11-Step Total Synthesis of Teleocidins B-1-B-4

Article abstract of DOI:10.1021/jacs.8b13697

A unified and modular approach to the teleocidin B family of natural products is presented that proceeds in 11 steps and features an array of interesting strategies and methods. Indolactam V, the known biosynthetic precursor to this family, was accessed through electrochemical amination, Cu-mediated aziridine opening, and a remarkable base-induced macrolactamization. Guided by a desire to minimize concession steps, the tactical combination of C-H borylation and a Sigman-Heck transform enabled the convergent, stereocontrolled synthesis of the teleocidins.

Full text of DOI:10.1021/jacs.8b13697

Communication
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1
1-Step Total Synthesis of Teleocidins B‑1−B‑4
Hugh Nakamura, Kosuke Yasui, Yuzuru Kanda, and Phil S. Baran*
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States
S Supporting Information
*
ABSTRACT: A unified and modular approach to the
teleocidin B family of natural products is presented that
proceeds in 11 steps and features an array of interesting
strategies and methods. Indolactam V, the known
biosynthetic precursor to this family, was accessed
through electrochemical amination, Cu-mediated aziridine
opening, and a remarkable base-induced macro-
lactamization. Guided by a desire to minimize concession
steps, the tactical combination of C−H borylation and a
Sigman−Heck transform enabled the convergent, stereo-
controlled synthesis of the teleocidins.
he discovery of teleocidins B-1, B-2, B-3, and B-4 (1−4,
T
Figure 1) from a bacterial strain (Streptomyces meclioci-
1
dius) dates back to a report in 1960 by the Sakai group. The
structures of these intriguing indole-alkaloids were first
elucidated shortly thereafter with the aid of X-ray crystallog-
2
raphy. Although they were regarded as general toxins early
1
on, it was later discovered that they exhibit potent protein
kinase-C (PKC) activation, similar to that of phorbol and
Figure 1. Unified approach to the teleocidins (1−4) through the
tactical combination of modern transforms.
3
related natural products. Early studies revealed indolactam V
4
5
(
5), itself a popular target for synthesis, as the biosynthetic
precursor to 1−4, with the terpenoid portion arriving from a
late-stage geranylation at C-22, followed by Friedel−Crafts
for a Friedel−Crafts reaction. This order of events is notably
6
6
cyclization to forge the C-19 aryl bond. Nature appears to
opposite to that employed by nature and prior synthetic
8
indiscriminately produce 1−4 without stereocontrol, as
indicated by reports of mixtures from isolation. A stereo-
controlled pathway is clearly a vexing problem, as the distal
nature of the amino acid macrocycle and dual quaternary-
approaches. The simple indole alkaloid 5 has been the subject
of numerous synthetic studies, culminating in 11 total
syntheses (7−15 steps, 20−63% ideality). It was envisaged
that a simplified approach could commence from 4-bromo-
indole (7) by enlisting electrochemically assisted Ni-catalyzed
7
center flanked terpene fragment make any chirality relay
1
3
amination (at C-4 with 8) followed by Cu-assisted
nucleophilic aziridine opening (at C-3 with 9) and base-
induced macrocyclization.
approach unworkable. Numerous studies toward the teleo-
8
cidins have been reported over the years. Thus far, two
syntheses of 3 and 4 have been reported that proceed in 17−
The 11-step route to 1−4, outlined in Scheme 1,
commences with acetylation of commercial 4-bromoindole
2
8 steps without stereocontrol at three of the four chiral
centers (see the Supporting Information (SI) for a full
summary). This Communication discloses a simple 11-step
9
(
7, ca. $4/gram) to furnish 10 (92% yield). The ensuing C−N
coupling with valine at C-4 has precedent from both the
route to 1−4, traversing through 5, and featuring strategic uses
of electrochemical aryl amination, Cu-mediated tryptophol
construction, C−H borylation, and stereocontrolled quater-
nary center formation via a Sigman−Heck reaction.
