Divergent Synthesis of Marine Natural Products ... - ACS Publications

Subscriber access provided by Kaohsiung Medical University

Note

Divergent Synthesis of Marine Natural Products Siphonodictyal B, Corallidictyals C/D and Liphagal Based on the Early Presence of an Aldehyde Group Instead of a Late-Stage Introduction Jun-Li Wang, Hui-Jing Li, and Yan-Chao Wu J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00989 • Publication Date (Web): 05 Jun 2018 Downloaded from http://pubs.acs.org on June 5, 2018

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

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

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

The Journal of Organic Chemistry

Divergent Synthesis of Marine Natural Products Siphonodictyal B, Corallidictyals C/D and Liphagal Based on the Early Presence of an Aldehyde Group Instead of a Late-Stage Introduction Jun-Li Wang,† Hui-Jing Li,† and Yan-Chao Wu*,†,‡ †

School of Marine Science and Technology, Harbin Institute of Technology, Weihai 264209, China.

‡

Beijing National Laboratory for Molecular Sciences, ICCAS, Beijing 100190, China.

CHO

CHO

NNHTs

i-PrO

i-PrO

Oi-Pr

Oi-Pr Oi-Pr

i-PrO H

+

Oi-Pr

I

Pd(PPh3)4 (cat.)

I2, sunlight

K2CO3, xylene, 120 °C, 10 h, 86% Oi-Pr

hexane/Et2O (2:1) rt, 2 h, 99%

H

Z/E = 53:47 siphonodictyal B corallidictyals C/D liphagal

CHO Oi-Pr

H

E/Z > 99:1

1 or 2 steps

ABSTRACT An iodine-promoted sunlight-induced olefin Z/E isomerization reaction together with a palladium-catalyzed direct cross-coupling reaction of a drimanal hydrazone and an iodobenzaldehyde, without touching the aromatic aldehyde group, facilitated a divergent and expeditious access to bioactive marine natural products siphonodictyal B, corallidictyals C/D and liphagal based on the early presence of an aldehyde group instead of a late-stage introduction.

The aldehyde group is presented in numerous natural products. In recent decades, aldehyde-containing marine natural products have attracted increasing attention due to their special chemical structures and intriguing biological activities.1 Antimicrobial natural product siphonodictyal B (1, Figure 1) was isolated from the marine sponge Aka coralliphaga (also known as Siphonodictyon coralliphagum).2 Marine natural product liphagal (2), isolated by Andersen in 2006 from Aka coralliphaga,3 exhibits the special “liphagane” carbon skeleton. Liphagal (2) has significant therapeutic potential in the treatment of autoimmune disorders, cancer, and cardiovascular diseases through selectively attenuating human phosphoinositide-3-kinase α (PI3Kα) signaling.3,4 Corallidictyal C (3) and corallidictyal D (4), two marine spirosesquiterpene products isolated from Aka coralliphaga, are potential protein kinase C inhibitors.5 HO

OH

CHO HO

OH

HO

H

OH

CHO

OH

1: siphonodictyal B

HO OH

CHO O

H

2: liphagal

CHO

O

H

3: corallidictyal C

O

H

4: corallidictyal D

Figure 1. Marine natural products 1–4. The importance of these marine natural products has served to stimulate the continual interest within the synthetic community.3,6-12 The pioneering work on the synthesis of natural product liphagal (2) was completed by Andersen, who introduced the aromatic aldehyde

ACS Paragon Plus Environment

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

Page 2 of 14

functionality by treatment of the brominated liphagane precursor 5 (X = Br) with n-butyl lithium in THF and subsequent reaction with DMF (Scheme 1a).3,6b George7a and Alvarez-Manzaneda7b independently reported an alternative total synthesis of liphagal (2) in 2010, in which the aromatic aldehyde group was installed by direct lithiation of the liphagane precursor 5 (X = H) with n-butyl lithium in the presence of TMEDA followed by quenching with DMF (Scheme 1a). Afterwards, Stoltz,7c Katoh7d and Ferreira7e reported elegant total syntheses of liphagal (2) respectively by direct introducing the aromatic aldehyde group to the liphagane precursor 5 (X = H) followed by 1–2 conventional steps (Scheme 1a). Chahboun and Alvarez-Manzaneda reported the first total synthesis of corallidictyal D (4) by installing spirodihydrobenzofuran 7 (X = H) with an aldehyde group followed by two conventional steps (Scheme 1b).8 Dethe introduced the aromatic aldehyde functionality of corallidictyal D (4) by the oxidation of benzyl alcohol 5 (X = CH2OH) with IBX in acetonitrile (Scheme 1b ).9 Recently, George10a and Katoh10c reported impressive total syntheses of siphonodictyal B (1) by introducing the aromatic aldehyde group to the siphonodictyal B precursor 9 followed by removal of the alkyl ether protecting groups (Scheme 1c). Siphonodictyal B (1) could be in turn converted to liphagal (2) 10a and corallidictyals C/D (3 and 4) 10b, respectively in one step (Scheme 1c). The aromatic aldehyde moieties of these natural products were all introduced only after the constructions of their molecular skeletons were completed. The ability to break this conception would make the natural product syntheses more convergent. However, the goal may be difficult to achieve as the aromatic aldehyde group is a quite reactive functional group. Herein, we wish to report a direct cross-coupling reaction of drimanal hydrazone 11 and iodobenzaldehyde 12, which facilitated an expeditious synthesis of siphonodictyal B, corallidictyals C/D and liphagal (Scheme 1d). a) Andersen3, 6b and Mehta's6a work (X = Br); George,7a AlvarezManzaneda,7b Stoltz,7c Katoh7d and Ferreira's7e work (X = H): OR

RO

OR

RO

X

CHO O

O 1) n-BuLi, THF

1-2 steps

liphagal (2)

2) DMF H

H

5

6

b) Alvarez-Manzaneda's8 work (X = H); Dethe's9 work (X = CH2OH): RO

X O

H

7

RO

OR

OR CHO

1) n-BuLi, THF 2) DMF (X = H)

O

or 3) IBX, CH3CN (X = CH2OH)

H

2 steps

corallidictyal D (4)

8

c) George10a, 10b and Katoh's10c work: CHO RO

OR

RO

OR

OR n-BuLi, THF then DMF H

siphonodictyal B (1) liphagal (2) 1-2 steps corallidictyals C/D (3,4)

OR

9

H

10

d) This work: NNHTs

CHO RO

+ H

11

I

12

1) Pd(PPh3)4, OR K CO , xylene 2 3 OR

2) I2, sunlight

10

siphonodictyal B (1) liphagal (2) corallidictyals C/D (3,4)

Scheme 1. Syntheses of marine natural products 1–4.

Our retrosynthesis of marine natural products 1–4 is outlined in Scheme 2. Liphagal (2), corallidictyal C (3) and corallidictyal D (4) were thought to be synthesized from siphonodictyal B (1), which could be prepared from sesquiterpene aldehyde 10 by removal of the alkyl


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


ether protecting groups. Intermediate 10 was planned to be assembled by the cross-coupling reaction between drimanal hydrazone 11 and iodobenzaldehyde 12. Compounds 11 and 12 were thought to be prepared from sclareolide (13) and 3,4-dihydroxybenzaldehyde (14), respectively (Scheme 2). CHO HO

OH OH

liphagal (2) corallidictyal C (3) corallidictyal D (4)

tandem reaction

OR deprotection reaction

H

siphonodictyal B (1) RO

OR

O

OR H cross-coupling reaction H

O

NNHTs

CHO

10

+

11

H

13

CHO RO

OHC

OR

I

OH OH

OR

12

14

Scheme 2. Retrosynthetic analysis.

Synthesis of drimanal hydrazone 11 is depicted in Scheme 3. The commercially available sclareolide (13) was converted to enol 16 in four conventional steps with 80% overall yield.13 Ozonolysis of 16 followed by quenching with NaBH4 afforded 1,2-decalindiol 17 in 98% yield. Rearrangement of 17 in the presence of BF3•Et2O provided drimanal 18 in 90% yield.11h Wittig-Horner reaction14 of 18 with Ph2P(O)CH2OCH3 gave allyl ether 19 in 75% yield, which underwent a hydrolysis with aqueous hydrochloric acid to give drimanal aldehydes 20a and 20b in 18% and 72% yields, respectively. Condensation of 20b with p-toluenesulfonyl hydrazide afforded drimanal hydrazone 11 in 95% yield (Scheme 3). O

I

O

OCHO

2 steps, 83% ref 13c,e

H

ref 13a,b,d

OH O3, CH2Cl2, -78 oC, 20 min then NaBH4, rt, 1 h, 98%

OH

O

BF3•Et2O (2.0 equiv) CH2Cl2, rt, 0.5 h 90%

H 17

aq 2 M HCl

H 18

n-BuLi, -78 oC to rt, THF, 1 h, 75% NNHTs

p-TsNH2NH2

+

rt, 10 min

O Ph2PCH2OMe

O

O

OMe

19

H 16

H 15

13

H

OH

2 steps, 96%

H

H

20a (18%)

20b (72%)

MeOH, rt, 5 h 95%

H

11

Scheme 3. Synthesis of drimanal hydrazone 11.

