Total synthesis of (-)-salicylihalamide.

Article abstract of DOI:10.1002/1521-3765(20011217)7:24<5286::AID-CHEM5286>3.0.CO;2-G

A concise total synthesis of the potent cytotoxic marine natural products salicylihalamide A and B (la, b) is reported. Key steps of our approach were the asymmetric hydrogenation reactions of beta-keto esters 18 and 32 catalyzed by [((S)-BINAP)Ru-Cl2]2. NEt3 and the cyclization of the macrolide core by ring closing olefin metathesis (RCM) using the "second-generation" ruthenium carbene complex 24 as the catalyst which bears an imidazol-2-ylidene ligand. The EIZ ratio obtained in this macrocyclization reaction was determined by the protecting groups at the remote phenolic OH group of the cyclization precursor. The elaboration of the resulting cycloalkene 37 into the final target involved a CrCl2-mediated synthesis of vinyliodide 49 which, after deprotection, did undergo a copper-catalyzed cross-coupling process with the (Z,Z)-configurated carboxamide 42 to form the labile enamide moiety of 1. Compound 42 was derived from a palladium-catalyzed Negishi coupling between butynylzinc chloride and 3-iodoacrylate 39 followed by a Lindlar reduction of enyne 40 thus obtained and a final aminolysis of the ester group.

Full text of DOI:10.1002/1521-3765(20011217)7:24<5286::AID-CHEM5286>3.0.CO;2-G

FULL PAPER
Total Synthesis of (À)-Salicylihalamide
Alois F¸rstner,* Thorsten Dierkes, Oliver R. Thiel, and Gaetano Blanda[a]
Abstract: A concise total synthesis of
the potent cytotoxic marine natural
imidazol-2-ylidene ligand. The E/Z ratio
obtained in this macrocyclization reac-
tion was determined by the protecting
groups at the remote phenolic OH group
of the cyclization precursor. The elabo-
ration of the resulting cycloalkene 37
into the final target involved a CrCl2-
mediated synthesis of vinyliodide 49
which, after deprotection, did undergo
a copper-catalyzed cross-coupling proc-
ess with the (Z,Z)-configurated carbox-
amide 42 to form the labile enamide
moiety of 1. Compound 42 was derived
from a palladium-catalyzed Negishi cou-
pling between butynylzinc chloride and
3-iodoacrylate 39 followed by a Lindlar
reduction of enyne 40 thus obtained and
a final aminolysis of the ester group.
products salicylihalamide A and
B
(1a, b) is reported. Key steps of our
approach were the asymmetric hydro-
genation reactions of b-keto esters 18
and 32 catalyzed by [((S)-BINAP)Ru-
Cl2]2 ¥ NEt3 and the cyclization of the
macrolide core by ring closing olefin
metathesis (RCM) using the ™second-
generation∫ ruthenium carbene com-
plex 24 as the catalyst which bears an
Keywords: cross-coupling ¥ macro-
cycles ¥ metathesis ¥ natural prod-
ucts ¥ ruthenium
Introduction
Bioassay-guided fractionation of the extracts of an unidenti-
fied sponge of the Haliclona genus collected off the South-
western Australian coast led to the discovery of two novel
macrolide antibiotics called salicylihalamide A (1a) and B
(1b).[1, 2] These compounds exhibited remarkably potent
cytotoxicity in the 60-cell-line human tumor assay from the
National Cancer Institute (NCI), with a mean GI50 concen-
tration of only about 15 nm. The melanoma cell lines showed
the highest average sensitivity (GI50 ˆ 7 nm, TGI ˆ 60 nm).
Most notably, however, the activity profile of salicylihalamide
in this assay showed no significant correlation to other
compounds in the NCI database, indicating a novel mecha-
nism of action.[1] From subsequent biochemical studies it was
lobatamide A (4),[6] or CJ-12950 (5).[7] In addition to the
obvious constitutional and topological resemblance, these
novel enamides also show pronounced cytotoxic activities
against various human cancer cell lines and share with 1 a
common mode of action.[3]
‡
concluded that 1 does inhibit mammalian vacuolar-type (H )-
While the promising biological properties render salicyli-
halamide and congeners relevant targets for total synthesis,
their unusual structural features provide an excellent forum
for the validation of new synthetic methods. In this context, a
truncated version of 1 was synthesized using olefin metathesis
for the cyclization of the 12-membered ring and its biological
activity has been evaluated.[8] Our study has provided strong
evidence that the cytotoxicity of 1 is intimately related to the
presence of an intact enamide bond and has also clearly
featured the relevance of ring closing metathesis (RCM) as a
strategic manoeuvre en route to this family of natural
products. In fact, RCM later became the key transformation
in all preparative approaches towards 1 and analogues thereof
ATPases (V-ATPases) with an unprecedented selectivity; this
suggests that these proton-translocating pumps may consti-
tute a novel molecular target for cancer therapeutic agents.[3]
The most striking structural motif of 1 is the labile enamide
linkage connecting a polyunsaturated domain with a salicylic
acid derived macrolactone core. Since the discovery of 1a, b
in 1997, several closely related natural products have been
reported, including oximidine I (2),[4] apicularene A (3),[5]
[a] Prof. Dr. A. F¸rstner, Dipl.-Chem. T. Dierkes, Dr. O. R. Thiel,
Dr. G. Blanda
Max-Planck-Institut f¸r Kohlenforschung
Kaiser-Wilhelm-Platz 1, 45470 M¸lheim an der Ruhr (Germany)
Fax : (‡49)208-306-2994
reported so far, including the first total syntheses of this
11]
E-mail: fuerstner@mpi-muelheim.mpg.de
rewarding target.[9
A particularly noteworthy spin-off of
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5286 5298
these studies is the fact that the absolute stereochemistry of
salicylihalamide had to be revised and is now assigned as it
appears in structure 1 (12S,13R,15S).[9a, 12]
Described below is a full account of our work in this field.
Specifically, we outline a concise and inherently flexible
approach to the core segment of 1 which relies on asymmetric
hydrogenation reactions for the formation of the chiral
centers. The efficient cyclization of the macrolide ring by
RCM lends further credence to the notion that ™second-
generation∫ ruthenium carbene complexes are superior
catalysts for this type of transformation. Finally, the enamide
moiety of the target was formed by a copper-catalyzed cross
coupling process which delivered this rather labile structural
motif in good yield.
Scheme 1. Retrosynthetic analysis of salicylihalamide 1.
reductions, ii) promises reagent control over the absolute
stereochemistry of the chiral centers formed, and hence
iii) provides access to all possible diastereoisomers of 1, if
desirable, simply by changing the chiral ligands to the
hydrogenation catalysts.
Preparation of the salicylic acid part: Two different syntheses
of the required salicylic acid part of 1a, b have been
developed. The first one used cheap 2,6-dihydroxybenzoic
acid (6) as the starting material which was converted on a
multigram scale into triflate 8 by formation of the isopropy-
lidene derivative 7[17] and subsequent reaction with triflic
anhydride under standard conditions (Scheme 2).[18] This
compound was allylated in high yield by a modified Suzuki-
type reaction[19] according to a procedure previously devel-
oped in this laboratory.[20] Specifically, 9-allyl-9-BBN was
treated with KOMe to afford a mixture of borate complexes
Results and Discussion
Retrosynthetic analysis: Anticipating the formation of the
macrolide ring by RCM,[13] salicylihalamide can be deconvo-
luted into three synthons as shown in Scheme 1. Among the
different possible disconnections for the enamide linkage,[14]
we opted for a cross-coupling approach aiming at the direct
À
formation the C N bond, which led back to a suitably
functionalized vinyl halide core and an unsaturated amide
side chain as the precursors. This strategy expands on model
studies that were recently disclosed;[15] it holds the promise to
be straightforward and flexible and may therefore outperform
the methodology previously used en route to 1.[9] Since the
enamide certainly constitutes a fragile linkage, its formation
was postponed to the very end of the synthesis. Preferentially,
it should be installed in the presence of the free OH groups
because any deprotection step after the enamide formation
might destroy this labile moiety. It was by no means clear at
the beginning of this study whether the envisaged cross-
coupling methodology would meet this serious constraint.
Although the aliphatic segment carrying the chiral centers
of the molecule is certainly accessible by various routes, the
application of asymmetric hydrogenation reactions seemed to
be particularly appealing.[16] This strategy can i) deliver the
target by two iterative cycles of b-keto ester formations/
Scheme 2. [a] Acetone, SOCl2, DMAP, DME, 96%; [b] triflic anhydride,
pyridine, 85%; [c] 9-allyl-9-BBN, KOMe, cat. [PdCl2(dppf)], THF, 83%;
[d] BCl3, CH2Cl2, 96%. BBN ˆ 9-borabicyclo[3.3.1]nonane, dppf ˆ Fe(h5-
C5H4PPh2)2, DMAP ˆ dimethylaminopyridine, DME ˆ dimethoxyethane.
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A. F¸rstner et al.
FULL PAPER
which rapidly transfer the allyl group to the triflate in the
presence of catalytic amounts of [PdCl2(dppf)]. Subsequent
cleavage of the isopropylidene moiety of 9 was best achieved
with BCl3 in CH2Cl2 at 08C, affording the desired salicylic acid
10 in almost quantitative yield.
Alternatively, the corresponding methyl ether 12 can be
conveniently prepared from commercial 2-methoxybenzoic
acid (11) by ortho-metalation using sBuLi followed by
trapping of the resulting aryllithium species with allyl bromide
at low temperature (Scheme 3).[21] Although the yield of this
reaction amounted only to 48%, this approach was appealing
in terms of its unrivaled ™economy of steps∫.[22]
Scheme 3. Synthesis of the required salicylic acid part by ortho-metal-
ation.[21]
Model studies on RCM: At the outset of our project, the
enantiomer of 1 was targeted because of the incorrect
assignment of the absolute stereochemistry of salicylihala-
mide in the original publication (see above).[1, 12] Therefore,
the model studies reported below concerning the crucial
RCM step have been conducted in the wrong enantiomeric
series.
Scheme 4. [a] i) LiHMDS, THF, À788C, 30 min; ii) dimethylallyl bro-
mide, 08C, 16 h, 85%; [b] LiOH, H2O2, THF/H2O, 0 8C, 99%; [c] 17,
CH2Cl2, 90 min; [d] i) LDA, methyl acetate, THF, À788C, 1 h; ii) addition
of crude 16, RT, 2 h, 81%; [e] [((R)-BINAP)RuCl2]2 ¥ NEt3 (0.8 mol%), H2
(4 atm), MeOH, 808C, 4 h, 96%; [f] TBSOTf, 2,6-lutidine, CH2Cl2, 08C,
1 h, 95%; [g] MOMCl, iPr2NEt, DMAP cat., CH2Cl2, 40 h, 90%; [ h]
LiBEt3H, THF, RT, 83% (R ˆ TBS), 98% (R ˆ MOM); [i] DEAD, PPh3,
Et2O, 96 % (25a), 81% (25b). DEAD ˆ diethyl azodicarboxylate,
MOMCl ˆ methoxymethyl chloride.
Our synthesis began with an asymmetric alkylation reaction
of the oxazolidinone derivative 13 with prenyl bromide
(Scheme 4), delivering product 14 in good yield.[23] Hydrolytic
[24]
cleavage of the chiral auxiliary in the presence of H2O2
afforded acid 15 which was converted into acid chloride 16
under strictly neutral conditions using the chloroenamine
reagent 17.[25] Reaction of crude 16 with the lithium enolate of
methyl acetate at low temperature provided b-keto ester 18,[26]
which did undergo a ligand controlled asymmetric hydro-
genation using [((R)-BINAP)RuCl2]2 ¥ NEt3 as the catalyst
(4 atm H2, 808C).[16, 27] This carbonyl reduction occured with
almost perfect diastereoselectivity (de >99%). In line with
literature precedence,[27a] the trisubstituted double bond of
the substrate remained fully intact under these conditions.[28]
We were well aware, however, that metathesis catalysts
such as the classical Grubbs ruthenium carbene complex 23[29]
are rather sensitive to the substitution pattern of the olefin.[30]
Therefore the trisubstituted alkene in 22 which was necessary
to impose a chemoselective path on the hydrogenation,[28]
would likely impede the projected macrocyclization by RCM.
To evaluate this aspect prior to launching the actual total
synthesis program, a model study was necessary. For this
purpose, the secondary hydroxyl group in compound 19 was
silylated and the resulting product 20 was reduced with
LiBEt3H to afford primary alcohol 22a. Subsequent ester-
ification with acid 10 under Mitsunobu conditions[31] afforded
diene 25a which allowed to test the crucial RCM step.
PCy3 ligand in 23 for a N-heterocyclic carbene up-graded the
performance of the catalyst to a significant extent and
rendered the catalyst suitable for the cyclization of tri- and
even tetrasubstituted cycloalkenes.[32] Gratifyingly, reaction of
diene 25 with the ™second-generation∫ ruthenium carbene
complex 24 in toluene at 808C afforded the 12-membered ring
26 in excellent yield (Scheme 5).[33] While this result suggested
that the envisaged cyclization of the macrolide core of
salicylihalamide itself was feasible, we were surprised to find
that the product was formed as a single isomer which was
assigned the (Z)-configuration based on a careful analysis of
its NMR data.
This stereochemical outcome was certainly unexpected for
the following reasons:
i) The vast majority of RCM-based macrocylizations report-
ed in the literature provided (E,Z)-mixtures, with the (E)-
isomer usually prevailing;[13]
In fact, the reluctance of complex 23 to react with highly
substituted alkenes[30] was responsible for the failure in
converting diene 25 into the desired macrocyclic product 26.
It has recently been shown, however, that the exchange of one
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(À)-Salicylihalamide
5286 5298
group in the substrates prevented free rotation in this part of
the molecule and hence enforced a strongly preferred
conformation of the cyclization precursors. While addressing
this issue, it was noticed that protection of the phenolic OH as
a TBS ether further increased the efficiency of the cyclization
(97% yield) and led to appreciable amounts of the desired
(E)-isomer 26c. Although the E:Z ˆ 30:70 ratio was far from
optimal, this result suggested that it might be possible to
approach salicylihalamide 1 by RCM, if the substituent at the
remote phenolic OH group was properly chosen.[38]
Synthesis of the fully functional core of salicylihalamide:
Based on the insights gained in this model study and learning
from the literature that the absolute stereochemistry of 1 had
originally been assigned incorrectly,[9, 12] we embarked into the
total synthesis of this promising antitumor agent.
Scheme 5. Model study concerning the formation of the core segment by
RCM.
