Minireviews
Gradillas
Macrocycles
Macrocyclization by Ring-Closing Metathesis in the
Total Synthesis of Natural Products: Reaction
Conditions and Limitations
Ana Gradillas and Javier Prez-Castells*
Keywords:
bioactivity · macrocycles · metathesis ·
natural products · synthesis design
The construction of macrocycles by ring-closing metathesis (RCM) is
often used as the key step in the synthesis of natural products
containing large rings. This reaction is attractive because of its high
functional group compatibility and the possibility for further trans-
formations. The finding of suitable reaction conditions is critical for
the success of the synthesis. In this Minireview we summarize the
efforts of many research groups to develop efficient RCM reactions on
their way towards the total synthesis of natural macrocyclic products.
Their findings should help in future synthesis to reduce the time-
consuming phase of the optimization of the reaction conditions.
1. Introduction
The metathesis reaction has attracted a great deal of
attention for a long time.[1] Ring-closing metathesis (RCM) of
alkenes allows the synthesis of cycles from 5- or 6-membered
rings to macrocycles. The reaction with alkynes, ring-closing
alkyne metathesis (RCAM), is also useful for the construction
of large rings. Successful metathesis reactions involving metal
carbenes has been achieved by the development of stable and
easy to handle catalysts.
Almost one third of current drugs are natural products, or
their derivatives, or mimics. Macrocycles are particularly
common in antitumoral, antibiotic, and antifungal com-
pounds. Total synthesis is crucial for confirming the structure
of the drugs and to open up the possibility of developing
derivatives that modulate the biological activity or the
pharmacokinetic properties. Synthetic efforts towards macro-
cycles are often expensive undertakings and unpractical. The
macrocyclization, usually the key step, is not unproblematic
since there is competition between the desired intramolecular
[*] Dr. A. Gradillas, Prof. J. P)rez-Castells
Departamento de Qu.mica
Facultad de Farmacia
Universidad San Pablo-CEU
Urb. Montepr.ncipe, 28668 Boadilla del Monte, Madrid (Spain)
Fax: (+ 34) 91-351-0475
E-mail: jpercas@ceu.es
6086  2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
J. Prez-Castells and A.
DOI: 10.1002/anie.200600641
reaction and intermolecular processes
that give polymers. Some classic syn-
thetic strategies used are macrolacto-
nizations, macrolactamizations, and
macroaldolizations. Organometallic reactions have joined
these strategies in recent years and metathesis is becoming
the most popular way to construct large rings. RCM has the
advantage of being compatible with a wide range of func-
tional groups and gives rise to double bonds which can be
transformed into other functional groups and which are
generally not affected in further stages of the synthesis. The
disadvantage is the control over the stereochemistry of the
double bond formed and the finding of appropriate reaction
conditions to maximize the yields and minimize the formation
of by-products.
This Minireview focuses on the total synthesis of natural
macrocycles through the use of diene and the diyne meta-
thesis reactions.[2] We aim to summarize the reaction con-
ditions used in the synthesis of natural and bioactive macro-
cycles to help those who are planning future syntheses. The
choice of the catalyst, solvent, temperature, concentration,
and reaction time is crucial in these transformations. We have
organized the information by families of natural products so
that the reaction conditions used with compounds with
structural similarities can be compared.
2. Reaction Conditions for RCM
There are numerous parameters that influence metathesis
reactions, and so there are no general conditions that can be
given that will guarantee the success of the process.[3]
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Macrocyclization
The catalysts A–E and G represent three generations of
ruthenium complexes, while F is the molybdenum Schrock
