 mL) at 0 oC, 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, and the residue was purified by a flash column chromatography on silica gel (petroleum ether/ethyl acetate = 10:1) to afford a ketal as a colorless oil, which is unstable at room temperature. To a solution of the ketal made above in toluene (400 mL) was added Hoyveda-Grubbs 2nd (237 mg, 0.4 mmol) and the resultant mixture was then warmed up to 80 oC, and stirred for 24 h. The reaction mixture was worked up by filtration through a pad of celite. The filtrate was concentrated under vacuum, and the residue was purified by a flash column chromatography on silica gel (petroleum ether/ethyl acetate = 10:1) to give product 23 (2.7 g, 54% yield in 2 steps) as a yellow oil; Rf = 0.3 (silica gel, petroleum ether/ethyl acetate = 4:1); IR (neat) νmax: 3395, 2920, 2855, 1732, 1376, 1085 cm-1; 1H NMR (400 MHz, CDCl3): δ 7.35-7.27 (m, 5H), 5.57 (s, 1H), 4.77 (d, J = 12.0 Hz, 1H), 4.54 (d, J = 12.0 Hz, 1H), 3.55 (d, J = 7.6 Hz, 1H), 2.72 (s, 1H), 2.48 (dt, J = 15.6, 7.6 Hz, 1H), 2.27-2.12 (m, 2H), 1.93-1.78 (m, 7H), 1.72-1.57 (m, 6H), 1.43-1.24 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 140.9, 138.5, 128.2, 127.7, 127.4, 125.9, 104.1, 91.3, 83.4, 71.8, 52.0, 40.2, 39.7, 31.3, 30.4, 29.6, 27.6, 27.0, 24.1 ppm; HRMS (ESI): m/z calcd for C21H29O3, [M + H]+ 329.2117, found 329.2113. Synthesis

of

(5aR,10R,11S,11aS)-11-(benzyloxy)-8-methyl-2,3,4,5,6,7,11,11a-octahydro-5a,10-epoxycyclohepta[ 8]annulen-10(1H)-yl but-2-ynoate (24):


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To a solution of 2-butynoic acid (1.8 g, 21.3 mmol) in THF (50 mL) was added NaH (1.0 g, 42.7 mmol) at 0 oC, and the resultant mixture was stirred at the same temperature for 10 min. To this solution was added PivCl (2.6 mL, 42.7 mmol), and the resultant mixture was stirred at 0 oC for 45 min to afford a solution of the mixed anhydride which will be used later. To a solution of compound 23 (1.4 g, 4.27 mmol) in THF (50 mL) in another flask was added the KHMDS (8.5 mL, 1.0 M, 8.5 mmol) at 0 oC, and the resultant mixture was stirred at the same temperature for 15 min. To the solution of the mixed anhydride prepared above was added the potassium salt of 23 made above at 0 oC, and resultant mixture was stirred at same temperature for 1h. The reaction mixture was quenched by addition of a saturated solution of NH4Cl (30 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, and the residue was purified by a flash column chromatography on silica gel (petroleum ether/ethyl acetate =20:1) to give product 24 (1.3 g, 76% yield) as yellowish oil; Rf = 0.4 (silica gel, petroleum ether/ethyl acetate = 4:1); IR (neat)νmax: 2952,2872, 2158, 1771, 1453, 1252 cm-1; 1H NMR (400 MHz, chloroform-d): δ 7.39 – 7.27 (m, 5H), 5.60 (s, 1H), 4.69 (d, J = 11.7 Hz, 1H), 4.50 (d, J = 11.6 Hz, 1H), 3.94 (d, J = 6.9 Hz, 1H), 2.48 (dt, J = 16.7, 6.0 Hz, 1H), 2.25 (ddd, J = 16.7, 7.9, 5.2 Hz, 1H), 2.09 (ddd, J = 10.5, 6.9, 3.6 Hz, 1H), 1.99 (s, 3H), 1.96 – 1.77 (m, 3H), 1.84 (s, 3H), 1.79 – 1.57 (m, 5H), 1.50 – 1.33 (m, 1H), 1.37 – 1.12 (m, 3H) ppm;

13

C

NMR (100 MHz, CDCl3): δ 151.1, 141.0, 138.3, 128.4, 127.9, 127.8, 123.6, 109.5, 90.9, 86.3, 85.0, 73.4, 72.4, 50.9, 39.9, 39.4, 31.4, 30.5, 30.0, 27.9, 26.9, 24.1, 3.9; HRMS (ESI): m/z calcd for C25H30O4Na [M + Na]+: 417.2042, found 417.2036.


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Synthesis

of

(4aS,6aR,11aS,12S,12aR)-12-(benzyloxy)-3,4a-dimethyl-2a1,4a,5,6,8,9,10,11,11a,12-decahydro-7H -1,13-dioxa-6a,12a-methanocyclohepta[5,6]cycloocta[1,2,3-cd]pentalene-2,4-dione (25): To a solution of compound 24 (99.8 mg, 0.25mmol) in benzene (5 mL) was added Co2(CO)8 (43.3 mg, 0.13 mmol) and TMTU (100.5 mg, 0.76 mmol) under N2 atmosphere. The resultant mixture was degassed with CO (balloon) for 3 times, and the mixture was stirred at 70 oC for 8 h under a balloon pressure of CO. The resultant mixture was worked up by filtration through a pad of celite. The filtrate 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 25 (76.8 mg, 72% yield) as yellowish solid; Rf = 0.4 (silica gel, petroleum ether/ethyl acetate = 4:1); IR (neat)νmax: 2924, 2856, 1783, 1453,1098, 910 cm-1; 1H NMR (400 MHz, chloroform-d): 1H NMR (400 MHz, chloroform-d) δ 7.40 – 7.28 (m, 5H), 4.65 (d, J = 2.8 Hz, 2H), 3.98 (d, J = 5.2 Hz, 1H), 3.48 (q, J = 3.0 Hz, 1H), 2.15 (dt, J = 9.5, 5.0 Hz, 1H), 2.07 (d, J = 3.0 Hz, 3H), 1.97 – 1.82 (m, 2H), 1.80 – 1.70 (m, 2H), 1.71 – 1.54 (m, 5H), 1.49 – 1.32 (m, 2H), 1.33 – 1.16 (m, 3H), 1.25 (s, 3H) ppm;

13

C NMR (100 MHz, CDCl3) δ 212.6, 164.5, 152.2,

142.9, 137.3, 128.6, 128.1, 127.7, 113.7, 87.3, 85.5, 73.1, 54.1, 51.7, 38.7, 37.0, 31.0, 30.9, 28.8, 28.2, 23.4, 22.4, 9.4 ppm; HRMS (ESI): m/z calcd for HRMS (ESI): m/z calcd for C26H30O5Na [M + Na]+: 445.1986, found 445.1991. Synthesis

of

(3aS,4R,5S,5aS,10aR,12aS)-5-(benzyloxy)-3-((S)-1-hydroxyallyl)-2,12a-dimethyl-4-((tri-

methylsilyl)oxy)-3a,4,5,5a,6,7,8,9,10,11,12,12a-dodecahydro-1H-4,10a-epoxycyclohepta[a]cyclopenta[e][8]annulen-1-one (38)

To a solution of compound 10 (422.4 mg, 0.85 mmol) in THF (10 mL) was added the vinyl magnesium bromide (0.9 mL, 1 M in THF, 0.9 mmol) at -78 oC slowly, and the mixture was then stirred


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at the same temperature for 30 min. The reaction mixture was quenched by addition of a saturated solution of NH4Cl (10 mL), and the mixture was extracted with EtOAc (3 × 30 mL). The combined organic layers were 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 = 4:1) to give product 38 (393.0 mg, 88 % yield) as a yellowish solid. Data for compound 38: Rf = 0.5 (silica gel, petroleum ether/ethyl acetate = 4:1); FT-IR (neat) νmax: 2921, 2853, 1690, 1635, 1452, 1248, 1092 cm-1; 1H NMR(400 MHz, CDCl3) δ: 7.24-7.12 (m, 5H), 5.84-5.75 (m, 1H), 5.21-5.17 (d, J = 16.8 Hz, 1H), 5.09-5.03 (m, 2H), 4.57-4.48 (m, 2H), 3.62-3.60 (d, J = 4.8 Hz, 1H), 3.23 (s, 1H), 2.61-2.60 (d, J = 6 Hz, 1H), 2.04-1.90 (m, 2H), 1.82-1.75 (m, 5H), 1.60-1.50 (m, 7H), 1.36-1.29 (m, 1H), 1.29-1.07 (m, 3H), 0.83 (s, 3H), 0.00 (s, 9H) ppm; 13C NMR (100 MHz, CDCl3) δ: 211.0, 167.1, 135.5, 135.1, 134.3, 126.1, 125.5, 125.4, 114.6, 108.0, 95.3, 86.8, 73.2, 70.3, 57.0, 49.4, 48.7, 36.5, 35.4, 31.0, 28.8, 28.7, 27.7, 25.9, 22.4, 7.4 ppm; HRMS (ESI): calcd for C31H45O5Si [M + H]+ 525.3031, found 525.3035. Synthesis

