Development of a general, sequential, ring-closing metathesis/ intramolecular cross-coupling reaction for the synthesis of polyunsaturated macrolactones

Article abstract of DOI:10.1021/ja1047363

A general strategy for the construction of macrocyclic lactones containing conjugated Z,Z-1,3-diene subunits is described. The centerpiece of the strategy is a sequential ring-closing metathesis (RCM) that forms an unsaturated siloxane ring, followed by an intramolecular cross-coupling reaction with a pendant alkenyl iodide. A highly modular assembly of the various precursors allowed the preparation of unsaturated macrolactones containing 11-, 12-, 13-, and 14-membered rings. Although the RCM process proceeded uneventfully, the intramolecular cross-coupling required extensive optimization of palladium source, solvent, fluoride source, and particularly fluoride hydration level. Under the optimal conditions (including syringe pump high dilution), the macrolactones were produced in 53-78% yield as single stereoisomers. A benzo-fused 12-membered-ring macrolactone containing an E,Z-1,3-diene unit was also prepared by the same general strategy. The E-2-styryl iodide was prepared by a novel Heck reaction of an aryl nonaflate with vinyltrimethylsilane followed by iododesilylation with ICl.

Full text of DOI:10.1021/ja1047363

Published on Web 07/28/2010
Development of a General, Sequential, Ring-Closing
Metathesis/Intramolecular Cross-Coupling Reaction for the
Synthesis of Polyunsaturated Macrolactones
Scott E. Denmark* and Joseck M. Muhuhi
Roger Adams Laboratory, Department of Chemistry, UniVersity of Illinois, Urbana, Illinois 61801
Received May 31, 2010; E-mail: sdenmark@illinois.edu
Abstract: A general strategy for the construction of macrocyclic lactones containing conjugated Z,Z-1,3-
diene subunits is described. The centerpiece of the strategy is a sequential ring-closing metathesis (RCM)
that forms an unsaturated siloxane ring, followed by an intramolecular cross-coupling reaction with a pendant
alkenyl iodide. A highly modular assembly of the various precursors allowed the preparation of unsaturated
macrolactones containing 11-, 12-, 13-, and 14-membered rings. Although the RCM process proceeded
uneventfully, the intramolecular cross-coupling required extensive optimization of palladium source, solvent,
fluoride source, and particularly fluoride hydration level. Under the optimal conditions (including syringe
pump high dilution), the macrolactones were produced in 53-78% yield as single stereoisomers. A benzo-
fused 12-membered-ring macrolactone containing an E,Z-1,3-diene unit was also prepared by the same
general strategy. The E-2-styryl iodide was prepared by a novel Heck reaction of an aryl nonaflate with
vinyltrimethylsilane followed by iododesilylation with ICl.
Introduction
Highly functionalized macrocycles are considered to be
privileged structures because their architectures provide specific
disposition of functionalities. Not surprisingly, they have found
application in supramolecular chemistry1 and in drug discovery.2
In drug development, complex macrocycles have been found
to bind selectively to proteins without significant loss in entropy
upon binding, and currently more than 100 marketed drugs are
derived from macrocycles that, on average, contain greater than
16-membered rings.2a The drug-like properties of macrocycles
notwithstanding, this class of molecules is still under-explored,
largely because of concerns about the difficulty of their syn-
thesis.2 Nevertheless, a number of macrocycles are in preclinical
and clinical development. From a chemical perspective, the
continuing discovery of macrocycles of natural origin that
possess both complex structures and sensitive functional groups
in a compact 12-14-membered macrocycle calls for the
development of newer, more efficient methods.
Figure 1. Macrolactone natural products possessing conjugated alkenes.
Recently discovered biologically active 12-14-membered
macrocycles include the oximidines I3 and III4 and the resor-
cylics5 (radicicol6 and monocilin7) that contain a salicylic acid
moiety embedded in a 12-membered macrolide ring (Figure 1).
These compounds also possess a conjugated diene or triene
moiety within the ring that imparts a high degree of strain within
the macrocycle. Efforts to synthesize these and similar lactones
have spurred the development of new synthetic methods capable
of efficiently constructing these polyunsaturated macrocycles.
In addition, examples of natural products with a conjugated
diene system that are not salicylic acid derived are known, such
as the 14-membered lactone lactimidimycin.8
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10.1021/ja1047363  2010 American Chemical Society

General Strategy for the Synthesis of Polyunsaturated Macrolactones
A R T I C L E S
achieve because of entropy and enthalpic contributions.9,10 To
overcome these contributions in macrocyclic synthesis, three
modes of cyclization are commonly used, and they are distin-
guished by the position of the reacting groups: (1) the end-to-
end, (2) the end-to-backbone, and (3) the backbone-to-backbone
cyclizations.11 To favor cyclization over oligomerization, high
dilution is effected in one of two ways: (1) the reaction is run
in a large volume of solvent to make a very dilute solution, or
(2) the precursor is added slowly over a long period time into
a given volume of solvent to maintain a high dilution of the
compound being cyclized. Pioneering kinetic studies done by
Galli and Mandolini on effective molarity (EM) now make it
possible to determine the optimal concentration required to favor
cyclization.12
The methods used to form macrocycles can be broadly
classified into two categories: (1) carbon-heteroatom-based
cyclization and (2) the carbon-carbon-based cyclization. The
carbon-heteroatom-based cyclization to build macrolactams and
macrolactones was reported first, and since then, many methods
of hydroxy acid lactonization or amino acid lactamization that
use different activating groups have been developed.13 In
addition, lactone formation via π-allylpalladium intermediates
has been reported.14 Cyclization via a carbon-carbon-based
strategy initially began with nucleophile- and electrophile-
promoted methods,9 and later radical- and metal-catalyzed
cyclizations appeared.15 More recently, metal-catalyzed cycliza-
tions have been performed using ring-closing metathesis
(RCM).16 For example, a ruthenium-catalyzed RCM has been
applied in a large-scale production of a 15-membered macro-
cyclic drug candidate.17 In addition, a major breakthrough in
RCM synthesis of macrolactones has been the ring-closing
enyne-yne metathesis18a that, in a stereocontrolled process,
furnishes a 1,3-diene motif within a macrocycle and conse-
quently has been applied in total synthesis.18b,c Another
carbon-carbon-based macrocyclization technique is the pal-
ladium-catalyzed cross-coupling reaction, such as the Stille,
Suzuki, and Hiyama reactions. The earliest examples of cross-
coupling reactions in macrocyclization employed organo-
boranes19 or organostannanes20 as the metallic donor because
they were stable and readily prepared. However, the use of
organotin has been limited because of tin toxicity, and as a result,
recent reports have focused on using organoboron donors21 or
other donors, such as silicon. The organosilicon-based partners
have emerged as competent donors in the synthesis of medium-
ring macrocyclic ethers22a and in the total synthesis of cyclic
natural products.22b
Background
The dominance of palladium catalysis in organic synthesis
is largely due to its specificity and functional group tolerance,
allowing the planning and execution of complex molecule total
synthesis.23 Among the earliest reports of a palladium-catalyzed
macrocyclization was the palladium-catalyzed intramolecular
alkylation of π-allylpalladium complexes with sulfone-stabilized
anions.24 The reaction affords medium- to large-ring macro-
lactones in good yields and has been applied as the key step in
total syntheses of natural products.25 Other reports of nucleo-
philic addition to π-allylpalladium complexes to form macro-
cycles and macrolactone natural product have appeared.14
Similarly, the assembly of macrocycles by palladium-cata-
lyzed cross-coupling is emerging as a viable alternative. Since
the first report19 that used haloalkenylboranes to synthesize the
sesquiterpene humulene, other palladium-catalyzed cross-
coupling reactions of organoboranes have been used to construct
complex natural products.21 At the same time that palladium-
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A R T I C L E S
Denmark and Muhuhi
Figure 2. Sequential RCM/silicon-assisted cross-coupling strategy.
catalyzed cross-coupling with organoboranes and organostan-
nanes was being developed, examples illustrating the use of
organosilicon in the synthesis of macrocycles appeared. Lastly,
macrocycles have also been synthesized by palladium-catalyzed
cross-coupling of alkynes.26
flexibility of a macrocycle is constrained by multiple degrees
of unsaturation. For example, the assembly of the oximidine II
core by either ruthenium-catalyzed metathesis29 or Suzuki cross-
coupling21d afforded the E,Z,Z-triene macrocycles V and VI in
48% and 42% yields, respectively (Figure 3, entries 1 and 2).
