Direct entry to erythronolides via a cyclic bis[allene]

Article abstract of DOI:10.1021/ja207496p

The complexity and low tractability of antibiotic macrolides pose serious challenges to addressing the problem of resistance through semi- or total synthesis. Here we describe a new strategy involving the preparation of a complex yet tractable macrocycle

Full text of DOI:10.1021/ja207496p

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Direct Entry to Erythronolides via a Cyclic Bis[Allene]
Kai Liu,† Hiyun Kim,† Partha Ghosh,† Novruz G. Akhmedov,‡ and Lawrence J. Williams*,†
†Department of Chemistry, Rutgers, The State University of New Jersey, 610 Taylor Road, Piscataway, New Jersey 08854, United States
‡Department of Chemistry, West Virginia University, 406 Clark Hall, Prospect Street, Morgantown, West Virginia 26506, United States
S Supporting Information
b
ABSTRACT: The complexity and low tractability of anti-
biotic macrolides pose serious challenges to addressing the
problem of resistance through semi- or total synthesis. Here
we describe a new strategy involving the preparation of a
complex yet tractable macrocycle and the transformation of
this macrocycle into a range of erythronolide congeners.
These compounds represent valuable sectors of erythromy-
cinoid structure space and constitute intermediates with the
potential to provide further purchase in this space. The
routes are short. The erythronolides were prepared in three
or fewer steps from the macrocycle, which was prepared in a
longest linear sequence of 11 steps.
rythromycin is the archetypal macrolide and represents an
E
important class of antibiotics.1 Despite their structural com-
plexity, erythromycin and its congeners have been used as front-
line treatments for human infections, particularly of the respira-
tory tract. The erythromycin antibiotics are thought to exercise
their protective properties primarily by blocking the elongation
tunnel of domain V of the large ribosomal particle in bacteria.2
Other functions include selective uptake by macrophages, extra-
cellular kinase activity, and perhaps antiasthmatic function at low
doses, among others.3 Many insights have been derived from
structural studies2 and efforts to manipulate the polyketide
synthase machinery.4 The largest contributions have come from
the chemical synthesis of macrolides derived from erythromycin
itself.5 The known structureÀactivity profile represents a hercu-
lean effort because of the intransigence of this natural product
toward selective modification. Despite the considerable strides
made in this area, the erythromycin structure has not been
evaluated fully, and the typical modes of drug resistance continue
to compromise effectiveness. Thus, the central problem remains:
limited access to erythromycinoid structure space severely
retards the search for effective macrolide antibiotics.
Figure 1. (top) Recursive assembly of a macrocyclic bis[allene] and
(bottom) functional macrolide motifs.
functionality in these regions (IV). The remaining C2ÀC3 and
C8ÀC9 partners would originate from opposite enantiomers of
the same precursor. Thus, an alkynol (I), an alkynal (II), and an
aldehyde (III) would enable a convergent, recursive alkynylation
sequence, coordinated allene installation, and then lactone for-
mation. A model study suggested that a macrocycle with two
allenyl groups positioned in this way would potentially undergo
stereo- and site-selective modification.8
Our strategy was driven in part by the key features of the
erythromycin structureÀactivity profile (Figure 1, bottom).5 In
brief, prior studies suggest the following: (a) portions of the
glycans, especially the amino sugar, are critical, and both the
hydrophilic character of the β-face and the hydrophobic char-
acter of the α-face of the macrolide contribute to binding (center
structure);5i (b) C9 amine or oxime functionality suppresses
Although unconventional for macrolides, we envisioned that
multiple targets could be derived from a common, advanced
macrocyclic intermediate (Figure 1, top). Previous syntheses of
erythromycin aimed to demonstrate new methods or superior
strategies to secure the natural product.6 As they were focused on
this single polyketide target, these routes are not necessarily
relevant to the discovery of new antibiotic leads. Nevertheless, de
novo synthesis represents a means by which to gain unrestricted
access to erythromycinoid structure space. Only recently has
total synthesis produced a new erythromycinoid antibiotic
candidate, namely, a desmethyl analogue that is thought to have
the potential to address resistance.7 The motif redundancy in
erythromycin at C4ÀC6 and C10ÀC12 led us to consider allenic
Received: August 9, 2011
Published: September 06, 2011
r
2011 American Chemical Society
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Scheme 1. Synthesis of 12a
Scheme 2. Erythronolides via Osmylationa
a Conditions: (a) OsO4, t-BuOH, H2O, rt, 83%. (b) Zn(BH4)2, Et2O,
0 °C, 68%. (c) TESOTf, 2,6-lutidine, DCM, rt, 83%. (d) OsO4, t-BuOH,
H2O, rt, 32%. (e) OsO4, t-BuOH, H2O, rt, 50%. (f) OsO4, t-BuOH,
H2O, rt, 46%. (g) TESOTf, 2,6-lutidine, DCM, rt, 78%.
