A Practical, Component-Based Synthetic Route to Methylthiolincosamine Permitting Facile Northern-Half Diversification of Lincosamide Antibiotics

Article abstract of DOI:10.1021/jacs.1c03536

The development of a flexible, component-based synthetic route to the amino sugar fragment of the lincosamide antibiotics is described. This route hinges on the application and extension of nitroaldol chemistry to forge strategic bonds within complex amino sugar targets and employs a glycal epoxide as a versatile glycosyl donor for the installation of anomeric groups. Through building-block exchange and late-stage functionalization, this route affords access to a host of rationally designed lincosamides otherwise inaccessible by semisynthesis and underpins a platform for the discovery of new lincosamide antibiotics.

Full text of DOI:10.1021/jacs.1c03536

pubs.acs.org/JACS
Communication
A Practical, Component-Based Synthetic Route to
Methylthiolincosamine Permitting Facile Northern-Half
Diversification of Lincosamide Antibiotics
Matthew J. Mitcheltree, Jack W. Stevenson, Amarnath Pisipati, and Andrew G. Myers*
Cite This: J. Am. Chem. Soc. 2021, 143, 6829−6835
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: The development of a flexible, component-based synthetic route to the amino sugar fragment of the lincosamide
antibiotics is described. This route hinges on the application and extension of nitroaldol chemistry to forge strategic bonds within
complex amino sugar targets and employs a glycal epoxide as a versatile glycosyl donor for the installation of anomeric groups.
Through building-block exchange and late-stage functionalization, this route affords access to a host of rationally designed
lincosamides otherwise inaccessible by semisynthesis and underpins a platform for the discovery of new lincosamide antibiotics.
he lincosamide antibiotics have been used to treat
Tstaphylococcal and streptococcal infections in humans
for more than 50 years, but widespread bacterial resistance and
safety concerns (specifically, a risk of C. difficile infection) have
diminished their use in patients. Methylthiolincosamine (MTL,
1) is the northern-half component of the prototypical
lincosamide, lincomycin (2),1 for which the thiogalactopyr-
anose plays an essential role in binding to the bacterial
ribosome, the lincosamides’ cellular target. X-ray co-crystallog-
raphy has shown that the pyranose hydroxyl groups of MTL
form an extensive hydrogen-bond network with the neck of the
peptide-exit tunnel, including with adenosine 2058, a key
residue whose mutation or post-transcriptional modification
confers resistance to lincosamides, macrolides, and streptog-
ramin B antibiotics, a multidrug resistance phenotype referred
to as MLSB.2,3 Early semisynthetic modifications to the
lincosamides support the idea that the 2,3,4-triol pharmaco-
phore is indispensable, as deoxygenation, O-methylation,
epimerization, and other modifications abolish activity.4 On
the other hand, modifications of positions C1 and C7 are
tolerated,5 a finding perhaps presaged by the naturally
occurring lincosamide antibiotic celesticetin (3, reported in
1955).6
Although no new lincosamide has been advanced since the
approval of clindamycin (4) in 1970,7 this is not for lack of
effort. Vicuron scientists discovered beneficial modifications of
C7 using both semisynthesis and de novo construction from a
carbohydrate precursor employing an extant method.8,9 In
addition, they discovered that azepane replacement of the
aminoacyl portion of the molecule (5) greatly improved the
spectrum and potency of antibacterial activity.8 Meiji-Seika
researchers have reported that semisynthetic modification of
C7 with a biarylthio substituent (as well as aminoacyl
modification, see 6) imparted potency against multidrug-
resistant strains.10 These and other precedents encouraged us
to attempt to develop a component-based, more streamlined
route to MTL that would permit structural modification of
positions 1 and 7. Here we report the successful realization of
such a route.
Our original retrosynthetic analysis targeted the protected
glycal 7 as a key subgoal, imagining in the forward direction
selective epoxidation of that intermediate from the bottom face
(as drawn) followed by stereoselective addition of various
nucleophiles to C1 (Scheme 1),11 following on earlier success
with a related transformation.12 In turn, we reasoned that
glycal 7 might be assembled by transition metal-catalyzed
cycloisomerization of a linear alkynol precursor, such as one
formed by regioselective opening of propargylic epoxide 8 with
a suitably protected oxygen nucleophile. The alkynyl epoxide 8
Received: April 2, 2021
Published: April 30, 2021
https://doi.org/10.1021/jacs.1c03536
J. Am. Chem. Soc. 2021, 143, 6829−6835
© 2021 American Chemical Society
6829

Journal of the American Chemical Society
pubs.acs.org/JACS
Communication
Scheme 1. Retrosynthetic Analysis and Construction of
Building Blocks for a Proposed Nitroaldol Coupling
Scheme 2. Unanticipated Formation of a Cyclic Nitroaldol
Adduct and Analogous Construction of the MTL 3,4,5-
Stereotriad
gel (in contrast to 8 itself), the potential use of cyclic
stereocontrol to bias the subsequent reduction of C6, and the
concise internal protection of the functionality at positions C4
and C6 in the form of a N−O linkage. We wondered whether
the 3,4,5-stereotriad of MTL might be established by a similar
chemical transformation, similar but not identical because our
original retrosynthetic analysis anticipated inversion at C3
rather than C4 (Scheme 1), as occurs in the formation of 17.
