Total synthesis of (-)-atrop-abyssomicin C

Article abstract of DOI:10.1002/anie.201108223

Rolling in the deep: An enantioselective synthesis of a marine antibiotic (-)-atrop-abyssomicin C (see scheme) is described. The key steps of the synthetic sequence are the application of dual catalysis in the formation of the cyclohexane core, the gold-catalyzed formation of a tricyclic spirotetronate unit, and a highly efficient eleven-membered ring closure by a Nozaki-Hiyama-Kishi reaction. Copyright

Full text of DOI:10.1002/anie.201108223

Angewandte
Chemie
DOI: 10.1002/anie.201108223
Natural Product Synthesis
Total Synthesis of (ꢀ)-atrop-Abyssomicin C**
Filip Bihelovic* and Radomir N. Saicic*
In 2004, Sꢀssmuth and co-workers reported the isolation of
abyssomicin C,[1] a naturally occurring antibiotic[2] of exotic
origin and complex structure. The mechanism of antibiotic
activity of abyssomicin C against Gram-positive bacteria,
including methycillin- and vancomycin-resistant Staphylococ-
cus aureus strains, was unprecedented: it inhibits tetrahydro-
folate biosynthesis at an early stage.[3] In addition to
abyssomicin C, several other congeners have been found in
both marine and terrestrial Streptomyces strains
(Scheme 1).[4] The combination of strong antibacterial activity
(Scheme 2) that would facilitate the synthesis of analogues
not accessible through an intramolecular epoxide ring open-
ing reaction. The eleven-membered ring could be discon-
Scheme 1. Some members of the abyssomicin family.
and complex molecular architecture made abyssomicin C an
attractive synthetic target.[5] Two total syntheses,[6,7] one
formal synthesis[8] and several synthetic studies[9] have been
reported. The common feature of all reported efforts is the
recognition that the central cyclohexane core can be con-
structed through a Diels–Alder reaction. Another pivotal
step, the formation of the oxygen bridge, has been invariably
performed by an intramolecular epoxide ring opening reac-
tion with a tetronate nucleophile, in a presumed biomimetic
fashion. An interesting structural insight was disclosed by
Nicolaou: the restricted rotation around one of the bonds in
the eleven-membered ring gives rise to atropisomerism.[7] The
compound named atrop-abyssomicin C turned out to be
a genuine secondary metabolite and the most active bacteri-
cide among its congeners, whereas the initially described
abyssomicin C derives from atrop-abyssomicin C.
Scheme 2. Retrosynthetic analysis of abyssomicin C. Bn=benzyl,
PG=protecting group.
nected by a combination of a Nozaki–Hiyama–Kishi coupling
and an organometallic addition, to give the key tricyclic
intermediate 1. We planned to create 1 by the nucleophilic
attack of a b-hydroxy group onto a tetronate motif, instead of
the alternative route involving ring opening of an epoxide by
the tetronate. We anticipated that this step would be
challenging, perhaps requiring the development of some
new chemistry. Retrosynthetic simplification of spirotetro-
nate 2 based on a Dieckmann condensation and stereoselec-
tive oxidation of the enolate led to ester 3, which is in turn
obtainable by the cyclization of precursor 4. The three
contiguous stereocenters in this intermediate would be
installed by an aldol reaction: whereas the absolute stereo-
chemistry of the oxygen-bearing carbon atoms would be
established in a reagent-controlled addition of Evans oxazo-
lidinone 5, the stereocenter bearing a methyl group would
originate from (ꢀ)-(R)-norcitronellal (6).
We set out to develop an enantioselective synthesis of
atrop-abyssomicin C based on an alternative strategy
[*] Dr. F. Bihelovic, Prof. Dr. R. N. Saicic
Faculty of Chemistry, University of Belgrade
Studentski trg 16, POB 51, 11158 Belgrade 118 (Serbia)
E-mail: filip@chem.bg.ac.rs
rsaicic@chem.bg.ac.rs
[**] Support from the Ministry of science and technological develop-
ment is acknowledged (Project No. 172027). We are grateful to Prof.
