Total synthesis and biological evaluation of (-)-atrop-abyssomicin C

Article abstract of DOI:10.1039/c3ob40692j

Enantioselective synthesis of a marine antibiotic (-)-atrop-abyssomicin C was accomplished in 21 steps, in 1.8% overall yield (4%, based on the recovered starting material). The key steps of the synthesis are the formation of the functionalized cyclohexane core by an organocatalyzed Tsuji-Trost reaction, the formation of a tricyclic spirotetronate unit by a gold-catalyzed reaction sequence and the highly efficient eleven-membered ring closure by a Nozaki-Hiyama-Kishi reaction. Biological tests showed all abyssomicin derivatives to possess strong antibacterial activity against methicillin resistant S. aureus strains; however, they also proved to be cytotoxic, both to malignant and to normal somatic cells. The Royal Society of Chemistry.

Full text of DOI:10.1039/c3ob40692j

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Total synthesis and biological evaluation of
(−)-atrop–abyssomicin C†
Cite this: DOI: 10.1039/c3ob40692j
Filip Bihelovic,*a Ivanka Karadzic,b Radomir Matovicc and Radomir N. Saicic*a
Enantioselective synthesis of a marine antibiotic (−)-atrop–abyssomicin C was accomplished in 21 steps,
in 1.8% overall yield (4%, based on the recovered starting material). The key steps of the synthesis are the
formation of the functionalized cyclohexane core by an organocatalyzed Tsuji–Trost reaction, the for-
mation of a tricyclic spirotetronate unit by a gold-catalyzed reaction sequence and the highly efficient
eleven-membered ring closure by a Nozaki–Hiyama–Kishi reaction. Biological tests showed all abyssomi-
cin derivatives to possess strong antibacterial activity against methicillin resistant S. aureus strains;
however, they also proved to be cytotoxic, both to malignant and to normal somatic cells.
Received 6th April 2013,
Accepted 18th June 2013
DOI: 10.1039/c3ob40692j
www.rsc.org/obc
abyssomicin C performs this by inhibiting the biosynthesis of
p-aminobenzoic acid, which is a novel, unprecedented mech-
Introduction
The discovery of antibiotics is considered as one of the greatest anism of action that distinguishes it from other tetrahydro-
contributions to human welfare, but unfortunately, not an folate synthesis inhibitors (i.e. sulfonamides), and it is active
everlasting one, as their excessive use, coupled with the un- against methicillin- and vancomycin-resistant Staphylococcus
paralleled ability of natural organisms to adapt to external threat, aureus strains.6 In addition to abyssomicin C, several other
brought about new generations of pathogenic microorganisms, congeners have been found (Fig. 1); while abyssomicins B,3 D,3 G
resistant even to the last line therapeutic agents.1 Therefore, and H,7 originating from the aforementioned marine strain, are
the search for new antibacterials remains an important aspect believed to be the products of post-synthetic transformations
of medicinal chemistry. Natural products have traditionally of abyssomicin C, abyssomicins E8 and I,9 isolated from terres-
been a rich source of biologically active compounds, with a trial Streptomyces strains, are produced by a genuine polyketide
vast diversity of molecular structures and modes of action.2 In biosynthetic pathway. Recently, ent-homoabyssomicins A and
2004, one such discovery was reported by Süssmuth et al.:3 the B have been reported,10 as well as abyssomicins J, K and L;11
rare actinomycete strain Verrucosispora AB-18-032, collected at the last three do justify the name of this family of compounds,
a depth of 289 m in the Japanese sea, was found to produce a as they were isolated from the marine Verrucosispora strain
secondary metabolite named abyssomicin C, which immedi- MS100128, collected at a depth of 2733 m. The combination of
ately attracted the attention of the scientific community, for strong antibacterial activity and structural complexity made
several reasons. This spirotetronate-polyketide,4 structurally abyssomicin C an attractive synthetic target.12 Two total synth-
related to several topologically complex natural products,5 con- eses have been reported,13,14 as well as one formal synthesis15
tains four interwoven ring systems (including an eleven- and several synthetic studies.16 A common feature of all these
membered one), and seven stereogenic centers (including a retrosynthetic concepts is the recognition of the central cyclo-
quaternary one). A salient feature of this molecule is its ability hexane core as a partial retron for the application of the Diels–
to inhibit the synthesis of tetrahydrofolate; as this coenzyme is Alder transform.17 While in Sorensen’s synthesis the crucial
synthesized in microorganisms, but not in humans, it offers a bond forming step was effected by an intramolecular
possibility for a selective antibacterial activity. Remarkably,
aFaculty of Chemistry, University of Belgrade, Studentski trg 16, POB 51, 11158
Belgrade 118, Serbia. E-mail: rsaicic@chem.bg.ac.rs; Fax: +38111 3282537;
Tel: +38111 3282537
bSchool of Medicine, Department of Chemistry, University of Belgrade,
Visegradska 26, Belgrade, Serbia
cICTM Center for Chemistry, Njegoseva 12, Belgrade, Serbia
†Electronic supplementary information (ESI) available. CCDC 868561. For
ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/c3ob40692j
Fig. 1 Some members of the abyssomicin family.
