Anomalous Chromophore Disruption Enables an Eight-Step Synthesis and Stereochemical Reassignment of (+)-Marineosin A

Article abstract of DOI:10.1021/jacs.9b00396

An eight-step asymmetric synthesis of (+)-marineosin A is described. The route proceeds by condensing fragments of reversed polarity relative to conventional prodiginine constructions. The resultant unstable chromophore is disrupted by a unique cycloisomerization promoted at a tailored manganese surface. This provides a premarineosin and subsequently marineosin A in a particularly concise manner. A pyridinophane N-oxide photorearrangement in flow and structural isomers of premarineosin are discussed, as is the reassignment of marineosin stereochemistry. The route gives access to the natural product as well as diastereomers, congeners and analogs that are currently inaccessible by other means.

Full text of DOI:10.1021/jacs.9b00396

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Communication
Anomalous Chromophore Disruption Enables an Eight-Step
Synthesis and Stereochemical Reassignment of (+)-Marineosin A
Zhengao Feng, Tyler K. Allred, Evan E. Hurlow, and Patrick G Harran
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b00396 • Publication Date (Web): 29 Jan 2019
Downloaded from http://pubs.acs.org on January 29, 2019
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Anomalous chromophore disruption enables an eight-step synthesis
and stereochemical reassignment of ()-marineosin A
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Zhengao Feng, Tyler K. Allred, Evan E. Hurlow and Patrick G. Harran*
Department of Chemistry and Biochemistry, University of California-Los Angeles, 607 Charles E. Young Drive East,
Los Angeles, California 90095-1569, United States
Supporting Information Placeholder
targets.4 Structures of this kind are biosynthesized
ABSTRACT: An eight-step asymmetric synthesis of
from acyclic hydrocarbon precursors, wherein a non-
heme iron oxygenase catalyzes dehydrogenative
macrocyclization via a mechanism reminiscent of
p450 hydroxylations.5
()-marineosin A is described. The route proceeds by
condensing fragments of reversed polarity relative to
conventional prodiginine constructions. The
resultant unstable chromophore is disrupted by a
unique cycloisomerization promoted at a tailored
manganese surface. This provides a premarineosin
and subsequently marineosin A in a particularly
In 2008, the discovery of marineosins A and B
(Scheme 1) revealed a new variant of this chemistry.6
Marineosins harbor oxygenation in their aliphatic
domain, and it is integrated into a spiroiminal motif
interrupting the typical prodiginine chromophore.
Reynolds et al. subsequently studied the marineosin
(mar) gene cluster from Streptomyces sp. CNQ-617,
an operon homologous to the red gene cluster in S.
coelicolor that produces streptorubin B (4).7 They
found spiroiminal formation is coupled with
macrocyclization during the MarG catalyzed
conversion of (S)-23-hydroxyundecylprodiginine (1b)
into premarineosin (assigned as 8). Similar to
proposals for 4, the result was rationalized in terms
of regio-controlled alkyl radical addition to the
chromophore.8 Yet the fate of the presumed cyclized
radical was less clear. Was it oxidized to afford 8
directly, or oxygenated to form a hemi-aminal
analogous to 3? Alternatively, could prodiginine 7 be
concise manner.
A
pyridinophane N-oxide
photorearrangement in flow and structural isomers
of premarineosin are discussed, as is the
reassignment of marineosin stereochemistry. The
route gives access to the natural product as well as
diastereomers, congeners and analogs that are
currently inaccessible by other means.
The prodiginine alkaloids have fascinated chemists
for decades. These bacterial lipochromophores
possess a range of biological activities1 and synthetic
variants have advanced to clinical trials as cancer
therapy.2,3 The ansa-bridged members of the family
(e.g. 4, Scheme 1) have been coveted synthetic
Proposed Biosynthesis
Me
Me
Me
R
Me
(S)
Me
H
MeO
LnFe
OMe
OMe
LnFe=O
LnFeOH
O
OH
NH
- H2O
RedH
MarH
RedG
MarG
N
N
+
HN
HN
HN
NH
HN
HN
NH
NH
1a R = H
1b R = OH
postulated
mechanism
4
streptorubin B ( )
2
3
This work (fragment polarity reversed)
Me
Me
Me
Me
Me
(S)
OH
OH
MeO
O
MeO
O
MeO
O
MeO
OMe
7
MarA
N
N
N
cyclo-
O
NH
- H2O
HN
HN
isomerization
H2
HN
N
+
HN
HN
NH
NH
NH
NR1
NR1
8
11
)
premarineosin A ( )
marineosin A
marineosin B (
5
6
7
9
- C7-(R) (original)
10
- C7-(S) (revised)
Scheme 1
. Marineosins are oxygenated, spirocyclic ansa-bridged prodiginines.