catalyst. Of these, catalyst A is the cheapest, but it is thermally
unstable and, in general, fails to react with substituted olefins.
Some derivatives of this first generation complex, such as B,
improve the kinetics of the initial reaction.[4] The second-
generation catalysts C and D are reported to give better
results with substituted olefins, as does the Hoveyda–Grubbs
catalyst E. Modification of E by substitution in the aromatic
ring has given rise to a new family of “third generation”
catalysts.[5] In general, complexes C–E are prepared in a
straightforward manner from the commercially available
catalyst A. The molybdenum species F is highly reactive but
sensitive to water, oxygen, and to several functional groups.
The mechanism of the RCM reaction is well established: it
begins with the dissociative loss of a phosphine group and the
formation of a 14 e intermediate (Scheme 1). The formation
Scheme 1. Initial steps of RCM.
Javier Prez-Castells was born in Madrid,
Spain, in 1967. He received his BSc in
Chemistry at the Universidad Complutense
de Madrid in 1990, and completed his PhD
in Organic Chemistry there in 1994 under
the supervision of Prof. Miguel A. Sierra and
Prof. Benito Alcaide. Since 1995 he has
been assistant professor at the Universidad
San Pablo-CEU, where he works on metal-
catalyzed cyclization reactions.
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Angewandte
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of this unusual unsaturated complex was demonstrated
through kinetic studies.[6] The increase in the activity of the
second-generation catalysts is not a result of an increase in the
rate of the phosphine dissociation but to a better ratio
between the rate constant k2 for the coordination of the olefin
and the rate constant k 1 for the recoordination of phosphine.
In the next step a ruthenacyclobutane is formed, which gives
rise to a new carbene. The reaction of this new species with
another unsaturated bond gives the final product and a
methylene carbene, which is thought to be a less-stable
intermediate in many metathesis reactions.[7] There are some
studies that suggest a different pathway for the different
generations of catalysts, and there are still unclear aspects of
the enyne reaction.[8]
Thermal stability plays a critical role in the lifetime of the
species and the turnover number (TON).[3] Thus, C is stable
for one hour at 100 8C in [D8]toluene, while A decomposes by
up to 75 % under the same conditions. The stability of C arises
from the stability gained from the incorporation of the N-
heterocyclic carbene (NHC) ligand. E is also thermally stable
and survives chromatography on silica gel, thus enabling it to
be purified, recovered, and reused after the reaction. Grubbs
and co-workers have shown the reaction is favored in
nonpolar solvents, and in most studies toluene or dichloro-
methane are preferred.[6]
The presence of heteroatoms in the substrates leads to a
variety of results.[9] Nitrogen is generally not tolerated unless
nonbasic functional groups such as tosylamides are used.
Certain metathesis reactions of amine-containing compounds
were carried out with one equivalent of p-toluenesulfonic acid
to prevent coordination of the electron pair on the nitrogen
atom to the catalysts.[10] Oxygen appears to be beneficial for
the metathesis in some studies,[11] while in other cases no
influence is observed. In the majority of cases, however,
oxygen has a negative influence on the reaction.[12, 13] The
thermal stability of the final product also influences the
metathesis reaction.[14]
Ring-closing alkyne metathesis (RCAM) has recently
been reviewed by F?rstner and Davies,[15] and so here we will
only summarize RCAM reaction conditions in Tables to
complete the overview. Common RCAM initiators include
compounds H and I.
Ana Gradillas worked in the research group
of Prof. J. V. Sinisterra in 1989 during her
undergraduate studies in the Pharmacy
Faculty of Complutense University of Ma-
drid. She obtained her PhD in 1995 with
Prof. E. F. Llama and Prof. C. Prez-
del Campo at Complutense University. Dur-
