Enantiospecific Synthesis and Cytotoxicity Evaluation of Oximidine II Analogues

DOI: 10.1002/cmdc.201600024

Full Papers

Enantiospecific Synthesis and Cytotoxicity Evaluation of

Oximidine II Analogues

Christopher M. Schneider,^[b]Wei Li,^[a]Kriangsak Khownium,^[b]Gerald H. Lushington,^[c]and

Gunda I. Georg*^[a]

Analogues of the anticancer natural product oximidine II were

prepared and evaluated for cytotoxicity. One analogue of oxi-

midine II that carries a C15 allylic amide side chain as well as

two analogues with C15 vinyl sulfone side chains were found

to lack cytotoxicity against the cancer cell line SK-Mel-5, there-

by confirming the necessity of the C15 enamide side chain of

oximidine II for cytotoxicity. Four analogues, designed by com-

parative molecular similarity index analysis (CoMSIA), that fea-

ture a less complex macrolactone scaffold were prepared and

tested. The two analogues carrying a C15 vinyl sulfone group

and the two analogues with a C15 oximidine II enamide side

chain showed weak cytotoxicity against the SK-Mel-5 cell line

and other cell lines, indicating that the designed simplified

macrocycles cannot replace the oximidine II macrocycle.

Introduction

Salicylihalamides A (1, Figure 1) and B were discovered as the

first members of a class of natural products that are character-

ized by the presence of an acyl enamine (enamide) side chain

appended to a salicylate macrolactone core.^[1,2]Subsequently,

four other members of this family were discovered including

the lobatamides,^[3]apicularens,^[4]CJ-compounds,^[5]and oximi-

dines^[6–8](oximidine II (2) in Figure 1). Testing of the benzolac-

tone enamide natural products by Boyd et al. revealed that

these molecules are potent cytotoxic agents with nanomolar

cytotoxicity across a variety of cell lines.^[9]By using a COMPARE

analysis,^[10]these researchers deduced that the benzolactone

enamides exert their mechanism of action by inhibition of the

eukaryotic transport protein vacuolar-(H⁺)-adenosine triphos-

phatase (V-ATPase). Further biological assessment showed that

these molecules are selective inhibitors of only mammalian

types of V-ATPases.

Figure 1. Structures of representative benzolactone natural products: sali-

cylihalamide A (1), oximidine II (2), and cruentaren A (3).

V-ATPases are responsible for pH homeostasis in various in-

tracellular organelles such as the Golgi apparatus, endo-

somes,^[11]and lysosomes.^[12,13]This pH control results in the reg-

ulation of cellular processes such as the degradation of pro-

teins and other molecules, receptor-mediated endocytosis, and

coupled transport of various small molecules. More specifically,

these enzymes are crucial in the processes of renal acidifica-

tion,^[14]bone resorption and degradation,^[15]control of cyto-

plasmic pH,^[13]and sperm maturation.^[16]As V-ATPases play a va-

riety of cellular roles, their malfunction has been implicated in

[a] Dr. W. Li, Prof. Dr. G. I. Georg

Department of Medicinal Chemistry and Institute for Therapeutics Discovery

and Development, University of Minnesota,

717 Delaware Street SE, Minneapolis, MN 55414 (USA)

E-mail: Georg@umn.edu

[b] Dr. C. M. Schneider, Dr. K. Khownium

Department of Medicinal Chemistry,

University of Kansas, 1251 Wescoe Hall Drive, Lawrence, KS 66045 (USA)

[c] Dr. G. H. Lushington

a

variety of diseases including HIV, osteoporosis, and

Molecular Graphics & Modeling Laboratory,

University of Kansas, 1251 Wescoe Hall Drive, Lawrence, KS 66045 (USA)

cancer.^[13,17]

Supporting information (¹H and ¹³C NMR spectra) and the ORCID identifi-

cation number(s) for the author(s) of this article can be found under

htt p ://dx.doi.org/10.1002/cmdc.201600024.

The benzolactone class of natural products has attracted sig-

nificant attention from both the synthetic and medicinal

chemistry communities due to their unique architecture and

their various bioactivities; particularly, their potent anticancer

properties.^[18,19]Analogue studies^[20,21]have been aimed mainly

at exploring the structure–activity relationships (SAR) for the

enamide side chain, stemming from the known instability of

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This is an open access article under the terms of the Creative Commons

Attribution-NonCommercial License, which permits use, distribution and

reproduction in any medium, provided the original work is properly

cited and is not used for commercial purposes.

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the salicylihalamide side chain.^[2]The enamide could be hydro-

lyzed into the corresponding aldehyde and amide fragments

in aqueous media and more importantly from a chemothera-

peutic discovery perspective, be inactivated prior to reaching

its intended target. Hydrolysis inside the acidic environment of

cancer cells is also a possible concern. Work by De Brabander

and co-workers has shown that the benzolactone enamides

are likely irreversible inhibitors of V-ATPase.^[22]However, their

efforts to incorporate isotopically labeled salicylihalamide into

the V-ATPase system and elucidate the exact binding mode

have not been successful.^[22]Medicinal chemistry campaigns to

replace the enamide with various electrophilic Michael accept-

ors has led to analogues that retain the V-ATPase-inhibitory

properties of their parent natural product(s) but in general had

lost cytotoxic potency.^[18]One notable exception is the saliphe-

nylhalamide analogue synthesized by De Brabander. This mole-

cule was able to retain cytotoxic properties while demonstrat-

ing enhanced aqueous stability relative to salicylihalamide.^[23]

The necessity of an enamide side chain for cytotoxicity was

brought into question with the isolation of another benzolac-

tone natural product, cruentaren A (3, Figure 1).^[24,25]Cruentare-

n A contains an allylic amide side chain—not a conjugated en-

amide—yet still possesses potent cytotoxicity. This molecule

acts through a different mechanism of action, targeting mito-

chondrial ATP synthase (F-ATPase), not V-ATPase as seen with

the enamide-containing natural products.^[24]

scaffolds and affix different side chains for investigation of the

anticancer properties of the analogues. To this end, we plan-

ned to install the various side chains onto either the oximidi-

ne II or structurally less complex salicylihalimide-like cores. The

design of the simplified analogues relied on an in silico analysis

using the CoMSIA field for V-ATPase inhibitors that had been

generated earlier by our research group.^[29]

Results and Discussion

The presence of the allylic side chain in cruentaren A led us to

question if the electrophilic enamide functionality is necessary

for cytotoxicity, or whether some other binding mode (such as

hydrogen bonding) could be responsible for cytotoxicity. The

synthesis of this oximidine II allylic amide homologue 10

began with vinyl iodide 4 (Scheme 1), an intermediate in previ-

ous syntheses of oximidine II.^[28,30]A palladium-mediated me-

thoxycarbonylation reaction^[31]stereospecifically installed the

allylic carbon with a functional handle to explore various

carbon–nitrogen bond formation reactions. Ultimately, we dis-

covered that reduction of the ester into the corresponding al-

lylic alcohol followed by a Mitsunobu reaction with maleimide

using a modified Walker protocol allowed us to install the

requisite allylic nitrogen atom.^[32,33]Under Luche reduction con-

ditions, mono-reduction of one of the amide bonds of malei-

mide 7 generated hemiaminal 8, which was condensed with

O-methoxyamine to generate oxime 9 as an inseparable mix-

ture of E/Z oxime stereoisomers (3:1 ratio). Bis-TBS removal re-

vealed the desired allylic amide homologue 10 as only the E-

oxime stereoisomer. As shown in Table 1, analogue 10 was not

cytotoxic, thereby confirming the need for an enamide side

chain for the cytotoxicity of oximidine II. We next questioned

whether the enamide was uniquely responsible for the cyto-

We are now reporting our efforts to discover bioactive ana-

logues with better chemical stability by installing physiological-

ly stable warheads onto the benzolactone framework to create

analogues that would retain the cytotoxic properties observed

with this natural product class. Drawing experience from our

syntheses of the salicylihalamides and oximidine II,^[26–28]we en-

visioned that we could rapidly assemble the benzolactone

Scheme 1. Synthesis of the allylic amide homologue 10: a) Pd(PPh₃)₄, DIPEA, CO (1 atm), MeOH, THF, 85%; b) THF, HF/pyridine, RT, 89% for 5b, 80% for 6b,

69% for 8b, 89% for 10; c) DIBAl-H, CH₂Cl₂, À788C, 90%; d) maleimide, DEAD, PPh₃, THF, 08C, 62%; e) CeCl₃·7H₂O, NaBH₄, MeOH, 08C, 86%; f) MeONH₃Cl,

NaHCO₃, MeOH, reflux, 34%, 3:1 E/Z oxime ratio.

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Table 1. Cytotoxicity evaluation of synthesized analogues.

Compound

IC₅₀[mm]^[a]

SK-Mel-5^[b]

SK-Mel-28^[b]

HL-60^[c]

MCF-7^[d]

0.0015Æ0.0007, n=3

paclitaxel

0.0083Æ0.0061, n=3

0.62Æ0.59, n=3

0.0079, n=1

50, n=1

>60, n=2

>60, n=1

49Æ7, n=2

ND

44, n=1

57, n=1

0.0051Æ0.0035, n=2

oximidine II (2)

allylic amide 10

diene sulfone 24

diene sulfone 25

triene sulfone 36

triene sulfone 46

diene enamide 55

diene enamide 56

ND

>60, n=2

ND

25Æ1, n=2

32Æ3, n=2

>60, n=1

30, n=1

32, n=1

24, n=1

41, n=1

52, n=1

ND

50, n=1

25, n=1

41, n=1

>60, n=2

ND

76, n=1

>100

[a] ND: not determined; n=number of times tested; values are the meanÆSEM for n=3 values, and the meanÆSD for n=2 values. [b] Human melanoma.

[c] Human promyelocytic leukemia. [d] Human breast carcinoma.

toxicity of oximidine II, or if other electrophilic warheads could

replace the unstable enamide.

Tripos Inc., St. Louis, MO (USA), 2009). Each molecule was

sketched in SYBYL and optimized according to default molecu-

lar mechanics parameters using the Tripos Molecular Force-

field^[39]and Gasteiger–Marsili electrostatics.^[40]Molecules were

then aligned according to best field fit within the CoMSIA field

for V-ATPase inhibitors generated by Blackman et al.^[29]CoMSIA

scores were then generated via the molecular spreadsheet for

each field-fit molecule, and corresponding pIC₅₀values were

predicted by perturbing the CoMSIA score with the three-pa-

rameter perturbation model described by Blackman et al.,^[29]in

which the perturbation terms were computed via the Dragon

molecular descriptor computation software package.^[41]In this

manner, we would preliminarily predict low-nanomolar IC₅₀

values for both compound 24 (2.7 nm) and 25 (6.1 nm) as ac-

tivities within the assay reported by Wu et al.^[34]The rationale

for this potency is evident from Figure 2 in that both com-

pound 24 and 25 align well with the CoMSIA features. In both

cases the terminal phenyl group is situated at the center of

a large feature with favorable van der Waals interactions. Com-

To date, only a,b-unsaturated ketones and esters have been

investigated as electrophilic enamide side chain replacements

in this natural product family.^[34]Although these Michael ac-

ceptors showed V-ATPase inhibition similar to their parent

compounds, they displayed 10- to 100-fold decreased anti-

cancer activities in cellular assays. These mixed results led us

to investigate the vinyl sulfone moiety as an electrophilic func-

tional group. Under normal physiological conditions, vinyl sul-

fone groups do not undergo nucleophilic addition. Nucleophil-

ic addition occurs only when strategic hydrogen bonding inter-

actions, typically present in an enzyme active site, are available

to activate the functionality.^[35]We designed these analogues

assuming that the acidic environment of the V-ATPase could

activate the electrophilic vinyl sulfone moiety for nucleophilic

addition, analogously to the activation of the enamide moiety.

Molecular modeling

We performed computational analysis studies to aid in the de-

velopment of simplified benzolactone-like core scaffolds in the

preparation of a SAR campaign to explore various enamide re-

placements. In particular, we focused on a benzolactone frame-

work with decreased rigidity, hypothesizing that these more

saturated molecules would be easier to synthesize, yet still dis-

play potent V-ATPase inhibition. This strategy is supported by

the fact that the known benzolactone enamides contain differ-

ent substituents and varying degrees of unsaturation within

the macrocycle. In addition, studies have shown that some

structural modifications to the lactone moiety can be tolerated

without significant loss of activity for salicylihalamide^[36]and re-

lated apicularen analogues.^[37]Using molecular modeling data

obtained from a previous comparative molecular similarity in-

dices analysis (CoMSIA)^[38]/3D-QSAR study completed by our

group as the training set,^[29]a simplified, partially saturated, ox-

imidine-like scaffold was discovered with predicted V-ATPase

activity similar to that of the parent oximidine II molecule. In si-

lico predictions of oximidine analogues considered for synthe-

sis and testing were performed via the CoMSIA^[38]module

within the Tripos Molecular Spreadsheet in SYBYL (version 8.0;

Figure 2. Overlay of compounds 24 and 25 onto CoMSIA fields showing iso-

surfaces for the following pharmacophore features: favorable van der Waals

regions, steric barriers (green), and areas favorable for electropositive (red)

and electronegative (blue) interactions with ligand polar groups. Both com-

pounds are rendered according to default CPK coloring for heteroatoms;

compound 24 has white carbon atoms, and compound 25 has black.

CoMSIA isosurfaces correspond to default mean·coefficient values as imple-

mented in the Tripos Molecular Spreadsheet.

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pound 24 is able to orient its sulfone oxygen atoms favorably

toward an electropositive feature, thus providing a prediction

for enzymatic activation of the electrophilic moiety; the extra

carbon atom on the side chain of compound 25 disrupts this

electrostatic complementarity, but is able to position itself in

a manner that enables the phenyl group to exploit a somewhat

greater lipophilic overlay.

a Horner–Wadsworth–Emmons (HWE) olefination with phos-

phonate 26 installed the desired vinyl sulfone unit. Global de-

protection revealed the vinyl sulfone analogue 24. Two-carbon

vinyl sulfone analogue 25 was synthesized in an analogous

manner following these established protocols. Using this se-

quence, we were able to access the (5E)-7,8-dihydromacrolac-

tone vinyl sulfone analogues in only eight linear steps from

known starting materials.

With this knowledge in hand, we developed a synthetic

route toward a (5E)-7,8-dihydromacrolactone core, with an ap-

pended vinyl sulfone functionality (analogues 24 and 25,

Figure 2). Both one- and two-carbon methylene spacer ana-

logues 24 and 25 were synthesized (Scheme 2), as we were

uncertain how the distance between the electrophilic vinyl sul-

fone moiety and the macrocycle would affect cytotoxicity. A

Brown asymmetric allylation^[42]reaction between butanal 11

and protected allylic alcohol 13 began our synthesis of ana-

logue 24, producing secondary alcohol 14 as a single diaste-

reomer in excellent yield and enantioselectivity (95:5). Transes-

terification of alcohol 14 with salicylate diene 31 followed by

TBS protection of the resultant phenol generated triene 16 as

the precursor for the ring-closing metathesis (RCM) reaction to

form the macrocycle. The salicylate diene 31 was prepared

from stannylpentenol 27^[43]by oxidation to aldehyde 28 fol-

lowed by methenylation to form diene 29 and reaction with

the known^[3]salicylate 30.

When biological testing revealed that derivatives 24 and 25

showed only weak cytotoxic effects (Table 1), we decided to

synthesize the vinyl sulfone side chain analogue 36 (Scheme 3)

containing the oximidine II triene macrocyclic core and its C15

vinyl sulfone homologue 46 (Scheme 4). In the oximidine II

system (and in other benzolactone enamide molecules), the

electrophilic position of the enamide side chain is located at

a position three carbon atoms away from the macrolactone

core. Both analogues were readily available using chemistry

previously developed in our laboratories.

The synthesis of the vinyl sulfone side chain analogue 36

began with triene macrocycle 32, an intermediate in our

recent synthesis of oximidine II.^[28]Silyl group removal, oxida-

tion of the primary alcohol to the corresponding aldehyde,

and HWE olefination using phosphonate 26^[43]yielded vinyl

phenylsulfone intermediate 34. Subjecting this compound to

a two-step alkyl ether deprotection sequence generated the

desired vinyl sulfone 36. Assays (Table 1) revealed that this

compound is devoid of cytotoxicity in the cell lines tested.

RCM reactions are well-established strategies in the synthesis

of various macrocyclic benzolactone enamides, including oxi-

midine II.^[30,44]The usefulness of this methodology is demon-

strated here in the synthesis of vinyl sulfone analogue 46

In agreement with previous trends^[26,27]and our design ra-

tionale, reaction of seco-cycle 16 using the Grubbs second-

generation ruthenium catalyst produced diene macrocycle 18

in 60% yield over two steps (from 14). Oxidative cleavage of

the para-methoxybenzyl (PMB) ether, oxidation of the resultant

primary alcohol to the corresponding aldehyde, followed by

Scheme 2. Synthesis of vinyl sulfone analogues 24 and 25: a) 13, sBuLi, THF, À788C, then (+)-b-methoxydiisopinocamphenylborane, THF, À788C to À908C,

then BF₃·OEt₂, then 11/12, 80% for 14, 88% for 15; b) NaHMDS, THF, 08C, then 31, THF, 08C, then TBSCl, imidazole; c) Grubbs 2nd-gen. catalyst, PhMe, reflux,

60%, two steps for 18, 61%, two steps for 19; d) DDQ, CH₂Cl₂, 08C, 50% for 20, 63% for 21; e) SO₃·Py, Et₃N, DMSO, CH₂Cl₂, 08C; f) phosphonate 26, NaH, THF,

08C, then aldehyde, 48%, two steps for 22, 65%, two steps for 23; f) 4m HCl, MeOH, 82% for 24, 85% for 25; g) SO₃·Py, Et₃N, DMSO, CH₂Cl₂, 08C;

h) CH₃PPh₃Br, tBuOK, 08C to RT; i) Pd(PPh₃)₄, LiCl, THF, 708C, 93%, three steps.

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terial throughput toward the final desired analogue. Dimeriza-

tion produced the major by-product in this macrocyclization

reaction. Removal of the PMB ether from macrocycle 43 under

oxidative conditions, followed by oxidation to the correspond-

ing aldehyde, HWE olefination with phosphonate 26, and

global protecting group removal provided the target vinyl sul-

fone 46.

Unfortunately, biological testing revealed that oximidine sul-

fone analogue 46 does not possess cytotoxic activity. To verify

the validity of our in silico modeling and design of the simpli-

fied oximidine II macrolactone core, we synthesized and tested

analogues 55 and 56 (Scheme 5) possessing the enamide side

chain.

Analogue 55 (Scheme 5) was prepared from the previously

described intermediate 20 (Scheme 2), which underwent alco-

hol oxidation followed by Takai olefination of the resultant al-

dehyde to provide vinyl iodide 49. Protecting group manipula-

tion prepared iodide 53 for installation of the enamide side

chain. The side chain was attached via a copper-mediated CÀN

coupling reaction with amide 57, and global desilylation final-

ized the synthesis of analogue 55. Two-carbon enamide ana-

logue 56 was synthesized in a similar manner by following the

established procedure.