of

(2S,3S,3aS,4S,5S,5aS,10aR,12aS)-5-(benzyloxy)-4-hydroxy-3-((S)-1-hydroxyallyl)-2,12a-dimethylt etradecahydro-1H-4,10a-epoxycyclohepta[a]cyclopenta[e][8]annulen-1-one (39). To a solution of compound 38 (115.3 mg, 0.22 mmol) in THF (5 mL) was added TBAF▪3H2O ( 217.7 mg, 0.7 mmol) at room temperature, and the mixture was stirred at the same temperature for 10 min. The reaction was quenched addition of water, and the mixture was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine, and dried over Na2SO4. The solvent was removed under vacuum, and the residue was used in the next step without purification.


34

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To a solution of the above compound (100.3 mg, 0.22 mmol) in THF (8 mL) was added LiAlH2(OMe)2 (2.2 mL, 1.0 M, 2.2 mmol) at -78 oC, and the resultant mixture was stirred at the same temperature for 3 h. The reaction was quenched by addition of MeOH (1 mL) and water (10 mL), and the resultant mixture was then extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine, and dried over Na2SO4. The solvent was removed under vacuum, which was then dissolved in DCM (5 mL). To this solution was added DBU (0.1 mL) at room temperature, the resultant mixture was then stirred at 30 oC for 3 h. The solvent was removed under vacuum, and the residue was purified by a flash column chromatography on silica gel (petroleum ether/ethyl acetate = 8:1) to give product 39 (77.0 mg, 70% yield for 3 steps) as yellowish solid. Data for compound 39: Rf = 0.3 (silica gel, petroleum ether/ethyl acetate = 4:1); FT-IR (neat) νmax: 3431, 2925, 2858, 1733, 1457, 1358 cm-1; 1

H NMR (400 MHz, CDCl3) δ: 7.39-7.30 (m, 5H), 6.15-6.07 (m, 1H), 5.32-5.27 (d, J = 16.8 Hz, 1H),

5.16-5.13 (d, J = 10.4 Hz, 1H), 4.91 (s, 1H), 4.65-4.58 (m, 2H), 3.77-3.76 (d, J = 3.2 Hz, 1H), 3.13 (s, 1H), 2.92-2.87 (m, 1H), 2.73-2.71 (d, J = 6 Hz, 1H), 2.44-2.36 (m, 1H), 2.31-2.26 (dd, J = 6.4 Hz, J = 14.4Hz, 1H), 2.04-2.02 (m, 1H), 1.87-1.73 (m, 3H), 1.70-1.58 (m, 5H), 1.36-1.23 (m, 6H), 1.11-1.01 (d, J = 6.8 Hz, 3H), 1.06 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ: 224.1, 141.4, 138.2, 128.4, 127.7, 127.4, 114.9, 107.9, 100.2, 89.2, 53.5, 52.1, 51.7, 50.2, 43.6, 39.5, 39.2, 33.6, 31.0, 30.9, 29.4, 28.7, 24.3, 15.5 ppm; HRMS (ESI): calcd for C28H38O5Na [M + Na]+ 477.2612, found 477.2615. Synthesis

of

(2aS,2a1S,3S,4aS,6aR,11aS,12S,12aR)-12-(benzyloxy)-2-hydroxy-3,4a-dimethyl-2-

vinyldodeca-hydro-7H-1,13-dioxa-6a,12a-methanocyclohepta[5,6]cycloocta[1,2,3-cd]pentalen-4(2 H)-one (40). To a solution of compound 39 (409.2 mg, 0.9 mmol) in anhydrous DCM (10 mL) was added MnO2 (783 mg, 9.0 mmol), and the mixture was then stirred at 35 oC for 24 h. The reaction was worked


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up by filtration of the reaction mixture through a silica gel pad, and the filtrate was concentrated under vacuum. The residue was purified by a chromatography on silica gel to give compound 40 (367.2 mg, 90% yield) as a yellowish solid. Data for compound 40: Rf = 0.4 (silica gel, petroleum ether/ethyl acetate = 4:1) FT-IR (neat) νmax: 3451, 2925, 2853, 1727, 1459, 1096, 1028 cm-1; 1H NMR (400 MHz, CDCl3) δ: 7.40-7.30 (m, 5H), 6.10-6.03 (dd, J = 10.4Hz, J = 16.8 Hz, 1H), 5.643-5.640 (d, J = 1.2 Hz, 1H), 5.352-5.349 (d, J = 1.2 Hz, 1H), 4.95-4.92 (d, J = 11.6 Hz, 1H), 4.63-4.60 (d, J = 11.6 Hz, 1H), 3.89-3.87 (d, J = 8.4 Hz, 1H), 3.36-3.35 (d, J = 7.2 Hz, 1H), 2.74 (s, 1H), 2.55-2.50 (m, 1H), 2.40-2.38 (m, 1H), 2.21-2.16 (m, 1H), 1.93-1.92 (m, 1H), 1.78-1.60 (m, 6H), 1.56-1.53 (m, 3H), 1.47-1.42 (m, 2H), 1.35-1.25 (m, 1H), 1.21-1.19 (m, 1H), 1.13-1.12 (d, J = 7.2 Hz, 3H), 1.08 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ: 221.6, 140.7, 138.4, 137.6, 128.4, 128.0, 127.8, 127.5, 117.8, 114.9, 105.5, 87.4, 86.3, 84.8, 56.3, 53.4, 50.4, 47.5, 44.3, 39.8, 37.7, 31.3, 30.4, 29.8, 27.7, 24.1, 16.8 ppm; HRMS (ESI): calcd for C28H36O5Na [M + Na]+ 475.2438, found 475.2435. Synthesis of methyl (E)-3-((2aS,2a1S,3S,4aS,6aR,11aS,12S,12aR)-12-(benzyloxy)-2-hydroxy-3,4adimethyl-4-oxotetradecahydro-7H-1,13-dioxa-6a,12a-methanocyclohepta[5,6]cycloocta[1,2,3-cd]-p entalen-2-yl)acrylate (44). To a solution of compound 40 (226.1 mg, 0.5 mmol ) in anhydrous toluene (10 mL ) was added methyl acrylate (2.0 mL, 5.0 mmol) and Hoveyda-Grubbs II (42 mg, 0.05 mmol) at room temperature, and the mixture was then stirred 100 oC for 4 h. After cooling to the room temperature, the solvent in the reaction mixture was removed under vacuum, and the residue was purified by a flash chromatography on silica gel to give product 44 (215.0 mg, 84% yield) as a yellowish oil. Data for 44: Rf = 0.3 (silica gel, petroleum ether/ethyl acetate = 4:1): FT-IR (neat) νmax: 3430, 2921, 2853, 1726, 1661, 1455, 1087 cm-1;1H NMR(400 MHz, CDCl3) δ: 7.38-7.31 (m, 5H), 7.02-6.98 (d, J = 15.6 Hz, 1H), 6.33-6.29 (d, J =


36

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15.6 Hz, 1H), 4.89-4.86 (d, J = 11.6 Hz, 1H), 4.64-4.61 (d, J = 11.6 Hz, 1H), 3.89-3.87 (m, 1H), 3.77 (s, 3H), 3.37-3.35 (d, J = 7.2 Hz, 1H), 2.87 (s, 1H), 2.62-2.58 (m, 1H), 2.38-2.33 (m, 1H), 2.20-2.17 (m, 1H), 1.94-1.92 (m, 2H), 1.74-1.44 (m, 8H), 1.35-1.20 (m, 4H), 1.11-1.10 (d, J = 7.2 Hz, 3H), 1.08 (s, 3H) ppm; 13C NMR(100 MHz, CDCl3) δ: 221.8, 166.4, 147.9, 145.4, 138.2, 137.9, 128.5, 128.0, 127.9, 127.8, 127.5, 123.3, 120.2, 115.3, 115.0, 104.7, 103.5, 87.2, 86.7, 85.2, 56.6, 55.2, 54.4, 53.2, 51.9, 50.4, 50.2, 47.6, 44.2, 44.1, 39.7, 39.6, 37.7, 31.6, 31.3, 31.0, 30.5, 30.0, 29.8, 27.6, 27.0, 24.3, 24.1 ppm; HRMS (ESI): calcd for C30H38O7Na [M + Na]+ 533.2515,found 533.2510. Synthesis

