Asymmetric Dearomatization/Cyclization Enables Access to Polycyclic Chemotypes

Article abstract of DOI:10.1002/ejoc.201601003

Enantioenriched, polycyclic compounds were obtained from a simple acylphloroglucinol scaffold. Highly enantioselective dearomatization was accomplished using a Trost ligand–palladium(0) complex. A computational DFT model was developed to rationalize observed enantioselectivities and revealed a key reactant-ligand hydrogen bonding interaction. Dearomatized products were used in visible light-mediated photocycloadditions and oxidative free radical cyclizations to obtain novel polycyclic chemotypes including tricyclo[4.3.1.0^1,4]decan-10-ones, bicyclo[3.2.1]octan-8-ones and highly substituted cycloheptanones.

Full text of DOI:10.1002/ejoc.201601003

A Journal of
Accepted Article
Title: Asymmetric Dearomatization/Cyclization Enables Access to Novel Chemoty-
pes
Authors: John Porco; Lauren E. Brown; Mikayo Hayashi
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201601003
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Asymmetric Dearomatization/Cyclization Enables Access to
Novel Chemotypes
Mikayo Hayashi, Lauren E. Brown,* and John A. Porco, Jr.*
Dedicated to Professor Stuart L. Schreiber on the occasion of his 60th birthday
Abstract: Enantioenriched, polycyclic compounds were obtained
access complex compound libraries in minimal steps from
simple starting materials, the development of efficient,
complexity-generating synthetic methodology is critical. Herein,
we report a new strategy for generation of enantioenriched,
polycyclic compounds via two-step dearomatization/cyclization
sequences. Asymmetric, dearomative cinnamylation of simple
benzoyl phloroglucinol 1 produces chemotype 4 bearing multiple
olefinic functional handles that can be exploited for subsequent
intramolecular cyclizations to produce novel polycyclic
chemotypes (Figure 2).
from a simple acylphloroglucinol scaffold. Highly enantioselective
dearomatization was accomplished using
a
Trost ligand-
palladium(0) complex. A computational DFT model was developed
to rationalize observed enantioselectivities and revealed a key
reactant-ligand hydrogen bonding interaction. Dearomatized
products were used in visible light-mediated photocycloadditions and
oxidative free radical cyclizations to obtain novel polycyclic
chemotypes
including
tricyclo[4.3.1.01,4]decan-10-ones,
bicyclo[3.2.1]octan-8-ones and highly-substituted cycloheptanones.
Introduction
Polyprenylated polycyclic acylphloroglucinols (PPAPs) are
a natural product class well-known for their diverse biological
activities,[1] and their complex structures have attracted the
attention of many chemists in the field of natural product total
synthesis.[2] We have previously shown that dearomative
alkylation at the 6-position of 4,6-diallyl-2-benzoyl-5-O-methyl-
phloroglucinol (1) enables the synthesis of PPAPs such as 7-
epi-nemorosone (2)[3] and plukenetione A (3)[4] (Figure 1).
Figure 2. Asymmetric cinnamylation of 1 and further cyclizations of 4 gives
rise to novel chemotypes
Results and Discussion
We
first
evaluated
dearomative,
asymmetric
cinnamylation[7] of substrate 1 using Trost ligand-Pd0 complexes
(Table 1). Treatment of 1 with cinnamyl carbonate 5a, (S,S)-
[8]
DACH-phenyl Trost ligand (L1), Cs2CO3, and Pd2(dba)3
afforded the cinnamylated product 4a in 72% yield and 99 % ee
(Entry 1). The absolute stereochemistry of 4a was determined
by X-ray crystallography of the derived p-bromobenzoate 6a
(Figure 3).[9] Use of (R,R)-DACH-phenyl Trost ligand (L2)
afforded the opposite enantiomer (ent-4a, not shown) in 81%
yield (Entry 2). The DPEDA-type Trost ligand L3 gave a slightly
lower yield and % ee than was observed with L1 (Entry 3).
(S,S)-DACH-naphthyl ligand (L4) was not effective for the
reaction (Entry 4). Use of the (S,S)-ANDEN-phenyl type ligand
(L5) provided the opposite enantiomer in 44% yield and 24 % ee
(Entry 5).
Figure 1. Natural products derived from acylphloroglucinol scaffold 1
Diversity-oriented synthesis (DOS) enables the assembly
of small molecule screening libraries with high sp3 carbon and
chiral center content for use in drug discovery.[5][6] In order to
We next investigated substrate scope (Table 2). Both
naphthyl- (5b) and 4-bromophenyl-substituted (5c) substrates
were well tolerated. Reactions of carbonates with electron-
donating groups such as 4-methoxyphenyl (5d) or 2-furanyl (5e)
were more sluggish, requiring 48 h for full consumption of 1.
Enantiopurities of the products (4b-e) were high (91-99 % ee).
Conversely, 4-nitrophenyl substrate (5f) showed only moderate
enantioselectivity. Altering the substitution at the allylic double
bond completely prevented the reaction (g and h).
[a]
[b]
Prof. Dr. L. E. Brown, Prof. Dr. J. A. Porco, Jr.
Department of Chemistry
Center for Molecular Discovery, Boston University
590 Commonwealth Avenue, Boston, MA 02215 (USA)
E-mail: brownle@bu.edu, porco@bu.edu
M. Hayashi
Department of Chemistry
Center for Molecular Discovery, Boston University
590 Commonwealth Avenue, Boston, MA 02215 (USA)
Present address: Otsuka Pharmaceutical Co., Ltd. 463-10
Kagasuno Kawauchi-cho, Tokushima 771-0192, Japan
Supporting information for this article is given via a link at the end of
the document.
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model, experimental evidence suggests that the allyl group is
situated remotely from the DACH ligand in a complex that is not
symmetric on the NMR timescale.[11] Given the complexity of 1
and the asymmetry of the cinnamyl cation, we relied on
computational modeling with DFT-optimized L1-Pd-η3-cinnamyl
complexes using the Lloyd-Jones/Norrby geometry. DFT
optimizations of pro-R and pro-S outer-sphere approaches of the
Table 1. Asymmetric Cinnamylation: Ligand Screening
naked anion of
1 (a hydrogen-bond stabilized exocyclic
enolate)[12] in toluene indicated that for each input complex, the
pro-R (observed) approach was energetically favored.[13] In the
lowest-energy complex, L1 participates in a hydrogen bond with
1, as well as a π-stacking interaction with the cinnamyl cation. A
similar hydrogen bond was observed in Lloyd-Jones’ transition
state calculations of cesium malonate with an L2-Pd-η3-allyl
complex, giving rise to a quasi-inner sphere transition state
wherein enantioselectivity is governed by pre-coordination of the
nucleophile to the ligand rather than the Pd atom.[14]
Table 2. Asymmetric Cinnamylation: Substrate Scope
Entry
Ligand
Yield[a] [%]
ee[b] [%]
99
1
2
3
4
5
(S,S)-DACH-phenyl Trost (L1)
(R,R)-DACH-phenyl Trost (L2)
(S,S)-DPEDA-phenyl Trost (L3)
(S,S)-DACH-naphthyl Trost (L4)
(S,S)-ANDEN-phenyl Trost (L5)
72
81
63
0
-97
86
Entry
1
Substrate
R’
Product
Yield[a]
[%]
ee[b]
[%]
--
44
-24
5b
4b
96
97
98
[a] Yields of isolated products. [b] Determined by HPLC analysis.
2
3
5c
5d
4c
4d
87
69[c]
91
4
5
5e
5f
4e
4f
79[d]
77
99
41
6
7
5g
5h
4g
4h
0
0
-
-
Figure 3. Determination of absolute stereochemistry of p-bromobenzoate 6a
Our provisional model to rationalize enantioselectivity is
depicted in Figure 4. For Tsuji-Trost allylic alkylations involving
prochiral π-allyl complexes, a wall/flap cartoon mnemonic aids in
predicting stereochemical outcomes.[10] This model has also
been used to predict the facial discrimination of simple prochiral
enolates.[10b-d] Lloyd-Jones, Norrby, and coworkers have
reported computational and NMR studies indicating that, in
contrast to the C2-symmetric geometry assumed in the wall/flap
[a] Yields of isolated products. [b] Determined by chiral HPLC analysis.
[c] 48 h reaction time.
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In the event, compound 4a was converted to three different
chemotypes on treatment with Ir(dFCF3ppy)2(dtbbpy)PF6 ("Ir
catalyst") under blue LED irradiation (Table 3, Entry 1). After
detailed NMR analysis, it was determined that the expected
photoredox product (9a) was produced in 11% yield, as well as
tricycles 7a and 8a in 22% and 13% yields, respectively. These
compounds presumably arise via [2+2] photocyclization (De
Mayo reaction)[17] between the styrenyl alkene and exo-enol, with
the Ir catalyst serving as photosensitizer.[18] In contrast, 2-
naphthyl enol (4b) did not afford 8b and 9b, presumably due to
steric hindrance (Entry 2). The 4-bromophenyl (4c) and 4-
nitrophenyl (4e) substrates were slow to react (Entries 2 and 5).
4-Methoxyphenyl-substituted 4d reacted smoothly with a product
distribution similar to that observed with 4a.
Figure 4. DFT-optimized (B3LYP-LACV3P**++) structure (Schrödinger’s
Jaguar) of the lowest-energy L1-Pd-η3-cinnamyl-enolate approach indicating a
hydrogen bond between the incoming enolate and ligand N-H
With enantioenriched dearomatized cores bearing multiple
olefinic moieties in hand, we next pursued oxidative cyclization
reactions as a strategy to rapidly generate structural complexity.
We first explored visible light photoredox catalysis.[15] Knowles
and coworkers have shown that visible light catalysts can
generate heteroatom radicals by proton-coupled electron
transfer (PCET), and that the radicals may be trapped by
alkenes to access heterocycles.[16] Inspired by this approach, we
postulated that the enol 4 may be an excellent substrate for
radical generation at the 2-position, with subsequent trapping by
the pendant cinnamyl group.
Scheme 1. Photoisomerization of the styrene moieties of 4a and isomer 4a′
Table 3. Photoreactions of cinnamylated substrates 4[a]
Subsequent in situ NMR experiments indicated that prior to
cyclization to 7a/8a, clean photoisomerization of the styrene of
4a occurs, suggestive of triplet energy transfer. Identical E/Z
ratios were obtained irrespective of the starting isomer (Scheme
1). Based on these observations, a mechanistic proposal for the
formation of [2+2]-cycloadducts and the cyclization product 9a is
shown in Scheme 2. First, the styrenyl moiety (ca. 60 kcal/mol
triplet energy)[17a] is sensitized by the visible light-excited Ir
catalyst (61 kcal/mol triplet energy).[11a] The exo-enol is then
excited through intramolecular triplet energy transfer from the
excited styrene and reacts via [2+2] cycloaddition with the trans-
cinnamyl group to afford compounds 7a and 8a. The conformer
enabling [2+2] cycloaddition with the cis-cinnamyl substrate is
likely disfavored due to allylic strain. Instead, cis-cinnamyl
isomer 4a′ is converted to [3.2.1]-bicycle 9a via a redox process.
Yield [%] of[a]
Entry
Substrate
Time [h]
7
8
9
1
2
3
4
5
4a
4b
4c
4d
4e
24
24
48
6
22 (7a)
20 (7b)
17 (7c)
27 (7d)
23 (7e)
13 (8a)
11 (9a)
-
-
13 (8c)
13 (8d)
-
5 (9c)
11 (9d)
-
48
[a] Yields of isolated products.
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radical to a stabilized benzyl cation which may then trapped by
acetate to form 11 (Entry 3).[13]
Scheme 2. Mechanistic proposal for formation of cyclobutanols 7a/8a and
[3,2,1]-tricycle 9a
Scheme 3. Proposed mechanism for formation of [3.2.1]-bicycle 10
We
next
explored
further
reactivity
of
the
Table 4. Oxidative free radical cyclization of cinnamylated substrates 4[a]
dearomatization/cyclization-derived polycycles. First, [3.2.1]-
bicycle 10a was treated with LiOH in methanol to give the highly
substituted 7-membered ester 12a via
a retro-Dieckmann
process (Scheme 4A). Compound 7a was subjected to similar
conditions, producing decarbonylated cycloheptanone 13a as a
single diastereomer in 53% yield (Scheme 4B). Next, compound
7a was treated with the non-nucleophilic base NaH. Under these
conditions, bicyclo-[3.2.1] derivative 14a was obtained in 20%
yield along with 22% of recovered 7a. This product may
presumably be obtained via protonation of an anti-Bredt enolate
carbanion[20] after retro-aldol cleavage of the cyclobutanol.
[3.2.1]-Bicycle 14a was converted to 13a in 38% yield upon
LiOH treatment (Scheme 5). We propose that the one-pot
conversion of 7a to 13a may also arise via a retro-aldol–retro-
Dieckmann sequence. Alternatively, a mechanism in which
retro-Dieckmann fragmentation precedes retro-aldol reaction
may be operative. In either case, the retro-Dieckmann
fragmentation for 14a occurs orthogonally to that observed for
10a, presumably due to the absence of a benzoyl group
stabilizing the resulting anion.
Yield of[a]
10 [%]
Entry
4
R
11 [%]
1
2
3
4a
4c
4d
Ph-
19 (10a)
20 (10c)
24 (10d)
-
4-BrPh-
4-MeOPh-
-
51 (11d, dr = 1:1)
[a] Yields of isolated products.
In order to further probe the intramolecular reactivity of 4,
we also investigated oxidative free radical cyclization using
Mn(OAc)3/Cu(OAc)2.[19] While treatment with MnIII and CuII gave
intractable mixtures, treatment of 4a with Mn(OAc)3 in acetic
acid produced acetate 10a in 19% yield (Table 4, Entry 1).
Scheme
3 depicts a proposed mechanism. The radical
generated at the 2-position cyclizes with the cinnamyl group
positioned to minimize torsional strain with the benzoyl group in
the 5-centered transition state. The resultant benzyl radical may
undergo one electron oxidation by MnIII to afford a benzylic
cation, stabilized as the oxonium by the adjacent benzoyl
carbonyl, which may be trapped by acetic acid with
stereochemical inversion to afford 10a. 4-Bromophenyl
derivative 4c similarly gave 10c (Entry 2). A competing pathway,
in which the cinnamyl alkene undergoes 5-exo-trig cyclization
with the 1-O-radical, was observed with 4-methoxy-substituted
substrate 4d. We propose that the electron-donating group
enables further MnIII-mediated oxidation of the resultant benzylic
Scheme 4. Fragmentation of compounds 10a (A) and 7a (B)
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Keywords: asymmetric catalysis • dearomatization •
photocatalysis • polycycles • radical reactions
[1]
[2]
R. Ciochina, R. B. Grossman, Chem. Rev. 2006, 106, 3963.
a) I. P. Singh, J. Sidana, S. B. Bharate, W. J. Foley, Nat. Prod. Rep.
2010, 27, 393; b) J.-A. Richard, R. H. Pouwer, D. Y.-K. Chen, Angew.
Chem. Int. Ed. 2012, 51, 4536; c) J. H. Boyce, J. A. Porco, Jr., Angew.
Chem. Int. Ed. 2014, 53, 7832; d) S. J. Spessard, B. M. Stoltz, Org. Lett.
2002, 4, 1943; e) F. Horeischi, N. Biber, B. Plietker, J. Am. Chem. Soc.
2014, 136, 4026; f) B. A. Sparling, D. C. Moebius, M. D. Shair, J. Am.
Chem. Soc. 2012, 135, 644; g) M. Uwamori, A. Saito, M. Nakada, J.
Org. Chem. 2012, 77, 5098.
Scheme 5. Further reactions of scaffold 7a
[3]
[4]
Q. Zhang, J. A. Porco, Jr., Org. Lett. 2012, 14, 1796.
Conclusions
Q. Zhang, B. Mitasev, J. Qi, J. A. Porco, Jr., J. Am. Chem. Soc. 2010,
132, 14212.
In summary, we have established a new strategy for generating
unique enantioenriched mono- and polycyclic chemotypes.
Highly enantioselective cinnamylation of
[5]
[6]
a) M. D. Burke, S. L. Schreiber, Angew. Chem. Int. Ed. 2004, 43, 46; b)
S. L. Schreiber, Science. 2000, 287, 1964.
a
phloroglucinol
A. Trabocchi, S. L. Schreiber in Diversity-Oriented Synthesis; Basics
and Applications in Organic Synthesis, Drug Discovery, and Chemical
Biology, Wiley-VCH, Weinheim, 2013.
scaffold provided dearomatized substrates which were
converted by divergent cyclizations to structures including
tricyclo[4.3.1.01,4]decan-10-ones and bicyclo[3.2.1]heptanones.
The polycyclic chemotypes were ring-opened to afford highly
substituted 7-membered products. Preliminary computational
studies indicated the potential for interesting pre-organizing
intramolecular interactions between the ligand/Pd0/substrate
complex and the incoming enolate nucleophile. Studies
exploring further intramolecular transformations of the
dearomatized scaffolds, as well as rigorous computational
examination of the asymmetric allylic alkylation using transition
state calculations, are currently in progress and will be reported
in due course.
[7]
[8]
C.-X. Zhuo, S.-L. You, Angew. Chem. Int. Ed. 2013, 52, 10056.
A screen of Li2CO3, K2CO3 and DBU as bases afforded no improvement,
with all bases delivering similar % ee in lower yields.
[9]
CCDC 1487867 (6a) contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
Cambridge
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/data_request/cif.
[10] a) B. M. Trost, M. R. Machacek, A. Aponick, Acc. Chem. Res. 2006, 39,
747. b) B. M. Trost, J. Xu, T. Schmidt, J. Am. Chem. Soc. 2009, 131,
18343. c) B. M. Trost, R. N. Bream, J. Xu, Angew. Chem. Int. Ed. 2006,
45, 3109. d). B. M. Trost, J. Xu, J. Am. Chem. Soc. 2005, 127, 17180.
[11] C. P. Butts, E. Filali, G. C. Lloyd-Jones, P.-O. Norrby, D. A. Sale, Y.
Schramm, J. Am. Chem. Soc. 2009, 131, 9945.
[12] Y. Zhu, D. G. Drueckhammer, J. Org. Chem. 2005, 70, 7755.
[13] See Supporting Information for details.
Experimental Section
[14] J. A. Keith, D. C. Behenna, N. Sherden, J. T. Mohr, S. Ma, S. C.
Marinescu, R. J. Nielsen, J. Oxgaard, B. M. Stoltz, W. A. Goddard III, J.
Am. Chem. Soc. 2012, 134, 19050.
Full experimental details for the preparation of the compounds described
herein, as well as details related to computational and mechanistic
experiments, are provided in the Supporting Information.
[15] J. Xuan, W.-J. Xiao, Angew. Chem. Int. Ed. 2012, 51, 6828.
[16] G. J. Choi, R. R. Knowles, J. Am. Chem. Soc. 2015, 137, 9226.
[17] a) A. C. Weedon in CRC Handbook of Organic Photochemistry and
Photobiology (Eds.: W. M. Horspool, P.-S. Song), CRC Press, Boca
Raton, 1995, pp 670-684. b) M. D. Karkas, J. A. Porco, Jr., C. R. J.
Stephenson. Chem. Rev. 2016, 116, ASAP.
Acknowledgements
[18] a) Z. Lu, T. P. Yoon, Angew. Chem. Int. Ed. 2012, 51, 10329; (b) A. E.
Hurtley, Z. Lu, T. P. Yoon, Angew. Chem. Int. Ed. 2014, 53, 8991.
We thank Otsuka Pharmaceuticals Co.Ltd. for research support.
We thank Dr. Jeffrey Bacon (BU) for X-ray crystal structure
analysis. NMR (CHE-0619339) and MS (CHE-0443618) facilities
at BU are supported by the National Science Foundation. Work
at the BU-CMD is supported by National Institute of Health
R24GM111625. We thank Prof. Alex Grenning (U. Florida) and
Prof. Robert Knowles (Princeton) for helpful discussions.
[19]
a) B. Mitasev, J. A. Porco, Jr. Org. Lett. 2009, 11, 2285; b) J. H.
George, M. D. Hesse, J. E. Baldwin, R. M. Adlington, Org. Lett. 2010,
12, 3532. c) N. S. Simpkins, M. D. Weller, Tetrahedron Lett. 2010, 51,
4823.
[20]
C. J. Hayes, N. S. Simpkins, Org. Biomol. Chem., 2013, 11, 8458.
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COMMUNICATION
Dearomatization-Cyclization
Mikayo Hayashi, Lauren E. Brown,* and
John A. Porco, Jr*
Page No. – Page No.
Asymmetric
Enantioenriched, polycyclic compounds were obtained from a simple
acylphloroglucinol scaffold. Highly enantioselective dearomatization was
accomplished using a Trost ligand- palladium(0) complex. Dearomatized products
were used in visible light-mediated photocycloadditions and oxidative free radical
cyclizations to obtain novel polycyclic chemotypes.
Dearomatization/Cyclization Enables
Access to Novel Chemotypes
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