Ring-closing metathesis: A powerful tool for the synthesis of simplified salicylihalamide-based V-ATPase inhibitors

Article abstract of DOI:10.1016/j.tet.2004.06.146

Based on our synthetic strategy developed for the total synthesis of the macrocyclic salicylate natural product salicylihalamide, we describe herein the synthesis of a series of simplified salicylihalamide-based analogs. Alterations in the aromatic fragment, the macrolactone scaffold and side-chain were evaluated for in vitro inhibition of V-ATPase activity and human tumor cell growth. Graphical abstract.

Full text of DOI:10.1016/j.tet.2004.06.146

Tetrahedron 60 (2004) 9635–9647
Ring-closing metathesis: a powerful tool for the synthesis of
simplified salicylihalamide-based V-ATPase inhibitors
Sylvain Lebreton,a Xiao-Song Xie,b Deborah Fergusonc and Jef K. De Brabandera,
*
aDepartment of Biochemistry, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd.,
Dallas, TX 75390-9038, USA
bEugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center at Dallas,
Dallas, TX 75390, USA
cReata Discovery, Inc., Richardson, TX 75081, USA
Received 4 May 2004; revised 7 June 2004; accepted 9 June 2004
Available online 21 August 2004
Abstract—Based on our synthetic strategy developed for the total synthesis of the macrocyclic salicylate natural product salicylihalamide,
we describe herein the synthesis of a series of simplified salicylihalamide-based analogs. Alterations in the aromatic fragment, the
macrolactone scaffold and side-chain were evaluated for in vitro inhibition of V-ATPase activity and human tumor cell growth.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
The prospect to target specific subsets of V-ATPases with
compounds potentially resulting from a chemical program
around these structurally novel macrocyclic salicylates has
prompted intense research activities by us, as well as
others.9,10 Based on a synthetic blueprint that resulted in the
total synthesis of salicylihalamide by our group, we have
prepared and evaluated numerous side-chain modified
derivatives for structure-function studies.11 Biochemical
studies have further revealed that salicylihalamides bind to
the trans-membranous proton-translocating domain (Vo) of
the V-ATPase through a mechanism distinct from bafilo-
mycin.12 They are conditionally irreversible inhibitors, and
experimental information gathered with carefully crafted
side-chain modifications has led us to suggest a covalent
binding mechanism initiated by enamine protonation and
capture of a transient N-acyl iminium by an active site lysine
residue, followed by a fragmentation to a covalent protein/
small molecule imine complex with loss of the side chain
(Eq. (1)).12
The past seven years has witnessed the disclosure of a
variety of marine and terrestrial metabolites grouped into a
common structural family by virtue of a signature N-acyl-
enamine appended macrocyclic salicylate–salicylihalamide
A (1) the first to be isolated (Fig. 1).1–5 These compounds
have been attributed growth-inhibitory activities against
cultured human tumor cells and oncogene-transformed cell-
lines through mechanisms distinct from standard clinical
antitumor agents.1–3,5 Boyd and co-workers subsequently
found that the NCI 60 cell-line profiles of salicylihalamides,
lobatamides, oximidines and apicularens gave consistently
high correlations with the historical database profiles of
bafilomycin and concanamycin, prototypical vacuolar
(HC)-ATPase (V-ATPase) inhibitors.6 Biochemical studies
have confirmed the ability of these compounds to inhibit
mammalian V-ATPase activity, but unlike any previously
known inhibitor of this enzyme, not those of yeast or other
fungi.6 V-ATPases are potential therapeutic targets for the
development of pharmacological agents to treat a variety of
diseases, notably osteoporosis and cancer.7,8 Despite
substantial efforts, the lack of tissue specificity, structural
complexity and chemical stability associated with previous
inhibitors has hampered progress towards the development
of clinically useful compounds.8
(1)
Total synthesis has been crucial to advance our knowledge
of salicylihalamide’s molecular pharmacology and define
the structure-function boundaries related to the side chain.13
The aspiration to advance a synthetic salicylihalamide-like
Keywords: Olefin-metathesis; Macrocyclic; Natural product; Vacuolar
ATPase; Cancer.
* Corresponding author. Tel.: C1-214-648-7808; fax: C1-214-648-0320;
e-mail: jdebra@biochem.swmed.edu
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.06.146

9636
S. Lebreton et al. / Tetrahedron 60 (2004) 9635–9647
Figure 1.
small molecule through preclinical development prompted
us to investigate simplified macrolactone scaffolds that
could be prepared by shorter, scalable routes. Initial results
related to this goal are detailed in this manuscript.
into the macrocyclic scaffolds. The acyclic fragment 7 was
prepared in three steps from aldehyde 6,11 an intermediate
for the synthesis of salicylihalamide A, via reduction,
allylation and silyl deprotection. Treatment of alcohol 7
with the respective carboxylic acids 1–5 under Mitsunobu
reaction conditions cleanly afforded the bis-olefins 8a,c–f in
76–99% yields.16 The phenol in salicylate ester 8a was
protected as the acetate 8b prior to the subsequent ring-
closing olefin metathesis.
2. Results and discussion
Our scaffold selection and synthetic approach are depicted
in Figure 2. Smith and co-workers have shown that deletion
of the C12-Me and C13-OH substituents had no dramatic
impact on activity at the cell-based level.14 A direct
consequence of our RCM approach, the endocyclic double
bond was perceived as a beneficial conformation-restricting
unit. Incorporation of the cyclic ether derives from synthetic
considerations. Influenced by our earlier work,11 a con-
vergent combination of an allyl-substituted (hetero)cyclic
carboxylic acid (B) and an allylated 1,3,5-pentanetriol
derivative (C) via Mitsunobu esterification / RCM and final
installation of the side chain was projected to efficiently
generate the desired targets (A).
Ring-closing olefin metathesis with ruthenium carbene
complexes was shown to be a powerful method to form
the macrocyclic skeleton of the salicylihalamides.9,17 In line
with a highly significant study from the Grubbs lab,18 which
provided the inspiration for our RCM studies, we had
observed that first generation pre-catalyst i induces kinetic
selectivity whereas the H2IMes-containing pre-catalyst ii
affords thermodynamic selectivity. Not expected however,
was the highly selective formation of the E-isomer under
kinetic conditions (9–10:1, E/Z) contrasting the rather non-
selective thermodynamic ratio (2:1) obtained with the
second generation catalyst.11b In addition, Fu¨rstner and
co-workers reported a dramatic influence of the phenolic
protecting group on E/Z ratios in their synthetic work on
salicylihalamides.19 In light of these results, we explored the
As shown in Scheme 1, we selected a series of readily
accessible aryl, indole, cyclohexenyl and proline derived
carboxylic acid building blocks B (1–5)15 for incorporation
Figure 2.

S. Lebreton et al. / Tetrahedron 60 (2004) 9635–9647
9637
Scheme 1.
RCM reactions of substrates 8b–f with both first and second
generation catalysts to empirically identify the most
E-selective conditions.20
olefin position, and aromatic fragment as the salicylihala-
mide macrocycle. Similar results were obtained for the
non-substituted benzoate counterpart 9c. In both of these
ð2Þ
cases, a thermodynamic cyclization with second generation
catalyst ii was now significantly favoring formation of the
E-isomer. Re-exposure of isomerically pure E-9c and Z-9c
to the reaction conditions confirmed that thermodynamic
Our results are presented in Eq. (2) and Table 1. In contrast
to salicylihalamide, salicylic macrocycle 9b was obtained as
an almost equimolar mixture of E/Z-isomers under kinetic
RCM conditions, despite displaying the same ring-size,

9638
S. Lebreton et al. / Tetrahedron 60 (2004) 9635–9647
Table 1. Ring-closing olefin metathesis studies
p-methoxybenzyl ether provided four primary alcohols
10b–e in 78–95% yield. Dess–Martin periodinane oxidation
delivered the corresponding aldehydes,21 which were
subsequently homologated via HWE-reaction with tri-
methylsilyl dimethylphosphonoactetate. Aqueous work-up
provided the a,b-unsaturated acids 11b–e with high E-
selectivity in 53–61% yield for the two steps. These
materials were converted to acylazides 12b–e, precursors
for the corresponding isocyanates 13b–e. For the first series
of analogs, we opted for the addition of lithium phenyl-
acetylide. The corresponding analog 15 with salicylihala-
mide’s macrolactone was found to be equipotent to
salicylihalamide (1) but prepared in higher yields and
more resistant to decomposition.11 In the event, addition of
in situ prepared isocyanate 13b–e (benzene, reflux) to a cold
(K78 8C) solution of freshly deprotonated phenylacetylene
(BuLi, THF) resulted in a clean conversion to compounds
14b–e (50–97% yields). A portion of acetate 14b was stirred
in a basic methanol solution (K2CO3) to liberate the free
phenol 14a.
Substrate
t (h)
Product
E/Z ratioa (% conversion)a
Catalyst i
Catalyst ii
8b
8b
8c
8c
8d
8e
8f
1.3
6.3
1.3
6.3
6.3
4
4
5
5
9b
9b
9c
9c
9d
9e
42:48 (80)
54:46 (92)b
52:48 (O80)
54:46 (100)b
45:55 (80)c
29:71 (70)
—
95:5 (95)
98:2 (100)b
82:18 (O90)
84:16 (100)b
32:68 (80)c
49:51 (90)d
—
e
—
E-9c
Z-9c
9c
9c
98:2 (K)
11:89 (K)
89:11 (K)
82:18 (K)
a
Determined by 1H NMR analysis of crude product mixtures.
Isolated yields between 90–99%.
Some decomposition occurred; 34–41% isolated yield.
75% Isolated yield.
No reaction; higher temperatures or the addition of BF3$OEt2 or
Ti(OiPr)4 led to decomposition of the starting material.
b
c
d
e
equilibrium was reached with catalyst ii, but not with
catalyst i. Interestingly, cyclohexenyl- and indolyl-tethered
substrates 8d and 8e respectively, behaved quite differently
and no E-selective conditions could be identified—Z-
selectivity predominated with catalyst ii for indolyl
substrate 8d and with catalyst i for the cyclohexenyl
substrate 8e. Also, reaction with the indolyl substrate 8d
gave low yields of product 9d, the remainder accounted for
as starting material and decomposition products. These
results are fascinating because all these products (9b–e)
have an identical macrocycle fused with the smaller ring
through sp2-hybridized atoms. Evidently, subtle effects
influenced by the nature of the fused ring are at play here.
The proline-derived bis-olefin 8f was not a viable substrate
for RCM under all conditions explored.
Comparing the biological activity of this series of
compounds with the corresponding analog 15 would (1)
indicate if the endocyclic allyl ether presents a viable
alternative to the more complex macrocyclic backbone of
salicylihalamide, and (2) provide the first SAR-data related
to the nature of the fused ring (aryl, indole, cyclohexenyl).
As shown in Table 2, direct comparison of analogs 14a and
15 indicates that this simplified allyl ether scaffold (14a)
retains the ability to potently inhibit proton-pumping of
purified V-ATPase (w4.5-fold less than 15). Larger
differences (w10-fold) are observed in the growth inhi-
bition assay with two selected lung tumor cell lines, perhaps
related to altered drug transport and availability character-
istics. Compared to phenol 14a, the similar cytotoxicity, but
not in vitro potency of the corresponding acetate 14b, is
likely a manifestation of esterase-mediated release of
phenol 14a in the cell-based assay. Any other permutation
With four macrocyclic lactones 9b–e at hand, we were set to
complete the synthesis by appending an N-acyl enamide
side chain following our sequence described previously
(Scheme 2).11 Thus, oxidative deprotection of the primary
Scheme 2.

