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Macrocyclization by Ring-Closing Metathesis in the Total Synthesis of Natural Products Reaction Conditions and Limitations.

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Minireviews
J. Prez-Castells and A. Gradillas
DOI: 10.1002/anie.200600641
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 transformations. 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 timeconsuming 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 compounds. 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 macrocycles 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
reaction and intermolecular processes
that give polymers. Some classic synthetic strategies used are macrolactonizations, 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 functional 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 metathesis reactions.[2] We aim to summarize the reaction conditions used in the synthesis of natural and bioactive macrocycles 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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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 secondgeneration 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 metalcatalyzed cyclization reactions.
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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 Nheterocyclic 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 dichloromethane 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 Madrid. She obtained her PhD in 1995 with
Prof. E. F. Llama and Prof. C. Prezdel Campo at Complutense University. During 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 macrocyclic 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 macrocyclic 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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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 oxidation/elimination of thioether 33 prior to RCM at 120 8C led
exclusively to 37 in 10 minutes (Scheme 5). Table 1 summarizes 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 salicylihalamides A and B (38) and oximidines I–III, (39–41).[24] The
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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 salicylihalamide 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
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
Scheme 4. Synthesis of macrolactone 31 by RCM.
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
CH2Cl2, DT
toluene, 80 8C, 15 h
toluene, 80 8C, 4 h
CH2Cl2, DT, 30 min, 1 mm
CH2Cl2, DT, 1 h, 0.5 mm
CH2Cl2, DT, 10 h.
toluene, 120 8C, 10 min, 2 mm
C (5–10 mol %), 60 %
D (5 mol %), 85 % (E)
D (6 mol %), 69 % (E)
D (5 mol %), 91 % (E)
C (10 mol %), 67 %
C (2 mol %), 40 %
C (25 mol %), 38 %
C (5 mol %), 87 %
12
22
24
26
28
6
31
37
[17]
[18]
[18]
[18]
[20]
[20]
[22]
[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 temperature.[24]
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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
Table 2: Reaction conditions for the macrocyclization by RCM in the
total synthesis of salicylate macrolides.
Conditions
Catalyst, yield
toluene, 70 8C, 2 h, 1 mm
C (10 mol %),
43
75 % (E)
C (5 mol %), 48 % 45
E (10 mol %),
47
71 %
CH2Cl2, DT, 70 min, 2 mm
(ClCH2)2, 50 8C, addition time
30 min, 2.0 mm
Compd Ref.
[25]
[26]
[24]
Numerous biologically active macrocycles are antibiotics,
which have been isolated from various microorganisms. The
wide variety of antibiotic macrolide structures is illustrated by
compounds 48–54. Table 3 summarizes the reaction conditions that resulted in macrocyclization.
3.4. Macrocyclic Musk
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
mixture
CH2Cl2, 40 8C, 30–72 h,
A (20–30 mol %), 88–91 %
0.25–0.5 mm
E/Z mixture
C6H6, 60 8C
C (20 mol %), 90 %
toluene, DT, 0.5 m M
C (20 mol %), 50 %
C (5 mol %), 46 %
CH2Cl2, DT
CH2Cl2, RT, 1.5 mm
A (5 mol %), 83 % (Z)
toluene, 100 8C, 1 mm
A (30 mol %), 37–42 % (E)
48
[27]
49
[28]
50
51
52
53
54
[29]
[30]
[31]
[32]
[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
toluene, 80 8C
CH2Cl2, 40 8C
CH2Cl2, 40 8C
CH2Cl2, DT, 14 h, 6 mm
CH2Cl2, 40 8C
CH2Cl2, 40 8C
A (7 mol %), 56 %
H (10 mol %, 65 %
G (4 mol %), 79 %
G (3 mol %), 80 %
B (10 mol %), 57 %
I (5 mol %), 62 %
I (5 mol %), 69 %
55
56
57
58
59
60
61
[34]
[35]
[36]
[37]
[38]
[39]
[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
Lindlar hydrogenation or an equivalent semireduction.
3.5. Other Macrolides
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 20membered 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 %
(E/Z=5:1)
I (10 mol %), 78 %
62
[40]
63
[41]
A (3 mol %) Ti(OiPr)4 (30
mol %), 80 %
J (10 mol %), 70 %
J (10 mol %), 70 %
C (10 mol %), 77 %
J (10 mol %), 80 %
C (30 mol %), 70 %
64
[36]
65
81
68
69 a
69 b
[42]
[48]
[43]
[2]
[2]
70 a
[2]
71, 72
73
74
[44]
[45]
[46]
75
[47]
toluene, 85 8C, 1 h,
8.5 mm
CH2Cl2, 40 8C
CH2Cl2/toluene
CH2Cl2/toluene, 80 8C
CH2Cl2, RT
CH2Cl2/toluene, 80 8C
toluene, 110 8C, 10–
20 min, 3 mm
CH2Cl2, 40 8C, 8–48 h,
3 mm
C6H6, 60 8C
CH2Cl2, DT, 24 h
toluene, 110 8C
CH2Cl2, DT, 24 h
C (30 mol %), 89 %
(E:Z = 1:1)
C (50 mol %), 77 % (E)
C (50 mol %), 35 %
C (20 mol %), 82 %
(E:Z = 2:1)
B (50 % mol), 86 %
(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.