In theory, this could be rectified by using the enantiomer of
epoxy aldehyde 9, which we prepared by a two-step route
analogous to the one used to provide the (3S,4R) isomer, with
some changes to address scalability.21 When we prepared
(3R,4S)-9 and attempted coupling with 10 in the presence of
cesium carbonate (EtOH, 23 °C), we obtained after
chromatography the desired cycloadduct 18 in 32% yield
(minor) and, separately, the C5 epimeric cycloadduct in 50%
yield (major, not depicted, dr 45:55).
From a screen examining the ability of various chiral
catalysts to steer the diastereoselectivity of the coupling of
(3R,4S)-9 and 10 toward the desired diastereoisomer 18, we
found that a copper(II) system employing cyclohexanediamine
ligand 2022 afforded the initial nitroaldol product 21 with a C5
dr of ∼95:5 (1H NMR analysis; though inconsequential, the
distribution of indeterminate C6 epimers was estimated to be
∼85:15).23 Following disappearance of the limiting epoxyalde-
hyde component, triethylamine was introduced, and the
mixture was warmed to promote smooth cyclization of 21 to
isoxazoline N-oxide 18 (Scheme 3).24 Thus, this optimized
coupling was scaled to produce 16.4 g of 18 in 88% isolated
yield in one operation. C-Desilylation of this product with
tetra-n-butylammonium fluoride, followed by selective O-
protection of the sterically less encumbered propargylic alcohol
provided silyl ethers 22 (a = TBDPS, b = TIPS) in good yield;
the crystallinity of 22b permitted unambiguous assignment of
all stereochemistry by single-crystal X-ray diffractometry.
With suitably protected alkynols 22 in hand, we then sought
to identify conditions for transition metal-catalyzed cyclo-
isomerization to form the corresponding glycal. We observed
that both the isoxazoline N-oxide 22a and its reduced
counterpart 23 (formed in 70% yield upon warming 22a
with trimethylphosphite) were unreactive toward tung-
sten(0),25 rhodium(I),26 and ruthenium(II)27 catalysts for
glycal formation, leading us to speculate that the polar
isoxazoline N-oxide and isoxazoline functional groups might
serve as catalyst poisons. We elected instead to reduce the
by design also comprises a β-hydroxy nitro function,13
permitting its convergent assembly by a proposed diaster-
eoselective Henry reaction of components 9, an epoxy
aldehyde, and the nitro ether 10. Varying the latter
component, particularly through inclusion of an easily varied
element such as an alcohol, alkene, or masked aldehyde, would
permit facile diversification of C7.
Building blocks 9 and 10 were each prepared in multigram
amounts by known sequences of 4−5 steps from starting
materials available in bulk. The allylic alcohol precursor 12 was
prepared by formylation of tri-iso-propylsilylacetylene (11),
Horner−Wadsworth−Emmons olefination, then ester reduc-
tion.14 Sharpless epoxidation followed by Dess−Martin
oxidation then furnished epoxy aldehyde (3S,4R)-9 (90% ee,
determined by Mosher analysis of the epoxy alcohol
precursor).15 The nitro ether 10 was prepared from
enantiopure nitro acetate 1516 by acetate hydrolysis and O-
benzylation under acidic conditions, then recrystallization from
ethyl acetate−hexane (17.6 g, 66% yield from enantiopure 15).
Spectroscopic data and melting-point determination of the
resulting white solid matched literature reports for 10;17 the
product was found to be optically pure (≥99% ee) by chiral
HPLC analysis.
With building blocks 9 and 10 in hand, we investigated their
proposed coupling to form nitroaldol adduct 8 (Scheme 2).
Under a variety of conditions commonly employed for such
couplings (e.g., potassium tert-butoxide−tetrahydrofuran,
potassium carbonate−methanol, potassium fluoride−isopropa-
nol, silica gel), we observed complex mixtures of diastereo-
meric nitroaldol addition products, the separation and
characterization of which were complicated by their apparent
instability toward retro-Henry fragmentation on silica gel.
However, when we attempted coupling of 9 and 10 using the
chiral ligand 16 and copper(II) bromide,18 we observed the
formation of a notably polar byproduct, which was isolated in
30% yield and proved to be isomeric with the desired Henry
adduct. X-ray analysis of this crystalline material revealed it to
be the isoxazoline N-oxide 17, arising from the desired Henry
adduct (8) by nitronate formation and consequent cyclization.