On the other hand, the synthesis of a simpler substrate under
Mitsunobu conditions (Figure 3, entry 3) afforded the macro-
cycle VII in 23% yield.30
The RCM reaction16 has revolutionized the synthesis of
macrocyclic products. Both molybdenum27 (Schrock) and ru-
thenium28 (Grubbs) complexes have been used to good advan-
tage. Because of their functional group tolerance, ruthenium
catalyst are preferred for the synthesis of natural and unnatural
products. However, in substrates containing electron-deficient
dienes and/or sterically encumbered double bonds, the more
reactive molybdenum catalysts are used.
Clearly, both palladium-catalyzed cyclizations and RCM
reactions enable synthetic strategies for the total synthesis of
macrocyclic natural products. Therefore, the amalgamation of
these reactions into a tandem sequence should open new and
highly simplifying strategies for the synthesis of macrocycles.
Recent disclosures from these laboratories have described a
sequential, ring-closing metathesis/silicon-assisted intramolecu-
lar cross-coupling reaction for the synthesis of medium-sized
rings (9-12) containing a cis,cis-diene motif as well as a
9-membered-ring ether that culminated in a total synthesis of
(+)-brasilenyne.22 The advantages of this approach for macro-
cycle synthesis are illustrated in Figure 2. To accomplish the
strategic disconnection between the double bonds of a generic
macrocyclic polyene I with a cross-coupling reaction, the acyclic
precursor II must be constructed, and the reactive termini
bearing X and M must locate each other under catalysis by a
transition metal. By constraining one double bond in a smaller
ring, the cross-coupling precursor III is less flexible and the
distance between the reacting termini is reduced, thus favoring
macrocyclization. Moreover, the size and substitution of the
smaller ring can be easily adjusted in the preparation of RCM
precursor IV.
Figure 3. Methods applied to synthesize benzo-fused lactones.
The benzo-fused lactone VII, while simple in appearance,
was an especially attractive target for a sequential RCM cross-
coupling sequence because it contains the conjugated diene motif
within the lactone core. The formation of the constrained
macrocycle III under palladium catalysis was envisioned to
proceed via a larger-ring organopalladium intermediate. Because
the carbon-palladium-carbon bonds in the intermediate are
longer than carbon-carbon bonds, the intermediate would have
less strain than the product being formed.21d Facile reductive
elimination simultaneously afforded the desired lactone and
regenerated the catalyst. The ultimate end goal now became
the efficient assembly of an embellished lactone III analogue.
Although this process provided efficient access to medium-
ring ethers, the general applicability and transferability of this
chemistry to the synthesis of larger rings as well as the assembly
of the more sensitive macrolactones is still unknown. As an
extension of scope, the synthesis of medium- to large-ring (11-
to 14-membered) lactones was targeted as a proving ground.
This challenge becomes even more formidable when the
Research Plan
In contrast to the use of the RCM/cross-coupling sequence
for the synthesis of medium-sized macrocyclic ethers, the
assembly of large-ring lactones such as VII presents additional
problems to unite the reacting ends of the now longer acyclic
chain. For example, because of the basic nature of fluoride,
tetrabutylammonium fluoride (TBAF)-assisted intramolecular
cross-coupling may lead to the cleavage of the lactone. In
addition, lactone VII possesses a trans,cis-diene system con-
jugated to a benzene ring that causes the compound to behave
as a conjugated triene system that is inherently more rigid, and
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Soc. 1990, 112, 8378–8387. (b) Bazan, G. C.; Oskam, J. H.; Cho,
H. N.; Park, L. Y.; Schrock, R. R. J. Am. Chem. Soc. 1991, 113, 6899–
6907. (c) Schrock, R. R.; Murdzek, J. S.; Bazan, G. C.; Robbins, J.;
Dimare, M.; Oregan, M. J. Am. Chem. Soc. 1990, 112, 3875–3886.
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Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953–956. (d)
Trnka, T. M.; Morgan, J. P.; Sanford, M. S.; Wilhelm, T. E.; Scholl,
M.; Choi, T. L.; Ding, S.; Day, M. W.; Grubbs, R. H. J. Am. Chem.
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General Strategy for the Synthesis of Polyunsaturated Macrolactones
A R T I C L E S
thus it is more difficult to fuse the reacting termini. Of these
problems, the greater ring size and the lability of the ester group
in the basic TBAF reaction medium were potentially most
challenging and thus led to the investigation of lactones VIII
(Figure 4) that are easier to access and modify. These lactones
were chosen because they addressed the consequences of placing
the carboxyl and hydroxyl groups in different locations with
respect to the diene moiety. Various ring sizes of VIII could
be accessed from the cyclic siloxanes such as IX. The strategy
to use cyclic siloxanes IX was chosen to fix one end of the
macrocycle to be formed in a smaller ring to reduce both
flexibility and distance between the two reacting termini. The
siloxane IX would be derived from RCM of silyl ethers X. The
silyl ethers X could be elaborated with ease from diols XI and
the acid XII. The key step in this route is the sequential ring-
closing metathesis/intramolecular cross-coupling reaction.
with diimide31 generated in situ from potassium azodicarboxyl-
ate,32 to afford (Z)-5-iodo-4-pentenol (1)33 in 62% yield over
two steps. Alcohol 1 was then oxidized by a CrO3-catalyzed
periodate oxidation34 to form (Z)-5-iodopent-4-enoic acid (2)33
in 97% yield. Hex-5-ene-1,2-diol (3a) was synthesized from
glycidol following the established sequence.35
Scheme 1a
a Conditions: (a) 1. I2, KOH, MeOH; 2. KO2CNdNCO2K, AcOH, THF/
i-PrOH, (62%); (b) CrO3/H5IO5, MeCN/H2O (9/1), (97%); (c) 1. COCl2,
benzene; 2. 3a, collidine, CH2Cl2, -78 °C, (79%); (d) chlorodimethyl-
vinylsilane, Et3N, CH2Cl2 (93%); (e) 6, benzene, rt (87%). The yields are
of analytically pure material.
Acid 2 was converted to its acid chloride, and the crude acid
chloride solution was added dropwise to a solution of diol 3
and collidine36 in dichloromethane at -78 °C to afford ester
4a in 79% yield over two steps. Silylation of ester 4a with
chlorodimethylvinylsilane gave the sensitive silyl ether 5a in
93% yield after purification with silica gel buffered with 1%
triethylamine. The alkenylsilyl ether 5a was then subjected to
RCM using the Schrock molybdenum carbene complex 627 to
afford the alkenylsiloxane 7a in 87% yield.
Figure 4. General synthetic sequence for the construction of macrolactones.
2. Optimization of the Intramolecular Cross-Coupling Re-
action. With alkenylsiloxane 7a in hand, the palladium-catalyzed
intramolecular cross-coupling was attempted using the reaction
conditions previously developed in these laboratories, namely,
allylpalladium chloride dimer (APC) as the catalyst and tetra-
butylammonium fluoride trihydrate (TBAF ·3H2O) as the activa-
tor.22 The reaction was carried out under high dilution such that
a 0.1 M solution of siloxane 7a was slowly added using a
syringe-pump into a mixture of APC (0.1 equiv) and a 1 M
solution of TBAF ·3H2O in THF (10 equiv) over a 40 h period
at room temperature. At the 10 h time point, precipitation of
palladium black was observed. After 40 h, H NMR analysis
of the reaction mixture showed traces of opened siloxane and
hydrolyzed silyl ether products.
The presence of palladium black implied that catalyst death
was occurring during the extended reaction time. To determine
if catalyst death was caused by oxygen poisoning, the reaction
was repeated under the same conditions but in a Schlenk flask
instead of a three-necked, round-bottomed flask. In this case
The conjugated triene problem will be investigated by the
synthesis of siloxane XIII from alcohol XIV. Alcohol XIV in
turn would arise from elaboration of 2,6-dihydroxybenzoic acid
(XV) and alcohol XVI. We describe herein the successful
implementation of this plan, which culminated in the syntheses
of medium- to large-ring macrolactones VIII and the fused
benzolactone VII.
Results
1
To initiate the study of the silicon-assisted cross-coupling
macrocyclization, an efficient and versatile synthetic sequence
was needed to generate the cycloalkenylsiloxanes 7a-e (Schemes
1 and 3) and 10 (Scheme 5) in high yield. The cyclic al-
kenylsiloxanes were prepared in seven steps from 4-pentyn-1-
ol. The synthesis of the styryl siloxane 10, on the other hand,
required eight steps. The selection of the reaction sequence was
guided by the stability of the products along each pathway.
Because the silyl ethers and the siloxanes are sensitive com-
pounds, the syntheses of these products were designed such that
they are the last compounds prepared prior to macrocyclization.
The details of each synthetic sequence are described below.
