An Enantioselective Cross-Dehydrogenative Coupling Catalysis Approach to Substituted Tetrahydropyrans

Article abstract of DOI:10.1021/jacs.8b03063

An enantioselective cross-dehydrogenative coupling (CDC) reaction to access tetrahydropyrans has been developed. This process combines in situ Lewis acid activation of a nucleophile in concert with the oxidative formation of a transient oxocarbenium electrophile, leading to a productive and highly enantioselective CDC. These advances represent one of the first successful applications of CDC for the enantioselective couplings of unfunctionalized ethers. This system provides efficient access to valuable tetrahydropyran motifs found in many natural products and bioactive small molecules.

Full text of DOI:10.1021/jacs.8b03063

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Communication
An Enantioselective Cross Dehydrogenative Coupling
Catalysis Approach to Substituted Tetrahydropyrans
Ansoo Lee, Rick Betori, Erika Crane, and Karl A. Scheidt
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b03063 • Publication Date (Web): 01 May 2018
Downloaded from http://pubs.acs.org on May 1, 2018
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An Enantioselective Cross Dehydrogenative Coupling Catalysis Ap-
proach to Substituted Tetrahydropyrans
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Ansoo Lee, Rick C. Betori, Erika A. Crane and Karl A. Scheidt*
Department of Chemistry, Center for Molecular Innovation and Drug Discovery, Northwestern University, 2145
Sheridan Road, Evanston, Illinois 60208, United States
ally, moving beyond preformed nucleophiles such as
dioxinones to simple β-ketoester systems presents
opportunities for enantiocontrol, most likely
through two-point/chelate binding, but also re-
quires different activation modes to operate simul-
taneously in a single reaction flask.
An enantioselective cross-dehydrogenative coupling
(CDC) reaction to access tetrahydropyrans has been
developed. This process combines in situ Lewis acid
activation of a nucleophile in concert with the oxida-
tive formation of a transient oxocarbenium electro-
phile, leading to a productive and highly enantiose-
lective CDC. These advances represent one of the
first successful applications of CDC for the enanti-
oselective couplings of unfunctionalized ethers. This
system provides efficient access to valuable THP mo-
tifs found in many natural products and bioactive
small molecules.
Scheme 1. CDC Processes and Reaction Design
(a) General Concept of CDC Reactions
• Simple starting materials
oxidation
+
• C–H functionalization
• Multiple reaction modes
(metals, oxidants, light)
Nuc
H
E
H
Nuc E
– “H2”
Tetrahydropyrans (THPs) are key structural ele-
ments in numerous bioactive natural products and
medicinally relevant compounds.1 Due to the preva-
lence of THPs, multiple stereoselective processes
have been developed for their construction, includ-
ing Prins cyclizations,2 hetero-Diels-Alder reac-
tions,3 and intramolecular nucleophilic conjugate
additions.4 Established methods to construct THPs
in an enantioselective fashion typically focus on con-
jugate additions5 or activation by enamine/iminium
intermediates,6 two approaches that are deployed
extensively in total synthesis. Inspired by natural
product targets of interest in our laboratory, as well
as small molecules possessing intriguing biological
activity, we envisioned a complementary and direct
method for the enantioselective synthesis of substi-
tuted tetrahydropyran-4-ones. We have disclosed
the use of β-hydroxy dioxinones as nucleophiles with
aldehydes and isatins to undergo mild and stereose-
lective cyclizations in the presence of catalytic Lewis
or Brønsted acids to access enantioenriched THPs.7
Our efforts in this area have enabled total syntheses
of various natural products including exiguolide,8
neopeltolide,9 okilactomycin,10 and other naturally
occurring compounds containing THPs.11 Conceptu-
H
Nuc–H:
E–H:
H
H
EWG
O
O
EDG
Ar
Ar
R
R
H
H
R2
R1
X = O, N-P
R
H
X
(b) Potential Enantioselective CDC Substrates:
Challenging
Established
H
H
H
R2
R2
R1
X
R2
R1
R1
O
N
H
unactivated C–H
bond
Guo, Wang, Chi, Tung16
currently no general,
high er process
(c) This Work
*
N
N
O
O
O
O
[M]
H
