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Comments on Recent Achievements in Biomimetic Organic Synthesis.

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M. C. de la Torre and M. A. Sierra
Biomimetic Synthesis
Comments on Recent Achievements in Biomimetic
Organic Synthesis
Mara C. de la Torre* and Miguel A. Sierra*
biomimetic synthesis · enzymes ·
natural products · organic
Dedicated to Professor Louis S. Hegedus
on the occasion of his 60th birthday
2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/anie.200200545
Angew. Chem. Int. Ed. 2004, 43, 160 – 181
Biomimetic Syntheses
The appealing beauty of the routes that Nature uses to build
natural products is breathtaking and the quest for laboratory
syntheses that mimic these routes is longstanding. Since Robert
Robinson introduced the concept of biomimetic synthesis in 1917,
debates have been conducted about the participation of specific
enzymes in every step of the biogenesis of every class of natural
product. The successful synthesis of many natural products often
follows routes analogous to processes that occur in the living cell
with minimum enzyme participation. It should not be concluded,
however, that we are only able to imitate biogenetic processes in
which enzymes are not involved. Perhaps the most appealing
facet of a biomimetic strategy is that it pursues the development of
synthetic methodology inspired by biogenesis, even if the
mimicked biogenetic route is only hypothetical. Improved
biogenetic syntheses could be brought about by artificial enzymes
that catalyze specific transformations.
1. Introduction
“For all natural products, there exists a synthesis from
ubiquitous biomolecules. The inherent interconnectivity of
natural products implies that a truly biomimetic total synthesis
represents a general solution not to the preparation of a
compound but to the preparation of all similarly derived
natural products (discovered and undiscovered).” These words
were recently written by Skyler and Heathcock[1] to illustrate
their work toward a general solution to the synthesis of the
pyridoacridine family of alkaloids and summarize the general
idea of biomimetic synthesis.[2] The concept of biomimetic
synthesis was coined by Robinson, following his straightforward synthesis of tropinone (3) from glutaraldehyde (1),
methylamine, and acetone dicarboxylic acid 2 reported in
1917 (Scheme 1).[3]
Van Tamelen systematized the different ideas and the
philosophy underlying the terms biomimetic or biogenetictype synthesis in his seminal work written in 1961.[4] The
definitions and ideas collected in van Tamelen's work are still
valid. Van Tamelen defined biomimetic synthesis as a specific
reaction or a sequence of reactions that mimic a proposed
biological pathway. The process being imitated usually has a
solid biochemical background.[5]
From the Contents
1. Introduction
2. Polyether Biomimetic Synthesis
3. The Diels–Alder Biomimetic Approach
4. The Jewel of the Biomimetic
Synthesis: Cyclization of Isoprenoids
5. Biomimetic Synthesis with Rigid
6. The Biomimetic Oxidative Coupling
of Phenols: The Closest to Reality?
7. Stepping Stones: Physiological-type
Artificial Syntheses
8. Conclusions and Outlook
The synthesis of angucyclinone derivatives tetrangomycin
(4) and rabelomycin (5) by Krohn et al. exemplifies this
definition (Scheme 2).[6] The biogenetic route to these compounds is well-known. It involves the decaketide 6, which is
transformed into the angucyclinone skeleton by intramolecular aldol condensation. The cyclization process may occur
either with concomitant or subsequent enzymatic oxidations
and reductions.[7] To mimic the biogenetic process, severe
restrictions have to be introduced in the starting material. The
cyclization substrate, 1,4-naphtoquinone derivative 7, lacks
the quasi-benzylic carbonyl group. This group had been
connected with preferential linear cyclization,[8] and was used
to reduce the many unwanted aldol condensations to two
cyclization modes: linear and angular. With these restrictive
conditions in hand, compound 7 was prepared and cyclized in
a stepwise fashion to the desired products via tricyclic
intermediates 8.
The term biomimetic synthesis is also used to describe a
sequence of reactions carried out to support a biogenetic
hypothesis. In this case, a reaction is effected on a putative
substrate of the transformation under study. Should the
reaction succeed, the biosynthetic route would be generally
accepted. The synthesis of the indole alkaloid ervitsine (9) by
[*] Dr. M. C. de la Torre
Instituto de Qumica Org!nica
Consejo Superior de Investigaciones Cientficas
C/Juan de la Cierva 3, 28 006 Madrid (Spain)
Fax: (+ 34) 91-562-2900
Scheme 1. Robinson's one-pot preparation of tropinone, the first
example of a biomimetic synthesis.[3]
Angew. Chem. Int. Ed. 2004, 43, 160 – 181
Prof. M. A. Sierra
Departamento de Qumica Org!nica
Facultad de Qumica, Universidad Complutense
28 040 Madrid (Spain)
Fax: (+ 34) 91-394-4103
DOI: 10.1002/anie.200200545
2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
M. C. de la Torre and M. A. Sierra
Scheme 2. Left: cyclization of polyketides to angucyclinone derivatives;
right: biomimetic synthesis of tetrangomycin and rabelomycin by
Krohn and co-workers.[6]
Bosch and co-workers exemplifies this meaning of biomimetic
synthesis (Scheme 3).[9] The biogenetic pathway to this
compound was proposed to involve the key intermediate
10,[10] which is formed from a vobasine N-oxide equivalent 11.
Intermediate 10 would be transformed into ervitsine (9) by
1,2-addition of the indole nucleus to the a,b-unsaturated
iminium group. The more favorable 1,4-addition would lead
to the related alkaloid methuenine (12). In fact, both alkaloids
9 and 12 are biogenetically related.[11]
The key intermediate 16 was prepared by the nucleophilic
addition of the enolate derived from 13 to the g position of the
pyridinium salt 14 (Scheme 3). The resulting 1,4-dihydropyridine 15 was trapped with the Eschenmoser salt (Me2N+=
CH2I), and adduct 16 was isolated under these conditions.
Compound 16 was transformed into the desired alkaloid 9 by
sequential Cope elimination, treatment with acid, and reduction with NaBH4 (Scheme 3). The success of this approach
was claimed to validate the proposed biogenetic pathway.
Sometimes the biomimetic synthesis fails and the biogenetic hypothesis remains unsupported. One such case
involved the attempt to convert phorbol (17) into 12hydroxydaphnetoxin (18; Scheme 4).[12] Evidence for the
Scheme 3. The synthesis of ervitsine by Bosch and co-workers supports the biogenetic hypothesis proposed for this alkaloid.[9] SEM = 2(trimethylsilyl)ethoxymethyl, LICA = lithium isopropylcyclohexylamide.
biogenetic conversion of the tigliane (phorbol) skeleton into
the daphnane skeleton rested on the isolation of compounds
that had both structural types from a single plant species.[13]
The biogenetic proposal suggests that the oxidation of the
C16 methyl group would provide the necessary activation to
trigger the C9-ester-assisted cyclopropyl-to-carbinyl rear-
Maria C. de la Torre studied chemistry at the
Universidad Complutense de Madrid (UCM)
and received her PhD in 1986. After postdoctoral stays at Imperial College (Prof.
Steven Ley) and Colorado State University
(Prof. Albert Meyers), she returned to
Madrid in 1989 as a Scientific Researcher at
the Consejo Superior de Investigaciones
Cient-ficas. Her current research interest
focuses on the chemistry of densely functionalized natural products, and in the preparation of natural product hybrids with mixed
and/or complementary biological properties.
