Total synthesis of abyssomicin C and atrop-abyssomicin C

Article abstract of DOI:10.1002/anie.200601116

(Figure Presented) Into the abyss: A total synthesis of abyssomicin C (1) through a metathesis-based strategy offers a highly convergent approach to the construction of analogues. A novel and potent atropisomer of the natural product 1 was thus discovered

Full text of DOI:10.1002/anie.200601116

Communications
Natural Product Synthesis
DOI: 10.1002/anie.200601116
Total Synthesis of Abyssomicin C and atrop-
Abyssomicin C**
K. C. Nicolaou* and Scott T. Harrison
Abyssomicin C (1) is a recently discovered antibiotic with a
novel molecular architecture and unique mechanism of
action.[1] Isolated from the actinomycete Verrucosispora
strain AB 18-032 cultivated from a sediment sample collected
from the depths of the Sea of Japan, this deftly named natural
product inhibits the biosynthesis of p-aminobenzoic acid in
bacteria, a pathway that is absent in human physiology. The
intriguing structural topology of abyssomicin C coupled with
its reported activity against both methicillin-resistant Staph-
ylococcus aureus (MRSA, 4 mgmLꢀ1) and vancomycin-resist-
ant Staphylococcus aureus (VRSA, 13 mgmLꢀ1) prompted
immediate interest from the synthetic community, culminat-
ing in a total synthesis by Sorensen and co-workers[2] and
several approaches toward its structure by a number of other
groups.[3] Herein, we report our efforts in this field which led
not only to a total synthesis of abyssomicin C (1) but also to
the recognition of atrop-abyssomicin C (2), a novel isomer of
the naturally occurring product 1 that exhibits even more
potent antibiotic activity than its originally isolated twin.
Aiming for maximum molecular diversity in the subse-
quent construction of analogues, our strategy for the total
synthesis of the abyssomicins was based on the highly
convergent retrosynthetic analysis depicted in Figure 1.
[*] Prof. Dr. K. C. Nicolaou, S. T. Harrison
Department of Chemistry and
The SkaggsInstitute for Chemical Biology
The Scripps Research Institute
10550 North Torrey PinesRoad, La Jolla, CA 92037 (USA)
Fax: (+1)858-784-2469
E-mail: kcn@scripps.edu
and
Department of Chemistry and Biochemistry
University of California, San Diego
9500 Gilman Drive, La Jolla, CA 92093 (USA)
[**] We thank Dr. D. H. Huang and Dr. R. Chadha for assistance with
NMR spectroscopic and X-ray crystallographic analyses, respec-
tively. Financial support for this work was provided by the Skaggs
Institute for Research (predoctoral fellowship to S.T.H.).
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Figure 1. Retrosynthetic analysis of abyssomicin C (1).
Thus, construction of the oxabicyclo[2.2.2]octane core of the
molecule was expected from a Diels–Alder reaction between
the hydroxy diene 3 and methyl acrylate. An acetate unit, the
acetoxy aldehyde 4,[4] and vinyl magnesium chloride were
chosen to provide the remaining carbon atoms with their
appropriate functionalities as needed for the target molecule.
Finally, a ring-closing metathesis reaction was projected as the
means to forge the strained 11-membered ring of the
abyssomicin skeleton.