Scheme 3. Erythronolides via Epoxidationa
a Conditions: (a) n-Bu2BOTf, NEt3, DCM, À78 °C, then (MeO)2-
CHCHO, warm to 0 °C, 90%. (b) BnBr, Ag2O, DCM, rt, 95%.
(c) LiBH4, Et2O, 0 °C, 95%. (d) DABCO, TsCl, DCM, 0 °C. (e) Lithium
acetylide ethylenediamine complex, DMSO, 15 °C, 82% (two steps).
(f) HOAc, H2O, CF3CO2H, rt, 95%. (g) n-BuLi, ZnBr2, Et2O, À78 to
0 °C, then 6, 64%, 8:1 dr. (h) HOAc, H2O, CF3CO2H, rt, 90%. (i) 9,
MeLi, Ti(OiPr)3Cl, THF, À78 °C, then 8, À78 to À40 °C, 89%, 6:1 dr.
(j) MsCl, NEt3, Et2O, rt, cool to À20 °C, MeCuCNLi, À20 °C to rt.
(k) HOAc, H2O, CF3CO2H, rt, 88% (two steps). (l) 2,4,6-Trichloro-
benzoyl chloride, NEt3, DMAP, tol, 80 °C, 64%.
a Conditions: (a) DMDO, CH3OH, À50 to À15 °C, 81%.
(b) DMDO, CHCl3, À40 to À15 °C, then MeCuCNLi, 2-methyl-
THF, À15 °C, 64%.
unwanted side effects (V);5c,f (c) C9ÀC11 or C11ÀC12 hetero-
annulation can improve binding and appears to represent
opportunities to overcome resistance (VI, VII);5b (d) C6ÀC9
heterocyclization leads to interesting (albeit nonantibiotic) ac-
tivity (VIII);5e and (e) retention of the C6 and C12 heteroatom
connectivity is desirable, and ether formation at C6 may improve
the antibiotic activity and suppress other activity (V, IX).5g C3
ketone derivatives5b (X) and alterations to the hydrophobic face
of the macrocycle (e.g., at C4, C8, and C10; XI and XII) may
overcome resistance.2b,7 Hence, modification of the C3ÀC6 and
C9ÀC12 regions offers opportunities to improve drug properties
and avoid bacterial resistance.
Three components were prepared and joined to provide
macrocycle 12 (Scheme 1). Addition of the enolate derived from
oxazolidinone 1 to commercially available dimethoxyacetalde-
hyde afforded the expected aldol product as a single isomer (2,
90%).9 Subsequent benzyl ether formation to give 3 (95%)
followed by hydride reduction provided the desired primary
alcohol 4 (95%). A tosylate was derived from this alcohol and
then without purification was subjected to lithium acetylide to
give component 5 (82% over two steps). The antipode of 3 was
exposed to mild acid and thereby furnished component 6 (95%;
see inset). The alkynylide derived from 5 was then combined
with 6 in the presence of zinc bromide.10 The addition products
spontaneously lactonized under the reaction conditions, and the
major product (7) was taken forward (64%, 8:1 dr). Mild acid
treatment of acetal 7 gave aldehyde 8 (90%). The alkynylide
derived from component 9 was combined with 8 in the presence
of chlorotriisopropoxytitanium,11 and the major product (10)
was taken forward (89%, 6:1 dr). A single-flask procedure
effected the conversion of the diyne to the corresponding
bis[allene];12 the crude material was then treated with mild acid
to furnish 11 (88% over two steps). The seco acid smoothly lac-
tonized, forming 12 (64%).8,13
Osmium tetroxide selectively converted the C4ÀC6 allenyl
group of 12 into the hydroxyketone (13, 83% yield; Scheme 2).
Reduction of the ketone cleanly gave 14 (68%).14 Triacetoxy-
borohydride15 reduction of the ketone gave the C5 epimer, and
sodium borohydride gave a 1:1 mixture of these products (data
not shown). Silylation of 13 to give 15 (83%) and then brief
osmylation resulted in the formation of 16 (32%), a C9ÀC12
hydroxyenone. In contrast, osmylation of 13, which contains a
hydroxyl, produced bicycle 17 (50%). Similarly, double osmyla-
tion of 12 gave 17 directly (46%). Silylation of 17 gave 18 as a
crystalline solid (78%; see the Supporting Information for the
X-ray crystal structure).
Scheme 3 shows products derived from allene epoxidation.16
Exposure of 12 to dimethyldioxirane (DMDO) in methanol
smoothly delivered the C3ÀC6 alkoxyenone 19 (81%). Epox-
idation with DMDO in chloroform17 followed by treatment
with Lewis acid,12 however, delivered the C3ÀC6 furanone 20.