Such cyclizations involving ethyl nitroacetate have been
documented by Righi and Jørgensen.19,20
While unanticipated, isoxazoline N-oxide 17 presented
several beneficial features in the context of our synthesis
goals. These included the stability of the product toward silica
6830
https://doi.org/10.1021/jacs.1c03536
J. Am. Chem. Soc. 2021, 143, 6829−6835

Journal of the American Chemical Society
pubs.acs.org/JACS
Communication
Scheme 3. Synthesis of MTL via Diastereoselective Nitroaldol Cyclization, Cycloisomerization, and cis-α-Thioglycosylation
and Extension of This Route to the Assembly of a C-Glycosidic Variant
isoxazoline 23, choosing conditions conducive toward internal
hydroxyl-directed reduction. Thus, exposure of 23 to sodium
triacetoxyborohydride in a mixed solvent system comprising
trifluoroacetic acid28 and acetonitrile led to smooth reduction
of the CN double bond to afford only a single
diastereoisomer. Protection of the resulting isoxazolidine as
its 2-(trimethylsilyl)ethoxycarbonyl (Teoc) derivative then
furnished 24, which proved to be an excellent substrate for
tungsten(0)-catalyzed glycal formation using conditions
reported by McDonald and co-workers.25a,b We found that
this sequence of transformations was readily scaled, providing
up to 3.5 g of glycal 25 in a single run.
Scheme 4. Elaboration of Vinyl Glycoside 28 to Diverse C1
Variants of MTL
The remaining steps of our original retrosynthetic plan
proceeded as envisioned, permitting the synthesis of MTL by a
straightforward sequence of epoxidation, thioglycosylation, and
deprotection. Epoxidation of glycal 25 with dimethyldioxir-
ane29,30 proceeded with perfect selectivity for the convex face,
providing the epoxide 26 in quantitative yield on scales up to
1.5 g. cis-α-Thioglycosylation was then achieved using
trimethyl(methylthio)silane as glycosyl acceptor and trime-
thylsilyl trifluoromethanesulfonate as a Lewis-acid promoter,
producing 27 in 86% yield and 91:9 dr when tetrahydrofuran
was used as solvent.31 Finally, O-desilylation, dissolving-metal
debenzylation, and N−O bond cleavage with zinc in acetic acid
(the latter two steps may be performed in the same flask)
furnished fully synthetic MTL (1) in 82% overall yield from
27.
Epoxide 26 provided a means by which to install alkyl
groups at the C1 position with high α-selectivity. Treatment of
26 with vinylzinc trifluoroacetate, an amphiphilic reagent that
putatively serves to activate the glycosyl donor while directing
nucleophilic attack to the same face of the nascent
oxocarbenium ion (pictured), provided the desired cis-α-C-
glycoside in 80% yield as a single diastereomer (Scheme 3).32
The resulting α-vinylated product 28 was readily transformed
into a number of diverse MTL analogs (Scheme 4). For
example, isosteric replacement of the methylthio group within
MTL was possible through desilylation and hydrogenation of
28, providing the α-ethyl MTL analog 29, while cyclo-
propanation provided access to the α-cyclopropyl analog 30.
Sequential exposure of a methanolic solution of 28 to ozone
gas and sodium borohydride produced the corresponding α-
hydroxymethyl analog, which could be selectively activated
with p-toluenesulfonyl chloride. Desilylation and hydro-
genation as before then furnished 1-(tosyloxy)methyl lincos-
amine analog 31, whose structure was established unambigu-
ously through single-crystal X-ray diffractometry. The latter
compound served as a valuable precursor to diverse
lincosamides bearing non-natural substitution at the C1
position.
Amino sugar 29 was transformed into fully synthetic
lincosamide analog 37 following established paths (Scheme
5).8b Subjecting 32, the N-trifluoroacetamide of 29, to 6 equiv
of 1-(chloromethylene)piperidinium chloride (33) resulted in
6831
https://doi.org/10.1021/jacs.1c03536
J. Am. Chem. Soc. 2021, 143, 6829−6835

Journal of the American Chemical Society
pubs.acs.org/JACS
Communication
Scheme 5. Assembly of a Fully Synthetic Azepanamide
Scheme 6. Assembly of 8-Norlincomycin through Building-
Block Exchange
regioselective 7-deoxychlorination;33 careful addition of
sodium hydroxide then effected hydrolysis of pyranose formate
esters and the nitrogen protecting group. Convergent coupling
to the aminoacyl component discovered by Vicuron scientists
was performed next, followed by N-Boc removal and
diastereoselective azepane hydrogenation34 to furnish azepa-
namide 37 in 50% yield from 34.
In order to explore C7 substitution effects within the
lincosamides, we substituted 2-nitroethanol (38) for the nitro
ether 10 in the key nitroaldol coupling, obtaining isoxazoline
39 in 45% yield on multigram scale (Scheme 6). The
diastereoselectivity of the latter addition was modest (62:38
dr in favor of 39) but serviceable; efforts to screen chiral
catalysts as with 10 afforded no practical advantage in this case.