of

(2S,2a'S,2a1'S,3'S,4a'S,6a'R,11a'S,12'S,12a'R)-12'-(benzyloxy)-3',4a'-dimethyl-

tetradeca-hydro-4'H,5H,7'H-1',13'-dioxaspiro[furan-2,2'-1,13-dioxa[6a,12a]methanocyclohepta[5,6]cycloocta[1,2,3-cd]pentalene]-4',5-dione (9). To a solution of compound 44 (28.2 mg, 0.06 mmol) in EtOAc (3 mL, HPLC grade) was added Pd/C (51.0 mg, 5% on charcoal), and the mixture was then stirred at room temperature for 0.5 h. The reaction was worked up by filtration of the reaction mixture through a silica gel pad, and the filtrate was concentrated under vacuum. The residue was purified by a flash chromatography on silica gel to give yellowish oil, which was used in the next step without purification. To a solution of the compound made above (26.2 mg, 0.05 mmol) in THF (2 mL) was added KHMDS (0.15 mL, 0.7 M, 0.1 mmol) at -20 oC slowly, and the mixture was stirred at same temperature for 0.5 h. The reaction was quenched by addition of a saturated solution of NH4Cl (5 mL), and the mixture was extracted with EtOAc (3 × 10 mL). The combined organic layers were 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 = 5:1) to give product 9 (20 mg, 81% yield for 2 steps) as a yellowish solid. Rf: (silica gel, petroleum ether/ethyl acetate = 3:1); IR


37


Page 38 of 42

(neat)νmax: 2927, 2853, 1788, 1738, 1453, 1107, 913, 736 cm-1; 1H NMR (500 MHz, chloroform-d) δ 7.43 – 7.27 (m, 5H), 4.90 (d, J = 11.9 Hz, 1H), 4.56 (d, J = 11.8 Hz, 1H), 3.79 (d, J = 8.8 Hz, 1H), 3.32 (d, J = 7.0 Hz, 1H), 2.87 (dt, J = 17.4, 9.7 Hz, 1H), 2.75 (dd, J = 9.9, 7.1 Hz, 1H), 2.58 (ddd, J = 17.5, 7.6, 4.4 Hz, 1H), 2.52 (dt, J = 10.0, 7.4 Hz, 1H), 2.49 – 2.44 (m, 2H), 2.16 (td, J = 9.6, 3.9 Hz, 1H), 1.95 (td, J = 5.6, 2.7 Hz, 2H), 1.77 (ddd, J = 13.8, 9.6, 3.8 Hz, 1H), 1.74 – 1.66 (m, 1H), 1.65 – 1.55 (m, 4H), 1.55 – 1.47 (m, 3H), 1.44 (dd, J = 14.2, 8.2 Hz, 1H), 1.40 – 1.32 (m, 1H), 1.30 (d, J = 7.4 Hz, 3H), 1.19 – 1.12 (m, 1H), 1.10 (s, 3H) ppm;

13

C NMR (126 MHz, CDCl3) δ: 219.7, 175.2, 138.0, 128.4, 128.2,

127.8, 115.9, 115.6, 86.2, 85.5, 72.8, 54.1, 52.8, 50.5, 47.2, 43.0, 39.7, 37.2, 31.3, 30.2, 30.0, 29.5, 28.5, 27.6, 27.0, 24.1, 17.6 ppm; HRMS (ESI): m/z calcd for C29H37O6 [M + H]+: 481.2585, found 481.2589. Synthesis of (2S,2a'S,2a1'S,3'S,4a'S,6a'R,11a'S,12'S,12a'R)-12'-hydroxy-3',4a'-dimethyltetradecahydro-4'H,5H,7'H-1',13'-dioxaspiro[furan-2,2'-1,13-dioxa[6a,12a]methanocyclohepta[5,6]-cycloocta [1,2,3-cd]pentalene]-4',5-dione (45). To a solution of compound 9 (10.0 mg, 0.02 mmol) in ethyl acetate (3 mL, HPLC grade) was added Pd(OH)2/C (5.0 mg), and the resultant mixture was stirred under a balloon pressure of hydrogen at room temperature for 0.5. The reaction was worked up by filtrate of the reaction mixture through a silica gel pad, and the filtrate was concentrated under vacuum. The residue was purified by a flash chromatography on silica gel (petroleum ether/ethyl acetate = 4 : 1) to give compound 45 (7.1 mg, 90% yield) as whitesolid. Rf = 0.25 (silica gel, petroleum ether/ethyl acetate = 2:1). FT-IR (neat) νmax: 3688, 3669, 2924, 2847, 1786, 1737, 1266, 1190, 941, 913 cm-1; 1H NMR (400 MHz, chloroform-d) δ: 3.97 (d, J = 9.7 Hz, 1H), 3.30 (d, J = 6.7 Hz, 1H), 2.83 (dt, J = 17.3, 9.6 Hz, 1H), 2.67 (dd, J = 9.7, 6.8 Hz, 1H), 2.63 – 2.52 (m, 1H), 2.51 – 2.39 (m, 3H), 2.17 (td, J = 9.7, 3.9 Hz, 1H), 2.01 (dt, J = 15.3, 4.0 Hz, 1H), 1.96 – 1.84 (m, 2H), 1.76 (dd, J = 14.1, 10.9 Hz, 1H), 1.68 – 1.57 (m, 6H), 1.52 – 1.43 (m, 2H),