2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Miguel A. Sierra studied chemistry at the
UCM (Madrid) and received his PhD in
1987, after which he was appointed to Assistant Professor. After a postdoctoral stay at
Colorado State University (Prof. Louis Hegedus), he returned to Madrid where he was
promoted to Professor in 1990. His research
encompasses the development of new processes based on transition-metal complexes,
the preparation of new bioorganometallic
compounds tailor-made for specific applications in crop protection, and the study of
environmental organic processes.
Angew. Chem. Int. Ed. 2004, 43, 160 – 181
Biomimetic Syntheses
Scheme 5. The attempt to reproduce the tigliane to daphnane
rearrangement in a complex molecule was also unsuccessful.[14]
Scheme 4. The attempted biomimetic rearrangement of tigliane to
daphnane was unsuccessful.[12] Ts = tosyl = 4-toluenesulfonyl;
py = pyridine.
rangement (19!21). Bicyclic cyclopropane 22 was prepared
and treated with 1 equivalent of tosyl chloride and pyridine to
mimic the cyclopropyl–carbinyl rearrangement. The desired
rearrangement did not occur (probably owing to the nonparticipation of the ester group). Instead, the b,g-unsaturated
ketone 23 was obtained as a result of the cleavage of the
“wrong” cyclopropane bond. This bond cleavage is probably a
consequence of assistance by the lone pair of electrons of the
tertiary alcohol, which undergoes transformation to the
p system of the incipient ketone. Different blocking groups
were used to avoid the participation of this tertiary alcohol,
without any success. Therefore, the biomimetic hypothesis
remained unsupported.
It can be argued that in the case discussed above, the
model was too simple to mimic the transformation that occurs
in a considerably more complex structure. However, the
analogous transformation was already tested in compound 24,
resulting again in the cleavage of the undesired cyclopropane
bond to produce ketone 25 (Scheme 5).[14] However, we
should remember that according to van Tamelen, “It seems
hardly necessary to add that the success of a 3biogenetic-type4
synthesis by itself does not constitute evidence for the operation
Angew. Chem. Int. Ed. 2004, 43, 160 – 181
of a particular chemical step in nature (although in a
remarkable case, the temptation to draw such a conclusion
will be great).”[4]
At this point it is worth discussing two coexisting, albeit
antagonistic, ideas about the biosynthesis of natural products:
The first idea is almost as old as the concept of biomimetic
synthesis itself and was sketched by Robinson in the following
way: “Previous suggestions have no laboratory analogy. It has
been assumed that plants have enormously powerful reagents
that can cause substances, the properties of which have been
investigated with considerable care, to undergo transformations that cannot be induced in the laboratory. To a certain
extent, specially in regard to oxidation and reduction, this must
be true, but it is probable that this aspect has been exaggerated
and that an equally important cause of the variety and
complexity of synthesis in plants resides in the highly reactive
nature of the substances that function as reactive intermediates.”[15]
As an alternative, Heathcock defined Nature as the
quintessential process development chemist. Thus “…we
think that the molecular frameworks of most natural products
arise by intrinsically favorable chemical pathways—favorable
enough that the skeleton could have arisen by a nonenzymic
reaction in the primitive organism. If a molecule produced in
this purely chemical manner was beneficial to the organism,
enzymes would eventually have evolved to facilitate the
production of this useful material. Further optimization of
the biological activity might have been accomplished by
cytochrome P450-mediated oxidations. Once again, those
oxidation products that conferred an evolutionary advantage
to the organism would have promoted selection of oxidase
variants with appropriate binding selectivity.”[16]
The two ideas are separated by almost one century, but, at
the dawn of the new millennium, there is still no clear proof to
tip the scales in either direction.
2. Polyether Biomimetic Synthesis
One of the most appealing controversies in the field of
biomimetic synthesis involves the biosynthesis of polyethers.[17] Currently, two biogenetic hypotheses for these
products coexist. The first hypothesis was postulated by Cane,
Celmer, and Westley[18] in 1983 (CCW hypothesis) and
proposes that the biosynthesis of polyethers is a two-step
process involving the enzymatic polyepoxidation of an acyclic
polyene precursor 26 to form polyepoxide 27 (Scheme 6,
2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
M. C. de la Torre and M. A. Sierra
Scheme 6. The Cane–Celmer–Westley polyepoxide[18] and the
Townsend–Basak oxidative cyclization[19a] hypotheses for the
biogenesis of monensin.
path A). From 27, a cascade of intramolecular epoxide-ringopening reactions forms the polyether skeleton 28 (anti
cyclization hypothesis). Townsend and Basak proposed[19]
10 years later that the polyether framework may be built
through a syn oxidative polycyclization of an open-chain
hydroxyolefin 29 (Scheme 6, path B). Premonensin triene 26
is the postulated starting material for the CCW hypothesis,
whereas triene 29 is the postulated starting material in the
Townsend–Basak proposal—neither of these trienes has yet
been found as natural product. Moreover, synthetic radiolabeled (E,E,E)-premonensin triene derivatives failed to
demonstrate isotopic incorporation in monensin (28).[20]
Neither of these hypotheses have been proved, nor have the
enzyme-induced transformations depicted in paths A or B
been reported to date.
2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
The CCW model gained rapid acceptance. In an impressive synthetic tour de force, the fundamental hypothesis
depicted in path A in Scheme 6 was validated in different
laboratories. For example, triepoxide 33 was prepared by
treatment of macrocyclic lactone 32 with MCPBA
(Scheme 7). Saponification of 33 and treatment with AcOH
formed the tricyclic polyether 34.[21] It was thence concluded
that the polycyclization behavior of epoxide 33 provided
strong support for the polyepoxide CCW biogenetic hypothesis. Simultaneously, diastereomeric polyepoxides 36 and 37
were prepared by oxidation of macrocyclic lactone 35 with
MCPBA. Saponification and stereoselective cyclization of 36
and 37 led to the formation of polyethers 38 and 39,
Analogously, an approach to the C12–C21 bistetrahydrofuran moiety of monensin was reported soon after the
Townsend–Basak hypothesis was formulated (Scheme 8).[23]
Triene 40 was dihydroxylated with AD-mixb to form 1,2-diol
41. The syn oxidative cyclization of 41 to form tetrahydrofuranyl ketone 42 was induced with Collins reagent. Reduction
of the ketone group of 42 occurred with complete Felkin–Ahn
stereocontrol to provide 43, which underwent oxidative
cyclization in the presence of (Cl2CHCO2)ReO3 to give the
trans,cis-bistetrahydrofuranyl alcohol 44. Alcohol 44 includes
the C and D rings of monensin (28). The stepwise construction of 44 required three different metal–oxo reagents (Os for
the dihydroxylation step, Cr for the first oxidative step, and
Re for the second). McDonald and co-workers speculate that
a single biosynthetic enzyme containing a metal–oxo site
might catalyze all three transformations (in the presence of an
external oxidizing agent, NAD+!NADH).[24]
The oxidative cyclization cascade used in the preparation
of goniocin (45), a fatty acid derivative isolated from
Goniothalamus giganteus,[25] was devised to use only one
metal reagent (Scheme 9). The synthesis involved the tandem
oxidative cyclization of an appropriate acyclic triene in the
presence of Re2O7 as the key step.[26] In the context of the
Townsend–Basak hypothesis, this approach to 45 would be a
perfect biomimetic synthesis. The relative configuration of
the six stereogenic centers in the trisfuran skeleton was
derived from the single stereogenic center of 46. Treatment of
triene 46 with CF3CO2ReO3 in TFAA resulted in the
formation of a single tristetrahydrofuranyl product 47 in
48 % yield (Scheme 9). Surprisingly, the product 47 has a
trans,threo,cis,threo,cis,threo configuration instead of the
desired trans,threo,trans,threo,trans,threo. The undesired stereochemical result was attributed to the absence of the
butenolide moiety present in goniocin. The oxidative cyclization was repeated in triene 48, which has much more
elaborated skeleton. Triene 48 formed compound 49, whose
stereochemistry is identical to that of 47 (Scheme 9). The
correct stereochemistry of the natural product could not be
accessed in this way.