S. Lebreton et al. / Tetrahedron 60 (2004) 9635–9647
Table 2. Biological properties of selected compounds
9639
While compounds 16, 19 and 20 still inhibit V-ATPase
activity (4–30 nM) in line with our previous observations
within the salicylihalamide series,11,12 heteroaromatic
substituents (17, 18, 21) are deleterious. The more
surprising result however, is that this ‘heteroatom effect’
does not translate to the cytotoxicity assay. Pyridinyl and
oxazoyl substituted derivatives 17 and 18 are still able to
inhibit cell growth at similar concentrations to compound
14a. These observations might indicate that 17 and 18
induce cytotoxicity through a different mechanism, or that
they target a different V-ATPase isoform than the one used
in this study.22
Compound
V-ATPase
inhibition
Cell growth inhibitionb
(HC-pumping)
IC50 (nM)a
A549 IC50
(mM)
NCI-H460 IC50
(mM)
15
1.0
4.5
0.086
1.03
1.38
0.018
0.20
0.31
14a
14b
14c
14d
14e
16f
17
18
19
20
21
125
No inhibitionc
d
d
—
—
—
—
—
—
O1000e
d
d
No inhibitionc
d
d
16
2300
1000
30
4
1900
3.05
1.50
0.88
4.62
1.03
1.23
0.55
1.62
In conclusion, we have identified a series of simplified
analogs (14a,b, 16, 19, 20) of the macrocyclic salicylate
natural product salicylihalamide A that retain the ability to
potently inhibit the V-ATPase. These and other derivatives
were conveniently prepared via a convergent assembly of a
series of allyl-substituted carboxylic acids 1–4 and the allyl
ether derivative 7 via Mitsunobu esterification and ring-
closing olefin metathesis. We also uncovered subtle effects
on E/Z-stereochemistry during RCM related to the nature of
the small ring fused to the macrocycle. Finally, structure-
function studies indicate that the salicylate moiety is
indispensable for activity and that heteroaryl terminating
side-chains behave differently than other inhibitors in the
salicylate family. Continuing efforts to study this intriguing
family of compounds are ongoing.
d
d
—
O10g
—
O10g
a
Assay performed as in Ref. 12.
See Section 3 for details.
Up to 1 mM.
b
c
d
e
f
Not measured.
10% Inhibition at 1 mM.
Racemic mixture.
20–29% Inhibition at 10 mM.
g
of the aromatic phenol (i.e. compounds 14c–e) virtually
abrogated in vitro V-ATPase inhibition, manifesting the
importance for a fused ortho-hydroxy benzoate (i.e.
salicylate) scaffold.
Having identified a promising, highly simplified salicylate
scaffold, we next prepared and evaluated a variety of side-
chain modifications in this series. To this end, we added
isocyanate 13b (from 12b) to a 2-fluorophenyl-, 2-
pyridinyl-, or 2-oxazoyl-substituted acetylide followed by
acetate hydrolysis (K2CO3, MeOH) to deliver the corre-
sponding analogs 16–18 (Scheme 3). Benzyl-, pentyl-, and
2-oxazoylmethyl carbamates 19–21 are obtained directly
from heating acylazide 12b in the presence of the
corresponding alcohols and acetate hydrolysis as before.
3. Experimental
3.1. General procedures
Commercially available materials were used without further
purification. All solvents used were of HPLC- or ACS-
grade. Solvents used for moisture sensitive operations were
distilled from drying agents under a nitrogen atmosphere:
Et2O and THF from sodium benzophenone ketyl; benzene
Scheme 3.

9640
S. Lebreton et al. / Tetrahedron 60 (2004) 9635–9647
from sodium; CH2Cl2 and NEt3 from CaH2. All moisture
sensitive reactions were carried out under a nitrogen
atmosphere with magnetic stirring. Flash chromatography
(FC) was performed using E Merck silicagel 60 (240–400
mesh). Thin Layer chromatography was performed using
precoated plates purchased from E. Merck (silicagel 60
PF254, 0.25 mm) that were visualized using a KMnO4 or
Ce(IV) stain.
d, JZ11.2 Hz), 4.39 (1H, d, JZ11.2 Hz), 3.98 (1H, app.t,
JZ6.0 Hz), 3.93 (2H, d, JZ6.0 Hz), 3.80 (3H, s), 3.51 (2H,
t, JZ6.8 Hz), 3.48 (2H, t, JZ6.8 Hz), 1.82–1.68 (4H, m),
0.87 (9H, s), 0.04 (6H, d, JZ2.4 Hz); 13C NMR (75 MHz,
CDCl3) d 159.3, 135.2, 130.9, 129.5, 116.9, 113.9, 72.8,
72.0, 67.1, 66.9, 59.8, 55.5, 37.6, 37.5, 26.1, 18.3, K4.4;
MS (ES) m/z 417.20 [MCNa]C; calcd for C22H38O4SiNa:
417.24.
Nuclear magnetic resonance (NMR) spectra were recorded
on either a Varian Inova-400 or Mercury-300 spectrometer
at operating frequencies of 400/300 MHz (1H NMR) or
100/75 MHz (13C NMR). Chemical shifts (d) are given in
ppm relative to residual solvent and coupling constants (J) in
Hz. Multiplicity is tabulated as s for singlet, d for doublet, t
for triplet, q for quadruplet, and m for multiplet, whereby the
prefix app is applied in cases where the true multiplicity is
unresolved, and br when the signal in question is broadened.
High-resolution mass spectra (HRMS) were recorded at the
NIH regional mass spectrometry facility at the University of
Washington, St. Louis, MO. Optical rotations were
measured at 23 8C on a Perkin–Elmer 241 MC polarimeter.
3.1.3. 1-Allyloxy-5-(4-methoxy-benzyloxy)-pentan-3-ol
7. To a solution of [1-(2-Allyloxy-ethyl)-3-(4-methoxy-
benzyloxy)-propoxy]-tert-butyl-dimethyl-silane (1.65 g,
4.18 mmol) in THF (30 mL) at 0 8C was added TBAF
(1.0 M in THF, 12.54 mL, 12.54 mmol). The reaction was
stirred at rt for 5 h and water (200 mL) was added. The
mixture was extracted with CH2Cl2 (3!150 mL). The
combined organic phases were washed with brine (300 mL)
and dried over MgSO4. After concentration in vacuo, the
residue was purified by FC (20% EtOAc in hexanes) to give
1
866 mg (74%) of 7 as a colorless oil. H NMR (400 MHz,
CDCl3) d 7.24 (2H, d, JZ8.8 Hz), 6.86 (2H, d, JZ8.8 Hz),
5.88 (1H, dddd, JZ16.8, 10.4, 5.2, 5.2 Hz), 5.26 (1H, dd,
JZ17.6, 1.6 Hz), 5.17 (1H, dd, JZ10.0, 1.6 Hz), 4.44 (2H,
s), 3.97 (2H, dt, JZ5.6, 1.2 Hz), 3.97–3.93 (1H, m), 3.78
(3H, s), 3.68–3.55 (4H, m), 3.38 (1H, br.s), 1.78–1.71 (4H,
m); 13C NMR (75 MHz, CDCl3) d 159.3, 134.7, 130.3,
129.4, 117.0, 113.9, 76.8, 72.1, 69.4, 68.4, 68.3, 55.3, 36.9;
MS (ES) m/z 303.10 [MCNa]C; calcd for C16H24O4Na:
303.15.
3.1.1. 3-(tert-Butyl-dimethyl-silanyloxy)-5-(4-methoxy-
benzyloxy)-pentan-1-ol. To a solution of aldehyde 6
(8.95 g, 25.38 mmol) in absolute ethanol (300 mL) at 0 8C
was added sodium borohydride (2.40 g, 63.45 mmol)
portionwise. After stirring at rt for 45 min, the reaction
mixture was cooled down to 0 8C and quenched with water
(300 mL) and acetic acid to pHw5. Following removal of
EtOH in vacuo, the mixture was extracted with EtOAc
(2!300 mL). The combined organic layers were dried over
MgSO4 and concentrated in vacuo. The residue was purified
by FC (20% EtOAc in hexanes) to give 8.3 g (92%) of the
desired alcohol as a colorless oil. 1H NMR (400 MHz,
CDCl3) d 7.25 (2H, d, JZ8.8 Hz), 6.87 (2H, d, JZ8.8 Hz),
4.44 (1H, d, JZ11.2 Hz), 4.39 (1H, d, JZ11.2 Hz), 4.09
(1H, quent, JZ5.2 Hz), 3.82–3.77 (1H, m), 3.80 (3H, s),
3.73–3.67 (1H, m), 3.49 (2H, app.t, JZ6.4 Hz), 2.43 (1H, t,
JZ5.0 Hz), 1.89–1.76 (3H, m), 1.65 (1H, dddd, JZ16.0,
6.0, 6.0, 3.6 Hz), 0.89 (9H, s), 0.08 (6H, d, JZ8.0 Hz); 13C
NMR (75 MHz, CDCl3) d 159.4, 130.6, 129.5, 114.0, 72.9,
69.2, 66.7, 60.2, 55.5, 38.5, 36.9, 26.0, 18.1, K4.4; MS (ES)
m/z 377.25 [MCNa]C; calcd for C19H34O4SiNa: 377.21.
3.1.4. Mitsunobu coupling. To a solution of acid 1–5
(1.5 equiv), alcohol 7 (1.0 equiv), and PPh3 (1.6 equiv) in
Et2O (0.1 M with respect to the alcohol) at 0 8C was added
diisopropylazodicarboxylate (1.6 equiv). The reaction was
stirred at rt until all alcohol reacted (2–12 h). The reaction
mixture was filtrated off and washed with Et2O. The filtrate
was washed with water. The aqueous phase was extracted
twice with Et2O. The combined organic layers were dried
over MgSO4 and concentrated in vacuo. The residue was
then purified by FC (EtOAc in hexanes) to give the
corresponding ester 8a–f.
3.1.4.1. 2-Allyl-6-hydroxy-benzoic acid 1-(2-allyloxy-
ethyl)-3-(4-methoxy-benzyloxy)-propyl ester 8a. In the
case of compound 8a, a 1:6 adduct:product resulted from
esterification of the phenolic group, which was hydrolyzed
in MeOH in the presence of K2CO3 (1 equiv) over 1 h. After
adding water, an extraction was performed with EtOAc. The
combined extracts were dried, concentrated in vacuo, and
purified by FC (20% EtOAc in hexanes) to give 1.26 g (96%
yield) of product 8a as pale yellowish oil. 1H NMR
(400 MHz, CDCl3) d 11.1 (1H, s), 7.31 (1H, t, JZ8.0 Hz),
7.20 (2H, d, JZ8.8 Hz), 6.87 (1H, d, JZ8.8 Hz), 6.82 (2H,
d, JZ8.8 Hz), 6.72 (1H, d, JZ7.2 Hz), 5.96 (1H, dddd, JZ
16.4, 10.4, 6.4, 6.4 Hz), 5.85 (1H, dddd, JZ16.0, 10.4, 5.6,
5.6 Hz), 5.59–5.53 (1H, m), 5.22 (1H, dd, JZ16.8, 1.2 Hz),
5.13 (1H, dd, JZ10.4, 1.2 Hz), 5.00 (1H, dd, JZ10.0,
1.2 Hz), 4.90 (1H, dd, JZ16.8, 1.6 Hz), 4.42 (1H, d, JZ
11.6 Hz), 4.38 (1H, d, JZ11.6 Hz), 3.92 (2H, d, JZ5.6 Hz),
3.77 (3H, s), 3.64 (2H, br.d, JZ6.0 Hz), 3.55–3.47 (4H, m),
2.05–1.97 (4H, m); 13C NMR (75 MHz, CDCl3) d 170.7,
162.5, 159.4, 142.7, 138.0, 134.8, 134.2, 130.3, 129.6,
122.6, 117.3, 116.4, 115.6, 113.9, 113.0, 73.0, 72.2, 72.0,
3.1.2. [1-(2-Allyloxy-ethyl)-3-(4-methoxy-benzyloxy)-
propoxy]-tert-butyl-dimethyl-silane. To a suspension of
sodium hydride (902 mg, 22.56 mmol, prewashed with
benzene) in THF (30 mL) was added 3-(tert-Butyl-
dimethyl-silanyloxy)-5-(4-methoxy-benzyloxy)-pentan-1-
ol (2 g, 5.64 mmol). After stirring at rt for 45 min, a solution
of allylbromide (1.95 mL, 22.56 mmol) in THF (5 mL) was
added dropwise and the reaction was stirred for another
20 h. The mixture was quenched with water (5 mL) and
brine (150 mL) was added. The separated aqueous phase
was extracted with EtOAc (2!150 mL). The combined
organic layers were washed with brine (2!150 mL), dried
over MgSO4, and concentrated in vacuo. The residue was
purified by FC (5% EtOAc in hexanes) to give 1.73 g (78%)
of the desired product as a colorless oil. 1H NMR (400 MHz,
CDCl3) d 7.25 (2H, d, JZ8.8 Hz), 6.87 (2H, d, JZ8.8 Hz),
5.90 (1H, dddd, JZ17.2, 10.8, 5.2, 5.2 Hz), 5.26 (1H, dd,
JZ17.2, 1.6 Hz), 5.16 (1H, dd, JZ10.4, 1.6 Hz), 4.42 (1H,