The [4+2] cycloaddition-based construction of the enan-
tiomerically enriched oxabicyclo[2.2.2]octane core 12 is
summarized in Scheme 1. The required hydroxy diene 3 was
prepared from the known and readily available Weinreb
amide 5[5] by reaction with the lithium derivative of thioani-
sole[6] (80% yield), followed by asymmetric reduction of the
resulting dienone with (R)-CBS (cat.)/catecholborane[7] (89%
yield, 90% ee[8]). The Diels–Alder reaction of 3 with methyl
acrylate needed considerable refinement before becoming a
practical process to produce the desired adduct 8. Reaction of
3 with methyl acrylate in the presence of MeMgBr in toluene
at room temperature according to the precedent of Ward and
Abaee[9] failed to yield any cycloadducts. Warming the
mixture to 558C led primarily to decomposition of the
diene, although some product 8 was obtained (25% yield
based on the diene). After further experimentation[10] we
discovered that mixing 1 equivalent of 3 with 3 equivalents of
ligand 6[11] and 4 equivalents of MeMgBr (3.0m solution in
ether) in toluene at 08C, followed by the addition of
10 equivalents of methyl acrylate and warming to 558C for
24 h, furnished the desired cycloadduct 8 as a single diaster-
eomer and in 80% yield. Despite the excess of reagents, the
isolation of 8 was simple, requiring only an acid wash (to
remove both the ligand and the magnesium salts) and flash
chromatography. The scope of this remarkable Lewis acid
templated Diels–Alder reaction, whose postulated transition
state (7) is depicted in Scheme 1, merits further investigation
as we envision potential applications in chemical synthesis in
general and particularly in asymmetric catalysis.[10]
Scheme 1. Synthesis of TES-protected oxabicyclo[2.2.2]octane inter-
mediate 12. Reagentsand conditions: a) thioanisole (1.3 equiv),
DABCO (1.3 equiv), nBuLi (1.3 equiv), THF, 08C, 1 h; then ꢀ788C;
then 5, 45 min, 80%; b) (R)-CBS (0.1 equiv), catecholborane
(1.25 equiv), CH2Cl2, ꢀ788C, 24 h, 89%, 90% ee;[8] c) 6 (3.0 equiv),
MeMgBr (4.0 equiv), PhCH3, 08C; then methyl acrylate (10 equiv),
558C, 24 h; 08C, wash with 3n aq. HCl, 80%; d) LiHMDS (1.5 equiv),
THF, ꢀ788C, 0.5 h; then (EtO)3P (2.0 equiv), bubbling O2, 74%;
e) 4,4’-di-tert-butylbiphenyl (0.5 equiv), Li (10 equiv), THF, 08C, 2 h;
ꢀ408C; then 9, 3 h; then MeOH quench, remove excess Li, concen-
trate; add DMF, K2CO3 (2.0 equiv), MeI (10 equiv), 608C, 10 min,
97%; f) VO(OEt)3 (0.2 equiv), tBuOOH (3.0 equiv), CH2Cl2, 258C, 3 h,
90%; g) Ac2O (10 equiv), DMAP (0.05 equiv), Et3N, 258C, 3 h, 93%;
h) LiHMDS (2.5 equiv), THF, ꢀ78 to 258C; then sat. aq. NH4Cl, reflux,
2 h; i) TESCl (1.3 equiv), imid. (2.6 equiv), DMAP (0.05 equiv), DMF,
258C, 2 h, 97%, two steps. TES=triethylsilyl, DABCO=1,4-
diazabicyclo[2.2.2]octane, (R)-CBS=(R)-(+)-2-methyl-CBS-oxazaboroli-
dine, LiHMDS=lithium bis(trimethylsilyl)amide, DMF=N,N-dimethyl-
formamide, DMAP=4-(dimethylamino)pyridine, imid.=imidazole.
conversion to the abyssomicins C (1 and 2). Further process-
ing of the phenylthiomethyl g-lactone 9 with the radical anion
species derived from catalytic amounts of 4,4’-di-tert-butylbi-
phenyl and Li metal resulted in the opening of the lactone
ring with concomitant olefin formation, which led, upon
quenching the carboxylate anion with methyl iodide, to a-
hydroxy methyl ester 10 in 97% overall yield. A vanadium-
directed epoxidation (tBuOOH) of the hydroxy diene 10 was
Returning to the sequence toward the targeted oxabicyclo
system 12 (Scheme 1), generation of the enolate by deproto-
nation of the g-lactone 8 with LiHMDS at ꢀ788C, followed by
quenching with O2 and (EtO)3P furnished a-hydroxy lactone
9 (74% yield), whose configuration was supported by its
spectroscopic data and unambiguously proven by its eventual
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then achieved, with exclusive delivery of the oxygen atom to
the bottom face of the molecule. This highly regio-and
stereoselective reaction proceeded in 90% yield when the
rarely utilized VO(OEt)3[12] catalyst was employed instead of
the more traditional VO(acac)2,[13] whose performance in this
case resulted in only 55–60% yield. Standard acetylation of
the so-obtained hydroxy epoxide then furnished acetate 11
(93% yield), which served admirably as a precursor to the
targeted intermediate 12. Thus, deprotonation of 11
(LiHMDS, THF) at ꢀ788C, followed by warming to ambient
temperature, addition of saturated aqueous NH4Cl (258C),[3c]
and heating at reflux for two hours, allowed first Dieckmann
cyclization[3a,c,14] to occur and then regioselective epoxide
opening[2,3a,c] (at C12) to give, after standard silylation,
compound 12 in 97% overall yield.