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Diels–Alder reaction, in line with the presumed biosynthetic steps in the synthesis: we planned to create this structural
pathway, the stereoselective assembly of the bicyclic core in subunit by the nucleophilic attack of a β-hydroxy group to the
Nicolaou’s synthesis was achieved through an intermolecular, tetronate structural unit. This “casting”, which confers on the
template-controlled Diels–Alder reaction. The second pivotal reacting centres the opposite roles, as compared to the pre-
step – the formation of the oxygen bridge – has been invariably vious approaches,13,14 was motivated by the need to develop a
performed by an intramolecular epoxide ring opening with a complementary synthetic method, which would be feasible for
tetronate nucleophile, in a presumed biomimetic fashion. An the syntheses of other polycyclic tetronate ethers, where the
interesting finding disclosed by Nicolaou is the fact that the epoxide ring opening cannot provide a solution.
restricted rotation around one of the bonds in the eleven-mem-
Due to the considerable rigidity of the bicyclic core in 2, it
bered ring gives rise to atropisomerism.14 Thus, the compound was anticipated that this step may be difficult to achieve, and
named atrop–abyssomicin C turned out to be the genuine sec- that some new chemistry would have to be developed, in order
ondary metabolite and the most active bactericide, while the to solve this problem. Retrosynthetic simplification of the
initially described abyssomicin C was a conformational arte- spirotetronate 2 relies on a Dieckmann condensation, followed
fact. Recently, in a preliminary communication,18 we reported by a stereoselective oxidation of the enolate corresponding to
an enantioselective synthesis of atrop–abyssomicin C; we now 3, which is in turn obtainable by the cyclisation of the suitable
wish to provide the full account of this research, along with precursor 4. The installation of three contiguous stereocenters
some observations on the chemical reactivity and biological in this intermediate was conferred to the reliable Evans aldol
activity of the intermediates and products.
methodology:19 the absolute stereochemistry of the oxygen-
bearing carbon atoms would be established in the reagent-
controlled reaction, whereas the stereocenter bearing a methyl
group would be imported from a chiral synthon – (R)-2,6-
dimethylhept-5-enal 5 (also known as (−)-norcitronellal).
Results and discussion
We set out to develop an enantioselective synthesis of atrop–
abyssomicin C, which would rely on an alternative strategy, as
compared to those previously described,13,14 and which would
be complementary to the Diels–Alder based approach, in
terms of a flexible synthetic access to the analogues for struc-
ture–activity relationship (SAR) studies. The retrosynthetic
blueprint is represented in Scheme 1. The initial disconnec-
tion of the eleven-membered ring by a combination of a
Nozaki–Hiyama–Kishi transform and the organometallic
addition reveals the key tricyclic intermediate 1. The introduc-
tion of the oxygen bridge in 1 was considered as one of the key
Stereoselective formation of the cyclohexane core
The synthesis commenced with a boron enolate-mediated dia-
stereoselective aldol addition of α-benzyloxyacetyloxazoli-
dinone 720 to (R)-2,6-dimethylhept-5-enal 5,21 which furnished
the expected adduct 8 in 77% yield (90% based on the recov-
ered starting material (BRSM) 7), as a single diastereoisomer.
The stereochemical outcome of the reaction was unambigu-
ously established by the NOESY analysis of the dioxane 9,
which was derived from the aldol product 8, as represented in
Scheme 2. The 6-exo-cyclisation leading to 18 was planned to
be effected as an intramolecular allylation of an ester enolate.
The aldol adduct 8 contains all three stereogenic centres and
the proenolate functionality (in a latent form, as an isopropyli-
dene moiety), but the nucleofugic part of the cyclisation pre-
cursor remained to be elaborated. To this end, the secondary
hydroxy group was protected as the TBDMS-ether 10,22 and the
oxazolidinone auxiliary was reductively removed with sodium
borohydride (Scheme 3). The alcohol 11 thus obtained was
Scheme 2 Reagents and conditions: (a) nBu2BOTf, Et3N, CH2Cl2, −78 °C; then
H2O2, MeOH, phosphate buffer, 77% (90% BRSM); (b) NaBH4, THF, H2O; (c)
2,2-dimethoxypropane, pTsOH (cat.), 64% from 8.
Scheme 1 Retrosynthetic analysis of abyssomicin C.
