Diastereoselective Methylation at the Congested Î²-Position of

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Diastereoselective Methylation at the Congested #Position of a Butenolide Ring: Studies toward the Synthesis of seco-Prezizaane-Type Sesquiterpenes Tomoyoshi Kawamura, Hirokazu Moriya, Masatoshi Shibuya, and Yoshihiko Yamamoto J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02017 • Publication Date (Web): 06 Sep 2019 Downloaded from pubs.acs.org on September 6, 2019

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The Journal of Organic Chemistry

Diastereoselective Methylation at the Congested β-Position of a Butenolide

Ring:

Studies

toward

the

Synthesis

of

seco-Prezizaane-Type Sesquiterpenes Tomoyoshi Kawamura, Hirokazu Moriya, Masatoshi Shibuya*, Yoshihiko Yamamoto*

Department of Basic Medicinal Sciences, Graduate School of Pharmaceutical Sciences, Nagoya University, Furo-cho, Chikusa, Nagoya 464-8601, Japan

O

O O H

HO

O H

1. (CH3)2Si(Cl)CH2Cl OTBS O O

2. NaI 3. SmI2 silicon-tethered radical cyclization

O Si

O OTBS

1. H2O2, KHCO3

H

2. Barton-McCombie deoxygenation

O O

O H

OTBS H

HO H 3C

O O

ABSTRACT: We established a method for installing a methyl group at the β-position of a butenolide ring. The methylated position is located at the congested ring juncture of a 5,6,5-tricyclic lactone, which is common to neurotrophic seco-prezizaane-type sesquiterpenes. The samarium(Ⅱ)-mediated conjugate addition of the halomethylsilyl ethers tethered to the proximal hydroxy groups efficiently formed the desired C-C bond. Subsequent fluoride-free Tamao oxidation and Barton–McCombie deoxygenation converted the resultant cyclic silyl ether into the corresponding methyl group.

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INTRODUCTION Therapeutic advances for neurodegenerative diseases that include Alzheimer’s and Parkinson’s diseases are strongly desired. Several sesquiterpenoids isolated from Illicium species were reported to have potent neurotrophic activities in primary cultured cortical neurons (Figure 1).1 The biological activities of these compounds suggest that they have high potential value. In addition, this class of compound has a unique structural feature, namely a highly oxygenated fused tetra- or pentacyclic structure with several continuous stereocenters. These distinguishing biological activities and structures have attracted the interests of synthetic chemists and several fascinating total syntheses of the sesquiterpenoids 1-4 have been reported.2-6 In addition, the groups of Danishefsky and Theodorakis examined the neurotrophic activities of the synthetic analogs of seco-prezizaane-type sesquiterpenes and found several analogs that are more potent than the original natural products.7-8 These results motivated us to develop a flexible synthetic route to obtaining seco-prezizaane-type sesquiterpenes, which facilitates the preparation of diverse synthetic analogs. We aimed to develop synthetic routes to jiadifenin (1) and jiadifenolide (2) via the transition-metal-catalyzed [2 + 2 + 2] cyclization of an enediyne (Scheme 1). We previously reported a strategy for the construction of a 5,6,5-tricyclic lactone scaffold from the corresponding enediyne via the ruthenium-catalyzed [2 + 2 + 2] cyclization.9 Although the ether-tethered enediynes (X = O) were employed as the model compounds in the previous studies, we found that methylene-tethered enediynes (X = CH2) also efficiently underwent the ruthenium-catalyzed [2 + 2 + 2] cyclization to afford the corresponding 5,6,5-tricyclic lactones as shown in this manuscript. The resultant 5,6,5-tricyclic lactones with a carbocyclic five-membered ring corresponds to the ABC ring of 1 and 2. The cyclizations of diverse enediynes, in which the alkene and two alkynes are tethered


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HO O

A

CO2CH3 O B

OH O C O jiadifenin (1)

O OH O

E D

O

B

OH O C O jiadifenolide (2) A

O

HO

H O

HO O

O

O

merrilactone A (3)

OH O

O

HO 11-O-debenzoyltashironin (4)

Figure 1. Neurotrophic sesquiterpenoids isolated from Illicium species by different moieties, should readily lead to the preparation of diverse tricyclic compounds, and enable the syntheses of their diverse analogs. On the other hand, this strategy requires the methylation of the C5 position of the resultant 5,6,5-tricyclic compounds. The C5 position is a congested BC ring juncture and located next to the C4 tetrasubstituted carbon. In addition, the butenolide ring is readily γ-deprotonated to form an aromatic furan oxide. Therefore, considerable difficulties were anticipated. In fact, no desired product 6 was obtained when we attempted the conjugated addition of dimethyl cuprate to butenolide 5 in initial studies (Scheme 1, also see Schemes S1-S4); instead the anticipated deprotonation at the proximal carbon and the undesired methylation at the C7 position occurred to produce 7 and 8. Methylation using Al(CH3)3, in the expectation that the adjacent C4 hydroxy group would act as a directing group, did not proceed10 and even the attempted conjugate addition of thiophenol failed.



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Scheme 1. Synthetic Plan and Initial Attempts to Methylate the C5 Position R

R

O 1) [2+2+2] X

X

4

1

5

2) O2 HO 3) [H] H congested ring juncture O

(X = CH2)

R

OR

methylation

O

OR

X

H O

HO H 3C

O

O

acidic proton

1 and 2

O

O O H

O H

conditions OAc

O

O O H

OAc +

CH3

O H

+

7

4

5

HO

O O

5

O

HO H 3C 6

conditions CuI, CH3Li, TMSCl CuBr • S(CH3)2, CH3MgI Al(CH3)3 PhSH, CsCO3

O

O

HO

O 7

0%

ca.40%

0%

0%

O

HO

O 8

0% trace

no reaction complex mixture

Gademann’s group also reported similar efforts to install such a methyl group.11 They attempted a conjugate cuprate addition as well as Corey–Chaykovsky cyclopropanation reactions12 and reported that their attempts to methylate the tricyclic lactone were unsuccessful. Therefore, they temporarily opened the A ring in order to install a methyl group at the C5 position. These studies suggest that methylation at the C5 position following the construction of the tricyclic structure is very challenging. However, if a method for installing the methyl group can be developed, it would serve as a powerful tool for the synthesis of these sesquiterpenes. In addition, as it would enable the installation of the C5 methyl group at a relatively later stage of the synthesis, this approach would also


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be effective for the preparation of the C5–modified synthetic analogs. Hence, we sought to realize this challenging methylation method. Herein, we report a methylation procedure based on a silicon-tethered cyclization strategy. The effectiveness of the samarium(Ⅱ)-mediated conjugate addition of a halomethylsilyl ether for the C-C bond formation at the congested β-position of a butanolide is demonstrated.13 RESULTS AND DISCUSSION We initially examined the diastereoselective β-methylation of the butenolide ring using readily available 9 as a model compound. It can be synthesized by the ruthenium-catalyzed [2 + 2 + 2] cyclization, Diels–Alder reaction with singlet oxygen, and reduction sequence9 from the corresponding enediyne that is readily prepared from 2-methallyl alcohol in the following six steps: Johnson–Claisen rearrangement, LiAlH4 reduction, tosylation, iodination, the SN2 reaction with dilithium salts of propargyl alcohol, and the condensation with propiolic acid (Scheme S5). At the outset, the methylation of 9 by conjugate addition was further examined under a variety of conditions. However, no positive results were obtained. We then attempted the 1,3-rearrangement of the allylic alcohol 9 using Re2O7 for a subsequent SN1-type methylation; this reaction afforded dienol 10 in 87% yield instead of 11. (Scheme 2).14 Hence, we examined the methylation of dienol 10 through a [2,3]- or [3,3]-sigmatropic rearrangement. Although the [2,3]-Wittig rearrangement and Ireland– and Johnson–Claisen rearrangements failed, the Eschenmoser–Claisen rearrangement proceeded efficiently to afford the C5 acetamide 12 in 82% yield. Subsequent chemoselective hydrolysis of the amide moiety in the presence of the lactone afforded 13 through an iodolactonization reaction. After the condensation of 13 and N-hydroxyphthalimide, Barton decarboxylation provided a byproduct suggesting the interconversion of the homoallyl radical intermediate to the corresponding