The first steps simply translate the sequence outlined above
into the other enantiomeric series. For this purpose, however,
it turned out advantageous to use Oppolzer×s bornanesultam
auxiliary to control the diastereoselectivity of the prenylation
step.[39] Since compound 31 is crystalline (while the corre-
sponding oxazolidinone derivative 14 is not) the purification
of the crude product and hence the up-scaling of the reaction
to multigram amounts was greatly facilitated. Saponification
of 31, conversion of the resulting acid ent-15 into the acid
chloride ent-16 as described, followed by chain extension with
lithio methyl acetate provided b-oxo ester ent-18 which did
undergo a chemo- and stereoselective hydrogenation in the
presence of [((S)-BINAP)RuCl2]2 ¥ NEt3 as the catalyst (4 atm
H2, 808C). Protection of the resulting OH function in ent-19
by a MOM group sets the stage for the iterative construction
of the remaining stereocenter. For this purpose, a chain
extension was carried out using the lithium enolate of tert-
butyl acetate as the reagent, followed by a diastereoselective
reduction of the resulting b-keto ester 32 using the same
catalyst, that is [((S)-BINAP)RuCl2]2 ¥ NEt3. This hydrogena-
tion provided best results under slightly modified conditions
by lowering the temperature to 258C but increasing the
hydrogen pressure to 80 atm. Product 33 thus formed (de
>98%) was reduced with LiAlH4 and the resulting diol 34
was converted into the mono-PMB ether derivative 35 by
double deprotonation with excess NaH followed by addition
of one equivalent of PMBCl; under these conditions, the
alkylation of the primary alkoxide was strongly favored over
the competing protection of the secondary one.[40] Esterifica-
tion of alcohol 35 with acid 10 under Mitsunobu conditions
gave the desired ester 36 which served as a substrate for the
envisaged macrocyclization.
ii) This trend pertained to our previous approach to a
truncated salicylihalamide core which was obtained in a
ratio of E:Z ˆ 2.3:1;[8]
iii) NHC-containing metathesis catalysts were recently shown
to be particularly (E)-selective;[34, 35]
iv) Complex 24, when applied to the total synthesis of
zearalenone 29, a fungal metabolite that is closely related
to the salicylihalamide core in structural terms, led to the
exclusive formation of the desired (E)-isomer in excellent
yield.[35a]
Since it is mandatory to form the (E)- rather than the (Z)-
isomer en route to 1, we studied whether the stereochemical
outcome of the RCM reaction can be rectified (see Table 1).
A simple means might be the use of ™participating∫ protecting
groups.[36] Unfortunately, however, replacement of the TBS
group by a more strongly ligating methoxymethyl (MOM)
ether had no effect on the course of the reaction, delivering
(Z)-26b as the only product of RCM in 72% yield. Similarly,
inversion of the stereocenter at C-13 of the cyclization
precursor (easily achieved by reducing ketoester 18 with a
ruthenium catalyst containing (S)-BINAP rather than (R)-
BINAP as the ligand) did not change the outcome of the
reaction; thus, cyclization of diene 27 again led to the
exclusive formation of the (Z)-configurated product 28.[37]
In trying to rationalize this surprising yet seemingly
invariable stereochemical course, we speculated whether a
hydrogen bond between the phenolic OH and the COOR
In line with the observations made in the model studies, the
stereochemical outcome of RCM depends on the remote
substituents on the phenolic OH group (Table 2). Thus, the
unprotected derivative 36a led to the exclusive formation of
the (Z)-configurated product 37a, the TBS-protected ana-
logue 37b afforded a E:Z ˆ 40:60 mixture of both isomers,
whereas the (E)-isomer prevailed when a methyl- (37c) or a
MOM group (37d) blocked the phenolic site. We are unaware
of any precedence, in which the choice of a remote protecting
group allowed to alter the course of RCM to a similar
extent.[38]
Table 1. Model study on RCM. All reactions were carried out using
complex 24 (5 mol%) as the catalyst in toluene at 808C unless stated
otherwise.
Entry
Substrate
R1
R2
Product
Yield [%]
E:Z
1
2
3
4
25a
25b
25c
27
TBS
H
H
TBS
H
26a
26b
26c
28
89
0:100
MOM
MOM
TBS
72[a]
97
0:100
30:70
0:100
80[a]
[a] Using 7.5 mol% of the catalyst.
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that a direct interaction between the unprotected OH group
of substrate 36a with the ruthenium catalyst (e.g. via
phenolate complex formation)[50] accounted for the observed
(Z)-selectivity in this particular case. Thus, cyclization of the
methoxy protected diene 36c in the presence of one equivalent
of salicylic acid methyl ester takes the same course as the
cyclization of this substrate in the absence of the phenol in
terms of yield and stereoselectivity. Since we are presently not
able to provide a conclusive explanation for the observed
stereochemical results, we take this case as an excellent
opportunity to initiate in-depth theoretical investigations. The
results of these studies will be reported in due course.
For the sake of the synthesis, it was fortunate to find that the
methyl ether derivative 36c afforded macrolide 37c in
excellent yield and reasonable selectivity in favor of the
desired (E)-alkene. Substrate 36c was particularly well
accessible by direct esterification of fragment 35 with acid
12 (prepared in only one step as described above). Moreover,
the retention times of (E)-37c and (Z)-37c were sufficiently
different to allow separation of these isomers by conventional
flash chromatography. (E)-37c constituted the fully functional
core of salicylihalamide and was converted into the target as
outlined below.
Synthesis of (Z,Z)-2,4-heptadienoic acid amide and model
studies on the copper-catalyzed enamide formation: Encour-
aged by a recent report on enamide formations by copper
catalyzed cross-coupling reactions of vinyl iodides with
carboxylic acid amides,[15] we envisaged to use this strategy
for the final assembly of salicylihalamide. This publication,
however, left open whether this method would be compatible
with ester and unprotected OH groups; this aspect is not
obvious as rather high loadings of the copper(i)thiophenecar-
boxylate (CuTC)[41] catalyst and excess base are required.
Moreover, it was not clear if a fairly labile (Z,Z)-configured
a,b,g,d-unsaturated amide can be used without loss of
configurational integrity.[42] These issues were addressed by
the model studies summarized below.
The required amide 42 was prepared as outlined in
Scheme 7. Addition of iodide to methyl propynoic acid
afforded (Z)-39 in good yield according to a literature
procedure.[43] A subsequent Negishi coupling with butynylzinc
chloride in the presence of catalytic amounts of [Pd(PPh3)4]
furnished product 40,[44] which did undergo Lindlar reduction
to afford the (Z,Z)-configurated ester 41. This step required
Scheme 6. [a] Lithium (cyclohexyl)(isopropyl)amide, THF, À788C,
60 min; then dimethylallyl bromide, HMPA, À788C ! RT, 79 %;
[b] LiOH, H2O2, THF/H2O 4:1, 24 h, 95%; [c] chloroenamine 17, CH2Cl2,
90 min; [d] lithio methyl acetate, THF, À788C ! RT, 81%; [e] [((S)-
BINAP)RuCl2]2 ¥ NEt3 (0.4 mol%), H2 (4 atm), MeOH, 808C, 4 h, 94%;
[f] MOMCl, iPr2NEt, cat. DMAP, CH2Cl2, 40 h, 89%; [g] lithio tert-butyl
acetate, THF, À408C, 3 h, 95%; [h] [((S)-BINAP)RuCl2]2 ¥ NEt3
(1.2 mol%), H2 (80 atm), MeOH, 258C, 6.5 h, 93%; [i] LiAlH4, Et2O,
08C, 6 h, 90%; [j] NaH, PMBCl, DMF, 90 min, 76%; [k] acid 12, PPh3,
DEAD, Et2O, 20 h, 93%. PMB-Cl ˆ para-methoxybenzyl chloride.
Table 2. RCM-based cyclization of diene 36 to cycloalkene 37. All
reactions were carried out using complex 24 (5 mol%) as the catalyst in
toluene at 808C unless stated otherwise.
Entry
Substrate
R
Product
t [h]
Yield [%]
E:Z
1
2
3
4
36a
36b
36c
36d
H
TBS
Me
37a
37b
37c
37d
20
1
1.5
3
69[a]
91
93
91[a]
0:100
40:60
66:34
68:32
MOM
[a] Using 10 mol% of the catalyst.
It should be pointed out that the pronounced stereochem-
ical preferences observed during these RCM reactions cannot
be correlated with the thermodynamic stabilities of the
isomeric products formed.[38d] Moreover, it is most unlikely
Scheme 7. [a] LiI, CH3CN, HOAc, 708C, 12 h, 80%; [b] butynylzinc
chloride, cat. [Pd(PPh3)4], THF, 3 h, 90%; [c] H2 (1 atm), Lindlar catalyst,
cat. quinoline, CH2Cl2, 50 min, 80%; [d] NH4OH, NH4Cl, 4 d, 62%.
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(À)-Salicylihalamide
5286 5298
careful monitoring by TLC to avoid overreduction. Amin-
olysis of ester 41 then provided the required amide 42 which
was immediately used for the cross-coupling experiments.
We were pleased to see that this amide did undergo a
smooth reaction with vinyl iodide 43a bearing a methoxy
substituent on the arene ring in the presence of CuTC
(50 mol%) and excess Rb2CO3 as the base in anhydrous
dimethylacetamide (DMA) at 908C (Scheme 8). Note, how-
ever, that an excess of 42 was necessary to drive the
Scheme 9. [a] DDQ, H2O/CH2Cl2 1:18, RT, 12 h, 94%; [b] Dess Martin
periodinane, CH2Cl2, 08C ! RT, 18 h, 87%; [c] CHI3, CrCl2, THF/1,4-
dioxane 1:6, RT, 16 h, 87% (E:Z ˆ 9:1); [d] BBr3, CH2Cl2, À788C ! RT,
1 h, 88%; [e] amide 42 (3 equiv), copper(i) thiophene-2-carboxylate
(50 mol%), Rb2CO3 (3 equiv), DMA, 908C, 2 h, 57%. DDQ ˆ 2,3-
dichloro-5,6-dicyano-1,4-benzoquinone.
and B in 57% isolated yield (1a:1b ca. 2.5:1). The isomers
could be separated by HPLC and were identical in all respects
to the natural products.[1, 9, 12] It is worth mentioning, however,
that the copper-catalyzed enamide formation leading to 1
proceeded if Rb2CO3 was employed as the base. Although we
can presently provide no satisfactory explanation, the use of
Cs2CO3 failed to afford any of the desired target molecule
under otherwise identical conditions, despite the fact that this
base had worked well in model studies.[15]
Scheme 8. [a] amide 42 (5 equiv), copper(i) thiophene-2-carboxylate
(50 mol%), Rb2CO3 (3 equiv), DMA, 908C, 2 h, 89% (R ˆ Me, E:Z ˆ
2:1)), 86% (R ˆ H, only E); [b] benzamide, copper(i) thiophene-2-carbox-
ylate (30 mol%), Cs2CO3 (1.5 equiv), NMP, 908C, 70%. NMP ˆ N-
methylpyrrolidone, DMA ˆ dimethyl acetamide.
conversion. The cross-coupling of substrate 43b containing an
unprotected phenol group proceeded similarly well. In the
latter case, the resulting enamide 44b was obtained as a single
diastereoisomer in high yield. This result proved that the (Z)-
configuration of both alkene groups in the amide part was
fully retained, whereas isomerization of the double bond of
vinyl iodide 43b (E:Z ˆ 8:1) obviously could not be avoided.
A third model reaction probing the stability of an ester group
under the reaction condition also gave a satisfactory result
(45 ! 46).
Conclusion
A concise and inherently flexible approach to the potent
antitumor agent salicylihalamide 1 was outlined. This strongly
cytotoxic agent was assembled from three well accessible
fragments by relying on the power of transition metal
À
À
catalyzed C C and C X bond forming reactions. Scheme 10
illustrates this aspect. Particularly noteworthy are the rigor-
ously chemo- and stereoselective hydrogenation reactions
Completion of the total synthesis: Since these model studies
provided an encouraging outlook on the end game of the total
synthesis of 1, the macrolide core 37 prepared by RCM was
converted into a suitable vinyl iodide as shown in Scheme 9.
For this purpose, the -OPMB group was cleaved off by means
of DDQ,[45] the resulting primary alcohol 47 was oxidized with
Dess Martin periodinane,[46] and aldehyde 48 thus formed
was subjected to a Takai olefination.[47] Specifically, treatment
of 48 with CHI3 and CrCl2 in a mixed solvent system (THF/
1,4-dioxane 1:6)[48] furnished the desired vinyl iodide 49 as an
inseparable mixture of isomers (E:Z ˆ 9:1, as determined by
NMR). This material was fully deprotected on exposure to
BBr3, since cleavage of the -OMe and the -OMOM group
after the installation of the enamide might have endangered
the valuable product (c.f. retrosynthetic analyis).
Scheme 10. Summary of the total synthesis of salicylihalamide 1.
which guarantee reagent-control over the configuration of the
newly formed chiral centers, the high yielding closure of the
macrocyclic ring by RCM, and the use of the yet largely
unexplored copper-catalyzed cross-coupling technique allow-
ing the direct attachment of amides to unsaturated fragments.
Importantly, it has been shown that this reaction tolerates
With the iodide 50 at hand, the stage was set for the final
assembly of the target by the copper-catalyzed cross coupling
technique. Gratifyingly, reaction of 50 with amide 42 (3 equiv)
in the presence of CuTC (50 mol%) and Rb2CO3 (3 equiv)
proceeded cleanly, affording a mixture of salicylihalamide A
Chem. Eur. J. 2001, 7, No. 24
¹ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
0947-6539/01/0724-5291 $ 17.50+.50/0
5291

A. F¸rstner et al.
FULL PAPER
17.9, 14.3, À4.5, À4.7; IR (film): n ˆ 2956, 2929, 2894, 2857, 1744, 1473,
1463, 1437, 1408, 1378, 1362, 1341, 1290, 1255, 1193, 1172, 1134, 1078, 1034,
1006, 982, 947, 886, 835, 812, 776, 665 cmÀ1; MS (EI): m/z (%): 314 (<1)
sensitive functional groups and therefore holds promise for
further applications to complex targets in the future.
Finally, this total synthesis highlights once again the
excellent performance of ™second-generation∫ ruthenium
carbenes for olefin metathesis. At the same time, however,
it revealed that we still lack proper insight into the stereo-
determining step of this transformation, as the configuration
of the newly formed olefin may depend on subtle factors that
are difficult to rationalize and foresee. Therefore it is obvious
that further in-depth studies on this powerful transformation
are necessary. The accompanying paper in this issue reporting
the total synthesis of another potent antitumor agent, that is
epothilone A and C, will further illustrate this notion.[49]
Extensions of our studies on metathesis in general as well as
additional syntheses of bioactive target molecules are cur-
rently underway and will soon be disclosed.
‡
[M] , 299 (3), 283 (2), 257 (100), 225 (8), 199 (2), 182 (17), 147 (9), 131 (10),
115 (7), 109 (18), 89 (30), 73 (23), 69 (53), 41 (16); HR-MS (CI):
(C17H34O3Si ‡ H) calcd 315.2355; found 315.2358; elemental analysis calcd
for C17H34O3Si (314.54): C 64.92, H 10.90; found C 65.04, H 11.03.
