Total synthesis and stereochemical assignment of (±)-sorbiterrin A

Article abstract of DOI:10.1021/ja500854q

A concise, biomimetic approach to sorbiterrin A has been developed employing consecutive Michael additions of a 4-hydroxypyrone to a sorbicillinol derivative and silver nanoparticle-mediated bridged aldol/dehydration to construct the [3.3.1] ring system. The relative stereochemistry of sorbiterrin A was unambiguously confirmed by X-ray crystallographic analysis.

Full text of DOI:10.1021/ja500854q

Communication
pubs.acs.org/JACS
Total Synthesis and Stereochemical Assignment of ( )-Sorbiterrin A
Chao Qi,† Tian Qin,† Daisuke Suzuki,‡ and John A. Porco, Jr.*,†
†Department of Chemistry and Center for Chemical Methodology and Library Development (CMLD-BU), Boston University,
Boston, Massachusetts 02215, United States
‡Graduate School of Engineering, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8603, Japan
S
* Supporting Information
Scheme 2. Synthesis of Acetoxy Sorbicillinol 5
ABSTRACT: A concise, biomimetic approach to sorbi-
terrin A has been developed employing consecutive
Michael additions of a 4-hydroxypyrone to a sorbicillinol
derivative and silver nanoparticle-mediated bridged aldol/
dehydration to construct the [3.3.1] ring system. The
relative stereochemistry of sorbiterrin A was unambigu-
ously confirmed by X-ray crystallographic analysis.
orbicillinoids are a class of polyketides with high structural
S
diversity and bioactivity.1 The recently isolated sorbiterrin A
achieved under basic conditions with acetyl chloride to afford 8 in
91% yield. Treatment of 8 with [bis(trifluoroacetoxy)iodo]-
benzene (PIFA)4 in acetonitrile/water (9:1) afforded acetoxy
sorbicillinol 5 in 72% yield. One mechanism for this process
involves activation of 8 with PIFA to afford intermediate 9, ester
trapping5 to generate acetoxonium ion intermediate 10,6 and
hydrolysis. Alternatively, nucleophilic addition of water to 9,7
followed by acyl migration, may also generate 5.
(1) is a novel sorbicillin derivative featuring an intriguing bridged
[3.3.1] ring system and acetylcholinesterase inhibitory activity.2
The relative stereochemistries at C-2 and C-3 (Scheme 1) were
Scheme 1. Biosynthetic vs Biomimetic Pathways
To probe the feasibility for the Michael addition cascade to
construct the quaternary center in 2 using a 4-hydroxypyrone,8
we examined a number of basic and Lewis acid mediated
conditions. Unfortunately, we found that substrate 5 was highly
unstable under basic conditions which resulted in significant
degradation or dimerization.3 We also found that several Lewis
acid conditions (e.g., Yb(OTf)3, In(OTf)3, and Sc(OTf)3)
afforded trace amounts of 3-aryl-4-hydroxypyrone product 11.
Reaction partners 5 and 6 were further treated with Lewis acid
promoters under thermal conditions in which case only
decomposition was observed. Gratifyingly, thermolysis of 5
and 6 in the presence of silica gel (130 °C) produced the spiro
compounds 12 and 13 in 80% yield (d.r. = 1.5:1) (Scheme 3). By
lowering the reaction temperature to 90 °C, we were able to
isolate compound 11 in 28% yield along with the spiro
compounds 12 and 13 (50%). We found that 11 could also be
converted to 12 and 13 in 94% yield at 130 °C using silica gel as a
catalyst.
proposed based on coupling constant analysis (3J2,3 = 2.8 Hz).2
Herein, we describe a concise approach to sorbiterrin A along
with studies to confirm relative stereochemistry. The synthesis
employs a biomimetic process involving consecutive Michael
additions of a 4-hydroxypyrone to a protected sorbicillinol
derivative followed by silver nanoparticle-mediated bridged
aldol/dehydration to access the [3.3.1] framework.
Biosynthetically, sorbiterrin A (1) was proposed to originate
from vinylogous acid 2 through an intramolecular aldol/
dehydration reaction. Precursor 2 may be obtained from addition
of 4 to arene oxide 3. Inspired by previous syntheses of
sorbicillinoids,1 we envisioned that the quaternary center of 2
may be derived from consecutive Michael additions of the
commercially available 4-hydroxypyrone 6 to the known
sorbicillinol acetate derivative 5 followed by pyrone opening
(Scheme 1). The overall synthetic strategy would allow very
concise syntheses of sorbiterrin A and analogues.
1
The similarities in H NMR spectra, NOE correlations, and
the noncrystalline properties9 of 12 and 13 caused significant
difficulty with their stereochemical assignments. Accordingly, we
considered further derivatization to elucidate their structures.
