Asymmetric Total Synthesis of Fawcettimine-Type Lycopodium

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Asymmetric Total Synthesis of FawcettimineType Lycopodium Alkaloid, Lycopoclavamine-A Hiroki Kaneko, Shunsuke Takahashi, Noriyuki Kogure, Mariko Kitajima, and Hiromitsu Takayama J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00586 • Publication Date (Web): 28 Mar 2019 Downloaded from http://pubs.acs.org on March 28, 2019

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The Journal of Organic Chemistry

Asymmetric Total Synthesis of Fawcettimine-Type Lycopodium Alkaloid, Lycopoclavamine-A Hiroki Kaneko, Shunsuke Takahashi, Noriyuki Kogure, Mariko Kitajima, and Hiromitsu Takayama* Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan Table of Contents/Abstract Graphic O

O O

O

OH

Me

OTBDPS H

N Me

Ph

OMOM

H

O

H HO

OTBS

12

12

N

Lycopoclavamine-A Total 14.4% overall yeild

ABSTRACT: An asymmetric total synthesis of lycopoclavamine-A (1), a structurally unique fawcettimine-type Lycopodium alkaloid, was achieved via a stereoselective Pauson-Khand reaction and a stereoselective conjugate addition to construct a quaternary carbon center at C-12. INTRODUCTION Lycopoclavamine-A (1)1 isolated from Lycopodium clavatum by our group in 2011 is a unique Lycopodium alkaloid,2,3 the structure of which resembles fawcettimine (2), a representative of about one hundred twenty alkaloids in this class, but differs from it in that 1 has a -oriented methyl group at C-15 and a trans-decahydroquinoline ring system at the A/D-ring junction (Figure 1). The first total synthesis of this alkaloid was accomplished by Zaimoku and Taniguchi4 via the construction of its core by the Diels-Alder reaction. Herein, we report an asymmetric total synthesis of this alkaloid by a strategy involving a stereoselective Pauson-Khand reaction (PKR) and a stereoselective conjugate addition to construct a quaternary carbon center at C-12. Me H

H

15 A

H HO 13

O

7 12

N

OH

15

Me

A

4

N

3

H

12

O H

4

D

D

Lycopoclavamine-A (1)

Fawcettimine (2) 1

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Figure 1. Structures of fawcettimine-type Lycopodium alkaloids In our previous total syntheses of fawcettimine-type alkaloids, such as lycoposerramine-C5 and huperzine Q6 (Scheme 1), the vinyl Claisen rearrangement was adopted (from 5 to 6) to construct a quaternary carbon center at C-12 by installing a C2 unit stereoselectively. However, a one-carbon extension (from 6 to 7) was necessary to accomplish the total syntheses. Thus, we devised a new synthetic route that features a solution to this problem, as shown in the retrosynthetic analysis in Scheme 2. Scheme 1. Asymmetric Total Synthesis of Huperzine Q by Our Group (partly only) H

(R)-Me-CBS BH3·THF

O

H

H

MOMO

H

THF rt 88% (d.r. 9.8:1)

MOMO 12

OH

H

H

MOMO

SOPh NaH KH (cat.) THF rt 98%

MOMO 12

TBDPSO

TBDPSO

3

4 vinyl Claisen rearrangement

H

H

MOMO MOMO

O

SOPh NaHCO3

H 12

H

o-DCB 170 °C 89%

TBDPSO

H

MOMO MOMO

H 12

OHC TBDPSO

5

6 H

n-BuLi PPh3CH3Br

H

H

MOMO

THF rt 95%

H

OH

H

MOMO

O

H N

OTBDPS

Huperzine Q

7

RESULTS AND DISCUSSION The retrosynthetic analysis of 1 is shown in Scheme 2. A hemiaminal function with a trans-decahydroquinoline ring system at the A/D-ring junction in 1 would be constructed by the removal of the N-nosyl group in diketone 8. Tricyclic compound 8 would be derived by azonane ring formation by applying intramolecular Mitsunobu reaction7 to 9. The construction of the quaternary carbon center (C-12) would be achieved by a conjugate addition of nucleophile 11 having a C3 unit8 to enedione 12, in which the carbonyl group at C-3 would enhance the reactivity towards the nucleophile and would be utilized later to install a double bond between C-3 and C-4. Further, to achieve the stereoselective addition of the nucleophile from the -side in 12, we designed a -oriented alcohol function at C-13. 2 ACS Paragon Plus Environment

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Bicyclic enedione 12 would be constructed from 1,7-enyne compound 13 via cobalt-mediated PKR, the utility of which has already been ascertained in the total synthesis of lycoposerramine-C,5 huperzine Q,6 and fawcettimine.2f

Scheme 2. Retrosynthetic Analysis of 1 Mitsunobu reaction

Me H

O

H

HO

3

4

O

NNs

Me N

H O


8

Cuprate Conjugate addition O

O

OPG OH NHNs

3

Me

O

OMOM

OTBDPS OTBS

12

Me

OMOM

H

H

10

9 OTBS S

Cu CN

O O

11

12

OMOM 15

H

13

12 Diastereoselective Hosomi-Sakurai allylation

Asymmetric reduction MOMO HO

13

OTBDPS

3

7

Me

PKR & Oxidation (C3)

Me Me

O

15

MeO OTBDPS

N Me

15

14

(13S, 15S)-13

For the conjugate addition, we commenced with the preparation of bicyclic enedione compound 12 from commercially available crotonamide 15 (Scheme 3). Weinreb amide 14, which was prepared via the diastereoselective Hosomi-Sakurai allylation5,9 of 15, was coupled with alkynyl anion prepared from TMS acetylene to give alkynyl ketone 17. A three-step operation that included the stereoselective reduction of the carbonyl group in 17 with (S)-Corey-Bakshi-Shibata (CBS) reagent,5,6,10 MOM protection of the resulting secondary hydroxyl group, and removal of the TMS group afforded enyne compound 18. Subsequent coupling of alkynyl anion prepared from 18 with aldehyde 1911 generated enyne 13 in good yield. The cobalt-mediated intramolecular PKR5,12 afforded desired bicyclic enone 20, which was then oxidized with AZADOL13 to give enedione 12 for the next conjugate addition. The relative stereochemistry between C-13 and C-7, and between C-13 and C-15 was inferred from NOE observations, as shown in Scheme 3. 3 ACS Paragon Plus Environment


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Scheme 3. Synthesis of Bicyclic Compound 12 TMS O

O O

N Ph

15

1) H2O2 aq., LiOH aq. THF/H 2O, 0 °C to rt 2) CDI, HNMe(OMe) ·HCl CH 2Cl2, rt 93% in 2 steps

N Me

TMS i-PrMgCl

Me 15

THF, rt 98%

14

17

H

18

i-PrMgCl; then

H

19

Me

MOMO

OTBDPS

13

HO

THF, rt 93%

Co2(CO)8, CH2Cl2 rt, under Ar;

15

then NMO, CH2Cl2 rt, under CO 82%

OTBDPS

13 O OH OTBDPS 7

OMOM

Me 15

Me

MOMO

2) MOMCl, DIPEA CH 2Cl2, rt 3) K2CO3 MeOH, rt 92% in 2 steps

TMS

O

16

1) (S)-CBS, BH3·THF THF, –40 °C, 96%

Me

O

(S) Ph

O MeO

15

N

O

CH2Cl2, –78 °C 91% (S) : (R) = 16 : 1

Me

O

O

TiCl4

H 13

O O

AZADOL PhI(OAc)2

7

Me

CH2Cl2, rt quant

15

H

20

OTBDPS

13

OMOM

H H

1.9% 1.3%

: NOE

12

With key intermediate 12 in hand, we next examined the conjugate addition of a C3 unit to construct the quaternary carbon center at C-12 stereoselectively (Scheme 4). After several attempts, we finally found that a reaction using a cuprate reagent,8 which was prepared from bromide 21, 2-thienylcyano cuprate, and t-BuLi, in the presence of BF3•OEt2 provided desired compound 10 stereoselectively. All attempts at the conjugate addition using compound 20 or its O-acyl derivatives were unsuccessful, implying that the presence of a carbonyl function at C-3 was necessary for this reaction. The stereochemistry at C-12 was 4 ACS Paragon Plus Environment

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later confirmed by X-ray crystallographic analysis using compound 3-epi-27. To complete the total synthesis, discrimination between the two carbonyl groups at C-3 and C-5 was indispensable. Although chemoselective reduction of the two carbonyl functions was unsuccessful, we found that the triflation14 of -ketoenol in 10 with Comins reagent gave -keto enol triflate 22 regioselectively. This structure was confirmed from the HMBC correlation between H-1 (1H 4.00–3.89) and C-3 (13C 198.0). Next, reduction of the carbonyl group in 22 with DIBAL15 followed by MOM protection of the resulting secondary hydroxyl group gave an inseparable diastereomeric mixture of 23 at C-3. Removal of the TBS group in 23 gave diastereomers 24 and 3-epi-24, which turned out to be separable by flash column chromatography. The stereochemistry at C-3 was elucidated later by X-ray crystallographic analysis using compound 3-epi-27. First, we converted major diastereomer 24 into natural product 1 as follows. A nitrogen function was introduced on the primary alcohol in 24 by the Mitsunobu reaction.6,7 Then, the second primary alcohol in 25, which was generated by the removal of the TBDPS group, was subjected to intramolecular Mitsunobu reaction6,7 conditions under a highly diluted condition in toluene to give tricyclic compound 26 in 74% yield. Next, the two MOM groups on the secondary alcohols at C-3 and C-13 were removed with 12N HCl aq. in MeOH under heating condition16 to yield 27 (Scheme 5). Deprotection of triflate on the enol moiety in 27 by treatment with sodium hydroxide17 produced (Z)-enone 28 having an unnatural geometry at C-3 and C-4 positions. Dess-Martin oxidation of the secondary alcohol at C-135,6 gave diketo compound 29. Finally, deprotection of the nosyl group in 29 yielded target compound 1 by the formation of a hemiaminal function with a trans-decahydroquinoline ring system at the A/D-ring junction, which was accompanied by C-3–C-4 olefin isomerization, which would occur by transformation of more strained nine-membered ring of (Z)-isomer into the thermodynamically more stable (E)-isomer4 under the heating conditions and/or conjugate addition–E1cB mechanism involving thiophenol. Synthetic 1 was identical in all respects with natural lycopoclavamine-A (1).

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Scheme 4. Construction of Quaternary Carbon Center (C-12) and Synthesis of Tricyclic Compound 26 Br O O

OTBDPS

O

OH

2-Thienylcyano cuprate BF3·OEt2, t-BuLi

12

Me

OTBS

21

OMOM

H

OTBS

12

Me

THF, -78 °C 70%

OTBDPS

4

OMOM

H

12

10 OTf

NaH Comins reagent

5

OTBDPS 1

4

Me

THF, 0 °C 91%

O 3

OTBS

OMOM H

1) DIBAL, Toluene, –78 °C quant, d.r. 3–4 : 1 (C3) 2) MOMCl, DIPEA DMAP, CH2Cl2, reflux quant, d.r. 3-4 : 1 (C3)

22 OMOM OTBDPS

OTf

1N HCl aq.