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Scheme 3 Reagents and conditions: (a) TBDMSOTf, sym-collidine, CH2Cl2, 0 °C, 99%; (b) NaBH4, THF, H2O, 86%; (c) DMP, CH2Cl2, rt, then Ph3PvCHCO2Et, 82%; (d)
DIBAL, Et2O, −40 °C, 85%; (e) CBr4, Ph3P, CH2Cl2, 0 °C, 95%; (f) mCPBA, CH2Cl2, rt; then: H5IO6, Et2O, 100%; (g) Oxone, DMF; then CH2N2, 75%; (h) LDA, THF,
−78 °C; (i) KHMDS, Pd(PPh3)4, THF, −78 °C to rt, 87%.
homologated into conjugated ester 12 via a two-step, one pot
procedure involving Dess–Martin periodinane (DMP) oxi-
dation/Wittig olefination.23 To transform the conjugated ester
into a leaving group, 12 was reduced with DIBAL, and the
resulting alcohol 13 was treated with PPh3/CBr4 reagent, to
afford allylic bromide 14 in excellent yield. Oxidative cleavage
of the isopropylidene group in 14, effected by a combination of
regioselective epoxidation and the treatment of the resulting
epoxide with the etheral periodic acid,24 revealed aldehyde 15.
Oxidation of the aldehyde with Oxone®, followed by esterifica-
tion, furnished cyclisation precursor 16.25 Disappointingly,
cyclisation of an enolate derived from ester 16 turned out to be
unfeasible, under a variety of reaction conditions, even with
modifications of protecting groups in the molecule.26 An
attempt to increase the reactivity of the allylic part of the mole-
cule by performing the reaction in the presence of tetrakis-
(triphenylphosphine)palladium gave rise to the elimination
product 17; apparently, the ester enolate is a too hard nucleo-
phile, which acts rather as a base.
We then turned our attention to aldehyde 15, in the hope
that the corresponding enamine intermediates would be
softer, better nucleophiles, with respect to the ester enolate.
However, pyrrolidine did not promote the cyclisation of alde-
Scheme 4 Reagents and conditions: (a) Pd(PPh3)4, pyrrolidine, THF, rt, 83%,
dr = 5 : 1; (b) Ac2O, Et3N, DMAP, CH2Cl2, 91%; (c) mCPBA, CH2Cl2, rt; then:
hyde 15, and proline catalyzed reaction afforded the cyclized
product only in a low yield.27 Therefore, a new cyclisation
method was developed,28 based on the concept of dual cata-
lysis,29 i.e. the combination of organotransition metal catalysis
and organocatalysis.30 Thus, when submitted to the simul-
H5IO6, Et2O, 96%; (d) Pd(PPh3)4, pyrrolidine, DMSO, rt, 43%.
There were some ambiguities concerning the stereochemi-
taneous action of catalytic amounts of Pd(PPh3)4 and pyrroli- cal outcome of the reaction. The product was obtained as a
mixture of diastereoisomers in a 5 : 1 ratio,31 and initially the
dine, aldehyde 15 was smoothly converted into a cyclohexane
carbaldehyde derivative 19 (83% from 15; Scheme 4). The cycli- configuration of the major isomer was wrongly assigned as 23.
sation could be effected via the corresponding allylic acetate To determine the stereochemistry of the product without
21 as well, but in inferior yield (43%).
any uncertainty, it was converted into crystalline diol 25
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conditions (KHMDS, THF, −78 °C, followed by O2 and
P(OMe)3, either in the presence or absence of HMPA).5f,33
However, the reaction worked well with the model com-
pound – methyl cyclohexanecarboxylate – indicating that the
problem is in a hindered approach of a base to the axially posi-
tioned acidic hydrogen in 18. Substituting Me for the TBDMS
protecting group in 26 did not resolve the problem. α-Hydroxy-
lation of aldehyde 19 with N-methyl-O-benzoylhydroxylamine
afforded exclusively the undesired stereoisomer 27.34 As these
attempts at direct hydroxylation of the ester and aldehyde
derivatives failed, TIPS-enol ether 28 was prepared from 19 in
quantitative yield, and submitted to several oxidation proto-
cols, such as the Sharpless asymmetric dihydroxylation,35 or
reactions with modified Davis reagent,36 dimethyldioxirane
(DMDO),37 methyl trioxorhenium(VII)38 and peroxyacids.39
While most of these reagents produced stereoselectively again
the undesired stereoisomer 30, mCPBA provided an unsepar-
able diastereoisomeric mixture (with a predominance of the
desired diastereoisomer in a 1.5 : 1 ratio) in a 85% combined
yield.40 Although this result was not satisfactory, it allowed us
to investigate the reactivity of hydroxyaldehyde 29 and the
possibility of its conversion to spirotetronate 31.41
Scheme 5 Reagents and conditions: (a) oxone, DMF; then CH2N2, 65%; (b)
BBr3, CH2Cl2, −78 °C, 85%, (c) HF, 91%.
