A Diels-Alder macrocyclization enables an efficient asymmetric synthesis of the antibacterial natural product abyssomicin C

Article abstract of DOI:10.1002/anie.200502119

An efficient and highly diastereoselective intramolecular Diels-Alder reaction is the basis of a concise asymmetric synthesis of the potent antibacterial natural product abyssomicin C (see formula). The complexity of the target structure was reduced to three fragments and required two carbonyl addition reactions to achieve key bond formations. (Figure Presented).

Full text of DOI:10.1002/anie.200502119

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the syntheses of “complex compounds related to or identical
with natural products” and speculated that this process may
also be involved in the biosyntheses of natural products.[1] As
the premier method for the construction of functionalized and
stereochemically complex six-membered-ring systems,[2] the
Diels–Alder reaction is the foundation of some of the most
important achievements in chemical synthesis, and the ques-
tion concerning its relevance in biosynthesis is the subject of
much active research.[3] There is a wealth of natural products
that could conceivably arise from biosyntheses that feature
the Diels–Alder reaction.[4] We reasoned that much of the
architectural complexity of the polycyclic marine natural
product abyssomicin C (1) could arise from a Diels–Alder
macrocyclization step and were intrigued by the possibility
that such a transformation may also occur in the biogenesis of
this natural product.
Süssmuth and co-workers recently described the isolation
of abyssomicin C and two related compounds from a sedi-
ment sample collected 289 m beneath the surface of the Sea of
Japan.[5] These natural products are produced by the rare
actinomycete Verrucosispora and possess complex polyke-
tide-like structures that were elucidated through extensive
NMR spectroscopic studies and an X-ray crystallographic
analysis. Abyssomicin C is unique within this new class of
marine natural product in its ability to inhibit Gram-positive
bacteria, including pathogenic methicillin-resistant and van-
comycin-resistant Staphylococcus aureus strains.[5,6] Although
its biomolecular target in bacteria is not yet known, abysso-
micin C blocks the conversion of chorismate to para-amino-
benzoic acid (pABA) and is thus an early-stage inhibitor of
the biosynthesis of tetrahydrofolate (Scheme 1).
Inhibitors of the biosynthesis of pABA are highly
attractive as potential antibacterial drugs because pABA is
produced in many microorganisms but not in humans. As the
first bacterial metabolite that inhibits the biosynthesis of
pABA, abyssomicin C is an attractive lead structure for the
development of new inhibitors of pathogenic bacteria and a
compelling objective for research in chemical synthesis.[7]
Herein, we describe a remarkably diastereoselective Diels–
Alder macrocyclization in the context of a convergent
asymmetric synthesis of (ꢀ)-abyssomicin C (1). Our preferred
design reduced the complexity of the target structure to three
fragments and called for two carbonyl addition reactions to
achieve key bond formations (Scheme 2).
In this scenario, an intermolecular aldol reaction between
the hypothetical ketone enolate 2 and commercially available
trans,trans-2,4-hexadienal (3) would be followed by the
addition of a lithiated tetronate 4 to an aldehyde carbonyl
group. A simple adjustment of the oxidation state would then
furnish the needed g-methylene-b-tetronate derivative 5 for
the crucial intramolecular Diels–Alder step.[8] Some impres-
sive large-ring formations that were achieved by the Diels–
Alder method[9] bolstered our confidence in the idea that 5
might cycloisomerize to tricycle 6. If successful, this trans-
formation would establish a substantial portion of the
architecture of abyssomicin C and afford a valuable cyclo-
hexenyl double bond for a late-stage epoxidation reaction.
Provided that such an oxidation reaction could be achieved in
a site- and diastereoselective fashion, we hoped to form the
Natural Product Synthesis
DOI: 10.1002/anie.200502119
A Diels–Alder Macrocyclization Enables an
Efficient Asymmetric Synthesis of the
Antibacterial Natural Product Abyssomicin C**
Christoph W. Zapf, Bryce A. Harrison, Carmen Drahl,
and Erik J. Sorensen*
In memory of Murray Goodman
In their pioneering report on the diene synthesis, or the Diels–
Alder reaction, Otto Diels and Kurt Alder recognized the
profound impact that this pericyclic reaction would have in
[*] Dr. C. W. Zapf, Dr. B. A. Harrison, C. Drahl, Prof. Dr. E. J. Sorensen
Department of Chemistry
Princeton University
Princeton, NJ 08544-1009 (USA)
Fax: (+1)609-258-1980
E-mail: ejs@princeton.edu
[**] This work was supported by Princeton University, a Bristol-Myers
Squibb unrestricted research grant in synthetic organic chemistry
(E.J.S.), the NationalInstitute of GeneralMedicalSciences
(GM065483), Merck Research Laboratories (E.J.S.), a NRSA
fellowship (1F32GM070235) from the National Institutes of Health
(USA; B.A.H.), and a NationalScience Foundation (USA) Predoc-
toral Fellowship (C.D.). We thank Prof. Robert Pascal, Jr. for the
conformationalanaylsis of compound 5 and Dr. Istvµn Pelczer for
assistance with the NMR spectroscopic analysis.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Scheme 1. The marine naturalproduct abyssomicin C ( 1) inhibits the conversion of chorismate into para-aminobenzoic acid (pABA).
