Total Synthesis and Structural Establishment/Revision of Antibiotics A54145

Article abstract of DOI:10.1021/acs.orglett.9b01972

A54145 is a family of antibacterial cyclic lipodepsipeptides structurally resembling daptomycin. Since its discovery in 1990, only the ambiguous structures of the methoxy-aspartic acid (MeO-Asp) and the hydroxy-asparagine (HO-Asn) have been reported. We have developed efficient routes to obtain the fully protected l-MeO-Asp and l-HO-Asn building blocks compatible with Fmoc-SPPS, and a total synthesis of A54145 that enabled us to establish its structure, consisting of l-3S-HO-Asn and l-3R-MeO-Asp, revising the wrongly proposed structure of l-3S-MeO-Asp.

Full text of DOI:10.1021/acs.orglett.9b01972

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Total Synthesis and Structural Establishment/Revision of Antibiotics
A54145
Delin Chen,†,§ Hoi Yee Chow,†,§ Kathy Hiu Laam Po,‡ Wenjie Ma,† Emily Lok Yee Leung,†
Zhenquan Sun,† Ming Liu,† Sheng Chen,‡ and Xuechen Li*,†
†Department of Chemistry, State Key Laboratory of Synthetic Chemistry, The University of Hong Kong, Hong Kong, P. R. China
‡Department of Applied Biology and Chemical Technology, State Key Lab of Chiroscience, The Hong Kong Polytechnic University,
Hung Hom, Kowloon, Hong Kong, P. R. China
S
* Supporting Information
ABSTRACT: A54145 is a family of antibacterial cyclic
lipodepsipeptides structurally resembling daptomycin. Since
its discovery in 1990, only the ambiguous structures of the
methoxy-aspartic acid (MeO-Asp) and the hydroxy-asparagine
(HO-Asn) have been reported. We have developed efficient
routes to obtain the fully protected L-MeO-Asp and L-HO-Asn
building blocks compatible with Fmoc-SPPS, and a total
synthesis of A54145 that enabled us to establish its structure,
consisting of L-3S-HO-Asn and L-3R-MeO-Asp, revising the
wrongly proposed structure of L-3S-MeO-Asp.
yclic peptides represent an important class of antibiotics,
Cmost of which exert antibacterial effects through inhibiting
nonprotein/enzyme targets,1 such as vancomycin binding to
lipid II,1 polymyxin targeting lipopolysaccharide (LPS),2 and
daptomycin inserting into membranes.3 The tendency to
develop resistance to these antibiotics among bacteria is lower
than those targeting bacterial enzymes or protein receptors.1
According to the World Health Organization (WHO) in 2018,4
antibiotic resistance became one of the biggest challenges to
global health. Given the fact that bacteria have lower tendency to
develop resistance to cyclic peptide antibiotics, development of
an efficient chemical synthesis strategy of cyclic lipodepsipeptide
antibiotic A54145 and analogues is worth investigating. The
total synthesis will help the search of next-generation cyclic
peptide antibiotics.
A54145 is a class of cyclic lipodepsipeptide isolated from
Streptomyces fradiae whose structure exhibits remarkable
similarities to daptomycin (Figure 1).5 In addition to the
nonproteinogenic 3-methyl-glutamic acid (3-mGlu), which is
also present in daptomycin, A54145 contains two other
nonproteinogenic amino acids: L-methoxy-aspartic acid (L-
MeO-Asp) and L-hydroxy-asparagine (L-HO-Asn).
Figure 1. Structures of daptomycin and A54145B.