(3S,4R)-3-(tert-Butyldimethylsilanyloxy)-4,7-dimethyl-oct-6-en-1-ol (22a):
LiBEt3H (1m in THF, 1.62 mL, 1.62 mmol) was added at 08C to a solution
of ester 20 (255 mg, 0.81 mmol) in THF (20 mL). After stirring for 2 h at
ambient temperature, the reaction was quenched with water, the aqueous
layer was extracted with Et2O (3 Â 20 mL), the combined organic phases
were dried over Na2SO4 and evaporated. Flash chromatography of the
residue (hexanes/ethyl acetate 1:1) afforded product 22a as a colorless
syrup (193 mg, 83%). [a]D20 ˆ À20.9 (c ˆ 0.91, CH2Cl2); 1H NMR (CD2Cl2,
300 MHz): d ˆ 5.17 5.09 (m, 1H), 3.78 (dt, J ˆ 6.8, 4.7 Hz, 1H), 3.69 (t, J ˆ
6.2 Hz, 2H), 2.06 1.94 (m, 1H), 1.83 1.58 (m, 11H), 0.90 (s, 9H), 0.86 (d,
J ˆ 6.7 Hz, 3H), 0.08 (s, 3H), 0.07 (s, 3H); 13C NMR (CD2Cl2, 75.5 MHz):
d ˆ 132.5, 123.6, 74.7, 61.0, 40.0, 34.2, 32.0, 26.0, 25.8, 18.3, 17.9, 14.1, À4.3,
À4.6; IR (KBr): n ˆ 3364, 2958, 2929, 2885, 2857, 1472, 1463, 1407, 1377,
1361, 1256, 1083, 1062, 1034, 1005, 967, 938, 836, 774, 735, 666 cmÀ1; MS
‡
(EI): m/z (%): 286 (<1) [M] , 229 (18), 189 (6), 173 (3), 154 (11), 137 (26),
Experimental Section
105 (11), 95 (24), 89 (13), 81 (40), 75 (38), 69 (100), 55 (10), 41 (20); HR-MS
(CI): (C16H34O2Si ‡ H) calcd 287.2406; found 287.2406; elemental analysis
calcd for C16H34O2Si (286.53): C 67.07, H 11.96; found C 67.14, H 11.99.
General: All reactions were carried out under Ar. The solvents used were
purified by distillation over the drying agents indicated and were trans-
ferred under Ar: THF, Et2O (Mg/anthracene), CH2Cl2 (P4O10), CH3CN,
Et3N (CaH2), MeOH (Mg), DMF, DMA (Desmodur, dibutyltin dilaurate),
hexane, toluene (Na/K). Flash chromatography: Merck silica gel 60 (230
400 mesh). NMR: Spectra were recorded on a DPX 300 or DMX 600
spectrometer (Bruker) in the solvents indicated; chemical shifts (d) are
given in ppm relative to TMS, coupling constants (J) in Hz. IR: Nicolet FT-
7199 spectrometer, wavenumbers in cmÀ1. MS (EI): Finnigan MAT 8200
(70 eV), HRMS: Finnigan MAT 95. Melting points: Gallenkamp melting
point apparatus (uncorrected). Optical rotation: Perkin Elmer 343 at l ˆ
589 nm (Na-D line). Elemental analyses: Kolbe, M¸lheim/Ruhr. All
commercially available compounds (Lancaster, Aldrich) were used as
received.
(3S,4R)-3-Methoxymethyl-4,7-dimethyl-oct-6-en-1-ol (22b): Prepared in
98% yield as described above starting from ester 21 (366 mg, 1.5 mmol).[10]
1H NMR (CD2Cl2, 300 MHz): d ˆ 5.17 5.09 (m, 1H), 4.66 (d, J ˆ 6.8 Hz,
1H), 4.60 (d, J ˆ 6.8 Hz, 1H), 3.98 3.52 (m, 3H), 3.34 (s, 3H), 2.50 1.62
(m, 6H), 1.68 (s, 3H), 1.60 (s, 3H), 0.86 (d, J ˆ 6.4 Hz, 3H); 13C NMR
(CD2Cl2, 75.5 MHz): d ˆ 132.5, 123.5, 96.5, 78.7, 60.7, 55.8, 37.4, 32.5, 31.8,
25.9, 17.9, 14.5; IR (film): n ˆ 3436, 2962, 2931, 2886, 1672, 1460, 1405, 1377,
1343, 1218, 1151, 1100, 1038, 918, 860, 825, 764 cmÀ1; MS (EI): m/z (%): 216
‡
(<1) [M] , 184 (14), 154 (11), 139 (6), 121 (10), 109 (13), 97 (22), 87 (22), 69
(39), 55 (24), 45 (100) 41 (27); HR-MS (CI): (C12H24O3 ‡ H) calcd 217.1804;
found 217.1803; elemental analysis calcd for C12H24O3 (216.32): C 66.63, H
11.18; found C 66.72, H 11.16.
(3S,4R)-2-Allyl-6-hydroxybenzoic acid 3-(tert-butyldimethylsilanyloxy)-
4,7-dimethyloct-6-enyl ester (25a): A solution of alcohol 22a (175 mg,
0.66 mmol) and PPh3 (194 mg, 0.74 mmol) in Et2O (25 mL) was added
dropwise to a suspension of acid 10 (132 mg, 0.74 mmol) and DEAD
(116 mL, 0.74 mmol) in Et2O (35 mL). After stirring for 20 h, the suspension
was concentrated to a total volume of ca. 10 mL, the precipitates were
filtered off, the filtrate was dried over Na2SO4 and evaporated, and the
residue was purified by flash chromatography (hexanes/ethyl acetate 30:1)
to afford ester 25a as a colorless syrup (265 mg, 96%). [a]2D0 ˆ À26.4 (c ˆ
1.10, CH2Cl2); 1H NMR (CD2Cl2, 300 MHz): d ˆ 11.18 (s, 1H), 7.33 (dd, J ˆ
8.3, 7.5 Hz, 1H), 6.85 (dd, J ˆ 8.3, 0.7 Hz, 1H), 6.76 (dd, J ˆ 7.5, 0.7 Hz, 1H),
6.01 (ddt, J ˆ 16.6, 10.2, 6.2 Hz, 1H), 5.18 5.09 (m, 1H), 5.03 (dd, J ˆ 10.2,
1.6 Hz, 1H), 4.97 (dd, J ˆ 16.6, 1.7 Hz, 1H), 4.53 4.38 (m, 2H), 3.84 3.76
(, m, 1H), 3.72 (dd, J ˆ 6.1, 1.3 Hz, 2H), 2.07 1.65 (m, 5H), 1.67 (s, 3H),
1.59 (s, 3H), 0.91 (s, 9H), 0.88 (d, J ˆ 6.8 Hz, 3H), 0.07 (s, 3H), 0.06 (s, 3H);
13C NMR (CD2Cl2, 75.5 MHz): d ˆ 171.8, 163.1, 143.3, 138.1, 134.6, 132.7,
123.4, 122.7, 116.4, 115.6, 112.7, 72.6, 64.1, 40.6, 40.1, 31.8, 31.0, 26.0, 25.8,
18.3, 17.9, 14.0, À4.3, À4.5; IR (film): n ˆ 3079, 3060, 2958, 2929, 2886, 2857,
1730, 1662, 1608, 1579, 1451, 1409, 1377, 1342, 1312, 1296, 1219, 1194, 1165,
1119, 1097, 1067, 1006, 912, 867, 836, 817, 774, 713, 667 cmÀ1; MS (EI): m/z
Starting materials and model studies
2-Allyl-6-hydroxy-benzoic acid (10): A solution of BCl3 (1m in CH2Cl2,
30 mL, 30 mmol) was slowly added to a solution of compound 9 (1.00 g,
4.54 mmol)[20] in CH2Cl2 (80 mL) at 08C and the resulting mixture was
stirred for 5 h at ambient temperature. The organic phase was diluted with
ethyl acetate (50 mL), washed with brine and dried over Na2SO4.
Evaporation of the solvent and flash chromatography (hexanes/ethyl
acetate/acetic acid 10:1:1) afforded acid 10 as colorless crystals (0.78 g,
96%). M.p. 98 998C; 1H NMR (CDCl3, 300 MHz): d ˆ 11.15 10.75 (br s,
1H), 7.38 (dd, J ˆ 8.2, 7.7 Hz, 1H), 6.90 (dd, J ˆ 8.2, 0.9 Hz, 1H), 6.79 (dd,
J ˆ 7.7, 0.9 Hz, 1H), 6.02 (ddt, J ˆ 17.0, 10.2, 6.3 Hz, 1H), 5.07 4.96 (m,
2H), 3.76 (d, J ˆ 6.3 Hz, 2H); 13C NMR (CDCl3, 75.5 MHz): d ˆ 175.2,
163.6, 144.3, 137.3, 135.6, 122.7, 116.5, 115.7, 110.6, 40.1; IR (KBr): n ˆ 3047,
2853, 2704, 2589, 1643, 1606, 1576, 1441, 1410, 1309, 1293, 1275, 1237, 1193,
1169, 1124, 1068, 1014, 1002, 915, 814, 792, 757, 707, 573 cmÀ1; MS (EI): m/z
‡
(%): 178 (33) [M] , 160 (100), 132 (24), 115 (3), 104 (26), 77 (12), 63 (4), 51
(11); HR-MS (EI): (C10H10O3) calcd 178.0630; found 178.0632; elemental
analysis calcd (%) for C10H10O3 (178.20): C 67.41, H 5.66; found C 67.53, H
5.75.
‡
(%): 446 (<1) [M] , 389 (5), 314 (4), 269 (2), 235 (12), 171 (5), 161 (100),
(3S,4R)-3-(tert-Butyldimethylsilanyloxy)-4,7-dimethyl-oct-6-enoic methyl
ester (20): 2,6-Lutidine (303 mL, 2.60 mmol) and TBSOTf (360 mL,
1.56 mmol) were added at 08C to a solution of alcohol 19 (260 mg,
1.3 mmol)[10] in CH2Cl2 (20 mL). After stirring for 1 h, the reaction was
quenched with aq. NaOH (2n, 10 mL), the mixture was extracted with
CH2Cl2 (80 mL), the organic layer was washed with aq. sat. NH4Cl (2 Â
10 mL) and brine (10 mL), dried over Na2SO4 and evaporated. Flash
chromatography of the crude product (hexanes/ethyl acetate 20:1) afforded
product 20 as a colorless syrup (389 mg, 95%). [a]2D0 ˆ À22.8 (c ˆ 1.34,
CH2Cl2); 1H NMR (CD2Cl2, 300 MHz): d ˆ 5.18 5.10 (m, 1H), 4.16 4.08
(m, 1H), 3.63 (s, 3H), 2.36 (d, J ˆ 6.6 Hz, 2H), 2.04 1.92 (m, 1H), 1.83
1.72 (m, 1H), 1.71 1.62 (m, 1H), 1.70 (s, 3H), 1.60 (s, 3H), 0.87 (s, 9H), 0.86
(d, J ˆ 6.7 Hz, 3H), 0.06 (s, 3H), 0.02 (s, 3H); 13C NMR (CD2Cl2,
75.5 MHz): d ˆ 173.0, 132.8, 123.3, 73.2, 51.7, 40.4, 38.5, 31.6, 25.9, 25.8, 18.3,
133 (9), 69 (12), 41 (6); HR-MS (CI): (C26H42O4Si ‡ H) calcd 447.2931;
found 447.2930; elemental analysis calcd for C26H42O4Si (446.70): C 69.91, H
9.48; found C 70.18, H 9.12.
(3S,4R)-2-Allyl-6-hydroxybenzoic acid 3-methoxymethyl-4,7-dimethyloct-
6-enyl ester (25b): Prepared as described above from alcohol 22b (382 mg,
1.77 mmol) and acid 10 (315 mg, 2.12 mmol). Colorless syrup (537 mg,
81%). [a]2D0 ˆ À39.0 (c ˆ 1.85, CH2Cl2); 1H NMR (CD2Cl2, 300 MHz): d ˆ
11.09 (s, 1H), 7.33 (dd, J ˆ 8.3, 7.5 Hz, 1H), 6.85 (dd, J ˆ 8.3, 1.0 Hz, 1H),
6.76 (dd, J ˆ 7.5, 0.9 Hz, 1H), 6.01 (ddt, J ˆ 16.4, 10.2, 6.1 Hz, 1H), 5.17
4.93 (m, 3H), 4.67 (d, J ˆ 6.8 Hz, 1H), 4.60 (d, J ˆ 6.8 Hz, 1H), 4.58 4.42
(m, 2H), 3.72 (d, 6.1 Hz, 2H), 3.67 3.58 (m, 1H), 3.36 (s, 3H), 2.08 1.81
(m, 5H), 1.68 (s, 3H), 1.59 (s, 3H), 0.89 (d, J ˆ 6.4 Hz, 3H); 13C NMR
(CD2Cl2, 75.5 MHz): d ˆ 171.6, 162.9, 143.3, 138.2, 134.6, 132.9, 123.1, 122.7,
5292
¹ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
0947-6539/01/0724-5292 $ 17.50+.50/0
Chem. Eur. J. 2001, 7, No. 24

(À)-Salicylihalamide
5286 5298
116.3, 115.5, 112.8, 96.6, 78.7, 63.8, 56.0, 40.5, 37.2, 31.7, 29.4, 25.8, 17.9, 14.2;
IR (film): n ˆ 3385, 3077, 2965, 2931, 2889, 2823, 1727, 1661, 1607, 1578, 1451,
1377, 1343, 1313, 1296, 1249, 1220, 1165, 1142, 1121, 1100, 1038, 987, 916, 817,
320.1624; found 320.1625; elemental analysis calcd for C18H24O5 (320.39): C
67.48, H 7.55; found C 67.35, H 7.62.
(9S,10R)-4-(tert-Butyldimethylsilanyloxy)-9-methoxymethyl-10-methyl-
7,8,9,10,11,14-hexahydro-6-oxa-benzocyclododecen-5-one (26c): Colorless
syrup. E:Z ˆ 30:70; [a]2D0 ˆ À10.4 (c ˆ 0.73, CH2Cl2); data of (E)-26c:
1H NMR (C6D6, 300 MHz): d ˆ 6.94 (dd, J ˆ 8.2, 7.6 Hz, 1H), 6.68 6.53 (m,
2H), 5.45 4.96 (m, 2H), 4.62 (s, 2H), 4.40 3.57 (m, 4H), 3.32 3.23 (m,
1H), 3.21 (s, 3H), 2.21 1.48 (m, 5H), 0.98 (s, 9H), 0.87 (d, J ˆ 6.5 Hz, 3H),
0.13 (s, 6H); 13C NMR (C6D6, 75.5 MHz): d ˆ 168.5, 153.2, 140.4, 130.8,
129.9, 128.3, 128.0, 123.2, 117.4, 96.4, 76.3, 63.0, 55.2, 38.3, 37.8, 34.4, 31.9,
25.7, 18.2, 14.0, À4.4.
‡
769, 713 cmÀ1; MS (EI): m/z (%): 376 (<1) [M] , 344 (15), 205 (13), 183
(13), 160 (100), 133 (10), 121 (24), 93 (8), 69 (22), 55 (7), 45 (37); HR-MS
(CI): (C22H32O5 ‡ H) calcd 377.2328; found 377.2325; elemental analysis
calcd for C22H32O5 (376.49): C 70.19, H 8.57; found C 70.28, H 8.52.