ADC=aminodeoxychorismate.[6]
an acid-catalyzed lactonization to 10, a known substance[12]
that was judged to have an optical purity of 93% ee by HPLC
analysis. The action of methyllithium on lactone 10 gave the
corresponding lactol, after which a simple alcohol silylation
step caused ring-opening and afforded methyl ketone 11.
Our aim was to utilize 11 in an intermolecular aldol
addition reaction with 3. The commercially obtained dienal 3
is admixed with as much as 10mol% of the 4-cis geometrical
isomer, so we opted to produce this compound from all-trans
2,4-hexadien-1-ol through a Swern oxidation.[13] Aldehyde 3,
prepared in this manner, was taken forward into the key aldol
step in crude form. Under the reaction conditions shown, 3
joined efficiently with the kinetic lithium enolate derived
from 11, thus resulting in the formation of a 1:1 mixture of
secondary alcohol epimers. A straightforward alcohol silyla-
tion step then gave a diastereoisomeric mixture of silyl ethers,
shown as 12. Our intent was to unveil the sensitive triene
array of the targeted Diels–Alder substrate immediately
before (or perhaps during) the key cycloaddition event
through a simple b elimination. Therefore, the production of
epimers in the aldol construction of 12 was ultimately
inconsequential.
Scheme 2. Design for a synthesis of abyssomicin C which features a
Diels–Alder macrocyclization.
It was pleasing to discover that the triethylsilyl ether in 12
could be directly transformed to keto aldehyde 13 by a Swern
oxidation.[14] Our expectation that this electrophilic com-
pound would react chemoselectively with organolithium
reagent 4, the conjugate base derived from the known
methyl tetronate 14,[15] was justified by the construction of
intermediate 15 under the conditions shown. This reaction,
which established a key carbon–carbon bond and afforded
material that contains all of the carbon atoms of abyssomi-
cin C, can be performed on gram scales, although its yield is
typically modest and variable (e.g., 35–55%).[16] This alde-
hyde addition process also yielded a mixture of alcohol
diastereoisomers that could be resolved by chromatography
on silica gel. However, it was our custom to convert this
mixture of four diastereoisomers into two through an alcohol
oxidation with the Dess–Martin periodinane reagent.[17] This
oxidation proceeded efficiently and yielded the desired acyl
tetronate 16.
rigid oxabicyclo[2.2.2]octane substructure of 1 b y atrans-
diaxial opening of the epoxide by a tetronic acid function that
would be exposed by demethylation. The successful execution
of this general plan is described below.
Because of the symmetrical nature of the hypothetical
species 2, meso-2,4-dimethylglutaric anhydride (7) was con-
sidered to be an ideal starting material for our synthesis
(Scheme 3). This substance was prepared on a 100-gram scale
by a combination of the procedures developed by Paquette
and Boulet[10] and Lautens and co-workers[11] and was
subsequently advanced to the known prochiral dimethyl
ester 8 in the straightforward fashion shown. The enzymatic
desymmetrization procedure of Lautens and co-workers,
which had previously been applied to the acyclic meso-diester
8,[11] provided a smooth high-yielding route to the optically
active monocarboxylic acid 9. A chemoselective reduction of
the ester function with lithium borohydride was followed by
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Scheme 3. a) MeOH, reflux, 24 h; b) MeOH, H2SO4 (cat.), benzene, reflux, 18 h (87%, 2 steps); c) a-chymotrypsin, phosphate buffer pH 7.8,
238C, 4 days (96%); d) LiBH4 (2 equiv), THF, 508C, 5 h; then HCl, H2O, 238C, 15 h (60%, 93% ee); e) MeLi (1.3 equiv), THF, ꢀ788C, 1.5 h;
f) TESCl(1.1 equiv), imidazoel (2 equiv), DMF, 0 8C, 1.5 h (79%, 2 steps); g) LDA, THF, ꢀ788C, 2.5 h; then trans,trans-2,4-hexadienal(1.1 equiv),
1.5 h (94%, d.r. =1:1); h) TBSOTf (1 equiv), 2,6-lutidine (2 equiv), CH2Cl2, 08C, 0.5 h (85%); i) (COCl)2 (5 equiv), DMSO (10 equiv), Et3N
(10 equiv), CH2Cl2, ꢀ40!ꢀ788C, 5 h (60–70%); j) LDA, toluene, ꢀ788C, 6 min; then aldehyde 13, 1.5 h (35–55%, d.r.=1:1); k) DMP (1.5 equiv),
CH2Cl2, 0!238C, 1.5 h (84%). TES=triethylsilyl, TBS=tert-butyldimethylsilyl, Tf=trifluoromethanesulfonyl, DMF=N,N-dimethylformamide,
DMSO=dimethylsufloxide, LDA =lithium diisopropylamide, DMP=Dess–Martin periodinane.