Elaboration of 39 to aminotetraol 40 was achieved as in the
synthesis of MTL and proceeded in 21% yield over the 9 steps.
Finally, in this illustration we chose to couple with trans-4-n-
propylhygric acid 4135 to produce 8-norlincomycin (42) in
74% yield. Selective functionalization of the primary alcohol
group within 42 was possible, permitting the synthesis of 15
additional propylhygramides bearing non-natural substitution
to C7.
In this fashion and through a combination of building-block
exchange and late-stage derivatization, a library of 41
lincosamides bearing diverse substitutions at positions 1 and
7 was prepared for evaluation against a panel of pathogenic
Table 1. Structures and Minimum Inhibitory Concentrations (μg/mL) of Selected Lincosamides Prepared by the Route
Described
6832
https://doi.org/10.1021/jacs.1c03536
J. Am. Chem. Soc. 2021, 143, 6829−6835

Journal of the American Chemical Society
pubs.acs.org/JACS
Communication
bacteria (Table 1). Of these analogs, 18 displayed minimum
inhibitory concentrations (MICs) of ≤4 μg/mL against the
standard Streptococcus pneumoniae strain ATCC 49619, a
Gram-positive isolate susceptible toward canonical lincosa-
mides such as lincomycin and clindamycin (MICs = 0.5 and
0.125 μg/mL, respectively). Analysis of structure−activity
relationships of a selection of representative lincosamides
illuminates a subtle reliance on the C1 thiomethyl substituent
of 5 on activity, for instance, as nearly isosteric replacement
with ethyl (37) or chloromethyl (43) groups produced analogs
with diminished activities, particularly against Gram-negative36
and MLSB Gram-positive strains. Similarly, C7 methylation (as
in lincomycin [2]) proved critically beneficial to antimicrobial
activity, as 8-norlincomycin (42), 7-azidolincomycin (47), and
biarylsulfide 49 each displayed significantly greater MICs in all
tested organisms relative to their methylated counterparts (for
a complete listing of lincosamides synthesized by the routes
described here, with corresponding MIC data, see ref 5.).
Together these results suggest particular electronic require-
ments at the C1 position and conformationally rigidifying
requirements at C7, which may be incorporated into the design
and evaluation of new lincosamides targeting challenging drug-
resistant pathogens.
Jack W. Stevenson − Department of Chemistry and Chemical
Biology, Harvard University, Cambridge, Massachusetts
02138, United States; orcid.org/0000-0001-7261-4958
Amarnath Pisipati − Department of Chemistry and Chemical
Biology, Harvard University, Cambridge, Massachusetts
02138, United States
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c03536
Notes
The authors declare the following competing financial
interest(s): A.G.M. and M.J.M. have filed an international
patent application, WO/2019/032956, Lincosamide Anti-
biotics and Uses Thereof.
ACKNOWLEDGMENTS
■
This work was generously supported by the Blavatnik
Biomedical Accelerator Program at Harvard University and
by the LEO Foundation (grant LF18006). M.J.M. was
supported by the National Science Foundation Graduate
Research Fellowship under Grant No. DGE1144152. J.W.S.
thanks the Harvard College Research Program for summer
undergraduate research funding. The authors thank Dr. Shao-
Liang Zheng for conducting X-ray crystallographic analyses,
Dr. William Weiss (University of North Texas Health Science
Center) and Micromyx L.L.C. for performing antimicrobial
screening, and Drs. Ziyang Zhang, Fan Liu, Thomas
Dougherty, and Su Chiang for their valuable insights
contributed during the execution of this work.
Extending nitroaldol chemistry for amino sugar synthesis,13
we have developed a platform to discover new lincosamides
with variations at positions 1 and 7. These modifications would
have been difficult or impossible to achieve using semisyn-
thesis. The route features two-component assembly by a
nitroaldol cyclization reaction with full diastereocontrol and a
versatile glycal epoxide intermediate. With concurrent develop-
ment of similarly flexible routes to novel southern-half
residues,37,38 this work provides the basis for broad discovery
within this underexplored antibiotic class.
REFERENCES
■
(1) Hoeksema, H.; Bannister, B.; Birkenmeyer, R. D.; Kagan, F.;
Magerlein, B. J.; MacKellar, F. A.; Schroeder, W.; Slomp, G.; Herr, R.
R. Chemical Studies on Lincomycin. J. Am. Chem. Soc. 1964, 86,
4223−4224.