3

Me

3

OTBS THF, rt

OMOM H

OMOM OTBDPS

OTf

Me

OMOM H

23

24 74%

24

OTf

1) DEAD, PPh3, NH2Ns Toluene, rt, 92% 2) CSA, MeOH rt, quant

OMOM OH NHNs

Me

OMOM H

25 OTf

OMOM

DEAD, PPh3 Toluene, rt 74%

NNs Me

OMOM H

26


OH

3-epi-24 22%

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Scheme 5. Total Synthesis of Lycopoclavamine-A (1) OTf

OMOM 3

Me H

13

OTf

12N HCl aq.

OH 3

NNs

MeOH, 65 °C quant

OMOM

Me H

13

26

NNs

OH

27 O

O

(Z)

1N NaOH aq. Dioxane/MeOH Me rt

NNs

THF Me rt 95% in 2 steps

OH H

DMP

13

28

MeCN, 60 °C 79%

NNs

H O

Synthetic product []D25 55.9 (c 0.14, CHCl3) O Natural product []D25 48.8 (c 0.11, CHCl3)

H H HO

3

29

Me PhSH, K2CO3

4

N


Next, we carried out the conversion of 3-epi-24 into lycopoclavamine-A (1) (Scheme 6) using a procedure that was almost the same as that developed for 24. Briefly, a four-step operation, i.e., nosylation of the primary alcohol, deprotection of the TBDPS group, intramolecular Mitsunobu reaction, and deprotection of MOM, afforded intermediate 3-epi-27 smoothly, the structure of which was confirmed by X-ray crystallographic analysis. However, in contrast to compound 27, deprotection of triflate on the enol moiety in 3-epi-27 by treatment with sodium hydroxide gave (E)-enone 30, which possesses the same geometry as the natural product. Synthetic 1 derived from 30 via oxidation of the secondary alcohol and removal of the nosyl group was also identical in all respects with the natural product. The stereoselective formation of (Z)-enone 28 from 27 and (E)-enone 30 from 3-epi-27 could be interpreted as follows (Scheme 7). The reactions would proceed via an E1cB-like mechanism. In the reaction intermediate of enolate form, the p orbital of the double bond at C4-C5 and the sigma bond between carbon (C-3) and oxygen atom would align perpendicularly to the plane of the C4-C5 bond, which would restrict the rotation of the C3-C4 single bond. The concerted elimination process arising from the intermediate described above, (Z)-enone 28 and (E)-enone 30 would be generated from 27 and 3-epi-27, respectively.



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Scheme 6. Total Synthesis of 1 from 3-epi-24 OTf

OMOM OTBDPS 3

Me

OTf

1) NH2Ns, PPh3, DEAD THF, rt, 85% 2) CSA, MeOH, rt, 62%

OH

OMOM

3) PPh3, DEAD Toluene, rt, 78% 4) 12N HCl aq. MeOH, rt, 60%

H

3-epi-24 O

OH NNs

3

Me

OH H

3-epi-27

(E)

1N NaOH aq.

NNs

Dioxane/MeOH, 0 °C

Me H

OH

13

30 O DMP

(E)

K2CO3, PhSH NNs

CH2Cl2, rt 66% in 2 steps

Me

MeCN, 60 °C 76%

13

1

H O

8

Scheme 7. Plausible E1cB-like mechanism OTf

3

Me H

H H

O

OH NNs

Me

OH

OH

5

NaOH

H

4 3 (R)

H H

O

NNs

5

Me H

H H

3 (R)

H

O

Me H

NNs

OH

OH

5

NaOH Me H

4 3 (S)

H H

O

NNs

5

4

OH

pro-E conformer

H

3

NNs

OH

H H

O 5

Me H

3-epi-27

4

28

OH

3 H (S)

(Z)

5

pro-Z conformer

OH 3

4

OH

27

OTf

O

OH

H H

(E)

H

4

3

NNs OH

30

CONCLUSIONS In conclusion, we have achieved an asymmetric total synthesis of lycopoclavamine-A (1) (22 steps, 14.4% overall yield, which incorporated the yields from 24 to 1 and from 3-epi-24 to 1), starting from commercially available crotonamide 15. The highlights of this synthesis are as follows: (1) the stereoselective construction of 6-5 bicyclic ,-unsaturated ketone 20 by cobalt-mediated Pauson-Khand reaction; (2) the stereoselective conjugate addition of a nucleophile with a C3 unit to construct the quaternary carbon center at C-12 in 10; and (3) the construction of a hemiaminal function with 8 ACS Paragon Plus Environment

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trans-decahydroquinoline ring system at the A/D-ring junction and an (E)-enone at B/C-ring in 1. EXPERIMENTAL SECTION General Experimantal Procedures. IR: recorded on a JASCO FT/IR-230 spectrophotometer. 1H and 13C

NMR spectra: recorded on JNM ECZ400 and JNM ECS400 at 400 MHz (1H) or 100 MHz (13C{1H}),

JNM ECZ600 and JNM ECA600 at 600 MHz (1H) or 150 MHz (13C{1H}), respectively. J values are given in Hz. HR-ESI-MS: recorded on JEOL AccuTOF LC-plus JMS-T100LP and JEOL JMS-700 JMS-T100LC. HR-EI-MS: recorded on JEOL JMS-700 JMS-T100LC. Optical rotation: measured with a JASCO P-1020 polarimeter. Melting point: measured with a Yanagimoto Micro Melting Point Apparatus 1631A. TLC: precoated silica gel 60 F254 plates (Merck, 0.25 mm thick) and precoated amino-silica gel plates (Fuji Silysia Chemical). Column chromatography: silica gel 60N [Kanto Chemical, 40-50 µm (for flash column chromatography)] and Chromatorex NH [Fuji Silysia Chemical, 60 µm (for amino-silica gel flash column chromatography)]. Medium pressure liquid chromatography (MPLC): C.I.G. prepacked column CPS-HS-221-05 (Kusano Kagakukikai, SiO2). Oxazolidinone 16. To a stirred solution of croton amide 15 (11.5 g, 49.7 mmol) in CH2Cl2 (250 mL) was

added TiCl4 (100 mL, 100 mmol, 1.0 M in toluene) via a cannula over a period of 20 minutes at –78 °C under Ar atmosphere. After stirring for 10 minutes at the same temperature, allyltrimethylsilane (11.5 mL, 74.6 mmol) was added, and the reaction mixture was stirred at the same temperature for 2 hours. The reaction was quenched by adding saturated aqueous Na2CO3 at –78 °C, and the mixture was filtered through Celite® with CHCl3. After separation of the two layers, the aqueous layer was extracted three times with CHCl3. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by flash silica gel chromatography (AcOEt/n-hexane = 20/80) to afford 12.3 g (91%, d.r. = 16:1) of 16 as a white solid: [α]23D = –56.4 (c = 0.88 , CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.40–7.28 (overlapped, 5H), 5.73 (m, 1H), 5.42 (dd, J = 8.8, 3.8 Hz, 1H), 5.00–4.96 (overlapped, 2H), 4.67 (t, J = 8.8 Hz, 1H), 4.25 (dd, J = 8.8, 3.8 Hz, 1H), 2.90 (dd, J = 16.0, 6.4 Hz, 1H), 2.82 (dd, J = 16.0, 6.9 Hz, 1H), 2.15–2.01 (overlapped, 2H), 1.95 (m, 1H), 0.89 (d, J = 6.9 Hz, 3H);

13C{1H}

NMR (100 MHz, CDCl3) δ 172.1, 153.7, 139.2, 136.5, 129.1, 9

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128.6, 125.8, 116.4, 69.8, 57.6, 41.7, 40.7, 29.4, 19.5; IR max (ATR) cm-1 1776, 1703, 1383, 1321, 1194, 749; HR-MS (ESI) calcd for C16H19NO3Na [M+Na]+ 296.1263, found 296.1256. (S)-N-Methoxy-N,3-dimethylhex-5-enamide (14). To a stirred solution of 16 (13.3 g, 48.6 mmol) in THF/H2O (180/45 mL, 4:1) was added 30% aqueous H2O2 (39.8 mL, 389 mmol) and LiOH (147 mL, 63.2 mmol, 0.43 M in H2O) at 0 °C under Ar atmosphere, and the reaction mixture was stirred at the same temperature for 1 hour. Then, the reaction mixture was warmed to room temperature, and stirred for 1 hour. The reaction was quenched by adding saturated aqueous Na2SO3 at 0 °C, and diluted with CH2Cl2 after evaporation of THF in the mixture. After separation of the two layers, the aqueous layer was washed three times with CH2Cl2. Then, the aqueous layer was added 3N HCl at 0 °C to reach pH=1, and the aqueous layer was extracted four times with CH2Cl2, dried over MgSO4, filtered, and evaporated under reduced pressure to afford a crude product (6.67 g) as a yellow oil, which was used in the next reaction without further purification. To a stirred solution of the crude product (6.67 g) in CH2Cl2 (146 mL) was added CDI (3.93 g, 24.3 mmol) at 0 °C for three times every 10 minutes under Ar atmosphere. After stirring for 10 minutes at the same temperature, NH(OMe)Me ・ HCl (7.11 g, 72.9 mmol) was added, and the reaction mixture was stirred at room temperature for 13 hours. The reaction was quenched by adding saturated aqueous NH4Cl at 0 °C, and diluted with CH2Cl2. After separation of the two layers, the aqueous layer was extracted four times with CH2Cl2. The combined organic layers were washed with saturated aqueous NaHCO3, dried over MgSO4, filtered, and evaporated under reduced pressure. The residue was purified by flash silica gel chromatography (AcOEt/n-hexane = 40/60) to afford 7.70 g (93%) of 14 as a colorless oil: [α]24D = +11.5 (c = 1.01, CHCl3); 1H NMR (400 MHz, CDCl3) δ 5.79 (m, 1H), 5.05–5.00 (overlapped, 2H), 3.67 (s, 3H), 3.18 (s, 3H), 2.43 (dd, J = 14.9, 5.3 Hz, 1H), 2.24 (dd, J = 14.9, 7.5 Hz, 1H), 2.19–2.07 (overlapped, 2H), 2.01 (m, 1H), 0.96 (d, J = 6.4 Hz, 3H);

13C{1H}

NMR (100 MHz, CDCl3) δ 174.1, 136.8, 116.2, 61.1,

41.2, 38.3, 32.0, 29.5, 19.8; IR max (ATR) cm-1 2959, 1660, 1382, 1000, 911; HR-MS (ESI) calcd for C9H17NO2Na [M+Na]+ 194.1157, found 194.1154. (S)-5-Methyl-1-(trimethylsilyl)oct-7-en-1-yn-3-one (17). To a stirred solution of TMSacetylene (4.50 10 ACS Paragon Plus Environment

