Total Synthesis of Divergolides E and H

Article abstract of DOI:10.1002/anie.201810336

This manuscript describes the first total syntheses of divergolides E and H. The route employs a telescoped hetero-Diels–Alder and oxidative carbon–hydrogen bond cleavage as an entry into the central bridged bicyclic acetal unit. Additional key steps of the highly convergent route include a desymmetrizing epoxidation, a chelation-controlled alkenylzinc addition, an amide formation between a hindered aniline and an acylating agent that is prone to ketene formation, and a challenging macrolactonization.

Full text of DOI:10.1002/anie.201810336

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Accepted Article
Title: Total Synthesis of Divergolides E and H
Authors: Paul Floreancig and Scott Caplan
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201810336
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10.1002/anie.201810336
Angewandte Chemie International Edition
COMMUNICATION
Total Synthesis of Divergolides E and H
Scott M. Caplan and Paul E. Floreancig*[a]
This manuscript describes the first total syntheses of divergolides E
and H. The route employs a telescoped hetero Diels-Alder and
oxidative carbon–hydrogen bond cleavage as an entry into the
central bridged bicyclic acetal unit. Additional key steps of the highly
convergent route include a desymmetrizing epoxidation, a chelation-
divergolide I, the only member of the family to be synthesized,
was recently reported by Trauner.[5] This manuscript describes
the first total synthesis of divergolide E and its acyl-migrated
isomer divergolide H (4).
Our interest in these structures arose from a desire to access
the bridged acetal unit of 1 and related structures by broadening
the scope of our one-pot sequence of bimolecular cycloaddition
followed by oxidative carbon–hydrogen bond cleavage and
cyclization (Scheme 1).[6] The initial applications of this method
utilized hetero Diels-Alder reactions between aldehydes and
silyloxy dienes containing pendent protected nucleophiles in the
fragment-coupling stage. DDQ mediated carbon–hydrogen bond
cleavages generate dihydropyrones (5), and protecting group
cleavage deliver spirocyclic acetals (6). This sequence provides
a powerful approach to increasing molecular complexity in a
single reaction vessel. We postulated that the sequence could
generate bridged bicyclic systems if the protected nucleophile
were attached to the aldehyde rather than the diene. Thus
cycloaddition and oxidation would generate dihydropyrone 7,
with protecting group cleavage and nucleophilic addition
providing bridged acetal 8. Realizing this objective leads to the
key subunit of divergolide E (1) being accessible from diene 9
and aldehyde 10 followed by the incorporation of the linker
subunit through acylation reactions. The diene can arise through
a chelation-controlled addition of a vinylzinc reagent into an α-
alkoxy aldehyde.
controlled alkenylzinc addition, an amide formation between
a
hindered aniline and an acylating agent that is prone to ketene
formation, and a challenging macrolactonization.
The divergolides are a family of ansa macrolides that are
produced by the endophyte Streptomyces sp. found in
mangroves off the Chinese coast.[1] Hertweck showed that,
despite impressive structural heterogeneity due to differences in
oxidation state and hydration levels, these compounds are
derived from the same polyketide synthase system.[1a]
Subsequent studies based on genomic analyses provided
greater insights into the biosyntheses of these structures.[1c],[2],[3]
Structurally disparate members of this family (Figure 1) include
the bridged bicyclic acetal divergolide E (1), the naphthoquinone
divergolide I (2), and the alkylidene chromene divergolide B (3).
These compounds have been reported to show moderate
antibiotic activity against a number of strains, including some
that show drug resistance, though these studies are limited to
zone inhibition assays. These structures have been the subject
of several synthetic studies[4] and the total synthesis of
O
O
H
N
O
OH
O
O
O
Prior studies
HO
O
HN
R3SiO
O
O
O
O
O
cycloaddition
then DDQ
O–P
+
O
O
H
O
H
cleavage
R
O
OP
O
OH
R
OP
OH
Divergolide E
O
R
H
Divergolide I
2
5
6
1
This work
R3SiO
OH
O
O
O
O
O
OH
O
O
O–P
cycloaddition
then DDQ
HN
O
O
H
O
+
R
R
H
cleavage
HN
O
R
O
O
H
PO
PO
O
O
7
8
O
HO
HO
O
Divergolide E retrosynthesis
hetero
Diels-Alder
OSiR3
O
1
Divergolide B
3
Divergolide H
4
Myers
alkylation
OH
3
O
H
acylation
5
O
OP
O
Figure 1. Members of the divergolide family of natural products.