Remarkably, lithium methylcyanocuprate promoted the forma-
tion of 20 in good yield (64%).8,17f
Sequential allene osmylation and allene halohydration18 is
shown in Scheme 4. Following osmylation of 12, C4ÀC6
ketoalcohol 13 was transformed by N-bromosuccinimide
(NBS)/water in MeCN into the C11 bromo/C12 hydroxyl
compound 21, which upon ketone reduction gave 22
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Scheme 4. Erythronolides via Combined Methodsa
Scheme 6. Mechanistic Rationale for Epoxidation of 12
a Conditions: (a) NBS/H2O, MeCN, rt, 99%. (b) Zn(BH4)2, Et2O,
0 °C, 98%.
Scheme 5. Mechanistic Rationale for Osmylation of 12
esters, these intermediates are also enolates.24 β-Elimination
and subsequent intramolecular conjugate addition is reason-
able. Interestingly, the C3 benzyloxy group is retained, whereas
the C9 group is lost. These phenomena are most likely traceable
to the stereoelectronics of the osmate ester intermediates.25
We suggest that the formation of 19 and 20 is closely related
and involves opening of the allene oxide (26 f 27) or spirodi-
epoxide (29 f 30) and capture of the C3 benzyloxy group
(Scheme 6). The transfer of benzyloxy from C3 to C6 may well
be promoted by 3,4-elimination in the case of 19. The analogous
spirodiepoxide pathway is interrupted and the benzyl group lost
under conditions that lead to 20. Interestingly, the configuration
at C6 in 19 is opposite that in 20. This may reflect the
comparatively high stability of oxyallyl zwitterion 27, which
could explain benzyloxy capture with overall retention of con-
figuration at C6. In the case of 29, the comparatively low stability
of a cation derived from the spirodiepoxide combined with the
proximity of the C3 OBn to C6 could lead to 30 directly with
inversion at C6. This mechanistic framework is also consistent
with the reaction conditions used for these transformations. We
favor this rationale, but further studies are needed to evaluate
these hypotheses.
The face selectivity of the allene halohydration differs from
that of the allene oxidation reactions. Nevertheless, the (Z)-
bromo/β-C12 hydroxyl of 22 was expected. Whereas oxidation
occurs from the more accessible face of the reacting allenyl
double bond, bromination occurs from the less accessible face
and water adds to the more accessible face (mechanism not
shown). Although these reactions have not been studied in
complex allenes, this sort of selectivity is well-known for
acyclic systems.18
The strategy presented herein focuses on substances that can
be called upon to react along differing pathways.26 The longest
linear sequence to 12 is 11 steps, and compounds 13À22 were
prepared from this intermediate in three or fewer steps; this
compares well to previous work in the area.6,7 Compound 12 is a
processable intermediate that integrates the routes to targets
that occupy underexplored erythromycinoid structure space,
including valuable desmethyl, cyclic, and other functionalized
variants. Taken together, the convergent assembly of 5, 6, and
9, the conversion of 10 to 11, and the reactions summarized in
Schemes 2À4 suggest a realistic route by which to effect exten-
sive and expeditious changes to the macrolide scaffold repre-
sented by erythromycin.
(Scheme 4).14 Both of these reactions proceeded in excellent
yield (>95%).
Allenes are central to this strategy. The coordinated synthesis
of both allenes from 10 allowed the concurrent installation of the
C12 and C6 methyl groups to give 11 (Scheme 1). However, the
C6 allenyl group formed slowly in comparison with the C12
allenyl group, suggesting that the substituents need not be
identical. The extended conformational constraints imposed by
allenyl groups relative to alkynyl and alkenyl functionality and the
presence of two such groups in seco acid 11 probably facilitate
the macrocyclization.6j The four sites of unsaturation housed
within 12 were transformed with apparently complete selectivity
(Schemes 2À4). The observed order of reactivity is C5ÀC6 >
C4ÀC5 > C11ÀC12 > C10ÀC11. The C5ÀC6 π bond
was expected to be most reactive because of the high substitution
and the fact that the reactivity of the C11ÀC12 π bond is
attenuated by the C13 ester. After oxygen delivery to C5ÀC6
via epoxidation or osmylation, the C4ÀC5 π bond is the most
highly reactive nucleophilic site of unsaturation remaining.8
The allenyl groups also provide a topological bias. In all of the
allene reactions shown, the products were isolated as single
isomers. The outcomes reflect the cooperative effects of intrinsic
allene stereoselectivity, macrocyclic stereocontrol,19 and (for the
intramolecular transformations) proximity of the reacting part-
ners. Although late-stage modification of isolated π bonds is
a known strategy in terpene syntheses,20 it is rare in macro-
lide synthesis,6g and the use of cyclic bis[allenes] in synthesis is
rarer still.21
Allene oxidation methods are underutilized. For example, a
disproportionately small number of reports on allene osmyla-
tion22 appear in the literature in comparison with alkene osmy-
lation.23 Although allene osmylation is not well studied, it is clear
that the osmium adducts formed and hydrolyzed (e.g., 23 f 13,
24 f 25; Scheme 5). Unlike simple alkene-derived osmate
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This paper is dedicated to Professor Samuel J. Danishefsky for
his continuing accomplishments in synthesis. Financial support
from the NIH (GM078145) is gratefully acknowledged.
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