Total Synthesis of Tambromycin by Combining Chemocatalytic and Biocatalytic C?H Functionalization

Article abstract of DOI:10.1002/anie.201801165

A combination of genomic and metabolomic approaches recently resulted in the identification of a nonribosomal tetrapeptide tambromycin, which possesses promising antiproliferative activity and several unusual structural features, including a densely substituted indole, a methyloxazoline ring, and an unusual pyrrolidine-containing amino acid called tambroline. In this work, we identify a concise synthetic route to access tambromycin, which relies on the strategic use of biocatalytic and chemocatalytic C?H functionalization methods to prepare two key precursors to the natural product in an efficient and scalable manner. The success of our study highlights the benefits of applying the principles of biocatalytic retrosynthesis as well as C?H functionalization logic to the synthesis of complex molecular scaffolds.

Full text of DOI:10.1002/anie.201801165

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International Edition
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Accepted Article
Title: Efficient Total Synthesis of Tambromycin by Interfacing
Chemocatalytic and Biocatalytic C-H Functionalization Logic
Authors: Xiao Zhang, Emma King-Smith, and Hans Renata
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201801165
Angew. Chem. 10.1002/ange.201801165
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10.1002/anie.201801165
Angewandte Chemie International Edition
COMMUNICATION
Total Synthesis of Tambromycin by Interfacing Chemocatalytic and Bio-
catalytic C–H Functionalization Logic
Xiao Zhang,+ Emma King-Smith,+ Hans Renata*
Abstract: A combination of genomic and metabolomic approach
recently resulted in the identification of a nonribosomal tetrapeptide
tambromycin, which possesses promising antiproliferative activity
and several unusual structural features, including a densely substi-
tuted indole, a methyloxazoline ring, and an unusual pyrrolidine-
containing amino acid called tambroline. Here, we identify a concise
synthetic route to access tambromycin, which relies on the strategic
use of biocatalytic and chemocatalytic C–H functionalization meth-
ods to prepare two key precursors to the natural product in an effi-
cient and scalable manner. The success of our study highlights the
benefits of applying the principles of biocatalytic retrosynthesis as
well as C–H functionalization logic in the synthesis of complex mo-
lecular scaffolds.
synthetic challenges of nonribosomal peptide natural products,
which are often characterized by the high density of noncanoni-
cal amino acids and extensive topological modifications.
A
Me
N
Cl
rare
methyloxazoline
motif
OH
OH
N
O
OH
densely
substituted
indole
Me
H
N
O
N
H
Me
O
O
NH
tambromycin (1)
tambroline
B
O
R
O
H2N
Advances in whole-genome sequencing and bioinformatic anal-
ysis have contributed to the identification of many silent biosyn-
thetic gene clusters and led to the development of new discov-
ery strategies that reinvigorate the field of natural product re-
search.1,2,3 A recent approach that combines whole genome
sequencing and annotation with metabolomics analysis, termed
metabologenomics, has allowed the discovery of tambromycin
(1), a nonribosomal peptide natural product, from a range of
Streptomyces strains.4 Incidentally, tambromycin was found to
be identical in structure to JBIR-126, isolated independently by
Izumikawa et al. from Streptomyces sp. NBRC 111228.5 Prelim-
inary bioactivity assays against five different cancerous B- and
T-cell lines indicated selective antiproliferative activity at 20
µg/mL, though the molecular mechanism behind this activity
remains unclear. Structurally, tambromycin is derived from four
highly modified amino acid monomers. A highly substituted
indole fragment is proposed to arise from 6-chlorotryptophan.