(3S,4R)-2-Allyl-6-(tert-butyldimethylsilanyloxy)-benzoic acid 3-methoxy-
methyl-4,7-dimethyloct-6-enyl ester (25c): A solution of compound 25b
(113 mg, 0.3 mmol), imidazole (204 mg, 3 mmol) and TBSCl (362 mg,
2.4 mmol) in DMF (20 mL) was stirred for 18 h at ambient temperature.
The mixture was diluted with EtOAc (50 mL) and washed with brine (3 Â
20 mL). Drying of the organic phase over Na2SO4, evaporation of the
solvent followed by flash chromatography of the residue (hexanes/ethyl
acetate 20:1) afforded product 25c as a colorless syrup (145 mg, 99%).
[a]2D0 ˆ À21.3 (c ˆ 1.47, CH2Cl2); 1H NMR (CD2Cl2, 300 MHz): d ˆ 7.20 (dd,
J ˆ 8.2, 7.6 Hz, 1H), 6.82 (dd, J ˆ 7.6 Hz, 1H), 6.73 (dd, J ˆ 8.2 Hz, 1H), 5.92
(ddt, J ˆ 16.2, 9.5, 6.6 Hz, 1H), 5.14 5.01 (m, 3H), 4.65 (d, J ˆ 6.8 Hz, 1H),
4.60 (d, J ˆ 6.8 Hz, 1H), 4.47 4.37 (m, 1H), 4.33 4.24 (m, 1H), 3.57 3.52
(m, 1H), 3.36 (s, 3H), 3.32 (d, 6.6 Hz, 2H), 2.07 1.94 (m, 1H), 1.90 1.77
(m, 4H), 1.67 (s, 3H), 1.57 (s, 3H), 0.97 (s, 9H), 0.88 (d, J ˆ 6.4 Hz, 3H),
0.23 (s, 6H); 13C NMR (CD2Cl2, 75.5 MHz): d ˆ 168.3, 152.7, 138.9, 137.0,
132.8, 130.3, 127.2, 123.2, 122.2, 117.2, 116.3, 96.6, 78.9, 63.1, 55.9, 37.9, 37.4,
31.7, 29.7, 25.8, 25.7, 18.3, 17.9, 14.4, À4.3; IR (film): n ˆ 3078, 2962, 2931,
2887, 2859, 2823, 1731, 1662, 1640, 1594, 1584, 1464, 1409, 1377, 1363, 1285,
1264, 1211, 1142, 1108, 1064, 1039, 994, 969, 917, 841, 806, 783, 741, 719, 669,
1
Data of (Z)-26c: H NMR (C6D6, 300 MHz): d ˆ 6.97 (dd, J ˆ 8.2, 7.6 Hz,
1H), 6.68 6.53 (m, 2H), 5.45 4.96 (m, 2H), 4.50 (d, J ˆ 6.8 Hz, 1H), 4.44
(d, J ˆ 6.8 Hz, 1H), 4.40 3.57 (m, 4H), 2.96 2.88 (m, 1H), 3.12 (s, 3H),
2.21 1.48 (m, 5H), 0.99 (s, 9H), 0.84 (d, J ˆ 6.5 Hz, 3H), 0.10 (s, 3H), 0.09
(s, 3H); 13C NMR (C6D6, 75.5 MHz): d ˆ 168.1, 152.5, 139.8, 130.1, 129.6,
128.4, 128.3, 122.6, 116.7, 96.3, 78.9, 62.3, 55.1, 36.3, 32.1, 30.5, 29.5, 25.7,
18.2, 13.8, À4.4; IR (KBr): n ˆ 3068, 2957, 2931, 2887, 2858, 2822, 1729,
1660, 1592, 1583, 1464, 1378, 1363, 1284, 1261, 1211, 1153, 1106, 1065, 1040,
974, 939, 919, 902, 842, 783, 739, 701, 670, 574 cmÀ1; MS (EI): m/z (%): 434
‡
(<1) [M] , 377 (75), 315 (19), 247 (22), 221 (24), 207 (42), 141 (10), 73 (32),
57 (9), 45 (100); HR-MS (CI): (C24H38O5Si ‡ H) calcd 435.2567; found
435.2562; elemental analysis calcd for C24H38O5Si (434.65): C 66.32, H 8.81;
found C 66.28, H 8.88.
(Z)-(9R,10R)-9-(tert-Butyldimethylsilanyloxy)-4-hydroxy-10-methyl-
7,8,9,10,11,14-hexahydro-6-oxa-benzocyclododecen-5-one [(Z)-28]: Color-
less syrup. [a]2D0 ˆ À54.2 (c ˆ 0.99, CH2Cl2); 1H NMR (C6D6, 600 MHz):
d ˆ 12.32 (s, 1H), 6.99 (dd, J ˆ 8.3, 7.2 Hz, 1H), 6.95 (dd, J ˆ 8.3, 1.6 Hz,
1H), 6.50 (dd, J ˆ 7.2, 1.6 Hz, 1H), 5.52 5.46 (m, 1H), 5.35 5.30 (m, 1H),
4.49 4.42 (m, 1H), 4.14 4.05 (m, 2H), 3.32 3.27 (m, 1H), 3.26 3.19 (m,
1H), 2.37 2.31 (m, 1H), 1.98 1.93 (m, 1H), 1.59 1.56 (m, 1H), 1.54 1.45
(m, 2H), 0.98 0.94 (m, 3H), 0.92 (s, 9H), À0.01 (s, 3H), À0.06 (s, 3H);
13C NMR (C6D6, 151 MHz): d ˆ 172.4, 164.8, 144.2, 134.7, 130.7, 126.5,
122.9, 116.7, 111.9, 74.4, 62.6, 40.1, 34.6, 33.6, 30.7, 26.0, 18.2, 17.5, À4.2,
À4.5; IR (KBr): n ˆ 3450, 3009, 2956, 2930, 2895, 2857, 1734, 1655, 1605,
1576, 1471, 1463, 1449, 1389, 1360, 1337, 1309, 1295, 1251, 1217, 1177, 1166,
‡
578, 555 cmÀ1; MS (EI): m/z (%): 490 (<1) [M] , 433 (16), 401 (7), 275 (44),
249 (37), 235 (100), 199 (27), 167 (17), 137 (19), 81 (21), 69 (41), 57 (8), 45
(57); HR-MS (CI): (C28H46O5Si ‡ H) calcd 491.3193; found 491.3193;
elemental analysis calcd for C28H46O5Si (490.76): C 68.53, H 9.45; found C
68.62, H 9.54.
Representative procedure for RCM
(Z)-(9S,10R)-9-(tert-Butyldimethylsilanyloxy)-4-hydroxy-10-methyl-
7,8,9,10,11,14-hexahydro-6-oxa-benzocyclododecen-5-one [(Z)-26a]: Com-
plex 24 (4.2 mg, 0.005 mmol) was added to a solution of diene 25a (44.6 mg,
0.1 mmol) in toluene (50 mL). After stirring for 3 h at 808C, the reaction
was quenched with ethyl vinyl ether (1 mL). Evaporation of the solvent
followed by flash chromatography (hexanes/ethyl acetate 50:1) of the crude
product afforded cycloalkene (Z)-26a as a colorless syrup (34.7 mg, 89%).
1117, 1073, 1037, 995, 905, 886, 862, 837, 816, 773, 721, 710, 669, 598 cmÀ1
MS (EI): m/z (%): 390 (<1) [M] , 375 (1), 333 (100), 315 (6), 285 (9), 241
(10), 205 (12), 171 (14), 161 (15), 149 (12), 131 (16), 93 (28), 73 (34), 59 (7),
41 (9).
;
‡
1
[a]2D0 ˆ À63.7 (c ˆ 1.02, CH2Cl2); H NMR (C6D6, 300 MHz): d ˆ 12.12 (s,
Total synthesis of salicylihalamide
1H), 7.02 6.92 (m, 2H), 6.48 (dd, J ˆ 6.6, 2.1 Hz, 1H), 5.32 5.13 (m, 2H),
4.42 4.32 (m, 1H), 4.17 (dd, J ˆ 15.0, 9.3 Hz, 1H), 3.85 (dt, J ˆ 10.1, 3.2 Hz,
1H), 3.81 3.75 (m, 1H), 2.85 (dd, J ˆ 15.0, 2.4 Hz, 1H), 2.08 1.92 (m, 1H),
1.70 1.52 (m, 3H), 1.35 1.24 (m, 1H), 0.94 (s, 9H), 0.86 (d, J ˆ 6.7 Hz,
3H), 0.00 (s, 3H), À0.01 (s, 3H); 13C NMR (C6D6, 75.5 MHz): d ˆ 172.1,
164.5, 144.8, 134.8, 131.2, 127.8, 123.1, 116.8., 111.9, 71.7, 64.8, 39.8, 35.4,
31.8, 31.3, 26.0, 18.1, 13.6, À4.4; IR (KBr): n ˆ 3425, 3057, 3022, 3006, 2957,
2930, 2895, 2857, 1658, 1631, 1607, 1574, 1471, 1448, 1386, 1347, 1311, 1289,
1251, 1216, 1158, 1127, 1089, 1071, 1052, 1017, 1005, 965, 932, 904, 876, 862,
836, 819, 791, 775, 714, 699, 662, 592 cmÀ1; MS (EI): m/z (%): 390 (<1)
N-Acylsultam (31):[39] A solution of nBuLi (1.6m in hexane, 14.20 mL,
22.7 mmol) and cyclohexylisopropylamine (382 mL, 2.27 mmol) was added
over 60 min at À788C to
a solution of N-acylsultam (30) (6.17 g,
22.7 mmol) in THF (120 mL, 0.19m). The resulting lithium enolate was
stirred at À788C for 1 h before freshly distilled dimethylallyl bromide
(7.94 mL, 68.2 mmol) in HMPA (11.92 mL, 68.2 mmol) was added. The
reaction mixture was allowed to warm to ambient temperature, was
quenched with water (150 mL) and extracted with Et2O (3 Â 150 mL).
Drying (Na2SO4) of the combined organic phases and evaporation of the
solvents gave the crude product which was crystallized from methanol to
afford pure 31 (6.09 g, 79%) as a colorless solid. [a]2D0 ˆ À52.5 (c ˆ 2.2,
CH2Cl2); m.p. 87 898C; 1H NMR (CD2Cl2, 300 MHz): d ˆ 5.09 (t, J ˆ
7.5 Hz, 1H), 3.85 (dd, J ˆ 4.8, 7.5 Hz, 1H), 3.43 (q, J ˆ 11.1 Hz, 2H), 3.12
3.05 (m, 1H), 2.76 (d, 2H), 2.44 2.34 (m, 2H), 2.13 1.82 (m, 3H), 1.63 (s,
3H), 1.57 (s, 3H), 1.42 1.15 (m, 2H), 1.11 (dd, J ˆ 6.8 Hz, 6H), 0.96 (s,
3H); 13C NMR (CD2Cl2, 75.5 MHz): d ˆ 176.5, 134.4, 121.5, 65.6, 54.7, 53.3,
48.7, 48.2, 45.4, 40.6, 34.5, 33.3, 26.9, 26.1, 21.1, 20.2, 18.0, 16.7; IR (KBr):
n ˆ 2970, 2930, 2882, 1689, 1461, 1394, 1336, 1272, 1239, 1220, 1166, 1135,
‡
[M] , 375 (1), 333 (100), 315 (6), 285 (9), 241 (10), 205 (12), 171 (14), 161
(15), 149 (12), 131 (16), 93 (28), 73 (34), 59 (7), 41 (9); HR-MS (CI):
(C22H34O4Si ‡ H) calcd 391.2305; found 391.2307; elemental analysis calcd
for C22H34O4Si (390.60): C 67.65, H 8.77; found C 67.57, H 8.84.
The following products were obtained analogously:
(Z)-(9S,10R)-4-Hydroxy-9-methoxymethyl-10-methyl-7,8,9,10,11,14-hexa-
hydro-6-oxa-benzocyclododecen-5-one [(Z)-26b]: Colorless syrup. [a]D20
ˆ
À82.5 (c ˆ 0.89, CH2Cl2); 1H NMR (C6D6, 300 MHz): d ˆ 12.23 (s, 1H),
7.01 6.93 (m, 2H), 6.46 (dd, J ˆ 6.3, 2.5 Hz, 1H), 5.26 5.07 (m, 2H), 4.46
(d, J ˆ 6.9 Hz, 1H), 4.37 (d, J ˆ 6.9 Hz, 1H), 4.38 4.28 (m, 1H), 4.08 (dd,
J ˆ 14.7, 8.9 Hz, 1H), 3.85 (dt, J ˆ 10.9, 3.1 Hz, 1H), 3.66 3.60 (m, 1H),
3.11 (s, 3H), 2.89 2.80 (m, 1H), 2.04 1.49 (m, 4H), 1.41 1.30 (m, 1H),
0.87 (d, J ˆ 6.7 Hz, 3H); 13C NMR (C6D6, 75.5 MHz): d ˆ 172.1, 164.5,
144.8, 134.8, 131.3, 127.6, 123.1, 116.8., 112.0, 95.9, 77.8, 65.2, 55.0, 36.6, 35.5,
31.9, 28.9, 13.7; IR (KBr): n ˆ 3419, 3051, 2961, 2934, 1750, 1716, 1659, 1606,
1575, 1450, 1385, 1312, 1295, 1250, 1220, 1166, 1152, 1125, 1100, 1068, 1038,
‡
1120, 1062, 1037, 976, 769 cmÀ1; MS (EI): m/z (%): 339 (27) [M] , 271 (57),
152 (16), 136 (11), 135 (78), 134 (27), 125 (10), 107 (12), 97 (70), 96 (100), 81
(15), 79 (10), 69 (40), 67 (11), 55 (61), 43 (11), 41 (37); HR-MS (EI):
(C18H29NO3S) calcd 339.1868; found 339.1867.
(2S)-2,5-Dimethyl-hex-4-enoic acid (ent-15): Aqueous H2O2 (30% w/w,
22.7 mL) and a suspension of LiOH ¥ H2O (7.89 g, 188.3 mmol) in water
(40 mL) were added at 08C to a solution of compound 31 (15.98 g,
47.1 mmol) in THF (400 mL) and water (100 mL). The reaction was first
stirred for 60 min at 08C and then at ambient temperature for 24 h.