Daptomycin was approved by the FDA in 2003 for infections
caused by Gram-positive pathogens, such as methicillin-resistant
Staphylococcus aureus (MRSA) and vancomycin-resistant Enter-
ococci (VRE). However, daptomycin failed to treat community-
acquired pneumonia (CAP) in clinical trials due to the
inhibition by pulmonary surfactant.6 Interestingly, A54145
antibacterial activities are much less affected by surfactant,
despite the structural similarities with daptomycin, with only a 2-
fold increase in its minimum inhibitory concentration (MIC) in
the presence of surfactant. Nonetheless, A54145 is 2-fold less
potent and more toxic than daptomycin.7 It is conceivable that
hybrid compounds of daptomycin and A54145 may exhibit
optimal bactericidal activity in the presence of bovine surfactant,
with the potential to treat CAP that is unresponsive to
daptomycin. Toward this goal, Cubist scientists used bioengin-
eering approaches to generate an array of daptomycin−A54145
Received: June 7, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01972
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Scheme 1. Synthesis of HO-Asn Building Blocks
Scheme 3. Synthesis of 3-mGlu Building Block
relationship between the stereochemistry of the β carbon of HO-
Asn and MeO-Asp and the antibacterial activity of A54145.
At the outset, we need to develop synthetic routes to access
two diastereomeric building blocks of both L-HO-Asn and L-
MeO-Asp, which are compatible with Fmoc-solid phase peptide
synthesis (Fmoc-SPPS), the strategy that will be used to build
the whole A54145 molecule.
Scheme 2. Synthesis of MeO-Asp Building Blocks
L-HO-Asn is a nonproteinogenic amino acid found in many
natural products.16 L-HO-Asn building blocks with various
protecting groups have been synthesized chemically by several
enantioselective synthetic strategies.15,17−20 However, the fully
protected L-HO-Asn for Fmoc-SPPS, with Trt (trityl) and TBS
(tert-butyldimethylsilyl) protecting the side-chain amide and
hydroxy group, respectively, was only reported in 2017 by Inoue
group through a 12-step synthesis.20 As we had to get access to
both diastereomers of L-HO-Asn with opposite configurations at
the β carbon, we developed a strategy comprising eight steps
only to gain two diastereomeric L-Fmoc-HO(TBS)-Asn(Trt)-
OH 6a and 6b in gram-scale, based on the three-component
coupling Passerini reaction,21,22 with easy separation of the
diastereomers in the penultimate step of the synthetic route.
The synthesis started with Fmoc-D-Ser-OH 1 as shown in
Scheme 1. After TBS protection, thioesterification and the
Fukuyama reduction,23,24 the resultant aldehyde 2 was reacted
with trityl isocyanide (TrtNC)25 and formic acid in an atom-
economical manner with excellent yield (86%). After switching
the formyl protecting group on the hydroxy group with TBS, the
primary TBS group on the resulting product 4 was removed
selectively in the presence of the secondary TBS group. Through
the extensive screening of the desilylation conditions including
PTSA, PPTS, TBAF/AcOH, or CSA in different solvents and
temperature, we found that using PTSA in MeOH at room
temperature for 1 h was optimal and afforded the desired two
diastereomers (88% in total), which could be easily separated by
chromatography. The resultant primary alcohol anti-5a and syn-
5b underwent a one-pot two-step oxidation to give rise to two
Fmoc building blocks anti-6a and syn-6b. Both H and 13C
NMR spectra of the compound syn-6b were identical to those
published in the literature.20 Hence, the absolute configuration
of the two diastereomers was defined.