Scheme 3. Synthesis of vinyl sulfone analogue 36: a) TBAF, THF, 88%;

b) 1. PDC, 4 MS, CH₂Cl₂, 08C, 2. 26, NaH, THF, then aldehyde, THF, 08C,

47%, two steps; c) CBr₄, iPrOH, 758C, 78%; d) BCl₃, CH₂Cl₂, 08C, 75%.

(Scheme 4). Our synthesis of analogue 46 began with the

above-mentioned alcohol 15 (see Scheme 2). Silylation, oxida-

tive cleavage of the terminal olefin, Wittig olefination, and de-

silylation furnished diene 40, ready for a transesterification re-

action with salicylate 41.^[28]Transesterification reactions are

well-established protocols for the generation of salicylate

esters.^[45]This transesterification followed by silylation of the re-

sultant phenol gave the RCM precursor 42 in excellent yield

over two steps. The RCM reaction, using the Grubbs second-

generation catalyst, gave 43 in low yields but allowed for ma-

Cytotoxicity testing

The NIH cytotoxicity screen showed that the benzolactone en-

amides display their most significant cytotoxicity toward mela-

noma and leukemia cell lines.^[9]These natural products are es-

pecially potent against SK-Mel-5, SK-Mel-28, and HL-60 cells.

Based on this precedent, our analogues were tested against

these cell lines in addition to the breast cancer cell line MCF-7.

Each of our analogues displayed significant lower cytotoxicity

Scheme 4. Synthesis of vinyl sulfone analogue 46: a) TBSCl, imidazole, DMF, 758C, 71%; b) 1. OsO₄, NMO, H₂O, THF, 2. Pb(OAc)₄, K₂CO₃, MeOH, 08C;

c) Ti(OiPr)₄, allyldiphenylphosphine, tBuLi, THF, À788C to 08C, then MeI; d) TBAF, THF, 19%, four steps; e) NaHMDS, THF, 08C, then 41, THF, 08C, then TBSCl,

imidazole, 91%; f) Grubbs 2nd-gen. catalyst, PhMe, reflux, 22%; g) DDQ, CH₂Cl₂, 08C to RT, 98%; h) 1. PDC, 4 MS, CH₂Cl₂, 2. 26, NaH, THF, 08C, then alde-

hyde, 47%, two steps; i) 4m HCl, MeOH, 68%.

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Scheme 5. Synthesis of simplified benzolactones with an oximidine enamide side chain: a) DMP, CH₂Cl₂, 88% for 47, 72% for 48; b) CrCl₂, CHI₃, THF/dioxane,

86%, 9:1 E/Z ratio for 49, 84%, 9:1 E/Z ratio for 50; c) CBr₄, iPrOH, 758C, 86% for 51, 96% for 52; d) TBSOTf, 2,6-lutidine, CH₂Cl₂, À788C to 08C, 78% for 53,

84% for 54; e) 1. 57, CuI, DMEDA, Cs₂CO₃, DMA, 2. HF·Py, Py, THF, 40%, two steps for 55, 30%, two steps for 56.

than synthetic oximidine II. Additionally, the respective depro-

tected versions of intermediates 5a, 6a, and 8a, compounds

5b, 6b, and 8b, toward the synthesis of the allylic amide ana-

logue were also inactive, including the Michael acceptor Z-

enoate compound 5b (data not shown). Some weak cytotoxic

activity was retained for diene sulfone 25 and the enamides

55 and 56. These results provide further support for previous

analogue studies that demonstrated the necessity of an acyl

enamine side chain for bioactivity and that the designed mac-

rolactone scaffold investigated herein cannot replace the rigid

macrocycle of the natural products.

To rationalize a structural basis for the observed differences

in activity, a molecular overlay was generated for compounds

Figure 3. Graphic showing the alignment of compound 2 (black carbon

2 and 55. Plausible low-energy conformations for both com-

pounds were obtained by structural optimization using the

VEGA ZZ software package^[46]and were aligned via the PyMOL

program.^[47]Using pairwise alignment among conserved atoms,

the macrocycles of the two compounds overlay very closely;

however, the polar side chains exhibit much greater variation.

To enhance the comparison, a survey of side chain conforma-

tional variations were explored for compound 55, with

Figure 3 illustrating the structure producing the closest align-

ment with compound 2.

It is unlikely that the very minor structural differences within

the macrocycles of the two compounds can explain the varia-

tion in bioactivity; however, the one structurally unconserved

double bond within the side chains does produce a key differ-

ence in the electrostatic profiles of the two molecules. In con-

trasting a cis configuration adjacent to the amide in compound

2 with a trans structure in compound 55, one concludes that

the two side chains are unlikely to avail themselves of the

same set of receptor hydrogen bonding features, even if

a broad range of side chain conformational space is explored.

The superior activity of compound 2 may thus be likely as-

cribed to an ability to form side chain hydrogen bonds that

compound 55 is unable to access.

atoms) with compound 55. Non-carbon atoms (oxygen, nitrogen and polar

hydrogens) are rendered by CPK coloring.

Conclusions

In summary, side chain analogues of oximidine II were synthe-

sized to probe the hypothesis that the enamide functionality

of the parent compound could be replaced with physiological-

ly stable functional groups bearing an allylic amide or an elec-

trophilic vinyl sulfone functionality, and that the analogues

would retain bioactivity. However, because the allylic amide

and sulfone side chain analogues lack cytotoxicity, we have

added further evidence that an enamide moiety is required for

the biological activity of the benzolactone enamide family of

natural products. Analogues were also designed and synthe-

sized following computational studies which predicted that

flexible and less complex macrolactones would fit well into the

V-ATPase binding pocket. These analogues showed weak cyto-

toxic activities, demonstrating that this simplified scaffold

cannot replace the macrocycle of the natural products.

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Methyl (Z)-4-((3S,4S,5Z,7Z,9E)-4,14-dihydroxy-1-oxo-3,4-dihydro-

1H-benzo[c][1]oxacyclododecin-3-yl)but-2-enoate (5b). To a THF

solution (0.220 mL) of bis-TBS ester 5a (13 mg, 0.022 mmol) at RT

was added HF/pyridine solution (5m, 0.135 mL). The reaction was

stirred for 24 h, and then quenched with phosphate (pH 7) buffer.

The aqueous layer was extracted with EtOAc (3), the organic ex-

tracts washed with brine and dried over MgSO₄. Purification of the

crude material by flash column chromatography (hexanes/EtOAc,

80:20–50:50) gave 7 mg of a colorless oil (5b, 89%): TLC (hexanes/

Experimental Section

Chemistry

General: Infrared (IR) spectra were recorded on an FT-IR instrument

from thin films on NaCl plates. All NMR experiments were recorded

on either 400 MHz (100 MHz) or 500 MHz (125 MHz) spectrometers

as noted. Chemical shifts are reported as parts per million (ppm)

using the solvent residual peak as the internal standard. Samples

obtained in CDCl₃were referenced to 7.27 ppm for ¹H NMR and

77.0 ppm for ¹³C NMR spectra. Samples obtained in [D₆]DMSO were

referenced to 2.50 ppm for ¹H NMR and 39.5 ppm for ¹³C NMR

spectra. Samples obtained in [D₆]acetone were referenced to

1

EtOAc, 60:40): R_f=0.10; H NMR (400 MHz, CDCl₃): d=1.28 (br, 1H),

2.88 (br, 1H), 3.10–3.04 (m, 1H), 3.26 (br, 1H), 3.68 (s, 3H), 4.42 (br,

1H), 5.59 (br, 1H), 5.81 (dd, J=12, 4.9 Hz, 1H), 5.87 (d, J=11 Hz,

1H), 6.07 (brd, J=12 Hz, 1H), 6.22 (br, 1H), 6.38 (br, 1H), 6.77–6.71

(brm, 3H), 6.88 (d, J=8.2 Hz, 1H), 7.30 (t, J=8.0 Hz, 1H),

10.30 ppm (br, 1H); HRMS (ESI), m/z calcd for C₂₀H₂₁O₆[M+H]⁺:

357.1338, found: 357.1323; LC–MS analysis revealed 94.6% purity

prior to biological testing.

1

2.05 ppm for H NMR and 29.9 ppm for ¹³C NMR spectra. Coupling

constants (J) are reported in Hz. The multiplicities of the signals are

assigned using the following abbreviations: s=singlet, d=doublet,

t=triplet, q=quartet, qu=quintet, se=sextet, br=broad. Optical

rotations were recorded using a polarimeter at room temperature

(RT). LRMS and HRMS were obtained using the electrospray ioniza-

tion (ESI) technique.

(3S,4S,5Z,7Z,9E)-4,14-Bis(tert-butyldimethylsilyloxy)-3-((Z)-4-hy-

droxybut-2-enyl)-3,4-dihydro-1H-benzo[c][1]oxacyclododecin-1-

one (6a). Ester 5a (9.5 mg, 0.016 mmol) was dissolved in anhy-

drous CH₂Cl₂(0.160 mL) and cooled to À788C. To this cooled solu-

tion was added DIBAl-H (0.037 mL, 0.037 mmol, 1m solution in

CH₂Cl₂) dropwise (Note: very slow addition of DIBAl-H is required to

prevent side reactions.) After 1.5 h the cooling bath was removed,

and the reaction was quenched with EtOAc and then Rochelle’s

salt solution was added. The mixture was warmed to RT and stirred

for 2 h, or until both aqueous and organic layers were clear. The

aqueous layer was extracted with EtOAc (3), and the organic ex-

tracts were combined, washed with brine, and dried over MgSO₄.

Purification via flash column chromatography (hexanes/EtOAc,

95:5–85:15) yielded 8 mg of pure allylic alcohol 6a as a colorless

oil (90%): TLC (hexanes/EtOAc, 80:20): R_f=0.30; a²_D⁵=À94.5 (c=

Moisture-sensitive reactions were run in flame-dried glassware

under an atmosphere of nitrogen unless otherwise specified. THF,

CH₂Cl₂, Et₂O, and toluene were dried and deoxygenated by passing

the nitrogen-purged solvents through activated alumina columns

on a solvent purification system. DMF was similarly dried by pass-

ing through a column of activated 4 molecular sieves on a sol-

vent purification system. All other reagents and solvents were used

as received from commercial sources unless otherwise noted. Reac-

tion progress was monitored by thin-layer chromatography (TLC,

silica gel, 1020 cm, 250 mm), visualizing with UV light (l 254 nm)

and developing the plates with Hanessian’s stain (blue stain). All

compounds were purified by column chromatography with 230–

400 mesh silica gel as described. All compounds were concentrat-

ed using standard rotary evaporator and high-vacuum techniques.

1

1.32, CHCl₃); H NMR (400 MHz, CDCl₃): d=0.01 (s, 3H), 0.10 (s, 3H),

0.17 (s, 3H), 0.19 (s, 3H), 0.86 (s, 9H), 0.99 (s, 9H), 1.63 (br, 1H),

2.56–2.63 (m, 1H), 2.74–2.79 (m, 1H), 4.10–4.16 (m, 1H), 4.28–4.32

(m, 1H), 4.63 (dd, J=10, 2.8 Hz, 1H), 5.08 (brd, J=10 Hz, 1H),

5.71–5.81 (m, 3H), 5.87 (dd, J=11, 4.0 Hz, 1H), 5.97 (dd, J=12,

4.0 Hz, 1H), 6.34 (t, J=11 Hz, 1H), 6.63 (d, J=16 Hz, 1H), 6.76 (d,

J=8.2 Hz, 1H), 6.80 (d, J=7.6 Hz, 1H), 7.05 (dd, J=16, 11 Hz, 1H),

7.17 ppm (t, J=8.0 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃): d=168.4,

152.0, 138.8, 132.2, 131.3, 130.7, 130.6, 129.7, 129.3, 128.7, 128.5,

127.9, 126.7, 121.6, 118.5, 79.6, 66.4, 58.5, 25.9, 25.8, 25.7 18.4, 17.9,

À4.0, À4.4, À4.5, À4.9 ppm; IR (neat, NaCl): n˜_max=3430 (br), 2959,

1729, 1256, 745 cm^À1; HRMS (ESI) m/z calcd for C₃₁H₄₈NaO₅Si₂[M+

Na]⁺: 579.2938, found: 579.2909.

Methyl

(Z)-4-((3S,4S,5Z,7Z,9E)-4,14-bis(tert-butyldimethylsily-

loxy)-1-oxo-3,4-dihydro-1H-benzo[c][1]oxacyclododecin-3-yl)but-

2-enoate (5a). A flask containing Pd(PPh₃)₄(71 mg, 0.661 mmol)

was flushed with CO (1 atm). To this flask was added N,N’-diisopro-

pylethylamine (DIPEA; 0.044 mL, 0.245 mmol) and anhydrous

MeOH (4.90 mL) at RT and the flask was flushed with CO again. A

THF solution of vinyl iodide 4^[28](160 mg, 0.245 mmol in 1.23 mL

THF) was added and the reaction was stirred under CO (1 atm) for

45 min. The reaction mixture was filtered through a pad of Celite,

and the Celite layer was eluted with Et₂O until the eluent was col-

orless. The crude material was purified by flash column chromatog-

raphy (hexanes/Et₂O, 100:0–95:5) to collect 122 mg of the desired

ester 5a as a yellow oil (85%): TLC (hexanes/Et₂O, 80:20): R_f=0.80;

(3S,4S,5Z,7Z,9E)-4,14-Dihydroxy-3-((Z)-4-hydroxybut-2-enyl)-3,4-

dihydro-1H-benzo[c][1]oxacyclododecin-1-one (6b). To a THF so-

lution (0.230 mL) of bis-TBS Z-allylic alcohol 6a (13 mg,

0.023 mmol) at RT was added HF/pyridine solution (5m, 0.143 mL).

The reaction was stirred for 24 h, and then quenched with phos-

phate (pH 7) buffer. The aqueous layer was extracted with EtOAc

(3), the organic extracts washed with brine and dried over

MgSO₄. Purification of the crude material by flash column chroma-

tography (hexanes/EtOAc, 50:50–30:70) gave 6 mg of a white solid

(6b, 80%): TLC (hexanes/EtOAc, 40:60): R_f=0.15; ¹H NMR

(400 MHz, [D₆]DMSO): d=2.39–2.31 (m, 1H), 2.73 (m, 1H), 4.10–

3.98 (m, 2H), 4.36 (td, J=10, 4.0 Hz, 1H), 4.58 (t, J=5.2 Hz, 1H),

5.04 (td, J=12, 2.0 Hz, 1H), 5.31 (d, J=4.6 Hz, 1H), 5.61–5.49 (m,

2H), 5.79 (t, J=11 Hz, 1H), 5.96 (ddd, J=17, 11, 4.2 Hz, 2H), 6.35 (t,

J=11 Hz, 1H), 6.68 (t, J=8.4 Hz, 1H), 6.70 (s, 1H), 6.75 (d, J=

8.0 Hz, 1H), 6.92 (dd, J=16, 12 Hz, 1H), 7.16 (t, J=7.9 Hz, 1H),

9.34 ppm (s, 1H); ¹³C NMR (100 MHz, [D₆]DMSO): d=168.2, 153.8,

1

a²_D⁵=À148 (c=0.600, CHCl₃); H NMR (400 MHz, CDCl₃): d=0.01 (s,

3H), 0.09 (s, 3H), 0.20 (s, 3H), 0.22 (s, 3H), 0.88 (s, 9H), 0.98 (s, 9H),

3.00–3.09 (m, 1H), 3.55–3.63 (m, 1H), 3.74 (s, 3H), 4.64 (dd, J=10,

3.2 Hz, 1H), 5.24 (td, J=9.1, 4.0 Hz, 1H), 5.82 (t, J=12 Hz, 1H),

5.85–5.89 (m, 2H), 5.97 (dd, J=12, 4.1 Hz, 1H), 6.34 (t, J=11 Hz,

1H), 6.46 (ddd, J=12, 7.7, 5.6 Hz, 1H), 6.64 (d, J=16 Hz, 1H), 6.75

(d, J=8.1 Hz, 1H), 6.79 (d, J=7.4 Hz, 1H), 7.06 (ddd, J=16, 10,

0.5 Hz, 1H), 7.17 ppm (t, J=8.0 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃):

d=168.4, 166.6, 152.3, 146.3, 138.0, 132.4, 130.8, 130.6, 129.7,

129.3, 128.5, 128.0, 126.4, 121.2, 120.4, 117.8, 78.9, 66.5, 51.1, 29.7,

27.9, 25.8, 25.7, 18.4, 17.9, À4.1, À4.5, À5.0 ppm; IR (neat, NaCl):

n˜_max=2972, 2861, 1732, 1648, 1561, 1152, 1056, 963 cm^À1; HRMS

(ESI) m/z calcd for C₃₂H₄₈NaO₆Si₂[M+Na]⁺: 607.2887, found:

607.2861.

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Full Papers

137.4, 132.5, 132.1, 130.7, 129.8, 129.6, 129.5, 128.5, 128.4, 125.8,

121.8, 118.6, 114.1, 79.0, 64.5, 57.0, 24.9 ppm; HRMS (ESI) m/z calcd

for C₁₉H₂₁O₅[M+H]⁺: 329.1389, found: 329.1393; LC–MS analysis

revealed 82.1% purity prior to biological testing.

5.45 (m, 1H), 5.67–5.61 (m, 1H), 5.81 (t, J=11 Hz, 1H), 5.97 (ddd,

J=15, 11, 4.0 Hz, 2H), 6.09 (dd, J=7.8, 6.0 Hz, 1H), 6.19 (dd, J=9.1,

6.5 Hz, 1H), 6.36 (t, J=11 Hz, 1H), 6.68 (t, J=7.0 Hz, 1H), 6.70 (s,

1H), 6.76 (dd, J=8.0, 5.0 Hz, 1H), 6.98–6.90 (m, 1H), 7.01 (d, J=

6.0 Hz, 1H), 7.16 (t, J=7.9 Hz, 1H), 9.93 ppm (d, J=12 Hz, 1H);

¹³C NMR (100 MHz, [D₆]DMSO): d=168.4, 168.2, 153.9, 147.6, 137.4,

132.1, 130.7, 129.9, 129.6, 129.5, 128.6, 128.5, 128.4, 127.1, 121.8,

118.7, 114.2, 82.0, 81.9, 64.6, 35.4, 24.7, 20.8 ppm; HRMS (ESI) m/z

calcd for C₂₃H₂₄NO₆[M+H]⁺: 410.1604, found: 410.1591; LC–MS

analysis revealed 85.5% purity prior to biological testing.

1-((Z)-4-((3S,4S,5Z,7Z,9E)-4,14-Bis(tert-butyldimethylsilyloxy)-1-

oxo-3,4-dihydro-1H-benzo[c][1]oxacyclododecin-3-yl)but-2-enyl)-

1H-pyrrole-2,5-dione (7). Allylic alcohol 6a (27 mg, 0.048 mmol),

maleimide (5 mg, 0.053 mmol) and PPh₃(23 mg, 0.086 mmol) were

dissolved in anhydrous THF (0.480 mL) and cooled to 08C. A solu-

tion of diethyl azodicarboxylate (DEAD; 0.039 mL, 0.086 mmol,

40% w/w solution in toluene) was added dropwise, watching the

initial yellow color to dissipate before an additional drop was

added. The reaction was stirred for 15 min and then the volatiles

were removed by rotary evaporation. Purification of the crude ma-

terial by flash column chromatography (hexanes/CH₂Cl₂, 80:20–

30:70, then hexanes/EtOAc, 80:20) yielded 19 mg of the desired al-

lylic maleimide derivative 7 and 2 mg of the allylic alcohol 6a

(62%, 67% based on recovered starting material): TLC (hexanes/

EtOAc, 80:20): R_f=0.35; a²_D⁵=À110 (c=0.31, CHCl₃); ¹H NMR

(400 MHz, CDCl₃): d=0.02 (s, 3H), 0.11 (s, 3H), 0.18 (s, 3H), 0.19 (s,

3H), 0.89 (s, 9H), 0.97 (s, 9H), 2.68–2.76 (m, 1H), 2.91–2.97 (m, 1H),

4.13 (dd, J=15, 7.1 Hz, 1H), 4.24 (dd, J=15, 7.1 Hz, 1H), 4.63 (dd,

J=10, 3.0 Hz, 1H), 5.14 (td, J=10, 3.0 Hz, 1H), 5.50–5.56 (m, 1H),

5.76–5.81 (m, 1H), 5.85 (t, J=12 Hz, 1H), 5.87 (dd, J=11, 4.1 Hz,

1H), 6.00 (dd, J=12, 4.0 Hz, 1H), 6.34 (t, J=11 Hz, 1H), 6.59 (s, 2H),

6.63 (d, J=16 Hz, 1H), 6.74 (d, J=8.0 Hz, 1H), 6.79 (d, J=7.7 Hz,

1H), 7.06 (dd, J=16, 11 Hz, 1H), 7.16 ppm (t, J=8.0 Hz, 1H);

¹³C NMR (100 MHz, CDCl₃): d=170.2, 168.4, 152.4, 137.8, 134.0,

132.2, 130.8, 130.70, 130.68, 129.7, 129.2, 128.3, 128.0, 126.6, 125.2,

121.2, 118.1, 79.6, 66.6, 34.5, 29.7, 25.82, 25.77, 18.4, 17.9, À4.1,

(2Z)-N-((Z)-4-((3S,4S,5Z,7Z,9E)-4,14-Bis(tert-butyldimethylsily-

loxy)-1-oxo-3,4-dihydro-1H-benzo[c][1]oxacyclododecin-3-yl)but-

2-enyl)-4-(methoxyimino)but-2-enamide (9). Hydroxypyrrolone

8a (13 mg, 0.020 mmol), NaHCO₃(17 mg, 0.203 mmol), and

MeONH₃Cl (17 mg, 0.203 mmol) were suspended in MeOH

(0.200 mL) in a sealed vial. This suspension was heated at 758C for

12 h. Upon cooling, the solvent was removed by rotary evapora-

tion and the crude material purified by flash column chromatogra-

phy (hexanes/EtOAc, 90:10–50:50) to yield 4.5 mg of the desired

oxime amide 9 as a colorless oil (a 3:1 ratio of E/Z oxime ether ste-

reoisomers by ¹H NMR) and 5 mg of the starting material (34%,

54% based on recovered starting material): TLC (hexanes/EtOAc,

1

70:30): R_f=0.65; H NMR (400 MHz, CDCl₃): d=0.01 (s, 3H), 0.10 (s,

3H), 0.15 (s, 3H), 0.17 (s, 3H), 0.89 (s, 9H), 0.98 (s, 9H), 2.68–2.71

(m, 2H), 3.91 (s, 3H), 3.85–3.93 (m, 1H), 3.99–4.09 (m, 1H), 4.63

(dd, J=10, 3.0 Hz, 1H), 5.08–5.12 (m, 1H), 5.46 (dt, J=11, 0.8 Hz,

1H), 5.64–5.71 (m, 1H), 5.75 (t, J=11 Hz, 1H), 5.72–5.79 (m, 1H),

5.84 (br, 1H), 5.88 (dd, J=11, 4.2 Hz, 1H), 5.98 (dd, J=12, 4.1 Hz,

1H), 6.21 (dd, J=12, 10 Hz, 1H), 6.34 (t, J=11 Hz, 1H), 6.63 (d, J=

16 Hz, 1H), 6.77 (d, J=8.5 Hz, 1H), 6.85 (dd, J=7.7, 3.6 Hz, 1H),

7.02 (dd, J=16, 11 Hz, 1H), 7.18–7.23 (m, 1H), 8.96 (dd, J=10,

0.8 Hz, 1H). Minor Z-oxime ether isomer peaks: 3.94 (s, 3H),

8.42 ppm (dd, J=9.6, 0.9 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃): d=

168.2, 164.7, 151.9, 147.8, 138.2, 133.2, 132.2, 131.3, 130.7, 130.5,

129.5, 128.7, 128.1, 127.5, 125.5, 122.1, 118.7, 79.5, 66.3, 62.1, 35.9,

29.7, 25.9, 25.7, 18.4, 17.9, À4.0, À4.4, À4.5, À4.9 ppm; IR (neat,

À4.2, À4.5, À4.9 ppm; IR (neat, NaCl): n˜_max=1729, 1155 cm^À1

;

HRMS (ESI) m/z calcd for C₃₅H₅₀NO₆Si₂: 636.3177 [M+H]⁺, found:

636.3169.

1-((Z)-4-((3S,4S,5Z,7Z,9E)-4,14-Bis(tert-butyldimethylsilyloxy)-1-

oxo-3,4-dihydro-1H-benzo[c][1]oxacyclododecin-3-yl)but-2-enyl)-

5-hydroxy-1H-pyrrol-2(5H)-one (8a). Allyl maleimide 7 (15 mg,

0.0236 mmol) and CeCl₃·7H₂O (6 mg, 0.0236 mmol) were suspend-

ed in MeOH (0.100 mL) and cooled to 08C. NaBH₄(0.9 mg,

0.0236 mmol) was added in one portion and the reaction stirred

for 30 min. The reaction was diluted with MeOH (5 mL) and the

volatiles removed by rotary evaporation. This process was repeated

two more times, then the crude material was purified by flash

column chromatography (hexanes/EtOAc, 90:10–50:50) to yield

NaCl): n˜_max=3308 (br), 1733, 1674, 1569, 1539, 1049, 700 cm^À1

;

HRMS (ESI) m/z calcd for C₃₆H₅₅N₂O₆Si₂: 667.3599 [M+H]⁺, found:

667.3607.

(2Z)-N-((Z)-4-((3S,4S,5Z,7Z,9E)-4,14-Dihydroxy-1-oxo-3,4-dihydro-

1H-benzo[c][1]oxacyclododecin-3-yl)but-2-enyl)-4-(methoxyimi-

no)but-2-enamide (10). To a THF solution (0.09 mL) of bis-TBS

oxime ether 9 (6 mg, 0.009 mmol) at RT was added 0.055 mL of

5m HF/pyridine solution. The reaction was stirred for 24 h and

then quenched with a pH 7 buffer solution. The aqueous layer was

extracted with EtOAc (3), the organic extracts washed with brine

and dried over MgSO₄. Purification of the crude material by flash

column chromatography (hexanes/EtOAc, 80:20–40:60) gave

3.5 mg of a tan solid (89%): TLC (hexanes/EtOAc, 50:50): R_f=0.10;

¹H NMR (400 MHz, CDCl₃): d=1.29 (br, 1H), 2.51 (br, 1H), 2.67 (br,

1H), 3.02 (br, 1H), 3.87 (br, 1H), 3.93 (s, 3H), 4.40 (br, 1H), 5.47 (br,

1H), 5.58 (br, 1H), 5.61–5.65 (m, 1H), 5.75 (d, J=7.5 Hz, 1H), 5.79

(br, 1H), 5.93 (br, 1H), 6.08 (d, J=13 Hz, 1H), 6.30 (br, 1H), 6.40 (t,

J=11 Hz, 2H), 6.76–6.78 (m, 3H), 6.90 (d, J=7.9 Hz, 1H), 7.32 (br,

1H), 8.99 (dd, J=10, 0.6 Hz, 1H), 10.48 (br, 1H) ppm; HRMS (ESI)

m/z calcd for C₂₄H₂₇N₂O₆: 439.1869 [M+H]⁺, found: 439.1863;

UPLC–MS analysis established 95.4% purity prior to biological test-

ing.

1

13 mg of a dark-yellow oil (8a), determined by H NMR and LC–MS

to be a 55:45 ratio of diastereomers (86%). These diastereomers

were not separated, and the mixture was used in the subsequent

step: TLC (hexanes/EtOAc, 70:30): R_f=0.20; IR (neat, NaCl): n˜_max

=

3337 (br), 1732, 1690, 1596, 1455, 1253, 1168, 701 cm^À1; HRMS (ESI)

m/z calcd for C₃₅H₅₂NO₆Si₂: 638.3333 [M+H]⁺, found: 638.3342.

1-((Z)-4-((3S,4S,5Z,7Z,9E)-4,14-Dihydroxy-1-oxo-3,4-dihydro-1H-

benzo[c][1]oxacyclododecin-3-yl)but-2-enyl)-5-hydroxy-1H-

pyrrol-2(5H)-one (8b). To a THF solution (0.141 mL) of bis-TBS hy-

droxypyrrole 8a (9 mg, 0.0141 mmol) at RT was added HF/pyridine

solution (5m, 0.086 mL). The reaction was stirred for 24 h, and then

quenched with phosphate (pH 7) buffer. The aqueous layer was ex-

tracted with EtOAc (3), the organic extracts washed with brine

and dried over MgSO₄. Purification of the crude material by flash

column chromatography (hexanes/EtOAc, 70:30–0:100) gave 4 mg

of a tan solid (69%): TLC (hexanes/EtOAc, 40:60): R_f=0.04; 1H NMR

(400 MHz, [D₆]DMSO): d=2.58–2.50 (m, 1H), 2.86–2.78 (m, 1H),

3.81 (dd, J=15, 7.8 Hz, 1H), 4.12–4.07 (m, 1H), 4.38 (td, J=10,

3.8 Hz, 1H), 5.08 (td, J=9.3, 5.0 Hz, 1H), 5.36–5.32 (m, 2H), 5.51–

(E)-5-(Hexa-1,5-dienyl)-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-

one (31). To a flask containing Pd₂dba₃(50.3 mg, 0.0549 mmol), tri-

cyclohexylphosphonium tetrafluoroborate (79.2 mg, 0.215 mmol)

and iPr₂NEt (0.30 mL, 1.7 mmol) was added CH₂Cl₂(100 mL) and

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the resulting mixture was stirred at RT for 10 min. 4-Pentyn-1-ol

(1 mL, 11 mmol) was added and the reaction mixture was cooled

to 08C. Bu₃SnH (3.45 mL, 13.0 mmol) diluted in CH₂Cl₂(30 mL) was

added dropwise via syringe over 15 min. The reaction was then al-

lowed to stir at 08C for 4 h. The reaction mixture was condensed

to ~30 mL of organic mixture and was used directly to the next

step without any workup. The crude product showed only (E)-5-

(tributylstannyl)pent-4-en-1-ol (27), identical with ¹H NMR and ¹³C

properties as reported by Darwish.^[43]

the cooling bath). The boron trifluoride etherate (1.72 mL,

13.7 mmol) was added dropwise. Immediately afterward, 3-(4-me-

thoxybenzyloxy)propanal 11^[49](2 g, 10.3 mmol) was added drop-

wise and the mixture was kept at À908C for 3 h. The reaction was

warmed to RT over 15 h to give a clear colorless solution, and was

then quenched with a mixture of 35% H₂O₂(12.5 mL) and saturat-

ed NaHCO₃solution (20.0 mL). After stirring at RT for 30 min, the

mixture was extracted with Et₂O (215 mL). The combined organic

extracts were washed with brine, dried over Na₂SO₄, and concen-

trated in vacuo. Purification by column chromatography (30%

EtOAc in hexanes) provided 2.44 g (8.23 mmol, 80%) of alcohol 14

as a colorless oil: a_D²⁵= +50.6 (c=1.50, CHCl₃), (90% ee);^{[30] 1}H NMR

(400 MHz, CDCl₃): d=1.79 (m, 2H), 3.22 (brs, 1H), 3.39 (s, 1H), 3.66

(m, 2H), 3.80 (s, 4H), 3.82 (m, 1H), 3.92 (dd, J=7.0, 7.0 Hz, 1H),

4.46 (s, 2H), 4.60 (d, J=6.7 Hz, 1H), 4.73 (d, J=6.7 Hz, 1H), 5.31 (d,

J=16.9 Hz, 1H), 5.31 (d, J=11.0 Hz, 1H), 5.72 (ddd, J=7.7, 11.4,

16.3 Hz, 1H), 6.87 (d, J=8.6 Hz, 2H), 7.25 ppm (d, J=8.6 Hz, 2H);

¹³C NMR (100 MHz, CDCl₃): d=159.2, 134.4, 130.1, 129.4, 120.1,

113.8, 94.0, 81.0, 72.8, 71.8, 67.5, 55.7, 55.3, 32.4 ppm; IR (neat,

To crude 27 was added Et₃N (7.6 mL, 54 mmol) and DMSO (30 mL).

The mixture was cooled to 08C, and SO₃·Py (52.0 mg, 0.324 mmol)

was added in portions over 2 min. The mixture was stirred at 08C

for 15 min, and then diluted with hexanes (100 mL) and phosphate

buffer pH 7 (20 mL). The organic layer was separated, and then the

aqueous layer was extracted with hexanes (330 mL). The com-

bined organic layer was concentrated in vacuo to afford a bright-

yellow crude product. The crude aldehyde 28 was used directly in

the next step without further purification.

NaCl): n˜ =2955 (br), 2953 (br), 1613, 1515, 1460, 1249, 1170 cm^À1

;

To a mixture of CH₃PPh₃Br (8.50 g, 23.8 mmol) in anhydrous THF

(30 mL), cooled at 08C under N₂atmosphere, was added dropwise

a solution of tBuOK (2.42 g, 21.6 mmol) over 3 min. After the addi-

tion was completed, the mixture turned bright yellow. The mixture

was stirred at 08C for 30 min and a solution of crude aldehyde 28

diluted in THF (30 mL) was added dropwise over 10 min. The reac-

tion mixture was stirred at 08C and warmed to RT overnight, and

then diluted with hexanes (100 mL) and quenched with phosphate

buffer pH 7 (50 mL). The organic layer was separated and the aque-

ous layer was extracted with hexanes (3100 mL), dried over

NaSO₄and concentrated in vacuo to afford crude stannyl diene 29

as a yellow oil, which was used directly in the next reaction.

HRMS (ESI+) m/z calcd for C₁₆H₂₄NaO₅[M+Na]⁺: 319.1516, found:

319.1518.

(4S,5E,9E)-14-(tert-Butyldimethylsilyloxy)-3-(2-(4-methoxybenzy-

loxy)ethyl)-4-(methoxymethoxy)-3,4,7,8-tetrahydro-1H-benzo[c]

[1]oxacyclododecin-1-one (18). Alcohol 14 (500 mg, 1.69 mmol)

was subjected to azeotropic distillation in vacuo with benzene (2

5 mL), dissolved in anhydrous THF (5.0 mL) and cooled to 08C.

NaHMDS (1.0m, 3.20 mL, 3.20 mmol) was added dropwise. After

stirring at 08C for 30 min, salicylate 31 (413 mg, 1.60 mmol) dis-

solved in distilled THF (5.0 mL) was added dropwise. The reaction

was warmed to RT and stirred for 2 h, and then TBSCl (482 mg,

3.20 mmol) and imidazole (218 mg, 3.20 mmol) were added to the

reaction mixture as solids. The reaction was stirred overnight and

diluted with hexanes (30 mL). The mixture was filtered through

a thin silica gel plug, which was rinsed with 20% Et₂O in hexanes

(235 mL). The combined organic layer was concentrated in vacuo

and subjected to azeotropic distillation with benzene (25 mL).

The crude ester 16 was used directly in the next step without fur-

ther purification.

To a flask containing Pd(PPh₃)₄(129.0 mg, 0.1116 mmol), LiCl

(475.0 mg, 11.21 mmol), and 2,2-dimethyl-4-oxo-4H-benzo[d]

[1,3]dioxin-5-yl

trifluoromethanesulfonate

30^[48]

(731.0 mg,

2.241 mmol) was added anhydrous and degassed THF (10 mL) at

RT under a N₂atmosphere. Then the crude stannyl diene 29 (~

2.7 mmol) dissolved in anhydrous and degassed DMF was added

dropwise over 15 min. The resulting mixture was stirred and

heated at 708C for 90 h, and then cooled to RT. After 10% NH₄OH

(15 mL) was added, the mixture was extracted with hexanes (5

50 mL), washed with brine (20 mL), dried over Na₂SO₄, and concen-

trated in vacuo. Purification by column chromatography (10%

EtOAc in hexanes) provided 538.4 mg (2.084 mmol, 93%) of dienyl

To a flask containing crude ester 16 was added anhydrous and de-

gassed toluene (1 L). Ruthenium Grubbs second-generation cata-

lyst (50.0 mg, 0.0589 mmol) in degassed toluene (1.0 mL) was

added in one portion under a nitrogen atmosphere. The solution

was heated at reflux and stirred for 20 h. The reaction mixture was

allowed to cool to RT and DMSO (15 mL) was added into the reac-

tion flask prior the removal of toluene in vacuo to obtain a dark-

brown liquid. The crude product was loaded directly on to a silica

column for purification (0 to 20% EtOAc in hexanes) to afford

553.3 mg (0.9528 mmol, 60%) of macrocyclic diene 18 as a light-

1

acetonide 31 as an opaque oil: H NMR (400 MHz, CDCl₃): d=1.71

(s, 6H), 2.27 (m, 2H), 2.39 (m, 2H), 5.00 (dd, J=1.86, 10.2 Hz, 1H),

5.08 (dd, J=1.7, 17.1 Hz, 1H), 5.88 (tdd, J=6.6, 10.4, 17.0 Hz, 1H),

6.23 (td, J=6.8, 15.6 Hz, 1H), 6.82 (dd, J=0.9, 8.1 Hz, 1H), 7.22 (d,

J=7.8 Hz, 1H), 7.42 (t, J=8.0 Hz, 1H), 7.48 ppm (d, J=15.7 Hz,

1H); ¹³C NMR (100 MHz, CDCl₃): d=160.4, 156.8, 142.5, 138.0,

135.0, 134.6, 128.5, 121.3, 115.6, 115.0, 110.6, 105.1, 33.3, 32.5,

25.6 ppm; IR (neat, NaCl): n˜ =2990, 1735, 1598, 1467, 1320 cm^À1

;

1

yellow oil: a²_D¹= +76.3 (c=1.53, CHCl₃); H NMR (400 MHz, CDCl₃):

HRMS (ESI⁺) m/z calcd for C₁₆H₁₈NaO₃[M+Na]⁺: 281.1148, found:

d=0.23 (s, 3H), 0.24 (s, 3H), 0.98 (s, 9H), 2.18 (m, 4H), 2.36 (m,

2H), 3.35 (s, 3H), 3.64 (m, 2H), 3.81 (s, 3H), 4.39 (q, J=2.6 Hz, 1H),

4.43 (d, J=11.4 Hz, 1H), 4.51 (d, J=11.4 Hz, 1H), 4.57 (d, J=6.8 Hz,

1H), 4.67 (d, J=6.8 Hz, 1H), 5.29 (td, J=3.35, 6.7 Hz, 1H), 5.32 (dd,

J=5.5, 15.9 Hz, 1H), 5.50 (ddd, J=5.6, 6.3, 15.9 Hz, 1H), 5.77 (td,

J=6.2, 15.9 Hz, 1H), 6.22 (d, J=15.9 Hz, 1H), 6.68 (d, J=8. Hz, 1H),

6.87 (m, 3H), 7.13 (t, J=7.8 Hz, 1H), 7.29 ppm (d, J=8.6 Hz, 2H);

¹³C NMR (100 MHz, CDCl₃): d=168.2, 159.1, 152.1, 137.6, 132.2,

131.5, 130.9, 130.6, 129.9, 129.6, 129.3, 125.7, 118.7, 117.1, 113.8,

94.9, 76.3, 75.3, 72.4, 66.6, 56.1, 55.3, 30.63, 30.61, 30.0, 25.8, 18.3,

À4.0, À4.2 ppm; IR (neat, NaCl): n˜ =2910, 2857, 1730, 1613, 1600,

281.1149.

(3S,4S)-1-(4-Methoxybenzyloxy)-4-(methoxymethoxy)hex-5-en-3-

ol (14). To

a flask containing 3-(methoxymethoxy)prop-1-ene

(13)^[42](1.27 g, 12.4 mmol) dissolved in anhydrous THF (25 mL) was

added sec-butyllithium in cyclohexane (1.40m, 7.3 mL, 10.3 mmol)

at À788C dropwise. The resulting orange solution was stirred at

À788C for an additional 30 min, and (+)-b-methoxydiisopinocam-

phenylborane (3.26 g, 10.3 mmol) dissolved in THF (25 mL) was

added dropwise. The reaction mixture was stirred at À788C for

1 h, then cooled to À908C (using MeOH and liquid N₂to prepare

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1608 ꢀ 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Papers

1565, 1505, 1463, 1250, 1160, 1033 cm^À1; HRMS (ESI+) m/z calcd

for C₃₃H₄₆NaO₇Si [M+Na]⁺: 605.2905, found: 605.2907.

2H); ¹³C NMR (100 MHz, CDCl₃): d=168.1, 152.0, 141.5, 140.4,

137.7, 133.4, 133.2, 132.4, 132.2, 131.0, 130.1, 129.6, 129.3, 127.7,

125.1, 118.8, 117.0, 94.6, 75.9, 75.5, 56.2, 32.3, 30.8, 30.1, 25.7, 18.2,

À4.0, À4.5 ppm; IR (neat, NaCl): n˜ =2935, 1731, 1570, 1460, 1292,

1270, 1148, 1101 cm^À1; HRMS (ESI+) m/z calcd for C₃₂H₄₂NaO₇SSi

[M+Na]⁺: 621.2313, found: 621.2317.

(3S,4S,5E,9E)-14-(tert-Butyldimethylsilyloxy)-3-(2-hydroxyethyl)-

4-(methoxymethoxy)-3,4,7,8-tetrahydro-1H-benzo[c][1]oxacyclo-

dodecin-1-one (20). To a flask containing macrocyclic diene 18

(177.7 mg, 0.3049 mmol) was added CH₂Cl₂(10.0 mL) and H₂O

(1.0 mL). The mixture was cooled to 08C, and 2,3-dichloro-5,6-di-

cyano-1,4-benzoquinone (DDQ; 74.9 mg, 0.330 mmol) was added

in one portion. The cooling bath was removed and the reaction

was stirred at RT for 1 h. The reaction mixture was diluted with sa-

turated NaHCO₃(20 mL), and then extracted with CH₂Cl₂(2

20 mL). The organic layer was washed with saturated NaHCO₃

(10 mL) and brine (10 mL). The crude mixture was dried over

Na₂SO₄, and concentrated in vacuo. Purification by column chroma-

tography (30% EtOAc in hexanes) provided 70.9 mg (0.153 mmol,

50%) of alcohol 20 as a colorless oil: a²_D¹= +108 (c=2.86, CHCl₃);

¹H NMR (400 MHz, CDCl₃): d=0.24 (s, 3H), 0.27 (s, 3H), 0.98 (s, 9H),

2.09 (m, 2H), 2.18 (m, 2H), 2.39 (m, 2H), 3.39 (s, 3H), 3.78 (m, 2H),

4.39 (br, 1H), 4.58 (d, J=6.8 Hz, 1H), 4.69 (d, J=6.8 Hz, 1H), 5.31

(d, J=4.2 Hz, 1H), 5.34 (dd, J=5.04, 15.8 Hz, 1H), 5.54 (td, J=5.9,

15.8 Hz, 1H), 5.80 (td, J=5.9, 15.9 Hz, 1H), 6.21 (d, J=15.9 Hz, 1H),

6.70 (d, J=8.2 Hz, 1H), 6.90 (d, J=7.7 Hz, 1H), 7.14 ppm (t, J=

8.0 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃): d=169.4, 152.1, 137.5,

132.2, 131.4, 130.8, 130.1, 129.9, 125.2, 118.6, 117.2, 94.8, 77.2, 75.5,

58.8, 56.1, 34.0, 30.4, 29.8, 25.8, 18.5, À4.0, À4.1 ppm; IR (neat,

NaCl): n˜ =3450 (br), 3005, 2930, 1731, 1460, 1380 cm^À1; HRMS

(ESI+) m/z calcd for C₂₅H₃₈NaO₆Si [M+Na]⁺: 485.2330, found:

485.2335.

(3S,4S,5E,9E)-4,14-Dihydroxy-3-((E)-3-(phenylsulfonyl)allyl)-

3,4,7,8-tetrahydro-1H-benzo[c][1]oxacyclododecin-1-one (24). To

a flask containing phenylsulfone 22 (19.0 mg, 0.0318 mmol) was

added 4m HCl in MeOH (1.0 mL). The mixture was stirred at RT for

120 h, and then concentrated in vacuo. Purification by column

chromatography (50% EtOAc in hexanes) provided 11.5 mg

(0.0262 mmol, 82%) of the desired analogue 24 as a colorless oil:

a²_D²=À35.0 (c=0.575, CHCl₃); ¹H NMR (400 MHz, CDCl₃): d=1.98

(brs, 1H) 2.20 (m, 2H), 2.41 (m, 2H), 2.72 (m, 1H), 2.95 (m, 1H),

4.38 (brs, 1H), 5.27 (m, 1H), 5.45 (dd, J=5.8, 15.9 Hz, 1H), 5.62 (qd,

J=4.49, 15.8 Hz, 2H), 6.44 (d, J=15.0 Hz, 1H), 6.52 (d, J=15.8 Hz,

1H), 6.74 (d, J=7.4 Hz, 1H), 6.85 (dd, J=0.9, 8.3 Hz, 1H), 7.05 (ddd,

J=7.1, 8.0, 15.1 Hz, 1H), 7.30 (t, J=7.9 Hz, 1H), 7.46 (m, 3H), 7.81

(m, 2H), 10.41 ppm (s, 1H); ¹³C NMR (100 MHz, CDCl₃): d=170.5,

161.5, 142.1, 141.7, 140.0, 135.0, 134.8, 134.3, 133.3, 133.1, 129.7,

129.2, 128.8, 127.5, 120.0, 116.3, 111.4, 75.0, 72.5, 32.4, 31.7,

29.8 ppm; IR (neat, NaCl): n˜ =3415 (br), 3050, 2920, 2865, 1737,

1630, 1464, 1406, 1044 cm^À1

; HRMS (ESI+) m/z calcd for

C₂₄H₂₄NaO₆S [M+Na]⁺: 463.1186, found: 463.1193.

(3S,4S)-7-(4-Methoxybenzyloxy)-3-(methoxymethoxy)hept-1-en-

4-ol (15). To a flask containing 3-(methoxymethoxy)prop-1-ene

(13)^[4](4.98 g, 48.8 mmol) dissolved in anhydrous THF (100 mL) was

added sec-butyllithium in cyclohexane (1.40m, 29.0 mL, 40.7 mmol)

at À788C dropwise. The resulting orange solution was stirred at

À788C for an additional 30 min, and (+)-b-methoxydiisopinocam-

phenylborane (12.9 g, 40.7 mmol) dissolved in THF (100 mL) was

added dropwise. After the reaction mixture was stirred at À788C

for 1 h, it was cooled to À908C (using MeOH and liquid N₂to pre-

pare the cooling bath). Then boron trifluoride etherate (6.80 mL,

54.1 mmol) was added dropwise. Immediately afterward, aldehyde

12^[5](7.90, 40.7 mmol) was added dropwise and the mixture was

kept at À908C for 3 h. The reaction was warmed to RT over 18 h to

give a clear colorless solution, and quenched with a mixture of

35% H₂O₂(30 mL) and saturated NaHCO₃solution (60 mL). After

stirring at RT for 30 min, the mixture was extracted with EtOAc (3

200 mL). The combined organic extracts were washed with brine,

dried over Na₂SO₄, and concentrated in vacuo. Purification by

column chromatography (30% EtOAc in hexanes) provided 11.14 g

(35.89 mmol, 88%) of alcohol 15 as a colorless oil: a²_D³= +44.1 (c=

(3S,4S,5E,9E)-14-(tert-Butyldimethylsilyloxy)-4-(methoxyme-

thoxy)-3-((E)-3-(phenylsulfonyl)allyl)-3,4,7,8-tetrahydro-1H-

benzo[c][1]oxacyclododecin-1-one (22). To a flask containing alco-

hol 20 (50.0 mg, 0.108 mmol) was added CH₂Cl₂(0.5 mL), Et₃N

(75.0 mL, 0.540 mmol) and DMSO (0.5 mL). The mixture was cooled

to 08C, and SO₃·Py (52.0 mg, 0.324 mmol) was added in one por-

tion. The mixture was stirred at 08C for 20 min, diluted with Et₂O

(4 mL) and phosphate buffer pH 7 (2 mL). The organic layer was

separated, and then the aqueous layer was extracted with Et₂O

(34 mL). The combined organic layer was washed with saturated

NH₄Cl (4 mL), and then with saturated CuSO₄(24 mL). The organ-

ic layer was concentrated in vacuo to afford an opaque oil of the

corresponding aldehyde. The crude aldehyde was used directly in

the next step without further purification.

To a solution of diethyl [(phenylsulfonyl)methyl]phosphonate (26;

31.4 mg, 0.108 mmol) in anhydrous THF (1.0 mL) was added 60%

NaH (5.0 mg, 0.12 mmol). The mixture was cooled to 08C, and was

stirred for 5 min. The aldehyde in THF (1.0 mL) was added drop-

wise over 3 min. The mixture was stirred at 08C for 40 min, and

then diluted with 10% HCl (0.25 mL) and phosphate (pH 7) buffer

(2.0 mL). The crude mixture was extracted with EtOAc (2.0 mL). The

organic layer was separated, and washed with saturated NaHCO₃

(1.0 mL). The organic layer was washed with brine (1.0 mL), dried

over MgSO₄, and concentrated in vacuo. Purification by column

chromatography (20% EtOAc in hexanes) provided 31.0 mg

(0.0518 mmol, 48%) of phenylsulfone 22 as an opaque oil: a²_D⁵= +

100 (c=1.20, CHCl₃); ¹H NMR (400 MHz, CDCl₃): d=0.21 (s, 3H),

0.22 (s, 3H), 0.94 (s, 9H), 2.10 (m, 2H), 2.37 (m, 2H), 2.72 (m, 1H),

2.94 (m, 1H), 3.30 (s, 3H), 4.35 (q, J=3.0 Hz, 1H), 4.49 (d, J=6.7 Hz,

1H), 4.63 (d, J=6.7 Hz, 1H), 5.08 (m, J=2.9 Hz, 1H), 5.25 (dd, J=

6.1, 15.8 Hz, 1H), 5.52 (td, J=6.2, 15.4 Hz, 1H), 5.75 (td, J=6.2,

15.7 Hz, 1H), 6.12 (d, J=15.9 Hz, 1H), 6.47 (td, J=1.3, 15.2 Hz, 1H),

6.68 (d, J=8.2 Hz, 1H), 6.87 (d, J=7.7 Hz, 1H), 7.05 (td, J=7.4,

14.9 Hz, 1H), 7.15 (t, J=8.0 Hz, 1H), 7.56 (m, 3H), 7.88 ppm (m,

1

1.31, CHCl₃); H NMR (400 MHz, CDCl₃): d=1.48 (m, J=4.9 Hz, 1H),

1.69 (m, J=3.0 Hz, 2H), 1.83 (m, J=3.1 Hz, 1H), 3.05 (brs, 1H), 3.39

(s, 3H), 3.48 (t, J=6.1 Hz, 2H), 3.58 (m, 1H), 3.80 (s, 3H), 3.88 (t, J=

7.3 Hz, 1H), 4.45 (s, 2H), 4.59 (d, J=6.6 Hz, 1H), 4.74 (d, J=6.6 Hz,

1H), 5.31 (d, J=16.8 Hz, 1H), 5.32 (d, J=10.3 Hz, 1H), 5.69 (m, 1H),

6.87 (d, J=8.6 Hz, 2H), 7.25 ppm (d, J=8.5 Hz, 2H);¹³C NMR

(100 MHz, CDCl₃): d=159.2, 134.6, 130.3, 129.4, 120.1, 113.8, 94.0,

81.3, 73.3, 72.6, 69.9, 55.8, 55.3, 29.5, 25.8 ppm; IR (neat, NaCl): n˜ =

3450 (br), 2950 (br), 1610, 1580, 1455, 1420, 1302, 1240 cm^À1

;

HRMS (ESI+) m/z calcd for C₁₇H₂₆NaO₅[M+Na]⁺: 333.1672, found:

333.1677.

(3S,4S,5E,9E)-14-(tert-Butyldimethylsilyloxy)-3-(3-(4-methoxyben-

zyloxy)propyl)-4-(methoxymethoxy)-3,4,7,8-tetrahydro-1H-

benzo[c][1]oxacyclododecin-1-one (19). Alcohol 15 (1.19 g,

3.83 mmol) was subjected to azeotropic distillation in vacuo with

benzene (210 mL), dissolved in anhydrous THF (15.0 mL) and

cooled to 08C. NaHMDS (1.0m, 7.26 mL, 7.26 mmol) was added

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Full Papers

dropwise. After stirring at 08C for 30 min, salicylate 31 (0.93 g,

3.63 mmol) dissolved in distilled THF (15.0 mL) was added drop-

wise. The reaction was warmed to RT and stirred for 2 h, and then

TBSCl (1.09 g, 7.26 mmol) and imidazole (0.50 g, 7.26 mmol) were

added to the reaction mixture as solids. The reaction was stirred

overnight and filtered through a thin silica gel plug, which was

rinsed with 20% Et₂O in hexanes (250 mL). The combined organ-

ic layer was concentrated in vacuo and subjected to azeotropic dis-

tillation with benzene (210 mL). The crude ester 17 was used di-

rectly in the next step without further purification.

hol 21 (70.3 mg, 0.147 mmol) was added CH₂Cl₂(1.0 mL), Et₃N

(0.15 mL, 1.07 mmol) and DMSO (1.0 mL). The mixture was cooled

to 08C, and SO₃·Py (73.0 mg, 0.459 mmol) was added in three por-

tions over 3 min. The mixture was stirred at 08C for 30 min, and

then diluted with Et₂O (2.5 mL) and phosphate buffer pH 7

(2.5 mL). The organic layer was separated, and then the aqueous

layer was extracted with Et₂O (51 mL). The combined organic

layer was washed with saturated NH₄Cl (5 mL), and then washed

with H₂O (25 mL) and saturated CuSO₄(25 mL). The organic

layer was dried over MgSO₄and concentrated in vacuo to afford

an opaque oil of the corresponding aldehyde. The crude aldehyde

was used directly in the next step without further purification.

To a flask containing crude ester 17 was added anhydrous and de-

gassed toluene (2 L). Ruthenium Grubbs second-generation cata-

lyst (98.0 mg, 0.116 mmol) in degassed toluene (3.0 mL) was added

in one portion under a nitrogen atmosphere. The solution was

heated at reflux and stirred for 4 h. The reaction mixture was al-

lowed to cool to RT and DMSO (20 mL) was added into the reac-

tion flask prior the removal of toluene in vacuo to obtain a dark-

brown liquid. The crude product was loaded directly on to silica

To a solution of diethyl [(phenylsulfonyl)methyl]phosphonate (26;

43.7 mg, 0.179 mmol) in anhydrous THF (2.0 mL) was added 60%

NaH (6.8 mg, 0.17 mmol). The mixture was cooled to 08C, and

stirred for 10 min. The aldehyde in THF (1.0 mL) was added drop-

wise over 3 min. The mixture was stirred at 08C for 40 min, and

then diluted with 10% HCl (0.5 mL) and phosphate buffer pH 7

column for purification (0 to 10% EtOAc in hexanes) to afford (4.0 mL). The crude mixture was extracted with Et₂O (315 mL).

1.321 g (2.212 mmol, 61%) of macrocyclic diene 19 as a light-

The combined organic layer was washed with 10% NaHCO₃

(20.0 mL) and brine (10.0 mL), dried over MgSO₄, and concentrated

in vacuo. Purification by column chromatography (30% EtOAc in

hexanes) provided 60.1 mg (0.0959 mmol, 65%) of phenylsulfone

23 as an opaque oil: a_D²²= +90.3 (c=2.43, CHCl₃); ¹H NMR

(400 MHz, CDCl₃): d=0.18 (s, 3H), 0.19 (s, 3H), 0.89 (s, 9H), 1.98 (m,

2H), 2.19 (m, 2H), 2.38 (m, 4H), 3.34 (s, 3H), 4.37 (m, 1H), 4.55 (d,

J=6.8 Hz, 1H), 4.67 (d, J=6.8 Hz, 1H), 5.09 (td, J=3.4, 10.0 Hz,

1H), 5.27 (dd, J=5.4, 15.6 Hz, 1H), 5.48 (td, J=6.3, 15.2 Hz, 1H),

5.75 (td, J=6.1, 15.9 Hz, 1H), 6.19 (d, J=15.9 Hz, 1H), 6.36 (td, J=

1.5, 15.0 Hz, 1H), 6.67 (d, J=7.7 Hz, 1H), 6.85 (d, J=7.7 Hz, 1H),

7.02 (td, J=6.4, 15.1 Hz, 1H), 7.13 (t, J=8.0 Hz, 1H), 7.56 (m, 3H),

7.88 ppm (m, 2H); ¹³C NMR (100 MHz, CDCl₃): d=168.2, 152.0,

145.8, 140.6, 137.6, 133.3, 132.5, 132.4, 130.9, 130.8, 129.8, 129.3,

128.8, 127.6, 125.3, 119.0, 117.2, 94.8, 76.2, 76.0, 56.2, 30.5, 30.1,

28.2, 27.7, 25.7, 18.3, À4.1, À4.3 ppm; IR (neat, NaCl): n˜ =2933,

1735, 1550, 1480, 1282, 1255, 1138, 1111 cm^À1; HRMS (ESI⁺) m/z

calcd for C₃₃H₄₄NaO₇SSi [M+Na]⁺: 635.2469, found: 635.2471.