(this work)
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an intermediate and proceed non-enzymatically to 8?
circumscribed a jacketed mercury lamp in small-bore
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Scheme 2.
17
Photochemical synthesis of ketopyrrolophane
While replicating actions of MarG was likely not
feasible, we felt insight into these questions could be
achieved with a synthesis that passed through 7,
wherein methods to ‘bleach’ that chromophore by
internal hydroalkoxylation could be examined.
MgBr
Cl
a)
13
MgBr
b) mCPBA
N
N
O
N
cat. NiCl2(dppp)
Cl
12
14
15
c) hv
The novel structure of marineosins and the
selective cellular cytotoxicity attributed to 96 drew
attention. The Lindsley, Snider, and Shi laboratories
each developed synthetic routes to marineosin
substructures.9 In fact, Shi’s experiments culminated
in a 19-step synthesis of 9.9f The identity of synthetic
O
O
9
N
by-products
N
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ii
i
O
9
was confirmed by crystallography, but its
spectroscopic data differed from that reported for the
natural product. Evaluation of Shi’s data, relative to
that published by Fenical6, suggested the discrepancy
was subtle and likely an issue of relative
stereochemistry rather than composition or
connectivity (vide infra).
H
N
NH
N
H
O
O
O
16
17
18
To assemble chromophore 7, wherein only one of
two bonds formed by MarG was present, we choose
to reverse the polarity of fragments joined during
prodiginine biosyntheses (Scheme 1) and previous
laboratory preparations.1,4,8 In our case the
prodiginine would derive from condensation of a
nucleophilic bispyrrole (5) with ketopyrrolophane 6.
The latter was seen as the product of alkylating
pyrrolophane 17 (Scheme 2) with propylene oxide.
12
13
(1 eq.), 0.8 mol% NiCl2(dppp) Et2O, 10 °C,
Reagents and conditions: a)
6 h, 50%; b) mCPBA (1.5 eq.), CHCl3, rt, 48 h, 82%; c) hv (254 nm), THF (0.01 M), -78
14 16 17 18
(18%). See
(1 eq.),
°C in flow, residence time = 2 min.
(15%),
(5%),
(25%) and
also Table S2. X-ray structures are drawn in ORTEP format (50% probability thermal
ellipsoids). H atoms removed for clarity.
FEP tubing. In that case an exposure time of only 2
minutes afforded 17 in yields (25%) exceeding our
best batch reaction while minimizing formation of 16
(Scheme 2). Photolysis in flow greatly increased
throughput and allowed grams of pure 17 to be
isolated in short order.
Weber et al. had isolated trace amounts (0.6%
yield) of compound 17 during the UV photolysis of
pyridinophane N-oxide 15.10 Because 15 could be
Deprotonation of 17 with 3.1 eq. LDA in rigorously
anhydrous, deoxygenated THF at 0˚C, followed by
addition of (S)-propylene oxide and AlMe3 gave
alkylation products 6 in 71% yield (dr = 2:1). The two
isomers of 6 were separable by chromatography,
although they would readily equilibrate under mildly
acidic conditions (to the same 2:1 ratio observed in
crude reaction mixtures, see SI), presumably via their
enol tautomer.
When ketones 6 and bipyrrole 2014 were dissolved
in anhydrous MeOH and treated with HCl, the
solution turned deep red within seconds. This was
consistent with condensation product 21 (Scheme 3)
being formed. However, after 30 min, predominantly
starting materials were recovered following aqueous
workup. Despite repeated attempts, target 21 could
not be isolated from the reaction. Prodiginines
bearing a hydrogen at C9 (e.g. 4) are isolable
species,15 but branched ansa bridge connectivity at
C9 appeared to destabilize the system. Condensation
product 21 hydrolyzed readily and, standing in
MeOH, it would degrade via an unusual sigmatropic
rearrangement of the 2-hydroxypropyl branch onto
prepared
readily
from
commercial
2,6-
dichloropyridine and 1,8-dibromoctane,11 we sought
to optimize its photorearrangement. We observed a
solvent effect, with ethers being superior to the
originally reported hydrocarbon (see Table S2). THF
at -78˚C provided the best result (19% isolated yield
of 17). It had been reported that inclusion of aq.