(Scheme 5). Single crystal X-ray diffraction analysis of this com-
pound confirmed that the absolute configuration of the cyclic
aldehyde corresponds to 19.32 This stereochemical outcome
indicates that the reaction proceeds via transition state 22, in
which two oxygen substituents occupy pseudoaxial positions
(Scheme 4). The reasons for this preference are currently not
clear, although dipole moment and steric hindrance of the
protecting groups certainly play a role.
The tertiary hydroxy group in 29 could not be acetylated
under a variety of conditions;42 under forcing conditions
(Ac2O, Sc(OTf)3)43 triacetate 32 was obtained, and could not be
selectively hydrolyzed into 33 (Scheme 7). An indirect approach
to 33 involved the reduction of aldehyde 29 into diol 34, fol-
Formation of the tricyclic spirotetronate
The first step towards the elaboration of spirotetronate 1 was
stereoselective α-hydroxylation of aldehyde 19. The accom-
plishment of this task turned out to be surprisingly difficult. lowed by acetylation and selective hydrolysis; however, this last
step could not be accomplished, as the hydrolysis of diacetate
35 provided only diol 34 (most probably due to the rapid
migration of the tertiary acetate in the monoacetylated
intermediate).
Some of the problems encountered are delineated in
Scheme 6. Ester 18 could not be hydroxylated under standard
Based on a successful model-study with α-hydroxycyclo-
hexane carbaldehyde, an attempt was made to proceed with
the Reformatsky reaction on hydroxyaldehyde 29; lactonization
of the expected product, followed by oxidation, should give
Scheme 6 Reagents and conditions: (a) KHMDS, O2, THF, −78 °C; then
P(OMe)3; (b) 1. HF, MeCN, Δ, 90%; 2. NaH, MeI, THF, 64%; (c) N-methyl-O-
benzoylhydroxylamine hydrochloride, DMSO, 50 °C, 33%; (d) TIPSOTf, Et3N,
CH2Cl2, 50 °C, 99%. TIPSOTf = triisopropylsilyl triflate; MMPP = magnesium
monoperphthalate.
Scheme 7 Reagents and conditions: (a) Sc(OTf)3, Ac2O, 0 °C, 76%; (b) K2CO3,
MeOH, H2O; (c) NaBH4, THF, H2O, 100%; (d) Ac2O, Et3N, DMAP, 70 °C, 50%.
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Scheme 10 Reagents and conditions: (a) TMS-acetylene, n-BuLi, THF, −78 °C,
83%; (b) K2CO3, MeOH, 88%; (c) HF, MeCN, 63%.
cyanohydrin 39 was confirmed by its conversion into aldehyde
29. Unfortunately, cyanohydrin 39 could not be acetylated, nor
did it undergo the Blaise reaction:47 under both reaction con-
ditions it underwent fragmentation into ketone 37.
Scheme 8 Reagents and conditions: (a) BrZnCH2CO2Et; (b) DMP, CH2Cl2, 49%
from 29.
Therefore, we focused our attention on acetylide-based syn-
thons. Addition of lithium trimethylsilylacetylide to ketone 37
gave propargylic alcohol 40 which, after consecutive deprotec-
tion of two silyl groups, gave rise to alkyne diol 42 – a precur-
sor for the intramolecular alkyne etherification (Scheme 10).
In principle, this type of reaction could be promoted by tran-
sition metals, which would allow us to intercept vinyl metal
intermediates with carbon monoxide and effect a one-pot
intramolecular etherification/alkoxycarbonylation reaction (i.e.
transformation 42 → 47 in Scheme 11). An attempt to effect
this reaction sequence with a palladium catalyst in THF, in the
presence of CuCl2 as a stoichiometric oxidant, resulted in
Glaser coupling to give dimer 43.48 When the reaction was per-
formed in methanol, a spiro β-lactone 44 was formed, by a
mechanism which involves a combination of intra- and inter-
molecular alcoxycarbonylation;49 apparently, carbonylation of
tertiary alcohol was faster than the desired etherification.
Treatment of diol 42 with silver carbonate in refluxing benzene
resulted in the fragmentation of the alkyne moiety and the iso-
merization of the vinylic double bond, to give enone 45.50
Mercuric acetate, or perchlorate, was also ineffective. Diol 42
spirotetronate 31 (Scheme 8). However, the exposure of alde-
hyde 29 to a Reformatsky reagent and subsequent treatment of
the initial product with DMP did not result in a two carbon
atom chain elongation: instead, the product of α-ketol
rearrangement – cycloheptadione derivative 36 – was obtained
as a single product.44
These disappointing findings thwarted the approach to the
spirotetronate via hydroxyaldehyde 29. As all of the attempted
procedures worked well on structurally simpler model systems,
it was clear that the specific stereoelectronic profile of 19 and
the related structures is responsible for the unfavorable reac-
tion outcomes. Analysis of NMR spectra of 18 and 19, and
their comparison with the spectra of 25, for which the X-ray
structural analysis was obtained, revealed that these cyclo-
hexane derivatives (be it the two hydroxy groups protected, or
free) adopt chair-like conformations with the oxygen substitu-
ents in the axial positions.45 Thus, these compounds have a
pronounced stereochemical bias and exert substrate control in
their reactions, which can hardly be overridden by the reagent.
