Enantioselective Synthesis of Azamerone

Article abstract of DOI:10.1021/jacs.8b12566

A concise and selective synthesis of the dichlorinated meroterpenoid azamerone is described. The paucity of tactics for the synthesis of natural-product-relevant chiral organochlorides motivated the development of unique strategies for accessing these motifs in enantioenriched forms. The route features a novel enantioselective chloroetherification reaction, a Pd-catalyzed cross-coupling between a quinone diazide and a boronic hemiester, and a late-stage tetrazine [4+2]-cycloaddition/oxidation cascade.

Full text of DOI:10.1021/jacs.8b12566

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Enantioselective Synthesis of Azamerone
Matthew L. Landry, Grace M. McKenna, and Noah Z. Burns
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b12566 • Publication Date (Web): 01 Feb 2019
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Enantioselective Synthesis of Azamerone
Matthew L. Landry, Grace M. McKenna, Noah Z. Burns*
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Department of Chemistry, Stanford University, Stanford, California 94305, United States
Supporting Information Placeholder
hydroxyquinone 10 (a reaction with no enantioselective
variants, Figure 1D), a hindered carbon–carbon bond
formation between 9 and 7, and an
ABSTRACT: A concise and selective synthesis of the
dichlorinated meroterpenoid azamerone is described.
The paucity of tactics for the synthesis of natural
product-relevant chiral organochlorides motivated the
development of unique strategies for accessing these
motifs in enantioenriched forms. The route features a
novel enantioselective chloroetherification reaction, a
Pd-catalyzed cross-coupling between a quinone diazide
and a boronic hemiester, and a late-stage tetrazine [4+2]-
cycloaddition/oxidation cascade.
The napyradiomycins are
a
diverse class of
halogenated meroterpenoids that have been isolated
from terrestrial and marine actinomycetes (Figure 1A).1
Initial isolation efforts were driven by a desire to
identify novel antibiotic scaffolds; the napyradiomycins
have since demonstrated potent inhibition of gastric (H+-
K+)-ATPase, nonsteroidal estrogen antagonism, cancer
cell cytotoxicities, and activity against Gram-positive
bacteria.1c-f Of the over 40 members within this class,
only napyradiomycin A1 has succumbed to chemical
synthesis (2, Figure 1A).2 Syntheses of more highly
oxidized members of the napyradiomycins (e.g. 1 and 3,
Figure 1A), which feature densely functionalized, chiral
halocycle appendages, remain elusive, representing an
exciting arena for synthetic development.
Azamerone is structurally unique among the
napyradiomycins. It is the lone example of
a
phthalazinone-containing natural product.3 Moore has
postulated that this nitrogen–nitrogen bond-containing
heterocycle arises from oxidative rearrangement of
SF2415A1 (5) via intermediate 6 (Figure 1B).3a,b In
addition to its unusual hetereocycle, azamerone’s highly
oxidized structure, diversity of heteroatoms, two
stereogenic tertiary alcohols, and two distinct chlorine-
bearing stereogenic centers pose significant synthetic
challenges. We envisaged that azamerone could be
retrosynthetically traced to
a
chlorobenzopyran,
tetrazine, and chlorocyclohexane of general forms 7, 8,
and 9 (Figure 1C). A challenging enantioselective
chloroetherification
on
prenyl-containing
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Figure
1.
(A)
Representative
napyradiomycin
enantioselective bromochlorination and dichlorination of
olefins.2b,6 Cognizant of these methodological gaps and
the challenge of chiral organochloride synthesis in
general, we set out to develop a new method for
1
2
3
4
5
6
7
8
meroterpenoids. (B) Proposed biosynthesis of azamerone.
(C) Retrosynthetic analysis of azamerone. (D)
Methodological gap.