Synthetic routes to access MeO-Asp have been reported by
several groups,15,26,27 with the Fmoc-SPPS compatible L-Fmoc-
threo-MeO-Asp(OtBu)-OH building block reported by the
Taylor group through five steps15 in late 2018. As shown in
Scheme 2, our 7-step synthesis to obtain both diastereomeric L-
Fmoc-MeO-Asp(OtBu)-OH building blocks 11a and 11b
started with the dihydroxylation of the commercially available
alkene 7 with OsO4/NMO/AcOH in THF/water (3:1) at room
1
hybrid analogues. However, restricted by the inherent limitation
of the biosynthetic method employed, structural variations were
limited to several sites.8 The structure of A54145 was elucidated
in 1990, but the absolute configurations of the β carbon of L-
HO-Asn and L-MeO-Asp were not established at the time.5
These two amino acids have been proposed as L-3S-HO-Asn and
L-3S-MeO-Asp in all the later literatures.9−15 In order to
establish the absolute configurations, we initiated the synthetic
studies to prepare all four diastereomeric A54145B analogues
with diastereomeric L-HO-Asn and L-MeO-Asp, with which we
expected to establish the bona fide structure and to evaluate the
B
DOI: 10.1021/acs.orglett.9b01972
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Organic Letters
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Scheme 4. Syntheses of A54145 and Analogues
Sharpless asymmetric dihydroxylation could allow us to get a
single diastereomer in the first step of the synthetic route once
we define the stereocenters of L-MeO-Asp in A54145. The
primary alcohol of diol 8 was selectively protected with TBS
group, followed by methylation of the secondary hydroxy group
with Ag2O and MeI to yield the corresponding methyl ether
epimers 10a and 10b that could be easily separated by
chromatography. Both of the resulting epimers were trans-
formed to the desired carboxylic acid 11a and 11b by a four-step
sequence involving: (1) removal of the TBS protect group via
TBAF/AcOH; (2) oxidation of the resulting hydroxy group to
the corresponding carboxylic acid by treating with TEMPO/
BAIB/NaH2PO4 in DCM/THF/H2O; (3) esterification of the
carboxylic acid using tert-butyl trichloroacetimindate (TBTA)
under the catalysis of BF3·Et2O; (4) removal of the benzyl group
by catalytic hydrogenation. In order to confirm the absolute
stereochemistry at the 3-OMe position, compounds 11a and
Table 1. Minimal Inhibitory Concentrations (in μg/mL) of
A54145 Analogues
bacterial strain
MRSA86
0.5
⩾32
MRSA88
0.5
⩾32
SA ATCC29213
0.5
Daptomycin
24a
a
a
a
⩾32
24b
24c
24d
1
⩾32
⩾32
0.5
⩾32
⩾32
0.5
⩾32
⩾32
a
a
a
a
a
a
25a
16
8
8
25b
8
8
8
25c
25d
2
⩾32
2
16
2
16
a
a
The highest concentration tested was 16 μg/mL.
temperature overnight to afford compound 8 as a pair of epimers
in 3:2 ratio. Dihydroxylation with higher stereoselectivity using
C
DOI: 10.1021/acs.orglett.9b01972
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Nα-Fmoc group deprotection (20 min, rt) and HATU-mediated
amine coupling (1 h, rt), the on-resin esterification was achieved
by reacting the freshly prepared symmetric anhydride of Fmoc-
Ile-OH by DIC with the threonine−OH catalyzed by DMAP for
48 h. Then the resultant resin-linked peptide was subsequently
coupled with Fmoc-3-mGlu(OtBu)-OH 18 and Fmoc-D-
Asn(Trt)-OH under standard SPPS conditions to afford the
whole linear sequence. After deprotecting the N-terminal Fmoc
group and TBS group of the linear peptide, the side-chain
protected linear peptide was released from the trityl resin with
AcOH/TFE/DCM (1:1:8, v/v/v) to give the acyclic precursor
22a−d. The macrocyclization proceeded smoothly in DCM/
DMF(3:1) with PyBOP as the coupling reagent to afford the
cyclic peptide. Then global deprotection of the side chain
protecting groups (tBu, Trt, Boc) via TFA/TIPS/H2O
(95:2.5:2.5, v/v/v) afforded all four possible diastereomeric
A54145B analogues 24a−d (as shown in Scheme 4) in around
3% yield in average after semipreparative reverse-phase HPLC
purification (calculated based on the resin loading).
Figure 2. Comparison of NMR spectra of synthetic A54145B nucleus
(400 MHz) and the natural A54145B nucleus (270 MHz).33
The antimicrobial activities of all four possible diastereomeric
A54145B analogues synthesized were assessed by determining
their MICs against Gram-positive bacteria strains including SA
ATCC29213 and MRSA clinical isolated strains. Our data
indicated that 24a, 24c, and 24d showed low antibacterial
activities, while compound 24b has MICs in agreement with the
reported A54145B7 (Table 1). This suggested that 24b is the
synthetic version of A54145B, consisting of L-3S-HO-Asn and L-
3R-MeO-Asp.