1. Preparation of Alkenylsiloxane 7a. Siloxane 7a (the cross-
coupling precursor used for optimization) was prepared from
4-pentyn-1-ol as depicted in Scheme 1. Iodination of 4-pentyn-
1-ol with iodine in aqueous KOH furnished 5-iodo-4-pentyn-
1-ol that was immediately subjected to a selective cis reduction
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(32) Groves, J. T.; Ma, K. W. J. Am. Chem. Soc. 1977, 99, 4076–4082.
(33) Wu, Y.; Gao, J. Org. Lett. 2008, 10, 1533–1536.
(34) Zhao, M. Z.; Li, J.; Song, Z. G.; Desmond, R.; Tschaen, D. M.;
Grabowski, E. J. J.; Reider, P. J. Tetrahedron Lett. 1998, 39, 5323–
5326.
(35) Pospisil, J.; Marko, I. E. Tetrahedron Lett. 2006, 47, 5933–5937.
(36) Ishihara, K.; Kurihara, H.; Yamamoto, H. J. Org. Chem. 1993, 58,
3791–3793.
9
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A R T I C L E S
Denmark and Muhuhi
Table 1. Optimization of the Fluoride Source and Solvent for the
the desired lactone 8a was isolated together with an isomeric
lactone 8a′ as an inseparable 3:1 mixture in 43% yield (Scheme
2). The identity and ratio of 8a/8a′ were determined by 1H NMR
analysis.37 Further structural evidence was secured by converting
the components to their triethylsilyl (TES)-protected ethers
followed by exposure of the mixture to CrO3 ·2py oxidation,38
which converted the primary TES-protected 8a′ to an aldehyde
while the TES-protected secondary alcohol 8a was recovered
intact.37 The isomeric lactone 8a′ most likely arose from a base-
promoted translactonization initiated by the fluoride ion. Ac-
cordingly, further optimization was needed to suppress this
undesired process and increase the yield of the desired product.
Macrocyclizationa
8a + 8a′
entry
fluoride source
equiv
solvent
yield, %
ratiob
1
2
3
4
5
6
7
8
TBAF ·3H2O
TBAF ·3H2O
TBAF ·4H2O
TBAF ·6H2O
TBAF ·6H2O
TBAF ·6H2O
TBAF ·6H2O
TBAF ·6H2O
TBAF ·7H2O
TBAF ·10H2O
TBAF ·15H2O
10
10
10
10
5
2.5
5
5
THF
THF
THF
THF
THF
THF
dioxane
DMF
DMF
THF
THF
0
43
64
59
72
26
76
84
79
46
39
3:1
3:1
3:1
3:1
3:1
3:1
2:1
2:1
100:0
100:0
Scheme 2
9
10
11
5
5
5
a Reaction conditions employed 0.25 mmol of 7a at 0.1 M. b Ratio
1
determined by H NMR analysis.
2.1. Optimization of TBAF Hydration Level and Solvent.
Operating under the hypothesis that the isomeric lactone 8a′
arose from 8a because of the basic character of TBAF, measures
to lower its basicity while maintaining fluoride anion strength
were taken. Detailed studies of the nucleophilicity of quaternary
ammonium fluorides have shown that the trihydrated fluoride
anion is both very basic and nucleophilic.39 These properties
can be attenuated with protic solvents and modulated by varying
the hydration level of the quaternary ammonium salt. This
strategy was critical for the successful cross-coupling of silanols
with aryl triflates40 and alkenyl iodides.41 To address the
problem of ester hydrolysis, two experiments were performed.
The fluoride source (TBAF ·3H2O) was further hydrated by
adding the appropriate amounts of water to a 1 M solution of
TBAF · 3H2O in THF to form solutions of TBAF · 4H2O and
TBAF·6H2O. The palladium-catalyzed macrocyclization reac-
tion using the TBAF ·4H2O afforded a higher yield of product
(64%), but again as a 3:1 mixture of lactones 8a and 8a′,
whereas the reaction with TBAF ·6H2O produced the macro-
lactones in a slightly lower yield of 59% (Table 1, entries 3
and 4). Higher hydration levels, TBAF · 10H2O and
TBAF·15H2O, gave lower yields (46% and 39%, respectively)
but afforded excellent selectivity, only macrocycle 8a being
formed (Table 1, entries 10 and 11). TBAF ·6H2O was chosen
as the fluoride source in the next stage of optimization because
of its lower fluoride anion strength.39
Because the reaction optimization up to this juncture had been
conducted with an ethereal solvent (THF), dioxane was selected
next because it is a competent solvent for alkenyl-alkenyl cross-
coupling reactions.40 The use of dioxane led to an increase in
yield (76%) of the macrocycles (Table 1, entry 7). This result
suggested that solvent polarity may have an effect on product
yield because dioxane is marginally more polar than THF
[dioxane (Aj + Bj) ) 0.86 versus THF (Aj + Bj) ) 0.84].42
The use of DMF [(Aj + Bj) ) 1.23] led to a still higher yield
of the macrocycles 8a and 8a′ (84%) but lower selectivity (2:1
ratio) (Table 1, entry 8). Because DMF afforded the macrolac-
tones 8a and 8a′ in higher yield compared to THF or dioxane,
it was selected as the solvent of choice going forward.43
2.2. Survey of Fluoride Sources. Many fluoride sources are
commercially available or are easily accessed in a few synthetic
steps. The survey of fluoride sources other than TBAF ·6H2O
began with the commercially available tetramethylammonium
fluoride tetrahydrate (TMAF · 4H2O). This salt is superior to
TBAF·3H2O in the cross-coupling of aryl triflates and alkenyl-
silanols.40 Tetramethylammonium is the smallest of all tetralkyl-
ammonium cations and has a symmetrical, almost spherical
structure.44 By adapting the conditions developed previously,
but now with TMAF ·4H2O as the fluoride source, the cross-
coupling of siloxane 7a afforded macrocycle 8a as a single
isomer, albeit in only 47% yield (Table 2, entry 1). Increasing
the hydration level to TMAF ·6H2O afforded the cross-coupled
product in 34% yield (Table 2, entry 2). Despite the low yields
of 8a obtained with TMAF ·6H2O, the high selectivity was
particularly attractive and encouraged further study.
The problem of post facto isomerization was addressed by
adjusting the amount of TBAF · 6H2O. Lowering the
TBAF·6H2O loading from 10 to 5 equiv improved the yield
significantly to 72%, but the ratio of the two isomers 8a and
8a′ remained the same (Table 1, entry 5). However, when the
amount of TBAF ·6H2O was reduced to 2.5 equiv, the macro-
lactones 8b and 8b′ were isolated in only 26% yield (Table 1,
entry 6). For the purpose of further optimization, 5 equiv of
TBAF·6H2O was selected.
Benzyltrimethylammonium fluoride (BTMAF) is a close
analogue of TMAF and was easily prepared from benzyltri-
(42) Reichardt, C. SolVents and SolVents Effects in Organic Chemistry, 3rd
updated and enlarged ed.; Wiley-VCH: Weinheim, 2003; Chapter 7.
Aj represents acidity, a solvent anion-solvating tendency, while Bj
represents basicity, a solvent cation-solvating tendency. The sum of
acidity and basicity is a solvent solvation capability or its polarity.
(43) The DMF used in these investigations was dried by percolation through
an activity 1 alumina bed. The water content was determined by
triplicate Karl Fischer titration to be 3.3 µg/100 µL, or 33 ppm.
(44) Harmon, K. M.; Gennick, I. Inorg. Chem. 1975, 14, 1840–1845.
(37) See Supporting Information for details.
(38) Smith, A. B., III; Lupo, A. T.; Ohba, M.; Chen, K. J. Am. Chem. Soc.
1989, 111, 6648–6656.
(39) Landini, D.; Maia, A.; Rampoldi, A. J. Org. Chem. 1989, 54, 328–
332.
(40) Denmark, S. E.; Sweis, R. F. Org. Lett. 2002, 4, 3771–3774.
(41) Denmark, S. D.; Liu, J. H.-C.; Muhuhi, M. J. J. Am. Chem. Soc. 2009,
131, 14188–14189.