chiral LA
oxidant
O
O
OMe
OMe
OMe
O
R
*
O
R
H
O
R
• Highly stereoselective
• Privileged scaffold
• Diversifiable
R
= Ar and
Ar
electrophile & nucleophile
generated in situ
R’
Cross-dehydrogenative coupling (CDC) reactions
have emerged as powerful approaches to forge C–C
bonds from inert C–H bonds.12 As a subset of C–H
functionalization processes,13 CDC reactions are at-
tractive because they do not require prefunctional-
ized starting materials, relying instead on oxidative
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activation followed by net loss of H2 to facilitate C–C
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1
bond formation. Specifically, 2,3-dichloro-5,6-
dicyano-1,4-benzoquinone (DDQ) a strong oxidizing
agent, promotes the formation of stabilized carbo-
cations by benzylic and allylic C–H bond activation,
and subsequent C–C bond formation.14 Mechanisti-
cally, DDQ mediated CDC reactions proceed via sin-
gle electron transfer to form stabilized radical cati-
ons, followed by hydrogen atom abstraction to form
the electrophilic coupling partner (e.g., oxocarbeni-
um ion, iminium ion). Floreancig has effectively
demonstrated that DDQ activation can facilitate
racemic access to carbocycles and heterocycles via
the oxidation of allylic ethers.15 Although enantiose-
lective CDC reactions have been reported during the
last decade,16 there is a dearth of highly enantiose-
lective CDC reactions using oxocarbenium ion elec-
trophiles in contrast to a plethora of enantioselective
CDC reactions using iminium electrophiles (Scheme
1b).17 A major challenge to this approach is success-
fully integrating strongly oxidative conditions for
oxocarbenium ion formation (e.g., DDQ) with ste-
reodefining catalysts necessary for nucleophile acti-
vation (e.g., chiral Lewis acids) to a) promote a pro-
ductive reaction, and b) induce stereocontrol around
a transient, highly reactive oxocarbenium ion. Here-
in we report an enantioselective CDC of β-ketoesters
with oxocarbenium ions to access substituted tetra-
hydropyrans with high yields and enantioselectivity
through a merged chiral Lewis acid/oxidation strat-
egy (Scheme 1c).
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aThe reactions were performed with 1a (0.2 mmol),
LꢀCu(OTf)2 (10 mol %), DDQ (0.26 mmol), Na2HPO4
(0.4 mmol), and MS 4Å (250 mg) in CH2Cl2 (0.04 M).
Absolute configuration of 2a was determined based on
X-ray crystal analysis of 2h.18 bYield of isolated prod-
uct. cDetermined by chiral-phase SFC analysis.
After optimization the basic asymmetric CDC re-
action with β-ketoester 1a, the general scope was
explored (Table 1). When the aromatic ring on the
cinnamyl ether was substituted with electron-
donating groups at its para, meta, or ortho position,
the reactions provided desirable tetrahydropyran-4-
ones 2c−2g in high yields and stereoselectivity with
exception of 2b. We observed that substrate 1b pos-
sessing a p-methoxycinnamyl group produced side
products due to over-oxidation. Furthermore, reac-
tion of 1b without a Cu(II) catalyst produced rac-2b
in 70% yield in only 1 hour, suggesting the competi-
tive background reaction of this highly reactive sub-
strate also contributed to the observed reduction in
stereoselectivity.
Table 1. Substrate Scope of β-Keto Esters 1a
We initiated our investigations of this chiral Lewis
acid/oxidant process using β-ketoester substrate 1a
and found that Cu(II)-bisoxazoline (BOX) complex
L1ꢀCu(OTf)2 gave the desired product 2a as the sole
diastereomer in 72% yield and 92:8 er at –70 ºC
(Scheme 2). Additional screening with chiral BOX
ligands L2−L5 identified ligand L3 as optimal, fur-
nishing 2a in 83% yield and 95:5 er upon further re-
action dilution to 0.02 M. Finally, substrates bearing
more sterically encumbered esters were screened
with no improvement in observed stereoselectivity
(see Supp. Info.).
Scheme 2. Ligand Screening for CDC Reactionsa
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L3 Cu(OTf)2 (10 mol %)
DDQ (1.3 equiv)
Na2HPO4 (2 equiv)
O
O
O
R
O
O
is observed (see Supp. Info.). However, with this suc-
cessful proof of concept, investigations with various
oxidation methods and Lewis acids to engage an
even larger range of substrate classes are ongoing.