S. Lebreton et al. / Tetrahedron 60 (2004) 9635–9647
9641
66.7, 66.4, 55.4, 40.1, 34.7; MS (ES) m/z 463.20 [MC
[a]DZK36.3 (cZ1.23, CH2Cl2). 1H NMR (400 MHz,
CDCl3) d 7.25 (2H, d, JZ8.8 Hz), 6.86 (2H, d, JZ
8.8 Hz), 5.96–5.83 (2H, m), 5.24 (1H, dd, JZ17.2,
1.6 Hz), 5.20–5.15 (1H, m), 5.16 (1H, dd, JZ17.6,
1.2 Hz), 5.15 (1H, dd, JZ10.4, 1.2 Hz), 5.07 (1H, dd, JZ
10.4, 1.2 Hz), 4.42 (1H, d, JZ11.6 Hz), 4.39 (1H, d, JZ
11.6 Hz), 3.92 (2H, dt, JZ5.6, 1.6 Hz), 3.80 (3H, s), 3.51–
3.39 (4H, m), 3.32 (1H, ddt, JZ13.2, 6.4, 1.2 Hz), 3.16–
3.10 (2H, m), 3.07 (1H, app.ddt, JZ13.2, 7.2, 1.2 Hz), 2.37
(1H, app.q, JZ8.0 Hz), 2.13–2.06 (1H, m), 1.93–1.76 (7H,
m); 13C NMR (75 MHz, CDCl3) d 173.9, 159.4, 135.7,
135.0, 130.6, 129.5, 117.5, 117.2, 113.9, 72.9, 72.1, 69.8,
66.7, 66.5, 65.4, 57.7, 55.4, 53.5, 34.8, 29.7, 23.2, 22.1; MS
(ES) m/z 418.25 [MCH]C; calcd for C24H36NO5: 418.26.
Na]C; calcd for C26H32O6Na: 463.21.
3.1.4.2. 2-Allyl-benzoic acid 1-(2-allyloxy-ethyl)-3-(4-
methoxy-benzyloxy)-propyl ester 8c. Reaction mixture
purified by FC (10% EtOAc in hexanes) to give 295 mg
(97% yield) of product 8c. [a]DZK9.9 (cZ1.60, CH2Cl2).
1H NMR (400 MHz, CDCl3) d 7.80 (1H, d, JZ7.6 Hz), 7.43
(1H, t, JZ7.6 Hz), 7.28–7.22 (4H, m), 6.83 (2H, d, JZ
8.4 Hz), 6.00 (1H, dddd, JZ16.4, 10.0, 6.4, 6.4 Hz), 5.87
(1H, dddd, JZ16.8, 10.0, 5.6, 5.6 Hz), 5.42–5.36 (1H, m),
5.23 (1H, dd, JZ17.2, 1.6 Hz), 5.13 (1H, dd, JZ10.4,
1.6 Hz), 5.02 (1H, dd, JZ10.0, 1.6 Hz), 4.99 (1H, dd, JZ
17.2, 1.6 Hz), 4.41 (2H, s), 3.93 (2H, br.d, JZ5.6 Hz), 3.77
(3H, s), 3.74 (2H, d, JZ6.4 Hz), 3.56–3.49 (4H, m), 2.04–
1.97 (4H, m); 13C NMR (75 MHz, CDCl3) d 167.2, 159.3,
141.6, 137.7, 135.0, 132.0, 131.1, 130.6, 130.3, 129.5,
126.3, 117.1, 115.8, 113.9, 72.9, 72.1, 70.4, 66.9, 66.6, 55.4,
38.4, 34.9; MS (ES) m/z 447.20 [MCNa]C; calcd for
C26H32O5Na: 447.22.
3.1.5. 2-Acetoxy-6-allyl-benzoic acid 1-(2-allyloxy-ethyl)-
3-(4-methoxy-benzyloxy)-propyl ester 8b. To a solution
of phenol 8a (1.23 g, 2.79 mmol) equiv) in CH2Cl2 (20 mL)
at 0 8C was added pyridine (243 mg, 3.07 mmol), acetic
anhydride (314 mg, 3.07 mmol) and a catalytic amount of
DMAP. After stirring at rt for 3 h the reaction mixture was
concentrated in vacuo, and purified by FC (10% EtOAc in
hexanes) to give 1.28 g (95% yield) of the product 8b as a
colorless oil. [a]DZK7.5 (cZ0.15, CH2Cl2). 1H NMR
(400 MHz, CDCl3) d 7.36 (1H, t, JZ8.0 Hz), 7.25 (2H, d,
JZ8.4 Hz), 7.12 (1H, d, JZ7.6 Hz), 7.01 (1H, d, JZ
7.6 Hz), 6.86 (2H, d, JZ8.4 Hz), 5.97–5.84 (2H, m), 5.37
(1H, app.quint, JZ6.0 Hz), 5.26 (1H, dd, JZ16.8, 1.2 Hz),
5.16 (1H, dd, JZ10.4, 1.2 Hz), 5.07 (1H, dd, JZ10.0,
1.2 Hz), 5.04 (1H, dd, JZ17.2, 1.2 Hz), 4.45 (1H, d, JZ
11.6 Hz), 4.41 (1H, d, JZ11.6 Hz), 3.95 (2H, d, JZ5.6 Hz),
3.80 (3H, s), 3.58–3.49 (4H, m), 3.44 (2H, d, JZ6.4 Hz),
2.24 (3H, s), 2.04–1.95 (4H, m); 13C NMR (75 MHz,
CDCl3) d 169.3, 166.2, 159.4, 148.2, 139.6, 136.4, 134.9,
130.7, 130.5, 129.5, 127.5, 127.0, 121.1, 117.1, 117.0,
114.0, 72.9, 72.1, 71.5, 66.6, 66.5, 55.5, 37.7, 34.6, 34.5,
21.1; MS (ES) m/z 505.25 [MCNa]C; calcd for
C28H34O7Na: 505.22.
3.1.4.3. 1-Allyl-1H-indole-2-carboxylic acid 1-(2-ally-
loxy-ethyl)-3-(4-methoxy-benzyloxy)-propyl ester 8d.
Reaction mixture purified by FC (10% EtOAc in hexanes)
to give 755 mg (100% yield) of product 8d as pale yellowish
1
oil. [a]DZK11.2 (cZ1.18, CH2Cl2). H NMR (400 MHz,
CDCl3) d 7.67 (1H, d, JZ8.0 Hz), 7.37–7.31 (2H, m), 7.28
(1H, s), 7.20 (2H, d, JZ8.8 Hz), 7.15 (1H, ddd, JZ8.0, 6.4,
1.6 Hz), 6.78 (2H, d, JZ8.4 Hz), 5.99 (1H, dddd, JZ16.8,
10.0, 4.8, 4.8 Hz), 5.86 (1H, dddd, JZ17.2, 10.8, 5.6,
5.6 Hz), 5.44–5.37 (1H, m), 5.22 (1H, dd, JZ17.2, 3.2 Hz),
5.21–5.20 (2H, m), 5.12 (1H, dd, JZ10.4, 2.8 Hz), 5.08
(1H, dd, JZ10.8, 2.4 Hz), 4.89 (1H, dd, JZ17.2, 3.26 Hz),
4.39 (2H, s), 3.93 (2H, ddd, JZ5.6, 1.2, 1.2 Hz), 3.71 (3H,
s), 3.57–3.50 (4H, m), 2.05–1.98 (4H, m); 13C NMR
(75 MHz, CDCl3) d 161.6, 159.3, 139.4, 135.0, 134.2,
130.5, 129.5, 127.7, 126.2, 125.2, 122.8, 120.9, 117.1,
116.1, 113.9, 110.8, 110.7, 73.0, 72.2, 70.0, 66.8, 66.6, 55.4,
47.0, 35.0, 21.8; MS (ES) m/z 486.15 [MCNa]C; calcd for
C28H33NO5Na: 486.23.
3.1.6. Ring closure metathesis. A solution of bis-olefin
8b–e in degassed CH2Cl2 (0.07 M) and a solution of Grubbs
catalyst (10 mol%) in degassed CH2Cl2 (0.01 M) were
added dropwise simultaneously to a flask containing
degassed CH2Cl2 (0.07 M with respect to bis-olefin). The
reaction was stirred at rt until no further evolution (as
monitored by TLC) was observed (4–6 h). The solvent was
removed in vacuo and the residue was purified by FC to give
the corresponding lactone 9b–e.
3.1.4.4. 2-Allyl-cyclohex-1-enecarboxylic acid 1-(2-
allyloxy-ethyl)-3-(4-methoxy-benzyloxy)-propyl ester
8e. Reaction mixture purified by FC (5% EtOAc in hexanes)
to give 272 mg (84% yield) of product 8e. 1H NMR
(400 MHz, CDCl3) d 7.24 (2H, d, JZ8.4 Hz), 6.86 (2H, d,
JZ8.4 Hz), 5.88 (1H, dddd, JZ17.2, 10.8, 5.6, 5.6 Hz),
5.80 (1H, dddd, JZ16.8, 10.0, 6.8, 6.8 Hz), 5.25 (1H, dd,
JZ17.2, 1.6 Hz), 5.22–5.17 (1H, m), 5.15 (1H, dd, JZ10.4,
1.6 Hz), 5.02 (1H, dd, JZ17.2, 1.6 Hz), 4.99 (1H, dd, JZ
10.4, 1.6 Hz), 4.4 (2H, s), 3.93 (2H, dt, JZ5.6, 1.6 Hz), 3.80
(3H, s), 3.50–3.43 (4H, m), 3.08 (2H, br.d, JZ6.4 Hz),
2.25–2.19 (2H, m), 2.13–2.08 (2H, m), 1.91 (4H, app.quent.,
JZ6.4 Hz), 1.60–1.56 (4H, m); 13C NMR (75 MHz, CDCl3)
d 168.5, 159.3, 146.1, 142.8, 136.3, 135.1, 130.7, 129.5,
125.8, 117.1, 115.9, 114.0, 72.9, 72.1, 69.3, 67.0, 66.6, 55.5,
39.9, 34.9, 30.9, 26.8, 22.5; MS (ES) m/z 451.20 [MC
Na]C; calcd for C26H36O5Na: 451.25.
3.1.6.1. Acetic acid 7-[2-(4-methoxy-benzyloxy)-
ethyl]-5-oxo-8,9,11,14-tetrahydro-5H,7H-6,10-dioxa-
benzocyclododecen-4-yl ester E-9b. Reaction mixture
purified by FC (10% EtOAc in hexanes) to give 93 mg
(94% yield, catalyst ii) of product E-9b as a colorless oil.
[a]DZK34.0 (cZ1.29, CH2Cl2). 1H NMR (400 MHz,
CDCl3) d 7.34 (1H, t, JZ8.0 Hz), 7.26 (2H, d, JZ
8.4 Hz), 7.11 (1H, d, JZ7.2 Hz), 7.03 (1H, d, JZ8.4 Hz),
6.88 (2H, d, JZ8.4 Hz), 5.62 (1H, dddd, JZ14.8, 10.0, 4.0,
1.6 Hz), 5.49 (1H, ddd, JZ14.8, 10.8, 3.2 Hz), 5.22 (1H,
dddd, JZ12.8, 6.4, 6.4, 2.0 Hz), 4.48 (1H, d, JZ11.6 Hz),
4.43 (1H, d, JZ11.6 Hz), 4.13 (1H, br.dd, JZ11.6, 3.2 Hz),
3.90 (1H, dd, JZ14.0, 11.2 Hz), 3.80 (3H, s), 3.61–3.58
(2H, m), 3.46 (1H, ddd, JZ10.4, 3.6, 2.4 Hz), 3.37 (1H, dd,
3.1.4.5. 1-Allyl-pyrrolidine-2-carboxylic acid 1-(2-
allyloxy-ethyl)-3-(4-methoxy-benzyloxy)-propyl ester
8f. Reaction mixture purified by FC (30% EtOAc in
hexanes) to give 305 mg (72% yield) of product 8f.