ASSOCIATED CONTENT
■
sı
* Supporting Information
(2) (a) Schlunzen, F.; Zarivach, R.; Harms, J.; Bashan, A.; Tocilj, A.;
̈
Albrecht, R.; Yonath, A.; Franceschi, F. Structural basis for the
interaction of antibiotics with the peptidyl transferase centre in
eubacteria. Nature 2001, 413, 814−821. (b) Tu, D.; Blaha, G.; Moore,
P. B.; Steitz, T. A. Structures of MLSBK Antibiotics Bound to Mutated
Large Ribosomal Subunits Provide a Structural Explanation for
Resistance. Cell 2005, 121, 257−270. (c) Dunkle, J. A.; Xiong, L.;
Mankin, A. S.; Cate, J. H. D. Structures of the Escherichia coli
ribosome with antibiotics bound near the peptidyl transferase center
explain spectra of drug action. Proc. Natl. Acad. Sci. U. S. A. 2010, 107,
17152−17157. (d) Matzov, D.; Eyal, Z.; Benhamou, R. I.; Shalev-
Benami, M.; Halfon, Y.; Krupkin, M.; Zimmerman, E.; Rozenberg, H.;
Bashan, A.; Fridman, M.; Yonath, A. Structural insights of
lincosamides targeting the ribosome of. Nucleic Acids Res. 2017, 45,
10284−10292.
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c03536.
Detailed experimental procedures and characterization
data for all new compounds (PDF)
Accession Codes
CCDC 2072279−2072281 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
(3) Courvalin, P.; Ounissi, H.; Arthur, M. Multiplicity of
Macrolide−Lincosamide−Streptogramin Antibiotic Resistance Deter-
minants. J. Antimicrob. Chemother. 1985, 16 (SupplA), 91−100.
(4) (a) Bannister, B. Modifications of lincomycin involving the
carbohydrate portion. Part I. The 2-O-methyl and 2-deoxy-analogues.
J. Chem. Soc., Perkin Trans. 1 1972, 3025−3030. (b) Bannister, B.
Modifications of lincomycin involving the carbohydrate portion. Part
II. Analogues with d-gluco and d-ido-stereochemistry. J. Chem. Soc.,
Perkin Trans. 1 1972, 3031−3036. (c) Bannister, B. Modifications of
lincomycin involving the carbohydrate portion. Part III. The 7-O-
methyl and 6-de-(1-hydroxyethyl) analogues. J. Chem. Soc., Perkin
Trans. 1 1973, 1676−1682. (d) Bannister, B. Modifications of
lincomycin involving the carbohydrate portion. Part IV. (7S)-7-
alkoxy-7-deoxy-analogues. J. Chem. Soc., Perkin Trans. 1 1974, 360−
369.
AUTHOR INFORMATION
■
Corresponding Author
Andrew G. Myers − Department of Chemistry and Chemical
Biology, Harvard University, Cambridge, Massachusetts
02138, United States; orcid.org/0000-0001-9602-6915;
Email: myers@chemistry.harvard.edu
Authors
Matthew J. Mitcheltree − Department of Chemistry and
Chemical Biology, Harvard University, Cambridge,
Massachusetts 02138, United States; orcid.org/0000-
0003-3774-628X
6833
https://doi.org/10.1021/jacs.1c03536
J. Am. Chem. Soc. 2021, 143, 6829−6835

Journal of the American Chemical Society
pubs.acs.org/JACS
Communication
(5) For a comprehensive review of lincosamide structure−activity
relationship data, see: Mitcheltree, M. J. A platform for the discovery
of new lincosamide antibiotics. Ph.D. Dissertation, Harvard
University, Cambridge, MA, 2018, http://nrs.harvard.edu/urn-
3:HUL.InstRepos:40050042 (Accessed 2021-04-20).
(15) Dale, J. A.; Mosher, H. S. Nuclear magnetic resonance
enantiomer reagents. Configurational correlations via nuclear
magnetic resonance chemical shifts of diastereomeric mandelate, O-
methylmandelate, and α-methoxy-α-trifluoromethylphenylacetate
(MTPA) esters. J. Am. Chem. Soc. 1973, 95, 512−519.
(16) Kitayama, T. Asymmetric syntheses of pheromones for
Bactrocera nigrotibialis, Andrena wilkella, and Andrena haemorrhoa F
from a chiral nitro alcohol. Tetrahedron 1996, 52, 6139−6148.
(17) Bartoli, G.; Marcantoni, E.; Petrini, M. Enantioselective
synthesis of nitrogen derivatives by allyl Grignard addition on
optically active nitroalkanes. J. Chem. Soc., Chem. Commun. 1991,
793−794.
(18) Xu, K.; Lai, G.; Zha, Z.; Pan, S.; Chen, H.; Wang, Z. A Highly
anti-Selective Asymmetric Henry Reaction Catalyzed by a Chiral
Copper Complex: Applications to the Syntheses of (+)-Spisulosine
and a Pyrroloisoquinoline Derivative. Chem. - Eur. J. 2012, 18,
12357−12362.