1

yellow oil: a²_D¹= +97.7 (c=1.33, CHCl₃); H NMR (400 MHz, CDCl₃):

d=0.21 (s, 3H), 0.22 (s, 3H), 0.95 (s, 9H), 1.81 (m, 3H), 2.00 (m,

1H), 2.29 (m, 4H), 3.37 (s, 3H), 3.49 (m, 2H), 3.79 (s, 3H), 4.40 (m,

1H), 4.43 (s, 2H), 4.57 (d, J=6.8 Hz, 1H), 4.68 (d, J=6.8 Hz, 1H),

5.17 (m, 1H), 5.32 (dd, J=4.8, 15.7 Hz, 1H), 5.47 (td, J=6.0,

15.7 Hz, 1H), 5.76 (td, J=5.9, 15.9 Hz, 1H), 6.24 (d, J=15.9 Hz, 1H),

6.67 (d, J=8.2 Hz, 1H), 6.85 (t, J=7.3 Hz, 3H), 7.11 (t, J=8.0 Hz,

1H), 7.25 ppm (d, J=8.5 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃): d=

168.2, 159.1, 152.1, 137.5, 132.3, 131.6, 130.7, 129.5, 129.4, 129.2,

125.8, 118.9, 117.1, 113.7, 94.9, 77.1, 75.9, 72.5, 69.9, 60.4, 56.1, 55.2,

30.6, 30.1, 27.4, 25.9, 25.8, 18.3, À4.1, À4.3 ppm; IR (neat, NaCl):

n˜ =2915, 2865, 1735, 1620, 1600, 1565, 1525, 1460, 1245, 11 450,

1083 cm^À1; HRMS (ESI⁺) m/z [M+Na]⁺calcd for C₃₄H₄₈NaO₇Si:

619.3062, found: 619.3065.

(3S,4S,5E,9E)-14-(tert-Butyldimethylsilyloxy)-3-(3-hydroxypropyl)-

4-(methoxymethoxy)-3,4,7,8-tetrahydro-1H-benzo[c][1]oxacyclo-

dodecin-1-one (21). To a flask containing macrocyclic diene 19

(404.6 mg, 0.6779 mmol) was added CH₂Cl₂(15.0 mL) and H₂O

(1.5 mL). The mixture was cooled to 08C, and DDQ (185.0 mg,

0.8149 mmol) was added in one portion. The cooling bath was re-

moved and the reaction was stirred at RT for 1 h and 10 min. The

reaction mixture was diluted with EtOAc (100 mL), and then

washed with 10% NaHCO₃solution (215 mL). The organic layer

was washed with brine, dried over Na₂SO₄, and concentrated in va-

cuo. Purification by column chromatography (30% EtOAc in hex-

anes) provided 204.5 mg (0.4290 mmol, 63%) of alcohol 21 as a col-

orless oil: a²_D⁵= +112 (c=1.51, CHCl₃); ¹H NMR (400 MHz, CDCl₃):

d=0.22 (s, 3H), 0.22 (s, 3H), 0.96 (s, 9H), 1.71 (m, 3H), 1.87 (m,

1H), 2.00 (m, 1H), 2.22 (m, 2H), 2.34 (m, 2H), 3.39 (s, 3H), 3.69 (m,

2H), 4.42 (t, 1H), 4.58 (d, J=6.8 Hz, 1H), 4.69 (d, J=6.8 Hz, 1H),

5.16 (td, J=3.47, 9.9 Hz, 1H), 5.33 (dd, J=5.0, 15.7 Hz, 1H), 5.50

(td, J=6.2, 15.1 Hz, 1H), 5.77 (td, J=6.2, 15.9 Hz, 1H), 6.23 (d, J=

15.9 Hz, 1H), 6.67 (d, J=8.1 Hz, 1H), 6.85 (d, J=7.7 Hz, 1H),

7.12 ppm (t, J=8.0 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃): d=168.4,

152.1, 137.6, 132.3, 131.8, 130.8, 129.7, 129.3, 125.6, 118.9, 117.1,

94.9, 77.2, 76.0, 62.7, 56.1, 30.6, 30.1, 28.7, 26.7, 25.7, 18.3, À4.1,

À4.3 ppm; IR (neat, NaCl): n˜ =3455 (br), 3015, 2935, 1733, 1466,

1380, 1115 cm^À1; HRMS (ESI⁺) m/z calcd for C₂₆H₄₀NaO₆Si [M+Na]⁺:

499.2486, found: 499.2489.

(3S,4S,5E,9E)-4,14-Dihydroxy-3-((E)-4-(phenylsulfonyl)but-3-enyl)-

3,4,7,8-tetrahydro-1H-benzo[c][1]oxacyclododecin-1-one (25). To

a flask containing phenylsulfone 23 (48.7 mg, 0.0777 mmol) was

added 4m HCl in MeOH (5.0 mL). The mixture was stirred at RT for

99 h, and then concentrated in vacuo. Purification by column chro-

matography (50% EtOAc in hexanes) provided 31.0 mg

(0.0662 mmol, 85%) of the desired analogue 25 as a colorless oil:

a²_D⁰=À13.8 (c 0.975, CHCl₃); ¹H NMR (400 MHz, CDCl₃): d=1.78

(brs, 1H), 1.91 (m, 1H), 2.20 (m, 3H), 2.40 (m, 4H), 4.33 (t, J=

4.8 Hz, 1H), 5.18 (m, 1H), 5.47 (dd, J=6.10, 15.6 Hz, 1H), 5.61 (m,

2H), 6.41 (d, J=15.2 Hz, 1H), 6.61 (d, J=15.7 Hz, 1H), 6.78 (d, J=

7.5 Hz, 1H), 6.86 (d, J=8.3 Hz, 1H), 7.02 (td, J=6.7, 14.7 Hz, 1H),

7.31 (t, J=7.9 Hz, 1H), 7.57 (m, 3H), 7.88 (d, J=7.9 Hz, 2H),

10.47 ppm (s, 1H); ¹³C NMR (100 MHz, CDCl₃): d=169.7, 160.4,

144.5, 140.7, 139.4, 134.2, 133.8, 133.3, 132.3, 130.2, 128.7, 128.3,

128.0, 126.6, 119.0, 115.2, 110.6, 75.1, 71.6, 31.5, 28.7, 26.9,

26.2 ppm; IR (neat, NaCl): n˜ =3415 (br), 3055, 2910, 2855, 1735,

1632, 1484, 1426, 1134 cm^À1

;

HRMS (ESI⁺) m/z calcd for

C₂₅H₂₆NaO₆S [M+Na]⁺: 477.1342, found: 477.1348.

(3S,4S,5Z,7Z,9E)-3-(2-Hydroxyethyl)-14-methoxy-4-(methoxyme-

thoxy)-3,4-dihydro-1H-benzo[c][1]oxacyclododecin-1-one (33). To

a flask containing macrocyclic triene 32^[1](47.4 mg, 0.0792 mmol)

was added anhydrous THF (1.0 mL), and then TBAF (1m in THF,

87.0 mL, 0.0870 mmol) was added dropwise over 5 min at RT. The

mixture was stirred at RT for 1.5 h, and then concentrated in vacuo.

(3S,4S,5E,9E)-14-(tert-Butyldimethylsilyloxy)-4-(methoxyme-

thoxy)-3-((E)-4-(phenylsulfonyl)but-3-enyl)-3,4,7,8-tetrahydro-1H-

benzo[c][1]oxacyclododecin-1-one (23). To a flask containing alco-

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Full Papers

Purification by column chromatography (40% EtOAc in hexanes)

1H), 5.76 (t, J=11.2 Hz, 1H), 5.87 (dd, J=3.8, 11.0 Hz, 1H), 6.10 (dd,

J=3.8, 11.9 Hz, 1H), 6.34 (t, J=11.2 Hz, 1H), 6.52 (d, J=15.2 Hz,

1H), 6.69 (d, J=15.9 Hz, 1H), 6.83 (dd, J=8.0, 15.0 Hz, 2H), 6.98

(dd, J=11.6, 15.9 Hz, 1H), 7.18 (ddd, J=5.4, 8.1, 15.1 Hz, 1H), 7.29

(t, J=8.0 Hz, 1H), 7.57 (m, 3H), 7.89 ppm (m, 2H); ¹³C NMR

(100 MHz, CDCl₃): d=168.5, 156.3, 143.1, 140.6, 138.0, 133.3, 132.8,

132.3, 131.6, 131.1, 130.1, 130.0, 129.3, 128.7, 127.6, 127.2, 122.9,

120.4, 109.6, 76.3, 65.5, 56.0, 29.3 ppm; IR (neat, NaCl): n˜ =3470,

3014, 2927, 1731, 1634, 1572, 1469, 1305, 1271, 1107, 1060,

961 cm^À1; HRMS (ESI+) m/z calcd for C₂₅H₂₄NaO₆S [M+Na]⁺:

475.1186, found: 475.1181.

provided 26.6 mg (0.0694 mmol, 88%) of alcohol 33 as a colorless

1

oil: a²_D¹=À207 (c=1.33, CHCl₃); H NMR (400 MHz, CDCl₃): d=2.18

(m, 2H), 3.37 (s, 3H), 3.84 (s, 3H), 3.90 (s, 2H), 4.53 (d, J=6.4 Hz,

1H), 4.58 (d, J=6.4 Hz, 1H), 4.66 (dd, J=3.4, 10.8 Hz, 1H), 5.55

(ddd, J=3.2, 3.2, 10.7 Hz, 1H), 5.71 (dd, J=11.3, 11.3 Hz, 1H), 5.90

(dd, J=3.9, 11.0 Hz, 1H), 6.21 (dd, J=3.8, 11.9 Hz, 1H), 6.36 (dd, J=

11.3, 11.3 Hz, 1H), 6.68 (d, J=15.9 Hz, 1H), 6.82 (t, J=8.3 Hz, 2H),

7.00 (dd, J=11.5, 15.9 Hz, 1H), 7.27 ppm (d, J=5.0 Hz, 1H);

¹³C NMR (100 MHz, CDCl₃): d=168.2, 155.7, 138.5, 133.3, 132.6,

130.7, 129.9, 129.5, 127.8, 126.9, 123.3, 120.8, 109.4, 93.3, 77.3, 68.4,

61.2, 55.8, 55.5, 30.7 ppm; IR (neat, NaCl): n˜ =3432 (br), 3010, 2943,

1729, 1599, 1571, 1468, 1438, 1154, 1089, 1058 cm^À1; HRMS (ESI⁺)

m/z calcd for C₂₀H₂₄NaO₆[M+Na]⁺: 383.1465, found: 383.1462.

(3S,4S,5Z,7Z,9E)-4,14-Dihydroxy-3-((E)-3-(phenylsulfonyl)allyl)-

3,4-dihydro-1H-benzo[c][1]oxacyclododecin-1-one (36). To a flask

containing alcohol 35 (10.0 mg, 0.0221 mmol) was added anhy-

drous CH₂Cl₂(2.2 mL). The mixture was cooled to À788C, and BCl₃

1m in CH₂Cl₂(0.22 mL, 0.22 mmol) was added dropwise over

1 min. The mixture was stirred at À788C for 10 min, and warmed

to RT and stirred for 15 min. The reaction mixture was quenched

with H₂O (2 mL) and extracted with EtOAc (35 mL). The com-

bined organic layer was washed with brine and dried over MgSO₄.

The crude mixture was concentrated in vacuo. Purification by

column chromatography (50% EtOAc in hexanes) provided 7.2 mg

(0.016 mmol, 75%) of the desired analogue 36 as a bright-yellow

oil: a²_D⁰=À130 (c=0.36, CHCl₃); ¹H NMR (400 MHz, CD₃OD): d=

2.70 (m, 1H), 2.82 (m, 1H), 4.53 (dd, J=3.3, 10.5 Hz, 1H), 5.18 (td,

J=2.8, 10.9 Hz, 1H), 5.69 (dd, J=11.2, 11.2 Hz, 1H), 5.81 (dd, J=

3.9, 11.1 Hz, 1H), 5.98 (dd, J=3.8, 11.9 Hz, 1H), 6.25 (dd, J=11.2,

11.2 Hz, 1H), 6.56 (d, J=16.0 Hz, 1H), 6.65 (m, 3H), 6.90 (dd, J=

11.4, 15.9 Hz, 1H), 7.08 (ddd, J=7.2, 7.2, 15.2 Hz, 2H), 7.51 (m, 3H),

7.82 ppm (m, 2H); ¹³C NMR (100 MHz, CD₃OD): d=170.8, 155.6,

145.2, 142.1, 139.4, 134.5, 133.9, 133.8, 131.62, 131.57, 131.1, 130.9,

130.53, 130.48, 130.4, 128.7, 123.1, 120.2, 115.1, 78.6, 66.3,

30.3 ppm; IR (neat, NaCl): n˜ =3408 (br), 3052, 3014, 2927, 2854,

1727, 1635, 1464, 1219, 1144, 1085, 1057 cm^À1; HRMS (ESI+) m/z

calcd for C₂₄H₂₂NaO₆S [M+Na]⁺: 461.1029, found: 461.1037.

(3S,4S,5Z,7Z,9E)-14-Methoxy-4-(methoxymethoxy)-3-((E)-3-(phe-

nylsulfonyl)allyl)-3,4-dihydro-1H-benzo[c][1]oxacyclododecin-1-

one (34). To a flask containing alcohol 33 (25.0 mg, 0.0694 mmol)

were added anhydrous CH₂Cl₂(1.2 mL) and molecular sieves 4

(70 mg). The mixture was cooled to 08C, and pyridinium dichro-

mate (PDC; 104.0 mg, 0.2764 mmol) was added in one portion. The

cooling bath was removed and the reaction was stirred at RT for

1.5 h The reaction mixture was diluted with hexanes (3 mL), then

filtered through a silica gel plug and rinsed with 40% EtOAc in

hexanes (20 mL). The combined organic layer was concentrated in

vacuo to afford an opaque oil of the corresponding aldehyde. The

crude aldehyde was used directly in the next step without further

purification.

To

a solution of diethyl [(phenylsulfonyl)methyl]phosphonate

(26)^[43](22.0 mg, 0.0759 mmol) in anhydrous THF (1.0 mL) was

added 60% NaH (3.4 mg, 0.086 mmol). The mixture was cooled to

08C, and was stirred for 5 min. The aldehyde in THF (1.0 mL) was

added dropwise over 3 min. The mixture was stirred at 08C for

30 min, and then diluted with saturated NH₄Cl (3.0 mL) and phos-

phate buffer pH 7 (4.0 mL). The crude mixture was extracted with

EtOAc (34 mL). The combined organic layer was washed with

brine (5 mL), dried over Na₂SO₄, and concentrated in vacuo. Purifi-

cation by column chromatography (30% EtOAc in hexanes) provid-

ed 17.8 mg (0.0358 mmol, 47%) of phenylsulfone 34 as an opaque

oil: a²_D²=À179 (c=0.890, CHCl₃); ¹H NMR (400 MHz, CDCl₃): d=

2.83 (m, J=3.0 Hz, 2H), 3.33 (s, 3H), 3.95 (s, 3H), 4.49 (d, J=

6.52 Hz, 1H), 4.54 (d, J=6.5 Hz, 1H), 4.66 (dd, J=3.36, 10.8 Hz, 1H),

5.44 (ddd, J=3.1, 3.1, 10.8 Hz, 1H), 5.59 (dd, J=11.3, 11.3 Hz, 1H),

5.88 (dd, J=3.7, 11.4 Hz, 1H), 6.2 (dd, J=3.8, 11.8 Hz, 1H), 6.37 (dd,

J=11.3, 11.3 Hz, 1H), 6.52 (d, J=15.2 Hz, 1H), 6.69 (d, J=16.0 Hz,

1H), 6.83 (dd, J=8.0, 13.8 Hz, 2H), 6.99 (dd, J=11.7, 15.7 Hz, 1H),

7.19 (ddd, J=5.5, 7.9, 15.2 Hz, 1H), 7.29 (t, J=8.0 Hz, 1H), 7.57 (m,

3H), 7.90 ppm (m, 2H); ¹³C NMR (100 MHz, CDCl₃): d=168.3, 156.4,

143.0, 140.6, 138.1, 133.29, 133.25, 132.8, 132.3, 131.1, 130.0, 129.9,

129.3, 127.6, 127.3, 126.0, 123.0, 120.4, 109.5, 93.3, 75.5, 68.3, 56.0,

55.6, 30.0 ppm; IR (neat, NaCl): n˜ =3012, 2945, 2842, 1732, 1635,

1572, 1469, 1318, 1305, 1105, 1087, 1059, 953 cm^À1; HRMS (ESI+)

m/z calcd for C₂₇H₂₈NaO₇S [M+Na]⁺: 519.1448, found: 519.1454.

(5S,6S)-6-(3-(4-Methoxybenzyloxy)propyl)-8,8,9,9-tetramethyl-5-

vinyl-2,4,7-trioxa-8-siladecane (37). To a stirred solution of alcohol

15 (3.00 g, 9.65 mmol) dissolved in anhydrous DMF (5.0 mL) were

added TBSCl (10.5 g, 69.7 mmol) and imidazole (4.74 g, 69.6 mmol)

as solids. The resulting mixture was heated at 758C for 4 h. The re-

action mixture was cooled to RT and quenched with phosphate

buffer pH 7 (100 mL). The mixture was extracted with CH₂Cl₂(3

100 mL). The combined organic layer was dried over Na₂SO₄and

concentrated in vacuo. Purification by column chromatography

(30% EtOAc in hexanes) provided 2.90 g (6.84 mmol, 71% yield) of

1

alkene 37 as a colorless oil: a²_D²= +3.86 (c=1.01, CHCl₃); H NMR

(400 MHz, CDCl₃): d=0.06 (s, 3H), 0.08 (s, 3H), 0.89 (s, 9H), 1.39 (m,

1H), 1.66 (m, 3H), 3.35 (s, 3H), 3.42 (t, J=6.5 Hz, 2H), 3.72 (ddd,

J=3.3, 4.9, 8.0 Hz, 1H), 3.80 (s, 3H), 3.99 (dd, J=5.4, 6.5 Hz, 1H),

4.42 (s, 2H), 4.58 (d, J=6.6 Hz, 1H), 4.67 (d, J=6.6 Hz, 1H), 5.25 (d,

J=10.5 Hz, 1H), 5.27 (d, J=16.7 Hz, 1H), 5.78 (m, 1H), 6.87 (d, J=

8.6 Hz, 2H), 7.25 ppm (d, J=8.2 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃):

d=159.1, 134.8, 130.8, 129.2, 117.9, 113.7, 94.6, 79.9, 74.0, 72.4,

70.3, 55.5, 55.3, 29.1, 25.9, 25.6, 17.7, À4.3, À4.7 ppm; IR (neat,

(3S,4S,5Z,7Z,9E)-4-Hydroxy-14-methoxy-3-((E)-3-(phenylsulfony-

l)allyl)-3,4-dihydro-1H-benzo[c][1]oxacyclododecin-1-one (35). To

a flask containing phenyl sulfone 34 (17.0 mg, 0.0359 mmol) was

added iPrOH (0.37 mL), and CBr₄(48.0 mg, 0.144 mmol) in one por-

tion. The mixture was heated at 758C for 2 h, and then concentrat-

ed in vacuo. Purification by column chromatography (40% EtOAc

in hexanes) provided 12.6 mg (0.0278 mmol, 78%) of alcohol 35 as

NaCl): n˜ =2930, 2880, 2853, 1620, 1510, 1471, 1250, 1100 cm^À1

;

HRMS (ESI+) m/z calcd for C₂₃H₄₀NaO₅Si [M+Na]⁺: 447.2537,

found: 447.2539.