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mL, 31.8 mmol) in THF (80 mL) was added i-PrMgCl (16.4 mL, 31.8 mmol, 2.0 M in THF) at 0 °C under Ar atmosphere, and the reaction mixture was stirred at the same temperature for 1 hour. Next, 14 (2.72 g, 15.9 mmol) in THF (55 mL) was added via a cannula at 0 °C, and the reaction mixture was warmed to room temperature, and stirred for 2 hours. The reaction was quenched by adding saturated aqueous NH4Cl at 0 °C, and diluted with CHCl3. After separation of the two layers, the aqueous layer was extracted three times with CHCl3, dried over MgSO4, filtered, and evaporated under reduced pressure. The residue was purified by flash silica gel chromatography (CHCl3/n-hexane = 5/95 to 50/50) to afford 3.23 g (98%) of 17 as a colorless oil: [α]23D = –9.5 (c = 0.33, CHCl3); 1H NMR (400 MHz, CDCl3) δ 5.76 (m, 1H), 5.06–5.01 (overlapped, 2H), 2.59 (dd, J = 15.8, 5.7 Hz, 1H), 2.36 (dd, J = 15.8, 8.0 Hz, 1H), 2.21 (m, 1H), 2.10–1.97 (overlapped, 2H), 0.95 (d, J = 6.9 Hz, 3H), 0.24 (s, 9H);

13C{1H}

NMR (100

MHz, CDCl3) δ 187.6, 136.3, 116.8, 102.3, 97.6, 51.8, 40.9, 29.4, 19.5, –0.8; IR max (ATR) cm-1 2962, 1677, 1254, 866, 848, 763; HR-MS (ESI) calcd for C12H20OSiNa [M+Na]+ 231.1179, found 231.1181. (3S,5S)-5-Methyl-1-(trimethylsilyl)oct-7-en-1-yn-3-ol (S1). To a stirred solution of (S)-CBS reagent (6.04 g, 21.8 mmol) in THF (40 mL) was added BH3 ・THF (58.0 mL, 58 mmol, 1.0 M in THF) at 0 °C under Ar atmosphere, and the reaction mixture was stirred at the same temperature for 1 hour. After the cooling at –40 °C, 17 (3.02 g, 14.5 mmol) in THF (49 mL) was added via a cannula at the same temperature, and the reaction mixture was stirred for 2 hours. The reaction was quenched by adding MeOH at –40 °C, and stirred for 1 hour at the same temperature. The mixture was evaporated under reduced pressure. The residue was purified by flash silica gel chromatography (AcOEt/n-hexane = 5/95) to afford 2.94 g (96%) of S1 as a colorless oil: [α]23D = –11.7 (c = 0.38, CHCl3); 1H NMR (400 MHz, CDCl3) δ 5.78 (m, 1H), 5.05–5.01 (overlapped, 2H), 4.43 (dd, J = 13.0, 7.1 Hz, 1H), 2.12 (m, 1H), 1.96 (m, 1H), 1.81 (m, 1H), 1.75–1.67 (overlapped, 2H), 1.56 (m, 1H), 0.93 (d, J = 6.6 Hz, 3H), 0.17 (s, 9H); 13C{1H}

NMR (150 MHz, CDCl3) δ 136.9, 116.1, 106.8, 89.5, 61.5, 44.4, 41.1, 29.5, 19.6, –0.1; IR max

(ATR) cm-1 2958, 1250, 1015, 839, 759; HR-MS (EI) calcd for C11H19OSi [M–Me]+ 195.1205, found 195.1205. (4S,6S)-6-(Methoxymethoxy)-4-methyloct-1-en-7-yne (18). To a stirred solution of S1 (1.42 g, 6.76 11 ACS Paragon Plus Environment


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mmol) in CH2Cl2 (68 mL) was added DIPEA (7.10 mL, 40.6 mmol) and MOMCl (3.00 mL, 40.6 mmol) at 0 °C under Ar atmosphere, and the reaction mixture was stirred at room temperature for 8 hours. The reaction was quenched by adding saturated aqueous NaHCO3 at 0 °C, and diluted with CHCl3. After separation of the two layers, the aqueous layer was extracted three times with CHCl3, dried over MgSO4, filtered, evaporated under reduced pressure, and filtered through a SiO2-short pad with AcOEt to afford a crude product as a yellow oil, which was used in the next reaction without further purification. To a stirred solution of the crude product in MeOH (68 mL) was added K2CO3 (1.12 g, 8.11 mmol) at 0 °C under Ar atmosphere, and the reaction mixture was stirred at room temperature for 14 hours. The reaction was quenched by adding saturated aqueous NH4Cl at 0 °C, and diluted with CHCl3. After separation of the two layers, the aqueous layer was extracted three times with CHCl3, dried over MgSO4, filtered, and evaporated under reduced pressure. The residue was purified by flash silica gel chromatography (AcOEt/n-hexane = 5/95) to afford 1.13 g (92%) of 18 as a colorless oil: [α]23D = –132.7 (c = 0.56, CHCl3); 1H NMR (400 MHz, CDCl3) δ 5.78 (m, 1H), 5.05–5.00 (overlapped, 2H), 4.96 (d, J = 6.9 Hz, 1H), 4.60 (d, J = 6.9 Hz, 1H), 4.41 (td, J = 7.3, 2.3 Hz, 1H), 3.39 (s, 3H), 2.41 (d, J = 2.3 Hz, 1H), 2.14 (m, 1H), 1.96 (m, 1H), 1.85 (m, 1H), 1.76 (m, 1H), 1.61 (m, 1H), 0.94 (d, J = 6.4 Hz, 3H); 13C{1H}

NMR (100 MHz, CDCl3) δ 136.7, 116.2, 94.1, 82.5, 73.6, 64.0, 55.7, 42.1, 41.0, 29.2, 19.5; IR

max (ATR) cm-1 3306, 2956, 1640, 1463, 1441, 1155, 1098, 1031, 918; HR-MS (EI) calcd for C10H15O2 [M–Me]+ 165.1072, found 165.1066. (5S)-13,13-Dimethyl-5-((S)-2-methylpent-4-en-1-yl)-12,12-diphenyl-2,4,11-trioxa-12-silatetradec-6-yn8-ol (13). To a stirred solution of 18 (1.51 g, 8.30 mmol) in THF (37 mL) was added i-PrMgCl (4.10 mL, 8.30 mmol, 2.0 M in THF) at 0 °C under Ar atmosphere, and the reaction mixture was stirred at the same temperature for 1 hour. Next, aldehyde 19 (1.91 g, 6.12 mmol) in THF (20 mL) was added via a cannula at 0 °C. Then, the reaction mixture was warmed to room temperature, and stirred for 20 hours. The reaction was quenched by adding saturated aqueous NH4Cl at 0 °C, and diluted with CHCl3. After separation of the two layers, the aqueous layer was extracted three times with CHCl3, dried over MgSO4, filtered, and evaporated under reduced pressure. The residue was purified by flash silica gel 12 ACS Paragon Plus Environment

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chromatography (AcOEt/n-hexane = 10/90) to afford 2.83 g (93%) of 13 as a pale yellow oil: 1H NMR (400 MHz, CDCl3) δ 7.70–7.66 (overlapped,4H), 7.45–7.38 (overlapped,6H), 5.75 (m, 1H), 5.03–4.98 (overlapped, 2H), 4.94 (d, J = 6.4 Hz, 1H), 4.75 (m, 1H), 4.56 (d, J = 6.4 Hz, 1H), 4.46 (t, J = 7.3 Hz, 1H), 4.03 (m, 1H), 3.82 (m, 1H), 3.37 (s, 3H), 3.28 (d, J = 6.0 Hz, 1H), 2.12 (m, 1H), 2.03 (m, 1H), 1.96– 1.80 (overlapped, 3H), 1.73 (m, 1H), 1.60 (m, 1H), 1.05 (s, 9H), 0.92 (d, J = 6.6 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 136.7, 135.51, 135.49, 132.94, 132.90, 129.8, 127.8, 116.2, 94.0, 86.2, 86.1, 83.5, 77.2, 64.2, 61.8, 61.5, 55.7, 42.3, 40.9, 38.9, 29.3, 26.8, 19.6, 19.0; IR max (ATR) cm-1 2955, 2931, 2891, 2858, 1428, 1112, 1034, 705; HR-MS (ESI) calcd for C30H42O4SiNa [M+Na]+ 517.2750, found 517.2775. Bicyclic enone 20. To a stirred solution of 13 (20.3 mg, 0.0410 mmol) in CH2Cl2 (2.00 mL) was added Co2(CO)8 (17.8 mg, 0.0492 mmol) at room temperature, and the reaction mixture was stirred at the same temperature for 1.5 hours under Ar atmosphere. Then, N-methyl morpholine N-oxide (50.1 mg, 0.410 mmol) was added, and the reaction mixture was stirred at room temperature for 18 hours under CO atmosphere. The reaction mixture was filtered through a SiO2-short pad with AcOEt after evaporation under reduced pressure. The residue was purified by SiO2-MPLC (AcOEt/n-hexane = 20/80) to afford 17.4 mg (82%) of 20 (20a and 20b) as a pale yellow oil:20a [α]24D = +6.3 (c = 2.11, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.70–7.66 (overlapped, 4H), 7.43–7.34 (overlapped, 6H), 5.12 (td, J = 10.5, 3.9 Hz, 1H), 4.71 (d, J = 7.1 Hz, 1H), 4.58 (d, J = 7.1 Hz, 1H), 4.42 (dd, J = 11.7, 5.3 Hz, 1H), 4.06 (d, J = 11.4 Hz, 1H), 3.87–3.78 (overlapped, 2H), 3.30 (s, 3H), 2.60–2.51 (overlapped, 2H), 2.29 (m, 1H), 2.07–1.95 (overlapped, 3H), 1.83 (m, 1H), 1.75 (m, 1H), 1.24 (ddd, J = 12.4, 11.9, 11.9 Hz, 1H), 1.05 (s, 9H), 0.98 (d, J = 6.4 Hz, 3H), 0.78 (ddd, J = 12.4, 12.4, 12.4 Hz, 1H); 13C{1H} NMR (150 MHz, CDCl3) δ 209.0, 172.5, 138.8, 135.61, 135.56, 134.1, 133.9, 129.5, 127.6, 94.9, 77.4, 64.4, 61.1, 55.9, 43.1, 41.7, 41.2, 40.5, 39.4, 30.5, 26.9, 21.1, 19.2; IR max (ATR) cm-1 2954, 2929, 1700, 1684, 1112, 1033, 707; HR-MS (ESI) calcd for C31H42O5SiNa [M+Na]+ 545.2699, found 545.2657: 20b [α]23D = –83.2 (c = 0.26, CHCl3); 1H

NMR (400 MHz, CDCl3) δ 7.70–7.67 (overlapped, 4H), 7.43–7.34 (overlapped, 6H), 5.01 (m, 1H),