In addition, aldehyde 29 shows proclivity towards rearrange-
ments and fragmentation, under the reaction conditions
designed for its homologization. Evidently, a modification of
the approach was necessary, and we next considered the attack
of a carbon nucleophile (instead of oxygen electrophiles used
in the preceding examples) on a cyclohexanone-type precursor.
To this end, silyl enol ether 28 was oxidatively fragmented
into cyclohexanone derivative 37 using the aforementioned
two step procedure (Scheme 9; 87% overall yield). Ketone 37
was then submitted to the action of trimethylsilyl cyanide/zinc
iodide to give the corresponding cyanohydrin in good yield
and with correct stereoselectivity.46 The stereochemistry of
Scheme 9 Reagents and conditions: (a) mCPBA, CH2Cl2, rt; then: H5IO6, Et2O,
87%; (b) TMSCN, ZnI2, CH2Cl2, rt, 90%; on purification on SiO2 38 was partially
deprotected to give 39; (c) DIBAL, CH2Cl2, −78 °C; then HCl, 50%.
Scheme 11 Reagents and conditions: (a) Pd(OAc)2, TMTU, CuCl2, NH4OAc,
propene oxide, CO, THF, 55 °C, 50%; (b) Pd(MeCN)2Cl2, CO, MeOH, Δ, 77%; (c)
Ag2CO3, benzene, Δ, 39%; (d) NBS, AgNO3, acetone, 85%; (e) NaOMe, MeOH, Δ.
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Scheme 12 Reagents and conditions: (a) LiCCCO2Et, THF, −78 °C, 33% (89%
BRSM); (b) LiCCC(OEt)3, toluene, −78 °C to rt, 88%; (c) HF, MeCN, 60 °C, 91%.
was converted into bromoalkyne 46; the latter, however, proved
inert under the reaction conditions previously reported as suit-
able for the cyclisation of structurally related, but confor-
mationally more flexible sugar derivatives.51
As the etherification/alkoxycarbonylation sequence proved
unfeasible, we decided to introduce a three-carbon unit into a
cyclohexane core, and to obtain a cyclisation precursor with an
alkoxycarbonyl group already in place, activating the alkyne for
etherification. Addition of the ethyl propiolate anion to ketone
37 under standard conditions provided the desired product 48
Scheme 13 Reagents and conditions: (a) From 48: Mg(OMe)2, MeOH, 65%,
52 : 53 = 5 : 4, R = R2 = Me; (b) from 51: iPr2NMgBr, THF, Δ, 65%, 54 : 55 = 4 : 3,
R = R2 = Et; (c) Nafion-Hg, ROH, H2O; (d) HF, MeCN, 40 °C, 91%.
stereoselectively, but in low yield (Scheme 12). In the presence diisopropylamide promoted the formation of nearly equimolar
of HMPA, elimination of the benzyloxy group gave enone 49 mixture of spirotetronates 53 (55), and the hetero-Michael
(52%). Low yield in this reversible reaction was a consequence adducts 52 (54) (Scheme 13). The spirotetronate structures 53
of the enolization of ketone 37, as well as of the unfavorable and 56 could be accessed in high yields by treatment of pro-
equilibrium between the starting compounds and the product. pargylic alcohol 50 with mercury-modified Nafion resin;56
Literature methods to circumvent this obstacle were not however, 56 proved to be a dead end intermediate, as its con-
helpful.52 We observed that the precursor/product ratio is version to tricyclic ether 47 proved impossible. Neither trans-
more favorable at higher reaction temperatures, but we could etherification nor hydrolysis into tetronic acid 57, which was
not exploit this observation, as ethyl propiolate rapidly decom- expected to be a better cyclisation precursor than the tetronic
poses at temperatures above −78 °C (methyl propiolate at ether, could be accomplished under a variety of conditions
>−100 °C).53 Therefore, a thermally more stable synthetic equi- (BBr3,54 HCl,54 HBr,54 NaSPr/HMPA,57 and PhSTMS/ZnI258).59
valent of a propiolate anion was needed. The lithium anion of In retrospect, the failure of 55 to cyclize should not be surpris-
ethyl orthopropiolate was such a reactive species, but its reac- ing, given that an extremely unfavorable, distorted confor-
tion with ketone 37 at 0 °C produced adduct 50 in only 36% mation of the rigid spirobicycle is required in the transition
yield, indicating that the reversibility of the reaction was still a state 55-A for the intramolecular hetero-Michael addition (i.e.