Examination of the π-orbital alignments for compounds 12 and
139 suggested that they may have different reactivities under
photocycloaddition conditions. The parallel arrangement of the
We initiated our study with the preparation of acetoxy
Received: January 25, 2014
Published: February 19, 2014
sorbicillinol 5 (Scheme 2).3 Acetylation of sorbicillin (7) was
© 2014 American Chemical Society
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With advanced intermediates 15/16 in hand, we attempted the
key intramolecular bridged aldol/dehydration step to construct
the [3.3.1] ring system of sorbiterrin A. The base sensitivity13 of
both 15 and 16 prompted us to focus on examination of acidic
conditions. We initiated our study by screening various Brønsted
and Lewis acid catalysts including HCl in dioxane,14 trifluoro-
acetic acid, p-toluenesulfonic acid,15 and BF3·Et2O16 for
cyclization of 15. Based on our previous studies employing
silica-supported silver nanoparticles (AgNP’s) as catalysts for
activation of 2′-hydroxychalcones toward [4 + 2] cyclo-
additions,17 this catalyst system was also evaluated. To our
surprise, only conditions employing silver nanoparticles afforded
the desired product; other conditions either degraded the
starting materials or gave no reactivity.9 After optimization, best
results involved treatment of 15 with 0.25 mol % AgNP’s at 135
°C in chlorobenzene which afforded a 72% yield of the cyclized
product 17 (Scheme 6). Compound 17 was further treated with
Scheme 3. Michael Additions of 4-Hydroxypyrone 6 to 5
two double bonds in 12 should allow for [2 + 2] photo-
cycloaddition10 which may not occur with compound 13 as
substrate. Upon photoirradiation, only diastereomer 12 was
converted to [4.2.1.03.8] tricyclic structure1114 as confirmed by
X-ray crystallographic analysis (Scheme 4).9
Scheme 6. Synthesis of Sorbiterrin A
Scheme 4. Tricyclo [4.2.1.03.8] Derivative 14
MgI2 in toluene to effect demethylation which afforded
sorbiterrin A in 85% yield after acidic workup. Treatment of
the diastereomeric substrate 16 under similar conditions (0.25
mol % AgNP’s, 135 °C, chlorobenzene) afforded a mixture of
diastereomers 17 and 18 in a 1:2 ratio and 50% combined yield
(Scheme 7). The inseparable mixture of 17 and 18 was
demethylated using MgI2 to provide sorbiterrin A (1) and 3-
epi-sorbiterrin A (20) in a 1:2 ratio and 88% combined yield.
Scheme 7. Synthesis of 3-epi-Sorbiterrin A
In order to prepare intramolecular aldol substrate 2, spiro
compound 13 was treated with various acidic (e.g. HCl, H2NTf,
p-TsOH) and basic (e.g. NaOH, NaOMe, pyrrolidine)
conditions. Unfortunately, all conditions led to degradation or
decarboxylation products. Accordingly, we targeted the synthesis
of the corresponding methyl ester 15 through transesterification.
A number of Lewis acids including Cu(OTf)2, Mg(OTf)2,
Ti(OEt)4, and Zn(OTf)212 were evaluated on substrate 13 using
methanol as solvent. We were pleased to observe that Zn(OTf)2
(80 °C, MeOH) efficiently catalyzed the desired transester-
ification in the presence of 4 Å molecular sieves. However, we
also observed epimerization in this reaction; a 1:1 mixture of
methyl esters 15 and 16 was observed using either 12 or 13 as
starting material. No reaction was observed after treatment of 12
or 13 with Zn(OTf)2 in 1,2-dichloroethane (80 °C) which
indicates the epimerization likely occurs on products 15 and 16.
Accordingly, a mixture of 12 and 13 was submitted to the
Zn(OTf)2 conditions to prepare 15 and 16 in 74% yield and in a
1:1 ratio (Scheme 5). The relative stereochemistries of 15 and 16
were determined by correlation to sorbiterrin A (vide infra).
Sorbiterrin A (1) and 3-epi-sorbiterrin A (20) were found to
have very similar 1H NMR coupling constants between H-2 and
H-3;9 in particular 20 has a 3J2,3 = 2.3 Hz in comparison to 3J2,3
=
2.8 Hz for 1 (cf. Scheme 1). These similar coupling constant
values called into question the assignment of the relative
stereochemistry at H-2 and H-3 for 1. Numerous modes of
derivatization were attempted on both 1 and 20. Luckily, both 1
and 20 were found to form the corresponding iodolactonization
products.18 However, only compound 22 was found to be
crystalline (Scheme 8).9 X-ray crystallographic analysis revealed a
cis configuration between C-2 and C-3 in 22 which confirmed the
proposed2 trans configuration between H-2 and H-3 in 1.