The successful approach to goniocin (45)[27] defined the
correct stereochemistry on the first THF ring by treatment of
diene 50 with CF3CO2ReO3 in TFA to yield 51 (Scheme 10).
Compound 51 was converted into tristetrahydrofuranyl 53 by
asymmetric dihydroxylation and ring closure of bismesylate
52. The same sequence of reactions was repeated with ent-50
Angew. Chem. Int. Ed. 2004, 43, 160 – 181
Biomimetic Syntheses
Scheme 7. Early successful synthetic routes developed to prove the CCW hypothesis for the biogenesis of polyether antibiotics.[21]
MCPBA = meta-chloroperbenzoic acid.
Scheme 8. The stepwise building of bistetrahydrofuran 44 using three different metals supports the Townsend–Basak hypothesis for the
biogenesis of polyether antibiotics.[23] DMAP = 4-(dimethylamino)pyridine.
to form ent-53, which was transformed into cyclogoniodenin T
(54). The authors hypothesized that the coexistence of the two
natural products 45 and 54 with different configurations in the
same organism is the result of two alternative modes of
tandem ring closures. Both routes would start from a common
polyepoxide intermediate.
The fused polycyclic ethers of marine origin are closely
related to the polyether antibiotics. For example, brevetoxin B (55) may, according to Nicolaou and Sorensen,[28] arise in
one dramatic event from the polyepoxide precursors 56 or 57.
Clearly, biosynthetic path A (Scheme 11), originally proposed
by Nakanishi and co-workers,[29] is closely related to the CCW
hypothesis for the biosynthesis of polyether antibiotics. The
event leading to brevetoxin B is initiated synchronously by
attack of the carboxylate ion at the oxirane carbon atom at
the left terminus (as drawn). The protonation of the unconjugated double bond on the right-hand side would occur
either prior or simultaneously to the attack by the carboxylate
group. Path B was also proposed in the context of the CCW
Angew. Chem. Int. Ed. 2004, 43, 160 – 181
hypothesis by Shimizu.[30] It involves the amphiphilic intramolecular attack of the hydroxy group (right-hand side of
drawn structure) at the proximal oxirane carbon atom upon
protonation of the carbonyl oxygen atom on the left-hand side
of the polyepoxide 57. Although modest advances to implement this methodology have been made,[31] it has not been
successful in the syntheses of fused cyclic polyethers.[32]
The examples above show how two coexisting biogenetic
hypotheses may trigger substantial efforts to achieve the
synthesis of the classes of compounds involved.
3. The Diels–Alder Biomimetic Approach
Does nature know about the Diels–Alder reaction? The
question posed by Laschat in a Highlight[33] was answered by
stating that “until now [early 1996], there is no case known
where the corresponding enzyme system, that is the Diels–
Alderase, could be detected”. And further in the same article,
2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
M. C. de la Torre and M. A. Sierra
Scheme 9. The one-step oxidative cyclization approach to goniocin
(45) to produce the wrong stereoisomer.[25, 26] TFAA = trifluoroacetic
anhydride; TBDPS = tert-butyldiphenylsilyl.
the author stated that “in view of the difficulties in detecting
and isolating Diels–Alderases, one might assume that there are
no enzyme-catalyzed [4+2] cycloadditions involved in natural
systems. However, this assumption seems to be incorrect!”
Timely and thorough reviews on the topic are available.[34]
Therefore, we will limit our discussion to only two examples:
One synthesis mimics a probable enzyme-catalyzed biogenetic process, and the other mimicks a possible uncatalyzed
but spontaneous biogenetic process. It should be clear that
current experimental evidence for enzyme involvement in the
biological Diels–Alder reaction is circumstantial.[35]
The solanapyrones 58 and 59 are two phytotoxins
produced by the fungus Alternaria solani. The hypothetical
involvement of Diels–Alderases in these processes was
reported by Oikawa et al.[36] based on the different endo/exo
ratios obtained for adducts 58 and 59 when either a cell-free
extract of A. solani (58/59 47:53) or water (58/59 97:3) were
used in the synthesis of these compounds from precursor 60
(Scheme 12).
2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Although the involvement of Diels–Alderases in the
biogenesis of the solanapyrones is a strong possibility, such
enzymes may be excluded from the biosynthesis of the
bisorcibillinols. Bisorcibillinoids[37] are structurally related
dodecaketides, all of which potentially originate from the
natural product sorbicillin (61). The proposed biosynthetic
pathways (Scheme 13) for bisorbicillinol (62), bisorbibutenolide (63), and bisorbicillinolide (64) involved the initial regioand stereospecific [4+2] dimerization of sorbicillin (61) and
2’,3’-dihydrosorbicillin after an enantioselective oxidation.
From 62, two successive anionic rearrangements and a final
Michael addition provide 63 and 64.[38] This biogenetic
proposal was fully mimicked by Nicolaou and co-workers[39]
starting from a-diacetoxy dienone 65. Treatment of dienone
65 with base led to the Diels–Alder adduct 62 in 40 % yield.
The same reaction was repeated with (S)-65, and the optical
rotation of the synthetic 62 was in good agreement with that
reported for the natural product. This reaction provided four
stereogenic centers, two of which are fully substituted, with
complete region- and endo selectivity. Furthermore, the fully
thermal reaction (heating of 65 in benzene or in AcOH for
several hours) did not give any Diels–Alder product. The
treatment with base should reveal a diquinolate system by
hydrolysis of the acetyl group to form the reactive 66 after
protonation. Therefore, it seems reasonable that the thermal
reaction could not produce satisfactory results (Scheme 13).
Afterwards, following the hypothesis of Abe et al., 62 was
transformed into 63 by treatment with KHMDS. However,
although treatment of 62 with KHMDS led smoothly to 63,
any other base failed to convert 62 or 63 into bisorbicillinolide
(64). This is noteworthy since 63 is hypothetically a biogenetic
intermediate of the anionic cascade for the formation of 64.