problem. We surmised that the coordination of the metal ion to allow the approach of the hydroxy group to the alkene accep-
(of the corresponding propargylic alkoxide) with the solvent tor at a Burgi–Dunitz angle of 105°). Therefore, an inversion of
(THF) increases the basicity of the alkoxide and favors the steps was required; i.e. intramolecular etherification should be
elimination; in this case, performing the reaction in a non- performed on a conformationally more flexible alkyne deriva-
coordinating solvent should be beneficial. Indeed, when tive, prior to the spirotetronate formation.
the reaction was performed in toluene, the desired adducts
For this purpose, we considered the application of gold
(48 + 50) were obtained in 88% yield.
catalysis – a rapidly emerging field where significant advances
We first tried to convert propargylic diol 51 into tricyclic have been made, notably in the domain of activation of
spirotetronate 47 by a hetero-Michael addition/lactonization carbon–carbon multiple bonds towards nucleophilic
sequence. Treatment of diol 51 with sodium methoxide addition.60 Initial experiments with AuCl3, either alone or in
induced only transesterification of the starting com- the presence of silver triflate, were unsuccessful, so we turned
pound.16b,54 Magnesium based reagents were more effective,55 our attention to the highly active Au(I) catalyst described by
due to the enhanced coordinating ability of the Mg2+ cation, Gagosz.61 While no reaction occurred in boiling THF, heating
which activates propiolate fragment towards nucleophilic a CH2Cl2 solution of alkyne diol 51 and a catalytic amount of
addition: both magnesium methoxide and bromomagnesium Gagosz’s catalyst, PPh3AuNTf2, at 120 °C (in a sealed tube)
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However, the stereospecific reaction produced exclusively
the Z-isomer Z-63, while only the corresponding E-isomer
could cyclize into spirotetronate 47. Whereas the radical-
based methods failed,63 isomerization could be effected by
irradiation with UV light in a quartz vessel (isomerization does
not occur in Pyrex glassware), and the E-isomer could be
cyclized into spirotetronate by the action of sodium hydride.
After some experimentation we found that this three-step
transformation could be accomplished more elegantly and
much more efficiently as a one-pot sequence, which involved
the initial heating of 51 in the presence of PPh3AuNTf2,
followed by irradiation in the presence of a catalytic amount of
sodium isopropoxide (Scheme 16): in this way, although the
Z-isomer Z-63 predominated in the photostationary state, it
was funneled into spirotetronate 47, thus shifting the Z/E
equilibrium, obviating the need for the separation of isomers
and recycling, and affording spirotetronate 47 in a 60% yield
(over three steps).
Macrocyclisation and the completion of the synthesis
Scheme 14 Reagents and conditions: (a) Ph3PAuNTf2, CH2Cl2, 120 °C, 77%.
With spirotetronate 47 in hand, the stage was set for the
attachment of the side chain and completion of the synthesis.
We anticipated that the closure of the eleven-membered ring
might be difficult; in line with this presumption, the work of
Nicolaou has shown that the ring closing metathesis on
related systems can be capricious, highly dependent on the
substitution pattern.14 Therefore our first choice was to effect
this step by a Nozaki–Hiyama–Kishi reaction64 – a powerful
cyclisation method that has given good results in some
resulted in the formation of a bicyclic ketone 58 (Scheme 14).
This was an encouraging result, as the presumed mechanism
of formation of 58 might involve the initial formation of the
desired bicyclic ether 59, followed by its subsequent rearrange-
ment into 58 (path a). A less favorable mechanistic possibility
would involve Au-catalyzed rearrangement as the first step
(path b). As the silylated derivative 48 did not react under the
same conditions, we excluded path b and focused our efforts
on finding the reaction conditions that would preserve structure
59 and secure a synthetically fruitful outcome of the reaction
sequence. After a screening of solvents and reaction conditions,
we found that the intramolecular etherification could be
effected by heating a solution of 51 and a catalytic amount of
PPh3AuNTf2 in methanol (Scheme 15). Yet, the yield of Z-63 was
low and the product was accompanied by several side products,
arising from a nucleophilic attack of methanol to the reaction
intermediates. Substituting sterically more demanding isopro-
panol for methanol substantially diminished side reactions and
improved the yield of Z-63 (60%). Interestingly, a catalytic
cocktail that was described in the literature as more active –
[P(C6F6)3AuCl]/AgSbF6 – proved unsuitable for this type of trans-
formation, due to its thermal instability.62
Scheme 16 Reagents and conditions: (a) PPh3AuNTf2, iPrOH, 70 °C; (b) hv,
iPrONa, 60% from 51.