9
11772 J. AM. CHEM. SOC. VOL. 132, NO. 33, 2010

General Strategy for the Synthesis of Polyunsaturated Macrolactones
A R T I C L E S
Table 2. Survey of the Fluoride Sources for the Macrocyclizationa
yield in a 2:1 ratio. The diagnostic alkene resonances of 8a,
namely HC(6) and HC(7), appeared at 6.08 ppm (dd, 3J ) 10.8,
3
7.0 Hz) and 5.98 ppm (dd, J ) 11.0, 7.0 Hz), respectively.
The resonance for H2C(12) appeared as an ABX quartet at 4.19
3
3
ppm (dd, J ) 11.3, 3.0 Hz) and 3.93 ppm (dd, J ) 11.5, 5.0
Hz). On the other hand, compound 8a′ displayed a single, well-
resolved alkene resonance for HC(6) and HC(7) at 5.88 ppm
(d, 3J ) 11.0 Hz). The signal for H2C(12) appeared as an ABX
quartet at 3.66 ppm (ddd, 3J ) 11.9, 5.8, 3.5 Hz) and 3.55 ppm
8a + 8a′
entry
fluoride source
solvent
equiv
yield, %
ratiob
3
(dd, J ) 12.0, 10.0 Hz). All attempts to resolve alkene peaks
1
2
3
4
5
6
7
8
9
TMAF ·4H2O
TMAF ·6H2O
BTMAF
BTMAF ·6H2O
BTMAF ·10H2O
TEAF ·2H2O
TEAF ·6H2O
TBAT
DMF
DMF
DMF
DMF
DMF
DMF
DMF
THF
5
5
5
5
5
5
5
5
5
5
47
34
39
49
0
32
40
29
22
0
100:0
100:0
2:1
for HC(5) and HC(8) were not successful,50 but to the best of
our knowledge the macrolactones are formed in a stereospecific
manner.
6:1
Preliminary molecular modeling calculations51 show that 8a
is 0.26 kcal/mol lower in energy than 8a′, which corresponds
to a predicted ratio of 1.6:1 at room temperature, close to the
observed ratio of 2:1. Although a good yield of the 12-ring
macrolactone could be obtained, it was not possible to suppress
the formation of the 11-ring isomer without a substantial
decrease in yield. Thus, before further optimization was
undertaken, it was deemed prudent to establish if isomerization
is a general phenomenon or is unique to this structure.
Accordingly, a selection of other precursors was prepared to
evaluate the generality of the cross-coupling macrocyclization.
3. Scope of the Intramolecular Cross-Coupling Reaction. To
evaluate the scope of this cross-coupling reaction for the
construction of macrocycles, the siloxanes 7b-f (Scheme 3)
were synthesized in a fashion similar to that shown for synthesis
of siloxane 7a. The assembly began with the conversion of acid
2 to the acid chloride that was then added dropwise to cooled
solutions of known diols 3b-f52 in collidine to provide esters
4b-f in 72-79% yields (Table 3). The esters were converted
to their respective silyl ethers 5b-f and then were subjected to
RCM with catalyst 6 as before to afford siloxanes 7b-f.
2:1
2:1
100:0
100:0
TASF
CsF
THF
DMF
10
a Reaction conditions employed 0.25 mmol of 7 at 0.1 M. b Ratio
1
determined by H NMR.
methylammonium hydroxide in 73% yield.45 The use of
BTMAF (with hydration assumed to be <0.5 after drying)46 in
the macrocyclization reaction of 7a afforded the macrocycles
8a and 8a′ in 39% yield in a 2:1 ratio (Table 2, entry 3). To
suppress the isomerization, hydrated BTMAF was used
(BTMAF·6H2O), and the product was formed in higher yield
(49% versus 39%) and improved selectivity (6:1 versus 2:1)
(Table 2, entry 4). Unfortunately, increasing the hydration level
to BTMAF ·10H2O was not productive (Table 2, entry 5).
Next, the commercially available tetraethylammonium fluo-
ride dihydrate (TEAF ·2H2O) was investigated. With this acti-
vator, the desired macrocycle was obtained in a 32% yield as a
2:1 ratio of 8a and 8a′ (Table 2, entry 6). Increasing the
hydration level to TEAF ·6H2O gave a modest increase in yield
of 8a and 8a′ (40%), but the selectivity remained the same
(Table 2, entry 7).
Scheme 3
The last phase of this survey was the investigation of anhydrous
fluoride sources. A number of anhydrous fluoride sources have
been used for silicon-based cross-coupling, such as tris(diethyl-
amino)sulfonium difluorotrimethylsilicate (TASF),47 tetrabutyl-
ammonium triphenyldifluorosilicate (TBAT),48 and cesium fluoride
(CsF).49 Reaction of siloxane 7a with TBAT afforded the macro-
cycle 8a in 29% yield as a single isomer (Table 2, entry 8), while
the activation with TASF afforded 8a in 22% and with the same
selectivity (Table 2, entry 9). Cesium fluoride led only to
decomposition of the starting material, and no macrocycle was
detected (Table 2, entry 10).
Integrating all of the optimization data, the combination that
employed 0.1 equiv of APC, 5 equiv of TBAF ·6H2O as the
fluoride source, and DMF as the solvent was chosen as the
optimal conditions because it afforded the highest yield of 8a.
A 1.0-mmol-scale macrocyclization reaction of siloxane 7a
under these conditions after 48 h furnished 8a and 8a′ in 78%
The scope of the intramolecular cross-coupling reaction was
investigated on a 1.0 mmol scale under the optimized reaction
conditions (0.1 equiv of APC and 5 equiv of TBAF ·6H2O in
DMF (0.1 M) using syringe pump addition at room temperature).
1
(50) All attempts to resolve the olefinic region by recording the H NMR
spectra with various deuterated solvents (CDCl3, CD2Cl2, C6D6,
CD3OD, toluene-d, DMSO-d, pyridine-d, tetrahydrofuran-d, 1,4-
dioxane-d) and with lanthanide shift reagents (EuFOD and YbFOD)
were unsuccessful.
(45) Kuwajima, I.; Nakamura, E.; Shimizu, M. J. Am. Chem. Soc. 1982,
104, 1025–1030.
(46) (a) Cox, D. F.; Terpinski, J.; Lawrynowicz, W. J. Org. Chem. 1984,
49, 3216–3219. (b) Albanese, D.; Landini, D.; Penso, M. J. Org. Chem.
1998, 63, 9587–9589.
(51) Spartan 08, DFT, B3LYP, 6-31*G.
(52) (a) Takaoka, L. R.; Buckmelter, A. J.; LaCruz, T. E.; Rychnovsky,
S. D. J. Am. Chem. Soc. 2005, 127, 528–529. (b) Crawford, R. J.;
Lutener, S. B.; Cockcroft, R. D. Can. J. Chem. 1976, 54, 3364–3376.
(c) Sugawara, M.; Yoshida, J. Tetrahedron Lett. 1999, 40, 1717–1720.
(d) Nishikawa, T.; Shinokubo, H.; Oshima, K. Tetrahedron 2003, 59,
9661–9668. (e) Klos, A. M.; Heintzelman, G. R.; Weinreb, S. M. J.
Org. Chem. 1997, 62, 3758–3761.
(47) Hatanaka, Y.; Hiyama, T. J. Org. Chem. 1988, 53, 918–920.
(48) (a) DeShong, P.; Handy, C. J.; Mowery, M. E. Pure Appl. Chem. 2000,
72, 1655–1658. (b) Mowery, M. E.; DeShong, P. J. Org. Chem. 1999,
64, 3266–3270.
(49) Denmark, S. E.; Kobayashi, T. J. Org. Chem. 2003, 68, 5153–5159.
9
J. AM. CHEM. SOC. VOL. 132, NO. 33, 2010 11773

A R T I C L E S
Denmark and Muhuhi
Table 3. Preparation of Esters 4, Silyl Ether 5, and Siloxanes 7
of 11-, 12-, 13-, and 14-membered lactones was gratifying and
served to demonstrate that this method could be applied in
synthesis of natural products that contain the conjugated diene
moiety as a part of a macrolactone. However, a more challenging
goal was to apply this approach to synthesize a conjugated triene
motif. As an extension of the chemistry described above, the
synthesis of lactone 9 (Scheme 5) was identified as a model
study that could be used to access oximidine III and eventually
the triene-conjugated oximidine II natural product.
product (yield, %)a
m, n
ester 4
silyl ether 5
siloxane 7
1, 1
2, 0
1, 0
2, 1
3, 0
3, 1
4a (79)
4b (72)
4c (76)
4d (70)
4e (76)
4f (72)
5a (93)
5b (79)
5c (89)
5d (90)
5e (95)
5f (91)b
7a (87)
7b (89)
7c (81)b
7d (84)
7e (83)
7f (76)
a Yields of analytically pure material. b Yields of chromatographically
homogeneous material.
Scheme 5
The cyclization of siloxane 7b was carried out first because the
product, 12-membered macrocycle 8b, had the same ring size
as 8a obtained earlier (Scheme 4). Under the conditions
described above, siloxane 7b afforded macrocycle 8b in 70%
yield as a single isomer. This outcome suggested that the
translactonization observed in synthesis of 8a may be substrate
dependent.