The elaboration of the oxabicyclo[2.2.2]octane system 12
to atrop-abyssomicin C (2) is summarized in Scheme 2. Thus,
lithiation of 12 with tBuLi at ꢀ788C, followed by quenching
with the known aldehyde 4 (90% ee),[4a] which was obtained
through a facile enzymatic desymmetrization,[4b] led to a
mixture of epimeric alcohols (ca. 1:1 ratio, 75% yield) which
was smoothly oxidized with IBX to afford ketone 13 in 90%
yield. Exposure of the 13 to excess 1,2-ethanedithiol and
BF3·OEt2 resulted in thioketalization and concomitant desil-
ylation to afford the corresponding hydroxy thioketal (90%
yield), from which the acetate group was removed by the
action of K2CO3 in methanol to furnish diol 14 (97% yield). A
shorter route from 12 to 14 was also developed. Therein, the
lithio derivative obtained from 12 as described above was
quenched with enantiomerically enriched lactone 15,[15] and
the crude lactol so-obtained was subjected to thioketalization
with 1,2-ethanedithiol and TMSOTf to afford 14 in 75%
overall yield. Compound 14 was homogeneous according to
1H NMR spectroscopy (CDCl3, 500 MHz), indicating over
98% diastereomeric purity at this stage of the synthesis.
Chemoselective oxidation of the primary hydroxy group
within 14 with IBX in DMSO, followed by addition of
vinylmagnesium chloride to the crude aldehyde so-obtained
led to the diastereomeric mixture (ca. 3:2) of alcohols 16 in
65% overall yield. The much anticipated ring-closing meta-
thesis of compound 16 proceeded smoothly under the
initiating influence of the Grubbs catalyst II (17)[16] in
refluxing CH2Cl2 to afford a mixture of diastereomeric
products (ca. 3:2), which were trans-configured about the
newly formed double bond (1H NMR spectroscopic analysis).
The corresponding cis isomer, which was considered unlikely
on the basis of molecular models, was not observed. A second
chemoselective oxidation performed with IBX in DMSO then
converted the two allylic alcohols into a single hydroxy enone
(18, 50% yield; Table 1), whose precise conformational
geometry (transoid versus cisoid) around the enone function-
ality remains unknown. Seemingly, only a single step sepa-
rated this intermediate, 18, from our targeted molecule,
abyssomicin C (1). Indeed, treatment of 18 with PhI(OTFA)2
cleaved, as expected, its thioketal protecting group and
afforded a stable crystalline compound (EtOH, m.p.: 2208C
(decomp.)), whose spectroscopic data were consistent with
the overall structure of the expected compound (Table 1),
however, these data did not exactly match those reported[1,2]
Scheme 2. Completion of the total synthesis of atrop-abyssomicin C
(2). Reagentsand conditions: a) tBuLi (1.2 equiv), THF, ꢀ788C, 0.5 h;
then 4 (1.1 equiv), 10 min, 75%; b) IBX (1.5 equiv), DMSO, 258C, 1 h,
90%; c) 1,2-ethanedithiol (4.0 equiv), BF3·OEt2 (4.0 equiv), CH2Cl2, 0!
258C, 12 h, 90%; d) K2CO3 (5.0 equiv), MeOH, 4 h, 258C, 97%;
e) tBuLi (1.2 equiv), THF, ꢀ788C, 0.5 h; then 15 (1.1 equiv), 10 min;
f) 1,2-ethanedithiol (4.0 equiv), CH2Cl2, ꢀ788C; then TMSOTf
(1 equiv), 30 min; then 1n aq. HCl, ꢀ78 to 258C, 30 min, 75%, two
steps; g) IBX (1.5 equiv), DMSO, 258C, 1.5 h; h) vinyl MgCl
(3.0 equiv), THF, ꢀ788C, 65%, two steps; i) 17 (0.05 equiv), CH2Cl2
(0.002m), reflux, 1 h, 85%; j) IBX (1.5 equiv), DMSO, 258C, 1.5 h,
50%; k) PhI(OTFA)2 (2.0 equiv), CH3CN/H2O (5:1), 50%. IBX=o-
iodoxybenzoic acid, DMSO=dimethyl sulfoxide, TMSOTf=trimethyl-
silyl trifluoromethanesulfonate, TFA=trifluoroacetyl.
for natural abyssomicin C (1), suggesting a close relationship
between the two compounds. The conundrum was solved by
X-ray crystallographic analysis of the synthetic compound
(2):[17] its structure was revealed as an atropisomer[18] of
abyssomicin C (1)[1] (see Figure 2a for ORTEP structures).