9642
S. Lebreton et al. / Tetrahedron 60 (2004) 9635–9647
JZ12.0, 10.4 Hz), 3.28 (1H, ddd, JZ12.0, 10.8, 1.2 Hz),
3.20 (1H, dddd, JZ14.0, 3.6, 1.6, 1.6 Hz), 2.21 (3H, s),
2.08–2.00 (1H, m), 1.94–1.83 (2H, m), 1.54 (1H, dddd, JZ
14.4, 12.4, 2.0, 2.0 Hz); 13C NMR (75 MHz, CDCl3) d
168.9, 166.6, 159.4, 148.2, 139.6, 133.1, 130.6, 130.5,
129.7, 129.6, 127.9, 127.7, 121.6, 114.0, 73.0, 70.6, 69.8,
67.0, 61.9, 55.4, 37.7, 36.2, 35.1, 21.0; MS (ES) m/z 477.15
[MCNa]C; calcd for C26H30O7Na: 477.19.
(1H, dd, JZ12.4, 10.4 Hz), 3.27 (1H, ddd, JZ11.6, 9.6,
2.0 Hz), 2.03–1.89 (3H, m), 1.69 (1H, dddd, JZ14.4, 12.0,
2.4, 2.4 Hz); 13C NMR (75 MHz, CDCl3) d 164.0, 159.3,
138.4, 132.8, 131.4, 130.6, 130.2, 129.6, 126.9, 124.3,
122.5, 120.8, 114.0, 110.0, 107.3, 73.1, 70.0, 66.8, 62.6,
55.4, 46.1, 35.6, 35.4; MS (ES) m/z 458.15 [MCNa]C;
calcd for C26H29NO5Na: 458.19.
3.1.6.5.
7-[2-(4-Methoxy-benzyloxy)-ethyl]-
3.1.6.2. 7-[2-(4-Methoxy-benzyloxy)-ethyl]-8,9,11,14-
tetra-hydro-7H-6,10-dioxa-benzocyclododecen-5-one E-
9c. Reaction mixture purified by FC (10% EtOAc in
hexanes) to give 237 mg of product E-9c (94% yield,
catalyst ii) as a colorless oil. [a]DZK72.8 (cZ1.66,
1,2,3,4,8,9,11,14-octahydro-7H-6,10-dioxa-benzocyclo-
dodecen-5-one E-9e. Reaction mixture purified by FC
(15% EtOAc in hexanes) to give 172 mg of non-separable
E- and Z-isomers (75% combined yield, catalyst ii) as a
colorless oil. 1H NMR (400 MHz, CDCl3) d 7.25 (2H, d, JZ
8.0 Hz), 6.86 (2H, d, JZ8.0 Hz), 5.48–5.34 (2H, m), 5.15
(1H, dddd, JZ11.6, 6.0, 6.0, 2.0 Hz), 4.43 (1H, d, JZ
11.6 Hz), 4.38 (1H, d, JZ11.6 Hz), 4.09 (1H, br.dd, JZ
11.2, 3.2 Hz), 3.80 (3H, s), 3.50–3.35 (6H, m), 2.27 (2H,
br.d, 14.0), 2.15 (2H, br.s), 2.0–1.92 (1H, m), 1.87 (2H,
app.dt, JZ6.8, 6.4 Hz), 1.82 (1H, dddd, JZ16.4, 14.8, 3.6,
2.4 Hz), 1.66–1.61 (5H, m); 13C NMR (75 MHz, CDCl3) d
170.1, 159.3, 138.8, 132.4, 130.5, 129.6, 128.5, 114.0, 73.0,
70.6, 69.3, 66.8, 61.9, 55.4, 36.9, 35.6, 35.1, 32.4, 27.0,
22.7, 21.8; MS (ES) m/z 423.15 [MCNa]C; calcd for
C24H32O5Na: 423.21.
1
CH2Cl2). H NMR (400 MHz, CDCl3) d 7.34 (1H, app.t,
JZ8.0 Hz), 7.29 (1H, d, JZ7.6 Hz), 7.26 (2H, d, JZ
8.4 Hz), 7.21 (1H, d, JZ8.8 Hz), 7.20 (1H, app.t, JZ
8.0 Hz), 6.85 (2H, d, JZ8.8 Hz), 5.63 (1H, dddd, JZ14.8,
10.4, 4.4, 1.6 Hz), 5.44 (1H, ddd, JZ14.8, 10.8, 3.6 Hz),
5.35 (1H, dddd, JZ11.6, 4.8, 4.8, 2.0 Hz), 4.45 (1H, d, JZ
11.6 Hz), 4.41 (1H, d, JZ11.6 Hz), 4.13 (1H, dd, JZ12.0,
4.4 Hz), 4.02 (1H, dd, JZ14.0, 11.2 Hz), 3.79 (3H, s), 3.60
(2H, app.t, JZ6.8 Hz), 3.45 (1H, dt, JZ12.8, 2.8 Hz), 3.36
(1H, dd, JZ12.0, 10.4 Hz), 3.28 (1H, ddd, JZ12.0, 10.4,
1.6 Hz), 3.15 (1H, br.d, JZ14.0 Hz), 2.05–1.95 (2H, m),
1.87 (1H, dddd, JZ14.8, 12.0, 3.6, 2.4 Hz), 1.63 (1H, dddd,
JZ14.4, 12.4, 2.0, 2.0 Hz); 13C NMR (75 MHz, CDCl3) d
169.2, 159.3, 138.3, 134.6, 133.3, 130.6, 130.4, 129.8,
129.6, 127.8, 126.6, 113.9, 73.0, 70.7, 69.4, 67.0, 62.1, 55.4,
37.7, 35.6, 35.1; MS (ES) m/z 419.15 [MCNa]C; calcd for
C24H28O5Na: 419.18.
3.1.7. PMB deprotection. To a solution of the lactone 9b–e
(1 equiv) in CH2Cl2 (0.05 M with respect to the lactone) and
water (1.0 M with respect to the lactone) was added DDQ
(1.2 equiv). After stirring for 2–3 h, the slurry was poured
into sat. aq. NaHCO3 and water and extracted with EtOAc
(4!). The combined organic layers were dried, concen-
trated in vacuo, and purified by FC.
3.1.6.3. 7-[2-(4-Methoxy-benzyloxy)-ethyl]-8,9,11,14-
tetra-hydro-7H-6,10-dioxa-benzocyclododecen-5-one Z-
1
9c. [a]DZK73.2 (cZ1.0, CH2Cl2). H NMR (400 MHz,
3.1.7.1. Acetic acid 7-(2-hydroxy-ethyl)-5-oxo-
8,9,11,14-tetrahydro-5H,7H-6,10-dioxa-benzocyclo-
dodecen-4-yl ester 10b. Reaction mixture purified by FC
(60% EtOAc in hexanes) to give 760 mg (95% yield) of
CDCl3) d 7.39 (1H, d, JZ7.6 Hz), 7.35 (1H, t, JZ7.6 Hz),
7.29 (1H, d, JZ7.6 Hz), 7.25 (2H, d, JZ8.4 Hz), 7.12 (1H,
t, JZ7.6 Hz), 6.82 (2H, d, JZ8.4 Hz), 5.78 (1H, dt, JZ
10.8, 6.0 Hz), 5.64–5.58 (1H, m), 5.51 (1H, dddd, JZ12.8,
9.2, 4.0, 1.6 Hz), 4.52 (1H, dd, JZ12.0, 12.0 Hz), 4.48 (1H,
d, JZ11.6 Hz), 4.42 (1H, d, JZ11.6 Hz), 4.03 (1H, t, JZ
9.2 Hz), 3.77 (1H, app.t, JZ10.8 Hz), 3.72 (3H, s), 3.64–
3.55 (4H, m), 3.20 (1H, dd, JZ12.8, 6.0 Hz), 2.04–1.88
(3H, m), 1.76 (1H, dddd, JZ15.6, 4.4, 2.0, 2.0 Hz); 13C
NMR (75 MHz, CDCl3) d 168.9, 159.3, 140.3, 137.5, 132.3,
131.1, 130.8, 130.4, 129.9, 129.6, 125.8, 124.1, 114.0, 73.0,
71.8, 69.2, 66.0, 65.1, 55.4, 35.7, 35.5, 30.6; MS (ES) m/z
419.15 [MCNa]C; calcd for C24H28O5Na: 419.18.
1
product 10b. H NMR (400 MHz, CDCl3) d 7.37 (1H, t,
JZ8.0 Hz), 7.14 (1H, d, JZ7.6 Hz), 7.05 (1H, d, JZ
7.6 Hz), 5.63 (1H, dddd, JZ14.8, 10.4, 4.0, 1.6 Hz), 5.51
(1H, ddd, JZ14.8, 11.2, 3.6 Hz), 5.33 (1H, dddd, JZ10.8,
8.4, 2.4, 2.4 Hz), 4.15 (1H, br.d, JZ12.4 Hz), 3.92 (1H,
dd, JZ13.6, 10.8 Hz), 3.77–3.73 (2H, m), 3.48 (1H, dt,
JZ10.0, 2.8 Hz), 3.38 (1H, dd, JZ12.0, 10.0 Hz), 3.28
(1H, ddd, JZ12.0, 10.4, 1.6 Hz), 3.22 (1H, ddt, JZ14.0,
3.2, 1.6 Hz), 2.94 (1H, dd, JZ7.6, 6.0 Hz), 2.22 (3H, s),
1.99–1.91 (1H, m), 1.82 (1H, dddd, JZ16.4, 12.8, 3.6,
2 Hz), 1.69 (1H, ddt, JZ13.6, 10.0, 3.2 Hz), 1.62–1.56
(1H, m); 13C NMR (75 MHz, CDCl3) d 168.8, 168.4,
148.3, 139.8, 133.3, 130.9, 129.7, 128.0, 127.2, 121.7,
70.5, 69.3, 61.8, 58.3, 39.0, 37.6, 35.6, 21.0; MS (ES) m/z
357.10 (100%) [(MCNa)C; calcd for C18H22O6Na:
357.13].
3.1.6.4. 12-[2-(4-Methoxy-benzyloxy)-ethyl]-5,8,11,
12-tetrahydro-10H-9,13-dioxa-4b-aza-cyclododeca[a]-
inden-14-one E-9d. Reaction mixture purified by FC (20%
EtOAc in hexanes) to give 86 mg of product E-9d (18%
1
yield E-isomer, catalyst i; 41% combined yield ECZ). H
NMR (400 MHz, CDCl3) d 7.64 (1H, d, JZ8.0 Hz), 7.42
(1H, d, JZ8.4 Hz), 7.33 (1H, app.t, JZ8.0 Hz), 7.27 (2H, d,
JZ8.8 Hz), 7.15 (1H, t, JZ8.0 Hz), 6.91 (1H, s), 6.85 (2H,
d, JZ8.8 Hz), 5.80 (1H, ddd, JZ15.2, 10.0, 4.4 Hz), 5.49–
5.43 (1H, m), 5.38 (1H, ddd, JZ14.8, 10.0, 3.6 Hz), 5.02
(1H, dd, JZ14.4, 10.0 Hz), 4.88 (1H, br.d, JZ14.4 Hz),
4.47 (1H, d, JZ11.6 Hz), 4.43 (1H, d, JZ11.6 Hz), 4.10
(1H, dd, JZ12.0, 4.8 Hz), 3.78 (3H, s), 3.60 (2H, ddd, JZ
6.4, 2.0, 2.0 Hz), 3.45 (1H, ddd, JZ10.0, 3.6, 3.6 Hz), 3.39
3.1.7.2. 7-(2-Hydroxy-ethyl)-8,9,11,14-tetrahydro-7H-
6,10-dioxa-benzocyclododecen-5-one 10c. Reaction mix-
ture purified by FC (50% EtOAc in hexanes) to give 155 mg
(94% yield) of product 10c. 1H NMR (400 MHz, CDCl3) d
7.40 (1H, app.t, JZ7.6 Hz), 7.37 (1H, d, JZ7.6 Hz), 7.27
(1H, app.t, JZ7.6 Hz), 7.25 (1H, d, JZ7.6 Hz), 5.63 (1H,
dddd, JZ15.2, 10.4, 4.4, 1.6 Hz), 5.46 (1H, ddd, JZ14.8,
11.2, 3.2 Hz), 5.42–5.35 (1H, m), 4.15 (1H, br.dd, JZ10.8,