(19) (a) Rosini, G.; Galarini, R.; Marotta, E.; Righi, P. Stereo-
selective synthesis of 3-(ethoxycarbonyl)-4-hydroxy-5-(1-hydroxyalk-
yl)-2-isoxazoline 2-oxides by reaction of 2,3-epoxy aldehydes and
ethyl nitroacetate on alumina surface. J. Org. Chem. 1990, 55, 781−
783. (b) Marotta, E.; Micheloni, L. M.; Scardovi, N.; Righi, P. One-
Pot Direct Conversion of 2,3-Epoxy Alcohols into Enantiomerically
Pure 4-Hydroxy-4,5-dihydroisoxazole 2-Oxides. Org. Lett. 2001, 3,
727−729.
(20) Jiang, H.; Elsner, P.; Jensen, K. L.; Falcicchio, A.; Marcos, V.;
Jørgensen, K. A. Achieving Molecular Complexity by Organocatalytic
One-Pot StrategiesA Fast Entry for Synthesis of Sphingoids, Amino
Sugars, and Polyhydroxlyated α-Amino Acids. Angew. Chem., Int. Ed.
2009, 48, 6844−6848.
(21) Namely, by lowering the catalyst loading in the Sharpless
asymmetric epoxidation reaction (to 40 mol % from 128 mol %) and
by substituting Parikh−Doering oxidation for Dess−Martin, we could
prepare up to 12 g of (3R,4S)-9 in a single batch (57% yield over 2
steps, 88% ee). See Supporting Information for details.
(22) (a) Chougnet, A.; Zhang, G.; Liu, K.; Häussinger, D.; Kägi, A.;
Allmendinger, T.; Woggon, W.-D. Diastereoselective and Highly
Enantioselective Henry Reactions using C1-Symmetrical Copper(II)
Complexes. Adv. Synth. Catal. 2011, 353, 1797−1806. (b) Zhang, G.;
Yashima, E.; Woggon, W.-D. Versatile Supramolecular Copper(II)
Complexes for Henry and Aza-Henry Reactions. Adv. Synth. Catal.
2009, 351, 1255−1262.
(23) Although the melting point of 1,4-dioxane is 12 °C, freezing-
point depression prevents the reaction mixture from solidifying.
(24) The overall diastereoselectivity of this transformation was
determined by 1H NMR analysis of the reaction mixture at
completion, revealing by integration of epimeric C5 methine
resonances a dr of 98:2.
(25) (a) McDonald, F. E.; Reddy, K. S.; Díaz, Y. Stereoselective
Glycosylations of a Family of 6-Deoxy-1,2-glycals Generated by
Catalytic Alkynol Cycloisomerization. J. Am. Chem. Soc. 2000, 122,
4304−4309. (b) Koo, B.-S.; McDonald, F. E. Fischer Carbene
Catalysis of Alkynol Cycloisomerization: Application to the Synthesis
of the Altromycin B Disaccharide. Org. Lett. 2007, 9, 1737−1740.
(c) Wipf, P.; Graham, T. H. Photoactivated Tungsten Hexacarbonyl-
Catalyzed Conversion of Alkynols to Glycals. J. Org. Chem. 2003, 68,
8798−8807.
(26) (a) Trost, B. M.; Rhee, Y. H. A Rh(I)-Catalyzed Cyclo-
isomerization of Homo- and Bis-homopropargylic Alcohols. J. Am.
Chem. Soc. 2003, 125, 7482−7483. (b) Codelli, J. A.; Puchlopek, A. L.
A.; Reisman, S. E. Enantioselective Total Synthesis of (−)-Acetylar-
anotin, a Dihydrooxepine Epidithiodiketopiperazine. J. Am. Chem. Soc.
2012, 134, 1930−1933.
(27) (a) Trost, B. M.; Rhee, Y. H. A. Ru Catalyzed Divergence:
Oxidative Cyclization vs Cycloisomerization of Bis-homopropargylic
Alcohols. J. Am. Chem. Soc. 2002, 124, 2528−2533. (b) Trost, B. M.;
Rhee, Y. H. A Flexible Approach toward trans-Fused Polycyclic
Tetrahydropyrans. A Synthesis of Prymnesin and Yessotoxin Units.
Org. Lett. 2004, 6, 4311−4313. (c) Zeng, M.; Li, L.; Herzon, S. B. A
(6) (a) De Boer, C.; Dietz, A.; Wilkins, J. R.; Lewis, C. N.; Savage,
G. M. Celesticetin − a new crystalline antibiotic. I. Biologic studies of
celesticetin. In Antibiotics Annual 1954−55; Welch, H., Marti-Ibanez,
F., Eds.; Medical Encyclopedia: New York, 1955; p 831.
(b) Hoeksema, H.; Hinman, J. W. Proceedings of the 129th National
Meeting for the American Chemical Society, American Chemical
Society: Washington, DC, 1956. (c) Hoeksema, H. Celesticetin. IV.
The Structure of Celesticetin. J. Am. Chem. Soc. 1964, 86, 4224−4225.
(7) (a) Magerlein, B. J.; Birkenmeyer, R. D.; Kagan, F. Lincomycin.
VI. 4′-Alkyl Analogs of Lincomycin. Relationship between Structure
and Antibacterial Activity. J. Med. Chem. 1967, 10, 355−359.
(b) Magerlein, B. J.; Kagan, F. Lincomycin. VIII. 4′-Alkyl-1′-
demethyl-4′-depropylclindamycins, potent antibacterial and antima-
larial agents. J. Med. Chem. 1969, 12, 780−784. (c) Birkenmeyer, R.
D.; Kagan, F. Lincomycin. XI. Synthesis and structure of clindamycin,
a potent antibacterial agent. J. Med. Chem. 1970, 13, 616−619.
(8) (a) O’Dowd, H.; Erwin, A. L.; Lewis, J. G. Lincosamide
Antibacterials. In Natural Products in Medicinal Chemistry; Hanessian,
S., Ed.; Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim,
Germany, 2014; pp 251−270. (b) Lewis, J. G.; Anandan, S. K.;
O’Dowd, H.; Gordeev, M. F.; Li, L. Lincomycin derivatives possessing
antibacterial activity. US Patent 7,361,743 B2, April 22, 2008.
(9) Dondoni, A.; Franco, S.; Merchan, F.; Merino, P.; Tejero, T.
Stereocontrolled addition of 2-Thiazolyl Organometallic Reagents to
C-Galactopyranosylnitrone. A Formal Synthesis of Destomic Acid and
Lincosamine. Synlett 1993, 1993, 78−80.
(10) (a) Umemura, E.; Wakiyama, Y.; Kumura, K.; Ueda, K.;
Masaki, S.; Watanabe, T.; Yamamoto, M.; Hirai, Y.; Fushimi, H.;
Yoshida, T.; Ajito, K. Synthesis of novel lincomycin derivatives and
their in vitro antibacterial activities. J. Antibiot. 2013, 66, 195−198.
(b) Wakiyama, Y.; Kumura, K.; Umemura, E.; Masaki, S.; Ueda, K.;
Sato, Y.; Hirai, Y.; Hayashi, Y.; Ajito, K. Synthesis and SARs of novel
lincomycin derivatives Part 5: optimization of lincomycin analogs
exhibiting potent antibacterial activities by chemical modification at
the 6- and 7-positions. J. Antibiot. 2018, 71, 298−317. (c) Umemura,
E.; Kumura, K.; Masaki, S.; Ueda, K.; Wakiyama, Y.; Sato, Y.;
Yamamoto, M.; Ajito, K.; Watanabe, T.; Kaji, C. Lincosamide
Derivatives and Antimicrobial Agents Comprising the Same as Active
Ingredient. U. S. Patent 7,867,980 B2, January 11, 2011.
(11) Danishefsky, S. J.; Bilodeau, M. T. Glycals in Organic Synthesis:
The Evolution of Comprehensive Strategies for the Assembly of
Oligosaccharides and Glycoconjugates of Biological Consequence.
Angew. Chem., Int. Ed. Engl. 1996, 35, 1380−1419.
(12) Lim, S. M.; Hill, N.; Myers, A. G. A Method for the Preparation
of Differentiated trans-1,2-Diol Derivatives with Enantio- and
Diastereocontrol. J. Am. Chem. Soc. 2009, 131, 5763−5765.
(13) (a) Zhang, Z.; Fukuzaki, T.; Myers, A. G. Synthesis of d-
Desosamine and Analogs by Rapid Assembly of 3-Amino Sugars.
Angew. Chem., Int. Ed. 2016, 55, 523. (b) Zhang, Z. A platform for the
synthesis of new macrolide antibiotics. Ph.D. Dissertation, Harvard
University, 2016. (c) Liu, F. Development of a component-based
synthesis of new aminoglycoside antibiotics, and diastereoselective
Michael−Claisen cyclizations en route to 5-oxatetracyclines. Ph.D.
Dissertation, Harvard University, 2017.
(14) (a) Robles, O.; McDonald, F. E. Modular Synthesis of the C9−
C27 Degradation Product of Aflastatin A via Alkyne−Epoxide Cross-
Couplings. Org. Lett. 2008, 10, 1811−1814. (b) Sohn, S. S.; Rosen, E.
L.; Bode, J. W. N-Heterocyclic Carbene-Catalyzed Generation of
Homoenolates: γ-Butyrolactones by Direct Annulations of Enals and
Aldehydes. J. Am. Chem. Soc. 2004, 126, 14370−14371. (c) Candy,
M.; Tomas, L.; Parat, S.; Heran, V.; Bienaymé, H.; Pons, J.-M.; Bressy,
C. A Convergent Approach to (−)-Callystatin A Based on Local
Symmetry. Chem. - Eur. J. 2012, 18, 14267−14271.