Comparison of the reported X-ray crystal structural data
of abyssomicin C (1)[1] to those of atrop-abyssomicin C (2)
reveals subtle but important structural differences (Fig-
ure 2b). Chiefly, the carbonyl group at C7 adopts a more
transoid conformation with the C8–C9 double bond in the
=
=
natural product 1 (dihedral angle O C7-C8 C9 144.88),
whereas the conformation of this group in 2 is more cisoid
=
=
(dihedral angle O C7-C8 C9 26.48). Because 2 exhibits an
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Table 1: Selected physical properties for synthetic dithiolane abyssomi-
cin C 18, atrop-abyssomicin C (2), and abyssomicin C (1).[a]
18: Rf =0.31 (silica gel, EtOAc/hexanes 3:2); [a]2D5 =ꢀ39.4 (c=0.18,
CHCl3); IR (film): n˜max =3449, 2964, 2927, 2871, 1749, 1727, 1694, 1658,
1
1626, 1455 cmꢀ1; H NMR (500 MHz, CDCl3): d=6.48 (dd, J=16.7,
4.1 Hz, 1H), 6.44 (d, J=16.7 Hz, 1H), 4.57 (dd, J=4.6, 1.6 Hz, 1H),
4.53 (dd, J=4.5, 1.9 Hz, 1H), 3.36–3.28 (m, 1H), 3.27–3.18 (m, 1H),
3.17–3.07 (m, 2H), 3.05 (dd, J=3.7, 2.1 Hz, 1H), 2.83–2.74 (m, 1H),
2.65 (dd, J=12.6, 11.0 Hz, 1H), 2.40 (ddd, J=10.3, 7.0, 3.1 Hz, 1H),
1.92–1.82 (m, 2H), 1.37 (dd, J=12.6, 2.5 Hz, 1H), 1.32 (ddd, J=14.7,
7.9, 3.0 Hz, 1H), 1.20 (d, J=6.6 Hz, 3H), 1.14 (d, J=7.1 Hz, 3H),
1.13 ppm (d, J=7.2 Hz, 3H); 13C NMR (125 MHz, CDCl3): d=203.4,
171.0, 169.5, 138.4, 129.1, 107.7, 81.2, 79.1, 71.1, 65.9, 49.2, 47.8, 41.8,
40.9, 39.7, 38.6, 34.6, 24.8, 18.6, 17.9, 17.3 ppm; HRMS (ESI-TOF): calcd
for C21H27O5S2+ [M+H+]: 423.1294; found: 423.1297.
2: Rf =0.21 (silica gel, EtOAc/hexanes 3:2); colorless crystals (EtOH),
m.p.: 2208C (decomp.); [a]2D5 =ꢀ71.4 (c=0.33, MeOH); IR (film):
n˜max =3442, 2967, 2933, 2866, 1757, 1690, 1637, 1457 cmꢀ1; 1H NMR
(600 MHz, MeOD): d=6.66 (dd, J=16.5, 5.8 Hz, 1H), 6.53 (d,
J=16.6 Hz, 1H), 4.63 (dd, J=4.3, 1.5 Hz, 1H), 4.42 (dd, J=4.2, 3.0 Hz,
1H), 3.20 (dd, J=5.8, 2.9 Hz, 1H), 2.85–2.76 (m, 1H), 2.71 (dd, J=12.5,
11.1 Hz, 1H), 2.67–2.61 (m, 1H), 2.54 (dqd, J=14.3, 7.1, 3.6 Hz, 1H),
1.88 (ddd, J=15.7, 12.1, 2.5 Hz, 1H), 1.49–1.43 (m, 2H), 1.17 (d,
J=7.3 Hz, 3H), 1.15 (d, J=7.2 Hz, 3H), 1.13 ppm (d, J=6.7 Hz, 3H);
13C NMR (150 MHz, MeOD): d=203.5, 200.5, 179.4, 170.8, 140.2, 129.0,
106.2, 84.5, 81.1, 67.0, 50.6, 49.1, 43.5, 38.6, 33.7, 25.7, 18.2, 17.5,
Figure 2. a) ORTEP drawings of abyssomicin C (1)[1] and atrop-abysso-
micin C (2)[15] generated from X-ray crystallographic analysis. Spheres
are drawn at a 50% probability level. b) Computer-generated stick
modelsof 1 and 2 based on X-ray crystallographic data.
