Synthesis and antiproliferative evaluation of new zampanolide mimics

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Synthesis and antiproliferative evaluation of new

zampanolide mimics†

Cite this: DOI: 10.1039/c9ob00556k

a

b,c

Guanglin Chen, Manee Patanapongpibul, Ziran Jiang, Qiang Zhang,

b,c

d

a

Shilong Zheng, Guangdi Wang, James D. White and Qiao-Hong Chen

*

(−)-Zampanolide is a marine microtubule-stabilizing macrolide that has been shown by in vitro experiments

to be a promising anticancer lead compound. Through its unique covalent-binding with β-tubulin,

zampanolide exhibits cytotoxic potency towards multi-drug resistant cancer cells that is superior to

paclitaxel. However, the limited availability of zampanolide impedes its further in vivo evaluation as a viable

drug candidate. Zampanolide is envisioned to become more drug-like if its chemically fragile side chain can

be stabilized; hence, this project aims to develop mimics of zampanolide with a stable side chain using

straightforward synthetic methods. To this end, twelve novel zampanolide mimics (51–62) with conjugated

and planar side chains have been synthesized via a 24-step sequence for each mimic from commercially

available 2-butyn-1-ol as starting material. A Horner–Wadsworth–Emmons reaction incorporates the

α,β-unsaturated ketone side chain and also closes the core macrocycle. WST-1 cell proliferation assays in

three docetaxel-sensitive and two docetaxel-resistant human prostate cancer cell models conﬁrm that a

suitably designed side chain can serve as a bioisostere for the N-acyl hemiaminal side chain in zampanolide.

Mimic 52 with a 17R chiral center was identiﬁed as the optimal candidate with IC₅₀values of 0.29–0.46 µM

against both docetaxel-sensitive (PC-3 and DU145) and docetaxel-resistant prostate cancer cell lines

Received 8th March 2019,

Accepted 25th March 2019

DOI: 10.1039/c9ob00556k

(PC-3/DTX and DU145/DTX). Zampanolide mimic 52 exhibited equivalent antiproliferative potency towards

rsc.li/obc

both docetaxel-sensitive and docetaxel-resistant cell lines, with relative resistance in the range of 0.9–1.6.

accumulation of androgen receptor that is the driving force for

Introduction

5

,6

prostate cancer cell growth and progression.

7

Prostate cancer has the highest incidence and the second

highest mortality rate of all cancers in American men.

The marine macrolide (−)-zampanolide (1, Fig. 1) is a

1

unique MSA with covalent-binding to β-tubulin and low nano-

8

Approximately 30 000 US men die each year of castration-resist- molar cytotoxic potency against multi-drug resistant cancers. Its

ant prostate cancer (CRPC) due to progression of resistance to mechanism of action is similar to that of the clinically proven

the current treatments. Two microtubule-stabilizing cytotoxic drug paclitaxel (Taxol®) and its sister drugs docetaxel and cab-

9

agents (MSA), docetaxel and cabazitaxel, are the only chemo- azitaxel which bind to the taxane luminal pocket of β-tubulin.

therapeutic agents that show a survival benefit for patients However, the covalent nature of zampanolide binding to tubulin

with prostate cancer. Currently, they are standard first-line and distinguishes it from paclitaxel which involves non-covalent

2

–4

second-line treatments for CRPC. Two mechanisms respon- binding to β-tubulin. A 1.8 Å high-resolution crystal structure of

sible for the action of MSAs as anti-prostate cancer agents are α,β-tubulin in complex with (−)-zampanolide (1) established that

(

1) promotion of mitotic arrest, and (2) suppression of nuclear the macrolide binds covalently at residues Asn228 and His229 at

10

the taxane luminal site. (−)-Zampanolide (1) is therefore an

extremely promising drug candidate and/or lead compound for

clinical treatment of both drug-sensitive and resistant prostate

cancer. This expectation is based on the fact that covalently

bound agents in contrast to their non-covalently bound counter-

parts are eﬀective in P-glycoprotein overexpressing cells because

(1) they cannot be pumped out of the cell after they bind, and

a

Department of Chemistry, California State University, Fresno, 2555 E. San Ramon

Avenue, M/S SB70, Fresno, CA 93740, USA. E-mail: qchen@csufresno.edu

b

Department of Chemistry, Xavier University of Louisiana, 1 Drexel Drive,

New Orleans, LA 70125, USA

c

RCMI Cancer Research Center, Xavier University of Louisiana, 1 Drexel Drive,

New Orleans, LA 70125, USA

d

(

2) they are not aﬀected by upregulation of tubulin isotypes or by

Department of Chemistry, Oregon State University, 153 Gilbert Hall, Corvallis,

11

mutations in tubulin.

OR 97331, USA

Although (−)-zampanolide is a unique and promising MSA

that opens new routes to more eﬀective chemotherapeutics for

†

Electronic supplementary information (ESI) available. See DOI: 10.1039/

c9ob00556k

This journal is © The Royal Society of Chemistry 2019

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Fig. 1 Structures of (−)-zampanolide (1) and epothilone A (2).

Scheme 1 Thermolysis of (+)-zampanolide (7) to (+)-dactylolide (8).

1

5

CRPC, this important lead compound needs further investi- the N-acetyl hemiaminal side chain (Scheme 1) and Higa

gation of its in vivo anticancer eﬃcacy, pharmacokinetics, and and co-workers described the instability of (−)-zampanolide in

1

2

toxicity, in order to guide the compound towards a clinical CDCl

3

when they initially characterized its structure.

chemotherapeutic. Unfortunately, the limited supply of Furthermore, four synthetic approaches to zampanolide

(

−)-zampanolide creates a serious obstacle for its further evalu- encountered diﬃculties in assembling the N-acyl hemiaminal

1

3,15–18

ation as a viable drug candidate. (−)-Zampanolide was isolated side chain of the molecule.

from marine sponge sources in only 0.001% yield at best

The N-acyl hemiaminal side

8

,12

chain of 1 is critical for its nanomolar antiproliferative potency

and its syntheses proceed with a highest overall yield at barely in certain cell models, and removal of the side chain results in

1

3–19

8,9,20

0

.9%.

Equally important is the probability that zampano- a loss of 10- to 1000-fold potency in those cell models.

lide will possess poor pharmacokinetic profiles as a drug can- This report describes the synthesis and antiproliferative evalu-

didate, due in part to its chemically fragile side chain. Thus, ation of zampanolide mimics in which the N-acyl hemiaminal

Smith and co-workers reported that synthetic (+)-zampanolide side chain is replaced by more stable and easily accessible

(

7) decomposed at 85 °C into (+)-dactylolide (8) by cleavage of planar and conjugated appendages (6, Fig. 2).

Fig. 2 Structures of (17S)-desTHPzampanolide (3), desTHPdactylolides (4 & 5) and generalized structure (6) for target mimics.

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Synthesis

Our synthetic strategy envisioned attachment of side chains to

Results and discussion

Design of zampanolide mimics

Our set of side chains was inspired by the fact that the side (17S) and (17R) aldehydes 13 and 14 prior to closure of the

chains of (−)-zampanolide (1) and epothilone A (2) bind to the macrolactone by intramolecular Horner–Wadsworth–Emmons

same M-loop of β-tubulin (Fig. 3). Six side chains with (HWE) condensation since this would avoid potential inter-

diﬀerent aromatic rings were selected as bioisosteric substi- ference by latent functional groups within the ester framework

tutions for the zampanolide N-acyl hemiaminal side chain and (Scheme 2). Esters 9 and 10 have been previously synthesized

were designed to have the chemically unstable hemiaminal by us from commercially available 2-butyn-1-ol via a 17-step

2

1

moiety (blue circle in Fig. 3) replaced by an α,β-unsaturated sequence and were used as source materials for 13 and 14.

ketone. Since the epothilone side chain (Fig. 3) does not As shown in Scheme 2, debenzylation of p-methoxybenzyl

contain a hydroxyl substituent, the C20 alcohol of zampano- ethers 9 and 10 with DDQ followed by oxidation of the result-

lide is removed to aﬀord a more facile synthesis. The carbonyl ing primary alcohols 11 and 12 with Dess–Martin periodinane

oxygen of the zampanolide side chain is preserved in order to (DMP) yielded aldehydes 13 and 14 in an overall 48% yield.

retain hydrogen bonding to the NH group of Thr276 in

Commercially available methyl aryl carboxylates 15–20 were

β-tubulin and the conjugated E,Z-pentadiene moiety of zampa- used as starting materials to prepare six keto phosphonates

nolide is replaced by planar benzenoid and heteroaromatic 21–26 (Scheme 3). Treatment of the carboxylates with the

rings to retain hydrophobic contacts between the mimic side lithium anion of diethyl methyl phosphonate, obtained by

chain and residues in the M-loop of β-tubulin. For the exposure of the phosphonate to n-butyllithium in THF, gave

macrolactone core, we have adopted Altmann’s (17S)- the keto phosphonates in 50–99% yield as illustrated in

desTHPdactylolide (4) and its (17R)-enantiomer (5) as our tem- Scheme 3. In order to avoid a diﬃcult separation of the keto

plate on the ground that desTHP-zampanolide (3) in which the phosphonate products 21–26 from unreacted diethyl methyl

tetrahydropyran subunit is replaced by a direct ether linkage, phosphonate, it was necessary to restrict the quantity of the

1

8

exhibits submicromolar activity. This simplification which latter reagent to no more than 1.2 equivalents. Horner–

removes two stereogenic centers enables a more practical syn- Wadsworth–Emmons (HWE) condensation of each keto phos-

thesis of our mimics. A generalized structure (6) representing phonate with aldehydes 13 and 14 gave trans α,β-unsaturated

our target mimics is shown in Fig. 2.

ketones 27–38 containing six terminal aryl units represented

Fig. 3 Design of stabilized side chains.

Scheme 2 Synthesis of key intermediates (17S)-13 and (17R)-14.

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mimics with IC50 values of 0.29–0.86 µM towards docetaxel-

sensitive prostate cancer cell lines (PC-3, DU145, and LNCaP).

It is noteworthy that our (17S) zampanolide mimic 51 has

1

8

potency similar to the known zampanolide analog (3), with

mimic 51 showing about 13–18 times increased potency

against three docetaxel-sensitive prostate cancer cell lines and

3

exhibiting 18-fold greater potency towards PC-3 cells com-

pared to (17S) desTHPdactylolide (4) (Fig. 4). This indicates

that an appropriately designed side chain can serve as a bio-

isostere for the chemically unstable N-acetyl hemiaminal side

chain of zampanolide. Interestingly, inversion of the C17

chiral center of 51 as its (17R)-enantiomer 52 resulted in sig-

nificantly improved potency towards five human prostate

cancer cell lines, especially against docetaxel-resistant cell

lines. Compound 52 was therefore identified as the optimal

mimic with IC50 values of 0.29–0.46 µM against both doce-

taxel-sensitive (PC-3 and DU145) and docetaxel-resistant pros-

tate cancer cell lines (PC-3/DTX and DU145/DTX). The relative

resistance of PC-3/DTX over PC-3 is 0.9 while the relative resis-

tance of DU145/DTX over DU145 is 1.6.

Eﬀects of 52 on PC-3 cell apoptosis

The F2N12S and SYTOX AADVanced double staining assay in a

flow cytometer was used for discrimination between early

apoptotic PC-3 cells and late apoptotic/necrotic PC-3 cells

when treated with 52 at 0, 1, 5, 10, 20, 30, 50, and 100 µM con-

centrations for 16 h. As shown in Fig. 5, mimic 52 can signifi-

cantly induce apoptotic cell death in the androgen-insensitive

PC-3 prostate cancer cell line in a dose-dependent manner

after a 16 h treatment. Specifically, treatment of 52 at 1–10 µM

led to 13–18% of PC-3 cells in the early phase of apoptosis as

compared with control cells; exposure of PC-3 cells to 52 at

Scheme 3 Synthesis of side chain precursors (21–26).

as Ar1–Ar6 (Scheme 4). Since extractive work-up of these reac-

tions resulted in partial hydrolysis of the ester, the reaction

mixture in each case was filtered through a pad of anhydrous

sodium sulfate and silica gel which was rinsed with THF. The

crude product was then purified by preparative TLC. Global de-

protection of bis-TBS ethers 27–38 with HF-pyridine complex

furnished diols 39–50 which were oxidized with Dess–Martin

periodinane to the corresponding keto aldehydes. Since chro-

matographic purification of these keto aldehydes caused sig-

nificant decomposition, they were used directly in an intra-

molecular HWE condensation mediated by Ba(OH)₂to

2

9

0–50 µM induces 43–51% early apoptotic cells together with

–16% late apoptotic/necrotic cells.

Conclusion

produce zampanolide mimics 51–62. As with ketones 27–38, In summary, twelve new zampanolide mimics with diﬀerent

extractive work-up again caused partial hydrolysis of the ester planar and conjugated side chains have been synthesized via a

and purification of 51–62 was therefore carried out as before 24-step sequence for each mimic starting from commercially

by filtration followed by preparative TLC.

available 2-butyn-1-ol. Horner–Wadsworth–Emmons reactions

were used for incorporating the stable mimic side chains and

for closing the macrolactone ring. All mimics showed greater

potency than desTHPdactylolide in both docetaxel-sensitive

Anti-proliferative activity towards prostate cancer cell lines and

structure–activity relationships

The anti-proliferative activity of twelve zampanolide mimics and docetaxel-resistant prostate cancer cell lines, suggesting

51–62, six pairs of enantiomers) has been evaluated in three that the planar, conjugated side chains of these compounds

(

docetaxel-sensitive prostate-cancer cell lines (PC-3, DU145, and do make a significant contribution to their potency. Our find-

LNCaP) and two docetaxel-resistant prostate cancer cell lines ings indicate that an appropriately designed side chain can

(PC-3/DTX and DU145/DTX) using the WST-1 cell proliferation serve as a bioisostere for the chemically unstable N-acetyl

assay with docetaxel as a positive control. As illustrated in hemiaminal side chain in (−)-zampanolide. The IC50 values of

Table 1, the IC50 values for our twelve zampanolide mimics are the optimal mimic 52 fall in the range 0.29–0.46 µM against

in the range of 0.29–5.59 µM. These values are smaller than both docetaxel-sensitive (PC-3 and DU145) and docetaxel-

those of desTHPdactylolides 4 and 5, suggesting that the side resistant prostate cancer cell lines (PC-3/DTX and DU145/DTX).

chain can make a significant contribution to the potency of The relative resistance of 52 towards docetaxel-resistant pros-

this group of compounds. Mimics 51 and 52 are the optimal tate cancer cell lines falls in the range 0.9–1.6.

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Scheme 4 Synthesis of zampanolide mimics (51–62).

chromatography plates loaded with silica gel 60 GF254 (EMD

Experimental section

General information

Millipore Corporation). Starting materials 9 and 10 were syn-

21

thesized using the procedure previously described by us.

Optical rotations were measured on a RUDOLPH Research

Analytical Autopol III Automatic Polarimeter. IR spectra were

recorded on a Nicolet Nexus 470 FTIR spectrophotometer.