Adjoining the indole at the C3 carbon is a rare methyloxazoline
moiety, which likely originates from dehydrative cyclization of 2-
methylserine and a carboxylic acid motif. The third amino acid
monomer is comprised of tambroline, an unusual pyrrolidine-
containing amino acid proposed to be biosynthesized from L-
lysine through a dehydrogenation event and a subsequent 5-
exo-trig cyclization of the ε-amino group (Figure 1B). Finally,
another 2-methylserine monomer, appended to the C-terminus
of tambroline, completes the structure of tambromycin. The
intriguing array of rare structural features, in combination with
the promising initial cytotoxicity data and the need to elucidate
the underlying mechanism of action, renders tambromycin an
attractive target for synthetic pursuit. Herein, we report the first
total synthesis of tambromycin, which is predicated upon the
strategic application of chemocatalytic and biocatalytic C–H
functionalization logic6 for the efficient and scalable preparation
of two key building blocks (7 and 10, respectively) en route to
the target molecule. The brevity of our synthesis argues for a
more widespread application of this strategy in addressing the
H2N
OH
actual enzyme(s)
unknown
NH
NH2
tambroline
R = OH or SCoA
C
O
O
PhthN
HLF
conditions
OMe
PhthN
OMe
NNs
NO2
H
N
S
O2
2
D
O
O
O
enzymatic C3-
hydroxylation
H2N
PG1HN
PG1HN
OR
OR
OH
OH
3
NPG2
NHPG2
biocatalytic retrosynthesis
NH2
L-lysine (3)
Figure 1. (A) The chemical structure of tambromycin (1), a cytotoxic nonribo-
somal peptide containing several rare structural motifs. (B) Proposed biogene-
sis of tambroline, a unique pyrrolidinyl amino acid contained in 1. (C) Failed
attempt at synthesizing protected tambroline with chemical C–H functionaliza-
tion method. (D) Alternative preparation of protected tambroline by applying
the principles of biocatalytic retrosynthesis (this work).
Retrosynthetically, peptide coupling disconnections resulted in
three key building blocks: a 3,4,6-trisubstituted indole fragment,
methylserine, and tambroline. Our initial work focused on the
construction of a suitably protected tambroline monomer. A
synthesis of the 2-amino-2-(pyrrolidin-2-yl)acetic acid motif was
previously reported by Hanessian,7 relying on an Arndt–Eistert
homologation, followed by α-oxidation with Davis oxaziridine,
and stereoinvertive displacement with diphenylphosphoryl azide
(DPPA) under Mitsunobu conditions. From the standpoint of
synthesis economy, this route poses major disadvantages,
particularly in the context of scale-up, due to the use of toxic and
atom-inefficient, high-mass reagents such as CH2N2, Davis
oxaziridine, diethyl azodicarboxylate (DEAD), and DPPA. Alter-
natively, a route featuring silyl enol ether addition to protected α-
ethoxypyrrolidine was reported in 2015.8 However, this approach
proceeded in racemic fashion and lacked stereocontrol, leading
to formation of both the rac-(l) and rac-(u) diastereomers in
41:59 ratio. Drawing inspiration from the proposed biogenesis of
tambroline, we envisioned the use of an intramolecular C–H
[*]
Dr. Xiao Zhang,[+] Emma King-Smith,[+] Prof. Dr. Hans Renata
Department of Chemistry
The Scripps Research Institute
130 Scripps Way, Jupiter, FL 33458
E-mail: hrenata@scripps.edu
These authors contributed equally to this work.
[+]
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/anie.201801165
Angewandte Chemie International Edition
COMMUNICATION
amination disconnection that would allow a rapid construction of
the pyrrolidine ring from a suitably protected lysine precursor.
Unfortunately, reaction of 2 with hypervalent iodine species
under various thermal and photolytic initiation conditions9 failed
to elicit any desired intramolecular cyclization (Figure 1C). This
failure led us to consider an alternative approach predicated on
the principles of biocatalytic retrosynthesis (Figure 1D).10 Under
this paradigm, target molecules are disconnected based on
available biocatalytic methods to produce the corresponding
synthons. In the case of tambroline, scission of C3–N6 bond
through a redox-neutral displacement reaction leads back to a
C3-oxidized lysine intermediate. At this stage, we were cogni-
zant that a suite of hydroxylases belonging to the iron- and α-
ketoglutarate-dependent dioxygenase (Fe/αKG) superfamily are
capable of performing regioselective C–H oxidation of free ami-
no acids.11 We were specifically drawn to a lysine hydroxylase,
KDO1, which catalyzes a regio- and stereoselective C3 hydrox-
ylation of free lysine (3).12 In the forward sense, suitable activa-
tion of C3 alcohol, followed by a stereoinvertive displacement
with the ε-amino group is anticipated to forge the requisite pyr-
rolidine ring of tambroline with complete stereocontrol. It should
be noted that relative to the P450s and Rieske dioxygenases,
the utility of Fe/αKGs in organic synthesis is still largely over-
looked.13 Thus, we reasoned that our strategy would also pro-
vide a testing ground to validate the synthetic utility of this en-
zyme superfamily.