5m
5n
Tokuyama and Billingsley groups using Ullmann (Cu-
based) conditions. In those studies, an N-Ts group was
required on the indole nitrogen. To avoid the Ts deprotection
step, an Ac group was chosen as it is easily removed upon
simple basic workup conditions. As Ullmann conditions were
unsuccessful on 10, an electrochemical (e) approach for
Our retrosynthetic analysis (Figure 1) was guided by a desire
10
to minimize concession steps and to controllably access 1−4
11
via indolactam (5). As such, C−H functionalization logic was
employed to disconnect the quaternary centers at C-19−C-6
and C-22−C-7. In a forward sense, the chirality of the C-19−
C-6 bond could be controlled by adding different ligands via a
13
amination was evaluated. Under the originally reported
conditions, only a low yield of adduct 11 was obtained. A series
12
Sigman−Heck reaction onto olefin 6, whereas the C-22−C-7
Received: December 22, 2018
Published: January 13, 2019
bond could be addressed through screening of Bronsted acids
̈
©
XXXX American Chemical Society
A
DOI: 10.1021/jacs.8b13697
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
a
Scheme 1. Total Synthesis of the Teleocidins 1−4
a
Reagents and conditions: (1) Ac O (1.5 equiv), Et N (4.1 equiv), DMAP (1 mol%), CH Cl , rt, 3 h. (2) NiBr ·glyme (19 mol%), L1 (75 mol%),
2
3
2
2
2
LiBr (8.0 equiv), DBU (4.0 equiv), DMA, rt, 7 h. (3) K CO (10.8 equiv), MeI (108 equiv), DMF, 60 °C, 58 h then MeOH, rt, 1.5 h. (4) MeMgCl
2
3
(
2.5 equiv), toluene, −78 °C, 20 min then 9 (3.0 equiv), CuCl (4.0 equiv), rt, 2.5 h. (5) MeOH/CH Cl /TMSCl (1:1:1), rt, 3 h then LDA (7.5
2
2
equiv), THF, rt, 1 h then aqueous workup (for 5) or TIPSCl (1.05 equiv), rt, 2 h (for 14). (6) TBSCl (1.2 equiv), imid. (2.6 equiv), DMF, rt, 0.5
h. (7) [Ir(cod)OMe] (10 mol%), L2 (20 mol%), B pin (4.0 equiv), octane/THF (2:1), 80 °C, 6 h then TBAF in THF (1.0 equiv), rt, 2 h then
Boc O (12.0 equiv) and DMAP (3.0 equiv), rt, 1 h. (8) NaIO (11.0 equiv), NH OAc (23.0 equiv), aq. acetone, rt, 9 h. (9) 6 (4.5 equiv),
2
2
2
2
4
4
Pd(MeCN) (OTs) (60 mol%), L3 or L4 (120 mol%) 2,6-di-tBu-py (2.4 equiv), 3 Å MS, THF/MeOH (2:1), rt, 12 h then 50 °C, 6 h. (10)
2
2
Tributyl(vinyl)stannane (21 equiv), n-BuLi (18 equiv), −78 °C, 1 h, then HFIP, 110 °C, 5 h. (11) CSA (2.1 equiv), PhH/CH Cl (1:1) 0 °C, 6 h
2
2
then rt, 6 h or HFIP, 0 °C, 1 h then MeOH. Abbreviations: DMAP = N,N-dimethyl-4-aminopyridine; DBU = 1,8-diazobicyclo[5.4.0]undec-7-ene;
DMA = N,N-dimethylacetamide; DMF = N,N-dimethylformamide; LDA = lithium diisopropylamide; imid. = imidazole; cod = 1,5-cyclooctadiene;
TBAF = tetrabutylammonium fluoride; HFIP = 1,1,1,3,3,3-hexafluoro-2-propanol; CSA = camphorsulfonic acid.
of ligands were evaluated (see SI for a list), and L1 emerged as
optimum, along with DBU as a base. The e-amination could be
easily conducted using a commercial potentiostat either on ca.
optimized conditions without a Lewis acid additive, only ca.
30% yield of tryptophol 13 was obtained, along with significant
amounts of a ketone byproduct arising from attack of the C-3
position onto the methyl ester side chain. It was found that
addition of CuCl (4.0 equiv) was essential for both the
reproducibility and scalability of this pivotal transformation
(57%, gram-scale; yield could be improved to 67% by recycling
recovered starting material). To complete the synthesis of
indolactam (5), the Boc and TBS groups were removed using
dry HCl followed by evaporation, re-dissolution, and addition
of LDA (7.5 equiv) to effect direct macrolactamization. Of
note, in this step, hydrolysis of the methyl ester in 13 was
completely unworkable under a variety of conditions due to
steric hindrance imposed after N-methylation (the N−H
4
00 mg scale or employing a carousel assembly to easily
process >1 g every 7 h (51% isolated yield; see inset
photograph for setup). N-Methylation (K CO /MeI) followed
2
3
by basic workup furnished the indole-valine 12 in 82% yield.