Scheme 4
The synthesis of the benzo-fused lactone 9 would result from
macrocyclization of the styryl iodide 10 (Scheme 5). The
siloxane portion of 10 would arise from elaboration of the silyl
ether 11, itself prepared from coupling of styryl iodide 12 with
alcohol 13. Synthesis of such styryl iodides can be achieved by
Takai olefination of aromatic aldehydes,53 halodecarboxylation
of cinnamic acids (Hunsdiecker reaction),54 reduction of dihalo-
alkenes,55 base-promoted homologation of benzyl bromides,56
or ruthenium-catalyzed silylation of styrene.57 Although useful,
all of the above methods have various drawbacks. A simpler
approach would involve the iododesilylation58 of vinylsilanes
themselves, obtained by either a Mizoroki-Heck59 reaction of
an aryl halide with vinyltrimethylsilane60 or a hydrosilylation
of an aryl alkyne61 obtained from a Sonagashira reaction of an
aryl halide. However, in the case at hand, these methods could
Gratifyingly, siloxane 7c afforded the 11-membered macro-
lactone 8c in 58% yield, again as a single isomer. The diagnostic
alkene resonances for HC(6) and HC(7) appeared at 6.04 ppm
3
(dd, J ) 9.8, 9.8 Hz). The synthesis of 11-membered macro-
(53) (a) Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986, 108,
7408–7410. (b) Takai, K.; Ichiguchi, T.; Hikasa, S. Synlett 1999, 1268–
1270. (c) Haack, T.; Kurtkaya, S.; Snyder, J. P.; Georg, G. I. Org.
Lett. 2003, 5, 5019–5022.
cycles is known to be more difficult than that of 12-membered
rings.10
Next, this process was extended to the synthesis of 13- and
14-membered rings. Thus, cross-coupling of siloxane 7d af-
forded the 13-membered macrocycle 8d in 61% yield. The
closure of this macrolactone required longer reaction time (54
h) compared to that of the 12-membered lactone (40 h). The
synthesis of another 13-membered ring, 8e, that contained a
different substitution pattern proceeded in 53% yield after 48 h.
Unfortunately, the alkene region of the 1H NMR spectra of both
13-membered lactones 8d and 8f could not be fully analyzed.50
Finally, the synthesis of the 14-membered ring 8f was achieved
from siloxane 7f in 69% yield after 54 h. Gratifyingly, the alkene
resonances for HC(6) and HC(7) were well resolved and showed
two doublets of doublets at 6.32 ppm (dd, 3J ) 10.5, 10.5 Hz)
(54) (a) Kuang, C. X.; Yang, Q.; Senboku, H.; Tokuda, M. Synthesis 2005,
1319–1325. (b) Das, J. P.; Roy, S. J. Org. Chem. 2002, 67, 7861–
7864. (c) You, H.-W.; Lee, K.-J. Synlett 2001, 105–107. (d) Naskar,
D.; Roy, S. Tetrahedron 2000, 56, 1369–1377.
(55) Horibe, H.; Kondo, K.; Okuno, H.; Aoyama, T. Synthesis 2004, 986–
988.
(56) Bull, J. A.; Mousseau, J. J.; Charette, A. B. Org. Lett. 2008, 10, 5485–
5488.
(57) Pawluc, P.; Hreczycho, G.; Szudkowska, J.; Kubicki, M.; Marciniec,
B. Org. Lett. 2009, 11, 3390–3393.
(58) (a) Stamos, D. P.; Taylor, A. G.; Kishi, Y. Tetrahedron Lett. 1996,
37, 8647–8650. (b) Tamao, K.; Akita, M.; Maeda, K.; Kumada, M. J.
Org. Chem. 1987, 52, 1100–1106.
(59) (a) Mizoroki, T.; Mori, K.; Ozaki, A. Bull. Chem. Soc. Jpn. 1971, 44,
581. (b) Heck, R. F.; Nolley, J. P. J. Org. Chem. 1972, 37, 2320–
2322.
3
(60) (a) Karabelas, K.; Hallberg, A. J. Org. Chem. 1986, 51, 5286–5290.
(b) Garst, M. E.; McBride, B. J. J. Org. Chem. 1989, 54, 249–250.
(c) Battace, A.; Zair, T.; Doucet, H.; Santelli, M. J. Organomet. Chem.
2005, 690, 3790–3802.
and 6.23 ppm (dd, J ) 10.8, 10.8 Hz), respectively.
4. Formation of Benzo-Fused Macrocyclic Diene (E,Z)-9. The
success of the intramolecular cross-coupling for the synthesis
9
11774 J. AM. CHEM. SOC. VOL. 132, NO. 33, 2010

General Strategy for the Synthesis of Polyunsaturated Macrolactones
A R T I C L E S
not be used because a suitable aryl halide precursor to compound
14 is not readily available. An alternative solution was to find
conditions that could effect a Mizoroki-Heck59 reaction
between aryl triflate 1562 and vinyldimethylsilane.
(1) triphenylphosphine (Table 4, entry 6) provided a significantly
increased yield compared to 19 and 20 (Table 4, entries 4 and
5), and (2) palladium acetate (Table 4, entry 6) was the best
palladium source, affording the desired arylvinylsilane 14 in
54% yield together with a 46% yield of unreacted starting
material.69 Most importantly, this combination did not lead to
the formation of byproducts. Moreover, the reactivity and
selectivity of Pd(OAc)2 can be tuned with different phosphine
ligands.
Catalysis of the Heck reaction with palladium complexes
bearing electron-rich arylphosphines such as tri-o-tolylphosphine
[(o-Tol)3P] and 1,2-bis(diphenylphosphino)ferrocene (dppf)
often have higher reaction rates and turnovers compared to
Ph3P.70 In addition, tri-(tert-butyl)phosphine (t-Bu3P) and di(tert-
butylphosphino)ferrocene are effective ligands for Heck
reactions.67,71
4.1. Optimization of the Mizoroki-Heck Reaction of Vinyl-
trimethylsilane.Tothebestofourknowledge,theMizoroki-Heck
reaction of an aryl fluoroalkylsulfonate with vinyltrimethylsilane
is unprecedented, and this example represented an even more
daunting challenge because of the ortho substituent on aryl
triflate 15.63 The initial survey employed the phosphine-free
“Jeffrey conditions” 64 (Table 4, entry 1). Unfortunately, when
run at ambient temperature, the reaction stalled at 43% conver-
sion, but increasing the temperature to 80 °C improved the
conversion to 73% (Table 4, entry 2). Changing the solvent to
MeCN did not offer any significant improvement (Table 4, entry
3).
Thus, a survey of electron-rich, sterically hindered mono-
dentate and bidentate phosphine ligands was carried out with
Pd(OAc)2. The first reactions were run using the bidentate
ligands dppf and BIPHEP (Table 4, entries 7 and 8). The
use of dppf (Table 4, entry 7) gave the expected silyl ether
14 in 34% yield together with 27% yield of unreacted starting
material 15. In addition, the desilylated compound 16 and
the hydrolysis byproduct 17 were observed in 17% and 22%
yields, respectively. The ligand BIPHEP, on the other hand,
gave the desilylated product 16 in 71% yield and only 10%
yield of the desired material 14. Cleary, bidentate ligands
were inferior to Ph3P, so monodentate ligands were surveyed
next.
To evaluate t-Bu3P, the commercially available tri-tert-
butylphosphine tetrafluoroborate salt (t-Bu3P·HBF4) was em-
ployed, and complete consumption of the starting material
occurred to afford 14 in 60% yield together with reduction
product 18 in 30% yield; however, no other byproducts were
detected by GC analysis (Table 4, entry 9). The formation of
reduced products is known in cross-coupling reactions, particu-
larly in DMF with tertiary amines.72 To remedy this problem,
both DMSO and NMP were tested (Table 4, entries 10 and 11).
The use of DMSO increased the yield of 14 to 74% yield
together with 11% of 8 but also led to formation of the
hydrolyzed product 17 in 18% yield. The use of NMP led to an
increase in yield of 14 (88%), albeit with 12% yield of 18.