Scheme 15
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difficult cases.65 The side-chain was attached in the reaction of made to remove the benzyl group in 70 by hydrogenolysis:
lithiated 4714 with optically pure aldehyde 64;66 quenching the however, in these experiments the reduction of the alkene pre-
reaction with methoxymethyl bromide gave MOM-protected ceded the cleavage of the benzyl group, which resulted in the
allylic alcohol 65 as a mixture of diastereoisomers (ratio of formation of abyssomicin H. After some experimentation, the
isomers = 1.8 : 1) (Scheme 17). The conversion of the vinyl ultimate deprotection step was accomplished by treatment of
group into a vinyl iodide was effected via the corresponding 70 with boron tribromide at room temperature, which pro-
aldehyde, whose intermediacy was exploited to rectify the vided atrop–abyssomicin C identical to the natural compound
stereochemistry of the vinyl bearing stereocenter through base- in all respects. This total synthesis also constitutes the formal
catalyzed epimerization. Thus, a one-pot procedure, compris- synthesis of abyssomicins D,14 J, K and L.11
ing ozonolysis, followed by the addition of a catalytic amount
With the target compound in hand, we undertook an SAR
of DBU, furnished the required aldehyde 66 as a single study of abyssomicin analogues. Our first goal was to clarify
epimer, in 81% yield (over two steps). After Takai olefination the roles of the C-11 hydroxy group and of the C-3 carbonyl
of 66,67 the deprotection of the primary hydroxy group in 67, group for the antibacterial activity – two issues that have
followed by oxidation with DMP,68 furnished the precursor for remained ambiguous so far. An earlier study has indicated the
macrocyclisation, 68. The intramolecular Nozaki–Hiyama– presence of C-11 oxygen substituent to be essential for the
Kishi reaction proceeded with remarkable efficiency, affording antibacterial activity.70 Abyssomicin C-11 acetate was also
tetracyclic intermediate 69 in 90% yield (96% BRSM), as a strongly active, but it remained unclear whether its antibacter-
mixture of four diastereoisomers, which was without conse- ial activity is an inherent property of the acetate, or it acts as a
quence for the success of the synthesis, as the two stereo- prodrug.14b In another study on the mechanism of inhibition
centers in question would be destroyed in the penultimate of 4-amino-4-deoxychorismate synthase PabB by atrop–abysso-
oxidation step. After trying several Bronsted and Lewis acids micin, some importance was attributed to the propensity of
with limited success, the deprotection of the secondary atrop–abyssomicin C to undergo sequential reaction: thiol
alcohol was accomplished with methanolic hydrogen chloride. addition/cyclisation, with the formation of pentacyclic, abysso-
Without purification, upon treatment with freshly prepared micin D type product.6b Therefore, we wanted to investigate
DMP,69 the crude diol was converted into diketone 70 (78% the antibiotic activity of derivatives which cannot undergo this
from 69), whose NOESY spectrum showed correlations corres- sequential cyclisation reaction, or can only perform it by a
ponding to the atrop–abyssomicin derivative. Attempts were different mechanism.
For this purpose, in addition to atrop–abyssomicin C (AA)
and its benzyl ether 70, three more derivatives were prepared
from the late stage intermediate 69, according to Scheme 18,
namely chloro derivative 71 and two diastereoisomeric MOM-
ethers – 72 and 73. The first estimation of the antibacterial
activity of these compounds was obtained by the agar plate
diffusion assay, which has shown all compounds to be active
against ATCC 25923, as well as against four other methicillin
resistant Staphylococcus aureus strains (Table 1). Determination
of MIC values against two MRSA strains showed all com-
pounds to be active at a nanomolar level, benzyl ether 70 of
atrop–abyssomicin C being the most active (Table 2). From
these results several conclusions can be drawn: (1) for the
Scheme 17 Reagents and conditions: (a) t-BuLi, THF, −78 °C; then aldehyde
64, −78 °C to −40 °C; then MOMBr, −40 °C to −25 °C, 44% (79% BRSM). (b)
O3, CH2Cl2, −78 °C; then Me2S; then DBU (30 mol%), 81%. (c) CrCl2, CHI3, THF,
rt to 50 °C, 71%. (d) HCl, MeOH, 94%. (e) DMP, CH2Cl2, rt, 88%). (f) CrCl2, NiCl2,
DMF, rt to 45 °C, 90% (96% BRSM). (g) HClaq, MeOH, rt; then DMP, CH2Cl2,
78%. (h) H2, Pd/C, EtOAc, 74%. (i) BBr3, CH2Cl2, rt, 81%.
Scheme 18 Reagents and conditions: (a) HCl, MeOH; (b) DMP, CH2Cl2.