enantioselective chloroetherification to produce
a
benzochloropyran akin to 7 and to discover a means for
resolving the enantiomers of chlorocycle 9, which was
previously made in racemic form (9, X = OAc, Figure
1C).9a
Table 1. Enantioselective chloroetherification optimization
9
De novo development of an enantioselective
chloroetherification required the identification of a
substrate that was not only amenable to asymmetric
halogenation but also could be parlayed into a synthesis
of azamerone. Although considerable advances have
been made in the area of intramolecular catalytic,
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enantioselective
chlorolactonization
and
chloroetherification, high selectivity has been achieved
only for styrenyl substrates; use of non-stabilized olefins
is accompanied by
a
precipitous drop in
enantioselectivity.5,7 After extensive investigation of
potential substrate structures and chiral catalysts, we
discovered that prenylated hydroxyquinone 11 could be
chlorocyclized to a benzochloropyran by a TADDOL-
ligated titanium complex and tert-butyl hypochlorite in
modest yield and 10% ee (entry 1, Table 1). Application
of other common systems for enantioselective
chlorofunctionalization, including cinchona alkaloids,
returned racemic product.7 Unexpectedly, under the
conditions of entry 1, ortho-quinone 12 was formed as
the major product. Significant enol chlorination was
observed with formation of a racemic -chlorinated
triketone byproduct. Initial formation of intermediate 13
is proposed, as this is consistent with our hypothesis in a
related dihalogenation system that a coordinatively
saturated octahedral titanium complex is necessary for
high selectivity.6d Chloroether 12 likely arises via
trapping of the chloronium by the vinylogous
carboxylate carbonyl oxygen in 14; however, titanium is
not necessary for such regioselectivity, as the racemic
product could be produced in 52% yield solely by the
action of tert-butyl hypochlorite (see Supporting
Information). We anticipated that 12 could be leveraged
as a precursor to a para-quinone intermediate for the
synthesis of azamerone and, therefore, pursued
optimization of this chloroetherification.
a. Reactions were conducted on 0.035–0.176 mmol
scale, and 1H-NMR yields are reported based on 1,4-
dinitrobenzene as internal standard; b. 100 mol % ClTi(Oi-
Pr)3, 100 mol % B; c. 1.3 equiv t-BuOCl; d. reaction
conducted on 4.0 grams 11; e. isolated yield.
electronically mismatched late-stage tetrazine Diels–
Alder reaction were thus identified as key challenges for
this chemical synthesis.
A survey of chiral ligands afforded optimal TADDOL
ligand B,8 which produced chloropyran 11 in increased
yield but with similarly low enantioselectivity (entry 2,
Table 1). Although comparable to ligand A under the
conditions of entries 1 and 2, acyclic ligand B proved to
be more selective and higher yielding across a broader
range of conditions and was selected for further
optimization efforts. Screening of reaction solvents
revealed that 2-methyltetrahydrofuran increased the
selectivity of the chloroetherification to 57% ee (entries
3–8, Table 1). Use of other electrophilic chlorine sources
Our synthetic approach first required the assembly of
enantioenriched chlorocycles 7 and 9. Biosynthetically,
the chlorocycle motifs found in 7 and 9 are proposed to
derive from chloronium-initiated cyclizations of the
prenyl and geranyl fragments within 5 (Figure 1B,C).4
Neither of these transformations have enantioselective,
synthetic parallels (Figure 1D).5 In fact, the use of
enantioselective halogenation in natural product
synthesis has been limited thus far to the
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led to a reduction in the yield or enantioselectivity of the
process (entries 9–11, Table 1). Hypothesizing that
adventitious acid could be promoting a racemic
background reaction, we found that inclusion of
heterocyclic base additives, such as pyridine and
quinoline, increased the enantioselectivity of
chlorocyclization (entries 12, 13, Table 1); the precise
role of these additives is unclear, but they could serve as
general bases, activating agents for transfer of
electrophilic chlorine, or ligands on titanium. Employing
a stoichiometric amount of titanium and chiral ligand
delivered only a modest increase in selectivity but a
dramatic improvement in yield (entry 14, Table 1).