On the other hand, the use of 2-(di-tert-butylphosphino)biphenyl
(BPTBP) in DMF gave 14 in 74% yield together with 18 in 12%
yield, a significantly better result than that obtained with the use
of t-Bu3P and DMF (Table 4, entry 12). Moreover, DMSO led to
the formation of 14 in 87% yield together with 18 (10%) and 17
(3%) (Table 4, entry 13). In NMP, the reaction stalled, and 18
was obtained in 48% yield accompanied by a 10% yield of 18
Table 4. Optimization of the Heck Reaction of Aryl Triflate 15a
yield, %b
entrya
Pd source (5 mol % Pd), conditions
15
14
16
17
18
1c
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Pd(OAc)2, n-Bu4NOAc, DMF, rt
Pd(OAc)2, nBu4NOAc, DMF
Pd(OAc)2, nBu4NOAc, MeCN
19,d DMF
57
27
30
58
71
46
27
19
43
73
70
27 15
22
54
34 17 22
10 71
60
74 18
88
74
20,d DMF
7
Pd(OAc)2, Ph3P, DMF
Pd(OAc)2, dppf, DMF
Pd(OAc)2, BIPHEP, DMF
Pd(OAc)2, t-Bu3P·HBF4, DMF
Pd(OAc)2, t-Bu3P·HBF4, DMSO
Pd(OAc)2, t-Bu3P·HBF4,NMP
Pd(OAc)2, BPTBP,e DMF
Pd(OAc)2, BPTBP,e DMSO
Pd(OAc)2, BPTBP,e NMP
Pd(OAc)2, BPTBP,e MeCN
30
8
12
16
10
19
10
87
48
85
3
42
a Reaction conditions, unless indicated otherwise, employed 0.25
mmol of 15, 3 equiv of trimethylvinylsilane, and 2 equiv of Et3N, 80
°C. b Yield for 15 is unreacted starting material. Yields of 14, 16, 17,
and 18 were determined by GC analysis without an internal standard.
c No Et3N was used as base. d Ligands: VII and VIII. e BPTBP )
2-(di-tert-butylphosphino)biphenyl.
(65) Beletskaya, I. P.; Cheprakov, A. V. Chem. ReV. 2000, 100, 3009–
3066.
A survey of Pd sources that represent the three most widely
used ligand classes, namely N-heterocyclic carbene (NHC)
19,65-67 phosphite 20,65,68 and phosphines65,67 (Table 4, entries
4-6), was carried out. Two important observations were made:
(66) Herrmann, W. A. Angew. Chem., Int. Ed. 2002, 41, 1290–1309.
(67) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 4176–4211.
(68) Beletskaya, I. P.; Cheprakov, A. V. J. Organomet. Chem. 2004, 689,
4055–4082.
(69) (PPh3)2PdCl2 afforded 14 (49%) and 16 (38%) along with 15% of
recovered 15.
(61) Hamze, A.; Provot, O.; Brion, J. D.; Alami, M. J. Organomet. Chem.
2008, 693, 2789–2797.
(70) Qadir, M.; Mochel, T.; Hii, K. K. Tetrahedron 2000, 56, 7975–7979.
(71) (a) Shaughnessy, K. H.; Kim, P.; Hartwig, J. F. J. Am. Chem. Soc.
1999, 121, 2123–2132. (b) Barrios-Landeros, F.; Carrow, B. P.;
Hartwig, J. F. J. Am. Chem. Soc. 2008, 130, 5842–5843.
(72) (a) Ghosez, L.; Franc, C.; Denonne, F.; Cuisinier, C.; Touillaux, R.
Can. J. Chem. 2001, 79, 1827–1839. (b) Handy, S. T.; Bregman, H.;
Lewis, J.; Zhang, X. L.; Zhang, Y. N. Tetrahedron Lett. 2003, 44,
427–430.
(62) Fu¨rstner, A.; Dierkes, T.; Thiel, O. R.; Blanda, G. Chem. Eur. J. 2001,
7, 5286–5298.
(63) Neuville, L.; Bigot, A.; Dau, M. E. T. H.; Zhu, J. P. J. Org. Chem.
1999, 64, 7638–7642.
(64) (a) Jeffery, T.; Ferber, B. Tetrahedron Lett. 2003, 44, 193–197. (b)
Jeffery, T. Tetrahedron Lett. 1999, 40, 1673–1676. (c) Jeffery, T.
Tetrahedron 1996, 52, 10113–10130.
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J. AM. CHEM. SOC. VOL. 132, NO. 33, 2010 11775

A R T I C L E S
Denmark and Muhuhi
and a 42% recovery of the starting material 15 (Table 4, entry
14). However, upon using MeCN, 14 was obtained in 85% yield
together with a 10% yield of the reduced product 10.
sodium or potassium alkoxide of 1374 (Scheme 5) failed and led
to vinyl iodide decomposition and/or inconsistent conversion to
the expected ester 22. Similarly, attempts to effect acylation with
titanium(IV) isopropoxide75 met with failure. However, acylation
using 1-hydroxy-3-(isothiocyanato)tetrabutyldistannoxane (Otera’s
catalyst)76 in toluene at reflux furnished the analytically pure ester
22 in 89% yield after chromatography. Methylation of the hydroxyl
group of 22 with methyl iodide and Cs2CO3 afforded 23 in 96%
yield. Removal of the PMB group was then effected using ceric
ammonium nitrate (CAN) to afford alcohol 24 in 86% yield.
Alcohol 24 was then silylated with chlorodimethylvinylsilane to
afford the sensitive silyl ether 11 in 93% yield. The silyl ether 11
was then subjected to RCM with catalyst 6 to furnish siloxane 10
in 83% yield. Slow addition of a 0.1 M solution of siloxane 10 in
DMF into a solution of APC and TBAF ·6H2O by syringe pump
over 48 h furnished macrocycle 9 in a gratifying 74% yield as an
oil whose molecular composition was confirmed by high-resolution
mass spectrometry. The benzo-fused lactone 9 was formed ste-
reospecifically, as indicated by analysis of its 1H NMR spectrum.
The diagnostic alkene resonance for HC(8) appeared at 6.53 ppm
(d, 3J ) 15.5 Hz) that correlated well with the coupling constant
found for a simpler compound.77 The other alkenyl protons HC(9),
From the ligand and solvent survey conducted above, the
reaction conditions that employed t-Bu3P·HBF4 in NMP and
BPTBP in MeCN were identified as the best ligand/solvent
combinations that gave the highest yields of 14 without creating
more than one byproduct. However, of the two ligands
employed, BPTBP was chosen for scale-up because the reaction
appeared to be cleaner by GC analysis. On a 1.3-mmol scale
this reaction afforded the desired arylvinylsilane 14 in 66% yield
after chromatographic purification.
Among the optimization studies, entry 6 in Table 4 was
intriguing because, aside from the Jeffery conditions, this was the
only reaction that did not give byproducts. This result indicated
that a more reactive electrophile might be a better substrate.
Accordingly, an aryl nonaflate, known to be 1.4 times more
reactive73 than the corresponding aryl triflate, was tested. The
desired aryl nonaflate 21 (Scheme 6) was efficiently prepared in
88% yield from the corresponding phenol.74 Subjecting 19 to the
reaction conditions in Table 4, entry 6, afforded a single product
by GC analysis. On a 10-mmol scale this reaction yielded the
analytically pure arylvinylsilane 14 in 84% yield after chromatog-
raphy and Kugelrohr distillation (Scheme 6).
3
HC(10), and HC(11) appeared at 6.73 ppm (dd, J ) 15.5, 9.0
Hz), 6.13 ppm (app t, 3J ) 10.0 Hz), and 5.72 ppm (dt, 3J ) 10.5,
7.5 Hz), respectively, that also matched well with known ana-
logues.77
Scheme 6a
Discussion
The primary goals of this study were to develop an intramo-
lecular cross-coupling reaction of siloxanes that affords mac-
rolactones in good yields and to prepare a benzo-fused lactone
that could serve as the model system for the synthesis of
oximidine II. The preparation of macrolactones was enabled
by the discovery that fluoride activation of the cross-coupling
was effective. The generality of this finding was demonstrated
by the synthesis of various macrolactones. The second aim of
this study was facilitated by the development of a Mizoroki-Heck
reaction of aryl perfluoralkylsulfonates and a vinylsilane. The
elaboration of the Mizoroki-Heck product led to assembly of
a benzo-fused macrolactone possessing the core structure of
oximidine II.