4.70 (d, J = 7.1 Hz, 1H), 4.63 (d, J = 7.1 Hz, 1H), 4.45 (dd, J = 11.7, 5.3 Hz, 1H), 4.16 (d, J = 11.4 Hz, 1H), 3.81–3.79 (overlapped, 2H), 3.32 (s, 3H), 2.59–2.51 (overlapped, 2H), 2.22 (m, 1H), 2.04 (m, 1H), 13 ACS Paragon Plus Environment


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2.00–1.87 (overlapped, 3H), 1.76 (m, 1H), 1.16 (ddd, J = 12.4, 12.4, 11.9 Hz, 1H), 1.05 (s, 9H), 0.96 (d, J = 6.4 Hz, 3H), 0.70 (ddd, J = 12.2, 12.2, 12.2 Hz, 1H); 13C{1H} NMR (150 MHz, CDCl3) δ 209.0, 172.7, 138.7, 135.58, 135.56, 134.1, 134.0, 129.5, 127.57, 127.55, 95.0, 64.4, 61.2, 55.9, 43.2, 42.0, 41.0, 40.8, 39.3, 30.5, 26.9, 21.0, 19.2; IR max (ATR) cm-1 2954, 2930, 1700, 1685, 1113, 1035, 706; HR-MS (ESI) calcd for C31H42O5SiNa [M+Na]+ 545.2699, found 545.2724. Enedione 12. To a stirred solution of 20 (1.35 g, 2.58 mmol) in CH2Cl2 (12.9 mL) was added AZADOL® (40.0 mg, 0.258 mmol) and diacetoxyiodobenzene (1.25 g, 3.87 mmol) at room temperature under Ar atmosphere, and the reaction mixture was stirred at the same temperature for 19.5 hours. The reaction was quenched by adding saturated aqueous Na2S2O3 at room temperature, and diluted with CHCl3. After separation of the two layers, the aqueous layer was extracted three times with CHCl3, dried over MgSO4, filtered, and evaporated under reduced pressure. The residue was purified by flash silica gel chromatography (AcOEt/n-hexane = 1/3) to afford 1.32 g (quant.) of 12 as a pale yellow oil: [α]22D = – 73.9 (c = 0.69, CHCl3); 1H NMR (600 MHz, CDCl3) δ 7.68–7.67 (overlapped, 4H), 7.43–7.36 (overlapped, 6H), 4.44 (d, J = 6.9 Hz, 1H), 4.41 (d, J = 6.9 Hz, 1H), 4.37 (dd, J = 11.7, 6.2 Hz, 1H), 4.01–3.93 (overlapped, 2H), 3.22 (s, 3H), 3.01–2.90 (overlapped, 2H), 2.70 (m, 1H), 2.63 (dd, J = 18.8, 6.9 Hz, 1H), 2.24 (m, 1H), 2.11 (m, 1H), 2.71 (dd, J = 18.8, 1.7 Hz, 1H), 1.74 (m, 1H), 1.18 (ddd, J = 12.4, 12.4, 11.7 Hz, 1H), 1.04 (s, 9H), 1.00 (d, J = 6.2 Hz, 3H), 0.86 (ddd, J = 12.4, 12.4, 12.4 Hz, 1H); 13C{1H}

NMR (100 MHz, CDCl3) δ 203.1, 202.4, 176.6, 139.6, 135.5, 133.6, 133.5, 129.6, 127.6, 95.1,

74.5, 58.9, 55.8, 47.5, 42.3, 41.9, 41.7, 39.1, 29.9, 26.8, 21.1, 19.1; IR max (ATR) cm-1 2954, 2930, 1716, 1693, 1649, 1114, 1039, 707; HR-MS (ESI) calcd for C31H40O5SiNa [M+Na]+ 543.2543, found 543.2543. Conjugate adduct 10. To a stirred solution of 21 (4.79 g, 18.9 mmol) in THF (35 mL) was added t-BuLi (25.0 mL, 37.9 mmol, 1.52 M in pentane) via a cannula over a period of 15 minutes at –78 °C under Ar atmosphere, and the reaction mixture was stirred at the same temperature for 15 minutes. Then, 2-thienylcyano cuprate (75.7 mL, 18.9 mmol, 0.25 M in THF) was added with a syringe over a period of 8 minutes at –78 °C, and the reaction mixture was warmed to 0 °C, and stirred vigorously for 1.5 hours. After recooling at –78 °C, BF3・OEt2 (2.40 mL, 18.9 mmol) was added with a syringe over a period of 3 14 ACS Paragon Plus Environment

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minutes, and the reaction mixture was stirred at the same temperature for 15 minutes. Next, 12 (3.08 g, 5.91 mmol) in THF (20 mL) was added via a cannula at –78 °C, and the reaction mixture was stirred for 5 hours at the same temperature. The reaction was quenched by adding sat. NH4Cl aq./NH3 aq.(9:1, v:v) at –78 °C, and the mixture was stirred at room temperature until the aqueous layer turned blue. The mixture was diluted with CHCl3. After separation of the two layers, the aqueous layer was extracted three times with CHCl3, dried over MgSO4, filtered, and evaporated under reduced pressure. The residue was purified by flash silica gel chromatography (AcOEt/n-hexane = 10/90) to afford 2.89 g (70%) of 10 as a brown oil: [α]26D = –12.4 (c = 0.12, CHCl3); Major isomer 1H NMR (600 MHz, CDCl3) δ 10.4 (s, 1H), 7.73–7.72 (overlapped, 4H), 7.41–7.36 (overlapped, 6H), 4.92 (d, J = 6.9 Hz, 1H), 4.81 (d, J = 6.9 Hz, 1H), 3.96 (overlapped, 2H), 3.85 (dd, J = 8.1, 3.3 Hz, 1H), 3.62–3.53 (overlapped, 2H), 3.45 (s, 3H), 3.31 (m, 1H), 3.15 (m, 1H), 2.55 (dd, J = 16.8, 6.6 Hz, 1H), 2.07 (overlapped, 1H), 1.90 (overlapped, 1H), 1.87 (overlapped, 1H), 1.80 (d, J = 16.8 Hz, 1H), 1.59–1.47 (overlapped, 5H), 1.16 (ddd, J = 12.4, 12.4, 11.6 Hz, 1H), 1.07 (s, 9H), 0.90 (s, 9H), 0.87 (d, J = 6.6 Hz, 3H), 0.80 (ddd, J = 13.2, 12.4, 12.4 Hz, 1H), 0.03 (s, 6H); 13C{1H} NMR (150 MHz, CDCl3) δ 205.5, 167.8, 135.5, 134.8, 134.0, 129.3, 127.6, 113.5, 95.4, 80.4, 63.3, 61.9, 56.6, 52.8, 43.8, 39.1, 36.4, 35.7, 34.6, 31.3, 30.3, 27.5, 26.8, 25.9, 21.6, 19.1, 18.2, – 5.4; Minor isomer 1H NMR (600 MHz, CDCl3) δ 15.3 (s, 1H), 4.67 (d, J = 6.6 Hz, 1H), 4.53 (d, J = 6.6 Hz, 1H), 4.02 (overlapped, 2H), 3.65 (dd, J = 9.9, 3.3 Hz, 1H), 3.29 (s, 3H), 2.95 (overlapped, 2H), 2.65 (dd, J = 17.4, 9.9 Hz, 1H), 1.99 (d, J = 17.4 Hz, 1H); 13C{1H} NMR (150 MHz, CDCl3) δ 207.2, 180.3, 135.5, 133.6, 129.5, 127.6, 114.8, 95.6, 80.5, 63.2, 60.6, 55.7, 51.4, 42.6, 38.4, 37.6, 34.6, 32.8, 28.4, 27.9, 26.8, 25.9, 22.6, 19.1, 18.2, –5.4; IR max (ATR) cm-1 2953, 2930, 2857, 1749, 1699, 1472, 1110, 1036, 836, 706; HR-MS (ESI) calcd for C40H62O6Si2Na [M+Na]+ 717.3983, found 717.3978. β-Ketoenoltriflate 22. To a stirred solution of 10 (1.13 g, 1.63 mmol) in THF (16.3 mL) was added NaH (78.3 mg, 1.96 mmol, 60% dispersion in Paraffin Liquid) at 0 °C, and the reaction mixture was stirred at the same temperature for 15 minutes. Then, Comins reagent (768 mg, 1.96 mmol) was added at 0 °C, and the reaction mixture was stirred at the same temperature for 3 hours under Ar atmosphere. The reaction was quenched by adding saturated aqueous NH4Cl at 0 °C, and diluted with AcOEt. After separation of 15 ACS Paragon Plus Environment


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the two layers, the aqueous layer was extracted three times with AcOEt, dried over MgSO4, filtered, and evaporated under reduced pressure. The residue was purified by flash silica gel chromatography (Et2O/n-hexane = 5/95 to 10/90) to afford 1.22 g (91%) of 22 as a pale yellow oil. 22 was unstable, so we used for next step within a several hours after purification: []21D = +0.80 (c = 2.18, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.68–7.66 (overlapped, 4H), 7.41–7.38 (overlapped, 6H), 4.46 (d, J = 7.1 Hz, 1H), 4.32 (d, J = 7.1 Hz, 1H), 4.00–3.89 (overlapped, 2H), 3.70 (dd, J = 7.8, 6.4 Hz, 1H), 3.62–3.51 (overlapped, 2H), 3.19 (s, 3H), 3.06–2.90 (overlapped, 3H), 2.24–2.15 (overlapped, 2H), 1.87 (m, 1H), 1.79–1.65 (overlapped, 3H), 1.53–1.34 (overlapped, 3H), 1.27–1.18 (overlapped, 2H), 1.03 (s, 9H), 0.94 (d, J = 6.4 Hz, 3H), 0.88 (s, 9H), 0.03 (s, 6H); 13C{1H} NMR (150 MHz, CDCl3) δ 198.0, 148.7, 135.5, 134.8, 133.7, 133.6, 129.6, 127.6, 118.2 (q), 95.7, 78.5, 63.1, 58.8, 56.2, 55.7, 46.5, 38.50, 38.47, 38.0, 34.9, 32.2, 28.1, 26.84, 26.77, 25.9, 22.8, 19.1, 18.3, –5.3; IR max (ATR) cm-1 2953, 2932, 2859, 1699, 1427, 1219, 1143, 1110, 1039, 762; HR-MS (ESI) calcd for C41H61F3O8SSi2Na [M+Na]+ 849.3475, found 849.3443. β-Hydroxylenoltriflate S2. To a stirred solution of 22 (7.0 mg, 8.46 mol) in Toluene (0.17 mL) was added DIBAL (67.7 L, 67.7 mol, 1.0 M in n-hexane) at –78 °C, and the reaction mixture was stirred at the same temperature for 30 minutes under Ar atmosphere. The reaction was quenched by adding saturated aqueous potassium sodium tartrate at –78 °C, and the mixture was warmed to room temperature, and diluted with AcOEt. After separation of the two layers, the aqueous layer was extracted three times with AcOEt, dried over MgSO4, filtered, and evaporated under reduced pressure. The residue was purified by flash silica gel chromatography (AcOEt/n-hexane = 10/90) to afford 7.1 mg (quant.) of S2 as a colorless oil: 1H NMR (600 MHz, CDCl3) δ 7.71–7.69 (overlapped, 4H), 7.43–7.37 (overlapped, 6H), 4.85 (m, 1H), 4.77 (d, J = 6.9 Hz, 1H), 4.60 (d, J = 6.9 Hz, 1H), 3.96–3.87 (overlapped, 2H), 3.80 (m, 1H), 3.61 (m, 1H), 3.61–3.56 (overlapped, 2H), 3.36 (s, 3H), 2.88 (td, J = 15.5, 6.2 Hz, 1H), 2.21 (m, 1H), 2.09 (m, 1H), 2.02–1.95 (overlapped, 2H), 1.93–1.85 (overlapped, 2H), 1.62–1.38 (overlapped, 6H), 1.21 (m, 1H), 1.06 (s, 9H), 0.92 (d, J = 6.2 Hz, 3H), 0.88 (s, 9H), 0.04 (s, 6H); 13C{1H} NMR (150 MHz, CDCl3) δ 145.8, 145.0, 137.9, 137.8, 135.60, 135.56, 134.0, 133.8, 133.74, 133.70, 129.5, 127.6, 118.3 16 ACS Paragon Plus Environment