CuSO4 in the photolysis of substituted pyridine-N-
oxides markedly increased the yield of incipient 2-
formylpyrroles.12 This was explained by Cu(II)
stabilizing
a
postulated nitrene intermediate
analogous to ii. However, irradiating 15 in aq. CuSO4
provided 17 in only 4% yield. Photolysis of an isolated
Cu(NO3)2[15]2 complex (see SI) as well as solutions
of 15 containing Rh2(TFA)4 gave similarly low yields.
In all instances, irradiation of 15 produced significant
amounts of reduction product 14, along with newly
identified macrocycles 16 and 18.13 Moreover, control
experiments established 17 was photolabile and
degraded during the timeframe of the batch process.
We therefore adopted a flow technique wherein a
cold THF solution (-78 ˚C, 0.01 M) of 15
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the C ring pyrrole.16 To stabilize the molecule in situ,
case exposure to dry HCl in MeOH reformed a
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we quenched the condensation reaction with dry
NaOMe. This gave novel structural variants of
premarineosin (namely 22, dr 1:1) in good yield. These
tetrahydrofurans derive from the chromophore in 21
being internally disrupted at C9, the same position
attacked by water during hydrolysis (as depicted).
Compounds 22 were air-sensitive, but sufficiently
stable to be purified by rapid chromatography.
prodiginine chromophore via ring-opening of the
tetrahydrofuran ring. It was thought MnO2 might
oxygenate that product (i.e. 25) in a manner
analogous to 24, wherein a 6-exo trig cyclization of
the tethered alcohol could ensue. Compound 25 was
highly unstable and its handling was minimized to
avoid
the
aforementioned
sigmatropic
rearrangement.16 When freshly prepared 25 was
stirred with commercial MnO2 in acetone, workup
gave pyrrolinones 24, along with lesser amounts of
hydrolysis products 6. Notably, we also isolated trace
amounts (~1%) of a new, pale-yellow isomer of 25.
This substance was not an oxidation product, and it
had spectral data consistent with a premarineosin.
But its 1H NMR spectrum was slightly different from
that reported for premarineosin A.7b Gratifyingly,
hydrogenating the sample over Pd/BaSO4 gave a
molecule (10, see Scheme 5) whose spectroscopic
data was identical to that reported for natural
marineosin A.6
The question became how to ring-expand 22 in
route to hydropyran 8? The sulfonamide in 22 was
cleaved using Mg0 / MeOH and the unstable product
(23) was oxidized with MnO2.9d This cleanly
transformed the bipyrrole into oxo derivative 24
(Scheme 4), wherein C8 was now a potentially
electrophilic site. The intent was to activate the
pyrrolinone π system to induce the conjugated C9-O
bond to migrate to C8. Unfortunately, 24 degraded in
the presence of Brønsted and Lewis acids. Its
precursor 23 was also unstable to acid, but in that
With this exciting result, we were eager to refine
the sequence. Suspended manganese oxide was
required for the cycloisomerization, although the
nature of the surface promoting its non-oxidative
chemistry was unclear. Certain forms of MnO2 were
known to promote hydration of nitriles17, but the
analogy was tenuous. Other nitrile hydration
catalysts caused no isomerization of 25. On the other
hand, when preparing MnO2 in house (KMnO4 +
MnSO4), samples that were relatively poor oxidants
(see SI) retained an ability to hydrate p-MeOC6H4CN
in dry organic solvent, presumably by delivering
adsorbed water. These same samples mediated
cyclization in our system. Best results were achieved
18
using carefully dried, ‘acidic’ MnO2 wherein
isomerization products derived from both
diastereomers of 25 (namely 8 and 26, dr = 1:1, Scheme
4) formed within minutes at 25˚C and were isolated
in 12% combined yield. Relative to the behavior of 21,
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whose chromophore readily accepted nucleophiles at carbon shift. The chemistry offers means to prepare a
1
2
3
4
5
6
7
8
C9 (Scheme 3), the formation of 26 and 8 from 25 was
an anomaly, wherein the chromophore was disrupted
at C8 via a non-oxidative addition of the C23 alcohol
under ostensibly oxidative conditions.
new class of bridged prodiginines with previously
inaccessible substitution patterns. Studies along
those lines are ongoing, as are attempts to further
understand the key isomerization, improve yields
and to probe the antimalarial, immunosuppressive,
and antineoplastic properties of these structures in
detail.