General procedure for the synthesis of diethyl (2-oxo-2-

arylethyl)phosphonates (21–26)

HRMS were obtained on an Orbitrap mass spectrometer with To a solution of diethyl methyl phosphonate (182 mg,

electrospray ionization (ESI). NMR spectra were obtained on a 1.2 mmol) in anhydrous THF (2.5 mL) at −78 °C was added

Bruker Fourier 300 spectrometer in CDCl . The chemical shifts dropwise n-butyllithium (0.48 mL, 2.5 M, 1.2 mmol), and the

3

are given in ppm referenced to the respective solvent peak, and solution was stirred at −78 °C for 30 min prior to addition of a

coupling constants are reported in Hz. Anhydrous THF solution of the relevant methyl arylcarboxylate in anhydrous

and dichloromethane were purified by a PureSolv MD 7 THF (1 mL). The resulting mixture was stirred at −78 °C for an

Solvent Purification System from Innovative Technologies additional

5 h before being quenched with saturated

(MB-SPS-800). All other reagents and solvents were purchased ammonium chloride (20 mL). The mixture was extracted with

from commercial sources and were used without further purifi- ethyl acetate (10 mL × 3), and the combined organic extract

cation. Silica gel column chromatography was performed was dried over anhydrous sodium sulfate and was concen-

using silica gel (32–63 µm). Preparative thin-layer chromato- trated in vacuo. The crude product was subjected to PTLC puri-

graphy (PTLC) separations were carried out on thin layer fication, eluting with dichloromethane/methanol (95 : 5) three

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Table 1 Anti-proliferative activity of zampanolide mimics 51–62

a

IC50 : (µM)

a

IC50 ^:⁽g^µ^M⁾

b

c

d

e

f

c

Compounds

Docetaxel

PC-3

PC-3/DTX

R/S

DU145

DU145/DTX

R/S

LNCaP

0.0019 ± 0.0006

11.91 ± 3.68

0.88 ± 0.19

2.17 ± 0.19

2.30 ± 0.57

2.10 ± 0.28

2.85 ± 0.11

2.25 ± 0.83

5.27 ± 0.65

0.35 ± 0.05

3.04 ± 0.25

0.61 ± 0.01

1.03 ± 0.08

2.90 ± 0.30

2.65 ± 0.30

2.34 ± 0.25

15.42 ± 1.23

2.97 ± 0.09

4.07 ± 1.41

2.55 ± 0.63

2.13 ± 0.50

2.17 ± 0.02

1.72 ± 0.12

4.41 ± 0.44

0.30 ± 0.05

2.75 ± 0.05

0.94 ± 0.05

1.09 ± 0.10

2.91 ± 0.20

2.31 ± 0.40

1232

1.3

3.4

1.9

1.1

1.0

0.8

0.9

1.5

1.0

0.9

0.0012 ± 0.0003

11.58 ± 0.21

0.86 ± 0.25

2.70 ± 0.91

2.94 ± 0.09

5.59 ± 0.91

3.16 ± 0.38

2.30 ± 0.04

5.41 ± 0.11

0.29 ± 0.03

3.06 ± 0.24

3.73 ± 0.72

2.09 ± 0.48

4.50 ± 0.49

2.93 ± 0.65

8.58 ± 0.39

15.33 ± 1.24

2.78 ± 0.16

2.24 ± 0.22

2.31 ± 0.20

4.87 ± 1.44

1.92 ± 0.10

2.25 ± 0.67

8.03 ± 0.13

0.46 ± 0.10

3.35 ± 0.27

2.57 ± 0.76

1.66 ± 0.32

4.43 ± 0.23

3.43 ± 0.16

7150

1.3

3.2

0.8

0.9

0.6

1.0

1.5

1.6

1.1

0.7

0.8

1.0

1.2

0.0002 ± 0.00005

13.46 ± 0.90

0.76 ± 0.29

1.78 ± 0.52

3.85 ± 0.43

4.04 ± 0.49

2.10 ± 0.20

2.19 ± 0.66

3.22 ± 0.31

0.35 ± 0.02

3.19 ± 0.98

1.39 ± 0.18

3.00 ± 0.53

4.60 ± 0.76

3.74 ± 1.43

4

5

6

5

6

(17S)

1 (17S)

3 (17S)

5 (17S)

7 (17S)

9 (17S)

1 (17S)

(17R)

2 (17R)

4 (17R)

6 (17R)

8 (17R)

0 (17R)

2 (17R)

a

IC50 is the compound concentration eﬀective in inhibiting 50% of cell viability measured by WST-1 cell proliferation assay after 3 days of

b

exposure. The data are presented as the mean ± standard deviation of the mean. Human androgen-insensitive prostate cancer cell line derived

from bone metastasis of prostate tumor. Docetaxel-resistant PC-3 prostate cancer cell line. The relative resistance of the two cell lines obtained

by dividing the IC50 value of the resistance cell line by that of the parental cell line. Human androgen-insensitive prostate cancer cell line

derived from brain metastasis of prostate tumor. Docetaxel-resistant DU145 prostate cancer cell line. Human androgen-sensitive prostate

cancer cell line.

c

d

e

f

g

Fig. 4 Potency of mimics 51 and 3.

Fig. 5 Evolution of viable, apoptotic, and necrotic PC-3 cells populations in response to increasing dosages of 52.

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times, and the pure compound was retrieved from PTLC silica Synthesis of alcohols 11 and 12

gel by extraction with acetone. Characterization, yield and

NMR data for each product are given below:

To a solution of 9 (99 mg, 0.12 mmol) in dichloromethane

3 mL) was added water (0.6 mL) followed by 2,3-dichloro-5,6-

(

Diethyl (2-(1-methyl-1H-imidazol-5-yl)-2-oxoethyl)phospho-

1

cyano-1,4-benzoquinone (54 mg, 0.24 mmol), and the reaction

mixture was stirred vigorously at room temperature for 1 h

before being quenched by saturated aqueous sodium bi-

carbonate (20 mL). The mixture was extracted with dichloro-

methane (20 mL × 3), and the combined organic extracts

were dried over anhydrous sodium sulfate and concentrated

in vacuo. The crude product was purified by PTLC, using

nate (21). Pale yellow oil; 64% yield. H NMR (300 MHz,

CDCl

3

) δ 7.97 (s, 1H, imidazole–H), 7.26 (overlapped, 1H, imid-

CH ), 4.00 (s, 3H,

azole–H), 4.22–4.12 (m, 4H, 2 × OCH

2

3

N–CH ), 3.45 (d, J = 22.5 Hz, 2H, COCH PO), 1.33 (t, J = 6.9 Hz,

3

2

1

3

6

1

2 3 3

H, 2 × OCH CH ). C NMR (75 MHz, CDCl ) δ 181.8 (d, J =

.8 Hz), 144.1, 140.4, 130.8, 62.8 (d, J = 6.0 Hz), 39.9 (d, J =

27.5 Hz), 35.1, 16.5 (d, J = 6.0 Hz).

hexane/ethyl acetate (1 : 1) as eluent, to yield pure 11 as a color-

Diethyl (2-(oxazol-4-yl)-2-oxoethyl)phosphonate (22). Pale

1

less oil in 74% yield. H NMR (300 MHz, CDCl

3

) δ 7.81 (7.79)

yellow oil; 70% yield. H NMR (300 MHz, CDCl

3

) δ 8.31 (d, J =

(

dd, J = 16.2, 11.7 Hz, 1H, H-3), 6.07 (6.03) (d, J = 12.0 Hz, 1H,

H-4), 5.70 (d, J = 15.0 Hz, 1H, H-2), 5.39 (t, J = 6.6 Hz,

H, H-14), 5.06–4.95 (m, 1H, H-17), 4.17–3.99 (m, 5H,

0

(

1

7

.9 Hz, 1H, oxazole–H), 7.89 (d, J = 0.6 Hz, 1H, oxazole), 4.11

q, J = 7.2 Hz, 2H, 1 × OCH CH ), 4.09 (q, J = 7.2 Hz, 2H,

), 3.58 (d, J = 22.8 Hz, 2H, COCH PO), 1.24 (t, J =

.2 Hz, 6H, 2 × OCH CH ). C NMR (75 MHz, CDCl ) δ 186.8

2

3

1

× OCH

2

CH

3

2

1

3

2 × OCH

2

CH

3

2

& H-7), 3.94 (d, J = 6.6 Hz, 2H, H -13), 3.80–3.59

2

3

(

m, 2H, H -18), 3.68 (t, J = 6.3 Hz, 2H, H -11), 3.44 (t, J =

2

(d, J = 6.8 Hz), 151.6, 144.1, 140.7 (d, J = 2.3 Hz), 63.3 (d, J =

6.3 Hz, 2H, H

2

-9), 2.98 (2.72) (dd, J = 13.5, 3.0 Hz, 1H, H-16),

6

.0 Hz), 39.5 (d, J = 128.3 Hz), 16.8 (d, J = 6.3 Hz).

2.59 (2.43) (dd, J = 13.5, 7.2 Hz, 1H, H-16), 2.43–2.23 (m, 2H,

Diethyl (2-oxo-2-phenylethyl)phosphonate (23). Colorless oil;

1

H -8), 2.06–1.89 (m, 2H, H -6), 1.94 (1.93) (s, 3H, 5-CH ),

2

3

5

0% yield. H NMR (300 MHz, CDCl

3

) δ 8.01 (d, J = 7.2 Hz, 2H,

1

6

0

.80–1.72 (m, 2H, H

2

-10), 1.74 (s, 3H, 15-CH

3

), 1.33 (t, J =

phenyl–H), 7.59 (tt, J = 7.2, 1.5 Hz, 1H, phenyl–H), 7.48 (t, J =

2 3

.9 Hz, 6H, 2 × OCH CH ), 0.88 (s, 9H, TBS), 0.86 (s, 9H, TBS),

7

.8 Hz, 2H, phenyl–H), 4.15 (q, J = 7.2 Hz, 2H, 1 × OCH CH ),

2 3

.06 (0.05) (s, 3H, TBS), 0.04 (s, 6H, TBS), 0.02 (0.01) (s, 3H,

4

.12 (q, J = 7.2 Hz, 2H, 1 × OCH

PO), 1.28 (t, J = 7.2 Hz, 6H, 2 × OCH

75 MHz, CDCl ) δ 192.0, 136.6, 133.7, 129.1, 128.6, 62.7 (d, J =

2 3

CH ), 3.63 (d, J = 22.8 Hz,

13

1

3

TBS). C NMR (75 MHz, CDCl

141.4), 135.6, 126.9 (126.3), 125.0, 119.9 (119.8), 73.6 (73.5), 68.7

67.9), 67.3, 67.0, 63.7 (63.6), 62.0, 60.2, 41.1 (d, J = 36.8 Hz),

0.6, 34.8 (34.3) (d, J = 135.0 Hz), 26.6 (26.3), 26.1, 25.9 (25.8),

3

) δ 167.2, 147.5 (147.1), 141.7

COCH

(

2

2 3

CH ). C NMR

(

4

3

6

.0 Hz), 38.5 (d, J = 135 Hz), 16.3, 16.2.

Diethyl (2-oxo-2-(4-fluorophenyl)ethyl)phosphonate (24).

1

18.5 (18.0), 16.8, 16.6 (16.5), 16.4 (16.5), −3.4 (−4.7), −4.8 (−5.2).

Colorless oil; 86% yield. H NMR (300 MHz, CDCl ) δ 8.06

3

Antipode 12 was prepared from 10 in a similar way as a

(dd, J = 9.0, 5.4 Hz, 2H, phenyl–H), 7.15 (t, J = 9.0 Hz, 2H,

1

colorless oil in 83% yield. H NMR (300 MHz, CDCl

3

) δ 7.84

phenyl–H), 4.18–4.09 (m, 4H, 2 × OCH CH ), 3.60 (d, J =

2

3

(

7.82) (dd, J = 15.0, 11.7 Hz, 1H, H-3), 6.07 (6.05) (d, J =

2

2.8 Hz, 2H, COCH PO), 1.29 (t, J = 7.2 Hz, 6H, 2 × OCH CH ).

C NMR (75 MHz, CDCl ) δ 190.4 (d, J = 6.8 Hz), 166.1 (d, J =

3

2

3

1

3

12.0 Hz, 1H, H-4), 5.72 (d, J = 15.3 Hz, 1H, H-2), 5.41 (t, J =

6

2

.6 Hz, 1H, H-14), 5.06–4.97 (m, 1H, H-17), 4.21–3.92 (m, 5H,

× OCH CH & H-7), 3.93 (d, J = 6.6 Hz, 2H, H -13), 3.81–3.57

2

55 Hz), 133.0, 131.9 (d, J = 3.0 Hz), 115.8 (d, J = 21.8 Hz), 62.8

2

3

2

(d, J = 6.8 Hz), 38.7 (d, J = 129 Hz), 16.3 (d, J = 6.0 Hz).

(

m, 2H, H -18), 3.68 (t, J = 6.3 Hz, 2H, H -11), 3.45 (t, J = 6.6

2 2

Diethyl (2-oxo-2-(2-fluorophenyl)ethyl)phosphonate (25).

1

Hz, 2H, H

2

-9), 2.97 (2.71) (dd, J = 13.5, 3.3 Hz, 1H, H-16), 2.58

Colorless oil; 86% yield. H NMR (300 MHz, CDCl

3

) δ 7.88 (dt,

(

2.42) (dd, J = 13.2, 6.9 Hz, 1H, H-16), 2.42–2.22 (m, 2H, H -8),

2

J = 7.8, 2.1 Hz, 1H, phenyl–H), 7.60–7.52 (m, 1H, phenyl–H),

.28–7.22 (m, 1H, phenyl–H), 7.17 (dt, J = 8.1, 0.9 Hz, 1H,

phenyl–H), 4.19–4.10 (m, 4H, 2 × OCH CH ), 3.73 (dd, J = 22.2,

2

.05–1.88 (m, 2H, H -6), 1.94 (1.92) (s, 3H, 5-CH ), 1.83–1.71

2

3

7

(

m, 2H, H

2

-10), 1.73 (s, 3H, 15-CH

3

), 1.33 (1.32) (t, J = 6.9 Hz,

2

3

2 3

6H, 2 × OCH CH ), 0.88 (s, 9H, TBS), 0.86 (s, 9H, TBS), 0.06

1

.2 Hz, 2H, COCH PO), 1.28 (t, J = 6.9 Hz, 6H, 2 × OCH CH ).

C NMR (75 MHz, CDCl ) δ 189.9 (dd, J = 7.5, 3.0 Hz), 161.8

3

2

3

1

3

(0.04) (s, 3H, TBS), 0.03 (s, 6H, TBS), 0.01 (−0.02) (s, 3H, TBS).

1

3

C NMR (75 MHz, CDCl

3

) δ 167.2, 147.6 (147.2), 141.8 (141.5),

(d, J = 247.5 Hz), 135.2 (d, J = 9.0 Hz), 131.0, 125.5 (dd, J = 11.3,

135.6, 126.9 (126.3), 125.0, 112.0 (119.8), 73.64 (73.59), 68.8

2

.3 Hz), 124.5 (d, J = 3.8 Hz), 116.6 (d, J = 24.0 Hz), 62.5 (d,

(

68.0), 67.4, 67.0, 63.7, 61.9, 60.2, 41.2 (d, J = 37.5 Hz), 40.7

40.6), 34.8 (34.3) (d, J = 135.0 Hz), 26.6 (26.4), 26.1, 25.9 (25.8),

J = 6.0 Hz), 42.4 (dd, J = 129.8, 8.3 Hz), 16.2 (d, J = 6.0 Hz).

Diethyl (2-oxo-2-(3-fluorophenyl)ethyl)phosphonate (26).

1

18.5 (18.0), 16.8, 16.6 (16.5), 16.4 (16.5), −4.65 (−4.69),

4.7 (−5.2).