ing 1996 she worked with Dr. J. Vulfson at
the Institute of Food Research (Reading,
UK). In 1997 she joined San Pablo-CEU
University (Madrid), where she also has had
a teaching position. Her research interests
include the synthesis of compounds for
antitumor drugs.
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3. Macrocyclic Lactones
Macrocyclic structures that have one or more ester
linkages are generally referred to as macrolides or macro-
cyclic ring lactones. Macrolides are very important target
molecules in synthetic studies because of their biological and
medicinal activity.
3.1. Resorcinylic Macrolides
The macrolides 1–8 from the resorcinylic family were
synthesized by using a RCM reaction for the construction of
the macrocycle. Several total synthesis of radicicol (1) have
been accomplished by using RCM to construct the macro-
cyclic ring.[16] Danishefsky and co-workers have optimized the
temperature and concentration conditions for the RCM used
for the synthesis of cycloproparadicicol (19, Scheme 2 a).[17]
RCM of 9, which bears an epoxide at the C7’/C8’ position and
an OTBS group, occurred under mild conditions (0.2 mm,
CH2Cl2, 42 8C) to give the monomeric macrocyclic product 12.
However, when similar conditions were applied to the
cyclopropyl precursor 15, the majority of the isolated
products were dimeric 28-membered macrocycles. However,
performing the reaction at 110 8C in toluene and quenching
after a short period of time resulted in clean conversion of 15
into the primary cyclization product 17.
F?rstner et al. developed an RCM-based approach to
zeranol (2, Scheme 2 b).[18] The poor reactivity of diene 20
resulted in them deprotecting the ketone prior to ring closure.
The same authors[18] synthesized (R)-(+)-lasiodiplodin (4,
Scheme 2 c). Complex A was totally ineffective for the
construction of the macrocycle of (S)-( )-zearalenone (3);
however, complex D proved to be an effective catalyst
(Scheme 2 d).[18]
The syntheses of trans- and cis-resorcylides 5 and 6 were
the first examples of RCM cyclizations of enolizable enones.
Thus, trans-alkene 28 was isolated as a sole isomer and in
relatively high yield by subjecting diene 27 to the modified
protocol developed by Danishefsky and co-workers for the
synthesis of radicicol (Scheme 3).[19] The cyclization of diene
29 was rather problematic and only the combination of
extremely high dilution, elevated temperature (0.5 mm,
CH2Cl2, reflux), and low catalyst loading enabled the cis-
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J. Prez-Castells and A. Gradillas
resorcylide to be isolated in reasonable yield, along with the
head-to-tail, 24-membered macrocyclic dimer.[20]
Danishefsky and co-workers designed a new and highly
efficient synthetic route—the “ynolide” methodology—which
provided an efficient route to cycloproparadicicol (19)[21] and
to other resorcinylic macrolides such as aigialomycin D (7).[22]
The synthesis involved a cobalt-complexation-promoted
RCM to generate the ynolide 32 in excellent yield, followed
by a Diels–Alder reaction using a disiloxydiene to elaborate
the benzenic system (Scheme 4). The complexation of the
ethynyl linkage to cobalt avoids competitive enyne metathesis
reactions and brings C-7’ and C-8’ into proximity, thus
favoring RCM.
Polyene RCM has been used for the synthesis of
pochocin C (8).[23] Thus, treatment of intermediate 33 with
catalyst C in toluene at 120 8C led to 34 as an inseparable
mixture of cis and trans olefins (1:1). The thioether group was
then removed to obtain 35. The selectivity of the elimination
reaction suggested that carrying out the metathesis on diene
36 should lead to the desired trans,cis-diene. Indeed oxida-
tion/elimination of thioether 33 prior to RCM at 120 8C led
exclusively to 37 in 10 minutes (Scheme 5). Table 1 summa-
rizes the studies on the RCM reaction conditions used for the
macrolide syntheses described in this section.
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Scheme 2. Synthesis of a) macrocycle 1 (top) and 19 (bottom) by RCM, b) zeranol, c) (R)-(+)-lasiodiplodin, and d) (S)-( )-zearalenone.