Synthesis of iodobenzaldehyde 12a is shown in Scheme 4. Treatment of a DMF solution of 3,4-dihydroxybenzaldehyde (14) with 2-iodopropane and K2CO3 afforded ether 21 in 89% yield.15 Oxidation of aldehyde 21 with 30% H2O2 in the presence of sulfuric acid at room temperature, and the concurrent transesterification reaction of the in situ generated ester with methanol were achieved in one pot to give phenol 22 in 85% yield.15 O-isopropylation of phenol 22 in the presence of tetrabutylammonium iodide (TBAI) furnished aromatic ether 23 in 70% yield. Lithiation of 23 with n-butyl lithium followed by quenching with DMF gave benzaldehyde 24, which underwent a Bi(OTf)3-catalyzed electrophilic aromatic iodination to afford iodobenzaldehyde 12a in 78% yield (Scheme 4).



OH

Oi-Pr OH

Oi-Pr Oi-Pr

i-PrI, K2CO3, DMF 70 oC, 12 h, 89%

CHO

Page 4 of 14

Oi-Pr

30% H2O2, H2SO4 MeOH, rt, 7 h, 85%

CHO

14

OH

21

Oi-Pr Oi-Pr

i-PrI, TBAI, K2CO3, DMF o

Oi-Pr

n-BuLi, THF, 0 oC, 1 h then DMF, 10 min, 80%

78 C, 12 h, 70% Oi-Pr

22

Oi-Pr

CHO Oi-Pr 24

23

Oi-Pr Oi-Pr

NIS, Bi(OTf)3, MeCN rt, overnight, 78%

I

CHO Oi-Pr

12a

Scheme 4. Synthesis of iodobenzaldehyde 12a.

Synthesis of siphonodictyal B (1) and liphagal (2) is shown in Scheme 5. The facile reaction of N-tosylhydrazones with aromatic aldehydes,16a−f ketones16g and esters16h is well known, which was even used for the synthesis of 8-epipuupehedione,16d a natural product stereoisomer with a molecular structure similar to that of siphonodictyal B (1). Thus, how to suppress the competitive reaction of a

N-tosylhydrazone with the benzaldehyde moiety of an iodobenzaldehyde becomes a high priority for the highly selective cross-coupling reaction of the N-tosylhydrazone with the iodobenzene moiety of the iodobenzaldehyde. To the best of our knowledge, the cross-coupling reaction of drimanal hydrazones and iodobenzaldehyde derivatives with an intact preservation of aromatic aldehyde moieties is still a challenge to date. This demanding task was carried out by us due to its synthetic importance as well as our curiosity about it.17 The direct cross-coupling reaction of drimanal hydrazone 11 and iodobenzaldehyde 12a, without touching the benzaldehyde moiety, has been accomplished. Indeed, the treatment of 11 and 12a in the presence of Pd(PPh3)4 (10 mol%) and K2CO3 in xylene at 120 °C for 10 h afforded vinyl benzaldehydes (ZE)-10a (Z/E = 53:47) in 86% yield.18 The isopropyl ether protecting groups were used to shield the benzaldehyde moiety of iodobenzaldehyde 12a from the attack of drimanal hydrazone 11. Decreasing yields were observed with primary alkyl ether protecting groups in comparison to secondary alkyl ether protecting groups, indicating that the steric factor of the ether affects the selective cross-coupling reaction. For example, when methyl ether protecting groups were used instead of isopropyl ether protecting groups, the reaction became relatively complex and the yield of the cross-coupling product was decreased down to 72% yield (Z/E = 55:45). CHO i-PrO NNHTs

Oi-Pr Pd(PPh ) (10 mol %) i-PrO 3 4

+ I

H

CHO Oi-Pr 12a

11

K2CO3, xylene, 120 °C 10 h, 86% H (ZE)-10a

CHO i-PrO

CHO i-PrO

Oi-Pr

I2, sunlight hexane/Et2O (2:1) rt, 2 h, 99%

Oi-Pr

i-PrO I

I

H 26

H 25

OH

CHO Oi-Pr

HO

CHO

OH

BCl3 CH2Cl2, 0 oC 3 h, 76%

HO

OH

Oi-Pr

H (E)-10a

Oi-Pr

isomerization

CHO i-PrO

Oi-Pr

Oi-Pr

O

1 step H

1

42% ref 10a

H

2

Scheme 5. Synthesis of siphonodictyal B (1) and liphagal (2).


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


The conversion of alkene (Z)-10a to alkene (E)-10a was next investigated, and the representative results are summarized in the Table 1. Irradiation of alkenes (ZE)-10a (Z/E = 53:47) under direct sunlight in a co-solvent of hexane/Et2O (v/v, 2:1) at room temperature for 6 hours afforded alkenes (ZE)-10a (Z/E = 49:51) in 99% yield, in which only small part of alkene (Z)-10a was converted to the thermodynamically more stable alkene (E)-10a (entry 1). With the addition of benzanthrone or (diacetoxyiodo)benzene (PIDA) to the reaction system under similar reaction conditions, no obviously better results were obtained (entries 1−3). In contrast, when iodine (I2) was used as a promoter, nearly all the alkene (Z/E)-10a was converted to the alkene (E)-10a within a shorter reaction time (entries 1 and 4). The photoisomerization reaction of (Z)-10a to (E)-10a with a 150 W mercury lamp or a 200 W flood lamp was not as effective as that with direct sunlight (entries 4−6). The olefin Z/E isomerization reaction did not take place at all in the dark (entry 7). Sunlight has a broad spectrum, which might be essential for providing the required light wavelength for this transformation. A sunlight intensity of no less than 300 Lux was found to be enough for the smooth photoisomerization reaction. Thus, sunlight might have been already used consciously or unconsciously for the iodine-promoted olefin Z/E isomerization. 19 Further parameter optimization identified the co-solvent of hexane/Et2O (v/v, 2:1) as the most effective reaction media (entries 4 and 8−13).

Table 1. Survey of Conditions for the Z/E Isomerization of Olefin 10a a CHO i-PrO

CHO Oi-Pr

i-PrO

CHO i-PrO

Oi-Pr

i-PrO

H

H

i-PrO conditions

Oi-Pr

δH 6.18

δH 5.86

Oi-Pr

+

H

H

(ZE)-10a (Z/E = 53:47)

H

(Z)-10a

(E)-10a

entry

promoter

light

solvent

time

Z/E b

1 2 3 4 5 6 7 8 9 10 11 12 13

-benzanthrone PIDA I2 I2 I2 I2 I2 I2 I2 I2 I2 I2

sunlight sunlight sunlight sunlight Hg lampc flood lampd -sunlight sunlight sunlight sunlight sunlight sunlight

hexane/Et2O (2:1) hexane/Et2O (2:1) hexane/Et2O (2:1) hexane/Et2O (2:1) hexane/Et2O (2:1) hexane/Et2O (2:1) hexane/Et2O (2:1) benzene hexane THF Et2O hexane/Et2O (1:1) hexane/Et2O (3:1)

6h 6h 6h 2h 6h 6h 6h 2h 2h 2h 2h 2h 2h

49:51 46:54 47:53 1:99 25:72 45:55 53:47 47:53 24:76 35:65 23:77 6:94 3:97

a

General conditions: (ZE)-10a (1.0 equiv., Z/E = 53/47) and promoter (2.0 equiv.) in solvent (c = 0.04 M) at room temperature for 2 or 6

hours, all yields were nearly 99%. bThe ratio of Z/E was detected by 1H NMR spectrum. c150 W. d200 W. According to the literature,19 a possible reaction mechanism is illustrated in Scheme 5. Iodine radical is easily formed from I2 under direct sunlight. Attachment of an iodine radical to (ZE)-10a generated radical 25, which underwent an internal rotation to provide a relatively less sterically hindered radical 26. Detachment of the iodine radical from 26 afforded (E)-10a. As the olefin Z/E isomerization reaction did not take place in the dark (Table 1, entry 7), herein the potential reaction mechanism involved the formation of an iodonium ion was not proposed. Removal of the isopropyl ether protecting groups of (E)-10a in the presence of BCl3 provided siphonodictyal B (1) in 76% yield. Following George’s procedure,10a treatment of siphonodictyal B (1) with m-CPBA at 0 °C and subsequent reaction with TFA afforded liphagal (2) in 42% yield (Scheme 5). The spectroscopic and spectrometric data (1H NMR,