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(q), 95.5, 95.3, 79.1, 78.9, 64.8, 64.2, 63.3, 63.2, 61.3, 61.1, 56.3, 56.2, 54.7, 39.9, 39.8, 39.1, 38.93, 38.87,36.7, 36.4, 36.3, 32.1, 32.0, 29.3, 29.1, 28.0, 26.8, 25.9, 22.1, 21.9, 19.1, 18.3, –5.4; IR max (ATR) cm-1 2953, 2932, 2858, 1423, 1214, 1110, 837, 704; HR-MS (ESI) calcd for C41H63F3O8SSi2Na [M+Na]+ 851.3632, found 851.3620. MOM protected compound 23. To a stirred solution of S2 (377 mg, 0.455 mmol) in CH2Cl2 (4.60 mL) was added DMAP (111 mg, 0.910 mmol), DIPEA (2.15 mL, 11.4 mmol) and MOMCl (0.85 mL, 11.4 mmol) at room temperature under Ar atmosphere, and the reaction mixture was warmed to 70 °C, and stirred for 15 hours. After the reaction mixture allowed to cool to room temperature, the reaction was quenched by adding saturated aqueous NaHCO3, and diluted with CHCl3. After separation of the two layers, the aqueous layer was extracted three times with CHCl3, dried over MgSO4, filtered, and evaporated under reduced pressure. The residue was purified by flash silica gel chromatography (AcOEt/n-hexane = 10/90) to afford 401 mg (quant.) of 23 as a colorless oil: 1H NMR (400 MHz, CDCl3); Major (selected assignment 1H NMR) δ 4.89 (t, J = 6.2 Hz, 1H), 4.67 (d, J = 7.3 Hz), 4.63 (d, J = 7.3 Hz), 4.54 (d, J = 6.9 Hz), 4.45 (d, J = 6.9 Hz), 2.81 (dd, J = 15.3, 5.3 Hz); Minor (selected assignment 1H-NMR) δ: 4.79 (dd, J = 8.5, 3.4 Hz, 1H), 4.60 (d, J = 7.3 Hz), 4.54 (d, J = 6.9 Hz), 4.48 (d, J = 6.9 Hz), 4.36 (d, J = 7.3 Hz), 2.85 (overlapped, 1H);

13C{1H}

NMR (150 MHz, CDCl3) δ 145.9,

138.6, 135.5, 134.13, 134.09, 134.0, 129.5, 127.6, 95.4, 95.1, 95.0, 94.7, 78.4, 69.8, 68.3, 63.4, 63.3, 61.4, 61.2, 55.62, 55.58, 54.0, 53.4, 39.5, 39.0, 38.8, 37.9, 37.8, 37.3, 37.1, 37.0, 36.1, 31.3, 30.5, 29.4, 29.0, 27.9, 27.8, 26.9, 25.92, 25.88, 22.2, 22.1, 19.3, 18.3, 18.2, –5.30, –5.32, –5.4; IR max (ATR) cm-1 2953, 2928, 2858, 1422, 1210, 1146, 1106, 1036, 836; HR-MS (ESI) calcd for C43H67F3O9SSi2Na [M+Na]+ 895.3894, found 895.3846. Alcohol 24 & 3-epi-24. To a stirred solution of 23 (348 mg, 0.399 mmol) in THF (11.0 mL) was added 1N HCl aq. (11.0 mL) at room temperature under Ar atmosphere, and the reaction mixture was stirred for 5 hours. The reaction was quenched by adding saturated aqueous NaHCO3, and diluted with CHCl3. After separation of the two layers, the aqueous layer was extracted three times with CHCl3, dried over MgSO4, filtered, and evaporated under reduced pressure. The residue was purified by flash silica gel 17 ACS Paragon Plus Environment


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chromatography (AcOEt/n-hexane = 20/80 to 50/50) to afford 224 mg (74%) of 24 as a colorless oil and 68.1 mg (22%) of 3-epi-24 as a colorless oil. 24: []29D = +39.9 (c = 0.83, CHCl3); 1H NMR (600 MHz, CDCl3)  7.68–7.65 (overlapped, 4H), 7.42–7.35 (overlapped, 6H), 4.91 (dd, J = 8.3, 4.1 Hz, 1H), 4.68 (d, J = 6.9 Hz, 1H), 4.61 (d, J = 6.9 Hz, 1H), 4.56 (d, J = 6.9 Hz, 1H), 4.43 (d, J = 6.9 Hz, 1H), 3.88– 3.79 (overlapped, 2H), 3.62 (t, J = 5.5 Hz, 2H), 3.53 (dd, J = 11.4, 3.8 Hz, 1H), 3.27 (s, 3H), 3.25 (s, 3H), 2.80 (dd, J = 15.5, 5.9 Hz, 1H), 2.14 (quin, J = 5.7 Hz, 1H), 2.01–1.98 (overlapped, 2H), 1.96–1.88 (overlapped, 3H), 1.67–1.59 (overlapped, 3H), 1.54 (m, 1H), 1.44 (m, 1H), 1.41–1.36 (overlapped, 2H), 1.24 (ddd, J = 12.4, 11.7, 11.7 Hz, 1H), 1.05 (s, 9H), 0.91 (d, J = 6.2 Hz, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 146.1, 138.4, 135.5, 134.1, 129.6, 129.5, 127.58, 127.57, 118.3 (q), 95.5, 95.2, 78.7, 69.6, 63.1, 61.2, 55.64, 55.58, 53.9, 39.0, 38.7, 37.9, 37.1, 36.0, 31.3, 29.4, 27.8, 26.9, 22.2, 19.3; IR vmax (ATR) cm-1: 2954, 2933, 1419, 1144, 1033; HR-MS (ESI) calcd for C37H53F3O9SSiNa [M+Na]+ 781.3029, found 781.3056. 3-epi-24: []23D = –17.6 (c = 1.59, CHCl3); 1H NMR (400 MHz, CDCl3)  7.69–7.65 (overlapped, 4H), 7.42–7.34 (overlapped, 6H), 4.78 (dd, J = 7.1, 5.3 Hz, 1H), 4.61–4.54 (overlapped, 2H), 4.50 (d, J = 6.9 Hz, 1H), 4.37 (d, J = 6.9 Hz, 1H), 3.85 (t, J = 6.6 Hz, 2H), 3.64–3.63 (overlapped, 2H), 3.53 (dd, J = 11.7, 3.9 Hz, 1H), 3.27 (s, 3H), 3.25 (s, 3H), 2.86 (dd, J = 15.6, 6.4 Hz, 1H), 2.16–2.08 (overlapped, 3H), 1.96–1.83 (overlapped, 3H), 1.74–1.44 (overlapped, 5H), 1.34 (m, 1H), 1.06 (s, 9H), 1.06 (overlapped, 1H), 0.91 (d, J = 6.4 Hz, 3H), 0.91 (overlapped, 1H);

13C{1H}

NMR (100 MHz,

CDCl3) δ 146.7, 138.0, 135.5, 134.0, 129.50, 129.48, 127.5, 118.2 (q), 95.2, 94.7, 78.9, 68.4, 62.9, 61.3, 55.7, 55.6, 53.3, 39.5, 37.9, 37.2, 37.1, 31.0, 28.9, 27.7, 26.9, 22.0, 19.2; IR max (ATR) cm-1 2954, 2933, 1420, 1212, 1146, 1038, 705; HR-MS (ESI) calcd for C37H53F3O9SSiNa [M+Na]+ 781.3029, found 781.3014. Nosyl amine adduct S3. To a stirred solution of 24 (281 mg, 0.370 mmol) in Toluene (37.0 mL) was added PPh3 (369 mg, 1.41 mmol), NsNH2 (224 mg, 1.11 mmol) and DEAD (0.44 mL, 1.11 mmol, 40% in toluene) at 0 °C under Ar atmosphere, and the reaction mixture was stirred at room temperature for 2.5 hours. The reaction was quenched by adding cold water, and diluted with CHCl3. After separation of the two layers, the aqueous layer was extracted three times with CHCl3, dried over MgSO4, filtered, and 18 ACS Paragon Plus Environment