Colorless oil; 99% yield. H NMR (300 MHz, CDCl ) δ 7.81

3

−

(ddd, J = 7.5, 1.5, 0.9 Hz, 1H, phenyl–H), 7.70 (ddd, J = 9.3, 2.4,

1

7

2

7

.8 Hz, 1H, phenyl–H), 7.47 (dt, J = 8.1, 5.4 Hz, 1H, phenyl–H),

.29 (ddt, J = 8.4, 2.7, 1.2 Hz, 1H, phenyl–H), 4.20–4.09 (m, 4H,

Synthesis of aldehydes (17S) 13 and (17R) 14

× OCH

.2 Hz, 6H, 2 × OCH

2

CH

3

), 3.51 (d, J = 22.8 Hz, 2H, COCH

2

PO), 1.29 (t, J = To a solution of 11 (134 mg, 0.19 mmol) in dichloromethane

1

3

2

CH

3

). C NMR (75 MHz, CDCl ) δ 190.8 (2 mL) at room temperature was added Dess–Martin periodi-

3

(

1

dd, J = 6.8, 2.3 Hz), 162.8 (d, J = 246.8 Hz), 138.6 (dd, J = 6.2, nane (118 mg, 0.28 mmol) and the reaction mixture was

.7 Hz), 130.4 (d, J = 7.5 Hz), 125.0 (d, J = 3.0 Hz), 120.8 (d, stirred for 10 min after which a second portion of Dess–Martin

J = 22.5 Hz), 115.7 (d, J = 22.5 Hz), 62.8 (d, J = 6.8 Hz), 38.8 (d, periodinane (118 mg, 0.28 mmol) was added. The resulting

J = 129.0 Hz), 16.3 (d, J = 6.0 Hz).

mixture was stirred for an additional 30 min, and saturated

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sodium bicarbonate (8 mL) and saturated sodium thiosulfate (dd, J = 15.3 Hz, 1H, H-19), 6.75 (dd, J = 15.0, 4.2 Hz, 1H,

8 mL) were added. The suspension was stirred for 15 min and H-18), 6.12 (d, J = 11.7 Hz, 1H, H-4), 5.83 (d, J = 15.0 Hz, 1H,

was extracted with dichloromethane (10 mL × 3). The com- H-2), 5.75–5.68 (m, 1H, H-17), 5.45 (t, J = 6.3 Hz, H-14),

bined organic extracts were dried over anhydrous sodium 4.16–4.03 (m, 5H, 2 × OCH CH & H-7), 4.06 (s, 3H, N–CH ),

(

2

3

sulfate and the dried extract was concentrated under vacuum. 3.95 (d, J = 6.6 Hz, 2H, H -15), 3.68 (t, J = 6.3 Hz, 2H, H -11),

2

The crude product was subjected to PTLC purification, eluting 3.47 (t, J = 6.3 Hz, 2H, H

with hexane/ethyl acetate (40 : 60, v/v), to give pure 13 as a pale 2.13–1.95 (m, 2H, H

2

-9), 2.67–2.37 (m, 4H, H

-6), 1.93 (s, 3H, 5-CH ), 1.80–1.72

3

2

-16 & H -8),

2

1

yellow oil in 74% yield. H NMR (300 MHz, CDCl ) δ 9.55 (d, (m, 2H, H -10), 1.74 (s, 3H, 15-CH ), 1.33 (t, J = 7.2 Hz, 6H,

3

2

3

J = 6.3 Hz, 1H, H-18), 7.67 (dd, J = 15.0, 11.7 Hz, H-3), 6.11 (d, 2 × OCH

J = 11.1 Hz, 1H, H-4), 5.84 (d, J = 15.0 Hz, 1H, H-2), 5.45 (t, J = (s, 3H, TBS), 0.04 (s, 6H, TBS), −0.02 (s, 3H, TBS). C NMR

2

CH

3

), 0.88 (s, 9H, TBS), 0.83 (0.81) (s, 9H, TBS), 0.06

13

6

2

6

4

1

6

0

.3 Hz, 1H, H-14), 5.19–5.13 (m, 1H, H-17), 4.18–4.06 (m, 5H, (300 MHz, CDCl ) δ 179.7, 166.5, 147.33 (147.29), 144.02

3

× OCH

2

CH

3

& H-7), 3.96 (d, J = 6.3 Hz, 2H, H

2

-13), 3.68 (t, J = (143.98), 142.4, 139.0, 136.7, 134.21 (134.17), 127.8, 126.72

.3 Hz, 2H, H

2

-11), 3.47 (t, J = 6.3 Hz, 2H, H -9), 2.61–2.42 (m, (126.68), 126.1, 125.85 (125.75), 118.7, 70.86 (70.79), 67.2, 67.1,

2

H, H -16 & H -8), 2.05–1.97 (m, 2H, H -6), 1.92 (s, 3H, 5-CH ), 66.94 (66.85), 61.75 (61.67), 60.1, 44.6, 41.8, 36.2, 35.0, 34.4,

2

3

.81–1.74 (m, 2H, H

.0 Hz, 6H, 2 × OCH

.05 (s, 3H, TBS), 0.04 (s, 6H, TBS), −0.03 (s, 3H, TBS).

2

-10), 1.72 (s, 3H, 15-CH

3

), 1.33 (t, J = 34.3, 33.1, 26.1, 25.9, 25.28 (25.22), 18.5, 17.9, 16.9, 16.6 (16.5),

2

CH

3

), 0.89 (s, 9H, TBS), 0.83 (s, 9H, TBS), −4.6, −4.7, −5.2.

(17R) Di-TBS ether 28. Yellow oil, 63% yield. H NMR

) δ 198.8, 167.0 (166.9), 148.0 (147.9), (300 MHz, CDCl ) δ 8.32 (8.31) (d, J = 0.9 Hz, 1H, oxazole–H),

43.2, 133.6, 126.6, 126.1, 117.9, 76.53 (76.49), 67.2, 67.1, 67.0 7.94 (7.92) (d, J = 0.9 Hz, 1H, oxazole–H), 7.63 (7.62) (dd, J =

1

3

C NMR (75 MHz, CDCl

3

1

(

1

66.9), 61.9 (61.8), 60.1, 41.8, 39.1, 36.3, 34.5, 33.1, 26.1, 25.9, 15.0, 11.7 Hz, 1H, H-3), 7.164 (7.158) (dd, J = 15.9, 4.8 Hz,

8.0, 16.8, 16.63 (16.55), −4.59 (−4.66), −5.20. H-18), 7.04 (7.03) (dd, J = 15.6, 1.2 Hz, 1H, H-19), 6.09 (d, J =

Antipode 14 was prepared from 12 in a similar way as a 11.7 Hz, 1H, H-4), 5.82 (d, J = 15.0 Hz, 1H, H-2), 5.75–5.68

1

colorless oil in 80% yield. H NMR (300 MHz, CDCl ) δ 9.52 (d, (m, 1H, H-17), 5.43 (t, J = 6.6 Hz, 1H, H-14), 4.21–4.03 (m, 5H,

3

J = 2.1 Hz, 1H, H-18), 7.64 (dd, J = 15.0, 11.7 Hz, H-3), 6.08 (d, 2 × OCH

2

CH

3

, H-7), 3.94 (d, J = 6.6 Hz, 2H, H

2

-13), 3.67 (t, J =

J = 11.7 Hz, 1H, H-4), 5.81 (d, J = 15.0 Hz, 1H, H-2), 5.43 (t, J = 6.0 Hz, 2H, H

2

-11), 3.45 (t, J = 6.6 Hz, 2H, H -9), 2.62–2.42 (m,

2

6

2

6

4

1

.6 Hz, 1H, H-14), 5.16–5.11 (m, 1H, H-17), 4.15–4.02 (m, 5H, 4H, H -16 & H -8), 2.05–1.95 (m, 2H, H -6), 1.91 (s, 3H, 5-CH ),

2

3

× OCH

2

CH

3

& H-7), 3.93 (d, J = 6.6 Hz, 2H, H

2

-13), 3.65 (t, J = 1.76–1.70 (m, 2H, H

2

-10), 1.72 (s, 3H, 15-CH

3

), 1.34–1.28 (m,

.3 Hz, 2H, H

2

-11), 3.44 (t, J = 6.3 Hz, 2H, H -9), 2.61–2.39 (m, 6H, 2 × OCH

2

CH ), 0.87 (s, 9H, TBS), 0.86 (s, 3H, TBS), 0.82 (s,

3

H, H -16 & H -8), 2.02–1.92 (m, 2H, H -6), 1.89 (s, 3H, 5-CH ), 3H, TBS), 0.80 (s, 3H, TBS), 0.04 (s, 3H, TBS), 0.03 (s, 6H, TBS),

2

3

1

3

.73 (quin., J = 6.3 Hz, 2H, H

CH

TBS), 0.03 (s, 3H, TBS), 0.01 (s, 6H, TBS), −0.06 (s, 3H, TBS). 126.1, 125.5 (125.4), 118.9, 88.7, 70.9, 67.3, 67.1, 61.8 (61.7),

2

-10), 1.69 (s, 3H, 15-CH

3

), 1.30 (t, −0.03 (s, 3H). C NMR (300 MHz, CDCl

3

) δ 183.1, 166.5, 151.2,

J = 6.9 Hz, 6H, 2 × OCH

2

3

), 0.86 (s, 9H, TBS), 0.80 (s, 9H, 147.2 (147.1), 146.2, 143.6, 142.3, 140.7, 134.2, 126.8 (126.7),

1

3

C NMR (75 MHz, CDCl

3

) δ 198.8 (198.7), 166.9 (166.8), 148.0 60.2, 44.58 (44.55), 41.84 (41.78), 36.2 (34.4), 33.2, 26.1,

(147.9), 143.1, 133.5, 126.6, 126.1, 117.9, 76.5 (76.4), 67.2, 67.1, 26.0 (25.9), 25.3 (25.2), 18.5, 17.9, 16.91 (16.88), 16.7 (16.6),

6

2

7.0 (66.9), 61.8 (61.7), 60.1, 41.8, 39.1, 36.3, 34.5, 33.1, 26.1, −4.5 (−4.6), −5.2.

5.9, 18.0 (17.9), 16.8, 16.62 (16.54), −4.611 (−4.69), −5.2. (17S) Di-TBS ether 29. Pale yellow oil, 42% yield. H NMR

300 MHz, CDCl ) δ 7.80 (d, J = 3.9 Hz, 1H, imidazole–H), 7.78

d, J = 3.9 Hz, 1H, imidazole–H), 7.62 (dd, J = 15.3, 11.7 Hz,

H, H-3), 6.94 (6.93) (dd, J = 15.3, 4.8 Hz, 1H, H-19), 6.75 (6.74)

1

(

1

3

General procedure for synthesis of α,β-unsaturated ketones

7–38

2

To a solution of the relevant diethyl (2-oxo-2-arylethyl)phos- (dd, J = 15.3, 3.9 Hz, 1H, H-18), 6.09 (d, J = 11.7 Hz, 1H, H-4),

phonate (0.11 mmol, 21–26) in THF (0.4 mL) and water (16 µL) 5.80 (d, J = 14.7 Hz, 1H, H-2), 5.72–5.66 (m, 1H, H-17), 5.42 (t,

was added activated barium hydroxide (18.4 mg, 0.10 mmol). J = 5.7 Hz, H-14), 4.14–4.02 (m, 5H, 2 × OCH

After stirring the mixture for 15 min at 0 °C, aldehyde 13 or 14 (s, 3H, N–CH ), 3.92 (d, J = 6.6 Hz, 2H, H

2

CH

3

& H-7), 3.95

3

2

-15), 3.65 (t, J =

(

60 mg, 0.083 mmol) in THF (0.4 mL) was added dropwise to 6.0 Hz, 2H, H -11), 3.44 (t, J = 6.0 Hz, 2H, H -9), 2.65–2.34 (m,

2

the solution. The ice-bath was removed after 30 min and the 4H, H

2

-16 & H

2

-8), 2.03–1.95 (m, 2H, H

2

3

-6), 1.89 (s, 3H, 5-CH ),

reaction was allowed to proceed with stirring at room tempera- 1.75–1.68 (m, 2H, H

2 3

-10), 1.71 (s, 3H, 15-CH ), 1.30 (1.29) (t, J =

ture for 2.5 h. The reaction mixture was filtered through a pad 7.2 Hz, 6H, 2 × OCH CH ), 0.85 (s, 9H, TBS), 0.80 (0.78) (s, 9H,

2

3

of anhydrous sodium sulfate and silica gel which was rinsed TBS), 0.02 (s, 3H, TBS), 0.01 (s, 6H, TBS), −0.05 (s, 3H, TBS).

1

3

with THF. The filtrate was concentrated under vacuum to give

3

C NMR (300 MHz, CDCl ) δ 179.5, 166.5, 147.39 (147.35),

the crude product which was subjected to PTLC purification, 144.5, 143.5, 142.5, 137.6, 134.17 (134.13), 131.3, 126.7, 126.1,

using dichloromethane/methanol (95/5, v/v) as eluent, to give 125.6 (125.5), 118.7, 70.79 (70.75), 67.2, 67.1, 66.92 (66.85),

pure product. Characterization, yield and NMR data for each 61.76 (61.67), 60.1, 44.5, 41.7, 36.2, 35.2, 34.4, 33.1, 26.1, 25.9,

product are given below:

25.28 (25.24), 18.4, 17.9, 16.8, 16.6 (16.5), −4.6, −4.7, −5.2.

(17R) Di-TBS ether 30. Yellow oil, 93% yield. H NMR

1

(17S) Di-TBS ether 27. Pale yellow oil, 73.5% yield. H NMR

3 3

(300 MHz, CDCl ) δ 8.30 (s, 1H, imidazole–H), 7.92 (s, 1H, (300 MHz, CDCl ) δ 8.31 (8.30) (d, J = 0.9 Hz, 1H, oxazole–H),

imidazole–H), 7.65 (dd, J = 14.4, 11.7 Hz, 1H, H-3), 7.02 (7.01) 7.94 (7.92) (d, J = 0.9 Hz, 1H, oxazole–H), 7.62 (7.61) (dd,

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J = 15.0, 11.7 Hz, 1H, H-3), 7.16 (7.15) (dd, J = 15.6, 4.8 Hz, J = 16.5, 2.1 Hz, 1H, H-18), 6.10 (d, J = 11.7 Hz, 1H, H-4), 5.82

H-18), 7.04 (7.03) (dd, J = 15.6, 1.2 Hz, 1H, H-19), 6.08 (d, J = (d, J = 15.3 Hz, 1H, H-2), 5.74–5.68 (m, 1H, H-17), 5.44 (t, J =

1

1.7 Hz, 1H, H-4), 5.81 (d, J = 15.0 Hz, 1H, H-2), 5.74–5.67 7.2 Hz, 1H, H-14), 4.16–4.05 (m, 5H, 2 × OCH

2

CH

3

& H-7), 3.94

-11), 3.45

(m, 1H, H-17), 5.42 (t, J = 5.4 Hz, 1H, H-14), 4.22–4.03 (m, 5H, (d, J = 6.3 Hz, 2H, H -13), 3.66 (t, J = 6.0 Hz, 2H, H

2

6

4

1

6

3

−

× OCH CH , H-7), 3.93 (d, J = 6.3 Hz, 2H, H -13), 3.66 (t, J = (t, J = 6.3 Hz, 2H, H -9), 2.61–2.42 (m, 4H, H -16 & H -8), 2.03

2

3

2

.0 Hz, 2H, H

2

-11), 3.44 (t, J = 6.3 Hz, 2H, H

2

-9), 2.61–2.41 (m, (1.97) (d, J = 6.3 Hz, 2H, H

2

-6), 1.91 (s, 3H, 5-CH

3

), 1.74 (quin.,

H, H

2

-16 & H

2

-8), 2.04–1.96 (m, 2H, H -6), 1.90 (s, 3H, 5-CH

2

3

), J = 5.4 Hz, 2H, H -10), 1.73 (s, 3H, 15-CH ), 1.34–1.27 (m, 6H,

2 3

.77–1.71 (m, 2H, H -10), 1.72 (s, 3H, 15-CH ), 1.33–1.28 (m, 2 × OCH CH ), 0.87 (s, 9H, TBS), 0.81 (0.79) (s, 9H, TBS), 0.04

2

3

2

3

2 3

H, 2 × OCH CH ), 0.87 (s, 9H, TBS), 0.86 (s, 3H, TBS), 0.81 (s, (0.03) (s, 3H, TBS), 0.03 (s, 6H, TBS), −0.03 (−0.04) (s, 3H,

1

3

H, TBS), 0.79 (s, 3H, TBS), 0.04 (s, 3H, TBS), 0.02 (s, 6H, TBS), TBS). C NMR (75 MHz, CDCl

3

) δ 188.79 (188.75), 166.5, 165.9

1

3

0.04 (s, 3H). C NMR (300 MHz, CDCl ) δ 183.1, 166.5, 151.1, (d, J = 253 Hz), 147.4 (d, J = 3.0 Hz), 145.7 (d, J = 3.0 Hz), 142.5,

3

1

4

1

47.2 (147.1), 146.2, 143.5, 142.3, 140.7, 134.2, 126.8 (126.7), 134.2 (d, J = 2.2 Hz), 131.4 (d, J = 9.3 Hz), 128.8, 126.1, 125.1

26.1, 125.3, 118.9, 88.9, 70.9, 67.3 (67.1), 61.8 (61.7), 60.1, (d, J = 8.6 Hz), 118.8, 116.1, 115.8, 71.0, 67.3, 67.1, 66.9 (66.8),

4.5, 41.8, 36.2 (34.4), 33.1, 26.1, 25.92 (25.90), 25.3 (25.2), 61.8 (61.7), 60.1, 44.5, 41.8, 36.2 (34.5), 33.2, 26.1, 25.93

8.5, 18.0, 16.90 (16.87), 16.64 (16.56), −4.5, −4.6, −5.2.