HN
O
7
+
chelation-
controlled
addition
PO
9
X
11
OP
O
OP
Sharpless
desymmetrization
OH
O
macrolactonization
1
9
10
[a]
S. M. Caplan, Prof. Dr. P. E. Floreancig*
Department of Chemistry
University of Pittsburgh
Pittsburgh, Pennsylvania 15260, USA
E-mail: florean@pitt.edu
Scheme 1. Telescoped approaches to bicyclic acetals, and
retrosynthetic analysis of divergolide E. DDQ = 1,2-dichloro-5,6-dicyano-1,4-
benzoquinone; P = protecting group; X = nitrogen-containing group.
a
basic
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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10.1002/anie.201810336
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COMMUNICATION
The syntheses of the diene subunits are shown in Scheme 2. to form the THP analog of 12 proceeded very inefficiently,
The desymmetrizing Sharpless epoxidation of 1,4-pentadien-3-ol
(11) developed by Smith and Schreiber[7] set the absolute
stereochemistry at C12. The resulting enantiomerically pure
epoxy alcohol was protected as a PMB ether prior to cross
metathesis with isobutylene[8] to provide 12. Epoxide opening
particularly on large scale, presumably due to coordination
between the ring oxygen of the THP with the ruthenium carbene
intermediate.[18] The conversion of 20 to silyloxy diene 21
proceeded with TBSOTf and Hünig's base.[19]
OTBS
O
[9]
with KOH followed by diol cleavage with NaIO4 yielded C11
aldehyde 13. The synthesis of the C5-C10 subunit was based on
H
sequence developed by Fürstner[10] and began by
a
a
e
b-d
a
16
diastereoselective enolate alkylation of Myers amide 14[11] with
the TBS ether of 3-iodo-1-propanol followed by amide
reduction[12] to form 15. Oxidation to the aldehyde and
homologation with the Ohira-Bestmann reagent[13] generated
alkyne 16.
10
11
OH
OAlloc
OPMB
OPMB
17
18
O
O
OTBS
H
11
O
a-c
d-e
12
12
O
f-g
h
OH
OPMB
OPMB
13
OTBS
11
12
OTBS
OAlloc
OAlloc
OTHP
OAlloc
OTHP
OPMB
f-g
h-i
8
8
Ph
OH
19
20
21
O
N
Scheme 3. Completion of the diene synthesis. a) Cp2Zr(H)Cl, CH2Cl2, then
Me2Zn, then 13, –78 °C to rt, 79%, dr = 4:1; b) Allyl chloroformate, pyridine,
THF, 85%; c) NH4F, MeOH, 55 °C, 98%; d) ClC(O)C(O)Cl, DMSO, Et3N,
CH2Cl2, –78 °C to rt; e) EtC(O)CH2P(O)(OMe)2, LiCl, DBU, CH3CN, 78%, 2
steps; f) DDQ, pH = 7 buffer, CH2Cl2, 97%; g) Dihydropyran, PPTs, 1,2-
dichloroethane, 90%; h) TBSOTf, iPr2NEt, Et2O, –78 to 0 °C, 82%. Cp =
cyclopentadienyl, DBU = 1,8-diazabicyclo(5.4.0)undec-7-ene, Alloc = allyloxy
HO
10
14
15
16
Scheme 2. Synthesis of the diene subunits. a) Cumene hydroperoxide,
Ti(OiPr)4, L-(+)-diisopropyl tartrate, 4 Å MS, CH2Cl2, –35 °C, 60%, ee> 99%; b)
NaH, THF, then PMBBr, Bu4NI, 84%; c) Isobutylene, Hoveyda-Grubbs 2nd
generation metathesis catalyst, 83%; d) KOH, H2O, DMSO, 75 °C, 92%. e)
NaIO4, H2O, THF, 99%; f) LDA, LiCl, THF, –78 °C, then I(CH2)3OTBS, –78 to
0 °C, 92%, dr = 97:3; g) LDA, H3B•NH3, THF, –78 °C to rt, 87%; h) SO3•Py,
Et3N, DMSO, CH2Cl2, 0 °C, 89%. I) Ohira-Bestmann reagent, NaOMe, THF, –
carbonyl, Tf
=
trifluoromethanesulfonyl, PPTs
=
pyridinium para-
toluenesulfonate.
78 to –40 °C, 74%. PMB
=
para-methoxybenzyl; LDA
=
lithium
diisopropylamide, TBS = tert-butyl dimethylsilyl, Py = pyridine.
Model studies indicated that the hetero Diels-Alder reaction
would proceed most readily with a highly electron-deficient
aldehyde, and this guided our selection of the peripheral groups
on the aromatic ring. The synthesis (Scheme 4) commenced
with the known monoacylation and formylation[20] of
hydroquinone to yield aldehyde 22. Nitration followed by
acylation with anhydride 23, prepared through dehydrative
dimerization of the known[21] (two steps from butyrolactone) acid,
generated 24. The incorporation of the unusual protecting group
was necessary to enhance the electron deficiency of the
aldehyde while providing a handle for selective cleavage later in
the sequence, as described below.