and stereocontrol (>99% conversion). Unlike other oxygenases,
A
KDO1, αKG,
Fe2+, O2
1. Boc2O
2. BnBr
H2N
H2N
HO
BocHN
HO
>99% conversion
>10 g prepared H2N
62% over
3 steps
OH
OH
OBn
H2N
BocHN
[gram-scale]
[biocatalytic hydroxylation]
[gram-scale]
O
O
O
L-lysine (3)
4
5
SOCl2;
cat. RuCl3, NaIO4
[gram-
scale]
6
BocHN
DMA,
70 ºC
BocHN
CO2Bn
NBoc
O
O2S
OBn
O
61% over
2 steps
N
Boc
[gram-scale]
7
6
B
conditions [Lys]
LC-MS
(in lysate) (mM) conversion (%)
KDO1^
KDO1^
10
35
>95
31
35
>99
KDO1 +
GroES/
GroEL#
C
O
O
O
O
H2N
H2N
VioD
VioD
H2N
H2N
OH
OH
OH
NH
OH
OH
NH
OH
NH2
NH
NH
To ensure adequate material supply for multi-step synthesis, it is
crucial that biotransformation with KDO1 (Scheme 1) be able to
provide multi-gram quantities of the hydroxylated product. How-
ever, at the outset of our work, the scalability of this reaction was
unknown, as previous use of KDO1 was only carried out on up
to 50 mg scale. While the turnover number of this enzyme was
reported to be moderately high, the large-scale practicality of
KDO1 is also contingent upon the expression yield of the en-
zyme. To address this issue, we first evaluated the relative
expression level of KDO1 as C-His6-tagged (pET-22b(+)-KDO1)
and N-His6-tagged (pET-28a(+)-KDO1) constructs. Soluble
protein expression was observed only with pET-28a(+)-KDO1,
although the protein yield remained suboptimal (Scheme 1B). To
further improve the protein expression, we explored co-
expression of KDO1 with a variety of chaperones. From this
study, co-expression of chaperones14 GroEL and GroES using
commercially available plasmid pGro7 was found to greatly
increase soluble protein expression. The high protein concentra-
tion afforded by chaperone co-expression enabled multi-gram
scale enzymatic hydroxylation of L-Lys using clarified cell lysate.
Starting from 1 L of expression culture, a total volume of 800 mL
of clarified lysate was obtained (pre-lysis OD600 = 20) and used
directly to hydroxylate L-Lys at high substrate concentration (35
mM) in the presence of Fe2+ and αKG (Scheme 1A). Using this
protocol, 4.1 g of L-Lys could be oxidized in a single pass to
generate the C3-hydroxylated counterpart with complete regio-
N
H
4
HN
NH2
(2S,3R)-
capreomycidine
(3S)-OH-L-Arg
Scheme 1. (A) Gram-scale chemoenzymatic synthesis of protected tambroline
(7) featuring Fe/αKG-catalyzed hydroxylation of 3. (B) Improved soluble
expression of KDO1 in the presence of GroES/GroEL chaperones and subse-
quent improvement in reaction conversion using clarified cell lysate. (C) Failed
biocatalytic cascade towards tambroline employing VioD, a PLP-dependent
enzyme from the capreomycidine biosynthesis pathway. ^Cell lysis was per-
formed at OD600 = 45. #Cell lysis was performed at OD600 = 20. See Supporting
Information for full experimental details.