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evaporated under reduced pressure. The residue was purified by flash silica gel chromatography (AcOEt/n-hexane = 20/80 to 25/75) to afford 320 mg (92%) of S3 as a white amorphous solid: []23D = +42.0 (c = 0.49, CHCl3); 1H NMR (600 MHz, CDCl3)  8.12 (m, 1H), 7.84 (m, 1H), 7.72–7.69 (overlapped, 2H), 7.67–7.64 (overlapped, 4H), 7.42–7.39 (overlapped, 2H), 7.37–7.35 (overlapped, 4H), 5.36 (t, J = 5.9 Hz, 1H), 4.86 (dd, J = 9.0, 2.8 Hz, 1H), 4.65 (d, J = 6.9 Hz, 1H), 4.60 (d, J = 6.9 Hz, 1H), 4.54 (d, J = 6.9 Hz, 1H), 4.40 (d, J = 6.9 Hz, 1H), 3.86–3.77 (overlapped, 2H), 3.45 (dd, J = 11.7, 3.4 Hz, 1H), 3.25 (s, 3H), 3.23 (s, 3H), 3.11–3.01 (overlapped, 2H), 2.70 (dd, J = 15.8, 5.5 Hz, 1H), 2.04 (m, 1H), 1.95–1.84 (overlapped, 5H), 1.64 (m, 1H), 1.59 (m, 1H), 1.52 (m, 1H), 1.34 (m, 1H), 1.26 (m, 1H), 1.18 (ddd, J = 13.1, 11.7, 11.7 Hz, 1H), 1.05 (s, 9H), 1.01 (ddd, J = 12.4, 12.4, 12.4 Hz, 1H), 0.90 (d, J = 6.2 Hz, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 148.1, 146.0, 138.2, 135.5, 134.0, 133.9, 133.6, 132.7, 131.1, 129.59, 129.57, 127.6, 125.4, 95.3, 95.1, 78.3, 69.5, 61.0, 55.7, 55.6, 53.8, 44.2, 38.9, 38.6, 37.8, 37.1, 35.7, 32.0, 29.3, 26.9, 24.9, 22.1, 19.3; IR max (ATR) cm-1 2953, 2933, 1543, 1418, 1216, 1145, 1034, 762; HR-MS (ESI) calcd for C43H57F3N2O12S2SiNa [M+Na]+ 965.2972, found 965.2933. Intramolecular Mitsunobu reaction substrate 25. To a stirred solution of S3 (184 mg, 0.195 mmol) in MeOH (11.0 mL) was added CSA (63.0 mg, 0.273 mmol) at room temperature under Ar atmosphere, and the reaction mixture was stirred at the same temperature for 12 hours. The reaction was quenched by adding saturated aqueous NaHCO3, and diluted with CHCl3. After separation of the two layers, the aqueous layer was extracted three times with CHCl3, dried over MgSO4, filtered, and evaporated under reduced pressure. The residue was purified by flash silica gel chromatography (AcOEt/n-hexane = 50/50 to 70/30) to afford 138 mg (quant.) of 25 as a white amorphous solid: []23D = +53.8 (c = 1.92, CHCl3); 1H

NMR (400 MHz, CDCl3)  8.13 (m, 1H), 7.87 (m, 1H), 7.78–7.73 (overlapped, 2H), 5.45 (t, J = 6.0

Hz, 1H), 4.96 (dd, J = 8.0, 3.9 Hz, 1H), 4.74–4.70 (overlapped, 2H), 4.61–4.57 (overlapped, 2H), 3.82– 3.70 (overlapped, 2H), 3.48 (dd, J = 11.9, 3.7 Hz, 1H), 3.42 (s, 3H), 3.37 (s, 3H), 3.12-3.03 (overlapped, 2H), 2.76 (dd, J = 16.0, 5.0 Hz, 1H), 2.37 (m, 1H), 2.08 (m, 1H), 1.97–1.86 (overlapped, 5H), 1.69–1.53 (overlapped, 3H), 1.33 (overlapped, 2H), 1.15 (ddd, J = 12.4, 11.9, 11.9 Hz, 1H), 1.00 (ddd, J = 12.8, 12.4, 12.4 Hz, 1H), 0.91 (d, J = 6.4 Hz, 3H);

13C{1H}

NMR (100 MHz, CDCl3) δ 148.0, 146.3, 137.3,



Page 20 of 30

133.6, 133.4, 132.8, 131.0, 125.4, 118.2 (q), 95.7, 94.9, 78.6, 71.4, 60.4, 55.9, 55.8, 53.7, 44.0, 39.1, 38.7, 37.1, 37.0, 36.1, 32.0, 29.3, 24.8, 22.0; IR max (ATR) cm-1 2950, 1544, 1418, 1214, 1146, 1034; HR-MS (ESI) calcd for C27H39F3N2O12S2Na [M+Na]+ 727.1794, found 727.1766. Tricyclic compound 26. To a stirred solution of 25 (85.0 mg, 0.121 mmol) in Toluene (12.1 mL) was added PPh3 (121 mg, 0.460 mmol) and DEAD (0.14 mL, 0.363 mmol, 40% in toluene) at 0 °C under Ar atmosphere, and the reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched by adding cold water, and diluted with CHCl3. After separation of the two layers, the aqueous layer was extracted three times with CHCl3, dried over MgSO4, filtered, and evaporated under reduced pressure. The residue was purified by flash silica gel chromatography (Et2O/n-hexane = 60/40) to afford 61.0 mg (74%) of 26 as a white amorphous solid: []30D = +4.5 (c = 0.73, CHCl3); 1H NMR (600 MHz, CDCl3)  7.93 (m, 1H), 7.71–7.67 (overlapped, 2H), 7.59 (m, 1H), 4.72 (d, J = 6.9 Hz, 1H), 4.68 (d, J = 6.9 Hz, 1H), 4.64 (d, J = 6.9 Hz, 1H), 4.63 (overlapped, 1H), 4.62 (d, J = 6.9 Hz, 1H), 3.54–3.49 (overlapped, 2H), 3.40 (overlapped, 1H) 3.40 (s, 3H), 3.39 (s, 3H), 3.06 (ddd, J = 15.2, 11.0, 4.1 Hz, 1H), 2.94 (dd, J = 13.8, 4.8 Hz, 1H), 2.81 (dd, J = 15.8, 8.3 Hz, 1H), 2.63 (m, 1H), 2.30 (m, 1H), 2.23 (dd, J = 15.8, 4.1 Hz, 1H), 2.09 (m, 1H), 2.01 (td, J = 13.8, 5.2 Hz, 1H), 1.93 (td, J = 13.8, 4.8 Hz, 1H), 1.86 (m, 1H), 1.73 (m, 1H), 1.67–1.55 (overlapped, 3H), 1.41–1.28 (overlapped, 2H), 0.97 (d, J = 6.2 Hz, 3H); 13C{1H}

NMR (150 MHz, CDCl3) δ 148.7, 147.5, 133.6, 132.9, 131.3, 130.9, 130.8, 124.0, 118.2 (q),

97.0, 96.1, 82.9, 70.9, 55.9, 55.7, 54.4, 50.6, 44.5, 39.4, 39.0, 37.5, 35.0, 33.6, 31.6, 27.2, 23.1, 22.2; IR max (ATR) cm-1 2929, 1549, 1418, 1374, 1214, 1144, 1042; HR-MS (ESI) calcd for C27H37F3N2O11S2Na [M+Na]+ 709.1689, found 709.1656. Diol 27. To a stirred solution of 26 (20.6 mg, 0.030 mmol) in MeOH (0.60 mL) was added 12N HCl aq. (110 L) at room temperature under Ar atmosphere, and the reaction mixture was stirred at 65 °C for 1.5 hours. The reaction was quenched by adding saturated aqueous NaHCO3, and diluted with CHCl3. After separation of the two layers, the aqueous layer was extracted three times with CHCl3, dried over MgSO4, filtered, and evaporated under reduced pressure. The residue was purified by flash silica gel chromatography (AcOEt/CHCl3 = 50/50) to afford 18.4 mg (quant.) of 27 as a white amorphous solid: 20 ACS Paragon Plus Environment

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[]26D = +7.3 (c = 0.13, CHCl3); 1H NMR (400 MHz, CDCl3)  7.92 (m, 1H), 7.76–7.68 (overlapped, 2H), 7.59 (m, 1H), 4.51 (dt, J = 11.2, 5.0 Hz, 1H), 3.96 (m, 1H), 3.53 (td, J = 12.8, 4.1 Hz, 1H), 3.39 (dd, J = 15.3, 5.3 Hz, 1H), 2.95–2.86 (overlapped, 2H), 2.78 (dd, J = 13.1, 3.4 Hz, 1H), 2.64 (m, 1H), 2.43 (d, J = 4.6 Hz, 1H), 2.38 (d, J = 1.8 Hz, 1H), 2.32 (dd, J = 16.7, 5.7 Hz, 1H), 2.25 (td, J = 11.9, 3.7 Hz, 1H), 2.16 (m, 1H), 2.05 (m, 1H), 1.73–1.62 (overlapped, 5H), 1.50–1.37 (overlapped, 3H), 1.00 (d, J = 6.0 Hz, 3H);

13C{1H}

NMR (100 MHz, CDCl3) δ 148.9, 147.7, 133.9, 133.0, 131.3, 130.9, 129.9, 124.0, 118.2

(q), 72.1, 62.4, 55.3, 50.5, 43.6, 38.7, 36.9, 36.2, 35.4, 33.5, 29.3, 24.8, 23.8, 20.0; IR max (ATR) cm-1 3491, 3326, 2985, 2936, 2871, 1800, 1748, 1549, 1372, 1267, 1102; HR-MS (ESI) calcd for C23H29F3N2O9S2Na [M+Na]+ 621.1164, found 621.1139. Diketone 29. To a stirred solution of 27 (284 mg, 0.474 mmol) in dioxane/MeOH (8.0 mL/4.0 mL) was added 1N NaOH aq. (12.0 mL) at room temperature under Ar atmosphere, and the reaction mixture was stirred at the same temperature for 15 minutes. The reaction was quenched by adding saturated aqueous NH4Cl at 0 °C, and diluted with AcOEt. After separation of the two layers, the aqueous layer was extracted five times with AcOEt, dried over MgSO4, filtered, and evaporated under reduced pressure to afford a crude product as a white solid, which was used in the next reaction without further purification. To a stirred solution of the crude product in THF (9.5 mL) was added DMP (241 mg, 0.569 mmol) at room temperature under Ar atmosphere, and the reaction mixture was stirred at the same temperature for 40 minutes. The reaction was quenched by adding saturated aqueous Na2S2O3/saturated aqueous NaHCO3 (1:1) at 0 °C, and diluted with AcOEt. After separation of the two layers, the aqueous layer was extracted three times with AcOEt, dried over MgSO4, filtered, and evaporated under reduced pressure. The residue was purified by flash amino-silica gel chromatography (CHCl3) to afford 202 mg (95% in 2 steps) of 29 as a white amorphous solid. 28: []25D = +12.0 (c = 0.04, CHCl3); 1H NMR (600 MHz, CDCl3, 55 °C)  7.85 (m, 1H), 7.65–7.59 (overlapped, 2H), 7.54 (m, 1H), 6.81 (dd, J = 9.6, 7.3 Hz, 1H), 3.82 (dt, J = 11.4, 3.2 Hz, 1H), 3.73 (m, 1H), 3.59 (m, 1H), 3.39 (ddd, J = 15.1, 7.3, 3.2 Hz, 1H), 3.25 (dt, J = 14.7, 5.5 Hz, 1H), 2.70 (dd, J = 17.9, 6.4 Hz, 1H), 2.58 (ddd, J = 15.1, 7.1, 3.4 Hz, 1H), 2.44 (m, 1H), 2.35 (m, 1H), 2.03–1.89 (overlapped, 3H), 1.83 (m, 1H), 1.65-1.58 (overlapped, 4H), 1.36 (ddd, J = 11.9, 11.4, 21 ACS Paragon Plus Environment