(4S,5S,Z)-1-(4-Methoxybenzyloxy)-5-(methoxymethoxy)nona-6,8-

dien-4-ol (40). To

a stirred solution of alkene 37 (2.90 g,

1

a bright-yellow oil: a²_D⁰=À183 (c=0.630, CHCl₃); H NMR (400 MHz,

6.84 mmol) dissolved in THF (54 mL) and H₂O (27 mL) was added

NMO (0.96 g, 8.2 mmol) and OsO₄in toluene (1.0m, 0.74 mL,

0.74 mmol). The resulting solution was stirred at RT for 24 h, then

CDCl₃): d=2.78 (m, J=3.50 Hz, 1H), 2.93 (dd, J=8.1, 15.5 Hz, 1H),

3.95 (s, 3H), 4.77 (dd, J=3.2, 10.5 Hz, 1H), 5.40 (td, J=2.6, 11.5 Hz,

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quenched with a saturated Na₂S₂O₃solution (20 mL) and extracted

with EtOAc (350 mL). The combined organic extracts were dried

over Na₂SO₄and concentrated in vacuo. The crude product was

dried under high vacuum for 4 h before use in the next step. To

a flask containing the crude diol was added anhydrous MeOH

(60 mL) and the reaction was cooled to 08C. To this mixture was

added K₂CO₃(1.54 g, 11.1 mmol) and Pb(OAc)₄(3.96 g, 8.93 mmol)

and the resulting solution was stirred at 08C for 15 min before

being quenched with saturated NaHCO₃(40 mL). The reaction mix-

ture was extracted with EtOAc (350 mL), and the combined or-

ganic extracts were washed with brine (20 mL), dried over Na₂SO₄,

and concentrated in vacuo. The crude aldehyde 38 was used di-

rectly in the next step without further purification.

in hexanes) provided 0.578 g (0.907 mmol, 91% yield) of ester 42

1

as a colorless oil: a²_D⁵= +32.9 (c=1.50, CHCl₃); H NMR (400 MHz,

CDCl₃): d=0.22 (s, 6H), 0.96 (s, 9H), 1.61 (m, 1H), 1.78 (m, 5H), 1.92

(m, 1H), 3.27 (s, 3H), 3.46 (m, 2H), 3.79 (s, 3H), 4.42 (s, 2H), 4.50 (d,

J=6.7 Hz, 1H), 4.63 (d, J=6.8 Hz, 1H), 4.72 (dd, J=5.5, 9.7 Hz, 1H),

5.20 (m, 2H), 5.28 (d, J=16.7 Hz, 1H), 5.39 (dd, J=10.4, 10.4 Hz,

1H), 5.81 (m, 1H), 6.15 (dd, J=10.5, 15.0 Hz, 1H), 6.27 (dd, J=11.1,

11.1 Hz, 1H), 6.46 (d, J=15.5 Hz, 1H), 6.69 (m, 3H), 6.86 (d, J=

8.6 Hz, 2H), 7.13 (m, 2H), 7.24 ppm (d, J=8.5 Hz, 2H); ¹³C NMR

(100 MHz, CDCl₃): d=171.1, 167.8, 159.1, 152.5, 136.4, 134.7, 131.9,

131.7, 131.6, 131.2, 130.7, 129.6, 129.1, 126.9, 126.7, 120.4, 117.6,

117.4, 113.7, 93.4, 76.4, 72.4, 70.5, 69.7, 55.5, 55.2, 27.5, 25.8, 25.6,

25.5, 18.3, À4.1, À4.2 ppm; IR (neat, NaCl): n˜ =2950, 2873, 1720,

1565, 1505, 1440, 1280, 1100 cm^À1; HRMS (ESI+) m/z calcd for

C₃₇H₅₂NaO₇Si [M+Na]⁺: 659.3375, found: 659.3381.

To a flask containing allyldiphenylphosphine (2.62 mL, 8.21 mmol)

dissolved in anhydrous THF (30 mL) was added tert-butyllithium

(1.70m, 4.83 mL, 8.21 mmol) dropwise at À788C, and this mixture

was stirred at 08C for 30 min. Ti(OiPr)₄(2.63 mL, 8.90 mmol) was

added dropwise at À788C, and the resulting solution was stirred

for 5 min. The crude aldehyde 38, dissolved in THF (3.0 mL), was

added over 4 min via syringe at À788C, and this mixture was

stirred at À788C for 10 min and then at 08C for 1 h. Methyl iodide

(1.28 mL, 20.6 mmol) was added at 08C and the reaction mixture

was stirred at RT overnight. The reaction mixture was diluted with

hexanes (130 mL), filtered through a silica gel plug (13 g), washed

with 20% EtOAc in hexanes (100 mL), and concentrated in vacuo.

The resulting cis-diene 39 was used directly in the next step with-

out further purification.

(3S,4S,5Z,7Z,9E)-14-(tert-Butyldimethylsilyloxy)-3-(3-(4-methoxy-

benzyloxy)propyl)-4-(methoxymethoxy)-3,4-dihydro-1H-benzo[c]

[1]oxacyclododecin-1-one (43). To a flask containing bis-diene 42

(100 mg, 0.157 mmol) was added anhydrous and degassed toluene

(80 mL). Ruthenium Grubbs second-generation catalyst (6.7 mg,

0.0079 mmol) in degassed toluene was added in one portion

under a nitrogen atmosphere. The solution was heated at reflux

and stirred for 60 min. The reaction mixture was allowed to cool to

RT and DMSO (5 mL) was added into the reaction flask prior to the

removal of toluene in vacuo to obtain a dark-brown liquid. The

crude product was loaded directly on to a silica column for combi-

flash purification (0 to 10% EtOAc in hexanes) to afford 20.6 mg

(0.0346 mmol, 22%) of the macrocyclic triene 43 as a light-yellow

The crude cis-diene 39 was dissolved in anhydrous THF (18 mL)

and treated with TBAF in THF (1.0m, 10.3 mL, 10.3 mmol). The reac-

tion mixture was stirred at RT for 25 h before being diluted with

H₂O (20 mL) and extracted with EtOAc (320 mL). The combined

organic extracts were washed with brine (20 mL), dried over

Na₂SO₄, and concentrated in vacuo. Purification by column chroma-

tography (30% EtOAc in hexanes) provided 0.43 g (1.3 mmol, 19%)

of alcohol 40 as a colorless oil: a²_D²= +46.9 (c=1.30, CHCl₃);

¹H NMR (400 MHz, CDCl₃): d=1.43 (m, 1H), 1.63 (m, 1H), 1.72 (m,

1H), 1.82 (m, 1H), 2.86 (brs, 1H), 3.38 (s, 3H), 3.46 (m, 2H), 3.57 (m,

1H), 3.80 (s, 3H), 4.36 (dd, J=7.10, 9.70 Hz, 1H), 4.42 (s, 2H), 4.54

(d, J=6.64 Hz, 1H), 4.69 (d, J=6.7 Hz, 1H), 5.27 (m, 3H), 6.29 (dd,

J=11.1, 11.8 Hz, 1H), 6.67 (ddd, J=10.3, 11.7, 16.7 Hz, 1H), 6.86 (d,

J=8.7 Hz, 2H), 7.24 ppm (d, J=8.6 Hz, 2H); ¹³C NMR (100 MHz,

CDCl₃): d=159.1, 134.9, 131.7, 130.6, 129.2, 127.5, 120.4, 113.7,

93.6, 74.8, 73.5, 72.4, 69.9, 55.6, 55.2, 29.6, 26.0 ppm; IR (neat,

1

oil: a²_D⁰=À81.9 (c=1.03, CHCl₃); H NMR (400 MHz, CDCl₃): d=0.19

(s, 3H), 0.20 (s, 3H), 0.96 (s, 9H), 1.73 (m, 2H), 1.86 (m, 1H), 1.97

(m, 1H), 2.07 (m, 1H), 3.35 (s, 3H), 3.49 (m, 2H), 3.80 (s, 3H), 4.52

(d, J=6.6 Hz, 1H), 4.55 (d, J=6.4 Hz, 1H), 4.60 (dd, J=2.9, 10.7 Hz,

1H), 5.32 (ddd, J=2.9, 2.88, 10.3 Hz, 1H), 5.68 (dd, J=11.4, 11.4 Hz,

2H), 5.87 (dd, J=4.1, 11.0 Hz, 1H), 6.18 (dd, J=4.1, 12.0 Hz, 1H),

6.34 (t, J=11.2 Hz, 1H), 6.64 (d, J=16.0 Hz, 1H), 6.74 (d, J=

8.20 Hz, 1H), 6.78 (d, J=7.7 Hz, 1H), 6.87 (d, J=8.5 Hz, 2H), 7.01

(dd, J=11.5, 16.01 Hz, 1H), 7.16 (dd, J=7.9, 7.9 Hz, 1H), 7.26 ppm

(d, J=8.6 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃): d=168.4, 159.0,

152.3, 137.9, 132.2, 131.9, 131.0, 130.8, 129.9, 129.2, 129.1, 127.2,

127.1, 126.6, 121.2, 117.9, 113.7, 93.1, 78.2, 72.5, 69.8, 69.0, 55.4,

55.3, 26.9, 25.8, 25.5, 18.4, À4.0, À4.2 ppm; IR (neat, NaCl): n˜ =

2930, 2857, 1730, 1612, 1570, 1513, 1463, 1362, 1292, 1250, 1172,

1155, 1102, 1032, 1001, 927, 863, 839, 807, 783, 753, 714, 670 cm^À1

;

HRMS (ESI+) m/z calcd for C₃₄H₄₆NaO₇Si [M+Na]⁺: 617.2905,

NaCl): n˜ =3430 (br), 2940 (br), 1630, 1509, 1473, 1250, 1120 cm^À1

;

found: 617.2907.

HRMS (ESI+) m/z calcd for C₁₉H₂₈NaO₅[M+Na]⁺: 359.1829, found:

359.1831.

(3S,4S,5Z,7Z,9E)-14-(tert-Butyldimethylsilyloxy)-3-(3-hydroxy-

propyl)-4-(methoxymethoxy)-3,4-dihydro-1H-benzo[c][1]oxacy-

clododecin-1-one (44). To a flask containing macrocyclic triene 43

(15.9 mg, 0.0274 mmol) was added CH₂Cl₂(1.0 mL) and H₂O

(0.1 mL). The mixture was cooled to 08C, and DDQ (7.5 mg,

0.033 mmol) was added in one portion. The cooling bath was re-

moved and the reaction was stirred at RT for 1 h. The reaction mix-

ture was diluted with EtOAc (10 mL), and then washed with 10%

NaHCO₃solution (25 mL). The organic layer was washed with

brine, dried over Na₂SO₄, and concentrated in vacuo. Purification

by column chromatography (30% EtOAc in hexanes) provided

(4S,5S,Z)-1-(4-Methoxybenzyloxy)-5-(methoxymethoxy)nona-6,8-

dien-4-yl 2-(tert-Butyldimethylsilyloxy)-6-((1E,3E)-penta-1,3-dien-

yl)benzoate (42). Alcohol 40 (350 mg, 1.04 mmol) was subjected

to azeotropic distillation in vacuo with benzene (24 mL), dis-

solved in anhydrous THF (4.0 mL) and cooled to 08C. NaHMDS

(1.0m, 1.98 mL, 1.98 mmol) was added dropwise. After stirring at

08C for 30 min, salicylate 41^[6](242 mg, 0.991 mmol) dissolved in

distilled THF (4.0 mL) was added dropwise. The reaction was

warmed to RT and stirred for 2 h, and then TBSCl (298 mg,

1.98 mmol) and imidazole (135 mg, 1.98 mmol) were added to the

reaction mixture as solids. The reaction was stirred overnight and

then quenched by an ice-cold solution of 5% HCl (30 mL). The mix-

ture was extracted with Et₂O (230 mL) and the combined organic

layer was washed with 10% NaHCO₃(50 mL). The organic layer

was washed with brine (30 mL), dried over MgSO₄and concentrat-

ed in vacuo. Purification by column chromatography (20% EtOAc

12.7 mg (0.0267 mmol, 98%) of alcohol 44 as a colorless oil: a_D²²

=

1

À88.1 (c=0.630, CHCl₃); H NMR (400 MHz, CDCl₃): d=0.20 (s, 3H),

0.21 (s, 3H), 0.97 (s, 9H), 1.66 (m, 2H), 1.91 (m, 2H), 3.36 (s, 3H),

3.72 (m, 2H), 4.53 (d, J=6.44 Hz, 1H), 4.56 (d, J=6.5 Hz, 1H), 4.61

(dd, J=2.9, 10.7 Hz, 1H), 5.34 (td, J=2.8, 10.3 Hz, 1H), 5.68 (dd, J=

11.3, 11.3 Hz, 1H), 5.87 (dd, J=3.6, 11.1 Hz, 1H), 6.19 (dd, J=4.1,

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12.0 Hz, 1H), 6.35 (dd, J=11.2, 11.2 Hz, 1H), 6.64 (d, J=16.0 Hz,

1H), 6.75 (d, J=8.2 Hz, 1H), 6.79 (d, J=7.6 Hz, 1H), 7.01 (ddd, J=

0.5, 11.3, 16.0 Hz, 1H), 7.16 ppm (t, J=8.0 Hz, 1H); ¹³C NMR

(100 MHz, CDCl₃): d=168.3, 152.3, 137.9, 132.2, 132.1, 131.1, 129.9,

129.2, 127.2, 127.0, 121.3, 117.9, 93.2, 78.1, 69.0, 62.7, 60.4, 55.5,

29.9, 25.8, 25.0, 18.4, À4.0, À4.2 ppm; IR (neat, NaCl): n˜ =3438.92

(br), 2931, 2859, 1731, 1570, 1255, 1153, 1102, 1030 cm^À1; HRMS

(ESI+) m/z calcd for C₂₆H₃₈NaO₆Si [M+Na]⁺: 497.2330, found:

497.2337.

2H); ¹³C NMR (100 MHz, CD₃OD): d=170.8, 155.3, 147.7, 142.1,

139.4, 134.5, 134.1, 132.9, 131.5, 131.2, 130.9, 130.83, 130.75, 130.5,

128.9, 128.5, 123.4, 120.3, 115.0, 78.6, 66.4, 28.6, 26.3 ppm; IR (neat,

NaCl): n˜ =3440 (br), 3060, 2950, 2854, 1730, 1640, 1457, 1115,

1070 cm^À1; HRMS (ESI+) m/z calcd for C₂₅H₂₄NaO₆S [M+Na]⁺:

475.1186, found: 475.1186.

2-((3S,4S,5E,9E)-14-((tert-Butyldimethylsilyl)oxy)-4-(methoxyme-

thoxy)-1-oxo-3,4,7,8-tetrahydro-1H-benzo[c][1]oxacyclododecin-

3-yl)acetaldehyde (47). To a solution of alcohol 20 (188 mg,

0.406 mmol) in CH₂Cl₂(4.1 mL) was added Dess–Martin periodinane

(259 mg, 0.610 mmol) as a solid. The resultant mixture was stirred

at RT for 2.5 h before it was filtered. The filtrate was concentrated

by rotary evaporation. Purification by column chromatography

(20% EtOAc in hexanes) provided 165 mg (0.0358 mmol, 88%) of

(3S,4S,5Z,7Z,9E)-14-(tert-Butyldimethylsilyloxy)-4-(methoxyme-

thoxy)-3-((E)-4-(phenylsulfonyl)but-3-enyl)-3,4-dihydro-1H-

benzo[c][1]oxacyclododecin-1-one (45). To a flask containing alco-

hol 44 (10.0 mg, 0.0210 mmol) was added anhydrous CH₂Cl₂

(0.4 mL) and molecular sieves 4 (21 mg). The mixture was cooled

to 08C, and PDC (32.0 mg, 0.0842 mmol) was added in one portion.

The cooling bath was removed and the reaction was stirred at RT

for 1.5 h. The reaction mixture was diluted with hexanes (1 mL),

and then filtered through a silica gel plug and rinsed with 40%

EtOAc in hexanes (7 mL). The combined organic layer was concen-

trated in vacuo to afford an opaque oil of the corresponding alde-

hyde (6.0 mg). The crude aldehyde was used directly in the next

step without further purification.

1

aldehyde 47 as a colorless oil: H NMR (400 MHz, CDCl₃): d=0.230

(s, 3H), 0.234 (s, 3H), 0.96 (s, 9H), 2.05–2.16 (m, 2H), 2.34–2.43 (m,

2H), 2.83 (ddd, J=17.3, 4.8, 2.1 Hz, 1H), 3.07 (ddd, J=17.3, 4.8,

2.1 Hz, 1H), 3.32 (s, 3H), 4.49–4.51 (m, 2H), 4.66 (d, J=6.7 Hz, 1H),

5.30 (dd, J=15.8, 6.3 Hz, 1H), 5.48–5.52 (m, 1H), 5.57 (dt, J=15.9,

6.2 Hz, 1H), 5.76 (dt, J=15.9, 6.2 Hz, 1H), 6.14 (d, J=15.9 Hz, 1H),

6.69 (d, J=8.2 Hz, 1H), 6.88 (d, J=7.6 Hz, 1H), 7.16 (t, J=8.0, 1H),

9.82 ppm (s, 1H).