1
2
3
4
5
6
7
OMe
OMe
O
R
DCM (0.02 M), MS 4Å,
–70 oC, 12 h
1
2
O
O
O
O
O
O
O
Scheme 3. CDC Reaction Extension
OMe
OMe
OMe
O
O
OMe
Me
8
9
2b, p-MeO, 60%, 78:22 er
2c, m-MeO, 78%, 96:4 er
2d, o-MeO, 70%, 92:8 er
2e, p-Me, 84%, 95:5 er
2f, m-Me, 71%, 95:5 er
2g, o-Me, 81%, 96:4 er
2a, 83%
95:5 er
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O
O
O
O
OMe
OMe
O
O
Br
Cl
2h, p-Br, 59%, 94:6 er
2i, m-Br, 55%, 95:5 er
2j, m-Cl, 68%, 96:4 er
2k, o-Cl, 58%, 97:3 er
X-ray of 2h
O
O
O
O
O
O
OMe
OMe
OMe
O
O
O
Me
2l, 77%
94:6 er
2m, 80%
95:5 er
2n, 87%
97:3 er
O
O
O
O
O
O
O
O
O
OMe
OMe
OMe
S
Ph
Attempts to access enantioenriched tetrahydropy-
ran-4-ones without the β-ketoester were unsuccess-
ful, as enol acetate 3 provided racemic 4 in 68% yield
(Scheme 3a). This observation supports the hypoth-
esis that the β-ketoester is crucial for stereoselectivi-
ty by coordination with the Cu(II)/BOX catalyst. In
an attempt to probe whether an enantioselective
intermolecular CDC reaction was possible, cinnamyl
methyl ether was exposed to methyl acetoacetate in
the presence of L3ꢀCu(OTf)2 to afford 5 (Scheme
3b). Although the intermediate oxocarbenium ion
could potentially undergo both 1,2- and 1,4-addition,
the 1,2-addition adduct 5 was observed (as detected
by NMR spectroscopy). Unfortunately, attempts to
isolate 5 have been unsuccessful, due to facile elimi-
nation of the β-methoxy group to form enone 6
(2.7:1 E/Z mixture). Lastly, we evaluated α-methyl-β-
ketoester 1z, which would forge a quaternary C-
center (Scheme 3c). To our satisfaction, the reaction
of 1z provided the desired (2R,3R)-7 in 65% yield
(>20:1 dr, 96:4 er)23 which provides a roadmap for
future intermolecular asymmetric CDC reactions.
N
Ts
2o, 55%
87:13 er
2p, 69%
88:12 er
2q, 50%
91:9 er
O
O
O
O
O
O
OMe
OMe
OMe
OMe
OMe
OMe
OMe
O
O
O
OMe
OMe
2rb, 20 h
50%, 91:9 er
2sb, 4 h
50%, 89:11 er
2tb, 45 h
56%, 91:9 er
aSee Supp. Info. for reaction details. Er determined by
chiral-phase SFC analysis. Products 2 were obtained
b
with >20:1 dr (trans/cis). Performed at –30 ºC.
We then evaluated substrates substituted with
electron-withdrawing groups at para, meta, and or-
tho positions. The reactions of 1h−1k provided de-
sired products 2h−2k in moderate yields and high
stereoselectivity. The results showed that high yields
and stereoselectivity were observed for 1l and 1m
containing naphthyl groups. The reaction of 1n con-
taining a trisubstituted cinnamyl alkene afforded 2n
in 87% yield and 97:3 er, while heteroaryl and conju-
gated ethers 1o−1q gave tetrahydropyran-4-ones
2o−2q in somewhat decreased yields and stereose-
lectivities. A survey of benzyl ethers revealed that
only 4-methoxy-substituted substrates 1r–1t were
capable of producing desired products 2r−2t with
high stereoselectivity and moderate yield. Under the
current conditions, we have not observed productive
reactions using propargylic, unsubstituted allylic,
alkyl, or ether substrates leading to tetrahydrofurans
(i.e., 5 atom tether length). Instead, over-oxidation,
resulting in 2,3-dihydropyran-4-one, or no oxidation
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(Scheme 4). Conventional heating in DMF/H2O
Page 4 of 6
replace
H2Os with
1
2
3
4
5
6
7
8
from ref. 19
provided the decarboxylated product 4 in 77% yield,
where methylation of 2a gave 3,3-disubstituted tet-
rahydropyran-4-one (2R,3S)-7 in excellent yield with
13:1 dr.23 Exposure of β-ketoesters 2a or 7 to L-
selectride provided the corresponding tetrahydropy-
ran-4-ol 8 or 9, while LiAlH4 reduction of 7 fur-
nished diol 10.20 Functionalization of the 6-position
of the 7 has also been demonstrated. First, cyclic
enone 11 was prepared via dehydrogenation using 1
atm of O2 in the presence of Pd(TFA)2 in DMSO.21
Rh(I)-catalyzed 1,4-addition of phenylboronic acid
produced 12,22 and conjugate addition of an alkyl
cuprate provided 13 as the trans diastereomers in
both reactions.20,23 Lastly, a Mukaiyama-Michael ad-
dition proceeded to afford 14 with 10:1 diasteromeric
ratio.23,24 Notably, while many synthetic methods
exist for cis-2,6-tetrahydropyran structures,25 there
are far fewer preparations for trans-2,6-
tetrahydropyrans.26
H
O
O
2 SbF6
2
Me Me
OMe
Ph
2’
1’
t-Bu group blocks
O
O
top side
O
N
N
1
1
2
2
Cu
C1’-C2’ length
fixed to 2.2 Å
t-Bu
t-Bu
H2O OH2
1
2
O1-Cu-N1-C1:
dihedral∠ +30.2°
C1’
9
O2-Cu-N2-C2:
dihedral∠ +35.9°
Re face
addition
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Figure 1. Stereochemical induction model with
1a/DDQ intermediate (see Supp. Info. for details)
The stereochemical model of the reaction with 1a,
Cu(II)/BOX and DDQ is based on a reported X-ray
crystal structure of [L1ꢀCu(H2O)2](SbF6)2 by re-
placement of H2O ligands with the oxocarbenium
ion of 1a (Figure 1).19 With the oxidized substrate
bound to the Cu(II) center via bidentate chelation,
the bulky tert-butyl group of the L3•Cu(II) complex
shields the top face of the bound substrate (Si face)
which in turn places the transient oxocarbenium ion
below. During the reaction, the metal-bound
enol(ate) adds to the Re face of the oxocarbenium
ion via a pseudo chair-like conformation to provide
product 2a with S configuration at the C1’ position,
consistent with observed stereochemistry. This
model also supports the observed relative C1’-C2’
trans relationship of the products.