11.4 Hz, 1H), 0.90 (d, J = 6.0 Hz, 3H), 0.72 (ddd, J = 13.3, 12.4, 11.9 Hz, 1H);

Page 22 of 30 13C{1H}

NMR (150

MHz, CDCl3, 55 °C) δ 182.4, 134.4, 128.3, 127.3, 121.9, 121.8, 120.4, 119.7, 114.6, 80.1, 59.8, 57.6, 55.7, 51.1, 48.1, 47.9, 47.6, 47.5, 39.6, 38.7, 37.6, 32.8; IR vmax (ATR) cm-1: 3435, 2955, 2926, 1716, 1700, 1542, 1259, 1029, 776; HR-MS (ESI) calcd for C22H28N2O6S1Na [M+Na]+ 471.15658, found 471.15718. 29: []29D = +3.6 (c = 0.17, CHCl3); 1H NMR (400 MHz, CDCl3)  7.86 (m, 1H), 7.69–7.61 (overlapped, 2H), 7.56 (m, 1H), 5.79 (dd, J = 10.8, 6.6 Hz, 1H), 3.90 (m, 1H), 3.78 (dt, J = 14.7, 5.0 Hz, 1H), 3.70 (ddd, J = 14.7, 5.5, 3.2 Hz, 1H), 2.94–2.79 (overlapped, 3H), 2.40–2.16 (overlapped, 6H), 1.99–1.75 (overlapped, 4H), 1.36 (dd, J = 14.4, 8.5 Hz, 1H), 1.21 (ddd, J = 13.3, 12.4, 12.4 Hz, 1H), 0.99 (d, J = 6.4 Hz, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 210.3, 205.9, 148.5, 139.5, 137.5, 133.4, 132.4, 131.3, 130.5, 124.0, 61.9, 54.6, 50.5, 47.1, 44.8, 42.2, 39.9, 34.2, 32.5, 29.1, 24.7, 22.0; IR max (ATR) cm-1 2925, 1713, 1699, 1631, 1542, 1347, 1168, 745; HR-MS (ESI) calcd for C22H26N2O6SNa [M+Na]+ 469.1409, found 469.1397. Synthesis of Lycopoclavamine-A (1) from 29. To a stirred solution of 29 (197 mg, 0.441 mmol) in MeCN (22.1 mL) was added PhSH (180 L, 1.76 mmol) and K2CO3 (244 mg, 1.76 mmol) at room temperature under Ar atmosphere, and the reaction mixture was stirred at 60 °C for 1 hour. The reaction mixture was evaporated under reduced pressure. The residue was purified by flash amino-silica gel chromatography (CHCl3/n-hexane = 30/70) to afford 90.8 mg (78%) of Synthetic Lycopoclavamine-A (1) as a white amorphous solid: []25D = –55.9 (c = 0.14, CHCl3); 1H NMR (400 MHz, CDCl3)  6.91 (dd, J = 7.6, 2.1 Hz, 1H), 3.74 (ddd, J = 14.0, 14.0, 4.4 Hz, 1H), 3.53 (ddd, J = 16.3, 12.0, 4.4 Hz, 1H), 2.94 (dd, J = 15.3, 6.6 Hz, 1H), 2.79 (m, 1H), 2.73 (dd, J = 14.0, 5.3 Hz, 1H), 2.56 (dd, J = 17.6, 6.6 Hz, 1H), 2.29 (m, 1H), 2.25 (m, 1H), 2.11 (m, 1H), 2.09 (m, 1H), 1.92 (dd, J = 12.8, 12.8 Hz, 1H), 1.91 (d, J = 17.9 Hz, 3H), 1.69 (overlapped, 2H), 1.58 (m, 1H), 1.50 (m, 1H), 1.32 (ddd, J = 12.8, 2.3, 2.3 Hz, 1H), 0.88 (d, J = 6.9 Hz, 3H), 0.55 (ddd, J = 14.2, 12.4, 11.9 Hz, 1H); 13C{1H} NMR (150 MHz, CDCl3) δ 206.5, 141.3, 136.1, 85.0, 53.3, 46.6, 45.9, 43.1, 42.9, 40.4, 37.2, 30.4, 29.7, 27.2, 22.9, 22.2; IR max (ATR) cm-1 1722, 1644; HR-MS (ESI) calcd for C16H24NO2 [M+H]+ 262.1807, found 262.1793. Nosyl amine adduct S4. To a stirred solution of 3-epi-24 (89.9 mg, 0.118 mmol) in THF (11.8 mL) was 22 ACS Paragon Plus Environment

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added PPh3 (118 mg, 0.448 mmol), NsNH2 (71.8 mg, 0.354 mmol) and DEAD (0.14 mL, 0.354 mmol, 40% in toluene) at 0 °C under Ar atmosphere, and the reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched by adding cold water, and diluted with CHCl3. After separation of the two layers, the aqueous layer was extracted three times with CHCl3, dried over MgSO4, filtered, and evaporated under reduced pressure. The residue was purified by flash silica gel chromatography (AcOEt/CHCl3 = 5/95) to afford 94.7 mg (85%) of S4 as a white amorphous solid: []23D = –17.5 (c = 1.96, CHCl3); 1H NMR (400 MHz, CDCl3)  8.12 (m, 1H), 7.83 (m, 1H), 7.75–7.71 (overlapped, 2H), 7.68–7.64 (overlapped, 4H), 7.41–7.34 (overlapped, 6H), 5.54 (t, J = 5.7 Hz, 1H), 4.76 (t, J = 5.9 Hz, 1H), 4.56 (d, J = 7.3 Hz, 1H), 4.50–4.46 (overlapped, 2H), 4.32 (d, J = 7.3 Hz, 1H), 3.86–3.81 (overlapped, 2H), 3.46 (dd, J = 11.7, 3.9 Hz, 1H), 3.25 (s, 3H), 3.24 (s, 3H), 3.10–3.04 (overlapped, 2H), 2.76 (dd, J = 15.8, 6.2 Hz, 1H), 2.10–2.01 (overlapped, 3H), 1.91–1.51 (overlapped, 6H), 1.44–1.26 (overlapped, 2H), 1.05 (s, 9H), 1.05 (overlapped, 1H), 0.90 (d, J = 6.4 Hz, 3H), 0.90 (overlapped, 1H); 13C{1H}

NMR (100 MHz, CDCl3) δ 148.1, 146.8, 137.8, 135.5, 134.02, 133.97, 133.5, 133.4, 132.7,

131.1, 129.54, 129.50, 127.6, 125.3, 118.2 (q), 95.0, 94.7, 78.9, 77.2, 68.2, 61.2, 55.7, 55.6, 53.3, 44.1, 39.6, 38.0, 37.2, 36.9, 32.1, 28.9, 26.9, 24.6, 22.0, 19.3; IR max (ATR) cm-1 2953, 2932, 1544, 1418, 1212, 1145, 1035; HR-MS (ESI) calcd for C43H57F3N2O12S2SiNa [M+Na]+ 965.2972, found 965.2960. Intramolecular Mitsunobu reaction substrate S5. To a stirred solution of S4 (94.6 mg, 0.100 mmol) in MeOH (5.0 mL) was added CSA (28.0 mg, 0.120 mmol) at room temperature under Ar atmosphere, and the reaction mixture was stirred at the same temperature for 21.5 hours. The reaction was quenched by adding saturated aqueous NaHCO3, and diluted with CHCl3. After separation of the two layers, the aqueous layer was extracted three times with CHCl3, dried over MgSO4, filtered, and evaporated under reduced pressure. The residue was purified by SiO2-MPLC (AcOEt/n-hexane = 50/50) to afford 54.2 mg (62%) of S5 as a white amorphous solid: []23D = –32.1 (c = 1.00, CHCl3); 1H NMR (600 MHz, CDCl3)  8.14 (m, 1H), 7.86 (m, 1H), 7.78–7.73 (overlapped, 2H), 5.54 (t, J = 5.9 Hz, 1H), 4.82 (dd, J = 8.3, 4.1 Hz, 1H), 4.69 (d, J = 6.9 Hz, 1H), 4.55–4.51 (overlapped, 3H), 3.82 (m 1H), 3.75 (m, 1H), 3.49 (dd, J = 12.1, 3.8 Hz, 1H), 3.40 (s, 3H), 3.38 (s, 3H), 3.09 (m, 1H), 2.80 (dd, J = 15.8, 6.2 Hz, 1H), 2.46 (t, J = 23 ACS Paragon Plus Environment


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5.9 Hz, 1H), 2.10–2.03 (overlapped, 3H), 1.89–1.84 (overlapped, 3H), 1.75–1.64 (overlapped, 3H), 1.58 (m, 1H), 1.43 (td, dd, J = 13.4, 3.2 Hz, 1H), 1.32 (m, 1H), 1.03 (ddd, J = 12.4, 11.7, 11.7 Hz, 1H), 0.93 (overlapped, 1H), 0.90 (d, J = 6.2 Hz, 3H);

13C{1H}

NMR (150 MHz, CDCl3) δ 148.1, 147.0, 137.0,

133.6, 133.5, 132.7, 131.1, 125.4, 118.2 (q), 95.8, 94.6, 79.7, 70.3, 60.5, 55.94, 55.86, 53.2, 44.0, 39.7, 37.9, 37.4, 37.3, 36.5, 32.2, 28.9, 24.8, 21.0; IR max (ATR) cm-1 2949, 1542, 1417, 1209, 1143, 1032; HR-MS (ESI) calcd for C27H39F3N2O12S2Na [M+Na]+ 727.1794, found 727.1786. Tricyclic compound S6. To a stirred solution of S5 (8.3 mg, 11.8 mol) in Toluene (1.18 mL) was added PPh3 (11.7 mg, 44.8 mol) and DEAD (13.9 L, 35.4 mol, 40% in toluene) at 0 °C under Ar atmosphere, and the reaction mixture was stirred at room temperature for 3 hours. The reaction was quenched by adding cold water, and diluted with CHCl3. After separation of the two layers, the aqueous layer was extracted three times with CHCl3, dried over MgSO4, filtered, and evaporated under reduced pressure. The residue was purified by flash silica gel chromatography (Et2O/n-hexane = 60/40) to afford 6.3 mg (78%) of S6 as a white amorphous solid: []23D = –38.3 (c = 1.96, CHCl3); 1H NMR (600 MHz, CDCl3)  7.87 (m, 1H), 7.70–7.65 (overlapped, 2H), 7.58 (m, 1H), 4.72 (dd, J = 10.3, 3.4 Hz, 1H), 4.67 (d, J = 6.9 Hz, 1H), 4.66 (overlapped, 1H), 4.65 (d, J = 6.9 Hz, 1H), 4.55 (d, J = 6.2 Hz, 1H), 3.71 (m, 1H), 3.50 (m, 1H), 3.40 (s, 3H), 3.36 (s, 3H), 3.29 (m, 1H), 3.14 (m, 2H), 2.89 (dd, J = 16.2, 7.9 Hz, 1H), 2.66 (m, 1H), 2.30 (m, 1H), 2.23 (dd, J = 15.8, 3.4 Hz, 1H), 2.20–2.13 (overlapped, 2H), 1.99 (m, 1H), 1.94 (m, 1H), 1.80 (m, 1H), 1.69–1.65 (overlapped, 2H), 1.51 (m, 1H) 1.44 (m, 1H), 1.32 (m, 1H), 0.93 (d, J = 6.2 Hz, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 148.6, 148.1, 133.4, 131.7, 131.5, 131.3, 130.5, 123.9, 118.2 (q), 96.8, 94.7, 82.5, 70.8, 55.8, 55.7, 54.7, 49.6, 45.7, 40.0, 38.7, 38.2, 34.9, 33.7, 32.2, 26.9, 23.7, 22.9; IR max (ATR) cm-1 2930, 1547, 1416, 1374, 1219, 1142, 1040, 909, 736, 651; HR-MS (ESI) calcd for C27H37F3N2O11S2Na [M+Na]+ 709.1689, found 709.1672. Diol 3-epi-27. To a stirred solution of S6 (6.3 mg, 9.17 μmol) in MeOH (0.18 mL) was added 12N HCl aq. (44.4 μL) at room temperature under Ar atmosphere, and the reaction mixture was stirred at the same temperature for 1 hour. The reaction was quenched by adding saturated aqueous NaHCO3, and diluted with CHCl3. After separation of the two layers, the aqueous layer was extracted three times with CHCl3, 24 ACS Paragon Plus Environment