The above syntheses mimicked a biogenetic hypothesis
that involves the Diels–Alder reaction. The same chemical
process may be used for different organisms to produce
different secondary metabolites.[40] However, it is unusual to
propose so many biotransformations based on a process for
which an enzymatic system has not been unambiguously
proved to exist. We use Williams's words to summarize this
point: “…despite the increasing number of natural products
that have been identified and proposed to arise via a biological
Diels–Alder reaction, a great deal of experimental and
intellectual penetration into the mechanistic subtleties of
putative biosynthetic Diels–Alder reactions need to be conducted”.[34a]
4. The Jewel of the Biomimetic Synthesis: Cyclization of Isoprenoids
The research behind the achievements in the field of
isoprenoid biogenesis and the efforts to mimic their biosynthesis are fundamental milestones in the history of organic
chemistry.[41, 42] Isoprenoids have amazingly diverse structures
whose construction are mediated by cyclases. Several polycyclic isoprenoids are generated from simple linear polyene
substrates such as geranyl pyrophosphate (GPP, 68) farnesyl
pyrophosphate (FPP, 69), or geranylgeranyl pyrophosphate
(GGPP, 70) (Figure 1).
Angew. Chem. Int. Ed. 2004, 43, 160 – 181
Biomimetic Syntheses
Scheme 10. The sequential and successful approach to goniocin (45) and cyclogoniodenin T (54). TBDMS = tert-butyldimethylsilyl;
DMF = N,N-dimethylformamide; Ms = mesyl = methanesulfonyl.[27]
Scheme 12. A possible Diels–Alderase-catalyzed Diels–Alder reaction.[36]
Scheme 11. Two alternatives to the cascade cyclization leading to
brevetoxin B.
Angew. Chem. Int. Ed. 2004, 43, 160 – 181
The formation of polycyclic isoprenoids, which bear
diverse stereocenters, is mediated by cyclases in a single
enzyme-controlled asymmetric reaction (Figure 1).[43] The
beauty of the process rests in the fact that the same substrate
can form diverse families of isoprenoid structures which
depend on the enzymes used. It is thought[44] that the specific
cyclizations occur in a four-step sequence: 1) generation of a
carbocation, 2) control of the conformation of the substrate,
3) stabilization of intermediates, and 4) quenching of the final
2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
M. C. de la Torre and M. A. Sierra
Figure 1. Cyclase cyclization of linear polyenes.
Scheme 13. The biogenetic proposal for the biosynthesis of bisorcibillinols; synthesis by Nicolaou and co-workers. HMDS = bis(trimethylsilyl)amide.[39]
carbocation. Based on this scheme, the origin of the stereoselectivity of the polycyclic system rests on the generation of
the carbocation.[44a] Two question arise: What is the level of
involvement of cyclases in these processes? Can truly
enantioselective biomimetic cyclization of isoprenoids be
achieved in vitro?
The first question is addressed by the theory of “minimal
enzymatic assistance”.[43] This theory postulated the possibility that “for the formation of novel and unexpected products
by the cyclases, it is also possible that the active sites are simply
permissive and therefore do not intervene completely in the
folding and cyclization of substrates which they do not
normally encounter. The role of the cyclase is most likely to
involve initiation of cyclization and prevention of alternative
modes of cyclization”.
2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
The second question has been addressed experimentally
by using artificial cyclases based on the combined system of a
Lewis acid and a chiral Brønsted acid (LBA) (see below).
An elegant illustration of the minimal-enzymatic-assistance hypothesis is the synthesis of a steroid nucleus reported
by Demuth and Heinemann.[45] The philosophy of this
approach parallels the ionic-cyclization process. The initial
step is the regioselective oxidation of the terpenoid polyalkene 71 at the w position by photoinduced electron transfer
(PET). The oxidation process generates the parent radical
cation 72, which evolve in a productive way by trapping of a
nucleophile (usually water). The trapping is followed by
radical cyclization and termination by quenching of the
resulting neutral radical (Scheme 14).[46] Ring closure (6endo- or 5-exo-trig) could terminate the cyclization, leading to
73 or 74, respectively.
The enantiomerically pure (E,E,E)-geranylgeranylmethyldioxinones 75 and 76 were irradiated in the presence of
Scheme 14. Two alternatives for the photoinduced electron transfer
(PET) cyclization of terpenoid polyalkene 71.[46]
Angew. Chem. Int. Ed. 2004, 43, 160 – 181
Biomimetic Syntheses
(DCTMB) and biphenyl (BP) as the electron donor–acceptor
couple (Scheme 15). The major photoproducts of 75 were 77
the PET). The main reaction paths proceed through the
a folding of the polyalkene chain such as in intermediates 81
and 82. The b-folded intermediates 83 and 84 are disfavored.
This case of remote asymmetric induction supports the
feasibility of effecting a highly selective cyclization of the
polyene by anchoring a portion of the molecule in the enzyme
(minimal enzymatic assistance). The covalently tethered
chiral auxiliary plays the role of the enzyme center. Remarkably, the analogous transformation via cationic intermediates
does not take place in vitro.
The enantioselective polyene cyclization has been mimicked through an external chiral promoter. This shows that it
is feasible to mimic the remote participation of the enzyme in
the initial protonation of the polyene. Since the coordination
of a Lewis acid to a Brønsted acid restricts directional access
to the proton and increases the Brønsted acidity, chiral Lewis–
Brønsted acids (LBAs) can be considered as “protons”
surrounded by chiral environments, and hence have been
used in enantioselective protonations.[47] As stated above, the
generation of the carbocation is the key step in determining
the absolute stereoselectivity of a polyene cationic cyclization.[44, 47a] Therefore, LBAs may be used as surrogates in the
enzymatic enantiodifferentiating protonation steps. Yamamoto and co-workers demonstrated this concept by synthesizing the acetate 85 of ( )-chromazonarol, a minor constituent
of the brown Pacific seaweed Dictyopteris undulata, from the
corresponding farnesyl derivative 86 (Scheme 16). Thus, 4benzyloxyphenyl farnesyl ether (86) was treated with a
stoichiometric amount of chiral LBA 87 for 24 h at 78 8C.
Under these conditions, the tetracyclic derivative 85 was
obtained with 44 % ee, after debenzylation and acetylation, in
a process involving an initial Claisen rearrangement followed
by cationic cyclization. Furthermore, the restrictive element
introduced by the aromatic ring in 86 is not needed as ( )ambrox (88), the main odorant component of ambergris, was
Scheme 15. The bias for a folding over b folding of the chiral polyalkenes 75 and 76 is shown in their PET cyclization.
and 78 as a diastereomeric mixture (1:7). Analogously,
irradiation of the diastereomer 76 led to a mixture (2:1) of
cyclization products 79 and 80. In both cases, the termination
occurs exclusively in the 5-exo-trig mode. The degree of
asymmetric induction observed in both cases is remarkable
and is due to the geometry of the double bonds of 75 and the
sequential formation of six-membered rings. The chiral
auxiliary is remote from the initial radical cation center.
This undoubtedly suggests a diastereoselective folding of the
polyalkene chain immediately after the initial PET oxidation
steps (it is not likely that such a preorganization exists before
Angew. Chem. Int. Ed. 2004, 43, 160 – 181
Scheme 16. Biomimetic enantioselective polyene cyclization using a
chiral Lewis–Brønsted acid (LBA).