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Table 1 Preliminary screening of antibiotic activity of selected compoundsa
Table 3 Cytotoxicities of selected abyssomicin analogues on HeLa cells and
peripheral blood mononuclear cellsa
Compound, 20 µg mL−1
HeLa
IC50
PBC
IC50
Microorganism
AA
70
71
72
73
Compound
IC90
IC90
Staphylococcus aureus ATCC 25923
MRSA, 100b
MRSA, 2775
MRSA, 106
MRSA, 58
16
17
16
13
11
32
27
28
28
26
18
18
18
16
15
20
21
17
15
21
21
23
19
18
21
AA
70
71
72
73
31.8
18.4
18.4
18.4
10.7
68.3
45.5
40.1
50.7
80.5
7.48
6.21
6.16
5.07
5.01
23.0
15.1
17.4
28.1
13.5
a Zones of inhibition (mm) determined by the agar plate diffusion
assay (well diameter 8 mm), according to the literature procedure.6a,71
a Cytotoxicities determined by the MTT assay; concentrations are
expressed in nM.73
Table 2 MIC values of selected compounds against two types of MRSAa
that cyclisation is not essential for the activity and neither is
the presence of the C-3 carbonyl group.
MIC against methicillin resistant
S. aureus (MRSA), µg mL−1
The presence of a reactive enone moiety in organic mole-
cules can give rise to cytotoxicity. Therefore, abyssomicin
derivatives were probed for cytotoxicity on HeLa cells. Indeed,
this assay showed that all analogues investigated possess
strong cytotoxic activity at a nanomolar level (Table 3).
However, and unfortunately, they also proved to be even more
cytotoxic on normal somatic cells, as shown by the test on per-
ipheral blood mononuclear cells. Therefore, if the develop-
ment of novel, abyssomicin based antibiotics is considered,
the reduction of these unwanted effects should be a sine qua
non for any therapeutic perspective.
Compound
MRSA, 100b
MRSA, 2775
AA
70
71
72
73
20
8
15
12
12
20
10
15
15
15
a Determined according to the literature procedure.6a,72
antibacterial activity, it is not necessary that the oxygen func-
tionality at C-11 be present as a free hydroxy group (as in the
natural product). The fact that benzyl ether 70 has superior
activity, as compared to the free alcohol (i.e. atrop–abyssomi-
cin C), indicates that the C-11 probably serves as a hydrogen
bond acceptor, but also that hydrophobic interactions may
play a role. (2) While the hetero-Michael addition is the necess-
ary first step for the covalent binding of abyssomicin deriva-
tives to PabB, the second addition (i.e. transannular
cyclisation) is not necessary. This is confirmed by the fact that
both MOM-diastereoisomers 72 and 73, as well as chloride 71,
show only a minor decrease of activity, with respect to the
parent compound. Neither 72 nor 73 is expected to cyclize, as
the tetronate unit is only singly activated. Compound 71 allows
for the cyclisation to occur, as the chlorine atom is properly
oriented for an SN2 substitution with allylic transposition;
such a reaction would give rise to a 3-deoxy abyssomicin D
type derivative. A model study on this compound, however, has
shown that it does not undergo phenylthio anion induced
cyclisation, but only a simple addition (Scheme 19). The fact
that all three compounds retain antibacterial activity indicates
Conclusions
Enantioselective total synthesis of (−)-atrop–abyssomicin C
(which also constitutes formal syntheses of abyssomicins B, D,
G, J, K and L, as well as the total synthesis of abyssomicin H)
was accomplished in 21 steps, in 1.8% overall yield (4.0%
based on the recovered starting compounds). The pivotal steps
in the synthesis were stereoselective formation of the cyclo-
hexane core 19, formation of tricyclic spirotetronate intermedi-
ate 47 and the eleven-membered ring closure (i.e. formation of
69). Much attention has been paid to the flexibility of the syn-
thetic sequence, i.e. in providing several mechanistic alterna-
tives for effecting the envisaged key structural transformations.
The importance of this precautionary aspect of synthetic plan-
ning was fully confirmed during the execution of the synthesis:
two of the aforementioned key transformations could not be
accomplished according to the initial plan, and new protocols,
namely cyclisation by dual catalysis (15 → 19) and gold cata-
lyzed cyclisation cascade (51 → 47), were developed to
overcome the encountered difficulties. The SAR study on abys-
somicin derivatives showed that neither the free C-11 hydroxy
group nor the C-3 carbonyl group is needed for antibiotic
activity and that C-11 benzyl ether shows superior activity with
respect to the natural product. However, all compounds tested
also showed strong cytotoxic activity on both HeLa and normal
somatic cells, which may prove to be a serious obstacle in
further development of this class of antibiotics.
Scheme 19 Reagents and conditions: PhSH, Et3N, THF, 48% (obtained as a
1 : 1 mixture of diastereoisomers separable by HPLC).
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I. Ortel and R. D. Süssmuth, Angew. Chem., Int. Ed., 2007,
46, 8284–8286.
Acknowledgements
Support from the Serbian Ministry of Education and Science is
acknowledged (project no. 172027). The authors acknowledge
support from the FP7 RegPot project FCUB ERA GA no.
256716. The authors are grateful to Prof. Tanja Cirkovic-
Velickovic (Faculty of Chemistry, University of Belgrade) for the
determination of cytotoxicities.
7 Abyssomicins G and H: S. Keller, G. Nicholson, C. Drahl,
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