Increasing the amount of tert-butyl hypochlorite to 1.3
1
2
3
4
5
6
7
8
Scheme 1. Short enantioselective synthesis of azamerone.a
9
Me Me
Me Me
a. ClTi(Oi-Pr)3 (25 mol %)
ligand B (25 mol %)
t-BuOCl (1.3 equiv)
O
O
Cl
Cl
O
O
Me
10
11
12
13
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O
O
b. aq. HClO4
Cl
Cl
PhO
77%
PhO
O
Me
Me
Me
quinoline (1.0 equiv)
2-Me-THF, - 78 ˚C
40%, 84% ee
c. (COCl)2
DMF
O
OH
O
O
93%
O
12
Cl
[4 grams]
15
h. TsNHNH2
then NaOH
11
AcO
Me
OH
Me
O
B
OH
O
Me OH
Me OH
d. Hg(OTFA)2;
Me
f. Tf2O
Cl
Cl
Cl2, LiCl
g. BH3•SMe2
then DBU
+
H
H
Me
O
e. K2CO3
MeOH
52%
71%
80%
Me
Me
Me
Me
Me
Me
N2
19
Cl
Cl
Cl
Me
Me
SiO2 separation
of (S)- -methoxy-
16
17
46%
i. SPhos-Pd
18
=
(±)
(– ) 90% ee

K3PO4
phenylacetic esters
[X-ray]
O
Me
O
O
OH
j. SPhos-Pd
K2CO3
Cl
Cl
Cl
Cl
N
N
Scheme 2
56%
Me
O
Me
Me
Me
O
O
≈
TBSO Me
H
HO Me
H
HO Me
Me
Me
OH
OH
34%
overall
k. TBSOTf
87%
l. PhI(OTFA)2
42%
H
Me
Me
Me
Me
Me
20-Ac
[X-ray]
Me
Cl
Cl
Cl
1: azamerone
21
20
aReagents and conditions: (a) ClTi(Oi-Pr)3 (0.25 equiv), B (0.25 equiv), quinoline (1.0 equiv), t-BuOCl (1.3 equiv), 2-Me-
THF, –78 ˚C, 40%, 84% ee; (b) aq. HClO4 (1.3 equiv), Et2O, 77%; (c) oxalyl chloride (1.1 equiv), DMF (1.4 equiv), MeCN,
0 ˚C, 93%; (d) Hg(OTFA)2 (1.1 equiv), MeNO2; Cl2, LiCl (3.0 equiv), pyridine; (e) K2CO3, MeOH, 50 ˚C, 52% overall; (f)
Tf2O (1.05 equiv), 2,6-lutidine (1.2 equiv), then DBU (2.5 equiv), DCM, –78 ˚C to RT, 80%; (g) BH3·SMe2 (2.0 equiv),
THF, 0 ˚C to RT, 71%; (h) TsNHNH2 (1.1 equiv), MeOH, then 1M aq. NaOH, DCM; (i) (SPhos)Pd-G3: (SPhos)[2-(2′-
amino-1,1′-biphenyl)]palladium(II) methanesulfonate (0.1 equiv), K3PO4 (1.3 equiv), dioxane, 60 ˚C, 46% over 2 steps, 10:1
dr; (j) (SPhos)Pd-G3 (0.1 equiv), K2CO3 (2.0 equiv), i-PrOH, 90 ˚C 56%; (k) TBSOTf (3.0 equiv), (i-Pr)2NEt (4.0 equiv),
DCM then 3M aq. NaOH (7.5 equiv), i-PrOH, 87%; (l) PhI(OTFA)2 (1.1 equiv), 3:1 MeCN/H2O, 42%.
equivalents provided an improvement in yield when
using 25 mol % titanium and ligand (entry 15, Table 1).
Gratifyingly, performing the reaction on 4-gram scale
under these conditions resulted in an isolated 40% yield
(entry 16, Table 1) which was deemed sufficient for
completing the synthesis.
converted to its corresponding ortho-chloro-para-
quinone 15 with oxalyl chloride and DMF.
Pyranoquinone 15 is embedded within nearly all
members of the napyradiomycins (e.g. 1–4, Figure 1).
Our synthesis of the chlorocyclohexane of azamerone
focused on first establishing a means to resolve racemic
16 (Scheme 1). In 2010, the Snyder group reported the
direct chlorocyclization of geranyl acetate with
chlorodiethylsulfonium hexachloroantimonate (see
Scheme S2 in Supporting Information).9a This reaction
provides the primary acetate of diol 16 in racemic form.
Important recent work by Gulder,9b along with a
protocol used here by Snyder9c on a mercury-based two-
step mimic for halopolyene cyclizations, provided
With an enantioselective chloroetherification in hand,
we commenced our synthesis of azamerone.