16.3 ppm; HRMS (ESI-TOF): calcd for C19H23O6 [M+H+]: 347.1489;
+
found: 347.1484.
1: Rf =0.28 (silica gel, EtOAc/hexanes 3:2); [a]2D5 =ꢀ43.1 (c=0.1,
MeOH); colorless crystals (MeOH), m.p.: 1808C (decomp.) [lit.
m.p.: 1808C (decomp.)][1]; IR (film): n˜max =3461, 2968, 2933, 2876, 1757,
1686, 1615, 1457, 1434 cmꢀ1; 1H NMR (600 MHz, MeOD): d=6.53 (d,
J=13.6 Hz, 1H), 5.97 (dd, J=13.6, 9.6 Hz, 1H), 5.05 (dd, J=6.1,
3.4 Hz, 1H), 4.56 (dd, J=3.4, 0.7 Hz, 1H), 3.50 (dqd, J=13.4, 6.7,
2.7 Hz 1H)), 2.97 (dd, J=9.6, 6.1 Hz, 1H), 2.93 (ddd, J=10.8, 7.2,
1.5 Hz, 1H), 2.75–2.69 (m, 1H), 2.69–2.64 (m, 1H), 1.99 (td, J=14.1,
11.1 Hz, 1H), 1.41 (ddd, J=14.1, 2.6, 1.6 Hz, 1H), 1.25 (dd, J=11.8,
4.8 Hz, 1H), 1.17 (d, J=7.0 Hz, 3H), 1.09 (d, J=7.2 Hz, 3H), 1.06 ppm
(d, J=6.7 Hz, 3H); 13C NMR (150 MHz, MeOD): d=206.2, 200.5,
187.5, 171.5, 135.3, 135.1, 104.6, 86.8, 78.9, 73.8, 48.1, 49.4, 43.1, 40.2,
obtaining NMR spectroscopic data for 2 in unstabilized
CDCl3, it was observed that compound 2 slowly converted
into 1, cleanly affording a 2:1 mixture of 1/2 after 24 h. The
same equilibrium (1/2 2:1) was reached from pure 1 (CDCl3,
258C, 5 days). This phenomenon may be explained by either
of two hypothetical scenarios (Scheme 3). The first (path a)
postulates that catalytic amounts of hydrochloric acid present
in CDCl3 provides activation such that the tetronate becomes
a sufficiently good leaving group, allowing the hydroxy group
at C11 to initiate an attack upon C12 to generate the epoxide
proposed for the biogenesis of the natural product.[2] This
intermediate may then exhibit enhanced torsional freedom,
allowing interconversion between the two atropisomers
before retrapping the epoxide that would freeze them in
stable conformations. Alternatively (path b), acid-catalyzed
activation of the tetronate core would leave C16 electron-
deficient and capable of drawing p-electron density from the
suitably poised double bond at C2 (C2–C16 3.19 Š in 2 and
3.27 Š in 1 from X-ray crystallographic analysis). This
bridging interaction would draw C2 even closer to C16 of
the tetronate, relieving torsional strain in the macrocycle, and
thus lowering the energy barrier to rotation of the s bond as
needed for the atropisomer interconversion. Synthetic abys-
somicin C (1) was chromatographically separated from its
atropisomer 2 and fully characterized (Table 1). Its physical
properties were identical to those reported for the natural
product.[1,2]
+
37.3, 25.9, 21.0, 19.3, 17.2 ppm; HRMS (ESI-TOF): calcd for C19H23O6
[M+H+]: 347.1489; found: 347.1485.
[a] We assume that the systematic differences (ꢁ2 ppm) between the
originally reported 13C NMR data[1] and those of our synthetic abysso-
micin C (1) are a consequence of differing calibration. We used the signal
for CD3OD at d=49.05 ppm asreference. The data provided above are
consistent with those reported by Sorensen and co-workers for their
synthetic material.[2]
increased degree of conjugation between the carbonyl group
and the double bond moiety, it was anticipated that it might
be a more powerful Michael acceptor than 1. This change in
conformation at C7 has structural ramifications throughout
the rest of the macrocyclic system, most notably the
orientation of the carbonyl group at C3. In the natural
=
=
compound 1 the O C3-C2 C16 dihedral angle is 33.88,
whereas in atrop-abyssomicin C (2) the corresponding angle
is 56.28.