(25.91), 25.3 (25.2), 18.5, 18.0, 16.9, 16.7 (16.6), −4.56 (−4.63),

17S) Di-TBS ether 31. Pale yellow oil; 74% yield. H NMR −5.2.

300 MHz, CDCl ) δ 7.91 (d, J = 6.9 Hz, 2H, phenyl–H), 7.65 (17R) Di-TBS ether 34. Colorless oil; 51% yield. H NMR

dd, J = 15.3, 11.7 Hz, 1H, H-3), 7.56 (t, J = 7.2 Hz, 1H, phenyl– (300 MHz, CDCl ) δ 7.94 (dd, J = 8.4, 5.4 Hz, 2H, phenyl–H),

1

(

1

(

3

H), 7.46 (t, J = 6.9 Hz, 2H, phenyl–H), 7.01 (7.00) (d, J = 15.6 7.63 (dd, J = 14.7, 11.7 Hz, 1H, H-3), 7.12 (t, J = 8.4 Hz, 2H,

Hz, 1H, H-19), 6.93 (6.92) (dd, J = 15.0, 1.8 Hz, 1H, H-18), 6.11 phenyl–H), 7.00–6.88 (overlapped, 2H, H-18 & H-19), 6.10 (d,

(

d, J = 11.7 Hz, H-4), 5.83 (d, J = 15.0 Hz, 1H, H-2), 5.76–5.70 J = 11.7 Hz, 1H, H-4), 5.82 (d, J = 15.3 Hz, 1H, H-2), 5.74–5.66

m, 1H, H-17), 5.45 (t, J = 6.9 Hz, 1H, H-14), 4.19–4.06 (m, 5H, (m, 1H, H-17), 5.44 (t, J = 6.3 Hz, 1H, H-14), 4.22–4.05 (m, 5H,

2

× OCH CH and H-7), 3.95 (d, J = 6.6 Hz, 2H, H -13), 3.67 (t, 2 × OCH CH & H-7), 3.94 (d, J = 6.6 Hz, 2H, H -13), 3.66 (t, J =

2

3

2

3

2

J = 6.3 Hz, 2H, H

2

-11), 3.46 (t, J = 6.3 Hz, 2H, H

2

-9), 2.62–2.39 6.3 Hz, 2H, H

2

-11), 3.45 (t, J = 6.3 Hz, 2H, H

2

-9), 2.61–2.42 (m,

(m, 4H, H

2

-16 & H

2

-8), 2.04 (1.98) (d, J = 6.3 Hz, 2H, H

2

-6), 1.92 4H, H -16 & H -8), 2.03 (1.97) (d, J = 6.0 Hz, 2H, H -6), 1.91 (s,

2

(

s, 3H, 5-CH ), 1.77 (quin., J = 6.3 Hz, 2H, H -10), 1.74 (s, 3H, 3H, 5-CH ), 1.79–1.70 (m, 2H, H -10), 1.73 (s, 3H, 15-CH ),

3

2

3

2

3

1

5-CH

3

2 3 2 3

), 1.35–1.28 (m, 6H, 2 × OCH CH ), 0.88 (s, 9H, TBS), 1.34–1.27 (m, 6H, 2 × OCH CH ), 0.87 (s, 9H, TBS), 0.81 (0.78)

0

.82 (0.80) (s, 9H, TBS), 0.04 (s, 6H, TBS), −0.03 (−0.04) (s, 6H, (s, 9H, TBS), 0.06 (s, 3H, TBS), 0.02 (s, 6H, TBS), −0.04 (−0.05)

1

3

13

TBS). C NMR (75 MHz, CDCl ) δ 190.5, 166.5, 147.2, 145.5, (s, 3H, TBS). C NMR (75 MHz, CDCl ) δ 188.79 (188.75),

3

1

6

2

42.4, 137.7, 134.3 (134.2), 133.1, 128.8, 128.7, 126.8 (126.7), 166.5, 165.9 (d, J = 253 Hz), 147.4 (d, J = 3.0 Hz), 145.7 (d, J =

26.1, 125.6 (125.5), 118.8, 71.1 (71.0), 67.3, 67.1, 66.9 (66.8), 3.0 Hz), 142.5, 134.2 (d, J = 2.2 Hz), 131.4 (d, J = 9.8 Hz), 126.7,

1.8 (61.7), 60.1, 44.6, 41.8, 36.2 (34.5), 33.2, 26.1, 25.9 (25.8), 126.1, 125.1 (d, J = 8.3 Hz), 118.8, 116.0, 115.7, 71.1, 67.3, 67.1,

5.3 (25.2), 18.5, 18.0 (17.9), 17.0 (16.9), 16.7 (16.6), −4.56 66.9 (66.8), 61.8 (61.7), 60.1, 44.5, 41.8, 36.2 (34.4), 33.1, 26.1,

(

−4.63), −5.2.

17R) Di-TBS ether 32. Pale yellow oil; 43% yield. H NMR (−4.64), −5.2.

300 MHz, CDCl ) δ 7.90 (dt, J = 6.9, 1.8 Hz, 2H, phenyl–H), (17S) Di-TBS ether 35. Colorless oil; 76% yield. H NMR

.63 (dd, J = 15.0, 11.7 Hz, 1H, H-3), 7.55 (tt, J = 7.5, 1.2 Hz, (300 MHz, CDCl ) δ 7.72 (tt, J = 7.2, 1.8 Hz, 1H, phenyl–H),

H, phenyl–H), 7.45 (tt, J = 7.8, 1.2 Hz, 2H, phenyl–H), 7.62 (dd, J = 15.0, 11.7 Hz, 1H, H-3), 7.53–7.45 (m, 1H, phenyl–

.02–6.93 (m, 2H, H-18 & H-19), 6.10 (d, J = 11.7 Hz, H-4), 5.82 H), 7.22 (dt, J = 7.5, 0.9 Hz, 1H, phenyl–H), 7.12 (tt, J = 9.6,

25.92 (25.90), 25.3 (25.2), 18.5, 18.0, 16.9, 16.7 (16.6), −4.57

1

(

1

(

3

7

1

7

3

(d, J = 15.3 Hz, 1H, H-2), 5.85–5.69 (m, 1H, H-17), 5.44 (t, J = 1.5 Hz, 1H, phenyl–H), 6.91 (6.88) (dd, J = 15.3, 3.3 Hz, 1H,

6

3

2

6

2

.3 Hz, 1H, H-14), 4.18–4.04 (m, 5H, 2 × OCH CH and H-7), H-18), 6.85 (6.84) (d, J = 15.0 Hz, 1H, H-19), 6.09 (d, J =

2 3

.94 (d, J = 6.3 Hz, 2H, H

2

-13), 3.66 (t, J = 6.0 Hz, 2H, H

2

-11), 11.7 Hz, 1H, H-4), 5.81 (d, J = 15.0 Hz, 1H, H-2), 5.74–5.67

-8), (m, 1H, H-17), 5.43 (t, J = 6.0 Hz, 1H, H-14), 4.18–4.05 (m, 5H,

.45 (t, J = 6.3 Hz, 2H, H -9), 2.61–2.41 (m, 4H, H

2

-16 & H

2

.04–1.94 (m, 2H, H -6), 1.91 (s, 3H, 5-CH ), 1.75 (quin., J = 2 × OCH CH & H-7), 3.94 (d, J = 6.6 Hz, 2H, H -13), 3.67 (t, J =

2

3

2

3

2

.3 Hz, 2H, H

× OCH CH

2

-10), 1.72 (s, 3H, 15-CH

), 0.87 (s, 9H, TBS), 0.82 (0.79) (s, 9H, TBS), 0.03 4H, H

3

), 1.33–1.26 (m, 6H, 6.0 Hz, 2H, H

-8 & H

2

-11), 3.46 (t, J = 6.3 Hz, 2H, H

2 3

-16), 2.05–1.90 (m, 2H, H -6), 1.91 (s, 3H, 5-CH ),

2

-9), 2.62–2.37 (m,

2

3

2

1

3

(s, 6H, TBS), −0.03 (−0.04) (s, 6H, TBS). C NMR (75 MHz, 1.75 (quin., J = 6.3 Hz, 2H, H -10), 1.73 (s, 3H, 15-CH ),

2

3

3 2 3

CDCl ) δ 190.5, 166.5, 147.3 (147.2), 145.5 (145.4), 142.4, 137.8, 1.35–1.29 (m, 6H, 2 × OCH CH ), 0.88 (s, 9H, TBS), 0.81 (0.80)

1

4

34.3 (134.2), 133.1, 128.8, 128.7, 126.8, 126.1, 125.6 (125.5), (s, 9H, TBS), 0.03 (s, 9H, TBS), −0.03 (−0.04) (s, 3H, TBS).

1

3

18.9, 71.1 (71.0), 67.3, 67.1, 66.9 (66.8), 61.8 (61.7), 60.1, 44.6,

1.8, 36.3 (34.5), 33.2, 26.1, 25.9 (25.8), 25.3 (25.2), 18.5, 18.0 Hz), 147.2 (147.1), 145.8, 142.3, 140.4, 134.2, 131.1, 128.8

(128.7), 126.8 (126.7), 126.1, 124.6, 118.9, 116.9 (116.6), 70.9,

17S) Di-TBS ether 33. Colorless oil; 73% yield. H NMR 67.3, 67.1, 61.8, 61.7, 60.2, 44.5, 41.8, 36.3, 34.5, 33.2, 26.1,

300 MHz, CDCl ) δ 7.94 (dd, J = 8.4, 5.4 Hz, 2H, phenyl–H), 25.9, 18.5, 18.0, 16.7, 16.6, −4.6, −5.2.

.63 (dd, J = 15.0, 11.7 Hz, 1H, H-3), 7.13 (t, J = 8.7 Hz, 2H, (17R) Di-TBS ether 36. Pale yellow oil; 50% yield. H NMR

phenyl–H), 6.97 (dd, J = 15.6, 0.6 Hz, 1H, H-19), 6.91 (6.90) (dd, (300 MHz, CDCl ) δ 7.72 (tt, J = 7.5, 1.8 Hz, 1H, phenyl–H),

C NMR (75 MHz, CDCl ) δ 188.9, 166.5, 161.5 (d, J = 266.6

3

(17.9), 16.9, 16.7 (16.6), −4.5 (−4.6), −5.2.

1

(

7

3

1

3

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7.62 (dd, J = 15.0, 11.7 Hz, 1H, H-3), 7.53–7.46 (m, 1H, phenyl–H), added to quench the reaction and the suspension was

7.22 (dt, J = 7.5, 0.9 Hz, 1H, phenyl–H), 7.12 (tt, J = 9.3, 1.5 Hz, extracted with ethyl acetate (20 mL × 3). The combined organic

1H, phenyl–H), 6.91 (6.90) (dd, J = 15.6, 3.6 Hz, 1H, H-18), 6.85 extracts were dried over anhydrous sodium sulfate and the

(

6.84) (d, J = 15.6 Hz, 1H, H-19), 6.09 (d, J = 11.7 Hz, 1H, H-4), dried extract was concentrated under vacuum. The crude

.81 (d, J = 15.0 Hz, 1H, H-2), 5.73–5.68 (m, 1H, H-17), 5.43 (t, product was purified by PTLC, eluting with dichloromethane/

J = 6.3 Hz, 1H, H-14), 4.18–4.05 (m, 5H, 2 × OCH CH & H-7), methanol (93 : 7; v/v), and the pure diol was retrieved by

-13), 3.67 (t, J = 6.3 Hz, 2H, H -11), extracting the PTLC silica gel with acetone. Characterization,

5

2

3

2

6

2

.94 (d, J = 6.3 Hz, 2H, H

2

.46 (t, J = 6.3 Hz, 2H, H -9), 2.63–2.37 (m, 4H, H -8 & H -16), yield and NMR data for each diol are listed below:

2

1

.05–1.90 (m, 2H, H

.3 Hz, 2H, H

× OCH CH ), 0.88 (s, 9H, TBS), 0.81 (0.79) (s, 9H, TBS), 0.03 (dd, J = 15.3, 3.6 Hz, 1H, H-18), 6.76 (d, J = 15.3 Hz, 1H, H-19),

2

-6), 1.91 (s, 3H, 5-CH

3

), 1.75 (quin., J =

3

(17S) Diol 39. H NMR (300 MHz, CDCl ) δ 7.80 (s, 1H, imid-

2

3

-10), 1.73 (s, 3H, 15-CH ), 1.35–1.29 (m, 6H, azole–H), 7.66–7.55 (overlapped, 2H, imidazole–H & H-3), 6.92

2

3

1

3

(

s, 9H, TBS), −0.03 (−0.04) (s, 3H, TBS). C NMR (75 MHz, 6.15 (d, J = 11.4 Hz, H-4), 5.84 (d, J = 15.0 Hz, 1H, H-2),

CDCl ) δ 188.9, 166.5, 161.5 (d, J = 245 Hz), 147.2 (147.1), 5.77–5.65 (m, 1H, H-17), 5.41 (t, J = 5.4 Hz, 1H, H-14),

45.8, 142.4, 140.4, 134.2, 131.2, 128.7 (128.6), 126.9 (126.8), 4.14–4.03 (m, 5H, 2 × OCH CH & H-7), 3.96–3.92 (overlapped,

3

1

6

1

2

3

26.1, 124.7, 118.9, 116.9 (116.6), 71.0, 67.2, 67.1, 61.9, 61.8, 2H, H

0.2, 44.5, 41.8, 36.2, 34.4, 33.2, 26.1, 25.9, 18.5, 18.0, 16.7, 3.52 (t, J = 4.8 Hz, 2H, H

6.6, −4.6, −5.2.