2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
M. C. de la Torre and M. A. Sierra
prepared by enantioselective cyclization of homofarnesol (89)
promoted by 90 in 56 % yield (42 % ee) (Scheme 16).[47b]
The cyclization of polyenes by PET or LBAs demonstrates
that it is feasible to mimic the biogenetic processes at least
partially. Evidently, the number of cyclization modes and the
diastereoselectivity are dependent on the spontaneous preorganization of substrates in the applied media at the
temperatures used. A synthetic cyclase would need to solve
the problem of the organization of the conformation of the
substrates during the cyclization of the intermediates. Such
additional cavities together with the use of catalytic amounts
of chirality-transfer agents would undoubtedly lead to truly
biomimetic processes. The synthesis of ( )-sophoradiol (91)
by Johnson and Fish is a classical attempt to solve the problem
(Scheme 17).[48] Whereas the enzymatic cyclization of oxidosqualene (92) leads to the pentacyclic triterpenoids of the
oleanane series 91,[49] the acid-catalyzed reaction of 92 leads
instead to tricyclic products such as 93. The premature
termination of the acid-catalyzed reaction is rationalized by
comparison of the relative stabilities of the cationic inter-
mediates 94 and 95. The initial cyclization of 92 generates
bicyclic cation 96 both in acid or enzyme-catalyzed processes.
However, whereas the enzymatic process leads to the antiMarkovnikov tricyclic cation 94, the acid-induced process
produces the favored cation 95. Evolution of both cations
leads to the observed penta- and tricyclic products 91 and 93,
During the seminal work of Johnson and co-workers on
the cyclization of polyenes,[50] a fluorine atom was introduced
in the substrates as a cation-stabilizing auxiliary
(Scheme 18).[51] The regiochemistry of the cyclization is
Scheme 18. The fluorine atoms acts as a cation-stabilizing auxiliary in
the cyclization of polyenes. TFA = trifluoroacetic acid.[50, 51]
Scheme 17. The enzymatic cyclization of oxidosqualene leads to pentacyclic triterpenoids, whereas its acid-catalyzed cyclization forms
tricyclic compounds.[48, 49]
2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
controlled by the fluorine atom to give exclusively the sixmembered ring, whereas the five-membered ring is formed in
its absence. In this regard, the polyene cyclization substrate 99
was prepared and treated with SnCl4 at 78 8C for 10 min.
Cyclization with loss of HF led to the formation of pentacyclic
derivative 100 in 50 % yield. Treatment of 99 with trifluoroacetic acid (TFA) gave fluorinated derivative 101 in 31 %
Angew. Chem. Int. Ed. 2004, 43, 160 – 181
Biomimetic Syntheses
yield. ( )-Sophoradiol (91) was prepared from 101 in four
steps. The key step in this sequence was the dehydrodefluorination of intermediate 102, which was obtained from 101 by
oxidative cleavage of the allene and alkene functions.
Derivative 103 is formed by treatment with SnCl4 as a
consequence of the strain within the structure of the
fluoropentacyclic derivative. The Lewis acid facilitates dehydrofluorination and produces a planar sp2-hybridized carbon
center at C13, thus relieving the strain. The exclusive
formation of 103 is due to the favored anti 1,2-diaxial
elimination of HF (C13-Fax, C12-Hax); the disfavored syn
1,2-elimination (C13-Fax, C18-Heq) would lead to the isomer
104. Therefore, the fluorine atom not only directs the
polycyclization to the pentacyclic all-trans six-memberedring system, but also defines the position of the double bond,
either during the cyclization process (formation of compound
100), or thereafter during the completion of the synthesis of
91 (102!103).
These syntheses mimic three different aspects of the
biosynthesis of terpenes: 1) remote induction by an enzyme,
2) chiral discrimination promoted by a chiral proton source,
and 3) stabilization of the carbocation intermediates. The
remaining point to be mimicked is the conformational
organization. It is foreseeable that processes in which the
four key points of the action of cyclases are combined will be
reported in a near future. Such a process would yield known
structural types, but may also lead to new non-natural
structures. Again, we can speculate that the combination of
the three factors (in vitro) would lead to preorganization. The
required folding of the cyclization substrates would emanate
from the highly chiral surfaces in the cell. Johnson raised this
question as early as 1968 in his review on nonenzymatic
biogeneticlike olefin cyclizations: “The theoretical question to
be answered is, how important is the enzyme in directing the
course of the cyclization? One popular view is that the enzyme
plays an all-important role, i.e., it serves as template which
holds the substrate in a single rigidly folded conformation with
the olefinic bonds appropriately juxtaposed for cyclization.
There are, on the other hand, some good a priori reasons for
entertaining the hypothesis that squalene-like (all-trans) polyolefins should have an intrinsic susceptibility to cyclize stereoselectively to give a product having 3natural4 configuration.”[50e]
pyrazine core structure is assembled through dimerization
and oxidation of steroidal a-aminoketones (Scheme 19).[54]
Scheme 19. Random formation versus biological oxidation in the biosynthesis
of tridecacyclic pyrazines to form steroidal a-aminoketones.
5. Biomimetic Synthesis with Rigid Substrates
The required restriction of the conformational freedom of
the cyclization substrates is a general cul de sac in designing
cascade biomimetic synthesis (this is also true in conventional
cascade syntheses). Therefore, the use of rigid substrates
usually ensures the success of the biomimetic approach. The
success in mimicking processes of dimerization of rigid
substrates is seen in the appealing total synthesis of (+)cephalostatin 7 (105), (+)-cephalostatin 12 (106), and (+)ritterazine K (107) reported by Fuchs and co-workers.[52]
Cephalostatins and other tridecacylic pyrazines were isolated
from the marine tube worm Cephalodiscus gilchristi and from
the tunicate Ritterella tokioka.[53] The biogenetic hypothesis
for this kind of compounds is based on the premise that the
Angew. Chem. Int. Ed. 2004, 43, 160 – 181
A fascinating question regards the timing of the dimerization step. It can be envisaged that a single precursor, steroid
108 or 109, undergoes dimerization to produce the C2symmetrical dimers 106 or 107, respectively, whereas unsymmetrical 105, would be formed from a mixture of the aaminoketones 108 and 109. The result of this last scenario
would be the formation of 106, 105, and 107 (1:2:1). In this
case, the precursors 108 and 109 should be present in the same
concentration, and the dimerization rates for all the aaminoketones should be approximately the same. This
appealing hypothesis that random coupling is responsible
for the observed distribution of products falls apart, however,
as the unsymmetrical 105 was isolated in 100-fold higher yield
than the symmetrical 106 or 107 (Scheme 19).
2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
M. C. de la Torre and M. A. Sierra
Therefore, a second pathway for biosynthesis of the
cephalostatins must involve the biological deoxygenation of
symmetrical 106 at C23, followed by acid-catalyzed rearrangement of the 5/5 spiroketal to the 6/5 spiroketal present in
105.[55] This last transformation can be mimicked in the
laboratory by the use of selective protecting groups to ensure
differentiation of functional groups. It is necessary to indicate
that the 5/5!6/5 spiroketal rearrangement does not require
the participation of enzymes, as it occurs spontaneously
in vitro.
The biomimetic approach used by Fuchs and co-workers[52] to prepare compounds 105–107 was the statistical
combination of a-aminoketones 108 and 109. A 1:1 mixture of
a-azidoketones 110 and 111 was treated with NaHTe and then
with mildly acidic silica gel. A mixture of pyrazines 112, 113,
and 114 was obtained in 14, 35, and 23 % yields, respectively
(Scheme 20). The bias observed for compound 114 (as
opposed to the expected 1:1 ratio of 112/114) was explained
by the reductive cleavage of azides 110 and 111. This side
Scheme 20. Random approach to tridecacyclic pyrazines by Fuchs and
Jeong.[55] TMS = trimethylsilyl.
2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
reaction formed the reduced by-products 115 and 116 in 36 %
and 15 % yields, respectively. As the reductive cleavage of 110
and 111 by NaHTe disturbed the 1:1 ratio of a-aminoketones
derived from 110 and 111, it is reasonable that the coupling
reaction was biased toward the ritterazine K precursor 114.
The synthesis of pyrazine-derived alkaloids sketched in
Scheme 20 shows that these compounds may be formed by
dimerization of the appropriate a-aminoketone precursors
without enzyme intervention. A synthesis that mimics the
selective formation of unsymmetrical cephalostatins still
remains open.[56]
The idea of mimicking the evolution of enzyme-generated
precursors underlies the synthesis of the pentacyclic alkaloid
( )-nirurine (117) reported by Magnus et al.[57] Nirurine was
isolated from Phyllanthus niruri L. and was thought to be
biogenetically related to norsecurinine (118), which was also
isolated from Phyllanthus. Towards the synthesis of ( )-117,
alcohol 119 was cleanly rearranged to 118 via its mesylate
(Scheme 21). Alternatively, alcohol 119 was oxidized to
ketone 120, which was reduced to prenirurine (121), the
hypothetical precursor of 117. Thus, 121 was treated with
MCPBA to give the rearranged product 122, presumably
through a Cope elimination of the unstable N-oxide 123.
Optimization of the reaction conditions finally led to the use
of dichloromethane as solvent to handle the N-oxide 123.
Small amounts of ( )-nirurine (117) were obtained, together
with the main reaction product 122 (Scheme 21). The outcome of this synthesis led the authors to change the biogenetic
Scheme 21. Synthesis of nirurine by Magnus et al.[57]
Angew. Chem. Int. Ed. 2004, 43, 160 – 181
Biomimetic Syntheses
proposal: “…in view of the low yield of ( )-nirurine 117
because of the competing rearrangement, it seems likely that
prenirurine 121 is not the biogenetic precursor to ( )-nirurine
117, and that aminal formation (oxidation adjacent to nitrogen) takes place at an earlier stage”.
Within the scope of strychnine synthesis,[58] the approach
to this alkaloid reported by Martin and co-workers[59] is an
exceptional example of the successful application of an
hypothetic biotransformation to obtain the synthetic target.
The critical element in the design of this synthetic plan was
inspired by the proposed biogenetic reorganization of the
indole alkaloids based on the corynantheoid skeleton into the
alkaloids of the Strychnos family.[60] The Corynanthe alkaloid
geissoschizine (125) is the biosynthetic precursor of strychnine (126) and akuammicine (127). Several mechanistic
pathways have been proposed to explain the extensive
series of skeletal rearrangements involved in the transformation of one family of alkaloids into the other. Could these
rearrangements be mimicked in the laboratory? Deformylgeissoschizine (128) was chlorinated with tBuOCl to form the
epimeric chloroindolines 129 (Scheme 22). Reaction of 129
with lithium diisopropylamide produced a complex reaction
mixture, which contained traces of 127. Apparently, the
epimeric chloroindolines 129 are deprotonated at the position
a to the CO2Me group. The resulting enolate cyclizes onto the
iminium carbon atom to yield 130. Skeletal reorganization of
130 into 131 followed by tautomerization yielded 127.
Further experimentation demonstrated that only b-chloroindoleine (b-129) and not its a isomer, a-129, is involved in
the rearrangement of 128 into 127. The key, therefore, was to
produce exclusively the b isomer. This problem was solved by
the addition of a Lewis acid to the chlorinating mixture
applied to 128. The rearrangement 128 into 127 could be
effected in 52 % yield in the presence SnCl4/tBuOCl followed
by treatment with LHMDS base. The conditions were applied
to tetracyclic derivative 132 to furnish 18-hydroxyakuammicine (133) in 22 % yield (Scheme 22). Compound 133 was
previously transformed into strychnine (126) by Overman and
co-workers in four steps.[61]
Thus, even if we do not know the biogenetic mechanism,
we can devise conditions to run successfully a feasible
transformation in the laboratory. The mastery demonstrated
by Martin and co-workers to effect the transformation of 128
into 127 shows how cytosollike conditions can be mimicked in
the laboratory.
Scheme 22. Fine-tuning of the reaction conditions to effect the
rearrangement of chloroindoline into akuammicine by Martin et al.[59]
The fact that Nature provides a vast number of biaryl
natural products with great structural diversity has made the
topic of mimicking the phenol coupling an exceptionally
active area or research.[65] The key point, regardless of the
diverse hypotheses that may be postulated for each particular
biogenetic route, is the laboratory oxidant used to mimic the
6. The Biomimetic Oxidative Coupling of Phenols:
The Closest to Reality?
The singular achievement by Barton[62] which demonstrated that the tetracylic skeleton of salutaridine (134) arises
from oxidative coupling of (R)-( )-reticuline (135)
(Scheme 23), a proposal made by Robinson more than
30 years before,[63] and his subsequent synthesis of the
salutaridine nucleus by biomimetic oxidation of a reticuline
in 0.03 % yield clearly demonstrated that this class of process
could be mimicked in the laboratory.[64]
Angew. Chem. Int. Ed. 2004, 43, 160 – 181
Scheme 23. Oxidative coupling of reticuline to form salutaridine, as
proposed by Robinson[63] and effected by Barton 30 years later.[64]
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M. C. de la Torre and M. A. Sierra
one-electron transfer that triggers the biaryl coupling in the
biological media. The efficiency of the mimetic process is
increased as the oxidant reagent used is finely tuned. The
diverse routes for the preparation of ( )-galanthamine (136)
developed through the years illustrate this point.
( )-Galanthamine 136 is considered to be synthesized
biologically by the phenolic oxidative coupling of norbelladine (137; Scheme 24).[66] Galanthamine was initially prepared by Barton and Kirby[67] by using K3[Fe(CN)6] to effect
the oxidative coupling. The process occurred in very low yield
(0.92 %), and during the following 40 years, several other
oxidative methods to effect this coupling were published.[68]
Yields of the pivotal oxidative step in the synthesis of
galanthamine were consistently below 50 %. Recently, the
aromatic rings of norbelladine-like derivative 138 were
coupled by using phenyliodine(iii) bis(trifluoroacetate)
(PIFA) to give the coupled product 139 in 82 % yield.
Remarkably, the ideal substrate 140 that yields the narwe-
dine-type product 141 (the direct precursor of 136) only gives
a 12 % yield in this transformation. ( )-Galanthamine (136)
was accessed from 139, debenzylation of which provided 142.