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cyclopropylcarbinyl radical together with several unidentified byproducts.15,16 The reduction of Weinreb amide 14 followed by deformylation to prepare 15 was also examined. Although the reduction of 14 afforded the corresponding aldehyde, the subsequent deformylation using (PPh3)3RhCl resulted in no reaction.

Scheme 2. Attempts to Methylate C5 Using Eschenmoser–Claisen Rearrangement OH 4 5

HO 9

OH

3 mol % Re2O7

O O

CH2Cl2 rt, 4 h

O O 10 (87%)

CH3C(OCH3)2N(CH3)2 toluene reflux 2 h, 82%

HO HO O 11 (not detected)

O

1) I2, THF/H2O 0 °C, 2 h, 59% 2) 5% aq NaOH 0 °C, 10 min, 94%

O CON(CH3)2 12

tBu L1 = N 1) CDI, CH2Cl2 rt,1 h 2) CH3NHOCH3·HCl rt, 88% (2 steps)

O

N

O

O

O CO2H 13 1. NHPI CDI tBu 2. NiCl2, L1, PhSiH3, Zn

1) DIBALH, THF O 14

O

O CON(CH3)OCH3

2) (Ph3P)3RhCl

O 15

O O

We next examined the installation of the methyl group through silicon-tethered cyclization (Scheme 3).17 Because the introduction of the bromomethylsilyl group onto the C4 tertiary hydroxy group did not proceed efficiently (vide infra), bromomethylsilyl ether 16 was initially prepared and subjected to the radical cyclization involving nBu3SnH and AIBN.18 Unfortunately, undesired cyclization was promoted to afford the five-membered silyl ether 17 in 28% yield.


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Scheme 3. Preparation of Bromomethylsilyl Ether 16 and its Radical Cyclization OH O

HO 9

O Si

(CH3)2Si(Cl)CH2Br imidazole, rt, 76%

O

CH2Br O

HO

O

O

HO

H O 17 (28%)

HO

benzene reflux, 5 h

O

16

Si

AIBN, nBu3SnH

O H Si O

O 18 (not detected)

The result suggests that the halomethylsilylation of the hindered C4 tertiary hydroxy group was necessary for the desired cyclization. After preparing TBS ether 19 from 9, we initially examined the introduction of the bromomethylsilyl group (Scheme 4). Due to steric hindrance, a high temperature was required, which resulted in chlorination to afford a mixture of bromomethylsilyl ether 20 and chloromethylsilyl ether 21 in moderate yields. After considerable investigation, we found that the chloromethylsilylation of 19 followed by Finkelstein iodination with NaI efficiently proceeded to afford iodomethylsilyl ether 22 in high yield.19 Scheme 4. Preparation of the Halomethylsilyl Ethers OTBS

OR (CH3)2Si(Cl)CH2Br

4 5

HO

O O

R = H, 9 R = TBS, 19

imidazole, 60 °C TBSCl imidazole, rt

HO 19

O O

O

O Si

O CH2Cl 21 (10%)

OTBS (CH3)2Si(Cl)CH2Cl

5

+

O CH2Br 20 (38%)

OTBS 4

O

O Si

OTBS

imidazole, 60 °C

O Si

O O CH2Cl 21

OTBS NaI acetone 60 °C, 10 h


O Si

O

O CH2I 22 72% (3 steps from 9)