To a solution of diethyl [(phenylsulfonyl)methyl]phosphonate 26

(6.7 mg, 0.023 mmol) in anhydrous THF (0.3 mL) was added 60%

NaH (1.0 mg, 0.026 mmol). The mixture was cooled to 08C, and

was stirred for 5 min. The aldehyde in THF (1.0 mL) was added

dropwise over 3 min. The mixture was stirred at 08C for 30 min,

and then diluted with saturated NH₄Cl (4.0 mL) and phosphate

buffer pH 7 (4.0 mL). The crude mixture was extracted with EtOAc

(34 mL). The combined organic layer was washed with brine

(5.0 mL), dried over Na₂SO₄, and concentrated in vacuo. Purification

by column chromatography (30% EtOAc in hexanes) provided

6.0 mg (0.0098 mmol, 47%) of phenylsulfone 45 as an opaque oil:

a²_D²=À66 (c=0.30, CHCl₃); ¹H NMR (400 MHz, CDCl₃): d=0.17 (s,

3H), 0.19 (s, 3H), 0.93 (s, 9H), 1.97 (m, 1H), 2.11 (m, 1H), 2.37 (m,

1H), 2.63 (m, 1H), 3.30 (s, 3H), 4.47 (d, J=6.5 Hz, 1H), 4.51 (d, J=

6.5 Hz, 1H), 4.59 (dd, J=2.9, 10.7 Hz, 1H), 5.29 (td, J=2.9, 10.4 Hz,

1H), 5.60 (dd, J=11.3, 11.3 Hz, 1H), 5.87 (dd, J=3.9, 11 Hz, 1H),

6.20 (dd, J=4.0, 11.84 Hz, 1H), 6.33 (d, J=11.3 Hz, 1H), 6.39 (d, J=

15.1 Hz, 1H), 6.64 (d, J=16.0 Hz, 1H), 6.74 (d, J=8.2 Hz, 1H), 6.79

(d, J=7.6 Hz, 1H), 6.95 (dd, J=11.5, 16.0 Hz, 1H), 7.05 (td, J=6.4,

15.1 Hz, 1H), 7.17 (t, J=8.0 Hz, 1H), 7.56 (m, 3H), 7.88 ppm (d, J=

7.2 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃): d=168.2, 152.2, 145.7,

140.6, 137.9, 133.3, 132.6, 132.2, 131.1, 130.9, 129.9, 129.4, 129.2,

127.6, 127.1, 126.4, 126.1, 121.3, 117.9, 93.1, 77.2, 68.7,55.5, 28.5,

26.4, 25.8, 18.4, À4.0, À4.1 ppm; IR (neat, NaCl): n˜ =2930, 1731,

1570, 1463, 1292, 1252, 1148, 1101, 1027 cm^À1; HRMS (ESI+) m/z

calcd for C₃₃H₄₂NaO₇SSi [M+Na]⁺: 633.2313, found: 633.2303.

(3S,4S,5E,9E)-14-((tert-Butyldimethylsilyl)oxy)-3-((E)-3-iodoallyl)-

4-(methoxymethoxy)-3,4,7,8-tetrahydro-1H-benzo[c][1]oxacyclo-

dodecin-1-one (49). To a suspension of CrCl₂(350 mg, 2.84 mmol)

in THF (1.7 mL) was added a solution of aldehyde 47 (109 mg,

0.237 mmol) and iodoform (373 mg, 0.947 mmol) in dioxane

(10.2 mL). The resultant mixture was stirred at RT for 22 h and then

quenched with brine and extracted with EtOAc. The combined or-

ganic layer was washed with brine, dried with MgSO₄, and concen-

trated by rotary evaporation. Purification by column chromatogra-

phy (10% EtOAc in hexanes) provided 120 mg (0.205 mmol, 86%)

of iodide 49 as a colorless oil (9:1 ratio of E/Z vinyl iodide isomers

by ¹H NMR): a_D²³= +96.7 (c=1.19, CHCl₃); ¹H NMR (400 MHz,

CDCl₃): d=0.237 (s, 3H), 0.244 (s, 3H), 0.98 (s, 9H), 2.12–2.21 (m,

2H), 2.32–2.42 (m, 2H), 2.52–2.59 (m, 1H), 2.70–2.78 (m, 1H), 3.41

(s, 3H), 4.40–4.42 (m, 1H), 4.58 (d, J=6.7, 1H), 4.70 (d, J=6.8 Hz,

1H), 5.04 (ddd, 8.5, 5.4, 3.1 Hz, 1H), 5.30 (dd, J=15.8, 5.6 Hz, 1H),

5.52 (dt, J=15.7, 6.1 Hz, 1H), 5.77 (dt, J=15.7, 6.1 Hz, 1H), 6.17 (d,

J=15.9 Hz, 1H), 6.25 (d, J=14.4 Hz, 1H), 6.60 (dt, J=14.4, 7.2 Hz,

1H), 6.68 (d, J=8.0 Hz, 1H), 6.86 (d, J=7.7 Hz, 1H), 7.14 ppm (t, J=

8.0 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃): d=168.0, 152.0, 140.8,

137.6, 132.2, 131.9, 130.9, 129.8, 129.6, 125.3, 118.7, 117.0, 94.9,

78.5, 76.1, 75.4, 56.2, 36.5, 30.7, 30.0, 25.7, 18.2, À4.0, À4.4 ppm; IR

(neat, NaCl): n˜ =3064, 2928, 2856, 1730, 1574, 1466, 1290, 1255,

1107, 1036, 841 cm^À1; HRMS (ESI+) m/z calcd for C₂₆H₃₇INaO₅Si

[M+Na]⁺: 607.1347, found: 607.1357.

(3S,4S,5E,9E)-14-((tert-Butyldimethylsilyl)oxy)-4-hydroxy-3-((E)-3-

iodoallyl)-3,4,7,8-tetrahydro-1H-benzo[c][1]oxacyclododecin-1-

one (51). To a flask containing iodide 49 (117 mg, 0.200 mmol) was

added iPrOH (4 mL), and CBr₄(266 mg, 0.801 mmol) in one portion.

The mixture was heated at 758C for 2 h, cooled to RT and then

concentrated by rotary evaporation. Purification by column chro-

matography (15% EtOAc in hexanes) provided 93.1 mg

(0.172 mmol, 86%) of alcohol 51 as a colorless oil: a²_D²= +37.6 (c=

(3S,4S,5Z,7Z,9E)-4,14-Dihydroxy-3-((E)-4-(phenylsulfonyl)but-3-

enyl)-3,4-dihydro-1H-benzo[c][1]oxacyclododecin-1-one (46). To

a flask containing phenylsulfone 45 (6.0 mg, 0.0098 mmol) was

added 4m HCl in MeOH (0.7 mL). The mixture was stirred at RT for

211 h, and then concentrated in vacuo. Purification by column

chromatography (60% EtOAc in hexanes) provided 3.0 mg (68%)

of the desired analogue 46 as a colorless oil: a²_D⁰=À120 (c=0.15,

1

CHCl₃); H NMR (400 MHz, CD₃OD): d=1.87 (m, 1H), 2.03 (m, 1H),

1.22, CHCl₃); H NMR (400 MHz, CDCl₃): d=0.24 (3H), 0.25 (s, 3H),

2.38 (m, 1H), 2.48 (m, 1H), 4.48 (dd, J=3.6, 10.5 Hz, 1H), 5.07 (td,

J=2.7, 11.8 Hz, 1H), 5.72 (dd, J=11.3, 11.3 Hz, 1H), 5.81 (dd, J=4.0,

11.0 Hz, 1H), 5.96 (dd, J=4.0, 12.0 Hz, 1H), 6.23 (dd, J=11.4,

11.4 Hz, 1H), 6.53 (d, J=15.9 Hz, 1H), 6.61 (t, J=7.1 Hz, 3H), 6.88

(dd, J=11.5, 15.8 Hz, 1H), 6.95 (ddd, J=6.1, 8.5, 14.8 Hz, 1H), 7.05

(t, J=7.9 Hz, 1H), 7.51 (m, J=5.0 Hz, 3H), 7.77 ppm (m, J=2.2 Hz,

0.98 (s, 9H), 1.73 (br, 1H), 2.23–2.38 (m, 4H), 2.43–2.50 (m, 1H),

2.69–2.77 (m, 1H), 4.36 (s, 1H), 5.13 (ddd, J=9.9, 4.9, 2.0 Hz, 1H),

5.47 (s, 2H), 5.75 (dt, J=15.8, 5.8 Hz, 1H), 6.21 (d, J=16.1 Hz, 1H),

6.28 (d, J=14.4 Hz, 1H), 6.57 (ddd, J=15.0, 8.5, 6.8 Hz, 1H), 6.70 (d,

J=8.3 Hz, 1H), 6.87 (d, J=7.7 Hz, 1H), 7.16 ppm (t, J=8.0 Hz, 1H);

¹³C NMR (100 MHz, CDCl₃): d=167.6, 152.2, 140.4, 137.3, 132.9,

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132.7, 130.2, 129.9, 129.2, 125.2, 118.8, 117.0, 79.1, 75.5, 70.8, 36.9,

30.7, 29.8, 25.7, 18.2, À4.0, À4.4 ppm; IR (neat, NaCl): n˜ =3326 (br),

3435, 2955, 2929, 2856, 1726, 1645, 1573, 1466, 1253, 1106, 840,

783 cm^À1; HRMS (ESI+) m/z calcd for C₂₄H₃₃INaO₄Si [M+Na]⁺:

563.1085, found: 563.1085.

3-((3S,4S,5E,9E)-14-((tert-Butyldimethylsilyl)oxy)-4-(methoxyme-

thoxy)-1-oxo-3,4,7,8-tetrahydro-1H-benzo[c][1]oxacyclododecin-

3-yl)propanal (48). To

a solution of alcohol 21 (28.4 mg,

0.0596 mmol) in CH₂Cl₂(1.2 mL) was added Dess–Martin periodi-

nane (37.9 mg, 0.0894 mmol) as a solid. The resultant mixture was

stirred at RT for 3 h before it was filtered. The filtrate was concen-

trated by rotary evaporation. Purification by column chromatogra-

phy (20% EtOAc in hexanes) provided 20.3 mg (0.0428 mmol,

72%) of aldehyde 48 as a colorless oil: a²_D¹= +150 (c=1.0, CHCl₃);

¹H NMR (400 MHz, CDCl₃): d=0.23 (s, 3H), 0.24 (s, 3H), 0.98 (s, 9H),

2.13–2.23 (m, 4H), 2.30–2.41 (m, 2H), 2.63–2.68 (m, 2H), 3.39 (s,

3H), 4.41–4.43 (m, 1H), 4.58 (d, J=6.8 Hz, 1H), 4.69 (d, J=6.8 Hz,

1H), 5.16 (ddd, J=7.8, 5.8, 3.2 Hz, 1H), 5.32 (dd, J=15.6, 5.3 Hz,

1H), 5.48–5.55 (m, 1H), 5.76 (dt, J=15.9, 6.2 Hz, 1H), 6.23 (d, J=

15.9 Hz, 1H), 6.70 (d, J=8.2 Hz, 1H), 6.86 (d, J=7.7 Hz, 1H), 7.14 (t,

J=7.9 Hz, 1H), 9.80 ppm (s, 1H).

(3S,4S,5E,9E)-4,14-Bis((tert-butyldimethylsilyl)oxy)-3-((E)-3-io-

doallyl)-3,4,7,8-tetrahydro-1H-benzo[c][1]oxacyclododecin-1-one

(53). A solution of alcohol 51 (76.9 mg, 0.142 mmol) and 2,6-luti-

dine (33 mL, 0.28 mmol) in CH₂Cl₂(1.4 mL) was cool to À788C and

TBSOTf (65 mL, 0.28 mmol) was added. The solution was stirred at

À788C for 3 h and then left at 08C overnight. EtOAc was added

and the organic mixture was washed with saturated NaHCO₃solu-

tion. The aqueous layer was re-extracted with EtOAc. The com-

bined organic layer was washed with brine, dried with MgSO₄, and

concentrated by rotary evaporation. Purification by column chro-

matography (5% EtOAc in hexanes) provided 72.3 mg (0.110 mmol,

78%) of iodide 53 as a colorless oil: a²_D²= +79.8 (c=1.02, CHCl₃);

¹H NMR (400 MHz, CDCl₃): d=0.01 (s, 3H), 0.06 (s, 3H), 0.24 (s, 6H),

0.88 (s, 9H), 0.98 (s, 9H), 1.91–2.21 (m, 2H), 2.25–2.41 (m, 2H),

2.43–2.59 (m, 1H), 2.61–2.74 (m, 1H), 4.46 (dd, J=6.6, 3.7 Hz, 1H),

4.84 (ddd, J=7.4, 6.2, 3.7 Hz, 1H), 5.32 (dd, J=15.7, 6.7 Hz, 1H),

5.39–5.48 (m, 1H), 5.69–5.76 (m, 1H), 6.13 (d, J=15.8 Hz, 1H), 6.18

(d, J=14.5 Hz, 1H), 6.54 (dt, J=14.6, 7.3 Hz, 1H), 6.71 (d, J=8.2 Hz,

1H), 6.88 (d, J=7.5 Hz, 1H), 7.17 ppm (t, J=7.9 Hz, 1H); ¹³C NMR

(100 MHz, CDCl₃): d=168.3, 151.8, 141.6, 137.9, 133.3, 132.1, 131.3,

130.4, 129.8, 125.8, 118.9, 117.3, 78.4, 77.8, 72.6, 36.0, 30.9, 30.4,

25.9, 25.8, 18.2, 18.1, À3.8, À4.1, À4.3, À4.9 ppm.

(3S,4S,5E,9E)-14-((tert-Butyldimethylsilyl)oxy)-3-((E)-4-iodobut-3-

en-1-yl)-4-(methoxymethoxy)-3,4,7,8-tetrahydro-1H-benzo[c]

[1]oxacyclododecin-1-one (50). To a suspension of CrCl₂(114 mg,

0.924 mmol) in THF (0.55 mL) was added a solution of aldehyde 48

(36.7 mg, 0.0770 mmol) and iodoform (121 mg, 0.308 mmol) in di-

oxane (3.3 mL). The resultant mixture was stirred at RT for 23 h and

then quenched with brine and extracted with EtOAc. The com-

bined organic layer was washed with brine, dried with MgSO₄, and

concentrated by rotary evaporation. Purification by column chro-

matography (10% EtOAc in hexanes) provided 38.9 mg

(0.0650 mmol, 84%) of iodide 50 as a colorless oil (9:1 ratio of E/Z

vinyl iodide isomers by ¹H NMR): a_D²²= +110 (c=1.0, CHCl₃);

¹H NMR (400 MHz, CDCl₃): d=0.22 (s, 3H), 0.23 (s, 3H), 0.97 (s, 9H),

1.89–2.00 (m, 2H), 2.13–2.42 (m, 6H), 3.39 (s, 3H), 4.38–4.40 (m,

1H), 4.57 (d, J=6.8 Hz, 1H), 4.69 (d, J=6.8 Hz, 1H), 5.14 (td, J=6.9,

3.1 Hz, 1H), 5.32 (dd, J=15.7, 5.1 Hz, 1H), 5.46–5.53 (m, 1H), 5.77

(dt, J=15.8, 6.1 Hz, 1H), 6.08 (d, J=14.4 Hz, 1H), 6.24 (d, J=

15.7 Hz, 1H), 6.55 (dt, J=14.1, 6.9 Hz, 1H), 6.68 (d, J=8.1 Hz, 1H),

6.85 (d, J=7.6 Hz, 1H), 7.13 ppm (t, J=8.0 Hz, 1H); ¹³C NMR

(100 MHz, CDCl₃): d=168.1, 152.1, 145.3, 137.5, 132.4, 132.2, 130.7,

129.7, 128.9, 125.5, 118.9, 117.1, 94.9, 76.2, 76.0, 75.2, 56.2, 32.2,

30.5, 30.1, 29.0, 25.7, 18.3, À4.1, À4.3 ppm; IR (neat, NaCl): n˜ =

3065, 2929, 2857, 1728, 1573, 1466, 1032, 841 cm^À1; HRMS (ESI+)

m/z calcd for C₂₇H₃₉INaO₅Si [M+Na]⁺: 621.1504, found: 621.1509.

(2Z,4E)-N-((E)-3-((3S,4S,5E,9E)-4,14-Dihydroxy-1-oxo-3,4,7,8-tetra-

hydro-1H-benzo[c][1]oxacyclododecin-3-yl)prop-1-en-1-yl)-4-(me-

thoxyimino)but-2-enamide (55). To a flask containing iodide 53

(71.4 mg, 0.109 mmol), amide 57 (69.8 mg, 0.545 mmol), CuI

(41.5 mg, 0.218 mmol) and Cs₂CO₃(178 mg, 0.545 mmol) was

charged dimethylacetamide (DMA; 11 mL). The resultant mixture

was degassed under high vacuum for 5 min before N,N’-dimethyle-

thylenediamine (DMEDA; 59 mL, 0.55 mmol) was added. The reac-

tion was stirred at RT for 24 h and then H₂O was added. The crude

mixture was extracted with EtOAc. The combined organic layer

was washed with brine, dried over MgSO₄, and concentrated by

rotary evaporation. The crude bis-TBS enamide was directly used in

the next step without further purification.

(3S,4S,5E,9E)-14-((tert-Butyldimethylsilyl)oxy)-4-hydroxy-3-((E)-4-

iodobut-3-en-1-yl)-3,4,7,8-tetrahydro-1H-benzo[c][1]oxacyclodo-

The crude bis-TBS enamide was dissolved in THF (1 mL) and 5m

HF·Py solution (HF·Py (70% HF, Aldrich): pyridine/THF=1:2:4.7,

1.3 mL, 6.5 mmol) was added. The reaction was stirred for 48 h and

quenched with phosphate (pH 7) buffer. The aqueous layer was ex-

tracted with EtOAc. The organic extracts were washed with brine,

dried over MgSO₄, and concentrated by rotary evaporation. Purifi-

cation by column chromatography (60% EtOAc in hexanes) provid-

ed 18.6 mg (0.0436 mmol, 40%) of analogue 55 as a white solid:

decin-1-one (52). To

a flask containing iodide 50 (38.9 mg,

0.0650 mmol) was added iPrOH (1.3 mL), and CBr₄(86.2 mg,

0.260 mmol) in one portion. The mixture was heated at 758C for

2 h, cooled to RT and then concentrated by rotary evaporation. Pu-

rification by column chromatography (15% EtOAc in hexanes) pro-

vided 34.5 mg (0.0622 mmol, 96%) of alcohol 52 as a colorless oil:

1

a²_D¹= +31 (c=0.50, CHCl₃); H NMR (400 MHz, CDCl₃): d=0.227 (s,

1

a²_D¹=À45.4 (c=0.372, CHCl₃); H NMR (400 MHz, [D₆]acetone): d=

3H), 0.233 (s, 3H), 0.97 (s, 9H), 1.65 (d, J=9.7 Hz, 1H), 1.86–1.98

(m, 2H), 2.13–2.41 (m, 6H), 4.31 (d, J=8.8 Hz, 1H), 5.19 (td, J=7.1,

2.0 Hz, 1H), 5.43–5.55 (m, 2H), 5.72–5.79 (m, 1H), 6.08 (d, J=

14.4 Hz, 1H), 6.26 (d, J=15.6 Hz, 1H), 6.54 (dt, J=14.1, 7.0 Hz, 1H),

6.72 (d, J=8.2 Hz, 1H), 6.86 (d, J=7.7 Hz, 1H), 7.16 ppm (t, J=

8.0 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃): d=167.8, 152.3, 145.1,

137.3, 133.1, 132.6, 130.1, 129.8, 129.4, 125.4, 119.0, 117.3, 76.3,

75.4, 72.1, 32.2, 30.6, 29.9, 29.4, 25.8, 18.4, À4.1, À4.2 ppm; IR

(neat, NaCl): n˜ =3326 (br), 3065, 2954, 2928, 2856, 1730, 1572,

1465, 1106, 840 cm^À1; HRMS (ESI+) m/z calcd for C₂₅H₃₅INaO₄Si

[M+Na]⁺: 577.1242, found: 577.1246.