3.2. Salicylate Macrolides
A family closely related to resorcinylic macrolides are the
salicylate enamide macrolides, which include salicylihal-
amides A and B (38) and oximidines I–III, (39–41).[24] The
complex structures of these natural products combined with
their novel mode of biological action have stimulated a
number of synthesis programs.
The three general approaches proposed for salicylihal-
amide A and B are the Mitsunobu/RCM strategy as well as

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Scheme 3. Synthesis of trans- and cis-resorcylides.

the Suzuki and Stille cross-coupling approaches.[25] The

careful study of the influence of remote substituents in
RCM precursors, such as 42, and of the catalyst activity on the Scheme 4. Synthesis of macrolactone 31 by RCM.
stereochemistry have led to the conditions
indicated in Scheme 6 and Table 2.[26]
Oximidine II and III were constructed
by using a relay RCM strategy to facilitate
the crucial macrocyclization reaction

Table 1: Reaction conditions used for the synthesis of resorcinylic

macrolides.[a]
Conditions Catalyst, yield Compd Ref.
toluene, 110 8C, 10 min, 0.2 mm C (5–10 mol %), 60 % 12 [17]
CH2Cl2, DT D (5 mol %), 85 % (E) 22 [18]
toluene, 80 8C, 15 h D (6 mol %), 69 % (E) 24 [18]
toluene, 80 8C, 4 h D (5 mol %), 91 % (E) 26 [18]
CH2Cl2, DT, 30 min, 1 mm C (10 mol %), 67 % 28 [20]
CH2Cl2, DT, 1 h, 0.5 mm C (2 mol %), 40 % 6 [20]
CH2Cl2, DT, 10 h. C (25 mol %), 38 % 31 [22]
toluene, 120 8C, 10 min, 2 mm C (5 mol %), 87 % 37 [23]
[a] The best conditions leading to the desired macrocycle are shown.

(Scheme 7).[26] A well-defined substrate

possessing two differently functionalized
RCM alkene partners was found to be
required for the RCM-RCM process. A
faster addition of the substrate resulted in
reduced decomposition of the product and
both catalysts E and C. The production of
oligomers was minimized at a higher tem-
perature.[24] Scheme 5. Synthesis of pochonin C by RCM.

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Scheme 6. Macrocyclization of ester 42 to give the core structure of

salicylihalamides.

3.3. Antibiotic Macrolides

Numerous biologically active macrocycles are antibiotics,

Table 2: Reaction conditions for the macrocyclization by RCM in the
total synthesis of salicylate macrolides. which have been isolated from various microorganisms. The
wide variety of antibiotic macrolide structures is illustrated by
Conditions Catalyst, yield Compd Ref.
compounds 48–54. Table 3 summarizes the reaction condi-
toluene, 70 8C, 2 h, 1 mm C (10 mol %), 43 [25] tions that resulted in macrocyclization.
75 % (E)
CH2Cl2, DT, 70 min, 2 mm C (5 mol %), 48 % 45 [26]
(ClCH2)2, 50 8C, addition time E (10 mol %), 47 [24]
3.4. Macrocyclic Musk
30 min, 2.0 mm 71 %

Muscone (55) and civetone (56) are two of the most

important classical sources of musk odors for perfumes. Both

Scheme 7. Application of relay RCM for the synthesis of oximidines.

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Table 3: Examples of macrolide antibiotics synthesized by RCM.[a]

Conditions Catalyst, yield Compd Ref.
(ClCH2)2, 82 8C, 6 h, 2 mm C (12 mol %), 60 % E/Z 48 [27]
mixture
CH2Cl2, 40 8C, 30–72 h, A (20–30 mol %), 88–91 % 49 [28]
0.25–0.5 mm E/Z mixture
C6H6, 60 8C C (20 mol %), 90 % 50 [29]
toluene, DT, 0.5 m M C (20 mol %), 50 % 51 [30]
CH2Cl2, DT C (5 mol %), 46 % 52 [31]
CH2Cl2, RT, 1.5 mm A (5 mol %), 83 % (Z) 53 [32]
toluene, 100 8C, 1 mm A (30 mol %), 37–42 % (E) 54 [33]
[a] The best conditions leading to the desired macrocycle are shown.

Table 4: Conditions for RCM to give simple musk macrolides.

Conditions Catalyst, yield Compd Ref.
(ClCH2)2, 50 8C A (7 mol %), 56 % 55 [34]
toluene, 80 8C H (10 mol %, 65 % 56 [35]
CH2Cl2, 40 8C G (4 mol %), 79 % 57 [36]
CH2Cl2, 40 8C G (3 mol %), 80 % 58 [37]
CH2Cl2, DT, 14 h, 6 mm B (10 mol %), 57 % 59 [38]
CH2Cl2, 40 8C I (5 mol %), 62 % 60 [39]
CH2Cl2, 40 8C I (5 mol %), 69 % 61 [39]
[a] The best conditions leading to the desired macrocycle are shown.

of these chemicals are nowadays produced synthetically by

RCM under the conditions shown in Table 4.
Other relatively simple macrolides include exaltolide (57),
which was the first macrolactone to be prepared by RCM,
recifeiolide (58), and muscopyridine (59). Other olfactory
molecules such as yuzu lactone (60) and ambretolide (61)
were obtained stereoselectively by RCAM followed by 3.5. Other Macrolides
Lindlar hydrogenation or an equivalent semireduction.
Other pharmacologically active macrolides have highly
substituted structures, as can be seen from the examples 62–65
(macrolides containing an 11- and a 14-membered lactone

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ring), 68–70 (macrolides containing a 16-membered lactone

ring), and 71–75 (macrolides containing an 18- and a 20-
membered lactone ring). The reaction conditions used for the
RCM key macrocyclization steps are summarized in Table 5.

Table 5: Macrolides containing a 11- to 20-membered lactone ring.

Conditions Catalyst, yield Compd Ref.
toluene, DT, 4 h, 2 mm D (20 mol %), 69 % 62 [40]
(E/Z=5:1)
toluene, 85 8C, 1 h, I (10 mol %), 78 % 63 [41]
8.5 mm
CH2Cl2, 40 8C A (3 mol %) Ti(OiPr)4 (30 64 [36]
mol %), 80 %
CH2Cl2/toluene J (10 mol %), 70 % 65 [42]
CH2Cl2/toluene, 80 8C J (10 mol %), 70 % 81 [48]
CH2Cl2, RT C (10 mol %), 77 % 68 [43]
CH2Cl2/toluene, 80 8C J (10 mol %), 80 % 69 a [2]
toluene, 110 8C, 10– C (30 mol %), 70 % 69 b [2]
20 min, 3 mm
CH2Cl2, 40 8C, 8–48 h, C (30 mol %), 89 % 70 a [2]
3 mm (E:Z = 1:1)
C6H6, 60 8C C (50 mol %), 77 % (E) 71, 72 [44]
CH2Cl2, DT, 24 h C (50 mol %), 35 % 73 [45]
toluene, 110 8C C (20 mol %), 82 % 74 [46]
(E:Z = 2:1)
CH2Cl2, DT, 24 h B (50 % mol), 86 % 75 [47]
(E:Z = 6:1)
[a] The best conditions leading to the desired macrocycle are shown.

The scope of RCM has been fully illustrated by the synthesis

of epothilones (Epo A–F; 69–70) and has been reviewed
recently.[2] The total synthesis of (+)-aspercylide C (62), was

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reported recently.[40] The key step was a kinetically controlled

RCM reaction to form an 11-membered cycle (Scheme 8).
Ring-closing alkyne metathesis was used as the key step in
the formation of the macrolide latrunculin B (65). A concise
and efficient synthesis of another congener, latrunculin A
(81), was recently achieved (Scheme 9).[48] Compound 76
underwent enyne-yne metathesis to give the desired product
77 in the presence of catalytic amounts of J, activated in situ
with CH2Cl2. The inability to cleave the remaining N-PMB
group prevented formation of 81. Conversion of 76 into the
Teoc derivative 79 allowed the crucial enyne-yne metathesis
to form the highly strained 16-membered cyclic product 80 in
70 % yield.

4. Macrocyclic Glycolipids

The performance and excellent application profile of

RCM and RCAM are illustrated by the total synthesis of
various resin glycosides and sugar-based macrodiolides such
as tricolorins A and G, woodrosin I, and sophorolipid. The
synthesis of these amphiphilic natural products has led to
advances in carbohydrate chemistry (Table 6).[15]
Scheme 8. Kinetically controlled RCM reaction to form 67.

Scheme 9. Ring-closing enyne-yne metathesis in the total synthesis of latrunculin A.