38

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1.41 – 1.30 (m, 1H), 1.29 (d, J = 7.4 Hz, 3H), 1.10 (s, 3H) ppm; 13C NMR (126 MHz, CDCl3) δ: 219.0, 175.4, 115.6, 115.3, 85.7, 79.4, 54.2, 51.4, 50.6, 46.1, 43.0, 39.6, 36.8, 31.4, 29.7, 29.5, 29.2, 28.7, 27.6, 26.4, 24.1, 17.6 ppm; HRMS (ESI): m/z calcd for C22H31O6 [M + H]+: 391.2115, found 391.2127. Synthesis

of

(2S,2a'S,2a1'S,3'S,4a'S,6a'R,11a'R,12a'R)-3',4a'-dimethyltetradecahydro-4'H,5H,12'H-1',13'-diox aspiro[furan-2,2'-1,13-dioxa[6a,12a]methanocyclohepta[5,6]cycloocta[1,2,3-cd]pentalene]-4',5,12'-trione (8). To a solution of compound 45 (9.1 mg, 0.02 mmol) in DCM (5 mL) was added sodium bicarbonate (10.2 mg, 0.12 mmol) and Dess-Martin periodinane (20.0 mg, 0.05 mmol), and the resulted mixture was stirred at room temperature for 2 h. The reaction was quenched by addition of a saturated solution of sodium thiosulphate (5 mL), and the mixture was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine, 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 = 4 : 1) to give product 8 (7.1 mg, 85% yield) as a white solid. Data for compound 8: Rf = 0.6 (silica gel, petroleum ether/ethyl acetate = 1:1); IR (neat) νmax: 2954, 2827, 1800, 1705, 1185, 966, 780 cm-1; 1H NMR (400 MHz, CDCl3) δ: 3.09 (d, J = 7.2 Hz, 1H), 2.90 (d, J = 6.8 Hz, 1H), 2.88 – 2.78 (m, 1H), 2.78 – 2.70 (m, 1H), 2.65 (dd, J = 14.9, 7.5 Hz, 1H), 2.55 (ddd, J = 16.9, 7.2, 3.8 Hz, 1H), 2.52 – 2.42 (m, 2H), 2.35 (dd, J = 9.8, 3.6 Hz, 1H), 1.98 (d, J = 15.3 Hz, 1H), 1.87 (dd, J = 32.5, 13.6 Hz, 3H), 1.80 – 1.67 (m, 5H), 1.59 (d, J = 22.8 Hz, 4H), 1.30 (d, J = 7.1 Hz, 3H), 1.06 (s, 3H);

13

C

NMR (101 MHz, CDCl3) δ: 218.69, 212.69, 174.63, 116.94, 108.50, 83.84, 58.87, 53.62, 50.96, 49.21, 43.17, 40.23, 38.29, 30.82, 30.17, 29.58, 29.02, 28.23, 26.63, 23.88, 17.79 ppm; HRMS (ESI) calcd for C22H29O6 [M + H]+ 389.1959, found 389.1955.


39


Page 40 of 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 45 (CIF) AUTHOR INFORMATION Corresponding Author [email protected] [email protected] ORCID

Zhen Yang: 0000-0001-8036-934X

Author Contributions The manuscript was written through contributions of all authors. / All authors have given approval to the final version of the manuscript. 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)

(3)

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42

Asymmetric Total Synthesis of Lancifodilactone G Acetate. 1

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