Vladimir Divjakovic (University of Novi Sad) for performing
X-ray structural analysis, and to Prof. Milan Stojanovic (Columbia
University) for helpful discussions.
The synthesis encompasses three main stages: 1) forma-
tion of the cyclohexane core 3 with all stereocenters installed;
2) formation of the tricyclic core 1; and 3) attachment of the
side chain and completion of the synthesis. The realization of
the first goal (Scheme 3) commenced with a boron enolate
mediated enantioselective aldol addition of a-benzyloxy-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201108223.
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cyclization precursor 12. Initially, the cyclization was planned
via an ester enolate but surprisingly, this reaction failed under
a variety of reaction conditions, even after modification of the
protecting groups in the molecule. Aldehyde 12 also did not
cyclize under previously described reaction conditions.[14]
Therefore, a new cyclization method was developed;[15] this
method was based upon the concept of dual catalysis,[16] that is
the combination of organotransition metal catalysis and
organocatalysis.[17] Thus, when submitted to the conditions
of the organocatalyzed Tsuji–Trost cyclization, that is when
treated with catalytic amounts of [(Ph3P)4Pd] and pyrrolidine,
aldehyde 12 was smoothly converted into cyclohexane
carbaldehyde derivative 13 (83% over three steps). The
assignment of the structure of 13 in our previous papers was
ambiguous and therefore aldehyde 13 was converted into the
corresponding methyl ester, the structure of which was
unambiguously confirmed by a single crystal X-ray diffraction
analysis (see Ref. [18]).
The planned elaboration of spirotetronate 2 via the a-
hydroxyaldehyde derived from 13 had to be abandoned:
a hydroxylation of 13 could not be performed stereoselec-
tively, and the hydroxylated product was prone to side
reactions.[18] Evidently, a modification of the approach was
necessary: a three-carbon unit that would constitute the
tetronate substructure had to be stereoselectively introduced
by a nucleophilic addition to cyclohexanone 15. To this end,
13 was first converted into silyl enolether 14, which was
converted into cyclohexanone derivative 15 using the afore-
mentioned two-step procedure (87% overall yield). The best
yield of propargylic derivative 16 was obtained by the
addition of the lithium anion of ethyl orthopropiolate to
a solution of 15 in toluene. Although 16 could undergo
cyclization to give spirotetronate 17, all attempts to convert 17
into tricyclic ether 19 failed. In retrospect, this failure was not
surprising, given that an extremely unfavorable distorted
conformation of the rigid spirobicycle is required in transition
state 18 for the intramolecular hetero-Michael addition (i.e.
to allow the approach of the hydroxy group to the alkene
acceptor at a Bꢀrgi–Dunitz angle of 1058). Therefore,
a change in the order of the steps was required, namely the
intramolecular etherification had to be performed on a
conformationally more flexible alkyne derivative, prior to
the spirotetronate formation.
For this purpose, we turned our attention to gold
complexes,[19] which are known to be efficient promoters of
nucleophilic additions to carbon–carbon multiple bonds. The
treatment of alkyne 20 with AuCl3, in the presence or absence
of silver triflate, gave no reaction, and therefore we resorted
to using the highly active AuI catalyst that was described by
Gagosz and co-workers.[20] The treatment of a solution of
alkyne 20 in THF with Gagoszꢁs gold catalyst resulted in no
reaction, but when a dichloromethane solution of the mixture
was heated to 1208C bicyclic ether 21 was obtained
(Scheme 4).[27] This result was encouraging, as the putative
mechanism of formation of ether 21 might involve the initial
formation of the desired bicyclic ether intermediate, and its
subsequent rearrangement. After a screen of solvents and
reaction conditions, we found that the intramolecular ether-
ification could be effected by heating a solution of alkyne 20
Scheme 3. Formation of the functionalized cyclohexane core:
a) nBu2BOTf, Et3N, CH2Cl2, ꢀ788C; then H2O2, MeOH, phosphate
buffer (77%; 90% based on the recovered starting material);
b) TBDMSOTf, sym-collidine, CH2Cl2, 08C (99%); c) NaBH4, THF, H2O
=
(86%); d) DMP, CH2Cl2, RT, then Ph3P CHCO2Et (82%); e) DIBAL-H,
Et2O, ꢀ408C (85%); f) CBr4, Ph3P, CH2Cl2, 08C (95%); g) mCPBA,
CH2Cl2, RT; h) H5IO6, Et2O; i) [Pd(PPh3)4], pyrrolidine, THF, RT (83%,
3 steps, from 11); j) TIPSOTf, Et3N, CH2Cl2, reflux (99%); k) mCPBA,
CH2Cl2; then H5IO6, Et2O (87%); l) LDA, 3,3,3-triethoxyprop-1-yne,
PhMe; then ketone 15 (88%); m) Nafion-Hg, MeOH, H2O (92%);
then: HF, MeCN, 608C (84%). DIBAL-H=diisobutylaluminum hy-
dride, DMP=Dess–Martin periodinane, L=ligand, LDA=lithium
diisopropylamide, mCPBA=meta-chloroperoxybenzoic acid,
TBDMS=tert-butyldimethylsilyl, Tf=trifluoromethanesulfonyl,
TIPS=triisopropylsilyl.