Fe/αKGs are self-sufficient and do not require any dedicated
reductase coupling partner or expensive biological reductant,
rendering the biocatalytic oxidation process highly economical,
even on multi-gram scale. With ample quantities of 4 in hand, we
next attempted a biocatalytic cascade for its direct conversion to
tambroline (Scheme 1C). The noncanonical amino acid capreo-
mycidine was previously shown to arise through the action of a
PLP-dependent enzyme, VioD, on (3S)-OH-L-Arg.15 This trans-
formation proceeded via the intermediacy of a PLP-bound 2,3-
dehydroarginine, followed by subsequent intramolecular cycliza-
tion of the pendant guanidino group. We reasoned that if a PLP-
bound 2,3-dehydrolysine could be formed from 4 and VioD, a
similar conjugate addition of the ε-amino group onto the aldimine
could ensue. However, all efforts to effect this transformation
with VioD were met with failure. As a workaround, a chemical
approach to tambroline starting from 4 was developed (Scheme
1A). First, the amine and the carboxylate motifs were protected
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10.1002/anie.201801165
Angewandte Chemie International Edition
COMMUNICATION
to set the stage for the key pyrrolidine ring construction. While
there exist precedents for differential protection of α- and ε-
amino groups of L-lysine, we elected for a global Boc protection
due to step economy considerations, reasoning that selective
unmasking and/or peptide coupling would be feasible at later
stages in the synthesis. Initial attempts using Appel or Mitsuno-
bu reaction on 5 resulted in undesired β-elimination to the 2-
amidoacrylate product. This issue was overcome by converting
the amino alcohol motif to the corresponding sulfamidate (6),16
followed by simple heating in DMA to generate the protected
tambroline fragment (7) in excellent yield and complete dia-
stereoselectivity. Notably, all transformations in this sequence
have been performed on at least one-gram scale, which serves
as a testament to the robustness and practicality of the route. In
addition, an X-ray crystal structure of the carboxylate salt of 7
was obtained to confirm the stereochemical assignment of the
cyclized product (See Supporting Information).
Biocatalytic methods to regioselectively halogenate this indole
fragment were briefly considered.21 However, examination of
known substrate profiles of RebH, Thal, and PrnH discouraged
us from pursuing this approach further, as indoles containing
ester or carboxylic acid at C3 are generally not accepted as
substrate by these halogenases. Instead, C6 borylation was
identified as a viable approach to access the desired trisubstitut-
ed indole fragment.22 To our delight, reaction of 8 (readily avail-
able from commercial 4-methoxyindole, see Supporting Infor-
mation) with B2Pin2 in the presence of catalytic [Ir(cod)OMe]2
and phenanthroline resulted in clean formation of the desired
C6-functionalized product without any regioisomeric byproducts.
Conversion of the borylated indole to the chlorinated counterpart
(9) was effected by treatment with CuCl2,23 which concomitantly
removed the TIPS group. While a telescoped process of this
sequence was possible (79% yield on 80 mg scale), a two-step
protocol with an intervening purification was found to be more
robust on gram scale. Subsequent N1 methylation and ester
hydrolysis furnished free acid 10.
A
O
O
O
O2,
CuSO4
(TFA)2Tl
OH
R
R
R
Tl(TFA)3
OH
O
BocHN
CO2Bn
NBoc
1. H2, Pd/C
2.
N
Me
N
Me
N
Me
Cl
Cl
• variable yields
Cl
RHN
N
CO2Me
H
Me
R = H or CF3
HO
• not scalable
NR
Me
B
1. Ir cat., phen,
B2pin2, HBpin
2. CuCl2
OMe
OMe
OMe
10
7
CO2Et
CO2Et 1. NaH,
MeI
CO2H
H2N CO2Me(11)
HATU, DIPEA
12; R = Boc
13; R = H
TFA, 90%
91% over
2 steps
53% over
2 steps
2. NaOH
N
TIPS
N
H
N
Me
Cl
Cl
73% over
2 steps
8
9
[regioselective C6–H functionalization]
[gram-scale]
O
H
N
OMe
10
Me
CO2H 11, DMTMM,
DIPEA
OMe
OH
CO2Me
N
Me
Cl
N
Me
Scheme 2. (A) Attempt at effecting C4-hydroxylation of 3,6-disubstituted
indoles. (B) The use of regioselective C6-borylation/chlorination sequence in
the preparation of trisubstituted indole 10. See Supporting Information for full
experimental details.