The two fragments were united through the hydrozirconation
of 16 followed by transmetalation with Me2Zn to form the vinyl
zincate intermediate,[14] which added smoothly to 13 to provide
17 as a 4:1 mixture of diastereomers with the major product
arising from a chelation-controlled transition state.[15] A Mosher
ester analysis[16] of 17 showed that the product was
enantiomerically
pure,
thereby
confirming
that
the
stereochemical integrity of 16 was not compromised during the
sequence. The resulting hydroxy group was protected as an allyl
carbonate. This transformation facilitated the separation of the
diastereomers from the addition reaction. TBS ether removal
under mild conditions and oxidation of the resulting alcohol
formed aldehyde 18. The Masamune-Roush variant[17] of the
Horner-Wadsworth-Emmons reaction successfully converted 18
to enone 19. Studies on model systems showed that the PMB
ether that served to guide the vinyl zincate addition is reactive
toward DDQ during the unusually slow oxidation step in the key
dihydropyranone forming sequence, leading to cleavage and
oxidation of the resulting allylic alcohol. Therefore the PMB ether
required replacement. Oxidative ether cleavage with DDQ
followed by THP ether formation with dihydropyran and PPTs
generated 20. Notably, no alcohol oxidation occurred prior to the
completion of the PMB ether cleavage. The THP ether could, in
principle, be introduced earlier in the sequence and serve as a
stereochemistry-directing group. However the cross-metathesis
The final subunit comprises the dicarboxylic acid derivative
that serves as the linker between the arene and the remainder of
the ansa bridge. A one pot oxidation of 1,3-propanediol and
Wittig reaction[22] with ylide 25 delivered ester 26. Trans-
esterification with the sodium salt of allyl alcohol followed by
oxidation and hydroxysuccinimidyl ester formation provided 27.
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10.1002/anie.201810336
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COMMUNICATION
H
Nitro group reduction of 29 and subsequent acylation with 27
required extensive experimentation to achieve a useful and
reproducible yield. The acyl group adjacent to the nitro group
needs to be cleaved prior to nitro group reduction to avoid O-
to N-acyl group migration. This process could, in principle, be
used in a productive manner by acylating that phenol with a
product-relevant group. Unfortunately attempts to acylate
derivatives of 22 with 27 or related structures led to
intramolecular aldol additions to the aldehyde because of the
high acidity of the linker chain that arises from its being a
vinylogous β-dicarbonyl group. Removing the acyl group from 29
proceeded by cleaving the silyl ether with HF•pyridine, resulting
in a rapid deacylation through lactone formation. Nitro group
reduction proceeded with Zn and NH4Cl to provide unstable
amine 30, which reacted with 27 selectively on the amino group.
Selective cleavage of one acyl group was optimal because the
presence of the phenol increases the nucleophilicity of the
amine. However cleaving both acyl groups forms a highly
electron-rich hydroquinone that, after nitro group reduction,
decomposes quickly. Additionally, acylating agents related to 27
readily decompose through ketene formation because of their
high acidity. The hydroxysuccinimidyl ester uniquely showed the
proper reactivity toward acylation and stability to destruction
through ketene formation. Partial cyclization to form bridged
acetal 31 occurred in the acylation reaction. Subjecting the
mixture of cyclized and non-cyclized products to Et3N proved to
be the easiest protocol for accessing completely cyclized
material, with a 46% yield of 31 being obtained through a three
step sequence.
H
OAc
OH
O
OAc
a-b
c-d
O
TBSO
O
HO
HO
NO2
O
22
OH
24
O
O
O
OH
N
e
f-h
O
EtO
O
OH
O
O
26
27
PPh3
O
TBSO
OTBS
EtO
O
O
O
25
23
Scheme 4. Synthesis of the aldehyde component for the hetero Diels-Alder
reaction. a) Ac2O, AcOH, 110 °C, 86%; b) Hexamethylene tetramine, TFA,
80 °C, 43%; c) Cu(NO3)2, Ac2O, 0 °C, 55%; d) 23, pyridine, 1,2-dichloroethane,
71%; e) MnO2, 25, CH2Cl2, 47%; f) NaH, allyl alcohol, 53%; g) CrO3, H2SO4,
H2O, acetone, 75%; h) Disuccinimidyl carbonate, pyridine, CH3CN, 67%.