CH2Cl2, DT, 22 h
CH2Cl2, DT, 24 h
CH2Cl2, 40 8C
toluene/CH2Cl2, 80 8C
G (10 mol %), 93 %
G (10 mol %), 90 %
B (10 mol %), 94 %
J (10 mol %), 78 %
82
83
84
85
[49]
[50]
[51]
[52]
Only a few natural terpenic compounds bearing large
cycles have also been obtained by using RCM.
5. Macrocyclic Lactams
5.1. Amsamycin Macrolides
Four new members of the ansamycin family, cytotrienins 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 dichloromethane, which afforded the expected (E,E,E)-triene 87 with
excellent selectivity and yield.
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6.1. Diterpenoids
Several strategies exist for the construction of macrocyclic
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 macrocyclic 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
Scheme 10. Synthesis of the macrocyclic core of cytotrienins.
The rich variety of biological
activities associated with both
plant-derived and animal-derived alkaloids has stimulated
many research groups to synthesize their core structures. Prototype alkaloids with spermidinelike 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 chelation 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 cycloalkene was hydrogenated directly without isolation of 104
(Scheme 13).[57]
The synthesis of cryptophycin-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 occurrence of at least one ester linkage. The total synthesis of
spongidepsin (100) was accomplished by a ring-closing metathesis 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
80 %. The two E alkenes (99 a–b) were obtained in a 1:1 ratio
and predominated over the Z isomers (> 10:1). The two C7
epimers 99 a–b could be separated by flash column chromatography.
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Table 7: Synthesis of coleophomones B and C by stereoselective RCM.
Conditions
Catalyst, yield
Compd
Ref.
CH2Cl2, 40 8C, 3 h
CH2Cl2, 40 8C, 1–5 h
C (10 mol %), 86 %
C (10 mol %), 80 %
96
97
[55]
[55]
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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.
defensive insect alkaloid, and 113, a manzamine from a family
of marine alkaloids, are also summarized in Table 8.
Table 8: Conditions for the RCM to give alkaloids.
Conditions
Catalyst, yield
Compd
Ref.
CH2Cl2, DT, 16 h
PhCl, DT
CH2Cl2, DT, 6 h
CH2Cl2, DT
CH2Cl2, DT
CH2Cl2, 50 8C, 24 h, 0.5 m M
B (6 mol %), 76 %
H (10 mol %), 68 %
A (10 mol %), 70 %
A (0.1 equiv), 75 %
I or J (5 mol %), 70 %
A (15 mol %), 26 %
(Z/E=41:59)
A (13 mol %), 67 %
A (13 mol %), 76 %
(Z/E=8:1)
C (10 mol %), 49 %
101
102
106
110
111
112
[57]
[60]
[58]
[59]
[61]
[62]
113
114
[63]
[63]
115
[64]
CH2Cl2, DT
CH2Cl2, DT, 3 h, 5 mm
CH2Cl2, DT, 5 h, 0.4 mm
[a] The best conditions leading to the desired macrocycle are shown.
Angew. Chem. Int. Ed. 2006, 45, 6086 – 6101
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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
Some naturally occurring cyclophanes (116, 117 (R = H,
cylindrocyclophane F; R = OH, cylindrocyclophane A and
118) have been synthesized by using RCM reactions
(Table 9). In the case of ( )-longithorone, an enyne RCM
was used for the construction of a macrocyclic diene, which
gave rise to ring C after a Diels–Alder cycloaddition.[65]
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Table 9: Conditions for RCM to give cyclophanes.
Conditions
Catalyst, yield
Compd Ref.
H2C=CH2, CH2Cl2, 45 8C, 40 h, 3 mm A (30–40 mol %), 116
31–47 %
C6H6, 40 8C, 1 h
C (34 mol %), 50 % 117
C6H5Cl, 135 8C, 6 h
I (10 mol %), 76 % 118
2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
[65]
[66]
[67]
Angew. Chem. Int. Ed. 2006, 45, 6086 – 6101
Angewandte
Chemie
Macrocyclization
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 metathesis 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
10. Prostaglandins
The RCAM strategy has also been applied to the synthesis
of the marine natural product prostaglandin E2-1,15-lactone
(Table 10).
Bn
CAN
Cy
L
Mes
MOM
PMB
PMP
RCAM
RCM
TBDPS
TBS
Teoc
TES
TIPS
TMS
benzyl
calcium ammonium nitrate
cyclohexyl
ligand
2,4,6-trimethylphenyl
methoxymethyl
4-methoxybenzyl
4-methoxyphenyl
ring-closing alkyne metathesis
ring-closing metathesis
tert-butyldiphenylsilyl
tert-butyldimethylsilyl
(2,2,2-trichloroethoxy)carbonyl
triethylsilyl
triisopropylsilyl
trimethylsilyl
Received: February 17, 2006
Published online: August 21, 2006
Table 10: Prostaglandin synthesis based on RCAM.
Conditions
Catalyst, yield
Compd
Ref.
toluene, 80 8C
J (7.5 mol %), 68–73 %
119
[68]
11. Outlook
Some criteria in the selection of reaction conditions for a
macrocycle construction by RCM are quite straightforward.
These are solvent selection (toluene, CH2Cl2, (ClCH2)2) and
the reaction temperature (from RT to refluxing toluene).
Angew. Chem. Int. Ed. 2006, 45, 6086 – 6101
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Chemie
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Angew. Chem. Int. Ed. 2006, 45, 6086 – 6101
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