Prenylquinone 11, which can be made in two steps from
commercially available materials, was cyclized to
chloropyran 12 using our optimized conditions (Scheme
1). Treatment of this ortho-quinone with aqueous acid
induced hydrolysis and isomerization to an intermediate
2-hydroxy-para-quinone,
which
was
smoothly
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strategies for accessing racemic chlorocycle 16 (Scheme
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Subsequent dechlorination, silylation, and hypervalent
iodine-mediated para oxidation14 of phenol 20 provided
the desired stereoisomer of para-quinol 21 as the major
product in 42% yield (Scheme 1). Protection of the
tertiary alcohol of 21 was necessary to prevent two
undesired pathways: (1) the unprotected tertiary alcohol
in 21 acting as a nucleophile during arene oxidation to
1
2
3
4
5
6
7
8
1). Attempts to catalytically resolve diol 16 by either
chemical or enzymatic means were met with limited
success. Investigations into resolution by chiral
derivatization revealed the (S)--methoxyphenylacetic
ester of diol 16 to be uniquely competent in providing
chromatographic resolution of diastereomers on silica
gel.10 This result is noteworthy given the challenges
associated with resolving primary alcohols,11 and we
anticipate that access to enantioenriched diol 16 will
enable syntheses of other chlorinated natural products.
Using this approach, multi-gram quantities of racemic
diol 16 can be separated into its constituent enantiomers.
exclusively form
a
diastereomeric mixture of
spirocycles; (2) in oxidized quinol structures such as 21,
free tertiary alcohols are prone to oxa-Michael additions
into the proximal enone (see Schemes S11, S15, S16 in
Supporting Information). Two diastereomeric products
from the latter of these undesired pathways were verified
via X-ray crystallography (see Supporting Information),
enabling relative stereochemical assignments.
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We next investigated the coupling of quinone 15 and
an appropriate derivative of chlorocyclohexane (–)-16.
Initial studies attempted to unite these pieces through a
1,2-addition of generalized organometallic 9 (X = metal,
Figure 1C) into the more electrophilic carbonyl of 15.
These efforts were hampered due to Grob-type
fragmentation of organometallic 9, which occurs at
temperatures above –78 ˚C, and due to preferential
reduction of the quinone by organometallic reagents.
Owing to these obstacles, a cross-coupling approach was
adopted for the union of these fragments (Scheme 1).
Chemoselective dehydration of the primary alcohol in
16 with triflic anhydride and DBU provided olefin 17,
which was hydroborated to form boronic hemiester 18 in
good yield and diastereoselectivity. Boronic hemiester
18 is stable to column chromatography, allowing for
Inspired by Boger, we envisioned that quinol 21 could
be expediently translated to azamerone through a [4+2]-
cycloaddition with an appropriately functionalized
tetrazine.15 Although it is
a
direct means for
phthalazinone construction, we recognized that electron-
deficient enone 21 was ill-matched to participate in this
inverse
electron-demand
cycloaddition.
After
discovering that acyltetrazine 8 (Figure 1C) had limited
stability, we chose its reduced variant 22 for further
study (Scheme 2). Unfortunately, initial attempts to
thermally induce reactivity between 21 and tetrazine 22
were unsuccessful. During our studies, Wegner and
coworkers reported that bisboron complex 23 is able to
catalyze the cycloaddition of tetrazines with
naphthoquinones.16 Encouraged by their auspicious
results, we applied complex 23 to our system and were
delighted to observe formation of silyl-azamerone 1-
TBS. This reaction was surprisingly regioselective, and
the alternate constitutional isomer was not observed.
This cascade is presumed to occur through initial [4+2]-
cycloaddition, subsequent expulsion of dinitrogen via
[4+2]-retrocycloaddition (to provide dihydropyridazine
24), and both in situ oxidative aromatization and benzyl
alcohol oxidation to 1-TBS. The alcohol oxidation
occurred to a varying extent in some experiments but
could also be accomplished with Dess–Martin
periodinane (see Supporting Information). Treatment
with hydrochloric acid affected desilylation and
provided azamerone 117 in 34% overall yield from 21.
facile removal of
a minor diastereomer; X-ray
crystallographic analysis of racemic 18 unambiguously
verified its relative configuration. This cross-coupling
partner has precedent in the synthesis of sclareolide
derivatives and was chosen to attenuate Grob-type
fragmentation.12
Quinone 15 was joined with boronic hemiester 18
through a quinone diazide-based coupling strategy
(Scheme 1). Chemoselective condensation of tosyl
hydrazide with quinone 15 followed by treatment with
base provided intermediate quinone diazide 19, which
was directly used as a cross-coupling electrophile
without purification. Screening of conditions revealed
3
that SPhos-ligated palladium was able to catalyze Csp –
2
Csp bond formation between sterically hindered boronic
Scheme 2. Tetrazine cycloaddition sequence.a
hemiester 18 and quinone diazide 19, providing phenol
20 in 46% overall yield from 15. Quinone diazide 19
was completely consumed in this reaction, and no
elimination of either alkly chloride was observed. The
structure and relative configuration of phenol 20 was
confirmed via X-ray crystallography of its acetate. Small
amounts of another diastereomer were produced due to
the presence of minor enantiomers of each substrate.