To substitute DDQ as a reagent, we investigated
complementary oxidation processes to form the oxo-
carbenium ion. A recent report of photoredox catal-
ysis being used to generate oxocarbenium ions27 in-
spired us to leverage this approach and trap the oxo-
carbenium ion with our tethered carbon nucleo-
phile. Gratifyingly, the use of Sc(OTf)3,
Ir[dF(CF3)ppy]2(dtbbpy)PF6, blue LEDs, and bromo-
chloroform provided access to rac-2a in 90% yield
(Scheme 5). To date, these photoredox conditions
are not yet compatible with various chiral ligands to
induce enantioselectivity.28
Scheme 4. Transformations of 2a
O
O
O
OH
O
O
a
c
OMe
R1
OMe
Scheme 5. Photoredox-Catalyzed CDC Reaction
R1
R1
2a
R1
O
O
4
=
8
Ph
b
OH
O
O
O
O
O
OH
Me
Me
Me
d
c
OMe
OMe
OH
R1
O
R1
R1
O
10
9
(2R,3S)-7
O
e
Me
f
OMe
OMe
In summary, a chiral Lewis acid-catalyzed intra-
molecular cross-dehydrogenative coupling of β-
ketoesters has been developed. This oxidative pro-
cess utilizes unfunctionalized starting materials to
provide chiral 2-substituted tetrahydropyrans with
excellent yields and stereoselectivity. The in situ
generation of both nucleophilic and electrophilic
partners specifically provides new opportunities for
enantioselective oxocarbenium ion-driven reactions
and CDC processes in general. Investigations in our
laboratory towards leveraging this chiral Lewis ac-
id/oxidation system with new substrate classes as
well as the use of visible light mediated oxidation in
asymmetric transformations are currently underway.
OTMS
O
O
O
Me
h
R1
O
Ph
O
O
6
2
Ph
OMe
15
12
O
O
R1
Me
Me
11
O
OMe
g
R1
R1
Ph
nBu
O 14
O 13
aConditions: (a) DMF/H2O, 130 ºC, 77% (b) MeI,
NaH, 97%, 13:1 dr (c) L-selectride, 64% for 8, 71% for 9
(d) LiAlH4, 62% (e) Pd(TFA)2, O2, 67% (f) Rh(cod)2BF4,
PhB(OH)2, 75%, 20:1 dr (g) nBu2CuLi, TMSCl, 76%, 20:1
dr (h) 15, InCl3, 93%, 10:1 dr
A practical advantage of this strategy is the ease of
synthetically elaborating these β-keto esters
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M.; Kim, S.-G.; MacMillan, D. W. C. Angew. Chem. Int. Ed. 2008,
47, 3568-3572; (b) Smith, A. B.; Tomioka, T.; Risatti, C. A.;
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Supp. Info. Experimental procedures and spectroscop-
ic, and crystallographic details. This material is availa-
ble free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
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*scheidt@northwestern.edu
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The authors declare no competing financial interest.
ACKNOWLEDGMENT
Financial support for this work has been provided by
the NCI (R01 CA126827) and the American Cancer So-
ciety (Research Scholar award 09-016-01 CDD). RCB
acknowledges financial support from the NIGMS
(T32GM105538). The authors thank Charlotte Stern
(Northwestern) for assistance with X-ray crystallog-
raphy.
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10 mol%
R1 = H, Me
O
O
O
O
O
O
O
N
N
R1
R1
Cu
tBu
tBu
TfO OTf
OMe
OMe
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R2
R2
oxidant
O
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Re face
addition
• Up to 97:3 er/20:1 dr
• Facile diversification
• Quaternary center formation
electrophile and nucleophile
generated in situ
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