17S) Di-TBS ether 37. Pale yellow oil; 57% yield. H NMR 5-CH

300 MHz, CDCl ) δ 7.69–7.56 (m, 3H, 2 × phenyl–H & H-3), 1.30 (t, J = 6.9 Hz, 6H, 2 × OCH

2

-13), 3.92 (s, 3H, N–CH

3

), 3.69 (t, J = 5.4 Hz, 2H, H

2

-11),

-16),

2

-9), 2.67–2.36 (m, 4H, H

2

-8 & H

2.14 (brs, 2H, 2 × OH), 1.96–1.89 (m, 2H, H -6), 1.93 (s, 3H,

2

1

(

3

), 1.77 (quin., J = 6.0 Hz, 2H, H

2

-10), 1.72 (s, 3H, 15-CH

3

),

1

3

(

3

2

CH

3

). C NMR (75 MHz,

7

6

5

4

3

2

.47–7.40 (m, 1H, phenyl–H), 7.30–7.22 (m, 1H, phenyl–H), CDCl ) δ 179.8, 166.5, 146.79 (146.75), 143.92, 143.85, 141.5

3

.98 (d, J = 15.3 Hz, 1H, H-19), 6.91 (dd, J = 15.6, 3.0 Hz, H-18), (141.4), 134.6, 134.5, 126.7 (126.6), 126.0, 125.9, 125.87

.10 (d, J = 11.7 Hz, 1H, H-4), 5.82 (d, J = 15.0 Hz, 1H, H-2), (125.80), 119.22 (119.15), 70.8 (70.7), 68.73 (68.70), 67.3, 65.4

.75–5.69 (m, 1H, H-17), 5.44 (t, J = 7.5 Hz, 1H, H-14), (65.3), 62.3 (62.2), 62.1 (62.0), 61.3 (61.2), 54.0, 44.5, 41.5

.15–4.05 (m, 4H, 2 × OCH

.66 (t, J = 6.3 Hz, 2H, H -11), 3.45 (t, J = 6.3 Hz, 2H, H

.62–2.42 (m, 4H, H -8 & H -16), 2.03–1.96 (m, 2H, H -6), 1.91

2

CH

3

), 4.01–3.93 (m, 2H, H

2

-13), (41.3), 35.0 (34.6), 32.8 (31.9), 32.4, 25.2 (25.0), 16.94 (16.91),

-9), 16.6 (16.5).

(17R) Diol 40. H NMR (300 MHz, CDCl ) δ 7.86 (7.83) (s,

2

1

2

3

(

1

s, 3H, 5-CH

3

), 1.76 (quin., J = 6.0 Hz, 2H, H

2

-10), 1.73 (s, 3H, 1H, imidazole–H), 7.83 (7.80) (s, 1H, imidazole–H), 7.62 (7.60)

), 0.87 (s, 9H, (dd, J = 16.5, 11.7 Hz, H-3), 6.94 (6.93) (dd, J = 15.3, 4.5 Hz, 1H,

5-CH

3

), 1.31 (t, J = 6.9 Hz, 6H, 2 × OCH CH

2

3

TBS), 0.81 (0.78) (s, 9H, TBS), 0.034 (0.026) (s, 3H, TBS), 0.02 H-18), 6.77 (6.76) (d, J = 15.3 Hz, 1H, H-19), 6.15 (d, J =

1

3

(

s, 6H, TBS), −0.04 (−0.05) (s, 3H, TBS). C NMR (75 MHz, 11.7 Hz, H-4), 5.84 (d, J = 15.3 Hz, 1H, H-2), 5.76–5.67 (m, 1H,

CDCl ) δ 189.0, 166.5, 162.9 (d, J = 246.8 Hz), 147.4 (d, J = H-17), 5.42 (t, J = 5.7 Hz, 1H, H-14), 4.17–4.05 (m, 5H,

.8 Hz), 146.3 (d, J = 3.0 Hz), 139.8 (d, J = 6.8 Hz), 134.15 2 × OCH CH & H-7), 3.96–3.90 (overlapped, 2H, H -13), 3.96

3

2

3

2

(

134.12), 130.5 (130.4), 126.7 (126.1), 125.0 (124.9), 124.5, (3.95) (s, 3H, N–CH

20.2, 119.6, 118.7, 115.6 (115.3), 70.9, 67.2, 67.1, 66.9 (66.8), (t, J = 6.0 Hz, 2H, H -9), 2.70–2.36 (m, 4H, H

1.8 (61.7), 60.1, 44.5, 41.8, 36.3, 34.4, 33.1, 26.1, 25.9, 18.5, 1.98–1.89 (m, 2H, H -6), 1.94 (s, 3H, 5-CH ), 1.77 (quin., J =

3

), 3.69 (t, J = 6.0 Hz, 2H, H

2

-11), 3.53 (3.52)

-8 & H -16),

1

6

1

2

3

7.9, 16.61, 16.53, −4.7, −5.2.

5.7 Hz, 2H, H

2

-10), 1.72 (s, 3H, 15-CH

3

), 1.31 (t, J = 6.9 Hz, 6H,

1

13

(17R) Di-TBS ether 38. Pale yellow oil; 55% yield. H NMR 2 × OCH CH ). C NMR (75 MHz, CDCl ) δ 179.7, 166.5, 146.8,

2 3 3

(

300 MHz, CDCl ) δ 7.69–7.56 (m, 3H, 2 × phenyl–H & H-3), 144.4, 144.2, 141.5 (141.4), 134.6, 134.5, 126.7, 126.0, 125.9,

3

7

6

5

4

1

2

.47–7.40 (m, 1H, phenyl–H), 7.28–7.21 (m, 1H, phenyl–H), 125.8, 119.2, 70.7, 68.8, 67.3, 65.3, 62.3, 62.1 (62.0), 61.3 (61.2),

.97 (d, J = 15.9 Hz, 1H, H-19), 6.91 (dd, J = 15.9, 3.0 Hz, H-18), 53.5, 44.4, 41.5 (41.3), 35.2, 32.4, 25.2 (25.1), 16.9, 16.6 (16.5).

1

.10 (d, J = 11.4 Hz, 1H, H-4), 5.82 (d, J = 15.3 Hz, 1H, H-2),

(17S) Diol 41. H NMR (300 MHz, CDCl ) δ 8.32 (s, 1H,

3

.76–5.69 (m, 1H, H-17), 5.44 (t, J = 6.0 Hz, 1H, H-14), oxazole–H), 7.98 (7.96) (s, 1H, oxazole–H), 7.61 (dd, J = 15.3,

.16–4.04 (m, 4H, 2 × OCH CH ), 3.94 (d, J = 6.6 Hz, 2H, H 12.0 Hz, 1H, H-3), 7.18 (dd, J = 15.6, 4.5 Hz, 1H, H-18), 7.07 (d,

2

3

2

-

3), 3.66 (t, J = 6.0 Hz, 2H, H -11), 3.45 (t, J = 6.3 Hz, 2H, H -9), J = 15.6 Hz, 1H, H-19), 6.16 (d, J = 11.7 Hz, 1H, H-4), 5.88 (5.85)

2

.62–2.42 (m, 4H, H

2

-8 & H

2

-16), 2.03–1.96 (m, 2H, H

2

-6), 1.91 (d, J = 15.0 Hz, 1H, H-2), 5.79–5.72 (m, 1H, H-17), 5.41 (t, J =

3 2 2 3

(s, 3H, 5-CH ), 1.76 (quin., J = 6.0 Hz, 2H, H -10), 1.73 (s, 3H, 6.3 Hz, 1H, H-14), 4.23–4.05 (m, 5H, 2 × OCH CH and 7-H),

1

5-CH ), 1.35–1.29 (m, 6H, 2 × OCH CH ), 0.87 (s, 9H, TBS), 3.96 (d, J = 6.6 Hz, 2H, H -13), 3.71 (t, J = 5.4 Hz, 2H, H -11),

3

2

3

2

0

.81 (0.78) (s, 9H, TBS), 0.034 (0.026) (s, 3H, TBS), 0.02 (s, 6H, 3.53 (dt, J = 6.9, 1.8 Hz, 2H, H

2

-9), 2.69–2.57 (m, 2H, H -8),

TBS), −0.04 (−0.05) (s, 3H, TBS).

2.52–2.40 (m, 2H, H

2

-16), 1.98–1.91 (m, 2H, H

2

-6), 1.95 (s, 3H,

5

1

-CH ), 1.82–1.73 (m, 2H, H -10), 1.73 (s, 3H, 15-CH ),

3

2

3

General procedure for synthesis of diols 39–50

13

.35–1.24 (m, 6H, 2 × OCH

2

CH

3

). C NMR (75 MHz, CDCl

3

)

To a solution of the relevant di-TBS ether (27–38, 0.041 mmol) δ 183.1, 166.5 (166.4), 151.4 (151.3), 146.6 (146.5), 146.2

in THF (1.7 mL) at 0 °C in a plastic bottle was added dropwise (146.1), 143.6, 141.4 (141.3), 140.7, 134.8 (134.7), 126.8, 125.8

hydrogen fluoride–pyridine complex (70%, 0.41 mL). The solu- (125.7), 125.3 (125.2), 119.4, 70.8, 69.0, 67.4, 65.4, 62.3 (62.1)

tion was stirred at 0 °C for 5 min and then at room tempera- (d, J = 6.8 Hz), 61.7 (d, J = 9.0 Hz), 44.5, 41.5 (41.3), 34.6 (34.5),

ture for 16 h. Saturated sodium bicarbonate (30 mL) was 32.8, 25.3 (25.1), 17.0, 16.6 (16.5).

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(

17R) Diol 42. H NMR (300 MHz, CDCl

3

) δ 8.32 (s, 1H, 1.74 (s, 3H, 15-CH

3

), 1.32 (t, J = 6.9 Hz, 6H, 2 × OCH

2 3

CH ).

1

3

oxazole–H), 7.98 (7.95) (d, J = 0.9 Hz, 1H, oxazole–H), 7.64 (dd,

J = 15.0, 11.7 Hz, 1H, H-3), 7.17 (dd, J = 15.6, 4.5 Hz, 1H, H-18), 166.5, 146.7, 145.6 (d, J = 5.3 Hz), 141.5 (d, J = 6.0 Hz), 134.7

C NMR (75 MHz, CDCl ) δ 188.7, 165.9 (d, J = 253.5 Hz),

3

7

5

.07 (d, J = 15.6 Hz, 1H, H-19), 6.16 (d, J = 11.7 Hz, 1H, H-4), (d, J = 5.3 Hz), 134.0 (d, J = 3.0 Hz), 131.5 (d, J = 9.0 Hz), 126.74

.86 (5.85) (d, J = 15.0 Hz, 1H, H-2), 5.79–5.73 (m, 1H, H-17), (126.69), 125.84 (125.76), 124.99 (124.93), 119.33 (119.28),

.40 (t, J = 6.6 Hz, 1H, H-14), 4.23–4.05 (m, 5H, 2 × OCH

2

CH

3

116.1, 115.8, 71.0, 69.10 (69.05), 67.4, 65.45 (65.38), 65.34

and 7-H), 3.96 (d, J = 6.6 Hz, 2H, H

2

-13), 3.70 (t, J = 5.4 Hz, 2H, (65.28), 62.32 (62.24), 62.21 (62.13), 61.83 (61.78), 44.5, 41.5

H -11), 3.52 (dt, J = 6.0, 2.1 Hz, 2H, H -9), 2.69–2.57 (m, 2H, (41.3), 34.6, 32.8, 32.3, 25.2 (25.1), 17.00 (16.96), 16.63 (16.55).

2

1

H

2

-8), 2.52–2.40 (m, 2H, H

2

-16), 1.98–1.91 (m, 2H, H

2

-6), 1.94

3

(17R) Diol 46. H NMR (300 MHz, CDCl ) δ 7.95 (ddd, J =

(

1

s, 3H, 5-CH

3

2

), 1.77 (quin., J = 5.7 Hz, 2H, H -10), 1.73 (s, 3H, 9.0, 5.4, 1.2 Hz, 2H, phenyl–H), 7.61 (7.60) (dd, J = 15.0,

1

3

5-CH ), 1.34–1.28 (m, 6H, 2 × OCH CH ). C NMR (75 MHz, 11.7 Hz, 1H, H-3), 7.14 (t, J = 8.7 Hz, 2H, phenyl–H), 7.01 (7.00)

3 2 3

3

CDCl ) δ 183.1, 166.6 (166.5), 151.4 (151.3), 146.6 (146.5), 146.2 (d, J = 15.6 Hz, 1H, H-19), 6.95 (6.94) (dd, J = 15.6, 3.0 Hz, 1H,

(

146.1), 143.6, 141.4 (141.3), 140.7, 134.8 (134.7), 126.8, 125.8 H-18), 6.17 (d, J = 11.7 Hz, 1H, H-4), 5.86 (d, J = 15.0 Hz, 1H,

125.7), 125.3 (125.2), 119.4, 70.8, 68.9, 67.3, 65.4, 62.2 (62.1), H-2), 5.79–5.73 (m, 1H, H-17), 5.42 (t, J = 5.4 Hz, 1H, H-14),

6

1

1.7 (d, J = 9.0 Hz), 44.5, 41.5 (41.3), 34.8, 32.4, 25.3 (25.1), 4.21–4.06 (m, 5H, 2 × OCH

2

CH

3

& H-7), 3.97 (d, J = 6.6 Hz, 2H,

-11), 3.54 (3.53) (t, J = 6.0 Hz,

7.0, 16.6 (16.5). -13), 3.71 (t, J = 5.7 Hz, 2H, H

H

2

1

(

17S) Diol 43. H NMR (300 MHz, CDCl ) δ 7.91 (d, J = H -9), 2.69–2.38 (m, 4H, H -8 & H -16), 1.97–1.89 (overlapped,

3

2

8

7

2

.1 Hz, 2H, phenyl–H), 7.60 (dd, J = 14.7, 11.7 Hz, 1H, H-3), 2H, H

2

-6), 1.95 (s, 3H, 5-CH

3

2

), 1.78 (quin., J = 6.0 Hz, 2H, H -

.56 (tt, J = 7.5, 1.2 Hz, 1H, phenyl–H), 7.46 (tt, J = 7.5, 1.2 Hz, 10), 1.74 (s, 3H, 15-CH

3

), 1.32 (t, J = 7.2 Hz, 6H, 2 × OCH

2 3

CH ).

1

3

H, phenyl–H), 7.02 (dd, J = 15.6, 2.7 Hz, 1H, H-19), 6.94 (ddd,

C NMR (75 MHz, CDCl ) δ 188.7, 165.9 (d, J = 255 Hz), 166.6

3

J = 15.3, 4.5, 1.2 Hz, 1H, H-18), 6.16 (d, J = 11.7 Hz, 1H, H-4), (166.5), 146.7, 145.6 (d, J = 5.3 Hz), 141.5 (d, J = 6.0 Hz), 134.7

5

.86 (dd, J = 15.0, 1.8 Hz, 1H, H-2), 5.79–5.72 (m, 1H, H-17), (d, J = 5.3 Hz), 134.0 (d, J = 3.0 Hz), 131.5 (d, J = 9.0 Hz), 126.7,

.42 (t, J = 5.4 Hz, 1H, H-14), 4.19–4.05 (m, 5H, 2 × OCH CH , 125.8, 124.9, 119.3, 116.1, 115.8, 70.9, 69.1, 67.4, 65.4, 65.3,

2

3

H-7), 3.97 (d, J = 6.6 Hz, 2H, H

2

-13), 3.71(3.60) (t, J = 5.7 Hz, 62.3 (62.2), 62.2 (62.1), 61.8 (61.7), 44.5, 41.5 (41.3), 34.6, 32.8,

2

4

1

H, H

2

-11), 3.53 (3.52) (t, J = 5.7 Hz, 2H, H -9), 2.69–2.38 (m, 32.3, 25.2 (25.1), 17.00 (16.96), 16.63, 16.55.