S. Lebreton et al. / Tetrahedron 60 (2004) 9635–9647
9643
4.0 Hz), 4.02 (1H, dd, JZ13.6, 10.8 Hz), 3.76–3.64 (2H,
m), 3.48 (1H, dt, JZ10.0, 2.8 Hz), 3.37 (1H, dd, JZ12.0,
10.4 Hz), 3.29 (1H, ddd, JZ12.0, 10.4, 1.6 Hz), 3.15 (1H,
br.d, JZ13.6 Hz), 3.07 (1H, br. s), 1.99–1.80 (2H, m), 1.78
(1H, dddd, JZ13.6, 10.0, 3.6, 3.6 Hz), 1.65 (1H, dddd, JZ
14.4, 12.4, 2.0, 2.0 Hz); 13C NMR (75 MHz, CDCl3) d
171.0, 138.3, 134.0, 133.5, 130.8, 130.5, 129.6, 127.7,
126.6, 70.6, 68.7, 62.0, 58.5, 38.4, 37.5, 35.5; MS (ES) m/z
299.00 [MCNa]C; calcd for C16H20O4Na: 299.13.
EtOAc (3!). The combined organic layers were dried over
MgSO4, concentrated in vacuo and purified by FC.
3.1.8.1. 4-(4-Acetoxy-5-oxo-8,9,11,14-tetrahydro-
5H,7H-6,10-dioxa-benzocyclododecen-7-yl)-but-2-enoic
acid 11b. Reaction mixture purified by FC (50% EtOAc in
hexanes with 1% AcOH) to give 111 mg of product 11b
(61% yield for 2 steps). 1H NMR (400 MHz, CDCl3) d 7.36
(1H, t, JZ7.6 Hz), 7.16–7.09 (2H, m), 7.06 (1H, d, JZ
8.4 Hz), 5.96 (1H, d, JZ15.6 Hz), 5.63 (1H, dddd, JZ15.2,
10.4, 4.0, 1.6 Hz), 5.52 (1H, ddd, JZ14.8, 10.8, 3.2 Hz),
5.24 (1H, dddd, JZ11.6, 6.4, 4.8, 1.6 Hz), 4.16 (1H, br.dd,
JZ12.4, 3.6 Hz), 3.87 (1H, dd, JZ13.6, 10.8 Hz), 3.53 (1H,
ddd, JZ10.0, 3.6, 2.4 Hz), 3.40 (1H, dd, JZ12.4, 10.4 Hz),
3.29 (1H, ddd, JZ12.0, 10.8, 1.2 Hz), 3.22 (1H, dddd, JZ
14.0, 3.2, 1.6, 1.6 Hz), 2.75–2.59 (2H, m), 2.27 (3H, s), 1.80
(1H, dddd, JZ16.4, 12.8, 3.6, 1.6 Hz), 1.54 (1H, dddd, JZ
14.4, 12.8, 1.6, 1.6 Hz); 13C NMR (75 MHz, CDCl3) d
177.6, 168.9, 166.6, 148.1, 146.1, 139.3, 133.6, 130.7,
130.4, 129.2, 128.7, 127.9, 127.5, 121.6, 70.7, 70.0, 61.9,
37.7, 34.1, 21.1; MS (ES) m/z 397.10 [MCNa]C; calcd for
C20H22O7Na: 397.13.
3.1.7.3. 12-(2-Hydroxy-ethyl)-5,8,11,12-tetrahydro-
10H-9,13-dioxa-4b-aza-cyclododeca[a]inden-14-one
10d. Reaction mixture purified by FC (40% EtOAc in
1
hexanes) to give 36 mg (94% yield) of product 10d. H
NMR (400 MHz, CDCl3) d 7.65 (1H, d, JZ8.0 Hz), 7.42
(1H, d, JZ8.4 Hz), 7.33 (1H, ddd, JZ8.0, 7.2, 1.2 Hz),
7.16 (1H, dd, JZ7.2, 7.2 Hz), 6.99 (1H, s), 5.80 (1H, ddd,
JZ15.2, 10.0, 4.4 Hz), 5.47 (1H, dddd, JZ11.2, 11.2, 2.4,
2.4 Hz), 5.38 (1H, ddd, JZ14.0, 10.0, 3.2 Hz), 5.00 (1H,
dd, JZ14.4, 10.0 Hz), 4.87 (1H, br d, JZ14.4 Hz), 4.14
(1H, dd, JZ11.6, 4.0 Hz), 3.76–3.70 (2H, m), 3.47 (1H, dt,
JZ10.0, 3.2 Hz), 3.36 (1H, dd, JZ12.4, 10.4 Hz), 3.25
(1H, ddd, JZ12.0, 10.0, 1.6 Hz), 2.79 (1H, br.s), 1.99–
1.83 (2H, m), 1.81 (1H, dddd, JZ14.4, 10.8, 3.6 Hz), 1.71
(1H, dddd, JZ14.0, 11.6, 2.0, 2.0 Hz); 13C NMR
(75 MHz, CDCl3) d 165.7, 138.5, 132.7, 131.1, 130.4,
126.9, 124.6, 122.5, 121.0, 110.0, 107.6, 70.0, 69.7, 62.6,
58.6, 46.1, 38.1, 35.6; MS (ES) m/z 338.10 [MCNa]C;
calcd for C18H21NO4Na: 338.14.
3.1.8.2. 4-(5-Oxo-8,9,11,14-tetrahydro-5H,7H-6,10-
dioxa-benzocyclododecen-7-yl)-but-2-enoic acid 11c.
Reaction mixture purified by FC (40% EtOAc in hexanes
with 1% AcOH) to give 100 mg (57% yield for 2 steps) of
1
the product 11c. H NMR (300 MHz, CDCl3) d 11.2 (1H,
br.s), 7.37–7.22 (4H, m), 7.13 (1H, dt, JZ15.6, 7.2 Hz),
5.96 (1H, d, JZ15.6 Hz), 5.62 (1H, dddd, JZ15.3, 10.5,
4.5, 1.8 Hz), 5.46 (1H, ddd, JZ14.4, 10.8, 2.7 Hz), 5.37
(1H, dddd, JZ11.7, 5.7, 5.7, 3.2 Hz), 4.17 (1H, br.dd, JZ
12.3, 4.2 Hz), 4.00 (1H, dd, JZ13.8, 10.8 Hz), 3.52 (1H, dt,
JZ10.2, 2.4 Hz), 3.38 (1H, dd, JZ12.3, 10.2 Hz), 3.29 (1H,
ddd, JZ12.3, 10.2, 2.1 Hz), 3.15 (1H, dddd, JZ13.8, 3.3,
1.5, 1.5 Hz), 2.75–2.55 (2H, m), 1.85 (1H, dddd, JZ15.9,
12.0, 3.3, 3.3 Hz), 1.63 (1H, dddd, JZ14.4, 12.3, 2.1,
2.1 Hz); 13C NMR (75 MHz, CDCl3) d 177.7, 171.4, 146.4,
138.1, 134.2, 133.7, 130.7, 130.5, 129.4, 127.5, 126.7,
123.9, 70.7, 70.0, 62.0, 38.0, 37.5, 34.3; MS (ES) m/z 339.00
[MCNa]C; calcd for C18H20O5Na: 339.12.
3.1.7.4. 7-(2-Hydroxy-ethyl)-1,2,3,4,8,9,11,14-octa-
hydro-7H-6,10-dioxa-benzocyclododecen-5-one 10e.
Reaction mixture purified by FC (30% EtOAc in hexanes)
to give 42 mg (35% yield, 78% combined yield ECZ) of the
1
E-isomer 10e. H NMR (400 MHz, CDCl3) d 5.48–5.36
(2H, m), 5.25–5.18 (1H, m), 4.10 (1H, br.d, JZ11.6 Hz),
3.64–3.61 (1H, m), 3.52–3.43 (3H, m), 3.39–3.32 (2H, m),
3.10 (1H, br. s), 2.36 (1H, br.d, JZ17.6 Hz), 2.68 (1H, br.d,
JZ14.0 Hz), 2.17 (2H, m), 2.06 (1H, br.d, JZ16.8 Hz),
1.84 (1H, dddd, JZ17.2, 10.4, 5.6, 2.8 Hz), 1.79 (1H, dddd,
JZ16.0, 12.0, 3.2, 2.0 Hz), 1.69–1.56 (6H, m); 13C NMR
(75 MHz, CDCl3) d 172.3, 139.7, 132.6, 129.4, 128.4, 70.6,
67.3, 61.8, 58.3, 38.4, 36.7, 35.6, 32.4, 26.8, 22.6, 21.8; MS
(ES) m/z 303.05 [MCNa]C; calcd for C16H24O4Na: 303.16.
3.1.8.3. 4-(14-Oxo-5,8,11,12-tetrahydro-10H,14H-
9,13-dioxa-4b-aza-cyclododeca[a]inden-12-yl)-but-2-
enoic acid 11d. Reaction mixture purified by FC (50%
EtOAc in hexanes with 1% AcOH) to give 21.4 mg of
3.1.8. Oxidation and HWE olefination. To a solution of
alcohol 10b–e in CH2Cl2 (0.04 M) was added Dess Martin
periodinane (3 equiv). The reaction was stirred at rt for 3–
4 h, after which time the solvent was removed in vacuo and
the residue was quickly passed through a short column of
silica (50% EtOAc in hexanes) to give the aldehyde. To a
suspension of NaH (60% in mineral oil, prewashed with
benzene, 4.5 equiv with respect to alcohol) in THF (0.3 M)
was added dimethyl(trimethylsiloxy-carbonylmethyl)-phos-
phonate (5.0 equiv) at 0 8C. After stirring for 30 min at the
same temperature, the solution was added to a solution of
the above prepared aldehyde (pre-washed with benzene) in
THF (0.1 M with respect to aldehyde) and stirring was
continued for 1 h after which time more phosphonate
solution (same amounts) was added. The mixture was stirred
at 0 8C for 30 min before being quenched with acetic acid.
Water was added, and the solution was extracted with
1
product 11d (53% yield for 2 steps). H NMR (400 MHz,
CDCl3) d 10.15 (1H, br s), 7.65 (1H, d, JZ8.0 Hz), 7.42
(1H, d, JZ8.4 Hz), 7.33 (1H, t, JZ6.8 Hz), 7.16 (1H, t, JZ
7.2 Hz), 7.11 (1H, dt, JZ15.2, 8.0 Hz), 6.9 (1H, s), 5.98
(1H, d, JZ15.2 Hz), 5.79 (1H, ddd, JZ14.8, 10.4, 4.0 Hz),
5.47 (1H, dddd, JZ11.6, 6.0, 6.0, 2.0 Hz), 5.38 (1H, ddd,
JZ14.0, 10.0, 3.6 Hz), 5.00 (1H, dd, JZ14.4, 10.0 Hz),
4.87 (1H, br.d, JZ15.2 Hz), 4.12 (1H, dd, JZ12.8, 6.0 Hz),
3.48 (1H, dt, JZ10.0, 3.2 Hz), 3.38 (1H, dd, JZ12.0,
10.0 Hz), 3.25 (1H, ddd, JZ12.0, 10.0, 2.0 Hz), 2.70–2.61
(2H, m), 1.89 (1H, dddd, JZ14.8, 12.0, 3.2, 3.2 Hz), 1.68
(1H, dddd, JZ14.4, 12.0, 2.4, 2.4 Hz); 13C NMR (75 MHz,
CDCl3) d 163.8, 146.3, 138.4, 132.7, 131.0, 130.4, 126.9,
124.5, 122.6, 120.9, 110.0, 107.5, 70.1, 69.8, 62.5, 46.1,
38.0, 34.7; MS (ES) m/z 378.05 [MCNa]C; calcd for
C20H21NO5Na: 378.13.