1. Preparation of Siloxanes 7a-f. The synthesis of the
siloxanes used in this study was accomplished in a multistep
sequence whereby each reaction step was a modification of a
closely related report. The syntheses of siloxanes 7a-f began
from 4-pentyn-1-ol and in a seven-step sequence proceeded
uneventfully to yield analytically pure materials in good to
excellent yields for all the steps and in all the cases. However,
the unexpected sensitivity of the silyl ethers 5a-f warrants
further comment. Initial attempts to purify the silyl ethers by
silica gel chromatography led to extensive desilylation and
a Conditions: (a) Pd(OAc)2 (5 mol %), Ph3P (10 mol %), chlorodimeth-
ylvinylsilane, Et3N, MeCN, 80 °C (84%); (b) ICl, MeCN, 0 °C (83%); (c)
13, Otera catalyst, toluene, reflux (89%); (d) CH3I, Cs2CO3, THF (96%);
(e) CAN, MeCN/H2O (86%); (f) chlorodimethylvinylsilane, Et3N, CH2Cl2
(93%); (g) 6, benzene, rt (83%); (h) [allylPdCl]2 (10 mol %), TBAF ·6H2O,
DMF (74%).
(73) (a) Rottlander, M.; Knochel, P. J. Org. Chem. 1998, 63, 203–208. (b)
Lipshutz, B. H.; Buzard, D. J.; Yun, C. S. Tetrahedron Lett. 1999,
40, 201–204. For reviews of nonafluorobutane sulfonate chemistry,
see: (c) Ho¨germeier, J.; Reissig, H. U. AdV. Synth. Catal. 2009, 351,
2747–2763. (d) Stang, P. J.; Hanack, M.; Subramanian, L. R. Synthesis
1982, 85–126.
Now with a robust and easily scaled process for synthesizing
arylvinylsilane 14 in hand, the elaboration to the macrocycliza-
tion precursor siloxane 10 began in earnest.
4.2. Synthesis of the Benzo-Fused Macrolactone (E,Z)-9.
Iododesilylation of 14 with ICl58 afforded arylvinyl iodide 12
in 83% yield with complete retention of the double bond
configuration (Scheme 6). Attempts to open lactone 12 with the
(74) Fu¨rstner, A.; Nagano, T.; Muller, C.; Seidel, G.; Muller, O. Chem.
Eur. J. 2007, 13, 1452–1462.
(75) Rehwinkel, H.; Steglich, W. Synthesis 1982, 826–827.
(76) Otera, J.; Danoh, N.; Nozaki, H. J. Org. Chem. 1991, 56, 5307–5311.
(77) For a less functionalized analogue of the same ring system: HC(8), d,
J ) 15.5 Hz; HC(9), dd, J ) 15.5, 11.1 Hz; HC(10), app t, J ) 11.1
Hz; HC(11), dt, J ) 10.6, 4.9 Hz. Coleman, R. S.; Garg, R. Org.
Lett. 2001, 3, 3487–3490.
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General Strategy for the Synthesis of Polyunsaturated Macrolactones
A R T I C L E S
inconsistent results. Although the use of neutral alumina
remedied the desilylation problem, the product contained an
impurity that led to death of the molybdenum catalyst in the
following RCM step. However, adding 1% of Et3N to the eluting
solvent for the silica gel purification eliminated the problem of
desilylation. Silyl ethers 5a-f could be isolated in analytically
pure form in excellent yields.
because at these levels free water is not bound within the TBAF
matrix, which affects the nucleophilicity of the fluoride anion.83
Decreasing the loading of TBAF from 10 to 5 equiv increased
the yield of lactones 8a and 8a′. Although this outcome appears
contradictory, it can be understood because the overall reaction
concentration has increased. The reaction solvent is a stock
solution of 1 M TBAF in THF, so reducing the number of
equivalents of TBAF also constitutes a reduction in the reaction
volume. The resulting higher concentration of palladium catalyst
leads to a faster rate and ultimately a higher yield. Further
increasing the concentration of palladium by using 2.5 equiv
of TBAF ·6H2O unfortunately led to low yields of isolated
macrolactone, presumably because at this loading fluoride
activation is not sufficient to promote transmetalation.
3. Survey of Fluoride Promoters for the Intramolecular
Cross-Coupling Reaction. A systematic survey of anhydrous and
hydrated fluoride promoters revealed that the hydrated fluoride
source afforded the highest yields of macrolactones 8a and 8a′,
while the anhydrous fluoride sources produced the best selectiv-
ity. The higher selectivity may be because TBAT and TASF
are fluorosilicates and are less basic and nucleophilic compared
to TBAF.84 The hydrated tetraalkylammonium salts gave
variable yields and selectivities that were largely influenced by
the structure of the alkyl groups comprising the ammonium salt.
For example, TMAF ·4H2O and BTMAF ·6H2O gave similar
yields of macrocycle 8a essentially as a single isomer (Table
3, entries 1-4). The similar reactivity exhibited by these two
tetraalkylammonium fluoride ions probably arises from the
similarity of their structures and therefore comparable electro-
static interactions of the two fluoride sources. The structure of
the tetraalkylammonium salt strongly affects the reactivity of
the fluoride ion. Whereas tetramethylammonium is a Td sym-
metrical ion, tetraethylammonium is found crystallographically
in a “Nordic cross” conformation (S4),85 and tetrabutylammo-
nium exists in both a flattened cross conformation of D2d
symmetry and a more tetrahedral-like conformation of S4
symmetry.86 These structures influence the reactivity of the
attendant fluoride ion in two ways, first through the accessibility
of the positive charge for Coulombic stabilization87 and second
through the availability of CH · · ·F- hydrogen-bonding interac-
tions.88 These two features combine to most effectively attenuate
the reactivity of the fluoride ion in the tetramethylammonium
salt. With only 4.0 equiv of water, TMAF does not induce the
base-promoted isomerization of 8a to 8a′, whereas 10.0 equiv
of water is required to suppress this isomerization with TBAF
(cf. Table 1, entry 10, vs Table 2, entry 1).44
2. Optimization of the Intramolecular Cross-Coupling Re-
action. In planning for the key intramolecular macrocyclization
reaction of siloxanes 7a-f, it was expected that only minor
adjustments of the conditions developed earlier would be required.
Orienting experiments with 7a quickly revealed the failure of that
assumption, but repeating the experiment with rigorous exclusion
of oxygen afforded the desired macrocycle 8a in 46% yield together
with the unexpected isomer 8a′ as an inseparable mixture. Isomer
8a′ most likely arose from a rapid, base-catalyzed translactonization
after formation of 8a. This assumption was confirmed by analyzing
the reaction every 10 h, which showed that the ratio of 8a:8a′
remained constant. Furthermore, when pure 8a (obtained from
subsequent, selective cyclizations) was exposed to TBAF/THF,
within 1 h the ratio of 8a:8a′ was 5.5:1 and after 40 h the ratio
1
was essentially 3:1 (by H NMR analysis). The ratio obtained
experimentally (2-3:1) correlates well with molecular modeling
calculations that predict a 1.6:1 ratio of 8a:8a′ from the 0.26 kcal/
mol difference between 8a and 8a′. Thus, to suppress the formation
of 8a′ and improve the yield of 8a, the basicity of TBAF was
attenuated. However, conclusive evidence that the fluoride was the
culprit could not be inferred since TBAF had been used successfully
before with macrolactones.78
Landini and Maia found that the basicity and nucleophilicity
of the fluoride ion in TBAF could be modulated by adjusting
the hydration levels, and this strategy succeeded here as
well.39,79,80 For example, TBAF ·4H2O or TBAF ·6H2O afforded
desired macrolactones 8a and 8a′ in higher yields (64% and
59%) compared to TBAF ·3H2O. In the more highly hydrated
ammonium salts, the fluoride anion forms H-bonds with the
water, leading to a decrease in the basicity of TBAF without
greatly affecting the nucleophilicity.39,81 Thus, at these higher
hydration levels the fluoride anion is nucleophilic enough to
form the pentacoordinate fluorosiliconate intermediate necessary
for transmetalation.82 The hydrated TBAF ·6H2O was selected
over TBAF ·4H2O because at this hydration level the fluoride
anion basicity is negligible.39 Investigation of higher hydration
levels (TBAF · 10H2O and TBAF · 15H2O) gave lower yields
The highest yields of the macrolactones 8a and 8a′ were
achieved with TBAF but with variable selectivities. The solvent
and the hydration level of the TBAF greatly influenced the
outcome. For example, ethereal solvents (THF and dioxane)
(78) (a) Anquetin, G.; Rawe, S. L.; McMahon, K.; Murphy, E. P.; Murphy,
P. V. Chem. Eur. J. 2008, 14, 1592–1600. (b) Williams, D. R.;
Plummer, S. V.; Patnaik, S. Angew. Chem., Int. Ed. 2003, 42, 3934–
3938. (c) Fettes, A.; Carreira, E. M. J. Org. Chem. 2003, 68, 9274-
9283; Angew. Chem., Int. Ed. 2002, 41, 4098-4101. (d) Evans, D. A.;
Hu, E.; Burch, J. D.; Jaeschke, G. J. Am. Chem. Soc. 2002, 124, 5654–
5655.