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Table 6: RCAM in the total synthesis of resin glycosides and the

sophorolipid lactone. 6. Terpenoids
Conditions Catalyst, yield Compd Ref.
Only a few natural terpenic compounds bearing large
CH2Cl2, DT, 22 h G (10 mol %), 93 % 82 [49] cycles have also been obtained by using RCM.
CH2Cl2, DT, 24 h G (10 mol %), 90 % 83 [50]
CH2Cl2, 40 8C B (10 mol %), 94 % 84 [51]
toluene/CH2Cl2, 80 8C J (10 mol %), 78 % 85 [52]
6.1. Diterpenoids

Several strategies exist for the construction of macrocyclic

5. Macrocyclic Lactams
5.1. Amsamycin Macrolides
Four new members of the ansamycin family, cytotrienin-
s A–D (89), have been described recently.[53] They have
stimulated the asymmetric synthesis of the fully elaborated
macrocyclic core 87. The synthetic route reported included
the use of a RCM reaction as a way to efficiently install the
(E,E,E)-triene and simultaneously construct the macrocyclic
lactam, by using the bis(1,3-diene) 86 as the triene precursor
(Scheme 10). Reaction of 86 with catalyst C unexpectedly
gave diene 88 in 47 % yield. To overcome this problem and
initiate the RCM at one of the terminal olefins, 86 was
exposed to the less reactive catalyst A in refluxing dichloro-
methane, which afforded the expected (E,E,E)-triene 87 with
excellent selectivity and yield.
diterpene tonantzitlolone (95) by RCM.[54] The formation of
the double bond between C-1 and C-2 was unsuccessful,
probably because of steric congestion created by the three
allylic methyl groups present in the starting material. Thus,
the position of macrocyclization was shifted to the less
congested site at C-4 and C-5. Indeed, desilylation of 90, and
subsequent RCM of 91 using catalyst C yielded the macro-
cyclic Z-configured diene 92 which unfortunately could not be
transformed into the final compound. Therefore, 90 was
transformed into 93 which provided the macrocycle 94 with
high E selectivity. Subsequent reactions led to the desired
tonantzitlolone (Scheme 11).
The highly strained and congested 11-membered ring of
coleophomones B–C (96–97) was constructed by using an
impressive olefin metathesis reaction to build the bond
between C-16 and C-17 (Table 7).[55]

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8. Macrocyclic Alkaloids

The rich variety of biological

activities associated with both
plant-derived and animal-de-
rived alkaloids has stimulated
many research groups to synthe-
size their core structures. Proto-
type alkaloids with spermidine-
like tails are ( )-isooncinotine
(101) and motuporamine C
(102).
As described in Section 2,
the presence of nitrogen atoms
is normally not tolerated in
RCM substrates. To avoid che-
lation of the catalyst with the
N atoms in the synthesis of 101,
precursor 103 was protonated,
and the bond between C-15 and
C-16 was selected to close the
macrocycle as a result of its
remote relative situation from
the carbonyl group of the amide.
The resulting 22-membered cy-
cloalkene was hydrogenated di-
rectly without isolation of 104
Scheme 10. Synthesis of the macrocyclic core of cytotrienins.
(Scheme 13).[57]
The synthesis of cryptophy-
cin-24 (arenastatin A, 106) was
achieved by using a RCM of 105. The reaction proceeded in
high yield with exclusive formation of the E isomer, despite
the presence of the chemically reactive styrene epoxide
moiety (Scheme 14).[58] In the total synthesis of pinnatoxin A
(110), the bulky silyl protecting groups in 107 had to be
removed, as they prevented RCM. Therefore, macro-RCM
reaction of 108 gave 109, from which pinnatoxin A was
synthesized (Scheme 15).[59] Some other recent applications of
RCM to the synthesis of other alkaloids, including 111, a

7. Depsipeptides

Cyclodepsipeptides are cyclic peptides with a wide range

of biological activities that are characterized by the occur-
rence of at least one ester linkage. The total synthesis of
spongidepsin (100) was accomplished by a ring-closing meta-
thesis as the key step (Scheme 12).[56] Exposure of 98 to
catalyst C in refluxing toluene yielded the four possible
macrocylic 5E/Z, 7R/S diastereomers in a combined yield of Table 7: Synthesis of coleophomones B and C by stereoselective RCM.
80 %. The two E alkenes (99 a–b) were obtained in a 1:1 ratio Conditions Catalyst, yield Compd Ref.
and predominated over the Z isomers (> 10:1). The two C7
epimers 99 a–b could be separated by flash column chroma- CH2Cl2, 40 8C, 3 h C (10 mol %), 86 % 96 [55]
CH2Cl2, 40 8C, 1–5 h C (10 mol %), 80 % 97 [55]
tography.