9644
S. Lebreton et al. / Tetrahedron 60 (2004) 9635–9647
3.1.8.4. 4-(5-Oxo-1,3,4,5,8,9,11,14-octahydro-2H,7H-
3.1.9.3. 4-(14-Oxo-5,8,11,12-tetrahydro-10H,14H-
9,13-dioxa-4b-aza-cyclododeca[a]inden-12-yl)-but-2-
enoyl azide 12d. Reaction mixture purified by FC (10%
EtOAc in hexanes) to give 20 mg (88% yield) of product
12d. 1H NMR (400 MHz, CDCl3) d 7.66 (1H, d, JZ8.0 Hz),
7.42 (1H, d, JZ8.4 Hz), 7.34 (1H, ddd, JZ8.0, 7.2, 0.8 Hz),
7.16 (1H, t, JZ7.6 Hz), 7.10 (1H, dt, JZ15.2, 7.6 Hz), 6.96
(1H, s), 5.97 (1H, d, JZ15.2 Hz), 5.79 (1H, ddd, JZ15.2,
10.4, 4.8 Hz), 5.47 (1H, dddd, JZ11.6, 6.8, 6.8, 2.4 Hz),
5.38 (1H, ddd, JZ14.4, 10.0, 3.6 Hz), 5.00 (1H, dd, JZ
14.4, 10.0 Hz), 4.87 (1H, br.d, JZ14.0 Hz), 4.12 (1H, dd,
JZ10.8, 3.6 Hz), 3.47 (1H, dt, JZ10.0, 3.2 Hz), 3.37 (1H,
dd, JZ12.4, 10.4 Hz), 3.24 (1H, ddd, JZ11.6, 10.0,
1.6 Hz), 2.68–2.61 (2H, m), 1.88 (1H, dddd, JZ14.4,
11.6, 3.2, 3.2 Hz), 1.67 (1H, dddd, JZ14.4, 12.4, 2.0,
2.0 Hz); 13C NMR (75 MHz, CDCl3) d 163.8, 146.3, 138.5,
132.7, 131.0, 130.3, 126.8, 125.8, 124.5, 122.6, 120.9,
110.0, 107.5, 70.1, 69.7, 62.4, 46.1, 38.2, 34.9; MS (ES) m/z
407.05 [MKN2CMeOHCNa]C; calcd for C21H24N2ONa:
407.16.
6,10-dioxa-benzocyclododecen-7-yl)-but-2-enoic acid
11e. Reaction mixture purified by FC (30% EtOAc in
hexanes with 1% AcOH) to give 25.5 mg of product 11e
(56% yield for 2 steps). 1H NMR (400 MHz, CDCl3) d 7.01
(1H, dt, JZ15.6, 8.0 Hz), 5.84 (1H, d, JZ15.6 Hz), 5.45–
5.34 (2H, m), 5.19 (1H, dddd, JZ11.6, 5.6, 5.6, 2.0 Hz),
4.10 (1H, br.d, JZ11.2 Hz), 3.53 (1H, dt, JZ10.0, 2.8 Hz),
3.44–3.32 (3H, m), 2.63–2.55 (1H, m), 2.45 (1H, dddd, JZ
14.4, 8.0, 7.2, 0.8 Hz), 2.33–2.25 (2H, m), 2.18–2.02 (3H,
m), 1.78 (1H, dddd, JZ16.4, 12.4, 3.6, 2.4 Hz), 1.68–1.56
(5H, m);); 13C NMR (75 MHz, CDCl3) d 171.2, 170.3,
146.8, 138.9, 132.7, 129.8, 128.3, 123.6, 70.8, 67.8, 61.9,
37.9, 36.9, 34.4, 32.4, 26.5, 22.7, 21.8; MS (ES) m/z 343.05
[MCNa]C; calcd for C18H24O5Na: 343.15.
3.1.9. Acyl azide formation. To a stirred solution of the
acid 11b–e and diphenylphosphorylazide (4 equiv) in
benzene (0.03 M) was added triethylamine (4.7 equiv).
The reaction mixture was stirred at rt for 2 h and
concentrated in vacuo prior to purification by FC.
3.1.9.4. 4-(5-Oxo-1,3,4,5,8,9,11,14-octahydro-2H,7H-
6,10-dioxa-benzocyclododecen-7-yl)-but-2-enoyl azide
12e. Reaction mixture purified by FC (10% EtOAc in
3.1.9.1. Acetic acid 7-(3-azidocarbonyl-allyl)-5-oxo-
8,9,11,14-tetrahydro-5H,7H-6,10-dioxa-benzocyclodo-
decen-4-yl ester 12b. Reaction mixture purified by FC
(10% EtOAc in hexanes) to give 82 mg (77% yield) of
product 12b as a colorless oil. 1H NMR (400 MHz, CDCl3)
d 7.36 (1H, t, JZ8.0 Hz), 7.12 (1H, d, JZ7.2 Hz), 7.10
(1H, dt, JZ15.6, 7.6 Hz), 7.06 (1H, d, JZ8.4 Hz), 5.94
(1H, d, JZ15.6 Hz), 5.62 (1H, dddd, JZ14.8, 10.4, 4.4,
1.6 Hz), 5.51 (1H, ddd, JZ14.8, 10.8, 3.6 Hz), 5.23 (1H,
dddd, JZ11.6, 6.4, 4.8, 1.6 Hz), 4.13 (1H, br.dd, JZ12.0,
4.4 Hz), 3.87 (1H, dd, JZ13.6, 10.4 Hz), 3.51 (1H, ddd,
JZ10.4, 3.2, 2.8 Hz), 3.39 (1H, dd, JZ12.4, 10.4 Hz), 3.27
(1H, ddd, JZ12.4, 10.8, 1.6 Hz), 3.21 (1H, dddd, JZ14.0,
3.2, 1.6, 1.6 Hz), 2.71–2.55 (2H, m), 2.26 (3H, s), 1.78
(1H, dddd, JZ16.4, 12.0, 3.6, 1.6 Hz), 1.53 (1H, dddd, JZ
14.4, 12.4, 2.0, 2.0 Hz); 13C NMR (75 MHz, CDCl3) d
171.5, 168.8, 166.7, 148.1, 146.1, 139.4, 133.5, 130.7,
129.4, 127.9, 125.7, 122.9, 121.6, 70.7, 69.9, 61.8, 37.7,
34.4, 21.2; MS (ES) m/z 356.20 [MKH]-; calcd for
C18H18N3O5: 356.13.
1
hexanes) to give 17 mg (67% yield) of product 12e. H
NMR (400 MHz, CDCl3) d 7.01 (1H, dt, JZ15.2, 7.6 Hz),
5.84 (1H, d, JZ15.2 Hz), 5.45–5.36 (2H, m), 5.19 (1H,
dddd, JZ11.6, 5.6, 5.6, 2.0 Hz), 4.10 (1H, br.d, JZ
11.2 Hz), 3.52 (1H, dt, JZ9.6, 2.4 Hz), 3.44–3.31 (3H,
m), 2.57 (1H, app.dt, JZ14.0, 6.8 Hz), 2.43 (1H, app.dt, JZ
14.0, 7.6 Hz), 2.36–2.25 (2H, m), 2.16–1.99 (3H, m), 1.76
(1H, dddd, JZ16.8, 12.4, 3.6, 2.4 Hz), 1.68–1.53 (5H, m);
13C NMR (75 MHz, CDCl3) d 171.6, 170.3, 147.0, 139.1,
132.6, 129.7, 128.3, 125.4, 70.8, 67.7, 61.8, 38.3, 36.9, 34.6,
32.4, 26.5, 22.7, 21.8; MS (ES) m/z 372.10 [MKN2C
MeOHCNa]C; calcd for C19H27NO5Na: 372.18.
3.1.10. Curtius rearrangement and alkyne addition. A
stirred solution of the acylazide 12b–e in benzene (0.02 M)
was heated at 80 8C for 5 h, after which the solvent was
steamed off with nitrogen and the residue dried under
vacuum for 10 min. To a solution of the alkyne (2.0 equiv)
in THF (0.1 M) at K78 8C was added n-BuLi (2.5 M in
hexanes, 1.7 equiv) or the alkyne was added to a freshly
prepared solution of LDA in THF (0.1 M). The stirring was
continued for 30 min, after which time a solution of the
isocyanate mixture in THF was added. The reaction mixture
was stirred at K78 8C for 30 min, and then quenched with
saturated NH4Cl and water. The mixture was extracted with
Et2O (3!). The combined organic layers were dried over
MgSO4 and concentrated in vacuo. If no acetate group was
present, the residue was purified by FC. When an acetate
group was present, the residue was dissolved in MeOH and
K2CO3 (1 equiv) was added. The mixture was stirred at rt
for 1 h, after which time water was added and the mixture
was extracted with Et2O (3!). The combined organic layers
were dried, concentrated in vacuo, and purified by FC.
3.1.9.2. 4-(5-Oxo-8,9,11,14-tetrahydro-5H,7H-6,10-
dioxa-benzocyclododecen-7-yl)-but-2-enoyl azide 12c.
Reaction mixture purified by FC (10% EtOAc in hexanes)
to give 61 mg (56% yield) of product 12c. 1H NMR
(400 MHz, CDCl3) d 7.37 (1H, app.dt, JZ7.6, 1.2 Hz), 7.33
(1H, d, JZ7.6 Hz), 7.27 (1H, app.t, JZ7.6 Hz), 7.23 (1H, d,
JZ7.6 Hz), 7.10 (1H, dt, JZ15.2, 8.0 Hz), 5.95 (1H, d, JZ
15.2 Hz), 5.61 (1H, dddd, JZ15.2, 10.4, 4.4, 1.6 Hz), 5.46
(1H, ddd, JZ14.4, 10.8, 3.2 Hz), 5.37 (1H, dddd, JZ12.0,
6.4, 6.4, 2.4 Hz), 4.14 (1H, dd, JZ12.0, 4.4 Hz), 4.00 (1H,
dd, JZ14.0, 10.8 Hz), 3.49 (1H, dt, JZ10.0, 2.8 Hz), 3.37
(1H, dd, JZ12.4, 10.4 Hz), 3.27 (1H, ddd, JZ12.0, 10.0,
1.6 Hz), 3.15 (1H, dddd, JZ14.0, 3.2, 1.6, 1.6 Hz), 2.72–
2.55 (2H, m), 1.82 (1H, dddd, JZ16.4, 12.0, 3.6, 2.4 Hz),
1.61 (1H, dddd, JZ13.6, 12.0, 2.0, 2.0 Hz); 13C NMR
(75 MHz, CDCl3) d 171.5, 169.0, 146.6, 138.2, 134.2,
133.6, 130.7, 130.6, 129.5, 127.4, 126.7, 125.6, 70.7, 68.9,
61.9, 38.3, 37.6, 34.6; MS (ES) m/z 368.10 [MKN2C
MeOHCNa]C; calcd for C19H23NO5Na: 368.15.
3.1.10.1. 3-Phenyl-propynoic acid [3-(4-hydroxy-5-
oxo-8,9,11,14-tetrahydro-5H,7H-6,10-dioxa-benzocyclo-
dodecen-7-yl)-propenyl]-amide 14a. n-BuLi was used.
Reaction mixture purified by FC (40% EtOAc in hexanes) to
give 23.6 mg (62% yield) of product 14a. [a]DZK19.3