13

C NMR, [α]D and HRMS) of the


Page 6 of 14

synthetic molecules are identical to those of natural siphonodictyal B and liphagal.2,3,6,7,10 As shown in Scheme 6, the treatment of siphonodictyal B (1) with NIS and PPh3 in DCM under the Chahboun and Alvarez-Manzaneda oxacyclization conditions8 afforded the marine natural products corallidictyal C (3) and corallidictyal D (4) as an inseparable mixture of diastereomers in a ratio of 1:1.2, similar to the 1:1.5 ratio of corallidictyal C (3) to corallidictyal D (4) found in nature.5 As mentioned by Chahboun and Alvarez-Manzaneda,8 the above oxacyclization reaction took place through an intermediate carbocation 26 that was formed from the tandem reaction of NIS, PPh3, one phenolic hydroxyl group, and the C9-C15 double bond of siphonodictyal B (1, Scheme 6), in which the phenolic hydroxyl group acted as a nucleophile and a proton donor simultaneously. Activated by the phosphoniun ion +PPh3I, the phenolic hydroxyl group transferred the proton to the C15 and thus the O-nucleophilic attacks at the C9 position took place from either the α-face or the β-face produced the intermediate carbocation 28, which formed corallidictyal D (4) and corallidictyal C (3), respectively (Scheme 6). I + Ph3P δ

CHO HO

OH

CHO

δ+ O H

OH

OH OH

H

IPPh3

1

27

O H

NIS, PPh3 DCM, rt 76%

NIS + PPh3

N O

HO

HO

HO OH CHO

CHO

O

H

CHO

O

H

3

OH

OH

4

O PPh 3 I N

O

H

28

O

Scheme 6. Synthesis of corallidictyals C/D (3 and 4). In summary, we described a palladium-catalyzed direct cross-coupling reaction of an iodobenzaldehyde and a drimanal hydrazine, without touching the aromatic aldehyde group, and an iodine-promoted sunlight-induced Z/E isomerization reaction of a sesquiterpene alkene, which are employed to a convergent and concise synthesis of marine natural products siphonodictyal B, corallidictyals C/D and liphagal from readily available and inexpensive starting materials. For the first time the aromatic aldehyde moieties of these marine natural products were introduced before the constructions of their molecular skeletons, which could make the natural product synthesis more convergent. Our work indicated that the concept of introducing an aromatic aldehyde group only at the late stage of the natural product synthesis might be changeable.

Experimental General experimental methods. Common reagents and materials were purchased from commercial sources and were used without further purification. All experiments were carried out under an argon atmosphere in flame-dried glassware using standard inert techniques for introducing reagents and solvents unless otherwise noted. TLC plates were visualized by exposure to ultra violet light (UV). IR spectra were recorded by using an Electrothemal Nicolet 380 spectrometer. High-resolution mass spectra (HRMS) were recorded by using an Electrothemal LTQ-Orbitrap mass spectrometer. Melting points were measured by using a Gongyi X-5 microscopy digital melting point apparatus and are uncorrected. 1H NMR and

13

C NMR spectra were obtained by using a Bruker Avance III 400

MHz NMR spectrometer.


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


Compound 15. To a solution of (+)-sclareolide (13, 1.2 g, 4.8 mmol) in 40 mL of CH2Cl2 at −78 °C was added DIBAL-H (1.5 M in toluene, 3.9 mL, 5.8 mmol) dropwise over 10 min by syringe along the wall of the flask. The resulting mixture was stirred at −78 °C for 1 h, added slowly with a solution of aqueous hydrochloric acid (2 M, 50 mL), warmed up to room temperature, and extracted with CH2Cl2 (3 × 50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford lactol (1.17 g, 97%) as a white solid that was used immediately in the next step.13c A solution of lactol (1.2 g, 4.8 mmol) in 50 mL of benzene was treated with PIDA (2.2 g, 6.7 mmol, 1.4 equiv) and I2 (1.7 g, 5.8 mmol). The purple reaction mixture was stirred at 70 °C with simultaneous irradiation using a 150-watt flood lamp for 1 h. The reaction mixture was cooled down to room temperature, diluted with water, and extracted with EtOAc (3 × 30 mL). The organic layers were combined, washed with saturated aqueous Na2S2O3, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was immediately diluted with anhydrous MeOH, swirled, and cooled in a −78 °C bath. The resulting white solid 15 (1.5 g, 86%) was collected via filtration: mp 54–56 °C; [α]ଶ଴ ஽ = −28 (c = 1 g/100 mL, CHCl3); HRMS m/z calcd for C16H28O2I [M+H]+ 379.1128, found 379.1130; IR (film) νmax 2919, 2840, 1703, 1393, 1203, 1168, 1146, 1122, 911, 769 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.01 (s, 1H), 3.36 (d, J = 10.6 Hz, 1H), 3.11–3.14 (m, 1H), 2.56 (d, J = 12.2 Hz, 1H), 2.46 (s, 1H), 1.85– 1.90 (m, 2H), 1.70 (d, J = 13.8 Hz, 1H), 1.46–1.62 (m, 5H), 1.18–1.41 (m, 4H), 1.05 (d, J = 12.3 Hz, 1H), 0.87 (s, 3H), 0.85 (s, 3H), 0.78 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 160.2, 88.3, 62.1, 55.2, 41.5, 40.8, 39.6, 38.9, 33.2, 33.1, 21.4, 20.3, 19.7, 18.3, 14.8, -3.0. Enol 16. A solution of compound 15 (1.5 g, 3.9 mmol) in anhydrous pyridine (20 mL) at room temperature was treated with silver (I) fluoride (1.0 g, 84.0 mmol). The reaction flask was wrapped with aluminium foil to protect from light. The reaction mixture was stirred at room temperature overnight, diluted with Et2O (50 mL), and filtered through a celite pad to remove the dark grey solid. The filter cake was rinsed with Et2O (50 mL). The organic layers were combined, washed with saturated aqueous NaHCO3 and saturated aqueous Na2S2O3 (v/v, 5:1, 50 mL), then washed with brine (150 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to afford an unstable pale yellow syrup (0.95 g, 98%), which was used immediately in the next step.13d A solution of the above compound (800 mg, 3.2 mmol) in 60 mL of MeOH was treated with K2CO3 (530 mg, 3.8 mmol) at 0 °C. The resulting mixture was warmed up to room temperature and stirred at this temperature for 2 h, extracted with Et2O (3 × 40 mL), washed with H2O (100 mL), and back-extracted with Et2O (100 mL). The organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford enol 16 (700 mg, 98%) as an ivory-white + solid:13a,b [α]ଶ଴ ஽ = +9 (c = 0.97 g/100 mL, CHCl3); HRMS m/z calcd for C15H26ONa [M+Na] 245.1876, found 245.1880; IR

(film) νmax 3018, 2927, 2850, 1769, 1215, 1081, 1011, 914, 757, 668 cm-1; 1H NMR (400 MHz, CDCl3) δ 5.22 (s, 1H), 4.84 (s, 1H), 2.01 (d, J = 9.7 Hz, 1H), 1.79 (d, J = 12.7 Hz, 1H), 1.63–1.73 (m, 2H), 1.31–1.53 (m, 6H), 1.15 (d, J = 13.5 Hz, 1H), 1.09 (s, 3H), 1.98 (d, J = 10.7 Hz, 1H), 0.87 (s, 6H), 0.85 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 166.3, 103.6, 73.1, 53.3, 43.9, 41.6, 39.8, 38.8, 33.6, 33.1, 30.4, 22.2, 21.5, 20.0, 18.9. 1,2-Decalindiol 17. To a solution of enol 16 (200 mg, 0.90 mmol) in CH2Cl2 (2 mL) was bubbled with O3 at −78 °C until the blue color appeared. The resulting reaction mixture was bubbled with N2 for 10 min, added NaBH4 (68 mg, 1.8 mmol), warmed up to room temperature and stirred at this temperature for 1 h, quenched with a solution of saturated aqueous NH4Cl (5 mL), and extracted with CH2Cl2 (3 × 5 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford 1,2-decalindiol 17 (198 mg, 98%) as a white solid: mp 102–104 oC; [α]ଶ଴ ୈ = +1.3 (c = 1 g/100 mL, CHCl3); HRMS m/z calcd for C14H26O2Na [M+Na]+ 249.1826, found 249.1825; IR (film) νmax 3347, 2925, 2852, 1079, 1062, 1030, 996, 979, 935, 912, 672 cm–1; 1H NMR (400 MHz, CDCl3) δ 3.12 (s, 1H), 2.25 (bs, 2H), 1.78–1.86 (m, 2H), 1.61 (d, J = 13.3 Hz, 2H), 1.38–1.46 (m, 4H), 1.27 (d, J = 12.2 Hz, 1H), 1.21 (s, 3H), 1.13 (dd, J = 3.5, 13.5 Hz, 1H), 0.98 (d, J = 10.7 Hz, 1H), 0.87 (s, 6H), 0.81 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 86.8, 73.9, 53.2, 41.8, 40.0, 39.3, 38.6, 33.1, 32.9, 22.2, 21.5, 19.8, 18.2, 13.6.