Based on the established structure of A54145B, we
synthesized other factors of A54145 25a−d (Scheme 4).
Their MICs are also in good agreement with the reported
studies that none of which showed better antibacterial activities
than A54145B, the most potent factor of A54145.7 A54145B
being the most effective among all factors reflected that Ile, 3-
mGlu, and the n-decanoyl tail are important for high
antibacterial activities. The MIC results of 24a−d showed that
the absolute configuration of the β carbon of both L-HO-Asn
and L-MeO-Asp also take important roles in the antibacterial
activities. This work therefore will provide a potential direction
for analogue designs for medicinal chemistry studies.
11b were, respectively, treated with TFA to remove the tBu
group followed by deprotecting the Fmoc group using
diethylamine (DEA) in DCM to yield the dicarboxylic acid
12a and 12b. Their 1H NMR spectra were compared to the same
compounds with known stereochemistry reported in the
literature26,27 (see Supporting Information). We also trans-
formed epimers 10a and 10b to the five-membered ring lactones
13a and 13b through four-step reaction to determine the
stereochemistry by 2D-NOESY NMR. The proton at C-2
position and proton of MeO group of compound 13a showed
NOE correlation (Scheme 2 and Supporting Information).
Results from the two NMR studies are consistent with each
other, and the evidence obtained provide additional con-
firmation of the absolute configurations of compounds 11a and
11b shown in Scheme 2.
The reported synthesis of (2S,3R)-3-mGlu building block 18
is lengthy (14 steps from L-glutamic acid) and labor-intensive;28
therefore, we developed an improved synthetic route that
consists of 10 steps for the synthesis of 18 based on C−H
activation strategy.29,30 As depicted in Scheme 3, stereoselective
alkylation of the known compound 1431 with tert-butyl-2-
iodoacetate successfully proceeded to provide the desired
product 15 in 73% yield utilizing the Chen’s condition for C−
H activation: Pd(OAc)2, Ag2CO3, and (BnO)2PO2H at 110 °C
in t-AmylOH.32 Deprotection of N-phthalimide of 15 with
ethylenediamine followed by conversion of the released free
amine into an azido group through treatment with TfN3 yielded
16. After activation of the amide group of 16 with the Boc group,
the free carboxylic acid 17 was obtained in 75% yield under
LiOH/H2O2 conditions. Reduction of the azido group into
amine via hydrogenation, followed by protection with
FmocOSu, furnished 18 in 76% yield over two steps.
As A54145B nucleus (A54145B without the lipid tail) has a
33
1
high-quality H NMR spectrum published in the literature,
while the literature reported 1H NMR spectrum of A54145B has
severe line broadening,34 we prepared the A54145B nucleus 26
for NMR comparison. The 1H NMR spectrum of the synthetic
A54145B nucleus 26 matched with the one reported in the
patent by Eli Lily33 (Figure 2). The optical rotation of the
synthetic A54145B 24b was in close agreement with reported
value34 (see Supporting Information). Thus, we are confident to
conclude that compound 24b has the same structure as
A54145B, comprising L-3S-HO-Asn and L-3R-MeO-Asp.