Each C21 epimer of 25 appeared to convert to a
single cycloisomerization product. The structure of
26 was secured by crystallography. The structure of 8
was assigned by inference, with the pyrrolophane
emanating from the pyran ring as equatorial
substituents and the C-N bond of the spiroiminal
oriented axial. These designations were fully
consistent with extensive NMR analyses (see SI). Our
revised structure of marineosin A (10) results from
hydrogenating the vinylogous imidate in 8 from its
less hindered face (Scheme 5, dr >19:1). NOESY
correlations between C25 protons and C11H/C12H
firmly supported this designation, whereas the
original C7 assignment6 based on an nOe signal
between C7H and C9H was ambiguous. The distance
between C7H and C9H is similar in both C7 epimers
9
Supporting Information
The Supporting Information is available free of charge
on the ACS Publications website.
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Optimization tables, experimental procedures,
characterization data, MnO2 oxidation study,
and NMR spectra (PDF)
Crystal structure of 16 (CIF)
Crystal structure of 17 (CIF)
Crystal structure of 18 (CIF)
Crystal structure of Cu(NO3)2•[15]2 (CIF)
Crystal structure for 26 (CIF)
Corresponding Author
*harran@chem.ucla.edu
ORCID
Patrick G. Harran: 0000-0001-8748-5167
Zhengao Feng: 0000-0001-8873-6984
Tyler K. Allred: 0000-0002-7293-0413
Evan E. Hurlow: 0000-0001-7046-989X
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
Funding provided by the D.J. & J.M. Cram Endowment,
the NIH (RO1CA184772) and NSF equipment grant
CHE-1048804. E.E.H. thanks the UCLA NIH CBI
training grant (T32GM008496) for fellowship support.
Dr. Hui Ding provided invaluable insight and advice.
of the structure.
To date, the minor, less biologically active
marineosin B isomer has not been observed in our
experiments. Data is consistent with marineosin B
being the C8 epimer of 10 (namely 11). It may arise via
equilibration of the spirocycle, precedent for which
exists in Snider’s model studies.9d
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In conclusion, we have developed an eight-step
asymmetric synthesis of marineosin A and reassigned
its stereochemistry.19 The route exploits
photorearrangement in flow followed by
a
a
2.
3.
Obatoclax at https://clinicaltrials.gov
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manganese
surface-mediated
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Bifunctional Enzyme Involved in the Condensation
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(b) Salem, S. M.; Kancharla, P.; Florova, G.; Gupta,
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16. Structure 21, and especially 25, were prone to the
sigmatropic shift shown below. See SI for details and
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rearrangement products.
8.
9.
Sydor, P. K.; Barry, S. M.; Odulate, O. M.; Barona-
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Me
OMe
unstable
OH
OMe
MeOH
N
H
NH
N
[1,7]
NR
Me
H
HN
NR
(a) Aldrich, L. N.; Dawson, E. S.; Lindsley, C. W.
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Macrocyclic Pyrrole and an Advanced, Functionalized
Spiroaminal Model. Eur. J. Org. Chem. 2013, 4215-
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t1/2 ~ 2-4 h @ 25ºC
Cl
OH
S27
21
25
R = Ts
R = H
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19. []25 reported for natural marineosin A was -101.7°
D
(c 0.06, MeOH), whereas we observe []25D= +138.7°
(c 0.02, MeOH) for 10. Notably, []25 reported for
D
marineosin B was +143.5° (c 0.09, MeOH), close to
our value. Reynolds et al. firmly established
marineosin A is biosynthesized from a C23-S
precursor (ref. 7). Absolute stereochemistry at C23 in
our synthesis derives from (S)-propylene oxide (98%
ee) and was confirmed in the X-ray structure of 26. We
believe natural marineosin A is dextrorotatory,
identical to synthetic 10. [] values for marineosins A
and B were likely interchanged in ref 6. Professor
Fenical informed us his samples of natural marineosins
have decomposed. We therefore synthesized the
antipode of 10 from (R)-propylene oxide. The
biological properties of both enantiomers will be
10. Weber, H.; Rohn, T. 2H-Azirine und 2-(-
Cyanalkyl)furan als neuartige Photoprodukte aus
[n](2,6)Pyridinophan-N-Oxiden und ihre Bedeutung
für den Reaktionsverlauf. Chem. Ber. 1989, 122, 945-
950.