Drimanal 18. To a solution of 1,2-decalindiol 17 (50 mg, 0.22 mmol) in CH2Cl2 (1 mL), BF3•Et2O (58 µL, 0.44 mmol) was added



Page 8 of 14

dropwise at 0 °C. The resulting mixture was warmed up to room temperature and stirred at this temperature for 30 min, diluted with brine (5 mL), and extracted with CH2Cl2 (3 × 5 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (petroleum ether/EtOAc = 20:1) to give drimanal 18 (42 + mg, 90%) as a colorless oil: [α]ଶ଴ ୈ = –23 (c 0.44 g/100 mL, CHCl3); HRMS m/z calcd for C14H25O [M+H] 209.1900, found 209.1904; IR

(film) νmax 2928, 2868, 1706, 1459, 1389, 1133, 1081, 991 cm–1; 1H NMR (400 MHz, CDCl3) δ 2.64–2.73 (m, 1H), 2.07–2.13 (m, 1H), 1.69–1.75 (m, 2H), 1.53–1.60 (m, 4H), 1.40 (d, J = 13.5 Hz, 1H), 1.18–1.28 (m, 2H), 1.14 (s, 3H), 1.08–1.10 (m, 1H), 0.98 (d, J = 6.4 Hz, 3H), 0.93 (s, 3H), 0.88 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 216.8, 54.2, 48.8, 41.5, 39.9, 35.7, 34.2, 33.2, 33.0, 22.0, 21.3, 18.7, 18.1, 15.0.

Allyl ether 19. To a stirred suspension of (methoxymethyl)-diphenylphosphine oxide (24.6 mg, 0.1 mmol) in dry THF (2 mL) under N2 atmosphere was added a solution of n-BuLi (2.5 M in THF, 4.8 uL, 0.12 mmol) at –78 °C. The resulting mixture was stirred at –78 °C for 30 min, added drimanal 18 (25 mg, 0.12 mmol), warmed up to room temperature and stirred at this temperature for 1 h, quenched with water (5 mL), and extracted with EtOAc (3 × 10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (petroleum ether/EtOAc = 30:1) to afford allyl ether 19 (25 mg, 75%) as a colorless oil: Rf = 0.8 (Hexane/EtOAc = 30:1); HRMS m/z calcd for C16H29O [M+H]+ 237.2213, found 237.2216; IR (film) νmax 3417, 2928, 2867, 2844, 2359, 1652, 1459, 1372, 1233, 1148, 1052, 1024, 1003, 823, 759, 633, 621 cm–1; 1H NMR (400 MHz, DMSO-d6) δ 5.36 (s, 1H), 3.39 (s, 3H), 2.01 (d, J = 14.1 Hz, 1H), 1.76–1.90 (m, 2H), 1.53–1.62 (m, 2H), 1.31–1.40 (m, 3H), 1.23 (s, 1H), 1.09–1.17 (m, 2H), 1.06 (s, 3H), 1.03 (d, J = 2.5 Hz, 1H), 0.89 (d, J = 6.4 Hz, 3H), 0.81 (s, 3H), 0.79 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 138.0, 127.5, 59.3, 53.2, 41.7, 40.4, 38.6, 37.4, 33.3 (d), 31.0, 22.0, 21.7, 20.7, 19.6, 18.5.

Drimanal aldehydes 20a/20b. To the solution of allyl ether 19 (20.0 mg, 0.08 mmol) in CH2Cl2 (3 mL) under N2 atmosphere was added aqueous HCl (2.0 M, 60 uL, 0.16 mmol) at room temperature. The resulting reaction mixture was stirred at room temperature for 10 min, quenched with saturated aqueous NaHCO3 (7 mL), and extracted with CH2Cl2 (3 × 10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (petroleum ether/EtOAc = 20:1) to give drimanal aldehydes 20a (3 mg, 18%) and 20b (13 mg, 72%) as a colorless oil: Data for 20b, Rf = 0.6 (Hexane/EtOAc = 30:1); HRMS m/z calcd for C15H27O [M+H]+ 223.2056, found 223.2058; IR (film) νmax 2927, 2869, 2847, 2363, 1715, 1459, 1388, 908, 733 cm–1; 1H NMR (400 MHz, CDCl3) δ 9.69 (d, J = 4.6 Hz, 1H), 1.98–2.08 (m, 1H), 1.72–1.86 (m, 2H) 1.45–1.54 (m, 2H), 1.29–1.38 (m, 3H), 1.02–1.17 (m, 2H), 1.04 (s, 3H), 0.85–1.01 (m, 3H), 0.81 (s, 3H), 0.79 (s, 3H),0.73 (d, J = 6.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 207.9, 70.3, 54.1, 41.8, 40.2, 38.1, 35.4, 33.4, 33.2, 27.5, 21.8, 21.5, 20.6, 18.3, 15.9.

Drimanal hydrazone 11. To a solution of drimanal aldehyde 20b (1.0 g, 4.5 mmol) in MeOH (20 mL) was added p-toluenesulfonyl hydrazide (1.1 g, 5.4 mmol) at room temperature. The resulting reaction mixture was stirred at room temperature for 5 h, and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (petroleum ether/EtOAc = 3:1) to afford drimanal hydrazone 11 a white solid (1.6 g, 95%): mp = 54–56 °C; Rf = 0.5 (Hexane/EtOAc = 3:1); HRMS m/z calcd for C22H34N2NaO2S [M+Na]+ 413.2233, found 413.2237; IR (film) νmax 3197, 2925, 1598, 1456, 1368, 1323, 1166, 1093, 1019, 907, 812, 731, 669, 648 cm–1; 1H NMR (400 MHz, CDCl3) δ 8.34 (s, 1H), 7.80 (d, J = 8.2 Hz, 2H), 7.25 (d, J = 8.2 Hz, 2H), 6.99 (d, J = 8.5 Hz, 1H), 2.38 (s, 3H), 1.75 (dd, J = 12.9, 2.7 Hz, 1H), 1.60 (m, 1H), 1.40–1.53 (m, 3H), 1.04–1.32 (m, 7H), 0.84–0.94 (m, 4H), 0.79 (s, 3H), 0.76 (s, 3H), 0.74 (s, 3H);

13

C NMR (100 MHz, CDCl3) δ 155.5, 143.7, 135.0, 129.4, 127.9, 60.8, 54.0, 41.8, 39.7, 37.2, 35.7, 33.2, 33.0, 29.4, 26.8,

21.6, 21.4, 20.5, 18.3, 15.3.

Ether 21. To a solution of 14 (5.0 g, 36.2 mmol) in DMF (150 mL) was added sequentially K2CO3 (11.0 g, 79.7 mmol) and 2-iodopropane (13.6 g, 79.7 mmol) at room temperature. The resulting reaction mixture was stirred at 70 °C for 12 h, cooled down to room temperature, and diluted with EtOAc (50 mL) and water (100 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (3 × 50 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc = 6:1) to give ether 21 as a colorless oil (7.2 g,


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


89%): Rf = 0. 5 (Hexane/EtOAc = 6:1); HRMS m/z calcd for C13H19O3 [M+H]+ 223.1329, found 223.1329; IR (film) νmax 2977, 2930, 1686, 1593, 1579, 1500, 1466, 1432, 1384, 1262, 1235, 1104, 1001, 987, 946, 909, 812, 929, 650 cm–1; 1H NMR (400 MHz, CDCl3) δ 9.75 (s, 1H), 7.37 (s, 2H), 6.91 (d, J = 8.5 Hz, 1H), 4.56 (quint, J = 5.9 Hz, 1H), 4.45 (quint, J = 5.9 Hz, 1H), 1.31 (d, J = 6.2 Hz, 6H), 1.28 (d, J = 6.2 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 190.5, 154.6, 148.6, 129.7, 126.2, 115.8, 114.5, 72.1, 71.4, 21.8, 21.7.

