Journal of the American Chemical Society
Communication
combined yield over two steps; see SI). We speculate that the
oxophilic multicoordinating nature of titanium tetrachloride
combined with the Lewis basic character of the 2,3-
butanediacetal group might help preorganize the approaching
silyl enol ether 9 and 1,1-dichloroacetone (6), thereby
resulting in the high diastereoselectivity of the aldol reaction.19
To incorporate the carbamate functionality required for the
projected C−H amination, aldol adduct 10 was exposed to
trichloroacetyl isocyanate, producing the corresponding
trichloroacetyl carbamate (not shown).20 However, the
subsequently attempted removal of the trichloroacetyl
protecting group under basic conditions (Et3N, CH3OH,
CH2Cl2, 0 to 22 °C) resulted solely in elimination of the
carbamate moiety, presumably due to a facile formation of an
extended π-system (see SI). To circumvent the undesired
reactivity, aldol adduct 10 was first hydrogenated over
palladium on charcoal, delivering ketone 11 in ≥99% yield
and with excellent diastereoselectivity (15:1 dr), at which point
the carbamate functionality could be introduced safely. In
practice, ketone 11 (15:1 mixture of C10 epimers) was
converted into separable carbamates, from which the desired
C10 epimer 12 was isolated in 92% yield over two steps.
With access to carbamate 12, we were poised to investigate
the intramolecular C−H amination reaction to form the
oxazolidinone ring and specifically the C4−N bond.21 The
multitude of C−H bonds potentially reactive in the amination
reaction, including the precarious C−H bond of the
dichloromethyl group, presented a particularly interesting
case for the rhodium(II)-catalyzed amination methodology
developed by the Du Bois laboratory.22 The initial screening of
catalysts, which followed the original Du Bois’ protocol,
revealed that rhodium(II) acetate dimer catalyzed the
transformation more efficiently than the other rhodium(II)
complexes examined (Rh2(tpa)4, Rh2(esp)2, Rh2(oct)4,
Rh2(tfa)4; see SI for details). Further optimization studies
showed that reaction temperature, solvent, and the amount of
oxidant also markedly influenced the conversion of carbamate
12 (see SI). Additionally, we noted that moisture-free
conditions were crucial for attaining high turnover of the
rhodium(II) catalyst, and thus, anhydrous magnesium sulfate
was adopted as a convenient drying agent in the reaction
mixture. Under the optimized conditions, a solution of
carbamate 12 in toluene was treated with rhodium(II) acetate
dimer (10 mol %) and (diacetoxyiodo)benzene (2.5 equiv) in
the presence of anhydrous magnesium sulfate at 80 °C to give
oxazolidinone 13 in 57% yield. Importantly, the C−H insertion
reaction proceeded with complete diastereoselectivity and
provided oxazolidinone 13 free of detectable amounts of its C4
epimer.
(−)-bactobolin A,13 we modified the reported protocol.25
Specifically, oxazolidinone 13 was activated by N-sulfonylation
with 2-nitrobenzenesulfonyl chloride (NsCl)26 and sodium
hydride in a tetrahydrofuran−acetonitrile mixture at 0 °C. The
use of an excess of sodium hydride led to a spontaneous
conversion of the in situ generated sulfonyl oxazolidinone 15
into δ-lactone 16. Our DFT computational analysis of the
alkoxycarbonylation step revealed a low-energy conformation
of an enolate intermediate with the enolate carbon atom
positioned within 3.3 Å of the oxazolidinone carbonyl.11f The
activation barrier for the alkoxycarbonylation reaction was
calculated to be 12.1 kcal/mol (see SI for details). On the basis
of the analysis, a direct attack of the enolate onto the
oxazolidinone is considered a plausible mechanistic pathway.
The 2-nitrobenzenesulfonyl activating group linked to the
axial amino group of δ-lactone 16 was cleaved by exposure to
4-tert-butylbenzenethiol in the presence of potassium carbo-
nate, thus furnishing amine 17 in 62% yield over two steps.
Single crystal X-ray analysis of amine 17 unambiguously
confirmed the correct relative configurations of all five
contiguous stereocenters.
Amine 17 with the amino group in an axial position proved
to be a challenging substrate for amide coupling with N-(tert-
butyloxycarbonyl)-L-alanine, since many of the common
coupling reagents (e.g., DCC, HATU, PyBOP) failed to
provide amide 18, and only the unreacted amine 17 was
recovered. Fortunately, the COMU reagent27 delivered amide
18 with exceptional efficiency in 73% yield. Finally, the 2,3-
butanediacetal and tert-butyloxycarbonyl protecting groups
were removed in one step under acidic conditions (TFA, H2O,
CH2Cl2, 22 °C), thereby providing the trifluoroacetate salt of
(−)-bactobolin A (1) in 92% yield (90 mg). The free base of 1
could be readily obtained from the trifluoroacetate salt in
≥99% yield (see SI). The spectroscopic data for synthetic 1
were in full agreement with those reported by Clardy and co-
workers for the natural compound.6b
A sample of synthetic (−)-bactobolin A (1) was tested for
the inhibition of protein synthesis in cell-free systems. The
determined IC50 values (Escherichia coli BI21, IC50 = 1.70 μM;
Mycobacterium smegmatis, IC50 = 0.57 μM; rabbit reticulocyte,
IC50 = 0.84 μM; see SI for details) were consistent with the
literature data reported for natural (−)-bactobolin A.3
The use of substrate stereocontrol was central to our ability
to execute the synthesis of (−)-bactobolin A efficiently. We
demonstrated that the properly protected trans-diol of β-
methyl enone 8 allowed for remote stereocontrol at the
quaternary C3 center during the vinylogous aldol reaction. To
learn more about the stereocontrol elements involved in the
diastereoselective C−H amination of carbamate 12, we
pursued an experimental approach. Examination of structurally
modified carbamates 19, 21, 23, and 25 in the C−H amination
reaction revealed that the diastereoselectivity observed with 12
is the outcome of matched stereocontrol between the
stereochemical triad at the cyclohexanone ring and the
quaternary C3 stereocenter (Scheme 2). This can be well
appreciated by comparing the results of the C−H amination
reactions of carbamate 12 and the C3 epimeric carbamate 19.
The stereochemical outcome of the amination reaction of
carbamate 21 indicates that good selectivity can be achieved
also with substrates lacking the C3 stereocenter. On the other
hand, the C3 center served as a powerful stereocontrol element
in the C−H amination reactions of carbamates 23 and 25 that
miss the 2,3-butanediacetal moiety.28
Oxazolidinedione 14 was identified as a side-product in the
C−H amination reaction (20% yield), apparently originating
from a C−H functionalization at the carbon atom of the
dichloromethyl group. A preliminary study of the observed
novel reactivity revealed that the formation of 14 required the
presence of both Rh2(OAc)4 and PhI(OAc)2 in the reaction
mixture, and, unlike oxazolidinone 13, oxazolidinedione 14
gradually degraded under the C−H amination conditions.
Whether the formation of this product proceeds through a
concerted insertion into the C−H bond,23 a radical process
involving hydrogen atom abstraction,24 or a different reaction
pathway is currently unclear.
To effect the intramolecular alkoxycarbonylation, which was
first creatively applied in the Weinreb’s synthesis of
C
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX