Synthesis of Phthalans Via Copper-Catalyzed Enantioselective Cyclization/Carboetherification of 2-Vinylbenzyl Alcohols

Article abstract of DOI:10.1021/acs.orglett.8b02766

Enantiomerically enriched phthalans were synthesized efficiently via an enantioselective copper-catalyzed alkene carboetherification reaction. In this reaction, 2-vinylbenzyl alcohols enantioselectively cyclize then couple with vinylarenes. The utility of the method was demonstrated by the enantioselective synthesis of (R)-fluspidine, a σ₁ receptor ligand.

Full text of DOI:10.1021/acs.orglett.8b02766

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis of Phthalans Via Copper-Catalyzed Enantioselective
Cyclization/Carboetherification of 2‑Vinylbenzyl Alcohols
Dake Chen and Sherry R. Chemler*
Department of Chemistry, State University of New York at Buffalo, Buffalo, New York 14260, United States
S
* Supporting Information
ABSTRACT: Enantiomerically enriched phthalans were
synthesized efficiently via an enantioselective copper-catalyzed
alkene carboetherification reaction. In this reaction, 2-vinyl-
benzyl alcohols enantioselectively cyclize then couple with
vinylarenes. The utility of the method was demonstrated by
the enantioselective synthesis of (R)-fluspidine, a σ1 receptor
ligand.
Scheme 1. Phthalides and Phthalans from 2-Vinylbenzyl
Alcohols and 2-Vinylbenzoic Acids
hthalides and phthalans make up the core of important
Pbioactive compounds of both natural and unnatural
origins (Figure 1).1 Their attractive biological profiles have
inspired the development of a number of creative approaches
toward their de novo synthesis.1a,2
Figure 1. Bioactive phthalides and phthalans.
One surprisingly underexplored direct approach to the
synthesis of phthalides and phthalans is the intramolecular
cyclization of readily available 2-vinyl benzoic acids and
alcohols (Scheme 1).4 Along these lines, Kobayashi has
reported an iodine-promoted cycloetherification,3 while more
recently Waser has reported a palladium-catalyzed carboether-
ification/cyclization (Scheme 1a) and Zhu has reported a
copper-catalyzed carboetherification/cyclization (Scheme 1a).4
The synthesis of enantioenriched phthalides from 2-vinyl-
benzoic acids has been achieved by Sharpless asymmetric
dihydroxylation and subsequent lactonization.5 More recently,
progress has been made toward enantioselective organo-
catalytic bromolactonization and fluorolactonization, reported
by Yeung6 and Rueping,7 respectively. A catalytic enantiose-
lective cyclization of benzyl alcohols onto pendant ortho-α,β-
unsaturated ketones via intramolecular oxa-Michael reactions
has also been demonstrated by Ghorai (Scheme 1b).8 Herein
we disclose a copper-catalyzed enantioselective alkene
carboetherification as an approach to the synthesis of
enantioenriched phthalans from unactivated 2-vinyl benzyl
alcohols (Scheme 1c). Application of the method to the
synthesis of (R)-fluspidine, a σ1 receptor ligand, is also
demonstrated.
We have disclosed enantioselective copper-catalyzed alkene
carboetherifications for the synthesis of chiral tetrahydrofur-
ans.9a,b Related alkene carboetherification methods have also
been disclosed by other groups.9c−f We aimed to extend the
scope of this powerful methodology to the synthesis of chiral
phthalans and phthalides. Using this approach, requisite
Received: August 29, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02766
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
substrates are 2-vinylbenzyl alcohols and benzoic acids 1,
whose application in metal-catalyzed alkene cyclization/
difunctionalization is less common, possibly due to loss of
conjugation in the exo-cyclization transition state. The
envisioned reaction sequence for phthalan formation, analo-
gous to our prior tetrahydrofuran synthesis method,9a is
illustrated in Scheme 2. The benzylalcohol 1 is proposed to
diphenylethylene (3 equiv) in PhCF3 at 120 °C in the presence
of K2CO3 (1 equiv)9 provided phthalan 2a in 90% yield and
97% ee (Table 1, entry 1). An attempt to reduce loading of the
Cu(OTf)2 and (S,S)-t-Bu-Box to 15 and 18 mol %,
respectively, decreased the isolated yield to 74% (Table 1,
entry 2). Reducing the reaction temperature to 100 °C resulted
in reduced isolated yield (Table 1, entry 3). The reaction of 1a
under optimal conditions (Table 1, entry 1) was performed on
1 mmol scale and resulted in 70% isolated yield of 2a (>99%
ee, Table 1, entry 4). 2-Vinylbenzyl alcohol 1b, a primary
benzyl alcohol, was next investigated. Under the conditions
deemed optimal for 1a (Table 1, entry 1), cycloetherification
occurred to provide a 2:2:1 ratio (crude 1H NMR) of phthalan
2b, the benzaldehyde derived from 1b, and benzyl alcohol 1b,
respectively (Table 1, entry 5). The competitive oxidation of
the primary benzyl alcohol under these conditions, which
employ MnO2 as the stoichiometric oxidant, was not
surprising. Fortunately, upon changing to a milder oxidant,
Ag2CO3 (200 mol %), 71% of phthalan 2b could be obtained
in 80% ee (Table 1, entry 6). Reducing the amount of Ag2CO3
to 100 mol % provided 2b in even higher yield (93%, Table 1,
entry 7). Reducing the reaction temperature to 100 °C resulted
in lower conversion (Table 1, entry 8). It should be noted that
no reaction was observed when Cu(OTf)2 was omitted and
minimal reaction (ca. 5% conversion) was detected when
MnO2 was omitted in the reaction of 1a (not shown). Thus,
with the optimal conditions in hand (Table 1, entries 1 and 7),
the 2-vinylbenzyl alcohol scope was further explored (Scheme
3).