Phenol 22. To a solution of aldehyde 21 (7.0 g, 31.5 mmol) in MeOH (100 mL) was added dropwise H2SO4 (98%, 2.6 g, 26.1 mmol) at room temperature, and then added 30% H2O2 (25.2 mL, 242.5 mmol) in one portion. The resulting reaction mixture was stirred for at room temperature 7 h, quenched with saturated aqueous NaHCO3 (20 mL), and extracted with EtOAc (3 × 50 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc = 3:1) to afford phenol 22 as a yellow oil (5.6 g, 85%): Rf = 0.3 (Hexane/EtOAc = 6:1); HRMS m/z calcd for C12H19O3 [M+H]+ 211.1329, found 211.1329; IR (film) νmax 3372, 2975, 2931, 1601, 1504, 1455, 1383, 1372, 1290, 1212, 1180, 994, 918, 847, 731 cm–1; 1H NMR (400 MHz, CDCl3) δ 6.77 (d, J = 8.6 Hz, 1H), 6.41 (d, J = 2.6 Hz, 1H), 6.30 (dd, J = 8.6, 2.6 Hz, 1H), 5.91 (br, 1H), 4.39 (quint, J = 6.0 Hz, 1H), 4.28 (quint, J = 6.1 Hz, 1H), 1.27 (d, J = 6.1 Hz, 12H); 13C NMR (100 MHz, CDCl3) δ 151.5, 150.3, 141.6 (d), 121.0, 107.0, 104.5, 73.9, 71.2, 22.1, 21.9.

Aromatic ether 23. To a solution of 22 (5.0 g, 23.7 mmol) in DMF (100 mL) was added sequentially K2CO3 (3.6 g, 26.2 mmol), 2-iodopropane (4.5 g, 26.2 mmol) and TBAI (0.7 g, 1.9 mmol) at room temperature. The resulting reaction mixture was stirred at 78 °C for 12 h, cooled down to room temperature, diluted with EtOAc (50 mL) and water (100 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (3 × 50 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc = 12:1) to give aromatic ether 23 as a colorless oil (4.2 g, 70%): Rf = 0.8 (Hexane/EtOAc = 12:1); HRMS m/z calcd for C15H25O3 [M+H]+ 253.1798, found 253.1796; IR (film) νmax 2975, 2930, 1605, 1584, 1500, 1466, 1382, 1371, 1334, 1298, 1257, 1215, 1181, 1163, 1111, 1005, 953, 908, 854, 732 cm–1; 1H NMR (400 MHz, CDCl3) δ 6.82 (d, J = 8.7 Hz, 1H), 6.49 (d, J = 1.3 Hz, 1H), 6.39 (d, J = 8.7 Hz, 1H), 4.47 (quint, J = 6.1 Hz, 1H), 4.41 (quint, J = 6.1 Hz, 1H), 4.29 (quint, J = 6.1 Hz, 1H), 1.28–1.33 (m, 18H); 13C NMR (100 MHz, CDCl3) δ 153.2, 150.3, 142.6, 120.6, 107.4, 106.6, 73.3, 71.4, 70.3, 22.2, 22.1, 22.0.

Benzaldehyde 24. To a solution of aromatic ether 23 (4.0 g, 15.8 mmol) in anhydrous THF (50 mL) was added n-BuLi (2.5 M in toluene, 31.6 mL, 79.0 mmol) at 0 °C, and stirred at this temperature for 1 h. The resulting reaction mixture was added DMF (11.6 g, 158 mmol) dropwise, stirred at 0 °C for 10 min, quenched with saturated aqueous NH4Cl (50 mL), and extracted with EtOAc (3 × 50 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc = 6:1) to afford benzaldehyde 24 as a yellow oil (3.6 g, 80%): Rf = 0.5 (Hexane/EtOAc = 5:1); HRMS m/z calcd for C16H25O4 [M+H]+ 281.1747, found 281.1749; IR (film) νmax 2976, 2929, 2357, 1693, 1578, 1473, 1403, 1382, 1372, 1334, 1251, 1219, 1137, 1107, 1063, 910, 805, 732 cm–1; 1H NMR (400 MHz, CDCl3) δ 10.45 (s, 1H), 7.043 (d, J = 8.8 Hz, 1H), 6.61 (d, J = 9.0 Hz, 1H), 4.62 (quint, J = 6.1 Hz, 1H), 4.49 (quint, J = 6.1 Hz, 1H), 4.42 (quint, J = 6.1 Hz, 1H), 1.25–1.36 (m, 18H); 13C NMR (100 MHz, CDCl3) δ 190.3, 154.2, 151.4, 144.9, 124.4, 122.3, 109.8, 76.3, 72.6, 72.1, 22.2, 22.1, 21.9.

Iodobenzaldehyde 12a. To a solution of benzaldehyde 24 (3.5 g, 12.5 mmol) in MeCN (60 mL) was added subsequently NIS (2.4 g, 13.7 mmol) and Bi(OTf)3 (1.6 g, 2.5 mmol) at 0 °C. The resulting reaction mixture was stirred at room temperature overnight, quenched with saturated aqueous NH4Cl (50 mL), and extracted with EtOAc (3 × 50 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc = 20:1) to give iodobenzaldehyde 12a as a yellow oil (3.74 g, 78%): Rf = 0.7 (Hexane/EtOAc = 6:1); HRMS m/z calcd for C16H24IO4 [M+H]+ 407.0714, found 407.0718; IR (film) νmax 2976, 2930, 1693, 1551, 1450, 1399, 1382, 1371, 1332, 1285, 1237, 1215, 1175, 1101, 992, 909, 849, 815, 730, 648 cm–1; 1H NMR (400 MHz, CDCl3) δ 10.32 (s, 1H), 7.49 (s, 1H), 4.63 (quint, J = 6.1 Hz, 1H), 4.47 (quint, J = 6.1 Hz, 1H), 4.38 (quint, J = 6.1 Hz, 1H), 1.24–1.38 (m, 18H); 13C NMR (100 MHz, CDCl3) δ 189.8, 151.9, 151.3, 148.0, 131.1, 125.9, 86.3, 78.7, 76.6, 72.3, 22.2, 22.1, 22.0.



Page 10 of 14

Vinyl benzaldehydes (ZE)-10a. A mixture of drimanal hydrazone 11 (200 mg, 0.51 mmol), iodobenzaldehyde 12a (173 mg, 0.42 mmol), K2CO3 (265 mg, 1.92 mmol) and Pd(PPh3)4 (49 mg, 0.04 mmol) in xylene (20 mL) was stirred at 120 °C under N2 atmosphere for 10 h. The resulting reaction mixture was cooled down to room temperature, diluted with water (30 mL), and extracted with EtOAc (3 × 20 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc = 15:1) to afford a mixture of vinyl benzaldehydes (ZE)-10a as a colorless liquid (177 mg, 86%).

Vinyl benzaldehyde (E)-10a. To a solution of vinyl benzaldehydes (ZE)-10a (50 mg, 0.11 mmol) in a co-solvent of hexane (2 mL) and ethyl ether (1mL) was added iodine (28 mg, 0.11 mmol), and then stirred in sunlight under N2 atmosphere at room temperature for 2 h. The resulting reaction mixture was diluted with water (30 mL), and extracted with EtOAc (3 × 10 mL). The combined organic extracts were washed with Na2S2O3, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc = 15:1) to give vinyl benzaldehyde (E)-10a as a colorless liquid (49 mg, 99%): Rf = 0.8 (Hexane/EtOAc = 10:1): HRMS m/z calcd for C31H49O4 [M+H]+ 485.3631, found 485.3636; IR (film) νmax 2971, 2926, 2869, 2358, 2341, 1696, 1564, 1456, 1380, 1332, 1252, 1224, 1137, 1104, 1027, 916, 733, 667 cm–1; 1H NMR (400 MHz, CDCl3) δ 10.43 (s, 1H), 6.89 (s, 1H), 6.19 (s, 1H), 4.58 (septet, J = 6.2 Hz, 1H), 4.47 (septet, J = 6.0 Hz, 1H), 4.31 (septet, J = 6.2 Hz, 1H), 2.68– 2.60 (m, 1H), 1.81– 1.60 (m, 4H), 1.57–1.33 (m, 7H), 1.31 (d, J = 6.1 Hz, 6H), 1.29 (d, J = 6.0 Hz, 3H), 1.25 (d, J = 6.1 Hz, 3H), 1.22 (d, J = 6.2 Hz, 3H), 1.19 (d, J = 6.1 Hz, 3H), 1.17 (s, 3H), 0.91 (s, 3H), 0.88 (s, 3H), 0.86 (d, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 191.2, 157.2, 150.8, 148.6, 146.0, 130.0, 125.8, 125.6, 115.1, 76.1, 75.6, 72.2, 50.4, 42.4, 41.0, 39.7, 33.9, 33.2, 32.8, 32.7, 22.4, 22.3, 22.2 (d), 22.1, 21.9 (d), 21.6, 20.3, 19.5.

Siphonodictyal B (1). To a solution of vinyl benzaldehyde (E)-10a (30 mg, 0.07 mmol) in CH2Cl2 (2 mL) at –78 °C was added BCl3 (423 uL, 0.43 mmol) dropwise over 5 min. The resulting reaction mixture was stirred at room temperature for 3 h, quenched with water (10 mL), and extracted with CH2Cl2 (3 × 5 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc = 5:1) to afford siphonodictyal B (1) as a yellow solid (17 mg, 76%): Rf = 0.3 (Hexane/EtOAc = 5:1); [α]ଶ଴ ୈ = +28 (c = 1 g/100 mL, CHCl3); HRMS m/z calcd for C22H31O4 [M+H]+ 359.2217, found 359.2219; IR (film) νmax 3368, 2927, 2869, 1644, 1599, 1460, 1389, 1305, 1270, 907, 733 cm– 1 1

; H NMR (400 MHz, CDCl3) δ 11.47 (s, 1H), 10.31 (s, 1H), 6.84 (s, 1H), 5.92 (s, 1H), 5.43 (s, 1H), 5.13 (s, 1H), 2.61–2.56 (m, 1H),

1.83–1.74 (m, 3H), 1.60–1.46 (m, 5H), 1.27–1.17 (m, 3H), 1.18 (s, 3H), 0.91 (s, 3H), 0.89 (s, 3H), 0.77 (d, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 194.5, 165.7, 148.4, 147.5, 136.9, 123.6, 116.6, 109.3, 109.0, 52.3, 42.2, 41.8, 39.1, 34.7, 34.1, 33.9, 33.1, 22.5, 21.7, 21.2, 21.1, 19.3.

Liphagal (2). To a solution of siphonodictyal B (1, 50 mg, 0.14 mmol) and NaHCO3 (14 mg, 0.17 mmol) in CCl4 (5 mL) at 0 °C was added m-CPBA (24 mg, 0.14 mmol) in one portion. The resulting reaction mixture was stirred at 0 °C for 1 h, added TFA (31.8 mg, 0.28 mmol) at 0 °C dropwise, allowed to warm up to room temperature and stirred at this temperature for 2 h, quenched with saturated aqueous NaHCO3 (30 mL), and extracted with EtOAc (3 × 50 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc = 10:1) to give liphagal (2) as a yellow solid (21.0 mg, 42%): Rf = 0.6 (Hexane/EtOAc = 5:1); HRMS m/z calcd for C22H29O4 [M+H]+ 357.2066, found 357.2063; IR (film) νmax 3417, 2929, 2868, 1654, 1455, 1389, 1328, 1301, 1272, 906, 730 cm–1; 1H NMR (400 MHz, CDCl3) δ 11.24 (s, 1H), 10.45 (s, 1H), 7.55 (s, 1H), 5.32 (s, 1H), 3.21 (sextet, J = 7.0 Hz, 1H), 2.48–5.56 (m, 1H), 2.14–2.22 (m, 1H), 1.83–1.90 (m, 1H), 1.65–1.75 (m, 4H), 1.49–1.55 (m, 3H), 1.43 (d, J = 7.1 Hz, 3H), 1.34 (s, 3H), 1.26–1.28 (m, 1H), 0.98 (s, 3H), 0.94 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 192.7, 156.7, 148.2, 145.5, 139.6, 125.7, 120.5, 116.2, 106.5, 77.5, 77.2, 76.9, 53.9, 42.1, 40.5, 39.7, 35.4, 35.0, 33.9, 33.5, 24.4, 22.2, 21.9, 20.4, 19.0.

Corallidictyal C (3) and corallidictyal D (4). To a solution of PPh3 (7.3 mg, 0.028 mmol) in CH2Cl2 (2 mL) was added NIS (6.3 mg, 0.028 mmol) at room temperature. The resulting reaction mixture was stirred at room temperature for 20 min, added dropwise a solution of


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


1 (100 mg, 0.28 mmol) at 0 °C, stirred at room temperature for 1 h, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc = 10:1) to afford corallidictyals C/D (3 and 4) as a yellow solid (75 mg, 76%): Rf = 0.5 (Hexane/EtOAc = 10:1); HRMS m/z calcd for C22H31O4 [M+H]+ 359.2217, found 359.2219; IR (film) νmax 3340, 2922, 2852, 1732, 1651, 1575, 1466 cm–1. NMR of 3: 1H NMR (400 MHz, DMSO-d6) δ 10.53 (s, 1H, OH), 10.08 (s, 1H, CHO), 8.67 (br s, 1H, OH), 6.94 (s, 1H), 3.05 (d, J = 16.7 Hz, 1H, ArCH2–), 2.85 (d, J = 16.5 Hz, 1H, ArCH2–), 2.15–2.21 (m, 1H), 1.63–1.10 (m, 10H), 1.12 (s, 3H), 1.04 (dd, J = 12.2 Hz, J = 3.3 Hz, 1H), 0.85 (s, 3H), 0.82 (s, 3H), 0.68 (d, J = 6.7 Hz, 3H); 13C NMR (100 MHz, DMSO-d6) δ 191.6, 155.0, 147.0, 137.3, 120.6, 117.1, 106.05, 99.7, 47.0, 43.0, 41.2, 34.5, 33.13, 32.7, 30.5, 30.2, 29.0, 21.4, 20.8, 17.7, 14.8, 14.5; 1H NMR (400 MHz, CDCl3) δ 11.10 (s, 1H, OH), 10.13 (s, 1H， CHO), 6.96 (s, 1H), 5.05 (s, 1H, OH), 3.07 (d, J = 16.3 Hz, 1H, ArCH2–), 2.88 (d, J = 16.3 Hz, 1H, ArCH2–), 2.23– 2.29 (m, 1H), 0.99–1.70 (m, 10 H), 1.17 (s, 3H), 1.01 (dd, J = 12.3 Hz, J = 2.6 Hz, 1H), 0.88 (s, 3H), 0.86 (s, 3H), 0.74 (d, J = 6.4 Hz, 3H); 13

C NMR (100 MHz, CDCl3) δ 192.87, 156.44, 146.09, 136.7, 119.3, 117.7, 105.6, 100.9, 48.0, 42.5, 35.0, 33.48, 33.2, 33.0, 31.2, 30.9,

21.6, 21.2, 18.1, 15.2, 14.9. NMR of 4: 1H NMR (400 MHz, DMSO-d6) δ 10.56 (s, 1H, OH), 10.14 (s, 1H, CHO), 8.68 (br s, 1H, OH), 6.90 (s, 1H), 3.09 (d, J = 16.4 Hz, 1H, ArCH2–), 2.71 (d, J = 16.3 Hz, 1H, ArCH2–), 1.73–1.80 (m, 1H), 1.63–1.06 (m, 11H), 0.92 (s, 3H), 0.88 (s, 3H), 0.82 (s, 3H), 0.66 (d, J = 6.7 Hz, 3H); 13C NMR (100 MHz, DMSO-d6) δ 191.9, 155.6, 146.9, 137.3, 120.6, 116.7, 105.97, 98.1, 46.0, 41.9, 41.2, 36.3, 33.07, 32.8, 32.7, 30.6, 30.5, 21.7, 20.8, 17.7, 15.6, 15.4; 1H NMR (400 MHz, CDCl3) δ 11.09 (s, 1H, OH), 10.20 (s, 1H, CHO), 6.93 (s, 1H), 5.05 (s, 1H, OH), 3.15 (d, J = 16.0 Hz, 1H, ArCH2–), 2.73 (d, J = 16.0 Hz, 1H, ArCH2–), 1.74–1.81 (m, 1H), 0.99–1.70 (m, 10 H), 1.48 (dd, J = 12.5 Hz, J = 3.8 Hz, 1H), 0.96 (s, 3H), 0.91 (s, 3H), 0.85 (s, 3H), 0.74 (d, J = 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 192.92, 156.9, 146.1, 136.8, 119.3, 117.4, 105.6, 99.3, 46.7, 41.9, 41.6, 37.1, 33.50, 33.4, 31.27, 31.1, 29.7, 21.9, 21.3, 18.2, 16.2, 15.6.

ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website. Copies of 1H NMR, 13C NMR spectra for all compounds spectra (PDF).

AUTHOR INFORMATION Corresponding Author * E-mail: [email protected].

ACKNOWLEDGMENT This project was funded by the National Natural Science Foundation of China (21672046, 21372054), and the Fundamental Research Funds for the Central Univercities (HIT.NSRIF.201701).

Notes and references 1

Blunt, J. W.; Copp, B. R.; Munro, M. H.; Northcote, P. T.; Prinsep, M. R. Marine Natural Products. Nat. Prod. Rep. 2010, 27, 165-237.

2

(a) Sullivan, B.; Djura, P.; McIntyre, D. E.; Faulkner, D. J. Antimicrobial Constituents of the Sponge Siphonodictyon coralliphagum. Tetrahedron 1981, 37, 979-982. (b) Gothel, Q.; Köck, M. New Sesquiterpene Hydroquinones from the



Page 12 of 14

Caribbean Sponge Aka coralliphagum. Beilstein J. Org. Chem. 2014, 10, 613-621. The true configuration at the C8 position of siphonodictyal B was elucidated by George through total synthesis of this natural product, see ref 10a. 3

Marion, F.; Williams, D. E.; Patrick, B. O.; Hollander, I.; Mallon, R.; Kim, S. C.; Roll, D. M.; Feldberg, L.; Van Soest, R.; Andersen, R. J. Liphagal, a Selective Inhibitor of PI3 Kinase α Isolated from the Sponge Aka coralliphaga: Structure Elucidation and Biomimetic Synthesis. Org. Lett. 2006, 8, 321-324.

4

(a) Ward, S. G.; Finan, P. Isoform-specific Phosphoinositide 3-kinase Inhibitors as Therapeutic Agents. Curr. Opin. Pharmacol. 2003, 3, 426-434. (b) Ward, S.; Sotsios, Y.; Dowden, J.; Bruce, I.; Finan, P. Therapeutic Potential of Phosphoinositide 3-Kinase Inhibitors. Chem. Biol. 2003, 10, 207-213. (c) Wymann, M. P.; Zvelebil, M.; Laffargue, M. Phosphoinositide 3-kinase signalling – which way to target? Trends Pharmacol. Sci. 2003, 24, 366-376. (d) Blajecka, K.; Borgstrom, A.; Arcaro, A. Curr. Drug Targets 2011, 12, 1056. (e) Gao, Y.; Ma, Y.; Yang, G.; Li, Y. Molecular Dynamics Simulations to Investigate the Binding Mode of the Natural Product Liphagal with Phosphoinositide 3-Kinase α. Molecules 2016, 21, 857-868.

5

Grube, A.; Assmann, M.; Lichte, E.; Sasse, F.; Pawlik, J. R.; Köck, M. Bioactive Metabolites from the Caribbean Sponge Aka coralliphagum. J. Nat. Prod. 2007, 70, 504-509.

6

(a) Mehta, G.; Likhite, N. S.; Kumar, C. S. A. A Concise Synthesis of the Bioactive Meroterpenoid Natural Product (±)-Liphagal, a Potent PI3K Inhibitor. Tetrahedron Lett. 2009, 50, 5260-5262. (b) Pereira, A. R.; Strangman, W. K.; Marion, F.; Feldberg, L.; Roll, D.; Mallon, R.; Hollander, I.; Andersen, R. J. Synthesis of Phosphatidylinositol 3-Kinase (PI3K) Inhibitory Analogues of the Sponge Meroterpenoid Liphagal. J. Med. Chem. 2010, 53, 8523-8533.

7

(a) George, J. H.; Baldwin, J. E.; Adlington, R. M. Enantiospecific, Biosynthetically Inspired Formal Total Synthesis of (+)-Liphagal. Org. Lett. 2010, 12, 2394-2397. (b) Alvarez-Manzaneda, E.; Chahboun, R.; Alvarez, E.; Cano, M. J.; Haidour, A.; Alvarez-Manzaneda, R. A. Enantioselective Total Synthesis of the Selective PI3 Kinase Inhibitor Liphagal. Org. Lett. 2010, 12, 4450-4453. (c) Day, J. J.; McFadden, R. M.; Virgil, S. C.; Kolding, H.; Alleva, J. L.; Stoltz, B. M. The Catalytic Enantioselective Total Synthesis of (+)-Liphagal. Angew. Chem. Int. Ed. 2011, 50, 6814-6818. (d) Kamishima, T.; Kikuchi, T.; Narita, K.; Katoh, T. Biogenetically Inspired Total Synthesis of (+)-Liphagal: A Potent and Selective Phosphoinositide 3-Kinase α (PI3Kα) Inhibitor from the Marine Sponge Aka coralliphaga. Eur. J. Org. Chem. 2014, 3443-3450. (e) Huynh, K. Q.; Seizert, C. A.; Ozumerzifon, T. J.; Allegretti, P. A.; Ferreira, E. M. Platinum-Catalyzed α,β-Unsaturated Carbene Formation in the Formal Syntheses of Frondosin B and Liphagal. Org. Lett. 2017, 19, 294-297.

8

Cano, M. J.; Bouanou, H.; Tapia, R.; Alvarez, E.; Alvarez-Manzaneda, R.; Chahboun, R.; Alvarez-Manzaneda, E. NIS–PPh3: A Selective Reagent for the Spiroannulation of o-Allyl Phenols. Total Synthesis of Corallidictyal D. J. Org. Chem. 2013, 78, 9196-9204.

9

Dethe, D. H.; Dherange, B. D.; Ali, S.; Parsutkar, M. M. Enantiospecific Total Syntheses of Meroterpenoids (-)-F1839-I and (-)-Corallidictyals B and D. Org. Biomol. Chem. 2017, 15, 65-68.

10 (a) Markwell-Heys, A. W.; Kuan, K. K. W.; George, J. H. Total Synthesis and Structure Revision of (-)-Siphonodictyal B and Its Biomimetic Conversion into (+)-Liphagal. Org. Lett. 2015, 17, 4228-4231. (b) Markwell-Heys, A. W.; George, J. H. Some Chemical Speculation on the Biosynthesis of Corallidictyals A–D. Org. Biomol. Chem. 2016, 14, 5546-5549. (c) Kikuchi, T.; Narita,

K.;

Saijo,

K.;

Ishioka,

C.;

Katoh,

T.

Enantioselective

Total

Synthesis

of

(-)-Siphonodictyal

B

and

(+)-8-epi-Siphonodictyal B with Phosphatidylinositol 3-Kinase α (PI3Kα) Inhibitory Activity. Eur. J. Org. Chem. 2016, 5659-5666. 11 For the synthetic studies or reviews related to marine natural products 1–4, see: (a) Bernet, A.; Seifert, K. A New Approach to Sesquiterpene Arenes of the 9,11-Drimenyl Type (=[(1E,2RS,4aRS,8aRS)-Octahydro-2,5,5,8a-tetramethylnaphthalen-1(2H)ylidene]methyl Type). Helv. Chim. Acta 2006, 89, 784-796. (b) Zhang, Y.; Oblak, E. Z.; Bolstad, E. S. D.; Anderson, A. C.; Jasinski, J. P.; Butcher, R. J.; Wright, D. L. Synthetic and Computational Studies on Liphagal: A Natural Product Inhibitor of


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


PI-3K. Tetrahedron Lett. 2010, 51, 6120-6122. (c) Deore, V.; Lohar, M. K.; Mundada, R.; Roychowdhury, A.; Vishwakarma, R.; Kumar, S. Efficient Synthesis of Key Intermediate Toward Liphagal Synthesis. Synth. Commun. 2011, 41, 177-183. (d) Pepper, H. P.; Kuan, K. K. W.; George, J. H.; Kamishima, T.; Kikuchi, T.; Narita, K.; Katoh, T. Synthesis of a Liphagal–Frondosin C Hybrid and Speculation on the Biosynthesis of the Frondosins. Org. Lett. 2012, 14, 1524-1527. (e) Zhang, J.; Li, L.; Wang, Y.; Wang, W.; Xue, J.; Li, Y. A Novel, Facile Approach to Frondosin B and 5-epi-Liphagal via a New [4 + 3]-Cycloaddition. Org. Lett. 2012, 14, 4528-4530. (f) Jiang, H.; Tian, L. F.; Li, Z. T.; Liu, Q.; Li, C. C.; Yao, X. S.; Yang, Z. InCl3-mediated Intramolecular Friedel-Crafts-type Cyclization and Its Applications to Construct the [6-7-5-6] Tetracyclic Scaffled of Liphagal. Sci. China Chem. 2012, 55, 36-42. (g) Laplace, D. R.; Verbraeken, B.; Hecke, K. V.; Winne, J. M. Total Synthesis of (±)-Frondosin B and (±)-5-epi-Liphagal by Using a Concise (4+3) Cycloaddition Approach. Chem. Eur. J. 2014, 20, 253-262. (h) Wang, J. L.; Li, H. J.; Wang, H. S.; Wu, Y. C. Regioselective 1,2-Diol Rearrangement by Controlling the Loading of BF3·Et2O and Its Application to the Synthesis of Related Nor-Sesquiterene- and Sesquiterene-Type Marine Natural Products. Org. Lett. 2017, 19, 3811-3814. (i) Narita, K.; Katoh, T. Total Synthesis of Liphagal: A Potent and Selective Phosphoinoditide 3-Kinase α (PI3Kα) Inhibitor from the Marine Sponge Aka coralliphaga. Heterocycles 2018, 96, 3-41. 12 For selected examples on the synthesis of natural products with similar structures of marine natural aldehydes 1–4, see: (a) Inoue, M.; Carson, M. W.; Frontier, A. J.; Danishefsky, S. J. Total Synthesis and Determination of the Absolute Configuration of Frondosin B. J. Am. Chem. Soc. 2001, 123, 1878-1889. (b) Hughes, C. C.; Trauner, D. Concise Total Synthesis of (-)-Frondosin B Using a Novel Palladium-Catalyzed Cyclization. Angew. Chem. Int. Ed. 2002, 41, 1569-1572. (c) Oblak, E. Z.; Van Heyst, M. D.; Li, J.; Wiemer, A. J.; Wright, D. L. Cyclopropene Cycloadditions with Annulated Furans: Total Synthesis of (+)- and (-)-Frondosin B and (+)-Frondosin A. J. Am. Chem. Soc. 2014, 136, 4309-4315. 13 (a) Vlad, P. F.; Aryku, A. N.; Chokyrian, A. G. Synthesis of (+)-Drim-9(11)-en-8α-ol from Sclareol. Russ. Chem. Bull. 2004, 53, 443-446. (b) Vlad, P. F.; Kuchkova, K. I.; Aryku, A. N.; Deleanu, K. Efficient Synthesis of Onoceranediol from 12-Hydroperoxy-8α,12-epoxy-11-bishomodrimane. Russ. Chem. Bull. 2005, 54, 2656-2658. (c) Margaros, I.; Montagnon, T.; Vassilikogiannakis, G. Spiroperoxy Lactones from Furans in One Pot: Synthesis of (+)-Premnalane A. Org. Lett. 2007, 9, 5585-5588. (d) Dixon, D. D.; Lockner, J. W.; Zhou, Q.; Baran, P. S. Scalable, Divergent Synthesis of Meroterpenoids via “Borono-sclareolide”. J. Am. Chem. Soc. 2012, 134, 8432-8435. (e) Wang, J. L.; Li, H. J.; Wang, M. R.; Wang, J. H.; Wu, Y. C. A Six-step Synthetic Approach to Marine Natural Product (+)-Aureol. Tetrahedron Lett. 2018, 59, 945-948. 14 (a) Kluge, A. F.; Cloudsdale, I. S. Phosphonate Reagents for the Synthesis of Enol Ethers and One-carbon Homologation to Aldehydes. J. Org. Chem. 1979, 44, 4847. (b) Anderson, J. C.; Cornell, A. C.; Timothy, Hodgkinson, J.; Wilkinson, J. A. Efficient Diastereodelective Synthesis of either Form of meso-2,6-Dimethylcyclo-hexane Carboxaldehyde. Synth. Commun. 2001, 31, 939-946. 15 Yang, L. Y.; Chang, C. F.; Huang, Y. C.; Lee, Y. J.; Hu, C. C.; Tseng, T. H. The First Total Synthesis of Kynapcin-24 by Palladium Catalysis. Synthesis 2009, 1175-1179. 16 (a) Angle, S. R.; Neitzel, M. L. A Simple Method for the Synthesis of Substituted Benzylic Ketones: Homologation of Aldehydes via the in Situ Generation of Aryldiazomethanes from Aromatic Aldehydes. J. Org. Chem. 2000, 65, 6458-6461. (b) Aggarwal, V. K.; de Vicente, J.; Pelotier,; Holmes, I. P.; Bonnert, R. V. A Simple, User-friendly Process for the Homologation of Aldehydes Using Tosylhydrazone Salts. Tetrahedron Lett. 2000, 41, 10327-10331. (c) Aggarwal, V. K.; Alonso, E.; Hynd, G.; Lydon, K. M.; Palmer, M. J.; Porcelloni, M.; Studley, J. R. Catalytic Asymmetric Synthesis of Epoxides from Aldehydes Using Sulfur Ylides with In Situ Generation of Diazocompounds. Angew. Chem. Int. Ed. 2001, 40, 1430-1433. (d) Maiti, S.; Sengupta, S.; Giri, C.; Achari, B.; Banerjee, A. K. Enantiospecific Synthesis of 8-Epipuupehedione from (R)-(-)-carvone. Tetrahedron Lett. 2001, 42, 2389-2391. (e) Allwood, D. M.; Blakemore, D. C.; Ley, S. V. Preparation of Unsymmetrical Ketones from Tosylhydrazones and Aromatic Aldehydes via Formyl C–H Bond Insertion. Org. Lett. 2014, 16, 3064-3067. (f) Wang, Z.; Yang,



Page 14 of 14

Q.; Bai, Z.; Sun, J.; Jiang, X.; Song, H.; Wu, Y.; Zhang, W. Synthesis and Biological Evaluation of 2,3-Diarylthiophene Analogues of Combretastatin A-4. Med. Chem. Commun. 2015, 6, 971-976. (g) Xia, Y.; Qu, P.; Liu, Z.; Ge, R.; Xiao, Q.; Zhang, Y.; Wang, J. Catalyst-Free Intramolecular Formal Carbon Insertion into σ-C-C Bonds: A New Approach toward Phenanthrols and Naphthols. Angew. Chem. Int. Ed. 2013, 52, 2543-2546. (h) Su, N.; Theorell, J. A.; Wink, D. J.; Driver, T. G. Copper-Catalyzed Formation of α-Alkoxycycloalkenones from N-Tosylhydrazones. Angew. Chem. Int. Ed. 2015, 54, 12942-12946. 17 Whitesides, G. M. Curiosity and Science. Angew. Chem. Int. Ed. 2018, 57, 4126-4129. 18 Barluenga, J.; Moriel, P.; Valdés, C.; Aznar, F. N-Tosylhydrazones as Reagents for Cross-Coupling Reactions: A Route to Polysubstituted Olefins. Angew. Chem. Int. Ed. 2007, 119, 5683-5686. 19 (a) Dickinson, R. G.; Lotzkar, H. The Kinetics of the Thermal Isomerization of Cinnamic Acid Catalyzed by Iodine. J. Am. Chem. Soc. 1937, 59, 472-475. (b) Sonnet, P. E. Synthesis of the N-Isobutylamide of All-trans-2,6,8,10-Dodecatetraenoic Acid. J. Org. Chem. 1969, 34, 1147-1149. (c) Ping, B. G. Isolation and Identification of Amides from Piper callosum. Synthesis of Pipercallosine and Pipercallosidine. J. Chem. Soc. Perkin Trans. 1 1982, 1493-1498. (d) Gaukroger, K.; Hadfield, J. A.; Hepworth, L. A.; Lawrence, N. J.; McGown, A. T. Novel Syntheses of Cis and Trans Isomers of Combretastatin A-4. J. Org. Chem. 2001, 66, 8135-8138. (e) Hepperle, S. S.; Li, Q.; East, A. L. L. Mechanism of Cis/Trans Equilibration of Alkenes via Iodine Catalysis. J. Phys. Chem. A 2005, 109, 10975-10981.


Divergent Synthesis of Marine Natural Products ... - ACS Publications

Recommend Documents