The decision to utilize a b-tert-butyldimethylsilyloxy keto
function as a progenitor to the required trienone array proved
to be well founded. Preliminary observa-
tions indicated that trienone 5 is a rather
unstable substance. Fortunately, we could
generate this compound upon exposure of
a solution of intermediate 16 in dichloro-
methane to 5 mol% of the Lewis acid
scandium(iii) triflate (Scheme 4). Much to
our delight, the crude trienone 5 under-
went a remarkably efficient and highly
diastereoselective cycloisomerization to
tricycle 6 when heated to 1008C in tolu-
ene. To avoid handling the sensitive trien-
one 5, we searched for reaction conditions
that would permit the b-elimination/
Diels–Alder sequence to be conducted in
a one-pot process. We hoped to find a
Lewis acid catalyst that would effect the
required elimination of tert-butyldimethyl-
silanol on heating and that this event
would trigger the desired Diels–Alder
cyclization of the intermediate trienone 5
to 6. Among the metal triflates that were
examined, lanthanum(iii) triflate was
capable of inducing the direct conversion
of 16 into tricycle 6 under the conditions
shown. This transformation was also
into this interesting and fortunate selectivity, we located the
transition states for all of the possible intramolecular Diels–
highly diastereoselective;
6
formed
Scheme 4. a) Sc(OTf)3 (5 mol%), CH2Cl2, 08C, 40 min (65%); b) toluene, 1008C, 4 h (79%); c) [La-
(OTf)3] (10 mol%), toluene, 100 8C, 4 h (50%); d) DMDO (1 equiv), acetone, 0!238C, 18 h (67%);
cleanly, and we did not observe any other
regioisomeric or diastereoisomeric cyclo-
adducts. In an effort to gain some insight
e) LiCl(10 equiv), DMSO, 50 8C, 2 h (quant.); f) p-TsOH (1.2 equiv), LiCl(5 equiv), CH CN, 508C, 2 h
3
(50%). DMDO=dimethyldioxirane, p-TsOH=para-toluenesulfonic acid monohydrate.
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Alder reactions at the HF/3-21G level of theory.[18] The
lowest-energy transition-state conformation clearly resem-
bled 17, and the next lowest transition-state conformation was
5.7 kcalmolꢀ1 higher in energy. This analysis predicts that 5
should cycloisomerize through conformer 17, an asynchro-
nous transition state that has an anti relationship between the
two carbonyl groups that are part of the acyl tetronate moiety.
From the vantage of 6, only three seemingly straightfor-
ward transformations were needed to reach the target
structure. Fortunately, dimethyldioxirane was well suited to
the oxidation of the newly formed cyclohexenyl double
bond.[19] This site- and diastereoselective oxidation produced
the desired epoxide and was followed by a quantitative
nucleophilic demethylation of the acyl methyl tetronate
substructure. This two-step reaction sequence afforded 18, a
compound that appeared to be an ideal precursor to
abyssomicin C (1). Because of its carboxylic acid like
nature, the hydroxy group in 18 is a weak nucleophile.
Compound 18 is essentially impervious to basic reagents; all
efforts to achieve base-induced heterocyclizations to abysso-
micin C were unsuccessful. After much experimentation, we
found that warming a solution of 18, para-toluenesulfonic acid
monohydrate, and lithium chloride in acetonitrile to 508C for
2 h resulted in the formation of abyssomicin C (1) and a
regioisomeric substance that we named “iso-abyssomicin C”.
Under these conditions, the ratio of these two compounds is
1:1, but they are readily separated by chromatography on
silica gel. Optical rotation studies of our sample of synthetic
abyssomicin C (1) showed an [a]2D0 value of ꢀ40 (c = 0.1,
MeOH), and spectroscopic studies (1H and 13C NMR, UV,
and IR) resulted in data that matched those reported by
Süssmuth and co-workers.[5]
In summary, a concise enantioselective synthesis of (ꢀ)-
abyssomicin C was achieved in 15 steps from the known
meso-2,4-glutaric anhydride (7) by a reaction sequence that
features a highly diastereoselective Diels–Alder macrocycli-
zation. We can procure significant amounts of the natural
product by this route, which should facilitate an investigation
of the intriguing biological properties of abyssomicin C. It was
proposed that the rigid oxabicyclo[2.2.2]octane substructure
of abyssomicin C (1) may serve as a structural surrogate for
the conformation of chorismate in solution and that its
electrophilic enone system may inactivate one of the enzymes
involved in the biosynthesis of pABA in bacteria (Scheme 1)
through covalent alkylation.[5] By adapting the chemistry
described herein, we anticipate that it will be possible to
synthesize affinity-tagged variants of abyssomicin C for
studies of its potential chemical reactivity and binding
properties in human-tissue proteomes.[20,21] This information
would be part of a comprehensive analysis of the potential of
abyssomicin C as an antibacterial drug candidate. Further
studies of this fascinating early-stage inhibitor of the biosyn-
thesis of tetrahydrofolate in bacteria are clearly warranted.
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Received: June 17, 2005
Published online: September 15, 2005
Keywords: desymmetrization · Diels–Alder reaction · enzymes ·
.
naturalproducts
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