Acidification with HCl (2m, 500 mL), extraction with CH2Cl2 (3 Â 300 mL),
drying of the combined organic layers over Na2SO4, evaporation of the
‡
916, 818, 775, 738, 711, 542 cmÀ1; MS (EI): m/z (%): 320 (16) [M] , 288 (7),
258 (29), 240 (3), 214 (5), 201 (14), 172 (22), 160 (13), 134 (8), 115 (8), 99 (4),
85 (44), 81 (6), 69 (1), 55 (12), 45 (100); HR-MS (EI): (C18H24O5) calcd
Chem. Eur. J. 2001, 7, No. 24
¹ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
0947-6539/01/0724-5293 $ 17.50+.50/0
5293

A. F¸rstner et al.
FULL PAPER
solvents and trituration of the residue with pentane furnished the insoluble
auxiliary. The soluble carboxylic acid was purified by column chromatog-
raphy (pentane/Et2O 4:1, 1% acetic acid) affording compound ent-15
(6.36 g, 95%) as a colorless liquid. [a]2D0 ˆ ‡7.4 (c ˆ 2.08, CH2Cl2); 1H NMR
(CDCl3, 300 MHz): d ˆ 10.50 10.00 (br s, 1H), 5.12 5.04 (m, 1H), 2.52
2.28 (m, 2H), 2.19 2.08 (m, 1H), 1.67 (s, 3H), 1.59 (s, 3H), 1.14 (d, J ˆ
6.9 Hz, 3H); 13C NMR (CDCl3, 75.5 MHz): d ˆ 183.0, 134.0, 120.9, 39.8,
31.8, 25.8, 17.8, 16.3; IR (KBr): n ˆ 2975, 2935, 2661, 1710, 1463, 1417, 1378,
4.9 Hz, 1H), 2.08 1.95 (m, 1H), 1.88 1.75 (m, 2H), 1.70 (s, 3H), 1.60 (s,
3H), 0.86 (d, J ˆ 6.5 Hz, 3H); 13C NMR (CD2Cl2, 75.5 MHz): d ˆ 172.7,
133.0, 123.0, 96.7, 78.8, 55.8, 51.8, 37.7, 36.7, 31.5, 25.9, 17.9, 14.5; IR (KBr):
n ˆ 2962, 2932, 2889, 2824, 1742, 1673, 1437, 1378, 1343, 1290, 1272, 1214,
1194, 1173, 1150, 1100, 1043, 976, 919, 857, 821 cmÀ1; MS (EI): m/z (%): 244
(<1) [M] , 212 (12), 194 (3), 182 (18), 167 (3), 155 (4), 139 (6), 121 (19), 103
(23), 81 (9), 69 (33), 55 (24), 45 (100), 41 (25), 29 (9); HR-MS (CI):
(C13H24O3 ‡ H) calcd 245.1753; found 245.1754.
‡
1338, 1287, 1245, 1226, 1185, 1125, 1083, 1049, 933, 856, 812, 778, 625 cmÀ1
;
(5R,6S)-5-Methoxymethyl-6,9-dimethyl-3-oxo-dec-8-enoic tert-butyl ester
(32): A solution of tert-butyl acetate (8.37 mL, 62.40 mmol) in THF
(20 mL) was slowly added to a solution of LiHMDS (10.44 g, 62.40 mmol)
in THF (200 mL) at À458C. The temperature was raised to À308C over a
period of 90 min. A solution of compound ent-21 (2.55 g, 10.43 mmol) in
THF (40 mL) was then added at À408C. Stirring was continued for 3 h
while the temperature was increased to À308C. Quenching of the reaction
with aq. sat. NH4Cl, extraction with Et2O, drying of the combined organic
phases over Na2SO4, evaporation of the solvent and flash chromatography
(hexanes/ethyl acetate 10:1) afforded product 32 as a colorless syrup
(3.26 g, 95%). [a]2D0 ˆ ‡18.1 (c ˆ 1.29, CH2Cl2); according to NMR, the
product consists of a 13:1 mixture of the keto-enol tautomers. NMR Data
‡
MS (EI): m/z (%): 142 (24) [M] , 124 (2), 109 (1), 97 (3), 87 (5), 81 (5), 74
(17), 69 (100), 55 (10), 41 (55); HR-MS (EI): (C8H14O2) calcd 142.0994;
found 142.0993.
(2S)-2,5-Dimethylhex-4-enoyl chloride (ent-16): Chloroenamine 17 (7.30 g,
54.88 mmol)[25] was slowly added through a syringe to a solution of acid ent-
15 (6.50 g, 45.78 mmol) in CH2Cl2 (80 mL). After stirring for 90 min, the
solvent was evaporated in vacuo affording acid chloride ent-16 as a
colorless oil. The crude product was dissolved in THF (80 mL) and was
directly used in the next step.
(4S)-4,7-Dimethyl-3-oxo-oct-6-enoic methyl ester (ent-18): A solution of
nBuLi (1.6m in hexane, 109.0 mL, 174.4 mmol) was slowly added at À788C
1
for the major keto form: H NMR (CD2Cl2, 300 MHz): d ˆ 5.16 5.08 (m,
to
a solution of diisopropylamine (22.60 mL, 159.4 mmol) in THF
1H), 4.58 (s, 2H), 4.01 3.94 (m, 1H), 3.37 (s, 2H), 3.29 (s, 3H), 2.73 (dd,
J ˆ 16.2, 8.7 Hz, 1H), 2.52 (dd, J ˆ 16.2, 3.2 Hz, 1H), 2.04 1.92 (m, 1H),
1.87 1.76 (m, 2H), 1.70 (s, 3H), 1.59 (s, 3H), 1.45 (s, 9H), 0.86 (d, J ˆ
6.4 Hz, 3H); 13C NMR (CD2Cl2, 75.5 MHz): d ˆ 202.5, 166.7, 133.0, 122.9,
96.7, 81.9, 77.7, 55.9, 51.9, 44.4, 37.6, 31.7, 28.1, 25.9, 18.0, 14.5; IR (neat): n ˆ
2975, 2931, 2824, 1738, 1717, 1643, 1456, 1408, 1393, 1369, 1319, 1286, 1253,
1212, 1150, 1099, 1040, 944, 919, 840 cmÀ1; MS (EI): m/z (%): 328 (<1)
(400 mL). The reaction mixture was stirred for 30 min at À208C prior to
the slow addition of methyl acetate (12.70 mL, 159.4 mmol) at À788C.
After stirring for 1 h, a solution of acid chloride ent-16 (45.78 mmol, crude)
in THF (80 mL) was added and the reaction mixture was quickly warmed to
ambient temperature. After 2 h the reaction was quenched by addition of
aq. sat. NH4Cl. Extraction with Et2O, drying of the combined organic
phases over Na2SO4, evaporation of the solvent and flash chromatography
(hexanes/ethyl acetate 15:1) afforded keto ester ent-18 as a colorless oil
(7.31 g, 81%). [a]2D0 ˆ ‡35.1 (c ˆ 1.54, CH2Cl2); according to NMR, the
product consists of a 9:1 mixture of keto-enol tautomers. NMR Data for
major form: 1H NMR (CD2Cl2, 300 MHz): d ˆ 5.09 5.02 (m, 1H), 3.69 (s,
3H), 3.47 (s, 2H), 2.69 2.58 (m, 1H), 2.36 2.24 (m, 1H), 2.14 2.02 (m,
1H), 1.69 (s, 3H), 1.61 (s, 3H), 1.07 (d, J ˆ 7.0 Hz, 3H); 13C NMR (CD2Cl2,
75.5 MHz): d ˆ 206.6, 168.1, 134.4, 121.2, 52.4, 48.1, 47.2, 31.5, 25.8, 17.9,
15.8; IR (KBr): n ˆ 2971, 2934, 1752, 1715, 1653, 1626, 1450, 1438, 1405,
1377, 1318, 1237, 1195, 1155, 1119, 1039, 1006, 849, 842, 805, 778, 739, 703,
‡
[M] , 296 (2), 266 (1), 240 (25), 223 (5), 210 (15), 181 (9), 139 (15), 123 (14),
109 (22), 97 (15), 81 (10), 69 (32), 57 (72), 45 (100), 41 (31), 29 (13); HR-MS
(CI): (C18H32O5 ‡ H) calcd 329.2328; found 329.2328.
(3S,5R,6S)-3-Hydroxy-5-methoxymethyl-6,9-dimethyl-dec-8-enoic tert-bu-
tyl ester (33): A stainless steel autoclave (50 mL) was charged with a
solution of keto ester 32 (827 mg, 2.52 mmol) in MeOH (20 mL). After
addition of [((S)-BINAP)RuCl2]2 ¥ NEt3 (3.1 mm in THF, 10 mL,
0.031 mmol, 1.3 mol%) the autoclave was pressurized with H2 (80 atm)
and the reaction mixture was stirred for 6.5 h at 258C. After the autoclave
had been vented, the solvent was removed in vacuo and the residue was
purified by flash chromatography (hexanes/ethyl acetate 4:1) affording
product 33 (777 mg, 93%) as a colorless syrup. [a]2D0 ˆ ‡41.5 (c ˆ 1.20,
CH2Cl2); 1H NMR (CD2Cl2, 300 MHz): d ˆ 5.16 5.08 (m, 1H), 4.67 (d, J ˆ
6.8 Hz, 1H), 4.60 (d, J ˆ 6.8 Hz, 1H), 4.15 4.06 (m, 1H), 3.67 3.60 (m,
1H), 3.55 3.30 (br s, 1H), 3.36 (s, 3H), 2.41 (dd, J ˆ 15.7, 4.6 Hz, 1H), 2.32
(dd, J ˆ 15.7, 7.9 Hz, 1H), 1.98 1.78 (m, 3H), 1.70 (s, 3H), 1.69 1.41 (m,
2H), 1.60 (s, 3H), 1.44 (s, 9H), 0.86 (d, J ˆ 6.4 Hz, 3H); 13C NMR (CD2Cl2,
75.5 MHz): d ˆ 172.0, 132.8, 123.2, 96.0, 81.0, 80.5, 67.8, 56.1, 43.2, 36.8, 36.5,
31.7, 28.2, 25.9, 18.0, 14.1; IR (KBr): n ˆ 3468, 2971, 2932, 1729, 1632, 1455,
‡
658 cmÀ1; MS (EI): m/z (%): 198 (18) [M] , 180 (8), 166 (4), 143 (13), 130
(54), 125 (31), 109 (20), 101 (29), 96 (25), 81 (14), 74 (15), 69 (100), 55 (38),
41 (56); HR-MS (EI): (C11H18O3) calcd 198.1256; found 198.1254.
(3R,4S)-3-Hydroxy-4,7-dimethyl-oct-6-enoic methyl ester (ent-19):
A
stainless steel autoclave (200 mL) was charged with a solution of compound
ent-18 (2.80 g, 14.12 mmol) in MeOH (80 mL). After addition of [((S)-
BINAP)RuCl2]2 ¥ NEt3 (3.1 mm in THF, 18.4 mL, 0.057 mmol, 0.4 mol%)
the autoclave was pressurized with H2 (4 atm) and the reaction mixture was
stirred for 4 h at 808C. After venting the autoclave, the solvent was
removed in vacuo and the residue was purified by flash chromatography
(hexanes/ethyl acetate 6:1) affording product ent-19 (2.654 g, 94%) as a
colorless oil. [a]D20 ˆ ‡20.5 (c ˆ 1.29, CH2Cl2); 1H NMR (CD2Cl2,
300 MHz): d ˆ 5.14 (ddsept, J ˆ 7.8, 6.8, 1.4 Hz, 1H), 3.83 (dddd, J ˆ 9.5,
6.1, 4.0, 2.6 Hz, 1H), 3.68 (s, 3H), 2.82 (d, J ˆ 4.0 Hz, 1H), 2.50 (dd, J ˆ 16.1,
2.9 Hz, 1H), 2.38 (dd, J ˆ 16.1, 9.6 Hz, 1H), 2.15 (ddd, J ˆ 14.2, 6.8, 4.8 Hz,
1H), 1.89 (ddd, J ˆ 14.2, 8.6, 7.8 Hz, 1H), 1.70 (q, 1.3 Hz, 3H), 1.61 (d, J ˆ
0.8 Hz, 3H), 1.59 (dddq, J ˆ 8.4, 6.1, 4.8, 6.8 Hz, 1H), 0.86 (d, J ˆ 6.8 Hz,
3H); 13C NMR (CD2Cl2, 75.5 MHz): d ˆ 174.1, 133.0, 123.0, 72.0, 52.0, 39.6,
38.5, 31.2, 25.9, 17.9, 15.3; IR (neat): n ˆ 3472, 2964, 2925, 2881, 1739, 1438,
1405, 1377, 1339, 1288, 1260, 1196, 1170, 1113, 1051, 1018, 990, 880,
1392, 1368, 1340, 1302, 1258, 1214, 1151, 1097, 1034, 951, 917, 844, 774 cmÀ1
;
‡
MS (EI): m/z (%): 330 (<1) [M] , 242 (29), 224 (14), 212 (42), 183 (20), 145
(38), 123 (13), 115 (61), 95 (21), 81 (14), 69 (44), 57 (63), 45 (100); HR-MS
(CI): (C18H34O5 ‡ H) calcd 331.2484; found 331.2485.
(3R,5R,6S)-5-Methoxymethyl-6,9-dimethyl-dec-8-ene-1,3-diol
(34):
LiAlH4 (1.72 g, 45.3 mmol) was added to a solution of compound 33
(5.01 g, 15.1 mmol) in Et2O (600 mL) at 08C. Careful addition of aq. sat.
NH4Cl (100 mL) after 6 h, extraction with Et2O (3 Â 150 mL), drying of the
combined organic phases over Na2SO4, evaporation of the solvent and flash
chromatography of the residue (hexanes/ethyl acetate 1:1 ! 1:2) afforded
diol 34 as a colorless syrup (3.56 g, 90%). [a]2D0 ˆ ‡51.1 (c ˆ 1.19, CH2Cl2);
1H NMR (CD2Cl2, 300 MHz): d ˆ 5.15 5.07 (m, 1H), 4.67 (d, J ˆ 6.6 Hz,
1H), 4.62 (d, J ˆ 6.6 Hz, 1H), 4.05 3.95 (m, 1H), 3.81 3.65 (m, 4H), 3.37
(s, 3H), 3.20 2.85 (br s, 1H), 1.98 1.78 (m, 3H), 1.74 1.61 (m, 3H), 1.70
(s, 3H), 1.59 (s, 3H), 1.55 1.46 (m, 1H), 0.86 (d, J ˆ 6.0 Hz, 3H); 13C NMR
(CD2Cl2, 75.5 MHz): d ˆ 132.9, 123.1, 95.9, 81.9, 72.2, 61.6, 56.2, 39.3, 36.8,
36.7, 31.9, 25.8, 17.9, 13.8; IR (neat): n ˆ 3386, 2961, 2931, 2888, 1658, 1442,
1377, 1212, 1151, 1097, 1037, 969, 918, 864, 822, 724 cmÀ1; MS (EI): m/z (%):
‡
846 cmÀ1; MS (EI): m/z (%): 200 (11) [M] , 182 (55), 167 (9), 150 (14), 122
(40), 109 (62), 107 (56), 103 (24), 93 (25), 81 (22), 69 (84), 55 (57), 41 (100),
29 (37); HR-MS (EI): (C11H20O3) calcd 200.1412; found 200.1413.
(3R,4S)-3-Methoxymethyl-4,7-dimethyl-oct-6-enoic methyl ester (ent-21):
N,N-Dimethylaminopyridine (284 mg, 2.33 mmol), diisopropylethylamine
(12.20 mL, 70.0 mmol) and MOMCl (5.31 mL, 70.0 mmol) were added to a
solution of compound ent-19 (4.67 g, 23.3 mmol) in CH2Cl2 (500 mL).