6834
https://doi.org/10.1021/jacs.1c03536
J. Am. Chem. Soc. 2021, 143, 6829−6835

Journal of the American Chemical Society
pubs.acs.org/JACS
Communication
Highly Active and Air-Stable Ruthenium Complex for the Ambient
Temperature Anti-Markovnikov Reductive Hydration of Terminal
Alkynes. J. Am. Chem. Soc. 2014, 136, 7058−7067. (d) Zeng, M.;
Herzon, S. B. Synthesis of 1,3-Amino Alcohols, 1,3-Diols, Amines, and
Carboxylic Acids from Terminal Alkynes. J. Org. Chem. 2015, 80,
8604−8618.
(28) Less acidic additives resulted in little to no conversion of the
isoxazoline substrate. The pKa of protonated 3-methylisoxazole is 0.55
0.10, while the pKa of trifluoroacetic acid is 0.23, consistent with a
mechanistic model requiring isoxazoline protonation for CN bond
reduction. See: (a) Bauder, C. A convenient synthesis of orthogonally
protected 2-deoxystreptamine (2-DOS) as an aminocyclitol scaffold
for the development of novel aminoglycoside antibiotic derivatives
against bacterial resistance. Org. Biomol. Chem. 2008, 6, 2952−2960.
(b) Grunanger, P.; Vita-Finzi, P. Isoxazoles. In Chemistry of
̈
Heterocyclic Compounds: Isoxazoles, Part 1; Taylor, E. C., Ed.; Wiley:
New York, 1991; Vol. 49, pp 1−416.
(29) Halcomb, R. L.; Danishefsky, S. J. On the direct epoxidation of
glycals: application of a reiterative strategy for the synthesis of β-
linked oligosaccharides. J. Am. Chem. Soc. 1989, 111, 6661−6666.
(30) Murray, R. W.; Singh, M. Synthesis of Epoxides Using
Dimethyldioxirane: trans-Stilbene Oxide. Org. Synth. 1997, 74, 91.
(31) Notably, the diastereoselectivity of this transformation was
highly dependent on the solvent and is consistent with a double-
displacement model involving ethereal solvent participation. For
instance, when tert-butyl methyl ether was used as solvent, ∼90:10 α/
β selectivity was observed, with the isolation of the β-O-methyl
glycoside byproduct, presumably arising through loss of tert-butyl
cation from an intermediate sugar−solvent oxonium adduct.
(32) Xue, S.; Han, K.-Z.; He, L.; Guo, Q.-X. Zinc-Mediated
Synthesis of α-C-Glycosides from 1,2-Anhydroglycosides. Synlett
2003, 870−872.
(33) When attempted using less electron-withdrawing groups such
as N-Boc-protected azapenamides, deoxychlorination was not
observed. Instead, participation of the C6-amide carbonyl group
gave rise to undesired oxazoline cyclization products.
(34) Wishka, D. G.; Bédard, M.; Brighty, K. E.; Buzon, R. A.; Farley,
K. A.; Fichtner, M. W.; Kauffman, G. S.; Kooistra, J.; Lewis, J. G.;
O’Dowd, H.; Samardjiev, I. J.; Samas, B.; Yalamanchi, G.; Noe, M. C.
An Asymmetric Synthesis of (2S,5S)-5-substituted Azepane-2-
Carboxylate Derivatives. J. Org. Chem. 2011, 76, 1937−1940.
(35) Herr, R. R.; Slomp, G. Lincomycin. II. Characterization and
gross structure. J. Am. Chem. Soc. 1967, 89, 2444−2447.
(36) Polybasic analogs such as 46, 49, and 50 were designed in order
to probe the effects of net charge on Gram-negative activity. See:
Myers, A. G.; Clark, R. B. Discovery of Macrolide Antibiotics Effective
against Multi-Drug Resistant Gram-Negative Pathogens. Acc. Chem.
Res. 2021, 54, 1635−1645.
(37) Mitcheltree, M. J.; Pisipati, A.; Syroegin, E. A.; Silvestre, K. J.;
Klepacki, D.; Mason, J. D.; Terwilliger, D. W.; Testolin, G.; Pote, A.
R.; Wu, K. J. Y.; Ladley, R. P.; Chatman, K.; Mankin, A. S.; Polikanov,
Y. S.; Myers, A. G. A synthetic antibiotic scaffold effective against
multidrug-resistant bacterial pathogens. ChemRxiv 2021,
DOI: 10.26434/chemrxiv.14331407.v1.
(38) Mason, J. D.; Terwilliger, D. W.; Pote, A. R.; Myers, A. G.
Practical Synthesis of Iboxamycin, a Potent Antibiotic Candidate, in
Amounts Suitable for Studies in Animal Infection Models. ChemRxiv
2021, DOI: 10.26434/chemrxiv.14333411.v1.
6835
https://doi.org/10.1021/jacs.1c03536
J. Am. Chem. Soc. 2021, 143, 6829−6835