Preliminary minimal inhibitory concentration (MIC)
assays of 1, 2, and 18 for antibacterial activity against
MRSA revealed that they all exhibit activity, with the non-
natural atropisomer 2 being the most potent (3.5 mgmLꢀ1) as
compared to 1 (5.2 mgmLꢀ1) and 18 (17 mgmLꢀ1).[19] Our
Thermally induced conversion of 2 into 1 (refluxing
MeOH or toluene) was unsuccessful, leading either to no
reaction or decomposition at higher temperatures (1808C,
xylenes, microwave irradiation). Surprisingly, however, while
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[8] Determined by HPLC using a Chiracel OD-H
column and eluting with a solvent gradient of
hexane to 5% iPrOH in hexane over 35 min.
[9] D. E. Ward, M. S. Abaee, Org. Lett. 2000, 2, 3937.
[10] The use of BINOL in conjunction with Me2Zn
(2.0 equiv) and MeMgBr (1.0 equiv) heated to
558C furnished 7 in less than 5% yield, albeit with
80% recovery of the diene; see: D. E. Ward, M. S.
Souweha, Org. Lett. 2005, 7, 3533.
[11] Commercially available from a number of sour-
ces. However, we prepared it on an 85 g scale
under the following conditions: 2-aminophenol
(1.0 equiv), 1,4-dibromobutane (1.05 equiv), di-
isopropylethylamine (3.0 equiv), toluene (1.3m),
658C, 12 h (80%).
[12] For an example of homoallylic alcohol directed
epoxidation with (nPrO)3VO, see: J. M. Evans, J.
Kallmerten, Synlett 1992, 269. We thank Professor
K. B. Sharpless for suggesting the use of
(EtO)3VO in this reaction.
[13] S. Tanaka, H. Yamamoto, H. Nozaki, K. B.
Sharpless, R. C. Michaelson, J. D. Cutting, J.
Am. Chem. Soc. 1974, 96, 5254.
Scheme 3. Total synthesis of abyssomicin C (1) and postulated mechanisms (path a, involving
epoxide participation; path b, involving enone participation) for the interconversion of 1 and 2.
Reagentsand conditions: CDCl 3, 258C, 24 h, quantitative, 2/1 1:2.
[14] For other examples of Dieckmann cyclizations of this type, see:
a) K. Takeda, Y. Shibata, Y. Sagawa, M. Urahata, K. Funaki, K.
Hori, H. Sasahara, E. Yoshii, J. Org. Chem. 1985, 50, 4673;
b) W. R. Roush, M. L. Reilly, K. Koyama, B. B. Brown, J. Org.
Chem. 1997, 62, 8708.
[15] Prepared according to the sequence reported for ent-15 by using
(R)-(+)-a-methylbenzylamine; see: L. A. Paquette, S. L. Boulet,
Synthesis 2002, 888.
[16] M. Scholl, S. Ding, C. W. Lee, R. H. Grubbs, Org. Lett. 1999, 1,
953.
[17] CCDC-602361 (2) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[18] For examples of medium ring compounds that lack a biaryl axis
and exhibit atropisomerism, see: a) D. Anastasiou, E. M. Campi,
H. Chaouk, W. R. Jackson, Tetrahedron 1992, 48, 7467; b) W. H.
Pearson, E. J. Hembre, J. Org. Chem. 1996, 61, 5546; c) E. A.
Anderson, J. E. P. Davidson, J. R. Harrison, P. T. OꢀSullivan,
J. W. Burton, I. Collins, A. B. Holmes, Tetrahedron 2002, 58,
1943.
current hypothesis is that the difference in activity is due to 2
being a more powerful Michael acceptor than 1 as discussed
above.
The chemistry described above offers the opportunity for
a structure–activity relationship program within the abysso-
micin structural motif, while revealing an intriguing and rare
form of atropisomerism in medium-sized rings[16] of natural or
designed origin. Studies directed toward the discovery of
novel antibacterial agents through exploitation of these
findings are continuing.
Received: March 21, 2006
Published online: April 24, 2006
Keywords: abyssomicin · antibiotics · atropisomerism ·
.
natural products · total synthesis
[19] MIC values were determined with serial dilutions in 96-well
plates against 1:10000 dilution in nutrient broth of a 24 h culture
of methicillin-resistant Staphylococcus aureus (ATCC 33591) at
358C. We thank Ms. Desiree Thayer for assistance in performing
these assays.
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