S. Lebreton et al. / Tetrahedron 60 (2004) 9635–9647
9645
1
(cZ1.52, CH2Cl2). H NMR (400 MHz, CD3OD) d 7.59
to give 10 mg (50% yield) of product 14e. [a]DZK65.1
(cZ0.48, CH2Cl2). H NMR (400 MHz, CD3OD) d 7.59
1
(2H, d, JZ7.2 Hz), 7.48 (1H, t, JZ7.6 Hz), 7.41 (2H, d, JZ
8.0 Hz), 7.15 (1H, t, JZ8.0 Hz), 6.84 (1H, d, JZ14.4 Hz),
6.77 (1H, d, JZ8.4 Hz), 6.72 (1H, d, JZ7.6 Hz), 5.56–5.53
(2H, m), 5.49 (1H, dt, JZ14.4, 8.0 Hz), 5.11–5.05 (1H, m),
4.10 (1H, d, JZ10.8 Hz), 3.71 (1H, dd, JZ13.2, 10.0 Hz),
3.54 (1H, br d, JZ10.0 Hz), 3.44 (1H, dd, JZ12.4,
10.0 Hz), 3.38 (1H, d, JZ10.8 Hz), 3.15 (1H, d, JZ
13.2 Hz), 2.49 (2H, dd, JZ6.4, 6.4 Hz, m), 1.80 (1H, dd,
JZ14.8, 11.6 Hz), 1.60 (1H, dd, JZ14.4, 12.4 Hz); 13C
NMR (75 MHz, CD3OD3) d 170.5, 156.4, 152.4, 139.6,
135.3, 133.7, 131.7, 130.0, 129.9, 125.9, 123.9, 122.2,
121.5, 115.6, 111.7, 87.3, 83.7, 71.8, 71.6, 63.4, 38.7, 36.2,
34.7; MS (ES) m/z 454.20 [MCNa]C; calcd for
C26H25NO5Na: 454.16.
(2H, d, JZ8.4 Hz), 7.49 (1H, app.t, JZ7.6 Hz), 7.43 (2H,
d, JZ7.6 Hz), 6.76 (1H, d, JZ14.4 Hz), 5.46 (1H, ddd,
JZ14.8, 10.8, 3.6 Hz), 5.39–5.33 (1H, m), 5.35 (1H, dt,
JZ14.4, 7.2 Hz), 5.03 (1H, dddd, JZ11.6, 6.0, 6.0,
2.0 Hz), 4.05 (1H, br.dd, JZ12.0, 3.6 Hz), 3.51 (1H,
app.dt, JZ10.0, 2.8 Hz), 3.40 (1H, dd, JZ12.0, 10.0 Hz),
3.36–3.30 (2H, m), 2.40–2.16 (6H, m), 2.07–2.00 (1H, m),
1.78 (1H, dddd, JZ17.2, 12.8, 4.0, 2.4 Hz), 1.68–1.60
(4H, m), 1.55 (1H, dddd, JZ14.4, 12.4, 2.0, 2.0 Hz); 13C
NMR (75 MHz, CD3OD) d 170.6, 151.1, 138.6, 132.5,
132.4, 130.4, 129.9, 128.7, 128.0, 124.4, 120.1, 110.2,
86.0, 82.3, 70.2, 69.0, 61.8, 36.4, 35.4, 33.8, 31.9, 26.4,
22.5, 21.6; MS (ES) m/z 442.10 [MCNa]C; calcd for
C26H29NO4Na: 442.20.
3.1.10.2. 3-Phenyl-propynoic acid [3-(5-oxo-8,9,11,14-
tetrahydro-5H,7H-6,10-dioxa-benzocyclododecen-7-yl)-
propenyl]-amide 14c. n-BuLi was used. Reaction mixture
purified by FC (40% EtOAc in hexanes) to give 9.3 mg
(97% yield) of product 14c. [a]DZK66.8 (cZ0.63,
3.1.10.5. 3-(3-Fluoro-phenyl)-propynoic acid [3-(4-
hydroxy-5-oxo-8,9,11,14-tetrahydro-5H,7H-6,10-dioxa-
benzocyclododecen-7-yl)-propenyl]-amide 16. n-BuLi
was used. Reaction mixture purified by FC (40% EtOAc
1
1
CH2Cl2). H NMR (400 MHz, CD3OD) d 7.58 (2H, d, JZ
in hexanes) to give 9.2 mg (52% yield) of product 16. H
8.0 Hz), 7.47 (1H, d, JZ7.2 Hz), 7.43–7.37 (4H, m), 7.31–
7.27 (2H, m), 6.89 (1H, d, JZ14.4 Hz), 5.56 (1H, dddd, JZ
15.2, 10.4, 4.4, 1.6 Hz), 5.49 (1H, ddd, JZ14.4, 10.0,
3.2 Hz), 5.45 (1H, dt, JZ15.2, 8.4 Hz), 5.20 (1H, ddd, JZ
11.6, 6.0, 6.0, 2.0 Hz), 4.09 (1H, br.dd, JZ12.0, 3.2 Hz),
3.92 (1H, dd, JZ14.0, 10.8 Hz), 3.49 (1H, dt, JZ10.0,
2.4 Hz), 3.40 (1H, dd, JZ12.0, 9.6 Hz), 3.33–3.28 (1H, m),
3.19 (1H, br.d, JZ13.6 Hz), 2.53–2.38 (2H, m), 1.84 (1H,
dddd, JZ16.0, 12.4, 3.6, 2.4 Hz), 1.60 (1H, dddd, JZ14.4,
12.4, 2.0, 2.0 Hz); 13C NMR (75 MHz, CDCl3) d 170.8,
152.5, 139.2, 135.8, 134.9, 133.7, 131.7, 131.6, 130.6,
130.0, 128.6, 127.8, 125.9, 122.5, 11.5, 87.4, 83.6, 71.5,
71.3, 63.3, 38.4, 36.9, 35.2; MS (ES) m/z 438.15
[MCNa]C; calcd for C26H25NO4Na: 438.17.
NMR (400 MHz, CD3OD) d 7.47–7.40 (2H, m), 7.34 (1H,
ddd, JZ9.2, 2.8, 1.6 Hz), 7.25 (1H, dddd, JZ10.8, 8.8,
2.8, 1.6 Hz), 7.15 (1H, t, JZ7.6 Hz), 6.83 (1H, d, JZ
14.4 Hz), 6.75 (1H, d, JZ8.4 Hz), 6.73 (1H, d, JZ
7.2 Hz), 5.57–5.53 (2H, m), 5.50 (1H, dt, JZ14.4,
8.0 Hz), 5.08 (1H, dddd, JZ11.6, 5.6, 5.6, 2.4 Hz), 4.10
(1H, d, JZ12.0 Hz), 3.71 (1H, dd, JZ13.6, 10.0 Hz), 3.54
(1H, ddd, JZ10.4, 3.6, 2.4 Hz), 3.44 (1H, dd, JZ12.4,
10.0 Hz), 3.37 (1H, ddd, JZ12.0, 10.4, 1.6 Hz), 3.15 (1H,
br.d, JZ13.6 Hz), 2.49 (2H, ddd, JZ7.2, 6.0, 1.2 Hz),
1.80 (1H, dddd, JZ16.4, 12.8, 4.0, 2.4 Hz), 1.60 (1H,
dddd, JZ14.4, 12.0, 1.6, 1.6 Hz); 13C NMR (75 MHz,
CD3OD) d 170.5, 165.6, 162.3, 156.5, 152.0, 139.6, 135.3,
132.1, 132.0, 131.7, 129.9, 125.8, 123.9, 122.1, 120.3,
120.0, 119.1, 118.8, 115.6, 112.0, 85.5, 84.3, 71.8, 71.6,
63.4, 38.7, 36.2, 34.8; MS (ES) m/z 472.25 [MCNa]C;
calcd for C26H24FNO5Na: 472.15.
3.1.10.3. 3-Phenyl-propynoic acid [3-(14-oxo-
5,8,11,12-tetrahydro-10H,14H-9,13-dioxa-4b-aza-cyclo-
dodeca[a]inden-12-yl)-propenyl]-amide 14d. n-BuLi was
used. Reaction mixture purified by FC (30% EtOAc in
hexanes) to give 12 mg (79% yield) of product 14d.
[a]DZK167.6 (cZ0.50, CH2Cl2). 1H NMR (400 MHz,
CD3OD) d 7.62 (1H, d, JZ8.0 Hz), 7.57 (2H, d, JZ8.0 Hz),
7.52 (1H, d, JZ8.4 Hz), 7.45 (1H, d, JZ7.2 Hz), 7.40 (2H,
d, JZ8.0 Hz), 7.30 (1H, dd, JZ7.2, 7.2 Hz), 7.11 (1H, t,
JZ7.6 Hz), 6.95 (1H, s), 6.89 (1H, d, JZ14.4 Hz), 5.72
(1H, ddd, JZ14.8, 10.0, 4.8 Hz), 5.46 (1H, ddd, JZ14.4,
6.8, 6.8 Hz), 5.42–5.28 (2H, m), 5.01 (1H, br.d, JZ
10.4 Hz), 4.92 (1H, br.d, JZ14.8 Hz), 4.11–4.04 (1H, m),
3.46 (1H, br.d, JZ9.2 Hz), 3.42 (1H, dd, JZ12.0, 10.0 Hz),
3.31–3.26 (1H, m), 2.49–2.42 (2H, m), 1.90 (1H, dddd, JZ
14.4, 11.6, 3.2, 3.2 Hz), 1.65 (1H, dddd, JZ14.4, 12.0, 2.4,
2.4 Hz); 13C NMR (75 MHz, CD3OD) d 173.1, 165.4, 152.5,
139.9, 133.7, 133.6, 132.6, 131.8, 130.1, 130.0, 128.2,
126.0, 125.4, 123.3, 121.8, 121.5, 111.4, 111.1, 108.0, 87.4,
83.7, 72.3, 70.8, 63.8, 47.0, 36.8, 35.5; MS (ES) m/z 477.20
[MCNa]C; calcd for C28H26N2O4Na: 477.18.
3.1.10.6. 3-Pyridin-3-yl-propynoic acid [3-(4-
hydroxy-5-oxo-8,9,11,14-tetrahydro-5H,7H-6,10-dioxa-
benzocyclododecen-7-yl)-propenyl]-amide 17. LDA was
used. Reaction mixture purified by PTLC (neat EtOAc) to
give 1.8 mg (47% yield) of product 17. [a]DZK8.22 (cZ
0.18, CH2Cl2). 1H NMR (400 MHz, CD3OD) d 8.75 (1H, d,
JZ2.0 Hz), 8.63 (1H, dd, JZ4.8, 1.6 Hz), 8.04 (1H, ddd,
JZ8.0, 1.6, 1.6 Hz), 7.51 (1H, dd, JZ7.6, 4.8 Hz), 7.16
(1H, t, JZ7.6 Hz), 6.85 (1H, d, JZ14.4 Hz), 6.76 (1H, d,
JZ8.4 Hz), 6.73 (1H, d, JZ7.6 Hz), 5.58–5.49 (3H, m),
5.12–5.06 (1H, m), 4.11 (1H, d, JZ10.0 Hz), 3.73 (1H, dd,
JZ13.2, 10.0 Hz), 3.56 (1H, br d, JZ10.0 Hz), 3.45 (1H,
dd, JZ12.4, 10.0 Hz), 3.39 (1H, d, JZ10.4 Hz), 3.16 (1H,
br d, JZ13.2 Hz), 2.51 (2H, dd, JZ6.4, 6.4 Hz), 1.81 (1H,
dd, JZ14.8, 12.4 Hz), 1.62 (1H, dd, JZ14.8, 12.0 Hz); MS
(ES) m/z 455.10 [MCNa]C; calcd for C25H24N2ONa:
455.16.
3.1.10.7. 3-Oxazol-2-yl-propynoic acid [3-(4-
hydroxy-5-oxo-8,9,11,14-tetrahydro-5H,7H-6,10-dioxa-
benzocyclododecen-7-yl)-propenyl]-amide 18. LDA was
used. Reaction mixture purified by FC (50% EtOAc in
hexanes) to give 4.3 mg (56% yield) of product 18.
3.1.10.4. 3-Phenyl-propynoic acid [3-(5-oxo-
1,3,4,5,8,9,11,14-octahydro-2H,7H-6,10-dioxa-benzocy-
clododecen-7-yl)-propenyl]-amide 14e. n-BuLi was used.
Reaction mixture purified by FC (30% EtOAc in hexanes)