Limited precedent exists for Suzuki reactions with
quinone diazides, and to the best of our knowledge, this
represents the first example of this reaction type with a
13
3
Csp nucleophile.
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This work is dedicated to Prof. Dale Boger on the occasion
of his 65th birthday. We are grateful to Dr. A. Oliver (Notre
Dame) and Dr. N. Settineri (UC Berkeley) for X-ray
crystallographic analysis, Dr. S. Lynch (Stanford
University) for assistance with NMR spectroscopy, Prof. B.
Moore (Scripps Institute for Oceanography) for providing
an authentic sample of 1, Prof. Dr. H. Wegner (Justus
Liebig University Giessen) for providing an initial amount
of bisboron complex 23, Sajan Patel (Stanford University)
for the synthesis of additional 23, and Prof. Y. Xia
(Stanford University) for assistance with LCMS.
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aReagents and conditions: (a) 22 (15.0 equiv), 23 (2.0
equiv), CF3Ph, 110 ˚C, 40%; (b) 12M aq. HCl, MeOH,
84%, 34% from 21.
Napyradiomycins
A and B1: Non-steroidal estrogen-receptor
The first synthesis of azamerone has been reported.
Our successful route relied on development of an
enantioselective chloroetherification with a substrate
suitable for elaboration into the target. Identification of a
scalable resolution process provided access to an
enantioenriched chlorocyclohexane that had been made
previously in racemic form. A convergent cross-
coupling between a quinone diazide and a hindered
boronic hemiester, followed by a late-stage arene
oxidation and bisboron-mediated tetrazine [4+2]-
annulation installed the fully-oxidized framework of
azamerone. We anticipate that this sequence and the
strategies leveraged herein will find use in syntheses of
other members of the napyradiomycin meroterpenoids.
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antimicrobial
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Farnaes, L.; Coufal, N. G.; Kauffman, C. A.; Rheingold, A. L.;
DiPasquale, A. G.; Jensen, P. R.; Fenical, W. Napyradiomycin
derivatives, produced by a marine-derived actinomycete, illustrate
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(b) Snyder, S. A.; Tang, Z. Y.; Gupta, R. Enantioselective total
synthesis of (–)-napyradiomycin A1 via asymmetric chlorination of
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Miles, Z. D.; Diethelm, S.; Pepper, H. P.; Huang, D. M.; George, J.
H.; Moore, B. S. A unifying paradigm for naphthoquinone-based
meroterpenoids biosynthesis. Nat. Chem. 2017, 9, 1235–1242. (d)
McKinnie, S. M.; Miles, Z. D.; Jordan, P. A.; Awakawa, T.; Pepper,
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140, 17840–17845. While this manuscript was in review, a synthesis
of two fragments of azamerone was reported: (e) Schnell, S. D.;
Linden, A.; Gademann, K. Synthesis of two key fragments of the
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Lett. 2019 DOI: 10.1021/acs.orglett.9b00090.
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Fenical, W. Azamerone, a terpenoid phthalazinone from a marine-
derived bacterium related to the genus Streptomyces
(actinomycetales). Org. Lett. 2006, 8, 2471–2474. Using 13C- and 15N-
labeled precursors, Moore was able to show that both nitrogen atoms
in azamerone originate from the diazo group in 5: (b) Winter, J. M.;
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ASSOCIATED CONTENT
Supporting Information. Experimental procedures,
characterizations, spectral data, and CIF files. The
Supporting Information is available free of charge on the
ACS Publications website.
AUTHOR INFORMATION
Corresponding Author
*nburns@stanford.edu
Funding Sources
No competing financial interests have been declared. This
work was supported by Stanford University, the National
Institutes of Health (R01 GM114061), the National Science
Foundation (DGE-114747 GRF to MLL), and the Center
for Molecular Analysis and Design at Stanford (GRF to
GMM).
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ACKNOWLEDGMENT
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