Deoxygenation of the extra phenol group of 142 was followed
by transformation of the N-formyl into an N-methyl group
(Scheme 24).[69] Analogous coupling with hypervalent iodine
(in this case, the reagent of choice was PhI(OAc)2) was used
to prepare a library of galanthamine-like molecules[70]
through biomimetic diversity-oriented synthesis. Although
the diversity step was introduced once the biomimetic
oxidative coupling was effected, the efficiency of the biomimetic coupling was beyond doubt (Scheme 24).[71]
The exquisite stereoselectivity observed in many oxidative couplings might be asserted as a certain proof of enzyme
participation. However, this selectivity may in some cases be
intrinsic to the oxidative coupling. The monomeric ellagitannins are members of the hydrolyzable tannin class of
polyphenol extractives derived from the secondary metabolism of dicotyledonous species of Angiospermae.[72] Schmidt
and Mayer[73] established that ellagitannins, which are derived
from b-PGG (143) and have hexahydroxydibenzoyl residues
at the 4,6- (e.g. 144) and 2,3-positions (e.g. 145) of the
thermodynamically more stable 4C1 glucose conformer,
almost invariably contain the S atropisomer of the biaryl
unit (Scheme 25). This hypothesis was made without knowing
the enzymology of the biosynthesis of ellagitannins. The
stereochemical outcome of the CC oxidative biaryl coupling
would be governed by the conformational preferences of the
galloylated polyol core. Less-stable conformations of the
glucose framework would allow bridging between galloyl
groups at the 3,6-, 1,6-, and 2,4-positions of the six-membered
sugar rings. However, in these cases, the stereochemistry is
Scheme 24. The oxidative approach to galathamine from norbelladine:
a 40-year-old problem. PIFA = phenyliodine(iii) bis(trifluoroacetate).
Scheme 25. The Schmidt–Mayer hypothesis for the configuration of the
biaryl moiety of monomeric ellagitannins.[73] PGG = pyrogalloyl glucose.
2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2004, 43, 160 – 181
Biomimetic Syntheses
less predictable and in some cases both atropisomers are
The synthesis of sanguiin H-5 (145) by Feldman and
Sambandan[75] was based on the hypothesis of Schmidt and
Mayer.[73] Sugar 146 was esterified with acid 147 and the
TBDMS groups of the product 148 were cleaved by treatment
with TBAF to furnish free bisphenol 149 (Scheme 26). The
oxidative coupling (Pb(OAc)4) of the phenolic rings in 149
was effected, and a mixture of the three regioisomeric
biphenyls 150–152 was obtained (Scheme 26). Notably, the
three regioisomers maintain the S stereochemistry, which
proves that the coupling was highly diastereoselective. The
free phenol groups in the mixture were benzylated and the
anomeric O-protecting group was cleaved photolytically. bSelective galloylation with galloyl chloride (153) again
furnished a regioisomeric mixture 154 as a single stereoisomer
at C1 of the glucose ring. Cleavage of the remaining
protecting groups yielded sanguiin H-5 (145). The formation
of the S atropisomer with the exclusion of its R isomer is in
full agreement with the Schmidt–Mayer hypothesis. This
example can best be concluded in the words of Feldman and
Sambandam: “Implicit in the formation of only a single
atropisomer through selective oxidation of the cyclization
precursor in vitro is that diastereoselectivity in the in vivo
oxidative process does not require enzymic intervention.
Rather, the chirality of the biphenyl CC bond may be
governed by the conformational dictates of the polyol template
in vivo as well as in vitro.”[75, 76]
To end this section, the studies carried out by Evans
et al.,[77] which resulted in the synthesis of the vancomycin
aglycon 157, are especially clarifying. Vancomycin (158) was
isolated from Amycolatopsis orientalis and is a prototype for
antibiotics that have arylglycine heptapeptide aglycons tethered with a range of sugar residues (Figure 2).[78] In spite of
the tremendous importance of this class of antibiotics, the
nature and sequence of many essential steps of their biosynthesis as well as the structure of biosynthesis intermediates
Figure 2. Vancomycin and the vancomycin aglycon.
remain unknown. In fact, it was only recently that the
sequence of cyclization steps to form the cyclic peptides was
disentangled, and the CC oxidative coupling of the biaryl
moiety was proposed as the last step of the sequence.[79]
This step was carefully studied by Evans et al.[77b] The
oxidative cyclization of tripeptides such as 159 has a clear
kinetic bias for the non-natural atropisomer 160 (Scheme 27).
The stereochemical bias is maintained in the more complex
oxidative cyclization found in the cyclization of 161 to 162
(during the synthesis of orienticin C).[80] 1,3-Strain was
claimed to be the key stereochemical control element in
these cyclizations, as the tripeptide 163, which is epimeric at
C5 with respect to 159, formed the natural atropisomeric
product 164 (Scheme 27). Hence, the thermodynamic biaryl
atropisomer bias in vancomycin should be due to the global
structure and not to stereochemical elements proximal to the
Scheme 26. Synthesis of sanguiin H-5 by Feldman and Sambandan proving the Schmidt–Mayer hypothesis.[75] TBAF = tetrabutylammonium
Angew. Chem. Int. Ed. 2004, 43, 160 – 181
2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
M. C. de la Torre and M. A. Sierra
Scheme 27. Dissection of the CC oxidative coupling of the biaryl
moiety of vancomycin-related fragments by Evans and co-workers.[77]
DCB = 3,4-dichlorobenzyl; Tfa = trifluoroacetyl.
Scheme 28. Equilibrium between natural (right) and non-natural (left)
atropisomers of vancomycin-type compounds.[77a c 81a] Piv = pivaloyl.
biaryl link. The following results support and clarify this
hypothesis: Both isomers of actinoidinic acid (165) equilibrate at 100 8C to afford a 2:1 equilibrium ratio favoring the
non-natural isomer (Scheme 28). In contrast, thermal equilibration of cyclic tripeptide 166 favors the natural isomer 167
(89:11).[77c, 81] This bias is even enhanced in the bicyclic
tetrapeptides 168 and 169.[77a]
7. Stepping Stones: Physiological-type Artificial
According to van Tamelen,[4] “biogenetic-type syntheses
are thus to be distinguished from physiological-type synthesis,
in which not only plausible bio-organic substitutes are
employed, but also specific conditions of temperature, pH,
dilution, etc., which supposedly compare to those obtaining in
a living cell are used”. In an ideal situation, the biomimetic
synthesis should equal the physiological-type synthesis. This
definition suggests that smoothness, efficiency, and elegance
are intrinsic to physiological-type synthesis. Modern organic
synthesis pursues the same goals, often mimicking neither
biogenetic pathways nor physiological conditions. The following syntheses are only two of many examples, and they
masterly combine smoothness, efficiency, and superb elegance.
2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
The synthesis of ( )-cylindrocyclophane A (170) by
Smith et al.[82] was envisaged as a dimerization of two equal
chiral moieties 171, which in turn was obtained from iodide
172 by reaction with the alkoxide derived from the Myers
amide 173, reduction with (+)-DIPCl, and subsequent
silylation (Scheme 29). Compound 171 was submitted to
metathesis by using the Schrock catalyst 174 to furnish the
desired [7,7]-paracyclophane 175 as a single isomer in high
yield. Desilylation and hydrogenation produced the tetramethylated derivative of ( )-cylindrocyclophane A. Relatively
harsh reaction conditions were required to cleave the
methoxy groups (PhSH, K2CO3, 215 8C). The unexpected
efficiency and selectivity in the dimerization reactions suggested that the [7,7]-paracyclophane skeleton is the thermodynamically more favored isomer. Therefore, a cascade of
reversible olefin metatheses drives the reaction toward the
formation of this compound.