We next performed a series of mechanistic studies of the
AgNP-mediated aldol condensation. We initiated these studies
by conducting control experiments with substrate 15 using
several silver salts as Lewis acids including AgBF4, Ag2O, and
AgOTf which in all cases did not afford the desired products.9
Intermolecular aldol condensation between 2′,4′-dihydroxy-
Scheme 5. Spirocyclic Ring-Opening via Transesterification
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Scheme 8. Synthesis of Iodolactone 22
Scheme 10. Proposed Mechanisms for the AgNP-Mediated
Aldol Reaction
acetophenone 2319 and 24 was also found to be efficiently
catalyzed by AgNP’s affording chalcone 253c (Scheme 9). In
Scheme 9. Model Aldol Condensation Reactions
addition, no aldol condensation was observed when the
corresponding 2′,4′-methoxyacetophenone was used as the
substrate.9 In our previous studies, AgNP’s were employed as a
catalyst for Diels−Alder cycloadditions of 2′-hydroxychalcones
through a proposed radical cation intermediate. In line with our
previous mechanistic studies, we hypothesized that the aldol
condensation could also be catalyzed by the AgNP’s through an
electron transfer mechanism. To probe the involvement of
possible radical intermediates, 5,5-dimethyl-1-pyrroline N-oxide
(DMPO) was used as a spin trap20 to access long lifetime
radicals. Electron paramagnetic resonance (EPR) measurements
were conducted on a mixture of the silica-supported AgNP
catalyst, DMPO, and compound 16 in which case a strong radical
signal was evident in the EPR spectrum (Figure 1a). Similar
cation intermediate 28 may facilitate enolization of the ketone by
increasing the kinetic acidity of the α-hydrogen atoms to afford
enol tautomer 29. Intramolecular aldol reaction of 29 to 30 may
be followed by dehydration to intermediate 31 followed by back
electron transfer (BET) and protonation to product 17.
Alternatively, enol tautomer 32 (Scheme 10b) may undergo
radical cyclization24 to intermediate 33, which may be followed
by back electron transfer, protonation, and dehydration to obtain
product 17.
Analysis of molecular models of the two proposed aldol
transition states (Figure 2A and B, respectively, leading to 18 and
Figure 1. EPR spectra of spin trapping. (a) Experimental EPR spectrum
obtained from a mixture of silica-supported AgNP catalyst (150 mg), 16
(19.4 mg, 0.05 mmol), and DMPO (20 μL, 0.18 mmol) in CH2Cl2 (0.5
mL) at 25 °C. aN = 14.4 G, aHβ = 21.7 G. (b) Experimental EPR
spectrum obtained from a mixture of silica-supported AgNP catalyst
(150 mg), 23 (9.2 mg, 0.05 mmol), and DMPO (20 μL, 0.18 mmol) in
CH2Cl2 (0.5 mL) at 25 °C. aN = 14.1 G, aHβ = 22.4 G. (c) Experimental
EPR spectrum obtained from a mixture of silica-supported AgNP
catalyst (150 mg), 26 (11.0 mg, 0.05 mmol), and DMPO (20 μL, 0.18
mmol) in CH2Cl2 (0.5 mL) at 25 °C.
Figure 2. Molecular models of two proposed aldol transition states.
17) provides a plausible explanation for the C3 epimerization
observed for substrate 16 (Scheme 7). By comparing the two
models, we hypothesize that the equatorially positioned propenyl
substituent at C3 in transition state A may interact with the
methyl ketone (1,3-diaxial interaction) which should increase the
energy barrier for the intramolecular aldol reaction. This steric
repulsion is not observed in the corresponding transition state B.
Due to the higher projected energy barrier of A, C3-
epimerization may subsequentially occur by retro-Michael/
Michael addition.
In summary, we have developed a biomimetic synthesis of the
bicyclo [3.3.1] natural product sorbiterrin A. The quaternary
carbon center was established via consecutive Michael additions
of a 4-hydroxypyrone to acetoxy sorbicillinol. The [3.3.1] ring
system was constructed using a unique AgNP-catalyzed bridged
aldol condensation. Mechanistic studies including EPR experi-
experiments were conducted using both compound 23 and
vinylogous acid 26. A similar EPR signal was detected using 23
but not with 26 which supports the unique property of the 2′-
hydroxyacetophenone moiety to generate a radical species under
AgNP-catalyzed conditions.
Based on our experimental results, we propose a mechanism
for the AgNP-mediated intramolecular aldol reaction of substrate
15 as shown in Scheme 10. Absorption of 15 to the AgNP surface
may lead to proton removal and single electron transfer
(SET)17,21−23 from 15 to provide phenoxyl radical 27 (Scheme
10a) which is in resonance with the carbon-centered radical 28.
We hypothesize that the electron deficient character of radical
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ASSOCIATED CONTENT
* Supporting Information
■
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Experimental procedures and characterization data for all new
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AUTHOR INFORMATION
Corresponding Author
porco@bu.edu
■
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
(14) Huo, H.-H; Xia, X.-E; Zhang, H.-K; Huang, P.-Q. J. Org. Chem.
2013, 78, 455−465.
Financial support from the National Institutes of Health (GM-
073855 and GM-099920), Vertex Pharmaceuticals (graduate
fellowship to T.Q.), and the IGER program at Nagoya University
(graduate fellowship to D.S.) is gratefully acknowledged. We
thank Dr. Suwei Dong (Boston University) for methodology
development to prepare compound 5, Dr. Jeffrey Bacon (Boston
University) for X-ray crystal structure analyses, Dr. Paul Ralifo
(Boston University) for assistance with EPR experiments, Prof.
John Caradonna, Dr. Huan Cong, and Dr. Kiel Lazarski (Boston
University) for extremely helpful and stimulating discussions,
and Prof. Dehai Li (Ocean University, Qingdao, China) for
providing a natural sample of sorbiterrin A.
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