2

1

H, H -16 & H -8), 1.95 (s, 3H, 5-CH ), 1.97–1.89 (m, 2H, H -6),

(17S) Diol 47. H NMR (300 MHz, CDCl ) δ 7.73 (dt, J = 7.5,

2

3

2

3

.77 (quin., J = 6.0 Hz, 2H, H

.35–1.24 (m, 6H, 2 × OCH

2

-10), 1.73 (s, 3H, 15-CH

). C NMR (75 MHz, CDCl

3

), 1.8 Hz, 1H, phenyl–H), 7.59 (7.58) (dd, J = 15.0, 11.7 Hz, 1H,

1

3

2

CH

3

)

H-3), 7.53–7.46 (m, 1H, phenyl–H), 7.22 (dt, J = 7.5, 0.9 Hz, 1H,

δ 190.4, 166.6, 146.7, 145.3, 141.3, 137.6, 134.8, 134.7, 133.2, phenyl–H), 7.13 (dd, J = 10.8, 8.4 Hz, 1H, phenyl–H), 6.91–6.89

1

6

28.8, 126.7, 125.8, 125.4, 119.3, 71.0, 69.7, 69.0, 67.4, 62.2, (overlapped, 2H, H-18 & H-19), 6.15 (d, J = 11.7 Hz, 1H, H-4),

1.7, 54.0, 44.6, 32.3, 31.9, 29.4, 16.6, 16.5. 5.84 (5.83) (d, J = 15.0 Hz, 1H, H-2), 5.77–5.70 (m, 1H, H-17),

17R) Diol 44. H NMR (300 MHz, CDCl ) δ 7.90 (d, J = 5.41 (t, J = 5.4 Hz, 1H, H-14), 4.19–4.02 (m, 5H, 2 × OCH CH &

1

(

3

2

3

7

2

.8 Hz, 2H, phenyl–H), 7.60 (dd, J = 14.4, 11.7 Hz, 1H, H-3), H-7), 3.97 (d, J = 6.6 Hz, 2H, H

2

-13), 3.71 (t, J = 5.7 Hz, 1H,

-9), 2.65–2.43 (m, 4H,

.56 (tt, J = 7.2, 1.2 Hz, 1H, phenyl–H), 7.46 (tt, J = 7.8, 1.5 Hz, -11), 3.53 (3.52) (t, J = 6.0 Hz, 2H, H

H

2

H, phenyl–H), 7.02 (dd, J = 16.2, 2.4 Hz, 1H, H-19), 6.93 (ddd, H -8 & H -16), 1.97–1.89 (m, 2H, H -6), 1.94 (s, 3H, 5-CH ),

2

3

J = 15.8, 4.5, 1.2 Hz, 1H, H-18), 6.16 (d, J = 11.4 Hz, 1H, H-4), 1.78 (quin., J = 5.7 Hz, 2H, H

2

-10), 1.73 (s, 3H, 15-CH

3

), 1.32

1

3

5

.86 (dd, J = 15.0, 1.5 Hz, 1H, H-2), 5.79–5.72 (m, 1H, H-17), (t, J = 7.2 Hz, 6H, 2 × OCH

2 3 3

CH ). C NMR (75 MHz, CDCl )

5

.41 (t, J = 6.6 Hz, 1H, H-14), 4.19–4.05 (m, 5H, 2 × OCH CH , δ 188.9, 166.6 (166.5), 161.4 (d, J = 252.0 Hz), 146.6, 145.6,

2

3

H-7), 3.96 (d, J = 6.3 Hz, 2H, H

2

-13), 3.70 (3.69) (t, J = 5.7 Hz, 141.4 (141.2), 134.8 (134.7), 134.4 (134.3), 131.2 (131.1), 128.7

-9), 2.69–2.38 (m, (128.6), 126.7, 126.6, 125.8 (125.7), 124.7 (124.6), 119.3, 116.9,

H, H -16 & H -8), 1.94 (s, 3H, 5-CH ), 1.98–1.89 (m, 2H, H -6), 70.8, 69.02 (68.98), 67.4, 65.5 (65.4), 65.4 (65.3), 62.33 (62.25),

2

4

1

2 2

H, H -11), 3.52 (3.51) (t, J = 6.0 Hz, 2H, H

2

3

2

2 3

.76 (quin., J = 5.7 Hz, 2H, H -10), 1.73 (s, 3H, 15-CH ), 62.21 (62.13), 61.79 (61.76), 44.5, 41.5 (41.3), 35.6, 32.7, 32.3,

1

3

.34–1.28 (m, 6H, 2 × OCH

2

CH

3

). C NMR (75 MHz, CDCl

3

)

25.2 (25.1), 16.96, 16.61 (16.55).

(17R) Diol 48. H NMR (300 MHz, CDCl ) δ 7.73 (dt, J = 7.8,

1

δ 190.4, 166.7 (166.6), 146.8, 145.3, 141.4, 137.6, 134.8, 134.7,

3

1

6

33.2, 128.8, 126.7, 125.8, 125.4, 119.3, 71.0, 68.8, 67.3, 62.2, 1.8 Hz, 1H, phenyl–H), 7.60 (7.59) (dd, J = 14.7, 11.7 Hz, 1H,

2.1, 61.6, 50.8, 44.5, 32.8, 32.3, 25.2 (25.0), 17.0, 16.6 (16.5). H-3), 7.54–7.46 (m, 1H, phenyl–H), 7.23 (dt, J = 7.8, 1.2 Hz, 1H,

17S) Diol 45. H NMR (300 MHz, CDCl ) δ 7.96 (ddd, J = 9.0, phenyl–H), 7.13 (dd, J = 10.8, 8.4 Hz, 1H, phenyl–H), 6.91–6.89

1

(

3

5

1

.4, 1.2 Hz, 2H, phenyl–H), 7.61 (7.56) (ddd, J = 15.0, 11.7 Hz, (overlapped, 2H, H-18 & H-19), 6.16 (d, J = 11.7 Hz, 1H, H-4),

H, H-3), 7.14 (t, J = 8.7 Hz, 2H, phenyl–H), 7.01 (7.00) (d, J = 5.85 (5.84) (d, J = 15.0 Hz, 1H, H-2), 5.77–5.70 (m, 1H, H-17),

5.3 Hz, 1H, H-19), 6.95 (6.94) (dd, J = 14.7, 3.0 Hz, 1H, H-18), 5.41 (t, J = 6.6 Hz, 1H, H-14), 4.19–4.02 (m, 5H, 2 × OCH CH &

2

3

6

.17 (d, J = 11.7 Hz, 1H, H-4), 5.87 (d, J = 14.4 Hz, 1H, H-2), H-7), 3.97 (d, J = 6.9 Hz, 2H, H

2

-13), 3.72 (t, J = 5.7 Hz, 1H,

-9), 2.68–2.39 (m, 4H,

5

.79–5.72 (m, 1H, H-17), 5.42 (t, J = 5.4 Hz, 1H, H-14), -11), 3.54 (3.53) (t, J = 6.0 Hz, 2H, H

H

2

4

.22–4.06 (m, 5H, 2 × OCH CH & H-7), 3.97 (d, J = 6.6 Hz, 2H, H -8 & H -16), 1.98–1.89 (m, 2H, H -6), 1.95 (s, 3H, 5-CH ),

2

3

2

3

H

2

-13), 3.72 (t, J = 5.7 Hz, 2H, H

2

-11), 3.54 (3.53) (t, J = 6.0 Hz, 1.79 (quin., J = 6.0 Hz, 2H, H

2

-10), 1.73 (s, 3H, 15-CH

3

), 1.33

1

3

-9), 2.69–2.39 (m, 4H, H -8 & H -16), 1.97–1.89 (overlapped, (1.32) (t, J = 6.9 Hz, 6H, 2 × OCH CH ). C NMR (75 MHz,

2

3

2

H, H -6), 1.95 (s, 3H, 5-CH ), 1.78 (quin., J = 6.0 Hz, 2H, H -10), CDCl ) δ 188.9, 166.6, 161.4 (d, J = 251.3 Hz), 146.6, 145.6,

2 3 2 3

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7

6

41.4, 134.8 (134.7), 134.5 (134.3), 131.1, 128.7 (128.6), 126.7, lowed by activated barium hydroxide (7.4 mg, 0.04 mmol). The

26.5, 125.8 (125.7), 124.7 (124.6), 119.4 (119.3), 116.9 (116.6), reaction mixture was stirred at 0 °C for 30 min and at room

0.8, 69.1 (69.0), 67.4, 65.4 (65.3), 62.25 (62.22), 62.13 (62.09), temperature for 2.5, then was filtered through a pad of sodium

1.9, 44.5, 41.5 (41.3), 34.6, 32.7, 32.3, 25.2 (25.1), 16.96, 16.61 sulfate and a pad of silica gel which was rinsed with THF.

(

16.55).

After evaporation of the solvent, the crude product was sub-

) δ 7.70–7.56 (m, jected to PTLC purification, using dichloromethane/methanol

1

(17S) Diol 49. H NMR (300 MHz, CDCl

3

7

H, 2 × phenyl–H & H-3), 7.48–7.41 (m, 1H, phenyl–H), (95 : 5) as eluent, to yield the pure zampanolide mimic.

.29–7.22 (m, 1H, phenyl–H), 6.97–6.96 (overlapped, 2H, H-18 Characterization, yield and NMR data for each mimic are given

&

H-19), 6.17 (d, J = 11.7 Hz, 1H, H-4), 5.87 (5.86) (d, J = below:

5.3 Hz, 1H, H-2), 5.78–5.73 (m, 1H, H-17), 5.42 (t, J = 7.5 Hz, (17S) Zampanolide mimic 51. Colorless oil. Yield: 52%.

H, H-14), 4.15–4.06 (m, 5H, 2 × OCH CH & H-7), 3.97 (d, J = [α] : +17.8 (c = 0.18). H NMR (300 MHz, CDCl ) δ 7.86 (s, 1H,

1

6

1

5

2

1

2

0

1

2

3

D

3

.6 Hz, 2H, H

.0, 2.1 Hz, 2H, H

2

-13), 3.71 (t, J = 5.7 Hz, 2H, H

2

-11), 3.53 (dt, J = imidazole–H), 7.69 (s, 1H, imidazole–H), 7.66 (dd, J = 15.0,

-8 & H -16), 11.4 Hz, 1H, H-3), 7.01 (dd, J = 15.3, 4.5 Hz, 1H, H-18), 6.88

2

-9), 2.69–2.38 (m, 4H, H

2

.97–1.89 (m, 2H, H -6), 1.95 (s, 3H, 5-CH ), 1.77 (quin., J = (dt, J = 16.2, 6.6 Hz, 1H, H-9), 6.84 (d, J = 15.3 Hz, 1H, H-19),

2

3

.7 Hz, 2H, H

× OCH CH

66.60 (166.55), 163.0 (d, J = 247.5 Hz), 146.9 (146.8), 146.23 J = 6.6 Hz, 1H, H-14), 4.03 (dd, J = 12.0, 7.8 Hz, 1H, H-13), 3.98

146.17), 141.6 (141.5), 139.8 (139.7), 134.7 (134.6), 130.5 (s, 3H, N–CH ), 3.90 (dd, J = 12.0, 4.5 Hz, 1H, H-13), 3.71 (d, J =

130.4), 126.71 (126.66), 125.9 (125.8), 124.91 (124.86), 124.55 12.9 Hz, 1H, H-6), 3.54–3.43 (m, 2H, H -11), 3.37 (d, J =

124.52), 120.4 (120.1), 119.23 (119.16), 115.7 (115.4), 70.9, 13.0 Hz, H-6), 2.44–2.31 (m, 4H, H -10 & H -16), 1.87 (s, 3H,

2

-10), 1.74 (s, 3H, 15-CH

3

), 1.32 (t, J = 6.9 Hz, 6H, 6.17 (d, J = 11.7 Hz, 1H, H-4), 6.08 (d, J = 15.9 Hz, 1H, H-8),

1

3

2

3 3

). C NMR (75 MHz, CDCl ) δ 189.03 (189.00), 5.95 (d, J = 15.3 Hz, 1H, H-2), 5.90–5.84 (m, 1H, H-15), 5.37 (t,

(

3

2

1

3

6

2

9.0, 67.4, 65.4, 62.3 (62.2), 61.7, 44.5, 41.5 (41.3), 34.6, 32.3, 5-CH

5.2 (25.1), 17.0, 16.6 (16.5). δ 197.0, 179.6, 166.1, 146.9, 144.2, 144.1, 143.2, 140.1, 140.0,

17R) Diol 50. H NMR (300 MHz, CDCl ) δ 7.72–7.56 139.1, 133.6, 131.4, 130.3, 125.9, 125.6, 120.7, 69.8, 68.1, 67.7,

3 3 3

), 1.74 (s, 3H, 15-CH ). C NMR (75 MHz, CDCl )

1

(

3

(

7

&

1

6

m, 3H, 2 × phenyl–H & H-3), 7.48–7.41 (m, 1H, phenyl–H), 54.0, 46.0, 44.9, 33.0, 24.3, 16.8. IR (film) νmax: 1708, 1666,

−

1

.29–7.22 (m, 1H, phenyl–H), 6.97–6.96 (overlapped, 2H, H-18 1624, 1532, 1140 cm . HRMS (ESI): m/z calculated for

+

H-19), 6.16 (d, J = 11.4 Hz, 1H, H-4), 5.87 (5.86) (d, J = C H N O [M + H] : 439.2233. Found: 439.2231.

25 31 2 5

2

0

5.3 Hz, 1H, H-2), 5.79–5.70 (m, 1H, H-17), 5.42 (t, J = 6.3 Hz,

(17R) Zampanolide mimic 52. Yellow oil. Yield: 45%. [α] :

D

1

H, H-14), 4.15–4.06 (m, 5H, 2 × OCH CH

2

3

& H-7), 3.96 (d, J = −35.6 (c = 0.18, MeOH). H NMR (300 MHz, CDCl

3

) δ 7.85 (s,

.6 Hz, 2H, H -13), 3.72 (3.71) (t, J = 5.7 Hz, 2H, H -11), 3.53 1H, imidazole–H), 7.73 (s, 1H, imidazole–H), 7.66 (dd, J = 15.0,

2

(

1

5

3.52) (t, J = 6.0 Hz, 2H, H

2

-9), 2.66–2.38 (m, 4H, H

-6), 1.94 (s, 3H, 5-CH

.7 Hz, 2H, H -10), 1.73 (s, 3H, 15-CH ), 1.32 (1.31) (t, J = 6.9 6.17 (d, J = 11.7 Hz, 1H, H-4), 6.07 (d, J = 16.2 Hz, 1H, H-8), 5.94

2

-8 & H -16), 11.4 Hz, 1H, H-3), 7.00 (dd, J = 15.3, 4.5 Hz, 1H, H-18), 6.86 (dt,

.97–1.89 (m, 2H, H

2

3

), 1.78 (quin., J = J = 16.2, 6.6 Hz, 1H, H-9), 6.83 (dd, J = 15.3, 1.2 Hz, 1H, H-19),

2

3

1

3

Hz, 6H, 2 × OCH

66.6 (166.5), 163.0 (d, J = 246.8 Hz), 146.8, 146.2, 141.6, 139.8 6.0 Hz, 1H, H-14), 4.03 (dd, J = 12.0, 7.8 Hz, 1H, H-13), 3.98

139.7), 134.7 (134.6), 130.4, 126.7, 125.8 (125.7), 124.9 (124.8), (s, 3H, N–CH ), 3.89 (dd, J = 12.3, 4.8 Hz, 1H, H-13), 3.71 (d, J =

2 3 3

CH ). C NMR (75 MHz, CDCl ) δ 189.0, (d, J = 15.3 Hz, 1H, H-2), 5.92–5.83 (m, 1H, H-15), 5.36 (t, J =

1

(

3

1

6

2

24.5, 120.4 (120.1), 119.2, 115.7 (115.4), 70.9, 69.0, 67.3, 65.4, 12.9 Hz, 1H, H-6), 3.54–3.41 (m, 2H, H

2.3 (62.2), 62.2 (62.1), 61.7, 44.5, 41.5 (41.3), 34.6, 32.8, 32.3, H-6), 2.45–2.32 (m, 4H, H -10 & H -16), 1.86 (s, 3H, 5-CH

(s, 3H, 15-CH₃). C NMR (75 MHz, CDCl ) δ 196.9, 179.6, 166.1,

2

-11), 3.37 (d, J = 13.2 Hz,

2

3

), 1.74

13

5.7 (25.1), 16.9, 16.6 (16.5).

3

1

46.9, 144.5, 144.0, 143.3, 140.2, 140.1, 138.4, 133.6, 131.5,

30.4, 126.0, 125.6, 120.7, 69.8, 68.1, 67.7, 54.0, 46.0, 44.8,

General procedure for synthesis of zampanolide mimics 51–62

To a solution of the relevant diol (39–50, 0.05 mmol) in di- 33.0, 24.3, 16.8. IR (film) ν : 2916, 2855, 1706, 1664, 1622,

max

−1

chloromethane (3 mL) at room temperature was added Dess– 1533, 1378, 1357, 1140 cm . HRMS (ESI): m/z calculated for

+

Martin periodinane (64 mg, 0.15 mmol). The reaction mixture

C H N O

25 31 2 5

[M + H] : 439.2233. Found: 439.2223.

was stirred for 30 min before a second portion of Dess–Martin

periodinane (64 mg, 0.15 mmol) was added. The reaction was [α] : +59.6 (c = 0.07, MeOH). H NMR (300 MHz, CDCl ) δ 8.33

3

(17S) Zampanolide mimic 53. Colorless oil. Yield: 72%.

2

0

1

D

allowed to proceed with stirring at room temperature for an (s, 1H, oxazole–H), 7.94 (s, 1H, oxazole–H), 7.66 (dd, J = 15.0,

additional 1 h. The reaction mixture was poured into a stirred 11.7 Hz, 1H, H-3), 7.23 (dd, J = 15.9, 4.2 Hz, H, H-18), 7.13 (d,

mixture of saturated sodium bicarbonate (10 mL) and satu- J = 15.9 Hz, 1H, H-19), 6.87 (dt, J = 15.9, 6.6 Hz, 1H, H-9), 6.16

rated sodium thiosulfate (10 mL), and the resulting suspen- (d, J = 11.4 Hz, 1H, H-4), 6.07 (d, J = 16.2 Hz, 1H, H-8), 5.96 (d,

sion was stirred for 30 min before being extracted with di- J = 15.0 Hz, 1H, H-2), 5.91–5.86 (m, 1H, H-17), 5.35 (t, J =

chloromethane (20 mL × 3). The combined organic extracts 6.3 Hz, 1H, H-14), 4.02–3.88 (m, 2H, H

were dried over anhydrous sodium sulfate and the dried 13.2 Hz, 1H, H-6), 3.53–3.42 (m, 2H, H -11), 3.37 (d, J = 12.9

extract was concentrated under vacuum. The crude product Hz, 1H, H-6), 2.47–2.38 (m, 4H, H -10 & H -16), 1.86 (s,

2

-13), 3.72 (d, J =

2

1

3

was used for the next reaction without further purification.

3 3 3

3H, 5-CH ), 1.74 (s, 3H, 15-CH ). C NMR (75 MHz, CDCl )

To a solution of the crude diketone (0.05 mmol) obtained δ 197.1, 183.1, 166.1, 151.1, 146.9, 146.5, 143.6, 143.1, 140.7,

above in THF (50 mL) at 0 °C was added water (1.05 mL) fol- 140.0, 133.7, 130.4, 126.0, 125.9, 125.2, 120.8, 69.9, 68.1, 67.7,

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1

C

6.0, 44.8, 33.0, 24.2, 16.9. IR (film) νmax: 2924, 1716, 1683,

(17S) Zampanolide mimic 57. Pale yellow oil. Yield: 89%.

−1

20

1

635, 1559, 1507, 1250 cm ; HRMS (ESI): m/z calculated for [α] : +55.3 (c = 0.2, MeOH). H NMR (300 MHz, CDCl ) δ 7.97

D

3

+

24

H

28NO

6

[M + H] : 426.1917. Found: 426.1915.

(dd, J = 9.0, 5.4 Hz, 2H, phenyl–H), 7.66 (dd, J = 15.3, 11.7 Hz,

2

0

(

17R) Zampanolide mimic 54. Colorless oil. Yield: 15%. [α] : 1H, H-3), 7.15 (t, J = 8.7 Hz, 2H, phenyl–H), 7.06 (d, J =

D

1

−

55.1 (c = 0.05, MeOH). H NMR (300 MHz, CDCl ) δ 8.33 (d, J = 15.9 Hz, 1H, H-19), 6.99 (dd, J = 15.3, 3.6 Hz, 1H, H-18), 6.87

3

0

.9 Hz, 1H, oxazole–H), 7.93 (d, J = 1.2 Hz, 1H, oxazole–H), 7.66 (dt, J = 16.2, 6.6 Hz, 1H, H-9), 6.17 (d, J = 11.1 Hz, 1H, H-4),

dd, J = 15.3, 11.7 Hz, 1H, H-3), 7.24 (dd, J = 15.6, 4.2 Hz, H, 6.07 (d, J = 16.2 Hz, 1H, H-8), 5.95 (d, J = 15.0 Hz, 1H, H-2),

H-18), 7.12 (dd, J = 15.9, 1.5 Hz, 1H, H-19), 6.87 (dt, J = 16.2, 5.93–5.86 (m, 1H, H-17), 5.37 (t, J = 6.6 Hz, 1H, H-14), 4.04 (dd,

.6 Hz, 1H, H-9), 6.16 (d, J = 11.4 Hz, 1H, H-4), 6.07 (d, J = 16.2 J = 12.0, 7.8 Hz, 1H, H-13), 3.90 (dd, J = 12.0, 4.8 Hz, 1H, H-13),

Hz, 1H, H-8), 5.96 (d, J = 15.0 Hz, 1H, H-2), 5.91–5.86 (m, 1H, 3.72 (d, J = 13.2 Hz, 1H, H-6), 3.54–3.43 (m, 2H, H -11), 3.37 (d,

H-17), 5.36 (t, J = 5.7 Hz, 1H, H-14), 4.32 (dd, J = 12.3, 7.8 Hz, J = 13.2 Hz, 1H, H-6), 2.43–2.39 (m, 4H, H -10 & H -16), 1.87 (s,

(

6

2

1

3

1

H, H-13), 3.89 (dd, J = 12.0, 5.1 Hz, 1H, H-13), 3.71 (d, J = 13.2 3H, 5-CH

3 3 3

), 1.74 (s, 3H, 15-CH ). C NMR (75 MHz, CDCl )

Hz, 1H, H-6), 3.53–3.42 (m, 2H, H -11), 3.38 (d, J = 13.2 Hz, 1H, δ 196.9, 188.6, 166.1, 166.0 (d, J = 259.0 Hz), 146.9, 145.8,

2

H-6), 2.47–2.38 (m, 4H, H -10 & H -16), 1.86 (s, 3H, 5-CH ), 1.74 143.3, 140.1, 134.0 (d, J = 2.9 Hz), 133.7, 131.5, 131.4, 130.4,

2

3

1

3

(

s, 3H, 15-CH

3

). C NMR (75 MHz, CDCl

3

) δ 197.0, 183.1, 166.1, 125.9 (d, J = 2.3 Hz), 124.8, 120.7, 116.0 (d, J = 21.8 Hz), 70.0,

1

4

51.1, 146.9, 146.5, 143.6, 143.1, 140.8, 140.0, 133.7, 130.4, 68.1, 67.7, 45.9, 44.8, 33.0, 24.3, 16.8. IR (film) νmax: 2923,

−

1

26.0, 125.9, 125.3, 120.9, 70.0, 68.1, 67.8, 46.0, 44.8, 33.0, 24.3, 2853, 1712, 1663, 1629, 1597, 1507 cm . HRMS (ESI): m/z cal-

+

6.9. IR (film) νmax: 2922, 2853, 1708, 1676, 1628, 1560, culated for C27

H

30FO

5

[M + H] : 453.2077. Found: 453.2064.

092 cm⁻; HRMS (ESI): m/z calculated for C24

1

+

(17R) Zampanolide mimic 58. Pale yellow oil. Yield: 33%.

[α] : −65.0 (c = 0.10, MeOH). H NMR (300 MHz, CDCl₃)

D

6

H28NO [M + H] :

2

0

1

26.1917. Found: 426.1910.

(

17S) Zampanolide mimic 55. Colorless oil. Yield: 24%. δ 7.98 (dd, J = 8.7, 5.4 Hz, 2H, phenyl–H), 7.66 (dd, J = 15.0,

2

0

1

[

α] : +47.2 (c = 0.06, MeOH). H NMR (300 MHz, CDCl

3

) δ 7.94 11.4 Hz, 1H, H-3), 7.16 (t, J = 8.4 Hz, 2H, phenyl–H), 7.06 (d,

D

(d, J = 6.9 Hz, 2H, phenyl–H), 7.67 (dd, J = 15.3, 11.7 Hz, 1H, J = 15.6 Hz, 1H, H-19), 6.99 (dd, J = 15.3, 3.6 Hz, 1H, H-18),

H-3), 7.58 (t, J = 7.8 Hz, 1H, phenyl–H), 7.48 (t, J = 7.5 Hz, 2H, 6.87 (dt, J = 15.9, 6.9 Hz, 1H, H-9), 6.17 (d, J = 11.4 Hz, 1H,

phenyl–H), 7.09 (d, J = 15.6 Hz, 1H, H-19), 7.00 (dd, J = 15.3, H-4), 6.07 (d, J = 16.2 Hz, 1H, H-8), 5.95 (d, J = 15.3 Hz, 1H,

4

.2 Hz, 1H, H-18), 6.87 (dt, J = 15.9, 6.9 Hz, 1H, H-10), 6.17 (d, H-2), 5.92–5.86 (m, 1H, H-17), 5.37 (t, J = 6.3 Hz, 1H, H-14),

J = 11.1 Hz, 1H, H-4), 6.07 (d, J = 16.2 Hz, 1H, H-8), 5.96 (d, J = 4.04 (dd, J = 12.0, 7.8 Hz, 1H, H-13), 3.90 (dd, J = 12.0, 4.8 Hz,

1

3

2

3

1

3

1

4

4.7 Hz, 1H, H-2), 5.93–5.81 (m, 1H, H-17), 5.37 (t, J = 5.4 Hz, 1H, H-13), 3.72 (d, J = 13.2 Hz, 1H, H-6), 3.54–3.42 (m, 2H,

H, H-14), 4.04 (dd, J = 12.0, 8.1 Hz, 1H, H-13), 3.90 (dd, J = H -11), 3.37 (d, J = 13.2 Hz, 1H, H-6), 2.45–2.39 (m, 4H, H -10

2

13

2.3, 4.8 Hz, 1H, H-13), 3.72 (d, J = 12.6 Hz, 1H, H-6), & H

2

-16), 1.87 (s, 3H, 5-CH

3 3

), 1.74 (s, 3H, 15-CH ). C NMR

.54–3.39 (m, 2H, H -11), 3.37 (d, J = 12.9 Hz, 1H, H-6), (75 MHz, CDCl ) δ 196.9, 188.6, 166.1, 165.9 (d, J = 255.0 Hz),

2 3

.45–2.35 (m, 4H, H -10 & H -16), 1.87 (s, 3H, 5-CH ), 1.75 (s, 146.9, 145.8, 143.3, 140.1, 134.0 (d, J = 3.0 Hz), 133.7, 131.5,

2

3

1

3

H, 15-CH

3

). C NMR (75 MHz, CDCl

3

) δ 197.0, 190.4, 166.2, 131.4, 130.4, 126.0, 124.8, 120.7, 116.1 (d, J = 22.5 Hz), 70.1,

46.9, 145.6, 143.2, 140.0, 137.7, 133.8, 133.3, 130.4, 128.9, 68.1, 67.7, 46.0, 44.8, 33.0, 24.3, 16.9. IR (film) νmax: 2916,

−

1

28.8, 126.0, 125.9, 125.2, 120.8, 70.1, 68.1, 67.7, 46.0, 44.9, 2857, 1709, 1672, 1628, 1597, 1507 cm . HRMS (ESI): m/z cal-

+

3.0, 24.3, 16.9. IR (film) νmax: 2923, 2853, 1715, 1670, 1628, culated for C27

H

30FO

5

[M + H] : 453.2077. Found: 453.2068.

597 cm⁻; HRMS (ESI): m/z calculated for C27

1

+

(17S) Zampanolide mimic 59. Red-brown oil. Yield: 38%.

31 5

H O [M + H] :

2

0

1

35.2172. Found: 435.2170.

[α] : +83.1 (c = 0.06, MeOH). H NMR (300 MHz, CDCl ) δ 7.75

D

3

(

17R) Zampanolide mimic 56. Colorless oil. Yield: 29%. (dt, J = 7.5, 1.8 Hz, 1H, phenyl–H), 7.65 (dd, J = 15.3, 11.7 Hz,

2

0

1

[

α] : −56.0 (c = 0.08, MeOH). H NMR (300 MHz, CDCl

3

)

1H, H-3), 7.56–7.48 (m, 1H, phenyl–H), 7.27–7.21 (overlapped,

δ 7.94 (dt, J = 7.2, 2.1 Hz, 2H, phenyl–H), 7.66 (dd, J = 15.0, 1H, phenyl–H), 7.14 (ddd, J = 10.8, 8.4, 0.9 Hz, 1H, phenyl–H),

1.7 Hz, 1H, H-3), 7.58 (tt, J = 7.2, 1.2 Hz, 1H, phenyl–H), 7.48 6.96–6.95 (overlapped, 2H, H-18 & H-19), 6.86 (dt, J = 15.9,

tt, J = 7.8, 1.5 Hz, 2H, phenyl–H), 7.08 (dd, J = 15.3, 0.9 Hz, 6.9 Hz, 1H, H-9), 6.16 (d, J = 11.4 Hz, 1H, H-4), 6.07 (d, J =

D

1

(

1

H, H-19), 7.00 (dd, J = 15.36, 4.2 Hz, 1H, H-18), 6.87 (dt, J = 16.2 Hz, 1H, H-8), 5.94 (d, J = 15.0 Hz, 1H, H-2), 5.87 (dt, J = 5.9,

5.9, 6.6 Hz, 1H, H-10), 6.17 (d, J = 11.4 Hz, 1H, H-4), 6.07 (d, 2.4 Hz, 1H, H-17), 5.36 (t, J = 6.3 Hz, 1H, H-14), 4.03 (dd, J =

J = 16.2 Hz, 1H, H-8), 5.96 (d, J = 15.3 Hz, 1H, H-2), 5.90–5.87 12.0, 7.8 Hz, 1H, H-13), 3.90 (dd, J = 12.0, 4.8 Hz, 1H, H-13),

m, 1H, H-17), 5.37 (t, J = 5.1 Hz, 1H, H-14), 4.04 (dd, J = 12.0, 3.69 (d, J = 13.2 Hz, 1H, H-6), 3.53–3.40 (m, 2H, H -11), 3.38

(

2

7

.8 Hz, 1H, H-13), 3.90 (dd, J = 12.3, 5.1 Hz, 1H, H-13), 3.72 (d, (d, J = 12.9 Hz, 1H, H-6), 2.45–2.39 (m, 4H, H

2

-16 & H

2

-10), 1.86

13

J = 12.9 Hz, 1H, H-6), 3.54–3.42 (m, 2H, H

2

3 3

-11), 3.37 (d, J = 12.9 (s, 3H, 5-CH ), 1.73 (s, 3H, 15-CH ). C NMR (75 MHz, CDCl )

3

Hz, 1H, H-6), 2.45–2.35 (m, 4H, H -10 & H -16), 1.87 (s, 3H, δ 197.0, 188.9, 166.1, 161.5 (d, J = 259.5 Hz), 146.9, 145.8, 143.1,

2

1

3

5

-CH

3

), 1.75 (s, 3H, 15-CH

3

). C NMR (75 MHz, CDCl

3

)

140.0, 134.4 (d, J = 8.3 Hz), 133.7, 131.2 (d, J = 2.3 Hz), 130.4,

δ 197.0, 190.4, 166.2, 146.9, 145.6, 143.2, 140.0, 137.7, 133.7, 128.6 (d, J = 6.8 Hz), 126.7 (d, J = 12.8 Hz), 126.0 (d, J = 7.5 Hz),

1

6

1

33.3, 130.4, 128.8, 128.8, 126.0, 126.0, 125.2, 120.8, 70.1, 68.1, 124.7 (d, J = 3.8 Hz), 120.8, 116.9, 116.6, 69.9, 68.0, 67.7, 45.9,

7.7, 45.9, 44.9, 33.0, 24.3, 16.9. IR (film) νmax: 2918, 1709, 44.7, 33.0, 24.3, 16.9. IR (film) νmax: 2923, 2855, 1712, 1671,

−

1

−1

672, 1629 cm ; HRMS (ESI): m/z calculated for C27

H

31

O

5

1628, 1610, 1480, 1452, 1279 cm . HRMS (ESI): m/z calculated

+

[M + H] : 435.2172. Found: 435.2162.

for C H FO [M + H] : 453.2077. Found: 453.2074.