9646
S. Lebreton et al. / Tetrahedron 60 (2004) 9635–9647
[a]DZK13.2 (cZ0.25, CH2Cl2). 1H NMR (400 MHz,
CD3OD) d 8.08 (1H, d, JZ0.8 Hz), 7.37 (1H, d, JZ
0.8 Hz), 7.15 (1H, t, JZ8.0 Hz), 6.83 (1H, d, JZ14.4 Hz),
6.77 (1H, d, JZ8.4 Hz), 6.73 (1H, d, JZ7.6 Hz), 5.59–
5.51 (3H, m), 5.09 (1H, dddd, JZ11.2, 6.8, 4.8, 2.0 Hz),
4.10 (1H, br.d, JZ12.0 Hz), 3.71 (1H, dd, JZ13.6,
10.0 Hz), 3.55 (1H, br.d, JZ9.2 Hz), 3.45 (1H, dd, JZ
12.0, 10.0 Hz), 3.38 (1H, d, JZ10.8 Hz), 3.16 (1H, br.d,
JZ13.6 Hz), 2.53–2.48 (2H, m), 1.80 (1H, dddd, JZ16.8,
12.4, 4.0, 2.4 Hz), 1.61 (1H, dd, JZ14.4, 12.4 Hz); 13C
NMR (75 MHz, CD3OD3) d 170.5, 156.5, 150.1, 143.8,
139.6, 135.3, 131.7, 130.1, 129.9, 125.5, 123.9, 122.1,
115.6, 113.0, 84.8, 71.7, 71.6, 63.4, 38.7, 36.2, 34.7; MS
(ES) m/z 445.10 [MCNa]C; calcd for C23H22N2O6Na:
445.14.
128.0, 124.0, 122.1, 115.5, 106.4, 72.2, 71.6, 66.4, 63.5,
38.7, 36.1, 34.5, 30.0, 29.3, 23.6, 14.5; MS (ES) m/z
440.20 [MCNa]C; calcd for C23H31NO6Na: 440.20;
481.30 [MCCH3CNCNa]C; calcd for C25H34N2O6Na:
481.23.
3.1.11.3. [3-(4-Hydroxy-5-oxo-8,9,11,14-tetrahydro-
5H,7H-6,10-dioxa-benzocyclododecen-7-yl)-propenyl]-
carbamic acid oxazol-2-ylmethyl ester 21. Reaction
mixture purified by FC (50% EtOAc in hexanes) to give
6.2 mg (58% yield) of product 21. [a]DZK11.0 (cZ0.26,
CH2Cl2). 1H NMR (400 MHz, CD3OD) d 7.94 (1H, s), 7.19
(1H, s), 7.15 (1H, t, JZ8.0 Hz), 6.75 (1H, d, JZ8.0 Hz),
6.72 (1H, d, JZ8.0 Hz), 6.52 (1H, d, JZ14.4 Hz), 5.56–
5.54 (2H, m), 5.21 (1H, dt, JZ13.6, 8.0 Hz), 5.20 (2H, s),
5.07–5.00 (1H, m), 4.10 (1H, br.d, JZ10.8 Hz), 3.70 (1H,
dd, JZ13.6, 10.4 Hz), 3.54 (1H, ddd, JZ9.6, 32, 2.4 Hz),
3.43 (1H, dd, JZ12.4, 10.4 Hz), 3.36 (1H, ddd, JZ12.0,
104, 1.6 Hz), 3.15 (1H, d, JZ13.6 Hz), 2.44 (2H, app.t, JZ
6.4 Hz), 1.78 (1H, br.dd, JZ14.8, 11.6 Hz), 1.59 (1H, br.dd,
JZ14.4, 12.4 Hz); 13C NMR (75 MHz, CD3OD) d 170.5,
161.6, 156.4, 141.8, 139.6, 135.3, 131.7, 129.8, 128.2,
127.7, 124.0, 122.1, 115.5, 107.5, 72.1, 71.6, 63.4, 59.2,
38.7, 36.0, 34.5; MS (ES) m/z 451.10 [MCNa]C; calcd for
C22H24N2O7Na: 451.15.
3.1.11. Curtius rearrangement and alcohol addition. To a
stirred solution of acylazide 12b in benzene (0.02 M) was
added the alcohol (20 equiv). The reaction mixture was
heated at 80 8C for 5 h, after which the solvent was steamed
off with nitrogen. The residue was dissolved in MeOH and
K2CO3 (1 equiv) was added. The mixture was stirred at rt
for 1 h, after which time water was added and the mixture
was extracted with Et2O (3!). The combined organic layers
were dried over MgSO4, concentrated in vacuo, and purified
by FC.
3.1.11.1. [3-(4-Hydroxy-5-oxo-8,9,11,14-tetrahydro-
5H,7H-6,10-dioxa-benzocyclododecen-7-yl)-propenyl]-
carbamic acid benzyl ester 19. Reaction mixture purified
by FC (30% EtOAc in hexanes) to give 6.5 mg (85% yield)
3.2. Cytotoxicity assay
Human non-small cell lung tumor cells (A549 and NCI-
H460) were plated in 96 well plates on Day 0. Cells were
treated with serial dilutions of analogue between 0.1 nM
and 10 mM (ranges were adjusted for the activity of each
analogue) on Day 1. Control cells were treated with
vehicle (DMSO) alone. The surviving fraction of cells in
the presence of drug was calculated using the sulforhoda-
mine B assay as previously described (Skehan, P. et al.
New colorimetric cytotoxicity assay for anticancer-drug
screening. J. Natl. Cancer Inst. 1990, 82, 1107–1112;
Papazisis, K. T.; Geromichalos, G. D.; Dimitriadis, K. A.;
Kortsaris, A. H. Optimization of the sulforhodamine B
colorimetric assay. J. Immunol. Methods 1997, 208, 151–
158). Briefly, the cells were fixed on Day 5 (96 h post-
treatment) with 50% w/v trichloroacetic acid, dried
overnight, and stained with 0.4% sulforhodamine B in
1% acetic acid. Fractional survival was determined by
dividing the average absorbance (A492) value of test wells
by control wells. Each condition was replicated in 6 wells.
The fractional survival values were plotted against the
log[analog concentration] to determine the IC50 value for
each analog and cell line.
1
of product 19. [a]DZK6.8 (cZ0.34, CH2Cl2). H NMR
(400 MHz, CD3OD) d 7.37–7.30 (5H, m), 7.15 (1H, t, JZ
8.0 Hz), 6.74 (1H, d, JZ8.8 Hz), 6.72 (1H, d, JZ8.0 Hz),
6.52 (1H, d, JZ14.4 Hz), 5.56–5.53 (2H, m), 5.17 (1H, dt,
JZ14.0, 8.0 Hz), 5.12 (2H, s), 5.05–4.99 (1H, m), 4.08 (1H,
d, JZ10.8 Hz), 3.70 (1H, dd, JZ13.6, 10 Hz), 3.53 (1H, br
d, JZ10 Hz), 3.43 (1H, dd, JZ11.6, 10 Hz), 3.36 (1H, br.t,
JZ10.8 Hz), 3.15 (1H, d, JZ13.2 Hz), 2.45–2.39 (2H, m),
1.79 (1H, dd, JZ14.4, 12.4 Hz), 1.57 (1H, dd, JZ13.6,
13.2 Hz); 13C NMR (75 MHz, CD3OD) d 170.6, 156.5,
139.6, 135.3, 131.7, 129.8, 129.7, 129.3, 129.1, 127.9,
124.0, 122.1, 115.6, 106.8, 101.8, 72.2, 71.6, 67.8, 63.5,
38.7, 36.0, 34.5; MS (ES) m/z 460.10 [MCNa]C; calcd for
C25H27NO6Na: 460.17.
3.1.11.2. [3-(4-Hydroxy-5-oxo-8,9,11,14-tetrahydro-
5H,7H-6,10-dioxa-benzocyclododecen-7-yl)-propenyl]-
carbamic acid pentyl ester 20. [a]DZK58.9 (cZ2.21,
CH2Cl2); Reaction mixture purified by FC (20% EtOAc
1
in hexanes) to give 7 mg (71% yield) of product 20. H
NMR (400 MHz, CD3OD) d 7.16 (1H, t, JZ8.0 Hz),
6.76 (1H, d, JZ8.0 Hz), 6.74 (1H, d, JZ8.0 Hz), 6.51
(1H, d, JZ14.4 Hz), 5.57–5.54 (2H, m), 5.15 (1H, dt,
JZ14.8, 8.0 Hz), 5.03 (1H, dddd, JZ12.0, 6.8, 4.4,
2.4 Hz), 4.12–4.06 (3H, m), 3.71 (1H, dd, JZ14.0,
10.4 Hz), 3.55 (1H, ddd, JZ10.4, 3.6, 2.4 Hz), 3.44 (1H,
dd, JZ12.4, 10.4 Hz), 3.37 (1H, ddd, JZ12.4, 10.4,
2.0 Hz), 3.16 (1H, d, JZ13.6 Hz), 2.46–2.38 (2H, m),
1.81 (1H, dddd, JZ16.8, 12.4, 3.6, 2.4 Hz), 1.67–1.62
(2H, m), 1.58 (1H, ddt, JZ14.4, 12.0, 2.4 Hz), 1.39–1.37
(4H, m), 0.94 (3H, t, JZ7.2 Hz); 13C NMR (75 MHz,
CD3OD) d 170.5, 156.4, 139.6, 135.3, 131.7, 129.9,
Acknowledgements
Financial support provided by the Robert A. Welch
Foundation and the National Institutes of Health through
grants CA 90349 and CA 95471 (J.K. De Brabander) and
DK 33627 (X.-S. Xie) is gratefully acknowledged. J.K.
De Brabander is a fellow of the Alfred P. Sloan
Foundation.

S. Lebreton et al. / Tetrahedron 60 (2004) 9635–9647
9647
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