(83) Rozhkov, I. N.; Kuleshova, N. D. Bull. Acad. Sci. USSR DiV. Chem.
Sci. 1976, 25, 1919-1923; IzV. Akad. Nauk SSSR, Ser. Khim. 1976,
9, 2048-2052.
(84) (a) Pilcher, A. S.; DeShong, P. J. Org. Chem. 1996, 61, 6901–6905.
(b) Pilcher, A. S.; Ammon, H. L.; DeShong, P. J. Am. Chem. Soc.
1995, 117, 5166–5167. (c) For an example of reduced TASF basicity
over TBAF in a total synthesis, see: Fu¨rstner, A.; Nagano, T. J. Am.
Chem. Soc. 2007, 129, 1906–1907.
(79) The structures of hydrated tetraalkylammonium ions have been the
subject of careful investigation for many years. A continuum of
structures has been identified (depending upon ion structure and
hydration level) that ranges from pure anion clathrates through
framework structures through hydrogen-bonded networks and finally
to discrete polyhedral cluster anions. See: (a) Jeffrey, G. A.; Mak,
T. C. Science 1965, 149, 178–179. (b) McLean, W. J.; Jeffrey, G. A.
J. Chem. Phys. 1967, 47, 414–417. (c) Gennick, I.; Harmon, K. M.;
Hartwig, J. Inorg. Chem. 1977, 16, 2241–2248.
(85) Wait, E.; Powell, H. M. J. Chem. Soc. 1958, 1872–1875.
(86) (a) Snow, M. R.; Ibers, J. A. Inorg. Chem. 1973, 12, 249–254. (b)
Andrenini, B. P.; Dell’Amico, D. B.; Calderazzo, F.; Venturi, M. G.
J. Organomet. Chem. 1988, 354, 369–380, and references cited therein.
(87) Halpern, M.; Sasson, Y.; Rabinovitz, M. Tetrahedron 1982, 38, 3183–
3187.
(80) Clark, J. H. Chem. ReV. 1980, 80, 429–452.
(81) It has been suggested that a stable geometry exists with six water
molecules around the fluoride ion of TBAF in an aqueous solution.
See: Craig, J. D. C.; Booker, M. H. J. Solution Chem. 2000, 29, 879.
(82) Denmark, S. E.; Sweis, R. F.; Wehrli, D. J. Am. Chem. Soc. 2004,
126, 4865–4875.
(88) Harmon, K. M.; Gennick, I.; Madeira, S. L. J. Phys. Chem. 1974, 78,
2585–2591.
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A R T I C L E S
Denmark and Muhuhi
afforded lower yields of the macrocycles 8a and 8a′ compared
with the more polar DMF but led to higher selectivity. The
higher yield in DMF may be due to increased catalytic efficiency
of palladium brought about by weak complexation with DMF.65
Another likely contribution by DMF might be its assistance in
ionic palladium ligand-exchange reactions.89 In silicon-based
cross-coupling reactions the critical, anionic hypervalent sili-
conate intermediate needed to effect transmetalation is formed
in a preequilibrium step from TBAF. The position of this
equilibrium is very likely solvent dependent.82,90
4. Scope of the Intramolecular Cross-Coupling Reaction. The
intramolecular cross-coupling reaction displayed good generality
for the construction of 11-, 12-, 13-, and 14-membered macrolac-
tones from siloxanes 8a-f. Comparison of the results shows that
even-numbered rings are formed in slightly higher yields compared
to the odd-numbered rings (Scheme 4). This trend has been
observed previously in the synthesis of macrocycles.11 It is worthy
to note that the size of the siloxane ring has a moderate effect on
the yields of the macrolactones. For example, in the synthesis of
the 12-membered macrolactones, the seven-membered siloxane 7a
afforded 8a and 8a′ in 78% yield compared to the six-membered
siloxane 7b that gave 8b in 70% yield. Similarly, in the synthesis
of the 13-membered macrolactone, the seven-membered siloxane
7d afforded 8d in 61% yield while the six-membered siloxane 7e
furnished 8e in 53% yield. The seven-membered siloxane has a higher
strain compared to the six-membered siloxanes and thus, upon fluoride
activation, will undergo a more facile transmetalation compared to
the six-membered lactone in order to relieve the strain. The less strained
siloxane, on the other hand, may undergo other destructive pathways
prior to transmetalation. While this indirect correlation cannot be
ascertained with the data at hand, a similar trend was observed in one
case in the synthesis of medium-ring cyclic ethers.22
pected because aryl nonaflates display higher reactivity than aryl
triflates.73 The enhanced electrophilicity of aryl nonaflates
renders them better electrophiles for rapid oxidative addition
onto the palladium center and thereupon renders the palladium
atom more electrophilic for the carbometalation of the vinylsilane.
6. Synthesis of the Benzo-Fused Lactone 9. The synthesis of
9 followed the established route, except for the opening of
lactone 12 with alcohol 13, by employing the Otera catalyst.
22 was then elaborated in four steps to siloxane 10. Under the
optimized cross-coupling conditions, siloxane 10 furnished the
benzo-fused macrocycle (E,Z)-9 in excellent yield (74%) as a
single isomer. The yield is comparable to those of the other
two 12-membered lactones 8a/8a′ and 8b that were obtained in
78% and 70% yield, respectively.
The high yield of this silicon-assisted cross-coupling reaction
over the Mitsunobu protocol used to synthesize a similar analogue30
can be ascribed to several factors: (1) the added rigidity provided
by the benzene ring reduces the entropic penalty of cyclization;
(2) the slow addition of the siloxane into the reaction mixture
maintains a low concentration of the reactive intermediates to avoid
polymerization; and (3) the palladium macrocycle intermediate
formed after oxidative addition and transmetalation has reduced
strain (compared to the lactonization transition structure) because
the two palladium-carbon bonds are longer compared to
carbon-carbon bonds. Furthermore, the energetically favored
reductive elimination step should overcome the barrier imposed
by ring formation more easily than the Mitsunobu reaction that
relies on the carboxylate to effect ring closure. This result brings
to the fore the power of palladium-catalyzed reactions in facile
formation of macrocycles21-24,93 that take advantage of reductive
elimination as the key step.
5. Mizoroki-Heck Reaction of Vinyltrimethylsilane. The
Mizoroki-Heck reaction of aryl triflates with vinyltrimethyl-
silane is challenging because aryl sulfonates possess moderate
reactivity.73,91 The Heck reaction of aryl triflate 21 under Jeffrey
conditions both at ambient temperature and under heating at
80 °C (Table 4, entries 1 and 2) stalled at 43% and 73%
conversions, respectively. The inability of the reactions to go
to full completion is presumably because oxidative addition
could not occur efficiently without ligands.
A survey of ligands known to be useful in Heck reactions
identified monodentate phosphines as superior additives. The higher
selectivity and yields exhibited by monodentate phosphines com-
pared to bidentate ligands arises because monodentate ligands do
not form the unreactive bisphosphine complexes formed by
bidentate ligands because of steric crowding.65 The success of the
bulky monophosphines arises from their ability to effect a fast
oxidative addition. In addition, they are able to generate the active
T-shaped, three-coordinate palladium complexes.71 Because of the
open coordinate site, these complexes are capable of undergoing
facile olefin insertion leading to the Heck product. The polar, aprotic
solvents acetonitrile and NMP gave the best results and are known
to increase the rate of Heck reactions.89,92
Conclusion
The intramolecular cross-coupling reaction of olefinic iodides
and cycloalkenylsiloxanes under fluoride activation effectively
produced 11-, 12-, 13-, and 14-membered macrolactones containing
a conjugated 4,6-Z,Z- or 1,3-E,Z-diene unit. The fluoride hydration
level was critical for controlling the yield and selectivity of
macrolactone formation. Key features of this process include (1)
high stereospecificity, (2) modular construction of cyclization
precursors, (3) flexibility in locating the hydroxyl group at multiple
positions in a macrocycle, and (4) generality of ring size. The
insights garnered from these studies are being applied in the total
syntheses of complex macrocyclic natural products. The results of
those studies will be disclosed in due course.
Acknowledgment. We are grateful to the National Institutes
of Health for generous financial support (GM63167). J.M.M.
acknowledges the NIH for a postdoctoral fellowship.
Supporting Information Available: Detailed experimental
procedures, optimization studies, and full characterization of
all products. This material is available free of charge via the
Internet at http://pubs.acs.org.
The successful reaction of aryl nonaflate 21 with trimeth-
ylvinylsilane under conditions wherein 15 stalled is not unex-
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