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Scheme 11. Two strategies to construct 95 by RCM.

Scheme 13. RCM in the synthesis of 101.

Scheme 12. RCM as a key step in the total synthesis of 100. Table 8: Conditions for the RCM to give alkaloids.
Conditions Catalyst, yield Compd Ref.
CH2Cl2, DT, 16 h B (6 mol %), 76 % 101 [57]
defensive insect alkaloid, and 113, a manzamine from a family PhCl, DT H (10 mol %), 68 % 102 [60]
of marine alkaloids, are also summarized in Table 8. CH2Cl2, DT, 6 h A (10 mol %), 70 % 106 [58]
CH2Cl2, DT A (0.1 equiv), 75 % 110 [59]
CH2Cl2, DT I or J (5 mol %), 70 % 111 [61]
CH2Cl2, 50 8C, 24 h, 0.5 m M A (15 mol %), 26 % 112 [62]
(Z/E=41:59)
CH2Cl2, DT A (13 mol %), 67 % 113 [63]
CH2Cl2, DT, 3 h, 5 mm A (13 mol %), 76 % 114 [63]
(Z/E=8:1)
CH2Cl2, DT, 5 h, 0.4 mm C (10 mol %), 49 % 115 [64]
[a] The best conditions leading to the desired macrocycle are shown.

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Chemie J. Prez-Castells and A. Gradillas

Scheme 14. RCM in the total synthesis of the cyclopeptide alkaloid

arenastatin A.

Scheme 15. RCM in the total synthesis of the cyclopeptide alkaloid

arenastatin A.

9. Cyclophanes
Table 9: Conditions for RCM to give cyclophanes.
Some naturally occurring cyclophanes (116, 117 (R = H,
Conditions Catalyst, yield Compd Ref.
cylindrocyclophane F; R = OH, cylindrocyclophane A and
118) have been synthesized by using RCM reactions H2C=CH2, CH2Cl2, 45 8C, 40 h, 3 mm A (30–40 mol %), 116 [65]
(Table 9). In the case of ( )-longithorone, an enyne RCM 31–47 %
was used for the construction of a macrocyclic diene, which C6H6, 40 8C, 1 h C (34 mol %), 50 % 117 [66]
C6H5Cl, 135 8C, 6 h I (10 mol %), 76 % 118 [67]
gave rise to ring C after a Diels–Alder cycloaddition.[65]

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 Angewandte
Macrocyclization Chemie

There is no clear rule that indicates the best catalyst to

use. Subtle variations in the substrate structure and in the type
of final product may lead to different results with each type of
carbene complex. In particular, the substitution pattern, the
steric demand of the substrate, the ring size to be formed, and
the presence of coordinating heteroatoms have an important
influence on the results. The yield and the E/Z ratio of the
product may be influenced by all these factors as well as by
secondary isomerization reactions mediated by the meta-
thesis complexes.[69] The catalyst loading varies from case to
case (from 1 to 25 %) and is highly dependent on the species
used. Other important aspects are concentration (0.25 to
8 mm) and the addition time, which is sometimes done slowly.
Long reaction times are sometimes recorded when working at
low temperatures as most catalytic species are not thermally
stable. When planning a new synthesis, it is worth testing
different catalysts, temperatures, and concentrations with
additional fine tuning of the loading and addition rate.

Abbreviations

Bn benzyl
CAN calcium ammonium nitrate
Cy cyclohexyl
L ligand
Mes 2,4,6-trimethylphenyl
MOM methoxymethyl
PMB 4-methoxybenzyl
PMP 4-methoxyphenyl
RCAM ring-closing alkyne metathesis
RCM ring-closing metathesis
10. Prostaglandins TBDPS tert-butyldiphenylsilyl
TBS tert-butyldimethylsilyl
The RCAM strategy has also been applied to the synthesis Teoc (2,2,2-trichloroethoxy)carbonyl
of the marine natural product prostaglandin E2-1,15-lactone TES triethylsilyl
(Table 10). TIPS triisopropylsilyl
TMS trimethylsilyl

Received: February 17, 2006

Published online: August 21, 2006

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