Cl
DAST,
CH2Cl2,
81%
14
Me
Me
over 2
steps
CO2H
CO2Me
O
O
BBr3
85%
N
N
OH
OMe
An initial survey of the literature revealed that two routes have
previously been described for the preparation of 3,4,6-
trisubstituted indole motifs: a nine-step approach17a from 2,6-
dinitrotoluene featuring a Batcho–Leimgruber indole synthesis
and an eight-step approach17b from 2-fluoro-4-halobenzaldehyde
featuring a Hemetsberger indole synthesis. While the latter was
found adequate for providing the initial supply of material in our
synthesis, the reliance on several inefficient and operationally-
tedious steps (e.g., thermal decomposition of azide, C2 decar-
boxylation under extreme heating, and sluggish Pinnick oxida-
tion, see Supporting Information for full scheme) detracts from
its large-scale utility. To address this gap, an alternative ap-
proach featuring a regioselective C–H functionalization of indole
was devised. We were initially drawn to a thallium-based meth-
odology that was reported to oxidize functionalized indoles se-
lectively at C4.18 However, in our hands, this route was found to
suffer from high variability in yields and a lack of scalability
(Scheme 2A). Additionally, attempts to attain C4 oxidation using
transition metal catalysis proved futile despite several prece-
dents on C4 alkenylation of indoles with rhodium and ruthenium
catalysis19 and C4 acetoxylation with palladium catalysis.20 As
an alternative, we focused our attention on the regioselective C6
functionalization of 3,4-disubstituted indole (e.g., 8, Scheme 2B).
N
Me
N
Me
Cl
Cl
16
15
Me
N
Cl
1. HATU, DIPEA
2. NaOH, H2O/MeOH
OH
+
N
O
13
16
OH
Me
O
H
N
O
OH
76% over 2 steps
N
H
Me
O
NH
tambromycin (1)
Scheme 3. Completion of total synthesis of 1 featuring chemoselective amide
bond formation between 13 and 16. See Supporting Information for full exper-
imental details.
Elaboration of key building blocks 7 and 10 was next pursued in
preparation for the final fragment coupling (Scheme 3). Starting
from 7, debenzylation and amide coupling with known me-
thylserine24 derivative 11 provided key fragment 12. Under the
hypothesis that selective peptide coupling could be effected on
the less hindered primary amine, global Boc deprotection was
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10.1002/anie.201801165
Angewandte Chemie International Edition
COMMUNICATION
performed to afford 13 as the TFA salt. While there are ample
precedents for the synthesis of methylthiazoline-containing
natural products, the methyloxazoline motif has only been pre-
pared in the context of medicinal chemistry analogs of halipeptin
D and largazole.25 Examination of various amide coupling condi-
tions led to the identification of DMTMM26 as the optimal reagent
to conjoin 10 and 11. Next, dehydrative cyclization to oxazoline
15 was achieved by treating amide 14 with DAST. Due to com-
plications associated with C4-OMe demethylation at later stages
in the synthesis, we chose to unmask the free phenol at this
point. Global demethylation proceeded in excellent yield to pro-
vide acid 16 and set the stage for the final fragment assembly
into tambromycin. Despite the presence of various free amines
and alcohols in 13 and 16, union of these fragments could be
effected in a chemoselective fashion in the presence of HATU
as the coupling agent. Remarkably, no undesired amide or ester
regioisomers could be detected under these conditions, validat-
ing our hypothesis that differential reactivity could be achieved
by relying on the local steric environment of the desired amine.
Subsequent removal of the methyl ester proceeded uneventfully
to complete our synthesis and afford the first synthetic sample of
tambromycin (1), whose NMR data match those reported in the
literature.
and M. Gembicky (University of California, San Diego) for X-ray
crystallographic analysis. We thank Michael G. Thomas (Univer-
sity of Wisconsin-Madison) for providing a plasmid containing
vioD. We acknowledge the Shen lab and the Roush lab for
generous access to their instrumentations.
Keywords: biocatalysis • dioxygenase • total synthesis • C–H
functionalization
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Financial support for this work was generously provided by The
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Entry for the Table of Contents
COMMUNICATION
X. Zhang, E. King-Smith, H. Renata*
Page No. – Page No.
Total Synthesis of Tambromycin by
Interfacing Chemocatalytic and Bio-
catalytic C–H Functionalization Logic
Text for Table of Contents
Cool Story, (Tam)Bro: Tambromycin, a cytotoxic nonribosomal peptide containing a rare pyrrolidinyl amino acid was synthesized in
an efficient manner by using a combination of chemocatalytic and biocatalytic C–H functionalization approach. Highlights of the route
include enzymatic C–H hydroxylation of unprotected amino acid on multiple-gram scale, a regioselective indole functionalization
using iridium catalysis, and a chemoselective peptide coupling in the presence of multiple reactive functional groups.
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