Stirring at ambient temperature was continued for 40 h. After dilution with
ethyl acetate (600 mL), the organic phase was washed with brine (3 Â
200 mL), dried over Na2SO4, evaporated, and the crude product was
purified by flash chromatography (hexanes/ethyl acetate 10:1) affording
ent-21 as a colorless syrup (5.11 g, 89%). [a]2D0 ˆ ‡15.6 (c ˆ 1.90, CH2Cl2);
1H NMR (CD2Cl2, 300 MHz): d ˆ 5.15 5.08 (m, 1H), 4.61 (s, 2H), 3.95
3.87 (m, 1H), 3.65 (s, 3H), 3.30 (s, 3H), 2.44 (d, J ˆ 7.4 Hz, 1H), 2.43 (d,
‡
260 (<1) [M] , 228 (5), 210 (2), 198 (8), 183 (10), 165 (2), 141 (7), 124 (8),
110 (14), 101 (43), 95 (17), 83 (17), 69 (34), 55 (29), 45 (100), 41 (25), 29 (12);
HR-MS (CI): (C14H28O4 ‡ H) calcd 261.2066; found 261.2065.
(3S,5S,6R)-1-(4-Methoxybenzyl)-5-methoxymethyl-6,9-dimethyl-dec-8-en-
3-ol (35): A solution of diol 34 (2.074 g, 7.96 mmol) in DMF (70 mL) was
added to a suspension of NaH (768 mg, 32.0 mmol) in DMF (100 mL). The
5294
¹ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
0947-6539/01/0724-5294 $ 17.50+.50/0
Chem. Eur. J. 2001, 7, No. 24

(À)-Salicylihalamide
5286 5298
mixture was stirred for 75 min before PMBCl (1080 mL, 7.96 mmol) was
added through a syringe. After stirring for another 90 min, the reaction was
quenched with diethylamine (1 mL), the mixture was diluted with ethyl
acetate (200 mL) and the organic phase was washed with brine (3 Â 50 mL).
Drying over Na2SO4, evaporation of the solvent and flash chromatography
(hexanes/ethyl acetate 2:1) gave product 35 as a colorless syrup (2.29 g,
76%). [a]2D0 ˆ ‡26.0 (c ˆ 1.32, CH2Cl2); 1H NMR (CD2Cl2, 300 MHz): d ˆ
7.25 (d, J ˆ 8.6 Hz, 2H), 6.86 (d, J ˆ 8.6 Hz, 2H), 5.16 5.07 (m, 1H), 4.67
(d, J ˆ 6.7 Hz, 1H), 4.60 (d, J ˆ 6.6 Hz, 1H), 4.42 (s, 2H), 3.94 3.84 (m,
1H), 3.79 (s, 3H), 3.69 3.53 (m, 3H), 3.50 3.25 (br s, 1H), 3.36 (s, 3H),
1.97 1.49 (m, 7H), 1.71 (s, 3H), 1.59 (s, 3H), 0.86 (d, J ˆ 6.3 Hz, 3H);
13C NMR (CD2Cl2, 75.5 MHz): d ˆ 159.6, 132.7, 131.0, 129.6, 123.3, 114.0,
95.9, 81.1, 73.1, 69.7, 68.3, 56.1, 55.5, 37.5, 37.1, 36.8, 31.8, 25.9, 17.9, 14.1; IR
(KBr): n ˆ 3463, 2930, 1613, 1586, 1514, 1463, 1442, 1375, 1302, 1248, 1210,
1173, 1152, 1096, 1036, 969, 917, 821, 773, 756, 707, 637, 571, 518 cmÀ1; MS
123.4, 114.5, 110.5, 97.7, 78.4, 73.5, 72.6, 67.2, 60.6, 56.1, 55.8, 55.2, 37.2, 37.1,
36.6, 33.4, 32.7, 14.1; IR (neat): n ˆ 3068, 2957, 2933, 1730, 1612, 1598, 1584,
1514, 1469, 1440, 1374, 1265, 1250, 1154, 1115, 1066, 1039 cmÀ1; MS (EI):
m/z (%): 498 (<1) [M] , 330 (5), 317 (8), 300 (10), 189 (7), 176 (12), 121
(100), 45 (27); HR-MS (CI): (C29H38O7) calcd 499.269; found 499.2697.
‡
(Z)-Hept-2-en-4-ynoic methyl ester (40): A suspension of 1-butynyl-
lithium (0.78 g, 13.0 mmol) in THF (15 mL) was treated at À508C with a
solution of anhydrous zinc chloride (2.04 g, 15.0 mmol) in THF (20 mL).
The resulting mixture was allowed to warm to ambient temperature. Ester
39 (2.12 g, 10.0 mmol) and a solution of [Pd(PPh3)4] (232 mg, 0.2 mmol,
2 mol%) in THF (20 mL) were subsequently added. The reaction mixture
was stirred for 3 h and quenched by the addition of water. The aqueous
layer was repeatedly extracted with Et2O, the combined organic phases
were washed with brine, dried over Na2SO4 and evaporated. Flash
chromatography (pentane/Et2O 30:1) afforded product 40 (1.24 g, 90%)
as a colorless liquid. 1H NMR (CD2Cl2, 300 MHz): d ˆ 6.13 (dt, J ˆ 11.5,
2.3 Hz, 1H), 6.01 (d, J ˆ 11.5 Hz, 1H), 3.71 (s, 3H), 2.43 (qd, J ˆ 7.5, 2.3 Hz,
2H), 1.19 (t, J ˆ 7.5 Hz, 3H); 13C NMR (CD2Cl2, 75.5 MHz): d ˆ 165.4,
127.4, 124.2, 105.4, 77.3, 51.5, 14.0, 13.7; IR (neat): n ˆ 3018, 2980, 2950,
2918, 2880, 2211, 1730, 1717, 1611, 1437, 1404, 1291, 1234, 1195, 1177,
‡
(EI): m/z (%): 380 (<1) [M] , 348 (1), 247 (1), 227 (2), 197 (4), 176 (2), 151
(1), 137 (13), 121 (100), 101 (7), 69 (7), 55 (4), 45 (15); HR-MS (CI):
(C22H36O5 ‡ H) calcd 381.2641; found 381.2640.
2-Allyl-6-methoxy-benzoic acid (1S,3R,4S)-1-[2-(4-methoxybenzyl)-eth-
yl]-3-methoxymethyl-4,7-dimethyl-oct-6-enyl ester (36c): A solution of
alcohol 35 (1.582 g, 4.16 mmol) and PPh3 (1.63 g, 6.21 mmol) in Et2O
(40 mL) was added dropwise to a solution of the carboxylic acid 12 (1.20 g,
6.21 mmol)[21] and DEAD (970 mL, 6.21 mmol) in Et2O (50 mL). After
stirring for 20 h, the mixture was concentrated to a volume of ca. 10 mL and
precipitated triphenylphosphine oxide was filtered off. Drying of the
filtrate over Na2SO4, evaporation of the solvent, and flash chromatography
(hexanes/ethyl acetate 20:1) afforded ester 36c as a colorless syrup (2.10 g,
93%). [a]2D0 ˆ ‡15.1 (c ˆ 1.02, CH2Cl2); 1H NMR (CD2Cl2, 300 MHz): d ˆ
11.09 (s, 1H), 7.31 (dd, J ˆ 8.0, 7.5 Hz, 1H), 7.21 (d, J ˆ 8.6 Hz, 2H), 6.84 (d,
J ˆ 8.0 Hz, 1H), 6.81 (d, J ˆ 8.6 Hz, 2H), 6.73 (d, J ˆ 7.5 Hz, 1H), 5.98 (ddt,
J ˆ 17.1, 10.2, 6.1 Hz, 1H), 5.62 5.53 (m, 1H), 5.12 5.05 (m, 1H), 5.01 (dd,
J ˆ 10.2, 1.6 Hz, 1H), 4.93 (dd, J ˆ 17.1, 1.6 Hz, 1H), 4.64 (d, J ˆ 6.8 Hz,
1H), 4.55 (d, J ˆ 6.8 Hz, 1H), 4.38 (s, 2H), 3.76 (s, 3H), 3.69 (d, J ˆ 6.0 Hz,
1H), 3.64 (d, J ˆ 6.0 Hz, 1H), 3.60 3.49 (m, 3H), 3.33 (s, 3H), 2.12 1.48
(m, 7H), 1.63 (s, 3H), 1.56 (s, 3H), 0.87 (d, J ˆ 6.4 Hz, 3H); 13C NMR
(CD2Cl2, 75.5 MHz): d ˆ 171.1, 162.7, 159.6, 143.0, 138.3, 134.3, 132.8, 130.8,
129.6, 123.1, 122.7, 116.3, 115.5, 113.9, 113.3, 96.9, 78.5, 73.0, 72.4, 66.8, 55.5,
54.5, 40.3, 37.4, 35.5, 35.2, 31.8, 25.7, 17.9, 13.8; IR (neat): n ˆ 3374, 3059,
2960, 2928, 1723, 1656, 1608, 1578, 1514, 1450, 1374, 1302, 1249, 1222, 1165,
1098, 1039, 999, 917, 818, 767, 712, 573 cmÀ1; MS (EI): m/z (%): 540 (<1)
‡
817 cmÀ1; MS (EI): m/z (%): 138 (100) [M] , 137 (28), 123 (31), 110 (14),
107 (48), 95 (36), 79 (38), 77 (41), 67 (37), 78 (12), 77 (41), 67 (37), 63 (13),
51 (20), 39 (12); HR-MS (EI): (C8H10O2) calcd 138.0681; found 138.0681;
elemental analysis calcd for C8H10O2 (138.17): C 69.55, H 7.30; found C
69.50, H 7.26.
(2Z,4Z)-Hepta-2,4-dienoic methyl ester (41): Quinoline (21 mL, 8 mol%)
and alkyne 40 (291 mg, 2.109 mmol) were dissolved in CH2Cl2 (30 mL).
Commercially available Lindlar catalyst (105 mg, 3 mol%) was added and
the resulting suspension was stirred for 50 min under an atmosphere of H2
(1 atm). The catalyst was filtered off through a pad of Celite, the solvent
was evaporated and the residue was purified by flash chromatography
(pentane/Et2O 30:1) affording diene 41 (237 mg, 80%) as a colorless liquid.
1H NMR (CD2Cl2, 300 MHz): d ˆ 7.21 (dd, J ˆ 11.4, 1.2 Hz, 1H), 6.95 (dd,
J ˆ 11.7, 0.8 Hz, 1H), 5.98 5.86 (m, 1H), 5.66 (d, J ˆ 11.4 Hz, 1H), 3.69 (s,
3H), 2.36 2.22 (m, 2H), 1.03 (t, J ˆ 7.5 Hz, 3H); 13C NMR (CD2Cl2,
75.5 MHz): d ˆ 167.1, 143.6, 139.2, 124.0, 117.2, 51.3, 21.2, 14.1; IR (neat):
n ˆ 3053, 2968, 2876, 1720, 1631, 1592, 1444, 1365, 1231, 1194, 1175,
‡
1132 cmÀ1; MS (GC-EI): m/z (%): 140 (17) [M] , 111 (100), 109 (19), 81
(48), 80 (12), 79 (39), 53 (20), 41 (18), 39 (20), 27 (10); HR-MS (EI):
(C8H12O2) calcd 140.0837; found 140.0837.
‡
[M] , 508 (2), 387 (1), 330 (1), 298 (2), 211 (2), 179 (3), 161 (7), 139 (1), 121
(2Z,4Z)-Hepta-2,4-dienoic acid amide (42): Compound 41 (300 mg,
2.141 mmol) was added to aq. ammonium hydroxide (50 mL, 30%). The
reaction mixture was stirred at ambient temperature for 4 days. The
resulting mixture was extracted with ethyl acetate, the combined organic
layers were dried over Na2SO4 and evaporated. The residue was purified by
flash chromatography (ethyl acetate) to afford amide 42 (167 mg, 62%) as
a white solid. 1H NMR (CDCl3, 300 MHz): d ˆ 7.22 7.12 (m, 1H), 6.77 (dd,
J ˆ 11.6, 1.1 Hz, 1H), 5.95 5.55 (br s, 2H), 5.88 5.77 (m, 1H), 5.62 (d, J ˆ
11.5 Hz, 1H), 2.23 (dtd, J ˆ 15.2, 7.5, 1.6 Hz, 2H), 1.02 (t, J ˆ 7.5 Hz, 3H);
13C NMR (CDCl3, 75.5 MHz): d ˆ 168.6, 141.9, 136.2, 123.6, 119.3, 20.7,
13.9; IR (KBr): n ˆ 3403, 3198, 3009, 2967, 2933, 1653, 1607, 1591, 1457, 1327,
(100), 109 (1), 69 (4), 45 (10); HR-MS (ESI pos): (C33H46O7 ‡ Na) calcd
577.3141; found 577.3143.
(7S,9R,10S)-4-Methoxy-7-[2-(4-methoxybenzyl)-ethyl]-9-methoxymethyl-
10-methyl-7,8,9,10,11,14-hexahydro-6-oxa-benzocyclododecen-5-one
(37c): Complex 24 (68 mg, 10 mol%) was added to a solution of diene 36c
(R ˆ Me, 450 mg, 0.811 mmol) in toluene (600 mL) at 808C. The reaction
was stopped after 90 min upon addition of ethoxy-ethene (5 mL).
Evaporation of the solvent and chromatography (hexanes/Et2O 4:1) on a
pre-packed column (LiChroprep Si 60, size A, E. Merck, Darmstadt,
Germany) afforded compound (E)-37c (246 mg, 61%) and (Z)-37c
(130 mg, 32%). (E)-37c: [a]2D0 ˆ À21.0 (c ˆ 1.0, benzene); 1H NMR
(C6D6, 300 MHz): d ˆ 7.40 (d, J ˆ 8.6 Hz, 2H), 7.05 (t, J ˆ 8.0 Hz, 1H),
6.91 (d, J ˆ 8.5 Hz, 2H), 6.66 (d, J ˆ 7.6 Hz, 1H), 6.45 (d, J ˆ 8.5 Hz, 1H),
6.01 5.90 (m, 1H), 5.58 5.31 (m, 2H), 5.13 (d, J ˆ 6.7 Hz, 1H), 4.91 (d,
J ˆ 6.7 Hz, 1H), 4.54 (m, 1H), 4.42 (s, 2H), 3.88 3.76 (m, 3H), 3.45 (s, 3H),
3.41 (s, 3H), 3.33 3.20 (m, 1H), 3.28 (s, 3H), 2.25 2.08 (m, 4H), 1.84 1.67
(m, 3H), 0.97 (d, J ˆ 6.0 Hz, 3H); 13C NMR (C6D6, 75.5 MHz): d ˆ 168.5,
160.2, 157.6, 140.1, 132.1, 132.0, 130.3, 129.5, 126.4, 123.5, 97.7, 80.1, 73.3,
72.6, 67.3, 55.9, 55.5, 55.3, 38.6, 38.5, 37.7, 36.9, 34.9, 27.6, 14.1; IR (neat): n ˆ
3067, 2956, 2932, 2839, 1724, 1584, 1513, 1468, 1301, 1274, 1249, 1204, 1154,
‡
808 cmÀ1; MS (GC-EI): m/z (%): 125 (6) [M] , 110 (3), 96 (100), 81 (15), 67
(12), 53 (12), 41 (17), 27 (12); elemental analysis calcd for C7H11NO
(125.17): C 67.17, H 8.86, N 11.19; found C 67.26, H 8.81, N 11.12.