In summary, A54145 is a class of antibacterial cyclic
lipodepsipeptides with potentials for drug development. We
have developed efficient synthetic routes to obtain diastereo-
meric building blocks compatible with Fmoc-SPPS of both L-
HO-Asn and L-MeO-Asp, with eight steps and seven steps,
respectively. We also reported a 10-step synthesis of L-Fmoc-3R-
mGlu(tBu)-OH via the C−H activation strategy. Furthermore,
we have established the first total synthesis of A54145 to obtain
all four possible A54145B diastereomers. After correlating the
structure to antibacterial activities, and comparing the NMR of
the synthetic compound to the literature, the bona fide structure
of A54145B was established to contain L-3S-HO-Asn and L-3R-
With all these building blocks in hand, we continued with the
total synthesis of A54145. Due to the small steric hindrance and
the absence of epimerization during fragment coupling, we
envisaged that the amide bond between Gly and D-Asn could be
selected for the macrolactamization step, and the requisite linear
peptide precursor was readily assembled via the standard Fmoc-
SPPS on 2-chlorotrityl chloride resins. After the resin-Gly-MeO-
Asp(OtBu)-D-Lys(Boc)-Asp(OtBu)-Ala-Sar-Thr-HO(TBS)-
Asn(Trt)-D-Glu(OtBu)-Trp(Boc)-C9H19 19a−d was as-
sembled with the cycles of 20% piperidine/DMF-promoted
D
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Baltz, R. H. Genetically engineered lipopeptide antibiotics related to
A54145 and daptomycin with improved properties. Antimicrob. Agents
Chemother. 2010, 54, 1404−1413.
(9) Miao, V.; Brost, R.; Chapple, J.; She, K.; Gal, M. F.; Baltz, R. H.
The lipopeptide antibiotic A54145 biosynthetic gene cluster from
Streptomyces fradiae. J. Ind. Microbiol. Biotechnol. 2006, 33, 129−140.
(10) Grunewald, J.; Marahiel, M. A. Chemoenzymatic and template-
directed synthesis of bioactive macrocyclic peptides. Microbiol. Mol.
Biol. Rev. 2006, 70, 121−146.
(11) Kopp, F.; Grunewald, J.; Mahlert, C.; Marahiel, M. A.
Chemoenzymatic design of acidic lipopeptide hybrids: new insights
into the structure-activity relationship of daptomycin and A54145.
Biochemistry 2006, 45, 10474−10481.
(12) Mahlert, C.; Kopp, F.; Thirlway, J.; Micklefield, J.; Marahiel, M.
A. Stereospecific enzymatic transformation of alpha-ketoglutarate to
(2S,3R)-3-methyl glutamate during acidic lipopeptide biosynthesis. J.
Am. Chem. Soc. 2007, 129, 12011−12018.
(13) Strieker, M.; Marahiel, M. A. The structural diversity of acidic
lipopeptide antibiotics. ChemBioChem 2009, 10, 607−616.
(14) Alexander, D. C.; Rock, J.; Gu, J. Q.; Mascio, C.; Chu, M.; Brian,
P.; Baltz, R. H. Production of novel lipopeptide antibiotics related to
A54145 by Streptomyces fradiae mutants blocked in biosynthesis of
modified amino acids and assignment of lptJ., lptK and lptL gene
functions. J. Antibiot. 2011, 64, 79−87.
MeO-Asp, correcting the structure of A54145 with L-3S-MeO-
Asp provided in all literature. Our study also showed that the
absolute configuration at the β carbon of L-HO-Asn and L-MeO-
Asp are critical for the A54145B activities.
The chemical synthesis of A54145, together with the total
synthesis of daptomycin,28 will enable generations of a library of
hybrid compounds of daptomycin and A54145. The high
flexibility in structural modifications of total synthesis, in
contrast to bioengineering approaches, will help the search of
analogues with better performance compared to both of the
parent antibiotics in the presence of bovine surfactant, thereby
expanding the antibiotic spectrum of daptomycin or enhancing
the potency of A54145 while reducing the toxicity.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.9b01972.
Experimental procedures, characterization data of the
synthetic compounds, and 1D and 2D NMR spectra
(PDF)
(15) Moreira, R.; Taylor, S. D. Asymmetric Synthesis of Fmoc-
Protected β-Hydroxy and β-Methoxy Amino Acids via a Sharpless
Aminohydroxylation Reaction Using FmocNHCl. Org. Lett. 2018, 20,
7717−7720.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: xuechenl@hku.hk.