A number of substrate functionalities including Cl, Me,
OMe, CF3, and a tertiary amine were tolerated under the
reaction conditions (Scheme 3). Tertiary alcohol substrates
uniformly provided higher levels of enantioselectivity than
primary benzyl alcohol substrates (e.g., compare 2a and 2h to
2b and 2c). A benzoic acid was able to cyclize to give phthalide
2e, albeit with low enantioselectivity. In this case, the soluble
base 2,6-di-tert-butyl-4-methylpyridine provided higher con-
version than when K2CO3 was used, possibly due to the
difference in solubility of the intermediate corresponding
benzoate salt. (2-(1-Phenylvinyl)phenyl)methanol provided
phthalan 2d, but the enantioselectivity was greatly diminished.
The absolute stereochemistry of the products was assigned by
conversion of phthalan 2c to its known corresponding primary
alcohol (using OsO4 and PhI(OAc)2, then NaBH4) and optical
rotation comparison (see Supporting Information).8
Scheme 2. Proposed Copper-Catalyzed Carboetherification
Mechanism
coordinate to the copper(II) center followed by intramolecular
cis-oxycupration. Homolysis of the resulting alkyl-Cu(II) bond
provides a methyl radical that can add to vinyl arenes.
Oxidation of the resulting benzylic radical then results in
formation of the higher substituted vinyl arene 2.
We investigated the optimal conditions for enantioselective
carboetherification of 2-vinylbenzyl alcohols 1a and 1b with
1,1-diphenylethylene, as shown in Table 1. Subjecting 1a to
Cu(OTf)2 (20 mol %), (S,S)-t-Bu-Box (25 mol %), and 1,1-
a
Table 1. Reaction Optimization
b
c
d
entry
1
substrate
oxidant (mol %)
yield (%)
ee (%)
1a
1a
1a
1a
1b
1b
1b
1b
MnO2 (260)
MnO2 (260)
MnO2 (260)
MnO2 (260)
MnO2 (260)
Ag2CO3 (200)
Ag2CO3 (100)
Ag2CO3 (100)
90
74
78
70
ca. 40
71
97
98
e
2
A survey of vinylarene coupling partners was also
investigated (Scheme 4). While 1,1-disubstituted vinyl arenes
are generally the best partners due to their greater ability to
react with the presumed carbon radical intermediates, 4-
methylstyrene also provided phthalan 2k in 99% yield and 96%
ee. Similarly, reaction with 4-methoxystyrene and unsubsti-
tuted styrene (5 equiv) provided 65% and 95% yields of
adducts 2l and 2m in 99% ee each. The less electron-rich 4-
chlorostyrene (5 equiv) underwent the reaction with alcohol
1a in 55% yield and 99% ee, while the 4-cyanostyrene was
unreactive under these conditions. Reaction of 1a with 2-
methoxystyrene provided 2p in 52% yield and 99% ee, while
reaction with 2-bromostyrene provided 2q in 33% yield and
99% ee. In these reactions with styrenes, use of the soluble 2,6-
di-tert-butyl-4-methylpyridine instead of K2CO3 significantly
reduced styrene polymerization. Reaction of 1a with 1,1-(4-
chlorophenyl)ethylene provided phthalan 2r in 90% yield and
f
3
g
4
h
>99
5
6
7
80
81
93
ca. 56
fh
8 ,
a
Reaction conditions: Cu(OTf)2 (0.037 mmol, 20 mol %) and (S,S)-
t-Bu-Box (25 mol %) were complexed in PhCF3 (1 mL) at 60 °C.
After 2 h, oxidant, alcohol 1 (0.185 mmol) in PhCF3 (1 mL), K2CO3
(1 equiv), 1,1-diphenylethylene (3 equiv), and 4 Å mol. sieves were
added at rt and the mixture was heated and stirred for 24 h at 120 °C
b
c
in a sealed tube. MnO2 (85%, <5 μ was used). Isolated yield unless
d
otherwise noted. Enantioselectivity determined by chiral HPLC.
Reaction run with 15 mol % Cu(OTf)2 and 18 mol % (S,S)-t-Bu-Box.
e
f
g
Reaction run at 100 °C. This reaction used substrate 1a at 1 mmol
h
scale. Yield estimated by crude 1H NMR. Ca. 40% of the
benzaldehyde derived from 1b was also formed.
B
DOI: 10.1021/acs.orglett.8b02766
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Letter
a
Scheme 3. Scope with Respect to 2-Vinylbenzyl Alcohol or
2-Vinylbenzoic Acid
Scheme 4. Scope of the Alkene Coupling Partner
a
a
(a) The reaction conditions described in Table 1, entry 1 were used
unless otherwise noted. (b) Yield is reported for products isolated by
chromatography on silica gel. (c) Enantiomeric excesses were
determined by chiral HPLC. (d) 2,6-Di-tert-butyl-4-methylpyridine
was used instead of K2CO3. (e) Five equiv of styrene was used.
Scheme 5. Enantioselective Synthesis of (R)-Fluspidine
a
(a) The reaction conditions described in Table 1, entry 1 were used
unless otherwise noted. (b) Yield is reported for product isolated by
chromatography on silica gel. (c) Enantiomeric excess was
determined by chiral HPLC. (d) Ag2CO3 (1 equiv) was used instead
of MnO2. (e) 2,6-Di-t-butyl-4-methylpyridine was used instead of
K2CO3. (f) The enantiomers were not separable on a number of chiral
columns. nd = not determined.
93% ee. Vinyl arenes with exocyclic alkenes provided
endocyclic alkenes 2s and 2t as major isomers.
The synthetic utility of this enantioselective phthalan
synthesis method is illustrated in the enantioselective synthesis
of (R)-fluspidine, a σ1 receptor probe (Scheme 5).1b−e This
compound was previously obtained in enantioenriched form
via chiral HPLC resolution,1c and more recently by
enantioselective synthesis using a catalytic asymmetric
reduction as the key step.1e Our synthesis began with
commercially available 2-bromostyrene, which was subjected
to lithium−halogen exchange followed by treatment with N-
benzoyl-piperidine-4-one, providing the corresponding 2-
vinylbenzyl alcohol in 78% yield. Enantioselective carboether-
ification with 1,1-diphenylethylene provided chiral phthalan 2u
in 81% yield and 86% ee. Alternatively, reaction with 4-
methylstyrene provided adduct 2v in 87% yield and 89% ee.
Oxidative cleavage of the alkene followed by reduction of the
resulting aldehyde and concomitant reduction of its amide
provided the known primary alcohol 4.1c,e Application of 2v
instead of 2u in this synthesis is slightly more atom economical
(less carbons removed in oxidation step). Direct fluorination of
4 with DAST as previously reported1e provided (R)-fluspidine.
The optical rotation of (R)-fluspidine (5) was similar to the
reported value (Scheme 5).1c,e Our enantioselective synthesis
fluspidine is two steps shorter than the racemic synthesis1c and
five steps shorter than the previously reported enantioselective
synthesis.1e
In summary, copper-catalyzed alkene carboetherification is
an effective method for the synthesis of enantioenriched
phthalans from 2-vinyl benzylalcohols. Further demonstrations
of the scope of the copper-catalyzed enantioselective alkene
carboetherification are underway and will be reported in due
course.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b02766.
C
DOI: 10.1021/acs.orglett.8b02766
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Experimental procedures, tabulated characterization data
Letter
Ed. 2016, 55, 5044−5048. (e) Zhang, G.; Cui, L.; Wang, Y.; Zhang, L.
J. Am. Chem. Soc. 2010, 132, 1474−1475. (f) For an alternative
copper-catalyzed carboetherification strategy, see: Cheng, Y.-F.;
Dong, X.-Y.; Gu, Q.-S.; Yu, Z. L.; Liu, X. Y. Angew. Chem., Int. Ed.
2017, 56, 8883−8886.
for all new compounds, HPLC traces of chiral products
(PDF)
1H and 13C NMR spectra for all new compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: schemler@buffalo.edu.
ORCID
Sherry R. Chemler: 0000-0001-6702-5032
Author Contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the National Institutes of Health (GM078383) for
financial support of this work.
■
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DOI: 10.1021/acs.orglett.8b02766
Org. Lett. XXXX, XXX, XXX−XXX