(7S,9R,10S,12E)-7-(2-Hydroxyethyl)-4-methoxy-9-methoxymethoxy-10-
methyl-7,8,9,10,11,14-hexahydro-6-oxa-benzocyclododecen-5-one (47): A
solution of compound 37c (420 mg, 0.843 mmol) and DDQ (239 mg,
1.053 mmol) in water (1 mL) and CH2Cl2 (18 mL) was stirred at ambient
temperature for 12 h. The reaction was diluted with ethyl acetate (40 mL)
and filtered through a pad of Celite, the filtrate was evaporated and the
residue was purified by flash chromatography (hexane/ethyl acetate 1:1)
affording compound 47 as a colorless syrup (300 mg, 94%). [a]2D0 ˆ À34.5
(c ˆ 1.0, CHCl3); 1H NMR (CD2Cl2, 300 MHz): d ˆ 7.14 (t, J ˆ 7.7 Hz, 1H),
6.73 (d, J ˆ 7.7 Hz, 1H), 6.68 (d, J ˆ 7.7 Hz, 1H), 5.36 5.30 (m, 2H), 5.25
5.20 (m, 2H), 4.68 (q, J ˆ 6.7 Hz, 2H), 4.02 3.93 (m, 2H), 3.69 (s, 2H),
3.68 3.52 (m, 2H), 3.30 (s, 3H), 3.25 3.22 (m, 1H), 1.79 1.58 (m, 4H),
1.36 1.27 (m, 2H), 1.15 1.06 (m, 2H), 0.74 (d, J ˆ 6.6 Hz, 3H); 13C NMR
(CD2Cl2, 75.5 MHz): d ˆ 168.5, 156.6, 139.5, 131.8, 130.4, 128.8, 125.0, 123.4,
109.7, 97.0, 79.6, 73.1, 59.5, 56.0, 55.7, 39.5, 38.1, 38.0, 36.2, 34.4, 13.5; IR
(neat): n ˆ 3438, 3068, 2956, 2930, 2843, 1723, 1597, 1584, 1468, 1439, 1275,
‡
1117, 1085, 1040, 972 cmÀ1; MS (EI): m/z (%): 498 (<1) [M] , 300 (10), 189
(6), 187 (7), 176 (10), 121 (100), 95 (3), 45 (26); HR-MS (ESI pos):
(C29H38O7 ‡ Na) calcd 521.2515; found 521.2514. (Z)-37c: [a]2D0 ˆ À18.5
(c ˆ 1.0, benzene); 1H NMR (C6D6, 300 MHz): d ˆ 7.41 (d, J ˆ 8.5 Hz, 2H),
7.11 (t, J ˆ 7.7 Hz, 1H), 6.92 (d, J ˆ 8.5 Hz, 2H), 6.72 (d, J ˆ 7.7 Hz, 1H),
6.50 (d, J ˆ 8.5 Hz, 1H), 5.94 5.89 (m, 1H), 5.52 5.36 (m, 2H), 4.98 (d,
J ˆ 6.7 Hz, 1H), 4.84 (d, J ˆ 6.7 Hz, 1H), 4.45 (s, 2H), 4.20 4.12 (m, 2H),
3.72 3.60 (m, 2H), 3.42 (s, 3H), 3.39 (s, 3H), 3.36 (s, 3H), 2.23 1.98 (m,
4H), 1.90 1.67 (m, 3H), 1.02 (d, J ˆ 6.6 Hz, 3H); 13C NMR (C6D6,
75.5 MHz): d ˆ 167.0, 160.1, 158.1, 140.8, 131.9, 130.9, 130.1, 130.0, 129.5,
‡
1119, 1085, 1071, 1038, 972 cmÀ1; MS (EI): m/z (%): 378 (3) [M] , 346 (9),
Chem. Eur. J. 2001, 7, No. 24
¹ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
0947-6539/01/0724-5295 $ 17.50+.50/0
5295

A. F¸rstner et al.
FULL PAPER
316 (12), 315 (10), 260 (9), 259 (13), 228 (16), 215 (21), 204 (12), 189 (18),
187 (49), 186 (13), 177 (11), 175 (24), 174 (20), 163 (15), 162 (39), 161 (27),
159 (13), 153 (11), 148 (12), 115 (16), 55 (18), 45 (100), 43 (13); HR-MS (ESI
pos): (C21H30O6 ‡ Na) calcd 401.1940; found 401.1942.
125.1, 124.1, 116.9, 79.4, 76.8, 73.7, 44.9, 40.7, 40.2, 38.9, 15.2; IR (neat): n ˆ
3433, 2958, 2914, 1691, 1652, 1605, 1589, 1465, 1295, 1268, 1249, 1216, 1126,
‡
1066, 1028, 968; MS (EI): m/z (%): 442 (12) [M] , 425 (12), 424 (17), 295
(10), 276 (14), 275 (12), 257 (14), 251 (25), 239 (11), 232 (31), 231 (519), 230
(14), 213 (17), 203 (11), 202 (14), 201 (18), 192 (14), 191 (24), 190 (20), 185
(15), 176 (17), 175 (32), 175 (38), 173 (68), 172 (100), 167 (13), 163 (11), 162
(16), 161 (27), 160 (23), 159 (15), 152 (11), 151 (14), 150 (14), 149 (29), 148
(33), 147 (25), 145 (22), 144 (11), 135 (11), 134 (17), 133 (10), 132 (11), 131
(15), 128 (13), 127 (22), 117 (11), 116 (20), 115 (28), 109 (11), 107 (14), 105
(17), 95 (19), 91 (17), 83 (23), 81 (21), 79 (17), 78 (10), 77 (17), 69 (16), 68
(13), 67 (31), 66 (21), 65 (11), 57 (17), 55 (40), 53 (14), 43 (31), 41 (41), 39
(19), 29 (19); HR-MS (EI): (C19H23IO4) calcd 442.0641; found 442.0637.
(7S,9R,10S,12E)-(4-Methoxy-9-methoxymethoxy-10-methyl-5-oxo-
7,8,9,10,11,14-hexahydro[5H]-6-oxa-benzocyclododecen-7-yl)-acetalde-
hyde (48): Dess Martin periodinane (403 mg, 0.950 mmol) was added at
08C to a solution of alcohol 47 (300 mg, 0.793 mmol) in CH2Cl2 (60 mL).
The solution was allowed to warm to room temperature and stirred for
18 h. The reaction was diluted with ethyl acetate (50 mL) and quenched by
the addition of sat. aq. NaHCO3 (50 mL) and sat. aq. Na2S2O3 (50 mL). The
mixture was vigorously stirred until a clear solution resulted. The aqueous
layer was repeatedly extracted with ethyl acetate, the combined organic
phases were washed with brine, dried over Na2SO4 and evaporated. Flash
chromatography (hexane/ethyl acetate 4:1) furnished aldehyde 48 (260 mg,
87%) as a colorless syrup. [a]2D0 ˆ À42.7 (c ˆ 2.0, benzene); 1H NMR
(C6D6, 300 MHz): d ˆ 9.65 (dd, J ˆ 4.0, 0.8 Hz, 1H), 7.00 (t, J ˆ 7.8 Hz, 1H),
6.62 (d, J ˆ 7.8 Hz, 1H), 6.38 (d, J ˆ 7.8 Hz, 1H), 6.11 (m, 1H), 5.41 (m, 1H),
5.10 (d, J ˆ 6.8 Hz, 1H), 4.94 (d, J ˆ 6.8 Hz, 1H), 4.50 (m, 1H), 4.01 (q,
7.3 Hz, 1H), 3.84 (m, 1H), 3.42 (s, 3H), 3.39 (s, 3H), 2.52 (m, 1H), 2.23
2.06 (m, 3H), 1.75 1.65 (m, 2H), 1.43 1.33 (m, 2H), 0.93 (d, J ˆ 6.6 Hz,
3H); 13C NMR (C6D6, 75.5 MHz): d ˆ 199.9, 168.4, 156.7, 139.8, 132.1,
130.5, 129.6, 123.2, 109.9, 97.9, 80.0, 70.2, 55.9, 55.5, 49.9, 38.5, 38.4, 36.5,
35.1, 27.6, 14.0; IR (neat): n ˆ 3497, 3068, 2957, 2930, 2733, 1728, 1597, 1584,
1469, 1439, 1274, 1254, 1147, 1116, 1085, 1037, 971 cmÀ1; MS (EI): m/z (%):
Salicylihalamide (1a, b): An oven-dried Schlenk flask was charged with
amide 42 (25 mg, 0.202 mmol), CuTC (13 mg, 0.068 mmol) and Rb2CO3
(46 mg, 0.202 mmol). Anhydrous DMA (1 mL) was added, the resulting
suspension was carefully degassed in vacuo, compound 50 (30 mg,
0.068 mmol) was introduced, and degassing was repeated prior to heating
the mixture to 908C for 2 h under argon. The red slurry was cooled to room
temperature and diluted wit Et2O, the organic phase was washed with pH 7
buffer, the aqueous layer was extracted twice with Et2O, the combined
organic phases were dried over Na2SO4 and evaporated. The residue was
purified by preparative HPLC (Shimadzu LC-8; column: 125/20 mm
BIAX; eluent: MeOH/H2O 7:3) giving both isomers of the title compound
(17 mg, 57%, 1a:1b ꢀ2.5:1) as colorless solids. Spectroscopic data of 1a:
[a]2D0 ˆ À33.0 (c ˆ 1.0, benzene); 1H NMR (CD3OD, 300 MHz): d ˆ 7.34 (t,
J ˆ 10.8 Hz, 1H), 7.17 (t, J ˆ 7.5 Hz, 1H), 6.91 (t, J ˆ 11.8 Hz, 1H), 6.87 (d,
J ˆ 13.3 Hz, 1 H), 6.77 (d, J ˆ 7.8 Hz, 1H), 6.70 (J ˆ 7.5 Hz, 1H), 5.85 (m,
1H), 5.73 (d, J ˆ 11.5 Hz, 1H), 5.52 5.34 (m, 4H), 4.15 (dd, J ˆ 8.7, 3.3 Hz,
1H), 3.59 (dd, J ˆ 16.4, 7.3 Hz, 1H), 3.39 (m, 1H), 2.46 (m, 1H), 2.37 2.28
(m, 4H), 1.97 1.74 (m, 3H), 1.41 (m, 1H), 1.07 (t, J ˆ 7.5 Hz, 3H), 0.90 (d,
J ˆ 6.7 Hz, 3H); 13C NMR (CD3OD, 75.5 MHz): d ˆ 172.3, 167.1, 158.4,
143.8, 141.9, 141.2, 138.9, 132.9, 132.8, 131.9, 127.4, 126.5, 123.6, 121.5, 116.5,
111.6, 77.2, 73.2, 40.1, 40.0, 39.7, 38.7, 37.8, 22.7, 15.5, 14.8; MS (EI) m/z (%)
‡
376 (3) [M] , 314 (22), 259 (17), 228 (11), 215 (18), 188 (10), 187 (47), 186
(13), 175 (11), 174 (14), 163 (11), 162 (13), 161 (14), 159 (12), 148 (11), 115
(13), 55 (11), 45 (100); HR-MS (ESI pos): (C21H28O6 ‡ Na) calcd 399.1784;
found 399.1783.
(7S,9R,10S,12E)-7-(3-Iodoallyl)-4-methoxy-9-methoxymethoxy-10-methyl-
7,8,9,10,11,14-hexahydro-6-oxa-benzocyclododecen-5-one (49): To a slurry
of flame-dried CrCl2 (1018 mg, 8.283 mmol) in THF (5 mL) was added a
solution of aldehyde 48 (260 mg, 0.691 mmol) and iodoform (1.10 g,
2.794 mmol) in 1,4-dioxane (30 mL). The resulting brown solution was
stirred at ambient temperature for 16 h, diluted with Et2O (40 mL), and
poured into water (ca. 40 mL). The aqueous layer was separated, saturated
with NaCl, and extracted with Et2O (50 mL, in several portions). The
combined organic phases were washed with brine, dried over Na2SO4,
filtered, and evaporated. Purification of the residue by flash chromatog-
raphy (hexanes/ethyl acetate 10:1) gave product 49 (302 mg, 87%) as a
syrup (9:1 mixture of E:Z isomers). [a]2D0 ˆ À37.5 (c ˆ 1.0, benzene);
1H NMR (C6D6, 300 MHz): d ˆ 7.05 (t, J ˆ 7.6 Hz, 1H), 7.01 6.89 (m, 1H),
6.65 (d, J ˆ 7.6 Hz, 1H), 6.47 (d, J ˆ 7.6 Hz, 1H), 5.89 (d, J ˆ 5.5 Hz, 1H),
5.57 (m, 1H), 5.49 5.39 (m, 1H), 5.08 (d, J ˆ 6.8 Hz, 1H), 4.88 (d, J ˆ
6.8 Hz, 1H), 4.46 (d, J ˆ 6.8 Hz, 1H), 3.90 (q, J ˆ 7.0 Hz, 1H), 3.85 (m, 1H),
3.53 (s, 3H), 3.40 (s, 3H), 2.36 2.07 (m, 3H), 1.79 1.32 (m, 5H), 0.95 (d,
J ˆ 6.6 Hz, 3H); 13C NMR (C6D6, 75.5 MHz): d ˆ 168.4, 157.7, 143.2, 139.9,
132.0, 130.4, 129.4, 123.4, 110.2, 97.8, 97.7, 80.0, 77.9, 73.8, 56.3, 55.9, 43.2,
38.5, 38.4, 34.9, 35.1, 14.0; IR (neat): n ˆ 3425, 2956, 2929, 2840, 1726, 1658,
1597, 1584, 1468, 1438, 1424, 1274, 1117, 1085, 1040, 972; MS (EI): m/z (%):
‡
439 (14) [M] , 192 (20), 191 (19), 173 (9), 149 (9), 127 (9), 109 (100), 108
(13), 83 (27), 82 (33), 81 (73), 79 (20), 57 (12), 56 (15), 55 (15), 53 (13), 41
1
(17); spectroscopic data of 1b: [a]2D0 ˆ À65.0 (c ˆ 0.5, benzene); H NMR
(C6D6, 300 MHz): d ˆ 8.03 (t, J ˆ 11.8 Hz, 1H), 7.86 (d, J ˆ 11.2, 1H), 7.38
(t, J ˆ 10.5 Hz, 1H), 7.04 (m, 1H), 6.73 (t, J ˆ 11.6 Hz, 1H), 6.57 (dd, J ˆ 7.0,
3.0 Hz, 1H), 5.73 (m, 1H), 5.59 (d, J ˆ 11.4, 1H), 5.45 5.17 (m, 3H), 4.69
(q, J ˆ 8.2 Hz, 1H), 3.64 (dd, J ˆ 16.6, 5.1 Hz, 1 H), 3.53 (d, J ˆ 7.7 Hz, 1 H),
3.43 (d, J ˆ 16.5 Hz, 1 H), 2.30 2.00 (m, 4H), 1.91 1.73 (m, 3H), 1.65 (m,
1H), 1.45 (s, 1H), 1.34 (dd, J ˆ 15.0, 8.0 Hz, 1 H), 0.93 (d, J ˆ 6.8 Hz, 3 H),
0.87 (m, 3H). The analytical data are in full agreement with those
previously reported.[1, 9]
Enamide formation–Model reactions
(2Z,4Z)-Heptadienoic acid [2-(3-methoxyphenyl)-vinyl]-amide (44a): An
oven-dried Schlenk flask was charged with amide 42 (43 mg, 0.345 mmol),
CuTC (7 mg, 0.035 mmol) and Rb2CO3 (32 mg, 0.138 mmol). Anhydrous
DMA (1 mL) was added, the resulting suspension was degassed, vinyl
iodide 43a (18 mg, 0.069 mmol) was introduced and the degassing
procedure was repeated prior to heating the mixture to 908C for 3 h under
argon. The red slurry was cooled to room temperature, diluted with Et2O
and washed with pH 7 buffer. The aqueous phase was extracted twice with
Et2O, the combined organic layers were dried over Na2SO4 and evaporated.