ORCID
(16) Zhang, Y.; Farrants, H.; Li, X. Adding a functional handle to
nature’s building blocks: the asymmetric synthesis of β-hydroxy-α-
amino acids. Chem. - Asian J. 2014, 9, 1752−1764.
Xuechen Li: 0000-0001-5465-7727
Author Contributions
§These authors contributed equally.
Notes
(17) Boger, D. L.; Lee, R. J.; Bounaud, P.-Y.; Meier, P. Asymmetric
Synthesis of Orthogonally Protected l-threo-β-Hydroxyasparagine. J.
Org. Chem. 2000, 65, 6770−6772.
(18) Jiang, W.; Wanner, J.; Lee, R. J.; Bounaud, P. Y.; Boger, D. L.
Total synthesis of the ramoplanin A2 and ramoplanose aglycon. J. Am.
Chem. Soc. 2003, 125, 1877−1887.
The authors declare no competing financial interest.
(19) Guzman-Martinez, A.; Vannieuwenhze, M. S. An Operationally
Simple and Efficient Synthesis of Orthogonally Protected L-threo-β-
Hydroxyasparagine. Synlett 2007, 2007, 1513−1516.
ACKNOWLEDGMENTS
■
This work was supported by the Research Grants Council-
Collaborative Research Fund of Hong Kong (C7038-15G,
C5026-16G) and the Area of Excellence Scheme of the
University Grants Committee of Hong Kong (AoE/P-705/16).
(20) Itoh, H.; Tokumoto, K.; Kaji, T.; Paudel, A.; Panthee, S.;
Hamamoto, H.; Sekimizu, K.; Inoue, M. Total Synthesis and Biological
Mode of Action of WAP-8294A2: A Menaquinone-Targeting Anti-
biotic. J. Org. Chem. 2018, 83, 6924−6935.
(21) Baker, R. H.; Stanonis, D. The Passerini Reaction. III.
Stereochemistry and Mechanism1,2. J. Am. Chem. Soc. 1951, 73,
699−702.
(22) Nair, V.; Rajesh, C.; Vinod, A. U.; Bindu, S.; Sreekanth, A. R.;
Mathen, J. S.; Balagopal, L. Strategies for heterocyclic construction via
novel multicomponent reactions based on isocyanides and nucleophilic
carbenes. Acc. Chem. Res. 2003, 36, 899−907.
(23) Fukuyama, T.; Lin, S. C.; Li, L. Facile reduction of ethyl thiol
esters to aldehydes: application to a total synthesis of (+)-neothramycin
A methyl ether. J. Am. Chem. Soc. 1990, 112, 7050−7051.
(24) Kanda, Y.; Fukuyama, T. Total synthesis of (+)-leinamycin. J.
Am. Chem. Soc. 1993, 115, 8451−8452.
(25) Cioc, R. C.; Preschel, H. D.; van der Heijden, G.; Ruijter, E.;
Orru, R. V. Trityl Isocyanide as a Mechanistic Probe in Multi-
component Chemistry: Walking the Line between Ugi- and Strecker-
type Reactions. Chem. - Eur. J. 2016, 22, 7837−7842.
(26) Raj, H.; Szymanski, W.; de Villiers, J.; Puthan Veetil, V.; Quax, W.
J.; Shimamoto, K.; Janssen, D. B.; Feringa, B. L.; Poelarends, G. J.
Kinetic resolution and stereoselective synthesis of 3-substituted aspartic
acids by using engineered methylaspartate ammonia lyases. Chem. - Eur.
J. 2013, 19, 11148−11152.
(27) Shimamoto, K.; Shigeri, Y.; Yasuda-Kamatani, Y.; Lebrun, B.;
Yumoto, N.; Nakajima, T. Syntheses of optically pure β-hydroxyas-
partate derivatives as glutamate transporter blockers. Bioorg. Med.
Chem. Lett. 2000, 10, 2407−2410.