acetyloxazolidinone 7[10] to (R)-norcitronellal (6),[11] which
furnished the expected adduct 8 in 77% yield, as a single
diastereoisomer. Silylation of the secondary hydroxy group,[12]
followed by reductive removal of the oxazolidinone auxiliary
with sodium borohydride afforded alcohol 9, which upon
homologation by a one-pot procedure involving DMP-
mediated oxidation and Wittig olefination gave conjugated
ester 10.[13] To transform the conjugated ester into a leaving
group, ester 10 was reduced with DIBAL, and the resulting
alcohol converted into allylic bromide 11 with PPh3/CBr4
(81% over two steps). Selective oxidative cleavage of the
isopropylidene group in 11 revealed the proenolate part of the
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Scheme 4. Gold-catalyzed formation of the key intermediate 19: a) HF,
MeCN, 608C (85%); b) [(PPh3)AuNTf2] (10 mol%), CH2Cl2, 1208C
(68%); c) [(PPh3)AuNTf2] (10 mol%), iPrOH, 708C; then hv (254 nm),
iPrONa (60%).
and a catalytic amount of [(PPh3)AuNTf2] in isopropanol.
However, the reaction produced the Z isomer of 22, (Z)-22,
while the E isomer of 22, (E)-22, was required for the
synthesis of spirotetronate 19. Isomerization of (Z)-22 could
be effected by irradiation with UV light in a quartz vessel, and
the E isomer cyclized to give spirotetronate when treated with
sodium hydride. After further experimentation, we found that
this three-step transformation could be accomplished much
more efficiently as a one-pot sequence, which involved the
initial heating of alkyne 20 in the presence of Gagoszꢁs gold
catalyst, followed by irradiation in the presence of a catalytic
amount of sodium isopropoxide. In this way, although (Z)-22
predominated in the photostationary state, it was converted
via (E)-22 into tetronate 19, thus shifting the Z/E equilibrium
and obviating the separation of isomers and recycling, and
affording tricyclic tetronate 19 in a 60% overall yield.
With the key intermediate 19 in hand, the stage was set for
investigating the attachment of the side chain and completion
of the synthesis (Scheme 5). Aldehyde 23 was obtained in
optically pure form, from cis-2,4-dimethylglutaranhydride,[21]
according to the literature procedure.[22] Treatment of 23 with
lithiated 19, followed by quenching the reaction with me-
thoxymethyl bromide, gave protected allylic alcohol 24 as
a mixture of diastereoisomers. The vinyl group was trans-
formed into an aldehyde to give 25; correction of the
stereochemistry of the aldehyde-bearing stereocenter was
accomplished through base-catalyzed epimerization. These
two steps were best accomplished as a one-pot procedure,
comprising ozonolysis, followed by the addition of a catalytic
amount of DBU; this procedure provided the required
aldehyde 25 as a single diastereoisomer in 81% overall
yield. Takai olefination of aldehyde 25[23] gave vinyl iodide 26
and deprotection of the primary hydroxy group with a sub-
sequent oxidation using DMP gave the precursor for macro-
cyclization, aldehyde 27. The intramolecular Nozaki–
Hiyama–Kishi reaction proceeded smoothly,[24] to afford
Scheme 5. Attachment of the side chain and completion of the
synthesis: a) tBuLi, THF, ꢀ788C; then aldehyde 23, ꢀ788C to ꢀ408C;
then MOMBr, ꢀ408C to ꢀ258C (44%; 79% based on recovered 19);
b) O3, CH2Cl2, ꢀ788C; then Me2S; then DBU (30 mol%) (81%);
c) CrCl2, CHI3, THF, RT to 508C (71%); d) HCl, MeOH (94%);
e) DMP, CH2Cl2, RT (88%); f) CrCl2, NiCl2, DMF, RT to 458C (90%;
96% based on recovered material); g) HClaq, MeOH, RT; then DMP,
CH2Cl2 (78%); h) H2, Pd/C, EtOAc; i) BBr3, CH2Cl2, RT (81%).