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dried over MgSO4, filtered, and evaporated under reduced pressure. The residue was purified by flash silica gel chromatography (AcOEt/CHCl3 = 0/100 to 50/50) to afford 3.3 mg (60%) of 3-epi-27 as a white solid. Then, the white solid of 3-epi-27 was recrystallized from AcOEt/n-hexane by the vapor diffusion method to afford 3-epi-27 as a white needles: []28D = +8.3 (c = 0.14, AcOEt); 1H NMR (600 MHz, CDCl3, 55 °C)  7.89 (m, 1H), 7.68–7.63 (overlapped, 2H), 7.57 (m, 1H), 4.78 (dd, J = 11.4, 3.1 Hz, 1H), 3.74 (dd, J = 8.6, 3.8 Hz, 1H), 3.50 (m, 1H), 3.43 (ddd, J = 13.1, 6.2, 2.8 Hz, 1H), 3.31–3.23 (overlapped, 2H), 3.18–3.13 (overlapped, 2H), 3.01 (dd, J = 16.2, 8.3 Hz, 1H), 2.55 (dddd, J = 12.1, 11.7, 11.7, 2.8 Hz, 1H), 2.37 (m, 1H), 2.18 (d, J = 16.2 Hz, 1H), 2.17–2.07 (overlapped, 3H), 1.90 (m, 1H), 1.83–1.76 (overlapped, 2H), 1.70 (m, 1H) 1.55 (m, 1H), 1.36 (dt, J = 13.8, 9.0 Hz, 1H), 1.26 (ddd, J = 13.1, 12.4, 11.7 Hz, 1H), 0.96 (d, J = 6.2 Hz, 3H); 13C{1H} NMR (150 MHz, CDCl3, 55 °C) δ 148.2, 133.5, 133.4, 132.0, 131.3, 130.7, 124.1, 76.3, 66.7, 55.3, 50.7, 47.9, 42.0, 39.4, 39.0, 38.4, 37.5, 36.0, 28.0, 27.8, 22.8; IR max (ATR) cm-1 3256, 2927, 2871, 1544, 1408, 1214, 1130, 1020; HR-MS (ESI) calcd for C23H29F3N2O9S2Na [M+Na]+ 621.1164, found 621.1201; m.p. 140.0-140.5 °C; CCDC deposit number CCDC-1895333. Diketone 8. To a stirred solution of 3-epi-27 (5.9 mg, 9.85 mol) in dioxane/MeOH (0.36 mL/0.18 mL) was added 1N NaOH aq. (0.54 mL) at 0 °C under Ar atmosphere, and the reaction mixture was stirred at the same temperature for 2.5 hours. The reaction was quenched by adding saturated aqueous NH4Cl at 0 °C, and diluted with AcOEt. After separation of the two layers, the aqueous layer was extracted three times with AcOEt, dried over MgSO4, filtered, and evaporated under reduced pressure to afford a crude product as a white solid, which was used in the next reaction without further purification. To a stirred solution of the crude product in CH2Cl2 (0.20 mL) was added DMP (5.0 mg, 11.8 μmol) at room temperature under Ar atmosphere, and the reaction mixture was stirred at the same temperature for 2 hours. The reaction was quenched by adding saturated aqueous Na2S2O3/saturated aqueous NaHCO3 (1:1) at 0 °C, and diluted with AcOEt. After separation of the two layers, the aqueous layer was extracted three times with AcOEt, dried over MgSO4, filtered, and evaporated under reduced pressure. The residue was purified by amino-silica gel preparative-TLC (AcOEt/n-hexane=5:5, 2 times) to afford 2.9 mg (66% 25 ACS Paragon Plus Environment


Page 26 of 30

in 2 steps) of 8 as a white amorphous solid. 30: []28D = +32.5 (c = 0.04, CHCl3); 1H NMR (600 MHz, CDCl3)  7.91 (m, 1H), 7.73–7.66 (overlapped, 2H), 7.62 (m, 1H), 6.75 (dd, J = 11.7, 6.9 Hz, 1H), 4.16 (m, 1H), 4.01 (dd, J = 13.1, 4.8 Hz, 1H), 3.46 (ddd, J = 15.1, 6.5, 2.1 Hz, 1H), 3.10 (ddd, J = 15.5, 11.7, 5.2 Hz, 1H), 3.03–2.91 (overlapped, 2H), 2.68 (dd, J = 18.9, 9.3 Hz, 1H), 2.55 (dt, J = 13.1, 6.2 Hz, 1H), 2.31–2.17 (overlapped, 4H), 2.08 (m, 1H), 1.92 (m, 1H), 1.85 (m, 1H), 1.74 (dd, J = 15.1, 6.9 Hz, 1H), 1.56–1.50 (overlapped, 2H), 1.47 (m, 1H), 1.35 (ddd, J = 15.1, 8.3, 2.1 Hz, 1H), 1.02 (d, J = 6.9 Hz, 3H); 13C{1H}

NMR (150 MHz, CDCl3) δ 207.0, 148.3, 144.0, 136.3, 133.6, 132.1, 131.5, 130.6, 124.2, 75.7,

49.8, 48.3, 48.0, 46.1, 36.4, 36.2, 35.9, 32.2, 29.5, 24.8, 24.2, 23.8; IR max (ATR) cm-1 3428, 2926, 1713, 1639, 1545, 1372, 1343, 1165, 746; HR-MS (ESI) calcd for C22H28N2O6SNa [M+Na]+ 471.1563, found 471.1517. 8: []25D = +11.2 (c = 0.12, CHCl3); 1H NMR (600 MHz, CDCl3)  7.90 (m, 1H), 7.70–7.64 (overlapped, 2H), 7.59 (m, 1H), 6.88 (dd, J = 12.1, 6.5 Hz, 1H), 3.56 (dt, J = 14.5, 4.0 Hz, 1H), 3.41 (ddd, J = 14.5, 11.7, 3.4 Hz, 1H), 3.24–3.16 (overlapped, 2H), 2.69 (dd, J = 17.9, 8.3 Hz, 1H), 2.62–2.49 (overlapped, 3H), 2.47–2.40 (overlapped, 2H), 2.26 (m, 1H), 2.20–2.12 (overlapped, 3H), 1.97 (m, 1H), 1.83 (dd, J = 15.1, 8.3 Hz, 1H), 1.72 (m, 1H), 1.07 (ddd, J = 13.8, 11.7, 11.7 Hz, 1H), 1.00 (d, J = 6.2 Hz, 3H);

13C{1H}

NMR (150 MHz, CDCl3) δ 211.7, 203.6, 148.3, 140.7, 138.6, 133.5, 132.4, 131.4,

130.8, 124.1, 59.5, 47.53, 47.48, 46.3, 44.0, 43.6, 39.1, 32.5, 32.4, 29.4, 25.7, 22.4; IR max (ATR) cm-1 2928, 1723, 1699, 1644, 1542, 1371, 1346, 1165; HR-MS (ESI) calcd for C22H26N2O6SNa [M+Na]+ 469.1409, found 469.1394. Synthesis of Lycopoclavamine-A (1) from 8. To a stirred solution of 8 (17.1 mg, 38.3 mol) in MeCN (1.90 mL) was added PhSH (15.9 L, 0.153 mmol) and K2CO3 (18.3 mg, 0.153 mmol) at room temperature under Ar atmosphere, and the reaction mixture was stirred at 60 °C for 1 hour. The reaction mixture was evaporated under reduced pressure. The residue was purified by flash amino-silica gel chromatography (CHCl3/n-hexane=30/70) to afford 7.6 mg (76%) of lycopoclavamine-A (1) as a white amorphous solid.

ASSOCIATED CONTENT 26 ACS Paragon Plus Environment

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Supporting Information The Supporting Information is available free of charge on the ACS Publications website at DOI:

Copies of 1H and

13C

NMR spectral data for 8, 10, 12-14, 16-18, 20, 22-30, 3-epi-24, 3-epi-27,

intermediates S1-S6, and synthetic and natural lycopoclavamine-A (1), and X-ray crystallographic data for 3-epi-27 (PDF) X-ray crystallographic data for 3-epi-27 (CIF) AUTHOR INFORMATION Corresponding Author *E-mail: [email protected] ORCID Hiromitsu Takayama: 0000-0003-3155-2214 Notes The authors declare no competing financial interest.

ACKNOWLEDGMENT This work was supported by JSPS KAKENHI Grant Numbers 16H05094 and 17H03993. REFERENCES (1) Katakawa, K.; Mito, H.; Kogure, N.; Kitajima, M.; Wongseripipatana, S.; Arisawa, M.; Takayama, H. Ten New Fawcettimine-related Alkaloids from Three Species of Lycopodium. Tetrahedron 2011, 67, 6561–6567. (2) Recent reviews on Lycopodium alkaloids: (a) Ayer, W. A.; Trifonov, L. S. Lycopodium Alkaloids. In The Alkaloids; Cordell, G. A., Brossi, A., Eds.; Academic Press: New York, 1994; Vol. 45, p. 233–266. (b) Ma, X.; Gang, D. R. The Lycopodium alkaloids. Nat. Prod. Rep. 2004, 21, 752–772. (c) Kobayashi, J.; Morita, H. The Lycopodium Alkaloids. In The Alkaloids; Cordell, G. A., Ed.; Academic Press: New York, 2005; Vol. 61, p. 1–57. (d) Hirasawa, Y.; Kobayashi, J.; Morita, H. The Lycopodium Alkaloids. 27 ACS Paragon Plus Environment


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Asymmetric Total Synthesis of Fawcettimine-Type Lycopodium

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