Appending the tryptophol side chain onto C-3 of the indole in
a scalable way required extensive experimentation (see SI for
optimization) and was inspired by the pioneering studies of
5
m
14
Tokuyama and Chung. In prior studies it was demon-
strated that aziridine opening could take place using 7 directly
rather than a fully elaborated system like 12 to avoid potential
epimerization of the valine side chain. Under Tokuyama’s
B
DOI: 10.1021/jacs.8b13697
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
derivative is easily hydrolyzed). The ketone byproduct
observed during optimization of the tryptophol-forming step
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.8b13697.
■
*
S
(12 → 13) suggested that such a base-induced cyclization
would proceed. Quenching the macrocyclization with acid led
directly to 5 (65%), whereas use of TIPSCl delivered 14
Experimental procedures, analytical data ( H and 13C
NMR, MS) for all new compounds, and optimization
tables (PDF)
1
(
72%). The five-step synthesis of 5 represents the shortest and
most ideal (80%) pathway yet reported to this simple alkaloid.
With access to 14 in gram quantities, the primary alcohol was
shielded with a TBS group to afford the borylation precursor
1
5
AUTHOR INFORMATION
Corresponding Author
*pbaran@scripps.edu
ORCID
Phil S. Baran: 0000-0001-9193-9053
Notes
The authors declare no competing financial interest.
1
5. In accord with prior work from this laboratory, ligand L2
■
proved ideal (even after a rescreening of ligands) for the
regioselective C−H borylation of 15 to deliver 16 in 81% yield
on gram scale. The only modification needed was the use of a
mixed solvent system (octane/THF = 2:1) due to the limited
solubility of 15 in pure octane.
The touchstone disconnection of our retrosynthetic strategy
rested on the success of the ensuing stereocontrolled union of
a terpene fragment onto the C-6 position followed by
annulation to complete the core. The recently reported
Sigman−Heck redox-relay transform appeared to be ideally
suited to this task, as it has been reported to generate a wide
variety of quaternary centers in a stereocontrolled fashion
dictated by the ligand. In what is the most complex
manifestation of this reaction, and the first in the context of
natural product synthesis, boronic acid 17 (derived from
oxidative cleavage of 16) was subjected to a modified variant of
Sigman’s conditions to access either diastereomeric ketone 18
ACKNOWLEDGMENTS
Financial support for this work was provided by NIH (GM-
18176), JSPS (postdoctoral fellowship to H. N. and
predoctoral fellowship to K. Y.), and Honjo international
scholarship (predoctoral fellowship to Y. K.). We also thank
Dr. Shota Asai and Dr. Yu Kawamata. We are grateful to Dr.
D.-H. Huang and Dr. L. Pasternack for NMR spectroscopic
assistance, Prof. A. L. Rheingold and Dr. C. E. Moore for X-ray
crystallographic analysis, and Dr. Jason Chen and Ms. Brittany
Sanchez for analytical support.
■
1
(
6.6:1 dr, 56%) or 19 (7:1, 85%) using L3 or L4, respectively.
Several points are notable regarding the success of this crucial
bond formation: (1) Cu-based co-catalysts that are normally
employed were excluded due to significant amounts of proto-
deborylation. (2) No reaction was observed using 16; a free
boronic acid was essential. (3) The addition of 2,6-di-tBu-
pyridine (2.4 equiv) also reduced proto-deborylation. (4) The
use of a mixed solvent system (MeOH/THF = 2:1) emerged
as ideal.
The final two carbon atoms needed to complete the
synthesis of the teleocidin B family were introduced through
the addition of vinyllithium, followed by addition of HFIP to
remove the labile Boc group (61% yield of 20 from 18; 94%
yield of 21 from 19). The final ring closures of these tertiary
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DOI: 10.1021/jacs.8b13697
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX