Total Syntheses of the Isomeric Aglain Natural Products Foveoglin A and Perviridisin B: Selective Excited-State Intramolecular Proton-Transfer Photocycloaddition

Article abstract of DOI:10.1002/anie.201707539

Selective excited-state intramolecular proton-transfer (ESIPT) photocycloaddition of 3-hydroxyflavones with trans, trans-1,4-diphenyl-1,3-butadiene is described. Using this methodology, total syntheses of the natural products (±)-foveoglin A and (±)-perviridisin B were accomplished. Enantioselective ESIPT photocycloaddition using TADDOLs as chiral hydrogen-bonding additives provided access to (+)-foveoglin A. Mechanistic studies have revealed the possibility for a photoinduced electron-transfer (PET) pathway.

Full text of DOI:10.1002/anie.201707539

A Journal of the Gesellschaft Deutscher Chemiker
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Accepted Article
Title: Total Syntheses of the Isomeric Aglain Natural Products
Foveoglin A and Perviridisin B via Selective ESIPT
Photocycloaddition
Authors: John Porco, Wenyu Wang, Anthony Clay, Retheesh Krishnan,
Neil J. Lajkiewicz, Lauren E. Brown, and Jayaraman Sivaguru
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201707539
Angew. Chem. 10.1002/ange.201707539
Link to VoR: http://dx.doi.org/10.1002/anie.201707539
http://dx.doi.org/10.1002/ange.201707539

10.1002/anie.201707539
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COMMUNICATION
Total Syntheses of the Isomeric Aglain Natural Products
Foveoglin A and Perviridisin B via Selective ESIPT
Photocycloaddition
Wenyu Wang,[a] Anthony Clay,[b,d] Retheesh Krishnan,[c] Neil J. Lajkiewicz,[a] Lauren E. Brown,[a]
Jayaraman Sivaguru,*[b,d] and John A. Porco, Jr.*[a]
Abstract: Selective ESIPT photocycloaddition of 3-hydroxyflavones
with trans, trans-1,4-diphenyl-1,3-butadiene is described. Using this
methodology, total syntheses of the natural products ()-foveoglin A
and ()-perviridisin B have been accomplished. Enantioselective
ESIPT photocycloaddition using TADDOLs as chiral hydrogen-
bonding additives provided access to (+)-foveoglin A. Mechanistic
studies have revealed the possibility for a photoinduced electron
transfer (PET) pathway.
rocaglates have been shown to exhibit anticancer and antiviral
activities.[4] Due to their structural complexity and intriguing
biological activities, a number of groups have reported chemical
syntheses of rocaglates and analogues.[5] Previously, we reported
a biomimetic approach towards these compounds in which 3-
hydroxyflavone (3-HF)
intramolecular proton
5
undergoes ESIPT (excited state
transfer)-mediated (3+2)
photocycloaddition[6] with dipolarophiles including methyl
cinnamate 6a.[7] Although this approach rapidly provides access
to rocaglates, recent isolation reports of the aglain derivatives
foveoglin A (3)[8] and perviridisin B (4),[9] as well as the related
aglapervirisins,[10] suggested new challenges to employ ESIPT
photocycloaddition to access their isomeric core structures in
comparison to ponapensin (2).
Flavagline (rocaglate) natural products are compounds[1]
which are biosynthetically derived from a flavonoid and a cinnamic
amide derivative and include the cyclopenta[b]benzofuran
rocaglamide (1)[2] and the cyclopenta[b,c]benzopyran (aglain)
ponapensin (2)[3] (Figure 1). Both natural and synthetic
.
Scheme 1. (3+2)-Photocycloaddition of 3-hydroxyflavones with dipolarophiles
6, 6a, and 8.
Figure 1. Rocaglamide (1), ponapensin (2), and the isomeric aglain natural
products (3) and (4).
We have previously reported that trans-stilbene 6 may be
used as a dipolarophile in ESIPT photocycloadditions of 3-
hydroxyflavones 5 (Scheme 1).[11] In the current study, we have
evaluated trans,trans-1,4-diphenyl-1,3-butadiene (DPBD, 8) as
dipolarophile. By extending the conjugation of the reaction partner,
we expected that four possible isomers could be formed (Scheme
1b). In particular, preferential formation of 11/12 vs. 9/10 would
provide access to aglain scaffolds required for syntheses of 3 and
4 wherein the styrene moiety serves as an amide precursor.
[a]
[b]
W. Wang, Dr. N. J. Lajkiewicz, Dr. L. E. Brown, Prof. Dr. J. A. Porco
Jr.
Department of Chemistry, Center for Molecular Discovery (BU-
CMD), Boston University, 590 Commonwealth Avenue, Boston,
Massachusetts 02215, United States
E-mail: porco@bu.edu
A. Clay, Prof. Dr. J. Sivaguru
Present address: Department of Chemistry and Center for
Photochemical Sciences Bowling Geen State University, Bowling
Green, OH 43403. USA
E-mail: sivagj@bgsu.edu
[c]
[d]
Dr. K. Retheesh
Department of Chemistry, Government College for Women,
Thiruvananthapuram 695014, India
The work was performed at North Dakota State University.
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201707539
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Scheme 4. Total synthesis of (±)-perviridisin B.
Scheme 2. ESIPT photocycloaddition of 3-HF 5 with DPBD 8.
In order to achieve the synthesis of the congener perviridisin
B (4), practical access to the exo-diastereomer 12 was required.
After thorough evaluation of conditions, flow photocycloaddition of
5 and 8 using 2:1 CH2Cl2:isopropanol as solvent afforded a 52%
We first examined photocycloadditions of 3-hydroxyflavone 5
and DPBD 8 (Scheme 2). Upon photoirradiation of 5 and 8 using
TFE/CHCl3 (3:7) in a continuous photoflow reactor,[5c] only
diastereomers 11 and 12 were produced (d.r. = 5:1). The
inseparable mixture was treated with NaBH4 to afford the
corresponding secondary alcohols (d.r.= 5:1) and isolation of the
major product 13 in 44% yield (2 steps). Compound 13 was
subsequently acylated to provide the (±)-p-bromobenzoate (±)-14
whose structure was established by single crystal X-ray
diffraction.[12]
yield of photocycloadducts 11 and 12 (d.r.
= 1:1). The
corresponding 10S-alcohol epimers were produced in 96% yield
and in 10:1 diastereoselectivity by reduction with NaBH(OAc)3 in
trifluorotoluene. Subsequent trimethylsilyl protection furnished the
mono-silylated product 18 which was subjected to oxidative
double bond cleavage to afford aldehyde 19 in 68% yield.
Oxidative amidation[13] of 19 with amine 20, followed by TMS
deprotection and in situ acetate hydrolysis, afforded (±)-
perviridisin B (4) (Scheme 4).
We next studied the corresponding enantioselective ESIPT
photocycloaddition using chiral hydrogen-bonding additives.[14]
Although we have reported use of TADDOL derivatives to mediate
enantioselective ESIPT photocycloaddition of 3-hydroxyflavones,
thus far dipolarophiles have been limited to cinnamates. Use of
DPBD 8 which lacks the ester moiety as a potential hydrogen-
bonding acceptor in comparison to dipolarophile 6a provides
further support for our proposal that host-guest complexation of
Scheme 3. Total synthesis of (±)-foveoglin A.
3-HF
5
by
hydrogen-bonding
additives
controls
The total synthesis of (±)-foveoglin
A (3) was next
enantioselectivity.14a In the presence of a stoichiometric amount
of a hydrogen-bonding additive, 3-HF 5 and DPBD 8 were
irradiated for 10 h at -78 °C. Limited solubility of DPBD 8 at low
temperatures was observed which prompted us to dilute the
reaction (0.005 M) to achieve homogeneity. Using TADDOL 21 as
accomplished as illustrated in Scheme 3. Bis-trimethylsilyl
protection of 13 to block cleavage of the C5-C10 bond followed
by OsO4-catalyzed dihydroxylation and subsequent oxidative
cleavage of the derived diol using Pb(OAc)4 provided aldehyde 15
(70% yield, 2 steps). Compound 15 was further treated with amine
16 to generate the corresponding imine which was transformed to
an amide using oxidative amidation conditions.[13] Subsequent
silyl deprotection using tetrabutylammonium fluoride furnished
(±)-foveoglin A (3).
a
stoichiometric additive, we obtained two inseparable
diastereomers which were reduced with NaBH4 to obtain major
diastereomer 13 for enantiomeric excess (e.e.) determination. As
maintaining low temperature is helpful for enantioselectivity,[14]
and to overcome significant heat release from use of traditional
UV lamp, a UV-LED ( = 365 nm) was chosen as a light source.[15]
After condition optimization,[16] TADDOL 21 was found to be an
optimal additive to provide compound (+)-13 in 67% yield and
83% e.e., whereas TADDOL 22 was able to facilitate the
photocycloaddition in a similar yield and in 49% e.e. (Scheme 5).
Interestingly, use of the chiral trifluoroethanol, Pirkle’s alcohol 23,
led to 13 in 71% e.e. Although Pirkle’s alcohol 23 was previously
reported as an NMR chiral shift reagent,[17] this study represents
the first application of Pirkle’s alcohol as a chiral hydrogen
bonding additive.
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10.1002/anie.201707539
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Due to difficulties in achieving absolute stereochemistry
assignment of (+)-13 or (+)-14 by X-ray crystal structure analysis,
the absolute configuration of (+)-13 was determined by VCD
analysis[18] of p-bromobenzoate (+)-14.[16] Further conversion of
(+)-13 (Scheme 5) afforded (+)-foveoglin A in 96% ee ([]D20 -30.0
natural (c 0.16, CHCl3), []D23 +25.3 synthetic (c 0.16, CHCl3)).
The absolute configuration of natural (-)-foveoglin A (3) is in
agreement with the aglain natural product, (-)-ponapensin (2).[3]
charge transfer interactions) as well as the approach of 8 towards
35T*. Based on our photophysical measurements,[16] we did not
observe an electron donor–acceptor (EDA) complex[23] between 5
and 8 in the ground state. The lack of a ground state EDA complex
is expected as triplet state 5 initiates the electron transfer pathway.
Figure 2. Proposed mechanism for ESIPT photocycloaddition of 3-HF 5 and
DPBD 8.
To further evaluate dipolarophile scope, we synthesized a
number of unsymmetrical DPBDs and tested their feasibility in
ESIPT photocycloaddition.[16] Use of the electron deficient
pentafluorophenyl
DPBD
27[24]
cleanly
afforded
photocycloadducts which were subjected to the previously
described reduction, silylation, and alkene cleavage sequence to
afford two aldehyde products 30 and 15 in a 4:1 ratio (Scheme 6).
This outcome indicates that the pentafluorophenyl moiety of 27
may stabilize negative charge after formation of a radical ion pair
(cf. 24, Figure 2) which appears to dominate the selectivity for the
photocycloaddition. Additionally, a - stacking (donor-acceptor)
interaction (cf. 28, Scheme 6) between 5 and 27 also appears to
orient photocycloaddition site-selectivity. This selectivity was also
observed with other fluorinated dipolarophiles including bis-
trifluoromethylphenyl DPBD and pentafluorostilbene.[16]
Scheme 5. Enantioselective ESIPT photocycloaddition and asymmetric
synthesis of (+)-foveoglin A.
Mechanistic studies were next conducted to provide a
rationale for the selectivity of the photocycloaddition. In polar
protic solvents (e.g. trifluoroethanol), dual fluorescence emission
(fluorescence of the normal state N and tautomer state T) was
observed both at room temperature and 77 K.[16] Based on the
fast ESIPT process and the singlet state energy for 5, singlet
energy transfer from excited 5 to 8 was ruled out.[20] As
determined by the phosphorescence spectrum, the lowest triplet
excited state of 3-HF 5 was found to be ~54 kcal/mol.[16] In
addition, using the Rehm-Weller equation,[21] the feasibility for
photoinduced electron transfer (PET)[22] initiating the
photocycloaddition from the triplet excited state was ascertained.
The free energy for electron transfer from the triplet excited state
was exergonic (GET = -5.3 kcal/mol) suggesting a facile PET
pathway initiating the photocycloaddition. To ascertain that
photoexcitation of 3-HF 5 rather than DPBD 8 is crucial for
Scheme 6. Use of pentafluorophenyl dipolarophile 27 in ESIPT
photocycloaddition.
photoreactivity, a control experiment using a purple LED (max
=
395 nm) as light source for selective excitation of 5 was found to
cleanly produce the photocycloadduct.[16] As shown in Figure 2,
the triplet excited state of 5 may initiate the photocycloaddition via
radical and/or electron transfer pathways. Formation of the triplet
diradical 25 either by direct addition of 8 to 35* or through radical
ion pair 24 followed by subsequent intersystem crossing (ISC)
leads to singlet diradical 26. Ring closure of 26 affords 11 and 12.
The selectivity in the system is dictated by the electronics (due to
In summary, total syntheses of the aglain natural products
foveoglin A (3) and perviridisin B (4) have been accomplished
employing selective ESIPT photocycloaddition of 3-HF 5 with
DPBD 8. Enantioselective ESIPT photocycloaddition was also
demonstrated using chiral hydrogen-bonding additives to access
(+)-foveoglin A. Mechanistic studies were conducted leading to
the identification of a photoinduced electron transfer (PET)
pathway. ESIPT photocycloadditions of 3-HF 5 with substituted,
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[8]
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Acknowledgements
We thank the National Institutes of Health (R35 GM118173) for
research support. J.S. and A.C. thank NDSU for support. J.S. and
A.C. thank the National Science Foundation (CHE-1465075) for
the purchase of Combiflash and solvent purification systems. We
thank Dr. Jeffrey Bacon (Boston University) for X-ray crystal
structure analysis and Dr. Sergey Shilov (Bruker Optics, Billerica,
MA) for VCD data acquisition. NMR (CHE-0619339) and MS
(CHE-0443618) facilities at Boston University are supported by
the NSF and Work at the BU-CMD is supported by R24
GM111625.
Cambridge
Crystallographic
Data
Center
via
www.ccdc.cam.ac.uk/data_request/cif. See the Supporting Information
for complete experimental details.
[13] K. S. Goh, C. Tan, RSC Adv. 2012, 2, 5536-5538.
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[16] Please see the Supporting Information for complete experimental details.
[17] W. H. Pirkle, D. L. Sikkenga, M. S. Pavlin, J. Org. Chem. 1977, 42, 384-
387.
Keywords: ESIPT photocycloaddition
• Total synthesis •
Photoinduced electron transfer • Asymmetric photoreaction
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10.1002/anie.201707539
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COMMUNICATION
COMMUNICATION
Wenyu Wang, Anthony Clay, Retheesh
Krishnan, Neil J. Lajkiewicz, Lauren E.
Brown, Jayaraman Sivaguru*, and John
A. Porco, Jr.*
Page No. – Page No.
Total Syntheses of the Isomeric
Aglain Natural Products Foveoglin A
and Perviridisin B via Selective ESIPT
Photocycloaddition
Selective ESIPT photocycloaddition of 3-hydroxyflavones with trans,trans-1,4-
diphenyl-1,3-butadiene has been achieved which enabled the total syntheses of
isomeric aglain natural products foveoglin A and perviridisin B. Mechanistic studies
have revealed the possibility of a photoinduced electron transfer (PET) pathway.
This article is protected by copyright. All rights reserved.