DBU=1,8-diazabicyclo[5.4.0]undec-7-ene, DMF=dimethylformamide,
MOM=methoxymethyl.
tetracyclic intermediate 28 in 90% yield (96% calculated
on the basis of recovered aldehyde 27), as a mixture of four
diastereoisomers.[25] Removal of the MOM ether in 28 was
accomplished with methanolic hydrogen chloride. The crude
diol was converted into diketone 29 in 78% yield by
treatment with freshly prepared DMP.[26] The NOESY
spectrum of this compound showed correlations correspond-
ing to the atrop-abyssomicin structure. An attempt to cleave
the benzyl group in diketone 29 by hydrogenolysis resulted in
concomitant reduction of the alkene and the formation of
abyssomicin H. After some experimentation, the final depro-
tection step was accomplished by treatment of diketone 29
with boron tribromide at room temperature. This provided
atrop-abyssomicin C identical to the natural product in all
respects.
To summarize, an enantioselective synthesis of (ꢀ)-atrop-
abyssomicin C was accomplished by a route that should allow
us to prepare analogues for further structure–activity rela-
tionship (SAR) studies. The key features of the synthesis are
the application of dual catalysis for the formation of the
cyclohexane core (12!13), the gold-promoted reaction
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an error, the correct configuration is S, and the aldol reaction
follows the normal stereochemical course, as expected for Evans
oxazolidinones (from a personal communication with Prof. M. T.
Crimmins).
cascade leading to the one-pot spirotetronate formation
(20!19), and the remarkably efficient eleven-membered
ring closure by the Nozaki–Hiyama–Kishi reaction (27!28).
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[18] Detailed analysis of the NMR spectra of 13 and their comparison
with the NMR spectra of the methyl ester 30, for which the
single-crystal X-ray diffraction was obtained, revealed that
cyclohexane derivatives of type 13 (with protected or free
hydroxy groups) assume the unexpected, chair-like conforma-
tion with the oxygen substituents in the axial positions. Thus,
these compounds have a pronounced stereochemical bias and
exert a substrate control in their reactions, which cannot be
overridden by the reagent.
Received: November 22, 2011
Revised: March 5, 2012
Published online: && &&, &&&&
Keywords: antibiotics · cyclization · gold · natural products ·
.
total synthesis
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4
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[27] The
putative
mechanism
of
formation
of
21:
a) [(PPh3)AuNTf2] (10 mol%), CH2Cl2, 1208C.
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7278.
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Communications
Natural Product Synthesis
Rolling in the deep: An enantioselective
synthesis of a marine antibiotic (ꢀ)-
atrop-abyssomicin C (see scheme) is de-
scribed. The key steps of the synthetic
sequence are the application of dual
catalysis in the formation of the cyclo-
hexane core, the gold-catalyzed formation
of a tricyclic spirotetronate unit, and
a highly efficient eleven-membered ring
closure by a Nozaki–Hiyama–Kishi reac-
tion.
F. Bihelovic,*
R. N. Saicic*
&&&& — &&&&
Total Synthesis of (ꢀ)-atrop-
Abyssomicin C
6
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These are not the final page numbers!