2.20–2.42 (m, 4H), 2.50–2.60 (m, 1H), 2.67–2.74 (m, 1H), 3.87 (s,

3H), 4.20 (d, J=6.4 Hz, 1H), 4.38 (s, 1H), 5.17 (ddd, J=7.7, 5.9,

3.2 Hz, 1H), 5.37 (dt, J=14.4, 7.2 Hz, 1H), 5.51–5.64 (m, 2H), 5.67–

5.76 (m, 1H), 6.12 (d, J=11.5 Hz, 1H), 6.47 (t, J=10.8 Hz, 1H), 6.60

(d, J=15.8 Hz, 1H), 6.79 (d, J=8.2 Hz, 1H), 6.81 (d, J=7.4 Hz, 1H),

6.90 (dd, J=14.4, 10.3 Hz, 1H), 7.27 (t, J=8.0 Hz, 1H), 9.08 (d, J=

10.2 Hz, 1H), 9.33 (d, J=10.4 Hz, 1H), 9.90 ppm (s, 1H); ¹³C NMR

(100 MHz, [D₆]acetone): d=170.4, 162.6, 159.4, 148.5, 141.1, 134.9,

134.2, 133.3, 132.5, 132.1, 131.5, 126.5, 126.1, 119.5, 117.0, 115.9,

109.8, 78.5, 72.5, 62.5, 32.5, 31.4, 30.7 ppm; IR (neat, NaCl): n˜ =3306

(br), 3419, 2928, 2852, 1652, 1526, 1465, 1259, 1118, 1043, 966,

819 cm^À1; HRMS (ESI+) m/z calcd for C₂₃H₂₆N₂NaO₆[M+Na]⁺:

449.1683, found: 449.1686.

(3S,4S,5E,9E)-4,14-Bis((tert-butyldimethylsilyl)oxy)-3-((E)-4-iodo-

but-3-en-1-yl)-3,4,7,8-tetrahydro-1H-benzo[c][1]oxacyclododecin-

ChemMedChem 2016, 11, 1600 – 1616

www.chemmedchem.org

1614 ꢀ 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Papers

1-one (54). A solution of alcohol 52 (34.5 mg, 0.0622 mmol) and

2,6-lutidine (14 mL, 0.12 mmol) in CH₂Cl₂(0.6 mL) was cool to

À788C and TBSOTf (29 mL, 0.12 mmol) was added. The solution

was stirred at À788C for 3 h and then left at 08C overnight. EtOAc

was added and the organic mixture was washed with saturated

NaHCO₃solution. The aqueous layer was re-extracted with EtOAc.

The combined organic layer was washed with brine, dried with

MgSO₄, and concentrated by rotary evaporation. Purification by

column chromatography (5% EtOAc in hexanes) provided 35.1 mg

(0.0525 mmol, 84%) of iodide 54 as a colorless oil: a²_D¹= +75 (c=

grown in normal RPMI 1640 culture medium containing 10% fetal

bovine serum. Human promyelocytic leukemia HL-60 cells were ob-

tained from ATCC and grown in suspension in IMDM (ATCC 30-

2005) containing 20% fetal bovine serum. Following growth in ex-

ponential-phase maintenance culture, adherent cells were dissoci-

ated with 0.25% trypsin, and then all cells were harvested by cen-

trifugation at 125 g for 5 min, the supernatant was removed, and

the cells were resuspended in fresh culture medium. The cell densi-

ty for all lines was adjusted to 110⁵cells per mL and dispensed

in triplicate on 96-well plates in 50 mL volumes. After incubation

overnight at 378C under 5% CO₂, 50 mL of culture medium con-

taining various concentrations of the test compounds were added.

Paclitaxel and oximidine II were used as positive controls. After

48 h incubation, the relative cell viability in each well was deter-

mined by using the AlamarBlue Assay Kit. Fluorescence intensity

(l_excitation=530 nm, l_emission=590 nm) was measured on a Spectra-

Max plate reader (Molecular Devices). The IC₅₀value of each com-

pound was determined by fitting the relative viability of the cells

to the drug concentration using Prism version 6 (GraphPad).

1

0.50, CHCl₃); H NMR (400 MHz, CDCl₃): d=0.02 (s, 3H), 0.06 (s, 3H),

0.22 (s, 3H), 0.23 (s, 3H), 0.89 (s, 9H), 0.97 (s, 9H), 1.80–1.95 (m,

2H), 2.05–2.37 (m, 6H), 4.43 (dd, J=5.5, 4.1, 1H), 4.95 (ddd, J=7.8,

5.5, 3.6 Hz, 1H), 5.36 (dd, J=15.6, 5.6 Hz, 1H), 5.43 (dt, J=15.7,

6.1 Hz, 1H), 5.73 (dt, J=15.9, 6.5 Hz, 1H), 6.04 (d, J=14.4 Hz, 1H),

6.22 (d, J=16.1 Hz, 1H), 6.54 (dt, J=14.1, 6.9 Hz, 1H), 6.71 (d, J=

8.2 Hz, 1H), 6.86 (d, J=7.7 Hz, 1H), 7.16 ppm (t, J=8.0 Hz, 1H);

¹³C NMR (100 MHz, CDCl₃): d=168.2, 151.9, 145.6, 137.8, 132.28,

132.26, 131.1, 131.0, 129.6, 126.0, 119.1, 117.3, 77.9, 75.0, 73.3, 32.5,

30.6, 30.4, 28.5, 25.9, 25.8, 18.3, 18.2, À4.0, À4.1, À4.2, À4.9 ppm;

IR (neat, NaCl): n˜ =3066, 2955, 2929, 2857, 1728, 1465, 1107, 840,

779 cm^À1; HRMS (ESI+) m/z calcd for C₃₁H₄₉INaO₄Si₂[M+Na]⁺:

691.2106, found: 691.2120.

Acknowledgements

These studies were supported by the University of Minnesota

through the Vince and McKnight Endowed Chairs. C.M.S. ac-

knowledges a pre-doctoral fellowship from the US National Insti-

tutes of Health (NIH) (NIH T32 GM 008545) while at the University

of Kansas. K.K. thanks the Royal Thai Government for fellowship

support. The cytotoxicity assays were performed by Defeng Tian

in the Institute for Therapeutics Discovery and Development at

the University of Minnesota. Special acknowledgements to Rebec-

ca A. Cuellar and Sara Coulup for their help in preparing the

spectra, and Dr. Subhashree Francis for LC–MS analyses.

(2Z,4E)-N-((E)-4-((3S,4S,5E,9E)-4,14-Dihydroxy-1-oxo-3,4,7,8-tetra-

hydro-1H-benzo[c][1]oxacyclododecin-3-yl)but-1-en-1-yl)-4-(me-

thoxyimino)but-2-enamide (56). To a flask containing iodide 54

(18.6 mg, 0.0278 mmol), amide 57 (17.8 mg, 0.139 mmol), CuI

(10.6 mg, 0.0556 mmol) and Cs₂CO₃(45.3 mg, 0.139 mmol) was

charged DMA (2.8 mL). The resultant mixture was degassed under

high vacuum for 5 min before DMEDA (15 mL, 0.14 mmol) was

added. The reaction was stirred at RT for 24 h and then H₂O was

added. The crude mixture was extracted with EtOAc. The com-

bined organic layer was washed with brine, dried over MgSO₄, and

concentrated by rotary evaporation. The crude bis-TBS enamide

was directly used in the next step without further purification.

The crude bis-TBS enamide was dissolved in THF (0.28 mL) and 5m

HF·Py solution (HF·Py (70% HF, Aldrich): pyridine/THF=1:2:4.7,

0.17 mL, 0.85 mmol) was added. The reaction was stirred for 24 h

and quenched with phosphate (pH 7) buffer. The aqueous layer

was extracted with EtOAc. The organic extracts were washed with

brine, dried over MgSO₄, and concentrated by rotary evaporation.

Purification by column chromatography (60% EtOAc in hexanes)

provided 3.7 mg (0.0084 mmol, 30%) of analogue 56 as a white

solid: a²_D²=À62 (c=0.050, CHCl₃); ¹H NMR (400 MHz, CDCl₃): d=

1.76 (d, J=5.9 Hz, 1H), 1.86 (dq, J=14.6, 7.9 Hz, 1H), 2.03–2.11 (m,

1H), 2.14–2.28 (m, 4H), 2.36–2.48 (m, 2H), 3.94 (s, 3H), 4.36 (q, J=

5.1 Hz, 1H), 5.21 (ddd, J=7.6, 5.4, 3.9 Hz, 1H), 5.28 (dt, J=14.1,

7.0 Hz, 1H), 5.49 (dd, J=15.7, 5.7 Hz, 1H), 5.57–5.66 (m, 2H), 5.84

(dd, J=11.5, 1.1 Hz, 1H), 6.50 (dd, J=11.4, 10.4 Hz, 1H), 6.65 (d, J=

15.7 Hz, 1H), 6.77–6.88 (m, 3H), 7.05–7.08 (m, 1H), 7.31 (t, J=

7.9 Hz, 1H), 9.01 (dd, J=10.3, 1.0 Hz, 1H), 10.49 ppm (s, 1H);

¹³C NMR (100 MHz, CDCl₃): d=170.8, 161.6, 161.2, 147.6, 141.6,

135.4, 135.0, 134.0, 129.7, 129.5, 125.8, 124.2, 122.9, 119.9, 116.2,

113.1, 112.1, 76.9, 72.5, 62.4, 32.4, 29.8, 29.0, 26.2 ppm; IR (neat,

NaCl): n˜ =3306 (br), 3044, 2954, 2928, 1652, 1603, 1450, 1217, 1122,

Keywords: antitumor agents

cytotoxicity · natural products · oximidines

· benzolactone enamides ·

[1] K. L. Erickson, J. A. Beutler, J. H. Cardellina II, M. R. Boyd, J. Org. Chem.

1997 , 62 , 818 8 –8 192.

[2] K. L. Erickson, J. A. Beutler, J. H. Cardellina II, M. R. Boyd, J. Org. Chem.

2001 , 66 , 1532.

[3] D. L. Galinis, T. C. McKee, L. K. Pannell, J. H. Cardellina II, M. R. Boyd, J.

Org. Chem. 1997 , 62 , 896 8 –8 969.

[4] B. Kunze, R. Jansen, F. Sasse, G. Hofle, H. Reichenbach, J. Antibiot. 1998 ,

51 , 107 5 –1 080.

[5] K. A. Dekker, R. J. Aiello, H. Hirai, T. Inagaki, T. Sakakibara, Y. Suzuki, J. F.

Thompson, Y. Yamauchi, N. Kojima, J. Antibiot. 1998 , 51 , 1 4 –2 0.

[6] Y. Hayakawa, T. Tomikawa, K. Shin-ya, N. Arao, K. Nagai, K.-i. Suzuki, J.

Antibiot. 2003 , 56 , 89 9 –9 04.

[7] Y. Hayakawa, T. Tomikawa, K. Shin-ya, N. Arao, K. Nagai, K.-i. Suzuki, K.

Furihata, J. Antibiot. 2003 , 56 , 90 5 –9 08.

[8] J. W. Kim, K. Shin-ya, K. Furihata, Y. Hayakawa, H. Seto, J. Org. Chem.

1999 , 64 , 15 3 –1 55.

[9] M. R. Boyd, C. Farina, P. Belfiore, S. Gagliardi, J. W. Kim, Y. Hayakawa, J. A.

Beutler, T. C. McKee, B. J. Bowman, E. J. Bowman, J. Pharmacol. Exp. Ther.

2001, 297, 114–120.

1045, 965, 838, 821, 778 cm^À1

; HRMS (ESI+) m/z calcd for

C₂₄H₂₈N₂NaO₆[M+Na]⁺: 463.1840, found: 463.1845.

[10] M. R. Boyd, K. D. Paull, Drug Dev. Res. 1995 , 34 , 9 1 –1 09.

[11] C. Lafourcade, K. Sobo, S. Kieffer-Jaquinod, J. Garin, F. G. van der Goot,

PLoS One 2008 , 3 , e2758.

[12] T. Nishi, M. Forgac, Nat. Rev. Mol. Cell Biol. 2002 , 3 , 9 4 –1 03.

[13] M. Forgac, Nat. Rev. Mol. Cell Biol. 2007 , 8 , 91 7 –9 29.

[14] H. Wieczorek, D. Brown, S. Grinstein, J. Ehrenfeld, W. R. Harvey, BioEssays

1999 , 21 , 63 7 –6 48.

Cytotoxicity assays

The adherent human melanoma SK-Mel-5 and SK-Mel-28 and

breast cancer MCF-7 cell lines were obtained from the NCI and

[15] C. Farina, S. Gagliardi, Drug Discovery Today 1999 , 4 , 16 3 –1 72.

ChemMedChem 2016, 11, 1600 – 1616

www.chemmedchem.org

1615 ꢀ 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Papers

[16] A. Hinton, S. Bond, M. Forgac, Pfluegers Arch. 2009 , 457 , 58 9 –5 98.

[17] M. PØrez-Sayµns, J. M. Somoza-Martín, F. Barros-Angueira, J. M. Gµndar-

a Rey, A. García-García, Cancer Treat. Rev. 2009 , 35 , 70 7 –7 13.

[18] L. Yet, Chem. Rev. 2003 , 103 , 428 3 –4 306.

[35] J. T. Palmer, D. Rasnick, J. L. Klaus, D. Bromme, J. Med. Chem. 1995 , 38 ,

319 3 –3 196.

[36] S. Lebreton, X.-S. Xie, D. Ferguson, J. K. De Brabander, Tetrahedron 2004 ,

60 , 963 5 –9 647.

[19] M. E. Maier, Org. Biomol. Chem. 2015 , 13 , 530 2 –5 343.

[20] Y. Sugimoto, K. Konoki, M. Murata, M. Matsushita, H. Kanazawa, T. Oishi,

J. Med. Chem. 2009 , 52 , 79 8 –8 06.

[21] D. Balan, C. J. Burns, N. G. Fisk, H. Huegel, D. C. S. Huang, D. Segal, C.

White, J. Wagler, M. A. Rizzacasa, Org. Biomol. Chem. 2012 , 10 , 814 7 –

8153.

[22] X.-S. Xie, D. Padron, X. Liao, J. Wang, M. G. Roth, J. K. De Brabander, J.

Biol. Chem. 2004 , 279 , 1975 5 –1 9763.

[23] S. Lebreton, J. Jaunbergs, M. G. Roth, D. A. Ferguson, J. K. De Brabander,

Bioorg. Med. Chem. Lett. 2008 , 18 , 587 9 –5 883.

[37] K. C. Nicolaou, W. Kim David, R. Baati, A. O’Brate, P. Giannakakou, Chem.

Eur. J. 2003 , 9 , 617 7 –6 191.

[38] G. Klebe, U. Abraham, T. Mietzner, J. Med. Chem. 1994 , 37 , 413 0 –4 146.

[39] M. Clark, R. D. Cramer III, N. Van Opdenbosch, J. Comput. Chem. 1989 ,

10 , 98 2 –1 012.

[40] J. Gasteiger, M. Marsili, Tetrahedron 1980 , 36 , 321 9 –3 222.

[41] Dragon (version 5): software for the calculation of molecular descriptors,

R. Todeschini, V. Consonni, A. Mauri, M. Pavan, Talete SRL, Milan (Italy),

2005: www.talete.mi.it/products/dragon_description.htm (accessed May

2016).

[24] L. Jundt, H. Steinmetz, P. Luger, M. Weber, B. Kunze, H. Reichenbach, G.

Hoefle, Eur. J. Org. Chem. 2006 , 503 6 –5 044.

[42] H. C. Brown, P. K. Jadhav, K. S. Bhat, J. Am. Chem. Soc. 1988 , 110 , 153 5 –

1538.

[25] B. Kunze, H. Steinmetz, G. Hoefle, M. Huss, H. Wieczorek, H. Reichen-

bach, J. Antibiot. 2006 , 59 , 66 4 –6 68.

[26] T. Haack, K. Haack, W. E. Diederich, B. Blackman, S. Roy, S. Pusuluri, G. I.

Georg, J. Org. Chem. 2005 , 70 , 759 2 –7 604.

[27] K. Yang, B. Blackman, W. Diederich, P. T. Flaherty, C. J. Mossman, S. Roy,

Y. M. Ahn, G. I. Georg, J. Org. Chem. 2003 , 68 , 1003 0 –1 0039.

[28] C. M. Schneider, K. Khownium, W. Li, J. T. Spletstoser, T. Haack, G. I.

Georg, Angew. Chem. Int. Ed. 2011 , 50 , 785 5 –7 857; Angew. Chem. 2011 ,

123 , 800 1 –8 003, S7855/1–S7855/67.

[43] A. Darwish, A. Lang, T. Kim, J. M. Chong, Org. Lett. 2008 , 10 , 86 1 –8 64.

[44] X. Wang, E. J. Bowman, B. J. Bowman, J. A. Porco, Jr., Angew. Chem. Int.

Ed. 2004 , 43 , 360 1 –3 605; Angew. Chem. 2004 , 116 , 368 5 –3 689.

[45] A. Bhattacharjee, J. K. De Brabander, Tetrahedron Lett. 2000 , 41 , 806 9 –

8073.

[46] VEGA ZZ (version 3.05), molecular modeling toolkit: nova.disfarm.uni-

mi.it/cms/index.ph p ?Software_project s :VEGA_ZZ (accessed May 2016).

[47] PyMOL Molecular Graphics System (version 1.7.0.1): sourceforge.net/

projects/pymol/ (accessed May 2016).

[29] B. Blackman, G. I. Georg, G. H. Lushington, Lett. Drug Des. Discovery

2006, 3, 104–107.

[30] X. Wang, J. A. Porco, Jr., J. Am. Chem. Soc. 2003 , 125 , 604 0 –6 041.

[31] A. Schoenberg, I. Bartoletti, R. F. Heck, J. Org. Chem. 1974 , 39 , 331 8 –

3326.

[48] A. Fürstner, I. Konetzki, Tetrahedron 1996 , 52 , 1507 1 –1 5078.

[49] Y. Hayashi, H. Yamaguchi, M. Toyoshima, K. Okado, T. Toyo, M. Shoji,

Org. Lett. 2008 , 10 , 140 5 –1 408

[32] M. A. Walker, T e trahedron Lett. 1994 , 35 , 66 5 –6 68.

[33] M. A. Walker, J. Org. Chem. 1995 , 60 , 535 2 –5 355.

[34] Y. Wu, X. Liao, R. Wang, X.-S. Xie, J. K. De Brabander, J. Am. Chem. Soc.

2002 , 124 , 324 5 –3 253.

Received: January 15, 2016

Revised: April 8, 2016

Published online on May 31, 2016

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1616 ꢀ 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Article Doi

Enantiospecific Synthesis and Cytotoxicity Evaluation of Oximidine II Analogues

DOI: 10.1002/cmdc.201600024

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