Jacobsen's catalyst[23] promoted the union of 21 and 24
(Scheme 5) to form silyloxy dihydropyran 28 in which the
absolute stereochemistry at C1 was controlled by the catalyst
and the relative stereochemistry at C2 was dictated by an endo-
transition state. The structural complexity of both fragments
–
caused this transformation to be quite slow. Therefore the SbF6
counterion in the catalyst was necessary to provide sufficient
reactivity and the TBS enolsilane was required to avoid the
regeneration of enone 20 from adventitious water. Diluting this
intermediate with CH2Cl2 and oxidizing with DDQ provided
dihydropyrone 29. The conversion of 28 to 29 was surprising
because it required one day to proceed to completion, while
previous oxidations of hetero Diels-Alder products were
OAc
OAc
1
1
TBSO
TBSO
H
2
NO2
NO2
2
+
H
O
O
O
O
H
O
O
a
5
complete
within
moments.[6]
We
have
observed
experimentally[24] and computationally[25] that the rates of DDQ-
mediated oxidative C–H cleavage reactions are dictated by the
oxidation potential of the substrate and the stability of the
intermediate carbocation. The enolsilane group has a very low
oxidation potential. The capacity of the oxygen in the ring to act
as an electron donor to stabilize a cation at C5, however, is
diminished by the multiple inductively electron-withdrawing
groups on the arene. We also observed that the full side chain at
C5 reduces the rate of the hetero Diels-Alder reaction in
comparison to dienes that contain truncated side chains,
suggesting that remote steric effects might also lower the rate of
oxidation. This is consistent with prior observations of steric
inhibition in quinone-mediated carbon–hydrogen bond cleavage
reactions.[26] However a suitable yield of 29 can be obtained for
completing the synthesis despite the sluggish cycloaddition and
oxidation kinetics, with the major component of the remainder of
the mass being enone 20. Attempts to increase the oxidation
rate through the use of Larock's variant of the Saegusa
oxidation[27] resulted in Alloc group cleavage with no oxidation.
IBX, another common reagent for the oxidation of enolsilanes,[28]
is not suitable for this transforation because of the difficulty in
forming the critical oxygen–iodine bond from an OTBS group
rather than the commonly employed OTMS group.
OTBS
OTBS
OAlloc
OAlloc
OTHP
OTHP
28
OAc
OAc
OH
O
O
NO2
NH2
H
H
O
O
O
O
b-c
d-e
5
OTBS
OAlloc
OAlloc
OTHP
OTHP
29
30
O
OAc
O
O
O
HN
N
O
Cr
O
–
SbF6
OAllyl
OAlloc
31
THPO
O
(1S,2R)-Jacobsen’s catalyst
Scheme 5. a) (1S,2R)-Jacobsen's catalyst, 4 Å MS, acetone, then DDQ,
CH2Cl2, 45%; b) HF•pyridine, pyridine, THF, 72%; c) Zn, NH4Cl, H2O, p-
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COMMUNICATION
dioxane; d) 27, 2,6-lutidine, p-dioxane; e) Et3N, 1,2-dichloroethane, 46% for
three steps. DDQ = 2,3-dichloro-5,6-dicyano-1,4-benzoquinone.
Acknowledgements
We thank the National Science Foundation (CHE-1362396) for
generous support of this work.
The completion of the synthesis (Scheme 6) began with a
palladium-mediated cleavage of the allyl groups[29] in 31 to yield
the seco acid, which was converted to macrocycle 32 using the
Shiina protocol.[30] Other macrolactonization conditions proved to
be ineffective, as did attempts at the transformation on
substrates in which the bridged acetal had yet to be formed.
THP ether removal under acidic conditions and deacetylation
with Me3SnOH[31] delivered divergolide E (1) and divergolide H
(4), which resulted from an acyl migration process, as a
separable 3:1 mixture in 73% yield.
Keywords: natural products • cycloaddition • oxidation • oxygen
heterocycles • macrocycles
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O
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1
4
Scheme 6. a) Pd(PPh3)4, Bu3SnH, HOAc, 1,2-dichloroethane, 50%; b) 2-
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divergolides. The key advance in the route is the development of
a telescoped sequence of fragment-coupling and oxidative
carbon–hydrogen bond cleavage that provides a mild and
functional group-tolerant approach to a precursor to the bridged
acetal. Additional noteworthy steps are the use of a chelation-
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10.1002/anie.201810336
Angewandte Chemie International Edition
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Scott M. Caplan, Paul E. Floreancig*
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Total Synthesis of Divergolides E and
H
The divergolides are a structurally disparate family of antibiotics that are
synthesized by endophytes and isolated from mangroves off the Chinese coast. We
report the first syntheses of two members of the family that contain a bridged
bicyclic acetal core. This unit was accessed by a telescoped sequence that
employs an asymmetric hetero Diels-Alder reaction for fragment coupling and an
oxidative carbon–hydrogen bond cleavage to enable acetal formation.
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