Page 8 of 47

The cyclization of 22 was then examined (Table 1). The reaction using nBu3SnH and AIBN afforded a mixture of the cyclized product 23 and uncyclized TMS ether 24 in moderate yields (entry 1). Increasing the amount of nBu SnH, 3

adding Lewis acid,20 or diluting the reaction mixture did not lead to an improvement in the yield of 23

(entries 2-4). When V-40, which decomposes at a higher temperature, was used as the radical initiator in refluxing toluene, the desired product 23 was obtained in slightly better yield (entry 5). However, the use of VAm-110, which decomposed at an even higher temperature, resulted in a lower yield of the desired product 23 (entry 6), and the formation of the undesired TMS ether 24 could not be suppressed. Further attempts to optimize the reaction using a radical initiator and a hydrogen donor did not improve the yield of 23 or suppress the formation of the undesired TMS ether 24. Eventually, we found that samarium(Ⅱ)-mediated conjugate addition effectively promoted the required cyclization to afford the desired product 23 in high yield (89%) without the formation of the TMS ether 24 (entry 7).21,22 The samarium (II)-mediated conjugate addition in the absence of HMPA or in the presence of DMPU required higher temperature than that in the presence of HMPA and afforded 23 in slightly lower yields (entries 8 and 9).


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Table 1. Cyclization of Iodomethylsilyl Ether 22

OTBS O Si

O

1

H

conditions O Si

O CH2I 22

entry

OTBS

OTBS O

O

+

O Si

23

conditions

AIBN (10 mol %), nBu3SnH (1.5 equiv)

solvent

O O CH3 24

t (°C)

yield (%) 23

24

80

41

23

80

33

50

80

18

11

80

34

40

111

45

33

139

33

31

THF

–78

89

0

benzene (10 mM)

2


benzene (10 mM)

3

4

AIBN (10 mol %), nBu3SnH (5.0 equiv), Et2AlCl

benzene

(2.0 equiv)

(10 mM)


benzene (2 mM)

5

V-40 (10 mol %), nBu3SnH (1.5 equiv)

toluene (0.01 M)

6

VAm-110 (10 mol %), nBu3SnH (1.5 equiv)

p-xylene (0.01 M)

7

SmI2 (4 equiv), CH3OH (10 equiv), HMPA (20 equiv)

8

SmI2 (4 equiv), CH3OH (10 equiv)

THF

–78 to 0

75

0

9

SmI2 (4 equiv), CH3OH (10 equiv), DMPU (20

THF

–78 to 0

82

0

equiv)



Page 10 of 47

Since chloromethylsilylation following the benzoylation of 9 in the presence of 10 equiv of triethylamine provided diene 26 with the elimination of PhCO2H, we also examined the ionic cyclization of 26 (Scheme 5). Methanolysis of 26 generated the corresponding enolate and promoted the desired cyclization to afford cyclic silyl ether 27 in 61% yield. However, the reconstruction of the lactone ring through the reduction of aldehyde 27 was unsuccessful. Scheme 5 Preparation of Chloromethylsilyl Ether 26 and its Ionic Cyclization OH 4

HO

OBz BzCl

5

O O

py, 91%

O

HO

9

O

(CH3)2Si(Cl)CH2Cl, Et3N (10 equiv) O Si

rt, 14 h, 52%

25

CH3OH (25 equiv) 15% NaOH, THF rt, 1 h, 61%

O Si

CO2CH3 CHO 27

O O CH2Cl 26

O

O Si

O 28

We next examined the transformation of the cyclic silyl ether 23 to the corresponding methylated tricyclic lactone (Scheme 6). Although the treatment of 23 with TBAF in THF did not promote scission of the silyl ether ring, treatment with an excess amount of TBAF in DMF furnished hydroxy acid 29 in low yield (

Diastereoselective Methylation at the Congested Î²-Position of

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