REFERENCES
■
(1) Breukink, E.; Wiedwmann, I.; Van Kraaij, C.; Kuipers, O. P.; Sahl,
H. G.; De Kruijff, B. Use of the Cell Wall Precursor Lipid II by a Pore-
Forming Peptide Antibiotic. Science 1999, 286, 2361−2364.
(2) Duff, G. W.; Atkins, E. The inhibitory effect of polymyxin B on
endotoxin-induced endogenous pyrogen production. J. Immunol.
Methods 1982, 52, 333−340.
(3) Pogliano, J.; Pogliano, N.; Silverman, J. A. Daptomycin-mediated
reorganization of membrane architecture causes mislocalization of
essential cell division proteins. J. Bacteriol. 2012, 194, 4494−4504.
(4) Antibiotic resistance. https://www.who.int/news-room/fact-
sheets/detail/antibiotic-resistance (accessed December 30, 2018).
(5) Fukuda, D. S.; Bus, R. H. D.; Baker, P. J.; Berry, D. M.; Mynderse, J.
S. A54145, a new lipopeptide antibiotic complex. Isolation and
characterization. J. Antibiot. 1990, 43, 594−600.
(6) Silverman, J. A.; Mortin, L. I.; Vanpraagh, A. D.; Li, T.; Alder, J.
Inhibition of daptomycin by pulmonary surfactant: in vitro modeling
and clinical impact. J. Infect. Dis. 2005, 191, 2149−2152.
(7) Counter, F. T.; Allen, N. E.; Fukuda, D. S.; Hobbs, J. N.; Ott, J.;
Ensminger, P. W.; Mynderse, J. S.; Preston, D. A.; Wu, C. Y. E. A54145
a new lipopeptide antibiotic complex. Microbiological evaluation. J.
Antibiot. 1990, 43, 616−622.
(8) Nguyen, K. T.; He, X.; Alexander, D. C.; Li, C.; Gu, J. Q.; Mascio,
C.; Van Praagh, A.; Mortin, L.; Chu, M.; Silverman, J. A.; Brian, P.;
E
DOI: 10.1021/acs.orglett.9b01972
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(28) Lam, H. Y.; Zhang, Y.; Liu, H.; Xu, J.; Wong, C. T.; Xu, C.; Li, X.
Total synthesis of daptomycin by cyclization via a chemoselective serine
ligation. J. Am. Chem. Soc. 2013, 135, 6272−6279.
(29) Newhouse, T.; Baran, P. S. If C-H bonds could talk: selective C-
H bond oxidation. Angew. Chem., Int. Ed. 2011, 50, 3362−3374.
(30) Roizen, J. L.; Harvey, M. E.; Du Bois, J. Metal-catalyzed nitrogen-
atom transfer methods for the oxidation of aliphatic C-H bonds. Acc.
Chem. Res. 2012, 45, 911−922.
(31) Reddy, B. V.; Reddy, L. R.; Corey, E. J. Novel acetoxylation and
C-C coupling reactions at unactivated positions in alpha-amino acid
derivatives. Org. Lett. 2006, 8, 3391−3394.
(32) Zhang, S. Y.; Li, Q.; He, G.; Nack, W. A.; Chen, G.
Stereoselective synthesis of β-alkylated α-amino acids via palladium-
catalyzed alkylation of unactivated methylene C(sp3)-H bonds with
primary alkyl halides. J. Am. Chem. Soc. 2013, 135, 12135−12141.
(33) Fukuda, D. S.; Mynderse, J. S. A54145 cyclic peptides. U.S.
Patent 5,039,789, August 13, 1991.
(34) Boeck, L. D.; Fukuda, D. S.; Mynderse, J. S.; Hoehn, M. M.;
Kastner, R. E.; Papiska, H. R. A54145 antibiotics and process for their
production. U.S. Patent 4,994,270, February 19, 1991.
F
DOI: 10.1021/acs.orglett.9b01972
Org. Lett. XXXX, XXX, XXX−XXX