One could get the wrong impression that only the
thermodynamically favored products can be accessed in a
physiological-like artificial synthesis. During the synthesis of
the ABCD ring system 176[83a] of azaspiracid (177), Nicolaou
et al.[83] were confronted with problem that the unfavorable
anomeric effects would lead to the favored epimer, (13S)-178,
rather than to the natural product (13R)-179 (Scheme 30).
The mimetic formation of the ABCD azaspiracid core was
achieved by the one-pot cyclization of ketotriol 180, which
Angew. Chem. Int. Ed. 2004, 43, 160 – 181
Biomimetic Syntheses
Scheme 29. Synthesis of ( )-cylindrocyclophane A by Smith et al.[82] DIPCl b-chlorodiisopinocampheylborane;TES = triethylsilyl.
was generated in situ from 181. The product 182
had, in fact, the wrong configuration at C13.
However, it was reasoned that an equatorial free
hydroxy group at C9 might invert the non-natural
13S configuration 182 to the natural 13R isomer by
the effect of its hydrogen bonding, which would
overcome the unfavorable anomeric effects. Thus,
the hydroxy group was constructed from the
masked carbonyl group on 182. Treatment of 184
with acid smoothly epimerized the C13 center to
form the desired epimer (13R)-176 in 56 % yield.
The two examples above resemble physiological conditions but neither is a biomimetic synthesis. The [7,7]-paracyclophane skeleton of cylindrocyclophane A (170) has been proposed to be
biogenetically formed by dimerization of two
identical resorcinol fragments, presumably involving electrophilic aromatic substitution, with an
appropriate alkene side chain.[84] No biogenetic
hypothesis for the formation of azaspiracid has
been reported to the best of our knowledge.
8. Conclusions and Outlook
Scheme 30. Preparation of the ABCD ring system of azaspiracid by Nicolaou and
co-workers.[83a] NBS = N-bromosuccinimide.
Angew. Chem. Int. Ed. 2004, 43, 160 – 181
A biomimetic synthesis can be defined as the
successful synthesis of a natural product by mimicking a proposed biological pathway. As the
proposed biological pathway often parallels analogous organic processes, without further biochemical support, it is not surprising that such biomimetic syntheses are successful.
Which biogenetic processes are most likely to
be mimicked successfully? The initial idea of
2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
M. C. de la Torre and M. A. Sierra
Robinson that organisms produce few very reactive starting
materials stands against the theory of evolution of enzymatic
processes for the many natural products known. It is difficult
to believe that specific enzymes have evolved to produce a
specific transformation in a specific substrate that is usually
produced in minute amounts. The enormous amount of
secondary metabolites and their unimaginable structural
diversity would make the number of enzymes involved in
their production astronomical. Of course the intervention of
multivalent and multifunctional enzymes, which are yet to be
discovered, can always be proposed. These enzymes would
have to be ubiquitous (and evasive), as is the distribution of
secondary metabolites.[85]
The rules of the game are the same for cells as for the
people working in the laboratory.[86] Hence, the lesson we can
learn from biomimetic synthesis is that both ideas can be the
extremes of the same process. The hypothesis of “minimum
enzymatic participation” in the production of secondary
metabolites could be the key. We have seen that a biomimetic
synthesis is more likely to be successful if the involvement of
enzymes in the mimicked processes is low. Once the enzyme
initiates the biogenetic process, the resulting initial substrate
has the structural requirements for the subsequent reactions,
and the biosynthetic process proceeds without further
involvement of the enzyme. Additional maturation of the
metabolite may occur after that, with the participation of
enzymes with a wide range of activities, as proposed by
In this way, we can learn from biomimetic synthesis which
steps are biogenetically non-enzymatic; such steps are fully
reproducible because the reactivity of the substrate is intrinsic
to its structure. Steps that require the intervention of external
reagents to mimic the enzyme (for example, a chiral Lewis
acid or a specific oxidant) would suggest an enzymatic
process. The use of artificial enzymes designed to achieve
specific transformations together with the use of the new
technologies of surface- and micelle-directed synthesis[87] will
probably lead to improved mimetic syntheses inspired by
biogenetic processes.
Support for this work under grant BQU2001-1283 from the
Ministerio de Ciencia y Tecnologa (Spain) is gratefully
acknowledged. We are indebted to Prof. Mar GHmez-Gallego
and Dr. Mara JosJ MancheKo (UCM) for continuous valued
help, many valuable suggestions, and for patiently correcting
the manuscript. We are grateful to Prof. Benjamn Rodrguez
(CSIC), who, despite our different opinions, shared his
invaluable knowledge about the chemistry of natural products.
We thank Prof. R. M. Williams (Colorado State University) for
kindly providing us with a copy of his review before
publication. We also thank the reviewers of this Review for
their invaluable critical discussions and suggestions.
[1] D. Skyler, C. H. Heathcock, Org. Lett. 2001, 3, 4323 – 4324.
[2] For selected reviews on the biomimetic synthesis some families
of natural products, see: a) U. Scholz, E. Winterfeldt, Nat. Prod.
2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Received: July 24, 2002 [A545]
Rep. 2000, 17, 349 – 366; b) C. H. Heathcock, Angew. Chem.
1992, 104, 675; Angew. Chem. Int. Ed. Engl. 1992, 31, 665 – 681;
c) E. Magnier, Y. Langlois, Tetrahedron 1998, 54, 6201 – 6258;
d) M. Arend, B. Westermann, N. Risch, Angew. Chem. 1998, 110,
1096 – 1122; Angew. Chem. Int. Ed. 1998, 37, 1044 – 1070.
a) R. Robinson, J. Chem. Soc. 1917, 111, 762 – 768; b) R.
Robinson, J. Chem. Soc. 1917, 111, 876 – 899; for additional
early seminal work on “model experiments on the question of
biogenesis of natural products”, see: c) C. SchOpf, H. Bayerle,
Justus Liebigs Ann. Chem. 1934, 513, 190 – 202; d) C. SchOpf, G.
Lehmann, Justus Liebigs Ann. Chem. 1935, 518, 1 – 37; e) C.
SchOpf, F. Oechler, Justus Liebigs Ann. Chem. 1936, 523, 1 – 29;
f) C. SchOpf, K. Thierfelder, Justus Liebigs Ann. Chem. 1935,
518, 127 – 155, and references therein; for a detailed discussion
of this topic, see: g) K. W. Bentley, Nat. Prod. Rep. 1987, 4, 13 –
E. E. van Tamelen, Fortschr. Chem. Org. Naturst. 1961, 19, 242 –
Strictly speaking, van Tamelen used the term biogenetic-type
synthesis to describe an organic synthesis that follow, at least in
its major aspects, biosynthetic pathways that have been proved
proved or presumed to be used in the natural construction of the
end product.; see reference [4], p. 245.
a) K. Krohn, N. BOker, U. FlOrke, C. Freund, J. Org. Chem. 1997,
62, 2350 – 2356; see also: b) K. Krohn, U. FlOrke, C. Freund, N.
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2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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