The residue was purified by flash chromatography (hexanes/ethyl acetate
10:1) affording compound 44a (16 mg, 89%) as a colorless oil. Mixture of
isomers (E:Z ˆ 2:1); data of the major isomer: 1H NMR (CD2Cl2,
300 MHz): d ˆ 7.63 7.51 (m, 2H), 7.39 7.31 (m, 1H), 7.19 (t, 1H), 6.95
6.87 (m, 2H), 6.72 (d, J ˆ 7.9 Hz, 1H), 6.12 (d, J ˆ 14.1 Hz, 1H), 5.92 (q, J ˆ
9.6 Hz, 1H), 5.64 (d, J ˆ 11.3 Hz, 1H), 5.53 (d, J ˆ 11.3 Hz, 1H), 3.79 (s,
3H), 2.32 2.20 (m, 2H), 1.01 (t, J ˆ 7.5 Hz, 3H); 13C NMR (CD2Cl2,
75.5 MHz): d ˆ 163.7, 160.6, 143.4, 138.4, 138.0, 130.1, 124.4, 123.6, 119.3,
118.7, 112.9, 112.8, 111.1, 55.7, 21.3, 14.3; IR (neat): n ˆ 3273, 3179, 3070,
2999, 2964, 2932, 2873, 1640, 1596, 1523, 1492, 1464, 1434, 1309, 1261, 1217,
1190, 1158, 1047, 954, 863, 810, 776, 712, 689 cmÀ1; MS (EI): m/z (%): 257
‡
500 (5) [M] , 455 (22), 438 (19), 307 (12), 275 (10), 260 (13), 259 (34), 245
(15), 229 (10), 228(13), 227 (18), 215 (24), 213 (11), 204 (10), 199 (13), 189
(11), 187 (41), 186 (13), 185 (11), 177 (11), 175 (13), 174 (12), 173 (10), 163
(17), 162 (13), 161 (23), 159 (13), 148 (10), 115 (15), 91 (11), 67 (12), 55 (13),
45 (100); elemental analysis calcd for C22H29IO5 (500.38): C 52.81, H 5.84;
found C 52.70, H 5.77.
(7S,9R,10S,12E)-4,9-Dihydroxy-7-(3-iodoallyl)-10-methyl-7,8,9,10,11,14-
hexahydro-6-oxa-benzocyclododecen-5-one (50): A solution of BBr3 (1m in
CH2Cl2, 450 mL) was added dropwise at À788C to a solution of compound
49 (90 mg, 0.179 mmol) in CH2Cl2 (20 mL). The resulting brownish red
solution was stirred at that temperature for 1 h and allowed to warm to
room temperature. The reaction was quenched by the addition of water
(50 mL). The aqueous layer was extracted with CH2Cl2, the organic
extracts were washed with brine, dried over Na2SO4 and evaporated.
Purification of the residue by flash chromatography (hexanes/ethyl acetate
4:1) afforded product 50 (70 mg, 88%) as a colorless wax. [a]2D0 ˆ À31.5
(c ˆ 1.0, benzene); 1H NMR (CD3OD, 300 MHz): d ˆ 7.20 (t, J ˆ 7.6 Hz,
1H), 6.91 6.37 (m, 3H), 6.36 (d, J ˆ 14.5 Hz, 1H), 5.44 5.40 (m, 3H), 4.92
(s, 2H), 4.25 (d, J ˆ 8.5 Hz, 1H), 3.72 3.62 (m, 2H), 2.58 2.48 (m, 3H),
1.89 1.81 (m, 3H), 1.42 (m, 1H), 0.94 (d, J ˆ 6.6 Hz, 3H); 13C NMR
(CD3OD, 75.5 MHz): d ˆ 172.7, 158.5, 145.4, 142.3, 140.6, 133.7, 133.2, 132.2,
‡
(60) [M] , 228 (9), 149 (100), 109 (91), 81 (68).
(2Z,4Z)-Heptadienoic acid [2-(3-hydroxyphenyl)-vinyl]-amide (44b): The
reaction was performed as described above using amide 42 (38 mg,
0.305 mmol), CuTC (5 mg, 0.030 mmol), Rb2CO3 (42 mg, 0.183 mmol), and
3-(2-iodo-vinyl)-phenol 43b (15 mg, 0.061 mmol). A standard extractive
work-up followed by flash chromatography (hexanes/ethyl acetate 4:1)
5296
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Chem. Eur. J. 2001, 7, No. 24

(À)-Salicylihalamide
5286 5298
afforded compound 44b (13 mg, 86%) as a colorless syrup. 1H NMR
(CD2Cl2, 300 MHz): d ˆ 7.54 7.46 (m, 2H), 7.31 (m, 1H), 7.07 (t, J ˆ 7.7 Hz,
1H), 6.89 6.76 (m, 2H), 6.60 (d, J ˆ 7.7 Hz, 1H), 6.03 (d, J ˆ 14.2 Hz, 1H),
5.87 (q, J ˆ 7.7 Hz, 1H), 5.76 (s, 1H), 5.61 (d, J ˆ 11.5 Hz, 1H), 2.20 (m,
2H), 1.12 (t, J ˆ 6.5 Hz, 3H); 13C NMR (CD2Cl2, 75.5 MHz): d ˆ 163.9,
156.7, 143.4, 138.3, 138.0, 130.2, 124.2, 123.3, 119.0, 118.6, 114.1, 112.9, 112.2,
21.2, 14.1; IR (neat): n ˆ 3281, 3074, 2967, 2933, 2873, 1666, 1640, 1591, 1526,
1492, 1262, 1217, 1159, 950, 869, 778, 689 cmÀ1; MS (EI): m/z (%): 243 (58)
[10] A. F¸rstner, O. R. Thiel, G. Blanda, Org. Lett. 2000, 2, 3731
3734.
[11] Partial syntheses: a) G. I. Georg, Y. M. Ahn, B. Blackman, F. Farokhi,
P. T. Flaherty, C. J. Mossman, S. Roy, K. L. Yang, Chem. Commun.
2001, 255 256; b) Y. Wu, O. R. Seguil, J. K. De Brabander, Org. Lett.
2000, 2, 4241 4244; c) A. Bhattacharjee, J. K. De Brabander, Tetra-
hedron Lett. 2000, 41, 8069 8073; d) for a comparison of the RCM
and macrolactonization strategy see: J. T. Feutrill, G. A. Holloway, F.
Hilli, H. M. Hugel, M. A. Rizzacasa, Tetrahedron Lett. 2000, 41, 8569
8572.
‡
[M] , 214 (8), 135 (79), 109 (100), 108 (10), 81 (63), 79 (16), 53 (17), 41 (13).
(10E)-11-Benzoylamino-undecenoic isopropyl ester (46): An oven-dried
Schlenk flask was charged with benzoic acid amide (51 mg, 0.421 mmol),
CuTC (16 mg, 0.084 mmol) and Cs2CO3 (138 mg, 0.421 mmol). Anhydrous
NMP (1 mL) was added and the suspension formed was carefully degassed.
Compound 45 (100 mg, 0.282 mmol) was added, the mixture was degassed
again prior to heating to 908C for 4 h under argon. The red slurry was
cooled to ambient temperature, diluted with Et2O and washed with pH 7
buffer. The aqueous layer was extracted twice with Et2O, the combined
organic layers were dried over Na2SO4 and concentrated in vacuo. The
residue was purified by flash chromatography (hexanes/ethyl acetate 10:1)
to afford compound 46 (65 mg, 70%) as a colorless syrup. 1H NMR
(CD2Cl2, 300 MHz): d ˆ 7.79 (d, J ˆ 8.1 Hz, 3H), 7.55 7.42 (m, 3H), 6.93
(dd, J ˆ 14.2, 10.3 Hz, 1H), 5.32 (dd, J ˆ 14.2 Hz, 7.1 Hz, 1H), 4.95 (sept,
J ˆ 6.2 Hz, 1H), 2.23 (t, J ˆ 7.2 Hz, 2H), 2.06 (q, J ˆ 7.2 Hz, 2H), 1.60 1.30
(m, 10H), 1.20 (d, J ˆ 6.2 Hz, 6H), 0.92 0.87 (m, 2H); 13C NMR (CD2Cl2,
75.5 MHz): d ˆ 173.5, 164.3, 134.4, 132.1, 129.0, 127.3, 123.1, 114.5, 67.5, 35.0,
30.3, 30.2, 29.7, 29.6, 29.4, 29.3, 25.4, 24.0, 22.0; IR (neat): n ˆ 3310, 2197,
3066, 2927, 2854, 1731, 1677, 1640, 1579, 1527, 1489, 1374, 1322, 1259, 1190,
[12] See also the following corrigendum: K. L. Erickson, J. A. Beutler,
J. H. Cardellina, M. R. Boyd, J. Org. Chem. 2001, 66, 1532.
[13] For pertinent reviews see: a) T. Trnka, R. H. Grubbs, Acc. Chem. Res.
2001, 34, 18 29; b) A. F¸rstner, Angew. Chem. 2000, 112, 3140 3172;
Angew. Chem. Int. Ed. 2000, 39, 3012 3043; c) R. H. Grubbs, S.
Chang, Tetrahedron 1998, 54, 4413 4450; d) M. Schuster, S. Blechert,
Angew. Chem. 1997, 109, 2124 2144; Angew. Chem. Int. Ed. Engl.
1997, 36, 2037 2056; e) A. F¸rstner, Top. Catal. 1997, 4, 285 299;
f) S. K. Armstrong, J. Chem. Soc. Perkin Trans. 1 1998, 371 388;
g) K. J. Ivin, J. Mol. Catal. A: Chem. 1998, 133, 1 16; h) M. L.
Randall, M. L. Snapper, J. Mol. Catal. A: Chem. 1998, 133, 29 40;
i) R. R. Schrock, Tetrahedron 1999, 55, 8141 8153; j) M. E. Maier,
Angew. Chem. 2000, 112, 2153 2157; Angew. Chem. Int. Ed. 2000, 39,
2073 2077.
[14] For methods allowing the formation of enamides see: a) B. B. Snider,
F. Song, Org. Lett. 2000, 2, 407 408; b) P. F. Hudrlik, A. M. Hudrlik,
R. J. Rona, R. N. Misra, G. P. Withers, J. Am. Chem. Soc. 1977, 99,
‡
¬
1109, 956, 707 cmÀ1; MS (EI): m/z (%): 345 (4) [M] , 240 (14), 122 (29), 105
1993 1996; c) D. A. Alonso, E. Alonso, C. Najera, M. Yus, Synlett
1997, 491 492; d) T. Ogawa, T. Kiji, K. Hayami, H. Suzuki, Chem.
Lett. 1991, 1443 1446; e) I. Stefanuti, S. A. Smith, R. J. K. Taylor,
Tetrahedron Lett. 2000, 41, 3735 3738; f) B. M. Trost, J.-P. Surivet,
Angew. Chem. 2001, 113, 1516 1519; Angew. Chem. Int. Ed. 2001, 40,
1468 1471.
(100), 77 (22); HR-MS (ESI pos): (C21H31NO3) calcd 345.2304; found
345.2301.
[15] R. Shen, J. A. Porco, Jr., Org. Lett. 2000, 2, 1333 1336.
[16] For comprehensive treatises, see: a) R. Noyori, Asymmetric Catalysis
in Organic Synthesis, Wiley, New York, 1994; b) T. Ohkuma, R.
Noyori, in Comprehensive Asymmetric Catalysis, Vol. 1 (Eds.: E. N.
Jacobsen, A. Pfaltz, H. Yamamoto), Springer, Berlin, 1999, pp. 199
246.
Acknowledgements
Generous financial support by the Deutsche Forschungsgemeinschaft
(Leibniz award to A.F.) and the Fonds der Chemischen Industrie is
gratefully acknowledged. We thank Dr. Y. Cancho for model studies on the
enamide part which will be reported in a separate publication, Dr. R.
Mynott for his help with the unambiguous assignment of the stereo-
chemistry of the RCM products, and Dr. K. Angermund for semiempirical
calculations.
[17] A. Hadfield, H. Schweitzer, M. P. Trova, K. Green, Synth. Commun.
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[22] For a discussion of this and other strategic goals in total synthesis see:
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ˆ
the C C double bond is avoided only if the alkene is tri-substituted; in
contrast to the results reported in ref. [27a], a disubstituted alkene is
not inert under the reaction conditions; for similar experiences see:
b) C. R. Harris, S. D. Kuduk, A. Balog, K. Savin, P. W. Glunz, S. J.
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Chem. Eur. J. 2001, 7, No. 24
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A. F¸rstner et al.
FULL PAPER
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increased thermodynamic stability of the corresponding (E)-cyclo-
alkene 26c relative to its (Z)-isomer. Semiempirical calculations
(MNDO(AM1)) indicate that in both cases the corresponding (E)-
alkenes are thermodynamically slightly more stable. We thank Dr. K.
Angermund for carrying out these calculations.
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2312 2313.
[42] Note that the (Z,Z)-configurated amide 42 is rather labile and that in
the paper of Porco et al. (ref. [15]) only E,E-configurated dienoic acid
amides have been cross coupled.
[43] S. Ma, X. Lu, Z. Li, J. Org. Chem. 1992, 57, 709 713.
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[33] It is essential to quench the reaction mixture by addition of ethyl vinyl
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[34] C. W. Lee, R. H. Grubbs, Org. Lett. 2000, 2, 2145 2147.
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[38] For previous examples showing the influence of remote substituents
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RCM reactions, see: S. Chang, L. Jones, C. Wang, L. M. Henling, R. H.
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Received: July 10, 2001 [F3407]
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