11. Weber, H.; Pant, J.; Wunderlich, H. Darstellung und
Eigenschaften
von
N-Methyl-[n](2,6)
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7
Proposed Biosynthesis
Me
Me
Me
R
Me
(S)
Me
H
MeO
LnFe
OMe
OMe
LnFe=O
LnFeOH
8
O
9
OH
NH
- H2O
RedH
MarH
RedG
MarG
10
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N
N
+
HN
HN
HN
NH
HN
HN
NH
NH
postulated
mechanism
1a R = H
1b R = OH
streptorubin B (4)
2
3
This work (fragment polarity reversed)
Me
Me
Me
Me
Me
(S)
OH
OH
MeO
O
MeO
O
MeO
O
MeO
OMe
7
MarA
N
N
N
cyclo-
isomerization
O
NH
- H2O
HN
HN
H2
HN
N
+
HN
HN
NH
NH
NH
NR1
NR1
premarineosin A (8)
marineosin A
9 - C7
(original)
marineosin B (11)
5
6
7
-(R)
(this work) 10 - C7-(S) (revised)
Scheme 1. Marineosins are oxygenated, spirocyclic ansa-bridged prodiginines.
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Scheme 2. Photochemical synthesis of ketopyrrolophane 17
MgBr
Cl
a)
13
MgBr
b) mCPBA
N
O
N
N
cat. NiCl2(dppp)
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48
Cl
14
15
12
c) hv
O
O
N
by-products
N
ii
i
O
H
N
NH
N
H
O
O
O
16
17
18
Reagents and conditions: a) 12 (1 eq.), 13 (1 eq.), 0.8 mol% NiCl2(dppp) Et2O, 10 °C, 6
h, 50%; b) mCPBA (1.5 eq.), CHCl3, rt, 48 h, 82%; c) hv (254 nm), THF (0.01 M), -78 °C
in flow, residence time = 2 min. 14 (15%), 16 (5%),17 (25%) and 18 (18%). See also
Table S2. X-ray structures are drawn in ORTEP format (50% probability thermal
ellipsoids). H atoms removed for clarity.
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Scheme 3. Rapid synthesis of ‘iso’-premarineosins.
OMe
Me
Me
Me
unstable
OH
OH
MeO
Me
NH
OMe
O
21
O
20
NaOMe
MeOH
NTs
O
O
d) LDA;
e) HCl
9
HN
NH
N
HN
H
HN
AlMe3
O
HN
HN
NTs
Cl
NR
Me
6 (2:1 dr)
17
19
21
22 R = Ts
23 R = H
f) Mg
MeOH
))), r.t.
chromophore
disrupted at C9
OMe
OMe
[1,5]
H2O
O
N
OH
NH
Ar
Ar
H
Reagents and conditions: d) LDA (3.1 eq.), 0 °C, 1 h; (S)-propylene oxide (5 eq.), AlMe3 (1.1 eq.), -78 °C to rt, 12h, 72%, dr=2:1; e) 6 (1 eq.), 20 (1 eq.), 1.5 eq. HCl (1M in
MeOH), Na2SO4, toluene, 0 °C, 30 min; 1M NaOMe/MeOH, 58%, dr=1:1. f) 5 eq Mg0, MeOH (0.1M), 30 min, rt, 90%.
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Scheme 4. Competing cycloisomerization at a MnO2 surface
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Me
Me
unstable
OH
23
MeO
OMe
8
O
g) dry HCl
MnO2
23
8
N
HN
N
H
HN
NH
NH
Cl
24
25
O
“MnO2”
oxidation
cycloisomerization
Me
Me
21
MeO
O
MeO
O
NH
NH
NH
NH
HN
HN
Cl
Cl
26
chromophore disrupted at C8
26 (X-ray)
8
Reagents and conditions: g) 3.0 eq. HCl in MeOH; acidic MnO2 powder (see SI, ~80
eq.), MgSO4, acetone, rt, 5 min, 6% of 8 and 6% of 26 (overall from 22).
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Scheme 5. Vinylogous imidate hydrogenation
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NOESY
Me
HN
11
MeO
O
H
H
h) Pd/BaSO4
H2 (g)
HN
Me
N
NH
NH
12
EtOAc
9
7
HN
O
CH3
25
H
H
O
Cl
marineosin A (10)
(revised)
8
HN
MeO
HN
Me
HN
N
Me
9
more
accessible
face
N
8
O
HN
O
H
OMe
marineosin B (11)
Reagents and conditions: h) 5 mol% Pd/BaSO4, 1 atm H2 (g), rt, 16 h, 30%.
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