27

30

5

Org. Biomol. Chem.

View Article Online

Paper

Organic & Biomolecular Chemistry

(

17R) Zampanolide mimic 60. Light yellow oil. Yield: 20%. Cell culture

2

0

1

[

α] : −91.0 (c = 0.05, MeOH). H NMR (300 MHz, CDCl₃)

D

All cell lines were initially purchased from American Type

Culture Collection (ATCC). The PC-3 and LNCaP prostate

cancer cell lines were routinely cultured in RPMI-1640 medium

supplemented with 10% FBS and 1% penicillin/streptomycin.

Cultures were maintained in a high humidity environment

supplemented with 5% carbon dioxide at a temperature of

δ 7.75 (dt, J = 7.8, 2.1 Hz, 1H, phenyl–H), 7.65 (dd, J = 15.0,

1

7

1

(

6

5

1.4 Hz, 1H, H-3), 7.56–7.48 (m, 1H, phenyl–H), 7.24 (dt, J =

.5, 0.9 Hz, 1H, phenyl–H), 7.14 (ddd, J = 11.1, 8.4, 1.2 Hz,

H, phenyl–H), 6.96–6.95 (overlapped, 2H, H-18 & H-19), 6.87

dt, J = 16.2, 6.6 Hz, 1H, H-9), 6.16 (d, J = 11.7 Hz, 1H, H-4),

.07 (d, J = 16.2 Hz, 1H, H-8), 5.94 (d, J = 15.0 Hz, 1H, H-2),

.87 (dt, J = 8.1, 3.6 Hz, 1H, H-17), 5.36 (t, J = 5.4 Hz, 1H,

37 °C. The DU-145 prostate cancer cells were routinely cultured

in Eagle’s Minimum Essential Medium (EMEM) supplemented

with 10% FBS and 1% penicillin/streptomycin.

H-14), 4.03 (dd, J = 12.0, 7.8 Hz, 1H, H-13), 3.90 (dd, J = 12.0,

5

2

.1 Hz, 1H, H-13), 3.69 (d, J = 12.9 Hz, 1H, H-6), 3.53–3.40 (m,

H, H -11), 3.39 (d, J = 13.2 Hz, 1H, H-6), 2.45–2.39 (m, 4H,

-16 & H -10), 1.86 (s, 3H, 5-CH ), 1.73 (s, 3H, 15-CH ).

Docetaxel-resistant prostate cancer cell lines were estab-

2

22,23

lished based on the procedure illustrated in the literature.

H

2

3

Docetaxel resistant DU145 and PC-3 cell lines (DU145/DTX and

PC-3/DTX) were developed over a period of one year by stepwise

increased concentrations of docetaxel. Cells were continuously

maintained in docetaxel, with treatments beginning at the

initial IC50 of the respective parent cell lines. Media containing

docetaxel were changed every 2–3 days. As cells displayed

resistance to treatments of docetaxel the concentration was

increased.

1

3

C NMR (75 MHz, CDCl ) δ 197.0, 188.9, 166.1, 161.5 (d, J =

3

2

1

68.5 Hz), 146.9, 145.8, 143.1, 134.4 (d, J = 9.8 Hz), 133.7,

31.2, 130.4, 128.6, 126.6, 126.0 (d, J = 6.0 Hz), 124.7, 120.8,

16.8, 116.6, 69.9, 68.0, 67.7, 45.9, 44.7, 33.0, 24.3, 16.9.

IR (film) νmax: 2919, 2852, 1709, 1669, 1627, 1609, 1481,

1

[

−

1

452 cm . HRMS (ESI): m/z calculated for C27H30FO

5

+

M + H] : 453.2077. Found: 453.2068.

17S) Zampanolide mimic 61. Red-brown oil. Yield: 50%.

(

2

0

1

[

3

α] : +57.7 (c = 0.08, MeOH). H NMR (300 MHz, CDCl )

D

WST-1 cell proliferation assay

δ 7.71 (dt, J = 7.8, 1.2 Hz, 1H, phenyl–H), 7.67–7.60 (m, 2H,

phenyl–H & H-3), 7.50–7.43 (m, 1H, phenyl–H), 7.31–7.24 (m,

1

(

6

5

PC-3, DU-145, or LNCaP cells were plated in 96-well plates at a

density of 3200 each well in 200 µL of culture medium. The

cells were then treated with positive reference, or synthesized

mimics separately at diﬀerent doses for 3 days, while equal

treatment volumes of DMSO were used as vehicle control. The

H, phenyl–H), 7.03–7.02 (overlapped, 2H, H-19 & H-18), 6.87

dt, J = 16.2, 6.6 Hz, 1H, H-9), 6.17 (d, J = 11.4 Hz, 1H, H-4),

.07 (d, J = 16.2 Hz, 1H, H-8), 5.96 (d, J = 15.0 Hz, 1H, H-2),

.92–5.87 (m, 1H, H-17), 5.36 (t, J = 6.6 Hz, 1H, H-14), 4.04

cells were cultured in a CO

0 µL of the premixed WST-1 cell proliferation reagent

Clontech) was added to each well. After mixing gently for one

2

incubator at 37 °C for three days.

(

dd, J = 12.3, 7.8 Hz, 1H, H-13), 3.90 (dd, J = 12.3, 4.8 Hz, 1H,

H-13), 3.72 (d, J = 12.9 Hz, 1H, H-6), 3.54–3.42 (m, 2H, H -11),

.37 (d, J = 12.9 Hz, 1H, H-6), 2.45–2.34 (m, 4H, H -16 &

1

(

2

3

2

1

3

min on an orbital shaker, the cells were incubated for an

additional 3 h at 37 °C. To ensure homogeneous distribution

of color, it was important to mix gently on an orbital shaker

for 1 min. The absorbance of each well was measured using a

microplate-reader (Synergy HT, BioTek) at a wavelength of

430 nm. The IC₅₀value is the concentration of each compound

that inhibits cell proliferation by 50% under the experimental

conditions and is the average from triplicate determinations

that were reproducible and statistically significant. For calcu-

lating the IC50 values, a linear proliferative inhibition was

made based on at least five dosages for each compound.

H -10), 1.87 (s, 3H, 5-CH ), 1.74 (s, 3H, 15-CH ). C NMR

(

Hz), 146.9, 146.5, 143.3, 140.11, 140.07, 139.8 (139.7), 133.6,

1

IR (film) νmax: 2921, 2851, 1716, 1675, 1628, 1521, 1507cm

HRMS (ESI): m/z calculated for C H FO [M + H] : 453.2077.

Found: 453.2075.

17R) Zampanolide mimic 62. Red-brown oil. Yield: 29%.

2

3

75 MHz, CDCl ) δ 196.9, 188.9, 166.1, 163.0 (d, JCF = 246.8

30.6 (130.5), 130.4, 125.9, 124.7, 124.5, 120.7, 120.4 (120.2),

15.7 (115.4), 70.0, 68.1, 67.7, 45.9, 44.8, 33.0, 24.3, 16.9.

−

1

.

+

2

7

30

5

(

2

0

1

[α] : −69.0 (c = 0.10, MeOH). H NMR (300 MHz, CDCl₃)

D

δ 7.71 (dt, J = 8.4, 1.5 Hz, 1H, phenyl–H), 7.67–7.60 (m, 2H,

phenyl–H & H-3), 7.50–7.43 (m, 1H, phenyl–H), 7.31–7.24 (m,

1

F2N12S and CYTOX AADvanced double staining assay

H, phenyl–H), 7.03–7.02 (overlapped, 2H, H-19 & H-18), 6.87

(dt, J = 16.2, 6.6 Hz, 1H, H-9), 6.17 (d, J = 11.4 Hz, 1H, H-4), PC-3 cells were plated in 24-well plates at a density of 200 000

6

5

.07 (d, J = 16.2 Hz, 1H, H-8), 5.96 (d, J = 15.3 Hz, 1H, H-2), each well in 400 µL of culture medium. After 3 h of cell

.96–5.89 (m, 1H, H-17), 5.36 (t, J = 7.2 Hz, 1H, H-14), 4.04 (dd, attachment, the cells were treated with the test compound at

J = 12.0, 7.8 Hz, 1H, H-13), 3.90 (dd, J = 12.6, 5.1 Hz, 1H, H-13), diﬀerent concentrations and cultured in a CO

.72 (d, J = 13.2 Hz, 1H, H-6), 3.54–3.42 (m, 2H, H -11), 3.37 37 °C for 16 h while equal treatment volumes of DMSO were

d, J = 13.2 Hz, 1H, H-6), 2.45–2.33 (m, 4H, H -16 & H -10), used as vehicle control. Both attached and floating cells were

2

incubator at

3

2

(

1

2

1

3

.87 (s, 3H, 5-CH

) δ 197.0, 189.0, 166.1, 163.1 (d, JCF = 250.5 Hz), 146.9, 450g for 5 min. The collected cells were re-suspended with

46.5, 143.3, 143.1, 140.1, 139.7, 133.6, 130.4, 126.0, 124.7, 500 µL HBSS to remove proteins which may aﬀect flow signal

24.6, 120.7, 120.2, 115.7, 70.0, 68.1, 67.7, 45.9, 44.8, 33.0, and centrifuged again. After discarding the supernatant, the

3 3

), 1.74 (s, 3H, 15-CH ). C NMR (75 MHz, collected in a centrifuge tube by centrifugation at rcf value of

CDCl

3

1

2

4

+

4.3, 16.9. HRMS (ESI): m/z calculated for C27

H

30FO

5

[M + H] : collected cells were re-suspended with 300 µL HBSS and

53.2077. Found: 453.2075.

stained with 0.3 µL of F2N12S for 3–5 min followed by 0.3 µL

Org. Biomol. Chem.

View Article Online

Organic & Biomolecular Chemistry

Paper

SYTOX AADvanced for an additional 5 min. The fluorescence

intensity of the two probes was further measured in individual

PC-3 cells using an Attune flow cytometer (Life Technologies)

within 0.5–1 h after staining.

6 M. Thadani-Mulero, D. M. Nanus and P. Giannakakou,

Cancer Res., 2012, 72, 4611–4615.

7 Q.-H. Chen and D. G. I. Kingston, Nat. Prod. Rep., 2014, 31,

1202–1226.

8

9

J. J. Field, A. J. Singh, A. Kanakkanthara, T. I. Halafihi,

P. T. Northcote and J. H. Miller, J. Med. Chem., 2009, 52,

Statistical analysis

7328–7332.

All data are represented as the mean ± standard deviation

J. J. Field, B. Pera, E. Calvo, A. Canales, D. Zurwerra,

C. Trigili, J. Rodriguez-Salarichs, R. Matesanz,

A. Kanakkanthara, S. J. Wakefield, A. J. Singh, J. Jimenez-

Barbera, P. Northcote, J. H. Miller, J. A. Lopez, E. Hamel,

I. Barasoain, K.-H. Altman and J. F. Diaz, Chem. Biol., 2012,

(S.D.) for the number of experiments indicated. Other diﬀer-

ences between treated and control groups were analyzed using

the Student’s t-test. A p-value < 0.05 was considered statistically

significant.

19, 686–698.

1

0 A. E. Prota, K. Bargsten, D. Zurwerra, J. J. Field, J. F. Diaz,

K.-H. Altmann and M. O. Steinmetz, Science, 2013, 339,

Conﬂicts of interest

587–590.

There are no conflicts to declare.

1

1 J. Singh, R. C. Petter, T. A. Baillie and A. Whitty, Nat. Rev.

Drug Discovery, 2011, 10, 307–317.

2 J. Tanaka and T. Higa, Tetrahedron Lett., 1996, 37, 5535–

Acknowledgements

5538.

This work was financially supported by the National Institutes 13 T. R. Hoye and M. Hu, J. Am. Chem. Soc., 2003, 125, 9576–

of Health (National Institute of General Medical Sciences)

9577.

through grant SC2GM121185 (Q-H. Chen). The content is 14 A. K. Ghosh and X. Cheng, Org. Lett., 2011, 13, 4108–

solely the responsibility of the authors and does not necess-

4111.

arily represent the oﬃcial views of the National Institutes of 15 A. B. Smith, I. G. Safonov and R. M. Corbett, J. Am. Chem.

Health. This work was also partially supported by the NIH

Soc., 2002, 124, 11102–11113.

RCMI program at Xavier University of Louisiana through grant 16 J. Uenishi, T. Iwamoto and J. Tanaka, Org. Lett., 2009, 11,

G12MD007595-064 (G. Wang).

3262–3265.

1

7 D. Zurwerra, J. Gertsch and K.-H. Altmann, Org. Lett., 2010,

12, 2302–2305.

8 D. Zurwerra, F. Glaus, L. Betschart, J. Schuster, J. Gertsch,

W. Ganci and K.-H. Altmann, Chem. – Eur. J., 2012, 18,

16868–16883.

Notes and references

1

R. L. Siegel, K. D. Miller and A. Jemal, Ca-Cancer J. Clin.,

018, 68, 7–30.

J. S. de Bono, S. Oudard, M. Ozguroglu, S. Hansen,

2

19 A. K. Ghosh, X. Cheng, R. Bai and E. Hamel, Eur. J. Org.

Chem., 2012, 4130–4139.

2

J.-P. Machiels, I. Kocak, G. Gravis, I. Bodrogi, 20 F. Ding and P. J. Michael, J. Org. Chem., 2008, 73, 5965–

M. Mackenzie, L. Shen, M. Roessner, S. Gupta and

A. O. Sartor, Lancet, 2010, 376, 1147–1154.

I. F. Tannock, R. de Wit, W. R. Berry, J. Horti, A. Pluzanska,

K. N. Chi, S. Oudard, C. Theodore, N. D. James,

5976.

21 G. Chen, R. Wang, B. Vue, M. Patanapongpibul, Q. Zhang,

S. Zheng, G. Wang, J. D. White and Q.-H. Chen, Bioorg.

Med. Chem., 2018, 26, 3514–3520.

3

4

5

I. Turesson, M. A. Rosenthal and M. A. Eisenberger, N. 22 A. J. O’Neill, M. Prencipe, C. Dowling, Y. Fan, L. Mulrane,

Engl. J. Med., 2004, 351, 1502–1512.

I. F. Tannock, R. de Wit, W. R. Berry, J. Horti, A. Pluzanska,

K. N. Chi, S. Oudard, C. Theodore, N. D. James,

W. M. Gallagher, D. O’Connor, R. O’Connor, A. Devery,

C. Corcoran, S. Rani and L. O’Driscoll, Mol. Cancer, 2011,

10, 126.

I. Turesson, M. A. Rosenthal and M. A. Eisenberger, N. 23 M. Shiota, E. Kashiwagi, A. Yokomizo, A. Takeuchi,

Engl. J. Med., 2004, 351, 1513–1520.

T. Dejima, Y. Song, K. Tatsugami, J. Inokuchi, T. Uchiumi

M. A. Jordan and L. Wilson, Nat. Rev. Cancer, 2004, 4, 253–265.

and S. Naito, Prostate, 2013, 73, 1336–1344.

Org. Biomol. Chem.

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Synthesis and antiproliferative evaluation of new zampanolide mimics

DOI: 10.1039/C9OB00556K

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Article abstract of DOI:10.1039/C9OB00556K

Full text of DOI:10.1039/C9OB00556K

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